Methods of preparing macrocyclic compounds and uses thereof

Abstract

The present disclosure relates to preparation of Compound 1, or a pharmaceutically acceptable form thereof, its pharmaceutical composition and preparation thereof, and uses thereof in the treatment of certain conditions, such as cancer.

Description

Attorney Docket No. 14168-128-228METHODS OF PREPARING MACROCYCLIC COMPOUNDS AND USES THEREOF1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Serial No. 63 / 725,271, filed November 26, 2024, which is incorporated herein by reference in its entirety.2. FIELD

[0002] Provided herein are methods of preparing Compound 1. or a pharmaceutically acceptable form thereof, its pharmaceutical composition and preparation thereof, and uses thereof in the treatment of certain conditions, such as cancer.3. SUMMARY

[0003] In one aspect, provided herein is a process for preparing Compound 1 :Compound 1, or a pharmaceutically acceptable form thereof, comprising treating Compound 2N:optionally wherein Rcis tert-butyl (Compound 2), or a salt thereof, or a solvate thereof, with a sulfmamide removal agent to provide Compound 1. or a pharmaceutically acceptable form thereof: wherein Rcis (a) -C(Rd)(Re)(Rf), wherein each of Rd. Re, and R1is independently Ci.4 alkyl, or (b) phenyl or monocyclic heteroaryl optionally substituted with one or more C1.4 alkyl substituents, or (c) cycloalkyl optionally substituted with one or more Ci-4 alkyl substituents, optionally wherein Rcis tert-butyl, 2,4,6-trimethylphenyl, (triethyl)methyl, 4-methylphenyl, phenyl, 2,4,6-triisopropylphenyl, or 2-methylbutan-2-yl.

[0004] In one aspect, the process comprises reacting Compound 3N:-1-NAI-5007198252vloptionally wherein Rcis tert-butyl (as Compound 3), or a salt thereof, or a solvate thereof, with a cyanide source, to provide Compound 2N (or where Rcis tert-butyl, Compound 2), or a salt thereof, or a solvate thereof.

[0005] In one aspect, tire process comprises reacting Compound 4N:optionally wherein Rcis tert-butyl (as Compound 4), or a salt thereof, or a solvate thereof, with a 5- metalated-1 -methylimidazole reagent to provide Compound 3N (optionally wherein Rcis tert-butyl (as Compound 3)), or a salt thereof, or a solvate thereof.

[0006] In one aspect, the process comprises cyclizing Compound 6N:or a salt thereof, or a solvate thereof, to provide Compound 4N, or a salt thereof, or a solvate thereof; optionally wherein Rcin Compound 6N is tert-butyl (Compound 6), and Compound 4N is Compound 4.

[0007] In one aspect, the process comprises deprotecting Compound 7PG / N:-2-NAI-5007198252vloptionally wherein Rcis tert-butyl, or a salt thereof, or a solvate thereof, to provide Compound 6N, or a salt thereof, or a solvate thereof, wherein each PG is independently a hydroxyl protecting group.

[0008] In one aspect, the process comprises reacting Compound 8PG:wherein each PG is independently a hydroxyl protecting group or a salt thereof, or a solvate thereof, withRC^S,NH2IIO to provide Compound 7PG / N, or a salt thereof, or a solvate thereof; wherein Rcis (a) - C(Rd)(Re)(R‘), wherein each of Rd, Re, and Rfis independently C i _4alkyl, or (b) phenyl or monocyclic heteroaryl optionally substituted with one or more CM alkyl substituents, or (c) cycloalkyl optionally substituted with one or more C alkyl substituents, optionally wherein Rcis tert-butyl, 2,4,6- trimethylphenyl. (triethyl)methyl, 4-methylphenyl, phenyl, 2,4,6-triisopropylphenyl, or 2-methylbutan-2- yL optionally wherein Rcis tert-butyl (CS')-tcrt-butylsulfmamidc): optionally wherein Rcis tert-butyl and each PG is TBDMS (with both options as Compound 7).

[0009] In another aspect, provided herein are the following compounds:-3-NAI-5007198252vlor a stereoisomer, salt, solvate, tautomer, or isotopologue thereof; wherein Rcis (a) -C(Rd)(Re)(Rf), wherein each ofRd, Re, and Rfis independently C 1-4 alkyl, or (b) phenyl or monocyclic heteroaryl optionally substituted w ith one or more Ci -4 alkyl substituents, or (c) cycloalkyl optionally substituted with one or more C1.4 alkyl substituents, optionally wherein Rcis tert-butyl, 2,4,6-trimethylphenyl, (triethyl)methyl. 4-methylphenyl, phenyl, 2,4,6-triisopropylphenyl, or 2-methylbutan-2-yl, optionally wherein Rcis tert-butyl; and each PG is independently a hydroxyl protecting group.

[0010] In another aspect, provided herein is a pharmaceutical composition comprising:-4-NAI-5007198252vl(i) a solid form comprising Compound 1:Compound 1 or a pharmaceutically acceptable salt and / or solvate thereof, in an amount of from about 1 mg to about 10 mg, or about 3 mg to about 8 mg free base equivalent, and(ii) one or more pharmaceutically acceptable excipients.

[0011] In one aspect, the solid form is a crystalline form of free base, hemi-hydrate of Compound 1.

[0012] In one aspect, the solid form comprises one or more of one or more of XI, X2, X3, X4, X5. and X6:or a pharmaceutically acceptable sa t or solvate thereof; optionally wherein the total % w / w of XI, X2, X3,X4, X5, and X6 present in the solid form is between 0.05 % w / w and 3.0 % w / w.

[0013] In one aspect, the one or more pharmaceutically acceptable excipients comprises one or more fdler, glidant, disintegrant, lubricant, or binder, or a combinations thereof.

[0014] In another aspect, provided herein is a tablet comprising:(i) a tablet core, comprising:-5-NAI-5007198252vl(a) a solid form comprising Compound 1 :Compound 1 or a pharmaceutically acceptable salt and / or solvate thereof in an amount of from about 1 to about 10, or about 3 mg to about 8 mg free base equivalent, and(b) one or more pharmaceutically acceptable excipients; and(ii) a tablet coating.

[0015] In another aspect, provided herein is a method of preparing the pharmaceutical composition described herein, comprising:(i) optionally, micronizing a solid form of the Compound 1, or pharmaceutically acceptable salt and / or solvate thereof;(ii) optionally, de-lumping the solid form of the Compound 1, or pharmaceutically acceptable salt and / or solvate thereof;(iii) mixing the solid fonn of the Compound 1, or pharmaceutically acceptable salt and / or solvate thereof, with a disintegrant, a glidant, and a first portion of a filler to form a first blend;(iv) de-lumping the first blend to form a de-lumped first blend;(v) de-lumping a second portion of the filler;(vi) blending the dc-lumpcd first blend and the dc-lumpcd second portion of the filler to form a second blend;(vii) blending the second blend with a lubricant to form a lubricated blend; and(viii) compressing the lubricated blend, optionally with a rotary press, into a tablet.

[0016] In another aspect, provided herein is a method of treating cancer dependent on a famesylated protein in a subject, comprising administering the pharmaceutical composition or tablet described herein, to the subject having cancer dependent on a famesylated protein, optionally wherein the subject is human.

[0017] In another aspect, provided herein is a method of treating a solid tumor in a subject, comprising administering the pharmaceutical composition or tablet described herein to the subject, optionally wherein the subject is human.

[0018] In one aspect, the method comprises administering to the subject one or more second active agents, optionally wherein tire one or more second active agents comprises one or more of a tyrosine-6-NAI-5007198252vlkinase inhibitor, a vascular endothelial grow th factor receptor (VEGFR) inhibitor, an EGFR-TKI inhibitor, a PI3K inhibitor, a KRAS inhibitor, and / or pan-RAS inhibitor.4. BRIEF DESCRIPTION OF THE FIGURES

[0019] FIG. 1 illustrates exemplary processes for preparing tablets having strengths of 3 mg, 5 mg, or 8 mg of Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof (free base equivalent amount).

[0020] FIG. 2 provides a representative XRPD pattern of Form 1 of a free base, hemi-hydrate of Compound 1 prepared from methanol / water.

[0021] FIG. 3 provides a representative XRPD pattern of Form 1 of a free base, hemi-hydrate of Compound 1 prepared from acetonitrile / water.

[0022] FIG. 4 provides a representative TGA thermogram of Form 1 of a free base, hemi-hydrate of Compound 1 prepared from methanol / water.

[0023] FIG. 5 provides a representative TGA thermogram of Form 1 of a free base, hemi-hydrate of Compound 1 prepared from acetonitrile / water.

[0024] FIG. 6 provides a representative DSC thermogram of Form 1 of a free base, hemi-hydrate of Compound 1 prepared from methanol / water.

[0025] FIG. 7 provides a representative HPLC chromatogram of Compound 1 (Column: CHIRALPAK IG-U 100x3.0 mm, 1.6 pm).5. DETAILED DESCRIPTION

[0026] Unless defined otherw ise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0027] As used herein, and in the specification and the accompanying claims, the indefinite articles “a” and an" and the definite article “the” include plural as well as single referents unless the context clearly indicates otherwise.

[0028] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges, including the endpoint numbers on both limits of the range, and specific embodiments therein are intended to be included. As used herein and unless otherwise specified, the terms “about” and “approximately,” when used in connection with a numeric value or a range of values which is provided to characterize a particular solid fonn, e.g., a specific temperature or temperature range, such as, for example, that describing a melting, dehydration, desolvation or glass transition temperature: a mass change, such as, for example, a mass change as a function of temperature or humidity; a solvent or water content, in terms of.-7-NAI-5007198252vlfor example, mass or a percentage; or a peak position, such as, for example, in analysis by IR or Raman spectroscopy or XRPD; indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the particular solid form. For example, in particular embodiments, the terms “about” and “approximately,” when used in this context, indicate that the numeric value or range of values may vary within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%. 2%, 1.5%, 1%. 0.5%, or 0.25% of the recited value or range of values. For example, in some embodiments, the value of XRPD peak position may vary by up to ± 0.2 degrees 20 while still describing the particular XRPD peak. For example, in some embodiments, the value of a DSC thermal event having an onset temperature or a DSC peak temperature (each expressed in degrees Celsius (°C)) may vary by up to ± 2 °C while still describing the particular temperature. As used herein, a tilde (i.e.,preceding a numerical value or range of values indicates “about” or “approximately.”

[0029] As used herein and unless otherwise specified, a numerical range described herein includes all continuous values from a minimum value to a maximum value of the range. Further, if such a range refers to integers, the range includes all integers from a minimum integer to a maximum integer. In the present specification, when a range is described for a variable, it will be understood that the variable includes all values including the end points described within the stated range. For example, the term “between” includes the endpoint numbers on both limits of the range. Thus, the range described by “between 3 and 5” is inclusive of the numbers “3” and “5”. Similarly, the range of “3 to 8” will be understood to include any subranges, such as 3 to 5, 5 to 8, 3 to 4, 5 to 6, and the like, as well as individual values of 3, 3.1, 3.5, 4, 4.1, 4.5, 5, 5.1, 5.5, 6, 6.5, 7, and 8, and the like.

[0030] As used herein, the temr “API correction factor” is understood to refer to a correction factor calculation that is used to characterize a particular lot of an active pharmaceutical ingredient (API), which is determined based on the purity of API, the amount of any water and any residual solvent content present, and residue on ignition (ROI): API correction factor = (purity of API) * (1 - water content - residual solvent - ROI). Purity of API is determined using methods known in the art, for example, HPLC and / or 'H NMR. Water content is determined using methods known in the art, for example, Karl Fischer analysis. ROI is determined using methods known in the art, for example, ignition of a sample and heating the residue at elevated temperature, such as about 450 to about 600 °C, and weighing the remaining material. Tire API correction factor used therein is at least about 0.95, or at least about 0.96, or at least about 0.97, or at least about 0.98, or at least about 0.99. In some aspects, the API correction factor is at least 0.97, is from about 0.97 to about 0.98, such as 0.9728.

[0031] As used herein, a “pharmaceutically acceptable form” of compounds disclosed herein includes, but is not limited to, a pharmaceutically acceptable salt, solvate, isomer, and isotopologuc (i.e., isotopically labeled derivative), of compounds disclosed herein, which includes combinations thereof-8-NAI-5007198252vl(e.g., a solvate of a pharmaceutically acceptable salt, or an isomer and / or isotopologue of a compound or of a solvate, salt, or solvate of salt of such compound). In some embodiments, a “pharmaceutically acceptable form” includes, but is not limited to, a pharmaceutically acceptable salt, solvate, isomer (e.g.. tautomer or stereoisomer), and isotopologue (i. e. , isotopically labeled derivative) of Compound 1 as disclosed herein, and combinations thereof.

[0032] In some embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term “pharmacally acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmacally acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail (see J. Pharm. Set. (1977) 66: 1-19).Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable pharmaceutically acceptable inorganic and organic acids and bases, such as suitable inorganic and organic addition acids and bases. For example, the pharmaceutically acceptable salt of the compounds provided herein is derived from suitable a pharmacally acceptable inorganic or organic acid, such as suitable inorganic or organic addition acid, which is sometimes referred to as the conjugate acid. In some embodiments, the pharmaceutically acceptable salt includes, but is not limited to, a benzoate salt, a besylate salt, a chloride salt, a citrate salt, a fumarate salt, a gentisate salt, a glutarate salt, a glycolate salt, a hippurate salt, a 1 -hydroxy-2 -naphthoate salt, a malate salt, a maleate salt, a mesylate salt, an oxalate salt, a phosphate salt, a sulfate salt, a tartrate salt, or a tosylate salt. In some embodiments, a pharmaceutically acceptable salt of Compound 1, or a pharmaceutically acceptable solvate and / or isotopologue fonn thereof, is or comprises Compound 1, or pharmacally acceptable solvate and / or isotopologue fonn thereof, and a conjugate acid (to form the pharmaceutically acceptable salt) in a molar ratio in the range of about 2: 1 to about 1:2. In some embodiments, a solid form comprises a pharmaceutically acceptable salt of Compound 1, or a pharmaceutically acceptable solvate and / or isotopologue form thereof, and a conjugate acid (to form the pharmacally acceptable salt) in a molar ratio in the range of about 2: 1 to about 1:2. In some embodiments, the molar ratio of the Compound 1 or pharmacally acceptable solvate thereof to the conjugate acid ranges from about 2: 1 to about 0.1: 1. In some embodiments, the molar ratio of the Compound 1 or pharmaceutically acceptable solvate thereof to the conjugate acid ranges from about 2: 1 to about 1: 1. In some embodiments, the molar ratio of the Compound 1 or pharmaceutically acceptable solvate thereof to the conjugate acid ranges from about 0.1: 1 to about 1:2. In some embodiments, tire molar ratio of the Compound 1 or pharmaceutically acceptable solvate thereof to the conjugate acid ranges from about 1: 1 to about 1:2. In some embodiments, the molar ratio of the Compound 1 or pharmacally acceptable solvate and / or isotopologue fonn thereof, and the-9-NAI-5007198252vlconjugate acid (the pharmaceutically acceptable salt) is about 2: 1, about 1.9: 1, about 1.8: 1, about 1.7: 1, about 1.6: 1, about 1.5: 1, about 1.4: 1, about 1.3: 1, about 1.2: 1, about 1.1 : 1, about 1: 1, about 0.9: 1, about0.8: 1, about 0.7: l, about 0.6: 1, about 0.5: 1, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:0.9, about 1: 1.1, about 1: 1.2, about 1: 1.3, about 1: 1.4, about 1:1.5, about 1: 1.6, about 1: 1.7, about 1: 1.8, about1: 1.9, or about 1:2, such as about 2: 1, about 1 : 1, or about 1:2. In some embodiments, the molar ratio of the Compound 1 or pharmaceutically acceptable solvate thereof to the conjugate acid is about 1:2. In some embodiments, the molar ratio of the Compound 1 or pharmaceutically acceptable solvate thereof to the conjugate acid is about 1: 1. In some embodiments, the molar ratio of the Compound 1 or pharmaceutically acceptable solvate thereof to tire conjugate acid is about 2: 1.

[0033] In some embodiments, the pharmaceutically acceptable form of a compound disclosed herein is exclusive of a salt form (i.e., is not a salt), sometimes referred to as a free form or free base form, of a compound disclosed herein. In some embodiments, a free base form of a compound disclosed herein is a pharmaceutically acceptable solvate and / or isotopologue form of said compound. In some embodiments, a free base form of a compound disclosed herein is a pharmaceutically acceptable solvate form of said compound.

[0034] In some embodiments, the pharmaceutically acceptable form is a solvate (e.g., a hydrate). As used herein, the terms “solvate,"’ “pharmaceutically acceptable solvate,” or “pharmaceutically acceptable solvent,” refer to a compound that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non -covalent intermolecular forces. In some embodiments, the solvate is a crystalline form of a molecule, atom, and / or ions that further comprises molecules of a solvent or solvents incorporated into the cry stalline lattice structure. The solvent molecules in the solvate may be present in a regular arrangement and / or a non-ordered arrangement. In some embodiments, the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. For example, a solvate with a nonstoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate. Solvates may occur as dimers or oligomers comprising more than one molecule or Compound ABC within the crystalline lattice structure. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a “hydrate.” In some embodiments, the solvate is a hydrate. Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 0.1, 0.25, 0.50, 0.75, or 1 solvent or water molecules, or can include 1 to about 100. or 1 to about 10, or one to about 2, about 3 or about 4, solvent or water molecules. In some embodiments, a pharmaceutically acceptable solvate of Compound 1, or a pharmaceutically acceptable salt and / or isotopologue form thereof, is or comprises Compound 1, or pharmaceutically acceptable salt and / or isotopologue form thereof, and a pharmaceutically acceptable solvent in a molar ratio in tire range of about 2: 1 to about 1:2. In some embodiments, the molar ratio of Compound 1 to the solvent ranges from-10-NAI-5007198252vlabout 2: 1 to about 0.1: 1. In some embodiments, the molar ratio of Compound 1 to the solvent ranges from about 2: 1 to about 1: 1. In some embodiments, the molar ratio of Compound 1 to the solvent ranges from about 0.1 : 1 to about 1:2. In some embodiments, the molar ratio of Compound 1 to the solvent ranges from about 1 : 1 to about 1:2. In some embodiments, the molar ratio of the Compound 1 to the solvent is about 2:1, about 1.9: 1, about 1.8: 1, about 1.7: 1, about 1.6: 1. about 1.5: 1, about 1.4: 1, about 1.3: 1, about 1.2: 1. about 1.1: 1, about 1: 1, about 0.9: 1, about 0.8: 1. about 0.7: 1, about 0.6: 1, about 0.5: 1. about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:0.9, about 1: 1.1, about 1: 1.2, about 1: 1.3, about 1: 1.4, about 1: 1.5, about 1: 1.6, about 1: 1.7, about 1: 1.8, about 1 : 1.9, or about 1:2, such as about 2: 1, about 1 : 1, or about 1:2. In some embodiments, the molar ratio of the Compound 1 to the solvent is about 1:2 (i.e., bis-solvate). In some embodiments, the molar ratio of the Compound 1 to the solvent is about 1:1 (i.e.. mono-solvate). In some embodiments, the molar ratio of the Compound 1 to the solvent is about 2: 1 (i.e.. hemi-solvate). In some embodiments, the pharmaceutically acceptable solvent (solvate) is or may comprise a hydrate, a hemi-hydrate, an iso-butyl acetate solvate, an iso-propyl acetate solvate, a tetrahydrofuran solvate, an acetone solvate, an acetonitrile solvate, or combinations thereof. For example, in some embodiments, the pharmaceutically acceptable solvate is water, and the molar ratio of the Compound 1 to the solvent is about 2: 1 (also referred to as a hemi-hydrate). In some embodiments, the pharmacally acceptable solvate of Compound 1, or a pharmaceutically acceptable salt and / or isotopologue form thereof, is a solid form of the Compound 1.

[0035] As used herein, the term “hemi-hydrate” refers to a solid that is crystalline and incorporates one molecule of water for every two molecules of the compound (i.e. , Compound 1) within the lattice structure.

[0036] In some embodiments, the term a “pharmaceutically acceptable salt or solvate” of compounds disclosed herein includes, but is not limited to, a pharmaceutically acceptable salt and / or solvate, of compounds disclosed herein, which includes combinations thereof (e.g., a solvate of a pharmaceutically acceptable salt), and further includes isotopologues thereof (i.e., isotopically labeled derivative) of the compound or of the solvate, salt, or solvate of salt of such compound.

[0037] In some embodiments, the pharmaceutically acceptable form of a compound disclosed herein is exclusive of a solvate form, sometimes referred to as a non-solvate, of a compound disclosed herein. For example, the pharmaceutically acceptable form of a compound disclosed herein may be exclusive of water, sometimes referred to as an anhydrate, of a compound disclosed herein. In some embodiments, a non-solvate form of a compound disclosed herein is a pharmaceutically acceptable salt and / or isotopologue form of said compound. In some embodiments, a non-solvate form of a compound disclosed herein is a pharmacally acceptable salt form of said compound. Unless otherwise specified, it is understood that a non-solvate form of a compound has a residual amount of solvate at-11-NAI-5007198252vlabout 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, about 0.5% or less, or about 0.25% or less. For example, an anhydrate form of a compound has a residual amount of water at about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, about 0.5% or less, or about 0.25% or less.

[0038] In some embodiments, the pharmaceutically acceptable form is an isomer. "‘Isomers” are different compounds that have the same molecular formula. In some embodiments, the isomer may be a stereoisomer. In some embodiments, the isomer may be a tautomer. In some embodiments, the isomer may be a geometric isomer. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. Stereoisomers include, for example, enantiomers, diastereomers, and atropisomers. Atropisomers are stereoisomers that arise because of hindered rotation about a single bond, where energy differences due to steric strain or other factors create a barrier to rotation sufficient to allow for identification and potentially isolation of individual conformers. As used herein, the term “isomer” includes any and all geometric isomers and stereoisomers. For example, “isomers” include geometric double bond cis- and tra s-isomers, also termed E- and Z- isomers; atropisomers; R- and S- enantiomers; diastereomers, (d)- -isomers and (Z)-isomers, racemic mixtures thereof; and other mixtures thereof, as falling within the scope of this disclosure.

[0039] As used herein and unless otherwise specified, the use of a wavy bond ('vw) attached to an alkene indicates that the stereochemistry of the alkene may be in E configuration, Z configuration, or a mixture of E configuration and Z configuration in any ratio.

[0040] It is further understood that reference to a compound as disclosed herein having one or more stereocenters without designating the specific chirality (e.g., R- or S-enantiomer) will be understood to refer to the compound as racemic mixture (or a mixture of diastereomers), while inclusion of R- or S- designations will be understood to refer to an enantiomer (or a diastereomer) form of the compound, such as an enantiomerically (or diastereomerically) enriched form of the compound, or an enantiomeric excess of the specified enantiomer form of the compound, in accordance with discussion above regarding enantiomeric enriched and enantiomeric excess. Notation of a compound with an R- or S- designation is understood to include an enantiomerically enriched or an enantiomeric excess of the specified enantiomer of the compound, and not limited to only 100% of the single specified enantiomer of the compound.

[0041] It should be noted that if there is a discrepancy between a depicted structure and a name for that structure, the depicted structure is to be accorded more weight.

[0042] “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any proportion can be known as a “racemic” mixture. The tenn “(±)” or “(rac)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.-12-NAI-5007198252vlThe absolute stereochemistry can be specified according to the Cahn-Ingold-Prelog R-S system. When a compound is an enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of tire sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry at each asymmetric atom, as ( / ?)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically substantially pure forms and intermediate mixtures.

[0043] Stereoisomers, such as optically active (+) and (-), or optically active ( / ?)- and (.S')-isomers. can be asymmetrically synthesized or prepared, for example, using chiral synthons or chiral reagents, or resolved using techniques, such as chromatography on a chiral stationary phase. For example, the stereoisomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, e.g., Jacques, J., et al., (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY. 1962); Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers : Synthetic Methods (Wiley-VCH Verlag gmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); Subramanian, G. Chiral Separation Technicpies: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0044] It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (.S') form.

[0045] In some embodiments, the pharmaceutically acceptable form is a tautomer. As used herein, the tenn “tautomer” is a type of isomer that includes two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a double bond, or a triple bond to a single bond, or vice versa). “Tautomerization” includes prototropic or proton-shift tautomerization, which is considered a subset of acid base chemistry. “Prototropic tautomerization” or “proton-shift tautomerization” involves tire migration of a proton accompanied by changes in bond order. Tire exact ratio of the tautomers depends-13-NAI-5007198252vlon several factors, including temperature, solvent, and pH. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. Tautomerizations ( / .< .. the reaction providing a tautomeric pair) can be catalyzed by acid or base, or can occur without the action or presence of an external agent. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether tire compound is a solid or is in an organic or aqueous solution. Exemplary tautomerizations include, but are not limited to, keto-enol; amide-imide; lactam-lactim: enamine-imine; and enamine-(a different) enamine tautomerizations. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0046] As readily understood by one skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism and all tautomers of a compound are within the scope of the compound as provided herein.

[0047] In some embodiments, the pharmaceutically acceptable form is an isotopologue. As used herein, the term "isotopologue" refers to isotopically-enriched compounds which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as2H,3H,13C,14C.15N,18O,170.32P,33P,33S,34S,35S,36S,18F.35C1,36CL and37C1, respectively, each of which is also within the scope of this description. For example, compounds having the present structures except for the replacement or enrichment of a hydrogen by deuterium or tritium at one or more atoms in the molecule, are within the scope of this disclosure. In some embodiments, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by deuterium. In some embodiments, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by tritium. Further, substitution with heavier isotopes such as deuterium (i.e..2H) can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Isotopically-enriched compounds, such as Compound 1, or a pharmacally acceptable fonn thereof, including a solid form of Compound 1. or a pharmaceutically-14-NAI-5007198252vlacceptable form thereof, can generally be prepared using procedures known to persons of ordinary skill in the art by substituting an appropriate isotopically-enriched reagent for a non-isotopically-enriched reagent. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement or enrichment of a hydrogen by deuterium or tritium at one or more atoms in the molecule, or the replacement or enrichment of a carbon by13C or14C at one or more atoms in the molecule, are within the scope of this disclosure. In some embodiments, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by deuterium. In some embodiments, provided herein are isotopically labeled compounds having 1-3 hydrogen atoms replaced by or enriched by deuterium. In some embodiments, provided herein are isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by tritium. In some embodiments, provided herein are isotopically labeled compounds having one or more carbon atoms replaced or enriched by13C. In some embodiments, provided herein are isotopically labeled compounds having one or more carbon atoms replaced or enriched by14C.

[0048] When the compounds are enriched with deuterium, the deuterium-to-hydrogen ratio on the deuterated atoms of the molecule substantially exceeds tire naturally occurring deuterium-to-hydrogen ratio.

[0049] As used herein and unless otherwise specified, the tenns “solid form” and related terms refer to a physical form which is not predominantly in a liquid or a gaseous state. As used herein, the terms “solid form” and “solid forms” encompass semi-solids. Solid forms may be crystalline, amorphous, partially crystalline, partially amorphous, or mixtures of forms.

[0050] The solid forms provided herein may have varying degrees of crystallinity or lattice order. The solid forms provided herein are not limited by any particular degree of crystallinity or lattice order, and may be 0 - 100% crystalline. Methods of determining the degree of crystallinity are known to those of ordinary skill in the, such as those described in Suryanarayanan, R., X-Ray Power Di ffractometry. Physical Characterization of Pharmaceutical Salts, H.G. Brittain, Editor, Mercel Dekkter, Murray Hill, N.J., 1995, pp. 187-199, which is incorporated herein by reference in its entirety. In some embodiments, the solid forms provided herein are about 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 % crystalline, such as about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5%, crystalline, or greater.

[0051] As used herein and unless otherwise specified, the term “crystalline” and related terms used herein, when used to describe a substance, component, product, or form, mean that the substance, component, product, or fomr is substantially crystalline, for example, as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 21stedition, Lippincott, Williams and-15-NAI-5007198252vlWilkins, Baltimore, MD (2005); The United States Pharmacopeia, 23rdedition, 1843-1844 (1995).

[0052] As used herein and unless otherwise specified, the term “crystal form,” “crystal forms,” and related terms herein refer to solid forms that are crystalline. Crystal forms include single -component cry stal forms and multiple-component crystal forms, and include, but are not limited to, polymorphs, solvates, hydrates, and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, cocrystals of salts, other molecular complexes of salts, and polymorphs thereof In certain embodiments, a crystal form of a substance may be substantially free of amorphous forms and / or other crystal forms. In certain embodiments, a crystal form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more amorphous fomi(s) and / or other crystal fonn(s) on a weight basis. In certain embodiments, a crystal form of a substance may be physically and / or chemically pure. In certain embodiments, a crystal form of a substance may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physically and / or chemically pure.

[0053] A “single-component” solid form comprising a compound consists essentially of the compound. A “multiple-component” solid form comprising a compound comprises a significant quantity of one or more additional species, such as ions and / or molecules, within the solid form. For example, in certain embodiments, a crystalline multiple -component solid form comprising a compound further comprises one or more species non-covalently bonded at regular positions in the crystal lattice. For another example, in certain embodiments, an amorphous multiple -component solid form comprising a compound further comprises one or more polymer(s), and the compound is dispersed in a solid matrix that comprises tire polymer(s).

[0054] Crystal forms of a substance may be obtained by a number of methods. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as, e.g., in nanopores or capillaries, recrystallization on surfaces or templates such as, e.g., on polymers, recrystallization in the presence of additives, such as, e.g., cocrystal counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding, wet milling, dry milling, temperature cycling, and solvent-drop grinding. Such methods also include continuous processing such as mixed suspension, mixed product removal, seeded crystallization, and solvent recrystallization using solvent / anti-solvent mixtures (including standard addition, co-addition, and reverse addition).

[0055] Unless otherwise specified, the terms “polymorph,” “polymorphic form,” “polymorphs,” “polymorphic forms,” and related terms herein refer to two or more crystal forms that consist essentially of the same molecule, molecules or ions. Like different crystal forms, different polymorphs may have different physical properties, such as, for example, melting temperatures, heats of fusion, solubilities,-16-NAI-5007198252vldissolution rates, and / or vibrational spectra as a result of a different arrangement or conformation of the molecules or ions in the crystal lattice. The differences in physical properties exhibited by polymorphs may affect pharmaceutical parameters, such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability). Differences in stability’ can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical changes (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically a more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). As a result of solubility / dissolution differences, in the extreme case, some polymorphic transitions may result in lack of potency or, at tire other extreme, toxicity. In addition, the physical properties of the crystal may be important in processing (for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities, and particle shape and size distribution might be different between polymorphs).

[0056] As used herein and unless otherwise specified, the term “amorphous,” “amorphous form,” and related terms used herein, mean that the substance, component or product in question is not substantially crystalline as determined by X-ray diffraction. In particular, the term “amorphous form” describes a disordered solid form, i.e., a solid form lacking long range crystalline order. In certain embodiments, an amorphous form of a substance may be substantially free of other amorphous forms and / or crystal forms. In other embodiments, an amorphous form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more other amorphous forms and / or crystal fonns on a weight basis. In certain embodiments, an amorphous form of a substance may be physically and / or chemically pure. In certain embodiments, an amorphous form of a substance may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physically and / or chemically pure. In certain embodiments, an amorphous form of a substance may comprise additional components or ingredients (for example, an additive, a polymer, or an excipient that may serve to further stabilize the amorphous form). In certain embodiments, amorphous form may be a solid solution.

[0057] Amorphous fonns of a substance can be obtained by a number of methods. Such methods include, but are not limited to, heating, melt cooling, rapid melt cooling, solvent evaporation, rapid solvent evaporation, desolvation, sublimation, grinding, ball-milling, cryo-grinding. spray drying, and freeze drying.

[0058] Techniques for characterizing crystal forms and amorphous forms include, but are not limited to, thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single-crystal X-ray diffractometry, vibrational spectroscopy, e.g., infrared (IR) and Raman spectroscopy, solid-state and solution nuclear magnetic resonance (NMR) spectroscopy,-17-NAI-5007198252vloptical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility measurements, dissolution measurements, elemental analysis and Karl Fischer analysis. Characteristic unit cell parameters may be determined using one or more techniques such as, but not limited to, X-ray diffraction and neutron diffraction, including single -crystal diffraction and powder diffraction. Techniques useful for analyzing powder diffraction data include profile refinement, such as Rietveld refinement, which may be used, e.g., to analyze diffraction peaks associated with a single phase in a sample comprising more than one solid phase. Other methods useful for analyzing powder diffraction data include unit cell indexing, which allows one of skill in the art to determine unit cell parameters from a sample comprising crystalline powder. In some embodiments, an XRPD pattern is obtained using Cu Ka radiation. In some embodiments, the peaks listed for an XRPD pattern have a relative intensity of greater than about 5%, greater than about 10%, greater than about 15%, or greater than about 20%. In some embodiments, the ramp rate (heating rate) for a DSC is about 10 °C per minute. In some embodiments, slow heating rate such as 0.5-2.0 °C per minute can be used for more accurate DSC testing. The sample pans used in a DSC testing include, e.g., aluminum, platinum, and stainless steel pans. The pans can have different configurations, e.g., open, pinhole, or hermetically-sealed pans. In some embodiments, the ramp rate for a TGA is about 10 °C per minute.

[0059] Unless otherwise specified, the terms "X-ray powder diffraction”, "pow der X-ray diffraction”, “PXRD”, and “XRPD” are used interchangeably in this application.

[0060] As used herein and unless otherwise specified, the term “particle size distribution” or PSD refers to values or mathematical functions that define the relative amount, typically in mass or volume, of particles present in a sample according to size. Particle size distribution can be characterized by one or more values, such as D90. D50, or D10. Tire particle size distribution may be determined by means well known to the skilled artisan e.g. by laser diffraction or particle size analyzer. “D90” refers to the value of particle size at which 90% of the particles are no larger than the indicated size. For example, if the D90 is 100 nm, it means that 90% of the sample has a particle size of 100 nm or smaller. Particle size distribution may be affected by the hydration state of the particles. A wet particle size distribution may differ from a dry particle size distribution and corresponding possess different characteristic of D90, D50, or D10. As used herein and unless otherwise specified, the D90 values described herein are measured using laser diffraction (e.g., with Malvern Mastersizer 3000) using a wet method (e.g., USP <429>, including suspension of the analyte (such as about 15 to 75 mg of analyte) in 0.5% Tween 80 in water, prepared with sonication with a 180W sonicator at 400 KHz, wet dispersing unit Hydro SM)).

[0061] As used herein and unless otherwise specified, the term “micronization” refers to any process or methods by which the size of the particles is reduced. For example, the particle sizes of the polymorph-18-NAI-5007198252vlform Compound 1 can be obtained by any milling, grinding, or other particle size reduction method known in the art to bring the polymorph form of Compound 1 into any of the desired particle size range. Micronization techniques are typically based on the use of friction to reduce particle size, e.g. by milling or grinding. Various micronization techniques can be used herein, such as jet milling, wet milling, ball milling, or supercritical fluid precipitation. In some embodiments, one or more jet milling or wet milling processes are used.

[0062] Solid forms may exhibit distinct physical characterization data that are unique to a particular solid form, such as the crystal forms provided herein. These characterization data may be obtained by various techniques known to those skilled in the art, including for example X-ray powder diffraction, differential scanning calorimetry, thermal gravimetric analysis, and nuclear magnetic resonance spectroscopy. Tire data provided by these techniques may be used to identify a particular solid form. One skilled in the art can determine whether a solid form is one of the forms provided herein by performing one of these characterization techniques and determining whether the resulting data '‘matches” or “substantially matches” the reference data provided herein, which is identified as being characteristic of a particular solid form. Characterization data that “matches” or “substantially matches” those of a reference solid fonn is understood by those skilled in the art to correspond to tire same solid form as the reference solid fonn. In analyzing whether data “match” or “substantially match,” a person of ordinary skill in tire art understands that particular characterization data points may vary to a reasonable extent while still describing a given solid form, due to, for example, experimental error and routine sample-to- sample analysis variation. For example, an XRPD pattern, DSC thermogram or TGA thermal curve that “matches” or “substantially matches” with one or more figures herein showing an XRPD pattern or DSC thermogram or TGA thermal curve, respectively, is one that would be considered by one skilled in tire art to represent the same single crystalline fonn of the compound as the sample of the compound that provided the pattern or thermogram or thermal curve of one or more figures provided herein. Thus, an XRPD pattern or DSC thermogram or TGA thermal curve that matches or is substantially in accordance may be identical to that of one of the figures or, more likely, may be somewhat different from one or more of the figures. For example, an XRPD pattern that is somewhat different from one or more of the figures may not necessarily show each of tire lines of tire diffraction pattern presented herein and / or may show a slight change in appearance or intensity of the lines or a shift in the position of the lines. These differences typically result from differences in the conditions involved in obtaining the data or differences in the purity of the sample used to obtain the data. A person skilled in the art is capable of determining if a sample of a crystalline compound is of the same fonn as or a different fonn from a form disclosed herein by comparison of the XRPD pattern or DSC thennogram or TGA thcnnal curve of the sample and the corresponding XRPD pattern or DSC thermogram or TGA thermal curve disclosed herein.-19-NAI-5007198252vl

[0063] “Substantially pure,’’ when used without further qualification, means the compound has a purity greater than about 90 weight percent, for example, greater than about 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 weight percent, and also including a purity equal to about 100 weight percent, based on the weight of the compound. Tire remaining material may comprise other fonn(s) of the compound and / or reaction impurities and / or processing impurities arising from its preparation. If the compound is “substantially pure” with respect to the presence of the other remaining materials, it can be referred to as “substantially physically pure”. When qualified, “substantially pure” means that the indicated compound contains less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.1% by weight of the indicated impurity. In some embodiments, the solid forms, e.g., crystal or amorphous forms, provided herein are substantially pure, i.e., substantially free of other solid fonns and / or of other chemical compounds, containing less than about 25%, 20%, 15%, 10%, 9%. 8%, 7%, 6%, 5%, 4%, 3%, 2%. 1%, 0.75%, 0.5%, 0.25% or 0.1% percent by weight of one or more other solid forms and / or of other chemical compounds. For example, in some embodiments, the solid form of Compound 1 is substantially pure (e.g., having the purity of at least about 90 wt. %, at least about 95 wt. %, at least about 96 wt. %, at least about 97 wt. %, at least about 98 wt. %, or at least about 99 wt. %). Purity can be assessed using techniques known in the art, for example, using an HPLC assay.

[0064] “Substantially pure” can also be qualified. If the compound is “substantially pure” with respect to the presence of chemical impurities (e.g., reaction impurities and / or processing impurities arising from its preparation), it can be referred to as “substantially chemically pure.” If the compound is “substantially pure” with respect to the presence of another stereoisomer, such as the other enantiomer, it can be referred to as “substantially stereoisomerically pure,” such as “substantially enantiomerically pure,” respectively. As used herein and unless otherwise indicated, the term stereoisomerically pure means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound.

[0065] As used herein, and unless otherw ise indicated, a chemical compound, solid form, or composition that is “substantially free” of another chemical compound, solid form, or composition means that the compound, solid form, or composition contains, in certain embodiments, less than about 50%, 45%, 40%, 35%, 30%, 25%. 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2% 0.1%, 0.05%, or 0.01% by weight of the other compound, solid fomr, or composition.

[0066] As used herein, and unless otherwise specified, a solid form that is “substantially physically pure” is substantially free from other solid forms. In certain embodiments, a crystal form that is substantially physically pure contains less than about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0. 1%, 0.05%, or 0.01% of one or more other solid forms on a weight basis. Hie detection of other solid fonns can be accomplished by any-20-NAI-5007198252vlmethod apparent to a person of ordinary skill in the art, including, but not limited to, diffraction analysis, thermal analysis, elemental combustion analysis and / or spectroscopic analysis.

[0067] As used herein, and unless otherwise specified, a solid form that is “substantially chemically pure” is substantially free from other chemical compounds (i.e., chemical impurities). In certain embodiments, a solid form that is substantially chemically pure contains less than about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%. 10%. 9%, 8%, 7%. 6%, 5%, 4%. 3%, 2%, 1%, 0.5%. 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% of one or more other chemical compounds on a weight basis. Tire detection of other chemical compounds can be accomplished by any method apparent to a person of ordinary skill in the art, including, but not limited to, methods of chemical analysis, such as, e.g., mass spectrometry analysis, spectroscopic analysis, thermal analysis, elemental combustion analysis and / or chromatographic analysis.

[0068] For instance, an enantiomer can, in some embodiments, be provided substantially free of the corresponding enantiomer, and can also be referred to as “optically enriched,” “enantiomerically enriched,” “enantiomerically pure” and “non-racemic,” as used interchangeably herein, in which the amount of one enantiomer is greater than the amount of that one enantiomer in a control mixture of the racemic composition (e.g., greater than 1 : 1 by weight). A typical enantiomerically pure compound comprises greater than about 80% by weight of one enantiomer of the compound and less than about 20% by weight of other enantiomer of the compound, greater than about 90% by weight of one enantiomer of the compound and less than about 10% by weight of the other enantiomer of the compound, greater than about 95% by weight of one enantiomer of the compound and less than about 5% by weight of the other enantiomer of the compound, or greater than about 97% by weight of one enantiomer of the compound and less than about 3% by weight of the other enantiomer of the compound,

[0069] For example, an enantiomerically enriched preparation of the 5 enantiomer, means a preparation of the compound having greater than about 50% by weight of the S enantiomer relative to the total weight of the preparation (e.g., total weight of S and R isomers), such as greater than about 60% by weight, greater than about 70% by weight, or greater than about 80% by weight. In some embodiments, the enrichment can be much greater than about 80% by weight, providing a “substantially enantiomerically enriched,” “substantially enantiomerically pure” or a “substantially non-racemic” preparation, which refers to preparations of compositions which have greater than about 85% by weight of one enantiomer relative to the total weight of the preparation, such as greater than about 90%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, greater than about 98.5%, greater than about 99%, greater than about 99.5% by weight. In some embodiments, the solid form of Compound 1 i.e., (.S')-3-ammo-3-( l -mcthyl- l / / -imidazol-5-yl)-6-oxa-2(4.6)-qiiinolma- l,4(l,3)-dibenzenacyclohexaphane-22.44-dicarbonitrile or darlifamib) is enantiomerically pure (i.e.,-21-NAI-5007198252vlsubstantially free of Compound lb (i.e., (7?)-3-amino-3-(l-methyl-177-imidazol-5-yl)-6-oxa-2(4,6)- quinolina-l,4(l,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile)). In some embodiments, the solid form of Compound 1 is substantially enantiomerically pure with the other enantiomer (e.g., Compound lb, the R enantiomer) present less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.1% by weight. In some embodiments, the solid form of Compound 1 is substantially enantiomerically pure (e.g. , having tire enantiomeric purity of at least about 98.0 wt. %, at least about 98.5 wt. %, at least about 99.0 wt. %, at least about 99.5 wt. %, or at least about 99.9 wt. %).

[0070] Tire use of stereoisomerically pure forms of such compounds, as well as the use of mixtures of those fonns, are encompassed by the embodiments provided herein. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound may be used in methods and compositions provided herein.

[0071] The “enantiomeric excess’’ or “% enantiomeric excess” of composition, for example a composition comprising a mixture of enantiomers of a compound, can be calculated using the equation shown below. In the example shown below, a mixture containing 90% of one enantiomer, e.g., an 5 enantiomer, and 10% of the other enantiomer, e.g., an R enantiomer, is said to have an enantiomeric excess of 80%. ee = (90-10) / 100 = 80%.

[0072] For example, in some embodiments, a compound described herein is a mixture of enantiomers of the compound (racemic) and contains an enantiomeric excess of greater than about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5%, of one enantiomer relative to the other enantiomer, such as an excess of the S enantiomer relative to the R enantiomer. For example, a compound provided herein may have greater than about 95% ee, such as about 96% ee, about 97% ee, about 98% ee, about 98.5% ee, about 99% ee, or about 99.5% ee of a single enantiomer. In some embodiments, the mixture of enantiomers of tire compound (racemic) has an enantiomeric excess of about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or more than about 99.5%, of one enantiomer relative to the other enantiomer, such as an enantiomeric excess of the 5 enantiomer relative to the R enantiomer.

[0073] As used herein and unless otherwise specified, the term “free base equivalent' ’ refers to the amount of the active agent (e.g., Compound 1) present in tire active agent or a pharmaceutically-22-NAI-5007198252vlacceptable form thereof. In other words, the term '‘free base equivalent,” as applied to Compound 1 or a pharmaceutically acceptable form thereof, means the amount of an amount of Compound 1 that is present as a free base. For example, the free base equivalent amount of a pharmaceutically acceptable salt or solvate of Compound 1 is the amount of Compound 1 as a free base that is provided by the pharmacally acceptable salt or solvate of Compound 1. For example, 10 mg of a mono-HCl salt of Compound 1, provides about 9.28 mg of the free base equivalent of Compound 1 and about 0.72 mg of HC1. Similarly, 10 mg of Compound 1, hemihydrate, provides about 9.81 mg of the free base equivalent of Compound 1 and about 0.19 mg of water. Other salts or solvates are expected to have different conversion factors, depending on the molecular weight of the particular salt or solvate, and the number of the particular salt or solvate, associated with the active agent (e.g., Compound 1).

[0074] As used herein and unless otherwise specified, the tenn “5 -metalated-1 -methylimidazole reagent ” refers t, wherein M is a metal cation, X is a counterion or absent, a is 1 to 3, b is 1 to 2, and c is 0 to 4 (selected as appropriate based on the valence of M). Non-limiting examples of M include Mg, Li. Al, Zn, Cu. Ni, or In. Non-limiting examples of X include halogen (I, Br, Cl, or F). In some embodiments, the 5-metalated- 1 -methylimidazole reagent is a Grignard reagent (e.g. , wherein a is 1 , M is Mg, b is 1, X is Br, Cl, or I, and c is 1; e.g., l-methyl-lH-imidazol-5-yl)magnesium bromide: (1- methyl-lH-imidazol-5-yl)magnesium chloride, or (1 -methyl- lH-imidazol-5-yl)magnesium iodide)), an organozinc reagent (e.g., wherein a is 2, M is Zn, b is 1, and c is 0; e.g., bis(l-methyl-lH-imidazol-5- yl)zinc), or an organolithium reagent (e.g., wherein a is 1, M is Li, b is 1, and c is 0; e g., (1-methyl-lH- imidazol-5 -yl)lithium) .

[0075] As used herein and unless otherwise specified, the tenn "Mitsuiiobu conditions” refers to reaction conditions suitable for converting an alcohol functional group into an ether or ester group in the presence of an azodicarboxylate reagent and a phosphine reagent. Non-limiting examples of an azodicarboxylate reagent include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-t-butyl azodicarboxylate, l,l’-(azocarbonyl)dipiperidine, and dibenzyl azodicarboxylate. Non-limiting examples of a phosphine reagent include dicyclohexylphenylphosphine, diethylphenylphosphine, tributylphosphine, diphenyl-2 -pyridylphosphine, 4- (dimethylamino)phenyldiphenylphosphine, isopropyldiphenylphosphine, tri-tert-butylphosphine, tri-n- octylphosphine, tricyclohexylphosphine, polystyryldiphenylphosphine, and triphenylphosphine (or substituted variants of triphenylphosphine). Exemplary Mitsunobu conditions are described in Reynolds, A. J. et al. Curr. Org. Chem. 2009, 13(16), 1610-1632, and Swamy, K.C. et al., Chem. Rev. 2009, 109(6),-23-NAI-5007198252vl2551-2651, which are incorporated herein by reference.

[0076] "‘Protecting group” has the meaning conventionally associated with it in organic synthesis, e.g., a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and such that the group can readily be removed after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in T.H. Greene and P. G. M. Wuts, supra. For example, a hydroxy protected form is where at least one of the hydroxy groups present in a compound is protected with a hydroxyl protecting group. Likewise, amines and other reactive groups can similarly be protected. Removal of the protecting group under conditions known to one skilled in the art provides the free hydroxy, amino, or other functional group, as applicable.

[0077] “Hydroxyl protecting group” has the meaning conventionally associated with it in organic synthesis, e.g.. a group that selectively blocks at least one of the hydroxyl groups in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site (including an unprotected hydroxyl group), and such that the hydroxyl protecting group can readily be removed after the selective reaction is complete to provide the corresponding free hydroxyl group. A variety of hydroxyl protecting groups are disclosed, for example, in T H. Greene and P. G. M. Wuts, supra.

[0078] As used herein and unless otherwise specified, the tenn “silyl protecting group” refers to a protecting group that contains a silicon atom covalently bonded to a heteroatom (e.g., O, S, or N), which blocks the heteroatom site (e.g., -OH, -SH, -NH, or -NH2) in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and such that the group can readily be removed after the selective reaction is complete. Exemplary silyl protecting groups are described in TH. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis. Fourth Edition. John Wiley & Sons, New York (2006), incorporated herein by reference in its entirety. In some embodiments, the silyl protecting group is covalently bound to an alcohol functional group to form a silyl ether. Non-limiting examples of silyl protecting groups include trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tcrt-butyldiphcnylsilyl (TBDPS), and triisopropylsilyl (TIPS).

[0079] As used herein, and unless otherwise specified, the tenn “alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is saturated. In one embodiment, the alkyl group has, for example, from one to twelve carbon atoms (C1-C12 alkyl), one to eight carbon atoms (Ci-Cs alkyl), one to six carbon atoms (Ci-Ce alkyl), or one to four carbon atoms (C1-C4 alkyl), and which is attached to the rest of the molecule by a single bond. Examples of alkyl groups include, but arc not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pcntyl, n- hexyl, and the like. Unless otherwise specified, an alkyl group is optionally substituted.-24-NAI-5007198252vl

[0080] As used herein, and unless otherw ise specified, the term “alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and in some embodiments, having from two to ten carbon atoms (i.e., C2-C10 alkenyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range; e.g., “2 to 10 carbon atoms” means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to five carbon atoms (e.g., C2-C5alkenyl). The alkenyl is attached to the parent molecular structure by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of Cf alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4) and the like. Examples of C2-6 alkenyl groups include the aforementioned CL 4 alkenyl groups as well as pentenyl (C5), pentadienyl (Cs), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless stated otherwise in the specification, an alkenyl group is optionally substituted.

[0081] As used herein, and unless otherwise specified, the term “alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having, in some embodiments, from two to ten carbon atoms (i.e., C2-C10 alkynyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range; e.g., "2 to 10 carbon atoms” means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to five carbon atoms (e.g., C2-C5 alkynyl). The alkynyl is attached to the parent molecular structure by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise in the specification, an alkynyl group is optionally substituted.

[0082] As used herein, and unless otherwise specified, the term “alkoxy” refers to the group -O-alkyl (in some embodiments, including from 1 to 10 carbon atoms), of a straight, branched, cyclic configuration and combinations thereof, attached to the parent molecular structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. “Lower alkoxy” refers to alkoxy groups containing one to six carbons. In some embodiments. C1-C4 alkoxy is an alkoxy group which encompasses both straight and branched chain alkyls of from 1 to 4 carbon atoms. Unless stated otherwise in the specification, an alkoxy group is optionally substituted.

[0083] As used herein, and unless otherwise specified, the temi “alkoxyalkyl” refers to a group of formula -alkyl-OR’, where R’ is H or alkyl. In one embodiment, the alkoxyalkyl is a hydroxyalkyl of the-25-NAI-5007198252vlformula -alkyl-OH.

[0084] As used herein, and unless otherwise specified, the term “cycloalkyl” refers to a monocyclic or polycyclic radical that contains at least one carbocyclic ring (i.e., a ring containing only carbon and hydrogen, which can be saturated or partially unsaturated). Partially unsaturated cycloalkyl groups can be termed “cycloalkenyl” if tire carbocycle contains at least one double bond, or “cycloalkynyl” if the carbocycle contains at least one triple bond. Cycloalkyl groups include groups having from 3 to 10 ring atoms (e.g. C3-C10 cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10” refers to each integer in the given range; e.g., “3 to 10 carbon atoms” means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 10 carbon atoms. The term “cycloalkyl” also includes bridged and spiro-fiised cyclic structures containing no heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: C3-6 carbocyclyl groups include, without limitation, cyclopropyl (Cs), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Examples of C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. Examples of C3-10 carbocyclyl groups include the aforementioned C3- s carbocyclyl groups as well as octahydro- 1 / 7-indenyl, decahydronaphthalenyl, spiro[4.5]decanyl, and the like. Unless stated otherwise in the specification, a cycloalkyl group is optionally substituted.

[0085] As used herein, and unless otherwise specified, the term “heterocyclyl” refers to any 3- to 18 membered non-aromatic radical monocyclic or polycyclic moiety comprising at least one ring heteroatom selected from nitrogen, oxygen, phosphorous, and sulfur. A heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein the polycyclic ring systems can be a fused, bridged or spiro ring system. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or more rings. A heterocyclyl group can be saturated or partially unsaturated. Partially unsaturated heterocycloalkyl groups can be termed “heterocycloalkenyl” if the heterocyclyl contains at least one double bond, or “heterocycloalkynyl” if the heterocyclyl contains at least one triple bond. Unless stated otherwise, heterocyclyl moieties are optionally substituted.

[0086] As used herein, and unless otherwise specified, the term “aryl” refers to a radical with six to fourteen ring atoms (e.g., Ce-Cu or Ce-Cio aryl) which has at least one carbocyclic ring having a conjugated pi electron system which is aromatic (e g., having 6, 10, or 14 TT electrons shared in a cyclic array) (e.g., phenyl, fluorenyl, and naphthyl). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Unless stated otherwise in the specification, an aryl moiety can be optionally substituted.-26-NAI-5007198252vl

[0087] As used herein, and unless otherw ise specified, the term “heteroaryl” refers to a monocyclic aromatic group and / or multicyclic aromatic group that contains at least one aromatic ring, w herein at least one aromatic ring contains one or more (e.g., one, one or two, one to three, or one to four) heteroatoms independently selected from 0, S, and N. The heteroaryl may be attached to the main structure at any heteroatom or carbon atom. In certain embodiments, the heteroaryl has from 5 to 12 ring atoms, from 5 to 10 ring atoms, from 5 to 8 ring atoms. 5 ring atoms, or 6 ring atoms. The term "heteroaryl” also refers to bicyclic, tricyclic, or other multicyclic rings, where at least one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N. Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl. isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl. pyrimidinyl, pyridazinyl, and triazinyl. Unless otherwise specified, a heteroaryl group is optionally substituted.

[0088] As used herein, and unless otherwise specified, the term “optional” or “optionally” (e.g., optionally substituted) means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means that the alkyl radical may or may not be substituted and that the description includes both substituted alkyl radicals and alkyl radicals having no substitution.

[0089] When the groups described herein are said to be “substituted,” they may be substituted with any appropriate substituent or substituents. Illustrative examples of substituents include, but are not limited to, halogen (chloro, iodo, bromo, or fluoro); alkyl; alkenyl; alkynyl; hydroxyl (-OH); alkoxy; alkoxyalkyl; amino (-NR2, wherein each R independently is, for example, H, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl); alkylamino (-NR2, wherein at least one R is alkyl); carboxy (-CO2H): nitro (-NO2); cyano (-CN); thiol (-SH); thioether (-SR, wherein R is, for example, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, but is not H); imine (=NR); imide (e.g., -C(=O)N(R')C(=O)R"); amidine (e.g., -C(=NR')NR"2); guanidine (e.g. -N(R)C(— NR')NR"2); enamine (e.g.. N(R)-C(R')=CR"2); aminocarbonyl (-C(=O)NR2); acylamino (-N(R)C(=0)R'); phosphonate (-P(=O)OR2); phosphine (-PR2); thiocarbonyl (>C(=S)); sulfinyl (-S(=O)R); sulfone (-S(=O)2R); sulfonamide (e.g., -S(=O)2NR'2); ketone (-C(=O)R, wherein R is, for example, alkyl, cycloalkyl, ary l . heterocyclyl, or heteroaryl. but is not H); aldehyde (-C(=O)H); ester (-C(=O)OR, wherein R is, for example, alkyl, cycloalkyl, ary l, heterocyclyl, or heteroaryl, but is not H); urea (e.g. .N(R)C(=0)NR"2); urethane (_N(R)C(=0)0R'); oxime (=N0H); hydroxyl amine (-N(OH)R); alkoxyamine (-N(OR)R', wherein R is alkyl); aryloxyamine (-N(OR)R', wherein R is ary l), aralkoxyamine (-N(0R)R', wherein R is alkyl and R' is ary l): N-oxide (-(R)N-0 or - R3N-O); hydrazine (R2N-NR2); hydrazone (-(R)C=N-NR2); azide (-N3); isocyanate (-NCO);-27-NAI-5007198252vlisothiocyanate (-NCS); cyanate (-OCN); thiocyanate (-SCN); oxo (=0); cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopcntyl, or cyclohcxyl), hctcrocyclyl (e.g., pyrrolidyl, piperidyl, pipcrazinyl, morpholinyl, or thiazinyl); aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl. tetrazolyl, pyrazolyl, pyridinyl. or quinolinyl).

[0090] As used herein, the term “pharmaceutically acceptable excipient” is understood to mean a carrier, excipient, or diluent approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, adjuvant (e.g., Freund’s adjuvant (complete and incomplete)), excipient, or vehicle with which a therapeutic agent is administered. Such pharmacal carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is a specific carrier for intravenously administered pharmaceutical compositions. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. For example, the term pharmaceutically acceptable carrier, excipient or diluent includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions as disclosed herein is contemplated.Supplementary active ingredients can also be incorporated into the pharmaceutical compositions. Typical compositions and dosage forms comprise one or more excipients. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to. the way in which the dosage form will be administered to a patient and the specific active ingredients in the dosage form. Examples of excipients that can be used in oral dosage forms provided herein include, but are not limited to, fillers, glidants, disintegrants, lubricants, or binders, or combinations thereof.

[0091] Definitions of specific functional groups and chemical terms are described in detail herein. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version. Handbook of Chemistry and Physics. 75th ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March Marc ’s Advanced Organic Chemistry, 5th ed., John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers. Some Modern Methods of Organic Synthesis, 3rd ed., Cambridge University Press, Cambridge, 1987.-28-NAI-5007198252vl

[0092] As used herein and unless otherwise indicated, the term '‘process(es)” provided herein refers to the methods provided herein which are usefill for preparing a compound as described herein or a solid form thereof (e.g., a crystalline form, partially cry stalline form, or an amorphous form) provided herein. Modifications to the methods provided herein (e.g., starting materials, reagents, protecting groups, solvents, temperatures, reaction times, purification) are also provided herein. In general, the technical teaching of one embodiment provided herein can be combined with that disclosed in any other embodiments provided herein.

[0093] As used herein, and unless otherwise indicated, the term “adding,” “reacting,” “treating,” or the like, used in the context of a production, synthesis, purification, or similar process, such as a reaction process or a crystallization process, means contacting one reactant, reagent, solvent, catalyst, reactive group or the like with another reactant, reagent, solvent, catalyst, reactive group, or the like. Reactants, reagents, solvents, catalysts, reactive group, or tire like can be added individually, simultaneously, or separately and can be added in any order. Reactants, reagents, solvents, catalysts, reactive group, or the like can each respectively be added in one portion, which may be delivered all at once or over a period of time, or in discrete portions, which also may be delivered all at once or over a period of time. They can be added in the presence or absence of heat and can optionally be added under an inert atmosphere. “Reacting” can refer to in situ formation or intramolecular reaction where the reactive groups are in the same molecule.

[0094] As used herein, the term “recovering” includes, but is not limited to, the action of obtaining one or more compounds by collection during and / or after a process step as disclosed herein, and tire action of obtaining one or more compounds by separation of one or more compounds from one or more other chemical entities during and / or after a process step as disclosed herein. The term “collection” refers to any action(s) known in the art for this purpose, including, but not limited to, filtration, decanting a mother liquor from a solid to obtain one or more compounds, and evaporation of liquid media in a solution or other mixture to afford a solid, oil, or other residue that includes one or more compounds. The solid can be crystalline, non-crystalline, partially cry stalline, or amorphous, a powder, granular, of varying particle sizes, of unifonn particle size, among other characteristics known in the art. An oil can vary in color and viscosity, and include one or more solid forms as a heterogeneous mixture, among other characteristics known in the art. Hie term “separation” or “separating” refers to any action(s) known in the art for this purpose, including, but not limited to, isolating one or more compounds from a solution or mixture using, for example, crystallization as described herein, seeded or seedless crystallization or other precipitation techniques (e.g., adding an anti-solvent to a solution to induce compound precipitation; heating a solution, then cooling to induce compound precipitation; scratching the surface of a vessel containing a solution with an implement to induce compound precipitation), and distillation techniques.-29-NAI-5007198252vlRecovering one or more compounds can involve preparation of a salt, solvate, hydrate, chelate or other complexes of the same, then collecting or separating as described above. The term “extracting” as used herein refers to a process of partitioning a target compound into either an organic phase or an aqueous phase. For example, extracting a target compound into the organic phase comprises agitating the compound in a mixture of an organic phase (e g ., a water-immiscible organic solvent, such as Et2O, EtOAc, DCM. THF. toluene, NMP, ACN. MTBE, or a mixture thereof) and an aqueous phase (e.g.. water, mild aqueous acid, mild aqueous base, aq. NaCl), separating the aqueous phase, and recovering the organic phase comprising the target compound.

[0095] As used herein, and unless otherwise specified, the terms “solvent,” “organic solvent,” or “inert solvent,” used in the context of a process, such as a reaction process or a cry stallization process, each mean a solvent inert under the conditions of the reaction being described. Unless specified to the contrary, for each gram of a limiting reagent, one cc (or mL) of solvent constitutes a volume equivalent (or “vol .”).

[0096] As used herein, and unless otherwise specified, the term “sulfinamide removal agent” refers to an agent capable of cleaving the N-S bond in a compound comprising a RCS(O)NR2 group, to remove the RCS(O)- moiety. Exemplary sulfinamide removal agents include acid, a reducing agent, a base, an oxidant, and a radical agent, or a combination thereof. In some aspects, reaction of a sulfinamide removal agent with a sulfinamide group of a compound replaces the RCS(O)- moiety in tire compound with an H.

[0097] As used herein, and unless otherwise specified, the term “cyanide source” refers to a compound capable of releasing one or more equivalents of cyanide anion (CN ), cyano radical (*CN), and / or hydrogen cyanide (HCN). Exemplary cyanide sources Zn(CN)2, LiCN, KCN, NaCN, CuCN, CU(CN)2, Ni(CN)2, Ca(CN)2, TMSCN, K;,| Fe(CN)e], K4[Fe(CN)e], benzene sulfonyl cyanide, tert-butyl cyanide. [Me4N]CN, tetraethylammonium cyanide, ethyl cyanoacetate, acetone cyanohydrin, cyanogen, and dimethylmalononitrile.

[0098] The disclosure can be understood more fiilly by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments.5.1 COMPOUNDS

[0099] In some embodiments, provided herein, is a process of preparing Compound 1, which can be named (S)-3-amino-3-( 1 -methyl- l / / -imidazol-5-yl)-6-oxa-2(4.6)-quinolina-l, 4(1,3)- dibenzenacyclohexaphane-22,44-dicarbonitrile, or which can be named darlifamib, and which has the structure:-30-NAI-5007198252vlCompound 1, or a pharmaceutically acceptable form thereof.

[0100] In some embodiments, provided herein, is a process of preparing Compound lb, which can be named ( ?)-3-amino-3-( 1 -methyl- 177-imidazol-5-yl)-6-oxa-2(4, 6)-quinolina-l, 4(1,3)- dibenzenacyclohexaphane-22,44-dicarbonitrile, and which has the structure:Compound lb, or a pharmaceutically acceptable form thereof.

[0101] In some embodiments, provided herein, is a process of preparing Compound 1c, which can be named (3-amino-3-(l-methyl-l / -imidazol-5-yl)-6-oxa-2(4,6)-quinolina-l,4(l,3)- dibenzenacyclohexaphane-22,44-dicarbonitrile, and which has the structure:Compound 1c, or a pharmaceutically acceptable form thereof.As used herein, Compound 1c depicts a racemic mixture of Compound 1 and Compound lb, but non-equal mixtures of Compound 1 and Compound lb are also contemplated as described herein.

[0102] As used herein, compounds disclosed herein include, but are not limited to, free base forms or pharmacally acceptable salts thereof, and solvates or hydrates thereof, and isotopologues of such compounds. In some embodiments are contemplated a free base or pharmaceutically acceptable salt of Compound 1 , or a hydrate or solvate and / or isotopologue thereof. Throughout the instant application, disclosures involving Compound 1, Compound lb, Compound 1c, or any synthetic intermediate-31-NAI-5007198252vlcompounds as disclosed herein in the synthesis of the same, are understood to also include salts and / or isotopologues as provided herein of said compounds.

[0103] Synthesis and certain uses, inhibition activities, and metabolic stabilities of the Compounds 1, lb, and 1c, and pharmaceutically acceptable forms thereof, as provided herein, are described in International Patent Application Publication Nos. WO 2023 / 102378 and WO 2024 / 245364, the entirety of each of which is incorporated herein by reference. Improved processes for preparing Compounds 1, lb. and 1c, and pharmaceutically acceptable forms thereof, are provided herein. In some embodiments, the compound for use in the methods of treating or the methods of inhibiting provided herein is Compound 1, or a pharmaceutically acceptable form thereof. In some embodiments, the compound for use in the methods of treating or the methods of inhibiting provided herein is a pharmaceutically acceptable salt of Compound 1, or a pharmaceutically acceptable solvate and / or isotopologue thereof. In some embodiments, the compound or solid form for use in the methods of treating or the methods of inhibiting provided herein is a solid form of Compound 1, or a pharmaceutically acceptable form thereof. In some embodiments, the compound for use in the methods of treating or the methods of inhibiting provided herein is a crystalline solid form of Compound 1, or a pharmaceutically acceptable form thereof.Throughout the instant application, disclosures involving the use of tire Compound 1, or pharmaceutically acceptable form thereof, such disclosures equally apply to the Compound lb, or pharmaceutically acceptable form thereof, or the Compound 1c, or pharmaceutically acceptable form thereof.

[0104] In some embodiments, provided herein is a compound that is an intermediate compound used in the synthesis of Compound 1, or a pharmaceutically acceptable form thereof.

[0105] In some embodiments, the intermediate compound is:-32-NAI-5007198252vlor a stereoisomer, salt, solvate, tautomer, or isotopologue thereof, wherein each PG is a hydroxyl protecting group, and each PG is optionally and independently selected from a silyl protecting group, an acetyl group, a benzyl group, a methoxymethyl group, a p-methoxybenzyl group, a pivaloyl group, a methoxyethoxymethyl group, a trityl group, or a tetrahydropyranyl group; and wherein Rcis (a) -C(Rd)(Rc)(Rf), wherein each of Rd, Rc, and Rfis independently C1.4 alkyl, or (b) phenyl or monocyclic heteroaryl optionally substituted with one or more C1.4 alkyl substituents, or (c) cycloalkyl optionally substituted with one or more C1-4 alkyl substituents.

[0106] In some embodiments of the Compound 7 group (e.g., Compounds 7PG / N, 7PG / N / Z, or 7PG / N / E), each PG is independently a silyl protecting group. In some embodiments, both PG groups are tert-butyldimethylsilyl (TBDMS). In some embodiments of the Compound 7 group, Rcis tert-butyl, 2,4,6-trimethylphenyl. (triethyl)methyl, 4-methylphenyl, phenyl, 2,4,6-triisopropylphenyl, or 2- methylbutan-2-yl. In some embodiments, Rcis tert-butyl.

[0107] In some embodiments. Compound 7PG / N is Compound 7PG / N / E, Compound 7PG / N / Z, or a mixture thereof. In some embodiments, Compound 7N is Compound 7N / Z, or Compound 7N / E, or a mixture thereof. In some embodiments, Compound 7 is Compound 7Z, or Compound 7E, or a mixture thereof.

[0108] In some embodiments, the intermediate compound is:-33-NAI-5007198252vlor a stereoisomer, salt, solvate, tautomer, or isotopologue thereof, wherein Rcis (a) -C(Rd)(Re)(Rf), wherein each of Rd, Re, and Rfis independently C 1-4 alkyl, or (b) phenyl or monocyclic hctcroaryl optionally substituted with one or more C1-4 alkyl substituents, or (c) cycloalkyl optionally substituted with one or more Ci -4 alkyl substituents.

[0109] In some embodiments of the Compound 6 group, Rcis tert-butyl, 2.4,6-trimethylphenyl, (triethyl)methyl, 4-methylphenyl, phenyl, 2,4,6-triisopropylphenyl, or 2-methylbutan-2-yl. In some embodiments, Rcis tert-butyl.

[0110] In some embodiments, Compound 6N is Compound 6N / Z, or Compound 6N / E, or a mixture thereof. In some embodiments, Compound 6 is Compound 6Z, or Compound 6E, or a mixture thereof.

[0111] In some embodiments, the intermediate compound is:-34-NAI-5007198252vlor a stereoisomer, salt, solvate, tautomer, or isotopologue thereof, wherein Rcis (a) -C(Rd)(Re)(Rf), wherein each ofRd, Re, and Rfis independently Ci-4alkyl, or (b) phenyl or monocyclic heteroaryl optionally substituted with one or more Ci-4alkyl substituents, or (c) cycloalkyl optionally substituted with one or more C1.4 alkyl substituents.

[0112] In some embodiments of the Compound 4 group, Rcis tert-butyl, 2,4,6-trimethylphenyl, (triethyl)methyl, 4-methylphenyl, phenyl, 2,4,6-triisopropylphenyl, or 2-methylbutan-2-yl. In some embodiments, Rcis tert-butyl.

[0113] In some embodiments, Compound 4N is Compound 4N / Z, or Compound 4N / E, or a mixture thereof. In some embodiments, Compound 4 is Compound 4Z, or Compound 4E, or a mixture thereof.

[0114] In some embodiments, the intermediate compound is:or a stereoisomer, salt, solvate, tautomer, or isotopologue thereof, wherein Rcis (a) -C(Rd)(Re)(Rf), wherein each ofRd, Re, and Rfis independently C 1.4 alkyl, or (b) phenyl or monocyclic heteroaryl optionally substituted with one or more C1.4 alkyl substituents, or (c) cycloalkyl optionally substituted with one or more Ci.4 alkyl substituents.

[0115] In some embodiments of the Compound 3 group, Rcis tert-butyl, 2,4,6-trimethylphenyl, (triethyl)methyl, 4-methylphenyl, phenyl, 2,4,6-triisopropylphenyl, or 2-methylbutan-2-yl. In some embodiments, Rcis tert-butyl.

[0116] In some embodiments, the intermediate compound is:-35-NAI-5007198252vlor a stereoisomer, salt, solvate, tautomer, or isotopologue thereof, wherein Rcis (a) -C(Rd)(Re)(Rf), wherein each of Rd, Re, and R1is independently C1.4 alkyl, or (b) phenyl or monocyclic heteroaryl optionally substituted with one or more Ci- 4 alkyl substituents, or (c) cycloalkyl optionally substituted with one or more Ci -4 alkyl substituents.

[0117] In some embodiments of tire Compound 2 group, Rcis tert-butyl, 2,4,6-trimethylphenyl, (triethyl)methyl. 4-methylphenyl, phenyl, 2,4,6-triisopropylphenyl, or 2-methylbutan-2-yl. In some embodiments, Rcis tert-butvL

[0118] In some embodiments, provided are the following compounds:-36-NAI-5007198252vlor a stereoisomer, salt, solvate, tautomer, or isotopologue thereof; wherein Rcis (a) -C(Rd)(Re)(Rf), wherein each of Rd, Re, and R1is independently C1.4 alkyl, or (b) phenyl or monocyclic heteroaryl optionally substituted with one or more Ci- 4 alkyl substituents, or (c) cycloalkyl optionally substituted with one or more C1-4 alkyl substituents, optionally wherein Rcis tert-butyl, 2,4,6-trimethylphenyl, (triethyl)methyl, 4-methylphenyl, phenyl, 2,4,6-triisopropylphenyl, or 2-methylbutan-2-yl, optionally wherein Rcis tert-butyl; and each PG is independently a hydroxyl protecting group.

[0119] In some embodiments, Rcis -C(Rd)(Re)(Rf), wherein each of Rd, Re, and Rfis independently Ci .4 alkyl. In some embodiments, the alkyl is unsubstituted. In some embodiments, the alkyl is substituted. In some embodiments, the alkyl is substituted with one or more of halogen or C1.3 alkoxy.

[0120] In some embodiments, Rcis optionally substituted phenyl. In some embodiments, Rcis phenyl, optionally substituted with one or more Cj.4 alkyl substituents. In some embodiments, Rcis phenyl substituted with 1. 2, 3, or 4 Ci.4 alkyl. In some embodiments, Rcis phenyl substituted with 1, 2. or 3 methyl or ethyl.

[0121] In some embodiments, Rcis optionally substituted monocyclic heteroaryl. Tn some embodiments, Rcis monocyclic heteroaryl, optionally substituted with one or more C1-4 alkyl substituents. In some embodiments, the monocyclic hctcroaryl (in Rc) is a 5 or 6-mcmbcrcd hctcroaryl. In some embodiments, the monocyclic heteroaryl is a 5 or 6-membered hctcroaryl having one or more O, N, or S atoms on the ring.

[0122] In some embodiments, Rcis optionally substituted cycloalkyl or optionally substituted monocyclic cycloalkyl.

[0123] In some embodiments, Rcis tert-butyl, 2,4,6-trimethylphenyl, (triethyl)methyl, 4- mcthylphcnyl, phenyl, 2,4,6-triisopropylphenyl, or 2-mcthylbutan-2-yl. In some embodiments, Rcis tert--37-NAI-5007198252vlbutyl.

[0124] In some embodiments, Rdis methyl. In some embodiments, Rdis ethyl. In some embodiments, Rdis propyl or isopropyl. In some embodiments, Rdis C4 alkyl.

[0125] In some embodiments, Reis methyl. In some embodiments, Reis ethyl. In some embodiments, Reis propyl or isopropyl. In some embodiments. Reis C4 alkyl.

[0126] In some embodiments, Rfis methyl. In some embodiments, R1is ethyl. In some embodiments. R1is propyl or isopropyl. In some embodiments, Rfis C4 alkyl.

[0127] In some embodiments, each PG is independently a hydroxyl protecting group, such as a silyl protecting group, an alkanoyl group (e.g., an acetyl group or a butyr l group), an aromatic alkanoyl group (e.g., a benzoyl group), a benzyl group, a triphenylmethyl group, an allyl group, an acetal group, a ketal group, p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), or diphenylmethyl (DPM). In some embodiments, each PG is independently a silyl protecting group. In some embodiments, each PG is independently tert-butyldimethylsilyl (TBDMS), tri-isopropylsilyl (TIPS), trimethylsilyl (TMS), triethylsilyl (TES), isopropyldimethyl silyl (IPDMS), diethylisopropylsilyl (DEIPS), or tertbutyldiphenylsilyl (TBDPS). In some embodiments, both PG groups (in a given compound) are tert- butyldimethylsilyl (TBDMS).

[0128] In some embodiments, the compound provided herein has enantiomeric excess or diastereomeric excess at the chiral carbon atom and / or at the sulfur atom of at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%.

[0129] In some embodiments, the compounds provided herein have enantiomeric excess at the chiral carbon of at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%. In some embodiments, the compounds provided herein have enantiomeric excess at the sulfur atom of at least 90%, at least 95%, at least 96%, at least 97%. at least 98%, at least 99%, at least 99.5%, or at least 99.9%. In some embodiments, Compounds 2, 2N, 3, or 3N each have a diastereomeric excess of at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%.

[0130] In some embodiments, provided herein is a mixture of (i): (a) Compound 1, lb, or 1c, or a pharmacally acceptable form thereof, or (b) Compound 1 or a pharmaceutically acceptable form thereof; (ii) and one or more of XI, X2, X3, X4. X5, and X6:-38-NAI-5007198252vlor a pharmaceutically acceptable form thereof.

[0131] In some embodiments, XI is present in an amount between 0.05 % w / w and 0.5 % w / w, or X2 is present in an amount between 0.05 % w / w and 0.5 % w / w, or X3 is present in an amount between 0.05 and 0.5 % w / w, or X4 is present in an amount between 0.05 % w / w and 0.5 % w / w, or X5 is present in an amount between 0.05 % w / w and 0.5 % w / w, or X6 is present in an amount between 0.05 % w / w and 0.5 % w / w. In some embodiments, the total % w / w of XI, X2, X3, X4, X5, and X6 present in the mixture is between 0.05 % w / w and 3.0 % w / w.5.2 SOLID FORMS

[0132] Potential pharmaceutical solids include crystalline solids and amorphous solids. Amorphous solids are characterized by a lack of long-range structural order, whereas crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends upon the specific application; amorphous solids are sometimes selected on the basis of, e.g., an enhanced dissolution profile, while crystalline solids may be desirable for properties such as, e.g., physical or chemical stability (see, e.g., S. R. Vippagunta t7 « / .. Adv. Drug. Deliv. Rev., (2001) 48:3-26; L. Yu, Adv. Drug. Deliv. Rev., (2001) 48:27-42). A change in solid form may affect a variety of physical and chemical-39-NAI-5007198252vlproperties, which may provide benefits or drawbacks in processing, formulation, stability, and bioavailability, among other important pharmaceutical characteristics.

[0133] Whether crystalline or amorphous, potential solid forms of a pharmaceutical compound may include single-component and multiple-component solids. Single-component solids consist essentially of the pharmacal compound in the absence of other compounds. Variety among single-component crystalline materials may potentially arise from the phenomenon of polymorphism, wherein multiple three-dimensional arrangements exist for a particular pharmaceutical compound (see. e.g., S. R. Bym et al.. Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette).

[0134] Additional diversity among the potential solid forms of a pharmaceutical compound may arise from the possibility of multiple-component solids. Crystalline solids comprising two or more ionic species are termed salts (see. e.g., Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, Eds., (2002), Wiley. Weinheim). Additional types of multiple-component solids that may potentially offer other property improvements for a pharmaceutical compound or salt thereof include, e.g., hydrates, solvates, co-crystal s and clathrates, among others (see, e.g., S. R. Bym et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). Multiple-component crystal forms may potentially be susceptible to polymorphism, wherein a given multiple-component composition may exist in more than one three-dimensional crystalline arrangement. Hie discovery of solid forms is of great importance in the development of a safe, effective, stable, and marketable pharmaceutical compound.

[0135] Notably, it is not possible to predict a priori if cry stalline forms of a compound even exist, let alone whether such forms have properties suitable for pharmaceutical development (physical properties, stability, dissolution, purity, etc.) or how to successfully prepare them (see, e.g., Braga and Grepioni, 2005, ‘‘Making crystals from crystals: a green route to crystal engineering and polymorphism,” Chem. Commun. : 3635 -3645 (with respect to crystal engineering, if instructions are not very precise and / or if other external factors affect the process, the result can be unpredictable); Jones et al., 2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement,” MRS Bulletin 37:875-879 (At present it is not generally possible to computationally predict the number of observable polymorphs of even the simplest molecules); Price, 2004, “The computational prediction of pharmacal crystal structures and polymorphism,” Advanced Drug Delivery Reviews 56:301-319 (“Price”); and Bernstein, 2004, “Crystal Structure Prediction and Polymorphism,” AG4 Transactions 39: 14-23 (a great deal still needs to be learned and done before one can state with any degree of confidence the ability to predict a crystal structure, much less polymorphic forms)).

[0136] Tire variety of possible solid forms creates potential diversity in physical and chemical properties for a given pharmaceutical compound. The discovery’ and selection of solid forms arc of great importance in the development of an effective, stable and marketable pharmacal product.-40-NAI-5007198252vl

[0137] The solid forms provided herein are usefill as active pharmaceutical ingredients for the preparation of formulations for use in animals or humans. Thus, embodiments herein encompass the use of these solid forms as a final drug product. Certain embodiments provide solid forms useful in making final dosage fonns with improved properties, e.g., powder flow properties, compaction properties, tableting properties, stability properties, and excipient compatibility properties, among others, that are needed for manufacturing, processing, formulation and / or storage of final drug products. Certain embodiments herein provide pharmaceutical compositions comprising a single-component crystal form, and / or a multiple-component crystal form comprising Compound 1 and a pharmaceutically acceptable excipient.

[0138] Solid form and related terms refer to a physical form which is not predominantly in a liquid or a gaseous state. Solid forms may be crystalline or mixtures of crystalline and amorphous forms. A “single -component” solid form comprising a particular compound consists essentially of that compound. A '‘multiple-component” solid form comprising a particular compound comprises that compound and a significant quantity of one or more additional species, such as ions and / or molecules, for example, solvent molecules, within the solid form. The solid forms provided herein may be crystalline or an intermediate fonn (e.g., a mixture of crystalline and amorphous fonns). Tire crystal fonns described herein, therefore, may have varying degrees of crystallinity or lattice order. The solid forms described herein are not limited to any particular degree of crystallinity or lattice order, and may be 0-100% crystalline. Methods of determining the degree of crystallinity are known to those of ordinary skill in the art, such as those described in Suryanarayanan, R., X-Ray Powder Diffractometry, Physical Characterization of Pharmaceutical Solids, H.G. Brittain, Editor, Marcel Dekker, Murray Hill, N.J., 1995, pp. 187-199, which is incorporated herein by reference in its entirety. In some embodiments, the solid fonns described herein are about 0, 5, 10, 15, 20. 25, 30, 35, 40, 45, 50, 55, 60, 65. 70, 75, 80, 85, 90, 91, 92, 93. 94. 95, 96, 97, 98. 99, or 100% crystalline.

[0139] Solid forms may exhibit distinct physical characterization data that are unique to a particular solid form, such as the cry stal forms described herein. These characterization data may be obtained by various techniques known to those skilled in the art, including for example, XRPD, DSC, TGA, and NMR spectroscopy. The data provided by these techniques may be used to identify a particular solid fonn. One skilled in the art can determine whether a solid form is one of the forms described herein by performing one of these characterization techniques and detennining whether the resulting data is “substantially similar” to the reference data provided herein, which is identified as being characteristic of a particular solid form. Characterization data that is “substantially similar” to those of a reference solid form is understood by those skilled in the art to correspond to the same solid form as the reference solid form. In analyzing whether data is “substantially similar,” a person of ordinary skill in the art understands that-41-NAI-5007198252vlparticular characterization data points may vary to a reasonable extent while still describing a given solid form, due to, for example, experimental error and routine sample-to-sample analysis.

[0140] In some embodiments, provided herein, are solid forms comprising Compound 1, or a pharmaceutically acceptable salt or solvate thereof:Compound 1.In some embodiments, the solid fomi comprising Compound 1 or pharmacally acceptable salt or solvate thereof can be a crystalline fonn, a substantially crystalline form, a partially crystalline form, or a mixture of crystalline form(s), or amorphous form(s). In some embodiments, the solid form is crystalline. In some embodiments, the solid form is an amorphous form. In some embodiments, the solid form is exclusive of an amorphous form. In some embodiments, the solid form is a pharmaceutically acceptable salt of the Compound 1, a pharmaceutically acceptable solvate of the Compound 1, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of the Compound 1. In some embodiments, the solid fonn comprises a free base of the Compound 1. In some embodiments, the solid fonn is a free base of the Compound 1. In some embodiments, the solid form is a pharmacally acceptable salt of the Compound 1. In some embodiments, the solid form is a pharmaceutically acceptable solvate of the Compound 1. In some embodiments, the solid form is a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of the Compound 1. In some embodiments, the solid form is a nonsolvate of the Compound 1 or pharmaceutically acceptable salt thereof. In some embodiments, the solid form is an anhydrate of the Compound 1 or pharmaceutically acceptable salt thereof. In some embodiments, the solid form is a crystalline, free base, hemi-hydrate of the Compound 1. In some embodiments, the solid form is substantially pure. In some embodiments, the solid form is substantially chemically pure. In some embodiments, the solid form is substantially physically pure. In some embodiments, the solid fomi is substantially enantiomerically pure. In some embodiments, the solid form of Compound 1 or pharmaceutically acceptable salt and or solvate thereof has an enantiomeric purity of at least about 98% (e.g., about 98.5%, about 99%, or about 99.5%).

[0141] In some embodiments, the pharmaceutically acceptable solvate of the solid form is selected from the group consisting of: a hydrate, a hemi-hydrate, an iso-butyl acetate solvate, an iso-propyl acetate solvate, a tetrahydrofuran solvate, an acetone solvate, an acetonitrile solvate, or combinations thereof. In some embodiments, the pharmaceutically acceptable solvate of the solid form is a hydrate. In-42-NAI-5007198252vlsome embodiments, the solid form is a hydrate of the Compound 1 or pharmaceutically acceptable salt thereof. In some embodiments, the Compound 1 or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable solvent in the solid form are present in a molar ratio in the range of 2: 1 to 1:2. In some embodiments, tire molar ratio of tire Compound 1 or pharmaceutically acceptable salt thereof to the solvent in the solid fonn ranges from about 2: 1 to about 1: 1. In some embodiments, the molar ratio of the Compound 1 or pharmaceutically acceptable salt thereof to the solvent in the solid form ranges from about 1 : 1 to about 1:2. In some embodiments, the molar ratio of the Compound 1 or pharmaceutically acceptable salt thereof to the solvent in the solid form is about 1:2 (i.e., bis-solvate). In some embodiments, the molar ratio of the Compound 1 or pharmaceutically acceptable salt thereof to the solvent in the solid form is about 1: 1 (i.e., mono-solvate). In some embodiments, the molar ratio of the Compound 1 or pharmaceutically acceptable salt thereof to the solvent in the solid fonn is about 2: 1 (i.e., hemi-solvate). In some embodiments, the solvent is water, and the Compound 1 or pharmaceutically acceptable salt thereof and the water are present in the solid form in a molar ratio of about 2: 1 (hemihydrate). In some embodiments, the solid fonn is a hemi-hydrate of the Compound 1 or pharmaceutically acceptable salt thereof. In some embodiments, the solid fonn is a hemi-hydrate of tire Compound 1 free base.

[0142] In some embodiments, the pharmaceutically acceptable salt of the solid form is selected from the group consisting of: a benzoate salt, a besylate salt, a chloride salt, a citrate salt, a fumarate salt, a gentisate salt, a glycolate salt, a 1 -hydroxy-2 -naphthoate salt, a malate salt, a maleate salt, a mesylate salt, an oxalate salt, a phosphate salt, a tartrate salt, and a tosylate salt. In some embodiments, the pharmaceutically acceptable salt of the solid form is a benzoate salt. In some embodiments, the pharmacally acceptable salt of the solid fonn is a fumarate salt. In some embodiments, the pharmacally acceptable salt of the solid fonn is a 1 -hydroxy-2 -naphthoate salt. In some embodiments, the Compound 1 or pharmaceutically acceptable solvate thereof and the pharmaceutically acceptable salt (conjugate acid) in the solid form are present in a molar ratio in the range of 2: 1 to 1 :2. In some embodiments, the molar ratio of the Compound 1 or pharmaceutically acceptable solvate thereof to the conjugate acid in the solid fonn ranges from about 2: 1 to about 1: 1. In some embodiments, the molar ratio of the Compound 1 or pharmacally acceptable solvate thereof to the conjugate acid in the solid form ranges from about 1:1 to about 1:2. In some embodiments, the molar ratio of the Compound 1 or pharmaceutically acceptable solvate thereof to the conjugate acid in the solid form is about 1: 1.

[0143] In some embodiments, provided herein are solid forms comprising a mixture of (i): (a) Compound 1, lb, or 1c, or a pharmaceutically acceptable salt or solvate thereof, or (b) Compound 1 or a pharmaceutically acceptable salt or solvate thereof; (ii) and one or more of XI, X2, X3, X4, X5, and X6:-43-NAI-5007198252vlor a pharmaceutically acceptable salt or solvate thereof.

[0144] In some embodiments, XI is present in an amount between 0.05 % w / w and 0.5 % w / w, or X2 is present in an amount between 0.05 % w / w and 0.5 % w / w, or X3 is present in an amount between 0.05 % w / w and 0.5 % w / w. or X4 is present in an amount between 0.05 % w / w and 0.5 % w / w, or X5 is present in an amount between 0.05 % w / w and 0.5 % w / w, or X6 is present in an amount between 0.05 % w / w and 0.5 % w / w. In some embodiments, the total % w / w of XI, X2, X3, X4, X5, and X6 present in the solid form is between 0.05 % w / w and 3.0 % w / w.5.2.1 Form 1 of Compound 1

[0145] In some embodiments, provided herein is Form 1 of Compound 1 (sometimes referred to herein as ‘"Compound 1 (Fonn I )"). In some embodiments, Fonn 1 of Compound 1 is a crystalline free base, hemi-hydrate of Compound 1. In some embodiments. Form 1 of Compound 1 is substantially free of amorphous Compound 1. In some embodiments, Form 1 of Compound 1 is substantially free of other crystalline forms (i.e., polymorphs) of Compound 1. In some embodiments, Form 1 of Compound 1 is substantially free of salt forms of Compound 1. In some embodiments, Fonn 1 of Compound 1 is provided as substantially pure Form 1 of Compound 1. In some embodiments, provided herein is a-44-NAI-5007198252vlmethod of preparing Form 1 of Compound 1. Form 1 of Compound 1 is described in International Patent Application Publication No. WO 2024 / 245364, the entirety of which is incorporated herein by reference.

[0146] A representative XRPD pattern of Form 1 of Compound 1 is provided in FIGs. 2 and 3.

[0147] In some embodiments, Form 1 has an enantiomeric purity of about 98%, about 98.5%, about99%, or about 99.5%, or greater. In some embodiments, Form 1 is cry stal 1 i nc . In some embodiments, Form 1 is substantially crystalline. In some embodiments, Form 1 is about 90%, about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, or about 99.5%, crystalline, or greater.

[0148] In some embodiments. Form 1 has an X-ray powder diffraction (XRPD) pattern comprising peaks at approximately 9.0, 12.8, and 16.6° 26. In some embodiments, Form 1 has an X-ray powder diffraction (XRPD) pattern comprising peaks at approximately 9.0, 12.8, 16.6, and 18.4° 20. In some embodiments, the XRPD pattern further comprises peaks at approximately 8.6, 12.0, 18.1, and 23.2° 26. In some embodiments, the XRPD pattern further comprises peaks at approximately 16.1, 17.1, 24.1, and 25.6° 26. In some embodiments, the XRPD pattern comprises peaks at approximately 8.6, 9.0, 12.0, 12.8, 16.1, 16.6, 17.1, 18.1, 18.4, 23.2, 24.1, and 25.6° 20.

[0149] In some embodiments, provided herein is a solid form comprising a free base, hemi-hydrate of Compound 1, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the XRPD peaks located at approximately the following positions (e.g., degrees 29 ± 0.2) when measured using Cu Ka radiation: 8.6. 9.0, 12.0, 12.8, 16.1, 16.6, 17.1, 18.1, 18.4, 23.2, 24.1. and 25.6° 26. In some embodiments, the solid form is characterized by at least 3 of the peaks. In some embodiments, the solid form is characterized by at least 5 of the peaks. In some embodiments, the solid form is characterized by at least 7 of the peaks. In some embodiments, the solid fomr is characterized by at least 9 of tire peaks. In some embodiments, the solid form is characterized by at least 11 of the peaks. In some embodiments, the solid form is characterized by all of the peaks.

[0150] In some embodiments, Form 1 has an XRPD pattern that substantially matches the XRPD pattern presented in FIG. 2 or FIG. 3.

[0151] Tire unit cell of Form 1 is described in International Patent Application Publication No. WO 2024 / 245364, the entirety of which is incorporated herein by reference. In some embodiments, Form 1 has approximately unit cell dimensions of: a = 15.2 A, b = 7.9 A, c = 20.7 A, a = 90°, = 107.8°, and y = 90°. In some embodiments, Fonn 1 has a unit cell of a space group of P2 . In some embodiments, Fomr 1 has a volume of about 2393.3 A3 / celL In some embodiments. Form 1 has a Z value of 2. In some embodiments, Form 1 has a density of about 1.325 g / cm3.

[0152] In some embodiments, Fomr 1 exhibits a thermal (endothermic) event with an onset temperature of about 209 °C, and / or an endothermic peak at about 218 °C, as characterized by DSC with a temperature ramp of about 10 °C / niin. In some embodiments, Fonn 1 is characterized by a DSC-45-NAI-5007198252vlthermogram substantially as shown in the DSC thermogram presented in FIG. 6.

[0153] In some embodiments. Form 1 exhibits no weight loss upon heating below about 75 °C, as characterized by TGA. In some embodiments, Form 1 exhibits weight loss of about 1.8% upon heating from about 75 °C to about 170 °C, as characterized by TGA. In some embodiments, Form 1 is characterized by a TGA thermogram substantially as shown in the TGA thermogram presented in FIGs. 4 or 5.

[0154] In some embodiments. Form 1 has a purity of at least 95%, 98%, 98.5%, 99%, or 99.5%.

[0155] In some embodiments. Form 1 has a solubility of about 4.69, 5.04, and 3.67 mg / mL in SGF media, at 0.5 h, 2 h, and 24 h, respectively. In some embodiments, Form 1 has a solubility of about 0.29, 0.31, and 0.33 mg / mL in FeSSIF media, at 0.5 h, 2 h, and 24 h, respectively.

[0156] In some embodiments, Form 1 is prepared according to the procedures of any one or more of Examples 1 to 10.

[0157] All of the combinations of the above embodiments are encompassed by this application.5.3 PHARMACEUTICALLY ACCEPTABLE SALTS OF COMPOUND 1

[0158] In some embodiments, provided herein, is a pharmaceutically acceptable salt of Compound 1 :Compound 1, or an isotopologue thereof, or a pharmaceutically acceptable solvate of the pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is a benzoate salt, a besylate salt, a chloride salt, a citrate salt, a fumarate salt, a gentisate salt, a glutarate salt, a glycolate salt, a hippurate salt, a l-hydroxy-2-naphthoate salt, a malate salt, a maleate salt, a mesylate salt, an oxalate salt, a phosphate salt, a sulfate salt, a tartrate salt, or a tosylate salt. In some embodiments, tire pharmaceutically acceptable salt of Compound 1, or pharmaceutically acceptable solvate thereof, is substantially pure. In some embodiments, the pharmaceutically acceptable salt of Compound 1, or pharmaceutically acceptable solvate thereof, is substantially chemically pure. In some embodiments, the pharmaceutically acceptable salt of Compound 1. or pharmaceutically acceptable solvate thereof, is substantially physically pure. In some embodiments, the pharmaceutically acceptable salt of Compound 1. or pharmaceutically acceptable solvate thereof, is substantially enantiomerically pure. In some embodiments, the pharmaceutically acceptable salt of Compound 1, or pharmaceutically acceptable solvate thereof, has an enantiomeric purity of at least about 98% (e.g, about 98.5%, about 99%, or about 99.5%). In some embodiments, theNAI-5007198252vlpharmaceutically acceptable salt of Compound 1, or pharmaceutically acceptable solvate thereof, has a Compound 1 / conjugate acid molar ratio in the range of about 2: 1 to about 1 :2. In some embodiments, the pharmaceutically acceptable salt of Compound 1, or pharmaceutically acceptable solvate thereof, has a Compound 1 / conjugate acid molar ratio in the range of about 2: 1 to about 1: 1. In some embodiments, the pharmacally acceptable salt of Compound 1, or pharmaceutically acceptable solvate thereof, has a Compound 1 / conjugate acid molar ratio in the range of about 1 : 1 to about 1:2. In some embodiments, the pharmaceutically acceptable salt of Compound 1, or pharmaceutically acceptable solvate thereof, has a Compound 1 / conjugate acid molar ratio is about 1: 1. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a non-solvate of the pharmaceutically acceptable salt of the Compound 1. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is an anhydrate of the pharmacally acceptable salt of the Compound 1. In some embodiments, the pharmacally acceptable salt of Compound 1 is a pharmacally acceptable solvate of the pharmaceutically acceptable salt of the Compound 1. In some embodiments, the pharmaceutically acceptable salt of Compound l is a pharmaceutically acceptable solvate of the pharmaceutically acceptable salt of the Compound 1, wherein the pharmaceutically acceptable solvate is a hydrate, a hemi-hydrate, an iso-butyl acetate, an iso-propyl acetate, a tetrahydrofuran solvate, an acetone solvate, an acetonitrile solvate, or combinations thereof. In some embodiments, the pharmaceutically acceptable solvate is a hydrate. In some embodiments, the pharmaceutically acceptable solvate of the pharmacally acceptable salt of the Compound 1 has a Compound 1 / solvent molar ratio in the range of about 2: 1 to about 1 :2. In some embodiments, the pharmaceutically acceptable solvate of the pharmaceutically acceptable salt of the Compound 1 has a Compound 1 / solvent molar ratio in the range of about 2: 1 to about 1: 1. In some embodiments, the pharmacally acceptable solvate of the pharmacally acceptable salt of the Compound 1 has a Compound 1 / solvent molar ratio in the range of about 1 : 1 to about 1:2. In some embodiments, the pharmaceutically acceptable solvate of the pharmaceutically acceptable salt of the Compound 1 has a Compound 1 / solvent molar ratio that is about 1: 1.

[0159] In some embodiments, the pharmacally acceptable salt of the Compound 1 is (5)-3- amino-3-( 1 -methyl- 177-im idazol-5-y 1 )-6-oxa-2(4,6)-quinol ina- 1 ,4( 1 ,3)-dibenzenacyclohexaphane-22,44- dicarbonitrile benzoate salt, or a pharmaceutically acceptable solvate thereof. In some embodiments, the benzoate salt of Compound 1 has a Compound 1 / benzoic acid molar ratio in the range of about 2: 1 to about 1:2, such as about 2: 1 to about 1: 1, or about I: I to about 1:2. In some embodiments, the benzoate salt of Compound 1 has a Compound 1 / benzoic acid molar ratio of about 1: 1.

[0160] In some embodiments, the pharmacally acceptable salt of the Compound 1 is (5)-3- amino-3-( 1 -methyl- 177-im idazol-5-y 1 )-6-oxa-2(4,6)-quinol ina- 1 ,4( 1 ,3)-dibcnzcnacyclohcxaphanc-22,44- dicarbonitrile besylate salt, or a pharmacally acceptable solvate thereof.-47-NAI-5007198252vl

[0161] In some embodiments, the pharmaceutically acceptable salt of the Compound 1 is (S)-3- amino-3-( 1 -methyl- 17 / -im idazol-5-y 1 )-6-oxa-2(4,6)-qui nol ina- 1 ,4( 1 ,3)-dibenzenacyclohexaphane-22,44- dicarbonitrile chloride salt, or a pharmaceutically acceptable solvate thereof.

[0162] In some embodiments, the pharmaceutically acceptable salt of the Compound 1 is (S)-3- amino-3-( 1 -methyl- I H-imidazol-5- l )-6-oxa-2(4.6)-quinol ina- 1 ,4( 1 ,3)-dibenzenacyclohexaphane-22,44- dicarbonitrile citrate salt, or a pharmaceutically acceptable solvate thereof.

[0163] In some embodiments, the pharmaceutically acceptable salt of the Compound 1 is (S)-3- amino-3-( 1 -methyl- 1 H-im idazol-5-y 1 )-6-oxa-2(4,6)-qui nol ina- 1 ,4( 1 ,3)-dibenzenacyclohexaphane-22,44- dicarbonitrile fumarate salt, or a pharmaceutically acceptable solvate thereof. In some embodiments, the fumarate salt of Compound 1 has a Compound 1 / fumaric acid molar ratio in the range of about 2: 1 to about 1:2, such as about 2: 1 to about 1: 1, or about 1: 1 to about 1:2. In some embodiments, the fumarate salt of Compound 1 has a Compound 1 / fumaric acid molar ratio of about 1: 1.

[0164] In some embodiments, the pharmaceutically acceptable salt of the Compound 1 is (S)-3- amino-3-( 1 -methyl- 1 H-im idazol-5-y 1 )-6-oxa-2(4,6)-quinol ina- 1 ,4( 1 ,3)-dibenzenacyclohexaphane-22,44- dicarbonitrile gentisate salt, or a pharmaceutically acceptable solvate thereof.

[0165] In some embodiments, the pharmaceutically acceptable salt of the Compound 1 is (<S)-3- amino-3-( 1 -methyl- 1 H-imidazol-5-yl )-6-oxa-2(4.6)-quinol ina- 1 ,4( 1 ,3)-dibenzenacyclohexaphane-22,44- dicarbonitrile glutarate salt, or a pharmaceutically acceptable solvate thereof.

[0166] In some embodiments, the pharmaceutically acceptable salt of the Compound 1 is (S)-3- amino-3-( 1 -methyl- 17 / -im idazol-5-y 1 )-6-oxa-2(4,6)-quinol ina- 1 ,4( 1 ,3)-dibenzenacyclohexaphane-22,44- dicarbonitrile glycolate salt, or a pharmaceutically acceptable solvate thereof.

[0167] In some embodiments, the pharmaceutically acceptable salt of the Compound 1 is (<S)-3- amino-3-( 1 -methyl- 1 H-imidazol-5-yl )-6-oxa-2(4.6)-quinol ina- 1 ,4( 1 ,3)-dibenzenacyclohexaphane-22,44- dicarbonitrile hippurate salt, or a pharmaceutically acceptable solvate thereof.

[0168] In some embodiments, the pharmaceutically acceptable salt of the Compound 1 is (S)-3- amino-3-( 1 -methyl- 1 H-im idazol-5-y 1 )-6-oxa-2(4,6)-quinol ina- 1 ,4( 1 ,3)-dibenzenacyclohexaphane-22,44- dicarbonitrile 1 -hydroxy-2 -naphthoate salt, or a pharmaceutically acceptable solvate thereof.

[0169] In some embodiments, the 1 -hydroxy -2 -naphthoate salt of Compound 1 has a Compound 1 / 1- hydroxy-2-naphthoic acid molar ratio in the range of about 2: 1 to about 1:2, such as about 2: 1 to about 1: 1, or about 1: 1 to about 1:2. In some embodiments, the l-hydroxy-2-naphthoate salt of Compound 1 has a Compound l / l-hydroxy-2-naphthoic acid molar ratio of about 1 : 1.

[0170] In some embodiments, the pharmaceutically acceptable salt of the Compound 1 is (5)-3- amino-3-( 1 -methyl- 17 / -im idazol-5-y 1 )-6-oxa-2(4,6)-quinol ina- 1 ,4( 1 ,3)-dibcnzcnacyclohcxaphanc-22,44- dicarbonitrile malate salt, or a pharmaceutically acceptable solvate thereof.-48-NAI-5007198252vl

[0171] In some embodiments, the pharmaceutically acceptable salt of the Compound 1 is (S)-3- amino-3-( 1 -methyl- 1 / 7-im idazol-5-y 1 )-6-oxa-2(4,6)-qui nol ina- 1 ,4( 1 ,3)-dibenzenacyclohexaphane-22,44- dicarbonitrile maleate salt, or a pharmaceutically acceptable solvate thereof.

[0172] In some embodiments, the pharmaceutically acceptable salt of the Compound 1 is (S)-3- amino-3-( 1 -methyl- I H-imidazol-5- l )-6-oxa-2(4.6)-quinol ina- 1 ,4( 1 ,3)-dibenzenacyclohexaphane-22,44- dicarbonitrile mesylate salt, or a pharmaceutically acceptable solvate thereof.

[0173] In some embodiments, the pharmaceutically acceptable salt of the Compound 1 is (S)-3- amino-3-( 1 -methyl- 1 H-im idazol-5-y 1 )-6-oxa-2(4,6)-qui nol ina- 1 ,4( 1 ,3)-dibenzenacyclohexaphane-22,44- dicarbonitrile oxalate salt, or a pharmaceutically acceptable solvate thereof.

[0174] In some embodiments, the pharmaceutically acceptable salt of the Compound 1 is (S)-3- amino-3-( 1 -methyl- I H-imidazol-5- l )-6-oxa-2(4.6)-quinol ina- 1 ,4( 1 ,3)-dibenzenacyclohexaphane-22,44- dicarbonitrile phosphate salt, or a pharmaceutically acceptable solvate thereof.

[0175] In some embodiments, the pharmaceutically acceptable salt of the Compound 1 is (S)-3- amino-3-( 1 -methyl- 1 H-im idazol-5-y 1 )-6-oxa-2(4,6)-quinol ina- 1 ,4( 1 ,3)-dibenzenacyclohexaphane-22,44- dicarbonitrile sulfate salt, or a pharmaceutically acceptable solvate thereof.

[0176] In some embodiments, the pharmaceutically acceptable salt of the Compound 1 is (<S)-3- amino-3-( 1 -methyl- 1 H-imidazol-5-yl )-6-oxa-2(4.6)-quinol ina- 1 ,4( 1 ,3)-dibenzenacyclohexaphane-22,44- dicarbonitrile tartrate salt, or a pharmaceutically acceptable solvate thereof.

[0177] In some embodiments, the pharmaceutically acceptable salt of the Compound 1 is (S)-3- amino-3-( 1 -methyl- 177-im idazol-5-y 1 )-6-oxa-2(4,6)-quinol ina- 1 ,4( 1 ,3)-dibenzenacyclohexaphane-22,44- dicarbonitrile tosylate salt, or a pharmaceutically acceptable solvate thereof.5.4 PHARMACEUTICAL COMPOSITIONS AND METHODS OF PREPARING

[0178] In some embodiments, provided herein, is a pharmaceutical composition comprising the compound described in Section 5. 1. In some embodiments, provided herein, is a pharmaceutical composition comprising the solid forms described in Section 5.2, such as Fomr 1 of Compound 1 described in Section 5.2.1. In some embodiments, provided herein, is a pharmaceutical composition comprising the pharmaceutically acceptable salts described in Section 5.3.

[0179] In some embodiments, provided herein, is a pharmaceutical composition comprising i) a solid fomr comprising Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof:-49-NAI-5007198252vlCompound 1. in an amount from about 1 mg to about 10 mg, or about 3 mg to about 8 mg free base equivalent, and, ii) one or more pharmaceutically acceptable excipients. In some embodiments, the solid form contained in the pharmaceutical composition is cry stalline. In some embodiments, the solid form is Form 1 of Compound 1. In some embodiments, the amount of Compound 1 in the pharmacal composition is about from about 1 mg to about 9 mg free base equivalent. In some embodiments, the amount of Compound 1 in the pharmaceutical composition is from about 2 mg to about 9 mg free base equivalent. For example, in some embodiments, the amount of Compound 1 in the pharmaceutical composition is about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or about 9 mg free base equivalent. In some embodiments, the amount of Compound 1 contained in the pharmaceutical composition is about 1 mg free base equivalent. In some embodiments, the amount of Compound 1 contained in tire pharmaceutical composition is about 2 mg free base equivalent. In some embodiments, the amount of Compound 1 contained in the pharmaceutical composition is about 3 mg free base equivalent. In some embodiments, the amount of Compound 1 contained in the pharmaceutical composition is about 4 mg free base equivalent. In some embodiments, the amount of Compound 1 contained in the pharmaceutical composition is about 5 mg free base equivalent. In some embodiments, the amount of Compound 1 contained in the pharmaceutical composition is about 6 mg free base equivalent. In some embodiments, the amount of Compound 1 contained in the pharmaceutical composition is about 7 mg free base equivalent. In some embodiments, the amount of Compound 1 contained in the pharmaceutical composition is about 8 mg free base equivalent. In some embodiments, the amount of Compound 1 contained in the pharmaceutical composition is about 9 mg free base equivalent. In some embodiments, the amount of Compound 1 contained in the pharmaceutical composition is about 10 mg free base equivalent. In some embodiments, the pharmaceutical composition comprises Compound 1 free base equivalent in an amount of from about 0.25 % w / w to about 10 % w / w, or about 1 % w / w to about 10 % w / w, or about 1 % w / w to about 5 % w / w, or about 2 % w / w to about 4 % w / w (or weight %; referring to weight of particular ingredient per total weight of composition; typically, for a tablet, relative to the uncoated tablet core weight). In some embodiments, the pharmacal composition comprises Compound 1 free base equivalent in an amount of about 0.25 % w / w, 0.5 % w / w, 1 % w / w, 2 % w / w, about 2.5 % w / w, about 3 % w / w, about 4 % w / w, about 5 % w / w, or about 10 % w / w, or in an amount of-50-NAI-5007198252vlabout 1 % w / w to about 5 % w / w.

[0180] In some embodiments, provided herein, is a pharmaceutical composition comprising i) Form 1 of Compound 1 :Compound 1, and, ii) one or more pharmaceutically acceptable excipients, wherein the amount of Form 1 in tire pharmacal composition is from about 1 % w / w to about 10 % w / w. In some embodiments, the amount of Form 1 in the pharmaceutical composition is from about 2 % w / w to about 9 % w / w. In some embodiments, the amount of Form 1 in the pharmaceutical composition is from about 1 % w / w to about 5 % w / w. In some embodiments, the amount of Form 1 in the pharmaceutical composition is from about 2 % w / w to about 5 % w / w (or weight %; referring to weight of particular ingredient per total weight of composition; typically, for a tablet, relative to tire uncoated tablet core weight). In some embodiments, the amount of Form 1 in the pharmaceutical composition is about 2.1 % w / w, about 2.6 % w / w, or about 4.1 % w / w.

[0181] In some embodiments, the pharmaceutical composition comprises a solid form of Compound 1, as disclosed herein. In some embodiments, the pharmaceutical composition comprises a solid form of a crystalline, free base, hemi-hydrate of the Compound I, as disclosed herein. In some embodiments, the pharmaceutical composition comprises Fonn 1 of Compound 1, as disclosed herein (e.g., Section 5.2.1). In some embodiments, the pharmaceutical composition is formulated as an immediate release oral dosage form. In some embodiments, the pharmaceutical composition is a tablet. In some embodiments, the pharmaceutical composition is a compressed tablet. In some embodiments, the tablet is a coated tablet. In some embodiments, the tablet coating is a spray dr ' fdm coating. In some embodiments, the tablet coating comprises a polymer, a plasticizer, and a pigment. In some embodiments, the tablet coating pigment is white or comprises one or more pigments. In some embodiments, the tablet coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. In some embodiments, the one or more pharmacally acceptable excipients comprises a filler, a glidant, a disintegrant, a lubricant, or a binder, or combinations thereof.

[0182] A large PSD for a drug substance batch (or a wide variability between batches) may reduce blend uniformity' and / or content uniformity' for a pharmacal composition (e.g., tablets) prepared from the drug substance, and may alter and / or increase variability of physicochemical (e.g., dissolution,-51-NAI-5007198252vlstability) and / or pharmacokinetic (e.g., absorption rate, Tmax, Cmax, AUC) properties associated with the formulation. Such variability can lead, in turn, to variability in biological exposure to the active agent, and therefore increases or decreases in safety or clinical activity outcomes. In addition, where crystallization techniques for a drug substance produce material with variable PSD ranges across batches, there may be a resulting increase in variability in physicochemical and / or pharmacokinetic properties across drug product batches. In some aspects, variability in PSD from batch to batch of Compound 1 from crystallization may arise due to slow or variable desaturation kinetics, oiling, chemical stability, and / or agglomeration.

[0183] In some embodiments, Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof has a D90 of less than about 100 pm, such as a D90 of less than about 75 pm, less than about 50 pm, less than about 40 pm, less than about 30 pm, less than about 25 pm, or less than about 20 pm. In some embodiments. Compound 1 has a D90 of between about 75 pm and about 20 pm or between about 50 pm and about 20 pm. In some embodiments. Compound 1 has a D90 of less than about 75 pm. In some embodiments, Compound 1 has a D90 of less than about 50 pm. In some embodiments, Compound 1 has D90 of less than about 20 pm. In some embodiments, crystallization techniques are employed to provide such D90 results directly, without the need for post-crystallization micronization such as jet milling. In some embodiments, if the PSD of a given batch of Compound 1 has a D90 of greater than about 20 pm, particle size reduction techniques, such as micronization, may be used to reduce D90. For example, in some embodiments, if the PSD of a given batch of Compound 1 has a D90 of about 30 pm or greater, about 40 pm or greater, about 50 pm or greater, about 60 pm or greater, about 70 pm or greater, about 75 pm or greater, about 80 pm or greater, about 90 pm or greater, or about 100 pm or greater, micronization is used to reduce D90. In some embodiments, if tire PSD of a given batch of Compound 1 has a D90 of between about 350 pm and about 50 pm, between about 330 pm and about 15 pm. between about 100 pm and about 20 pm, between about 100 pm and about 75 pm, between about 100 pm and about 50 pm, between about 75 pm and about 50 pm, between about 75 pm and about 25 pm, or between about 50 pm and about 25 pm, micronization may be used to reduce D90. In some embodiments, Form 1 of Compound 1 has a D90 of less than 50 pm, between 10 pm and 50 pm, between 1 pm and 20 pm, between 1 pm and 15 pm, between 1 pm and 10 pm, between 5 pm and 20 pm, between 5 pm and 15 pm, less than 20 pm, less than 15 pm. or less than 10 pm. Various techniques of micronization may be employed, such as wet milling or jet milling. In some embodiments, jet milling may be used instead of or in addition to other micronization techniques. Various techniques for crystallization can impact the resulting PSD, such as seeding, seed size selection, seed loading level, seed bed wet milling, temperature cycling, co-addition (c.g., mixing a solution of the compound in a first solvent with an antisolvcnt at respective rates that maintain a consistent v / v ratio of the solution and the antisolvent), or continuous-52-NAI-5007198252vlprocessing, or other processes, during crystallization. In some embodiments, the crystallization comprises seeding the crystallization mixture with crystalline Compound 1, such as Compound 1 (Form 1). In some embodiments, seeding employs crystalline seeds with a D90 of about 5 pm to about 30 pm, or about 5 pm to about 15 pm, or about 5 pm to about 10 pm. In some embodiments, the crystalline seed material is micronized. In some embodiments, crystallization comprises seeding at a seed load of about 0.1% to about 15%, or about 0.5% to about 10%. In some embodiments, micronization. such as wet milling, is used to reduce D90, such as to reduce D90 to less than about 75 pm, less than about 50 pm, or less than about 20 pm. In some embodiments, jet milling is used, such as to reduce D90 to reduce D90 to less than about 75 pm, less than about 50 pm, or less than about 20 pm. In some embodiments, the micronization technique, such as jet milling, is used more than once on a batch, for example jet-milling twice, to achieve the target D90.

[0184] In some embodiments, the pharmaceutical composition comprises a filler. In some embodiments, the filler is present in an amount of from about 40 % w / w to about 95 % w / w (or weight %: referring to weight of particular ingredient per total weight of composition; typically, for a tablet, relative to the uncoated tablet core weight). In some embodiments, the filler is silicified microcrystalline cellulose (SMCC), microcrystalline cellulose (MCC), D-mannitol, or a combination thereof. In some embodiments, the filler is SMCC. In some embodiments, the SMCC has a grade of 50, 50 LD (low density), 90, 90 HD (high density), or 90 LM (low moisture), or a combination thereof. In some embodiments, the filler is present in an amount from about 70 % w / w to about 95 % w / w. In some embodiments, the filler is present in an amount from about 80 % w / w to about 95 % w / w. In some embodiments, the filler is present in an amount of about 92.5% w / w, about 92 % w / w, or about 90.5 % w / w. In some embodiments, the filler is present in an amount from about 90 % w / w to about 93 % w / w, or about 90 % w / w, 90.5 % w / w, 91 % w / w. 91.5 % w / w, 92 % w / w, or 92.5 % w / w. In some embodiments, the filler is microcrystalline cellulose (MCC). In some embodiments, the pharmaceutical composition comprises multiple grades of MCC, such as grade 101, 102, 105, 301, 302, or 200, or a combination thereof.

[0185] In some embodiments, the pharmaceutical composition comprises a glidant. In some embodiments, the amount of glidant is colloidal silicon dioxide. In some embodiments, the colloidal silicon dioxide is present in an amount of about 0.5 % w / w to about 5 % w / w, or about 0.5 % w / w, about 1.0 % w / w, or about 1.5 % w / w, or about 1.0 % w / w (or weight %; referring to weight of particular ingredient per total weight of composition: typically, for a tablet, relative to the uncoated tablet core weight). In some embodiments, the glidant or colloidal silicon dioxide is present in an amount of about 1 % w / w.

[0186] In some embodiments, the pharmaceutical composition comprises a disintegrant. In some-53-NAI-5007198252vlembodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is present in an amount of from about 1 % w / w to about 6 % w / w, or about 2.0 % w / w, about 2.5 % w / w, about 3.0 % w / w, about 3.5 % w / w, or about 4.0 % w / w, or about 3.0 % w / w (or weight %; referring to weight of particular ingredient per total weight of composition; typically, for a tablet, relative to the uncoated tablet core weight). In some embodiments, the disintegrant or croscarmellose sodium is present in an amount of about 3.0 % w / w.

[0187] In some embodiments, the pharmaceutical composition comprises a lubricant. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is present in an amount of from about 0.5 % w / w to about 2.5 % w / w, from about 0.5 % w / w to about 1.5 % w / w, about 0.5 % w / w, about 1.0 % w / w, about 1.5 % w / w, about 2.0 % w / w, about 1.0 % w / w, or about 1.5 % w / w (or weight %; referring to weight of particular ingredient per total weight of composition; typically, for a tablet, relative to the uncoated tablet core weight). In some embodiments, the lubricant or magnesium stearate is present in an amount of about 1.5 % w / w. In some embodiments, tire lubricant or magnesium stearate is present in an amount of about 1.0 % w / w.

[0188] In some embodiments, the pharmaceutical composition comprises a binder. In some embodiments, the binder is povidone. In some embodiments, the binder is present in an amount of about 3 % w / w to about 10 % w / w (or weight %; referring to weight of particular ingredient per total weight of composition; typically, for a tablet, relative to the uncoated tablet core weight). In some embodiments, the binder is present in an amount of from about 3 mg to about 15 mg in a tablet having a tablet core weight of from about 100 mg to about 200 mg. In some embodiments, the pharmaceutical composition does not comprise a binder.

[0189] In some embodiments, provided herein is a pharmacal composition wherein tire solid form is present in an amount of from about 1 mg to about 10 mg, or about 3 mg to about 8 mg free base equivalent, and the silicified microcrystalline cellulose or microcrystalline cellulose is present in an amount from about 70 % w / w to about 95 % w / w (or weight %; referring to weight of particular ingredient per total weight of composition; typically, for a tablet, relative to the uncoated tablet core weight). In some embodiments, the solid form is present in an amount of about 1 mg free base equivalent, and the silicified microcrystalline cellulose or microcrystalline cellulose is present in an amount of about 75 % w / w to about 95 % w / w. In some embodiments, the solid fonn is present in an amount of about 3 mg free base equivalent, and the silicified microcrystalline cellulose or microcrystalline cellulose is present in an amount of about 75 % w / w to about 95 % w / w. In some embodiments, the solid form is present in an amount of about 5 mg free base equivalent, and the silicified microcrystallinc cellulose or microcry stallinc cellulose is present in an amount of about 75 % w / w to about 95 % w / w. In some embodiments, the solid form is present in an amount of about 8 mg free base-54-NAI-5007198252vlequivalent, and the silicified microcrystalline cellulose or microcrystalline cellulose is present in an amount of about 75 % w / w to about 95 % w / w. In some embodiments, the solid form is present in an amount of about 10 mg free base equivalent, and the silicified microcrystalline cellulose or microcrystalline cellulose is present in an amount of about 75 % w / w to about 95 % w / w.

[0190] In some embodiments, the pharmaceutical composition comprises about 0.25 / o w / ^v of Compound 1 free base equivalent, or about 1 % w / w to about 5 % w / w of Compound 1 free base equivalent: about 90 % w / w to about 95% w / w silicified microcrystalline cellulose or microcrystalline cellulose; about 0.5 % w / w to about 1.5% w / w colloidal silicon dioxide; about 2 % w / w to about 4% w / w croscarmellose sodium; and about 1 % w / w to about 2 % w / w magnesium stearate. In some embodiments, the pharmaceutical composition comprises 1 mg of Compound 1 free base equivalent, about 90 % w / w to about 95% w / w silicified microcrystalline cellulose or microcrystalline cellulose; about 0.5 % w / w to about 1.5% w / w colloidal silicon dioxide: about 2 % w / w to about 4% w / w croscarmellose sodium; and about 1 % w / w to about 2 % w / w magnesium stearate.

[0191] In some embodiments, the pharmaceutical composition comprises about 2 % w / w of Compound 1 free base equivalent; about 92 % w / w to about 93 % w / w, or about 92.5 % w / w, or about 93 % w / w silicified microcrystalline cellulose or microcrystalline cellulose; about 1 % w / w colloidal silicon dioxide; about 3 % w / w croscarmellose sodium: and about 1.0 % w / w to about 1.5 % w / w, or about 1.0 % w / w, or about 1.5 % w / w magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 2 % w / w of Compound 1 free base equivalent; about 93 % w / w silicified microcrystalline cellulose or microcrystal I inc cellulose; about 1 % w / w colloidal silicon dioxide; about 3 % w / w croscarmellose sodium; and about 1 % w / w magnesium stearate.

[0192] In some embodiments, the pharmaceutical composition comprises about 2.5 % w / w of Compound 1 free base equivalent: about 92 % w / w to about 93 % w / w, or about 92 % w / w, or about 92.5 % w / w silicified microcrystalline cellulose or microcrystalline cellulose; about 1 % w / w colloidal silicon dioxide; about 3 % w / w croscarmellose sodium; and about 1.0 % w / w to about 1.5 % w / w, or about 1.0 % w / w, or about 1.5 % w / w magnesium stearate (or weight %; referring to weight of particular ingredient per total weight of composition; typically, for a tablet, relative to the uncoated tablet core weight). In some embodiments, the pharmaceutical composition comprises about 2.5 % w / w of Compound 1 free base equivalent; about 92.5 % w / w silicified microcrystalline cellulose or microcrystalline cellulose; about 1 % w / w colloidal silicon dioxide; about 3 % w / w croscarmellose sodium; and about 1 % w / w magnesium stearate.

[0193] In some embodiments, the pharmaceutical composition comprises about 4 % w / w of Compound 1 free base equivalent; about 90 % w / w to about 91 % w / w, or about 90.5 % w / w, or about 91 % w / w silicified microcrystalline cellulose or microcrystalline cellulose; about 1 % w / w colloidal silicon-55-NAI-5007198252vldioxide; about 3 % w / w croscarmellose sodium; and about 1.0 % w / w to about 1.5 % w / w. or about 1.0 % w / w, or about 1.5 % w / w magnesium stearate (or weight %; referring to weight of particular ingredient per total weight of composition; typically, for a tablet, relative to the uncoated tablet core w eight). In some embodiments, the pharmaceutical composition comprises about 4 % w / w of Compound 1 ; about 91 % w / w silicified microcrystalline cellulose or microcrystalline cellulose; about 1 % w / w colloidal silicon dioxide: about 3 % w / w croscarmellose sodium: and about 1 % w / w magnesium stearate.

[0194] In some embodiments, the pharmaceutical composition comprises about 3 mg Compound 1 free base equivalent; about 138 mg to about 140 mg, or about 138.75 mg, or about 139.5 mg silicified microcrystalline cellulose or microcrystal line cellulose; about 1.5 mg colloidal silicon dioxide; about 4.5 mg croscarmellose sodium; and about 1.5 mg to about 2.25 mg, or about 1.5 mg, or about 2.25 mg magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 3.1 mg Form 1 of Compound 1: about 138 mg to about 140 mg. or about 138.67 mg, or about 139.42 mg silicified microcrystalline cellulose or microcrystalline cellulose: about 1.5 mg colloidal silicon dioxide; about 4.5 mg croscarmellose sodium; and about 1.5 mg to about 2.25 mg, or about 1.5 mg, or about 2.25 mg magnesium stearate.

[0195] In some embodiments, the pharmaceutical composition comprises about 5 mg Compound 1 free base equivalent; about 184 mg to about 185 mg, or about 184 mg, or about 185 mg silicified microcrystalline cellulose or microcrystalline cellulose; about 2 mg colloidal silicon dioxide; about 6 mg croscarmellose sodium; and about 2 mg to about 3 mg, or about 2 mg, or about 3 mg magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 5.1 mg Form 1 of Compound 1; about 183 mg to about 185 mg, or about 138.86 mg, or about 184.86 mg silicified microcrystalline cellulose or microcrystalline cellulose; about 2 mg colloidal silicon dioxide; about 6 mg croscarmellose sodium; and about 2 mg to about 3 mg, or about 2 mg, or about 3 mg magnesium stearate.

[0196] In some embodiments, the pharmaceutical composition comprises about 8 mg Compound 1 free base equivalent; about 181 mg to about 182 mg, or about 181 mg, or about 182 mg silicified microcrystalline cellulose or microcrystalline cellulose; about 2 mg colloidal silicon dioxide; about 6 mg croscarmellose sodium; and about 2 mg to about 3 mg, or about 2 mg, or about 3 mg magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 8.2 mg Form 1 of Compound 1; about 180 mg to about 182 mg, or about 180.78 mg. or about 181.78 mg silicified microcrystalline cellulose or microcrystalline cellulose; about 2 mg colloidal silicon dioxide: about 6 mg croscarmellose sodium; and about 2 mg to about 3 mg, or about 2 mg, or about 3 mg magnesium stearate.

[0197] In some embodiments, provided herein, is a tablet comprising the pharmaceutical composition provided herein and a tablet coating. In some embodiments, the pharmaceutical composition provided herein forms the tablet core.-56-NAI-5007198252vl

[0198] In some embodiments, provided herein, is a tablet comprising:(i) a tablet core, comprising:(a) a solid form comprising Compound 1:Compound 1, or a pharmacally acceptable salt and / or solvate thereof in an amount of about 1 mg to about 10 mg, or about 3 mg to about 8 mg free base equivalent, and(b) one or more pharmaceutically acceptable excipients; and(ii) a tablet coating.

[0199] In some embodiments of the pharmaceutical composition, e.g., the tablet core, the solid form comprising Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, is Form 1 of Compound 1.

[0200] In some embodiments of the pharmaceutical composition, e.g., the tablet core, the solid form comprises Compound 1. and one or more other compounds (e.g., intermediate compounds) described in Section 5.1. In some embodiments, the solid form comprises a mixture of Compound 1, lb, and 1c, or a pharmaceutically acceptable salt or solvate thereof.

[0201] In some embodiments of the pharmaceutical composition, e.g., the tablet core, the solid form comprises a mixture of: (i) Compound 1, lb, or 1c, or a pharmaceutically acceptable salt or solvate thereof, such as Compound 1 or a pharmaceutically acceptable salt thereof, Compound 1 free base hemihydrate, or Compound 1 (Form 1), and (ii) one or more of XI, X2, X3, X4. X5, and X6:-57-NAI-5007198252vlor a pharmaceutically acceptable salt or solvate thereof. In some embodiments, X 1 is present in the solid form in an amount between 0.05 % w / w and 0.5 % w / w, or X2 is present in the solid form in an amount between 0.05 % w / w and 0.5 % w / w, or X3 is present in the solid fonn in an amount between 0.05 % w / w and 0.5 % w / w, or X4 is present in an amount between 0.05 % w / w and 0.5 % w / w, or X5 is present in the solid fonn in an amount between 0.05 % w / w and 0.5 % w / w, or X6 is present in the solid form in an amount between 0.05 % w / w and 0.5 % w / w. In some embodiments, the total % w / w of XI, X2, X3, X4, X5, and X6 present in the solid form is between 0.05 % w / w and 3.0 % w / w. In some embodiments, the total % w / w of XI, X2, X3, X4, X5, and X6 present in the tablet core is between 0.001 % w / w and 0.15 % w / w.

[0202] In some embodiments, the pharmaceutical composition comprises a mixture of Compound 1, lb, or 1c, or a pharmaceutically acceptable salt or solvate thereof, such as Compound 1 or a pharmaceutically acceptable salt thereof. Compound 1 free base hemihydrate, or Compound 1 (Form 1), and X2 and / or X6. In some embodiments, when present, X2 and / or X6 are each present at about 0.1 % w / w to about 1.0 % w / w, respectively, or at not more than 1.0% w / w individually.

[0203] In some embodiments, the tablet comprises: (a) a tablet core comprising about 1 mg Compound 1 free base equivalent, silicified microcrystalline cellulose or microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate; and (b) a tablet coating.

[0204] In some embodiments, the tablet comprises: (a) a tablet core comprising about 3 mg Compound 1 free base equivalent; about 138 mg to about 140 mg, or about 138.75 mg, or about 139.5 mg silicified microcrystalline cellulose or microcrystalline cellulose; about 1.5 mg colloidal silicon dioxide; about 4.5 mg croscarmellose sodium; and about 1.5 mg to about 2.25 mg, or about 1.5 mg, or about 2.25-58-NAI-5007198252vlmg magnesium stearate; and (b) a tablet coating. In some embodiments, this tablet is a 3 mg Compound 1 (free base equivalent) strength composition. In some embodiments, the tablet comprises: (a) a tablet core comprising about 3.1 mg Form 1 of Compound 1; about 138 mg to about 140 mg, or about 138.67 mg, or about 139.42 mg silicified microcrystalline cellulose or microcrystalline cellulose; about 1.5 mg colloidal silicon dioxide; about 4.5 mg croscarmellose sodium; and about 1.5 mg to about 2.25 mg, or about 1.5 mg, or about 2.25 mg magnesium stearate; and (b) a tablet coating.

[0205] In some embodiments, the tablet comprises: (a) a tablet core comprising about 5 mg Compound 1 free base equivalent; about 184 mg to about 185 mg, or about 184 mg, or about 185 mg silicified microcrystalline cellulose or microcrystalline cellulose; about 2 mg colloidal silicon dioxide; about 6 mg croscarmellose sodium; and about 2 mg to about 3 mg, or about 2 mg, or about 3 mg magnesium stearate: and (b) a tablet coating. In some embodiments, this tablet is a 5 mg Compound 1 (free base equivalent) strength composition. In some embodiments, the tablet comprises: (a) a tablet core comprising about 5.1 mg Form 1 of Compound 1; about 183 mg to about 185 mg, or about 183.86 mg, or about 184.86 mg silicified microcrystalline cellulose or microcrystalline cellulose; about 2 mg colloidal silicon dioxide; about 6 mg croscarmellose sodium; and about 2 mg to about 3 mg, or about 2 mg, or about 3 mg magnesium stearate; and (b) a tablet coating.

[0206] In some embodiments, the tablet comprises: (a) a tablet core comprising about 8 mg Compound 1 free base equivalent: about 181 mg to about 182 mg, or about 181 mg, or about 182 mg silicified microcrystalline cellulose or microcrystalline cellulose: about 2 mg colloidal silicon dioxide; about 6 mg croscarmellose sodium; and about 2 mg to about 3 mg, or about 2 mg, or about 3 mg magnesium stearate; and (b) a tablet coating. In some embodiments, this tablet is a 8 mg Compound 1 (free base equivalent) strength composition. In some embodiments, the tablet comprises: (a) a tablet core comprising about 8.2 mg Form 1 of Compound 1; about 180 mg to about 182 mg, or about 180.78 mg, or about 181.78 mg silicified microcrystalline cellulose or microcrystalline cellulose; about 2 mg colloidal silicon dioxide; about 6 mg croscarmellose sodium; and about 2 mg to about 3 mg, or about 2 mg, or about 3 mg magnesium stearate; and (b) a tablet coating.

[0207] In some embodiments, the tablet core comprises: (a) an intragranular portion comprising the Compound 1 (Form 1), the silicified microcrystalline cellulose or microcrystalline cellulose, the colloidal silicon dioxide, the croscarmellose sodium, and optionally povidone; and (b) an extragranular portion comprising the magnesium stearate. In some embodiments, the tablet core is a 1 mg Compound 1 (free base equivalent) strength composition, In some embodiments, the tablet core is a 3 mg Compound 1 (free base equivalent) strength composition, In some embodiments, the tablet core is a 5 mg Compound 1 (free base equivalent) strength composition, In some embodiments, the tablet core is a 8 mg Compound 1 (free base equivalent) strength composition. In some embodiments, the tablet core is a 10 mg Compound 1-59-NAI-5007198252vl(free base equivalent) strength composition.

[0208] In some embodiment, the tablet coating comprises Opadry (which comprises polymer, plasticizer, and pigment, such as hypromellose and titanium dioxide). In some embodiments, the tablet coating comprises more than one pigment. In some embodiments, the pigment is white. In some embodiment, the tablet coating comprises Opadry II white. In some embodiment, the tablet coating comprises Opadry II yellow. In some embodiment, the tablet coating comprises Opadry II pink. In some embodiment, the tablet coating comprises Opadry II black.

[0209] In some embodiments, provided herein, is a method of preparing a pharmaceutical composition, as disclosed herein, the method comprising: i) optionally, micronizing a solid form of the Compound 1, or pharmacally acceptable salt and / or solvate thereof; ii) optionally, de-lumping the solid fonn of tire Compound 1, or pharmaceutically acceptable salt and / or solvate thereof; iii) mixing the solid form of the Compound 1, or pharmaceutically acceptable salt and / or solvate thereof, with a disintegrant, a glidant, and a first portion of a filler to form a first blend; iv) de-lumping the first blend to form a de-lumped first blend; v) de-lumping a second portion of the filler; vi) blending the de-lumped first blend and the de-lumped second portion of the filler to form a second blend; vii) blending the second blend with a lubricant to fonn a lubricated blend; and viii) compressing the lubricated blend, optionally with a rotary press, into a tablet. In some embodiments, the method comprises micronizing the solid form of the Compound 1, or pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the micronization method is jet milling, wet milling, dry milling, or a combination, or wet milling during crystallization and jet milling after isolation and drying. In some embodiments, the method comprises measuring the PSD of the solid form before and / or after micronization. In some embodiments, the micronization reduces the D90 of the solid fonn, such as to below 50 pm. In some embodiments, tire method comprises de-lumping the solid form of the Compound 1, or pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the method does not comprise step (i), optionally wherein the solid form has a D90 of less than 50 pm, between 10 pm and 50 pm, between 1 pm and 20 pm, between 1 pm and 15 pm, between 1 pm and 10 pm, between 5 pm and 20 pm, between 5 pm and 15 pm, less than 20 pm, less than 15 pm, or less than 10 pm. In some embodiments, tire compressing provides a compressed tablet and the method comprises ix) coating the compressed tablet. In some embodiments, the coating is a spray dry film coating. In some embodiments, the method further comprises x) packaging the film coated tablets into a container. In some embodiments, the amount of the solid form of the Compound 1, or pharmaceutically acceptable salt and / or solvate thereof, present in the pharmaceutical composition is about 1 mg, about 3 mg, about 5 mg, about 8 mg, or about 10 mg free base equivalent. In some embodiments, the amount of the solid form of the Compound 1, or pharmaceutically acceptable salt and / or solvate thereof, present in the pharmaceutical composition is about 3 mg, about 5-60-NAI-5007198252vlmg, or about 8 mg free base equivalent.

[0210] In some embodiment, the pharmaceutical composition is prepared using solid form of Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof having a D90 of less than 100 pm, less than 50 pm, between 10 pm and 50 pm, between 1 pm and 20 pm, between 1 pm and 15 pm, between 1 pm and 10 pm, between 5 pm and 20 pm, between 5 pm and 15 pm, less than 20 pm, less than 15 pm, or less than 10 pm. In some embodiments, the pharmaceutical composition is prepared using solid form of Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof having a D90 of less than 50 pm. In some embodiments, the pharmaceutical composition is prepared using solid form of Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof having a D90 of between 10 pm and 50 pm, or between 5 pm and 20 pm.

[0211] In some embodiments, provided herein, is a method of preparing a pharmacal composition, as disclosed herein, the method comprising: i) optionally, micronizing a solid form of the Compound 1, or pharmaceutically acceptable salt and / or solvate thereof ii) optionally, de-lumping the solid form of the Compound 1, or pharmaceutically acceptable salt and / or solvate thereof; iii) granulating the solid form of the Compound 1, or pharmaceutically acceptable salt and / or solvate thereof, a fdler, a glidant, and a disintegrant with a binder and water to fonn wet granules: iv) drying the wet granules to form dry granules: v) blending the granules with a lubricant to fonn a lubricated final blend; and vi) compressing the lubricated final blend, optionally with a rotary press, into a tablet. In some embodiments, the method comprises de-lumping the solid form of the Compound 1, or pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the compressing forms a compressed tablet and the method comprises viii) coating the compressed tablet. In some embodiments, tire coating is a spray dry film coating. In some embodiments, the method further comprises ix) packaging the film coated tablets into a container. In some embodiments, the method does not comprise step (i), optionally wherein the solid form has a D90 of less than 50 pm, between 10 pm and 50 pm, between 1 pm and 20 pm, between 1 pm and 15 pm, between 1 pm and 10 pm, between 5 pm and 20 pm, between 5 pm and 15 pm, less than 20 pm, less than 15 pm, or less than 10 pm. In some embodiments, the amount of the solid form of the Compound 1, or pharmaceutically acceptable salt and / or solvate thereof, present in the film coated tablet is about 1 mg, about 3 mg, about 5 mg, about 8 mg, or about 10 mg free base equivalent. In some embodiments, the amount of the solid form of the Compound 1, or pharmaceutically acceptable salt and / or solvate thereof, present in the film coated tablet is about 3 mg, about 5 mg, or about 8 mg free base equivalent. In some embodiments, the dry granules are milled prior to blending with the lubricant to form the lubricated final blend. In some embodiments, the granules are milled using a screen of about 0.5 mm to about 2 mm mesh, or about 1 mm mesh. In some embodiments, tire wet granules arc milled prior to drying using, for example, a 3 / 8 inch screen.-61-NAI-5007198252vl5.5 SYNTHESIS

[0212] In some embodiments, provided herein, is a process of preparing a compound described in Section 5.1, such as Compound 1, Compound lb, Compound 1c, and the intermediate compounds. In some embodiments, provided herein, is a process of preparing the solid forms described in Section 5.2, such as Form 1 of Compound 1 described in Section 5.2.1. In some embodiments, provided herein, is a process of preparing the pharmaceutically acceptable salts described in Section 5.3.

[0213] In some embodiments, provided herein, is a process for preparing Compound 1 :Compound 1, or a pharmaceutically acceptable form thereof, comprising one or more of the following steps as shown inSchemes A-EScheme A.NAI-5007198252vlScheme B.Scheme C.Scheme D.-63-NAI-5007198252vlScheme E.

[0214] In some embodiments, provided herein, is a process for preparing Compound 1 :or a pharmaceutically acceptable form thereof, comprising treating Compound 2N:optionally wherein Rcis tert-butyl (Compound 2), or a salt thereof, or a solvate thereof, with a sulfmamide removal agent to provide Compound 1, or a pharmaceutically acceptable form thereof; wherein Rcis (a) -C(Rd)(Rc)(Rf), wherein each of Rd, Rc, and Rfis independently Ci-4 alkyl, or (b) phenyl or monocyclic heteroaryl optionally substituted with one or more Ci-4 alkyl substituents, or (c) cycloalkyl optionally substituted with one or more Ci-4 alkyl substituents, optionally wherein Rcis tert-butyl, 2,4,6- trimethylphenyl, (triethyl)methyl, 4-methylphenyl, phenyl, 2,4,6-triisopropylphenyl, or 2-methylbutan-2- yi.-64-NAI-5007198252vl

[0215] In some embodiments, provided herein, is a process for preparing Compound 1 :Compound 1, or a pharmaceutically acceptable form thereof, comprising treating Compound 2:or a salt thereof, or a solvate thereof, with a sulfinanride removal agent to provide Compound 1, or a pharmacally acceptable form thereof.

[0216] In some embodiments, Compound 2N (or Compound 2) or salt thereof, or solvate thereof, is treated with the sulfmamide removal agent in the presence of a solvent to provide a reaction mixture. In some embodiments, Compound 2 or salt thereof, or solvate thereof, is treated with the sulfmamide removal agent in the presence of a solvent to provide a reaction mixture.

[0217] In some embodiments, the sulfmamide removal agent is an acid, a reducing agent, a base, an oxidant, or a radical agent, or a combination thereof. In some embodiments, the sulfmamide removal agent is an acid. In some embodiments, the sulfmamide removal agent is a reducing agent. In some embodiments, the sulfmamide removal agent is a base. In some embodiments, the sulfmamide removal agent is an oxidant. In some embodiments, the sulfmamide removal agent is a radical agent.

[0218] In some embodiments, the sulfmamide removal agent is Ti(OiPr)4, BmNBH light (350 nm), CRSO J I / EbN / Smb. Li / naphthalene, H2SO4, HBr, HC1, HNO3, CH3SO3H, p-toluene sulfonic acid, AcOH, AcCl / MeOH, I2, SOCh / MeOH, TMSCl / MeOH, Et3SiH, N-bromosuccinimide, N- iodosuccinimide, N-chlorosuccinimide, Br2. H3PO4. thiophenol / ZnCl2, NaBEL, L1AIH4. L1BH4. dibenzyltartaric acid, NaH, H2(e.g., with Ni or Pd catalyst, such as RaNi), NaOMe, NaOEt, t-BuOK, t- BuONa, KF, NbOCE, MeLi, Cl2, HCO2H, P(O-phenyl)3, Ac2O / MeOH, AICE, camphorsulfonic acid, InCl3, aspartic acid, Li, Na, (COCl)2 / MeOH, Sml3, or 1 -chloromethyl -4-fluoro- 1,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); optionally wherein the HC1 is aqueous HC1. or optionally wherein the aqueous HC1 is 3 M HC1.-65-NAI-5007198252vl

[0219] In some embodiments, the sulfinamide removal agent is Ti(0iPr)4. In some embodiments, the sulfinamide removal agent is Bi NBFfi / light (350 nm). In some embodiments, the sulfinamide removal agent is CF3SO3H / Et3N / SmI2. In some embodiments, the sulfinamide removal agent is Li / naphthalene. In some embodiments, the sulfinamide removal agent is H2SO4. In some embodiments, the sulfinamide removal agent is HBr. In some embodiments, the sulfinamide removal agent is HC1. In some embodiments, the sulfinamide removal agent is HNO3. In some embodiments, the sulfinamide removal agent is CH3SO3H. In some embodiments, the sulfinamide removal agent is p-toluenesulfonic acid. In some embodiments, the sulfinamide removal agent is AcOH. In some embodiments, the sulfinamide removal agent is AcCl / MeOH. In some embodiments, the sulfinamide removal agent is I2. In some embodiments, the sulfinamide removal agent is SOCl2 / MeOH. In some embodiments, tire sulfinamide removal agent is TMSCl / MeOH. In some embodiments, the sulfinamide removal agent is EtsSiH. In some embodiments, the sulfinamide removal agent is N-bromosuccinimide. In some embodiments, the sulfinamide removal agent is N-iodosuccinimide. In some embodiments, the sulfinamide removal agent is N-chlorosuccinimide. In some embodiments, the sulfinamide removal agent is Br2. In some embodiments, the sulfinamide removal agent is H3PO4. In some embodiments, the sulfinamide removal agent is thiophenol / ZnCl2. In some embodiments, the sulfinamide removal agent is NaBH . In some embodiments, the sulfinamide removal agent is LiAlEL. In some embodiments, the sulfinamide removal agent is L1BH4. In some embodiments, the sulfinamide removal agent is dibenzyltartaric acid. In some embodiments, the sulfinamide removal agent is NaH. In some embodiments, the sulfinamide removal agent is H2. In some embodiments, the sulfinamide removal agent is NaOMe. In some embodiments, the sulfinamide removal agent is NaOEt. In some embodiments, the sulfinamide removal agent is t-BuOK. In some embodiments, the sulfinamide removal agent is t-BuONa. In some embodiments, the sulfinamide removal agent is KF. In some embodiments, the sulfinamide removal agent is NbOCF. In some embodiments, the sulfinamide removal agent is MeLi. In some embodiments, the sulfinamide removal agent is Cl2. In some embodiments, the sulfinamide removal agent is HCO2H. In some embodiments, the sulfinamide removal agent is P(O-phenyl)3. In some embodiments, the sulfinamide removal agent is Ac2O / MeOH. In some embodiments, the sulfinamide removal agent is A1C13. In some embodiments, the sulfinamide removal agent is camphorsulfonic acid. In some embodiments, the sulfinamide removal agent is InC I , . In some embodiments, the sulfinamide removal agent is aspartic acid. In some embodiments, tire sulfinamide removal agent is Li. In some embodiments, the sulfinamide removal agent is Na. In some embodiments, the sulfinamide removal agent is (COCl)2 / MeOH. In some embodiments, the sulfinamide removal agent is Sml3. In some embodiments, the sulfinamide removal agent is 1 -chloromethyl -4-fluoro- 1,4- diazoniabicyclo[2.2.2]octanc bis(tctrafluoroboratc).

[0220] In some embodiments, the sulfinamide removal agent is HC1. In some embodiments, the-66-NAI-5007198252vlsulfinamide removal agent is aqueous HC1. In some embodiments, the sulfmamide removal agent is 3 M HC1.

[0221] In some embodiments, the solvent (used with the sulfmamide removal agent) is apolar aprotic solvent, optionally wherein the solvent is acetonitrile or 2 -methyltetrahydrofuran or a mixture thereof. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is 2- methyltetrahydrofuran. In some embodiments, the solvent is a mixture of acetonitrile and 2- methyltetrahydrofiiran.

[0222] In some embodiments, the process comprises recovering Compound 1 or a pharmaceutically acceptable form thereof as Compound 1, free base, from the reaction mixture by neutralizing the reaction mixture with a base. In some embodiments, the base is aqueous ammonia, aqueous NaOH, or aqueous KOH, optionally wherein the base is aqueous ammonia. In some embodiments, the base is aqueous ammonia.

[0223] In some embodiments, the process comprises purifying Compound 1, or a pharmaceutically acceptable form thereof. In some embodiments, tire purifying comprises crystallizing Compound 1, or a pharmaceutically acceptable form thereof. In some embodiments, the cry stallization process includes one or more of: jet milling, wet milling, dry milling, micronization, temperature cycling, seeding (optionally with particular seed size range, such as D90 < 20 pm, and / or seed loading range), continuous processing (e.g., mixed suspension, mixed product removal), solvent recrystallization using solvent / anti-solvent mixtures (including standard addition, co-addition, or reverse addition), high yield (e.g., greater than 90% or greater than 95%), a total crystallization solvent volume of less than 35-40 V, or less than 20 V, product with a PSD range of about 30 pm to about 50 pm (optionally with unimodal distribution), or a combination thereof. In some embodiments, crystallization employs a binary solvent system comprising a solvent and an anti-solvent, dissolving Compound 1 in a first solvent and adding the anti-solvent (standard addition), or adding a solution of Compound 1 in the first solvent to an anti-solvent (reverse addition), or combining a solution of Compound 1 in the first solvent with an anti-solvent at rates that maintain a v / v ratio range for the solvent and anti -solvent (co-addition). In some embodiments, the cry stallization process includes wet milling, temperature cycling, seeding, high yield (e.g., greater than 90% or greater than 95%), a crystallization solvent volume of less than about 35-40 V, or less than about 20 V, a PSD range of about 30 pm to about 50 pm (optionally with unimodal distribution), or a combination thereof. In some embodiments, the crystallization process employs seeding with crystalline seeds with a D90 of about 5 pm to about 30 pm, or about 5 pm to about 15 pm, or about 5 pm to about 10 pm. In some embodiments, the crystalline seed material is micronized. In some embodiments, cry stallization comprises seeding at a seed load of about 0.1% to about 15%, or about 0.5% to about 10%.

[0224] In some embodiments, the purifying comprises crystallizing Compound 1, or a-67-NAI-5007198252vlpharmaceutically acceptable form thereof, in a crystallization solvent to provide a crystalline form of Compound 1 or a pharmaceutically acceptable form thereof; optionally wherein the crystallization solvent is methanol, acetonitrile, or water, or a mixture thereof, optionally wherein the crystallization solvent is a mixture of methanol and water or is a mixture of acetonitrile and water. In some embodiments, the crystallization solvent is methanol, acetonitrile, acetone, cyclohexane, water, ethyl acetate, heptane, methyl ethyl ketone, or THF, or a mixture thereof. In some embodiments, the crystallization solvent comprises a mixture of two solvents, wherein the mixture is selected from the group consisting of: acetone / cyclohexane, acetone / water, ethyl acetate / heptane, ethyl acetate / cyclohexane, methyl ethyl ketone / heptane, methyl ethyl ketone / cyclohexane, THF / water, and THF / cyclohexane. In some embodiments, the crystallization solvent is acetone / cyclohexane or THF / cyclohexane. In some embodiments, the crystallization solvent is acetone / water. In some embodiments, where water is not a crystallization solvent, the non-aqueous solvents (e.g.. methanol, acetonitrile, acetone, cyclohexane, ethyl acetate, heptane, methyl ethyl ketone, THF) contain sufficient water (e.g., at least 0. 1 % v / v, or 0.1% to 10% v / v or 0.5% v / v to 5% v / v) to produce a hydrate of Compound 1 (e.g., a hemihydrate of Compound 1 as described herein). In some embodiments, the solvent pairs are used in a ratio range of about 20: 1 to about 1:20, or a range of about 5: 1 to 1:5. In some embodiments, crystallization employs a binary solvent system comprising a first solvent and an anti-solvent, dissolving Compound 1 in the first solvent and adding the anti-solvent, or adding a solution of Compound 1 in a first solvent to an anti -solvent, or mixing the solution of Compound 1 in the first solvent with the anti-solvent. In some embodiments, the first solvent is a polar aprotic solvent, optionally acetone, ethyl acetate, acetonitrile, methyl ethyl ketone, or THF. In some embodiments, the anti-solvent is water or a hydrocarbon solvent (such as cyclohexane or heptane). In some embodiments, the first solvent and the anti-solvent are: acetone (first solvent) / cyclohexane (anti-solvent), acetone (first solvent) / water (anti-solvent), ethyl acetate (first solvent) / heptane (anti-solvent), ethyl acetate (first solvent) / cyclohexane (anti-solvent), methyl ethyl ketone (first solvent) / heptane (anti-solvent), methyl ethyl ketone (first solvent) / cyclohexane (antisolvent), THF (first solvent) / water (anti-solvent), or THF (first solvent) / cyclohexane (anti -solvent).

[0225] In some embodiments, the cry stallization solvent is a mixture of methanol and water, optionally wherein the volumetric ratio of methanol and water is from about 40: 1 to about 1:5, from about 40: 1 to about 1: 1, from about 30: 1 to about 1: 1, from about 20: 1 to about 1: 1, from about 10: 1 to about 1: 1. about 34: 1, about 30: 1, about 5: 1, about 1.5: 1, or about 1: 1: and optionally wherein methanol is added before water.

[0226] In some embodiments, the cry stallization solvent is a mixture of acetonitrile and water, optionally wherein the volumetric ratio of acetonitrile and water is from about 4: 1 to about 1 :20, from about 2: l to about 1:20, from about 2: 1 to about 1: 10, from about 1:1 to about 1: 10, from about 1: 1 to-68-NAI-5007198252vlabout 1:5, about 1 : 1, about 1 : 2, about 1:3, about 1 : 4, or about 1:5; and optionally wherein acetonitrile is added before water.

[0227] In some embodiments, the cry stalline form of Compound 1, or a pharmaceutically acceptable fomi thereof, is a free base, hemi-hydrate of Compound 1. In some embodiments, the crystalline form is characterized by an XRPD pattern comprising peaks at approximately 9.0, 12.8, 16.6, and 18.4° 29, when measured using Cu Ka radiation. In some embodiments, the crystalline form is Form I of Compound 1 (Section 5.2.1).

[0228] In some embodiments. Compound 1 or a pharmaceutically acceptable form, or the cry stalline form of Compound 1 or a pharmaceutically acceptable form thereof, is prepared is prepared in an amount of at least 500 grams, at least 1 kg, at least 2 kg, at least 3 kg, at least 4 kg, or at least 5 kg, in a single batch. In some embodiments, Compound 1 or a pharmaceutically acceptable fonn, or the crystalline form of Compound 1 or a pharmaceutically acceptable form thereof, is prepared is prepared in an amount of at least 500 grams in a single batch.

[0229] In some embodiments, Compound 1 or a pharmaceutically acceptable form thereof, has a chemical purity of at least at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%. In some embodiments, Compound 1 or a pharmacally acceptable fonn thereof, has a chemical purity of at least at least 97%. In some embodiments, Compound 1 or a pharmaceutically acceptable form thereof, has a chemical purity of about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5%. In some embodiments, the chemical purity is determined by HPLC.

[0230] In some embodiments, Compound 1 or a pharmaceutically acceptable form thereof, has an enantiomeric excess of at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%. In some embodiments, the crystalline fonn of Compound 1 or a pharmaceutically acceptable fonn thereof, has an enantiomeric excess of at least 90%. at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%. In some embodiments, Compound 1 or a pharmaceutically acceptable form thereof, has an enantiomeric excess of at least 99%. In some embodiments, the cry stalline form of Compound 1 or a pharmaceutically acceptable fonn thereof, has an enantiomeric excess of at least 99%. In some embodiments, Fonn 1 of Compound 1, has an enantiomeric excess of at least 99%.

[0231] In some embodiments, the process comprises reacting Compound 3N :-69-NAI-5007198252vloptionally wherein Rcis tert-butyl (as Compound 3), or a salt thereof, or a solvate thereof, with a cyanide source, to provide Compound 2N (or wherein Rcis tert-butyl, Compound 2), or a salt thereof, or a solvate thereof.

[0232] In some embodiments, the process comprises reacting Compound 3:or a salt thereof, or a solvate thereof, with a cyanide source, to provide Compound 2, or a salt thereof, or a solvate thereof.

[0233] In some embodiments, the cyanide source is Zn(CN)2, LiCN, KCN, NaCN, CuCN, Cu(CN)2, Ni(CN)2, Ca(CN)2, TMSCN, K3[Fe(CN)e], K4[Fe(CN)e], benzenesulfonyl cyanide, tert-butyl cyanide, [Me4N]CN, tetraethylammonium cyanide, ethyl cyanoacetate, acetone cyanohydrin, cyanogen, and dimethylmalononitrile; and the reacting is done in the presence of a palladium catalyst, optionally in the presence of a zinc source and / or a phosphine ligand.

[0234] In some embodiments, the cyanide source is Zn(CN)2. In some embodiments, the cyanide source is LiCN. In some embodiments, the cyanide source is KCN. In some embodiments, the cyanide source is NaCN. In some embodiments, the cyanide source is CuCN. In some embodiments, the cyanide source is Cu(CN)2. In some embodiments, the cyanide source is Ni(CN)2. In some embodiments, the cyanide source is Ca(CN)-. In some embodiments, the cyanide source is TMSCN. In some embodiments, the cyanide source is K3[Fe(CN)e]. In some embodiments, the cyanide source is K4[Fe(CN)6]. In some embodiments, the cyanide source is benzenesulfonyl cyanide. In some embodiments, the cyanide source is tert-butyl cyanide. In some embodiments, the cyanide source is | Mc3N |CN. In some embodiments, the cyanide source is tetraethylammonium cyanide. In some embodiments, the cyanide source is ethyl cyanoacetate. In some embodiments, the cyanide source is acetone cyanohydrin. In some embodiments, the cyanide source is cyanogen. In some embodiments, the cyanide source is dimethylmalononitrile.-70-NAI-5007198252vl

[0235] In some embodiments, the cyanide source is Zn(CN)2, optionally in an amount of from about 1 to about 2 equivalents (relative to molar amount of Compound 3N or 3). In some embodiments, the cyanide source is Zn(CN)2, in an amount of about 1 equivalent, about 1.1 equivalent, about 1.2 equivalent, about 1.3 equivalent, about 1.4 equivalent, about 1.5 equivalent, about 1.6 equivalent, about 1.7 equivalent, about 1.8 equivalent, about 1.9 equivalent, or about 2 equivalents.

[0236] In some embodiments, the palladium catalyst is Pd(OAc)2, [PdCl(allyl)]2. Pd3(dba)3, Pd(PPh3)4, Pd(dppf)3C12, PdC’h. or a combination thereof. In some embodiments, the palladium catalyst is Pd(OAc)2. In some embodiments, the palladium catalyst is [PdCl(allyl)]2. In some embodiments, the palladium catalyst is Pd2(dba)3. In some embodiments, the palladium catalyst is Pd(PPh3)4. In some embodiments, the palladium catalyst is Pd(dppf)2C12. In some embodiments, the palladium catalyst is PdCk In some embodiments, the phosphine ligand is DPPF, PPh3, or R-BINAP. In some embodiments, the phosphine ligand is DPPF. In some embodiments, the phosphine ligand is PPh3. In some embodiments, the phosphine ligand is R-BINAP. In some embodiments, the zinc source is zinc dust, zinc powder, or zinc stripe. In some embodiments, the zinc source is activated zinc dust.

[0237] In some embodiments, the reacting (between Compound 3N or 3 and a cyanide source) is performed at a temperature of from about 15 °C to about 30 °C, followed by a temperature of from about 75 °C to about 95 °C. In some embodiments, the reacting is performed in a polar solvent, optionally the solvent is polar aprotic solvent, and optionally wherein the polar solvent is of N-methyl-2-pyrrolidone (NMP).

[0238] In some embodiments, the process comprises reacting Compound 4N :optionally wherein Rcis tert-butyl (as Compound 4), or a salt thereof, or a solvate thereof, with a 5- metalated-1 -methylimidazole reagent to provide Compound 3N (optionally wherein Rcis tert-butyl (as Compound 3)), or a salt thereof, or a solvate thereof.

[0239] In some embodiments, the process comprises reacting Compound 4:-71-NAI-5007198252vlor a salt thereof, or a solvate thereof, with a 5-metalated-l-methylimidazole reagent to provide Compound 3, or a salt thereof, or a solvate thereof.

[0240] In some embodiments, the 5-metalated-l-methylimidazole reagent is a Grignard reagent (e.g.,, Mgl jn someembodiments, the 5-metalated-l-methylimidazole reagent isjn someembodiments, the 5-metalated-l-methylimidazole reagent is an organozinc reagent (e.g.,In some embodiments, the 5-metalated-l-methylimidazole reagent is an organolithium reagent (e.g., 5 -lithio-l -methylimidazole).

[0241] In some embodiments, the process comprises forming the Grignard reagent by reacting 5- bromo-1 -methyl- IH-imidazole with an alkyl magnesium bromide, optionally wherein the alkyl magnesium bromide is CH3CH2MgBr; optionally in an aprotic solvent, optionally wherein the aprotic solvent is dichloromethane.

[0242] In some embodiments, the reacting of Compound 4N (optionally wherein Rcis tert-butyl, as Compound 4), or a salt thereof, or a solvate thereof, with the 5-metalated-l-methylimidazole reagent comprises conducting the reacting at a temperature of less than about 5 °C or less than about 0 °C. In some embodiments, the temperature is from about -30 °C to about 0 °C, from about -20 °C to about 0 °C, from about -15 °C to about 0 °C, or from about -10 °C to about 0 °C. In some embodiments, the molar ratio of the 5-metalated-l-methylimidazole reagent and Compound 4N (or Compound 4), or a salt thereof, or a solvate thereof, from about 1 : 1 to about 2 : 1. In some embodiments, the molar ratio is about 1: 1, about 1.1: 1, about 1.2: 1, about 1.3: 1, about 1.4: 1, about 1.5: 1, about 1.6: 1, about 1.7: 1, about 1.8: 1, about 1.9: 1, or about 2: 1. In some embodiments, the reaction is conducted in the presence of a polar, aprotic solvent, optionally wherein the polar, aprotic solvent is THF or diethyl ether, and optionally further in the presence of dichloromethane. In some embodiments, the process comprises quenching the reaction with-72-NAI-5007198252vlan acid. In some embodiments, the acid is acetic acid. In some embodiments, the quenching is performed at a temperature of less than about 10 °C. In some embodiments, the quenching is performed at a temperature of from about -30 °C to about 10 °C, from about -20 °C to about 10 °C, from about -10 °C to about 10 °C, or from about -10 °C to about 0 °C.

[0243] In some embodiments, the process comprises purifying Compound 3N (optionally Compound 3). or salt thereof, or a solvate thereof. In some embodiments, the purifying comprises extracting Compound 3N from the Compound 3N mixture to provide a separated organic layer comprising Compound 3N, and, concentrating the separated organic layer (e.g., under reduced pressure or by distillation, optionally wherein the distillation is performed at a temperature below about 50 °C) to provide a concentrated organic layer comprising Compound 3N. In some embodiments, tire purifying comprises crystallization, optionally wherein the crystallization is seed crystallization. In some embodiments, the crystallizing is performed in tire presence of a solvent, optionally wherein the solvent is DCM, Et20, THF, NMP, methyl tert-butyl ether (MTBE), water, or any mixture thereof, optionally wherein the solvent is THF, NMP, MTBE, water, or any mixture thereof.

[0244] In some embodiments, the reacting of Compound 4N, or a salt thereof, or a solvate thereof, and tire 5-metalated-l-methylimidazole reagent produces Compound 3N, or a salt thereof, or a solvate thereof,in a molar ratio of Compound 3N to Compound 3NR of at least 5: 1, at least 10: 1, at least 15: 1, at least 20: 1, at least 30: 1, at least 40: 1, or at least 50: 1; optionally wherein Compound 4N is Compound 4, Compound 3N is Compound 3, and Rcin Compound 3NR is tert-butyl (Compound 3R).

[0245] In some embodiments, the reacting of Compound 4, or a salt thereof, or a solvate thereof, and the 5-metalated-l -methylimidazole reagent produces Compound 3, or a salt thereof, or a solvate thereof,Compound 3R,-73-NAI-5007198252vlin a molar ratio of Compound 3 to Compound 3R of at least 5: 1, at least 10: 1, at least 15: 1, at least 20: 1, at least 30: 1, at least 40: 1, or at least 50: 1.

[0246] In some embodiments, the molar ratio of Compound 3N (or Compound 3) to Compound 3NR (or Compound 3R) is at least 5: 1. In some embodiment, the molar ratio is at least 10: 1. In some embodiment, the molar ratio is at least 15:1. In some embodiment, the molar ratio is at least 20: 1. In some embodiment, the molar ratio is at least 30: 1. In some embodiment, the molar ratio is at least 40: 1. In some embodiment, the molar ratio is at least 50: 1. In some embodiment, the molar ratio is about 10: 1, about15: 1, about 20: 1, about 25: 1, about 30: 1, about 31 : 1, about 32: 1, about 33: 1, about 34: 1, about 35: 1, about40: 1, about 45: 1, about 50: 1, or about 60: 1. In some embodiments, the molar ratio is measured before purification (e .. in the reaction mixture). In some embodiments, the molar ratio is measured using HPLC.

[0247] In some embodiments, Compound 3N (or Compound 3), or a salt thereof, or a solvate thereof, is prepared at a diastereomeric excess of at least at least 95%, at least 99%, at least 99.5%, or at least 99.9%. In some embodiments, Compound 3N (or Compound 3), or a salt thereof, or a solvate thereof, is prepared at a diastereomeric excess of about 95%, about 96%, about 97%, about 97.5%, about 98%, about 98.5%, about 99%, about 99.5%, about 99.7%, or about 99%. In some embodiments, the diastereomeric excess is measured after purification.

[0248] In some embodiments, the process comprises cyclizing Compound 6N:or a salt thereof, or a solvate thereof, to provide Compound 4N, or a salt thereof, or a solvate thereof; optionally wherein Rcin Compound 6N is tcrt-butyl (Compound 6), and Compound 4N is Compound 4.

[0249] In some embodiments, the process comprises cyclizing Compound 6:or a salt thereof, or a solvate thereof, to provide Compound 4, or a salt thereof, or a solvate thereof.-74-NAI-5007198252vl

[0250] In some embodiments, the cyclizing is performed under Mitsunobu conditions. In some embodiments, the cyclizing is performed in the presence of an azodicarboxylate reagent and a phosphine reagent. In some embodiments, the cyclizing is performed in a polar, aprotic solvent, such as THF or MTBE.

[0251] In some embodiments, the cyclizing is performed in the presence of an azodicarboxylate reagent and a phosphine reagent, wherein the azodicarboxylate reagent is diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-t-butyl azodicarboxylate, 1,1’- (azocarbonyl)dipiperidine, or dibenzyl azodicarboxylate, and the phosphine reagent is dicyclohexylphenylphosphine, diethylphenylphosphine, tributylphosphine, diphenyl-2 -pyridylphosphine, 4-(dimethylamino)phenyldiphenylphosphine, isopropyldiphenylphosphine, tri-tert-butylphosphine, tri-n- octylphosphine, tricyclohexylphosphine, polystyryldiphenylphosphine, or triphenylphosphine (or substituted variants thereof).

[0252] In some embodiments, the cyclizing is performed in the presence of an azodicarboxylate reagent and a phosphine reagent, wherein the azodicarboxylate reagent is a dialkyl azodicarboxylate, optionally selected from DEAD and DIAD; and the phosphine reagent is a trialkyl- or triarylphosphine, optionally selected from trioctylphosphine and triphenylphosphine.

[0253] In some embodiments, tire process comprises deprotecting Compound 7PG / N:optionally wherein Rcis tert-butyl, or a salt thereof, or a solvate thereof, to provide Compound 6N, or a salt thereof, or a solvate thereof, wherein each PG is independently a hydroxyl protecting group.

[0254] In some embodiments, the process comprises deprotecting Compound 7PG:or a salt thereof, or a solvate thereof, to provide Compound 6, or a salt thereof, or a solvate thereof, wherein each PG is independently a hydroxyl protecting group.

[0255] In some embodiments, each PG is a silyl protecting group. In some embodiments, the-75-NAI-5007198252vldeprotecting is performed in the presence of an acid or a fluoride source. In some embodiments, the acid is an inorganic acid. In some embodiments, the acid is an organic acid. In some embodiments, tire fluoride source is hydrogen fluoride, hydrogen fluoride pyridine, silver fluoride, cesium fluoride, potassium fluoride, tetramethylammonium fluoride, tetrabutylammonium fluoride (TBAF), or ammonium fluoride. In some embodiments, the fluoride source is tetrabutylammonium fluoride.

[0256] In some embodiments, the process comprises reacting Compound 8PG:or a salt thereof, or a solvate thereof, with O or a salt thereof, to provide Compound 7PG / N, or a salt thereof, or a solvate thereof; wherein each PG is independently a hydroxyl protecting group; and wherein Rcis (a) -C(Rd)(Re)(Rf), wherein each of Rd, Re, and Rfis independently C1.4 alkyl, or (b) phenyl or monocyclic heteroaryl optionally substituted with one or more C1.4 alkyl substituents, or (c) cycloalkyl optionally substituted with one or more Ci.4 alkyl substituents, optionally wherein Rcis tert-butyl. 2.4.6- trimethylphenyl, (triethyl)methyl, 4-methylphenyL phenyl, 2,4,6-triisopropylphenyl, or 2-methylbutan-2- yl, optionally wherein Rcis tert-butyl ((S)-tert-butylsulfmamide); optionally wherein Rcis tert-butyl and each PG is TBDMS (with both options as Compound 7).R^NH2s II

[0257] In some embodiments, O has an (S)-configuration at the sulfur atom. In some R<<S,NH2II embodiments, O has an enantiomeric excess of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 95.5%, at least 96%, at least 96.5%, at least 97%, at least 97.5%, at least 98%, at least 98.5%, at least 99%, at least 99.5%, or at least 99.9%, at the sulfur atom. In some embodiments, a carbon atom of Rcis connected to the S(O) group.

[0258] In some embodiments, the process comprises reacting Compound 8:-76-NAI-5007198252vlor a salt thereof, or a solvate thereof, with (5)-tert-butanesulfinamide, to provide Compound 7, or a salt thereof, or a solvate thereof.

[0259] In some embodiments, the reaction to provide Compound 7PG / N (or Compound 7) is performed in the presence of an acid. In some embodiments, the acid is an organic acid. In some embodiments, the acid is an inorganic acid. In some embodiments, the acid is a Lewis acid. In some embodiments, the acid is Ti(OEt)4, Ti(OiPr)4, TiCl4, CuSO4, MgSO4, MgCL, BF3OEt2, pyridinium p- toluenesulfonate, p-toluenesulfonic acid, HBF4, H2SO4, HC1, molecular sieves, acidic cation exchange resin (e.g.. Amberlyst), 12. (CFsSOs^Tb. CF3SO3H, HC1O4, H3PO4, (CEL^Al, or (octyl)3Al. In some embodiments, the Lewis acid is Ti(OEt)4.

[0260] In some embodiments, each PG is independently a silyl protecting group. In some embodiments, each PG is each PG is independently tert-butyldimethylsilyl (TBDMS), tri-isopropylsilyl (TIPS), trimethylsilyl (TMS), triethylsilyl (TES), isopropyldimethylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), or tert-butyldiphenylsilyl (TBDPS); In some embodiments, both PG groups (in a given compound) are tert-butyldimethylsilyl (TBDMS).

[0261] In some embodiments, where one or more steps of the processes disclosed herein employ a transition metal catalyst, the process may comprise reducing the amount of transition metal materials, such as palladium-based materials or zinc-based materials, from a reaction product or a subsequent reaction product. In some embodiments, the reducing is performed on Compound 1 or an intermediate in the synthetic process, so that Compound 1 meets transition metal or palladium specification guidelines (“Guideline on the Specification Limits for Residues of Metal Catalysts” European Medicines Agency Preauthorisation Evaluation of Medicines for Human Use, London. January 2007, Doc. Ref. CPMP / SWP / QWP / 4446 / 00 corr). In some embodiments, the process comprises reducing the amount of palladium and / or zinc in Compound 1 or an intermediate. In some embodiments, reducing the amount of palladium and / or zinc mixed with a reaction product such as Compound 1 comprises treating the reaction product / transition metal mixture with an adsorbing agent, and extracting agent, or a crystallizing agent, or a combination thereof. In some embodiments, reducing the amount of palladium comprises treating the reaction product with an extracting agent and then treating the resulting material with an adsorbing agent. In some embodiments, the reaction product may be treated once, more than once, or twice with an-77-NAI-5007198252vladsorbing agent.

[0262] Examples of adsorbing agents include, but are not limited to, trithiocyanuric acid (trimercaptotriazine; TMT), a TMT derivative (such as solid TMT, polystyrene-bound TMT, silica gelbound TMT, SiliaMetS® DMT, mercapto-porous polystyrene-bound TMT, or TMT-3Na), derivatized silica gel (such as silica gel-linker-thiol, silica gel-(CH2)s-SH, silica gel-(CH2)3-S-(CH2)2-SH, or such as silica gel-linker-amine, such as silica gel-(CH2)3-NH2. or silica gel-(CH2)3-[NH-(CH2)2]i-2-NH2, or silica gel-(CH2)3-NHC(S)NHCH3, such as SiliaMetS® metal scavengers), polystyrene-bound ethylenediamine, derivatized polyolefin fibers (e.g., grafted with acrylic acid, vinyl pyridine, styrene sulfonic acid, styryl thiol, styry l diphenylphosphine, mcrcaptoethylacrylate. or acry late alpha-hydroxyl thiol, such as Smopex® metal scavengers), activated charcoal (such as DARCO® KB-G and DARCO® KB-WJ), or glass bead sponges. Examples of crystallizing agents include, but are not limited to, N-acetylcysteine, thiourea, 2 -methyl -thiourea, thioglycerol, a hemi-maleate salt, or Bu .P. Examples of extracting agents include, but are not limited to, N-acetylcysteine, L-cysteine, and BmP in lactic acid. See, e.g., Garrett et al.. Adv. Synth. Catal. 2004, 346, 889-900.

[0263] Examples of additional adsorbing agents suitable for zinc removal include zinc chelators such as EDTA and EDTA derivatives, for example tetrasodium EDTA, and SiliaMetS® metal scavengers such as SiliaMetS DEAM, SiliaMetS diamine, SiliaMetS DOTA. SiliaMetS Imidazole, and SiliaMetS Triamine.

[0264] In some embodiments. Compound 1 is treated with a mixture of tetrasodium EDTA and TMT-3Na in water at a temperature of about 20 °C to about 40 °C, then optionally purified by, for example, column chromatography.

[0265] In some embodiments, after the reducing, the amount of palladium and / or in the reaction product is about 100 ppm or less, or about 10 ppm, or is undetectable. In some embodiments, the presence and / or amount of residual heavy metal (e.g., palladium or zinc) impurities is determined using methods known in the art. In some embodiments, the presence and / or amount of residual heavy metal (e.g., palladium or zinc) impurities is determined using inductively coupled plasma mass spectrometry' (I CP -MS). In some embodiments, the presence and / or amount of residual heavy metal (e.g., palladium) impurities is determined using techniques described in U.S. Pharmacopeia General Chapter <232> Elemental Impurities — Limits.

[0266] Also provided herein is a process of preparing Compound lb:-78-NAI-5007198252vlCompound lb. or a pharmaceutically acceptable form thereof.

[0267] Compound lb, or a pharmaceutically acceptable form thereof, can be prepared using theanalogous processes as described above, wherein O is replaced by O

[0268] Also provided herein is a process for preparing Compound 1c:Compound 1c, or a pharmaceutically acceptable fomi thereof.

[0269] Compound 1c, or a pharmacally acceptable fonn thereof, can be prepared using theanalogous processes as described above, wherein O is replaced by O5.6 USES AND METHODS

[0270] In some embodiments, provided herein, is a method of preventing, treating, or managing certain diseases or conditions in a subject using a compound described in Section 5.1, such as Compound 1, Compound lb, Compound 1c, or a pharmaceutically acceptable form thereof. In some embodiments, provided herein, is a method of preventing, treating, or managing certain diseases or conditions in a subject using the solid forms described in Section 5.2, such as Form 1 of Compound 1 described in Section 5.2.1. In some embodiments, provided herein, is a method of preventing, treating, or managing certain diseases or conditions in a subject using the pharmaceutically acceptable salts described in Section 5.3. In some embodiments, provided herein, is a method of preventing, treating, or managing certain diseases or conditions in a subject using the pharmaceutically compositions described in Section 5.4.5.6.1 THERAPEUTIC USES AND METHODS

[0271] Rat sarcoma virus (Ras) protein isoforms associate with the inner surface of the plasma-79-NAI-5007198252vlmembrane to transduce extracellular signals. To become active, Ras undergoes several post-translational modifications. Among the first steps in becoming activated is the famesylation of the cysteine in the CAAX box at the C-terminal end (where C represents cysteine, A represents an aliphatic amino acid, and X represents any amino acid). Rowinsky, E.K. et al., J. Clin. Oncol. 1999, 17, 3631-3652. The enzyme famesyltransferase (FTase) recognizes tire CAAX motif and transfers a 15 -carbon famesyl isoprenoid from famesyl diphosphate to the cysteine residue. The AAX amino acids subsequently are cleaved by Ras-converting enzyme I, and the famesylated cysteine is carboxymethylated by isoprenylcysteine carboxyl methyltransferase. Prior, I. A. et al., J. Cell Sci. 2001, 114, 1603-1608. Further palmitoylation (K-Ras4A, N-Ras, and Harvey rat sarcoma virus (H-Ras) or tire presence of a polybasic domain (K- Ras4B)) leads to anchoring of tire protein in tire plasma membrane. Hancock, J.F. et al., Cell 1990, 63, 133-139. Hie observations suggest prenylation is required for the function of all Ras isofonns, including their mutated forms. However, some famesylated proteins - including K-Ras and N-Ras - can be rescued from membrane displacement in the presence of a famesyltransferase inhibitor (FTI) by an alternative prenylation by the enzyme geranylgeranyltransferase (GGTase). Zhang, F.L. et al., J. Biol. Chem. 1997, 272, 10232-10239; Whyte, D.B. et al., J. Biol. Chem. 1997, 272, 14459-14464. Conversely, the third family member, H-Ras, is not a GGTase substrate, and thus its membrane localization and cellular function are diminished by an FTI. Id.

[0272] Genomic analyses have revealed that HRAS mutations occur in 6% of head and neck squamous cell carcinoma (HNSCC) cases at initial diagnosis (Hoadley, K.A., et al., Cell 2018, 173, 291- 304) and in 15% of patients during acquisition of resistance to cetuximab (Braig, F. et al., Oncotarget 2016, 7, 42988-42995), and that HRAS mutations correlate with reduced response of HNSCC patients to cetuximab treatment. Rampias, T. et al., Clin. Cancer Res. 2014, 20, 2933-2946. HRAS is also recurrently mutated in other cancer types, including urothelial cell carcinoma and salivary gland tumors. Ho, A.L., et al., J. Clin. Oncol. 2020, 38, 6504. Other tumor types exhibiting recurrent HRAS driver mutations include lung squamous cell carcinoma, thyroid cancer, pheochromocytoma and paraganglioma. Hoadley, K.A., supra.

[0273] Tire efficacy of the investigational FTI, tipifamib, was examined in a series of cell- and patient-derived xenograft models of HNSCC. Gilardi, M. et aL, Mol. Cancer Ther. 2020, 19, 1784-1796. Of 13 pts with recurrent / metastatic salivary gland tumors (SGT) treated with tipifamib, one experienced an objective response and an additional seven patients had stable disease as best response. Ho et al., supra.

[0274] In some embodiments, provided herein is a method of inhibiting a famesyltransferase, comprising contacting the famesyltransferase with an effective amount of the pharmaceutically acceptable salt of Compound 1, or pharmaceutically acceptable solvate thereof, or the solid form-80-NAI-5007198252vlcomprising Compound 1, or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. In some embodiments, the method of inhibiting a famesyltransferase comprises contacting the famesyltransferase with an effective amount of a pharmaceutical composition, as disclosed herein, comprising a pharmacally acceptable salt of Compound 1, or a pharmaceutically acceptable solvate thereof, or a solid form comprising Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmacally acceptable solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the contacting of the famesyltransferase takes place in a cell. In some embodiments, the famesyltransferase is present in a cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell a human cell. In some embodiments, the subject suffers from a cancer dependent on a famesylated protein. In some embodiments, the subject is a human.

[0275] In some embodiments, the method inhibits famesylation of H-Ras protein. In some embodiments, the method comprises exposing Compound 1, or a pharmaceutically acceptable form thereof, to a system (e.g., solution, cell, or subject) comprising H-Ras protein. In some embodiments, the H-Ras protein has a mutation. In some embodiments, the H Ras protein mutation is or comprises a modification at a specific position selected from G12, G13, Q61, Q22, KI 17, A 146, and any combination thereof, that is encoded by a modified codon in the HRAS gene that encodes for that amino acid (an HRAS mutation). In some embodiments, the inhibiting of the famesylation of tire H-Ras protein, such as an H-Ras protein having a mutation, takes place in a cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell a human cell. In some embodiments, the inhibition of the famesyltransferase present in tire cell takes place in a subject suffering from cancer dependent on a famesylated protein. In some embodiments, the subject is a human. In some embodiments, the cancer dependent on a famesylated protein is a cancer dependent on famesylated H-Ras protein, e.g., for the progression and / or survival of the cancer. In some embodiments, the cancer dependent on a famesylated protein has an H-Ras protein mutation. In some embodiments, the cancer dependent on a famesylated protein has an HRAS mutation. In some embodiments, the H-Ras protein mutation is or comprises a modification (e.g., a substitution) at a specific position selected from G12, G13, Q61, Q22, KI 17, A 146, and any combination thereof, that is encoded by a modified codon in the HRAS gene that encodes for that amino acid (an HRAS mutation). In some embodiments, the cancer dependent on a famesylated protein is head and neck cancer. In some embodiments, the head and neck cancer is HNSCC. In some embodiments, the cancer is HRAS-mutant HNSCC (with a modification as described herein). In some embodiments, the HNSCC or HRAS-mutant HSNCC is an HNSCC of the trachea, HNSCC of the maxilla, HSNCC of the salivary gland, or HNSCC of the oral cavity.

[0276] In some embodiments, provided herein is a method of treating cancer, such as a solid tumor-81-NAI-5007198252vlor a cancer dependent on a famesylated protein in a subject, comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt of Compound 1, or a pharmaceutically acceptable solvate thereof, or a solid form comprising Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, to the subject. In some embodiments, the method of treating cancer, such as a solid tumor or a cancer dependent on a famesylated protein in a subject comprises administering a therapeutically effective amount of a pharmaceutical composition, as disclosed herein, containing a pharmaceutically acceptable salt of Compound 1, or a pharmaceutically acceptable solvate thereof, or a solid form comprising Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient, to the subject. In some embodiments, the cancer, such as a solid tumor or a cancer dependent on a famesylated protein, is a cancer dependent on famesylated H-Ras protein, e.g., for the progression and / or survival of the cancer. In some embodiments, the cancer, such as a solid tumor or a cancer dependent on a famesylated protein, has an H-Ras protein mutation. In some embodiments, the H-Ras protein mutation is or comprises a modification (e.g., a substitution) at a specific position selected from G12, G13, Q61, Q22, KI 17, A 146, and any combination thereof, that is encoded by a modified codon in the HRAS gene that encodes for that amino acid (an HRAS mutation). In some embodiments, the cancer, such as a solid tumor or a cancer dependent on a famesylated protein, is head and neck cancer. In some embodiments, wherein the head and neck cancer is HNSCC. In some embodiments, the head and neck cancer, for example, HNSCC, has an H-Ras protein mutation. In some embodiments, the cancer is HRAS-mutant HNSCC. In some embodiments, the HNSCC or HRAS-mutant HNSCC is HNSCC of tire trachea, HNSCC of the maxilla, HSNCC of the salivary gland, or HNSCC of the oral cavity. In some embodiments, the HNSCC or HRAS-mutant HNSCC is relapsed, refractory, metastatic, or advanced, or a combination thereof.

[0277] In some embodiments, the method of treating cancer, such as a solid tumor or a cancer dependent on a famesylated protein, as disclosed herein, the presence or absence of the HRAS mutation has been determined prior to tire treating. In some embodiments, determining the presence or absence of the HRAS mutation comprises analyzing nucleic acids obtained from a sample from tire subject. In some embodiments, said sample is a tissue biopsy. In some embodiments, said sample is a tumor biopsy. In some embodiments, the HRAS mutation is determined by sequencing. Polymerase Chain Reaction (PCR), DNA microarray, Mass Spectrometry (MS), Single Nucleotide Polymorphism (SNP) assay, denaturing high-performance liquid chromatography (DHPLC), or Restriction Fragment Length Polymorphism (RFLP) assay. In some embodiments, the H-Ras mutation is determined by PCR. In some embodiments, the HRAS mutation is determined by sequencing.

[0278] In some embodiments, provided herein is a method of treating cancer in a subject having-82-NAI-5007198252vlcancer, such as a solid tumor, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable form thereof, optionally in combination with one or more second active agents. In some embodiments, Compound 1, or a pharmaceutically acceptable form thereof, is administered before, after, or concurrently with one or more second active agents. In some embodiments, the one or more second active agents comprise one or more of a tyrosine kinase inhibitor (TKI). a vascular endothelial growth factor receptor (VEGFR) inhibitor, an EGFR-TKI inhibitor, a PI3K inhibitor, a KRAS inhibitor, or a pan-RAS inhibitor. In some embodiments, the subject has been treated previously with a second active agent, and the combination comprises administering Compound 1 and the same second active agent, or a different second active agent from the same inhibitor class.

[0279] In some embodiments, provided herein is a method of treating cancer in a subject having cancer, such as a solid tumor, comprising administering to the subject a therapeutically effective amount of Compound 1. or a pharmaceutically acceptable form thereof, in combination with a VEGFR inhibitor. Combinations of Compound 1 or a pharmaceutically acceptable form thereof, and a VEGFR inhibitor are described in WO 2024 / 137751 Al, the entirety of which is incorporated herein by reference. In some embodiments, the cancer is renal cancer. In some embodiments, tire cancer is renal cell carcinoma (RCC). In some embodiments, the cancer is clear cell renal cell carcinoma (ccRCC), which is a highly vascularized tumor type, most commonly due to inactivation of the Von Hippel-Lindau (VHL) gene. In some embodiments, the cancer is non-ccRCC. In some embodiments, the cancer is a neuroendocrine tumor (NET). In another aspect is a method of mitigating, slowing the progression of. or overcoming drug resistance in an advanced solid tumor in a TKI-naive subject, comprising administering to the subject the compound of Formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same), and a VEGFR inhibitor. In another aspect, provided herein is a method of preventing or delaying emergence of TKI drug resistance in a subject having ccRCC. comprising administering to the subject Compound 1, or a pharmaceutically acceptable form thereof, and a VEGFR inhibitor. In some embodiment, the subject has been treated previously with the same or a different VEGFR inhibitor. In some embodiments, the VEGFR inhibitor is cabozantinib, lenvantinib, axitinib, regorafenib, vandetanib, pazopanib, sunitinib, sorafenib, tivozanib, fruquintinib, or zanzalintinib. In some embodiments, the method comprises administering to the subject an additional anticancer agent. In some embodiments, the subject has been treated previously with cabozantinib and the combination comprises Compound 1 and cabozantinib.

[0280] In some embodiments, provided herein is a method of treating cancer in a subject having cancer, such as a solid tumor, comprising administering to tire subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable fonn thereof, in combination with a KRAS inhibitor. Combinations of Compound 1 or a pharmaceutically acceptable form thereof, and a KRAS inhibitor are-83-NAI-5007198252vldescribed in International Patent Application Publication No. WO 2024 / 249551, the entirety of which is incorporated herein by reference. In some embodiments, the KRAS inhibitor is a KRAS G12C inhibitor, a KRAS G12D inhibitor, a KRAS G12V inhibitor, a KRAS G13D inhibitor, a KRAS G12R inhibitor, a KRAS G12S inhibitor, or a pan-KRAS inhibitor (e.g. , a pan-RAS inhibitor or “RAS(ON)” inhibitor, which targets mutant and / or wild-type protein in its active (or “on”) GTP-bound state). In some embodiments, the KRAS inhibitor selectively inhibits KRAS wild-type and KRAS-mutant protein in the inactive (or “off’) state. In some embodiments, a pan-KRAS inhibitor selectively inhibits more than one mutant form of KRAS. In some embodiments, the cancer is lung cancer, pancreatic cancer, gynecologic cancer, gastrointestinal cancer, breast cancer, neoplasm (metastatic neoplasm, germ cell cancer, plasma cell neoplasm, or myelodysplastic / myeloproliferative neoplasm), carcinoma of unknown primary (CUP), or leukemia. In some embodiments, the cancer is non-small cell lung cancer (NSCLC), non-squamous NSCLC, squamous NSCLC, or lung adenocarcinoma. In some embodiments, the cancer is colorectal cancer (CRC), colon cancer, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), biliary tract cancer, appendiceal cancer, small bowel cancer, stomach cancer, cholangiocarcinoma, ampullary cancer, gallbladder cancer, gastric cancer, gastric adenocarcinoma, esophageal cancer, esophageal adenocarcinoma, urinary tract cancer, Gl-neuroendocrine tumor, or gastroesophageal junction adenocarcinoma. In some embodiments, tire method comprises administering to the subject an additional anticancer agent. In some embodiments, the subject has been treated previously with the same or a different KRAS inhibitor.

[0281] In some embodiments, the KRAS inhibitor is a KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is adagrasib (KRAZATI®, MRTX849, Amgen), sotorasib (LUMAKRAS™, AMG-510, Amgen), divarasib (GDC-6036, Genentech / Roche), linperlisib (YL- 15293), RM007, D-1553 (InvestisBio), JDQ443 (Novartis), LY3537982 (Eli Lilly), LY3499446, ERAS-601, ERAS-007, BI 1823911 (Boehringer Ingelheim), JAB-21822 (glecirasib). MK-1084, MK-1086. MK- 1087, L-15293, D3S-001, RMC-6291 (elironrasib, Revolution), HBI-2438, FMC-376 (Frontier), BBO- 8520 (BridgeBio), ZG19018 (Suzhou Zelgen), UCT-001024 (1200 Pharma), TEB-17231 (280Bio unit of Yingli Pharma), HYP-2A (Sichuan Huiyu). ABSK071 (Abbisko), IBI351 (GFH925; Innovent / Genfleet), ARS-853, ARS-1620, or JNJ-74699157 (ARS-3248). In some embodiments, the KRAS G12C inhibitor is adagrasib. In some embodiments, the KRAS G12C inhibitor is sotorasib. In some embodiments, the KRAS G12C inhibitor is adagrasib and the cancer is NSCLC. In some embodiments, the KRAS G12C inhibitor is adagrasib and the cancer is CRC. In some embodiments, the KRAS inhibitor is a KRAS G12C (OFF) inhibitor. In some embodiments, the KRAS inhibitor is a KRAS G12C (ON) inhibitor. In some embodiments, the subject has been treated previously with a KRAS inhibitor and the method comprises administering Compound 1 and the same or a different KRAS inhibitor.-84-NAI-5007198252vl

[0282] In some embodiments, the KRAS inhibitor is a KRAS G12D inhibitor. In some embodiments, the KRAS G12D inhibitor is MRTX1133 (Mirati), TH-Z827 (Mao et al., Cell Discov. 2022, 8, 5), TH-Z835, KD-8, BI-KRAS12D1-3 (Boehringer Ingelheim), BI-KRASG12D3 (Boehringer Ingelheim; Hofmann et al., Cancer Discovery 2022, 12, 924), RMC-9805 (Revolution), ASP3082, ASP4396, LY3962673, INCB161734. HRS-4642. or QTX3046 (Quanta). In some embodiments, the KRAS G12D inhibitor is MRTX1133. In some embodiments, the KRAS G12D inhibitor is MRTX1133 and the cancer is pancreatic cancer or PDAC. In some embodiments, the KRAS G12D inhibitor is MRTX1133 and the cancer is CRC. In some embodiments, Compound (I) induced an increase in depth and / or duration of inhibition of phosphor lation of ERK, p90, or mTOR (e.g., measured by S6K and S6 levels), or an increase in cell cycle arrest (measured by phosphorylation of Rb) or cell death (measured by cleaved caspase 3), when combined with a KRAS G12D inhibitor such as MRTX1133.

[0283] In some embodiments, the KRAS inhibitor is a KRAS G12V inhibitor.

[0284] In some embodiments, the KRAS inhibitor is a KRAS G13D inhibitor.

[0285] In some embodiments, the KRAS inhibitor is a KRAS G12R inhibitor.

[0286] In some embodiments, the KRAS G12R inhibitor is KRAS G12R inhibitor 1 (Shokat). In some embodiments, the KRAS inhibitor is a KRAS G12S inhibitor.

[0287] In some embodiments, the KRAS G12S inhibitor is G12Si-5 (Shokat).

[0288] In some embodiments, the KRAS inhibitor is a pan-KRAS inhibitor. In some embodiments, the pan-KRAS inhibitor inhibits at least two mutant forms of KRAS. In some embodiments, the pan- KRAS inhibitor inhibits at least one mutant form of KRAS and wild-type KRAS. In some embodiments, the pan-KRAS inhibitor is BI-2852, BI-pan-KRASl-4 (BI1701963), RSC-1255, RMC-6236 (daraxonrasib), RSC-1255, QTX3034 (Quanta), JAB-23425 (Beijing Jacobio), BI-2493. LY4066434, or VRTX-153 (VRise). In some embodiments, the pan-KRAS inhibitor is BI-2852. In some embodiments, the KRAS inhibitor is a pan-RAS inhibitor. In some embodiments, the pan-RAS inhibitor inhibits at least two mutant forms of KRAS. In some embodiments, the pan-RAS inhibitor inhibits at least two of KRAS, NRAS, and HRAS, optionally at least one mutant form of KRAS, NRAS, or HRAS. In some embodiments, the KRAS inhibitor is a pan-RAS inhibitor that is a RAS(ON) inhibitor (selective for the active or “on” state of the target protein(s). In some embodiments, the pan-RAS inhibitor is selective for the active, GTO-bound or ON state of both mutant and wild-type variants of KRAS, NRAS. and HRAS. In some embodiments, the KRAS inhibitor is a pan-KRAS inhibitor that selectively inhibits wild-type and mutant forms of KRAS in the inactive (or “off’) state. In some embodiments, the pan-RAS inhibitor inhibits at least one mutant form of KRAS and the wild-type form of KRAS. In some embodiments, the KRAS inhibitor inhibits KRAS G12D, wild-type KRAS, wild-type NRAS, and wild- type HRAS, or any combination thereof. In some embodiments, the pan-RAS inhibitor is RMC-6236. In some-85-NAI-5007198252vlembodiments, the pan-RAS inhibitor is RSC-1255.

[0289] In some embodiments, the KRAS inhibitor inhibits KRAS G12D and KRAS G12V. In some embodiments, the pan-RAS inhibitor is RMC-6236 and the cancer is lung cancer, non-small cell lung cancer, pancreatic cancer, PDAC, or CRC. In some embodiments, the cancer is KRAS G12D, G12V, G12R. G12A, or G12S mutated, or G12D. G12V, or G12R mutated. In some embodiments, the cancer is CRC and is G13X and / or Q61X KRAS mutated cancer.

[0290] In some embodiments, the KRAS inhibitor is BI-2852 and the cancer is KRAS-amplified gastric cancer or esophageal cancer.

[0291] In some embodiments, the KRAS inhibitor is BI-1701963. In some embodiments, BI- 1701963 inhibits both mutant and wild-type inactive KRAS fonns.

[0292] In some embodiments, provided herein is a method of treating cancer in a subject having cancer, such as a solid tumor, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable form thereof, in combination with an EGFR-TKI inhibitor. Combinations of Compound 1 or a pharmaceutically acceptable form thereof, and an EGFR- TKI inhibitor are described in WO 2024 / 220600 Al, the entirety of which is incorporated herein by reference. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the method of treating includes mitigating EGFR-TKI resistance in NSCLC subject, optionally wherein the subject is currently or was previously treated with an EGFR-TKI, comprising administering to the NSCLC subject (a) Compound 1, or a pharmaceutically acceptable form thereof, or pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same), in combination with an EGFR-TKI treatment. In some embodiments, provided herein is a method of mitigating osimertinib resistance in an osimertinib-resistant NSCLC subject, comprising administering to the subject (a) Compound 1. or a pharmacally acceptable form thereof (or a pharmaceutical composition comprising the same), and (b) osimertinib, or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the same), wherein subject is currently being treated or was previously treated with osimertinib. In some embodiments, the method of treating includes preventing or delaying emergence of EGFR-TKI resistance in an EGFR-TKI -naive NSCLC subject, comprising administering to the subject (a) a compound of Formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same), before, during or after administering an EGFR- TKI. For example, in some embodiments, provided herein is a method of preventing or delaying emergence of osimertinib resistance in an osimertinib-naive NSCLC subject, comprising administering to the subject (a) a compound of Formula (I), or a pharmaceutically acceptable form thereof (or a pharmaceutical composition comprising the same), before, during or after administering osimertinib (or a pharmacal composition comprising the same). In some embodiments, the subject treated according to-86-NAI-5007198252vlthe methods of treating provided herein has, suffers from, has symptoms associated with, or is diagnosed as having, NSCLC. In some embodiments, the subject has or suffers from NSCLC. In some embodiments, the subject has symptoms associated with NSCLC. In some embodiments, the subject is diagnosed as having NSCLC. In some embodiments, the subject is a previously treated NSCLC subject. In some embodiments, the subject is an EGFR-TKI naive subject. In some embodiments, the subject is an EGFR-TKI naive subject for NSCLC. In some embodiments, the subject is an osimertinib naive subject. In some embodiments, the subject is an osimertinib-naive subject for NSCLC. In some embodiments, the subject has been treated previously with an EGFR-TKI. In some embodiments, the subject has been treated previously with osimertinib. In some embodiments, the subject is a NSCLC subject in remission. In some embodiments, the NSCLC subject is an EGFR-TKI resistant NSCLC subject, such as an osimertinib-resistant NSCLC subject. In some embodiments, the NSCLC has squamous histology.

[0293] In some embodiments, the EGFR-TKI used according to the methods provided herein is a second, third or fourth generation EGFR TKI. In some embodiments, the EGFR-TKI is an irreversible EGFR-TKI. In some embodiments, the EGFR-TKI is selected from tire group comprising, but is not limited to, afatinib (Gilotrif), avitinib (AC0010), BIBW2992, BLU-945, dacomitinib (Vizimpro), EAI045. lazertinib (YH25448 / GNS-1480), mavelertinib (PF-06747775; N-((3R,4R)-4-fluoro-l-(6-((3- methoxy-l-methyl-lH-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide), mobocertinib (TAK-788), nazartinib (EGF816), olmutinib (HM61713 / BI 1482694), osimertinib (AZD9291), poziotinib (HM781-36B), rociletinib (CO-1686), or tarloxotinib (Tarlox), or a pharmaceutically acceptable form thereof. In some embodiments, the EGFR-TKI is osimertinib or a pharmacally acceptable form thereof, such as osimertinib mesylate.

[0294] In some embodiments, provided herein is a method of treating cancer in a subject having cancer, such as a solid tumor, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable form thereof, in combination with a PI3K inhibitor. Combinations of Compound 1 or a pharmaceutically acceptable form thereof, and a PI3K inhibitor are described in WO 2024 / 233539 Al, the entirety of which is incorporated herein by reference. In some embodiments, the cancer is squamous cell carcinoma (SCC). hr some embodiments, the cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, the cancer is breast, endometrial, ovarian, cervical, urothelial, or lung cancer. In some embodiments, provided herein is a method of treating SCC, such as HNSCC, in a subject, comprising administering to the subject (a) Compound (I), or a pharmaceutically acceptable form thereof, and (b) a PI3K inhibitor, such as alpelisib. In some embodiments, the method of treating mitigates PI3K inhibitor (c.g., alpelisib) resistance. In some embodiments, the subject was previously treated with the PI3K inhibitor or alpelisib, and may be relapsed-87-NAI-5007198252vlor refracton' to such treatment. In some embodiments, the subject was not previously treated with a PI3K inhibitor- or alpelisib (e.g., alpelisib-naive). In some embodiments, the method of treating mitigates EGFR inhibitor (e.g., cetuximab) resistance. In some embodiments, the method of treating further comprises administering to the subject an EGFR inhibitor or cetuximab. In some embodiments, the subject was previously treated with the EGFR inhibitor or cetuximab, and may be relapsed or refractory to such treatment. In some embodiments, the subject was not previously treated with the EGFR inhibitor or cetuximab (e.g., cetuximab-naive). In some embodiments, the subject was previously treated with the PI3K inhibitor or alpelisib, and may be relapsed or refractory to such treatment. In some embodiments, the subject was not previously treated with a PI3K inhibitor or alpelisib (e.g., alpelisib-naive). In some embodiments, provided herein is a method of treating PI3K-dysregulated SCC or HNSCC in a subject comprising administering to the subject Compound (I), or a pharmaceutically acceptable form thereof. In some embodiments, provided herein is a method of treating PI3K-dysregulated SCC or HNSCC in a subject comprising administering to the subject (a) Compound (I), or a pharmaceutically acceptable form thereof, and (b) a PI3K inhibitor, such as alpelisib. In some embodiments, the method of treating comprises administering to the subject (a) a therapeutically effective amount of Compound (I), or a pharmacally acceptable form thereof, and (b) a therapeutically effective amount of a PI3K inhibitor, such as alpelisib. In some embodiments, the PI3K-dysregulated SCC or HNSCC is PIK3CA-mutant, PIK3CA-amplified, or PIK CA-overexpressed, or a combination thereof. In some embodiments, the PI3K-dysregulated SCC or HNSCC is PI3KCA -mutant. In some embodiments, the PI3K-dysregulated SCC or HNSCC is HRAS-dependent (HRAS-mutant, HRAS-amplified, or HRAS-overexpressed, or a combination thereof; particularly, HRAS-mutant or HRAS-overexpressed). In some embodiments, the PI3K-dysregulated SCC or HNSCC is HRAS wild-type (not HRAS-mutant, HRAS -amplified, or HRAS- overexpressed).

[0295] In some embodiments, the PI3K inhibitor is selected from the group comprising, but not limited to, inavolisib, RLY-2608, STX-478, alpelisib (PIQRAY®; BYL719), acalisib, AMG319, AZD8168, AZD8835, buparlisib, B591, CH5132799, copanlisib (aliqopa), delalisib (zydelig), duvelisib (copiktra), eganelisib, GSK2636771, idelalisib, leniolisib, linperlisib, omipalisib, parsaclisib, pictilisib, pilaralisib. RIDR-PI-103, serabelisib, sonolisib, taselisib, tenalisib, TG-100-115, umbralisib, zandelisib, ZSTK474. STX-478, RLY-2608, LOXO-783, or inavolisib, or a pharmaceutically acceptable form thereof. In some embodiments, the P13K inhibitor, for example, a PI3Ka inhibitor, used in the methods provided herein has the structure shown below, which can be named as (25)-N1-[4-Methyl-5-[2-(2,2,2- trifluoro-l,l-dimethylethyl)-4-pyridinyl] -2 -thiazolyl] -1,2-pyrrolidinedicarboxamide (or alternatively, as alpelisib, PIQRAY®, or BYL719).

[0296] In some embodiments, the pharmaceutically acceptable salt of Compound 1, or-88-NAI-5007198252vlpharmaceutically acceptable solvate thereof, or the solid form comprising Compound 1, or pharmaceutically acceptable salt or solvate thereof, as disclosed herein, is metabolically stable, for example, metabolically stable to liver metabolism in a subject, such as metabolically stable to liver metabolism in a human.5.6.2 DOSES AND REGIMENS

[0297] A compound described herein can be delivered in the fomi of a pharmaceutical composition that comprises a therapeutically effective amount of a pharmaceutically acceptable salt of Compound 1. or a pharmaceutically acceptable solvate thereof, or a solid form comprising Compound 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the therapeutically effective amount in the pharmaceutical composition is determined based on the free base equivalent amount of the pharmacally acceptable salt of Compound 1, or pharmaceutically acceptable solvate thereof, or the solid form comprising Compound 1. or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The pharmaceutical compositions disclosed herein are intended to be administered by a suitable route, including but not limited to orally, parenterally, rectally, topically and locally. In some embodiments, a selected dosage level will depend upon a variety of factors including, for example, the activity of the particular compound employed, the route of administration, the time of administration, tire rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0298] In some embodiments, the treatment with a pharmaceutically acceptable salt of Compound 1, or a pharmaceutically acceptable solvate thereof, or a solid form comprising Compound 1, or a pharmacally acceptable salt thereof, or a pharmacally acceptable solvate thereof, is administered in a free base equivalent amount of from about 1 mg to about 20 mg per day, from about 3 mg to about 20 mg per day, from about 3 mg to about 15 mg per day, from about 3 mg to about 10 mg per day, from about 3 mg to about 9 mg per day, from about 3 mg to about 8 mg per day, about 3 mg per day, about 4 mg per day, about 5 mg per day, about 6 mg per day, about 7 mg per day, about 8 mg per day, about 9 mg per day, about 10 mg per day, about 11 mg per day, about 12 mg per day, or about 15 mg per day. All doses provided in this paragraph are free base equivalent amounts.

[0299] In some embodiments, Compound 1, or a pharmaceutically acceptable solvate thereof, or a solid form comprising Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is administered once a day, twice a day, three times a day, or four times a day. In some embodiments, Compound 1, or a pharmaceutically acceptable solvate thereof, or a solid form-89-NAI-5007198252vlcomprising Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is administered once a day on days 1 to 7 of a 14-day cycle. In some embodiments, Compound 1, or a pharmaceutically acceptable solvate thereof, or a solid form comprising Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is administered once a day on days 1 to 7 and days 15 to 21 of a 28-day cycle. In some embodiments, Compound 1, or a pharmaceutically acceptable solvate thereof, or a solid form comprising Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is administered once a day on an on / off schedule, such as a weekly on / off schedule (e.g., 7 days on / 7 days off; or repeating 28-day cycles comprising 3 to 7 days on / 3 to 7 days off dosing, such as 7 days on / 7 days off in alternating weeks).

[0300] In some embodiments, the therapeutically effective amount of the pharmaceutically acceptable salt of Compound 1, or pharmaceutically acceptable solvate thereof, or the solid form comprising Compound 1, or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is contained in a pharmaceutical composition as described herein. Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein can be varied so as to obtain an amount of the active ingredient which is effective to achieve tire desired therapeutic response for a particular subject, such as a human patient, composition, and mode of administration, without being toxic to the subject. In some instances, dosage levels below the lower limit of the aforesaid range can be more than adequate, while in other cases still larger doses can be employed without causing any harmful side effect, e.g., by dividing such larger doses into several small doses for administration throughout the day. Dosages may reflect the amount of compound, or the amount of compound in a particular pharmaceutical fonn, or the free base form equivalent of the particular pharmaceutical fonn.

[0301] In some embodiments, the treatment with a pharmaceutically acceptable salt of Compound 1, or a pharmaceutically acceptable solvate thereof, or a solid form comprising Compound I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is administered in combination with radiotherapy, or radiation therapy.

[0302] It is understood that subheadings throughout this document do not limit the subject matter discussed to only those sections, but apply, and are contemplated to apply, to each embodiment disclosed in the instant application.

[0303] The disclosed compounds herein, including exemplified compounds and intermediate compounds, were named using ChemDraw® version 18.1.4.4 or later.6. EXAMPLES

[0304] Tire following Examples are presented by way of illustration, not limitation.SYNTHESIS EXAMPLES-90-NAI-5007198252vl

[0305] Abbreviations:

[0306] Analytical Methods

[0307] X-ray Powder Diffraction (XRPD): XRPD diffractograms were collected with an X-ray diffractometer (Instrument: PANalytical, Empyrean; Radiation, Cu Ka (X = 1.5418 A); Detector, PIXcel1D; Scan angle, 3-40° (20); Scan step, 0.013° (20); Tube voltage / current, 45 kV / 40 mA; Divergence slit, 1 / 8°; Rotation, On; Sample holder, Zero-background sample pan). Tire sample was prepared on a zero-background silicon afer by gently pressing onto the flat surface.

[0308] Polarized Light Microscopy (PLM): Light microscopy analysis was performed using an ECLIPSE LVIOOPOL microscope (Nikon, Japan). Each sample was placed on a glass slide with a drop of immersion oil and covered with a glass slip. The sample was observed using a 4 - 20x objective with polarized light.

[0309] Differential Scanning Calorimetry’ (DSC): DSC analysis was performed with a TA instrument (Discovery DSC 250). About 1-3 mg of sample was placed into an aluminum pan with a pin-91-NAI-5007198252vlhole and heated from 25 to 300 °C at a heating rate of 10 °C / min under N2 purge gas at a flow rate of 50 mL / min.

[0310] Thermogravimetric Analysis (TGA): TGA analysis was performed with a TA instrument (Discovery’ TGA 55). About 1-5 mg of sample was loaded onto a pre-tared aluminum pan and heated from rt to 300 °C at a heating rate of 10 °C / min under N2 purge gas at flow rates of 40 mL / min (balance chamber) and 60 mL / min (sample chamber).

[0311] High-performance Liquid Chromatography (HPLC): unless otherwise indicated, HPLC analysis for all polymorph, salt, and solubility in media experiments, was conducted on an Agilent 1260 series instrument, with a Waters XBridge Shield RP18 4.6* 150 mm, 3.5 pm column, column temperature 40 °C, mobile phase A: 0.1% H3PO4 in water; B: MeOH:ACN 3:7 v / v, with a flow rate of 1.5 mL / min, an injection volume of 5 pL, a DAD detector at a 210 nm wavelength, and a gradient of 12 min, 100% A, 3 min 50% A. 2. 1 min 5% A, 5 min 100% A.

[0312] Chiral HPLC: unless otherwise indicated, HPLC analysis for all chiral salt screen experiments was conducted on an Agilent 1290 series HPLC instrument, with Waters XBridge BEH Cl 8 XP (2.1 x 50 mm, 2.5 pm) column, with a flow rate of 0.6 mL / min, a DAD detector, at 215 nm and 252 nm wavelengths, Mobile phase A: 10 mM NELOAc (water / MeOH / ACN 900 / 60 / 40); Mobile phase B: 10 mM NELOAc (water / MeOH / ACN 100 / 540 / 360), with a gradient of 1.5 min 80% A, 1.5 min 0% A.

[0313] Gas Chromatography (GC): GC analysis was conducted on an Agilent 7890B equipped with headspace injector Agilent 7697A with Agilent DB-624 column (60 m x 530 um x 3.0 film thickness) and nitrogen as a carrier gas at a constant flow rate of 2.5 mL / min with a flame ionization detector.

[0314] Ultraperformance Convergence Chromatography (UPC): Unless otherwise indicated, UPC analysis was conducted on a Waters Acquity UPC2system with UV detector and QDA detector, using a Daicel Chiralpak ID-3 (3.0 x 150 mm. 3 pm) column, mobile phase A: 65% CO2. mobile phase B: 35% MeOH + 0.2% NH4OH (25%, aq.), isocratic pump program, run time of 10 min, a flow rate of 1.2 mL / min, UV detection at 250 nm, and a column temperature of 40 °C.

[0315] Particle Size Analysis (laser diffraction): Malvern Mastersizer 3000; software version 3.5; wet analysis method (USP <429>, including suspension of the analyte (about 15 to 75 mg) in 0.5% Tween 80 in water, prepared with sonication with a 180W sonicator at 400 KHz; wet dispersing unit Hydro SM)’ PSD detection range 0.01 pm to 3.5 mm.

[0316] In the synthesis examples that follow, it is understood that reference to a compound as disclosed herein having one or more stereocenters without designating the specific chirality (e.g., R- or S- enantiomer) will be understood to refer to the compound as racemic mixture (or a mixture of diastereomers), while inclusion of R- or S- designations will be understood to refer to an enantiomer (or a diastereomer) form of the compound, such as an enantiomerically (or diastereomerically) enriched form-92-NAI-5007198252vlof the compound, or an enantiomeric excess of the specified enantiomer form of the compound, in accordance with discussion above regarding enantiomeric enrichment and enantiomeric excess. Notation of a compound with an R- or S- designation is understood to include an enantiomerically enriched or an enantiomeric excess of the specified enantiomer of the compound, and not limited to only 100% of the single specified enantiomer of the compound. For example, reference to Compound 1 will be understood to refer to the compound prepared in Example 6 and in its single stereoisomer (S) form: (S)-3-amino-3- ( 1 -methyl- I / / -im idazol -5 -yl)-6-oxa-2(4,6)-quinolina- 1,4(1 ,3 )-dibenzenacyclohexaphane-22,44- di carbonitrile. Reference to a compound as having a center that confers geometric isomerism (e.g., E- or Z-isomers) without designating the geometry of that center will be understood to refer to the compound as a mixture of geometric isomers, or as one geometric isomer without specifying its identity.

[0317] Synthesis of certain intermediates, such as Compounds 8 to 21, are described in International Patent Application Publication No. WO 2024 / 245364. the entirety of which is incorporated herein by reference.

[0318] EXAMPLE 1: Synthesis of (4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)(4-(3-(( / er / -butyldimethylsilyl)oxy)phenyl)-2-chloroquinolin-6-yl)methanone (Compound 8).

[0319] Compound 8 was synthesized according to the protocols described in International Patent Application Publication No. WO 2024 / 245364, the entirety of which is incorporated herein by reference. ’H NMR (400 MHz, CDCh) 5 8.36 (d, J= 1.8 Hz, 1H), 8.18 (d, J= 8.7 Hz, 1H), 8.10 (dd, J= 8.7, 1.9 Hz, 1H), 7.99-7.95 (m, 1H), 7.64-7.55 (m, 2H), 7.43 (s, 1H), 7.36 (t, J= 7.8 Hz, 1H), 7.08 (d, J= 7.5 Hz, 1H), 6.99-6.91 (m, 2H), 4.74 (s, 2H), 0.98 (s, 9H), 0.82 (s, 9H), 0.19 (s, 6H), 0.07 (s, 6H); LCMS rn / z: [M + H]+calcd for C35H43BrClNO3Si2, 696.17; found, 696.2.-93-NAI-5007198252vlEXAMPLE 2: Synthesis of (S)-N-((4-bromo-3-(hydroxymethyl)phenyl)(2-chloro-4-(3- hydroxyphenyl)quinolin-6-yl)methylene)-2-methylpropane-2-sulfinamide (Compound 6).Stage-1 (Preparation of (S)-N-((4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)(4-(3-((tert- butyldimethylsilyl)oxy)phenyl)-2-chloroquinolin-6-yl)methylene)-2-methylpropane-2-sulfinamide (Compound 7).

[0320] To dry toluene (8 V; moisture content below 100 ppm) at 25 ± 5 °C was added Compound 8 (1.0 equiv ), followed by (S)-TBSA (1.3 equiv., 99.7% ee) and Ti(OEt)4(1.3 equiv.). The reaction mixture was slowly heated to 76 ± 3 °C and stirred for 4 h. Tire mixture w as distilled to reduce the volume to 5 V while maintaining an internal temperature below 76 °C. After distillation, the remaining mixture was heated to 76 ± 3 °C and stirred at 76 ± 3 °C for 4 h. and then cooled to below 60 °C. An in- process sample was analyzed by HPLC. which showed 1.6 % of Compound 8 and 94.8 % of Compound 7 (area under the curve). The mixture was further cooled to 20-25 °C, and THEED (2.0 equiv.) was charged over about 20 min. The mixture was heated to 50 ± 3 °C, stirred for 1 h, and cooled to 20-25 °C, to which 12% wAv aq. NaCl solution (2 V) was added solely over 30 min while maintaining an internal temperature at 20-25 °C. Tire resulting slurry was stirred for 2 h, allowed to settle for at least 1 h until a clear phase separation was observed. The bottom aqueous layer was drained, and the organic layer was distilled under vacuum (maintaining an internal temperature below 45 °C) to a target volume (3 V), to provide Compound 7 in toluene at a concentration of about 375 mg / mL, w hich was used in the next step (Stage-2) without further purification. MS: [M + H]+m / z calcd. for C39H52BrQN2O3SSi2, 799.2; found, 799.Stage-2 (Synthesis of Compound 6)

[0321] The crude toluene solution of Compound 7 was cooled to -5 to 0 °C, and TBAF solution (2.1 equiv., 1 M in THF) was slowly charged over a period of about 2 h while maintaining an internal-94-NAI-5007198252vltemperature of between -5 to 0 °C. The mixture was stirred at -5 to 0 °C for 30 min. In parallel, 2- butanone (1.5 V) was added to a separate reactor-2 followed by addition of potassium phosphate buffer at pH = 7 (1.5 V) and cooled to -5 to 0 °C. The reaction mixture was slowly added to reactor-2 while maintaining the internal temperature of reactor-2 below 0 °C, and formulation of yellow slurry was observed. The reactor was rinsed with toluene (0.25 V), followed by 2-butanone (0.25 V). and the resulting solution was transferred to reactor-2. The slurry in reactor-2 was stirred at -5 to 0 °C for 30 min and the mixture was warmed to 0-5 °C. Water (1.5 V) was slowly added while maintaining an internal temperature between 0 to 5 °C and stirred for 30 min. The internal temperature was raised to 28-33 °C and stirred for at least 30 min to get a clear solution. The mixture was allowed to settle for 15 min for phase separation, and the bottom aqueous layer was drained. Water (3 V) was added to tire organic layer, stirred for 30 min, settled for 15 min, and the bottom aqueous was drained. The organic layer was distilled under vacuum below 50 °C to reach target volume (4 V). Tire organic layer was warmed to 35- 40 °C, followed by addition of 1 wt % seeds of Compound 6, and stirred for 1 h. The distillation was continued to reach target volume (2 V) while maintaining internal temperature below 50 °C. ACN (8 V) was added to the reactor at 35 ± 10 °C , and the vacuum distillation was continued until target volume (2 V) was reached while maintaining internal temperature below 50 °C. ACN (4 V) was slowly added over 30 min, and the resulting mixture was distilled under vacuum to target volume of 2 V. Distillation was repeated by addition of 2 V ACN until the toluene content was below 1.7 wt %. The slurry was heated to 40-45 °C , stirred for 1 h, slowly cooled to 20-25 °C over 1.5 h and further stirred for 10 h. The slurry was cooled to 0-5 °C and then was stirred for 4 h. The yellow slurry was filtered, washed with 2 V ACN, followed by displacement wash with 3 V n-heptane. The isolated Compound 6 was dried in a vacuum oven at 45-50 °C until the moisture content was less than 0.7 wt % (yield: 72.7% over two steps; HPLC purity: 97.7%; assay (comparison to reference standard) purity: 98.1%). MS: m / z calcd for C27H24BrClN2O3S, 572.04; found. 572. 'H NMR (400 MHz, DMSO-d6. 343 K): 3 9.74 (s, 1 H), 8.12 (d, J = 8.6 Hz, 2 H), 7.82 (bs, 1 H), 7.68 (d, J= 8.3 Hz, 1 H), 7.61 (s, 1 H), 7.36-7.16 (m, 2H), 6.94-6.91 (m, 3 H), 5.52 (bs, 1 H), 4.54 (s, 2 H), 1.20 (s, 9 H).13C NMR (125 MHz, DMSO-d6, 343 K): 3 175.9, 157.8, 152.4, 141.5, 136.6, 132.6, 129.9, 128.9, 124.4, 122.6, 120.4, 116.44, 116.36.-95-NAI-5007198252vl

[0322] EXAMPLE 3: Synthesis of (S)-N-(44-bromo-22-chloro-6-oxa-2(4,6)-quinolina-l, 4(1,3)- dibenzenacyclohexaphane-3-ylidene)-2-methylpropane-2-sulfinamide (Compound 4).

[0323] To a uniform suspension of Compound 6 (1.0 equiv.) in THF (5 V) at 18-25 °C was added DIAD (1.3 equiv.) at 18-25 °C, and the resulting mixture was stirred for 25 min to form a clear solution. Tire clear solution was then added to a solution of trioctylphosphine (1.44 equiv.) in THF (5 V) at 18-25 °C over a period of about 8 h at 18-25 °C. rinsing with THF (about 0.2 V), with the formation of a yellow slurry observed after the addition was 50-60 % complete. The resulting mixture was stirred at 18-25 °C for 2 h. The organic layer was distilled under vacuum at below 45 °C to reach target volume (3 V). IPA (about 2 V) was added at 30 ± 10 °C, and the mixture was heated to 40-45 °C and stirred for 0.5 h. IPA (about 5 V) was slowly added over 2 h at 40-45 °C, and tire resulting mixture was stirred for 1 h, slowly cooled to 20-25 °C over 4 h, and stirred for another 12 h. Tire reaction mixture was filtered, washed with IPA (2 x 2 V). and washed with n-heptane (2 x 3 V). In-process HPLC analysis showed about 1.74% of dimer impurity. The isolated Compound 4 was dried in vacuum oven at 50-60 °C for at least 40 h to provide a yellow solid (yield: 76.9%; HPLC purity: 98.2 %; assay purity: 92.0 wt%). MS: [M + H]+m / z calcd for C27H22BrClN2O2S, 553; found, 553. 'H NMR (400 MHz, DMSO-d6, 343K): 3 8.49-8.36 (m, 1 H), 8.02 (d, J= 8.9 Hz, 1 H), 7.69 (s, 1 H), 7.63-7.53 (m, 1 H), 7.42 (s, 1 H), 7.35-7.28 (m, 3 H), 7.06- 7.04 (m, 2 H), 6.85-6.84 (m, 1 H), 5.49-5.42 (m. 1 H), 5.11-5.07 (m, 1 H). 1.30 (bs, 9 H).13C NMR (125 MHz, DMSO-d6, 343K): 3 155.9, 153.2. 151.9, 150.3, 137.9, 137.5, 136.4, 136.0, 134.7, 133.9, 133.7. 133.6. 133.0, 131.1. 130.5, 129.4. 129.1, 124.1, 122.0. 121.8, 121.2. 117.3.-96-NAI-5007198252vl

[0324] EXAMPLE 4: Synthesis of (S)-N-((S)-44-bromo-22-chloro-3-(l-inethyl-lH-imidazol-5- yl)-6-oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-3-yl)-2-methylpropane-2-sulfinamide (Compound 3).Stage-1 (Synthesis of (l-methyl-lH-imidazol-5-yl)magnesium bromide (5)):

[0325] To dry DCM (5.3 V; H2O content 86 ppm) under N2 was added Compound 5a (2.5 equiv.) at 18-25 °C, rinsing with DCM (0.8 V). The mixture was then added slowly over a period of 2.2 h to a solution of EtMgBr (2.55 equiv., 2.62 M in Et2O) in a separate vessel that had been pre-heated to 30-35 °C under water condensation, keeping the temperature at 32-40 °C. The resulting mixture was stirred at 32-40 °C for 1 h, cooled to 25-30 °C, and further stirred for 12 h. The solution was cooled to 15-20 °C. The molarity of Compound 5 in the solution was determined to be 0.50 M by titration (using 1 mmol iodine in 0.5 M Li Cl solution in THF).Stage-2 (Synthesis of Compound 3):

[0326] To THF (5.0 V; H2O content 108 ppm) under N2 was charged Compound 4 (1.0 equiv.) at 15-25 °C, rinsing with THF (1 V), and the resulting mixture was cooled to -5 to 0 °C. The Compound 5 solution from Stage- 1 was transferred slowly to the Compound 4 solution over a period of 2.2 h, maintaining the temperature below 0 °C. The resulting mixture was stirred at -2 to 2 °C for 15 h. The reaction mixture was quenched with 2 V aq. acetic acid (2 equiv.) over 2 h, maintaining the temperature below 10 °C. The resulting mixture was stirred at 0 to 10 °C for 20 min, warmed to 20-25 °C, stirred for 20 min, and allowed to settle for 20 min, and the bottom aqueous phase was drained. Water (3 V) was added to the organic layer over 5 min, and the mixture was stirred for 20 min at 20-25 °C and allowed to settle for 20 min, and the top aqueous layer was decanted. The remaining organic layer was distilled under vacuum to 2.5 V (at an internal temperature below 25 °C for the initial part and below 45 °C for the remaining part of the distillation). NMP (1.2 V) was added, the mixture was cooled to 22-28 °C, and then 0.5 wt% of Compound 3 seeds were added, and the resulting cloudy solution was stirred for 4 h. The reaction was further distilled under vacuum to 2.5 V at below 45 °C. MTBE (about 13 V) was then slowly added over a period of 3 h at 40-45 °C. Water (0.1 V) was added to the slurry at 40-45 °C over a period of 20 min, and the resulting mixture was stirred for 1 h, cooled to 2 °C, and stirred between -2 to 2 °C for 16 h. The concentration of Compound 3 was 2.6 mg / mL as detennined by HPLC. The slurry was-97-NAI-5007198252vlfiltered and washed with MTBE (2 x 2 V). Compound 3 was dried in vacuum oven at 50-60 °C for > 40 h (1.3 wt % moisture content; yield: 80.1%; HPLC purity: 98.5 %; assay purity: 84.9%). MS: [M + H]+m / z calcd for C3iH28BrClN4O2S, 635.08; found, 635. *H NMR (400 MHz, DMSO-d6, 343K): 3 8.28 (dd, J= 9.0, 2.3 Hz, 1H), 8.04 (d, J= 8.9 Hz, 1H), 7.77 (brs, 1H), 7.68-7.46 (m, 4H), 7.46-7.26 (m, 3H), 7.20 (dt, J= 7.7, 1.3 Hz, 1H), 7.05 (ddd, J= 8.3, 2.6, 1.0 Hz, 1H), 6.53 (s, 1H). 6.36 (s, 1H), 5.54-5.29 (m, 2H). 3.40 (s, 3H), 1.18 (s, 9H).13C NMR (101 MHz, DMSO-d6. 343K): 8 173.47, 155.18. 150.71. 150.09. 147.14, 141.76, 140.76, 139.58, 138.37, 135.64, 133.86, 133.19, 132.86, 132.44, 130.63, 130.11, 128.77, 127.09, 126.53, 122.73, 122.36, 121.56, 120.46, 119.86, 118.10, 69.05, 65.46, 57.21, 48.28, 33.56, 29.84, 28.73, 22.73, 16.99.

[0327] EXAMPLE 5: Synthesis of (S)-N-((S)-22,44-dicyano-3-(l-methyl-lH-imidazol-5-yl)-6- oxa-2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-3-yl)-2-methylpropane-2-sulfinamide (Compound 2).

[0328] A mixture of Compound 3 (1 equiv., assay-corrected) and NMP (3.5 V) was sparged with N2for 2 h at 20-25 °C to remove oxygen. Palladium acetate (13. 3 g, 1.5 mol%), DPPF (1.5 mol%), zinc cyanide (1.32 equiv.), and activated zinc (20 mol%) were added sequentially at 20-25 °C under N2. The reaction vessel was sparged with N2for 3 cycles, and the mixture was heated to 82-86 °C and stirred for 12 h. An in-process HPLC analysis showed 0.29 % of Compound 3 and 0.25 % of mono-cyano intennediate. The reaction mixture was cooled to 20-25 °C, passed through a pad of diatomaceous earth to remove excess zinc, and washed with NMP (1 V). To the organic layer was added water (1 V) over 20 min, followed by 1 wt% of Compound 2 seed at 20-25 °C. The resulting mixture was stirred for 1 h. The reaction was slowly quenched over 3 h with 6 V aq. tetrasodium EDTA (2.5 equiv.) and trithiocyanuric acid trisodium salt hydrate (TMT-3Na, 0.18 equiv.) at 20-25 °C. The resulting slurry was stirred for 16 h at 20-25 °C, filtered, and washed with water (4 x 1.5 V). Compound 2 was dried in vacuum oven at 50- 60 °C for about 22 h (3.8 wt % moisture content; yield: 74.7%).Purification of crude compound 2.

[0329] A 20-25 °C mixture of crude Compound 2 (51.0 equiv.) in ACN (13 V) and DMSO (0.65 V) was heated to 70-80 °C and stirred for 0.5 h. The mixture remained heterogeneous, was stirred for 1.5 h-98-NAI-5007198252vlat 70-80 °C, and was distilled under vacuum to reduce the volume to 9.5 V by maintaining internal temperature below 75 °C. After 2 h at 45-55 °C, the mixture was cooled to 20-25 °C over 2 h, and was stirred for another 16 h. The slurry was filtered and washed with 1: 1 v / v ACN / H2O (2 x 2 V). Compound 2 was dried in a vacuum oven at 50-60 °C for about 22 h (3.5 wt% moisture content; yield: 72.6%; HPLC purity: 98.5%; assay purity: 97.1%). MS: [M + H]+m / z calcd for CisH^NeCLS, 573.20; found, 573.5.1H NMR (400 MHz, DMSO-d6, 343 K): 3 8.40 (dd, J= 9.0, 2.3 Hz, 1H), 8.22 (d. J= 9.0 Hz. 1H), 8.13 (s, 1H), 7.90 (t, J= 12.2 Hz, 2H), 7.61 (s, 2H), 7.49-7.29 (m, 3H), 7.25 (dt, J= 7.6, 1.3 Hz, 1H), 7.08 (ddd, J= 8.3, 2.6, 1.0 Hz, 1H), 6.56 (d, J= 7.1 Hz, 2H), 5.52 (s, 2H), 3.44 (s, 3H), 1.20 (s, 9H).13C NMR (101 MHz, DMSO-d6, 343 K): 3 155.03, 149.02, 147.50, 145.09, 144.01, 141.02, 138.14, 136.88, 135.54, 133.96, 133.67, 133.14, 131.96, 130.98, 130.35, 127.75, 127.23, 126.68, 124.58, 122.72, 122.04, 119.81, 117.67, 117.39, 116.77, 110.50, 67.19, 65.79, 57.44, 33.62, 22.74.

[0330] EXAMPLE 6: Synthesis of (S)-3-amino-3-(l-methyl-lH-imidazol-5-yl)-6-oxa-2(4,6)- quinolina-l,4(l,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile (Compound 1).

[0331] To a uniform suspension of Compound 2 (1 .0 equiv.) in ACN (5 V) was added 3 M HC1 (6.0 equiv.) slowly at 20-25 °C over about 1 h. The resulting clear solution was wanned to 30-35 °C and stirred for 4.5 h. The mixture was cooled to 20-25 °C, treated with ACN (2 V), and stirred for about 10 min. NH4OH (28-30% in H2O; 8.0 equiv.) was added slowly while maintaining the internal temperature below 25 °C. The resulting mixture was stirred at 20-25 °C for 20 min, and the pH was determined to be about 10. The biphasic mixture was allowed to settle for 30 min, and the bottom aqueous layer was separated. The remaining organic layer was heated to 35-40 °C, followed by addition of Compound 1 seed (1 wt%), and the resulting mixture was stirred for 1 h at 35-40 °C to produce a cloudy mixture. H2O (11 V) was added slowly over 4 h at 35-40 °C, and the resulting mixture was stirred for 1 h, slowly- cooled to 20-25 °C in 2 h, and stirred for another 14 h. Hie slurry was filtered, washed with 40% ACN / H2O (2 x 2 V), followed by displacement washes with water (3 x 3 V), and the collected solid was allowed to air dry for about 2 h. Hie solid was further dried in vacuum oven at about 28 °C for about 13 h, and then at about 51 °C for about 19 h (2.9 wt% moisture content: yield: 88.4%: HPLC purity: 98.6%; assay purity: 92.0%). MS: [M+H]+m / z calcd for C29H20N6O, 469; found 469.3.1H NMR (400 MHz,-99-NAI-5007198252vlDMSO-d6, 343K): <5 8.38 (d, J= 9.0 Hz, 1H), 8.23 (d, J= 9.0 Hz, 1H), 8.10 (s, 1H), 8.05-7.72 (m, 2H), 7.58 (s, 1H), 7.49-7.36 (m, 1H), 7.35-7.19 (m, 3H), 7.09 (ddd, J= 8.3, 2.6, 1.0 Hz, 2H), 6.40 (s, 1H), 5.52 (t, J = 13.8 Hz, 2H), 3.50 (s, 3H).13C NMR (101 MHz, DMSO-de 343K): 8 154.81, 148.57, 148.12, 146.97, 140.01, 138.09, 135.70, 135.32, 134.04, 133.89, 132.59, 131.75, 130.13, 129.25, 128.51, 126.05, 124.31, 124.28, 122.58, 121.97, 119.74, 117.34, 117.21. 116.75, 109.74, 67.35, 61.58, 38.68, 32.93.

[0332] Analysis of Compound 1 with Chiral HPLC

[0333] Compound 1 prepared above was analyzed using the following chiral HPLC conditions.Column: CHIRALPAK IG-U 100x3.0 mm, 1.6 pmColumn Temperature: 30 °CSample Concentration about 0.1 mg / mLSample Temperature: AmbientUV Detection: 254 nmMobile Phase A: 20 mM Ammonia in n-HexMobile Phase B: 20 mM Ammonia and 1% H2O in EtOH: ACN = 9: 1 (v / v)Flow' Rate: 0.3 mL / minInjection Volume: 5 pLRun Time : 10 minute sInjector Wash: ACNGradient: Isocratic

[0334] A representative HPLC chromatograph is shown in FIG. 7. Under these conditions, Compound 1 had a retention time of about 6.48 min, with a chiral purity of about 99.97%. The amount of impurity under HPLC is less than 0.1%. In some embodiments, Compound 1 has a chiral purity not less than 99.0 %. as determined by the method described herein.-100-NAI-5007198252vl

[0335] EXAMPLE 7: Recrystallization of (S)-3-amino-3-(l-methyl-lH-imidazol-5-yl)-6-oxa- 2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile (Compound 1) using methanol / water.

[0336] Compound 1 (99.56 % HPLC purity) was combined with MeOH (15 V) at 20-25 °C and the resulting suspension was heated to 45-50 °C to form a clear solution. Polish filtration was performed at 45-50 °C, rinsing with MeOH (2 V). The filtrate was transferred into a reaction vessel, and distilled at 40- 45 °C until the total volume reached 10 V. A slurry of Compound 1 seed (2 wt%) in water (0.5 V) was added at 40±2 °C, and the resulting mixture was stirred for 5 h at 40±2 °C. The mixture was treated with a first portion of water (3 V) over 4 h at 40±2 °C, and a second portion of water (7 V) over 3 h at 40±2 °C, and was stirred for another 1 h at 40±2 °C. Tire mixture was cooled to 20-25 °C over 2 h, and stirred at 20-25 °C for another 8 h. The mixture was filtered, and the collected solid was washed with MeOH / H2O (1: 1; 3 V), slurry-washed with H2O (5 V), and washed with H2O (5 V). The resulting solid was dried in a vacuum oven at 20-25 °C for 16 h, and then at 40-45 °C for another 24 h. Compound 1 was isolated with 99.79% purity as determined by HPLC (0.2% of impurity; 97.3% of recovery yield). MS: [M+H]+m / z calcd for C29H20N6O, 469; found 469.3. *H NMR (400 MHz, DMSO-d6, 343K): 3 8.38 (d, J= 9.0 Hz, 1H), 8.23 (d, J= 9.0 Hz, 1H), 8.10 (s, 1H), 8.05-7.72 (m, 2H), 7.58 (s, 1H), 7.49-7.36 (m, 1H). 7.35-7.19 (m, 3H), 7.09 (ddd, J= 8.3, 2.6, 1.0 Hz, 2H). 6.40 (s, 1H), 5.52 (t, J= 13.8 Hz, 2H), 3.50 (s. 3H).13C NMR (101 MHz. DMSO-de 343 K): 5 154.81, 148.57, 148.12, 146.97, 140.01, 138.09. 135.70, 135.32, 134.04, 133.89, 132.59, 131.75, 130.13, 129.25, 128.51, 126.05, 124.31, 124.28, 122.58, 121.97, 119.74, 117.34, 117.21, 116.75, 109.74, 67.35, 61.58, 38.68, 32.93. The product was also characterized by XRPD (FIG. 2), TGA (FIG. 4), and DSC (Fig. 6). The XRPD in FIG. 2 is consistent with FIG. 3 in WO 2024 / 245364, confinning the recrystallized product is Form 1 of Compound 1.

[0337] EXAMPLE 8: Recrystallization of (S)-3-amino-3-(l-methyl-lH-imidazol-5-yl)-6-oxa- 2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile (Compound 1) using acetonitrile / water.

[0338] Compound 1 was dispersed in 4-7 V ACN, and the slurry was heated to above 55 °C and stirred for 15-30 min. The resulting mixture was filtered to remove insoluble material. Water (2-7 V) was added over 30-60 min at an internal temperature of at least 55 °C. The mixture was then cooled to 20-55 °C . Seed Compound 1 (2-5 wt% with respect to the crude Compound 1) was added and the resulting mixture was stirred for at least 3 h. Water (12.5 V) was added at a rate of at least 0.69 V per hour (in some cases, the last 4-7 V of the 12.5 V water was added at rates less than 3.5 V per hour) and the mixture was stirred for 1-4 hours. Tire slurry was then filtered. The wet filter cake was washed with ACN / H2O (1:2 v / v; at least 3 V) and then was slurry washed with H2O (5 V), and filtered and rinsed with-101-NAI-5007198252vlH;O (at least 3 V). The cake was vacuum dried at 20-25 °C for at least 12 h followed by drying at 45-65 °C for at least 24 h. MS: [M+H]+m / z calcd for C29H2oN60, 469; found, 469.3 H NMR (400 MHz, DMSO-d6, 343K): 5 8.38 (d, J = 9.0 Hz, 1H), 8.23 (d, J = 9.0 Hz, 1H), 8.10 (s, 1H), 8.05-7.72 (m, 2H), 7.58 (s, 1H), 7.49-7.36 (m, 1H), 7.35-7.19 (m, 3H), 7.09 (ddd, J = 8.3, 2.6, 1.0 Hz, 2H), 6.40 (s, 1H), 5.52 (t, J = 13.8 Hz, 2H), 3.50 (s, 3H).13C NMR (101 MHz, DMSO-d6 343 K): 5 154.81, 148.57, 148.12, 146.97, 140.01, 138.09, 135.70, 135.32. 134.04. 133.89. 132.59, 131.75, 130.13, 129.25, 128.51, 126.05, 124.31, 124.28, 122.58, 121.97, 119.74, 117.34, 117.21, 116.75, 109.74, 67.35, 61.58, 38.68, 32.93. The product was also characterized by XRPD (FIG. 3) and TGA (FIG. 5). Tire XRPD in FIG. 3 is consistent with FIG. 3 in WO 2024 / 245364, confirming the recry stallized product is Form 1 of Compound 1.

[0339] Alternatively, crude Compound 1 was dissolved in ACN (7 V) at ~66 °C and polish filtered through a 0.2 pm filter into a clean reactor, rinsing the line and polish filter with ACN (1 V). Water (5.7 V) was added to the filtrate over at least 15 min and the resulting solution was cooled to 40-45 °C before seeding with 2 wt % Compound 1 . The resulting mixture was held for at least 16 h until desaturation was achieved (~35 mg / mL Compound 1 in supernatant). The resulting slurry was wet milled at 40-45 °C for at least 20 turnovers at a tip speed of 15 m / s. Tire resulting slurry was then heated to 60-65 °C over 2 h and then held for at least 2 h at 60-65 °C before cooling to 40-45 °C over 2 h. Water (8.7 V) was added slowly over at least 5 h and the resulting mixture was then cooled to 20-25 °C over 6.5 h and aging for 3 h. The slurry was then filtered and washed with ACN / water ( 1 :2 v / v; 3 V), water (5 V), and water (3 V). The filtered solid was then dried at 55 °C until tire ACN content was not more than 3500 ppm. The resulting material was sieved with a 1000 pm screen to provide Form 1 of Compound 1 (molar yield, 89.9%).

[0340] EXAMPLE 9: Recrystallization of (S)-3-amino-3-(l-methyl-lH-imidazol-5-yl)-6-oxa- 2(4,6)-quinolina-l,4(l,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile (Compound 1) using various solvents.

[0341] Compound 1 is recrystallized from acetone / cyclohexane, acetone / water, ethyl acetate / heptane, ethyl acetate / cyclohexane, methyl ethyl ketone / heptane, methyl ethyl ketone / cyclohexane, THF / water, or THF / cyclohexane, optionally from acetone / cyclohexane or THF / cyclohexane. to provide a crystalline solid form of Compound 1. In particular, Compound 1 is dissolved in the first-listed solvent (a first solvent), such as a minimum volume of the first solvent, and is mixed (via standard addition, reverse addition, or co-addition) with the second-listed solvent (the antisolvent). In some aspects, the crystallization provides Form 1 of Compound 1. In some aspects, where the solvent pair docs not include water as one of the tw o components, the non-aqueous solvents arc not anhydrous, e.g., one or both contain sufficient water, e.g., at least 0.1 % w / w to 0.5 % w / w, to support-102-NAI-5007198252vlproduction of Form 1 of Compound 1. In some aspects, the process produces crystalline Compound 1, such as Form 1 of Compound 1, with a PSD of about 30 pm to about 50 pm (optionally with unimodal distribution). In some aspects, the process includes seeding with crystalline Compound 1. In some aspects, the process includes wet milling during the crystallization process. In some aspects, the process is high yielding (e g., greater than 90% or greater than 95%) and / or employs a total crystallization solvent volume of less than 35-40 V, or less than 20 V.EXAMPLE 10: Recrystallization of (S)-3-amino-3-(l-methyl-lH-imidazol-5-yl)-6-oxa-2(4,6)- quinolina-l,4(l,3)-dibenzenacyclohexaphane-22,44-dicarbonitrile (Compound 1) using modified mixing processes.

[0342] 10A: Compound 1 in acetone is charged by subsurface addition over 4 to 18 h into a rapidly stirred 90 / 10 water / acetone mixture (or 100% water) with seeded with crystalline Compound 1 (such as Compound 1 (Form 1)) at a loading of 0.5% to 15%. The resulting mixture is subjected to wet milling and thermal cycling and optionally aging, and then the mixture is fdtered to provide cry stalline Compound 1.

[0343] 10B: Crystallization of Compound 1 is conducted using continuous crystallization with a mixed suspension, mixed product removal (MSMPR) process, tee mixers, and high shear mixers in a solvent / antisolvent mixture.

[0344] In some aspects, these processes produce crystalline Compound 1, such as Form 1 of Compound 1, with a PSD of about 30 pm to about 50 pm (optionally with unimodal distribution). In some aspects, the processes include wet milling during the cry stallization process. In some aspects, tire processes are high yielding (e.g., greater than 90% or greater than 95%) and / or employ a total crystallization solvent volume of less than 35-40 V, or less than 20 V.

[0345] EXAMPLE 11: Specifications

[0346] In some embodiments, Compound 1 is obtained as a mixture with one or more of the following additional compounds, which were identified as by-products of the synthetic process. Analytical HPLC / MS data were obtained using an Agilent instrument with an Infinity Lab Poroshell 120 EC-C18 column [(2.7 pm particle size; 4.6x100 mm); mobile phase A, 0.1% formic acid in water; mobile phase B, 0.1% formic acid in ACN; flow rate 0.5 mL / min; solvent program, 0-10 min 95% A, 10-18 min 5% A)] and MS with ESI positive ionization. In some aspects, total impurities are not more than 3.0 % (w / w).-103-NAI-5007198252vl-104-NAI-5007198252vlFORMULATION EXAMPLES

[0347] In the formulation examples that follow, where the form of Compound 1 is not specified, the mg / tablet amounts for Compound 1 are based on the free base, non-solvate form of Compound 1 (free base equivalent amount). Where another form of Compound 1 is used, such as a solvate, for example a hydrate, salt, or combination thereof, the mg / tablet of Compound 1 material is increased as needed to achieve the free base equivalent strength listed, e.g., by accounting for purity of Compound 1, and solvent (solvate and / or residual solvent) or conjugate acid in the Compound 1 material. Tire amount of microcrystalline cellulose is reduced mg for mg so that the total mass of Compound 1 plus microcrystalline cellulose in the tablet matches the totals listed in Table 1 below.EXAMPLE 12: Tablet Formulation 1.

[0348] Tablets comprising Compound 1 (as free base, non-solvatc) may include the ingredients and dosage strengths shown in Table 1.

[0349] Table t. Tablet Formulation 1 Components* The "Strength" amount refers to the amount of Compound 1, free base, non-solvate form.-105-NAI-5007198252vl#The “Opadry II white (or other color)” is comprised of polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

[0350] Tablets comprising Compound 1 (Form 1) may include the ingredients and dosage strengths shown in Table 2.

[0351] Table 2 Tablet Formulation 1 Components using a correction factor of 0.9728.*The ‘’Strength” amount refers to the amount of Compound 1, free base, non-solvate form.*The “Opadry II white (or other color)” is comprised of polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

[0352] For Compound 1 (Fonn 1), a free base hemi-hydrate, an API correction factor of 0.9728 is used to maintain the target Compound 1 tablet strength, yielding the proportions shown in Table 2 (mg or % w / w free base equivalent / 0.9728 = mg or % w / w for Compound 1 (Form 1)). The API correction factor for the particular lot of Compound 1 evaluated in the instant example was determined as follows: API correction factor = (purity of API) * (1 - water content - residual solvent - ROI) = (0.994) * (1 - 0.021 - 0.000186 - 0.0001) = 0.9728.

[0353] In some embodiments, the fonnulation comprises silicified microcrystalline cellulose. In some embodiments, the formulation comprises microcrystalline cellulose (MCC), such as one or more grades of microcrystal line cellulose (MCC), for example, a combination of one or more grades of 101, 102, 105, 301, 302 and 200 MCC. In some embodiments, the formulation comprises one or more binders, such as poly vinylpyrrolidone (PVP; also known as povidone). In some embodiments, when the fonnulation comprises microcrystalline cellulose (MCC), and the formulation comprises a binder, the amount of MCC in the fonnulation is reduced mg for mg so that the total mass of Compound 1 plus microcrystalline cellulose and the binder in the tablet matches the totals listed in Table 1 above. In some-106-NAI-5007198252vlembodiments, the formulation comprises 5.0 % w / w of povidone. In some embodiments, the formulation does not comprise a binder.

[0354] In some embodiments, the formulation comprises about 1.0 % w / w to about 1.5 % w / w, or about 1.0 % w / w, or about 1.5 % w / w of lubricant (e.g., magnesium stearate). In some embodiments, the formulation comprises about 1 % w / w of lubricant. When the amount of lubricant is changed, the amount of the filler (e.g., SMCC or MCC) is adjusted accordingly to compensate for the change of lubricant. In some embodiments, the formulation comprises about 1 % w / w of lubricant (e.g., magnesium stearate) and about 90 % w / w to about 93 % w / w, or about 90 % w / w, 91 % w / w, 92 % w / w, or 93 % w / w of filler (e g., SMCC or MCC).Tablet Preparation:

[0355] Compound 1, free base, hemi-hydrate (Form 1) is comprised of fine, irregular-shaped crystals with agglomerates, and has low bulk density (about 0.2 g / mL) and poor flowability (Carr Index of 31). Use of silicified MCC or MCC showed improved uniformity of the blend. Use of aglidant, disintegrant, and lubricant allowed for acceptable tableting and disintegration characteristics.

[0356] Particle Size Distribution (PSD)

[0357] Prior to formulation, the PSD of Compound 1 is measured using laser diffraction to determine if the sample is suitable for formulation. A large PSD for a drug substance batch (or variability between batches) may reduce blend and / or content uniformity of the pharmaceutical composition (e.g., tablets) prepared from the drug substance and may alter and / or increase variability of physicochemical and pharmacokinetic properties associated with the formulation. In some embodiments, Compound 1 has a D90 of less than about 100 pm, such as a D90 of less than about 75 pm, less than about 50 pm, less than about 40 pm, less than about 30 pm, less than about 25 pm, or less than about 20 pm. In some embodiments, Compound 1 has a D90 of between about 75 pm and about 20 pm or between about 50 pm and about 20 pm. In some embodiments, Compound 1 has a D90 of less than about 75 pm. In some embodiments, Compound 1 has a D90 of less than about 50 pm. In some embodiments, Compound 1 has D90 of less than about 20 pm. In some embodiments, crystallization techniques are employed to provide such D90 results directly, without the need for post-crystallization micronization such as jet milling. In some embodiments, if the PSD of a given batch of Compound 1 has a D90 of greater than about 20 pm, micronization is used to reduce D90. For example, in some embodiments, if the PSD of a given batch of Compound 1 has a D90 of about 30 pm or greater, about 40 pm or greater, about 50 pm or greater, about 60 pm or greater, about 70 pm or greater, about 75 pm or greater, about 80 pm or greater, about 90 pm or greater, or about 100 pm or greater, micronization is used to reduce D90. In some embodiments, if the PSD of a given batch of Compound 1 has a D90 of between about 350 pm and about 50 pm, between about 330 pm and about 15 pm, between about 100 pm and about 20 pm, between about 100 pm and-107-NAI-5007198252vlabout 75 gm. between about 100 gm and about 50 gm, between about 75 gm and about 50 gm, between about 75 gm and about 25 gm, or between about 50 gm and about 25 gm, micronization is used to reduce D90. Various techniques of micronization may be employed, such as wet milling or jet milling, or various crystallization techniques such as seeding, seed bed wet milling, temperature cycling, continuous processing, solvent / anti-solvent crystallization with standard addition, reverse addition, sub-surface addition, co-addition, high shear mixing, or other processes. In some embodiments, jet milling may be used instead of or in addition to other micronization techniques. In some embodiments, crystallization produces D90 results as above directly, without the need for post-crystallization micronization such as jet milling. In some embodiments, micronization, such as wet milling, is used to reduce D90, such as to reduce D90 to less than about 75 pm, less than about 50 gm, or less than about 20 gm. In some embodiments, jet milling is used, such as to reduce D90 to reduce D90 to less than about 75 gm, less than about 50 gm, or less than about 20 gm. In some embodiments, the micronization technique, such as jet milling, is used more than once on a batch, for example jet-milling twice, to achieve the target D90.

[0358] For the 1 mg, 3 mg, 5 mg, 8 mg, and 10 mg strength tablets, Compound 1 with appropriate PSD may be de-lumped by sieving through a 150 gm hand screen as needed. Compound 1 was blended with colloidal silicon dioxide, croscarmellose sodium, and about half of the MCC or silicified MCC in a suitably sized blender (e.g. , V-blender) to obtain a first blend. The first blend and the remaining MCC or silicified MCC were sieved through a screen manually or mechanically using a suitable screen (e.g.. 300 gm hand screen or 813 gm Comil (milling) screen) and blended in a suitably sized blender to obtain a second blend. Magnesium stearate was de-lumped by sieving through a 500 gm screen, and was blended with the second blend to produce a lubricated blend. The lubricated blend was compressed into tablets of predetennined weights using a rotary tablet press to produce uncoated tablets. The uncoated tablets were coated in a perforated pan coater using an aqueous suspension of Opadry II (white or other color, or a mixture of colors / pigments) to yield the final cosmetically coated tablets.

[0359] Table 3. Effect of micronization on PSD of API (Compound 1, Form 1)

[0360] Exemplary processes for preparing tablets having strengths of 3 mg, 5 mg, or 8 mg ofCompound 1, or a pharmaceutically acceptable salt and / or solvate thereof (free base equivalent amount)-108-NAI-5007198252vlare illustrated in FIG. 1. Such processes are also used for preparing tablets having strengths of 1 mg or 10 mg.

[0361] Stability Testing:

[0362] A four-week excipient compatibility study at 40 °C / 75% relative humidity and 60°C accelerated stress conditions is used to test the stability of the formulations. Additional stability studies are conducted for 18-24 months at 25 °C / 60% relative humidity or for 6 months for 40 °C / 75% relative humidity. Suitable stability is observed for tested tablets over the respective test periods.

[0363] Dissolution Testing:

[0364] Dissolution testing of the 1 mg, 3 mg, 5 mg, 8, and 10 mg tablets is performed according to USP <711>, Apparatus 2 (paddles) using IL vessels, in 900 mL of aqueous solution at pH 4.5, 25 mM sodium acetate with 0.5% sodium lauryl sulfate buffer, at 37 °C, mixed with a paddle at 75 rpm. Sampling is performed at 5, 15, 30, 45, and 60 min, with HPLC with UV detection at 250 nm.6.1 INCORPORATION BY REFERENCE

[0365] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entireties to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Such citations or identifications of any publication, patent, or patent application in this application is not to be construed as an admission that it is prior art to the present application. In case of conflict, the present application, including any definitions herein, will control.-109-NAI-5007198252vl

Claims

What is claimed is:

1. A process for preparing Compound 1 :Compound 1, or a pharmaceutically acceptable form thereof, comprising treating Compound 2N:optionally wherein Rcis tert-butyl (Compound 2), or a salt thereof, or a solvate thereof, with a sulfmamide removal agent to provide Compound 1. or a pharmaceutically acceptable fonn thereof; wherein Rcis (a) -C(Rd)(Re)(R1), wherein each of Rd, Re, and Rfis independently Ci.4 alkyl, or (b) phenyl or monocyclic heteroaryl optionally substituted with one or more Ci -4 alkyl substituents, or (c) cycloalkyl optionally substituted with one or more Ci-4 alkyl substituents, optionally wherein Rcis tertbutyl, 2,4,6-trimethylphenyl, (triethyl)methyl, 4-methylphenyl, phenyl, 2,4,6-triisopropylphenyl, or 2- methylbutan-2-yl .

2. The process of claim 1, wherein the Compound 2N (or Compound 2) or salt thereof, or solvate thereof, is treated with tire sulfmamide removal agent in the presence of a solvent to provide a reaction mixture.

3. The process of claim 1, wherein the sulfmamide removal agent is an acid, a reducing agent, a base, an oxidant, or a radical agent, or a combination thereof.

4. Tire process of claim 1 or 2, wherein the sulfmamide removal agent is Ti(OiPr)4, BmNBkh / light (350 nm), C SOd f / EtsN / SmT, Li / naphthalene, H2SO4, HBr, HC1, HNO3, CH3SO3H, p-toluenesulfonic acid, AcOH. AcCl / MeOH, I2, SOCE / McOH. TMSCl / MeOH, Et3SiH, N-bromosuccinimide, N--110-NAI-5007198252vliodosuccinimide, N-chlorosuccinimide, Br2, H3PO4, thiophcnol / ZnCL. NaBHj. L1AIH4, L1BH4. dibenzyltartaric acid, NaH, H2(e.g., with Ni or Pd catalyst, such as RaNi), NaOMe, NaOEt, t-BuOK, t- BuONa, KF, NbOCE, MeLi, Cl2, HCO2H, P(O-phenyl)3, Ac20 / Me0H, AlCh, camphorsulfonic acid, InCE, aspartic acid, Li, Na, (COCIL / McOf I. Smfy or 1 -chloromethyl -4-fluoro- 1,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); optionally wherein the HC1 is aqueous HC1, or optionally wherein the aqueous HC1 is 3 M HC1.

5. The process of any one of claims 2 to 4, wherein the solvent is a polar aprotic solvent, optionally wherein the solvent is acetonitrile or 2-methyltetrahydrofiiran or a mixture thereof.

6. The process of any one of claims 2 to 5, comprising recovering Compound 1 or a pharmaceutically acceptable form thereof as Compound 1, free base, from the reaction mixture by neutralizing the reaction mixture with a base.

7. Tire process of claim 6, wherein the base is aqueous ammonia, aqueous NaOH, or aqueous KOH, optionally wherein the base is aqueous ammonia.

8. The process of any one of claims 1 to 7, comprising purifying Compound 1. or a pharmaceutically acceptable form thereof.

9. Tire process of claim 8, wherein tire purifying comprises cry stallizing Compound 1, or a pharmaceutically acceptable form thereof, in a crystallization solvent to provide a crystalline form of Compound 1 or a pharmaceutically acceptable fonn thereof: optionally wherein the crystallization solvent is:(i) methanol, acetonitrile, or water, or a mixture thereof;(ii) a mixture of methanol and water or a mixture of acetonitrile and water;(iii) methanol, acetonitrile, acetone, cyclohexane, water, ethyl acetate, heptane, methyl ethyl ketone, or THF, or a mixture thereof;(iv) a binary solvent system comprising a first solvent and an anti-solvent, optionally wherein the first solvent is a polar aprotic solvent, such as acetone, ethyl acetate, methyl ethyl ketone, or THF, and the anti-solvent is water or a hydrocarbon such as cyclohexane or heptane; optionally wherein the binary solvent system is acetone / cyclohexane, acetone / water, ethyl acctatc / hcptanc, ethyl acctatc / cyclohcxanc, methyl ethyl kctonc / hcptanc, methyl ethyl ketone / cyclohexane, THF / water, or THF / cyclohexane;-111-NAI-5007198252vl(a) optionally wherein the solvent and anti-solvent of the binary solvent system are used in a ratio of about 20: 1 to about 1:20, or about 5: 1 to about 1:5; optionally wherein the binary solvent system comprises sufficient water to produce Compound 1 free base hemihydrate (or Form 1 of Compound 1);(b) optionally wherein the crystallizing comprises mixing a solution of Compound 1 in the first solvent with the anti-solvent by standard addition, reverse addition, or co-addition;(v) optionally wherein the crystallization solvent is a mixture of solvents, wherein the mixture is selected from the group consisting of acetone / cyclohexane or THF / cyclohexane; optionally acetone / water; optionally wherein the crystallizing comprises one or more of wet milling, temperature cycling, and seeding: optionally wherein the crystallizing comprises seeding with crystalline seeds of CompoundI, or a pharmaceutically acceptable form thereof, having a D90 of about 5 pm to about 30 pm, or about 5 pm to about 15 pm, or about 5 pm to about 10 pm; optionally wherein the crystallizing comprises seeding with crystalline seeds of Compound 1, or a pharmaceutically acceptable form thereof, at a seed load of about 0. 1% to about 15%, or about 0.5% to about 10%; optionally wherein the purifying comprises crystallizing Compound 1, or a pharmaceutically acceptable fonn thereof, in a crystallization solvent volume of less than about 35-40 V or less than about 20 V; optionally wherein the crystal lizing produces a yield of crystalline Compound 1 of greater than 90% or greater than 95%; optionally wherein the crystallizing produces crystalline Compound 1, such as Compound 1 free base hemihydrate or Compound 1 (Form 1), with a PSD range of about 30 pm to about 50 pm (optionally with unimodal distribution).

10. The process of claim 9, wherein the crystallization solvent is a mixture of methanol and water, optionally wherein the volumetric ratio of methanol and water is from about 40: 1 to about 1:5, from about 40: 1 to about 1: 1, from about 30: 1 to about 1: 1, from about 20: 1 to about 1: 1, from about 10: 1 to about 1: 1, about 34: 1, about 30: 1, about 5:

1. about 1.5: 1, or about 1:1; and optionally wherein methanol is added before water.I I . The process of claim 9, wherein the crystallization solvent is a mixture of acetonitrile and water, optionally wherein the volumetric ratio of acetonitrile and water is from about 4: 1 to about 1 : 20, from about 2: l to about 1:20, from about 2: 1 to about 1: 10, from about 1:1 to about 1: 10, from about 1: 1 to-112-NAI-5007198252vlabout 1:5, about 1 : 1, about 1 : 2, about 1:3, about 1 : 4, or about 1:5; and optionally wherein acetonitrile is added before water.

12. Tire process of any one of claims 9 to 11, wherein the crystalline form of Compound 1, or a pharmaceutically acceptable form thereof, is a free base, hemi-hydrate of Compound 1.

13. The process of claim 12, wherein the crystalline form is characterized by an XRPD pattern comprising peaks at approximately 9.0, 12.8, 16.6, and 18.4° 20, when measured using Cu Ka radiation.

14. Tire process of claim 12 or 13, wherein the crystalline form is Form 1 of Compound 1.

15. The process of any one of claims 1 to 14, wherein Compound 1 or a pharmaceutically acceptable form, or the crystalline form of Compound 1 or a pharmaceutically acceptable form thereof, is prepared in an amount of at least 500 gram, at least 1 kg, at least 2 kg, at least 3 kg, at least 4 kg, or at least 5 kg, in a single batch.

16. The process of(a) any one of claims 1 to 8, wherein Compound 1 or a pharmaceutically acceptable form thereof, or(b) any one of claims 9 to 15, wherein the crystalline form of Compound 1 or a pharmaceutically acceptable form thereof, in each case, has an enantiomeric excess of at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%.

17. The process of any one of claims 1 to 16, comprising reacting Compound 3N:optionally wherein Rcis tert-butyl (as Compound 3), or a salt thereof, or a solvate thereof, with a cyanide source, to provide Compound 2N (or where Rcis tert-butyl, Compound 2), or a salt thereof, or a solvate thereof.-113-NAI-5007198252vl18. The process of claim 17, wherein the cyanide source is Zn(CN)2, LiCN, KCN, NaCN, CuCN, CU(CN)2, Ni(CN)2, Ca(CN)2, TMSCN, K3[Fe(CN)s], K4| Fc(CN),,|. benzene sulfonyl cyanide, tert-butyl cyanide, [Me4N]CN, tetraethylammonium cyanide, ethyl cyanoacetate, acetone cyanohydrin, cyanogen, or dimethylmalononitrile; and the reacting is done in tire presence of a palladium catalyst, optionally in the presence of a zinc source and / or a phosphine ligand.

19. Tire process of claim 18, wherein:(a) the cyanide source is Zn(CN)2, optionally in an amount of from about 1 to about 2 equivalents; or(b) the palladium catalyst is Pd(OAc)2, [PdCl(allyl)]2. Pd3(dba)3. Pd(PPh3)4. Pd(dppf)2C12, PdCT. or a combination thereof; or(c) the phosphine ligand is DPPF, PPh3, or R-BINAP; or(d) the zinc source is activated zinc dust; or(e) the reacting is performed at a temperature of from about 15 °C to about 30 °C, followed by a temperature of from about 75 °C to about 95 °C; or(f) the reacting is performed in a polar solvent, optionally the solvent is polar aprotic solvent, and optionally wherein the polar solvent is of N-methyl-2-pyrrolidone (NMP); or(g) any combination of (a)-(f).

20. Tire process of any one of claims 17 to 19, comprising reacting Compound 4N:optionally wherein Rcis tert-butyl (as Compound 4), or a salt thereof, or a solvate thereof, with a 5 -metalated-1 -methylimidazole reagent to provide Compound 3N (optionally wherein Rcis tertbutyl (as Compound 3)), or a salt thereof, or a solvate thereof.

21. The process of claim 20, wherein the 5 -metalated-1 -methylimidazole reagent is a Grignard-114-NAI-5007198252vlreagent (e.g.,an organozinc reagent (e.g.,an organolithium reagent (e.g., 5-lithio-l-methylimidazole).

22. The process of claim 20 or 21, wherein the 5 -metalated-1 -methylimidazole reagent is a Grignard reagent, optionally wherein the Grignard reagent is23. The process of claim 22, comprising forming the Grignard reagent by reacting 5 -bromo- 1- methyl-lH-imidazole with an alkyl magnesium bromide, optionally wherein the alkyl magnesium bromide is CH3CH2MgBr; optionally in an aprotic solvent, optionally wherein the aprotic solvent is dichloromethane .

24. The process of any one of claims 20 to 23, wherein the reacting of Compound 4N (optionally wherein Rcis tert-butyl, as Compound 4), or a salt thereof, or a solvate thereof, with the 5 -metalated-1 - methylimidazole reagent comprises:(a) conducting the reacting at a temperature of less than about 5 °C or less than about 0 °C; or(b) conducting the reacting at a molar ratio of the 5-mctalatcd-l-mcthylimidazolc reagent and Compound 4N (or Compound 4), or a salt thereof, or a solvate thereof, from about 1 : 1 to about 2:1; or(c) conducting the reacting in the presence of a polar, aprotic solvent, optionally wherein the polar, aprotic solvent is THF or diethyl ether, and optionally further in the presence of dichloromethane; or(d) quenching the reaction with an acid, optionally wherein tire acid is acetic acid, optionally wherein the quenching is perfonned at a temperature of less than about 10 °C; or(e) any combination of (a)-(d).

25. The process of any one of claims 20 to 24, comprising purifying Compound 3N (optionally Compound 3), or salt thereof, or a solvate thereof.

26. The process of claim 25, wherein the reacting of Compound 4N, or a salt thereof, or a solvate thereof, with tire 5-metalated-l -methylimidazole reagent provides a Compound 3N mixture, and the-115-NAI-5007198252vlpurifying comprises extracting Compound 3N from the Compound 3N mixture to provide a separated organic layer comprising Compound 3N, and, concentrating the separated organic layer (e.g., under reduced pressure or by distillation, optionally wherein the distillation is performed at a temperature below about 50 °C) to provide a concentrated organic layer comprising Compound 3N, optionally wherein Compound 4N is Compound 4 and Compound 3N is Compound 3.

27. The process of claim 25 or 26, wherein the purifying comprises crystallization, optionally wherein the crystallization is seed crystallization.

28. Tire process of claim 27, wherein the cry stallizing is performed in the presence of a solvent, optionally wherein the solvent is DCM, Et2O, THF, NMP. methyl tert-butyl ether (MTBE), water, or any mixture thereof, optionally wherein the solvent is THF, NMP. MTBE. water, or any mixture thereof.

29. The process of any one of claims 20 to 28, wherein the reacting of Compound 4N, or a salt thereof, or a solvate thereof, and the 5-metalated-l -methylimidazole reagent produces Compound 3N, or a salt thereof, or a solvate thereof,Compound 3NR, in a molar ratio of Compound 3N to Compound 3NR of at least 5: 1, at least 10: 1, at least 15: 1, at least20: 1, at least 30: 1, at least 40: 1, or at least 50: 1; optionally wherein Compound 4N is Compound 4, Compound 3N is Compound 3, and Rcin Compound 3NR is tert-butyl (Compound 3R).

30. The process of any one of claims 20 to 29, wherein Compound 3N (optionally Compound 3), or a salt thereof, or a solvate thereof, is prepared at a diastereomeric excess of at least 95%, at least 99%, at least 99.5%, or at least 99.9%.-116-NAI-5007198252vl31. The process of any one of claims 20 to 30, comprising cyclizing Compound 6N :or a salt thereof, or a solvate thereof, to provide Compound 4N, or a salt thereof, or a solvate thereof; optionally wherein Rcin Compound 6N is tert-buty l (Compound 6), and Compound 4N is Compound 4.

32. The process of claim 31, wherein the cyclizing is perfonned under Mitsunobu conditions.

33. The process of claim 31 or 32, wherein the cy clizing is performed in the presence of an azodicarboxylate reagent and a phosphine reagent, wherein the azodicarboxylate reagent is diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-t-butyl azodicarboxylate, 1,1’- (azocarbonyl)dipiperidine, or dibenzyl azodicarboxylate, and the phosphine reagent is dicyclohexylphenylphosphine, diethylphenylphosphine, tributylphosphine, diphenyl-2 -pyridylphosphine, 4-(dimethylamino)phenyldiphenylphosphine, isopropyldiphenylphosphine, tri-tert-butylphosphine, tri-n- octylphosphine, tricyclohexylphosphine, polystyryldiphenylphosphine, or triphenylphosphine (or substituted variants thereof).

34. The process of claim 31 or 32, wherein the cyclizing is perfonned in tire presence of an azodicarboxylate reagent and a phosphine reagent, wherein the azodicarboxylate reagent is a dialkyl azodicarboxylate, optionally selected from DEAD and DIAD; and the phosphine reagent is a trialkyl- or triarylphosphine, optionally selected from trioctylphosphine and triphenylphosphine.

35. Tire process of any one of claims 31 to 34, comprising deprotecting Compound 7PG / N:optionally wherein Rcis tert-butyl, or a salt thereof, or a solvate thereof, to provide Compound 6N, or a-117-NAI-5007198252vlsalt thereof, or a solvate thereof, wherein each PG is independently a hydroxyl protecting group.

36. The process of claim 35, wherein each PG is a silyl protecting group, optionally wherein the deprotecting is performed in the presence of an acid or a fluoride source, optionally wherein the fluoride source is tetrabutylammonium fluoride.

37. The process of claim 35 or 36, comprising reacting Compound 8PG:wherein each PG is independently a hydroxyl protecting group or a salt thereof, or a solvate thereof, withRC* ^NHS2O to provide Compound 7PG / N, or a salt thereof, or a solvate thereof; wherein Rcis (a) -C(Rd)(Re)(Rf), wherein each of Rd, Re, and Rfis independently Ci-4 alkyl, or (b) phenyl or monocyclic heteroaryl optionally substituted with one or more Ci.4 alkyl substituents, or (c) cycloalkyl optionally substituted with one or more Ci.4 alkyl substituents, optionally wherein Rcis tertbutyl, 2,4,6-trimethylphenyl, (triethyl)methyl, 4-methylphenyl, phenyl, 2,4,6-triisopropylphenyl, or 2- methylbutan-2-yl, optionally wherein Rcis tert-butyl ((.S)-tcrt-butylsiilfinamide): optionally wherein Rcis tert-butyl and each PG is TBDMS (with both options as Compound 7).

38. The process of claim 37, wherein the reaction is performed in the presence of an acid, optionally wherein the acid is Ti(OEt)4, Ti(OiPr)4, TiCL, CuSC>4, MgSCL. MgCL. BF3’OEt2, pyridinium p- toluenesulfonate, p-toluenesulfonic acid, HBF4, H2SO4, HC1, molecular sieves, acidic cation exchange resin (e.g., Amberlyst), I2, (CFsSOs^Tb, CF3SO3H, HCIO4, H3PO4, (CFE^Al, or (octyl^Al, or wherein the acid is a Lewis acid, optionally wherein the Lewis acid is Ti(OEt)4.

39. The process of any one of claims 35 to 38, wherein each PG is independently a silyl protecting group; optionally wherein each PG is independently tert-butyldimethylsilyl (TBDMS), tri-isopropylsilyl (TIPS), trimethylsilyl (TMS), triethylsilyl (TES), isopropyldimethylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), or tert-butyldiphenylsilyl (TBDPS); optionally wherein both PG groups are tert- butyldimethylsilyl (TBDMS).-118-NAI-5007198252vlor a stereoisomer, salt, solvate, tautomer, or isotopologue thereof;-119-NAI-5007198252vlwherein Rcis (a) -C(Rd)(Re)(Rf), wherein each of Rd, Re, and Rfis independently Ci .4 alkyl, or (b) phenyl or monocyclic heteroaryl optionally substituted with one or more Ci.4 alkyl substituents, or (c) cycloalkyl optionally substituted with one or more Ci -4 alkyl substituents, optionally wherein Rcis tertbutyl, 2,4,6-trimethylphenyl, (triethyl)methyl, 4-methylphenyl, phenyl, 2,4,6-triisopropylphenyl, or 2- methylbutan-2-yl, optionally wherein Rcis tert-butyl; and each PG is independently a hydroxyl protecting group.

41. The compound of claim 40, wherein the compound has an enantiomeric excess or diastereomeric excess at the chiral carbon atom and / or at the sulfur atom of at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%.

42. A pharmaceutical composition comprising: i) a solid form comprising Compound 1 :Compound 1 or a pharmaceutically acceptable salt and / or solvate thereof, in an amount of from about 1 mg to about 10 mg, or about 3 mg to about 8 mg free base equivalent, and ii) one or more phannaccutically acceptable excipients.

43. The pharmaceutical composition of claim 42, wherein the solid form is a free base of Compound 1, or a solvate thereof.

44. Tire pharmaceutical composition of claim 43, wherein the solid form is a crystalline form of free base, hemi-hydrate of Compound 1.

45. The pharmaceutical composition of any one of claim 42 to 44, wherein the solid fonn is characterized by an XRPD pattern comprising peaks at approximately 9.0, 12.8, 16.6, and 18.4° 29, when measured using Cu Ka radiation.-120-NAI-5007198252vl46. The pharmaceutical composition of any one of claim 42 to 45, wherein the solid form is Form 1 of Compound 1.

47. The pharmaceutical composition of any one of claim 42 to 46, wherein the solid form comprisesor a pharmaceutically acceptable salt or solvate thereof; optionally wherein the total % w / w of XI, X2, X3, X4, X5, and X6 present in tire solid form is between0.05 % w / w and 3.0 % w / w.

48. The pharmaceutical composition of any one of claims 42 to 47, wherein the solid form has a D90 of less than 50 pm, between 10 pm and 50 pm, between 1 pm and 20 pm, between 1 pm and 15 pm, between 1 pm and 10 pm, between 5 pm and 20 pm, between 5 pm and 15 pm, less than 20 pm, less than 15 pm, or less than 10 pm.

49. The pharmaceutical composition of any one of claims 42 to 48, wherein the one or more pharmaceutically acceptable excipients comprises one or more fdler, glidant, disintegrant, lubricant, or binder, or a combinations thereof.

50. The pharmaceutical composition of any one of claims 42 to 49, wherein the pharmaceutical composition comprises a fdler.-121-NAI-5007198252vl51. The pharmaceutical composition of claim 50, wherein the filler is silicified microcrystalline cellulose (SMCC), microcrystallinc cellulose (MCC), D-mannitol, or a combination thereof; optionally wherein the SMCC has a grade of 50, 50 LD, 90, 90 HD, or 90 LM, or a combination thereof.

52. The pharmaceutical composition of claim 50, wherein the filler is microcrystalline cellulose; optionally wherein the microcrystalline cellulose has a grade of 101, 102, 105, 301, 302, or 200. or a combination thereof.

53. Tire pharmaceutical composition of any one of claims 49 to 52, wherein tire filler is present in an amount of from about 70 to about 95 % w / w, from about 80 to about 95 % w / w, about 92.5% w / w, about 92 % w / w, about 90.5 % w / w, or about 90 % w / w to about 93 % w / w, or about 90 % w / w, 90.5 % w / w, 91 % w / w, 91.5 % w / w. 92 % w / w, or 92.5 % w / w.

54. The pharmaceutical composition of any one of claims 42 to 53, wherein tire pharmaceutical composition comprises a glidant.

55. The pharmaceutical composition of claim 54, wherein the glidant is colloidal silicon dioxide.

56. The pharmaceutical composition of claim 54 or 55, wherein the glidant is present in an amount of from about 0.5 % w / w to about 5 % w / w, or about 1.0 % w / w.

57. The pharmaceutical composition of any one of claims 42 to 56, wherein the pharmaceutical composition comprises a disintegrant.

58. The pharmaceutical composition of claim 57, wherein the disintegrant is croscarmellose sodium.

59. Tire pharmaceutical composition of claim 57 or 58, wherein the disintegrant is present in an amount of from about 1 % w / w to about 6 % w / w, or about 3.0 % w / w.

60. The pharmaceutical composition of any one of claims 42 to 59, wherein the pharmaceutical composition comprises a lubricant.

61. Tire pharmaceutical composition of claim 60, wherein the lubricant is magnesium stearate.-122-NAI-5007198252vl62. The pharmaceutical composition of claim 60 or 61, wherein the lubricant is present in an amount of from about 0.5 % w / w to about 2.5 % w / w, about 1 .5 % w / w, or about 1 % w / w.

63. Tire pharmaceutical composition of any one of claims 42 to 62, wherein tire pharmaceutical composition comprises a binder, optionally wherein the binder is povidone.

64. The pharmaceutical composition of any one of claims 42 to 63, wherein the amount of Compound 1 is about 3 mg free base equivalent.

65. Tire pharmaceutical composition of any one of claims 42 to 63, wherein tire amount of Compound 1 is about 5 mg free base equivalent.

66. The pharmaceutical composition of any one of claims 42 to 63, wherein the amount of Compound 1 is about 8 mg free base equivalent.

67. The pharmaceutical composition of any one of claims 42 to 66, comprising:(i) about 1 % w / w to about 5 % w / w of Compound 1 free base equivalent: about 90 % w / w to about 95 % w / w silicified microcrystalline cellulose or microcrystalline cellulose: about 0.5 % w / w to about 1.5 % w / w colloidal silicon dioxide; about 2 % w / w to about 4 % w / w croscarmellose sodium: and about 1 % w / w to about 2 % w / w magnesium stearate;(ii) about 2 % w / w of Compound 1 free base equivalent; about 92 % w / w to about 93 % w / w, or about 92.5 % w / w, or about 93 % w / w silicified microcrystalline cellulose or microcrystallinc cellulose; about 1 % w / w colloidal silicon dioxide; about 3 % w / w croscarmellose sodium; and about 1.0 % w / w to about 1.5 % w / w, or about 1.0 % w / w. or about 1.5 % w / w magnesium stearate:(iii) about 2.5 % w / w of Compound 1 free base equivalent; about 92 % w / w to about 93 % w / w, or about 92 % w / w, or about 92.5 % w / w silicified microcrystalline cellulose or microcrystalline cellulose; about 1 % w / w colloidal silicon dioxide; about 3 % w / w croscarmellose sodium; and about 1.0 % w / w to about 1.5 % w / w, or about 1.0 % w / w, or about 1.5 % w / w magnesium stearate; or(iv) about 4 % w / w of Compound 1 free base equivalent; about 90 % w / w to about 91 % w / w, or about 90.5 % w / w, or about 91 % w / w silicified microcrystalline cellulose or microcrystalline cellulose: about 1 % w / w colloidal silicon dioxide; about 3 % w / w croscarmellose sodium: and about 1.0 % w / w to about 1.5 % w / w, or about 1.0 % w / w, or about 1.5 % w / w magnesium stearate.

68. The pharmaceutical composition of any one of claims 42 to 67, comprising:-123-NAI-5007198252vl(i) about 3 mg Compound 1 free base equivalent; about 138 mg to about 140 mg, or about 138.75 mg, or about 139.5 mg silicified microcrystalline cellulose or microcrystalline cellulose; about 1.5 mg colloidal silicon dioxide; about 4.5 mg croscarmellose sodium; and about 1.5 mg to about 2.25 mg, or about 1.5 mg, or about 2.25 mg magnesium stearate;(ii) about 5 mg Compound 1 free base equivalent; about 184 mg to about 185 mg. or about 184 mg, or about 185 mg silicified microcrystalline cellulose or microcrystalline cellulose; about 2 mg colloidal silicon dioxide: about 6 mg croscarmellose sodium: and about 2 mg to about 3 mg, or about 2 mg, or about 3 mg magnesium stearate; or(iii) about 8 mg Compound 1 free base equivalent; about 181 mg to about 182 mg, or about 181 mg, or about 182 mg silicified microcrystalline cellulose or microcrystalline cellulose; about 2 mg colloidal silicon dioxide; about 6 mg croscarmellose sodium; and about 2 mg to about 3 mg, or about 2 mg, or about 3 mg magnesium stearate.

69. The pharmaceutical composition of any one of claims 42 to 68, wherein tire pharmaceutical composition is in the form of a tablet, a compressed tablet, or a coated tablet.

70. A tablet, comprising:(i) a tablet core, comprising:(a) a solid form comprising Compound 1:Compound 1 or a pharmaceutically acceptable salt and / or solvate thereof in an amount of from about 1 mg to about 10 mg, or about 3 mg to about 8 mg free base equivalent, and(b) one or more pharmaceutically acceptable excipients; and(ii) a tablet coating.

71. The tablet of claim 70, wherein the tablet core has a total weight of about 150 mg or about 200 mg.-124-NAI-5007198252vl72. The tablet of claim 70 or 71, wherein the tablet coating comprises one or more Opadry II of different colors (e.g., pigments), optionally the tablet comprises Opadry II white, Opadry II yellow, Opadry II blue, or Opadry II pink, Opadry black, or a combination thereof.

73. The tablet of any one of claims 70 to 72, wherein the tablet coating comprises one or more polymers, plasticizers, and pigments; or wherein the coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

74. A method of preparing the pharmaceutical composition of any one of claims 42 to 69 or the tablet of any one of claims 70 to 73, comprising:(i) optionally, micronizing a solid form of the Compound 1, or pharmaceutically acceptable salt and / or solvate thereof;(ii) optionally, de-lumping the solid form of the Compound 1 , or pharmaceutically acceptable salt and / or solvate thereof;(iii) mixing the solid form of the Compound 1, or pharmaceutically acceptable salt and / or solvate thereof, with a disintegrant, a glidant, and a first portion of a filler to fonn a first blend;(iv) de-lumping the first blend to form a de-lumped first blend;(v) de-lumping a second portion of the filler;(vi) blending the de-lumped first blend and the de-lumped second portion of the filler to form a second blend;(vii) blending the second blend with a lubricant to form a lubricated blend; and(viii) compressing the lubricated blend, optionally with a rotary press, into a tablet.

75. The method of claim 74, wherein the micronization in step (i) uses jet milling or wet milling, optionally wherein the micronized solid form of step (i) has a D90 of less than 50 pm, between 10 pm and 50 pm, between 1 pm and 20 pm, between 1 pm and 15 pm, between 1 pm and 10 pm, between 5 pm and 20 pm, betw een 5 pm and 15 pm, less than 20 pm, less than 15 pm, or less than 10 pm.

76. The method of claim 74, wherein the method does not comprise step (i), optionally wherein the solid form has a D90 of less than 50 pm, between 10 pm and 50 pm, between 1 pm and 20 pm, between 1 pm and 15 pm, between 1 pm and 10 pm, between 5 pm and 20 pm, between 5 pm and 15 pm, less than 20 pm, less than 15 pm, or less than 10 pm.

77. The method of any one of claims 74 to 76, comprising (ix) coating the compressed tablet.-125-NAI-5007198252vl78. The method of any one of claims 74 to 77, comprising (x) packaging the film coated tablets into a container.

79. A method of treating cancer, such as a solid tumor or a cancer dependent on a famesylated protein in a subject, comprising administering the pharmaceutical composition of any one of claims 42 to 69 or the tablet of any one of claims 70 to 73, to the subject , optionally wherein the subject is human.

80. Tire method of claim 79, wherein the cancer is a cancer dependent on famesylated H-Ras protein, optionally wherein the cancer has an HRAS mutation, optionally wherein the HRAS mutation is or comprises a modification at a specific position selected from G12. G13, Q61, Q22, KI 17, A146, and any combination thereof, optionally wherein the mutated amino acids are encoded by a modified codon in the HRAS gene; optionally wherein the presence or absence of the HRAS mutation has been determined by analysis of nucleic acids obtained from a sample from the subject, optionally wherein the sample is a tissue biopsy or is a tumor biopsy, optionally wherein the HRAS mutation has been determined by sequencing, Polymerase Chain Reaction (PCR), DNA microarray. Mass Spectrometry (MS), Single Nucleotide Polymorphism (SNP) assay, denaturing high-performance liquid chromatography (DHPLC), or Restriction Fragment Length Polymorphism (RFLP) assay.

81. Tire method of claim 79 or 80, wherein the cancer is thyroid cancer, head and neck cancer, urothelial cancer, salivary cancer, cancer of the upper digestive tract, bladder cancer, breast cancer, ovarian cancer, brain cancer, gastric cancer, prostate cancer, lung cancer, colon cancer, skin cancer, liver cancer, endometrial cancer, or pancreatic cancer.

82. The method of any one of claims 79 to 81, wherein the cancer is head and neck cancer, optionally wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC), optionally wherein the HNSCC is HRAS-mutant HNSCC; or optionally wherein the HNSCC or HRAS-mutant HNSCC is HNSCC of the trachea, HNSCC of the maxilla, HSNCC of the salivary gland, or HNSCC of the oral cavity; or optionally wherein the HNSCC or HRAS-mutant HNSCC is relapsed, refractory, metastatic, or advanced, or a combination thereof.

83. The method of any one of claims 79 to 82, comprising administering to the subject one or more-126-NAI-5007198252vlsecond active agents, optionally wherein the one or more second active agents comprises one or more of a tyrosine kinase inhibitor, a vascular endothelial growth factor receptor (VEGFR) inhibitor, an EGFR-TKI inhibitor, a PI3K inhibitor, a KRAS inhibitor, and / or pan-RAS inhibitor.-127-NAI-5007198252vl

Images