EP4669309A1 - Formulations solides et formes polymorphes d'inhibiteurs d'indoline de kif18a - Google Patents

Formulations solides et formes polymorphes d'inhibiteurs d'indoline de kif18a

Info

Publication number
EP4669309A1
EP4669309A1 EP24715930.4A EP24715930A EP4669309A1 EP 4669309 A1 EP4669309 A1 EP 4669309A1 EP 24715930 A EP24715930 A EP 24715930A EP 4669309 A1 EP4669309 A1 EP 4669309A1
Authority
EP
European Patent Office
Prior art keywords
crystalline form
formula
compound
formulation
determined
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24715930.4A
Other languages
German (de)
English (en)
Inventor
Derek A. Cogan
Michael Su
Scott DRUTMAN
Jianmin Mao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Volastra Therapeutics Inc
Original Assignee
Volastra Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Volastra Therapeutics Inc filed Critical Volastra Therapeutics Inc
Publication of EP4669309A1 publication Critical patent/EP4669309A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • KIF18A is a kinesin involved in assisting kinetochore-microtubule (kt-MT) attachment and chromosomal alignment during cell mitosis. Its cargo domain binds directly to protein phosphatase 1 (PP1) and carries it to the plus end of MT where PP1 dephosphorylates Hec1, a kinetochore complex component, further enhancing kt-MT attachment throughout metaphase and anaphase.
  • PP1 protein phosphatase 1
  • MT-binding motor domain has ATPase activity that powers KIF18A translocation along the MT lattice, enhanced by its C-terminal MT-binding site, and caps and depolymerizes the growing microtubule at the plus end, thus dampening MT dynamics.
  • This modulation of MT dynamics by KIF18A often occurs at the following (or trailing) sister chromatid, thereby providing a counterbalancing tension to the leading sister chromatid movement catalyzed by another kinesin Kif2C/MCAK.
  • KIF18A Loss of KIF18A function causes defective kt-MT attachments and loss of tension within the spindle in cells of high chromosome instability (CIN), leading to hyper stable, longer and multipolar spindles, mitotic arrest, centrosome fragmentation and spindle assembly checkpoint activation or cell death.
  • KIF18A is identified from DEPMAP RNAi data re-analysis as one of the top candidates essential for CIN-high cells.
  • Reported synthetic lethality screens also singled out KIF18A as a potential anticancer target whose knockdown preferentially renders CIN-high (but not CIN-low) aneuploid and whole-genome doubled cells vulnerable to death.
  • provided herein is a crystalline form of a compound of Formula (A-1): or a pharmaceutically acceptable salt thereof.
  • a method of inhibiting KIF18A comprising contacting a cell with an effective amount of (i) a formulation described herein, or (ii) a crystalline form of as described herein.
  • provided herein is a method of treating a disease or condition mediated by KIF18A in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (i) a formulation described herein, or (ii) a crystalline form of described herein.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of (i) a formulation described herein, or (ii) a crystalline form described herein.
  • a method of preparing the formulation described herein comprises spray-drying a solution of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, and a polymer to obtain an amorphous solid dispersion of the compound of Formula (A), or a pharmaceutically acceptable salt thereof.
  • a method of preparing the crystalline form described herein comprising forming a mixture of the compound of Formula (A), or a pharmaceutically acceptable salt thereof, and a solvent selected from the group consisting of acetone, isobutyl acetate, water, acetone nitrile, 1-butanol, dimethylacetamide, N,N- dimethylformamide, nitromethane, toluene, dimethyl sulfoxide, dioxane, cyclopentyl methyl ether, tert-amyl methyl ether, 2-ethoxyethanol, ethyl acetate, ethanol, hexafluoroisopropanol, diisopropyl ether, methyl ethyl ketone, hexane, methanol, 2-methyltetrahydrofuran, N- methyl-2-pyrrolidone, 2,2,2-trifluoroethanol, 1-propanol, iso
  • FIGS. 1A-1H show SEM micrographs of eight different SDDs captured at 5000 ⁇ magnification.
  • FIGS. 1A-1H show SEM micrographs of eight different SDDs captured at 5000 ⁇ magnification.
  • FIG. 2 shows the XRPD pattern of polymorphic Form A of compound of Formula (A-1).
  • FIG. 3 shows TGA and DSC thermograms of the polymorphic Form A of compound of Formula (A-1). Top: TGA; bottom: DSC.
  • FIG. 4 shows DVS isothermal plots of the polymorphic Form A of compound of Formula (A-1). The trace with diamonds is the sorption trace, and the trace with squares is the desorption trace.
  • FIG. 5 shows the XRPD pattern of the polymorphic Form C of compound of Formula (A-1), prepared by two methods. From top to bottom: polymorphic Form C prepared by slurring a gel from DMF in H 2 O, polymorphic Form C prepared by adding H 2 O to a DMF solution to obtain participates, and polymorphic Form A for reference.
  • FIG. 6 shows TGA thermogram of the polymorphic Form C of compound of Formula (A-1).
  • FIG. 7 shows TMDSC thermogram of the polymorphic Form C of compound of Formula (A-1).
  • FIG. 8 shows DVS isothermal plots of the polymorphic Form C of compound of Formula (A-1). The trace with diamonds is the sorption trace, and the trace with squares is the desorption trace.
  • FIGS. 9A-9E show graphs of tumor volume of vehicle- and compound-treated mice plotted as a function of time after start of treatment. [0025] FIG.
  • FIG. 9A shows Compound of Formula (A-2) (10 mg/kg BID, 30 mg/kg BID, 60 mg/kg BID) treatment of HCC15 implanted SCID Beige mice. Trace with circle: vehicle. Trace with square: Compound of Formula (A-2) at 10mg/kg BID, PO. Trace with triangle: Compound of Formula (A-2) at 30mg/kg BID, PO. Trace with flipped triangle: Compound of Formula (A-2) at 60 mg/kg BID, PO. [0026]
  • FIG. 9B shows Compound of Formula (A-2) (10 mg/kg QD, 30 mg/kg QD, 60 mg/kg QD) treatment of OVCAR-3 implanted Balb/C nude mice. Trace with circle: vehicle.
  • FIG. 9C shows Compound of Formula (A-1) (10 mg/kg BID, 30 mg/kg BID, 60 mg/kg BID) treatment of HCC15 implanted SCID Beige mice. Trace with circle: vehicle. Trace with square: Compound of Formula (A-1) at 10mg/kg BID, PO. Trace with triangle: Compound of Formula (A-1) at 30mg/kg BID, PO.
  • FIG. 9D shows Compound of Formula (A-1) (10 mg/kg BID, 30 mg/kg BID, 60 mg/kg BID) treatment of OVCAR-3 implanted Balb/C nude mice. Trace with circle: vehicle. Trace with square: Compound of Formula (A-1) at 10mg/kg BID, PO. Trace with triangle: Compound of Formula (A-1) at 30mg/kg BID, PO. Trace with flipped triangle: Compound of Formula (A-1) at 60 mg/kg BID, PO. [0029] FIG.
  • FIG. 10 shows XRPD pattern of polymorphic Form B of compound of Formula (A- 1).
  • FIG. 11 shows DSC thermogram of polymorphic Form B of compound of Formula (A-1).
  • FIG. 12 shows TGA thermogram of polymorphic Form B of compound of Formula (A-1).
  • FIG. 13 show DVS isothermal plots of polymorphic Form B of compound of Formula (A-1).
  • FIG. 14 shows XRPD pattern of polymorphic Form IV of mono-sodium salt of compound of Formula (A-1).
  • FIG. 15 shows DSC thermogram of polymorphic Form IV of mono-sodium salt of compound of Formula (A-1).
  • FIG. 16 shows TGA thermogram of polymorphic Form IV of mono-sodium salt of compound of Formula (A-1).
  • FIG. 17 shows XRPD pattern of polymorphic Form V of di-sodium salt of compound of Formula (A-1). [0038] FIG.
  • FIG. 18 shows DSC thermogram of polymorphic Form V of di-sodium salt of compound of Formula (A-1).
  • FIG. 19 shows TGA thermogram of polymorphic Form V of di-sodium salt of compound of Formula (A-1).
  • FIG. 20 shows XRPD pattern of polymorphic Form VI of mono-potassium salt of compound of Formula (A-1).
  • FIG. 21 shows DSC thermogram of polymorphic Form VI of mono-potassium salt of compound of Formula (A-1).
  • FIG. 22 shows TGA thermogram of polymorphic Form VI of mono-potassium salt of compound of Formula (A-1). [0043] FIG.
  • FIG. 23 shows XRPD pattern of polymorphic Form VII of di-potassium salt of compound of Formula (A-1).
  • FIG. 24 shows DSC thermogram of polymorphic Form VII of di-potassium salt of compound of Formula (A-1).
  • FIG. 25 shows TGA thermogram of polymorphic Form VII of di-potassium salt of compound of Formula (A-1).
  • FIG. 26 shows XRPD pattern of polymorphic Form VIII of di-sodium salt of compound of Formula (A-1).
  • FIG. 27 shows DSC thermogram of polymorphic Form VIII of di-sodium salt of compound of Formula (A-1).
  • FIG. 24 shows DSC thermogram of polymorphic Form VII of di-potassium salt of compound of Formula (A-1).
  • FIG. 28 shows TGA thermogram of polymorphic Form VIII of di-sodium salt of compound of Formula (A-1).
  • FIG. 29 shows one exemplary XRPD pattern of polymorphic Form IX of di- potassium salt of compound of Formula (A-1).
  • FIG. 30 shows one exemplary DSC thermogram of polymorphic Form IX of di- potassium salt of compound of Formula (A-1).
  • FIG. 31 shows one exemplary TGA thermogram of polymorphic Form IX of di- potassium salt of compound of Formula (A-1).
  • FIG. 32 shows one exemplary XRPD pattern of polymorphic Form X of di-sodium salt of compound of Formula (A-1).
  • FIG. 29 shows one exemplary XRPD pattern of polymorphic Form IX of di- potassium salt of compound of Formula (A-1).
  • FIG. 30 shows one exemplary DSC thermogram of polymorphic Form IX of di- potassium salt of compound of Formula (A-1).
  • FIG. 31 shows one exemplary TGA thermogram of polymorphic Form IX of di
  • FIG. 33 shows one exemplary DSC thermogram of polymorphic Form X of di- sodium salt of compound of Formula (A-1).
  • FIG. 34 shows one exemplary TGA thermogram of polymorphic Form X of di- sodium salt of compound of Formula (A-1).
  • FIG. 35 shows XRPD pattern of polymorphic Form XI of compound of di-sodium salt of Formula (A-1).
  • FIG. 36 shows DSC thermogram of polymorphic Form XI of compound of di-sodium salt of Formula (A-1).
  • FIG. 37 shows TGA thermogram of polymorphic Form XI of compound of di-sodium salt of Formula (A-1).
  • FIG. 34 shows one exemplary DSC thermogram of polymorphic Form X of di- sodium salt of Formula (A-1).
  • FIG. 38 shows XRPD pattern of polymorphic Form XII of compound of mono- sodium salt of Formula (A-1).
  • FIG. 39 shows DSC thermogram of polymorphic Form XII of compound of mono- sodium salt of Formula (A-1).
  • FIG. 40 shows TGA thermogram of polymorphic Form XII of compound of mono- sodium salt of Formula (A-1).
  • FIG. 41 shows another exemplary XRPD pattern of polymorphic Form X of di- sodium salt of compound of Formula (A-1).
  • FIG. 42 shows another exemplary DSC thermogram of polymorphic Form X of di- sodium salt of compound of Formula (A-1).
  • FIG. 43 shows another exemplary TGA thermogram of polymorphic Form X of di- sodium salt of compound of Formula (A-1).
  • FIG. 44 shows another exemplary DVS isothermal plot of polymorphic Form X of di- sodium salt of compound of Formula (A-1).
  • FIG. 45 shows another exemplary XRPD pattern of polymorphic Form IX of di- potassium salt of compound of Formula (A-1).
  • FIG. 46 shows another exemplary DSC thermogram of polymorphic Form IX of di- potassium salt of compound of Formula (A-1).
  • FIG. 47 shows another exemplary TGA thermogram of polymorphic Form IX of di- potassium salt of compound of Formula (A-1).
  • FIG. 44 shows another exemplary TGA thermogram of polymorphic Form IX of di- potassium salt of compound of Formula (A-1).
  • FIG. 48 shows another exemplary DVS isothermal plot of polymorphic Form IX of di-potassium salt of compound of Formula (A-1).
  • FIG. 49 shows XRPD pattern of polymorphic Form XIII of mono-sodium salt of compound of Formula (A-1).
  • FIG. 50 shows DSC thermogram of polymorphic Form XIII of mono-sodium salt of compound of Formula (A-1).
  • FIG. 51 shows TGA thermogram of polymorphic Form XIII of mono-sodium salt of compound of Formula (A-1).
  • DETAILED DESCRIPTION [0072] The following description is presented to enable a person of ordinary skill in the art to make and use the various embodiments. Descriptions of specific devices, techniques, and applications are provided only as examples.
  • references to a compound of Formula (A), Formula (A-1), Formula (A-2), or Formula (A-3) include all subgroups defined herein, such as Formula (B), (C), (A-1), (A-2), or (A-3), including all substructures, subgenera, preferences, embodiments, examples and particular compounds defined and/or described herein.
  • references to a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3) and subgroups thereof include ionic forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes and/or protected forms thereof.
  • references to a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3) and subgroups thereof include isomers, tautomers and/or oxides thereof.
  • references to a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3) and subgroups thereof include solvates thereof.
  • “Alkyl” encompasses straight and branched carbon chains having the indicated number of carbon atoms, for example, from 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 3 carbon atoms.
  • C 1-6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms.
  • alkyl residue having a specific number of carbons When an alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; thus, for example, “propyl” includes n- propyl and isopropyl; and “butyl” includes n-butyl, sec-butyl, isobutyl and t-butyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec- butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
  • a range of values e.g., C 1-6 alkyl
  • each value within the range as well as all intervening ranges are included.
  • C 1-6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 5-6 , C 1-5 , C 2-5 , C 3-5 , C 4-5 , C 1-4 , C 2-4 , C 3-4 , C 1-3 , C 2-3 , and C 1-2 alkyl.
  • Alkenyl refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond.
  • Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2- yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl).
  • propenyl e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2- yl
  • butenyl e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-
  • Alkynyl refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond.
  • Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl) and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3- yn-1-yl).
  • Cycloalkyl indicates a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, for example, 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms.
  • Cycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as bridged and caged ring groups (e.g., norbornane, bicyclo[2.2.2]octane).
  • one ring of a polycyclic cycloalkyl group may be aromatic, provided the polycyclic cycloalkyl group is bound to the parent structure via a non-aromatic carbon.
  • a 1,2,3,4-tetrahydronaphthalen-1-yl group (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group
  • 1,2,3,4-tetrahydronaphthalen-5- yl is not considered a cycloalkyl group.
  • Cycloalkenyl indicates a non-aromatic carbocyclic ring, containing the indicated number of carbon atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms) and at least one carbon-carbon double bond. Cycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
  • cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl, as well as bridged and caged ring groups (e.g., bicyclo[2.2.2]octene).
  • one ring of a polycyclic cycloalkenyl group may be aromatic, provided the polycyclic alkenyl group is bound to the parent structure via a non- aromatic carbon atom.
  • inden-1-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is considered a cycloalkenyl group
  • inden-4- yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkenyl group
  • polycyclic cycloalkenyl groups consisting of a cycloalkenyl group fused to an aromatic ring are described below.
  • Aryl indicates an aromatic carbocyclic ring having the indicated number of carbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms.
  • Aryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
  • both rings of a polycyclic aryl group are aromatic (e.g., naphthyl).
  • polycyclic aryl groups may include a non- aromatic ring fused to an aromatic ring, provided the polycyclic aryl group is bound to the parent structure via an atom in the aromatic ring.
  • a 1,2,3,4-tetrahydronaphthalen-5-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group
  • 1,2,3,4-tetrahydronaphthalen-1-yl is not considered an aryl group.
  • aryl does not encompass or overlap with “heteroaryl”, as defined herein, regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some instances, aryl is phenyl or naphthyl.
  • aryl is phenyl. Additional examples of aryl groups comprising an aromatic carbon ring fused to a non-aromatic ring are described below.
  • “Heteroaryl” indicates an aromatic ring containing the indicated number of atoms (e.g., 5 to 12, or 5 to 10 membered heteroaryl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon. Heteroaryl groups do not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2.
  • the total number of S and O atoms in the heteroaryl group is not more than 1.
  • heteroaryl groups may be bound to the parent structure by a carbon or nitrogen atom, as valency permits.
  • pyridyl includes 2-pyridyl, 3- pyridyl and 4-pyridyl groups
  • pyrrolyl includes 1-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl groups.
  • a heteroaryl group is monocyclic.
  • Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4- oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4- thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine) and tetrazine.
  • pyrrole pyrazole
  • imidazole e.g., 1,2,
  • both rings of a polycyclic heteroaryl group are aromatic.
  • examples include indole, isoindole, indazole, benzoimidazole, benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5- b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3- b]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3- c]pyridine
  • polycyclic heteroaryl groups may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided the polycyclic heteroaryl group is bound to the parent structure via an atom in the aromatic ring.
  • a non-aromatic ring e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl
  • a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl group
  • 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group.
  • polycyclic heteroaryl groups consisting of a heteroaryl ring fused to a non- aromatic ring are described below.
  • Heterocycloalkyl indicates a non-aromatic, fully saturated ring having the indicated number of atoms (e.g., 3- to 10-, or 3- to 7-, membered heterocycloalkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon.
  • Heterocycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
  • heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide.
  • one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocycloalkyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom.
  • a 1,2,3,4- tetrahydroquinolin-1-yl group (wherein the moiety is bound to the parent structure via a non- aromatic nitrogen atom) is considered a heterocycloalkyl group
  • 1,2,3,4- tetrahydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkyl group.
  • polycyclic heterocycloalkyl groups consisting of a heterocycloalkyl group fused to an aromatic ring are described below.
  • Heterocycloalkenyl indicates a non-aromatic ring having the indicated number of atoms (e.g., 3- to 10-, or 3- to 7-, membered heterocycloalkenyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon, and at least one double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms, adjacent nitrogen atoms, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl.
  • Heterocycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
  • heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g., 2,3- dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4- dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1,2,3,4- tetrahydropyridinyl, 1,2,3,6
  • one ring of a polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocycloalkenyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom.
  • a 1,2-dihydroquinolin-1-yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group
  • 1,2-dihydroquinolin-8-yl group is not considered a heterocycloalkenyl group.
  • polycyclic heterocycloalkenyl groups consisting of a heterocycloalkenyl group fused to an aromatic ring are described below.
  • polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3- dihydr
  • Halogen refers to fluoro, chloro, bromo or iodo.
  • Haloalkyl refers to alkyl substituted with one or more halogen.
  • a haloalkyl group may have a halogen substituent at any valence-permitted location on the alkyl and may have any number of halogen substituents ranging from one to the maximum valence-permitted number.
  • haloalkyl groups have 1, 2, or 3 halogen substituents.
  • haloalkyl groups include, but are not limited to, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 CH 2 Cl, -CH 2 CHCl 2 , -CH 2 CCl 3 .
  • compounds disclosed and/or described herein include all possible enantiomers, diastereomers, meso isomers and other stereoisomeric forms, including racemic mixtures, optically pure forms and intermediate mixtures thereof. Enantiomers, diastereomers, meso isomers and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Unless specified otherwise, when the compounds disclosed and/or described herein contain olefinic double bonds or other centers of geometric asymmetry, it is intended that the compounds include both E and Z isomers.
  • Protecting group has the meaning conventionally associated with it in organic synthesis, i.e., 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, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999).
  • a “hydroxy protected form” contains at least one hydroxy group protected with a hydroxy protecting group.
  • amines and other reactive groups may similarly be protected.
  • pharmaceutically acceptable salt refers to a salt of any of the compounds herein which are known to be non-toxic and are commonly used in the pharmaceutical literature.
  • the pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and are not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p- toluenesulfonic acid, stearic acid and salicylic acid.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19).
  • bases compounds see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19.
  • a “solvate” is formed by the interaction of a solvent and a compound.
  • Suitable solvents include, for example, water and alcohols (e.g., ethanol). Solvates include hydrates having any ratio of compound to water, such as monohydrates, dihydrates and hemi-hydrates. [0098]
  • substituted means that the specified group or moiety bears one or more substituents including, but not limited to, substituents such as alkoxy, acyl, acyloxy, alkoxycarbonyl, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl,
  • unsubstituted means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system.
  • a substituted group or moiety bears more than one substituent, it is understood that the substituents may be the same or different from one another.
  • a substituted group or moiety bears from one to five substituents.
  • a substituted group or moiety bears one substituent.
  • a substituted group or moiety bears two substituents.
  • a substituted group or moiety bears three substituents.
  • a substituted group or moiety bears four substituents. In some embodiments, a substituted group or moiety bears five substituents.
  • “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and/or inherently unstable.
  • the disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.
  • the compounds disclosed and/or described herein can be enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • the compound contains at least one deuterium atom.
  • deuterated forms can be made, for example, by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds may improve the efficacy and increase the duration of action of compounds disclosed and/or described herein.
  • Deuterium substituted compounds can be synthesized using various methods, such as those described in: Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” 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 pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
  • polymorph As used herein, the terms “polymorph”, “polymorphic”, “polymorphic form”, or “crystalline form”, which are used interchangeably, refer to polymorphic form of a compound. The polymorphic form can be crystalline or amorphous.
  • Different polymorphs may have different physical properties such as, for example, melting temperatures, heats of fusion, solubilities, dissolution rates, and/or vibrational spectra as a result of the 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, 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), mechanical changes (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph), or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity).
  • 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
  • mechanical changes e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph
  • both e.g., tablets of one polymorph are more susceptible to breakdown at high humidity.
  • solubility/dissolution differences in the extreme case, some polymorphic transitions may result in lack of potency or, at the other extreme, toxicity.
  • the physical properties of a crystalline form 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 (e.g., particle shape and size distribution might be different between polymorphs).
  • the term “substantially as shown in” when referring, for example, to an XRPD pattern, a DSC graph, a TGA graph, or a GVS graph includes a pattern or graph that is not necessarily identical to those depicted herein, but that falls within the limits of experimental error or deviations when considered by one of ordinary skill in the art.
  • the term “substantially free of” means that the composition comprising the crystalline form contains less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% by weight of the indicated substance or substances.
  • the terms “patient”, “individual”, and “subject” refer to an animal, such as a mammal, bird, or fish. In some embodiments, the patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows and humans.
  • the patient, individual, or subject is a human, for example a human that has been or will be the object of treatment, observation or experiment.
  • the compounds, compositions and methods described herein can be useful in both human therapy and veterinary applications.
  • the term “therapeutically effective amount” or “effective amount” refers to that amount of a compound disclosed and/or described herein that is sufficient to affect treatment, as defined herein, when administered to a patient in need of such treatment.
  • a therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation (e.g., inhibition) of KIF18a.
  • the therapeutically effective amount will vary depending upon, for example, the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound, the dosing regimen to be followed, timing of administration, the manner of administration, all of which can readily be determined by one of ordinary skill in the art.
  • the therapeutically effective amount may be ascertained experimentally, for example by assaying blood concentration of the chemical entity, or theoretically, by calculating bioavailability.
  • Treatment includes one or more of: inhibiting a disease or disorder; slowing or arresting the development of clinical symptoms of a disease or disorder; and/or relieving a disease or disorder (i.e., causing relief from or regression of clinical symptoms).
  • the term covers both complete and partial reduction of the condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder.
  • compounds described and/or disclosed herein may prevent an existing disease or disorder from worsening, assist in the management of the disease or disorder, or reduce or eliminate the disease or disorder.
  • Solid Formulations II-a Indoline inhibitors of KIF18A
  • a solid pharmaceutical formulation comprising a compound of Formula (A), as described herein, or a pharmaceutically acceptable salt thereof.
  • Any compound described herein may also be referred to as a drug or active pharmaceutical ingredient (API).
  • ring A is C 6-14 aryl or 5- to 12-membered heteroaryl, each optionally substituted as defined above or below. In some embodiments, ring A is optionally substituted C 6-14 aryl. In some embodiments, ring A is phenyl optionally substituted as defined above or below. In some embodiments, ring A is 5- to 12-membered heteroaryl optionally substituted as defined above or below. In some embodiments, ring A is 6-membered heteroaryl optionally substituted as defined above or below. In some embodiments, ring A is 5-membered heteroaryl optionally substituted as defined above or below.
  • ring A is indolyl, indazolyl, pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl, each optionally substituted as defined above or below. In some embodiments, ring A is thiophenyl optionally substituted as defined above or below.
  • R a14 and R a15 are each independently hydrogen or C 1-6 alkyl. In some embodiments, R a14 is hydrogen and R a15 is butyl. In some embodiments, R a15 is tert-butyl. [0114] In some embodiments of Formula (A), or a pharmaceutically acceptable salt thereof, ring B is C 5-7 cycloalkyl, C 5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon. In some embodiments, ring B is C 5-7 cycloalkyl.
  • ring B is cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, ring B is or , wherein * denotes the point of attachment to the rest of Formula (A). In some embodiments, ring B is C 5-7 cycloalkenyl. In some embodiments, ring B is cyclopentenyl, cyclohexenyl, or cycloheptenyl. In some embodiments, ring B is , wherein * denotes the point of attachment to the rest of Formula (A). In some embodiments, ring B is , wherein * denotes the point of attachment to the rest of Formula (A).
  • ring B is 5- to 7-membered heterocycloalkyl. In some embodiments, ring B is 5- to 7-membered heterocycloalkyl wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon. In some embodiments, ring B is tetrahydrofuranyl or 1,3- dioxanyl. In some embodiments, ring B is or , wherein * denotes the point of attachment to the rest of Formula (A).
  • ring B is substituted with two R B groups, wherein the two R B groups are attached to the same carbon atom on ring B and are taken together with the carbon atom to which they are attached to form C3-7 cycloalkyl. In some embodiments, the two R B groups are attached to the same carbon atom on ring B and are taken together with the carbon atom to which they are attached to form a cyclopropyl. [0116] In some embodiments, of Formula (A) is , wherein * denotes the point of attachment to the rest of Formula (A).
  • Y 1 is N or CR C1 ; Y 2 is N or CR C2 ; Y 3 is N or CR C3 ; and Y 4 is N or CR C4 .
  • no more than three of Y 1 , Y 2 , Y 3 , and Y 4 are N.
  • no more than two of Y 1 , Y 2 , Y 3 , and Y 4 are N.
  • no more than one of Y 1 , Y 2 , Y 3 , and Y 4 is N.
  • R c1 -R c15 are each independently hydrogen, C 3-10 cycloalkyl, or C 1-6 alkyl optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of halo and -OH.
  • R C1 , R C3 , and R C4 are each hydrogen, and R C2 is cyano, -OH, - CH 2 OH, bromo, -NO 2 , , , , , , , or .
  • R C1 , R C3 , and R C4 are each hydrogen, and R C2 is [0120]
  • the compound of Formula (A) is a compound of Formula (B): or a pharmaceutically acceptable salt thereof, wherein R a14 , R a15 , ring B, R B , m, and R C2 are as defined for Formula (A) or any variation or embodiment thereof.
  • R C2 is -NR c5 S(O) 2 R c6 .
  • R c5 is hydrogen and R c6 is C 1-6 alkyl.
  • R c5 is hydrogen and R c6 is ethyl.
  • R c5 is hydrogen.
  • R c6 is ethyl.
  • R c6 is methyl.
  • R a14 is hydrogen and R a15 is C 1-6 alkyl.
  • R a14 is hydrogen and R a15 is tert-butyl.
  • R a14 is hydrogen.
  • R a15 is tert-butyl.
  • ring B is , wherein * denotes the point of attachment to the rest of Formula (B).
  • of Formula (B) is .
  • the compound of Formula (A) is a compound of Formula (C): or a pharmaceutically acceptable salt thereof, wherein R a14 , R a15 , and R c6 are as defined for Formula (A) or any variation or embodiment thereof.
  • R a14 is hydrogen and R a15 is C 1-6 alkyl.
  • R a14 is hydrogen and R a15 is tert-butyl.
  • R a14 is hydrogen.
  • R a15 is tert-butyl.
  • R a14 and R a15 are each independently C 3-10 cycloalkyl, C 3-10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, or 3- to 10-membered heterocycloalkenyl.
  • R a14 and R a15 are taken together with the N atom to which they are attached to form a 3- to 10-membered heterocycloalkyl.
  • R c6 is C 1-6 alkyl optionally substituted with one or more halo. In some embodiments, R c6 is unsubstituted C 1-6 alkyl.
  • R c6 is ethyl. In some embodiments, R c6 is methyl.
  • the compound of Formula (A) is a compound of Formula (A-1): [0123]
  • the compound of Formula (A) is a compound of Formula (A-2): [0124]
  • the compound of Formula (A) is a compound of Formula (A-3): [0125]
  • Compounds of Formula (A), particularly a compound of Formula (A-1), Formula (A- 2), and Formula (A-3) as defined herein, are KIF18A inhibitors. However, these compounds are only sparingly soluble in aqueous media.
  • Solid pharmaceutical formulations of the compounds of Formula (A), including Formula (B), Formula (C), Formula (A-1) Formula (A-2), and Formula (A-3) that can significantly improve the pharmaceutical performances of these compounds, such as stability and solubility.
  • Such formulations may beneficially provide improved bioavailability and/or lower manufacturing cost.
  • Challenges to develop such solid pharmaceutical formulations include: 1) increasing solubility; 2) stabilizing the compounds, including reducing moisture sensitivity and potential ambient-temperature degradation, and 3) maintaining high physical stability and avoiding phase separation in a formulation.
  • a solid pharmaceutical formulation comprising a compound of Formula (A), wherein the formulation results in at least 2-fold increase in solubility compared to neat compound of Formula (A).
  • a method of preparing solid pharmaceutical formulations comprising a compound of Formula (A) and a polymer, particularly by a spray drying process.
  • a solid formulation comprising a pharmaceutically acceptable salt of the compound of Formula (A).
  • the pharmaceutically acceptable salt of the compound of Formula (A) retains the biological effectiveness of the compounds described herein.
  • the solid formulation is a spray dried formulation.
  • a solid formulation comprising a pharmaceutically acceptable salt of the compound of Formula (A-1).
  • a spray dried formulation comprising a pharmaceutically acceptable salt of the compound of Formula (A-1).
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is formed with inorganic and/or organic bases.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is derived from reacting the compound of Formula (A-1) with a base comprising NaOH, KOH, Mg(OH) 2 , Ca(OH) 2 , L-arginine, L-lysine, choline, betaine, diethylamine, or any combination thereof.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is derived from reacting the compound of Formula (A-1) with an inorganic base comprising NaOH, KOH, Mg(OH) 2 , Ca(OH) 2 , or any combination thereof.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) comprises a sodium salt, a potassium salt, a magnesium salt, a calcium salt, a zinc salt, or any combination thereof.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is a sodium salt.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is a sodium salt, wherein the stoichiometry between compound of Formula (A-1) and sodium ion is about 1:0.8 to 1:3, such as about any of 1:0.9 to 1:2.7, 1:1 to 1:2.5, 1:1 to 1:2.3, 1:1 to 1:1.5, or 1:2 to 1:2.3.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is a mono-sodium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a di-sodium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a potassium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a potassium salt, wherein the stoichiometry between compound of Formula (A-1) and potassium ion is about 1:0.8 to 1:3, such as about any of 1:0.9 to 1:2.7, 1:1 to 1:2.5, 1:1 to 1:2.3, 1:1 to 1:1.5, or 1:2 to 1:2.3.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is a mono-potassium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a di-potassium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a magnesium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a calcium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a zinc salt.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is derived from reacting the compound of Formula (A-1) with an organic base comprising L-arginine, L-lysine, choline, betaine, diethylamine, or any combination thereof.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) comprises a L-arginine salt, a L-lysine salt, a choline salt, a betaine salt, a diethylamine salt, or any combination thereof.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is a L-arginine salt.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is a L-lysine salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a choline salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a betaine salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a diethylamine salt.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is a sodium salt, wherein the sodium salt is in a polymorphic form selected from the group consisting of polymorphic Form IV, polymorphic Form V, polymorphic Form VIII, polymorphic Form X, polymorphic Form XI, polymorphic Form XII, and any mixture thereof.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is a potassium salt, wherein the potassium salt is in a polymorphic form selected from the group consisting of polymorphic Form VI, polymorphic Form VII, polymorphic Form IX, and any mixture thereof. II-c.
  • compositions [0133]
  • a solid pharmaceutical formulation of a compound of Formula (A) comprising: (i) a compound of Formula (A) or a pharmaceutically acceptable salt or solvate thereof and (ii) a pharmaceutically acceptable polymer.
  • a significant portion of the compound of Formula (A) is in amorphous form.
  • at least 50 wt.% e.g., at least 50 wt.%, at least 60 wt.%, at least 70 wt.%, at least 80 wt.%, or at least 90 wt.% of the compound of Formula (A) or a pharmaceutically acceptable salt or solvate thereof in the solid pharmaceutical formulation is amorphous.
  • At least 75 wt.% (e.g., 75-100 wt.%, 80-100 wt.%, 85-100 wt.%, 90-100 wt.%, or 95-100 wt.%) of the compound of Formula (A) or a pharmaceutically acceptable salt or solvate thereof in the solid pharmaceutical formulation is amorphous.
  • At least 90 wt.% (e.g., 91-100 wt.%, 92-100 wt.%, 93-100 wt.%, 94-100 wt.%, 95-100 wt.%, 96-100 wt.%, 97-100 wt.%, 98-100 wt.%, 99-100 wt.%, or 99.9-100 wt.%) of the compound of Formula (A) or a pharmaceutically acceptable salt or solvate thereof in the solid pharmaceutical formulation is amorphous.
  • the compound of Formula (A) is a compound of Formula (A-1). In some embodiments, in conjunction with the embodiments above or below, the compound of Formula (A) is a compound of Formula (A-2). In some embodiments, in conjunction with the embodiments above or below, the compound of Formula (A) is a compound of Formula (A-3).
  • the compound of Formula (A) or a pharmaceutically acceptable salt or solvate thereof can exist within the solid pharmaceutical formulation as a homogeneous phase, as a solid solution of a compound of Formula (A) or a pharmaceutically acceptable salt or solvate thereof homogeneously distributed throughout the polymer.
  • the solid pharmaceutical formulation is substantially homogeneous so that the compound of Formula (A) or a pharmaceutically acceptable salt or solvate thereof is dispersed substantially homogeneously throughout the solid formulation.
  • a compound of Formula (A) or a pharmaceutically acceptable salt or solvate thereof that is present in the solid dispersion as relatively high concentration domains and relatively low concentration domains.
  • the solid formulation has a single glass transition temperature, which demonstrates that the formulation is substantially homogeneous.
  • the compound of Formula (A) in conjunction with the embodiments above or below, is a compound of Formula (A-1). In some embodiments, in conjunction with the embodiments above or below, the compound of Formula (A) is a compound of Formula (A-2). In some embodiments, in conjunction with the embodiments above or below, the compound of Formula (A) is a compound of Formula (A-3).
  • a compound of Formula (A) or a pharmaceutically acceptable salt or solvate thereof is present in the formulation in an amount from about 10 % to about 70 % by weight, for example, from about 20 % to about 70 %, from about 20 % to about 60 %, from about 25 % to about 50 %, of about 25 %, of about 40 %, or of about 50 % by weight. In some embodiments, the a compound of Formula (A) or a pharmaceutically acceptable salt or solvate thereof is present in the formulation in an amount of about 25 % by weight. In some embodiments, the a compound of Formula (A) or a pharmaceutically acceptable salt or solvate thereof is present in the formulation in an amount of about 40 % by weight.
  • the a compound of Formula (A) or a pharmaceutically acceptable salt or solvate thereof is present in the formulation in an amount of about 50 % by weight.
  • the compound of Formula (A) is a compound of Formula (A-1).
  • the compound of Formula (A) is a compound of Formula (A- 2).
  • the compound of Formula (A) is a compound of Formula (A-3).
  • the solid pharmaceutical formulation provided herein comprises a polymer.
  • the polymer can comprise any pharmaceutically acceptable polymer that once co-processed with a compound of Formula (A) or a pharmaceutically acceptable salt or solvate thereof, functions to maintain the compound of Formula (A) or a pharmaceutically acceptable salt or solvate thereof in amorphous form or to improve its dissolution performance, stability, or bioavailability.
  • the compound of Formula (A) in conjunction with the embodiments above or below, is a compound of Formula (A-1).
  • the compound of Formula (A) is a compound of Formula (A-2).
  • the compound of Formula (A) is a compound of Formula (A-3).
  • the polymer comprises an enteric polymer.
  • the polymer is at least partially ionizable at physiologically relevant pHs.
  • the polymer is an ionizable polymer, wherein the ionizable polymer is an enteric polymer.
  • Exemplary enteric polymers include, but are not limited to, hydroxypropyl methylcellulose acetate succinate (HPMCAS), which includes HPMCAS L- grade (HPMCAS-L), HPMCAS M-grade (HPMCAS-M), and HPMCAS H-grade (HPMCAS-H), hydroxypropyl methyl cellulose phthalate (HPMCP), which includes HPMCP-HP55, hydroxypropyl methyl cellulose acetate phthalate (HPMCAP), hydroxypropyl methylcellulose (HPMC), which includes HPMC E5, HPMC E3LV, and HPMC 5CPS, methacrylic acid-ethyl acrylate copolymer, which includes methacrylic acid- ethyl acrylate copolymer (1:1) (available as Eudragit® L100-55), cellulose acetate trimellitate (CAT), hydroxypropyl cellulose acetate phthalate succinate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate,
  • the polymer comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the polymer is HPMCAS-L. In some embodiments, the polymer is HPMCAS-H. In some embodiments, the polymer is HPMCAS- M. In some embodiments, the polymer comprises hydroxypropyl methyl cellulose phthalate (HPMCP). In some embodiments, the polymer is HPMCP-HP55. In some embodiments, the polymer comprises hydroxypropyl methylcellulose (HPMC). In some embodiments, the polymer is HPMC E3LV. In some embodiments, the polymer comprises methacrylic acid- ethyl acrylate copolymer.
  • the polymer is methacrylic acid-ethyl acrylate copolymer (1:1), which is available as Eudragit® L 100-55.
  • the solid pharmaceutical formulation described herein has a weight ratio between the compound of Formula (A) and the polymer of from about 15:85 to about 90:10 (e.g., from about 20:80 to about 70:30, from about 25:75 to about 50:50, from about 25:75 to about 40:60, or from 40:60 to about 50:50). In some embodiments, the solid pharmaceutical formulation described herein has a weight ratio between the compound of Formula (A) and the polymer of from about 15:85 to about 90:10.
  • the solid pharmaceutical formulation described herein has a weight ratio between the compound of Formula (A) and the polymer of from about 15:85 to about 80:20. In some embodiments, the solid pharmaceutical formulation described herein has a weight ratio between the compound of Formula (A) and the polymer of from about 15:85 to about 70:30. In some embodiments, the solid pharmaceutical formulation described herein has a weight ratio between the compound of Formula (A) and the polymer of from about 20:80 to about 60:40. In some embodiments, the solid pharmaceutical formulation described herein has a weight ratio between the compound of Formula (A) and the polymer of from about 20:80 to about 30:70.
  • the solid pharmaceutical formulation described herein has a weight ratio between the compound of Formula (A) and the polymer of about 25:75. In some embodiments, the solid pharmaceutical formulation described herein has a weight ratio between the compound of Formula (A) and the polymer of from about 35:65 to about 45:55. In some embodiments, the solid pharmaceutical formulation described herein has a weight ratio between the compound of Formula (A) and the polymer of about 40:60. In some embodiments, the solid pharmaceutical formulation described herein has a weight ratio between the compound of Formula (A) and the polymer of from about 45:55 to about 55:45 In some embodiments, the solid pharmaceutical formulation described herein has a weight ratio between the compound of Formula (A) and the polymer of about 50:50.
  • the compound of Formula (A) is a compound of Formula (A-1). In some embodiments, in conjunction with the embodiments above or below, the compound of Formula (A) is a compound of Formula (A- 2). In some embodiments, in conjunction with the embodiments above or below, the compound of Formula (A) is a compound of Formula (A-3). [0141] In some embodiments, the formulation comprises a compound of Formula (A) and HPMCP-HP55 in a weight ratio of from about 20:80 to about 90:10. In some embodiments, the formulation comprises a compound of Formula (A) and HPMCP-HP55 in a weight ratio of from about 20:80 to about 80:20.
  • the formulation comprises a compound of Formula (A) and HPMCP-HP55 in a weight ratio of from about 20:80 to about 60:40. In some embodiments, the formulation comprises a compound of Formula (A) and HPMCP-HP55 in a weight ratio of from about 20:80 to about 30:70. In some embodiments, the formulation comprises a compound of Formula (A) and HPMCP-HP55 in a weight ratio of from about 30:70 to about 50:50. In some embodiments, the formulation comprises a compound of Formula (A) and HPMCP-HP55 in a weight ratio of from about 40:60 to about 60:40.
  • the formulation comprises a compound of Formula (A) and HPMCP-HP55 in a weight ratio of about 25:75. In some embodiments, the formulation comprises a compound of Formula (A) and HPMCP-HP55 in a weight ratio of about 40:60. In some embodiments, the formulation comprises a compound of Formula (A) and HPMCP- HP55 in a weight ratio of about 50:50. In some embodiments, in conjunction with the embodiments above or below, the compound of Formula (A) is a compound of Formula (A- 1). In some embodiments, in conjunction with the embodiments above or below, the compound of Formula (A) is a compound of Formula (A-2).
  • the compound of Formula (A) is a compound of Formula (A-3).
  • the formulation comprises a compound of Formula (A) and HPMCAS-M in a weight ratio of from about 10:90 to about 90:10. In some embodiments, the formulation comprises a compound of Formula (A) and HPMCAS-M in a weight ratio of from about 10:90 to about 70:30. In some embodiments, the formulation comprises a compound of Formula (A) and HPMCAS-M in a weight ratio of from about 10:90 to about 50:50. In some embodiments, the formulation comprises a compound of Formula (A) and HPMCAS-M in a weight ratio of from about 10:90 to about 40:60.
  • the formulation comprises a compound of Formula (A) and HPMCAS-M in a weight ratio of from about 20:80 to about 30:70. In some embodiments, the formulation comprises a compound of Formula (A) and HPMCAS-M in a weight ratio of about 25:75. In some embodiments, in conjunction with the embodiments above or below, the compound of Formula (A) is a compound of Formula (A-1). In some embodiments, in conjunction with the embodiments above or below, the compound of Formula (A) is a compound of Formula (A- 2). In some embodiments, in conjunction with the embodiments above or below, the compound of Formula (A) is a compound of Formula (A-3).
  • the formulation comprises a compound of Formula (A) and HPMC E3LV in a weight ratio of from about 20:80 to about 90:10. In some embodiments, the formulation comprises a compound of Formula (A) and HPMC E3LV in a weight ratio of from about 40:60 to about 60:40. In some embodiments, the formulation comprises a compound of Formula (A) and HPMC E3LV in a weight ratio of about 50:50. In some embodiments, in conjunction with the embodiments above or below, the compound of Formula (A) is a compound of Formula (A-1). In some embodiments, in conjunction with the embodiments above or below, the compound of Formula (A) is a compound of Formula (A- 2).
  • the compound of Formula (A) is a compound of Formula (A-3).
  • the formulation comprises a compound of Formula (A) and methacrylic acid-ethyl acrylate copolymer (1:1), (available as Eudragit® L 100-55) in a weight ratio of from about 10:90 to about 90:10.
  • the formulation comprises a compound of Formula (A) and methacrylic acid-ethyl acrylate copolymer (1:1), (available as Eudragit® L 100-55) in a weight ratio of from about 20:80 to about 60:40.
  • the formulation comprises a compound of Formula (A) and methacrylic acid-ethyl acrylate copolymer (1:1) (available as Eudragit® L 100-55) in a weight ratio of from about 20:80 to about 30:70. In some embodiments, the formulation comprises a compound of Formula (A) and methacrylic acid-ethyl acrylate copolymer (1:1) (available as Eudragit® L 100-55) in a weight ratio of from about 30:70 to about 50:50.
  • the formulation comprises a compound of Formula (A) and methacrylic acid- ethyl acrylate copolymer (1:1) (available as Eudragit® L 100-55) in a weight ratio of from about 40:60 to about 60:40. In some embodiments, the formulation comprises a compound of Formula (A) and methacrylic acid-ethyl acrylate copolymer (1:1) (available as Eudragit® L 100-55) in a weight ratio of about 25:75. In some embodiments, the formulation comprises a compound of Formula (A) and methacrylic acid-ethyl acrylate copolymer (1:1) (available as Eudragit® L 100-55) in a weight ratio of about 40:60.
  • the formulation comprises a compound of Formula (A) and methacrylic acid-ethyl acrylate copolymer (1:1) (available as Eudragit® L 100-55) in a weight ratio of about 50:50.
  • the compound of Formula (A) in conjunction with the embodiments above or below, is a compound of Formula (A-1). In some embodiments, in conjunction with the embodiments above or below, the compound of Formula (A) is a compound of Formula (A-2). In some embodiments, in conjunction with the embodiments above or below, the compound of Formula (A) is a compound of Formula (A-3). II-d.
  • the formulation provided herein may improve the dissolution and pharmacokinetic profile of the compound of Formula (A), including the compound of Formula (A-1), Formula (A-2), and Formula (A-3).
  • the dissolution profile of a compound of Formula (A) e.g., compound of Formula (A-1), Formula (A-2), and Formula (A-3)
  • AUC(t) area under a concentration-time curve over a time period t in a media
  • C max maximum plasma concentration
  • C t total drug dissolved over a period of t
  • a solid pharmaceutical formulation comprising a compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)), or pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical formulation increases the dissolved concentration of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in simulated intestinal media compared to pure crystalline compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)).
  • the simulated intestinal media comprises a fasted state simulated intestinal fluid (FaSSIF).
  • a solid pharmaceutical formulation comprising a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) or pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical formulation increases the dissolved concentration of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in simulated intestinal media compared to pure crystalline compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) by at least about 2-fold (e.g., at least about 3-fold, at least about 5-fold, at least about 7-fold, at least about 10-fold, at least about 12-fold, at least about 15-fold, or at least about 20-fold).
  • 2-fold e.g., at least about 3-fold, at least about 5-fold, at least about 7-fold, at least about 10-fold, at least about 12-fold, at least about 15-fold, or at least about 20-fold.
  • the solid formulation is a spray dried dispersion.
  • a solid pharmaceutical formulation comprising a compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) or pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical formulation is effective to provide a C max of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in FaSSIF of about 30 ⁇ g/mL to about 300 ⁇ g/mL (e.g., about 40 ⁇ g/mL to about 300 ⁇ g/mL, about 50 ⁇ g/mL to about 270 ⁇ g/mL, or about 100 ⁇ g/mL to about 200 ⁇ g/mL).
  • the solid pharmaceutical formulation is effective to provide a C max of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in FaSSIF of about 40 ⁇ g/mL to about 100 ⁇ g/mL. In some embodiments, the solid pharmaceutical formulation is effective to provide a C max of the compound of Formula (A) (e.g., compound of Formula (A- 1), Formula (A-2), or Formula (A-3)) in FaSSIF of about 100 ⁇ g/mL to about 150 ⁇ g/mL.
  • the solid pharmaceutical formulation is effective to provide a C max of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A- 3)) in FaSSIF of about 150 ⁇ g/mL to about 300 ⁇ g/mL.
  • the solid formulation is a spray dried dispersion.
  • a solid pharmaceutical formulation comprising a compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) or pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical formulation is effective to provide a C max of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in Gastric Buffer (GB) of about 8 ⁇ g/mL to about 100 ⁇ g/mL (e.g., about 8 ⁇ g/mL to about 90 ⁇ g/mL, about 8 ⁇ g/mL to about 20 ⁇ g/mL, or about 60 ⁇ g/mL to about 100 ⁇ g/mL).
  • GB Gastric Buffer
  • the solid pharmaceutical formulation is effective to provide a C max of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in GB of about 8 ⁇ g/mL to about 90 ⁇ g/mL. In some embodiments, the solid pharmaceutical formulation is effective to provide a C max of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in GB of about 50 ⁇ g/mL to about 90 ⁇ g/mL.
  • the solid pharmaceutical formulation is effective to provide a C max of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in GB of about 60 ⁇ g/mL to about 90 ⁇ g/mL.
  • the solid formulation is a spray dried dispersion.
  • the compound of Formula (A) in conjunction with the embodiments above or below, is a compound of Formula (A-1). In some embodiments, in conjunction with the embodiments above or below, the compound of Formula (A) is a compound of Formula (A-2).
  • the compound of Formula (A) is a compound of Formula (A- 3).
  • the solid pharmaceutical formulation is effective to provide a AUC 35-210 of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A- 2), or Formula (A-3)) in FaSSIF of about 1000 min* ⁇ g/mL to about 30000 min* ⁇ g/mL (e.g., about 4000 min* ⁇ g/mL to about 25000 min* ⁇ g/mL, about 4000 min* ⁇ g/mL to about 10000 min* ⁇ g/mL, about 10000 min* ⁇ g/mL to about 15000 min* ⁇ g/mL, or about 20000 min* ⁇ g/mL to about 30000 min* ⁇ g/mL).
  • the solid pharmaceutical formulation is effective to provide a AUC35-210 of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in FaSSIF of about 4000 min* ⁇ g/mL to about 10000 min* ⁇ g/mL.
  • the solid pharmaceutical formulation is effective to provide a AUC35-210 of the compound of Formula (A) (e.g., compound of Formula (A-1) or Formula (A-2)) in FaSSIF of about 10000 min* ⁇ g/mL to about 20000 min* ⁇ g/mL.
  • the solid pharmaceutical formulation is effective to provide a AUC35-210 of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in FaSSIF of about 20000 min* ⁇ g/mL to about 30000 min* ⁇ g/mL.
  • the solid formulation is a spray dried dispersion.
  • the compound of Formula (A) is a compound of Formula (A-1).
  • the compound of Formula (A) is a compound of Formula (A- 2).
  • the compound of Formula (A) is a compound of Formula (A-3).
  • the solid pharmaceutical formulation is effective to provide a total drug dissolved in FaSSIF over 210 minutes of about 3 ⁇ g/mL to about 120 ⁇ g/mL (e.g., about 3 ⁇ g/mL to about 10 ⁇ g/mL, about 10 ⁇ g/mL to about 120 ⁇ g/mL, about 10 ⁇ g/mL to about 50 ⁇ g/mL, or about 50 ⁇ g/mL to about 120 ⁇ g/mL).
  • the solid pharmaceutical formulation is effective to provide a total drug dissolved over 210 minutes of about 3 ⁇ g/mL to about 10 ⁇ g/mL. In some embodiments, the solid pharmaceutical formulation is effective to provide a total drug dissolved in FaSSIF over 210 minutes of about 10 ⁇ g/mL to about 50 ⁇ g/mL. In some embodiments, the solid pharmaceutical formulation is effective to provide a total drug dissolved in FaSSIF over 210 minutes of about 50 ⁇ g/mL to about 100 ⁇ g/mL. In some embodiments, the solid pharmaceutical formulation is effective to provide a total drug dissolved in FaSSIF over 210 minutes of about 100 ⁇ g/mL to about 120 ⁇ g/mL.
  • the solid formulation is a spray dried dispersion.
  • the pharmacokinetic profile of the compound of Formula (A) may be described with parameters such as area under a plasma concentration-time curve over a time period t (AUC(t)), area under a plasma concentration-time curve to infinite time (AUC (inf) ), maximum plasma concentration (C max ), and/or drug half-life (t1/2).
  • the pharmacokinetic profile of the compound of Formula (A) is determined in a mammal. In some embodiments, in conjunction with the embodiments above or below, the pharmacokinetic profile of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) is determined in a murine subject. In some embodiments, in conjunction with the embodiments above or below, the pharmacokinetic profile of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) is determined in a human subject.
  • a solid pharmaceutical formulation comprising the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A- 3)) or pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical formulation, when administered to a murine subject, is effective to provide a maximum plasma concentration (C max ) of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in the subject of about 5000 ng/mL to about 20000 ng/mL (e.g., about 5000 ng/mL to about 15000 ng/mL, about 7000 ng/mL to about 13000 ng/mL, about 9000 ng/mL to about 11000 ng/mL, or about 10000 ng/mL).
  • C max maximum plasma concentration
  • the solid pharmaceutical formulation when administered to a murine subject, is effective to provide a C max of about 8000 ng/mL to about 12000 ng/mL. In some embodiments, the solid pharmaceutical formulation, when administered to a murine subject, is effective to provide a C max of about 10000 ng/mL.
  • a solid pharmaceutical formulation comprising the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A- 3) or pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical formulation, when administered to a human subject, is effective to provide a maximum plasma concentration (C max ) of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in the subject of about 1.5 ⁇ mol/mL to about 5.0 ⁇ mol/mL (e.g., about 1.5 ⁇ mol/mL to about 4.5 ⁇ mol/mL, about 1.5 ⁇ mol/mL to about 4.0 ⁇ mol/mL, about 2.0 ⁇ mol/mL to about 3.5 ⁇ mol/mL, or about 2.7 ⁇ mol/mL).
  • C max maximum plasma concentration
  • the solid pharmaceutical formulation when administered to a human subject, is effective to provide a C max of about 2.0 ⁇ mol/mL to about 3.5 ⁇ mol/mL. In some embodiments, the solid pharmaceutical formulation, when administered to a human subject, is effective to provide a C max of about 2.7 ⁇ mol/mL. [0154] In some embodiments, the solid pharmaceutical formulation, when administered to a murine subject, is effective to achieve the C max at about 0.5 to about 2 hours (e.g., about 0.5 hour to 1.5 hours, about 0.7 hour to 1.3 hours, or about 0.9 to about 1.1 hours after administration of the formulation.
  • the solid pharmaceutical formulation when administered to a murine subject, is effective to achieve the C max at about 0.8 hours to about 1.2 hours. In some embodiments, the solid pharmaceutical formulation, when administered to a murine subject, is effective to achieve the C max at about 1.0 hours. [0155] In some embodiments, the solid pharmaceutical formulation, when administered to a human subject, is effective to achieve the C max at about 2 to about 10 hours (e.g., about 2 hour to 8 hours, about 3 hour to 7 hours, or about 4 to about 6 hours after administration of the formulation. In some embodiments, the solid pharmaceutical formulation, when administered to a human subject, is effective to achieve the C max at about 4 hours to about 6 hours.
  • the solid pharmaceutical formulation when administered to a human subject, is effective to achieve the C max at about 5.4 hours.
  • the solid pharmaceutical formulation described herein, when administered to a murine subject is effective to provide a C max of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in the subject at about 0.5 to about 2 hours after administration of the formulation, wherein the C max is from about 5000 ng/mL to about 15000 ng/mL.
  • the solid pharmaceutical formulation described herein when administered to a murine subject, is effective to provide a C max of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in the subject from about 0.8 to about 1.2 hours after administration of the formulation, wherein the C max is from about 7000 ng/mL to about 12000 ng/mL.
  • a C max of the compound of Formula (A) e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)
  • the C max is from about 7000 ng/mL to about 12000 ng/mL.
  • the solid pharmaceutical formulation described herein when administered to a murine subject, is effective to provide a C max of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in the subject from about 1 hours after administration of the formulation, wherein the C max is about 10000 ng/mL.
  • a C max of the compound of Formula (A) e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)
  • the C max is about 10000 ng/mL.
  • a solid pharmaceutical formulation comprising the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) or pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical formulation is effective to achieve an area under a plasma concentration-time curve between 0 to 24 hours (AUC0-24) of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in a murine subject of about 20000 ng ⁇ h/mL to about 70000 ng ⁇ h/mL (e.g., about 30000 ng ⁇ h/mL to about 60000 ng ⁇ h/mL, about 40000 ng ⁇ h/mL to about 60000 ng ⁇ h/mL, or about 50000 ng ⁇ h/mL).
  • the solid pharmaceutical formulation is effective to achieve an area under a plasma concentration-time curve between 0 to 24 hours (AUC0-24) of the compound of Formula (A) (e.g., compound of Formula (A-1),
  • the solid pharmaceutical formulation is effective to achieve an AUC 0-24 of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in a murine subject of about 30000 ng ⁇ h/mL to about 70000 ng ⁇ h/mL.
  • the solid pharmaceutical formulation is effective to achieve an AUC0-24 of at least 30000 ng/mL (e.g., at least 35000 ng ⁇ h/mL, at least 40000 ng ⁇ h/mL, at least 45000 ng ⁇ h/mL, at least 50000 ng ⁇ h/mL, or at least 55000 ng ⁇ h/mL).
  • the solid pharmaceutical formulation is effective to achieve an AUC0-24 in a murine subject of no more than 70000 ng ⁇ h/mL (e.g., no more than 70000 ng ⁇ h/mL, no more than 65000 ng ⁇ h/mL, no more than 60000 ng ⁇ h/mL, or no more than 55000 ng ⁇ h/mL).
  • a solid pharmaceutical formulation comprising the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) or pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical formulation is effective to achieve an area under a plasma concentration-time curve between 0 to 24 hour (AUC0-24) of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in a human subject of about 10 ⁇ mol ⁇ hr/mL to about 100 ⁇ mol ⁇ hr/mL (e.g., about 10 ⁇ mol ⁇ hr/mL to about 80 ⁇ mol ⁇ hr/mL, about 20 ⁇ mol ⁇ hr/mL to about 70 ⁇ mol ⁇ hr/mL, or about 50 ⁇ mol ⁇ hr/mL).
  • the solid pharmaceutical formulation is effective to achieve an area under a plasma concentration-time curve between 0 to 24 hour (AUC0-24) of the compound of Formula (A) (e.g., compound
  • the solid pharmaceutical formulation is effective to achieve an AUC 0-24 of the compound of Formula (A) (e.g., compound of Formula (A-1), Formula (A-2), or Formula (A- 3)) in a human subject of about 10 ⁇ mol ⁇ hr/mL to about 100 ⁇ mol ⁇ hr/mL. In some embodiments, the solid pharmaceutical formulation is effective to achieve an AUC 0-24 in a human subject of at least 20 ⁇ mol ⁇ hr/mL (e.g., at least 30 ⁇ mol ⁇ hr/mL, or at least 40 ⁇ mol ⁇ hr/mL).
  • the solid pharmaceutical formulation is effective to achieve an AUC 0-24 in a human subject of no more than 70 ⁇ mol ⁇ hr/mL (e.g., no more than 60 ⁇ mol ⁇ hr/mL, or no more than 50 ⁇ mol ⁇ hr/mL). In some embodiments, the solid pharmaceutical formulation is effective to achieve an AUC0-24 in a human subject of about 40 ⁇ mol ⁇ hr/mL. II-e. Method of Preparation [0159] Also provided herein is a process of preparing the solid pharmaceutical formulations described herein.
  • the process comprises spray-drying a solution of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) to obtain an amorphous solid dispersion of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)).
  • a compound of Formula (A) e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)
  • Spray-dried solid dispersion or spray-dried dispersion is a solid dispersion produced using spray-drying technology.
  • Spray drying processes generally involve breaking up liquid mixtures from a solution into small droplets, a step also known as atomization, and rapidly removing solvent from the mixture in a container (e.g., a spray-drying apparatus), where a strong driving force is provided to evaporate solvent from the droplets. A portion of the driving force for evaporation of solvent from the droplets may be provided by heating the solution.
  • a container e.g., a spray-drying apparatus
  • the strong driving force for solvent evaporation is generally provided by maintaining the partial pressure of solvent in the spray-drying apparatus well below the vapor pressure of the solvent at the temperature of the drying droplets.
  • the strong driving force for solvent evaporation may be accomplished by (1) maintaining the pressure in the spray-drying apparatus at a partial vacuum (e.g., 0.01 to 0.50 atm); (2) mixing the liquid droplets with a warm drying gas; or the combination of both (1) and (2).
  • the process comprises spray-drying a solution comprising: (i) a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) or a pharmaceutically acceptable salt thereof; (ii) a polymer; and (iii) a solvent.
  • the process comprises (1) preparing a solution comprising (i) a compound of Formula (A) (e.g., a Formula (A-1), Formula (A-2), or Formula (A-3)) or a pharmaceutically acceptable salt thereof; (ii) a polymer; and (iii) a solvent; (2) spray-drying the solution to obtain a powder; and optionally (3) further drying the powder of step (2) under heat.
  • the solvent comprises dichloromethane (DCM).
  • the solvent comprises alcohol.
  • the solvent comprises methanol.
  • the solvent comprises DCM and methanol.
  • the solvent comprises water.
  • the solvent comprises acetone.
  • the solvent comprises acetone and water.
  • the solvent is a mixture of acetone and water, optionally in a volume ratio of about 50:1 to about 1:50, such as about any of 30:1 to 1:30, 30:1 to 1:10, 30:1 to 1:1, 20:1 to 1:1, 15:1 to 1:1, 10:1 to 1:10, 10:1 to 1:1, 10:1 to 5:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, or 5:1.
  • the solvent is a mixture of DCM and methanol in a weight ratio of about 70:30 to about 90:10.
  • the solvent is a mixture of DCM and methanol in a weight ratio of about 87:13.
  • the polymer comprises HPMCAS-M.
  • the polymer comprises methacrylic acid-ethyl acrylate copolymer (1:1) (available as Eudragit® L 100-55).
  • the polymer comprises HPMC E3LV.
  • the polymer comprises HPMCP-HP55. III.
  • polymorphic forms of N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide also referred herein as a compound of Formula (A-1), having the structure shown below
  • compound of Formula (A-1) is also referred to as N-(tert- butyl)-3-(5''-(ethylsulfonamido)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indoline]-1''- carbonyl)benzenesulfonamide.
  • the polymorphs may have properties such as bioavailability and stability under certain conditions that are suitable for medical or pharmaceutical uses.
  • a polymorph of the compound of Formula (A-1) may provide the advantages of bioavailability and stability and may be suitable for use as an active agent in a pharmaceutical composition. Variations in the crystal structure of a pharmaceutical drug substance may affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ease of purification, ability to consistently prepare doses of known strength, etc.) and stability (e.g., thermal stability, shelf life (including resistance to degradation), etc.) of a pharmaceutical drug product.
  • dissolution rate which may affect bioavailability, etc.
  • manufacturability e.g., ease of handling, ease of purification, ability to consistently prepare doses of known strength, etc.
  • stability e.g., thermal stability, shelf life (including resistance to degradation), etc.
  • polymorphs may provide desired or suitable hygroscopicity or lack thereof, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, reproducibility, and/or process control.
  • polymorphs of the compound of Formula (A-1) may provide advantages of improving the manufacturing process of the active agent or the stability or storability of a drug product form of the active agent, or having suitable bioavailability and/or stability as an active agent.
  • polymorphic Form A (Free-Form Pattern A)
  • polymorphic Form A of N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide, which is referred to as polymorphic Form A hereinafter.
  • polymorphic Form A may also be referred to as polymorphic Form I.
  • polymorphic Form A has an XRPD pattern substantially as shown in FIG. 2.
  • Angles 2-theta and relative peak intensities observed for polymorphic Form A using XRPD are shown in Table III-1. Table III-1
  • polymorphic Form A has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at angles 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 2 or as provided in Table III-1. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Relative peak intensities and peak assignments can vary within experimental error.
  • peak assignments listed herein, including for polymorphic Form A can vary by about ⁇ 0.6 degrees, ⁇ 0.4 degrees, ⁇ 0.2 degrees, or ⁇ 0.1 degrees 2-theta.
  • polymorphic Form A has an XRPD pattern comprising peaks at angles 2-theta of 13.54 ⁇ 0.20, 17.89 ⁇ 0.20, 18.39 ⁇ 0.20, 19.39 ⁇ 0.20, and 19.73 ⁇ 0.20 degrees.
  • the polymorphic Form A has an XRPD pattern comprising additional peaks at angles 2-theta of 15.46 ⁇ 0.20 and 17.29 ⁇ 0.20 degrees.
  • polymorphic Form A has an XRPD pattern further comprising additional peaks at angles 2-theta of 8.61 ⁇ 0.20 and 15.04 ⁇ 0.20 degrees.
  • polymorphic Form A has an XRPD pattern comprising peaks at angles 2-theta of 6.13 ⁇ 0.20, 8.61 ⁇ 0.20, 10.37 ⁇ 0.20, 12.30 ⁇ 0.20, 13.54 ⁇ 0.20, 15.04 ⁇ 0.20, 15.46 ⁇ 0.20, 16.05 ⁇ 0.20, 17.29 ⁇ 0.20, 17.89 ⁇ 0.20, 18.39 ⁇ 0.20, 19.01 ⁇ 0.20, 19.39 ⁇ 0.20, 19.73 ⁇ 0.20, 19.86 ⁇ 0.20, 22.98 ⁇ 0.20 degrees. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG.
  • polymorphic Form A has a differential scanning calorimetry (DSC) graph substantially as shown in FIG. 3.
  • polymorphic Form A is characterized as having an endotherm onset at about 188 °C as determined by DSC.
  • polymorphic Form A is characterized as having an endotherm onset at 188 ⁇ 2 °C (e.g., 188 ⁇ 1.9 °C, 188 ⁇ 1.8 °C, 188 ⁇ 1.7 °C, 188 ⁇ 1.6 °C, 188 ⁇ 1.5 °C, 188 ⁇ 1.4 °C, 188 ⁇ 1.3 °C, 188 ⁇ 1.2 °C, 188 ⁇ 1.1 °C, 188 ⁇ 1.0 °C, 188 ⁇ 0.9 °C, 188 ⁇ 0.8 °C, 188 ⁇ 0.7 °C, 188 ⁇ 0.6 °C, 188 ⁇ 0.5 °C, 188 ⁇ 0.4 °C, 188 ⁇ 0.3 °C, 188 ⁇ 0.2 °C, or 188 ⁇ 0.1 °C) as determined by DSC.
  • endotherm onset at 188 ⁇ 2 °C e.g., 188 ⁇ 1.9 °C, 188 ⁇ 1.8 °C, 188 ⁇ 1.7 °C, 188 ⁇ 1.6 °C, 188 ⁇ 1.5 °C, 188 ⁇ 1.4
  • Form A is characterized as having an endotherm peak at about 194 °C as determined by DSC. In some embodiments, Form A is characterized as having an endotherm peak at 194 ⁇ 2 °C (e.g., 194 ⁇ 1.9 °C, 194 ⁇ 1.8 °C, 194 ⁇ 1.7 °C, 194 ⁇ 1.6 °C, 194 ⁇ 1.5 °C, 194 ⁇ 1.4 °C, 194 ⁇ 1.3 °C, 194 ⁇ 1.2 °C, 194 ⁇ 1.1 °C, 194 ⁇ 1.0 °C, 194 ⁇ 0.9 °C, 194 ⁇ 0.8 °C, 194 ⁇ 0.7 °C, 194 ⁇ 0.6 °C, 194 ⁇ 0.5 °C, 194 ⁇ 0.4 °C, 194 ⁇ 0.3 °C, 194 ⁇ 0.2 °C, or 194 ⁇ 0.1 °C) as determined by DSC.
  • 194 ⁇ 2 °C e.g., 194 ⁇ 1.9 °C, 194 ⁇ 1.8 °C, 194 ⁇ 1.7 °C,
  • polymorphic Form A has a thermographic analysis (TGA) graph substantially as shown in FIG. 3.
  • TGA thermographic analysis
  • polymorphic Form A exhibits a weight loss of about 0.01% or 0.01% ⁇ 0.005% (e.g., 0.01% ⁇ 0.004%, 0.01% ⁇ 0.003%, 0.01% ⁇ 0.002%, or 0.01% ⁇ 0.001%) between 52 °C and 150 °C as determined by TGA.
  • polymorphic Form A exhibits an apparent decomposition at 316 ⁇ 5 °C (e.g., 316 ⁇ 4.5 °C, 316 ⁇ 4.0 °C, 316 ⁇ 3.5 °C, 316 ⁇ 3.0 °C, 316 ⁇ 2.5 °C, 316 ⁇ 2.0 °C, 316 ⁇ 1.9 °C, 316 ⁇ 1.8 °C, 316 ⁇ 1.7 °C, 316 ⁇ 1.6 °C, 316 ⁇ 1.5 °C, 316 ⁇ 1.4 °C, 316 ⁇ 1.3 °C, 316 ⁇ 1.2 °C, 316 ⁇ 1.1 °C, 316 ⁇ 1.0 °C, 316 ⁇ 0.9 °C, 316 ⁇ 0.8 °C, 316 ⁇ 0.7 °C, 316 ⁇ 0.6 °C, 316 ⁇ 0.5 °C, 316 ⁇ 0.4 °C, 316 ⁇ 0.3 °C, 316 ⁇ 0.2 °C, or 316 ⁇ 0.1 °C).
  • 316 ⁇ 5 °C e.g., 316 ⁇ 4.5 °C, 316 ⁇
  • polymorphic Form A has a Dynamic Vapor Sorption (DVS) graph substantially as shown in FIG. 4.
  • polymorphic Form A exhibits a weight gain of about 0.095% or 0.095% ⁇ 0.005% (e.g., 0.095% ⁇ 0.004%, 0.095% ⁇ 0.003%, 0.095% ⁇ 0.002%, or 0.095% ⁇ 0.001%) from 5% relative humidity (RH) to 95% RH, as determined by DVS.
  • RH relative humidity
  • polymorphic Form A exhibits a weight loss of about 0.097% or 0.097% ⁇ 0.005% (e.g., 0.097% ⁇ 0.004%, 0.097% ⁇ 0.003%, 0.097% ⁇ 0.002%, or 0.097% ⁇ 0.001%) from 95% RH to 5% RH, as determined by DVS. [0175] In some embodiments, polymorphic Form A shows substantially no changes or no changes before and after the DVS measurement as determined by XRPD.
  • polymorphic Form A has an XRPD pattern comprising peaks at angles 2-theta of 13.54 ⁇ 0.20, 17.89 ⁇ 0.20, 18.39 ⁇ 0.20, 19.39 ⁇ 0.20, and 19.73 ⁇ 0.20 degrees; an XRPD pattern comprising additional peaks at angles 2-theta of 15.46 ⁇ 0.20 and 17.29 ⁇ 0.20 degrees; an XRPD pattern further comprising additional peaks at angles 2-theta of 8.61 ⁇ 0.20 and 15.04 ⁇ 0.20 degrees; or an XRPD pattern comprising peaks at angles 2-theta of 6.13 ⁇ 0.20, 8.61 ⁇ 0.20, 10.37 ⁇ 0.20, 12.30 ⁇ 0.20, 13.54 ⁇ 0.20, 15.04 ⁇ 0.20, 15.46 ⁇ 0.20, 16.05 ⁇ 0.2
  • polymorphic Form A has a DSC graph substantially as shown in FIG. 3;
  • polymorphic Form A is characterized as having an endotherm onset at 188 ⁇ 2 °C as determined by DSC;
  • polymorphic Form A is characterized as having an endotherm peak at 194 ⁇ 2 °C as determined by DSC;
  • polymorphic Form A has a TGA graph substantially as shown in FIG.
  • polymorphic Form A has a weight loss of about 0.01% or 0.01% ⁇ 0.005% between 52 °C and 150 °C as determined by TGA;
  • polymorphic Form A has an apparent decomposition at 316 ⁇ 5 °C;
  • polymorphic Form A has a DVS graph substantially as shown in FIG. 4.
  • polymorphic Form A has a weight gain of about 0.095% or 0.095% ⁇ 0.005% from 5% RH to 95% RH, as determined by DVS;
  • polymorphic Form A has a weight loss of about 0.097% or 0.097% ⁇ 0.005% from 95% RH to 5% RH, as determined by DVS. III-b.
  • Polymorphic Form B (Free-Form Pattern B) [0177]
  • polymorphic Form B comprises less than 10% w/w (e.g., less than any of 8% w/w, 5% w/w, 3% w/w, 2% w/w, 1% w/w, 0.5% w/w, 0.1% w/w, 0.05% w/w, or 0.01% w/w) water. In some embodiments, polymorphic Form B is substantially free of water.
  • polymorphic Form B comprises about 0.01% to 1% w/w (e.g., about any of 0.01% to 0.5% w/w, 0.02% to 0.2% w/w, 0.02% to 0.1% w/w, 0.05% to 0.1% w/w, or 0.07% w/w) acetonitrile.
  • polymorphic Form B has an XRPD pattern substantially as shown in FIG. 10.
  • Angles 2-theta and relative peak intensities observed for polymorphic Form B using XRPD are shown in Table III-1.
  • polymorphic Form B has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at angles 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 10 or as provided in Table III-1. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Relative peak intensities and peak assignments can vary within experimental error.
  • peak assignments listed herein, including for polymorphic Form B can vary by about ⁇ 1 degrees, ⁇ 0.8 degrees, ⁇ 0.6 degrees, ⁇ 0.4 degrees, ⁇ 0.2 degrees, or ⁇ 0.1 degrees 2-theta.
  • polymorphic Form B has an XRPD pattern comprising peaks at angles 2-theta of 15.62 ⁇ 0.20, 16.60 ⁇ 0.20, 19.87 ⁇ 0.20, 20.11 ⁇ 0.20, and 25.76 ⁇ 0.20 degrees.
  • the polymorphic Form B has an XRPD pattern comprising additional peaks at angles 2-theta of 17.50 ⁇ 0.20 and 21.13 ⁇ 0.20 degrees.
  • polymorphic Form B has an XRPD pattern further comprising additional peaks at angles 2-theta of 8.23 ⁇ 0.20 and 11.72 ⁇ 0.20 degrees. In some embodiments, polymorphic Form B has an XRPD pattern comprising peaks at angles 2-theta of 8.23 ⁇ 0.20, 11.72 ⁇ 0.20, 12.89 ⁇ 0.20, 15.62 ⁇ 0.20, 16.60 ⁇ 0.20, 16.83 ⁇ 0.20, 17.50 ⁇ 0.20, 18.60 ⁇ 0.20, 19.12 ⁇ 0.20, 19.87 ⁇ 0.20, 20.11 ⁇ 0.20, 21.13 ⁇ 0.20, 24.88 ⁇ 0.20, 25.76 ⁇ 0.20, 26.49 ⁇ 0.20, and 31.13 ⁇ 0.20 degrees.
  • polymorphic Form B has a differential scanning calorimetry (DSC) graph substantially as shown in FIG. 11.
  • polymorphic Form B is characterized as having an endotherm onset at about 196 °C as determined by DSC.
  • polymorphic Form B is characterized as having an endotherm onset at 196 ⁇ 2 °C (e.g., 196 ⁇ 1.9 °C, 196 ⁇ 1.8 °C, 196 ⁇ 1.7 °C, 196 ⁇ 1.6 °C, 196 ⁇ 1.5 °C, 196 ⁇ 1.4 °C, 196 ⁇ 1.3 °C, 196 ⁇ 1.2 °C, 196 ⁇ 1.1 °C, 196 ⁇ 1.0 °C, 196 ⁇ 0.9 °C, 196 ⁇ 0.8 °C, 196 ⁇ 0.7 °C, 196 ⁇ 0.6 °C, 196 ⁇ 0.5 °C, 196 ⁇ 0.4 °C, 196 ⁇ 0.3 °C, 196 ⁇ 0.2 °C, or 196 ⁇ 0.1 °C) as determined by DSC.
  • endotherm onset at 196 ⁇ 2 °C e.g., 196 ⁇ 1.9 °C, 196 ⁇ 1.8 °C, 196 ⁇ 1.7 °C, 196 ⁇ 1.6 °C, 196 ⁇ 1.5 °C, 196 ⁇ 1.4
  • Form B is characterized as having an endotherm peak at about 197 °C as determined by DSC. In some embodiments, Form B is characterized as having an endotherm peak at 197 ⁇ 2 °C (e.g., 197 ⁇ 1.9 °C, 197 ⁇ 1.8 °C, 197 ⁇ 1.7 °C, 197 ⁇ 1.6 °C, 197 ⁇ 1.5 °C, 197 ⁇ 1.4 °C, 197 ⁇ 1.3 °C, 197 ⁇ 1.2 °C, 197 ⁇ 1.1 °C, 197 ⁇ 1.0 °C, 197 ⁇ 0.9 °C, 197 ⁇ 0.8 °C, 197 ⁇ 0.7 °C, 197 ⁇ 0.6 °C, 197 ⁇ 0.5 °C, 197 ⁇ 0.4 °C, 197 ⁇ 0.3 °C, 197 ⁇ 0.2 °C, or 197 ⁇ 0.1 °C) as determined by DSC.
  • 197 ⁇ 2 °C e.g., 197 ⁇ 1.9 °C, 197 ⁇ 1.8 °C, 197 ⁇ 1.7 °C,
  • polymorphic Form B has a thermographic analysis (TGA) graph substantially as shown in FIG. 12.
  • polymorphic Form B exhibits a weight loss of about 0.05% or 0.05% ⁇ 0.01% (e.g., 0.05% ⁇ 0.005%, 0.05% ⁇ 0.004%, 0.05% ⁇ 0.003%, 0.05% ⁇ 0.002%, or 0.05% ⁇ 0.001%) from about 25 °C to about 100 °C (e.g., 100 ⁇ 5 °C, 100 ⁇ 4.5 °C, 100 ⁇ 4.0 °C, 100 ⁇ 3.5 °C, 100 ⁇ 3.0 °C, 100 ⁇ 2.5 °C, 100 ⁇ 2.0 °C, 100 ⁇ 1.9 °C, 100 ⁇ 1.8 °C, 100 ⁇ 1.7 °C, 100 ⁇ 1.6 °C, 100 ⁇ 1.5 °C, 100 ⁇ 1.4 °C, 100 ⁇ 1.3 °C, 100 ⁇ 1.2 °C, 100 ⁇ 1.1 °C, 100 ⁇ 1.0 °C, 100 ⁇ 0.9 °C, 100 ⁇ 0.8 °C, 100
  • polymorphic Form B exhibits a weight loss of about 0.1% or 0.1% ⁇ 0.05% (e.g., 0.1% ⁇ 0.04%, 0.1% ⁇ 0.03%, 0.1% ⁇ 0.03%, 0.1% ⁇ 0.01%, or 0.1% ⁇ 0.001%) about 100 °C to about 180 °C.
  • polymorphic Form B has a Dynamic Vapor Sorption (DVS) graph substantially as shown in FIG. 13.
  • polymorphic Form B exhibits a weight gain of about 0.03% or 0.03 % ⁇ 0.005% (e.g., 0.03% ⁇ 0.004%, 0.03% ⁇ 0.003%, 0.03% ⁇ 0.002%, or 0.03% ⁇ 0.001%) from 0.1 % relative humidity (RH) to 95% RH, as determined by DVS. In some embodiments, polymorphic Form B exhibits a weight loss of about 0.05% or 0.05% ⁇ 0.005% (e.g., 0.05% ⁇ 0.004%, 0.05% ⁇ 0.003%, 0.05% ⁇ 0.002%, or 0.05% ⁇ 0.001%) from 95 % relative humidity (RH) to 0.1% RH, as determined by DVS.
  • RH relative humidity
  • polymorphic Form B shows substantially no changes or no changes before and after the DVS measurement as determined by XRPD.
  • at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or all of the following (a)-(k) apply: (a) polymorphic Form B has an XRPD pattern comprising peaks at angles 2-theta of 15.62 ⁇ 0.20, 16.60 ⁇ 0.20, 19.87 ⁇ 0.20, 20.11 ⁇ 0.20, and 25.76 ⁇ 0.20 degrees; an XRPD pattern comprising additional peaks at angles 2-theta of 17.50 ⁇ 0.20 and 21.13 ⁇ 0.20 degrees; an XRPD pattern further comprising additional peaks at angles 2-theta of 8.23 ⁇ 0.20 and 11.72 ⁇ 0.20 degrees; or an XRPD pattern comprising peaks at angles 2-theta of 8.23 ⁇ 0.20, 11.
  • polymorphic Form B has a DSC graph substantially as shown in FIG. 11;
  • polymorphic Form B is characterized as having an endotherm onset at 196 ⁇ 2 °C as determined by DSC;
  • polymorphic Form B is characterized as having an endotherm peak at 197 ⁇ 2 °C as determined by DSC;
  • polymorphic Form B has a TGA graph substantially as shown in FIG.
  • polymorphic Form B has a weight loss of about 0.05% or 0.05% ⁇ 0.01% between 25 and 100°C as determined by TGA;
  • polymorphic Form B has a weight loss of about 0.1% or 0.1% ⁇ 0.01% between 100 and 180°C as determined by TGA;
  • polymorphic Form B has a DVS graph substantially as shown in FIG. 13;
  • polymorphic Form B has a weight gain of about 0.030% or 0.030% ⁇ 0.005% from 0.1 % RH to 95 % RH, as determined by DVS; and
  • polymorphic Form B has a weight loss of about 0.050% or 0.050% ⁇ 0.005% from 95% RH to 0.1% RH, as determined by DVS. III-c.
  • Polymorphic Form C (Amorphous Free-Form) [0187]
  • the polymorphic Form C can also be referred to as polymorphic Form II.
  • polymorphic Form C is substantially amorphous.
  • polymorphic Form C is a solvate of N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide (i.e., compound of Formula (A-1)) with DMF and/or water.
  • polymorphic Form C comprises DMF and a compound of Formula (A-1), wherein the molar ratio between DMF and the compound of Formula (A-1) is about 0.12:1.
  • polymorphic Form C comprises DMF and a compound of Formula (A-1), wherein the weight ratio of DMF is about 1.5 wt.%. In some embodiments, polymorphic Form C comprises water and a compound of Formula (A-1), wherein the weight ratio of water is about 0.5 wt.%. [0189] In some embodiments, polymorphic Form C has an XRPD pattern substantially as shown in FIG. 5. In some embodiments, polymorphic Form C has an XRPD pattern without recognizable characteristic peaks of a crystalline phase. [0190] In some embodiments, polymorphic Form C has a TGA graph substantially as shown in FIG. 6.
  • polymorphic Form C exhibits a weight loss of about 0.9% or 0.9% ⁇ 0.1% (e.g., 0.9% ⁇ 0.09%, 0.9% ⁇ 0.08%, 0.9% ⁇ 0.07%, 0.9% ⁇ 0.06%, 0.9% ⁇ 0.05%, 0.9% ⁇ 0.04%, 0.9% ⁇ 0.03%, 0.9% ⁇ 0.02%, or 0.9% ⁇ 0.01%) between 53 °C and 120 °C, as determined by TGA.
  • 0.9% ⁇ 0.09%, 0.9% ⁇ 0.08%, 0.9% ⁇ 0.07%, 0.9% ⁇ 0.06%, 0.9% ⁇ 0.05%, 0.9% ⁇ 0.04%, 0.9% ⁇ 0.03%, 0.9% ⁇ 0.02%, or 0.9% ⁇ 0.01% between 53 °C and 120 °C, as determined by TGA.
  • polymorphic Form C exhibits a weight loss of about 1.1% or 1.1% ⁇ 0.1% (e.g., 1.1% ⁇ 0.09%, 1.1% ⁇ 0.08%, 1.1% ⁇ 0.07%, 1.1% ⁇ 0.06%, 1.1% ⁇ 0.05%, 1.1% ⁇ 0.04%, 1.1% ⁇ 0.03%, 1.1% ⁇ 0.02%, or 1.1% ⁇ 0.01%) between 120 °C and 200 °C, as determined by TGA.
  • polymorphic Form C has a weight loss of about 0.9% or 0.9% ⁇ 0.1% (e.g., 0.9% ⁇ 0.09%, 0.9% ⁇ 0.08%, 0.9% ⁇ 0.07%, 0.9% ⁇ 0.06%, 0.9% ⁇ 0.05%, 0.9% ⁇ 0.04%, 0.9% ⁇ 0.03%, 0.9% ⁇ 0.02%, or 0.9% ⁇ 0.01%) between 53 °C and 120 °C, and a weight loss of about 1.1% or 1.1% ⁇ 0.1% (e.g., 1.1% ⁇ 0.09%, 1.1% ⁇ 0.08%, 1.1% ⁇ 0.07%, 1.1% ⁇ 0.06%, 1.1% ⁇ 0.05%, 1.1% ⁇ 0.04%, 1.1% ⁇ 0.03%, 1.1% ⁇ 0.02%, or 1.1% ⁇ 0.01%) between 120 °C and 200 °C, as determined by TGA.
  • 0.9% or 0.9% ⁇ 0.1% e.g., 0.9% ⁇ 0.09%, 0.9% ⁇ 0.08%, 0.9% ⁇ 0.07%, 0.9% ⁇ 0.06%, 0.9% ⁇ 0.05%, 0.9% ⁇ 0.04%, 0.9% ⁇ 0.03%, 1.1% ⁇ 0.02%, or 1.1% ⁇ 0.0
  • polymorphic Form C exhibits an apparent decomposition at 319 ⁇ 5 °C (e.g., 319 ⁇ 4.5 °C, 319 ⁇ 4.0 °C, 319 ⁇ 3.5 °C, 319 ⁇ 3.0 °C, 319 ⁇ 2.5 °C, 319 ⁇ 2.0 °C, 319 ⁇ 1.9 °C, 319 ⁇ 1.8 °C, 319 ⁇ 1.7 °C, 319 ⁇ 1.6 °C, 319 ⁇ 1.5 °C, 319 ⁇ 1.4 °C, 319 ⁇ 1.3 °C, 319 ⁇ 1.2 °C, 319 ⁇ 1.1 °C, 319 ⁇ 1.0 °C, 319 ⁇ 0.9 °C, 319 ⁇ 0.8 °C, 319 ⁇ 0.7 °C, 319 ⁇ 0.6 °C, 319 ⁇ 0.5 °C, 319 ⁇ 0.4 °C, 319 ⁇ 0.3 °C, 319 ⁇ 0.2 °C, or 319 ⁇ 0.1 °C).
  • polymorphic Form C has a DSC graph substantially as shown in FIG. 7.
  • polymorphic Form C is characterized as having a glass transition onset at 80 ⁇ 5 °C (e.g., 80 ⁇ 4.5 °C, 80 ⁇ 4.0 °C, 80 ⁇ 3.5 °C, 80 ⁇ 3.0 °C, 80 ⁇ 2.5 °C, 80 ⁇ 2.0 °C, 80 ⁇ 1.9 °C, 80 ⁇ 1.8 °C, 80 ⁇ 1.7 °C, 80 ⁇ 1.6 °C, 80 ⁇ 1.5 °C, 80 ⁇ 1.4 °C, 80 ⁇ 1.3 °C, 80 ⁇ 1.2 °C, 80 ⁇ 1.1 °C, 80 ⁇ 1.0 °C, 80 ⁇ 0.9 °C, 80 ⁇ 0.8 °C, 80 ⁇ 0.7 °C, 80 ⁇ 0.6 °C, 80 ⁇ 0.5 °C, 80 ⁇ 0.4 °C, 80 ⁇ 0.3 °C, 80 ⁇ 0.2 °C, or 80 ⁇ 0.1 °C), as determined by TMDSC.
  • 80 ⁇ 5 °C e.g., 80 ⁇ 4.5 °C,
  • polymorphic Form C is characterized as having a glass transition midpoint at 85 ⁇ 5 °C (e.g., 85 ⁇ 4.5 °C, 85 ⁇ 4.0 °C, 85 ⁇ 3.5 °C, 85 ⁇ 3.0 °C, 85 ⁇ 2.5 °C, 85 ⁇ 2.0 °C, 85 ⁇ 1.9 °C, 85 ⁇ 1.8 °C, 85 ⁇ 1.7 °C, 85 ⁇ 1.6 °C, 85 ⁇ 1.5 °C, 85 ⁇ 1.4 °C, 85 ⁇ 1.3 °C, 85 ⁇ 1.2 °C, 85 ⁇ 1.1 °C, 85 ⁇ 1.0 °C, 85 ⁇ 0.9 °C, 85 ⁇ 0.8 °C, 85 ⁇ 0.7 °C, 85 ⁇ 0.6 °C, 85 ⁇ 0.5 °C, 85 ⁇ 0.4 °C, 85 ⁇ 0.3 °C, 85 ⁇ 0.2 °C, or 85 ⁇ 0.1 °C), as determined by TMDSC.
  • the polymorphic Form C is characterized as having an endotherm peak at 191 ⁇ 2 °C (e.g., 191 ⁇ 1.9 °C, 191 ⁇ 1.8 °C, 191 ⁇ 1.7 °C, 191 ⁇ 1.6 °C, 191 ⁇ 1.5 °C, 191 ⁇ 1.4 °C, 191 ⁇ 1.3 °C, 191 ⁇ 1.2 °C, 191 ⁇ 1.1 °C, 191 ⁇ 1.0 °C, 191 ⁇ 0.9 °C, 191 ⁇ 0.8 °C, 191 ⁇ 0.7 °C, 191 ⁇ 0.6 °C, 191 ⁇ 0.5 °C, 191 ⁇ 0.4 °C, 191 ⁇ 0.3 °C, 191 ⁇ 0.2 °C, or 191 ⁇ 0.1 °C) as determined by TMDSC.
  • part of polymorphic Form C may crystallize above glass transition temperature and converts into polymorphic Form A.
  • polymorphic Form C has a Dynamic Vapor Sorption (DVS) graph substantially as shown in FIG. 8.
  • polymorphic Form C exhibits a weight gain of about 1.13% or 1.13% ⁇ 0.1% (e.g., 1.13% ⁇ 0.09%, 1.13% ⁇ 0.08%, 1.13% ⁇ 0.07%, 1.13% ⁇ 0.06%, 1.13% ⁇ 0.05%, 1.13% ⁇ 0.04%, 1.13% ⁇ 0.03%, 1.13% ⁇ 0.02%, or 1.13% ⁇ 0.01%) from 5% relative humidity (RH) to 95% RH, as determined by DVS.
  • RH relative humidity
  • polymorphic Form C exhibits a weight loss of about 1.57% or 1.57% ⁇ 0.1% (e.g., 1.57% ⁇ 0.09%, 1.57% ⁇ 0.08%, 1.57% ⁇ 0.07%, 1.57% ⁇ 0.06%, 1.57% ⁇ 0.05%, 1.57% ⁇ 0.04%, 1.57% ⁇ 0.03%, 1.57% ⁇ 0.02%, or 1.57% ⁇ 0.01%) from 95% RH to 5% RH, as determined by DVS.
  • polymorphic Form C at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, or all of the following (a)-(m) apply: (a) polymorphic Form C has an XRPD pattern without recognizable characteristic peaks of crystalline materials; (b) polymorphic Form C has an XRPD pattern substantially as shown in FIG. 5; (c) polymorphic Form C has a DSC graph substantially as shown in FIG.
  • polymorphic Form C is characterized as having glass transition onset temperature at 80 ⁇ 2 °C as determined by DSC;
  • polymorphic Form C is characterized as having glass transition midpoint temperature at 85 ⁇ 2 °C as determined by DSC;
  • polymorphic Form C is characterized as having an endotherm peak at 191 ⁇ 2 °C as determined by DSC;
  • polymorphic Form C has a TGA graph substantially as shown in FIG.
  • polymorphic Form C has a weight loss of about 0.9% or 0.9% ⁇ 0.1% between 53 °C and 120 °C as determined by TGA;
  • polymorphic Form C has a weight loss of about 1.1% or 1.1% ⁇ 0.1% between 120 °C and 200 °C as determined by TGA;
  • polymorphic Form C has an apparent decomposition at 319 ⁇ 5 °C;
  • polymorphic Form C has a DVS graph substantially as shown in FIG. 8.
  • compositions containing polymorphs described herein such as polymorphic Form A, polymorphic Form C, or a mixture thereof.
  • the composition contains polymorphic Form A.
  • the composition contains polymorphic Form C.
  • the composition contains a mixture of polymorphic Form A and polymorphic Form C.
  • the composition is substantially free of polymorphic Form C of the compound of Formula (A-1).
  • the composition is substantially free of salts of the compound of Formula (A-1).
  • composition containing Form A of the compound of Formula (A-1) at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition is polymorphic Form A.
  • composition containing polymorphic Form A of the compound of Formula (A-1) at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the compound of Formula (A-1) exists in Form A.
  • the composition is substantially free of polymorphic Form A of the compound of Formula (A-1).
  • the composition is substantially free of salts of the compound of Formula (A-1).
  • composition containing Form C of the compound of Formula (A-1) at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition is polymorphic Form C.
  • composition containing polymorphic Form C of the compound of Formula (A-1) at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the compound of Formula (A-1) exists in Form C. III-d.
  • Polymorphic Form IV (Mono-Sodium Salt Pattern A) [0199]
  • N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide is in the form of a salt.
  • the salt is an alkali metal salt (e.g., Na salt or K salt).
  • the molar ration between the compound of Formula (A-1) and metal ion (e.g., Na + ) is about 1:0.8 to about 1:1.5, or about 1:1.
  • polymorphic Form IV comprises less than 10 wt.%, such as less than about any of 8%, 6%, 4%, 2%, 1%, or 0.1% water.
  • polymorphic Form IV is an anhydrate salt of N-(1''-(3- (((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''- indolin]-5''-yl)ethanesulfonamide.
  • polymorphic Form IV has an XRPD pattern substantially as shown in FIG. 14. [0201] Angles 2-theta and relative peak intensities observed for polymorphic Form IV using XRPD are shown in Table IV-1. Table IV-1
  • polymorphic Form IV has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at angles 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 14 or as provided in Table IV-1. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Relative peak intensities and peak assignments can vary within experimental error.
  • peak assignments listed herein, including for polymorphic Form IV can vary by about ⁇ 1 degrees, ⁇ 0.8 degrees, ⁇ 0.6 degrees, ⁇ 0.4 degrees, ⁇ 0.2 degrees, or ⁇ 0.1 degrees 2-theta.
  • polymorphic Form IV has an XRPD pattern comprising peaks at angles 2-theta of 7.66 ⁇ 0.20, 8.45 ⁇ 0.20, 11.64 ⁇ 0.20, 17.92 ⁇ 0.20, and 22.82 ⁇ 0.20 degrees.
  • the polymorphic Form IV has an XRPD pattern comprising additional peaks at angles 2-theta of 16.91 ⁇ 0.20 and 17.13 ⁇ 0.20 degrees.
  • polymorphic Form IV has an XRPD pattern further comprising additional peaks at angles 2- theta of 13.60 ⁇ 0.20 and 18.34 ⁇ 0.20 degrees. In some embodiments, polymorphic Form IV has an XRPD pattern comprising peaks at angles 2-theta of 7.66 ⁇ 0.20, 8.45 ⁇ 0.20, 11.64 ⁇ 0.20, 12.35 ⁇ 0.20, 13.60 ⁇ 0.20, 16.91 ⁇ 0.20, 17.13 ⁇ 0.20, 17.92 ⁇ 0.20, 18.34 ⁇ 0.20, 18.62 ⁇ 0.20, 19.05 ⁇ 0.20, 20.44 ⁇ 0.20, 22.82 ⁇ 0.20, 23.43 ⁇ 0.20, 25.08 ⁇ 0.20, and 26.94 ⁇ 0.20degrees.
  • polymorphic Form IV has a differential scanning calorimetry (DSC) graph substantially as shown in FIG. 15. In some embodiments, polymorphic Form IV is characterized as having an endotherm onset at about 186 °C as determined by DSC.
  • polymorphic Form IV is characterized as having an endotherm onset at 186 ⁇ 2 °C (e.g., 186 ⁇ 1.9 °C, 186 ⁇ 1.8 °C, 186 ⁇ 1.7 °C, 186 ⁇ 1.6 °C, 186 ⁇ 1.5 °C, 186 ⁇ 1.4 °C, 186 ⁇ 1.3 °C, 186 ⁇ 1.2 °C, 186 ⁇ 1.1 °C, 186 ⁇ 1.0 °C, 186 ⁇ 0.9 °C, 186 ⁇ 0.8 °C, 186 ⁇ 0.7 °C, 186 ⁇ 0.6 °C, 186 ⁇ 0.5 °C, 186 ⁇ 0.4 °C, 186 ⁇ 0.3 °C, 186 ⁇ 0.2 °C, or 186 ⁇ 0.1 °C) as determined by DSC.
  • endotherm onset at 186 ⁇ 2 °C e.g., 186 ⁇ 1.9 °C, 186 ⁇ 1.8 °C, 186 ⁇ 1.7 °C, 186 ⁇ 1.6 °C, 186 ⁇ 1.5 °C, 186 ⁇ 1.4
  • Form IV is characterized as having an endotherm peak at about 190 °C as determined by DSC. In some embodiments, Form IV is characterized as having an endotherm peak at 190 ⁇ 2 °C (e.g., 190 ⁇ 1.9 °C, 190 ⁇ 1.8 °C, 190 ⁇ 1.7 °C, 190 ⁇ 1.6 °C, 190 ⁇ 1.5 °C, 190 ⁇ 1.4 °C, 190 ⁇ 1.3 °C, 190 ⁇ 1.2 °C, 190 ⁇ 1.1 °C, 190 ⁇ 1.0 °C, 190 ⁇ 0.9 °C, 190 ⁇ 0.8 °C, 190 ⁇ 0.7 °C, 190 ⁇ 0.6 °C, 190 ⁇ 0.5 °C, 190 ⁇ 0.4 °C, 190 ⁇ 0.3 °C, 190 ⁇ 0.2 °C, or 190 ⁇ 0.1 °C) as determined by DSC.
  • 190 ⁇ 2 °C e.g., 190 ⁇ 1.9 °C, 190 ⁇ 1.8 °C, 190 ⁇ 1.7 °C,
  • polymorphic Form IV is characterized as having an endotherm onset at 18 ⁇ 5 °C (e.g., 18 ⁇ 4 °C, 18 ⁇ 3 °C, 18 ⁇ 3 °C, 18 ⁇ 1.9 °C, 18 ⁇ 1.8 °C, 18 ⁇ 1.7 °C, 18 ⁇ 1.6 °C, 18 ⁇ 1.5 °C, 18 ⁇ 1.4 °C, 18 ⁇ 1.3 °C, 18 ⁇ 1.2 °C, 18 ⁇ 1.1 °C, 18 ⁇ 1.0 °C, 18 ⁇ 0.9 °C, 18 ⁇ 0.8 °C, 18 ⁇ 0.7 °C, 18 ⁇ 0.6 °C, 18 ⁇ 0.5 °C, 18 ⁇ 0.4 °C, 18 ⁇ 0.3 °C, 18 ⁇ 0.2 °C, or 18 ⁇ 0.1 °C) as determined by DSC.
  • 18 ⁇ 5 °C e.g., 18 ⁇ 4 °C, 18 ⁇ 3 °C, 18 ⁇ 3 °C, 18 ⁇ 1.9 °C, 18 ⁇ 1.8 °C, 18 ⁇ 1.7 °C, 18 ⁇ 1.6 °C, 18
  • Form IV is characterized as having an endotherm peak at about 43 °C as determined by DSC. In some embodiments, Form IV is characterized as having an endotherm peak at 43 ⁇ 5 °C (e.g., 43 ⁇ 4 °C, 43 ⁇ 3 °C, 43 ⁇ 2 °C, 43 ⁇ 1.9 °C, 43 ⁇ 1.8 °C, 43 ⁇ 1.7 °C, 43 ⁇ 1.6 °C, 43 ⁇ 1.5 °C, 43 ⁇ 1.4 °C, 43 ⁇ 1.3 °C, 43 ⁇ 1.2 °C, 43 ⁇ 1.1 °C, 43 ⁇ 1.0 °C, 43 ⁇ 0.9 °C, 43 ⁇ 0.8 °C, 43 ⁇ 0.7 °C, 43 ⁇ 0.6 °C, 43 ⁇ 0.5 °C, 43 ⁇ 0.4 °C, 43 ⁇ 0.3 °C, 43 ⁇ 0.2 °C, or 43 ⁇ 0.1 °C) as determined by DSC.
  • 43 ⁇ 5 °C e.g., 43 ⁇ 4 °C, 43 ⁇ 3 °C, 43 ⁇ 2 °C, 43 ⁇ 1.9
  • polymorphic Form IV has a thermographic analysis (TGA) graph substantially as shown in FIG. 16.
  • TGA thermographic analysis
  • polymorphic Form IV exhibits a weight loss of about 0.7% or 0.7% ⁇ 0.1% (e.g., 0.7% ⁇ 0.09%, 0.7% ⁇ 0.07%, 0.7% ⁇ 0.06%, 0.7% ⁇ 0.05%, 0.7% ⁇ 0.04%, 0.7% ⁇ 0.03%, 0.7% ⁇ 0.02%, or 0.7% ⁇ 0.01%) between 25 °C and 170 °C as determined by TGA.
  • polymorphic Form IV has an XRPD pattern comprising peaks at angles 2-theta of 7.66 ⁇ 0.20, 8.45 ⁇ 0.20, 11.64 ⁇ 0.20, 17.92 ⁇ 0.20, and 22.82 ⁇ 0.20 degrees; an XRPD pattern comprising additional peaks at angles 2-theta of 16.91 ⁇ 0.20 and 17.13 ⁇ 0.20 degrees; an XRPD pattern further comprising additional peaks at angles 2-theta of 13.60 ⁇ 0.20 and 18.34 ⁇ 0.20 degrees; or an XRPD pattern comprising peaks at angles 2-theta of 7.66 ⁇ 0.20, 8.45 ⁇ 0.20, 11.64 ⁇ 0.20, 12.35 ⁇ 0.20, 13.60 ⁇ 0.20, 16.91 ⁇ 0.20, 17.13 ⁇ 0.20, 17.92 ⁇ 0.20, 18.34 ⁇ 0.20, 18.62 ⁇ 0.20, 19.05
  • polymorphic Form IV has a DSC graph substantially as shown in FIG. 15;
  • polymorphic Form IV is characterized as having an endotherm onset at 186 ⁇ 2 °C as determined by DSC;
  • polymorphic Form IV is characterized as having an endotherm peak at 190 ⁇ 2 °C as determined by DSC;
  • polymorphic Form IV has a TGA graph substantially as shown in FIG. 16; and
  • polymorphic Form IV has a weight loss of about 0.7% or 0.7% ⁇ 0.1% between 25 °C and 170 °C as determined by TGA. III-e.
  • Polymorphic Form V (Di-Sodium Salt Pattern A) [0207]
  • polymorphic Form V of N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide which is referred to as polymorphic Form V hereinafter.
  • N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide is in the form of a salt.
  • the salt is an alkali metal salt (e.g., Na salt or K salt).
  • the molar ration between the compound of Formula (A-1) and metal ion (e.g., Na + ) is about 1:1.5 to about 1:2.5, about 1:1.5 to about 1:2, or about 1:2.
  • polymorphic Form V comprises less than 10 wt.%, such as less than about any of 8%, 6%, 4%, 2%, 1%, or 0.1% water.
  • polymorphic Form V is an anhydrate salt of N-(1''-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane- 1,1'-cyclohexane-4',3''-indolin]-5''-yl)ethanesulfonamide.
  • polymorphic Form V has an XRPD pattern substantially as shown in FIG. 17.
  • polymorphic Form V has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at angles 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 17 or as provided in Table V-1. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Relative peak intensities and peak assignments can vary within experimental error.
  • peak assignments listed herein, including for polymorphic Form V can vary by about ⁇ 1 degrees, ⁇ 0.8 degrees, ⁇ 0.6 degrees, ⁇ 0.4 degrees, ⁇ 0.2 degrees, or ⁇ 0.1 degrees 2-theta.
  • polymorphic Form V has an XRPD pattern comprising peaks at angles 2-theta of 6.39 ⁇ 0.20, 6.89 ⁇ 0.20, 16.32 ⁇ 0.20, 17.01 ⁇ 0.20, and 22.82 ⁇ 0.20 degrees.
  • the polymorphic Form V has an XRPD pattern comprising additional peaks at angles 2-theta of 12.50 ⁇ 0.20 and 16.52 ⁇ 0.20 degrees.
  • polymorphic Form V has an XRPD pattern further comprising additional peaks at angles 2- theta of 13.48 ⁇ 0.20 and 14.34 ⁇ 0.20 degrees.
  • polymorphic Form V has an XRPD pattern comprising peaks at angles 2-theta of 6.39 ⁇ 0.20, 6.89 ⁇ 0.20, 11.46 ⁇ 0.20, 12.50 ⁇ 0.20, 13.48 ⁇ 0.20, 14.34 ⁇ 0.20, 16.32 ⁇ 0.20, 16.52 ⁇ 0.20, 17.01 ⁇ 0.20, 19.03 ⁇ 0.20, 19.30 ⁇ 0.20, 19.73 ⁇ 0.20, and 19.91 ⁇ 0.20 degrees. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG.
  • polymorphic Form V has a differential scanning calorimetry (DSC) graph substantially as shown in FIG. 18.
  • DSC differential scanning calorimetry
  • polymorphic Form V is characterized as having an endotherm onset at about 203 °C as determined by DSC.
  • polymorphic Form V is characterized as having an endotherm onset at 203 ⁇ 2 °C (e.g., 203 ⁇ 1.9 °C, 203 ⁇ 1.8 °C, 203 ⁇ 1.7 °C, 203 ⁇ 1.6 °C, 203 ⁇ 1.5 °C, 203 ⁇ 1.4 °C, 203 ⁇ 1.3 °C, 203 ⁇ 1.2 °C, 203 ⁇ 1.1 °C, 203 ⁇ 1.0 °C, 203 ⁇ 0.9 °C, 203 ⁇ 0.8 °C, 203 ⁇ 0.7 °C, 203 ⁇ 0.6 °C, 203 ⁇ 0.5 °C, 203 ⁇ 0.4 °C, 203 ⁇ 0.3 °C, 203 ⁇ 0.2 °C, or 203 ⁇ 0.1 °C) as determined by DSC.
  • endotherm onset at 203 ⁇ 2 °C e.g., 203 ⁇ 1.9 °C, 203 ⁇ 1.8 °C, 203 ⁇ 1.7 °C, 203 ⁇ 1.6 °C, 203 ⁇ 1.5 °C, 203 ⁇ 1.4
  • Form V is characterized as having an endotherm peak at about 212 °C as determined by DSC. In some embodiments, Form V is characterized as having an endotherm peak at 212 ⁇ 2 °C (e.g., 212 ⁇ 1.9 °C, 212 ⁇ 1.8 °C, 212 ⁇ 1.7 °C, 212 ⁇ 1.6 °C, 212 ⁇ 1.5 °C, 212 ⁇ 1.4 °C, 212 ⁇ 1.3 °C, 212 ⁇ 1.2 °C, 212 ⁇ 1.1 °C, 212 ⁇ 1.0 °C, 212 ⁇ 0.9 °C, 212 ⁇ 0.8 °C, 212 ⁇ 0.7 °C, 212 ⁇ 0.6 °C, 212 ⁇ 0.5 °C, 212 ⁇ 0.4 °C, 212 ⁇ 0.3 °C, 212 ⁇ 0.2 °C, or 212 ⁇ 0.1 °C) as determined by DSC.
  • 212 ⁇ 2 °C e.g., 212 ⁇ 1.9 °C, 212 ⁇ 1.8 °C, 212 ⁇ 1.7 °C,
  • Form V is characterized as having an endotherm peak at about 60 °C as determined by DSC. In some embodiments, Form V is characterized as having an endotherm peak at 60 ⁇ 2 °C (e.g., 60 ⁇ 1.9 °C, 60 ⁇ 1.8 °C, 60 ⁇ 1.7 °C, 60 ⁇ 1.6 °C, 60 ⁇ 1.5 °C, 60 ⁇ 1.4 °C, 60 ⁇ 1.3 °C, 60 ⁇ 1.2 °C, 60 ⁇ 1.1 °C, 60 ⁇ 1.0 °C, 60 ⁇ 0.9 °C, 60 ⁇ 0.8 °C, 60 ⁇ 0.7 °C, 60 ⁇ 0.6 °C, 60 ⁇ 0.5 °C, 60 ⁇ 0.4 °C, 60 ⁇ 0.3 °C, 60 ⁇ 0.2 °C, or 60 ⁇ 0.1 °C) as determined by DSC.
  • 60 ⁇ 2 °C e.g., 60 ⁇ 1.9 °C, 60 ⁇ 1.8 °C, 60 ⁇ 1.7 °C, 60 ⁇ 1.6 °C, 60 ⁇ 1.5 °C, 60 ⁇ 1.4 °C, 60 ⁇ 1.3
  • Form V is characterized as having an endotherm peak at about 89 °C as determined by DSC. In some embodiments, Form V is characterized as having an endotherm peak at 89 ⁇ 2 °C (e.g., 89 ⁇ 1.9 °C, 89 ⁇ 1.8 °C, 89 ⁇ 1.7 °C, 89 ⁇ 1.6 °C, 89 ⁇ 1.5 °C, 89 ⁇ 1.4 °C, 89 ⁇ 1.3 °C, 89 ⁇ 1.2 °C, 89 ⁇ 1.1 °C, 89 ⁇ 1.0 °C, 89 ⁇ 0.9 °C, 89 ⁇ 0.8 °C, 89 ⁇ 0.7 °C, 89 ⁇ 0.6 °C, 89 ⁇ 0.5 °C, 89 ⁇ 0.4 °C, 89 ⁇ 0.3 °C, 89 ⁇ 0.2 °C, or 89 ⁇ 0.1 °C) as determined by DSC.
  • 89 ⁇ 2 °C e.g., 89 ⁇ 1.9 °C, 89 ⁇ 1.8 °C, 89 ⁇ 1.7 °C,
  • polymorphic Form V has a thermographic analysis (TGA) graph substantially as shown in FIG. 19.
  • TGA thermographic analysis
  • polymorphic Form V exhibits a weight loss of about 3.3% or 3.3% ⁇ 0.5% (e.g., 3.3% ⁇ 0.4%,3.3% ⁇ 0.3% 3.3% ⁇ 0.2% 3.3% ⁇ 0.1% 3.3% ⁇ 0.09%, 3.3% ⁇ 0.07%, 3.3% ⁇ 0.06%, 3.3% ⁇ 0.05%, 3.3% ⁇ 0.04%, 3.3% ⁇ 0.03%, 3.3% ⁇ 0.02%, or 3.3% ⁇ 0.01%) between 25 °C and 48 °C as determined by TGA.
  • polymorphic Form V exhibits a weight loss of about 2.1% or 2.1% ⁇ 0.5% (e.g., 2.1% ⁇ 0.4%,2.1% ⁇ 0.3% 2.1% ⁇ 0.2% 2.1% ⁇ 0.1% 2.1% ⁇ 0.09%, 2.1% ⁇ 0.07%, 2.1% ⁇ 0.06%, 2.1% ⁇ 0.05%, 2.1% ⁇ 0.04%, 2.1% ⁇ 0.03%, 2.1% ⁇ 0.02%, or 2.1% ⁇ 0.01%) between 48 °C and 100 °C as determined by TGA.
  • 2.1% or 2.1% ⁇ 0.5% e.g., 2.1% ⁇ 0.4%,2.1% ⁇ 0.3% 2.1% ⁇ 0.2% 2.1% ⁇ 0.1% 2.1% ⁇ 0.09%, 2.1% ⁇ 0.07%, 2.1% ⁇ 0.06%, 2.1% ⁇ 0.05%, 2.1% ⁇ 0.04%, 2.1% ⁇ 0.03%, 2.1% ⁇ 0.02%, or 2.1% ⁇ 0.01%
  • polymorphic Form V has an XRPD pattern comprising peaks at angles 2-theta of 6.39 ⁇ 0.20, 6.89 ⁇ 0.20, 16.32 ⁇ 0.20, 17.01 ⁇ 0.20, and 22.82 ⁇ 0.20 degrees; an XRPD pattern comprising additional peaks at angles 2-theta of 12.50 ⁇ 0.20 and 16.52 ⁇ 0.20 degrees; an XRPD pattern further comprising additional peaks at angles 2-theta of 13.48 ⁇ 0.20 and 14.34 ⁇ 0.20 degrees; or an XRPD pattern comprising peaks at angles 2-theta of 6.39 ⁇ 0.20, 6.89 ⁇ 0.20, 11.46 ⁇ 0.20, 12.50 ⁇ 0.20, 13.48 ⁇ 0.20, 14.34 ⁇ 0.20, 16.32 ⁇ 0.20, 16.52 ⁇ 0.20, 17.01 ⁇ 0.20, 19.03 ⁇ 0.2
  • polymorphic Form V has a DSC graph substantially as shown in FIG. 18;
  • polymorphic Form V is characterized as having an endotherm onset at 203 ⁇ 2 °C as determined by DSC;
  • polymorphic Form V is characterized as having an endotherm peak at 212 ⁇ 2 °C as determined by DSC;
  • polymorphic Form V is characterized as having an endotherm peak at 60 ⁇ 2 °C as determined by DSC;
  • polymorphic Form V has a TGA graph substantially as shown in FIG.
  • polymorphic Form V has a weight loss of about 3.3% or 3.3% ⁇ 0.5% between 25 °C and 48 °C as determined by TGA; and (i) polymorphic Form V has a weight loss of about 2.1 % or 2.1% ⁇ 0.5% between 48 °C and 100 °C as determined by TGA. III-f.
  • Polymorphic Form VI (Mono-Potassium Salt Pattern A) [0215]
  • polymorphic Form VI of N’ 1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-’,1'-cyclohexan’-4’’3''- indolin’’5''-yl)ethanesulfonamide, which is referred to as polymorphic Form VI hereinafter.
  • N’’1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-’,1'-cyclohexan’-4’’3''- indolin’’5''-yl)ethanesulfonamide is in the form of a salt.
  • the salt is an alkali metal salt (e.g., Na salt or K salt).
  • the molar ration between the compound of Formula (A-1) and metal ion (e.g., K + ) is about 1:0.8 to about 1:1.5, or about 1:1.2, or about 1:1.
  • polymorphic Form VI comprises less than 10 wt.%, such as less than about any of 8%, 6%, 4%, 2%, 1%, or 0.1% solvent.
  • polymorphic Form VI is an anhydrate salt of N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide.
  • polymorphic Form VI has an XRPD pattern substantially as shown in FIG. 20. [0217] Angles 2-theta and relative peak intensities observed for polymorphic Form VI using XRPD are shown in Table VI-1. Table VI-1
  • polymorphic Form VI has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at angles 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 20 or as provided in Table VI-1. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Relative peak intensities and peak assignments can vary within experimental error.
  • peak assignments listed herein, including for polymorphic Form VI can vary by about ⁇ 1 degrees, about ⁇ 0.6 degrees, ⁇ 0.4 degrees, ⁇ 0.2 degrees, or ⁇ 0.1 degrees 2-theta.
  • polymorphic Form VI has an XRPD pattern comprising peaks at angles 2-theta of 13.48 ⁇ 0.20, 16.62 ⁇ 0.20, and 16.62 ⁇ 0.20 degrees.
  • the polymorphic Form VI has an XRPD pattern comprising additional peaks at angles 2-theta of 12.25 ⁇ 0.20 and 19.69 ⁇ 0.20 degrees.
  • polymorphic Form VI has an XRPD pattern further comprising additional peaks at angles 2-theta of 11.21 ⁇ 0.20 and 24.83 ⁇ 0.20 degrees. In some embodiments, polymorphic Form VI has an XRPD pattern comprising peaks at angles 2-theta of 5.62 ⁇ 0.20, 6.28 ⁇ 0.20, 11.21 ⁇ 0.20, 12.25 ⁇ 0.20, 13.48 ⁇ 0.20, 16.62 ⁇ 0.20, 17.14 ⁇ 0.20, 19.69 ⁇ 0.20, 24.83 ⁇ 0.20, and 27.76 ⁇ 0.20 degrees. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG.
  • polymorphic Form VI has a differential scanning calorimetry (DSC) graph substantially as shown in FIG. 21.
  • DSC differential scanning calorimetry
  • Form VI is characterized as having an endotherm peak at about 39 °C as determined by DSC.
  • Form VI is characterized as having an endotherm peak at 39 ⁇ 5 °C (e.g., 39 ⁇ 4 °C, 39 ⁇ 3 °C, 39 ⁇ 2 °C, 39 ⁇ 1.9 °C, 39 ⁇ 1.8 °C, 39 ⁇ 1.7 °C, 39 ⁇ 1.6 °C, 39 ⁇ 1.5 °C, 39 ⁇ 1.4 °C, 39 ⁇ 1.3 °C, 39 ⁇ 1.2 °C, 39 ⁇ 1.1 °C, 39 ⁇ 1.0 °C, 39 ⁇ 0.9 °C, 39 ⁇ 0.8 °C, 39 ⁇ 0.7 °C, 39 ⁇ 0.6 °C, 39 ⁇ 0.5 °C, 39 ⁇ 0.4 °C, 39 ⁇ 0.3 °C, 39 ⁇ 0.2 °C, or 39 ⁇ 0.1 °C) as determined by DSC.
  • 39 ⁇ 5 °C e.g., 39 ⁇ 4 °C, 39 ⁇ 3 °C, 39 ⁇ 2 °C, 39 ⁇ 1.9 °C, 39 ⁇ 1.8 °C, 39 ⁇ 1.7 °C, 39 ⁇ 1.6 °C, 39 ⁇ 1.5 °
  • Form VI is characterized as having an endotherm peak at about 194 °C as determined by DSC. In some embodiments, Form VI is characterized as having an endotherm peak at 156 ⁇ 5 °C (e.g., 156 ⁇ 4 °C, 156 ⁇ 3 °C, 156 ⁇ 2 °C, 156 ⁇ 1.9 °C, 156 ⁇ 1.8 °C, 156 ⁇ 1.7 °C, 156 ⁇ 1.6 °C, 156 ⁇ 1.5 °C, 156 ⁇ 1.4 °C, 156 ⁇ 1.3 °C, 156 ⁇ 1.2 °C, 156 ⁇ 1.1 °C, 156 ⁇ 1.0 °C, 156 ⁇ 0.9 °C, 156 ⁇ 0.8 °C, 156 ⁇ 0.7 °C, 156 ⁇ 0.6 °C, 156 ⁇ 0.5 °C, 156 ⁇ 0.4 °C, 156 ⁇ 0.3 °C, 156 ⁇ 0.2 °C, or 156 ⁇ 0.1 °C) as determined by DSC.
  • 156 ⁇ 5 °C e.g.,
  • polymorphic Form VI has a thermographic analysis (TGA) graph substantially as shown in FIG. 22.
  • TGA thermographic analysis
  • polymorphic Form VI exhibits a weight loss of about 3.2% or 3.2% ⁇ 0.1% (e.g., 3.2% ⁇ 0.09%, 3.2% ⁇ 0.07%, 3.2% ⁇ 0.06%, 3.2% ⁇ 0.05%, 3.2% ⁇ 0.04%, 3.2% ⁇ 0.03%, 3.2% ⁇ 0.02%, or 3.2% ⁇ 0.01%) between 25 °C and 100 °C as determined by TGA.
  • polymorphic Form VI exhibits substantially continuous weight loss between 25 °C and 300 °C as determined by TGA.
  • polymorphic Form VI at least one, at least two, at least three, at least four, at least five, at least six, or all of the following (a)-(g) apply: (a) polymorphic Form VI has an XRPD pattern comprising peaks at angles 2-theta of 13.48 ⁇ 0.20, 16.62 ⁇ 0.20, and 16.62 ⁇ 0.20 degrees; an XRPD pattern comprising additional peaks at angles 2-theta of 12.25 ⁇ 0.20 and 19.69 ⁇ 0.20 degrees; an XRPD pattern further comprising additional peaks at angles 2-theta of 11.21 ⁇ 0.20 and 24.83 ⁇ 0.20 degrees; or an XRPD pattern comprising peaks at angles 2-theta of 5.62 ⁇ 0.20, 6.28 ⁇ 0.20, 11.21 ⁇ 0.20, 12.25 ⁇ 0.20, 13.48 ⁇ 0.20, 16.62 ⁇ 0.20, 17.14 ⁇ 0.20, 19.69 ⁇ 0.20, 24.83 ⁇ 0.20, and 27.76 ⁇ 0.20degrees; (b) polymorphic Form VI has
  • polymorphic Form VI has a DSC graph substantially as shown in FIG. 21;
  • polymorphic Form VI is characterized as having an endotherm peak at 39 ⁇ 5 °C as determined by DSC;
  • polymorphic Form VI is characterized as having an endotherm peak at 156 ⁇ 5 °C as determined by DSC;
  • polymorphic Form VI has a TGA graph substantially as shown in FIG. 22; and
  • polymorphic Form VI has a weight loss of about 3.2% or 3.2% ⁇ 0.1%between 25 °C and 100 °C as determined by TGA. III-g.
  • Polymorphic Form VII (Di-Potassium Salt Pattern A) [0223]
  • N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide is in the form of a salt.
  • the salt is an alkali metal salt (e.g., Na salt or K salt).
  • the molar ration between the compound of Formula (A-1) and metal ion (e.g., K + ) is about 1:2 to about 1:2.5, or about 1:2.25.
  • polymorphic Form VII comprises about 0.5 equiv. to about 1.5 equiv. such as about 1 equiv. of ethanol by molar ratio. [0224] In some embodiments, polymorphic Form VII has an XRPD pattern substantially as shown in FIG. 23. [0225] Angles 2-theta and relative peak intensities observed for polymorphic Form VII using XRPD are shown in Table VII-1. Table VII-1
  • polymorphic Form VII has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at angles 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 23 or as provided in Table VII-1. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Relative peak intensities and peak assignments can vary within experimental error.
  • peak assignments listed herein, including for polymorphic Form VII can vary by about ⁇ 1.0 degrees, ⁇ 0.6 degrees, ⁇ 0.4 degrees, ⁇ 0.2 degrees, or ⁇ 0.1 degrees 2-theta.
  • polymorphic Form VII has an XRPD pattern comprising peaks at angles 2-theta of 5.84 ⁇ 0.50, 5.91 ⁇ 0.50, 9.21 ⁇ 0.50, and 18.56 ⁇ 0.50 degrees.
  • the polymorphic Form VII has an XRPD pattern comprising additional peaks at angles 2-theta of 15.56 ⁇ 0.50 and 19.02 ⁇ 0.50 degrees.
  • polymorphic Form VII has an XRPD pattern further comprising additional peaks at angles 2-theta of 13.58 ⁇ 0.50 and 25.27 ⁇ 0.50 degrees.
  • polymorphic Form VII has an XRPD pattern comprising peaks at angles 2-theta of 5.84 ⁇ 0.50, 5.91 ⁇ 0.50, 9.21 ⁇ 0.50, 13.58 ⁇ 0.50, 14.29 ⁇ 0.50, 15.56 ⁇ 0.50, 16.74 ⁇ 0.50, 17.79 ⁇ 0.50, 18.56 ⁇ 0.50, 19.02 ⁇ 0.50, 21.30 ⁇ 0.50, 25.27 ⁇ 0.50, and 30.13 ⁇ 0.50 degrees. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG.
  • polymorphic Form VII has a differential scanning calorimetry (DSC) graph substantially as shown in FIG. 24.
  • DSC differential scanning calorimetry
  • Form VII is characterized as having an endotherm peak at about 70 °C as determined by DSC.
  • Form VII is characterized as having an endotherm peak at 70 ⁇ 10 °C (e.g., 70 ⁇ 8 °C, 70 ⁇ 6 °C, 70 ⁇ 5 °C, 70 ⁇ 4 °C, 70 ⁇ 2 °C, 70 ⁇ 2 °C, 70 ⁇ 1.7 °C, 70 ⁇ 1.6 °C, 70 ⁇ 1.5 °C, 70 ⁇ 1.4 °C, 70 ⁇ 1.3 °C, 70 ⁇ 1.2 °C, 70 ⁇ 1.1 °C, 70 ⁇ 1.0 °C, 70 ⁇ 0.9 °C, 70 ⁇ 0.8 °C, 70 ⁇ 0.7 °C, 70 ⁇ 0.6 °C, 70 ⁇ 0.5 °C, 70 ⁇ 0.4 °C, 70 ⁇ 0.3 °C, 70 ⁇ 0.2 °C, or 70 ⁇ 0.1 °C) as determined by DSC.
  • 70 ⁇ 10 °C e.g., 70 ⁇ 8 °C, 70 ⁇ 6 °C, 70 ⁇ 5 °C, 70 ⁇ 4 °C, 70 ⁇ 2 °C, 70 ⁇ 2 °C, 70 ⁇ 1.7 °
  • polymorphic Form VII is characterized as having an endotherm onset at about 122 °C as determined by DSC. In some embodiments, polymorphic Form VII is characterized as having an endotherm onset at 122 ⁇ 2 °C (e.g., 122 ⁇ 1.9 °C, 122 ⁇ 1.8 °C, 122 ⁇ 1.7 °C, 122 ⁇ 1.6 °C, 122 ⁇ 1.5 °C, 122 ⁇ 1.4 °C, 122 ⁇ 1.3 °C, 122 ⁇ 1.2 °C, 122 ⁇ 1.1 °C, 122 ⁇ 1.0 °C, 122 ⁇ 0.9 °C, 122 ⁇ 0.8 °C, 122 ⁇ 0.7 °C, 122 ⁇ 0.6 °C, 122 ⁇ 0.5 °C, 122 ⁇ 0.4 °C, 122 ⁇ 0.3 °C, 122 ⁇ 0.2 °C, or 122 ⁇ 0.1 °C) as determined by DSC.
  • 122 ⁇ 2 °C e.g., 122 ⁇ 1.9 °C, 122 ⁇ 1.8 °C,
  • Form VII is characterized as having an endotherm peak at about 132 °C as determined by DSC. In some embodiments, Form VII is characterized as having an endotherm peak at 132 ⁇ 2 °C (e.g., 132 ⁇ 1.9 °C, 132 ⁇ 1.8 °C, 132 ⁇ 1.7 °C, 132 ⁇ 1.6 °C, 132 ⁇ 1.5 °C, 132 ⁇ 1.4 °C, 132 ⁇ 1.3 °C, 132 ⁇ 1.2 °C, 132 ⁇ 1.1 °C, 132 ⁇ 1.0 °C, 132 ⁇ 0.9 °C, 132 ⁇ 0.8 °C, 132 ⁇ 0.7 °C, 132 ⁇ 0.6 °C, 132 ⁇ 0.5 °C, 132 ⁇ 0.4 °C, 132 ⁇ 0.3 °C, 132 ⁇ 0.2 °C, or 132 ⁇ 0.1 °C) as determined by DSC.
  • 132 ⁇ 2 °C e.g., 132 ⁇ 1.9 °C, 132 ⁇ 1.8 °C, 132 ⁇ 1.7 °C,
  • polymorphic Form VII is characterized as having an endotherm onset at about 151 °C as determined by DSC. In some embodiments, polymorphic Form VII is characterized as having an endotherm onset at 151 ⁇ 2 °C (e.g., 151 ⁇ 1.9 °C, 151 ⁇ 1.8 °C, 151 ⁇ 1.7 °C, 151 ⁇ 1.6 °C, 151 ⁇ 1.5 °C, 151 ⁇ 1.4 °C, 151 ⁇ 1.3 °C, 151 ⁇ 1.2 °C, 151 ⁇ 1.1 °C, 151 ⁇ 1.0 °C, 151 ⁇ 0.9 °C, 151 ⁇ 0.8 °C, 151 ⁇ 0.7 °C, 151 ⁇ 0.6 °C, 151 ⁇ 0.5 °C, 151 ⁇ 0.4 °C, 151 ⁇ 0.3 °C, 151 ⁇ 0.2 °C, or 151 ⁇ 0.1 °C) as determined by DSC.
  • 151 ⁇ 2 °C e.g., 151 ⁇ 1.9 °C, 151 ⁇ 1.8 °C,
  • polymorphic Form VII has a thermographic analysis (TGA) graph substantially as shown in FIG. 25. In some embodiments, polymorphic Form VII exhibits substantially continuous weight loss between 25 °C and 300 °C as determined by TGA.
  • TGA thermographic analysis
  • polymorphic Form VII has an XRPD pattern comprising peaks at angles 2-theta of 5.84 ⁇ 0.50, 5.91 ⁇ 0.50, 9.21 ⁇ 0.50, and 18.56 ⁇ 0.50 degrees; an XRPD pattern comprising additional peaks at angles 2-theta of 15.56 ⁇ 0.50 and 19.02 ⁇ 0.50 degrees; an XRPD pattern further comprising additional peaks at angles 2-theta of 13.58 ⁇ 0.50 and 25.27 ⁇ 0.50 degrees; or an XRPD pattern comprising peaks at angles 2-theta of 5.84 ⁇ 0.50, 5.91 ⁇ 0.50, 9.21 ⁇ 0.50, 13.58 ⁇ 0.50, 14.29 ⁇ 0.50, 15.56 ⁇ 0.50, 16.74 ⁇ 0.50, 17.79 ⁇ 0.50, 18.56 ⁇ 0.50, 19.02 ⁇ 0.50, 21.30 ⁇
  • polymorphic Form VII has a DSC graph substantially as shown in FIG. 24;
  • polymorphic Form VII is characterized as having an endotherm peak at 70 ⁇ 10 °C as determined by DSC;
  • polymorphic Form VII is characterized as having an endotherm onset at 122 ⁇ 2 °C as determined by DSC;
  • polymorphic Form VII is characterized as having an endotherm onset at 132 ⁇ 2 °C as determined by DSC;
  • polymorphic Form VII has a TGA graph substantially as shown in FIG. 25; and
  • polymorphic Form VII has a substantially continuous weight loss between 25 °C and 300 °C as determined by TGA. III-h.
  • Polymorphic Form VIII (Di-Sodium Salt Pattern B) [0231]
  • polymorphic Form VIII of N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide which is referred to as polymorphic Form VIII hereinafter.
  • N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide is in the form of a salt.
  • the salt is an alkali metal salt (e.g., Na salt or K salt).
  • the molar ration between the compound of Formula (A-1) and metal ion (e.g., Na + ) is about 1:2 to about 1:2.5, or about 1:2.3.
  • polymorphic Form VIII comprises about 0.5 equiv. to about 1.5 equiv. such as about 1 equiv. of ethanol by molar ratio. [0232] In some embodiments, polymorphic Form VIII has an XRPD pattern substantially as shown in FIG. 26. [0233] Angles 2-theta and relative peak intensities observed for polymorphic Form VIII using XRPD are shown in Table VIII-1. Table VIII-1
  • polymorphic Form VIII has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at angles 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 26 or as provided in Table VIII-1. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Relative peak intensities and peak assignments can vary within experimental error.
  • peak assignments listed herein, including for polymorphic Form VIII can vary by about ⁇ 1 degrees, ⁇ 0.8 degrees, ⁇ 0.6 degrees, ⁇ 0.4 degrees, ⁇ 0.2 degrees, or ⁇ 0.1 degrees 2-theta.
  • polymorphic Form VIII has an XRPD pattern comprising peaks at angles 2-theta of 5.26 ⁇ 0.50, 8.78 ⁇ 0.50, 16.75 ⁇ 0.50, and 17.72 ⁇ 0.50 degrees.
  • the polymorphic Form VIII has an XRPD pattern comprising additional peaks at angles 2-theta of 9.28 ⁇ 0.50 and 10.47 ⁇ 0.50 degrees.
  • polymorphic Form VIII has an XRPD pattern further comprising additional peaks at angles 2- theta of 8.37 ⁇ 0.50 and 21.32 ⁇ 0.50 degrees.
  • polymorphic Form VIII has an XRPD pattern comprising peaks at angles 2-theta of 5.26 ⁇ 0.50, 6.82 ⁇ 0.50, 8.37 ⁇ 0.50, 8.80 ⁇ 0.50, 9.28 ⁇ 0.50, 10.47 ⁇ 0.50, 14.06 ⁇ 0.50, 16.75 ⁇ 0.50, 17.72 ⁇ 0.50, 20.65 ⁇ 0.50, 21.32 ⁇ 0.50, 21.47 ⁇ 0.50, and 23.24 ⁇ 0.50 degrees. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG.
  • polymorphic Form VIII has a differential scanning calorimetry (DSC) graph substantially as shown in FIG. 27.
  • polymorphic Form VIII has a thermographic analysis (TGA) graph substantially as shown in FIG. 28.
  • polymorphic Form VIII exhibits a weight loss of about 5.4% or 5.4% ⁇ 0.1% (e.g., 5.4% ⁇ 0.09%, 5.4% ⁇ 0.07%, 5.4% ⁇ 0.06%, 5.4% ⁇ 0.05%, 5.4% ⁇ 0.04%, 5.4% ⁇ 0.03%, 5.4% ⁇ 0.02%, or 5.4% ⁇ 0.01%) between 25 °C and 140 °C as determined by TGA. In some embodiments, polymorphic Form VIII exhibits substantially continuous weight loss between 25 °C and 300 °C as determined by TGA.
  • polymorphic Form VIII has an XRPD pattern comprising peaks at angles 2-theta of 5.26 ⁇ 0.50, 8.80 ⁇ 0.50, 16.75 ⁇ 0.50, and 17.72 ⁇ 0.50 degrees; an XRPD pattern comprising additional peaks at angles 2-theta of 9.28 ⁇ 0.50 and 10.47 ⁇ 0.50 degrees; an XRPD pattern further comprising additional peaks at angles 2-theta of 8.37 ⁇ 0.50 and 21.32 ⁇ 0.50 degrees; or an XRPD pattern comprising peaks at angles 2-theta of 5.26 ⁇ 0.50, 6.82 ⁇ 0.50, 8.37 ⁇ 0.50, 8.80 ⁇ 0.50, 9.28 ⁇ 0.50, 10.47 ⁇ 0.50, 14.06 ⁇ 0.50, 16.75 ⁇ 0.50, 17.72 ⁇ 0.50, 20.65 ⁇ 0.50, 21.32 ⁇ 0.50, 21.47 ⁇ 0.50, and
  • polymorphic Form VIII has a DSC graph substantially as shown in FIG. 27;
  • polymorphic Form VIII has a TGA graph substantially as shown in FIG. 28; and
  • polymorphic Form VIII has a weight loss of 5.4% ⁇ 0.1% between 25 °C and 140 °C as determined by TGA. III-i.
  • Polymorphic Form IX (Di-Potassium Salt Pattern B) [0239]
  • N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide is in the form of a salt.
  • the salt is an alkali metal salt (e.g., Na salt or K salt).
  • the molar ration between the compound of Formula (A-1) and metal ion (e.g., K + ) is about 1:2 to about 1:3, or about 1:2.5.
  • polymorphic Form IX comprises about 0.01 equiv. to about 0.1 equiv. such as about 0.06 equiv. of ACN by molar ratio. In some embodiments, polymorphic Form IX comprises about 1.5 equiv. to about 3 equiv. such as about 2.2 equiv. of water by molar ratio. [0240] In some embodiments, polymorphic Form IX has an XRPD pattern substantially as shown in FIG. 29. [0241] Exemplary angles 2-theta and relative peak intensities observed for polymorphic Form IX using XRPD are shown in Table IX-1. Table IX-1
  • polymorphic Form IX has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at angles 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 29 or as provided in Table IX -1. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Relative peak intensities and peak assignments can vary within experimental error.
  • peak assignments listed herein, including for polymorphic Form VIII can vary by about ⁇ 1 degrees, ⁇ 0.8 degrees, ⁇ 0.6 degrees, ⁇ 0.4 degrees, ⁇ 0.2 degrees, or ⁇ 0.1 degrees 2-theta.
  • polymorphic Form IX has an XRPD pattern comprising peaks at angles 2-theta of 6.66 ⁇ 0.20, 17.43 ⁇ 0.20, 19.31 ⁇ 0.20, and 23.72 ⁇ 0.20 degrees.
  • the polymorphic Form IX has an XRPD pattern comprising additional peaks at angles 2-theta of 13.12 ⁇ 0.20 and 19.99 ⁇ 0.20 degrees.
  • polymorphic Form IX has an XRPD pattern further comprising additional peaks at angles 2-theta of 18.82 ⁇ 0.20 and 22.76 ⁇ 0.20 degrees.
  • polymorphic Form IX has an XRPD pattern comprising peaks at angles 2-theta of 6.66 ⁇ 0.20, 13.12 ⁇ 0.20, 16.74 ⁇ 0.20, 17.14 ⁇ 0.20, 17.43 ⁇ 0.20, 18.34 ⁇ 0.20, 18.82 ⁇ 0.20, 19.31 ⁇ 0.20, 19.99 ⁇ 0.20, 22.76 ⁇ 0.20, 23.72 ⁇ 0.20, and 28.34 ⁇ 0.20 degrees. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG.
  • polymorphic Form IX has a differential scanning calorimetry (DSC) graph substantially as shown in FIG. 30.
  • Form VII is characterized as having an endotherm onset at about 31 °C as determined by DSC.
  • Form IX is characterized as having an endotherm onset at 31 ⁇ 10 °C (e.g., 31 ⁇ 8 °C, 31 ⁇ 6 °C, 31 ⁇ 5 °C, 31 ⁇ 4 °C, 31 ⁇ 2 °C, 31 ⁇ 2 °C, 31 ⁇ 1.7 °C, 31 ⁇ 1.6 °C, 31 ⁇ 1.5 °C, 31 ⁇ 1.4 °C, 31 ⁇ 1.3 °C, 31 ⁇ 1.2 °C, 31 ⁇ 1.1 °C, 31 ⁇ 1.0 °C, 31 ⁇ 0.9 °C, 31 ⁇ 0.8 °C, 31 ⁇ 0.7 °C, 31 ⁇ 0.6 °C, 31 ⁇ 0.5 °C, 31 ⁇ 0.4 °C, 31 ⁇ 0.3 °C, 31 ⁇ 0.2 °C, or 31 ⁇ 0.1 °C) as determined by DSC.
  • 31 ⁇ 10 °C e.g., 31 ⁇ 8 °C, 31 ⁇ 6 °C, 31 ⁇ 5 °C, 31 ⁇ 4 °C, 31 ⁇ 2 °C, 31 ⁇ 2 °C, 31 ⁇ 1.7
  • polymorphic Form IX is characterized as having an endotherm peak at about 83 °C as determined by DSC.
  • polymorphic Form VII is characterized as having an endotherm peak at 83 ⁇ 2 °C (e.g., 83 ⁇ 1.9 °C, 83 ⁇ 1.8 °C, 83 ⁇ 1.7 °C, 83 ⁇ 1.6 °C, 83 ⁇ 1.5 °C, 83 ⁇ 1.4 °C, 83 ⁇ 1.3 °C, 83 ⁇ 1.2 °C, 83 ⁇ 1.1 °C, 83 ⁇ 1.0 °C, 83 ⁇ 0.9 °C, 83 ⁇ 0.8 °C, 83 ⁇ 0.7 °C, 83 ⁇ 0.6 °C, 83 ⁇ 0.5 °C, 83 ⁇ 0.4 °C, 83 ⁇ 0.3 °C, 83 ⁇ 0.2 °C, or 83 ⁇ 0.1 °C) as determined by DSC.
  • Form IX is characterized as having an endotherm peak at about 134 °C as determined by DSC. In some embodiments, Form IX is characterized as having an endotherm peak at 134 ⁇ 2 °C (e.g., 134 ⁇ 1.9 °C, 134 ⁇ 1.8 °C, 134 ⁇ 1.7 °C, 134 ⁇ 1.6 °C, 134 ⁇ 1.5 °C, 134 ⁇ 1.4 °C, 134 ⁇ 1.3 °C, 134 ⁇ 1.2 °C, 134 ⁇ 1.1 °C, 134 ⁇ 1.0 °C, 134 ⁇ 0.9 °C, 134 ⁇ 0.8 °C, 134 ⁇ 0.7 °C, 134 ⁇ 0.6 °C, 134 ⁇ 0.5 °C, 134 ⁇ 0.4 °C, 134 ⁇ 0.3 °C, 134 ⁇ 0.2 °C, or 134 ⁇ 0.1 °C) as determined by DSC.
  • 134 ⁇ 2 °C e.g., 134 ⁇ 1.9 °C, 134 ⁇ 1.8 °C, 134 ⁇ 1.7 °
  • polymorphic Form IX has a thermographic analysis (TGA) graph substantially as shown in FIG. 31.
  • TGA thermographic analysis
  • polymorphic Form IX exhibits a weight loss of about 0.3% or 0.3% ⁇ 0.1% (e.g., 0.3% ⁇ 0.09%, 0.3% ⁇ 0.07%, 0.3% ⁇ 0.06%, 0.3% ⁇ 0.05%, 0.3% ⁇ 0.04%, 0.3% ⁇ 0.03%, 0.3% ⁇ 0.02%, or 0.3% ⁇ 0.01%) between 25 °C and 40 °C as determined by TGA.
  • polymorphic Form IX exhibits a weight loss of about 2.7% or 2.7% ⁇ 0.1% (e.g., 2.7% ⁇ 0.09%, 2.7% ⁇ 0.07%, 2.7% ⁇ 0.06%, 2.7% ⁇ 0.05%, 2.7% ⁇ 0.04%, 2.7% ⁇ 0.03%, 2.7% ⁇ 0.02%, or 2.7% ⁇ 0.01%) between 40 °C and 75 °C as determined by TGA.
  • polymorphic Form IX exhibits a weight loss of about 3.1% or 3.1% ⁇ 0.1% (e.g., 3.1% ⁇ 0.09%, 3.1% ⁇ 0.07%, 3.1% ⁇ 0.06%, 3.1% ⁇ 0.05%, 3.1% ⁇ 0.04%, 3.1% ⁇ 0.03%, 3.1% ⁇ 0.02%, or 3.1% ⁇ 0.01%) between 75 °C and 170 °C as determined by TGA. In some embodiments, polymorphic Form IX exhibits substantially continuous weight loss between 25 °C and 300 °C as determined by TGA.
  • polymorphic Form IX has an XRPD pattern comprising peaks at angles 2-theta of 6.66 ⁇ 0.20, 17.43 ⁇ 0.20, 19.31 ⁇ 0.20, and 23.72 ⁇ 0.20 degrees; an XRPD pattern comprising additional peaks at angles 2-theta of 13.12 ⁇ 0.20 and 19.99 ⁇ 0.20 degrees; an XRPD pattern further comprising additional peaks at angles 2-theta of 18.82 ⁇ 0.20 and 22.76 ⁇ 0.20 degrees; or an XRPD pattern comprising peaks at angles 2-theta of 6.66 ⁇ 0.20, 13.12 ⁇ 0.20, 16.74 ⁇ 0.20, 17.14 ⁇ 0.20, 17.43 ⁇ 0.20, 18.34 ⁇ 0.20, 18.82 ⁇ 0.20, 19.31 ⁇ 0.20, 19.99 ⁇ 0.20, 22.76 ⁇ 0.20,
  • polymorphic Form IX has a DSC graph substantially as shown in FIG. 30;
  • polymorphic Form IX is characterized as having an endotherm onset at 31 ⁇ 10 °C as determined by DSC;
  • polymorphic Form IX is characterized as having an endotherm peak at 83 ⁇ 2 °C as determined by DSC;
  • polymorphic Form IX is characterized as having an endotherm peak 134 ⁇ 2 °C as determined by DSC;
  • polymorphic Form IX has a TGA graph substantially as shown in FIG.
  • polymorphic Form IX has a weight loss of about 0.3% or 0.3% ⁇ 0.1% between 25 °C and 40 °C as determined by TGA; (i) polymorphic Form IX exhibits a weight loss of about 2.7% or 2.7% ⁇ 0.1% between 40 °C and 75 °C as determined by TGA; (j) polymorphic Form IX exhibits a weight loss of about 3.1% or 3.1% ⁇ 0.1% between 75 °C and 170 °C as determined by TGA; (k) polymorphic Form IX exhibits a substantially continuous weight loss between 25 °C and 300 °C as determined by TGA. [0247] In some embodiments, polymorphic Form IX has an XRPD pattern substantially as shown in FIG. 45. [0248] Exemplary angles 2-theta and relative peak intensities observed for polymorphic Form IX using XRPD are shown in Table IX-2. Table IX-2
  • polymorphic Form IX has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at angles 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 45 or as provided in Table IX-2. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Relative peak intensities and peak assignments can vary within experimental error.
  • peak assignments listed herein, including for polymorphic Form IX can vary by about ⁇ 1.0 degrees, ⁇ 0.6 degrees, ⁇ 0.4 degrees, ⁇ 0.2 degrees, or ⁇ 0.1 degrees 2-theta.
  • polymorphic Form IX has an XRPD pattern comprising peaks at angles 2-theta of 6.65 ⁇ 0.20, 17.42 ⁇ 0.20, 19.30 ⁇ 0.20, and 23.75 ⁇ 0.20 degrees.
  • the polymorphic Form IX has an XRPD pattern comprising additional peaks at angles 2-theta of 20.00 ⁇ 0.20 and 22.78 ⁇ 0.20 degrees.
  • polymorphic Form IX has an XRPD pattern further comprising additional peaks at angles 2-theta of 13.13 ⁇ 0.20 and 18.82 ⁇ 0.20 degrees.
  • polymorphic Form IX has an XRPD pattern comprising peaks at angles 2-theta of 6.65 ⁇ 0.20, 13.13 ⁇ 0.20, 16.75 ⁇ 0.20, 17.15 ⁇ 0.20, 17.42 ⁇ 0.20, 18.35 ⁇ 0.20, 18.82 ⁇ 0.20, 19.30 ⁇ 0.20, 20.00 ⁇ 0.20, 22.78 ⁇ 0.20, 23.75 ⁇ 0.20, 24.35 ⁇ 0.20, and 28.37 ⁇ 0.20 degrees. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG.
  • polymorphic Form IX has a differential scanning calorimetry (DSC) graph substantially as shown in FIG. 46.
  • Form VII is characterized as having an endotherm peak at about 86 °C as determined by DSC.
  • Form IX is characterized as having an endotherm peak at 86 ⁇ 10 °C (e.g., 86 ⁇ 8 °C, 86 ⁇ 6 °C, 86 ⁇ 5 °C, 86 ⁇ 4 °C, 86 ⁇ 2 °C, 86 ⁇ 2 °C, 86 ⁇ 1.7 °C, 86 ⁇ 1.6 °C, 86 ⁇ 1.5 °C, 86 ⁇ 1.4 °C, 86 ⁇ 1.3 °C, 86 ⁇ 1.2 °C, 86 ⁇ 1.1 °C, 86 ⁇ 1.0 °C, 86 ⁇ 0.9 °C, 86 ⁇ 0.8 °C, 86 ⁇ 0.7 °C, 86 ⁇ 0.6 °C, 86 ⁇ 0.5 °C, 86 ⁇ 0.4 °C, 86 ⁇ 0.3 °C, 86 ⁇ 0.2 °C, or 86 ⁇ 0.1 °C) as determined by DSC.
  • 86 ⁇ 10 °C e.g., 86 ⁇ 8 °C, 86 ⁇ 6 °C, 86 ⁇ 5
  • polymorphic Form IX is characterized as having an endotherm peak at about 140 °C as determined by DSC.
  • polymorphic Form VII is characterized as having an endotherm peak at 140 ⁇ 2 °C (e.g., 140 ⁇ 1.9 °C, 140 ⁇ 1.8 °C, 140 ⁇ 1.7 °C, 140 ⁇ 1.6 °C, 140 ⁇ 1.5 °C, 140 ⁇ 1.4 °C, 140 ⁇ 1.3 °C, 140 ⁇ 1.2 °C, 140 ⁇ 1.1 °C, 140 ⁇ 1.0 °C, 140 ⁇ 0.9 °C, 140 ⁇ 0.8 °C, 140 ⁇ 0.7 °C, 140 ⁇ 0.6 °C, 140 ⁇ 0.5 °C, 140 ⁇ 0.4 °C, 140 ⁇ 0.3 °C, 140 ⁇ 0.2 °C, or 140 ⁇ 0.1 °C) as determined by DSC [0252]
  • polymorphic Form IX has a thermographic analysis (TGA) graph substantially as shown in FIG.
  • polymorphic Form IX exhibits a weight loss of about 0.7% or 0.7% ⁇ 0.1% (e.g., 0.7% ⁇ 0.09%, 0.7% ⁇ 0.07%, 0.7% ⁇ 0.06%, 0.7% ⁇ 0.05%, 0.7% ⁇ 0.04%, 0.7% ⁇ 0.03%, 0.7% ⁇ 0.02%, or 0.7% ⁇ 0.01%) between 25 °C and 42 °C as determined by TGA.
  • polymorphic Form IX exhibits a weight loss of about 6.0% or 6.0% ⁇ 0.1% (e.g., 6.0% ⁇ 0.09%, 6.0% ⁇ 0.07%, 6.0% ⁇ 0.06%, 6.0% ⁇ 0.05%, 6.0% ⁇ 0.04%, 6.0% ⁇ 0.03%, 6.0% ⁇ 0.02%, or 6.0% ⁇ 0.01%) between 42 °C and 94 °C as determined by TGA.
  • polymorphic Form IX has a Dynamic Vapor Sorption (DVS) graph substantially as shown in FIG. 48.
  • polymorphic Form IX exhibits a weight gain of about 62% or 62% ⁇ 5% (e.g., 62% ⁇ 4%, 62% ⁇ 3%, 62% ⁇ 2%, 62% ⁇ 1%, 62% ⁇ 0.5%, 62% ⁇ 0.04%, 62% ⁇ 0.03%, 62% ⁇ 0.02%, or 62% ⁇ 0.01%) from 1% relative humidity (RH) to 95% RH, as determined by DVS.
  • RH relative humidity
  • polymorphic Form IX exhibits a weight loss of about 70% or 70% ⁇ 5% (e.g., 70% ⁇ 4%, 70% ⁇ 3%, 70% ⁇ 2%, 70% ⁇ 1%, 70% ⁇ 0.5%, 70% ⁇ 0.04%, 70% ⁇ 0.03%, 70% ⁇ 0.02%, or 70% ⁇ 0.01%) from 95% RH to 1% RH, as determined by DVS.
  • 70% ⁇ 5% e.g., 70% ⁇ 4%, 70% ⁇ 3%, 70% ⁇ 2%, 70% ⁇ 1%, 70% ⁇ 0.5%, 70% ⁇ 0.04%, 70% ⁇ 0.03%, 70% ⁇ 0.02%, or 70% ⁇ 0.01%
  • polymorphic Form IX has an XRPD pattern comprising peaks at angles 2-theta of 6.65 ⁇ 0.20, 17.42 ⁇ 0.20, 19.30 ⁇ 0.20, and 23.75 ⁇ 0.20 degrees; an XRPD pattern comprising additional peaks at angles 2-theta of 20.00 ⁇ 0.20 and 22.78 ⁇ 0.20 degrees; an XRPD pattern further comprising additional peaks at angles 2-theta of 13.13 ⁇ 0.20 and 18.82 ⁇ 0.20 degrees; or an XRPD pattern comprising peaks at angles 2-theta of 6.65 ⁇ 0.20, 13.13 ⁇ 0.20, 16.75 ⁇ 0.20, 17.15 ⁇ 0.20, 17.42 ⁇ 0.20, 18.35 ⁇ 0.20, 18.82 ⁇ 0.20, 19.30 ⁇ 0.20, 20.00 ⁇ 0.20, 22.76 ⁇ 0.20,
  • polymorphic Form IX has a DSC graph substantially as shown in FIG. 46;
  • polymorphic Form IX is characterized as having an endotherm peak at 86 ⁇ 10 °C as determined by DSC;
  • polymorphic Form IX is characterized as having an endotherm peak at 140 ⁇ 2 °C as determined by DSC;
  • polymorphic Form IX has a TGA graph substantially as shown in FIG.
  • polymorphic Form IX has a weight loss of about 0.7% or 0.7% ⁇ 0.1% between 25 °C and 42 °C as determined by TGA;
  • polymorphic Form IX has a weight loss of about 6.0% or 6.0% ⁇ 0.1% between 42 °C and 94 °C as determined by TGA;
  • polymorphic Form IX has a DVS graph substantially as shown in FIG. 48.
  • polymorphic Form IX has a weight gain of about 62% or 62% ⁇ 5% from 1% RH to 95% RH, as determined by DVS;
  • polymorphic Form IX has a weight loss of about 70% or 70% ⁇ 5% from 95% RH to 1% RH, as determined by DVS. III-j.
  • Polymorphic Form X (Di-Sodium Salt Pattern C) [0255]
  • polymorphic Form X of N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide which is referred to as polymorphic Form X hereinafter.
  • N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide is in the form of a salt.
  • the salt is an alkali metal salt (e.g., Na salt or K salt).
  • the molar ration between the compound of Formula (A-1) and metal ion (e.g., K + ) is about 1:2 to about 1:3, or about 1:2.4.
  • polymorphic Form IX comprises about 1 equiv. to about 3 equiv. such as about 1.9 equiv. of water by molar ratio. In some embodiments, polymorphic Form X comprises less than 10% w/w (e.g., less than any of 8% w/w, 5% w/w, 3% w/w, 2% w/w, 1% w/w, 0.5% w/w, 0.1% w/w, 0.05% w/w, or 0.01% w/w) water. [0256] In some embodiments, polymorphic Form X has an XRPD pattern substantially as shown in FIG. 32.
  • polymorphic Form X has a differential scanning calorimetry (DSC) graph substantially as shown in FIG. 33.
  • polymorphic Form X is characterized as having an endotherm peak at about 52 °C as determined by DSC.
  • polymorphic Form X is characterized as having an endotherm onset at 52 ⁇ 2 °C (e.g., 52 ⁇ 1.9 °C, 52 ⁇ 1.8 °C, 52 ⁇ 1.7 °C, 52 ⁇ 1.6 °C, 52 ⁇ 1.5 °C, 52 ⁇ 1.4 °C, 52 ⁇ 1.3 °C, 52 ⁇ 1.2 °C, 52 ⁇ 1.1 °C, 52 ⁇ 1.0 °C, 52 ⁇ 0.9 °C, 52 ⁇ 0.8 °C, 52 ⁇ 0.7 °C, 52 ⁇ 0.6 °C, 52 ⁇ 0.5 °C, 52 ⁇ 0.4 °C, 52 ⁇ 0.3 °C, 52 ⁇ 0.2 °C, or 52 ⁇ 0.1 °C) as determined by DSC.
  • 52 ⁇ 2 °C e.g., 52 ⁇ 1.9 °C, 52 ⁇ 1.8 °C, 52 ⁇ 1.7 °C, 52 ⁇ 1.6 °C, 52 ⁇ 1.5 °C, 52 ⁇ 1.4 °C, 52 ⁇ 1.3 °C, 52 ⁇ 1.2 °C, 52 ⁇ 1.1 °C, 52 ⁇ 1.0 °C,
  • Form X is characterized as having an endotherm peak at about 84 °C as determined by DSC. In some embodiments, Form X is characterized as having an endotherm peak at 84 ⁇ 2 °C (e.g., 84 ⁇ 1.9 °C, 84 ⁇ 1.8 °C, 84 ⁇ 1.7 °C, 84 ⁇ 1.6 °C, 84 ⁇ 1.5 °C, 84 ⁇ 1.4 °C, 84 ⁇ 1.3 °C, 84 ⁇ 1.2 °C, 84 ⁇ 1.1 °C, 84 ⁇ 1.0 °C, 84 ⁇ 0.9 °C, 84 ⁇ 0.8 °C, 84 ⁇ 0.7 °C, 84 ⁇ 0.6 °C, 84 ⁇ 0.5 °C, 84 ⁇ 0.4 °C, 84 ⁇ 0.3 °C, 84 ⁇ 0.2 °C, or 84 ⁇ 0.1 °C) as determined by DSC.
  • 84 ⁇ 2 °C e.g., 84 ⁇ 1.9 °C, 84 ⁇ 1.8 °C, 84 ⁇ 1.7 °
  • Form X is characterized as having an endotherm peak at about 104 °C as determined by DSC. In some embodiments, Form X is characterized as having an endotherm peak at 104 ⁇ 2 °C (e.g., 104 ⁇ 1.9 °C, 104 ⁇ 1.8 °C, 104 ⁇ 1.7 °C, 104 ⁇ 1.6 °C, 104 ⁇ 1.5 °C, 104 ⁇ 1.4 °C, 104 ⁇ 1.3 °C, 104 ⁇ 1.2 °C, 104 ⁇ 1.1 °C, 104 ⁇ 1.0 °C, 104 ⁇ 0.9 °C, 104 ⁇ 0.8 °C, 104 ⁇ 0.7 °C, 104 ⁇ 0.6 °C, 104 ⁇ 0.5 °C, 104 ⁇ 0.4 °C, 104 ⁇ 0.3 °C, 104 ⁇ 0.2 °C, or 104 ⁇ 0.1 °C) as determined by DSC.
  • 104 ⁇ 2 °C e.g., 104 ⁇ 1.9 °C, 104 ⁇ 1.8 °C, 104 ⁇ 1.7 °
  • Form X is characterized as having an endotherm peak at about 128 °C as determined by DSC. In some embodiments, Form X is characterized as having an endotherm peak at 128 ⁇ 2 °C (e.g., 128 ⁇ 1.9 °C, 128 ⁇ 1.8 °C, 128 ⁇ 1.7 °C, 128 ⁇ 1.6 °C, 128 ⁇ 1.5 °C, 128 ⁇ 1.4 °C, 128 ⁇ 1.3 °C, 128 ⁇ 1.2 °C, 128 ⁇ 1.1 °C, 128 ⁇ 1.0 °C, 128 ⁇ 0.9 °C, 128 ⁇ 0.8 °C, 128 ⁇ 0.7 °C, 128 ⁇ 0.6 °C, 128 ⁇ 0.5 °C, 128 ⁇ 0.4 °C, 128 ⁇ 0.3 °C, 128 ⁇ 0.2 °C, or 128 ⁇ 0.1 °C) as determined by DSC.
  • 128 ⁇ 2 °C e.g., 128 ⁇ 1.9 °C, 128 ⁇ 1.8 °C, 128 ⁇ 1.7 °
  • polymorphic Form X has a thermographic analysis (TGA) graph substantially as shown in FIG. 34.
  • TGA thermographic analysis
  • polymorphic Form X exhibits a weight loss of about 11.9% or 11.9% ⁇ 3.0% (e.g., 11.9% ⁇ 2.0%, 11.9% ⁇ 1.5%, 11.9% ⁇ 1.0%, 11.9% ⁇ 0.05%, 11.9% ⁇ 0.004%, 11.9% ⁇ 0.003%, 11.9% ⁇ 0.002%, or 11.9% ⁇ 0.001%) between 30 °C and 110 °C. as determined by TGA.
  • polymorphic Form X has an XRPD pattern comprising peaks at angles 2-theta of 6.03 ⁇ 0.20, 7.66 ⁇ 0.20, 12.04 ⁇ 0.20, and 18.73 ⁇ 0.20 degrees; an XRPD pattern comprising additional peaks at angles 2-theta of 12.93 ⁇ 0.20 and 18.97 ⁇ 0.20 degrees; an XRPD pattern further comprising additional peaks at angles 2-theta of 19.91 ⁇ 0.20 and 24.62 ⁇ 0.20 degrees; or an XRPD pattern comprising peaks at angles 2-theta of 6.03 ⁇ 0.20, 7.66 ⁇ 0.20, 12.04 ⁇ 0.20, 12.93 ⁇ 0.20, 15.45 ⁇ 0.20, 18.08 ⁇ 0.20, 18.73 ⁇ 0.20, 18.97 ⁇ 0.20, 19.91 ⁇ 0.20, 24.62 ⁇ 0.20, 30
  • polymorphic Form X has a DSC graph substantially as shown in FIG. 33;
  • polymorphic Form X is characterized as having an endotherm peak at 52 ⁇ 2 °C as determined by DSC;
  • polymorphic Form X is characterized as having an endotherm peak at 84 ⁇ 2 °C as determined by DSC;
  • polymorphic Form X is characterized as having an endotherm peak at 104 ⁇ 2 °C as determined by DSC;
  • polymorphic Form X is characterized as having an endotherm peak at 128 ⁇ 2 °C as determined by DSC;
  • polymorphic Form X has a TGA graph substantially as shown in FIG.
  • polymorphic Form X has a weight loss of about 11.9%; and 11.9% ⁇ 3.0% between 30 °C and 110 °C as determined by TGA.
  • polymorphic Form X has an XRPD pattern substantially as shown in FIG. 41.
  • Angles 2-theta and relative peak intensities observed for polymorphic Form XIII using XRPD are shown in Table X-2. Table X-2
  • polymorphic Form X has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at angles 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 41 or as provided in Table X-2. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Relative peak intensities and peak assignments can vary within experimental error.
  • peak assignments listed herein, including for polymorphic Form X can vary by about ⁇ 0.6 degrees, ⁇ 0.4 degrees, ⁇ 0.2 degrees, or ⁇ 0.1 degrees 2-theta.
  • polymorphic Form X has an XRPD pattern comprising peaks at angles 2-theta of 6.07 ⁇ 0.20, 6.84 ⁇ 0.20, 12.07 ⁇ 0.20, 18.75 ⁇ 0.20, and 19.96 ⁇ 0.20 degrees.
  • the polymorphic Form X has an XRPD pattern comprising additional peaks at angles 2-theta of 18.10 ⁇ 0.20 and 20.47 ⁇ 0.20 degrees.
  • polymorphic Form X has an XRPD pattern further comprising additional peaks at angles 2- theta of 7.70 ⁇ 0.20 and 13.63 ⁇ 0.20 degrees.
  • polymorphic Form X has an XRPD pattern comprising peaks at angles 2-theta of 6.07 ⁇ 0.20, 6.84 ⁇ 0.20, 7.70 ⁇ 0.20, 9.25 ⁇ 0.20, 12.07 ⁇ 0.20, 12.97 ⁇ 0.20, 13.63 ⁇ 0.20, 18.10 ⁇ 0.20, 18.75 ⁇ 0.20, 19.96 ⁇ 0.20, and 20.47 ⁇ 0.20 degrees. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG.
  • polymorphic Form X has a differential scanning calorimetry (DSC) graph substantially as shown in FIG. 42.
  • polymorphic Form XIII is characterized as having an endotherm peak at about 73 °C as determined by DSC.
  • polymorphic Form XIII is characterized as having an endotherm onset at 73 ⁇ 2 °C (e.g., 73 ⁇ 1.9 °C, 73 ⁇ 1.8 °C, 73 ⁇ 1.7 °C, 73 ⁇ 1.6 °C, 73 ⁇ 1.5 °C, 73 ⁇ 1.4 °C, 73 ⁇ 1.3 °C, 73 ⁇ 1.2 °C, 73 ⁇ 1.1 °C, 73 ⁇ 1.0 °C, 73 ⁇ 0.9 °C, 73 ⁇ 0.8 °C, 73 ⁇ 0.7 °C, 73 ⁇ 0.6 °C, 73 ⁇ 0.5 °C, 73 ⁇ 0.4 °C, 73 ⁇ 0.3 °C, 73 ⁇ 0.2 °C, or 73 ⁇ 0.1 °C) as determined by DSC.
  • endotherm onset at 73 ⁇ 2 °C e.g., 73 ⁇ 1.9 °C, 73 ⁇ 1.8 °C, 73 ⁇ 1.7 °C, 73 ⁇ 1.6 °C, 73 ⁇ 1.5 °C, 73
  • Form X is characterized as having an endotherm peak at about 99 °C as determined by DSC. In some embodiments, Form X is characterized as having an endotherm peak at 99 ⁇ 2 °C (e.g., 99 ⁇ 1.9 °C, 99 ⁇ 1.8 °C, 99 ⁇ 1.7 °C, 99 ⁇ 1.6 °C, 99 ⁇ 1.5 °C, 99 ⁇ 1.4 °C, 99 ⁇ 1.3 °C, 99 ⁇ 1.2 °C, 99 ⁇ 1.1 °C, 99 ⁇ 1.0 °C, 99 ⁇ 0.9 °C, 99 ⁇ 0.8 °C, 99 ⁇ 0.7 °C, 99 ⁇ 0.6 °C, 99 ⁇ 0.5 °C, 99 ⁇ 0.4 °C, 99 ⁇ 0.3 °C, 99 ⁇ 0.2 °C, or 99 ⁇ 0.1 °C) as determined by DSC.
  • 99 ⁇ 2 °C e.g., 99 ⁇ 1.9 °C, 99 ⁇ 1.8 °C, 99 ⁇ 1.7 °C, 99 ⁇ 1.6 °C, 99 ⁇ 1.5 °C, 99 ⁇ 1.4 °C, 99 ⁇
  • Form X is characterized as having an endotherm peak at about 120 °C as determined by DSC. In some embodiments, Form X is characterized as having an endotherm peak at 120 ⁇ 2 °C (e.g., 120 ⁇ 1.9 °C, 120 ⁇ 1.8 °C, 120 ⁇ 1.7 °C, 120 ⁇ 1.6 °C, 120 ⁇ 1.5 °C, 120 ⁇ 1.4 °C, 120 ⁇ 1.3 °C, 120 ⁇ 1.2 °C, 120 ⁇ 1.1 °C, 120 ⁇ 1.0 °C, 120 ⁇ 0.9 °C, 120 ⁇ 0.8 °C, 120 ⁇ 0.7 °C, 120 ⁇ 0.6 °C, 120 ⁇ 0.5 °C, 120 ⁇ 0.4 °C, 120 ⁇ 0.3 °C, 120 ⁇ 0.2 °C, or 120 ⁇ 0.1 °C) as determined by DSC.
  • 120 ⁇ 2 °C e.g., 120 ⁇ 1.9 °C, 120 ⁇ 1.8 °C, 120 ⁇ 1.7 °C, 120 ⁇ 1.6 °C, 120 ⁇ 1.5 °C, 120 ⁇ 1.4 °C, 120 ⁇
  • polymorphic Form X has a thermographic analysis (TGA) graph substantially as shown in FIG. 43.
  • TGA thermographic analysis
  • polymorphic Form X exhibits a weight loss of about 0.6% or 0.6% ⁇ 0.5% (e.g., 0.6% ⁇ 0.4%, 0.6% ⁇ 0.3%, 0.6% ⁇ 0.2%, 0.6% ⁇ 0.1%, 0.6% ⁇ 0.05%, 0.6% ⁇ 0.004%, 0.6% ⁇ 0.003%, 0.6% ⁇ 0.002%, or 0.6% ⁇ 0.001%) between 30 °C and 48 °C, as determined by TGA.
  • polymorphic Form XIII exhibits a weight loss of about 4.2% or 4.2% ⁇ 0.5% (e.g., 4.2% ⁇ 0.4%, 4.2% ⁇ 0.3%, 4.2% ⁇ 0.2%, 4.2% ⁇ 0.1%, 4.2% ⁇ 0.05%, 4.2% ⁇ 0.004%, 4.2% ⁇ 0.003%, 4.2% ⁇ 0.002%, or 4.2% ⁇ 0.001%) between 48 °C and 81 °C. as determined by TGA.
  • 4.2% ⁇ 0.5% e.g., 4.2% ⁇ 0.4%, 4.2% ⁇ 0.3%, 4.2% ⁇ 0.2%, 4.2% ⁇ 0.1%, 4.2% ⁇ 0.05%, 4.2% ⁇ 0.004%, 4.2% ⁇ 0.003%, 4.2% ⁇ 0.002%, or 4.2% ⁇ 0.001%
  • polymorphic Form X exhibits a weight loss of about 2.7% or 2.7% ⁇ 0.5% (e.g., 2.7% ⁇ 0.4%, 2.7% ⁇ 0.3%, 2.7% ⁇ 0.2%, 2.7% ⁇ 0.1%, 2.7% ⁇ 0.05%, 2.7% ⁇ 0.004%, 2.7% ⁇ 0.003%, 2.7% ⁇ 0.002%, or 2.7% ⁇ 0.001%) between 81 °C and 140 °C. as determined by TGA.
  • polymorphic Form X has a Dynamic Vapor Sorption (DVS) graph substantially as shown in FIG. 44.
  • polymorphic Form X exhibits a weight gain of about 60% or 60% ⁇ 5% (e.g., 60% ⁇ 4%, 60% ⁇ 3%, 60% ⁇ 2%, 60% ⁇ 1%, 60% ⁇ 0.5%, 60% ⁇ 0.04%, 60% ⁇ 0.03%, 60% ⁇ 0.02%, or 60% ⁇ 0.01%) from 1% relative humidity (RH) to 95% RH, as determined by DVS.
  • RH relative humidity
  • polymorphic Form XIII exhibits a weight loss of about 58% or 58% ⁇ 5% (e.g., 58% ⁇ 4%, 58% ⁇ 3%, 58% ⁇ 2%, 58% ⁇ 1%, 58% ⁇ 0.5%, 58% ⁇ 0.04%, 58% ⁇ 0.03%, 58% ⁇ 0.02%, or 58% ⁇ 0.01%) from 95% RH to 1% RH, as determined by DVS.
  • polymorphic Form X has an XRPD pattern comprising peaks at angles 2-theta of 6.07 ⁇ 0.20, 6.84 ⁇ 0.20, 12.07 ⁇ 0.20, 18.75 ⁇ 0.20, and 19.96 ⁇ 0.20 degrees; an XRPD pattern comprising additional peaks at angles 2-theta of 18.10 ⁇ 0.20 and 20.47 ⁇ 0.20 degrees; an XRPD pattern further comprising additional peaks at angles 2-theta of 7.70 ⁇ 0.20 and 13.63 ⁇ 0.20 degrees; or an XRPD pattern comprising peaks at angles 2-theta of 6.07 ⁇ 0.20, 6.84 ⁇ 0.20, 7.70 ⁇ 0.20, 9.25 ⁇ 0.20, 12.07 ⁇ 0.20, 12.97 ⁇ 0.20, 13.63 ⁇ 0.20, 18.10 ⁇ 0.20, 18.75 ⁇ 0.20, 19.96
  • polymorphic Form X has a DSC graph substantially as shown in FIG. 42;
  • polymorphic Form X is characterized as having an endotherm peak at 73 ⁇ 2 °C as determined by DSC;
  • polymorphic Form X is characterized as having an endotherm peak at 99 ⁇ 2 °C as determined by DSC;
  • polymorphic Form X is characterized as having an endotherm peak at 120 ⁇ 2 °C as determined by DSC;
  • polymorphic Form X has a TGA graph substantially as shown in FIG.
  • polymorphic Form X has a weight loss of about 0.6%; or 0.6% ⁇ 0.5% between 30 °C and 48 °C as determined by TGA;
  • polymorphic Form X has a weight loss of about 4.1%; or 4.1% ⁇ 0.5% between 48 °C and 81°C as determined by TGA;
  • polymorphic Form X has a weight loss of about 2.7%; or 2.7 % ⁇ 0.5% between 81 °C and 140 °C as determined by TGA;
  • polymorphic Form X has a DVS graph substantially as shown in FIG. 44.
  • polymorphic Form X has a weight gain of about 60% or 60% ⁇ 5% from 1% RH to 95% RH, as determined by DVS;
  • polymorphic Form X has a weight loss of about 58% or 58% ⁇ 5% from 95% RH to 1% RH, as determined by DVS. III-k.
  • Polymorphic Form XI (Di-Sodium Salt Pattern D) [0269]
  • polymorphic Form XI of N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide which is referred to as polymorphic Form XI hereinafter.
  • N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide is in the form of a salt.
  • the salt is an alkali metal salt (e.g., Na salt or K salt).
  • the molar ration between the compound of Formula (A-1) and metal ion (e.g., Na + ) is about 1:2 to about 1:2.7, or about 1:2.4.
  • polymorphic Form XI has an XRPD pattern substantially as shown in FIG. 35. [0271] Angles 2-theta and relative peak intensities observed for polymorphic Form XI using XRPD are shown in Table XI-1. Table XI-1
  • polymorphic Form XI has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at angles 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 35 or as provided in Table XI-1. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Relative peak intensities and peak assignments can vary within experimental error.
  • peak assignments listed herein, including for polymorphic Form XI can vary by about ⁇ 1.0 degrees, ⁇ 0.6 degrees, ⁇ 0.4 degrees, ⁇ 0.2 degrees, or ⁇ 0.1 degrees 2-theta.
  • polymorphic Form XI has an XRPD pattern comprising peaks at angles 2-theta of 6.93 ⁇ 0.50, 20.10 ⁇ 0.50, 32.35 ⁇ 0.50, and 37.94 ⁇ 0.50 degrees.
  • the polymorphic Form XI has an XRPD pattern comprising additional peaks at angles 2-theta of 13.86 ⁇ 0.50 and 17.26 ⁇ 0.50 degrees.
  • polymorphic Form XI has an XRPD pattern further comprising additional peaks at angles 2-theta of 20.80 ⁇ 0.50 and 32.53 ⁇ 0.50 degrees.
  • polymorphic Form XI has an XRPD pattern comprising peaks at angles 2-theta of 6.93 ⁇ 0.50, 13.86 ⁇ 0.50, 15.46 ⁇ 0.50, 16.96 ⁇ 0.50, 17.26 ⁇ 0.50, 17.33 ⁇ 0.50, 18.13 ⁇ 0.50, 20.10 ⁇ 0.50, 20.80 ⁇ 0.50, 32.35 ⁇ 0.50, 32.53 ⁇ 0.50, 33.62 ⁇ 0.50, and 37.94 ⁇ 0.50 degrees. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG.
  • polymorphic Form XI has a differential scanning calorimetry (DSC) graph substantially as shown in FIG. 36.
  • polymorphic Form XI is characterized as having an endotherm peak at about 35 °C as determined by DSC.
  • polymorphic Form XI is characterized as having an endotherm peak at 35 ⁇ 2 °C (e.g., 35 ⁇ 1.9 °C, 35 ⁇ 1.8 °C, 35 ⁇ 1.7 °C, 35 ⁇ 1.6 °C, 35 ⁇ 1.5 °C, 35 ⁇ 1.4 °C, 35 ⁇ 1.3 °C, 35 ⁇ 1.2 °C, 35 ⁇ 1.1 °C, 35 ⁇ 1.0 °C, 35 ⁇ 0.9 °C, 35 ⁇ 0.8 °C, 35 ⁇ 0.7 °C, 35 ⁇ 0.6 °C, 35 ⁇ 0.5 °C, 35 ⁇ 0.4 °C, 35 ⁇ 0.3 °C, 35 ⁇ 0.2 °C, or 35 ⁇ 0.1 °C) as determined by DSC.
  • 35 ⁇ 2 °C e.g., 35 ⁇ 1.9 °C, 35 ⁇ 1.8 °C, 35 ⁇ 1.7 °C, 35 ⁇ 1.6 °C, 35 ⁇ 1.5 °C, 35 ⁇ 1.4 °C, 35 ⁇ 1.3 °C, 35 ⁇ 1.2 °C, 35 ⁇ 1.1 °C, 35 ⁇ 1.0 °C,
  • Form XI is characterized as having an endotherm peak at about 77 °C as determined by DSC. In some embodiments, Form XI is characterized as having an endotherm peak at 77 ⁇ 2 °C (e.g., 77 ⁇ 1.9 °C, 77 ⁇ 1.8 °C, 77 ⁇ 1.7 °C, 77 ⁇ 1.6 °C, 77 ⁇ 1.5 °C, 77 ⁇ 1.4 °C, 77 ⁇ 1.3 °C, 77 ⁇ 1.2 °C, 77 ⁇ 1.1 °C, 77 ⁇ 1.0 °C, 77 ⁇ 0.9 °C, 77 ⁇ 0.8 °C, 77 ⁇ 0.7 °C, 77 ⁇ 0.6 °C, 77 ⁇ 0.5 °C, 77 ⁇ 0.4 °C, 77 ⁇ 0.3 °C, 77 ⁇ 0.2 °C, or 77 ⁇ 0.1 °C) as determined by DSC.
  • 77 ⁇ 2 °C e.g., 77 ⁇ 1.9 °C, 77 ⁇ 1.8 °C, 77 ⁇ 1.7
  • Form XI is characterized as having an endotherm peak at about 128 °C as determined by DSC. In some embodiments, Form XI is characterized as having an endotherm peak at 128 ⁇ 2 °C (e.g., 128 ⁇ 1.9 °C, 128 ⁇ 1.8 °C, 128 ⁇ 1.7 °C, 128 ⁇ 1.6 °C, 128 ⁇ 1.5 °C, 128 ⁇ 1.4 °C, 128 ⁇ 1.3 °C, 128 ⁇ 1.2 °C, 128 ⁇ 1.1 °C, 128 ⁇ 1.0 °C, 128 ⁇ 0.9 °C, 128 ⁇ 0.8 °C, 128 ⁇ 0.7 °C, 128 ⁇ 0.6 °C, 128 ⁇ 0.5 °C, 128 ⁇ 0.4 °C, 128 ⁇ 0.3 °C, 128 ⁇ 0.2 °C, or 128 ⁇ 0.1 °C) as determined by DSC.
  • 128 ⁇ 2 °C e.g., 128 ⁇ 1.9 °C, 128 ⁇ 1.8 °C, 128 ⁇ 1.7
  • Form XI is characterized as having an endotherm peak at about 151 °C as determined by DSC. In some embodiments, Form XI is characterized as having an endotherm peak at 151 ⁇ 2 °C (e.g., 151 ⁇ 1.9 °C, 151 ⁇ 1.8 °C, 151 ⁇ 1.7 °C, 151 ⁇ 1.6 °C, 151 ⁇ 1.5 °C, 151 ⁇ 1.4 °C, 151 ⁇ 1.3 °C, 151 ⁇ 1.2 °C, 151 ⁇ 1.1 °C, 151 ⁇ 1.0 °C, 151 ⁇ 0.9 °C, 151 ⁇ 0.8 °C, 151 ⁇ 0.7 °C, 151 ⁇ 0.6 °C, 151 ⁇ 0.5 °C, 151 ⁇ 0.4 °C, 151 ⁇ 0.3 °C, 151 ⁇ 0.2 °C, or 151 ⁇ 0.1 °C) as determined by DSC.
  • 151 ⁇ 2 °C e.g., 151 ⁇ 1.9 °C, 151 ⁇ 1.8 °C, 151 ⁇ 1.7
  • polymorphic Form XI has a thermographic analysis (TGA) graph substantially as shown in FIG. 37.
  • TGA thermographic analysis
  • polymorphic Form XI exhibits a weight loss of about 2.7% or 2.7% ⁇ 0.1% (e.g., 2.7% ⁇ 0.09%, 2.7% ⁇ 0.07%, 2.7% ⁇ 0.06%, 2.7% ⁇ 0.05%, 2.7% ⁇ 0.04%, 2.7% ⁇ 0.03%, 2.7% ⁇ 0.02%, or 2.7% ⁇ 0.01%) between 25 °C and 64 °C as determined by TGA.
  • polymorphic Form XI exhibits a weight loss of about 2.4% or 2.4% ⁇ 0.1% (e.g., 2.4% ⁇ 0.09%, 2.4% ⁇ 0.07%, 2.4% ⁇ 0.06%, 2.4% ⁇ 0.05%, 2.4% ⁇ 0.04%, 2.4% ⁇ 0.03%, 2.4% ⁇ 0.02%, or 2.4% ⁇ 0.01%) between 65 °C and 100 °C as determined by TGA.
  • polymorphic Form XI exhibits a weight loss of about 0.9% or 0.9% ⁇ 0.1% (e.g., 0.9% ⁇ 0.09%, 0.9% ⁇ 0.07%, 0.9% ⁇ 0.06%, 0.9% ⁇ 0.05%, 0.9% ⁇ 0.04%, 0.9% ⁇ 0.03%, 0.9% ⁇ 0.02%, or 0.9% ⁇ 0.01%) between 100 °C and 140 °C as determined by TGA. In some embodiments, polymorphic Form XI exhibits substantially continuous weight loss between 25 °C and 300 °C as determined by TGA.
  • polymorphic Form XI has an XRPD pattern comprising peaks at angles 2-theta of 6.93 ⁇ 0.50, 20.10 ⁇ 0.50, 32.35 ⁇ 0.50, and 37.94 ⁇ 0.50 degrees; an XRPD pattern comprising additional peaks at angles 2-theta of 13.86 ⁇ 0.50 and 17.26 ⁇ 0.50 degrees; an XRPD pattern further comprising additional peaks at angles 2-theta of 20.80 ⁇ 0.50 and 32.53 ⁇ 0.50 degrees; or an XRPD pattern comprising peaks at angles 2-theta of 6.93 ⁇ 0.50, 13.86 ⁇ 0.50, 15.46 ⁇ 0.50, 16.96 ⁇ 0.50, 17.26 ⁇ 0.50, 17.33 ⁇ 0.50, 18.13 ⁇ 0.50, 20.10 ⁇ 0.50, 20.80
  • polymorphic Form XI has a DSC graph substantially as shown in FIG. 36;
  • polymorphic Form XI is characterized as having an endotherm peak at 35 ⁇ 2 °C as determined by DSC;
  • polymorphic Form XI is characterized as having an endotherm peak at 77 ⁇ 2 °C as determined by DSC;
  • polymorphic Form XI is characterized as having an endotherm peak at 128 ⁇ 2 °C as determined by DSC;
  • polymorphic Form XI is characterized as having an endotherm peak at 151 ⁇ 2 °C as determined by DSC;
  • polymorphic Form XI has a TGA graph substantially as shown in FIG.
  • polymorphic Form XI has a substantially continuous weight loss between 25 °C and 300 °C as determined by TGA. III-l.
  • Polymorphic Form XII (Mono-Sodium Salt Pattern B) [0277]
  • polymorphic Form XII of N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide, which is referred to as polymorphic Form XII hereinafter.
  • N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide is in the form of a salt.
  • the salt is an alkali metal salt (e.g., Na salt or K salt).
  • the molar ration between the compound of Formula (A-1) and metal ion (e.g., Na + ) is about 1:0.8 to about 1:1.5, or about 1:1.
  • polymorphic Form XII comprises about 0.5 equiv. to about 1.5 equiv. such as about 1 equiv. of ethanol by molar ratio.
  • polymorphic Form XII has an XRPD pattern substantially as shown in FIG. 38.
  • Angles 2-theta and relative peak intensities observed for polymorphic Form XII using XRPD are shown in Table XII-1.
  • polymorphic Form XII has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at angles 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 38 or as provided in Table XII-1. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Relative peak intensities and peak assignments can vary within experimental error.
  • peak assignments listed herein, including for polymorphic Form XII can vary by about ⁇ 1.0 degrees, ⁇ 0.6 degrees, ⁇ 0.4 degrees, ⁇ 0.2 degrees, or ⁇ 0.1 degrees 2-theta.
  • polymorphic Form XII has an XRPD pattern comprising peaks at angles 2-theta of 14.19 ⁇ 0.20, 17.44 ⁇ 0.20, 17.70 ⁇ 0.20, and 18.14 ⁇ 0.20 degrees.
  • the polymorphic Form XII has an XRPD pattern comprising additional peaks at angles 2-theta of 18.61 ⁇ 0.20 and 27.38 ⁇ 0.20 degrees.
  • polymorphic Form XII has an XRPD pattern further comprising additional peaks at angles 2-theta of 16.87 ⁇ 0.20 and 21.64 ⁇ 0.20 degrees.
  • polymorphic Form XII has an XRPD pattern comprising peaks at angles 2-theta of 12.10 ⁇ 0.20, 14.19 ⁇ 0.20, 15.87 ⁇ 0.20, 16.87 ⁇ 0.20, 17.44 ⁇ 0.20, 17.70 ⁇ 0.20, 18.14 ⁇ 0.20, 18.61 ⁇ 0.20, 21.02 ⁇ 0.20, 21.64 ⁇ 0.20, 24.46 ⁇ 0.20, 27.18 ⁇ 0.20, and 27.38 ⁇ 0.20 degrees. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG.
  • polymorphic Form XII has a differential scanning calorimetry (DSC) graph substantially as shown in FIG. 39.
  • polymorphic Form XII is characterized as having an endotherm onset at about 135 °C as determined by DSC.
  • polymorphic Form XII is characterized as having an endotherm onset at 135 ⁇ 2 °C (e.g., 135 ⁇ 1.9 °C, 135 ⁇ 1.8 °C, 135 ⁇ 1.7 °C, 135 ⁇ 1.6 °C, 135 ⁇ 1.5 °C, 135 ⁇ 1.4 °C, 135 ⁇ 1.3 °C, 135 ⁇ 1.2 °C, 135 ⁇ 1.1 °C, 135 ⁇ 1.0 °C, 135 ⁇ 0.9 °C, 135 ⁇ 0.8 °C, 135 ⁇ 0.7 °C, 135 ⁇ 0.6 °C, 135 ⁇ 0.5 °C, 135 ⁇ 0.4 °C, 135 ⁇ 0.3 °C, 135 ⁇ 0.2 °C, or 135 ⁇ 0.1 °C) as determined by DSC.
  • 135 ⁇ 2 °C e.g., 135 ⁇ 1.9 °C, 135 ⁇ 1.8 °C, 135 ⁇ 1.7 °C, 135 ⁇ 1.6 °C, 135 ⁇ 1.5 °C, 135 ⁇ 1.4 °C
  • Form XII is characterized as having an endotherm peak at about 166 °C as determined by DSC. In some embodiments, Form XII is characterized as having an endotherm peak at 166 ⁇ 2 °C (e.g., 166 ⁇ 1.9 °C, 166 ⁇ 1.8 °C, 166 ⁇ 1.7 °C, 166 ⁇ 1.6 °C, 166 ⁇ 1.5 °C, 166 ⁇ 1.4 °C, 166 ⁇ 1.3 °C, 166 ⁇ 1.2 °C, 166 ⁇ 1.1 °C, 166 ⁇ 1.0 °C, 166 ⁇ 0.9 °C, 166 ⁇ 0.8 °C, 166 ⁇ 0.7 °C, 166 ⁇ 0.6 °C, 166 ⁇ 0.5 °C, 166 ⁇ 0.4 °C, 166 ⁇ 0.3 °C, 166 ⁇ 0.2 °C, or 166 ⁇ 0.1 °C) as determined by DSC.
  • 166 ⁇ 2 °C e.g., 166 ⁇ 1.9 °C, 166 ⁇ 1.8 °C, 166
  • Form XII is characterized as having an endotherm peak at about 192 °C as determined by DSC. In some embodiments, Form XII is characterized as having an endotherm peak at 192 ⁇ 2 °C (e.g., 192 ⁇ 1.9 °C, 192 ⁇ 1.8 °C, 192 ⁇ 1.7 °C, 192 ⁇ 1.6 °C, 192 ⁇ 1.5 °C, 192 ⁇ 1.4 °C, 192 ⁇ 1.3 °C, 192 ⁇ 1.2 °C, 192 ⁇ 1.1 °C, 192 ⁇ 1.0 °C, 192 ⁇ 0.9 °C, 192 ⁇ 0.8 °C, 192 ⁇ 0.7 °C, 192 ⁇ 0.6 °C, 192 ⁇ 0.5 °C, 192 ⁇ 0.4 °C, 192 ⁇ 0.3 °C, 192 ⁇ 0.2 °C, or 192 ⁇ 0.1 °C) as determined by DSC.
  • 192 ⁇ 2 °C e.g., 192 ⁇ 1.9 °C, 192 ⁇ 1.8 °C, 192
  • Form XII is characterized as having an endotherm peak at about 208 °C as determined by DSC. In some embodiments, Form XII is characterized as having an endotherm peak at 208 ⁇ 2 °C (e.g., 208 ⁇ 1.9 °C, 208 ⁇ 1.8 °C, 208 ⁇ 1.7 °C, 208 ⁇ 1.6 °C, 208 ⁇ 1.5 °C, 208 ⁇ 1.4 °C, 208 ⁇ 1.3 °C, 208 ⁇ 1.2 °C, 208 ⁇ 1.1 °C, 208 ⁇ 1.0 °C, 208 ⁇ 0.9 °C, 208 ⁇ 0.8 °C, 208 ⁇ 0.7 °C, 208 ⁇ 0.6 °C, 208 ⁇ 0.5 °C, 208 ⁇ 0.4 °C, 208 ⁇ 0.3 °C, 208 ⁇ 0.2 °C, or 208 ⁇ 0.1 °C) as determined by DSC.
  • 208 ⁇ 2 °C e.g., 208 ⁇ 1.9 °C, 208 ⁇ 1.8 °C, 208
  • polymorphic Form XII has a thermographic analysis (TGA) graph substantially as shown in FIG. 40.
  • polymorphic Form XII exhibits a weight loss of about 0.3% or 0.3% ⁇ 0.1% (e.g., 0.3% ⁇ 0.09%, 0.3% ⁇ 0.07%, 0.3% ⁇ 0.06%, 0.3% ⁇ 0.05%, 0.3% ⁇ 0.04%, 0.3% ⁇ 0.03%, 0.3% ⁇ 0.02%, or 0.3% ⁇ 0.01%) between 25 °C and 80 °C as determined by TGA.
  • polymorphic Form XII exhibits a weight loss of about 7.3% or 7.3% ⁇ 0.1% (e.g., 7.3% ⁇ 0.09%, 7.3% ⁇ 0.07%, 7.3% ⁇ 0.06%, 7.3% ⁇ 0.05%, 7.3% ⁇ 0.04%, 7.3% ⁇ 0.03%, 7.3% ⁇ 0.02%, or 7.3% ⁇ 0.01%) between 80 °C and 190 °C as determined by TGA.
  • polymorphic Form XII has an XRPD pattern comprising peaks at angles 2-theta of 14.19 ⁇ 0.20, 17.44 ⁇ 0.20, 17.70 ⁇ 0.20, and 18.14 ⁇ 0.20 degrees; an XRPD pattern comprising additional peaks at angles 2-theta of 18.61 ⁇ 0.20 and 27.38 ⁇ 0.20 degrees; an XRPD pattern further comprising additional peaks at angles 2-theta of 16.87 ⁇ 0.20 and 21.64 ⁇ 0.20 degrees; or an XRPD pattern comprising peaks at angles 2-theta of 12.10 ⁇ 0.20, 14.19 ⁇ 0.20, 15.87 ⁇ 0.20, 16.87 ⁇ 0.20, 17.44 ⁇ 0.20, 17.70 ⁇ 0.20, 18.14 ⁇ 0.20, 18.61 ⁇ 0.20, 21
  • polymorphic Form XII has a DSC graph substantially as shown in FIG. 39;
  • polymorphic Form XII is characterized as having an endotherm onset at 135 ⁇ 2 °C as determined by DSC;
  • polymorphic Form XII is characterized as having an endotherm peak at 166 ⁇ 2 °C as determined by DSC;
  • polymorphic Form XII is characterized as having an endotherm peak at 192 ⁇ 2 °C as determined by DSC;
  • polymorphic Form XII is characterized as having an endotherm peak at 208 ⁇ 2 °C as determined by DSC;
  • polymorphic Form XII has a TGA graph substantially as shown in FIG.
  • polymorphic Form XII has a weight loss of 0.3% or 0.3% ⁇ 0.1% between 25 °C and 80 °C as determined by TGA; and (j) polymorphic Form XII has a weight loss of 7.3% or 7.3% ⁇ 0.1% between 80 °C and 190 °C as determined by TGA. III-m.
  • Polymorphic Form XIII (Mono-Sodium Salt Pattern C) [0285]
  • N-(1''-(3-(((tert- butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indolin]- 5''-yl)ethanesulfonamide is in the form of a salt.
  • the salt is an alkali metal salt (e.g., Na salt or K salt).
  • the molar ration between the compound of Formula (A-1) and metal ion (e.g., Na + ) is about 1:0.8 to about 1:1.5, or about 1:1.
  • polymorphic Form XIII has an XRPD pattern substantially as shown in FIG. 49. [0287] Angles 2-theta and relative peak intensities observed for polymorphic Form XIII using XRPD are shown in Table XIII-1. Table XIII-1
  • polymorphic Form XIII has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten of the peaks at angles 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 49 or as provided in Table XIII-1. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Relative peak intensities and peak assignments can vary within experimental error.
  • peak assignments listed herein, including for polymorphic Form XIII can vary by about ⁇ 1.0 degrees, ⁇ 0.6 degrees, ⁇ 0.4 degrees, ⁇ 0.2 degrees, or ⁇ 0.1 degrees 2-theta.
  • polymorphic Form XIII has an XRPD pattern comprising peaks at angles 2-theta of 6.85 ⁇ 0.20, 11.74 ⁇ 0.20, 17.14 ⁇ 0.20, and 18.92 ⁇ 0.20 degrees.
  • the polymorphic Form XIII has an XRPD pattern comprising additional peaks at angles 2-theta of 18.51 ⁇ 0.20 and 20.95 ⁇ 0.20 degrees.
  • polymorphic Form XIII has an XRPD pattern further comprising additional peaks at angles 2- theta of 16.64 ⁇ 0.20 and 24.73 ⁇ 0.20 degrees.
  • polymorphic Form XIII has an XRPD pattern comprising peaks at angles 2-theta of 6.85 ⁇ 0.20, 7.54 ⁇ 0.20, 9.12 ⁇ 0.20, 11.74 ⁇ 0.20, 15.19 ⁇ 0.20, 16.64 ⁇ 0.20, 17.14 ⁇ 0.20, 18.51 ⁇ 0.20, 18.92 ⁇ 0.20, 20.95 ⁇ 0.20, 22.61 ⁇ 0.20, and 24.73 ⁇ 0.20 degrees. It is to be understood that additional peaks in the XRPD pattern other than those shown in FIG.
  • polymorphic Form XIII has a differential scanning calorimetry (DSC) graph substantially as shown in FIG. 50.
  • polymorphic Form XIII is characterized as having an endotherm peak at about 53 °C as determined by DSC.
  • polymorphic Form XIII is characterized as having an endotherm peak at 53 ⁇ 2 °C (e.g., 53 ⁇ 1.9 °C, 53 ⁇ 1.8 °C, 53 ⁇ 1.7 °C, 53 ⁇ 1.6 °C, 53 ⁇ 1.5 °C, 53 ⁇ 1.4 °C, 53 ⁇ 1.3 °C, 53 ⁇ 1.2 °C, 53 ⁇ 1.1 °C, 53 ⁇ 1.0 °C, 53 ⁇ 0.9 °C, 53 ⁇ 0.8 °C, 53 ⁇ 0.7 °C, 53 ⁇ 0.6 °C, 53 ⁇ 0.5 °C, 53 ⁇ 0.4 °C, 53 ⁇ 0.3 °C, 53 ⁇ 0.2 °C, or 53 ⁇ 0.1 °C) as determined by DSC.
  • 53 ⁇ 2 °C e.g., 53 ⁇ 1.9 °C, 53 ⁇ 1.8 °C, 53 ⁇ 1.7 °C, 53 ⁇ 1.6 °C, 53 ⁇ 1.5 °C, 53 ⁇ 1.4 °C, 53 ⁇ 1.3 °C, 53 ⁇ 1.2 °C, 53 ⁇ 1.1 °C, 53 ⁇ 1.0 °C,
  • Form XIII is characterized as having an endotherm peak at about 98 °C as determined by DSC. In some embodiments, Form XIII is characterized as having an endotherm peak at 98 ⁇ 2 °C (e.g., 98 ⁇ 1.9 °C, 98 ⁇ 1.8 °C, 98 ⁇ 1.7 °C, 98 ⁇ 1.6 °C, 98 ⁇ 1.5 °C, 98 ⁇ 1.4 °C, 98 ⁇ 1.3 °C, 98 ⁇ 1.2 °C, 98 ⁇ 1.1 °C, 98 ⁇ 1.0 °C, 98 ⁇ 0.9 °C, 98 ⁇ 0.8 °C, 98 ⁇ 0.7 °C, 98 ⁇ 0.6 °C, 98 ⁇ 0.5 °C, 98 ⁇ 0.4 °C, 98 ⁇ 0.3 °C, 98 ⁇ 0.2 °C, or 98 ⁇ 0.1 °C) as determined by DSC.
  • 98 ⁇ 2 °C e.g., 98 ⁇ 1.9 °C, 98 ⁇ 1.8 °C, 98 ⁇ 1.7
  • Form XIII is characterized as having an endotherm peak at about 183 °C as determined by DSC. In some embodiments, Form XIII is characterized as having an endotherm peak at 183 ⁇ 2 °C (e.g., 183 ⁇ 1.9 °C, 183 ⁇ 1.8 °C, 183 ⁇ 1.7 °C, 183 ⁇ 1.6 °C, 183 ⁇ 1.5 °C, 183 ⁇ 1.4 °C, 183 ⁇ 1.3 °C, 183 ⁇ 1.2 °C, 183 ⁇ 1.1 °C, 183 ⁇ 1.0 °C, 183 ⁇ 0.9 °C, 183 ⁇ 0.8 °C, 183 ⁇ 0.7 °C, 183 ⁇ 0.6 °C, 183 ⁇ 0.5 °C, 183 ⁇ 0.4 °C, 183 ⁇ 0.3 °C, 183 ⁇ 0.2 °C, or 183 ⁇ 0.1 °C) as determined by DSC.
  • 183 ⁇ 2 °C e.g., 183 ⁇ 1.9 °C, 183 ⁇ 1.8 °C, 183 ⁇ 1.7
  • polymorphic Form XIII has a thermographic analysis (TGA) graph substantially as shown in FIG. 51.
  • TGA thermographic analysis
  • polymorphic Form XIII exhibits a weight loss of about 0.7% or 0.7% ⁇ 0.1% (e.g., 0.7% ⁇ 0.09%, 0.7% ⁇ 0.07%, 0.7% ⁇ 0.06%, 0.7% ⁇ 0.05%, 0.7% ⁇ 0.04%, 0.7% ⁇ 0.03%, 0.7% ⁇ 0.02%, or 0.7% ⁇ 0.01%) between 30 °C and 120 °C as determined by TGA.
  • polymorphic Form XIII exhibits a weight loss of about 4.2% or 4.2% ⁇ 0.1% (e.g., 4.2% ⁇ 0.09%, 4.2% ⁇ 0.07%, 4.2% ⁇ 0.06%, 4.2% ⁇ 0.05%, 4.2% ⁇ 0.04%, 4.2% ⁇ 0.03%, 4.2% ⁇ 0.02%, or 4.2% ⁇ 0.01%) between 120 °C and 230 °C as determined by TGA.
  • polymorphic Form XIII has an XRPD pattern comprising peaks at angles 2-theta of 6.85 ⁇ 0.20, 11.74 ⁇ 0.20, 17.14 ⁇ 0.20, and 18.92 ⁇ 0.20 degrees; an XRPD pattern comprising additional peaks at angles 2-theta of 18.51 ⁇ 0.20 and 20.95 ⁇ 0.20 degrees; an XRPD pattern further comprising additional peaks at angles 2-theta of 16.64 ⁇ 0.20 and 24.73 ⁇ 0.20 degrees; or an XRPD pattern comprising peaks at angles 2-theta of 6.85 ⁇ 0.20, 7.54 ⁇ 0.20, 9.12 ⁇ 0.20, 11.74 ⁇ 0.20, 15.19 ⁇ 0.20, 16.64 ⁇ 0.20, 17.14 ⁇ 0.20, 18.51 ⁇ 0.20, 18.92 ⁇
  • polymorphic Form XIII has a DSC graph substantially as shown in FIG. 50;
  • polymorphic Form XIII is characterized as having an endotherm peak at 53 ⁇ 2 °C as determined by DSC;
  • polymorphic Form XIII is characterized as having an endotherm peak at 98 ⁇ 2 °C as determined by DSC;
  • polymorphic Form XIII is characterized as having an endotherm peak at 183 ⁇ 2 °C as determined by DSC;
  • polymorphic Form XIII has a TGA graph substantially as shown in FIG.
  • polymorphic Form XIII has a weight loss of 0.7% or 0.7% ⁇ 0.1% between 30 °C and 120 °C as determined by TGA; (i) polymorphic Form XIII has a weight loss of 8.0 % or 8.0 % ⁇ 0.1% between 120 °C and 180 °C as determined by TGA; and (j) polymorphic Form XIII has a weight loss of 4.2 % or 4.2 % ⁇ 0.1% between 120 °C and 230 °C as determined by TGA.
  • compositions containing polymorphs described herein such as polymorphic Form A, C, B, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or any mixture thereof.
  • the composition contains polymorphic Form A.
  • the composition contains polymorphic Form C.
  • the composition contains polymorphic Form B.
  • the composition is substantially free of polymorphic Form C, B, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII of the compound of Formula (A-1). In some embodiments, the composition is substantially free of salts of the compound of Formula (A-1).
  • composition containing Form A of the compound of Formula (A-1) at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition is polymorphic Form A.
  • composition containing polymorphic Form A of the compound of Formula (A-1) at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the compound of Formula (A-1) exists in Form A.
  • the composition is substantially free of polymorphic Form A, B, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII of the compound of Formula (A-1).
  • the composition is substantially free of salts of the compound of Formula (A-1).
  • composition containing Form C of the compound of Formula (A-1) at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition is polymorphic Form C.
  • composition containing polymorphic Form C of the compound of Formula (A-1) at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the compound of Formula (A-1) exists in Form C.
  • the composition is substantially free of polymorphic Form A, II, IV, V, VI, VII, VIII, IX, X, XI, XII of the compound of Formula (A-1).
  • the composition is substantially free of salts of the compound of Formula (A-1).
  • composition containing Form B of the compound of Formula (A-1) at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition is polymorphic Form B.
  • composition containing polymorphic Form B of the compound of Formula (A-1) at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the compound of Formula (A-1) exists in Form B. III-n.
  • the solvent comprises acetone, 2-MeTHF, TFE, THF, methylcyclohexane, and water.
  • the solvent comprises acetone.
  • the solvent comprises 2- MeTHF.
  • the solvent comprises TFE.
  • the solvent comprises THF.
  • the solvent comprises THF and methylcyclohexane.
  • the solvent comprises acetone and water.
  • the solvent comprises ethyl acetate. In some embodiments, the solvent is ethyl acetate. In some embodiments, step (2) is evaporating the mixture of (1) fast. In some embodiments, step (2) is evaporating the mixture of step (1) when the mixture is directly exposed to air. In some embodiments, step (2) is achieved by drying the mixture under vacuum. In some embodiments, step (2) is evaporating the mixture of (1) slowly. In some embodiments, step (2) is evaporating the mixture of (1) at a controlled rate. In some embodiments, step (2) is evaporating the mixture of (1) a controlled rate, wherein the rate is controlled by the extent to which the mixture that is exposed to air.
  • step (2) is evaporating the mixture of (1) at a temperature that is 10 °C higher or lower than the room temperature, 5 °C higher or lower than the room temperature, 3 °C higher or lower than the room temperature, or about the room temperature.
  • the method further comprises: (1’) filtering the mixture of step (1), wherein the step (2) is evaporating the filtered mixture of (1’).
  • a method of preparing polymorphic Form A of the compound of Formula (A-1) comprising: (1) mixing the compound of Formula (A-1) with a solvent at a first temperature; (2) cooling the mixture of (1) to a second temperature; and (3) keeping the mixture of (2) at a third temperature.
  • the solvent comprises alcohol. In some embodiments, the solvent is ethanol. In some embodiments, the first temperature is from 30 °C to 70 °C, from 40 °C to 60 °C, about 50 °C, or about 55 °C. In some embodiments, the solvent is methanol. In some embodiments, the second temperature is 10 °C higher or lower than the room temperature, 5 °C higher or lower than the room temperature, 3 °C higher or lower than the room temperature, or about the room temperature. In some embodiments, the third temperature is higher than -50 °C, -40 °C, -35 °C, -30 °C, -25 °C, -20 °C, -15 °C, or -10 °C.
  • the third temperature is lower than 10 °C, 5 °C, 0 °C, -5 °C, or -10 °C. In some embodiments, the third temperature is from about -40 °C to about 10 °C, from about -30 °C to about 0 °C, from about -25 °C to about -5 °C, or from about -25 °C to about -10 °C. [0302] In some embodiments, provided is a method of preparing polymorphic Form A of the compound of Formula (A-1), the method comprising: (1) mixing the compound of Formula (A-1) with a first solvent and a second solvent at a first temperature; and (2) keeping the mixture of (1) at a second temperature.
  • the first solvent and the second solvent are selected from the group consisting of acetone, isobutyl acetate, water, acetone nitrile, 1-butanol, dimethylacetamide, N,N-dimethylformamide, nitromethane, toluene, dimethyl sulfoxide, dioxane, cyclopentyl methyl ether, tert-amyl methyl ether, 2- ethoxyethanol, ethyl acetate, ethanol, hexafluoroisopropanol, diisopropyl ether, methyl ethyl ketone, hexane, methanol, 2-methyltetrahydrofuran (2-MeTHF), N-methyl-2-pyrrolidone, 2,2,2-trifluoroethanol (TFE), 1-propanol, isopropanol alcohol, methylcyclohexane, tetrahydrofuran (THF), anisole, methyl
  • the first solvent is DMSO and the second solvent is nitromethane, or vice versa.
  • the first solvent is dioxane and the second solvent is TAME, or vice versa.
  • the first solvent is MEK and the second solvent is hexane, or vice versa.
  • the first solvent is TFE and the second solvent is 1- PrOH, or vice versa.
  • the first solvent is HFIPA and the second solvent is IPE, or vice versa.
  • the first solvent is acetone nitrile and the second solvent is 1-butanol, or vice versa.
  • the first solvent is DMF and the second solvent is water, or vice versa.
  • the first solvent is dioxane and the second solvent is CPME, or vice versa.
  • the first solvent is NMP and the second solvent is toluene, or vice versa.
  • the first solvent is THF and the second solvent is IPA, or vice versa.
  • the first temperature is higher than -50 °C, -40 °C, -35 °C, -30 °C, -25 °C, -20 °C, -15 °C, or -10 °C. In some embodiments, the first temperature is lower than 10 °C, 5 °C, 0 °C, -5 °C, or -10 °C.
  • the first temperature is from about -40 °C to about 10 °C, from about -30 °C to about 0 °C, from about -25 °C to about -5 °C, or from about -25 °C to about -10 °C. In some embodiments, the first temperature is from 30 °C to 70 °C, from 40 °C to 60 °C, about 50 °C, or about 55 °C. In some embodiments, the second temperature is higher than -50 °C, -40 °C, - 35 °C, -30 °C, -25 °C, -20 °C, -15 °C, or -10 °C.
  • the second temperature is lower than 10 °C, 5 °C, 0 °C, -5 °C, or -10 °C. In some embodiments, the second temperature is from about -40 °C to about 10 °C, from about -30 °C to about 0 °C, from about -25 °C to about -5 °C, or from about -25 °C to about -10 °C. In some embodiments, the second temperature is 10 °C higher or lower than the room temperature, 5 °C higher or lower than the room temperature, 3 °C higher or lower than the room temperature, or about the room temperature.
  • the mixture of (1) is kept at the second temperature for 1 days to 5 days, 2 days to 4 days, or about 3 days.
  • the method further comprises: (3) evaporating the mixture of (2).
  • the mixture of (2) is evaporated in a fast way.
  • step (3) is evaporating the mixture of (2) wherein the mixture of (2) is fully exposed to air.
  • step (3) is evaporating the mixture of (2) wherein the mixture of (2) is fully exposed to air and under purged N2.
  • the method further comprises: (4) adding a third solvent to the mixture of (2) or the mixture of (3) under a third temperature.
  • the third solvent is the same as the first solvent.
  • the third solvent is the same as the second solvent. In some embodiments, the third solvent is different from both the first and the second solvent. In some embodiments, the third solvent is toluene. In some embodiments, the third temperature is 10 °C higher or lower than the room temperature, 5 °C higher or lower than the room temperature, 3 °C higher or lower than the room temperature, or about the room temperature. In some embodiments, the mixture of (4) is stirred at about room temperature for about 3h to about 30h, from about 5h to about 24h, or about 5h, or about 24h.
  • the first solvent and the second solvent are selected from the group consisting of acetone, isobutyl acetate, water, dimethylacetamide, 2-ethoxyethanol (EGEE), ethyl acetate, and cyclohexane, provided that the first solvent is different from the second solvent.
  • the first solvent is iBuOAc and the second solvent is acetone, or vice versa.
  • the first solvent is DMA and the second solvent is water, or vice versa.
  • the first solvent is EGEE and the second solvent is water, or vice versa.
  • the first solvent is EtOAc and the second solvent is cyclohexane, or vice versa.
  • the first temperature is from 30 °C to 70 °C, from 40 °C to 60 °C, about 50 °C, or about 55 °C.
  • the second temperature is from 30 °C to 70 °C, from 40 °C to 60 °C, about 50 °C, or about 55 °C.
  • the first temperature is 10 °C higher or lower than the room temperature, 5 °C higher or lower than the room temperature, 3 °C higher or lower than the room temperature, or about the room temperature.
  • the second temperature is from 30 °C to 70 °C, from 40 °C to 60 °C, about 50 °C, or about 55 °C. In some embodiments, the second temperature is from 30 °C to 70 °C, from 40 °C to 60 °C, about 50 °C, or about 55 °C. In some embodiments, the second temperature is 10 °C higher or lower than the room temperature, 5 °C higher or lower than the room temperature, 3 °C higher or lower than the room temperature, or about the room temperature.
  • the method further comprises: (3) cooling the mixture of (2) to a third temperature.
  • the third temperature is 10 °C higher or lower than the room temperature, 5 °C higher or lower than the room temperature, 3 °C higher or lower than the room temperature, or about the room temperature.
  • the third temperature is higher than -5 °C, -3 °C, -1 °C, 0 °C, 1 °C, or 2 °C.
  • the third temperature is lower than 15 °C, 13 °C, 10 °C, 9 °C, or 8 °C.
  • the third temperature is from about -5 °C to about 15 °C, from about -3 °C to about 13 °C, from about 0 °C to about 10 °C, or from about 2 °C to about 8 °C.
  • the cooling is a fast cooling, wherein the mixture of (2) is directly removed from heating source and kept under the third temperature.
  • the method further comprises evaporating the mixture of step (2).
  • the method further comprises evaporating the mixture of step (3).
  • the method further comprises evaporating the mixture of step (4). III-o.
  • Method of Preparation – Polymorphic Form B [0304]
  • a method of preparing polymorphic Form B of the compound of Formula (A-1) comprising suspending the polymorphic Form A described herein in a solvent for a period of time, and re-isolating the solid in the mixture.
  • the polymorphic Form A is suspended in the solvent for at least 3 days, such as at least any of 4 days, 5 days, 6 days, or 7 days.
  • the polymorphic Form A is suspended in the solvent at about 0 °C to about 60 °C, such as about any of 5 °C to 50 °C, 5 °C to 25 °C, 15 °C, 25 °C, or 50 °C.
  • the solvent is selected from the group consisting of MeOH, MEK, EA, 2-MeTHF, ACN, water, and any combination thereof.
  • the solvent is a mixture of ACN and water.
  • polymorphic Form B seeds can be added to the suspension of polymorphic Form A in the solvent.
  • polymorphic Form A in the solvent is cooled slowly (e.g., by natural cooling) to isolate the solid in the mixture is isolated.
  • polymorphic Form B can be prepared by crystallization (e.g., direct crystallization) from a solution.
  • the solution comprises a single solvent.
  • the solution comprises a mixture of more than one solvents.
  • the compound of Formula (A-1) in step (i) is a polymorphic form provided herein.
  • the compound of Formula (A-1) in step (i) is polymorphic Form A.
  • the compound of Formula (A-1) in step (i) is suspended in the solvent together with a base.
  • the base comprises L-Lysine, Betaine, or a combination thereof.
  • the base is L-Lysine.
  • the base is betaine.
  • the solvent comprises acetonitrile, water, or a mixture thereof. In some embodiments, the solvent is a mixture of acetonitrile and water.
  • the volumetric ratio between acetonitrile and water in the solvent is at least about 1:1, such as at least about any of 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1. In some embodiments, the volumetric ratio between acetonitrile and water in the solvent is no more than about 20:1, such as no more than about any of 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, or 10:1. In some embodiments, the volumetric ratio between acetonitrile and water in the solvent is about 1:1 to about 10:1 or about 5:1 to 15:1.
  • the volumetric ratio between acetonitrile and water in the solvent is about any of 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, or 15:1.
  • the molar ratio between the base and the compound of Formula (A-1) in the mixture of step (i) is at least about 0.1:1, such as at least about any of 0.2:1, 0.4:1, 0.6:1, 0.8:1, 1:1, or 1.2:1.
  • the molar ratio between the base and the compound of Formula (A-1) in the mixture of (i) is no more than about 2:1, such as no more than about any of 1.8:1, 1.6:1, 1.4:1, 1.2:1, 1.1:1, or 1:1. In some embodiments, the molar ratio between the base and the compound of Formula (A-1) in the mixture of (i) is about 0.1:1 to about 1.5:1, such as about any of 0.5:1 to 1.2:1, 0.5:1 to 1.05:1, or about any of 0.5:1, 0.8:1, or 1.05:1.
  • the mixture of (i) is heated to an elevated temperature at or above about any of 30 °C, 35 °C, 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, 65 °C, or 70 °C. In some embodiments, the mixture of (i) is heated to an elevated temperature no more than about any of 90°C, 85 °C, 80 °C, 75 °C, 70 °C, 65 °C, 50 °C, 45 °C, or 40 °C.
  • the mixture of (i) is heated to an elevated temperature of about any of 30 °C, 35 °C, 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 90 °C, or 95 °C. In some embodiments, the mixture of (i) is heated to an elevated temperature of about 50 °C.
  • the mixture of (i), after reaching an elevated temperature is stirred for about or more than about any of 1 min, 10 min, 20 min, 30 min, 40 min, 50 min, 1 hour, 1.5 hour, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours.
  • the mixture of (i), after reaching an elevated temperature is stirred for no more than about any of 10 hours, 9 hour, 8 hours, 7 hours, 6 hours, 5 hours, 4.5 hours, 4 hours, 3.5 hours, 3 hours, 2.5 hours, 2 hours, or 1.5 hours.
  • the mixture of (i), after reaching an elevated temperature is stirred for about or more than about 2 hours.
  • the mixture of (i), after reaching an elevated temperature is stirred for about any of 1 min, 10 min, 20 min, 30 min, 40 min, 50 min, 1 hour, 1.5 hour, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours. In some embodiments, the mixture of (i), after reaching an elevated temperature, is stirred for about 2 hours. In some embodiments, the mixture of (ii) is cooled to a temperature of no more than 30 °C, such as about any of 25 °C, 20 °C, 15 °C, or 10 °C.
  • the mixture of (ii) is cooled to a temperature of at least 0 °C, such as at least about any of 5 °C, 10 °C, 15 °C, 20 °C, or 25 °C. In some embodiments, the mixture of (ii) is cooled over a period of at least a day, such as at least about any of 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. In some embodiments, the mixture of (ii) is cooled over a period of no more than 20 days, such as no more than about any of 18 days, 16 days, 14 days, 12 days, 10 days, or 7 days.
  • the mixture of (ii) is cooled over a period of about any of a day 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or 15 days.
  • the method further comprises (iv) filtering the solid from the mixture of (iii).
  • the method further comprises (v) drying the solid from step (vi) to obtain polymorphic Form B.
  • a method of preparing polymorphic Form B comprising (i) suspending compound of Formula (A-1) in a solvent to form a mixture; (ii) heating the mixture of step (i) at an elevated temperature and for a period of time; (iii) cooling the mixture of (ii); (iv) adding polymorphic Form B as seed; (v) heating the mixture of (iv); and (vi) cooling the mixture of (v).
  • the compound of Formula (A-1) in step (i) can be a polymorphic form provided herein.
  • the compound of Formula (A-1) in step (i) is polymorphic Form A.
  • the solvent comprises acetonitrile, water, or a mixture thereof. In some embodiments, the solvent is a mixture of acetonitrile and water. In some embodiments, the volumetric ratio between acetonitrile and water in the solvent is at least about 1:1, such as at least about any of 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1. In some embodiments, the volumetric ratio between acetonitrile and water in the solvent is no more than about 20:1, such as no more than about any of 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, or 10:1.
  • the volumetric ratio between acetonitrile and water in the solvent is about 1:1 to about 10:1 or about 5:1 to 15:1. In some embodiments, the volumetric ratio between acetonitrile and water in the solvent is about any of 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, or 15:1. In some embodiments, the mixture of (i) is heated to an elevated temperature of at or above about 30°C, such as about any of 30 °C, 35 °C, 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, 65 °C, or 70 °C.
  • the mixture of (i) is heated and stirred for at least about 1 minute, such as about any of 1 minute, 2 minutes, 3 minutes, 5 minutes, 7 minutes, or 10 minutes. In some embodiments, the mixture of (i) is heated and stirred for no more than about 120 minutes, such as no more than about any of 90 minute, 60 minutes, 45 minutes, 40 minutes, 30 minutes, 20 minutes, or 10 minutes. In some embodiments, the mixture of (i) is heated and stirred for about 10 minute, such as about any of 10 minute, 15 minutes, 20 minutes, 25 minutes, or 30 minutes.
  • the mixture of (ii) is cooled to a temperature of no more than 30 °C, such as about any of 30 °C, 25 °C, 20 °C, 15 °C, 10 °C, or 5 °C. In some embodiments, the mixture of (ii) is cooled to a temperature of at least about 0 °C, such as at least about any of 5 °C, 10 °C, 15 °C, 20 °C, or 25 °C. In some embodiments, the mixture of (ii) is cooled to a temperature of about any of 5 °C, 10 °C, 15 °C, 20 °C, or 25 °C.
  • the mixture of (iv) is heated up to an elevated temperature of at least about 30°C, such as at least about any of 30 °C, 35 °C, 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, 65 °C, or 70 °C. In some embodiments, the mixture of (iv) is heated to an elevated temperature no more than about any of 90°C, 85 °C, 80 °C, 75 °C, 70 °C, 65 °C, 50 °C, 45 °C, or 40 °C.
  • the mixture of (iv) is heated to an elevated temperature of about any of 30 °C, 35 °C, 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, or 65 °C.
  • the mixture of (iv) is heated up to an elevated temperature within an hour (e.g., within about any of 40 minutes, 30 minutes, 20 minutes, 10 minutes, or 5 minutes).
  • the mixture of (iv) is heated up to an elevated temperature over a period of at least 1 minute, such as at least about any of 1 min, 10 min, 20 min, 30 min, 40 min, 50 min, or 1 hour.
  • the mixture of (v) is cooled to a temperature of no more than 30 °C, such as about any of 25 °C, 20 °C, 15 °C, or 10 °C. In some embodiments, the mixture of (v) is cooled to a temperature of at least about 0 °C, such as at least about any of 5 °C, 10 °C, 15 °C, 20 °C, or 25 °C. In some embodiments, the mixture of (v) is cooled to a temperature of about any of 5 °C, 10 °C, 15 °C, 20 °C, or 25 °C.
  • the mixture of (v) is cooled to a temperature of no more than 30 °C at a cooling rate of about 1 °C/h to 20 °C/h, such as about any of 1 °C/h to 15 °C/h, 1 °C/h to 10 °C/h, or about 6 °C/h.
  • the method further comprises filtering the suspension obtained from step (vi). In some embodiments, the method further comprises drying the obtained polymorphic Form B.
  • a method of preparing polymorphic Form B comprising (i) suspending compound of Formula (A-1) (that is not the polymorphic Form B) in a solvent to form a mixture; and (ii) stirring the mixture of step (i) for a period of time.
  • the compound of Formula (A-1) in step (i) can be a polymorphic form provided herein (other than polymorphic Form B).
  • the compound of Formula (A-1) in step (i) is polymorphic Form A.
  • the method further comprises (i-a) adding polymorph Form B seed in the mixture of (i).
  • the mass ratio between polymorphic Form A and polymorphic Form B is about 1:1 to about 200:1, such as about any of 1:1 to 150:1, 50:1 to 150:1, or 100:1.
  • the purity of polymorphic Form A is higher than about any of 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, or 99.5%.
  • the purity of polymorphic Form A is higher than about 96%.
  • the purity of polymorphic Form A is higher than or equal to 97%.
  • the solvent comprises methanol (MeOH), methyl ethyl ketone (MEK), ethyl acetate (EA), 2-methyltetrahydrofuran (2-Me-THF), acetonitrile (ACN), or any mixture thereof.
  • the solvent is MeOH, MEK, EA, 2-Me-THF, or ACN.
  • the solvent is MEK.
  • the solvent comprises about 0% to about any of 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, 0.01%, 0.005%, or 0.001% EA. In some embodiments, the solvent comprises about 0% to about 0.3% EA.
  • the solvent does not comprise EA. In some embodiments, the solvent is ACN. In some embodiments, the mixture of (i) is stirred at or above about any of 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, 65 °C, 70 °C, 75 °C, or 80 °C.
  • the mixture of (i) is stirred at no more than about any of 120 °C, 115 °C, 110 °C, 105 °C, 100 °C, 95 °C, 80 °C, 75 °C, 70 °C, 65 °C, 60 °C, 55 °C, or 50 °C. In some embodiments, the mixture of (i) is stirred at or above about 50 °C.
  • the mixture of (i) is stirred at a temperature at about any of 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, 65 °C, 70 °C, 75 °C, or 80 °C. In some embodiments, the mixture of (i) is stirred at about 50 °C. In some embodiments, the mixture of (i) is stirred at a temperature at or above about 50 °C.
  • the mixture of (i) is stirred at a given temperature for less than about any of 5 days, 4 days, 3 days, 2 days, 25 hours, 24 hours, 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, 18 hours, 17 hours, 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour.
  • the mixture of (i) is stirred at a given temperature for at least about any of 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours. In some embodiments, the mixture of (i) is stirred at a given temperature for less than about 25 hours.
  • the mixture of (i) is stirred at a given temperature for about any of 5 days, 4 days, 3 days, 2 days, 25 hours, 24 hours, 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, 18 hours, 17 hours, 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour.
  • the mixture of (i) is stirred at a given temperature for about 24 hours.
  • the mixture of (i) is stirred at about 40 °C to about 60 °C for less than about 25 hours.
  • the mixture of (i) is stirred at about 50 °C for about 24 hours.
  • the method further comprises (iii) cooling the mixture of (ii).
  • the mixture of (ii) is cooled to a temperature of about 20 °C to about 30 °C, such as about 25 °C.
  • the mixture of (ii) is cooled quickly, such as within a period of less than 10 hours, such as less than about any of 7 hours, 5 hours, or 3 hours.
  • the method further comprises (iv) adding an antisolvent to the cooled mixture of (iii).
  • the antisolvent comprises n-heptane (HEP).
  • the solvent is MEK and the antisolvent is HEP. III-p.
  • Method of Preparation – Polymorphic Form C [0308]
  • the first solvent is DMF.
  • the second solvent is water.
  • the first solvent is DMF and the second solvent is water.
  • the second solvent is added at a temperature that is 10 °C higher or lower than the room temperature, 5 °C higher or lower than the room temperature, 3 °C higher or lower than the room temperature, or about the room temperature.
  • the solid of (3) is dried at a temperature that is 10 °C higher or lower than the room temperature, 5 °C higher or lower than the room temperature, 3 °C higher or lower than the room temperature, or about the room temperature.
  • the solid of (3) is dried under vacuum.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is formed with inorganic and/or organic bases.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is derived from reacting the compound of Formula (A-1) with a base comprising NaOH, KOH, Mg(OH) 2 , Ca(OH) 2 , L-arginine, L-lysine, choline, betaine, diethylamine, or any combination thereof.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is derived from reacting the compound of Formula (A-1) with an inorganic base comprising NaOH, KOH, Mg(OH) 2 , Ca(OH) 2 , or any combination thereof.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) comprises a sodium salt, a potassium salt, a magnesium salt, a calcium salt, a zinc salt, or any combination thereof.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is a sodium salt.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is a sodium salt, wherein the stoichiometry between compound of Formula (A-1) and sodium ion is about 1:0.8 to 1:3, such as about any of 1:0.9 to 1:2.7, 1:1 to 1:2.5, 1:1 to 1:2.3, 1:1 to 1:1.5, or 1:2 to 1:2.3.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is a mono-sodium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a di-sodium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a potassium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a potassium salt, wherein the stoichiometry between compound of Formula (A-1) and potassium ion is about 1:0.8 to 1:3, such as about any of 1:0.9 to 1:2.7, 1:1 to 1:2.5, 1:1 to 1:2.3, 1:1 to 1:1.5, or 1:2 to 1:2.3.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is a mono-potassium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a di-potassium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a magnesium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a calcium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a zinc salt.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is derived from reacting the compound of Formula (A-1) with an organic base comprising L-arginine, L-lysine, choline, betaine, diethylamine, or any combination thereof.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) comprises a L-arginine salt, a L-lysine salt, a choline salt, a betaine salt, a diethylamine salt, or any combination thereof.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is a L-arginine salt.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is a L-lysine salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a choline salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a betaine salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a diethylamine salt.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is a sodium salt, wherein the sodium salt is in a polymorphic form selected from the group consisting of polymorphic Form IV, polymorphic Form V, polymorphic Form VIII, polymorphic Form X, polymorphic Form XI, polymorphic Form XII, and any mixture thereof.
  • the pharmaceutically acceptable salt of the compound of Formula (A-1) is a potassium salt, wherein the potassium salt is in a polymorphic form selected from the group consisting of polymorphic Form VI, polymorphic Form VII, polymorphic Form IX, and any mixture thereof. V. Methods of Use V-a.
  • the solid formulation comprising a compound of Formula (A) or pharmaceutically acceptable salt thereof, a polymorphic form of a compound of Formula (A- 1), or a pharmaceutically acceptable salt form of a compound of Formula (A-1), as described herein, may be used to inhibit KIF18A.
  • the solid formulation comprising a compound of Formula (A) or the polymorphic form of a compound of Formula (A-1), as described herein may be used to treat or prevent a disease or condition in an individual.
  • the inhibitory activity of the solid formulation comprising a compound of Formula (A) or pharmaceutically acceptable salt thereof, a polymorphic form of a compound of Formula (A-1), or a pharmaceutically acceptable salt form of a compound of Formula (A-1), as described herein, against KIF18A may be determined and measured by methods known in the art including, but not limited to, inhibition of ATP hydrolysis in the presence of microtubules (Hackney D.D., Jiang W. (2001) Assays for Kinesin Microtubule-Stimulated ATPase Activity. In: Vernos I. (eds) Kinesin Protocols. Methods in Molecular BiologyTM, vol 164. Humana Press.
  • a method of inhibiting KIF18A comprising contacting a cell with an effective amount of the solid formulation comprising a compound of Formula (A) or pharmaceutically acceptable salt thereof, a polymorphic form of a compound of Formula (A-1), or a pharmaceutically acceptable salt form of a compound of Formula (A- 1), as described herein.
  • provided herein are methods of inhibiting KIF18A comprising contacting a cell with an effective amount of a solid formulation comprising a compound of Formula (A), Formula (B), Formula (C), Formula (A-1), Formula (A-2), and Formula (A-3) or pharmaceutically acceptable salt thereof, as described herein.
  • methods of inhibiting KIF18A comprising contacting a cell with an effective amount of a polymorphic form of a compound of Formula (A-1), as described herein.
  • provided herein are methods of inhibiting KIF18A comprising contacting a cell with an effective amount of a pharmaceutically acceptable salt form of a compound of Formula (A-1), as described herein.
  • the cell is contacted in vitro. In other variations of the aforementioned embodiments, the cell is contacted in vivo.
  • the solid formulation comprising a compound of Formula (A) or pharmaceutically acceptable salt thereof, a polymorphic form of a compound of Formula (A- 1), or a pharmaceutically acceptable salt form of a compound of Formula (A-1), as described herein, may be used to treat or prevent a disease or condition in an individual, comprising administering an effective amount of a compound or a pharmaceutical composition as described herein.
  • the solid formulation comprising a compound of Formula (A) or pharmaceutically acceptable salt thereof, the polymorphic form of a compound of Formula (A-1), or the pharmaceutically acceptable salt form of a compound of Formula (A-1), as described herein, may prevent a disease or disorder from developing in an individual at risk of developing the disease or disorder, or lessen the extent of a disease or disorder that may develop.
  • kits for treating or preventing a disease or condition in an individual comprising administering to the subject a therapeutically effective amount of a solid formulation comprising a compound of Formula (A) or pharmaceutically acceptable salt thereof, a polymorphic form of a compound of Formula (A- 1), or a pharmaceutically acceptable salt form of a compound of Formula (A-1), as described herein.
  • provided herein are methods of treating or preventing a disease or condition in an individual, comprising administering to the subject a therapeutically effective amount of a solid formulation comprising a compound of Formula (A), Formula (B), Formula (C), Formula (A-1), Formula (A-2), or Formula (A-3), or a pharmaceutically acceptable salt thereof, as described herein.
  • methods of treating or preventing a disease or condition in an individual comprising administering to the subject a therapeutically effective amount of a polymorphic form of a compound of Formula (A-1), as described herein.
  • provided herein are methods of treating or preventing a disease or condition in an individual, comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable salt form of a compound of Formula (A-1), as described herein.
  • the disease or condition is mediated by KIF18A.
  • the disease or condition is cancer.
  • the disease or condition is a cellular proliferation disorder, including uncontrolled cell growth, aberrant cell cycle regulation, centrosome abnormalities (structural and or numeric, fragmentation), a solid tumor, hematopoietic cancer and hyperproliferative disorder, such as thyroid hyperplasia (especially Grave's disease), and cyst (such as hypervascularity of ovarian stroma, characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome).
  • a cellular proliferation disorder including uncontrolled cell growth, aberrant cell cycle regulation, centrosome abnormalities (structural and or numeric, fragmentation), a solid tumor, hematopoietic cancer and hyperproliferative disorder, such as thyroid hyperplasia (especially Grave's disease), and cyst (such as hypervascularity of ovarian stroma, characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome).
  • Solid and hematologically derived tumors may include but are not limited to cancer of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, urothelium, liver, lung (including squamous cell and small cell lung cancer), pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gall-bladder, ovary, testicle, germ cell, uterus, pancreas, stomach, cervix, thyroid, prostate, salivary gland, and skin (including squamous cell carcinoma), hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodg
  • the disease or condition is cancer
  • the cancer is selected from the group consisting of advanced solid tumor, high grade serous adenocarcinoma of ovary, squamous non-small-cell lung cancer, triple negative breast cancer, gastric adenocarcinoma, colorectal adenocarcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, transitional cell carcinoma of bladder, head and neck squamous cell carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, uterine serous carcinoma, and endometrium cancer.
  • the disease or condition (e.g., cancer) is associated with chromosomal instability.
  • methods of treating or preventing cancer in an individual comprising administering to the individual in need thereof a solid formulation comprising a compound of Formula (A), Formula (B), Formula (C), Formula (A-1), Formula (A-2), or Formula (A-3) or a pharmaceutically acceptable salt thereof, as described herein.
  • methods of treating or preventing cancer in an individual comprising administering to the individual in need thereof, comprising administering to the subject a therapeutically effective amount of a polymorphic form of a compound of Formula (A-1), as described herein.
  • methods of treating or preventing cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one chemical entity as described herein.
  • a solid formulation comprising a compound of Formula (A), Formula (B), Formula (C), Formula (A- 1), Formula (A-2), or Formula (A-3), or a pharmaceutically acceptable salt thereof, as described herein, in the manufacture of a medicament for treatment of a disease in a subject.
  • Also provided herein is the use of a polymorphic form of a compound of Formula (A-1), as described herein, in the manufacture of a medicament for treatment of a disease in a subject. Also provided herein is the use of a pharmaceutically acceptable salt form of a compound of Formula (A-1), as described herein, in the manufacture of a medicament for treatment of a disease in a subject.
  • the cancer is selected from the group consisting of advanced solid tumor, high grade serous adenocarcinoma of ovary, squamous non-small-cell lung cancer, triple negative breast cancer, gastric adenocarcinoma, colorectal adenocarcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, transitional cell carcinoma of bladder, head and neck squamous cell carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, uterine serous carcinoma, endometrium cancer and endometrium cancer.
  • the disease or condition (e.g., cancer) is associated with chromosomal instability.
  • methods of treating cancer comprising administering to an individual in need thereof a solid formulation comprising a compound of Formula (A), Formula (B), Formula (C), Formula (A-1), Formula (A-2), or Formula (A-3), or a pharmaceutically acceptable salt thereof, as described herein.
  • methods of treating cancer comprising administering to an individual in need thereof a polymorphic form of a compound of Formula (A-1), or a pharmaceutically acceptable salt thereof, as described herein.
  • a solid formulation comprising a compound of Formula (A), Formula (B), Formula (C), Formula (A- 1), Formula (A-2), or Formula (A-3), or a pharmaceutically acceptable salt thereof, as described herein, in the manufacture of a medicament for treatment of a cancer.
  • provided herein are methods of treating a disease or condition mediated by KIF18A in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a formulation or polymorphic form as described herein.
  • methods of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a solid formulation comprising a compound of Formula (A) or pharmaceutically acceptable salt thereof, the polymorphic form of a compound of Formula (A-1), or the pharmaceutically acceptable salt form of a compound of Formula (A-1), as described herein.
  • the cancer is selected from the group consisting of carcinomas, cancer of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, urothelium, liver, lung, pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gall-bladder, ovary, testicle, germ cell, uterus, pancreas, stomach, cervix, thyroid, prostate, salivary gland, or skin, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, hematopoietic tumors of any lineage, myeloma, tumors of mesenchymal origin including sarcomas, tumors of the central and peripheral nervous system, tumor of neuroendocrine origin, tumor of endocrine origin, small cell tumors,
  • the cancer is selected from the group consisting of advanced solid tumor, high grade serous adenocarcinoma of ovary, squamous non-small-cell lung cancer, triple negative breast cancer, gastric adenocarcinoma, colorectal adenocarcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, transitional cell carcinoma of bladder, head and neck squamous cell carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, uterine serous carcinoma, and endometrium cancer.
  • the disease or condition e.g., cancer
  • the disease or condition is associated with chromosomal instability.
  • Administration of the compounds and formulations described herein can be via any accepted mode of administration for therapeutic agents including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration.
  • the compound or formulation is administered orally or intravenously.
  • the compound or formulation described herein is administered orally.
  • the compounds and formulations described herein is administered periodically. In some embodiments, the compound or formulation is administered daily.
  • the compound or formulation is administered every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 days. In some embodiments, the compound or formulation is administered every 28 days. In some embodiments, administrations of the compound or formulation are at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 days apart. In some embodiments, administrations of the compound or formulation are at least 28 days apart.
  • the compound or formulation is administered in 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, 20-, 21-, 22-, 23-, 24-, 25-, 26-, 27-, 28-, 29- , 30-, 31-, 32-, 33-, 34-, 35-, or 36-day cycles.
  • the compound or formulation is administered in 28-day cycles.
  • the compound or formulation is administered orally in 28-day cycles.
  • Kits [0325] Also provided are articles of manufacture and kits containing any of the solid formulation comprising a compound of Formula (A) or pharmaceutically acceptable salt thereof, the polymorphic form of a compound of Formula (A-1), or the pharmaceutically acceptable salt form of a compound of Formula (A-1), as described herein.
  • the article of manufacture may comprise a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed from a variety of materials such as glass or plastic. The container may hold a pharmaceutical composition provided herein. The label on the container may indicate that the pharmaceutical composition is used for preventing, treating or suppressing a condition described herein, and may also indicate directions for either in vivo or in vitro use.
  • kits containing a solid formulation comprising a compound of Formula (A) or a polymorphic form of a compound of Formula (A-1), as described herein, and instructions for use may contain instructions for use in the treatment of any disease or condition described herein in an individual in need thereof.
  • a kit may additionally contain any materials or equipment that may be used in the administration of the compound or composition, such as vials, syringes, or IV bags.
  • a kit may also contain sterile packaging. V-c.
  • the solid formulation comprising a compound of Formula (A) or pharmaceutically acceptable salt thereof, the polymorphic form of a compound of Formula (A-1), or the pharmaceutically acceptable salt form of a compound of Formula (A-1) described herein may be administered alone or in combination with other therapies and/or therapeutic agents useful in the treatment of the aforementioned disorders.
  • the solid formulation comprising a compound of Formula (A) or pharmaceutically acceptable salt thereof, the polymorphic form of a compound of Formula (A-1), or the pharmaceutically acceptable salt form of a compound of Formula (A-1) described herein may be combined with one or more other therapies to treat the diseases or conditions described herein.
  • the disease or condition is cancer.
  • the disease or condition is a cellular proliferation disorder, including uncontrolled cell growth, aberrant cell cycle regulation, centrosome abnormalities (structural and or numeric, fragmentation), a solid tumor, hematopoietic cancer and hyperproliferative disorder, such as thyroid hyperplasia (especially Grave's disease), and cyst (such as hypervascularity of ovarian stroma, characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome).
  • a cellular proliferation disorder including uncontrolled cell growth, aberrant cell cycle regulation, centrosome abnormalities (structural and or numeric, fragmentation), a solid tumor, hematopoietic cancer and hyperproliferative disorder, such as thyroid hyperplasia (especially Grave's disease), and cyst (such as hypervascularity of ovarian stroma, characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome).
  • Solid and hematologically derived tumors may include but are not limited to cancer of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, urothelium, liver, lung (including squamous cell and small cell lung cancer), pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gall-bladder, ovary, testicle, germ cell, uterus, pancreas, stomach, cervix, thyroid, prostate, salivary gland, and skin (including squamous cell carcinoma), hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodg
  • the cancer is selected from the group consisting of advanced solid tumor, high grade serous adenocarcinoma of ovary, squamous non-small-cell lung cancer, triple negative breast cancer, gastric adenocarcinoma, colorectal adenocarcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, transitional cell carcinoma of bladder, head and neck squamous cell carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, uterine serous carcinoma, and endometrium cancer.
  • the disease or condition e.g., cancer
  • the disease or condition is associated with chromosomal instability.
  • DSC Differential Scanning Calorimetry
  • thermodynamic properties SDIs prepared herein including the following: glass transition temperature (T g ) defined as the temperature at which amorphous materials transition from a low mobility glassy state to a high mobility rubbery state, cold crystallization temperature (Tc), defined as a crystallization event at a temperature lower than the melt temperature, and melting temperature (T m ).
  • T g glass transition temperature
  • Tc cold crystallization temperature
  • T m melting temperature
  • the system was purged by nitrogen flow at 50 mL/min to ensure inert atmosphere through the course of measurement.
  • Spray dried samples were placed in non-hermetic aluminum pans and heated at a constant rate of 2.0 °C/min. DSC parameters are summarized in Table 1-1.
  • XRPD X-Ray Powder Diffraction
  • a beam-stop, short anti-scatter extension, and an anti-scatter knife edge were used to minimize the background generated by air.
  • Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence.
  • Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v. 5.5.
  • XRPD patterns were collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu K ⁇ radiation produced using a long, fine- focus source and a nickel filter. The diffractometer was configured using the symmetric Bragg-Brentano geometry.
  • a silicon specimen (NIST SRM 640f) was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST- certified position.
  • a specimen of the sample was prepared as a thin, circular layer centered on a silicon zero-background substrate.
  • Anti-scatter slits (SS) were used to minimize the background generated by air.
  • Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence.
  • Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the sample and Data Collector software v. 5.5.
  • SEM samples were placed on a glass microscope slide and a 11 ⁇ 2 cover glass is placed over the sample. Then mineral oil was added to the edge of the cover glass to cover the sample by capillarity. Images were acquired at ambient temperature using Teledyne Lumenera INFINITY ANALYZE software version 7.1.0.1215. The camera was white balanced in accordance with the Initial Camera Configuration in the software. Particle Morphology by Scanning Electron Microscopy (SEM) [0337] SEM samples were prepared by dispersing powder onto an adhesive carbon-coated sample stub and coating with a thin conductive layer of gold-palladium using a Cressington 108 Auto.
  • the Dv 50 diameter is the diameter at which 50% of a sample’s volume is comprised of smaller particles.
  • Table 1-3 Assay and Impurities by High Performance Liquid Chromatography (HPLC) [0339] Assay and impurities of SDI samples were evaluated using an HPLC method provided by the client. Parameters are listed in Table 1-4. The method demonstrated passing system suitability criteria for early development work, including but not limited to reproducibility, standard agreement, injector precision, tailing, and signal to noise.
  • Table 1-4 Residual Solvent by Gas Chromatography – Headspace Sampling [0340] The residual solvent content of SDIs was measured by GC-HS after secondary drying.
  • TGA/DSC Combination Analyses were performed using a Mettler Toledo TGA/DSC3+ analyzer. Temperature and enthalpy adjustments were performed using phenyl salicylate, indium, tin, and zinc, and then verified with indium. Balance was verified with calcium oxalate. The sample was placed in an aluminum pan. The pan was hermetically sealed, the lid pierced, then inserted into the TG furnace. A weighed aluminum pan configured as the sample pan was placed on the reference platform. The furnace was heated under nitrogen. Dynamic vapor sorption (DVS) [0342] Moisture sorption/desorption data were collected on a Surface Measurement System DVS Intrinsic instrument.
  • DVS Dynamic vapor sorption
  • TMSC Temperature modulated differential scanning calorimetry
  • Example S-1 Synthesis of compounds of Formula (A) General synthetic methods [0344] Compounds of Formula (A), Formula (B), Formula (C), Formula (A-1), Formula (A- 2), and Formula (A-3) will now be described by reference to illustrative synthetic schemes for their general preparation below and the specific examples that follow.
  • starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product.
  • protecting groups may be used to protect certain functional groups (amino, carboxy, or side chain groups) from reaction conditions, and that such groups are removed under standard conditions when appropriate.
  • the variables are as defined above in reference to Formula (A), Formula (B), Formula (C), Formula (A-1), Formula (A-2), or Formula (A-3).
  • enantiomer of a compound may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers.
  • diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
  • Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
  • General methods of preparing compounds described herein are depicted in exemplified methods below. Variable groups in the schemes provided herein are defined as for Formula (A), Formula (B), Formula (C), Formula (A-1), Formula (A-2), or Formula (A- 3), or any variation thereof. Other compounds described herein may be prepared by similar methods.
  • an indoline of formula B in the presence of coupling reagent, such as HATU with a base such as iPr 2 NEt, or EDCI with a HOBt or DMAP.
  • Et3N an acid scavenger
  • Indoline intermediates of formula B may be prepared via the Fisher Indole Synthesis as described in Scheme 2.
  • Arylhydrazines of formula C e.g., formula C-i, formula C-ii, and formula C-iii
  • a Ring B-substituted carbaldehyde of formula D in the presence of acid, followed by reaction with a reducing agent such as NaBH 4 , Pd/C and H 2 gas, or Et3SiH.
  • Arylhydrazines of formula C-i which are para-mono-substituted, provide indolines of formula B-i, while hydrazines of formula C-ii, which contain at least one meta substituent and are not substituted in the ortho positions, provide a mixture of indolines of formulae B-ii-a and B-ii-b.
  • Arylhydrazines of formula C-iii, that are substituted at one ortho position, provide indolines of formula B-iii.
  • Scheme 3 [0351] Indolines of formula B may also be prepared via an 3,3-dialkylation method described in Scheme 3.
  • Indolines of formula B may also be prepared via the enolate alkylation of an indolin- 2-one of formula F.
  • the indolin-2-one of formula F is deprotonated with a strong base, such as butyllithium, sodium hexamethylsilazide, or potassium t-butoxide, and reacted with an optionally substituted 3-6 atom aliphatic and heteroaliphatic linear chain with two terminal leaving groups “LG” (formula E).
  • LG may be Cl, Br, I, or sulfonate ester, or another suitable group displaceable by a nucleophile.
  • This reaction may be mediated by an additive such as tetramethyldiaminoethane or hexamethylphosphorous triamide.
  • the spiroannulation reaction is followed by a reaction with a reducing agent such as LiAlH 4 or borane.
  • Step 1 To a mixture of ZnEt2 (1 M in hexanes, 180 mL), CH 2 Cl 2 (200 mL) at 0 °C under N2 was added slowly CH 2 l 2 (26 mL, 320 mmol), in CH 2 Cl 2 (60 mL). The mixture was stirred at 0 °C for 30 min and ethyl 4-methylenecyclohexanecarboxylate (12 g, 71 mmol) in CH 2 Cl 2 (50 mL) was slowly added. The mixture was stirred at 20 °C for 12 h, cooled to 0 °C, and saturated NH 4 Cl (100 mL) was added.
  • Step 2 To a mixture of ethyl spiro[2.5]octane-6-carboxylate (10 g, 55 mmol), THF (300 mL) at 0 °C under N 2 was added LiAlH 4 (3.1 g, 81 mmol) in portions.
  • Dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indole] was prepared from phenylhydrazine and spiro[2.5]octane-6-carbaldehyde in the manner described in Step 4a of the synthesis of B-01. [0361] Step 2. To a mixture of dispiro[cyclopropane-1,1'-cyclohexane-4',3''-indole] (1.0 g, 4.7 mmol) in MeOH (15 mL) and THF (15 mL) at 0 °C was added NaBH 3 CN (0.90 g, 14 mmol) in portions.
  • Example S-2 Synthesis of Compound 1, Compound 2 and Compound 9 [0362] A mixture of 3-[(4, 4-difluoro-1-piperidyl)sulfonyl]benzoic acid (88 mg, 0.28 mmol), DMF (1.5 mL), Et 3 N (0.11 mL, 0.78 mmol), and HATU (0.20 g, 0.52 mmol) was stirred at 20 °C for 30 min, and 4'-fluorospiro [cyclopentane-1,3'-indoline] (50 mg, 0.26 mmol) in DMF (1.0 mL) was added.
  • Example S-4 Synthesis of Compound 18 and compound of Formula (A-2) [0365]
  • a degassed mixture of Compound 2 (50 mg, 93 ⁇ mol), methanesulfonamide (13 mg, 0.14 mmol), CuI (9.0 mg, 46 ⁇ mol), K 3 PO 4 (59 mg, 0.28 mmol), N 1 ,N 2 - dimethylcyclohexane-1,2-diamine (7.0 mg, 46 ⁇ mol), and DMF (2.0 mL) was stirred at 150 °C for 2 h in a microwave reactor. The mixture was combined with H 2 O (30 mL) and extracted with EtOAc (2 x 30 mL).
  • Example F-1 Preparation of a spray-dried dispersion
  • Organic solubility of bulk compound of Formula (A-1) was determined visually in common spray drying solvents. This data is summarized in Table F-1.
  • the compound of Formula (A-1) showed no less than 10 wt. % solubility in the evaluated DCM:MeOH solvent system. 87:13 (w/w) DCM:MeOH was selected as the spray drying solvent based on sufficient compound solubility and manufacturability.
  • Table F-1 Organic solubility of the compound of Formula (A-1)
  • Eight spray dried dispersion (SDD) formulations comprising the compound of Formula (A-1) and various SDD polymers in varied weight ratios were prepared.
  • the eight SDD formulations prepared are shown in Table F-2.
  • the total solid for all eight samples was 7.0 wt%.
  • Drying gas mode was set as recycle, with a condenser temperature of about -21 °C to about -17°C.
  • Solution flow rate was about 16g/min and atomization pressure was set to 28 psi.
  • Inlet temperature for all eight samples was about 98 °C to about 115°C, and the outlet temperature was about 43 °C to about 59°C. Secondary drying was carried out to further remove residual solvents.
  • Table F-2 [0373] The physical appearance and coloration of the eight SDDs comprising a compound of Formula (A-1) prepared above were off-white powders.
  • Example F-2 Characterization of spray-dried dispersions
  • Thermal analysis by MDSC of SDDs in Table F-2 is shown in in Table F-3. All the prepared SDDs had a single T g , indicating a homogeneous amorphous solid dispersion. 25:75 compound of Formula (A-1):HPMCP-HP55 SDD had the highest T g , which was determined to be at around 118 °C. 50:50 compound of Formula (A-1):HPMC E3LV SDD had the lowest T g , which was determined to be at around 90 °C.
  • SDDs prepared in Example F-1 were amorphous dispersions with no crystalline peaks observed.
  • SEM scanning electron microscopy
  • FIGS. 1A-1H show images of SDDs with different formulations captured at 5000 ⁇ magnification. All SDDs have been observed with typical SDD morphology consisting of collapsed and un- collapsed spheres with smooth surfaces. No crystalline material was observed in any sample. For all SDDs, sizes of most observed individual particles were within 1-20 ⁇ m.
  • the four SDDs being tested were 25:75 compound of Formula (A- 1):HPMCP-HP55, 40:60 compound of Formula (A-1):HPMCP-HP55, 40:60 compound of Formula (A-1):Eudragit L100-55, and 50:50 compound of Formula (A-1):Eudragit L100-55, and the results are shown in Table F-4.
  • Table F-4 As shown in Table F-4, for all SDDs being tested, a single T g was observed at all relative humidity conditions, indicating all SDDs were still homogeneous. No significant differences were observed between different drug loadings in different SDD formulations for T g vs %RH. All SDDs tested showed significant T g suppression at 75% RH.
  • SDDs comprising the compound of Formula (A-1) with eight different formulations were successfully prepared. All prepared SDDs were analyzed by DSC, XRPD, SEM, PSD and potency and related substances for chemical and physical properties. Results indicated that the SDDs were fully amorphous by XRPD, homogeneous by DSC due to the single T g , had typical SDD surface morphology by SEM and tight particle size distribution by PSD.
  • Polymorphic Form C (i.e. amorphous form) of compound of Formula (A-1) was prepared using H 2 O and DMF.
  • H 2 O was added to a DMF solution of compound of Formula (A-1), resulting in precipitates with no birefringence/extinction.
  • the solids were isolated and washed with H 2 O, followed by vacuum drying. As determined by XRPD and shown in FIG. 5, middle trace, the post-dried solids however were a mixture of amorphous material (polymorphic Form C) and minor polymorphic Form A.
  • a DMF solution of compound of Formula (A-1) was dried under nitrogen to a gel. This gel was stirred in H 2 O briefly to yield a suspension.
  • the polymorphic Form A showed a single endothermic peak at 194 °C, possibly due to melting.
  • the polymorphic Form A gained 0.095 wt. % from 5-95% RH and lost 0.097 wt. % from 95-5% RH. Therefore the polymorphic Form A exhibited low kinetic hygroscopicity.
  • the post- DVS sample maintained the same form by XRPD.
  • the polymorphic Form C i.e. amorphous form of compound of Formula (A-1) prepared by slurring a gel from DMF in H 2 O is substantially amorphous.
  • amorphous form of compound of Formula (A-1) displayed a weight loss of about 0.9% from 53-120 °C and an additional weight loss of about 1.1% from 120-200 °C, likely due to loss of residual solvents (H 2 O and DMF).
  • Apparent decomposition started at about 319 °C, similar to the result of polymorphic Form A (FIG. 3).
  • T g glass transition
  • a T g can be measured by TMDSC, in which the total heat flow signal can be separated into its thermodynamic (heat capacity) and kinetic components. Therefore, the T g can typically be seen as a step change in the reversing signal.
  • TMDSC was performed for the polymorphic Form C (i.e. amorphous form) of compound of Formula (A-1), and the reversing heat flow is presented in FIG. 7.
  • a glass transition was observed at 85°C ( ⁇ C p 0.3 J/(g*K)). It should be noted that differences in solvent and/or water content within the sample can shift the temperature at which the glass transition occurs.
  • An endothermic peak was observed at 191 °C, similar to the result observed for polymorphic Form A (FIG. 3). This endotherm was likely indicative of a melt and would suggest that the material may have crystallized at a temperature above the glass transition during the analysis.
  • DVS by DVS, as shown in FIG. 8, the polymorphic Form C (i.e.
  • amorphous form of compound of Formula (A-1) gained 1.13 wt. % from 5-95% RH, while it lost 1.57 wt. % from 95-5%. This hysteresis of 0.44 wt% was likely due to water in the sample at the start of the analysis.
  • the as-generated the polymorphic Form C (i.e. amorphous form) of compound of Formula (A-1) contained about 0.12 moles of DMF, corresponding to about 1.5 wt%, while the TGA thermogram displayed a weight loss of about 2.0% from 53-200 °C (FIG. 6). Therefore the water content was estimated as 0.5 wt%, consistent with the DVS hysteresis.
  • the as-generated the polymorphic Form C (i.e. amorphous form) of compound of Formula (A-1) was used for crystallization experiments, as part of the polymorph screen (Table P-6). Common crystallization techniques were used including heat/RH stress, slurrying, evaporation, and solvent/anti-solvent addition. All samples exhibited partial or full crystallization to polymorphic Form A. Table P-6 Example P-3.
  • Example P-4 Salt screening [0404] Seven Class I bases, 2 Class II bases and 1 Class III base were selected to pursue potential salt opportunities. The selected counter ions for salt screening are summarized in Table P-8. Given consideration to the solubility of Compound of Formula (A-1) in various common solvents, ability of the solvents to dissolve counter ions, and solvent properties, ethanol, acetonitrile/water (90:10, v:v) and THF/water (90:10, v:v) were selected as screening solvents. Table P-8. Counter ions used for salt screening [0405] With the selected counter ions and solvents, slurry equilibration, cooling, slow evaporation, anti-solvent addition and salt metathesis were applied as screening methods.
  • Results are summarized in Table P-9. Table P-9. Results of Slurry Equilibration Cooling [0408] Clear solutions obtained in slurry equilibration experiments were cooled to 5°C to precipitate solids. Suspensions obtained after cooling were filtered through a 0.45 ⁇ m nylon membrane filter by centrifugation at 14,000 rpm. After being dried at 50°C under vacuum for 2h, solids were analyzed by XRPD. Results are summarized in Table P-10. Table P-10. Results of Cooling //: experiment not carried out Slow evaporation [0409] Clear solutions obtained from cooling experiments were further treated by slow evaporation under ambient condition. Solids obtained by slow evaporation were dried at 50°C under vacuum for 2h and analyzed by XRPD. Results are summarized in Table P-11. Table P-11. Results of Slow Evaporation
  • Polymorphic Form X was placed at 25°C/92.5%RH in an open container, at 40°C/75%RH in an open container and at 60°C in a closed container for 1 week, after which polymorphic Form XI was obtained and further characterized by DSC, TGA, 1 H-NMR, IC, and KF.
  • polymorphic Form XI exhibits a dehydration event with an onset temperature Tonset at 6 °C, 71.1°C, 112.8°C, and 138.8°C. As shown in FIG.
  • polymorphic Form XI exhibits a weight loss of about 2.7% at about 64 °C, a weight loss of about 2.4% from 64 °C to about 100 °C, and a weight loss of 0.9% from about 100 °C to about 140 °C.
  • 1 H NMR indicated that there was not detectable residual solvent.
  • IC indicated the stoichiometric ratio between free acid and NaOH is 1:2.35.
  • Example P-5. Scale-Up Preparation of Salts and Polymorphic Forms [0415] Polymorphic Form B, polymorphic Form X, and polymorphic Form IX were scaled up successfully. These scale-up batches are the same polymorphs as those of the screening samples.
  • Polymorphic Form B was prepared following these steps: 1) 700mg of the polymorphic Form A was weighed into a 20mL glass vial. 6.2mL of ACN/water (9:1, v:v) was added into the vial at 50°C. After stirring for about 5 min, a clear solution was obtained. 2) About 3-5mg of polymorphic Form B seeds were added into above solution. 3) After stirring at 50°C for about 10 min, the clear solution was cooled to 25°C by natural cooling. 4) About 3-5mg of polymorphic Form B seeds were added into above solution.
  • Polymorphic Form B was also prepared at a large scale (60 g) following these steps: 1) Adding 53.75 g Compound of Formula (A-1) solid, 215 mL MEK and 1 wt.% Form B seed into 500 ml crystallizer, and keeping the temperature at 50 °C; 2) Sampling for PLM and XRPD at 24 h, 36 h or 48 h; 3) After completely transforming Form A to Form B, cooling the system to 25 °C within 5 h; 4) Adding 215 mL HEP within 4 h; and 5) Filtering the suspension, and drying the wet cake in vacuum oven at 40 °C for 48 h.
  • Polymorphic Form IX was prepared following these steps: 1) 400mg of the polymorphic Form A was weighed into a 20mL glass vial. 3.9mL of ACN/water (9:1, v: v) was added into the vial at 50°C. After stirring for about 5 min, a clear solution was obtained. 2) 100.3mg of potassium hydroxide ( ⁇ 2.05 equiv.
  • Polymorphic Form XII was prepared following these steps: 1) 400mg of the polymorphic Form A was weighed into a 20mL glass vial.1mL of ethanol was added into the vial at 50°C. After stirring for about 5 min, a clear solution was obtained. 2) 31.3mg of sodium hydroxide ( ⁇ 1.05 equiv. by molar ratio) was weighed into a 4mL glass vial and 1.5mL of ethanol was added with stirring at 50°C. After stirring for about 10min, a clear solution was obtained. 3) Then sodium hydroxide clear solution was added into free acid clear solution slowly under stirring at 50°C.
  • polymorphic Form XII was characterized by DSC, TGA, 1 H- NMR, IC, and KF. Key results are summarized in Table P-14. Table P-14. Characterization of polymorphic Form XII Example P-6. Solubility of Salt Forms and Polymorphic Forms Solubility test in aqueous media [0430] Accurate 3.0mg or 4.0 mg of the polymorphic Form A, 3.0mg or 4.0mg of the polymorphic Form B, 4.6 mg of the polymorphic Form X and 5.0 mg of the polymorphic Form IX was weighed into a 4mL glass vial, respectively. 1.5mL or 2 mL of solubility medium was added.
  • the salt amount used is equivalent to 4mg anhydrous free acid. Obtained suspensions were stirred at 37°C at 400 rpm and sampled at 2 hours and at 24 hours. The samples were centrifuged at 37°C at 14,000 rpm for 5min. Supernatants were analyzed by UPLC and pH meter for solubility and pH value, respectively. Residual solids (wet cakes) from the 24 hours samples were also characterized by XRPD to determine physical form. The results are summarized in Table P-15. Table P-15. Solubility in aqueous media
  • Example S-1 Screening and preparation of salt forms
  • Free acid anhydrous form of compound of Formula (A-1) is prepared for salt form screening.
  • Salt forms of compound of Formula (A-1) derived from inorganic or organic bases including NaOH, KOH, Mg(OH) 2 , Ca(OH) 2 , L-Arginine, L-Lysine, Choline, Betaine Diethylamine, and Zn(OH) 2 are screened using methods including slurry equilibration, cooling, slow evaporation, anti-solvent addition, and salt metathesis.
  • Test compounds were plated in a 3 ⁇ dilution scheme in a 384-well plate.
  • Assay buffer 80 mM PIPES (pH 6.9), 1 mM MgCl 2 , 75 mM KCl, 1 mM EGTA, 1 mM DTT, 0.01% BSA, 0.005% Tween-20, 1 ⁇ M Taxol in H 2 O.
  • microtubule mix was added [0.2 mg/mL pre-formed microtubules, 2.0 mM ATP in assay buffer], the plate was centrifuged for 30 s and then incubated at 28 °C for 60 min.
  • 5 ⁇ L of Promega® ADP-Glo Max R1 was added, the plate was centrifuged for 30s, and the mixture incubated for 4 h at room temperature.
  • 10 ⁇ L of Promega® ADP-Glo Max R2 was added, the plate centrifuged for 30 s, and incubated for 60 min at room temperature.
  • Luminescence was measured with an Envision plate reader, and %Inhibition was calculated for each well as: ([max – min] – [test – min])/[max – min].
  • IC50 values were calculated from concentration vs. % Inhibition data via a four-parameter variable slope model.
  • Table B-1 indicates that compounds as provided herein are potent inhibitors of KIF18a.
  • AMG650 (2- ⁇ 6-azaspiro[2.5]octan-6-yl ⁇ -N-[2-(4,4- difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-4-(2-hydroxyethanesulfonamido)benzamide
  • AMG650 2- ⁇ 6-azaspiro[2.5]octan-6-yl ⁇ -N-[2-(4,4- difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-4-(2-hydroxyethanesulfonamido)benzamide
  • Binding kinetics to KIF18a-microtubule complex [0436] Compound binding kinetics parameters (k on and k off ) were determined by the method of global progress curve analysis (GPCA). KIF18A (0.25 nM) was incubated for up to 24 hr with serially diluted compound in the assay buffer containing 80mM PIPES, pH 6.9, 1 mM ATP, 0.1 mg/ml preformed microtubule from porcine brain (Cytoskeleton), 1 mM MgCl 2 , 1 ⁇ M Taxol, 75 mM KCl, 1 mM EGTA, 1 mM DTT, 0.01% BSA and 0.005% Tween-20.
  • GPCA global progress curve analysis
  • Test compounds were added to cells in a 20 ⁇ dilution scheme by adding 5 ⁇ L of serially diluted compound to the plate, and the treated cells were incubated for an additional 7 days in a 37 °C, 5% CO 2 incubator.
  • DMSO was used as the negative control (0% effect), and wells omitting cells were used as the positive control (100% effect).
  • the cells were incubated for seven days, and cell viability determined via the Promega Cell Titre-Glo® Assay kit. Luminescence units were converted to ATP concentrations via an ATP standard curve (10 point, 2-fold dilution from 5 uM).
  • %Inhibition was calculated for each well as: ([max – min] – [test – min])/[max – min]. IC 50 values were calculated from concentration vs. %Inhibition data via a four-parameter variable slope model. Results from the biological assay are summarized in Table B-2. [0440] Table B-3 indicates that compounds as provided herein potently inhibit cell growth or induce cell killing for KIF18a-senstive cancer cell lines.
  • OVCAR-3 (ATCC) tumor cells were maintained in vitro in RPMI-1640 medium supplemented with 20% fetal bovine serum, 0.01 mg/mL bovine insulin and 1% Anti-Anti at 37oC in an atmosphere of 5% CO 2 in air.
  • HCC15 (DSMZ) tumor cells were maintained in vitro in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% Anti-Anti at 37oC in an atmosphere of 5% CO 2 in air.
  • the tumor cells were sub-cultured twice weekly. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation.
  • Tumor cells (10 x 10 6 ) in 0.2 mL of PBS mixed with Matrigel (50:50) were inoculated subcutaneously on the right flank of each mouse. When the average tumor volume reached 110-175 mm 3 , animals were randomized into groups of 10 and treatment started.
  • OVCAR-3 cells were implanted in Balb/C nude mice, and HCC15 cell were implanted in SCID Beige mice.
  • SDD samples of the compound of Formula (A-1) and the compound of Formula (A-2) were prepared respectively.
  • the SDD sample for the compound of Formula (A-1) is 25:75 (w/w) the compound of Formula (A-1):HPMCAS-M.
  • TGI Tumor Growth Inhibition
  • Pharmacokinetics of the 50:50 compound of Formula (A- 1):Eudragit L100-55 SDD following oral administration to Male CD-1 Mice [0446]
  • the pharmacokinetic (PK) profile of 50:50 compound of Formula (A-1):Eudragit L100-55 SDD was first tested and evaluated in Male CD-1 Mice following oral administration (PO).
  • the study design is shown in Table B-5.
  • Table B-5 [0447] The 50:50 compound of Formula (A-1):Eudragit L100-55 SDD was provided as a neat powder and stored at 2-8 °C before the PK profile study.
  • the 50:50 compound of Formula (A-1):Eudragit L100-55 SDD was dissolved in an appropriate amount of vehicle(s) to achieve the desired concentration.
  • vehicle(s) Prior to starting the formulation, the approximate dosing volume of water was added to the container and a Q.S. line was marked. The water was discarded. A small amount of the vehicle (0.5% methylcellulose (MC) (400cp) in water) was added to the container and stirred continuously.
  • the appropriate amount of 50:50 compound of Formula (A-1):Eudragit L100-55 SDD was slowly be added to the stirring vehicle. After all the 50:50 compound of Formula (A- 1):Eudragit L100-55 SDD was added, the vehicle was added until the formulation reaches the Q.S.
  • PK pharmacokinetic
  • the collected blood samples were analyzed using a qualified bioanalytical method.
  • PK analysis was performed to include, at a minimum: T max , C max , AUC 0-24 , T max (median) and T max (range).
  • the plasma concentration data are shown in Table B-6.
  • the plasma PK parameter summary data are shown in Table B-7.
  • Table B-6. Mean Concentration Versus Time Summary of 50:50 compound of Formula (A- 1):Eudragit L100-55 SDD Following a Single PO Gavage Dose to Male CD-1 Mice Table B-7.
  • TPGS tocophersolan
  • MRT Mean Residence Time
  • Table B-10 Detailed dosing parameters and PK parameters are shown in Table B-10.
  • Table B-10 [0454] As shown in Table B-10, the oral PK profile of neat compound of Formula (A-1) was poor in typical suspension formulation. All suitable SDD formulations comprising the compound of Formula (A-1) showed similarly improved bioavailability compared to neat compound of Formula (A-1). These SDD formulations also showed similar C max , AUC, and half-life of the compound of Formula (A-1). The SDD formulations comprising the compound of Formula (A-2) exhibited high bioavailability as well. The loading of the compound of Formula (A-1) or (A-2) in SDD formulations was achieved up to 50%. The data also demonstrated that TPGS was not required to achieve satisfying exposure of the compound of Formula (A-1).
  • Biological Example B-7 Human PK parameters following oral administration of SDD formulation
  • the pharmacokinetic (PK) profile of the compound of Formula (A-1) after oral administration of the SDD formulations of the compound of Formula (A-1) was extrapolated based on rat and dog data to human subject and the details are summarized in Table B-11.
  • the human PK profile is consistent with oral administration and high target engagement with Q.D. or B.I.D. dosing. Table B-11

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente divulgation concerne des inhibiteurs de KIF18A, des formulations de ceux-ci, des formes polymorphes de ceux-ci, et des procédés d'utilisation desdites formulations et formes polymorphes de ceux-ci. Plus spécifiquement, la présente divulgation concerne des formulations solides et des formes polymorphes d'une série d'inhibiteurs d'indoline de KIF18A, des procédés de préparation de telles formulations et formes polymorphes, et des procédés d'utilisation de celles-ci pour traiter une maladie médiée par KIF18A, telle que le cancer.
EP24715930.4A 2023-02-23 2024-02-22 Formulations solides et formes polymorphes d'inhibiteurs d'indoline de kif18a Pending EP4669309A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202363486611P 2023-02-23 2023-02-23
US202363486613P 2023-02-23 2023-02-23
US202363611027P 2023-12-15 2023-12-15
PCT/US2024/016952 WO2024178255A1 (fr) 2023-02-23 2024-02-22 Formulations solides et formes polymorphes d'inhibiteurs d'indoline de kif18a

Publications (1)

Publication Number Publication Date
EP4669309A1 true EP4669309A1 (fr) 2025-12-31

Family

ID=90716922

Family Applications (1)

Application Number Title Priority Date Filing Date
EP24715930.4A Pending EP4669309A1 (fr) 2023-02-23 2024-02-22 Formulations solides et formes polymorphes d'inhibiteurs d'indoline de kif18a

Country Status (9)

Country Link
EP (1) EP4669309A1 (fr)
JP (1) JP2026508238A (fr)
KR (1) KR20250150655A (fr)
CN (1) CN121358466A (fr)
AU (1) AU2024226158A1 (fr)
IL (1) IL322409A (fr)
MX (1) MX2025009863A (fr)
TW (1) TW202438053A (fr)
WO (1) WO2024178255A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI844602B (zh) 2018-12-20 2024-06-11 美商安進公司 Kif18a抑制劑
TW202416973A (zh) 2022-08-18 2024-05-01 美商雅客森醫療公司 Ｋｉｆ１８ａ抑制劑及其用途

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1087725C (zh) 1994-03-25 2002-07-17 同位素技术有限公司 用氘代方法增强药物效果
US6334997B1 (en) 1994-03-25 2002-01-01 Isotechnika, Inc. Method of using deuterated calcium channel blockers
JP7676308B2 (ja) * 2018-12-20 2025-05-14 アムジエン・インコーポレーテツド Ｋｉｆ１８ａ阻害剤として有用なヘテロアリールアミド
CN119241504A (zh) * 2021-08-26 2025-01-03 沃拉斯查疗法公司 Kif18a的螺吲哚啉抑制剂

Also Published As

Publication number Publication date
KR20250150655A (ko) 2025-10-20
TW202438053A (zh) 2024-10-01
JP2026508238A (ja) 2026-03-10
IL322409A (en) 2025-09-01
MX2025009863A (es) 2025-09-02
WO2024178255A1 (fr) 2024-08-29
AU2024226158A1 (en) 2025-08-14
CN121358466A (zh) 2026-01-16

Similar Documents

Publication Publication Date Title
TWI736550B (zh) 製備ｐａｒｐ抑制劑、結晶形式的方法及其用途
WO2024178255A1 (fr) Formulations solides et formes polymorphes d'inhibiteurs d'indoline de kif18a
KR102845326B1 (ko) Gabaa 양성 알로스테릭 조절인자의 염 및 결정 형태
JP6193762B2 (ja) １−｛（２Ｓ）−２−アミノ−４−［２，４−ビス（トリフルオロメチル）−５，８−ジヒドロピリド［３，４−ｄ］ピリミジン−７（６Ｈ）−イ
CN113454081A (zh) 咪唑并吡啶基化合物及其用于治疗增生性疾病的用途
IL310703A (en) A crystalline form of lenifibrenor, a method for its preparation and use
AU2022334480A1 (en) Spiro indoline inhibitors of kif18a
RS67259B1 (sr) Kompozicije koje aktiviraju piruvat kinazu r (pkr)
KR20230038229A (ko) 우파다시티닙의 결정형, 이의 제조 방법 및 이의 용도
AU2021373814A1 (en) Bicyclic 1,4-diazepanones and therapeutic uses thereof
AU2010289337A1 (en) Stable SNS-595 compositions and methods of preparation
WO2025090640A1 (fr) Formulations solides et formes polymorphes d'inhibiteurs d'indoline de kif18a
KR20230060547A (ko) 결정질 edg-2 수용체 길항제 및 제조 방법
KR20260021641A (ko) Plk1 키나제 억제제의 염 형태, 결정형 및 이의 제조 방법과 용도
WO2020065667A1 (fr) Nouveaux polymorphes d'acalabrutinib, un inhibiteur de la tyrosine kinase de bruton
JP7707406B2 (ja) Ｍｏｒ受容体アゴニストの薬学的に許容できる塩、その多形体及びその使用
JP2026508943A (ja) 結晶形態
JP7187733B2 (ja) オクタヒドロチエノキノリン化合物のコハク酸塩及びその結晶
IL184781A (en) CRYSTALLINE 1H-IMIDAZO[4,5-b]PYRIDIN-5-AMINE, 7-[5-[(CYCLOHEXYLMETHYLAMINO)-METHYL]-1H-INDOL-2-YL]-2-METHYL, SULFATE (1:1), TRIHYDRATE AND ITS PHARMACEUTICAL USES
AU2016265801B2 (en) Crystal of salt of novel 3-azabicyclo[3.1.0]hexane derivative and pharmaceutical use thereof
CA2972746A1 (fr) Procede de production d'un derive thiazole
TWI921632B (zh) Kras抑制劑的多晶型物及其製備方法和用途
TW202606690A (zh) 吡啶并吡唑衍生物的晶型物、藥物組合物及其用途
CA3245090A1 (fr) Formes cristallines du (s)-5-benzyl-n-(5-méthyl-4-oxo-2, 3,4,5- tétrahydropyrido [3,2-b] [l,4]oxazépine-3-yl)-4h-l,2,4-triazole-3-carboxamide
HK40058867A (en) Imidazopyridinyl compounds and use thereof for treatment of proliferative disorders

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20250804

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC ME MK MT NL NO PL PT RO RS SE SI SK SM TR