Solid-state formulations and polymorphic forms of indoline inhibitors of KIF18A

Abstract

The present disclosure relates to inhibitors of KIF18A, their formulations, polymorphic forms thereof, and methods of using the formulations and polymorphic forms. More specifically, the present disclosure relates to solid formulations and polymorphic forms of a series of indoline inhibitors of KIF18A, methods of preparing such formulations and polymorphic forms, and methods of use thereof for treating diseases mediated by KIF18A, such as cancer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 486,611, filed February 23, 2023, U.S. Provisional Patent Application No. 63 / 486,613, filed February 23, 2023, and U.S. Provisional Patent Application No. 63 / 611,027, filed December 15, 2023, the disclosures of which are incorporated herein by reference in their entireties.

[0002] In some embodiments, the present disclosure relates to indoline inhibitors of KIF18A, their solid form formulations, and polymorphic forms thereof. In some embodiments, the present disclosure relates to methods for preparing solid form formulations and polymorphic forms of certain indoline KIF18A inhibitors, and methods of their use for treating diseases mediated by KIF18A, such as cancer. [Background technology]

[0003] KIF18A is a kinesin involved in supporting kinetochore-microtubule (kt-MT) binding and chromosome alignment during cell mitosis. Its cargo domain directly binds protein phosphatase 1 (PP1) and delivers it to the plus ends of MTs, where PP1 dephosphorylates Hec1 (a kinetochore complex component), further enhancing kt-MT binding throughout metaphase and anaphase. Its MT-binding motor domain possesses ATPase activity, which powers KIF18A's movement along the MT lattice, enhanced by its C-terminal MT-binding site. It caps and depolymerizes growing microtubules at the plus end, thereby dampening MT dynamics. This regulation of MT dynamics by KIF18A often occurs at the next (or subsequent) sister chromatid, thereby providing counterbalancing tension against the movement of the preceding sister chromatid, which is catalyzed by another kinesin, Kif2C / MCAK. Loss of KIF18A function causes defective kt-MT binding and loss of intramitotic spindle tension in cells with high chromosomal instability (CIN), resulting in hyperstable, elongated, and multipolar spindles, mitotic arrest, centrosome fragmentation, and spindle assembly checkpoint activation or cell death. Reanalysis of DEPMAP RNAi data identified KIF18A as one of the top candidates essential for CIN-high cells. Synthetic lethality screening also identified KIF18A as a potential anticancer target, where knockdown preferentially facilitates the killing of aneuploid and genome-doubled cells with high CIN (but not those with low CIN). Cytotoxicity assays in isogenic cell lines confirmed that cells with high CIN exhibited enhanced sensitivity to KIF18A inhibitors. Ongoing in vivo mouse models using KIF18A inhibitors or knockdown demonstrated tumor growth inhibition. Therefore, there is a need for new drugs that are effective in treating diseases mediated by KIF18A.

[0004] Specifically, there is a need for stable solid form formulations of KIF18A inhibitors. Summary of the Invention

[0005] In one aspect, provided herein is a solid pharmaceutical formulation, the solid pharmaceutical formulation comprising: (1) Formula (A): [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is halo, -OH, C 1-6 Alkyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 , -SR a21 , -C(O)R a22 , as well as -OH, cyano, C 3-10 C substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo. 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 6-14 is an aryl or a 5-12 membered heteroaryl; R a1 -R a22 are each independently hydrogen, or halo, cyano, -OH, -O(C 1-6 alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R1a2 , and halo, -OH, and -O(C 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6-14 aryl, or 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; m is 2; The Two R's B The groups are attached to the same carbon atom on ring B and together with the carbon atom to which they are attached form C 3-7 Forming a cycloalkyl; Y 1 is N or CR C1 and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; In the formula, Y 1 , Y 2 , Y 3 and Y 4 of which 3 or less are N; R C1 -R C4 are each independently hydrogen, halo, cyano, -OH, -NO2, or -C(O)NR c1 R c2 , -NRc3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1-6 is alkyl; R c1 -R c18 are independently hydrogen, C 3-10 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; 1-6 a compound of formula (A) or a pharmaceutically acceptable salt thereof, wherein (2) a pharmaceutically acceptable polymer.

[0006] In another embodiment, a compound of formula (A): [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is halo, -OH, C 1-6 Alkyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )Ra13 , -S(O)NR a14 R a15 , -S(O)2R a16 , -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 , -SR a21 , -C(O)R a22 , as well as -OH, cyano, C 3-10 C substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo. 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 6-14 is an aryl or a 5-12 membered heteroaryl; R a1 -R a22 are each independently hydrogen, or halo, cyano, -OH, -O(C 1-6 alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6-14 aryl, or 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7cycloalkenyl, or 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; m is 2; The Two R's B The groups are attached to the same carbon atom on ring B and together with the carbon atom to which they are attached form C 3-7 Forming a cycloalkyl; Y 1 is N or CR C1 and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; In the formula, Y 1 , Y 2 , Y 3 and Y 4 of which 3 or less are N; R C1 -R C4 are each independently hydrogen, halo, cyano, -OH, -NO2, or -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1-6 is alkyl; R c1 -R c18are independently hydrogen, C 3-10 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; 1-6 is alkyl, The formulation may be administered to a subject in need thereof, the subject being considered to have a clinically significant effect on the development of a compound of formula (A) or a pharmaceutically acceptable salt thereof. max ) to about 1.5 μmol / mL to about 5.0 μmol / mL.

[0007] In yet another embodiment, the compound of formula (A-1): [ka] Provided herein are crystalline forms of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0008] In yet another embodiment, the compound of formula (A-1): [ka] Provided herein are salt forms of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0009] In yet another aspect, provided herein is a method for inhibiting KIF18A, comprising contacting a cell with an effective amount of (i) a formulation described herein or (ii) a crystalline form described herein.

[0010] In yet another aspect, provided herein is a method of treating a disease or condition mediated by KIF18A in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of (i) a formulation described herein or (ii) a crystalline form described herein.

[0011] In yet another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of (i) a formulation described herein or (ii) a crystalline form described herein.

[0012] In yet another aspect, provided herein is a method for preparing the formulations described herein, the process comprising 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.

[0013] In yet another aspect, provided herein is a method of preparing the crystalline forms described herein, the method comprising forming a mixture of a 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, isopropanol alcohol, methylcyclohexane, tetrahydrofuran, anisole, methyl isopropyl ketone, dipropyl ether, chloroform, tert-amyl alcohol, and any mixture thereof.

[0014] In yet another embodiment, a compound of formula (A): [ka] Provided herein is a method for preparing a substantially amorphous form of a compound of formula (A), the method comprising: (1) forming a mixture of a compound of formula (A) and a solvent selected from the group consisting of N,N-dimethylformamide (DMF), water, and mixtures thereof; (2) isolating a solid from the mixture of (1); (3) washing the solid of (2) with water; and (4) drying the solid of (3) at room temperature, wherein Ring A is halo, -OH, C 1-6 Alkyl, 3-10 membered heterocycloalkyl, -NRa1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 , -SR a21 , -C(O)R a22 , as well as -OH, cyano, C 3-10 C substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo. 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 6-14 is an aryl or a 5-12 membered heteroaryl; R a1 -R a22 are each independently hydrogen, or halo, cyano, -OH, -O(C 1-6 alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6-14 aryl, or 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; m is 2; The Two R's B The groups are attached to the same carbon atom on ring B and together with the carbon atom to which they are attached form C 3-7 Forming a cycloalkyl; Y 1 is N or CR C1 and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; In the formula, Y 1 , Y 2 , Y 3 and Y 4 of which 3 or less are N; R C1 -R C4 are each independently hydrogen, halo, cyano, -OH, -NO2, or -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 , -NRc14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1-6 is alkyl; R c1 -R c18 are independently hydrogen, C 3-10 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; 1-6 It is alkyl.

[0015] The drawings illustrate certain embodiments of the features and advantages of the present disclosure. These embodiments are not intended to limit the scope of the appended claims in any way. [Brief explanation of the drawings]

[0016] [Figure 1A] Illustrated are SEM micrographs of eight different SDDs taken at 5000x magnification: 25:75 compound of formula (A-1):HPMCAS-M, 25:75 compound of formula (A-1):HPMCP-HP55, 40:60 compound of formula (A-1):HPMCP-HP55, 50:50 compound of formula (A-1):HPMCP-HP55, 50:50 compound of formula (A-1):HPMC E3LV, 25:75 compound of formula (A-1):Eudragit L100-55, 40:60 compound of formula (A-1):Eudragit L100-55, and 50:50 compound of formula (A-1):Eudragit L100-55. [Figure 1B]Illustrated are SEM micrographs of eight different SDDs taken at 5000x magnification: 25:75 compound of formula (A-1):HPMCAS-M, 25:75 compound of formula (A-1):HPMCP-HP55, 40:60 compound of formula (A-1):HPMCP-HP55, 50:50 compound of formula (A-1):HPMCP-HP55, 50:50 compound of formula (A-1):HPMC E3LV, 25:75 compound of formula (A-1):Eudragit L100-55, 40:60 compound of formula (A-1):Eudragit L100-55, and 50:50 compound of formula (A-1):Eudragit L100-55. [Figure 1C] Illustrated are SEM micrographs of eight different SDDs taken at 5000x magnification: 25:75 compound of formula (A-1):HPMCAS-M, 25:75 compound of formula (A-1):HPMCP-HP55, 40:60 compound of formula (A-1):HPMCP-HP55, 50:50 compound of formula (A-1):HPMCP-HP55, 50:50 compound of formula (A-1):HPMC E3LV, 25:75 compound of formula (A-1):Eudragit L100-55, 40:60 compound of formula (A-1):Eudragit L100-55, and 50:50 compound of formula (A-1):Eudragit L100-55. [Figure 1D] Illustrated are SEM micrographs of eight different SDDs taken at 5000x magnification: 25:75 compound of formula (A-1):HPMCAS-M, 25:75 compound of formula (A-1):HPMCP-HP55, 40:60 compound of formula (A-1):HPMCP-HP55, 50:50 compound of formula (A-1):HPMCP-HP55, 50:50 compound of formula (A-1):HPMC E3LV, 25:75 compound of formula (A-1):Eudragit L100-55, 40:60 compound of formula (A-1):Eudragit L100-55, and 50:50 compound of formula (A-1):Eudragit L100-55. [Figure 1E]Illustrated are SEM micrographs of eight different SDDs taken at 5000x magnification: 25:75 compound of formula (A-1):HPMCAS-M, 25:75 compound of formula (A-1):HPMCP-HP55, 40:60 compound of formula (A-1):HPMCP-HP55, 50:50 compound of formula (A-1):HPMCP-HP55, 50:50 compound of formula (A-1):HPMC E3LV, 25:75 compound of formula (A-1):Eudragit L100-55, 40:60 compound of formula (A-1):Eudragit L100-55, and 50:50 compound of formula (A-1):Eudragit L100-55. [Figure 1F] Illustrated are SEM micrographs of eight different SDDs taken at 5000x magnification: 25:75 compound of formula (A-1):HPMCAS-M, 25:75 compound of formula (A-1):HPMCP-HP55, 40:60 compound of formula (A-1):HPMCP-HP55, 50:50 compound of formula (A-1):HPMCP-HP55, 50:50 compound of formula (A-1):HPMC E3LV, 25:75 compound of formula (A-1):Eudragit L100-55, 40:60 compound of formula (A-1):Eudragit L100-55, and 50:50 compound of formula (A-1):Eudragit L100-55. [Figure 1G] Illustrated are SEM micrographs of eight different SDDs taken at 5000x magnification: 25:75 compound of formula (A-1):HPMCAS-M, 25:75 compound of formula (A-1):HPMCP-HP55, 40:60 compound of formula (A-1):HPMCP-HP55, 50:50 compound of formula (A-1):HPMCP-HP55, 50:50 compound of formula (A-1):HPMC E3LV, 25:75 compound of formula (A-1):Eudragit L100-55, 40:60 compound of formula (A-1):Eudragit L100-55, and 50:50 compound of formula (A-1):Eudragit L100-55. [Figure 1H]Illustrated are SEM micrographs of eight different SDDs taken at 5000x magnification: 25:75 compound of formula (A-1):HPMCAS-M, 25:75 compound of formula (A-1):HPMCP-HP55, 40:60 compound of formula (A-1):HPMCP-HP55, 50:50 compound of formula (A-1):HPMCP-HP55, 50:50 compound of formula (A-1):HPMC E3LV, 25:75 compound of formula (A-1):Eudragit L100-55, 40:60 compound of formula (A-1):Eudragit L100-55, and 50:50 compound of formula (A-1):Eudragit L100-55. [Figure 2] 1 shows the XRPD pattern of polymorphic form A of compound of formula (A-1). [Figure 3] 1 shows the TGA and DSC thermograms of polymorphic form A of compound of formula (A-1). Top: TGA, bottom: DSC. [Figure 4] 1 shows the DVS isotherm plot of polymorphic Form A of the compound of formula (A-1). The diamond plot trace is the sorption trace and the square plot trace is the desorption trace. [Figure 5] 1 shows XRPD patterns of polymorphic form C of compound of formula (A-1) prepared by two methods: from top to bottom: polymorphic form C prepared by slurrying a gel from DMF in HO, polymorphic form C prepared by adding HO to a DMF solution to obtain a precipitate, and reference polymorphic form A. [Figure 6] 1 shows the TGA thermogram of polymorphic Form C of compound of formula (A-1). [Figure 7] FIG. 1 shows the TMDSC thermogram of polymorphic Form C of compound of formula (A-1). [Figure 8] 1 shows the DVS isotherm plot of polymorphic Form C of the compound of formula (A-1). The diamond plot trace is the sorption trace and the square plot trace is the desorption trace. [Figure 9A]Graph showing tumor volume in vehicle-treated and compound-treated mice plotted as a function of time elapsed from the start of treatment. Treatment of HCC15-implanted SCID Beige mice with the compound of formula (A-2) (10 mg / kg BID, 30 mg / kg BID, 60 mg / kg BID) is shown. Circle plot trace: vehicle. Square plot trace: compound of formula (A-2) at 10 mg / kg BID PO. Triangle plot trace: compound of formula (A-2) at 30 mg / kg BID PO. Inverted square plot trace: compound of formula (A-2) at 60 mg / kg BID PO. [Figure 9B] Graphs showing tumor volume in vehicle-treated and compound-treated mice plotted as a function of time elapsed from the start of treatment are shown. Treatment of OVCAR-3-implanted Balb / C nude mice with the compound of formula (A-2) (10 mg / kg QD, 30 mg / kg QD, 60 mg / kg QD) is shown. Circle plot trace: vehicle. Square plot trace: compound of formula (A-2) at 10 mg / kg BID PO. Triangle plot trace: compound of formula (A-2) at 30 mg / kg BID PO. Inverted square plot trace: compound of formula (A-2) at 60 mg / kg BID PO. [Figure 9C] Graph showing tumor volume in vehicle-treated and compound-treated mice plotted as a function of time elapsed since the start of treatment. Treatment of HCC15-implanted SCID Beige mice with the compound of formula (A-1) (10 mg / kg BID, 30 mg / kg BID, 60 mg / kg BID) is shown. Circle plot trace: vehicle. Square plot trace: compound of formula (A-1) at 10 mg / kg BID PO. Triangle plot trace: compound of formula (A-1) at 30 mg / kg BID PO. Inverted triangle plot trace: compound of formula (A-1) at 60 mg / kg BID PO. [Figure 9D]Graphs showing tumor volume in vehicle-treated and compound-treated mice plotted as a function of time elapsed from the start of treatment are shown. Treatment of OVCAR-3-implanted Balb / C nude mice with the compound of formula (A-1) (10 mg / kg BID, 30 mg / kg BID, 60 mg / kg BID) is shown. Circular trace: vehicle. Square trace: compound of formula (A-1) at 10 mg / kg BID PO. Triangle trace: compound of formula (A-1) at 30 mg / kg BID PO. Inverted triangle trace: compound of formula (A-1) at 60 mg / kg BID PO. [Figure 9E] Graphs showing tumor volume in vehicle-treated and compound-treated mice plotted as a function of time elapsed from the start of treatment are shown. Treatment of OVCAR-3-implanted Balb / C nude mice with the compound of formula (A-1) (30 mg / kg BID, 30 mg / kg QD, 60 mg / kg QD) is shown. Circle plot trace: vehicle. Square plot trace: compound of formula (A-1) at 10 mg / kg BID PO. Triangle plot trace: compound of formula (A-1) at 30 mg / kg BID PO. Inverted triangle plot trace: compound of formula (A-1) at 60 mg / kg BID PO. [Figure 10] 1 shows the XRPD pattern of polymorphic form B of compound of formula (A-1). [Figure 11] 1 shows a DSC thermogram of polymorphic form B of compound of formula (A-1). [Figure 12] 1 shows the TGA thermogram of polymorphic form B of compound of formula (A-1). [Figure 13-1] 1 shows the DVS isotherm plot of polymorphic form B of compound of formula (A-1). [Figure 13-2] 1 shows the DVS isotherm plot of polymorphic form B of compound of formula (A-1). [Figure 14] 1 shows the XRPD pattern of polymorphic Form IV of the monosodium salt of the compound of formula (A-1). [Figure 15] 1 shows a DSC thermogram of polymorphic Form IV of the monosodium salt of the compound of formula (A-1). [Figure 16]1 shows a TGA thermogram of polymorphic Form IV of the monosodium salt of the compound of formula (A-1). [Figure 17] 1 shows the XRPD pattern of polymorphic Form V of the disodium salt of the compound of formula (A-1). [Figure 18] 1 shows a DSC thermogram of polymorphic Form V of the disodium salt of the compound of formula (A-1). [Figure 19] 1 shows a TGA thermogram of polymorphic Form V of the disodium salt of the compound of formula (A-1). [Figure 20] 1 shows the XRPD pattern of polymorphic Form VI of the monopotassium salt of the compound of formula (A-1). [Figure 21] 1 shows a DSC thermogram of polymorphic Form VI of the monopotassium salt of the compound of formula (A-1). [Figure 22] 1 shows a TGA thermogram of polymorphic Form VI of the monopotassium salt of the compound of formula (A-1). [Figure 23] 1 shows the XRPD pattern of polymorphic Form VII of the dipotassium salt of the compound of formula (A-1). [Figure 24] 1 shows a DSC thermogram of polymorphic Form VII of the dipotassium salt of the compound of formula (A-1). [Figure 25] 1 shows a TGA thermogram of polymorphic Form VII of the dipotassium salt of the compound of formula (A-1). [Figure 26] 1 shows the XRPD pattern of polymorphic Form VIII of the disodium salt of the compound of formula (A-1). [Figure 27] 1 shows a DSC thermogram of polymorphic Form VIII of the disodium salt of the compound of formula (A-1). [Figure 28] 1 shows a TGA thermogram of polymorphic Form VIII of the disodium salt of the compound of formula (A-1). [Figure 29] 1 shows an example of an XRPD pattern of polymorphic Form IX of the dipotassium salt of the compound of formula (A-1). [Figure 30] 1 shows an example of a DSC thermogram of polymorphic Form IX of the dipotassium salt of the compound of formula (A-1). [Figure 31]1 shows an example of a TGA thermogram of polymorphic Form IX of the dipotassium salt of the compound of formula (A-1). [Figure 32] 1 shows an example of an XRPD pattern of polymorphic form X of the disodium salt of the compound of formula (A-1). [Figure 33] 1 shows an example of a DSC thermogram of polymorphic form X of the disodium salt of the compound of formula (A-1). [Figure 34] 1 shows an example of a TGA thermogram of polymorphic form X of the disodium salt of the compound of formula (A-1). [Figure 35] 1 shows the XRPD pattern of polymorphic Form XI of the disodium salt of the compound of formula (A-1). [Figure 36] 1 shows a DSC thermogram of polymorphic Form XI of the disodium salt of the compound of formula (A-1). [Figure 37] 1 shows a TGA thermogram of polymorphic Form XI of the disodium salt of the compound of formula (A-1). [Figure 38] 1 shows the XRPD pattern of polymorphic Form XII of the monosodium salt of the compound of formula (A-1). [Figure 39] 1 shows a DSC thermogram of polymorphic Form XII of the monosodium salt of the compound of formula (A-1). [Figure 40] 1 shows a TGA thermogram of polymorphic Form XII of the monosodium salt of the compound of formula (A-1). [Figure 41] 1 shows another example of the XRPD pattern of polymorphic form X of the disodium salt of the compound of formula (A-1). [Figure 42] 1 shows another example of a DSC thermogram of polymorphic Form X of the disodium salt of the compound of formula (A-1). [Figure 43] 1 shows another example of a TGA thermogram of polymorphic Form X of the disodium salt of the compound of formula (A-1). [Figure 44-1] 1 shows another example of a DVS isotherm plot for polymorphic Form X of the disodium salt of the compound of formula (A-1). [Figure 44-2] 1 shows another example of a DVS isotherm plot for polymorphic Form X of the disodium salt of the compound of formula (A-1). [Figure 45]1 shows another example of the XRPD pattern of polymorphic Form IX of the dipotassium salt of the compound of formula (A-1). [Figure 46] 1 shows another example of a DSC thermogram of polymorphic Form IX of the dipotassium salt of the compound of formula (A-1). [Figure 47] 1 shows another example of a TGA thermogram of polymorphic Form IX of the dipotassium salt of the compound of formula (A-1). [Figure 48-1] 1 shows another example of a DVS isotherm plot of polymorphic Form IX of the dipotassium salt of the compound of formula (A-1). [Figure 48-2] 1 shows another example of a DVS isotherm plot of polymorphic Form IX of the dipotassium salt of the compound of formula (A-1). [Figure 49] 1 shows the XRPD pattern of polymorphic Form XIII of the monosodium salt of the compound of formula (A-1). [Figure 50] 1 shows a DSC thermogram of polymorphic Form XIII of the monosodium salt of the compound of formula (A-1). [Figure 51] 1 shows a TGA thermogram of polymorphic Form XIII of the monosodium salt of compound of formula (A-1). DETAILED DESCRIPTION OF THE INVENTION

[0017] The following description is provided to enable any person skilled in the art to make and use various embodiments. Descriptions of specific devices, techniques, and applications are provided merely as examples. Various modifications to the examples described herein will be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Accordingly, the various embodiments are not intended to be limited to the examples described and shown herein, but are to be accorded scope consistent with the appended claims.

[0018] I. Definition As used herein, the following words and phrases are generally intended to have the meanings indicated below, unless the context in which they are used indicates otherwise.

[0019] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly indicates otherwise.

[0020] As used herein, unless otherwise specified, the terms "about" and "approximately," when used in reference to a dose, amount, or weight percent of a component of a composition or dosage form, mean a dose, amount, or weight percent that would be recognized by one of ordinary skill in the art as providing an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. Specifically, where applicable, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent within 15% of the specified dose, amount, or weight percent.

[0021] Throughout this application, unless the context requires otherwise, references to compounds of Formula (A), Formula (A-1), Formula (A-2), or Formula (A-3) include all subgroups defined herein (e.g., Formula (B), (C), (A-1), (A-2), or (A-3)), including all substructures, subgenera, preferences, embodiments, examples, and specific compounds defined and / or described herein. In some embodiments, unless otherwise specified, references to compounds 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. In some embodiments, a reference to a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3), and subgroups thereof, includes isomers, tautomers, and / or oxides thereof. In some embodiments, a reference to a compound of Formula (A), (B), (C), (A-1), (A-2), or (A-3), and subgroups thereof, includes solvates thereof.

[0022] "Alkyl" includes straight and branched carbon chains having the indicated number of carbon atoms, e.g., 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 3 carbon atoms. For example, C 1~6 Alkyl includes both straight-chain and branched-chain alkyls of 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbon atoms is specified, all branched and straight-chain versions having that number of carbon atoms are intended to be included; thus, for example, "propyl" includes N-propyl and isopropyl, and "butyl" includes n-butyl, sec-butyl, isobutyl, and t-butyl. Examples of 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.

[0023] If a range of values ​​is specified (e.g., C 1~6 alkyl), each value within that range, as well as all ranges therebetween. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, 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 Contains alkyl.

[0024] "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. The group can be in either the cis or trans configuration (Z or E configuration) about the double bond(s). 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).

[0025] "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).

[0026] "Cycloalkyl" refers to a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, e.g., 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 cage ring groups (e.g., norbornane, bicyclo[2.2.2]octene). In addition, one ring of a polycyclic cycloalkyl group may be aromatic, provided that the polycyclic cycloalkyl group is connected to the parent structure through a non-aromatic carbon atom. For example, 1,2,3,4-tetrahydronaphthalen-1-yl (which is connected to the parent structure through a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3,4-tetrahydronaphthalen-5-yl (which is connected to the parent structure through an aromatic carbon atom) is not considered a cycloalkyl group. Examples of polycyclic cycloalkyl groups consisting of a cycloalkyl group fused to an aromatic ring are described below.

[0027] "Cycloalkenyl" refers to 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 can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl, as well as bridged and caged ring groups (e.g., bicyclo[2.2.2]octene). Furthermore, one ring of a polycyclic cycloalkenyl group can be aromatic, provided that the polycyclic alkenyl group is connected to the parent structure through a non-aromatic carbon atom. For example, inden-1-yl (which is connected to the parent structure through a non-aromatic carbon atom) is considered a cycloalkenyl group, while inden-4-yl (which is connected to the parent structure through an aromatic carbon atom) is not considered a cycloalkenyl group. Examples of polycyclic cycloalkenyl groups consisting of a cycloalkenyl group fused to an aromatic ring are set forth below.

[0028] "Aryl" refers to an aromatic carbocyclic ring having the indicated number of carbon atoms, e.g., 6 to 12 or 6 to 10 carbon atoms. Aryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some instances, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other instances, a polycyclic aryl group may contain a non-aromatic ring fused to an aromatic ring, provided that the polycyclic aryl group is attached to the parent structure through an atom in the aromatic ring. Thus, a 1,2,3,4-tetrahydronaphthalen-5-yl group (which is attached to the parent structure through an aromatic carbon atom) is considered an aryl group, while a 1,2,3,4-tetrahydronaphthalen-1-yl group (which is attached to the parent structure through a non-aromatic carbon atom) is not considered an aryl group. Similarly, a 1,2,3,4-tetrahydroquinolin-8-yl group (which is attached to the parent structure via an aromatic carbon atom) is considered an aryl group, while a 1,2,3,4-tetrahydroquinolin-1-yl group (which is attached to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "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 examples, an aryl is phenyl or naphthyl. In certain examples, an aryl is phenyl. Further examples of aryl groups comprising an aromatic carbocyclic ring fused to a non-aromatic ring are described below.

[0029] "Heteroaryl" refers to an aromatic ring (e.g., a 5- to 12-membered or 5- to 10-membered heteroaryl) containing the indicated number of atoms, composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, 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 a heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in a heteroaryl group is 1 or less. Unless otherwise stated, a heteroaryl group may be attached to the parent structure by a carbon or nitrogen atom, valence permitting. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl, and 4-pyridyl groups, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl groups.

[0030] In some examples, the 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.

[0031] In some cases, both rings of the polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzisothiazole, 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-pyrazolo[4,3-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrrolo[3,4-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrazolo[3,4 ... Pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine, oxazolo[5,4- b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo thiazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole, and imidazo[2,1-b]thiazole.

[0032] In other cases, polycyclic heteroaryl groups can contain a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided that the polycyclic heteroaryl group is attached to the parent structure through an atom in the aromatic ring. For example, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (which is attached to the parent structure through an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (which is attached to the parent structure through a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of a heteroaryl ring fused to a non-aromatic ring are listed below.

[0033] "Heterocycloalkyl" refers to a non-aromatic, fully saturated ring (e.g., a 3- to 10-membered or 3- to 7-membered heterocycloalkyl) having the indicated number of atoms composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, with the remaining ring atoms being carbon. Heterocycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Furthermore, one ring of a polycyclic heterocycloalkyl group can be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom. For example, a 1,2,3,4-tetrahydroquinolin-1-yl group (which is attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, while a 1,2,3,4-tetrahydroquinolin-8-yl group (which is attached to the parent structure through an aromatic carbon atom) is not considered a heterocycloalkyl group. Examples of polycyclic heterocycloalkyl groups consisting of a heterocycloalkyl group fused to an aromatic ring are listed below.

[0034] "Heterocycloalkenyl" refers to a non-aromatic ring (e.g., a 3- to 10- or 3- to 7-membered heterocycloalkenyl) having the indicated number of atoms, composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, with the remaining ring atoms being carbon, and having at least one double bond derived by removing one hydrogen atom from adjacent carbon atoms, nitrogen atoms, or carbon and nitrogen atoms of the corresponding heterocycloalkyl. Heterocycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of 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-tetrahydropyridinyl), and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). Additionally, one ring of a polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkenyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom. For example, a 1,2-dihydroquinolin-1-yl group (attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, while a 1,2-dihydroquinolin-8-yl group (attached to the parent structure through an aromatic carbon atom) is not considered a heterocycloalkenyl group. Examples of polycyclic heterocycloalkenyl groups consisting of a heterocycloalkenyl group fused to an aromatic ring are described below.

[0035] Examples of 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-Dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isoxazolyl, 2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydrobenzo[d]oxazolyl, 2,3-dihydrobenzo[b]thiophenyl, 1,3-dihydrobenzo[c]thiophenyl, 1,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl, 4,5,6,7-tetrahydrobenzo [d]thiazolyl, 5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one, indolin-3-one, isoindolin-1-one, 1,2-dihydroindazol-3-one, 1H-benzo[d]imidazol-2(3H)-one, benzofuran-2(3H)-one, benzofuran-3(2H)-one, isobenzofuran-1(3H)-one, benzo[c]isoxazol-3(1H)-one, benzo[d]isoxazol-3(2H)-one, benzo [d]oxazol-2(3H)-one, benzo[b]thiophen-2(3H)-one, benzo[b]thiophen-3(2H)-one, benzo[c]thiophen-1(3H)-one, benzo[c]isothiazol-3(1H)-one, benzo[d]isothiazol-3(2H)-one, benzo[d]thiazol-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol-6-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one, quinazolin-4(3H)-one, quinazolin-2,4(1H,3H)-dione, quinoxalin-2(1H)-one, quinoxalin-2,3(1H,4H)-dione, cinnolin-4(3H)-one, pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, 1H-pyrrolo[3,2-b]pyridin-2(3H)-one, 1H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one and 4,5-dihydropyrrolo[3,4-d]thiazol-6-one. As discussed herein, whether each ring is considered an aryl group, heteroaryl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, or heterocycloalkenyl group is determined by the atom through which the moiety is attached to the parent structure.

[0036] "Halogen" or "halo" refers to fluoro, chloro, bromo, and iodo.

[0037] "Haloalkyl" refers to an alkyl substituted with one or more halogens. Haloalkyl groups may have halogen substituents at any valence-allowed position on the alkyl and any number of halogen substituents ranging from one to the maximum number of valences allowed. Particular haloalkyl groups have one, two, or three halogen substituents. Examples of haloalkyl groups include, but are not limited to, -CHF, -CHF, -CF, -CHCHF, -CHCHF, -CHCF, -CHCl, -CHCl, -CCl, -CHCHCl, -CHCHCl, -CHCCl.

[0038] Unless otherwise indicated, the compounds disclosed and / or described herein include all possible enantiomers, diastereomers, mesoisomers, and other stereoisomeric forms, including racemic mixtures, optically pure forms, and intermediate mixtures thereof. Enantiomers, diastereomers, mesoisomers, and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. Unless otherwise specified, when a compound disclosed and / or described herein contains an olefinic double bond or other center of geometric asymmetry, it is intended that the compound include both the E and Z isomers. When a compound described herein contains a moiety capable of tautomerization, it is intended that the compound include all possible tautomers, unless otherwise specified.

[0039] "Protecting group" has the meaning customarily associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a polyfunctional compound, allowing a chemical reaction to be selectively carried out at an otherwise unprotected reactive site, and that allows the group to be easily removed after the selective reaction is complete. Various protecting groups are disclosed, for example, in T.H. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, a "hydroxy-protected form" comprises at least one hydroxy group protected with a hydroxy-protecting group. Similarly, amines and other reactive groups can be similarly protected.

[0040] The term "pharmaceutically acceptable salt" refers to any salt of the compounds herein that is known to be non-toxic and commonly used in pharmaceutical literature. In some embodiments, a pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and is 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 using inorganic 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 using 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. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0041] When the compounds described herein are obtained as acid addition salts, the solution of the acid salt can be basified to obtain free base.On the other hand, when the compound is a free base, addition salts, particularly pharmaceutically acceptable addition salts, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with acid according to the conventional procedure for preparing acid addition salts from basic compounds (see, for example, Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January, 1977, 66(1), 1-19).Those skilled in the art will understand that various synthetic methods can be used to prepare pharmaceutically acceptable addition salts.

[0042] 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 of any ratio of water to the compound, such as monohydrates, dihydrates, and hemihydrates.

[0043] The term "substituted" means that the specified group or moiety bears one or more substituents, including, but not limited to, 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, sulfonylamino, sulfonyl, oxo, and the like. The term "unsubstituted" means that the specified group bears no substituents. When the term "substituted" is used to describe a structural system, substitution is meant to occur at any position in that system where valency allows. When a group or moiety bears multiple substituents, it is understood that the substituents can be the same or different from one another. In some embodiments, a substituted group or moiety bears 1 to 5 substituents. In some embodiments, a substituted group or moiety has one substituent. In some embodiments, a substituted group or moiety has two substituents. In some embodiments, a substituted group or moiety has three substituents. In some embodiments, a substituted group or moiety has four substituents. In some embodiments, a substituted group or moiety has five substituents.

[0044] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. With respect to any group containing one or more substituents, it will be understood by those of skill in the art that such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically infeasible, and / or inherently unstable. When a group or moiety is optionally substituted, it will also be understood that the present disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is not substituted.

[0045] The compounds disclosed and / or described herein may be present in isotopically enriched form, e.g. 2 H, 3 H, 11 C. 13 C and / or 14The compound may be enriched in C. In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be made, for example, by the means described in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds can improve the efficacy and increase the duration of action of the compounds disclosed and / or described herein. Deuterium-substituted compounds can be synthesized using a variety of 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.

[0046] The term "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 the pharmaceutical compositions is contemplated. Supplementary active ingredients can also be included in the pharmaceutical compositions.

[0047] As used herein, the terms "polymorph," "polymorphic," "polymorphic form," or "crystalline form" are used interchangeably and refer to polymorphic forms of a compound. Polymorphic forms can be crystalline or amorphous. Different polymorphs can have different physical properties (e.g., melting temperature, heat of fusion, solubility, dissolution rate, and / or vibrational spectra) as a result of the arrangement or conformation of molecules or ions within the crystal lattice. Differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in formulation and product manufacturing), and dissolution rate (a key factor in bioavailability). Differences in stability can be due to changes in chemical reactivity (e.g., differential oxidation, such that a dosage form consisting of one polymorph discolors more quickly than one consisting of another), mechanical changes (e.g., a tablet that crumbles on storage as the kinetically favored polymorph converts to a thermodynamically more stable polymorph), or both (e.g., a tablet of one polymorph is more susceptible to disintegration at high humidity). As a result of differences in solubility / disintegration, some polymorphic transitions may be ineffective at one extreme or toxic at another. In addition, the physical properties of the crystalline form may be important in processing; for example, one polymorph may be more likely to form solvates or may be difficult to filter and wash free of impurities (e.g., particle shape and size distribution may differ between polymorphs).

[0048] As used herein, the term "substantially as shown," when referring to, for example, an XRPD pattern, a DSC graph, a TGA graph, or a GVS graph, includes a pattern or graph that is not necessarily identical to that shown herein, but that falls within the limits of experimental error or variation when considered by one of ordinary skill in the art.

[0049] As used herein, the term "substantially free" means that a composition including a 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 specified substance(s).

[0050] The terms "patient," "individual," and "subject" refer to an animal (such as a mammal, bird, or fish). In some embodiments, a patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows, and humans. In some embodiments, a patient, individual, or subject is a human, e.g., a human who has been the object of treatment, observation, or experiment, or who is a human subject. The compounds, compositions, and methods described herein can be useful in both human therapy and veterinary applications.

[0051] The term "therapeutically effective amount" or "effective amount" refers to an amount of a compound disclosed and / or described herein that, when administered to a patient in need of treatment as defined herein, is sufficient to affect such treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease that responds to modulation (e.g., inhibition) of KIF18a. A therapeutically effective amount will vary depending, for example, on the subject and condition being treated, the subject's weight and age, the severity of the condition, the specific compound, the dosing regimen to be followed, the timing of administration, and the mode of administration, all of which can be readily determined by one skilled in the art. A therapeutically effective amount can be experimentally confirmed (e.g., by assaying the blood concentration of the chemical) or theoretically confirmed by calculating bioavailability.

[0052] "Treatment" (and related terms such as "treat," "treated," "treating") includes one or more of inhibiting the disease or disorder, slowing or preventing the onset of clinical symptoms of the disease or disorder, and / or relieving the disease or disorder (i.e., causing the alleviation or regression of clinical symptoms). The term encompasses both complete and partial alleviation of the condition or disorder, and complete or partial alleviation of clinical symptoms of the disease or disorder. Thus, the compounds described and / or disclosed herein may prevent the worsening of an existing disease or disorder, may assist in the management of the disease or disorder, or may reduce or eliminate the disease or disorder.

[0053] It will be understood that embodiments described herein as "comprising" include "consisting of" and "consisting essentially of" the embodiments.

[0054] II. Solid Formulations II-a. Indoline inhibitors of KIF18A In some embodiments, provided herein are solid pharmaceutical formulations comprising a compound of Formula (A) described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are polymorphic forms of a compound of Formula (A-1) described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are salt forms of a compound of Formula (A-1). All compounds of Formula (A) described herein, including compounds of Formula (A-1), Formula (A-2), and Formula (A-3), and any subgenus thereof, are intended to encompass any and all stereoisomers, including geometric isomers (cis / trans), E / Z isomers, enantiomers, diastereomers, and mixtures thereof in any ratio (including racemic mixtures), salts, and solvates. Any of the compounds described herein may also be referred to as drugs or active pharmaceutical ingredients (APIs).

[0055] In some embodiments, the compound of formula (A): [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is halo, -OH, C 1-6 Alkyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 , -SR a21 , -C(O)R a22 , as well as -OH, cyano, C 3-10 C substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo. 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 6-14 is an aryl or a 5-12 membered heteroaryl; R a1 -R a22 are each independently hydrogen, or halo, cyano, -OH, -O(C 1-6 alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C 1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl1-6 C optionally substituted with one or more substituents independently selected from the group consisting of alkyl 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6-14 aryl, or 5-12 membered heteroaryl, wherein R 1a1 and R 1a2 are each independently hydrogen or C 1-6 is alkyl; Ring B is C 5-7 Cycloalkyl, C 5-7 cycloalkenyl, or 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; m is 2; The Two R's B The groups are attached to the same carbon atom on ring B and together with the carbon atom to which they are attached form C 3-7 Forming a cycloalkyl; Y 1 is N or CR C1 and; Y 2 is N or CR C2 and; Y 3 is N or CR C3 and; Y 4 is N or CR C4 and; In the formula, Y 1 , Y 2 , Y 3 and Y 4 of which 3 or less are N; R C1 -R C4 are each independently hydrogen, halo, cyano, -OH, -NO2, or -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1-6 is alkyl; R c1 -R c18 are independently hydrogen, C 3-10 C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; 1-6 It is alkyl.

[0056] In some embodiments of Formula (A) or a pharmaceutically acceptable salt thereof, ring A is selected from the group consisting of C 6-14 In some embodiments, ring A is an optionally substituted C 6-14 In some embodiments, ring A is an optionally substituted phenyl as defined above or below. In some embodiments, ring A is an optionally substituted 5-12 membered heteroaryl as defined above or below. In some embodiments, ring A is an optionally substituted 6 membered heteroaryl as defined above or below. In some embodiments, ring A is an optionally substituted 5 membered heteroaryl as defined above or below. In some embodiments, ring A is an optionally substituted indolyl, indazolyl, pyridinyl, thiophenyl, furanyl, pyrazolyl, pyrrolyl, oxazolyl, chromanyl, or quinolinyl, each of which is optionally substituted as defined above or below. In some embodiments, ring A is an optionally substituted thiophenyl as defined above or below.

[0057] In some embodiments of Formula (A), ring A is selected from halo, —OH, C 1-6 Alkyl, 3-10 membered heterocycloalkyl, -NR a1 C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR a10 , -S(O)R a11 , -S(O)(NR a12 )R a13 , -S(O)NR a14 R a15 , -S(O)2R a16 , -(CR a17 R a18 ) 0-1 C(O)NR a19 R a20 , -SR a21 , -C(O)R a22 , as well as -OH, cyano, C 3-10 C substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo. 1-6 In some embodiments, R is optionally substituted with 1, 2, 3, 4, 5, or more substituents independently selected from the group consisting of alkyl. a1 -R a22 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C 6-14 aryl, or 5- to 12-membered heteroaryl, each of which is selected from halo, cyano, —OH, —O(C 1-6 alkyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, -S(C 1-6 alkyl), =CR 1a1 R 1a2 , and halo, -OH, and -O(C1-6 C optionally substituted with 1, 2, 3, 4, 5, or more substituents independently selected from the group consisting of alkyl 1-6 optionally substituted with 1, 2, 3, 4, 5, or more substituents independently selected from the group consisting of alkyl, R 1a1 and R 1a2 are each independently hydrogen or C 1-6 It is alkyl.

[0058] In some embodiments, -S(O)NR a14 R a15 teeth, [ka] [ka] In some embodiments, -S(O)NR a14 R a15 teeth, [ka] [ka] In some embodiments, R a14 and R a15 are each independently hydrogen; C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, -OH, -O(C 1-6 alkyl), -S(C 1-6 C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of alkyl, and halo 1-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkenyl, C 3-10 Cycloalkyl, halo, cyano, -OH, -O(C 1-6 alkyl), =CR 1a1 R 1a2 , as well as -OH, -O(C 1-6C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of alkyl, and halo 1-6 C optionally substituted with 1, 2, 3, 4, 5 or more substituents independently selected from the group consisting of alkyl 3-10 cycloalkyl, where R 1a1 and R 1a2 are each independently hydrogen or C 1-6 Alkyl; C 3-10 cycloalkenyl; or 1, 2, 3, 4, 5 or more C 1-6 In some embodiments, R is a 3- to 12-membered heterocycloalkyl optionally substituted with alkyl. a14 and R a15 are each independently hydrogen or C 1~6 In some embodiments, R a14 is hydrogen and R a15 is butyl. In some embodiments, R a15 is tert-butyl.

[0059] In some embodiments of Formula (A) or a pharmaceutically acceptable salt thereof, ring B is C 5-7 Cycloalkyl, C 5-7 In some embodiments, ring B is C. 5-7 In some embodiments, Ring B is cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, Ring B is [ka] wherein * represents the point of attachment to the remainder of formula (A). In some embodiments, ring B is C 5-7 In some embodiments, Ring B is cyclopentenyl, cyclohexenyl, or cycloheptenyl. In some embodiments, Ring B is [ka] wherein * represents the point of attachment to the remainder of formula (A). In some embodiments, ring B is [ka] where * represents the point of attachment to the remainder of Formula (A). In some embodiments, Ring B is a 5-7 membered heterocycloalkyl. In some embodiments, Ring B is a 5-7 membered heterocycloalkyl where 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 [ka] where * represents the point of attachment to the remainder of formula (A).

[0060] In some embodiments, ring B is selected from two R B substituted with two R B The groups are attached to the same carbon atom on ring B and together with the carbon atom to which they are attached form C 3-7 In some embodiments, two R B The groups are attached to the same carbon atom on ring B and together with the carbon atom to which they are attached form a cyclopropyl.

[0061] In some embodiments, the compound of formula (A) [ka] teeth, [ka] where * represents the point of attachment to the remainder of formula (A).

[0062] In some embodiments of Formula (A) or a pharmaceutically acceptable salt thereof, Y 1 is N or CR C1 and;Y2 is N or CR C2 and;Y 3 is N or CR C3 and;Y 4 is N or CR C4 In some embodiments, Y 1 , Y 2 , Y 3 , and Y 4 In some embodiments, Y 1 , Y 2 , Y 3 , and Y 4 In some embodiments, Y 1 , Y 2 , Y 3 , and Y 4 In some embodiments, Y 1 is CR C1 and;Y 2 is CR C2 and;Y 3 is CR C3 and;Y 4 is CR C4 is.

[0063] In some embodiments, R C1 -R C4 are each independently hydrogen, halo, cyano, -OH, -NO2, or -C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 , -NR c14 C(O)OR c15 or C optionally substituted with 1, 2, 3, 4, 5, or more substituents independently selected from the group consisting of halo and —OH. 1-6 In some embodiments, R c1 -Rc15 are independently hydrogen, C 3-10 C optionally substituted with 1, 2, 3, 4, 5, or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; 1-6 It is alkyl.

[0064] In some embodiments, R C1 , R C3 , and R C4 are hydrogen, and R C2 are cyano, -OH, -CH2OH, bromo, -NO2, [ka] In some embodiments, R C1 , R C3 , and R C4 are each independently hydrogen, and R C2 teeth, [ka] is.

[0065] In one embodiment, the compound of formula (A) has formula (B): [ka] or a pharmaceutically acceptable salt thereof, wherein R a14 , R a15 , ring B, R B , m, and R C2 is as defined for formula (A) or any variation or embodiment thereof. In some embodiments, R C2 are halo, cyano, -OH, -NO2, C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )Rc12 , -S(O)2R c13 , -NR c14 C(O)OR c15 , -NR c16 S(O)2(CH2) 1-6 NR c17 C(O)R c18 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1-6 In some embodiments, R C2 are halo, cyano, -OH, -NO2, C(O)NR c1 R c2 , -NR c3 R c4 , -NR c5 S(O)2R c6 , -P(O)R c7 R c8 , -N=S(O)R c9 R c10 , -S(O)(NR c11 )R c12 , -S(O)2R c13 or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH 1-6 In some embodiments, R C2 Ha-NR c5 S(O)2R c6 In some embodiments, R c5 is hydrogen and R c6 is C 1-6 In some embodiments, R c5 is hydrogen and R c6 is ethyl. In some embodiments, R c5 is hydrogen. In some embodiments, R c6 is ethyl. In some embodiments, R c6 is methyl. In some embodiments, R a14 is hydrogen and R a15 is C 1-6 In some embodiments, R a14 is hydrogen and R a15 is tert-butyl. In some embodiments, R a14is hydrogen. In some embodiments, R a15 is tert-butyl. In some embodiments, ring B is [ka] where * represents the point of attachment to the remainder of formula (B). In some embodiments, [ka] teeth, [ka] is.

[0066] In one embodiment, the compound of formula (A) has formula (C): [ka] or a pharmaceutically acceptable salt thereof, wherein R a14 , R a15 , and R c6 is as defined for formula (A) or any variation or embodiment thereof. In some embodiments, R a14 is hydrogen and R a15 is C 1-6 In some embodiments, R a14 is hydrogen and R a15 is tert-butyl. In some embodiments, R a14 is hydrogen. In some embodiments, R a15 is tert-butyl. In some embodiments, Ra 14 and Ra 15 are each independently C 3-10 Cycloalkyl, C 3-10 In some embodiments, R is a cycloalkenyl, a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered heterocycloalkenyl. a14 and R a15 are taken together with the N atom to which they are attached to form a 3- to 10-membered heterocycloalkyl. In some embodiments, Rc6 is C optionally substituted with one or more halo 1-6 In some embodiments, R c6 is unsubstituted C 1-6 In some embodiments, R c6 is ethyl. In some embodiments, R c6 is methyl.

[0067] In one embodiment, the compound of formula (A) has the formula (A-1): [ka] is a compound of

[0068] In one embodiment, the compound of formula (A) has the formula (A-2): [ka] is a compound of

[0069] In one embodiment, the compound of formula (A) has the formula (A-3): [ka] is a compound of

[0070] Compounds of formula (A), specifically compounds of formulas (A-1), (A-2), and (A-3) defined herein, are KIF18A inhibitors. However, these compounds are poorly soluble in aqueous media. Therefore, there is a need to develop solid pharmaceutical formulations of compounds of formula (A), including formulas (B), (C), (A-1), (A-2), and (A-3), that can significantly improve the pharmaceutical performance (e.g., stability and solubility) of these compounds. Such formulations may beneficially improve bioavailability and / or reduce manufacturing costs. Challenges to developing 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 the formulation.

[0071] Furthermore, it is advantageous to develop various forms of compounds, such as polymorphs, salts, hydrates, and solvates of compounds of Formula (A), including Formula (A-1), Formula (A-2), and Formula (A-3). Developing various solid forms, particularly polymorphic or salt forms, not only facilitates understanding of the interactions between such compounds and various solvents, counterions, and conditions, but may also result in potentially more stable and / or more soluble forms of such compounds, both of which are beneficial in developing solid pharmaceutical formulations with enhanced stability and bioavailability.

[0072] In some aspects, provided herein are solid pharmaceutical formulations comprising a compound of Formula (A) and a polymer. In some aspects, provided herein are solid pharmaceutical formulations comprising a compound of Formula (A), wherein the formulation provides at least a two-fold increase in solubility compared to the compound of Formula (A) itself. In some aspects, provided herein are polymorphic forms of the compound of Formula (A-1). In some aspects, provided herein are methods for preparing solid pharmaceutical formulations comprising a compound of Formula (A) and a polymer, particularly by a spray-drying process. In yet other aspects, provided herein are methods for preparing both crystalline and amorphous forms of compounds of Formula (A), including Formula (A-1), Formula (A-2), and Formula (A-3).

[0073] II-b. Salt form In some aspects, provided herein are solid formulations comprising pharmaceutically acceptable salts of compounds of Formula (A). In some embodiments, the pharmaceutically acceptable salts of compounds of Formula (A) retain the biological effectiveness of the compounds described herein. In some of the foregoing embodiments, the solid formulation is a spray-dried formulation.

[0074] In some aspects, provided herein are solid formulations comprising a pharmaceutically acceptable salt of a compound of Formula (A-1). In some aspects, provided herein are spray-dried formulations comprising a pharmaceutically acceptable salt of a compound of Formula (A-1). In some embodiments, in conjunction with the above or below embodiments, the pharmaceutically acceptable salt of a compound of Formula (A-1) is formed with an inorganic base and / or an organic base. In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (A-1) is obtained by reacting a compound of Formula (A-1) with a base including NaOH, KOH, Mg(OH), Ca(OH), L-arginine, L-lysine, choline, betaine, diethylamine, or any combination thereof.

[0075] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (A-1) is obtained by reacting a compound of Formula (A-1) with an inorganic base, including NaOH, KOH, Mg(OH), Ca(OH), or any combination thereof. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (A-1) includes a sodium salt, a potassium salt, a magnesium salt, a calcium salt, a zinc salt, or any combination thereof. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (A-1) is a sodium salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (A-1) is a sodium salt, and the stoichiometry of the compound of Formula (A-1) to the sodium ion is about 1:0.8 to 1:3 (e.g., 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). In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a monosodium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a disodium 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, and the stoichiometry of the compound of Formula (A-1) to the potassium ion is about 1:0.8 to 1:3 (e.g., about 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). In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a monopotassium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a dipotassium 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.

[0076] In some embodiments, in conjunction with the above or below embodiments, a pharmaceutically acceptable salt of the compound of Formula (A-1) is obtained by reacting the compound of Formula (A-1) with an organic base comprising L-arginine, L-lysine, choline, betaine, diethylamine, or any combination thereof. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) comprises an L-arginine salt, an L-lysine salt, a choline salt, a betaine salt, a diethylamine salt, or any combination thereof. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is an L-arginine salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is an 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.

[0077] In some embodiments, 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. In some embodiments, 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.

[0078] II-c. Composition In some embodiments, provided herein is 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. In some embodiments, a substantial portion of the compound of Formula (A) is in amorphous form. For example, in some embodiments, 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. In some embodiments, 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. In some embodiments, 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 its pharmaceutically acceptable salt or solvate in the solid pharmaceutical formulation is amorphous. In some embodiments, the powder X-ray diffraction (PXRD) pattern of the solid pharmaceutical formulation does not contain any discernible peaks characteristic of a crystalline form of the compound of Formula (A) or its pharmaceutically acceptable salt or solvate. In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-1). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-2). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-3).

[0079] In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt or solvate thereof, may be present in the solid pharmaceutical formulation as a homogeneous phase, such that the compound of Formula (A), or a pharmaceutically acceptable salt or solvate thereof, is uniformly dispersed throughout the polymer. In some embodiments, the solid pharmaceutical formulation is substantially homogeneous, such that the compound of Formula (A), or a pharmaceutically acceptable salt or solvate thereof, is substantially uniformly dispersed throughout the solid formulation. In some embodiments, the compound of Formula (A), or a pharmaceutically acceptable salt or solvate thereof, is present in the solid dispersion as domains of relatively high concentration and domains of relatively low concentration. In some embodiments, the solid formulation has a single glass transition temperature, demonstrating that the formulation is substantially homogeneous. In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-1). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-2). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-3):

[0080] In some embodiments, the compound of Formula (A) or a pharmaceutically acceptable salt or solvate thereof is present in the formulation in an amount of about 10% to about 70% by weight (e.g., about 20% to about 70% by weight, about 20% to about 60% by weight, about 25% to about 50% by weight, about 25% by weight, about 40% by weight, or about 50% by weight). In some embodiments, the 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 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. In some embodiments, the 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. In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-1). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-2). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-3):

[0081] In some embodiments, the solid pharmaceutical formulations provided herein comprise a polymer. In some embodiments, the polymer may include any pharmaceutically acceptable polymer that, when processed with the 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 an amorphous form or to improve its solubility, stability, or bioavailability. In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-1). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-2). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-3).

[0082] Although specific polymers are discussed in the formulations described herein, blends of such polymers may also be suitable, and thus the term "polymer" is intended to encompass blends of polymers as well as a single type of polymer.

[0083] In some embodiments, the polymer comprises an enteric polymer. In some embodiments, the polymer is at least partially ionizable at physiologically relevant pH. In some other embodiments, the polymer is an ionizable polymer, and the ionizable polymer is an enteric polymer. Exemplary enteric polymers include, but are not limited to, hydroxypropyl methylcellulose acetate succinate (HPMCAS) (including HPMCAS L grade (HPMCAS-L), HPMCAS M grade (HPMCAS-M), and HPMCAS H grade (HPMCAS-H)), hydroxypropyl methylcellulose phthalate (HPMCP) (including HPMCP-HP55), hydroxypropyl methylcellulose acetate phthalate (HPMCAP), hydroxypropyl methylcellulose (HPMC) (HPMC E5, HPMC E3LV, and HPMC 5CPS), methacrylic acid-ethyl acrylate copolymer (including 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, cellulose acetate trimellitate, methylcellulose acetate trimellitate, ethylcellulose acetate trimethylolpropane, cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridine dicarboxylate, salicylic acid cellulose acetate, and hydroxypropyl salicylic acid cellulose acetate.

[0084] In some embodiments, 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 methylcellulose 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. In some embodiments, the polymer is methacrylic acid-ethyl acrylate copolymer (1:1), which is available as Eudragit® L100-55.

[0085] In some embodiments, the solid pharmaceutical formulations described herein have a weight ratio of the compound of Formula (A) to the polymer of about 15:85 to about 90:10 (e.g., about 20:80 to about 70:30, about 25:75 to about 50:50, about 25:75 to about 40:60, or 40:60 to about 50:50). In some embodiments, the solid pharmaceutical formulations described herein have a weight ratio of the compound of Formula (A) to the polymer of about 15:85 to about 90:10. In some embodiments, the solid pharmaceutical formulations described herein have a weight ratio of the compound of Formula (A) to the polymer of about 15:85 to about 80:20. In some embodiments, the solid pharmaceutical formulations described herein have a weight ratio of the compound of Formula (A) to the polymer of about 15:85 to about 70:30. In some embodiments, the solid pharmaceutical formulations described herein have a weight ratio of the compound of Formula (A) to the polymer of about 20:80 to about 60:40. In some embodiments, the solid pharmaceutical formulations described herein have a weight ratio of the compound of Formula (A) to the polymer of about 20:80 to about 30:70. In some embodiments, the solid pharmaceutical formulations described herein have a weight ratio of the compound of Formula (A) to the polymer of about 25:75. In some embodiments, the solid pharmaceutical formulations described herein have a weight ratio of the compound of Formula (A) to the polymer of about 35:65 to about 45:55. In some embodiments, the solid pharmaceutical formulations described herein have a weight ratio of the compound of Formula (A) to the polymer of about 40:60. In some embodiments, the solid pharmaceutical formulations described herein have a weight ratio of the compound of Formula (A) to the polymer of about 45:55 to about 55:45. In some embodiments, the solid pharmaceutical formulations described herein have a weight ratio of the compound of Formula (A) to the polymer of about 50:50. In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-1). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-2). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-3).

[0086] In some embodiments, the formulation comprises a compound of Formula (A) and HPMCP-HP55 in a weight ratio of 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 about 20:80 to about 80:20. In some embodiments, the formulation comprises a compound of Formula (A) and HPMCP-HP55 in a weight ratio of 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 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 about 30:70 to about 50:50. In some embodiments, the formulation comprises the compound of Formula (A) and HPMCP-HP55 in a weight ratio of about 40:60 to about 60:40. In some embodiments, the formulation comprises the compound of Formula (A) and HPMCP-HP55 in a weight ratio of about 25:75. In some embodiments, the formulation comprises the compound of Formula (A) and HPMCP-HP55 in a weight ratio of about 40:60. In some embodiments, the formulation comprises the compound of Formula (A) and HPMCP-HP55 in a weight ratio of about 50:50. In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-1). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-2). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-3).

[0087] In some embodiments, the formulation comprises a compound of Formula (A) and HPMCAS-M in a weight ratio of 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 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 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 about 10:90 to about 40:60. In some embodiments, the formulation comprises a compound of Formula (A) and HPMCAS-M in a weight ratio of 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 above or below embodiments, the compound of Formula (A) is a compound of Formula (A-1). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-2). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-3).

[0088] In some embodiments, the formulation comprises the compound of Formula (A) and HPMC E3LV in a weight ratio of about 20:80 to about 90:10. In some embodiments, the formulation comprises the compound of Formula (A) and HPMC E3LV in a weight ratio of about 40:60 to about 60:40. In some embodiments, the formulation comprises the compound of Formula (A) and HPMC E3LV in a weight ratio of about 50:50. In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-1). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-2). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-3).

[0089] In some embodiments, the formulation comprises a compound of Formula (A) and a 1:1 methacrylic acid-ethyl acrylate copolymer (available as Eudragit® L100-55) in a weight ratio of about 10:90 to about 90:10. In some embodiments, the formulation comprises a compound of Formula (A) and a 1:1 methacrylic acid-ethyl acrylate copolymer (available as Eudragit® L100-55) in a weight ratio of about 20:80 to about 60:40. In some embodiments, the formulation comprises a compound of Formula (A) and a 1:1 methacrylic acid-ethyl acrylate copolymer (available as Eudragit® L100-55) in a weight ratio of about 20:80 to about 30:70. In some embodiments, the formulation comprises a compound of Formula (A) and a 1:1 methacrylic acid-ethyl acrylate copolymer (available as Eudragit® L100-55) in a weight ratio of about 30:70 to about 50:50. In some embodiments, the formulation comprises a compound of Formula (A) and a 1:1 methacrylic acid-ethyl acrylate copolymer (available as Eudragit® L100-55) in a weight ratio of about 40:60 to about 60:40. In some embodiments, the formulation comprises a compound of Formula (A) and a 1:1 methacrylic acid-ethyl acrylate copolymer (available as Eudragit® L100-55) in a weight ratio of about 25:75. In some embodiments, the formulation comprises a compound of Formula (A) and a methacrylic acid-ethyl acrylate copolymer (1:1) (available as Eudragit® L100-55) in a weight ratio of about 40:60. In some embodiments, the formulation comprises a compound of Formula (A) and a methacrylic acid-ethyl acrylate copolymer (1:1) (available as Eudragit® L100-55) in a weight ratio of about 50:50. In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-1). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-2). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-3).

[0090] II-d. Pharmacokinetics The formulations provided herein may improve the dissolution and pharmacokinetic profile of compounds of Formula (A), including compounds of Formula (A-1), Formula (A-2), and Formula (A-3). The dissolution profile of a compound of Formula (A) (e.g., compounds of Formula (A-1), Formula (A-2), and Formula (A-3)) is measured by the area under the concentration-time curve (AUC) in a medium over a period of time, t. (t) ), maximum plasma concentration (C max ), and the total amount of drug dissolved over time t (C t ) can be described and evaluated using parameters such as

[0091] In some embodiments, provided herein is 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 a pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical formulation increases the dissolved concentration of the compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in an artificial intestinal medium compared to a pure crystalline compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)). In some embodiments, the artificial intestinal medium comprises fasting simulated intestinal fluid (FaSSIF). In some embodiments, provided herein is 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 a pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical formulation increases the dissolved concentration of the compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in an artificial intestinal medium 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) compared to a pure crystalline compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)). In some embodiments (which may be combined with any of the embodiments above or below), the solid formulation is a spray-dried dispersion.

[0092] In some embodiments, provided herein is 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 a pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical formulation is a solid pharmaceutical formulation comprising a C of the compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in FaSSIF. max In some embodiments, the solid pharmaceutical formulation is effective for achieving a C of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in FaSSIF of about 30 μg / mL to about 300 μg / mL (e.g., about 40 μg / mL to about 300 μg / mL, about 50 μg / mL to about 270 μg / mL, or about 100 μg / mL to about 200 μg / mL). max In some embodiments, the solid pharmaceutical formulation is effective to achieve a C of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in FaSSIF of about 40 μg / mL to about 100 μg / mL. max In some embodiments, the solid pharmaceutical formulation is effective to achieve a C of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in FaSSIF of about 100 μg / mL to about 150 μg / mL. max is effective to achieve a concentration of from about 150 μg / mL to about 300 μg / mL. In some embodiments (which may be combined with any of the embodiments above or below), the solid formulation is a spray-dried dispersion.

[0093]

[0013] In some embodiments, provided herein is 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 a pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical formulation is a solid pharmaceutical formulation comprising a C of the compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in a gastric buffer (GB). maxIn some embodiments, the solid pharmaceutical formulation is effective to achieve a C of the compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in GB. max In some embodiments, the solid pharmaceutical formulation is effective to achieve a C of the compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in GB of about 8 μg / mL to about 90 μg / mL. max In some embodiments, the solid pharmaceutical formulation is effective to achieve a C of the compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in GB of about 50 μg / mL to about 90 μg / mL. max is effective to achieve a saturation concentration of about 60 μg / mL to about 90 μg / mL. In some embodiments (which may be combined with any of the embodiments above or below), the solid formulation is a spray-dried dispersion. In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-1). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-2). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-3).

[0094] In some embodiments, the solid pharmaceutical formulation has a 500 mg / mL or higher AUC of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in FaSSIF. 35-210 to about 1000 min*μg / mL to about 30000 min*μg / mL (e.g., about 4000 min*μg / mL to about 25000 min*μg / mL, about 4000 min*μg / mL to about 10000 min*μg / mL, about 10000 min*μg / mL to about 15000 min*μg / mL, or about 20000 min*μg / mL to about 30000 min*μg / mL). In some embodiments, the solid pharmaceutical formulation is effective to achieve an AUC of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in FaSSIF.35-210 In some embodiments, the solid pharmaceutical formulation is effective to achieve an AUC of a compound of Formula (A) (e.g., a compound of Formula (A-1) or Formula (A-2)) in FaSSIF of about 4000 min*μg / mL to about 10000 min*μg / mL. 35-210 In some embodiments, the solid pharmaceutical formulation is effective to achieve an AUC of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in FaSSIF of about 10,000 min*μg / mL to about 20,000 min*μg / mL. 35-210 is effective to achieve a saturation of about 20,000 min*μg / mL to about 30,000 min*μg / mL. In some embodiments (which may be combined with any of the embodiments above or below), the solid formulation is a spray-dried dispersion. In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-1). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-2). In some embodiments, in conjunction with the above or below embodiments, the compound of Formula (A) is a compound of Formula (A-3).

[0095] In some embodiments, the solid pharmaceutical formulation is effective in dissolving about 3 μg / mL to about 120 μg / mL of total drug in FaSSIF over 210 minutes (e.g., about 3 μg / mL to about 10 μg / mL, about 10 μg / mL to about 120 μg / mL, about 10 μg / mL to about 50 μg / mL, or about 50 μg / mL to about 120 μg / mL). In some embodiments, the solid pharmaceutical formulation is effective in dissolving about 3 μg / mL to about 10 μg / mL of total drug over 210 minutes. In some embodiments, the solid pharmaceutical formulation is effective in dissolving about 10 μg / mL to about 50 μg / mL of total drug over 210 minutes. In some embodiments, the solid pharmaceutical formulation is effective in dissolving about 50 μg / mL to about 100 μg / mL of total drug over 210 minutes. In some embodiments, the solid pharmaceutical formulation is effective to provide about 100 μg / mL to about 120 μg / mL of total drug dissolved in FaSSIF over 210 minutes. In some embodiments (which may be combined with any of the above or below embodiments), the solid formulation is a spray-dried dispersion.

[0096] The pharmacokinetic profile of a compound of formula (A) (e.g., compounds of formula (A-1), formula (A-2), and formula (A-3)) is determined by the area under the plasma concentration-time curve (AUC) over a period of time t. (t) ), the area under the plasma concentration-time curve to infinity (AUC (inf) ), maximum plasma concentration C max , and / or drug half-life (t 1 / 2) and other parameters. In some embodiments, in connection with the above or below embodiments, the pharmacokinetic profile of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) is determined in a mammal. In some embodiments, in connection with the above or below embodiments, the pharmacokinetic profile of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) is determined in a mouse subject. In some embodiments, in connection with the above or below embodiments, the pharmacokinetic profile of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) is determined in a human subject.

[0097] In some aspects, provided herein is 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 a pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical formulation, when administered to a murine subject, increases a maximum plasma concentration (C) of the compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in the subject. max ) 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). In some embodiments, the solid pharmaceutical formulation, when administered to a murine subject, is effective to achieve a C of about 8000 ng / mL to about 12000 ng / mL. max In some embodiments, the solid pharmaceutical formulation, when administered to a murine subject, is effective in providing a C of about 10,000 ng / mL. max It is effective in providing

[0098] In some aspects, provided herein is 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 a pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical formulation, when administered to a human subject, achieves a maximum plasma concentration (C) of the compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in the subject. max ) to about 1.5 μmol / mL to about 5.0 μmol / mL (e.g., about 1.5 μmol / mL to about 4.5 μmol / mL, about 1.5 μmol / mL to about 4.0 μmol / mL, about 2.0 μmol / mL to about 3.5 μmol / mL, or about 2.7 μmol / mL). In some embodiments, the solid pharmaceutical formulation, when administered to a human subject, has a C of about 2.0 μmol / mL to about 3.5 μmol / mL. max In some embodiments, the solid pharmaceutical formulation, when administered to a human subject, is effective in providing a C of about 2.7 μmol / mL. max It is effective in providing

[0099] In some embodiments, the solid pharmaceutical formulation, when administered to a murine subject, exhibits a C of about 0.5 to about 2 hours (e.g., about 0.5 hours to 1.5 hours, about 0.7 hours to 1.3 hours, or about 0.9 hours to about 1.1 hours) after administration of the formulation. max In some embodiments, the solid pharmaceutical formulation, when administered to a murine subject, exhibits a C of about 0.8 hours to about 1.2 hours. max In some embodiments, the solid pharmaceutical formulation, when administered to a murine subject, has a C of about 1.0 hour. max It is effective in achieving this.

[0100] In some embodiments, the solid pharmaceutical formulation, when administered to a human subject, exhibits a C of about 2 to about 10 hours (e.g., about 2 to 8 hours, about 3 to 7 hours, or about 4 to about 6 hours) after administration of the formulation. max In some embodiments, the solid pharmaceutical formulation, when administered to a human subject, exhibits a C of about 4 hours to about 6 hours. maxIn some embodiments, the solid pharmaceutical formulation, when administered to a human subject, has a C of about 5.4 hours. max It is effective in achieving this.

[0101] In some embodiments, the solid pharmaceutical formulations described herein, when administered to a murine subject, result in a C of a compound of Formula (A) (e.g., a 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. max It is effective in providing C max In some embodiments, the solid pharmaceutical formulations described herein, when administered to a murine subject, result in a C of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in the subject at about 0.8 to about 1.2 hours after administration of the formulation. max It is effective in providing C max In some embodiments, the solid pharmaceutical formulations described herein, when administered to a murine subject, result in a C of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in the subject at about 1 hour after administration of the formulation. max It is effective in providing C max is approximately 10,000 ng / mL.

[0102] In some other aspects, provided herein is 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 a pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical formulation is measured using a plasma area under the concentration-time curve (AUC) of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) from 0 to 24 hours in a murine subject. 0-24) to about 20,000 ng·hr / mL to about 70,000 ng·hr / mL (e.g., about 30,000 ng·hr / mL to about 60,000 ng·hr / mL, about 40,000 ng·hr / mL to about 60,000 ng·hr / mL, or about 50,000 ng·hr / mL). In some embodiments, the solid pharmaceutical formulation is effective to increase the AUC of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in a murine subject. 0-24 In some embodiments, the solid pharmaceutical formulation is effective to achieve an AUC of at least 30,000 ng / mL (e.g., at least 35,000 ng / mL, at least 40,000 ng / mL, at least 45,000 ng / mL, at least 50,000 ng / mL, or at least 55,000 ng / mL). 0-24 In some embodiments, the solid pharmaceutical formulation is effective in achieving an AUC 0-24 is effective in achieving a concentration of 70,000 ng·h / mL or less (e.g., 70,000 ng·h / mL or less, 65,000 ng·h / mL or less, 60,000 ng·h / mL or less, or 55,000 ng·h / mL or less).

[0103] In some other aspects, provided herein is 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 a pharmaceutically acceptable salt thereof, wherein the solid pharmaceutical formulation is capable of measuring the area under the plasma concentration-time curve (AUC) of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) from 0 to 24 hours in a human subject. 0-24 ) from about 10 μmol·hr / mL to about 100 μmol·hr / mL (e.g., from about 10 μmol·hr / mL to about 80 μmol·hr / mL, from about 20 μmol·hr / mL to about 70 μmol·hr / mL, or about 50 μmol·hr / mL). In some embodiments, the solid pharmaceutical formulation is effective to achieve an AUC of a compound of Formula (A) (e.g., a compound of Formula (A-1), Formula (A-2), or Formula (A-3)) in a human subject. 0-24In some embodiments, the solid pharmaceutical formulation is effective to achieve an AUC 0-24 In some embodiments, the solid pharmaceutical formulation is effective to achieve an AUC 0-24 In some embodiments, the solid pharmaceutical formulation is effective to achieve an AUC 0-24 This is effective in achieving a dose of approximately 40 μmol·h / mL.

[0104] II-e. Preparation method Also provided herein is a process for preparing the solid pharmaceutical formulations described herein. In some embodiments, 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)).

[0105] A spray-dried solid dispersion or spray-dried dispersion (SDD) is a solid dispersion obtained using spray drying technology. The spray drying process generally involves breaking down a liquid mixture from a solution into small droplets (a step also known as atomization) and rapidly removing the solvent from the mixture in a vessel (e.g., a spray dryer), where a strong driving force is provided to evaporate the solvent from the droplets. Part of the driving force for evaporation of the solvent from the droplets can be provided by heating the solution. The spray drying process and spray drying equipment or devices are generally described, for example, in Perry's Chemical Engineers' Handbook (Eighth Edition 2007). The strong driving force for solvent evaporation is generally provided by maintaining a partial pressure of the solvent in the spray dryer sufficiently lower than the vapor pressure of the solvent at the temperature of the dried droplets. A strong driving force for solvent evaporation can be achieved by (1) maintaining the pressure in the spray-drying apparatus at a partial vacuum (e.g., 0.01-0.50 atm), (2) mixing the droplets with a warm drying gas, or a combination of both (1) and (2).

[0106] In some embodiments, 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. In some embodiments, the process comprises: (1) preparing 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; (2) spray-drying the solution to obtain a powder; and, optionally, (3) further drying the powder of step (2) under heat. In some embodiments, the solvent comprises dichloromethane (DCM). In some embodiments, the solvent comprises an alcohol. In some embodiments, the solvent comprises methanol. In some embodiments, the solvent comprises DCM and methanol. In some embodiments, the solvent comprises water. In some embodiments, the solvent comprises acetone. In some embodiments, the solvent comprises acetone and water. In some embodiments, 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 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). In some embodiments, the solvent is a mixture of DCM and methanol in a weight ratio of about 70:30 to about 90:10. In some embodiments, the solvent is a mixture of DCM and methanol in a weight ratio of about 87:13. In some embodiments, the polymer comprises HPMCAS-M. In some embodiments, the polymer comprises methacrylic acid-ethyl acrylate copolymer (1:1) (available as Eudragit® L100-55). In some embodiments, the polymer comprises HPMC E3LV. In some embodiments, the polymer comprises HPMCP-HP55.

[0107] III. Polymorphic forms In one aspect, provided herein is a polymorphic form of N-(1″-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indolin]-5″-yl)ethanesulfonamide (also referred to herein as the compound of formula (A-1)), having the structure shown below: [ka]

[0108] In some embodiments, the 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.

[0109] Polymorphs may have properties such as bioavailability and stability under certain conditions that make them suitable for medical or pharmaceutical use.

[0110] Polymorphs of the compound of Formula (A-1) may offer bioavailability and stability advantages and may be suitable for use as an active agent in pharmaceutical compositions. Differences in the crystalline structure of a drug substance can affect the drug's 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.). Such differences can affect how pharmaceutical compositions are prepared or formulated in different dosage or delivery forms (e.g., solid oral dosage forms including tablets and capsules). Compared to other forms, such as non-crystalline or amorphous forms, polymorphs may provide desirable or suitable hygroscopicity or lack thereof, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, reproducibility, and / or process control. Thus, polymorphs of the compound of formula (A-1) may provide the advantage of improving the manufacturing process of the active agent or the stability or shelf life of a pharmaceutical form of the active agent, or of having suitable bioavailability and / or stability as an active agent.

[0111] The use of certain conditions (such as the use of different solvents and / or temperatures) may give different polymorphs of the compound of formula (A-1) or solvates thereof (including polymorphic Form A and polymorphic Form C described herein), which may exhibit one or more of the preferred characteristics described herein. Processes for the preparation of the polymorphs described herein and the characterization of such polymorphs are described in more detail below.

[0112] III-a. Polymorphic Form A (Free Form Pattern A) In some embodiments, provided herein is polymorphic Form A of N-(1"-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indolin]-5"-yl)ethanesulfonamide (hereinafter referred to as polymorphic Form A). In some embodiments, polymorphic Form A may also be referred to as polymorphic Form I.

[0113] In some embodiments, polymorph Form A has an XRPD pattern substantially as shown in FIG.

[0114] Table III-1 shows the 2θ angles and relative peak intensities observed for polymorph Form A using XRPD. [Table 1-1] [Table 1-2]

[0115] In some embodiments, polymorph Form A has an XRPD pattern exhibiting 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 2θ angles with maximum intensity in an XRPD pattern substantially as shown in FIG. 2 or substantially as given in Table III-1. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrument and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for polymorph Form A, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees in 2θ.

[0116] In some embodiments, polymorphic form A has an XRPD pattern comprising peaks at angles 13.54±0.20, 17.89±0.20, 18.39±0.20, 19.39±0.20, and 19.73±0.20 degrees 2θ. In some embodiments, polymorphic form A has an XRPD pattern comprising additional peaks at angles 15.46±0.20 and 17.29±0.20 degrees 2θ. In some embodiments, polymorphic form A has an XRPD pattern further comprising additional peaks at angles 8.61±0.20 and 15.04±0.20 degrees 2θ. In some embodiments, polymorphic Form A has an XRPD pattern comprising peaks at 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, and 22.98±0.20 degrees 2θ. It will be understood that additional peaks may be observed in an XRPD pattern beyond those shown in FIG. 2 or provided in Table III-1 due to, for example, the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0117] In some embodiments, polymorph Form A has a differential scanning calorimetry (DSC) graph substantially as shown in Figure 3. In some embodiments, polymorph Form A is characterized as having an endothermic onset at about 188°C as determined by DSC. In some embodiments, polymorphic Form A is characterized as having an endothermic 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. In some embodiments, Form A is characterized as having an endothermic peak at about 194°C as determined by DSC. In some embodiments, Form A is characterized as having an endothermic 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.

[0118] In some embodiments, polymorph Form A has a thermographic analysis (TGA) graph substantially as shown in Figure 3. In some embodiments, polymorph 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. In some embodiments, polymorph Form A has a pH of 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±1.6°C, 316±1.7°C, 316±1.8°C, 316±1.9°C, 316±1.8°C, 316±1.9°C, 316±1.8°C, 316±1.8°C, 316±1.9 ... 0.4°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).

[0119] In some embodiments, polymorph Form A has a dynamic vapor sorption / desorption (DVS) graph substantially as shown in Figure 4. In some embodiments, polymorph Form A exhibits a weight gain from 5% relative humidity (RH) to 95% RH 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%). In some embodiments, polymorph Form A exhibits a weight loss from 95% RH to 5% RH 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%) as determined by DVS.

[0120] In some embodiments, polymorph Form A exhibits substantially no change or no change before and after DVS measurement as determined by XRPD.

[0121] In some embodiments of polymorphic Form A, 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) are true: (a) Polymorphic Form A has an XRPD pattern containing peaks at 13.54±0.20, 17.89±0.20, 18.39±0.20, 19.39±0.20, and 19.73±0.20 degrees 2θ; an XRPD pattern containing additional peaks at 15.46±0.20 and 17.29±0.20 degrees 2θ; an XRPD pattern containing additional peaks at 8.61±0.20 and 15.04±0.20 degrees 2θ; or an XRPD pattern containing additional peaks at 6.13±0.20 and 15.04±0.20 degrees 2θ. 20, having an XRPD pattern containing peaks at 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, and 22.98±0.20 degrees 2θ angles; (b) Polymorph Form A has an XRPD pattern substantially as shown in Figure 2; (c) Polymorph Form A has a DSC graph substantially as shown in Figure 3; (d) Polymorphic Form A is characterized as having an endothermic onset at 188±2°C as determined by DSC; (e) Polymorphic Form A is characterized as having an endothermic peak at 194±2°C as determined by DSC; (f) Polymorph Form A has a TGA graph substantially as shown in Figure 3; (g) 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; (h) Polymorphic Form A has an apparent decomposition at 316±5°C; (i) Polymorph Form A has a DVS graph substantially as shown in Figure 4; (j) Polymorph Form A has a weight gain of approximately 0.095% or 0.095% ± 0.005% from 5% RH to 95% RH as determined by DVS; (k) Polymorph Form A has a weight loss from about 95% RH to 5% RH of about 0.097% or 0.097%±0.005% as determined by DVS.

[0122] III-b. Polymorphic Form B (Free Form Pattern B) In some embodiments, provided herein is polymorphic Form B of N-(1"-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indolin]-5"-yl)ethanesulfonamide (hereinafter referred to as polymorphic Form B). In some embodiments, polymorphic Form B contains 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) of water. In some embodiments, polymorphic Form B is substantially free of water. In some embodiments, polymorph Form B contains about 0.01% to 1% w / w (e.g., about any of about 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.

[0123] In some embodiments, polymorph Form B has an XRPD pattern substantially as shown in FIG.

[0124] Table III-1 shows the 2θ angles and relative peak intensities observed for polymorph Form B using XRPD. [Table 2-1] [Table 2-2]

[0125] In some embodiments, polymorph Form B has an XRPD pattern exhibiting 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 2θ angles with maximum intensity in an XRPD pattern substantially as shown in FIG. 10 or substantially as given in Table III-1. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for polymorph Form B, may vary by about ±1 degree, ±0.8 degrees, ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees in 2θ.

[0126] In some embodiments, polymorphic form B has an XRPD pattern comprising peaks at angles 15.62±0.20, 16.60±0.20, 19.87±0.20, 20.11±0.20, and 25.76±0.20 degrees 2θ. In some embodiments, polymorphic form B has an XRPD pattern comprising additional peaks at angles 17.50±0.20 and 21.13±0.20 degrees 2θ. In some embodiments, polymorphic form B has an XRPD pattern further comprising additional peaks at angles 8.23±0.20 and 11.72±0.20 degrees 2θ. In some embodiments, polymorph Form B has an XRPD pattern comprising peaks at 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 2θ angles. It will be understood that additional peaks may be observed in an XRPD pattern beyond those shown in Figure 10 or provided in Table III-1 due, for example, to the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0127] In some embodiments, polymorph Form B has a differential scanning calorimetry (DSC) graph substantially as shown in Figure 11. In some embodiments, polymorph Form B is characterized as having an endothermic onset at about 196°C as determined by DSC. In some embodiments, polymorphic form B is characterized as having an endothermic 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. In some embodiments, form B is characterized as having an endothermic peak at about 197°C as determined by DSC. In some embodiments, Form B is characterized as having an endothermic 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.

[0128] In some embodiments, polymorphic form B has a thermographic analysis (TGA) graph substantially as shown in Figure 12. In some embodiments, polymorphic form B has a thermographic analysis (TGA) graph substantially as shown in Figure 12. In some embodiments, polymorphic form B has a thermographic analysis (TGA) graph substantially as shown in Figure 12. In some embodiments, polymorphic form B has a thermographic analysis (TGA) graph substantially as shown in Figure 12. In some embodiments, polymorphic form B has a thermographic analysis (TGA) graph substantially as shown in Figure 12. ±1.0°C, 100±0.9°C, 100±0.8°C, 100±0.7°C, 100±0.6°C, 100±0.5°C, 100±0.4°C, 100±0.3°C, 100±0.2°C, or 100±0.1°C), exhibiting 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%). In some embodiments, polymorph 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%) from about 100°C to about 180°C.

[0129] In some embodiments, polymorph Form B has a dynamic vapor sorption / desorption (DVS) graph substantially as shown in Figure 13. In some embodiments, polymorph Form B exhibits a weight gain from 0.1% relative humidity (RH) to 95% RH 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%). In some embodiments, polymorph 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.

[0130] In some embodiments, polymorph Form B shows substantially no change or no change before and after DVS measurement as determined by XRPD.

[0131] In some embodiments of polymorphic Form B, 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) are true: (a) Polymorphic Form B has an XRPD pattern containing peaks at 15.62±0.20, 16.60±0.20, 19.87±0.20, 20.11±0.20, and 25.76±0.20 degrees 2θ; an XRPD pattern containing additional peaks at 17.50±0.20 and 21.13±0.20 degrees 2θ; an XRPD pattern containing additional peaks at 8.23±0.20 and 11.72±0.20 degrees 2θ; or an XRPD pattern containing additional peaks at 8.23±0.2 having an XRPD pattern containing peaks at 2θ angles of 0, 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; (b) Polymorphic Form B has an XRPD pattern substantially as shown in Figure 10; (c) Polymorph Form B has a DSC graph substantially as shown in Figure 11; (d) Polymorphic Form B is characterized as having an endothermic onset at 196±2°C as determined by DSC; (e) Polymorphic Form B is characterized as having an endothermic peak at 197±2°C as determined by DSC; (f) Polymorph Form B has a TGA graph substantially as shown in Figure 12; (g) polymorphic form B has a weight loss of approximately 0.05% or 0.05% ± 0.01% from 25 to 100°C as determined by TGA; (h) polymorphic form B has a weight loss of approximately 0.1% or 0.1% ± 0.01% from 100 to 180°C as determined by TGA; (i) Polymorph Form B has a DVS graph substantially as shown in Figure 13; (j) 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 (k) Polymorph Form B has a weight loss from 95% RH to 0.1% RH of about 0.050% or 0.050%±0.005% as determined by DVS.

[0132] III-c. Polymorphic Form C (Amorphous Free Form) In some embodiments, provided herein is polymorphic Form C (hereinafter referred to as polymorphic Form C) of N-(1"-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indolin]-5"-yl)ethanesulfonamide (i.e., the compound of Formula (A-1)). In some embodiments, polymorphic Form C may also be referred to as polymorphic Form II.

[0133] In some embodiments, polymorphic form C is substantially amorphous. In some embodiments, 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., the compound of Formula (A-1)) and DMF and / or water. In some embodiments, polymorphic form C comprises DMF and the compound of Formula (A-1), wherein the molar ratio of DMF to the compound of Formula (A-1) is about 0.12:1. In some embodiments, polymorphic form C comprises DMF and the compound of Formula (A-1), wherein the weight percentage of DMF is about 1.5 wt.%. In some embodiments, polymorphic form C comprises water and the compound of Formula (A-1), wherein the weight percentage of water is about 0.5 wt.%.

[0134] In some embodiments, polymorph Form C has an XRPD pattern substantially as shown in Figure 5. In some embodiments, polymorph Form C has an XRPD pattern without discernible characteristic crystalline phase peaks.

[0135] In some embodiments, polymorphic form C has a TGA graph substantially as shown in Figure 6. In some embodiments, 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. In some embodiments, polymorph 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. In some embodiments, polymorph Form C has a pH 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% ± 0.04%) between 53°C and 120°C as determined by TGA. ±0.01%), and between 120°C and 200°C, the weight loss is approximately 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%). In some embodiments, polymorphic Form C exhibits a pH of 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±1.6°C, 319±1.7°C, 319±1.8°C, 319±1.9°C, 319±1.8 ... 0.4°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).

[0136] In some embodiments, polymorph Form C has a DSC graph substantially as shown in FIG. In some embodiments, 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. In some embodiments, 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. In some embodiments, the glass transition temperature of polymorph Form C may vary due to the type and / or amount of solvent therein. In some embodiments, polymorph Form C is characterized as having an endothermic peak at about 191° C. as determined by DSC. In some embodiments, polymorphic form C is characterized as having an endothermic 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. In some embodiments, a portion of polymorphic form C may crystallize above the glass transition temperature and convert to polymorphic form A.

[0137] In some embodiments, polymorph Form C has a dynamic vapor sorption / desorption (DVS) graph substantially as shown in Figure 8. In some embodiments, polymorph Form C exhibits a weight gain from 5% relative humidity (RH) to 95% RH 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%). In some embodiments, polymorph Form C exhibits a weight loss from 95% RH to 5% RH 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%).

[0138] In some embodiments of 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) are true: (a) Polymorphic Form C has an XRPD pattern with no discernible characteristic crystalline material peaks; (b) Polymorph Form C has an XRPD pattern substantially as shown in Figure 5; (c) Polymorph Form C has a DSC graph substantially as shown in Figure 7; (d) Polymorphic Form C is characterized as having a glass transition onset temperature at 80±2°C as determined by DSC; (e) Polymorphic Form C is characterized as having a glass transition midpoint temperature at 85±2°C as determined by DSC; (f) Polymorphic Form C is characterized as having an endothermic peak at 191±2°C as determined by DSC; (g) Polymorph Form C has a TGA graph substantially as shown in Figure 6; (h) 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; (i) Polymorphic Form C has a weight loss of approximately 1.1% or 1.1%±0.1% between 120°C and 200°C as determined by TGA; (j) Polymorphic form C has apparent decomposition at 319 ± 5°C; (k) Polymorph Form C has a DVS graph substantially as shown in Figure 8; (l) Polymorphic Form C has a weight gain of approximately 1.13% or 1.13% ± 0.1% from 5% RH to 95% RH as determined by DVS; (m) Polymorph Form C has a weight loss of about 1.57% or 1.57%±0.1% from 95% RH to 5% RH as determined by DVS.

[0139] Also provided herein are compositions containing a polymorph described herein (e.g., polymorph form A, polymorph form C, or a mixture thereof). In some embodiments, the composition contains polymorph form A. In some embodiments, the composition contains polymorph form C. In some embodiments, the composition contains a mixture of polymorph form A and polymorph form C.

[0140] In some embodiments, a composition is provided containing polymorphic Form A of the compound of Formula (A-1). In some embodiments, the composition is substantially free of polymorphic Form C of the compound of Formula (A-1). In some embodiments, the composition is substantially free of salts of the compound of Formula (A-1).

[0141] In some embodiments of a composition containing Form A of the compound of Formula (A-1), at least about 0.1 wt.%, at least about 0.3 wt.%, at least about 0.5 wt.%, at least about 0.8 wt.%, at least about 1.0 wt.%, at least about 5.0 wt.%, at least about 10 wt.%, at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 85 wt.%, at least about 90 wt.%, at least about 95 wt.%, at least about 96 wt.%, at least about 97 wt.%, at least about 98 wt.%, at least about 99 wt.%, or at least 99.9 wt.% of the total composition is polymorphic Form A. In some embodiments of a composition containing polymorphic Form A of the compound of Formula (A-1), at least about 0.1 wt.%, at least about 0.3 wt.%, at least about 0.5 wt.%, at least about 0.8 wt.%, at least about 1.0 wt.%, at least about 5.0 wt.%, at least about 10 wt.%, at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 85 wt.%, at least about 90 wt.%, at least about 95 wt.%, at least about 96 wt.%, at least about 97 wt.%, at least about 98 wt.%, at least about 99 wt.%, or at least 99.9 wt.% of the compound of Formula (A-1) is present in Form A.

[0142] In some embodiments, a composition is provided that contains polymorphic Form C of the compound of Formula (A-1). In some embodiments, the composition is substantially free of polymorphic Form A of the compound of Formula (A-1). In some embodiments, the composition is substantially free of salts of the compound of Formula (A-1).

[0143] In some embodiments of a composition containing Form C of the compound of Formula (A-1), at least about 0.1 wt.%, at least about 0.3 wt.%, at least about 0.5 wt.%, at least about 0.8 wt.%, at least about 1.0 wt.%, at least about 5.0 wt.%, at least about 10 wt.%, at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 85 wt.%, at least about 90 wt.%, at least about 95 wt.%, at least about 96 wt.%, at least about 97 wt.%, at least about 98 wt.%, at least about 99 wt.%, or at least 99.9 wt.% of the total composition is polymorphic Form C. In some embodiments of a composition containing polymorphic Form C of the compound of Formula (A-1), at least about 0.1 wt.%, at least about 0.3 wt.%, at least about 0.5 wt.%, at least about 0.8 wt.%, at least about 1.0 wt.%, at least about 5.0 wt.%, at least about 10 wt.%, at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 85 wt.%, at least about 90 wt.%, at least about 95 wt.%, at least about 96 wt.%, at least about 97 wt.%, at least about 98 wt.%, at least about 99 wt.%, or at least 99.9 wt.% of the compound of Formula (A-1) is present in Form C.

[0144] III-d. Polymorphic Form IV (Monosodium Salt Pattern A) In some embodiments, provided herein is polymorphic Form IV of N-(1″-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indolin]-5″-yl)ethanesulfonamide (hereinafter referred to as polymorphic Form IV). In some embodiments, in polymorphic Form IV, 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. In some embodiments, the salt is an alkali metal salt (e.g., a Na salt or a K salt). In some embodiments, a compound of Formula (A-1) and a metal ion (e.g., a Na salt) are reacted. + ) is about 1:0.8 to about 1:1.5 or about 1:1. In some embodiments, the salt is a monosodium salt. In some embodiments, polymorphic Form IV contains less than 10 wt.% water (such as less than any of about 8%, 6%, 4%, 2%, 1%, or 0.1%). In some embodiments, polymorphic Form IV is the anhydrous salt of N-(1″-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indolin]-5″-yl)ethanesulfonamide.

[0145] In some embodiments, polymorph Form IV has an XRPD pattern substantially as shown in FIG.

[0146] Table IV-1 shows the 2θ angles and relative peak intensities observed for polymorphic Form IV using XRPD. [Table 3-1] [Table 3-2]

[0147] In some embodiments, polymorph Form IV has an XRPD pattern exhibiting 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 2θ angles with maximum intensity in an XRPD pattern substantially as shown in FIG. 14 or substantially as given in Table IV-1. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for polymorph Form IV, may vary by about ±1 degree, ±0.8 degrees, ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees in 2θ.

[0148] In some embodiments, polymorphic Form IV has an XRPD pattern comprising peaks at angles 7.66±0.20, 8.45±0.20, 11.64±0.20, 17.92±0.20, and 22.82±0.20 degrees 2θ. In some embodiments, polymorphic Form IV has an XRPD pattern comprising additional peaks at angles 16.91±0.20 and 17.13±0.20 degrees 2θ. In some embodiments, polymorphic Form IV has an XRPD pattern further comprising additional peaks at angles 13.60±0.20 and 18.34±0.20 degrees 2θ. In some embodiments, polymorphic Form IV has an XRPD pattern comprising peaks at 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±0.20 degrees 2θ angles. It will be understood that additional peaks may be observed in an XRPD pattern beyond those shown in Figure 14 or provided in Table IV-1 due, for example, to the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0149] In some embodiments, polymorph Form IV has a differential scanning calorimetry (DSC) graph substantially as shown in Figure 15. In some embodiments, polymorph Form IV is characterized as having an endothermic onset at about 186°C as determined by DSC. In some embodiments, polymorphic Form IV is characterized as having an endothermic 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. In some embodiments, Form IV is characterized as having an endothermic peak at about 190°C as determined by DSC. In some embodiments, Form IV is characterized as having an endothermic 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. In some embodiments, polymorphic Form IV is characterized as having an endothermic 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. In some embodiments, Form IV is characterized as having an endothermic peak at about 43°C as determined by DSC.In some embodiments, Form IV is characterized as having an endothermic 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.

[0150] In some embodiments, polymorph Form IV has a thermographic analysis (TGA) graph substantially as shown in Figure 16. In some embodiments, polymorph 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.

[0151] In some embodiments of polymorph Form IV, 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) are true: (a) Polymorphic Form IV has an XRPD pattern containing peaks at angles of 7.66±0.20, 8.45±0.20, 11.64±0.20, 17.92±0.20, and 22.82±0.20 degrees 2θ; an XRPD pattern containing additional peaks at angles of 16.91±0.20 and 17.13±0.20 degrees 2θ; an XRPD pattern containing additional peaks at angles of 13.60±0.20 and 18.34±0.20 degrees 2θ; or an XRPD pattern containing peaks at angles of 7.66±0.2 having an XRPD pattern containing peaks at 2θ angles of 0, 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±0.20 degrees; (b) Polymorphic Form IV has an XRPD pattern substantially as shown in Figure 14; (c) Polymorph Form IV has a DSC graph substantially as shown in Figure 15; (d) Polymorphic Form IV is characterized as having an endothermic onset at 186±2°C as determined by DSC; (e) Polymorphic Form IV is characterized as having an endothermic peak at 190±2°C as determined by DSC; (f) Polymorphic Form IV has a TGA graph substantially as shown in Figure 16; and (g) Polymorphic Form IV has a weight loss of approximately 0.7% or 0.7%±0.1% between 25° C. and 170° C. as determined by TGA.

[0152] III-e. Polymorphic Form V (Disodium Salt Pattern A) In some embodiments, provided herein is polymorphic Form V of N-(1″-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indolin]-5″-yl)ethanesulfonamide (hereinafter referred to as polymorphic Form V). In some embodiments, in polymorphic Form V, 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. In some embodiments, the salt is an alkali metal salt (e.g., a Na salt or a K salt). In some embodiments, a compound of Formula (A-1) and a metal ion (e.g., a Na salt) are reacted. + ) is about 1:1.5 to about 1:2.5, about 1:1.5 to about 1:2, or about 1:2. In some embodiments, the salt is a disodium salt. In some embodiments, polymorphic Form V contains less than 10 wt.% water (such as less than any of about 8%, 6%, 4%, 2%, 1%, or 0.1%). In some embodiments, polymorphic Form V is the anhydrous salt of N-(1″-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indolin]-5″-yl)ethanesulfonamide.

[0153] In some embodiments, polymorph Form V has an XRPD pattern substantially as shown in FIG.

[0154] Table V-1 shows the 2θ angles and relative peak intensities observed for polymorphic Form V using XRPD. [Table 4]

[0155] In some embodiments, polymorph Form V has an XRPD pattern exhibiting 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 2θ angles with maximum intensity in an XRPD pattern substantially as shown in FIG. 17 or substantially as given in Table V-1. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for polymorph Form V, may vary by about ±1 degree, ±0.8 degrees, ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees in 2θ.

[0156] In some embodiments, polymorphic form V has an XRPD pattern comprising peaks at angles 6.39±0.20, 6.89±0.20, 16.32±0.20, 17.01±0.20, and 22.82±0.20 degrees 2θ. In some embodiments, polymorphic form V has an XRPD pattern comprising additional peaks at angles 12.50±0.20 and 16.52±0.20 degrees 2θ. In some embodiments, polymorphic form V has an XRPD pattern further comprising additional peaks at angles 13.48±0.20 and 14.34±0.20 degrees 2θ. In some embodiments, polymorphic Form V has an XRPD pattern comprising peaks at 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 2θ. It will be understood that additional peaks may be observed in an XRPD pattern beyond those shown in Figure 17 or provided in Table V-1 due to, for example, the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0157] In some embodiments, polymorphic Form V has a differential scanning calorimetry (DSC) graph substantially as shown in Figure 18. In some embodiments, polymorphic Form V is characterized as having an endothermic onset at about 203°C as determined by DSC. In some embodiments, polymorphic Form V is characterized as having an endothermic 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. In some embodiments, Form V is characterized as having an endothermic peak at about 212°C as determined by DSC. In some embodiments, Form V is characterized as having an endothermic 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. In some embodiments, Form V is characterized as having an endothermic peak at about 60°C as determined by DSC. In some embodiments, Form V is characterized as having an endothermic 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. In some embodiments, Form V is characterized as having an endothermic peak at about 89°C as determined by DSC.In some embodiments, Form V is characterized as having an endothermic 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.

[0158] In some embodiments, polymorphic Form V has a thermographic analysis (TGA) graph substantially as shown in Figure 19. In some embodiments, 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. In some embodiments, 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.

[0159] In some embodiments of polymorphic Form V, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all of the following (a)-(i) are true: (a) Polymorphic Form V has an XRPD pattern containing peaks at 6.39±0.20, 6.89±0.20, 16.32±0.20, 17.01±0.20, and 22.82±0.20 degrees 2θ; an XRPD pattern containing additional peaks at 12.50±0.20 and 16.52±0.20 degrees 2θ; and an XRPD pattern containing additional peaks at 13.48±0.20 and 14.34±0.20 degrees 2θ. pattern; or having an XRPD pattern containing peaks at 2θ angles 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; (b) Polymorph Form V has an XRPD pattern substantially as shown in Figure 17; (c) Polymorph Form V has a DSC graph substantially as shown in Figure 18; (d) Polymorphic Form V is characterized as having an endothermic onset at 203±2°C as determined by DSC; (e) Polymorphic Form V is characterized as having an endothermic peak at 212±2°C as determined by DSC; (f) Polymorphic Form V is characterized as having an endothermic peak at 60±2°C as determined by DSC; (g) Polymorph Form V has a TGA graph substantially as shown in Figure 19; (h) 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 approximately 2.1% or 2.1%±0.5% between 48°C and 100°C as determined by TGA.

[0160] III-f. Polymorphic Form VI (Monopotassium Salt Pattern A) In some embodiments, provided herein is polymorphic Form VI of N''1''-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-',1'-cyclohexa'-4''3''-indolin''5''-yl)ethanesulfonamide (hereinafter referred to as polymorphic Form VI). In some embodiments, in polymorphic Form VI, N''1''-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-',1'-cyclohexa'-4''3''-indolin''5''-yl)ethanesulfonamide is in the form of a salt. In some embodiments, the salt is an alkali metal salt (e.g., a Na salt or a K salt). In some embodiments, a compound of Formula (A-1) and a metal ion (e.g., a K salt) are reacted. + ) is about 1:0.8 to about 1:1.5, or about 1:1.2, or about 1:1. In some embodiments, the salt is a monopotassium salt. In some embodiments, polymorphic Form VI contains less than 10 wt.% solvent (such as less than any of about 8%, 6%, 4%, 2%, 1%, or 0.1%). In some embodiments, polymorphic Form VI is the anhydrous salt of N-(1″-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indolin]-5″-yl)ethanesulfonamide.

[0161] In some embodiments, polymorph Form VI has an XRPD pattern substantially as shown in FIG.

[0162] Table VI-1 shows the 2θ angles and relative peak intensities observed for polymorphic Form VI using XRPD. [Table 5]

[0163] In some embodiments, polymorph Form VI has an XRPD pattern exhibiting 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 2θ angles with maximum intensity in an XRPD pattern substantially as shown in FIG. 20 or substantially as given in Table VI-1. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for polymorph Form VI, may vary by about ±1 degree, about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees in 2θ.

[0164] In some embodiments, polymorphic Form VI has an XRPD pattern comprising peaks at angles 13.48±0.20, 16.62±0.20, and 16.62±0.20 degrees 2θ. In some embodiments, polymorphic Form VI has an XRPD pattern comprising additional peaks at angles 12.25±0.20 and 19.69±0.20 degrees 2θ. In some embodiments, polymorphic Form VI has an XRPD pattern further comprising additional peaks at angles 11.21±0.20 and 24.83±0.20 degrees 2θ. In some embodiments, polymorphic Form VI has an XRPD pattern comprising peaks at 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 2θ. It is understood that additional peaks may be observed in an XRPD pattern beyond those shown in Figure 20 or provided in Table VI-1 due to, for example, the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0165] In some embodiments, polymorphic Form VI has a differential scanning calorimetry (DSC) graph substantially as shown in Figure 21. In some embodiments, Form VI is characterized as having an endothermic peak at about 39°C as determined by DSC. In some embodiments, Form VI is characterized as having an endothermic 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. In some embodiments, Form VI is characterized as having an endothermic peak at about 194°C as determined by DSC. In some embodiments, Form VI is characterized as having an endothermic 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.

[0166] In some embodiments, polymorphic Form VI has a thermographic analysis (TGA) graph substantially as shown in Figure 22. In some embodiments, 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. In some embodiments, polymorphic Form VI exhibits a substantially continuous weight loss between 25°C and 300°C as determined by TGA.

[0167] In some embodiments of 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) are true: (a) Polymorphic Form VI has an XRPD pattern containing peaks at 13.48±0.20, 16.62±0.20, and 16.62±0.20 degrees 2θ; an XRPD pattern containing additional peaks at 12.25±0.20 and 19.69±0.20 degrees 2θ; an XRPD pattern containing additional peaks at 11.21±0.20 and 24.83±0.20 degrees 2θ; or an XRPD pattern containing peaks at 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 2θ; (b) Polymorphic Form VI has an XRPD pattern substantially as shown in Figure 20; (c) Polymorph Form VI has a DSC graph substantially as shown in Figure 21; (d) Polymorphic Form VI is characterized as having an endothermic peak at 39±5°C as determined by DSC; (e) Polymorphic Form VI is characterized as having an endothermic peak at 156±5°C as determined by DSC; (f) Polymorphic Form VI has a TGA graph substantially as shown in Figure 22; and (g) Polymorphic Form VI has a weight loss of approximately 3.2% or 3.2%±0.1% from 25° C. to 100° C. as determined by TGA.

[0168] III-g. Polymorphic Form VII (Dipotassium Salt Pattern A) In some embodiments, provided herein is polymorphic Form VII of N-(1"-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indolin]-5"-yl)ethanesulfonamide (hereinafter referred to as polymorphic Form VII). In some embodiments, in polymorphic Form VII, 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. In some embodiments, the salt is an alkali metal salt (e.g., a Na salt or a K salt). In some embodiments, a compound of Formula (A-1) and a metal ion (e.g., a K salt) are reacted. + ) is about 1:2 to about 1:2.5 or about 1:2.25. In some embodiments, the salt is a dipotassium salt. In some embodiments, polymorph Form VII comprises a molar ratio of about 0.5 equivalents to about 1.5 equivalents (e.g., about 1 equivalent) of ethanol.

[0169] In some embodiments, polymorph Form VII has an XRPD pattern substantially as shown in FIG.

[0170] Table VII-1 shows the 2θ angles and relative peak intensities observed for polymorphic Form VII using XRPD. [Table 6]

[0171] In some embodiments, polymorphic Form VII has an XRPD pattern exhibiting 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 2θ angles with maximum intensity in an XRPD pattern substantially as shown in FIG. 23 or substantially as given in Table VII-1. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for polymorphic Form VII, may vary by about ±1.0, ±0.6, ±0.4, ±0.2, or ±0.1 degrees 2θ.

[0172] In some embodiments, polymorphic Form VII has an XRPD pattern comprising peaks at angles 5.84±0.50, 5.91±0.50, 9.21±0.50, and 18.56±0.50 degrees 2θ. In some embodiments, polymorphic Form VII has an XRPD pattern comprising additional peaks at angles 15.56±0.50 and 19.02±0.50 degrees 2θ. In some embodiments, polymorphic Form VII has an XRPD pattern further comprising additional peaks at angles 13.58±0.50 and 25.27±0.50 degrees 2θ. In some embodiments, polymorphic Form VII has an XRPD pattern comprising peaks at 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 2θ. It will be understood that additional peaks may be observed in an XRPD pattern beyond those shown in Figure 23 or provided in Table VII-1 due to, for example, the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0173] In some embodiments, polymorphic Form VII has a differential scanning calorimetry (DSC) graph substantially as shown in Figure 24. In some embodiments, Form VII is characterized as having an endothermic peak at about 70°C as determined by DSC. In some embodiments, Form VII is characterized as having an endothermic 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. In some embodiments, polymorphic Form VII is characterized as having an endothermic onset at about 122°C as determined by DSC. In some embodiments, polymorphic Form VII is characterized as having an endothermic 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. In some embodiments, Form VII is characterized as having an endothermic peak at about 132°C as determined by DSC. In some embodiments, Form VII is characterized as having an endothermic 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.In some embodiments, polymorphic Form VII is characterized as having an endothermic onset at about 151° C., as determined by DSC. In some embodiments, polymorphic Form VII is characterized as having an endothermic 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.

[0174] In some embodiments, polymorphic Form VII has a thermographic analysis (TGA) graph substantially as shown in Figure 25. In some embodiments, polymorphic Form VII exhibits a substantially continuous weight loss between 25°C and 300°C as determined by TGA.

[0175] In some embodiments of polymorphic Form VII, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all of the following (a)-(h) are true: (a) Polymorphic Form VII has an XRPD pattern containing peaks at 5.84±0.50, 5.91±0.50, 9.21±0.50, and 18.56±0.50 degrees 2θ; an XRPD pattern containing additional peaks at 15.56±0.50 and 19.02±0.50 degrees 2θ; and an XRPD pattern containing additional peaks at 13.58±0.50 and 25.27±0.50 degrees 2θ. or having an XRPD pattern containing peaks at 2θ angles 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; (b) Polymorphic Form VII has an XRPD pattern substantially as shown in Figure 23; (c) Polymorph Form VII has a DSC graph substantially as shown in Figure 24; (d) Polymorphic Form VII is characterized as having an endothermic peak at 70±10°C as determined by DSC; (e) Polymorphic Form VII is characterized as having an endothermic onset at 122±2°C as determined by DSC; (f) Polymorphic Form VII is characterized as having an endothermic onset at 132±2°C as determined by DSC; (g) Polymorphic Form VII has a TGA graph substantially as shown in Figure 25; and (h) Polymorph Form VII has a substantially continuous weight loss between 25°C and 300°C as determined by TGA.

[0176] III-h. Polymorphic Form VIII (Disodium Salt Pattern B) In some embodiments, provided herein is polymorphic Form VIII of N-(1″-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indolin]-5″-yl)ethanesulfonamide (hereinafter referred to as Polymorphic Form VIII). In some embodiments, in Polymorphic Form VIII, 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. In some embodiments, the salt is an alkali metal salt (e.g., a Na salt or a K salt). In some embodiments, a compound of Formula (A-1) and a metal ion (e.g., a Na salt) are reacted. + ) is about 1:2 to about 1:2.5 or about 1:2.3. In some embodiments, the salt is a disodium salt. In some embodiments, polymorph Form VIII comprises a molar ratio of about 0.5 equivalents to about 1.5 equivalents (e.g., about 1 equivalent) of ethanol.

[0177] In some embodiments, polymorph Form VIII has an XRPD pattern substantially as shown in FIG.

[0178] Table VIII-1 shows the 2θ angles and relative peak intensities observed for polymorphic Form VIII using XRPD. [Table 7]

[0179] In some embodiments, polymorph Form VIII has an XRPD pattern exhibiting 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 2θ angles with maximum intensity in an XRPD pattern substantially as shown in FIG. 26 or substantially as given in Table VIII-1. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for polymorph Form VIII, may vary by about ±1 degree, ±0.8 degrees, ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees in 2θ.

[0180] In some embodiments, polymorphic Form VIII has an XRPD pattern comprising peaks at angles 5.26±0.50, 8.78±0.50, 16.75±0.50, and 17.72±0.50 degrees 2θ. In some embodiments, polymorphic Form VIII has an XRPD pattern comprising additional peaks at angles 9.28±0.50 and 10.47±0.50 degrees 2θ. In some embodiments, polymorphic Form VIII has an XRPD pattern further comprising additional peaks at angles 8.37±0.50 and 21.32±0.50 degrees 2θ. In some embodiments, polymorphic Form VIII has an XRPD pattern comprising peaks at 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 2θ. It is understood that additional peaks may be observed in an XRPD pattern beyond those shown in Figure 26 or provided in Table VIII-1 due to, for example, the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0181] In some embodiments, polymorph Form VIII has a differential scanning calorimetry (DSC) graph substantially as shown in FIG.

[0182] In some embodiments, polymorphic Form VIII has a thermographic analysis (TGA) graph substantially as shown in Figure 28. In some embodiments, 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 a substantially continuous weight loss between 25°C and 300°C as determined by TGA.

[0183] In some embodiments of polymorph Form VIII, at least one, at least two, at least three, at least four, or all of the following (a)-(e) are true: (a) Polymorphic Form VIII has an XRPD pattern containing peaks at angles of 5.26±0.50, 8.80±0.50, 16.75±0.50, and 17.72±0.50 degrees 2θ; an XRPD pattern containing additional peaks at angles of 9.28±0.50 and 10.47±0.50 degrees 2θ; and an XRPD pattern containing additional peaks at angles of 8.37±0.50 and 21.32±0.50 degrees 2θ. or having an XRPD pattern containing peaks at 2θ angles 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; (b) Polymorphic Form VIII has an XRPD pattern substantially as shown in Figure 26; (c) Polymorph Form VIII has a DSC graph substantially as shown in Figure 27; (d) Polymorphic Form VIII has a TGA graph substantially as shown in Figure 28; and (e) Polymorphic Form VIII has a weight loss of 5.4%±0.1% from 25° C. to 140° C. as determined by TGA.

[0184] III-i. Polymorphic Form IX (Dipotassium Salt Pattern B) In some embodiments, provided herein is polymorphic Form IX of N-(1"-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indolin]-5"-yl)ethanesulfonamide (hereinafter referred to as polymorphic Form IX). In some embodiments, in polymorphic Form IX, 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. In some embodiments, the salt is an alkali metal salt (e.g., a Na salt or a K salt). In some embodiments, a compound of Formula (A-1) and a metal ion (e.g., a K salt) are reacted. + ) is about 1:2 to about 1:3 or about 1:2.5. In some embodiments, the salt is a dipotassium salt. In some embodiments, polymorph Form IX comprises a molar ratio of about 0.01 equivalents to about 0.1 equivalents (e.g., about 0.06 equivalents) of ACN. In some embodiments, polymorph Form IX comprises a molar ratio of about 1.5 equivalents to about 3 equivalents (e.g., about 2.2 equivalents) of water.

[0185] In some embodiments, polymorph Form IX has an XRPD pattern substantially as shown in FIG.

[0186] Table IX-1 provides examples of 2θ angles and relative peak intensities observed for polymorphic Form IX using XRPD. [Table 8-1] [Table 8-2] [Table 8-3]

[0187] In some embodiments, polymorph Form IX has an XRPD pattern exhibiting 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 2θ angles with maximum intensity in an XRPD pattern substantially as shown in FIG. 29 or substantially as given in Table IX-1. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for polymorph Form VIII, may vary by about ±1 degree, ±0.8 degrees, ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees in 2θ.

[0188] In some embodiments, polymorphic Form IX has an XRPD pattern comprising peaks at angles 6.66±0.20, 17.43±0.20, 19.31±0.20, and 23.72±0.20 degrees 2θ. In some embodiments, polymorphic Form IX has an XRPD pattern comprising additional peaks at angles 13.12±0.20 and 19.99±0.20 degrees 2θ. In some embodiments, polymorphic Form IX has an XRPD pattern further comprising additional peaks at angles 18.82±0.20 and 22.76±0.20 degrees 2θ. In some embodiments, polymorphic Form IX has an XRPD pattern comprising peaks at 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 2θ. It is understood that additional peaks may be observed in an XRPD pattern beyond those shown in Figure 29 or provided in Table IX-1 due to, for example, the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0189] In some embodiments, polymorph Form IX has a differential scanning calorimetry (DSC) graph substantially as shown in Figure 30. In some embodiments, Form VII is characterized as having an endothermic onset at about 31°C as determined by DSC. In some embodiments, Form IX is characterized as having an endothermic 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. In some embodiments, polymorphic Form IX is characterized as having an endothermic peak at about 83°C as determined by DSC. In some embodiments, polymorphic Form VII is characterized as having an endothermic 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. In some embodiments, Form IX is characterized as having an endothermic peak at about 134°C as determined by DSC. In some embodiments, Form IX is characterized as having an endothermic 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.

[0190] In some embodiments, polymorphic Form IX has a thermographic analysis (TGA) graph substantially as shown in Figure 31. In some embodiments, 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. In some embodiments, polymorph 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. In some embodiments, polymorph 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, polymorph Form IX exhibits a substantially continuous weight loss between 25° C. and 300° C. as determined by TGA.

[0191] In some embodiments of polymorphic Form IX, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all of the following (a)-(k) are true: (a) Polymorphic Form IX has an XRPD pattern containing peaks at 6.66±0.20, 17.43±0.20, 19.31±0.20, and 23.72±0.20 degrees 2θ; an XRPD pattern containing additional peaks at 13.12±0.20 and 19.99±0.20 degrees 2θ; and an XRPD pattern containing additional peaks at 18.82±0.20 and 22.76±0.20 degrees 2θ. D pattern; or having an XRPD pattern containing peaks at 2θ angles 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; (b) Polymorph Form IX has an XRPD pattern substantially as shown in Figure 29; (c) Polymorph Form IX has a DSC graph substantially as shown in Figure 30; (d) Polymorphic Form IX is characterized as having an endothermic onset at 31±10°C as determined by DSC; (e) Polymorphic Form IX is characterized as having an endothermic peak at 83±2°C as determined by DSC; (f) Polymorphic Form IX is characterized as having an endothermic peak at 134±2°C as determined by DSC; (g) Polymorph Form IX has a TGA graph substantially as shown in Figure 31; and (h) 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 has a weight loss of approximately 2.7% or 2.7%±0.1% between 40°C and 75°C as determined by TGA; (j) polymorphic Form IX has a weight loss of about 3.1% or 3.1% ± 0.1% between 75°C and 170°C as determined by TGA; (k) Polymorph Form IX exhibits a substantially continuous weight loss between 25°C and 300°C as determined by TGA.

[0192] In some embodiments, polymorph Form IX has an XRPD pattern substantially as shown in FIG.

[0193] Table IX-2 provides examples of 2θ angles and relative peak intensities observed for polymorphic Form IX using XRPD. [Table 9-1] [Table 9-2] [Table 9-3]

[0194] In some embodiments, polymorph Form IX has an XRPD pattern exhibiting 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 2θ angles with maximum intensity in an XRPD pattern substantially as shown in Figure 45 or substantially as given in Table IX-2. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for polymorph Form IX, may vary by about ±1.0 degree, ±0.6 degree, ±0.4 degree, ±0.2 degree, or ±0.1 degree in 2θ.

[0195] In some embodiments, polymorphic Form IX has an XRPD pattern comprising peaks at angles 6.65±0.20, 17.42±0.20, 19.30±0.20, and 23.75±0.20 degrees 2θ. In some embodiments, polymorphic Form IX has an XRPD pattern comprising additional peaks at angles 20.00±0.20 and 22.78±0.20 degrees 2θ. In some embodiments, polymorphic Form IX has an XRPD pattern further comprising additional peaks at angles 13.13±0.20 and 18.82±0.20 degrees 2θ. In some embodiments, polymorphic Form IX has an XRPD pattern comprising peaks at 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 2θ. It is understood that additional peaks may be observed in an XRPD pattern beyond those shown in Figure 45 or provided in Table IX-2 due to, for example, the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0196] In some embodiments, polymorph Form IX has a differential scanning calorimetry (DSC) graph substantially as shown in Figure 46. In some embodiments, Form VII is characterized as having an endothermic peak at about 86°C as determined by DSC. In some embodiments, Form IX is characterized as having an endothermic 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. In some embodiments, polymorphic Form IX is characterized as having an endothermic peak at about 140°C as determined by DSC. In some embodiments, polymorphic Form VII is characterized as having an endothermic 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.

[0197] In some embodiments, polymorph Form IX has a thermographic analysis (TGA) graph substantially as shown in Figure 47. In some embodiments, polymorph 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. In some embodiments, polymorph 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.

[0198] In some embodiments, polymorph Form IX has a dynamic vapor sorption / desorption (DVS) graph substantially as shown in Figure 48. In some embodiments, polymorph Form IX exhibits a weight gain from 1% relative humidity (RH) to 95% RH 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%). In some embodiments, polymorph 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.

[0199] In some embodiments of polymorphic Form IX, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all of the following (a)-(h) are true: (a) Polymorphic Form IX has an XRPD pattern containing peaks at 6.65±0.20, 17.42±0.20, 19.30±0.20, and 23.75±0.20 degrees 2θ; an XRPD pattern containing additional peaks at 20.00±0.20 and 22.78±0.20 degrees 2θ; and an XRPD pattern containing additional peaks at 13.13±0.20 and 18.82±0.20 degrees 2θ; or having an XRPD pattern containing peaks at 2θ angles 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, 23.75±0.20, 24.35±0.20, and 28.37±0.20 degrees; (b) Polymorph Form IX has an XRPD pattern substantially as shown in Figure 45; (c) Polymorph Form IX has a DSC graph substantially as shown in Figure 46; (d) Polymorphic Form IX is characterized as having an endothermic peak at 86±10°C as determined by DSC; (e) Polymorphic Form IX is characterized as having an endothermic peak at 140±2°C as determined by DSC; (f) Polymorph Form IX has a TGA graph substantially as shown in Figure 47; and (g) 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; (h) Polymorph Form IX has a weight loss of approximately 6.0% or 6.0%±0.1% between 42° C. and 94° C. as determined by TGA. (i) Polymorph Form IX has a DVS graph substantially as shown in Figure 48; (j) polymorphic Form IX has a weight gain of about 62% or 62%±5% from 1% RH to 95% RH as determined by DVS; and (h) Polymorph Form IX has a weight loss of about 70% or 70%±5% from 95% RH to 1% RH as determined by DVS.

[0200] III-j. Polymorphic Form X (Disodium Salt Pattern C) In some embodiments, provided herein is polymorphic Form X of N-(1″-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indolin]-5″-yl)ethanesulfonamide (hereinafter referred to as polymorphic Form X). In some embodiments, in polymorphic Form X, 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. In some embodiments, the salt is an alkali metal salt (e.g., a Na salt or a K salt). In some embodiments, a compound of Formula (A-1) and a metal ion (e.g., a K salt) are reacted. + ) is about 1:2 to about 1:3 or about 1:2.4. In some embodiments, the salt is a disodium salt. In some embodiments, polymorph Form IX contains about 1 to about 3 equivalents (e.g., about 1.9 equivalents) of water by molar ratio. In some embodiments, polymorph Form X contains 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) of water.

[0201] In some embodiments, polymorphic Form X has an XRPD pattern substantially as shown in FIG.

[0202] It will be understood that additional peaks may be observed in an XRPD pattern beyond those shown in Figure 32 or provided in Table X-1 due, for example, to the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample. [Table 10-1] [Table 10-2]

[0203] In some embodiments, polymorphic form X has a differential scanning calorimetry (DSC) graph substantially as shown in Figure 33. In some embodiments, polymorphic form X is characterized as having an endothermic peak at about 52°C, as determined by DSC. In some embodiments, polymorphic form X is characterized as having an endothermic 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. In some embodiments, form X is characterized as having an endothermic peak at about 84° C., as determined by DSC. In some embodiments, form X is characterized as having an endothermic 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. In some embodiments, form X is characterized as having an endothermic peak at about 104° C., as determined by DSC. In some embodiments, Form X is characterized as having an endothermic 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. In some embodiments, Form X is characterized as having an endothermic peak at about 128°C as determined by DSC.In some embodiments, Form X is characterized as having an endothermic 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.

[0204] In some embodiments, polymorphic Form X has a thermographic analysis (TGA) graph substantially as shown in Figure 34. In some embodiments, 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.

[0205] In some embodiments of polymorphic form X, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all of the following (a)-(i) are true: (a) Polymorphic Form X has an XRPD pattern containing peaks at 6.03±0.20, 7.66±0.20, 12.04±0.20, and 18.73±0.20 degrees 2θ; an XRPD pattern containing additional peaks at 12.93±0.20 and 18.97±0.20 degrees 2θ; and an XRPD pattern containing additional peaks at 19.91±0.20 and 24.62±0.20 degrees 2θ. pattern; or having an XRPD pattern containing peaks at 2θ angles 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, 30.35±0.20, and 33.67±0.20 degrees; (b) Polymorphic Form X has an XRPD pattern substantially as shown in Figure 32; (c) Polymorphic Form X has a DSC graph substantially as shown in Figure 33; (d) Polymorphic Form X is characterized as having an endothermic peak at 52±2°C as determined by DSC; (e) Polymorphic Form X is characterized as having an endothermic peak at 84±2°C as determined by DSC; (f) Polymorphic Form X is characterized as having an endothermic peak at 104±2°C as determined by DSC; (g) Polymorphic Form X is characterized as having an endothermic peak at 128±2°C as determined by DSC; (h) Polymorphic Form X has a TGA graph substantially as shown in Figure 34; (i) Polymorphic Form X has a weight loss of approximately 11.9% between 30°C and 110°C; and 11.9% ± 3.0% as determined by TGA.

[0206] In some embodiments, polymorphic Form X has an XRPD pattern substantially as shown in FIG.

[0207] Table X-2 shows the 2θ angles and relative peak intensities observed for polymorphic Form XIII using XRPD. [Table 11-1] [Table 11-2] [Table 11-3]

[0208] In some embodiments, polymorph Form X has an XRPD pattern exhibiting 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 2θ angles with maximum intensity in an XRPD pattern substantially as shown in Figure 41 or substantially as given in Table X-2. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for polymorph Form X, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees in 2θ.

[0209] In some embodiments, polymorphic form X has an XRPD pattern comprising peaks at angles 6.07±0.20, 6.84±0.20, 12.07±0.20, 18.75±0.20, and 19.96±0.20 degrees 2θ. In some embodiments, polymorphic form X has an XRPD pattern comprising additional peaks at angles 18.10±0.20 and 20.47±0.20 degrees 2θ. In some embodiments, polymorphic form X has an XRPD pattern further comprising additional peaks at angles 7.70±0.20 and 13.63±0.20 degrees 2θ. In some embodiments, polymorphic Form X has an XRPD pattern comprising peaks at 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 2θ. It will be understood that additional peaks may be observed in an XRPD pattern beyond those shown in Figure 41 or provided in Table X-2 due to, for example, the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0210] In some embodiments, polymorphic form X has a differential scanning calorimetry (DSC) graph substantially as shown in Figure 42. In some embodiments, polymorphic form XIII is characterized as having an endothermic peak at about 73°C, as determined by DSC. In some embodiments, polymorphic form XIII is characterized as having an endothermic 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. In some embodiments, form X is characterized as having an endothermic peak at about 99° C., as determined by DSC. In some embodiments, form X is characterized as having an endothermic 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. In some embodiments, form X is characterized as having an endothermic peak at about 120° C., as determined by DSC. In some embodiments, Form X is characterized as having an endothermic 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.

[0211] In some embodiments, polymorphic form X has a thermographic analysis (TGA) graph substantially as shown in Figure 43. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0212] In some embodiments, polymorph Form X has a dynamic vapor sorption / desorption (DVS) graph substantially as shown in Figure 44. In some embodiments, polymorph Form X exhibits a weight gain from 1% relative humidity (RH) to 95% RH 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%). In some embodiments, polymorph 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.

[0213] In some embodiments of polymorphic form X, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all of the following (a)-(h) are true: (a) Polymorphic Form X has an XRPD pattern containing peaks at 6.07±0.20, 6.84±0.20, 12.07±0.20, 18.75±0.20, and 19.96±0.20 degrees 2θ; an XRPD pattern containing additional peaks at 18.10±0.20 and 20.47±0.20 degrees 2θ; and an XRPD pattern containing additional peaks at 7.70±0.20 and 13.63±0.20 degrees 2θ. or having an XRPD pattern including peaks at 2θ angles 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; (b) Polymorphic Form X has an XRPD pattern substantially as shown in Figure 41; (c) Polymorphic Form X has a DSC graph substantially as shown in Figure 42; (d) Polymorphic Form X is characterized as having an endothermic peak at 73±2°C as determined by DSC; (e) Polymorphic Form X is characterized as having an endothermic peak at 99±2°C as determined by DSC; (f) Polymorphic Form X is characterized as having an endothermic peak at 120±2°C as determined by DSC; (g) Polymorph Form X has a TGA graph substantially as shown in Figure 43; (h) 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; (i) Polymorphic Form X has a weight loss of approximately 4.1% or 4.1% ± 0.5% between 48°C and 81°C as determined by TGA; (j) 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; (k) Polymorphic Form X has a DVS graph substantially as shown in Figure 44; (l) Polymorphic Form X has a weight gain of approximately 60% or 60% ± 5% from 1% RH to 95% RH as determined by DVS; (m) Polymorph Form X has a weight loss of about 58% or 58%±5% from 95% RH to 1% RH as determined by DVS.

[0214] III-k. Polymorphic Form XI (Disodium Salt Pattern D) In some embodiments, provided herein is polymorphic Form XI of N-(1"-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indolin]-5"-yl)ethanesulfonamide (hereinafter referred to as polymorphic Form XI). In some embodiments, in polymorphic Form XI, 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. In some embodiments, the salt is an alkali metal salt (e.g., a Na salt or a K salt). In some embodiments, a compound of Formula (A-1) and a metal ion (e.g., a Na salt) are reacted. + ) is about 1:2 to about 1:2.7 or about 1:2.4. In some embodiments, the salt is a disodium salt.

[0215] In some embodiments, polymorphic Form XI has an XRPD pattern substantially as shown in FIG.

[0216] Table XI-1 shows the 2θ angles and relative peak intensities observed for polymorphic Form XI using XRPD. [Table 12]

[0217] In some embodiments, polymorphic Form XI has an XRPD pattern exhibiting 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 2θ angles with maximum intensity in an XRPD pattern substantially as shown in Figure 35 or substantially as given in Table XI-1. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for polymorphic Form XI, may vary by about ±1.0, ±0.6, ±0.4, ±0.2, or ±0.1 degrees 2θ.

[0218] In some embodiments, polymorphic form XI has an XRPD pattern comprising peaks at angles 6.93±0.50, 20.10±0.50, 32.35±0.50, and 37.94±0.50 degrees 2θ. In some embodiments, polymorphic form XI has an XRPD pattern comprising additional peaks at angles 13.86±0.50 and 17.26±0.50 degrees 2θ. In some embodiments, polymorphic form XI has an XRPD pattern further comprising additional peaks at angles 20.80±0.50 and 32.53±0.50 degrees 2θ. In some embodiments, polymorphic Form XI has an XRPD pattern comprising peaks at 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 2θ. It is understood that additional peaks may be observed in an XRPD pattern beyond those shown in Figure 35 or provided in Table XI-1 due to, for example, the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0219] In some embodiments, polymorphic form XI has a differential scanning calorimetry (DSC) graph substantially as shown in Figure 36. In some embodiments, polymorphic form XI is characterized as having an endothermic peak at about 35°C, as determined by DSC. In some embodiments, polymorphic form XI is characterized as having an endothermic 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. In some embodiments, Form XI is characterized as having an endothermic peak at about 77°C as determined by DSC. In some embodiments, Form XI is characterized as having an endothermic 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. In some embodiments, Form XI is characterized as having an endothermic peak at about 128°C as determined by DSC. In some embodiments, Form XI is characterized as having an endothermic 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. In some embodiments, Form XI is characterized as having an endothermic peak at about 151°C as determined by DSC.In some embodiments, Form XI is characterized as having an endothermic 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.

[0220] In some embodiments, polymorphic Form XI has a thermographic analysis (TGA) graph substantially as shown in Figure 37. In some embodiments, polymorphic Form XI exhibits a weight loss between 25°C and 64°C 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%) as determined by TGA. In some embodiments, 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. In some embodiments, 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 a substantially continuous weight loss between 25° C. and 300° C. as determined by TGA.

[0221] In some embodiments of polymorphic Form XI, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or all of the following (a)-(i) are true: (a) Polymorphic Form XI has an XRPD pattern containing peaks at 6.93±0.50, 20.10±0.50, 32.35±0.50, and 37.94±0.50 degrees 2θ; an XRPD pattern containing additional peaks at 13.86±0.50 and 17.26±0.50 degrees 2θ; and an XRPD pattern containing additional peaks at 20.80±0.50 and 32.53±0.50 degrees 2θ; or having an XRPD pattern containing peaks at 2θ angles 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; (b) Polymorphic Form XI has an XRPD pattern substantially as shown in Figure 35; (c) Polymorphic Form XI has a DSC graph substantially as shown in Figure 36; (d) Polymorphic Form XI is characterized as having an endothermic peak at 35±2°C as determined by DSC; (e) Polymorphic Form XI is characterized as having an endothermic peak at 77±2°C as determined by DSC; (f) Polymorphic Form XI is characterized as having an endothermic peak at 128±2°C as determined by DSC; (g) Polymorphic Form XI is characterized as having an endothermic peak at 151±2°C as determined by DSC; (h) Polymorphic Form XI has a TGA graph substantially as shown in Figure 37; and (i) Polymorphic Form XI has a substantially continuous weight loss between 25°C and 300°C as determined by TGA.

[0222] III-l. Polymorphic Form XII (Monosodium Salt Pattern B) In some embodiments, provided herein is polymorphic Form XII of N-(1″-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indolin]-5″-yl)ethanesulfonamide (hereinafter referred to as polymorphic Form XII). In some embodiments, in polymorphic Form XII, 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. In some embodiments, the salt is an alkali metal salt (e.g., a Na salt or a K salt). In some embodiments, a compound of Formula (A-1) and a metal ion (e.g., a Na salt) are reacted. + ) is about 1:0.8 to about 1:1.5 or about 1:1. In some embodiments, the salt is a monosodium salt. In some embodiments, polymorph Form XII comprises a molar ratio of about 0.5 equivalents to about 1.5 equivalents (e.g., about 1 equivalent) of ethanol.

[0223] In some embodiments, polymorph Form XII has an XRPD pattern substantially as shown in FIG.

[0224] Table XII-1 shows the 2θ angles and relative peak intensities observed for polymorphic Form XII using XRPD. [Table 13-1] [Table 13-2]

[0225] In some embodiments, polymorph Form XII has an XRPD pattern exhibiting 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 2θ angles with maximum intensity in an XRPD pattern substantially as shown in Figure 38 or substantially as given in Figure XII-1. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for polymorph Form XII, may vary by about ±1.0, ±0.6, ±0.4, ±0.2, or ±0.1 degrees 2θ.

[0226] In some embodiments, polymorphic Form XII has an XRPD pattern comprising peaks at angles 14.19±0.20, 17.44±0.20, 17.70±0.20, and 18.14±0.20 degrees 2θ. In some embodiments, polymorphic Form XII has an XRPD pattern comprising additional peaks at angles 18.61±0.20 and 27.38±0.20 degrees 2θ. In some embodiments, polymorphic Form XII has an XRPD pattern further comprising additional peaks at angles 16.87±0.20 and 21.64±0.20 degrees 2θ. In some embodiments, polymorphic Form XII has an XRPD pattern comprising peaks at 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 2θ. It is understood that additional peaks may be observed in an XRPD pattern beyond those shown in Figure 38 or provided in Table XII-1 due to, for example, the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0227] In some embodiments, polymorph Form XII has a differential scanning calorimetry (DSC) graph substantially as shown in Figure 39. In some embodiments, polymorph Form XII is characterized as having an endothermic onset at about 135°C as determined by DSC. In some embodiments, polymorph Form XII is characterized as having an endothermic 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. In some embodiments, Form XII is characterized as having an endothermic peak at about 166°C as determined by DSC. In some embodiments, Form XII is characterized as having an endothermic 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. In some embodiments, Form XII is characterized as having an endothermic peak at about 192°C as determined by DSC. In some embodiments, Form XII is characterized as having an endothermic 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.In some embodiments, Form XII is characterized as having an endothermic peak at about 208° C., as determined by DSC. In some embodiments, Form XII is characterized as having an endothermic 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.

[0228] In some embodiments, polymorph Form XII has a thermographic analysis (TGA) graph substantially as shown in Figure 40. In some embodiments, polymorph 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. In some embodiments, polymorph 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.

[0229] In some embodiments of polymorphic Form XII, 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, or all of the following (a)-(j) are true: (a) Polymorphic Form XII has an XRPD pattern containing peaks at 14.19±0.20, 17.44±0.20, 17.70±0.20, and 18.14±0.20 degrees 2θ; an XRPD pattern containing additional peaks at 18.61±0.20 and 27.38±0.20 degrees 2θ; and an XRPD pattern containing additional peaks at 16.87±0.20 and 21.64±0.20 degrees 2θ. or having an XRPD pattern containing peaks at 2θ angles 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; (b) Polymorphic Form XII has an XRPD pattern substantially as shown in Figure 38; (c) Polymorph Form XII has a DSC graph substantially as shown in Figure 39; (d) Polymorphic Form XII is characterized as having an endothermic onset at 135±2°C as determined by DSC; (e) Polymorphic Form XII is characterized as having an endothermic peak at 166±2°C as determined by DSC; (f) Polymorphic Form XII is characterized as having an endothermic peak at 192±2°C as determined by DSC; (g) Polymorphic Form XII is characterized as having an endothermic peak at 208±2°C as determined by DSC; (h) Polymorphic Form XII has a TGA graph substantially as shown in Figure 40; and (i) 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) Polymorph Form XII has a weight loss of 7.3% or 7.3%±0.1% between 80° C. and 190° C. as determined by TGA.

[0230] III-m. Polymorphic Form XIII (Monosodium Salt Pattern C) In some embodiments, provided herein is polymorphic Form XIII of N-(1″-(3-(((tert-butylamino)methyl)sulfonyl)benzoyl)dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-indolin]-5″-yl)ethanesulfonamide (hereinafter referred to as polymorphic Form XIII). In some embodiments, in polymorphic Form XIII, 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. In some embodiments, the salt is an alkali metal salt (e.g., a Na salt or a K salt). In some embodiments, a compound of Formula (A-1) and a metal ion (e.g., a Na salt) are reacted. + ) is about 1:0.8 to about 1:1.5 or about 1:1.

[0231] In some embodiments, polymorph Form XIII has an XRPD pattern substantially as shown in FIG.

[0232] XIII-1 shows the 2θ angles and relative peak intensities observed for polymorphic Form XIII using XRPD. [Table 14-1] [Table 14-2]

[0233] In some embodiments, polymorphic Form XIII has an XRPD pattern exhibiting 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 2θ angles with maximum intensity in an XRPD pattern substantially as shown in Figure 49 or substantially as given in Table XIII-1. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to acquire the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including those for polymorphic Form XIII, may vary by about ±1.0, ±0.6, ±0.4, ±0.2, or ±0.1 degrees 2θ.

[0234] In some embodiments, polymorphic Form XIII has an XRPD pattern comprising peaks at angles 6.85±0.20, 11.74±0.20, 17.14±0.20, and 18.92±0.20 degrees 2θ. In some embodiments, polymorphic Form XIII has an XRPD pattern comprising additional peaks at angles 18.51±0.20 and 20.95±0.20 degrees 2θ. In some embodiments, polymorphic Form XIII has an XRPD pattern further comprising additional peaks at angles 16.64±0.20 and 24.73±0.20 degrees 2θ. In some embodiments, polymorphic Form XIII has an XRPD pattern comprising peaks at 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 2θ. It is understood that additional peaks may be observed in an XRPD pattern beyond those shown in Figure 49 or provided in Table XIII-1 due to, for example, the presence of impurities, solvents, or other polymorphic or amorphous forms present in the test sample.

[0235] In some embodiments, polymorphic Form XIII has a differential scanning calorimetry (DSC) graph substantially as shown in Figure 50. In some embodiments, polymorphic Form XIII is characterized as having an endothermic peak at about 53°C, as determined by DSC. In some embodiments, polymorphic Form XIII is characterized as having an endothermic 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. In some embodiments, Form XIII is characterized as having an endothermic peak at about 98°C as determined by DSC. In some embodiments, Form XIII is characterized as having an endothermic 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. In some embodiments, Form XIII is characterized as having an endothermic peak at about 183°C as determined by DSC. In some embodiments, Form XIII is characterized as having an endothermic 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.

[0236] In some embodiments, polymorphic Form XIII has a thermographic analysis (TGA) graph substantially as shown in Figure 51. In some embodiments, 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. In some embodiments, polymorphic Form XIII exhibits a weight loss of about 8.0% or 8.0%±0.1% (e.g., 8.0%±0.09%, 8.0%±0.07%, 8.0%±0.06%, 8.0%±0.05%, 8.0%±0.04%, 8.0%±0.03%, 8.0%±0.02%, or 8.0%±0.01%) between 120°C and 180°C as determined by TGA. In some embodiments, 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.

[0237] In some embodiments of polymorphic Form XIII, 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, or all of the following (a)-(j) are true: (a) Polymorphic Form XIII has an XRPD pattern containing peaks at 6.85±0.20, 11.74±0.20, 17.14±0.20, and 18.92±0.20 degrees 2θ; an XRPD pattern containing additional peaks at 18.51±0.20 and 20.95±0.20 degrees 2θ; and an XRPD pattern containing additional peaks at 16.64±0.20 and 24.73±0.20 degrees 2θ. RPD pattern; or having an XRPD pattern containing peaks at 2θ angles 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; (b) Polymorphic Form XIII has an XRPD pattern substantially as shown in Figure 49; (c) Polymorph Form XIII has a DSC graph substantially as shown in Figure 50; (d) Polymorphic Form XIII is characterized as having an endothermic peak at 53±2°C as determined by DSC; (e) Polymorphic Form XIII is characterized as having an endothermic peak at 98±2°C as determined by DSC; (f) Polymorphic Form XIII is characterized as having an endothermic peak at 183±2°C as determined by DSC; (g) Polymorphic Form XIII has a TGA graph substantially as shown in Figure 51; and (h) 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.

[0238] Also provided herein are compositions containing a polymorph described herein (such as polymorphic Form A, C, B, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or any mixture thereof). In some embodiments, the composition contains polymorphic Form A. In some embodiments, the composition contains polymorphic Form C. In some embodiments, the composition contains polymorphic Form B.

[0239] In some embodiments, a composition is provided containing polymorphic Form A of the compound of Formula (A-1). In some embodiments, the composition is substantially free of polymorphic Forms C, B, IV, V, VI, VII, VIII, IX, X, XI, XII, and 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).

[0240] In some embodiments of a composition containing Form A of the compound of Formula (A-1), at least about 0.1 wt.%, at least about 0.3 wt.%, at least about 0.5 wt.%, at least about 0.8 wt.%, at least about 1.0 wt.%, at least about 5.0 wt.%, at least about 10 wt.%, at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 85 wt.%, at least about 90 wt.%, at least about 95 wt.%, at least about 96 wt.%, at least about 97 wt.%, at least about 98 wt.%, at least about 99 wt.%, or at least 99.9 wt.% of the total composition is polymorphic Form A. In some embodiments of a composition containing polymorphic Form A of the compound of Formula (A-1), at least about 0.1 wt.%, at least about 0.3 wt.%, at least about 0.5 wt.%, at least about 0.8 wt.%, at least about 1.0 wt.%, at least about 5.0 wt.%, at least about 10 wt.%, at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 85 wt.%, at least about 90 wt.%, at least about 95 wt.%, at least about 96 wt.%, at least about 97 wt.%, at least about 98 wt.%, at least about 99 wt.%, or at least 99.9 wt.% of the compound of Formula (A-1) is present in Form A.

[0241] In some embodiments, a composition is provided containing polymorphic Form C of the compound of Formula (A-1). In some embodiments, the composition is substantially free of polymorphic Forms A, B, IV, V, VI, VII, VIII, IX, X, XI, XII, and 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).

[0242] In some embodiments of a composition containing Form C of the compound of Formula (A-1), at least about 0.1 wt.%, at least about 0.3 wt.%, at least about 0.5 wt.%, at least about 0.8 wt.%, at least about 1.0 wt.%, at least about 5.0 wt.%, at least about 10 wt.%, at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 85 wt.%, at least about 90 wt.%, at least about 95 wt.%, at least about 96 wt.%, at least about 97 wt.%, at least about 98 wt.%, at least about 99 wt.%, or at least 99.9 wt.% of the total composition is polymorphic Form C. In some embodiments of a composition containing polymorphic Form C of the compound of Formula (A-1), at least about 0.1 wt.%, at least about 0.3 wt.%, at least about 0.5 wt.%, at least about 0.8 wt.%, at least about 1.0 wt.%, at least about 5.0 wt.%, at least about 10 wt.%, at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 85 wt.%, at least about 90 wt.%, at least about 95 wt.%, at least about 96 wt.%, at least about 97 wt.%, at least about 98 wt.%, at least about 99 wt.%, or at least 99.9 wt.% of the compound of Formula (A-1) is present in Form C.

[0243] In some embodiments, a composition is provided containing polymorphic Form B of the compound of Formula (A-1). In some embodiments, the composition is substantially free of polymorphic Forms A, II, IV, V, VI, VII, VIII, IX, X, XI, and XII of the compound of Formula (A-1). In some embodiments, the composition is substantially free of salts of the compound of Formula (A-1).

[0244] In some embodiments of a composition containing Form B of the compound of Formula (A-1), at least about 0.1 wt.%, at least about 0.3 wt.%, at least about 0.5 wt.%, at least about 0.8 wt.%, at least about 1.0 wt.%, at least about 5.0 wt.%, at least about 10 wt.%, at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 85 wt.%, at least about 90 wt.%, at least about 95 wt.%, at least about 96 wt.%, at least about 97 wt.%, at least about 98 wt.%, at least about 99 wt.%, or at least 99.9 wt.% of the total composition is polymorphic Form B. In some embodiments of a composition containing polymorphic Form B of the compound of Formula (A-1), at least about 0.1 wt.%, at least about 0.3 wt.%, at least about 0.5 wt.%, at least about 0.8 wt.%, at least about 1.0 wt.%, at least about 5.0 wt.%, at least about 10 wt.%, at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, at least about 70 wt.%, at least about 80 wt.%, at least about 85 wt.%, at least about 90 wt.%, at least about 95 wt.%, at least about 96 wt.%, at least about 97 wt.%, at least about 98 wt.%, at least about 99 wt.%, or at least 99.9 wt.% of the compound of Formula (A-1) is present in Form B.

[0245] III-n. Preparation method - polymorphic form A In some embodiments, a method for preparing polymorph Form A of a compound of Formula (A-1) is provided, the method comprising: (1) combining a compound of Formula (A-1) with a solvent; and (2) evaporating the mixture of (1). In some embodiments, the solvent comprises acetone, 2-MeTHF, TFE, THF, methylcyclohexane, and water. In some embodiments, the solvent comprises acetone. In some embodiments, the solvent comprises 2-MeTHF. In some embodiments, the solvent comprises TFE. In some embodiments, the solvent comprises THF. In some embodiments, the solvent comprises THF and methylcyclohexane. In some embodiments, the solvent comprises acetone and water. In some embodiments, the solvent comprises ethyl acetate. In some embodiments, the solvent is ethyl acetate. In some embodiments, step (2) is rapid evaporation of the mixture of (1). In some embodiments, step (2) is evaporation of the mixture of step (1) while directly exposing the mixture to air. In some embodiments, step (2) is accomplished by drying the mixture under vacuum. In some embodiments, step (2) is allowing the mixture of (1) to evaporate slowly. In some embodiments, step (2) is allowing the mixture of (1) to evaporate at a controlled rate. In some embodiments, step (2) is allowing the mixture of (1) to evaporate at a controlled rate, the rate being controlled by the degree to which the mixture is exposed to air. In some embodiments, step (2) is allowing the mixture of (1) to evaporate at a temperature 10° C. above or below room temperature, 5° C. above or below room temperature, 3° C. above or below room temperature, or about room temperature. In some embodiments, the method further comprises (1′) filtering the mixture of step (1), and step (2) is allowing the filtered mixture of (1′) to evaporate.

[0246] In some embodiments, a method for preparing polymorphic Form A of a compound of Formula (A-1) is provided, the method comprising: (1) combining a compound of Formula (A-1) with a solvent at a first temperature; (2) cooling the mixture of (1) at a second temperature; and (3) maintaining the mixture of (2) at a third temperature. In some embodiments, the solvent comprises an alcohol. In some embodiments, the solvent is ethanol. In some embodiments, the first temperature is 30°C to 70°C, 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 above or below room temperature, 5°C above or below room temperature, 3°C above or below room temperature, or about room temperature. In some embodiments, the third temperature is greater than -50°C, -40°C, -35°C, -30°C, -25°C, -20°C, -15°C, or -10°C. In some embodiments, 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.

[0247] In some embodiments, a method of preparing polymorphic Form A of a compound of Formula (A-1) is provided, the method comprising: (1) mixing a compound of Formula (A-1) with a first solvent and a second solvent at a first temperature; and (2) maintaining the mixture of (1) at a second temperature. In some embodiments, the first solvent and the second solvent are selected from the group consisting of acetone, isobutyl acetate, water, acetonitrile, 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 isopropyl ketone, dipropyl ether, chloroform, and tert-amyl alcohol, provided that the first solvent is different from the second solvent. In some embodiments, the first solvent is DMSO and the second solvent is nitromethane, or vice versa. In some embodiments, the first solvent is dioxane and the second solvent is TAME, or vice versa. In some embodiments, the first solvent is MEK and the second solvent is hexane, or vice versa. In some embodiments, the first solvent is TFE and the second solvent is 1-PrOH, or vice versa. In some embodiments, the first solvent is HFIPA and the second solvent is IPE, or vice versa. In some embodiments, the first solvent is acetonitrile and the second solvent is 1-butanol, or vice versa. In some embodiments, the first solvent is DMF and the second solvent is water, or vice versa. In some embodiments, the first solvent is dioxane and the second solvent is CPME, or vice versa.In some embodiments, the first solvent is NMP and the second solvent is toluene, or vice versa. In some embodiments, the first solvent is THF and the second solvent is IPA, or vice versa. In some embodiments, the first temperature is greater 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 less than 10°C, 5°C, 0°C, -5°C, or -10°C. In some embodiments, the first temperature is between about -40°C and about 10°C, between about -30°C and about 0°C, between about -25°C and about -5°C, or between about -25°C and about -10°C. In some embodiments, the first temperature is between 30°C and 70°C, between 40°C and 60°C, about 50°C, or about 55°C. In some embodiments, the second temperature is greater than -50°C, -40°C, -35°C, -30°C, -25°C, -20°C, -15°C, or -10°C. In some embodiments, the second temperature is less than 10°C, 5°C, 0°C, -5°C, or -10°C. In some embodiments, the second temperature is about -40°C to about 10°C, about -30°C to about 0°C, about -25°C to about -5°C, or about -25°C to about -10°C. In some embodiments, the second temperature is 10°C above or below room temperature, 5°C above or below room temperature, 3°C above or below room temperature, or about room temperature. In some embodiments, the mixture of (1) is maintained at the second temperature for 1 to 5 days, 2 to 4 days, or about 3 days. In some embodiments, the method further comprises evaporating the mixture of (3) and (2). In some embodiments, the mixture of (2) is evaporated in a rapid manner. In some embodiments, step (3) is evaporating the mixture of (2), where the mixture of (2) is completely exposed to air. In some embodiments, step (3) is evaporating the mixture of (2), where the mixture of (2) is completely exposed to air under a N2 purge. In some embodiments, the method further comprises (4) adding a third solvent to the mixture of (2) or the mixture of (3) at a third temperature. In some embodiments, the third solvent is the same as the first solvent. In some embodiments, the third solvent is the same as the second solvent.In some embodiments, the third solvent is different from the first solvent and the second solvent. In some embodiments, the third solvent is toluene. In some embodiments, the third temperature is 10° C. above or below room temperature, 5° C. above or below room temperature, 3° C. above or below room temperature, or about room temperature. In some embodiments, the mixture of (4) is stirred at about room temperature for about 3 hours to about 30 hours, about 5 hours to about 24 hours, or about 5 hours or about 24 hours.

[0248] In some embodiments, a method for preparing polymorphic Form A of a compound of Formula (A-1) is provided, the method comprising: (1) mixing a compound of Formula (A-1) with a first solvent at a first temperature; and (2) adding the mixture of (1) to a second solvent at a second temperature. In some embodiments, 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. In some embodiments, the first solvent is iBuOAc and the second solvent is acetone, or vice versa. In some embodiments, the first solvent is DMA and the second solvent is water, or vice versa. In some embodiments, the first solvent is EGEE and the second solvent is water, or vice versa. In some embodiments, the first solvent is EtOAc and the second solvent is cyclohexane, or vice versa. In some embodiments, the first temperature is 30°C to 70°C, 40°C to 60°C, about 50°C, or about 55°C. In some embodiments, the second temperature is 30°C to 70°C, 40°C to 60°C, about 50°C, or about 55°C. In some embodiments, the first temperature is 10°C above or below room temperature, 5°C above or below room temperature, 3°C above or below room temperature, or about room temperature. In some embodiments, the second temperature is 30°C to 70°C, 40°C to 60°C, about 50°C, or about 55°C. In some embodiments, the second temperature is 30°C to 70°C, 40°C to 60°C, about 50°C, or about 55°C. In some embodiments, the second temperature is 10°C above or below room temperature, 5°C above or below room temperature, 3°C above or below room temperature, or about room temperature. In some embodiments, the method further comprises cooling the mixture of (3)(2) to a third temperature. In some embodiments, the third temperature is 10° C. above or below room temperature, 5° C. above or below room temperature, 3° C. above or below room temperature, or about room temperature. In some embodiments, the third temperature is greater than −5° C., −3° C., −1° C., 0° C., 1° C., or 2° C.In some embodiments, the third temperature is lower than 15°C, 13°C, 10°C, 9°C, or 8°C. In some embodiments, the third temperature is about -5°C to about 15°C, about -3°C to about 13°C, about 0°C to about 10°C, or about 2°C to about 8°C. In some embodiments of step (3), the cooling is rapid cooling, and the mixture of (2) is removed directly from the heat source and maintained at the third temperature. In some embodiments, the method further comprises evaporating the mixture of step (2). In some embodiments, the method further comprises evaporating the mixture of step (3). In some embodiments, the method further comprises evaporating the mixture of step (4).

[0249] III-o. Preparation method - polymorphic form B In some embodiments, a method for preparing polymorphic Form B of a compound of Formula (A-1) is provided, the method comprising suspending polymorphic Form A described herein in a solvent for a period of time and re-isolating the solid in the mixture. In some embodiments, polymorphic Form A is suspended in the solvent for at least 3 days (e.g., at least 4, 5, 6, or 7 days). In some embodiments, polymorphic Form A is suspended in the solvent at about 0°C to about 60°C (e.g., about 5°C to 50°C, 5°C to 25°C, 15°C, 25°C, or 50°C). In some embodiments, the solvent is selected from the group consisting of MeOH, MEK, EA, 2-MeTHF, ACN, water, and any combination thereof. In some embodiments, the solvent is a mixture of ACN and water. In some embodiments, a suspension of polymorphic Form A in a solvent can be seeded with polymorphic Form B. In some embodiments, the suspension of polymorphic Form A in a solvent is slowly cooled (e.g., by natural cooling) to isolate the solid in the mixture. In some embodiments, polymorph Form B can be prepared by crystallization from solution (e.g., direct crystallization). In some embodiments, the solvent comprises a single solvent. In some embodiments, the solvent comprises a mixture of more than one solvent.

[0250] In some embodiments, provided herein are methods for preparing polymorphic Form B of a compound of Formula (A-1), the methods comprising: (i) suspending a compound of Formula (A-1) in a solvent to form a mixture; (ii) heating the mixture of step (i) at an elevated temperature and stirring the mixture for a period of time; and (iii) cooling the mixture of step (ii). In some embodiments, the compound of Formula (A-1) in step (i) is a polymorphic form provided herein. In some embodiments, the compound of Formula (A-1) in step (i) is polymorphic Form A. In some embodiments, the compound of Formula (A-1) in step (i) (e.g., polymorphic Form A) is suspended in a solvent with a base. In some embodiments, the base comprises L-lysine, betaine, or a combination thereof. In some embodiments, the base is L-lysine. In some embodiments, the base is betaine. In some embodiments, 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 volume ratio of acetonitrile to water in the solvent is at least about 1:1 (e.g., 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 volume ratio of acetonitrile to water in the solvent is about 20:1 or less (e.g., about 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, or 10:1 or less). In some embodiments, the volume ratio of acetonitrile to water in the solvent is about 1:1 to about 10:1, or about 5:1 to 15:1. In some embodiments, the volume ratio of acetonitrile to water in the solvent is about 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 molar ratio of base to 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).In some embodiments, the molar ratio of the base to the compound of Formula (A-1) in the mixture of (i) is about 2:1 or less (e.g., about 1.8:1, 1.6:1, 1.4:1, 1.2:1, 1.1:1, or 1:1 or less). In some embodiments, the molar ratio of the base to the compound of Formula (A-1) in the mixture of (i) is about 0.1:1 to about 1.5:1 (e.g., about 0.5:1 to 1.2:1, 0.5:1 to 1.05:1, or about 0.5:1, 0.8:1, or 1.05:1). In some embodiments, the mixture of (i) is heated to an elevated temperature or to a temperature of about 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, or 70°C or higher. In some embodiments, the mixture in (i) is heated to an elevated temperature of about 90° C., 85° C., 80° C., 75° C., 70° C., 65° C., 50° C., 45° C., or 40° C. or less. In some embodiments, the mixture in (i) is heated to an elevated temperature of about 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 in (i) is heated to an elevated temperature of about 50° C. In some embodiments, the mixture in (i) is stirred for about 1 minute, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 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 or more after reaching the elevated temperature. In some embodiments, the mixture in (i) is stirred for about 10 hours, 9 hours, 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 or less after reaching the elevated temperature. In some embodiments, the mixture in (i) is stirred for about 2 hours or more after reaching the elevated temperature. In some embodiments, the mixture in (i) is stirred for about 1 minute, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 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 after reaching the elevated temperature. In some embodiments, the mixture in (i) is stirred for about 2 hours after reaching the elevated temperature.In some embodiments, the mixture of (ii) is cooled to a temperature of 30° C. or less (such as about 25° C., 20° C., 15° C., or 10° C.). In some embodiments, the mixture of (ii) is cooled to a temperature of at least 0° C. (such as at least about 5° C., 10° C., 15° C., 20° C., or 25° C.). In some embodiments, the mixture of (ii) is cooled for a period of at least 1 day (such as at least about 2, 3, 4, 5, 6, or 7 days). In some embodiments, the mixture of (ii) is cooled for a period of 20 days or less (such as about 18, 16, 14, 12, 10, or 7 days or less). In some embodiments, the mixture of (ii) is cooled for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In some embodiments, the method further comprises (iv) filtering the solid from the mixture of (iii). In some embodiments, the method further comprises (v) drying the solid from step (vi) to obtain polymorph Form B.

[0251] In some embodiments, provided herein is a method for preparing polymorphic Form B, the method comprising: (i) suspending a 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 a seed; (v) heating the mixture of (iv); and (vi) cooling the mixture of (v). In some embodiments, the compound of Formula (A-1) in step (i) can be a polymorphic form provided herein. In some embodiments, the compound of Formula (A-1) in step (i) is polymorphic Form A. In some embodiments, 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 volume ratio of acetonitrile to water in the solvent is at least about 1:1 (e.g., 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 volume ratio of acetonitrile to water in the solvent is about 20:1 or less (e.g., about 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, or 10:1 or less). In some embodiments, the volume ratio of acetonitrile to water in the solvent is about 1:1 to about 10:1, or about 5:1 to 15:1. In some embodiments, the volume ratio of acetonitrile to water in the solvent is about 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 in (i) is heated to an elevated temperature of about 30° C. or higher, such as about 30° C., 35° C., 40° C., 45° C., 50° C., 55° C., 60° C., 65° C., or 70° C. In some embodiments, the mixture in (i) is heated to an elevated temperature of about 90° C., 85° C., 80° C., 75° C., 70° C., 65° C., 50° C., 45° C., or 40° C. or lower. In some embodiments, the mixture in (i) is heated to an elevated temperature of about 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 in (i) is heated and stirred for at least about 1 minute (such as about 1, 2, 3, 5, 7, or 10 minutes). In some embodiments, the mixture in (i) is heated and stirred for about 120 minutes or less (such as about 90, 60, 45, 40, 30, 20, or 10 minutes or less). In some embodiments, the mixture in (i) is heated and stirred for about 10 minutes (such as about 10, 15, 20, 25, or 30 minutes). In some embodiments, the mixture in (ii) is cooled to a temperature of 30° C. or less (such as about 30° C., 25° C., 20° C., 15° C., 10° C., or 5° C.). In some embodiments, the mixture in (ii) is cooled to a temperature of at least about 0° C. (such as at least about 5° C., 10° C., 15° C., 20° C., or 25° C.). In some embodiments, the mixture in (ii) is cooled to a temperature of about 5°C, 10°C, 15°C, 20°C, or 25°C. In some embodiments, after seeding with polymorphic Form B, the mixture in (iv) is heated to an elevated temperature of at least about 30°C (such as at least about 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, or 70°C). In some embodiments, the mixture in (iv) is heated to an elevated temperature of about 90°C, 85°C, 80°C, 75°C, 70°C, 65°C, 50°C, 45°C, or up to 40°C. In some embodiments, the mixture in (iv) is heated to an elevated temperature of about 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, or 65°C. In some embodiments, after adding polymorphic form B as a seed, the mixture in (iv) is heated to an elevated temperature for 1 hour or less (e.g., within about any of 40 minutes, 30 minutes, 20 minutes, 10 minutes, or 5 minutes). In some embodiments, after adding polymorphic form B as a seed, the mixture in (iv) is heated to an elevated temperature for a period of at least 1 minute (such as at least about any of 1 minute, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, or 1 hour). In some embodiments, the mixture in (v) is cooled to a temperature of 30° C. or less (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 5°C, 10°C, 15°C, 20°C, or 25°C. In some embodiments, the mixture of (v) is cooled to a temperature of 30°C or less at a cooling rate of about 1°C / hr to 20°C / hr (such as about 1°C / hr to 15°C / hr, 1°C / hr to 10°C / hr, or about 6°C / hr). In some embodiments, the method further comprises filtering the suspension obtained from step (vi). In some embodiments, the method further comprises drying the resulting polymorphic Form B.

[0252] In some embodiments, provided herein are methods for preparing polymorphic form B, the methods comprising: (i) suspending a compound of Formula (A-1) (other than polymorphic form B) in a solvent to form a mixture; and (ii) stirring the mixture of step (i) for a period of time. In some embodiments, the compound of Formula (A-1) in step (i) can be a polymorphic form provided herein (other than polymorphic form B). In some embodiments, the compound of Formula (A-1) in step (i) is polymorphic form A. In some embodiments, the method further comprises (ia) adding seeds of polymorphic form B to the mixture of (i). In some embodiments, the mass ratio of polymorphic form A to polymorphic form B is about 1:1 to about 200:1 (e.g., about any of about 1:1 to 150:1, 50:1 to 150:1, or 100:1). In some embodiments, the purity of polymorphic form A is greater than about 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, or 99.5%. In some embodiments, the purity of polymorphic form A is greater than about 96%. In some embodiments, the purity of polymorphic form A is 97% or greater. In some embodiments, the solvent comprises methanol (MeOH), methyl ethyl ketone (MEK), ethyl acetate (EA), 2-methyltetrahydrofuran (2-Me-THF), acetonitrile (ACN), or any mixture thereof. In some embodiments, the solvent is MeOH, MEK, EA, 2-Me-THF, or ACN. In some embodiments, the solvent is MEK. In some embodiments, the solvent contains about 0% to about 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 contains about 0% to about 0.3% EA. In some embodiments, the solvent does not contain EA. In some embodiments, the solvent is ACN. In some embodiments, the mixture of (i) is stirred at about 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 or higher.In some embodiments, the mixture in (i) is stirred at 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 or less. In some embodiments, the mixture in (i) is stirred at about 50°C or more. In some embodiments, the mixture in (i) is stirred 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 in (i) is stirred at about 50°C. In some embodiments, the mixture in (i) is stirred at a temperature of about 50°C or more. In some embodiments, the mixture of (i) is stirred at a given temperature for about 5, 4, 3, 2 days, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or less than 1 hour. In some embodiments, the mixture of (i) is stirred at a given temperature for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In some embodiments, the mixture (i) is stirred at a given temperature for less than about 25 hours. In some embodiments, the mixture (i) is stirred at a given temperature for about 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. In some embodiments, the mixture (i) is stirred at a given temperature for about 24 hours. In some embodiments, the mixture (i) is stirred at about 40°C to about 60°C for less than about 25 hours. In some embodiments, the mixture (i) is stirred at about 50°C for about 24 hours.In some embodiments, the method further comprises (iii) cooling the mixture of (ii). In some embodiments, the mixture of (ii) is cooled to a temperature of about 20° C. to about 30° C. (e.g., about 25° C.). In some embodiments, the mixture of (ii) is cooled rapidly (e.g., within a time period of less than 10 hours (e.g., less than about any of 7 hours, 5 hours, or 3 hours)). In some embodiments, the method further comprises (iv) adding an anti-solvent to the cooled mixture of (iii). In some embodiments, the anti-solvent comprises n-heptane (HEP). In some embodiments, the solvent is MEK and the anti-solvent is HEP.

[0253] III-p. Preparation method - polymorphic form C In some embodiments, a method for preparing polymorphic Form C of a compound of Formula (A-1) is provided, the method comprising: (1) mixing a compound of Formula (A-1) with a first solvent; (2) adding a second solvent to the mixture of (1) to obtain a solid; (3) washing the solid of (2) with the second solvent; and (4) drying the solid of (3). In some embodiments, the first solvent is DMF. In some embodiments, the second solvent is water. In some embodiments, the first solvent is DMF and the second solvent is water. In some embodiments of (2), the second solvent is added at a temperature 10° C. above or below room temperature, 5° C. above or below room temperature, 3° C. above or below room temperature, or at about room temperature. In some embodiments of (4), the solid of (3) is dried at a temperature 10° C. above or below room temperature, 5° C. above or below room temperature, 3° C. above or below room temperature, or at about room temperature. In some embodiments of (4), the solid of formula (3) is dried under vacuum.

[0254] IV. Salt Form In some aspects, provided herein are pharmaceutically acceptable salts of compounds of Formula (A-1). In some embodiments, pharmaceutically acceptable salts of compounds of Formula (A-1) are formed with inorganic and / or organic bases. In some embodiments, pharmaceutically acceptable salts of compounds of Formula (A-1) are obtained by reacting compounds of Formula (A-1) with a base including NaOH, KOH, Mg(OH), Ca(OH), L-arginine, L-lysine, choline, betaine, diethylamine, or any combination thereof.

[0255] In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (A-1) is obtained by reacting a compound of Formula (A-1) with an inorganic base, including NaOH, KOH, Mg(OH), Ca(OH), or any combination thereof. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (A-1) includes a sodium salt, a potassium salt, a magnesium salt, a calcium salt, a zinc salt, or any combination thereof. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (A-1) is a sodium salt. In some embodiments, a pharmaceutically acceptable salt of a compound of Formula (A-1) is a sodium salt, and the stoichiometry of the compound of Formula (A-1) to the sodium ion is about 1:0.8 to 1:3 (e.g., 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). In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a monosodium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a disodium 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, and the stoichiometry of the compound of Formula (A-1) to the potassium ion is about 1:0.8 to 1:3 (e.g., about 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). In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a monopotassium salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is a dipotassium 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.

[0256] In some embodiments, in conjunction with the above or below embodiments, a pharmaceutically acceptable salt of the compound of Formula (A-1) is obtained by reacting the compound of Formula (A-1) with an organic base comprising L-arginine, L-lysine, choline, betaine, diethylamine, or any combination thereof. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) comprises an L-arginine salt, an L-lysine salt, a choline salt, a betaine salt, a diethylamine salt, or any combination thereof. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is an L-arginine salt. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (A-1) is an 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.

[0257] In some embodiments, 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. In some embodiments, 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.

[0258] V. How to use Treatment method In one aspect, the solid formulation comprising the compound of formula (A) or its pharmaceutically acceptable salt, the polymorphic form of the compound of formula (A-1) or the pharmaceutically acceptable salt form of the compound of formula (A-1) as described herein can be used to inhibit KIF18A.In another aspect, the solid formulation comprising the compound of formula (A) or the polymorphic form of the compound of formula (A-1) as described herein can be used to treat or prevent disease or condition in an individual.

[0259] The inhibitory activity of the compound of formula (A) or a pharmaceutically acceptable salt thereof, a polymorphic form of the compound of formula (A-1), or a solid formulation comprising a pharmaceutically acceptable salt form of the compound of formula (A-1) described herein against KIF18A can 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 DD, Jiang W. (2001) Assays for Kinesin Microtubule-Stimulated ATPase Activity. In: Vernos I. (eds) Kinesin Protocols. Methods in Molecular Biology™, vol 164. Humana Press. https: / / doi.org / 10.1385 / 1-59259-069-1:65).

[0260] In one aspect, provided herein are methods for inhibiting KIF18A, the methods comprising contacting a cell with an effective amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof, a polymorphic form of a compound of Formula (A-1), or a solid formulation comprising a pharmaceutically acceptable salt form of a compound of Formula (A-1), as described herein. In some embodiments, provided herein are methods for inhibiting KIF18A, the methods 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 a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, provided herein are methods for inhibiting KIF18A, the methods comprising contacting a cell with an effective amount of a polymorphic form of a compound of Formula (A-1), as described herein. In some embodiments, provided herein are methods for inhibiting KIF18A, the methods comprising contacting a cell with an effective amount of a pharmaceutically acceptable salt form of a compound of Formula (A-1), as described herein. In one variation of the foregoing embodiment, the cells are contacted in vitro. In another variation of the foregoing embodiment, the cells are contacted in vivo.

[0261] In another aspect, a solid formulation comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a polymorphic form of the compound of formula (A-1), or a pharmaceutically acceptable salt form of the compound of formula (A-1) described herein can be used to treat or prevent a disease or condition in an individual, comprising administering an effective amount of a compound or pharmaceutical composition described herein. When used in a prophylactic manner, a solid formulation comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a polymorphic form of the compound of formula (A-1), or a pharmaceutically acceptable salt form of the compound of formula (A-1) described herein can prevent the onset of a disease or disorder in an individual at risk of developing the disease or disorder, or reduce the severity of the disease or disorder that may develop.

[0262] In some embodiments, provided herein are methods of treating or preventing a disease or condition in an individual, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula (A) or a pharmaceutically acceptable salt thereof, a polymorphic form of the compound of Formula (A-1), or a solid formulation comprising a pharmaceutically acceptable salt form of the compound of Formula (A-1) as described herein. In some embodiments, provided herein are methods of treating or preventing a disease or condition in an individual, the methods comprising administering to the subject a therapeutically effective amount of 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 some embodiments, provided herein are methods of treating or preventing a disease or condition in an individual, the methods comprising administering to the subject a therapeutically effective amount of a polymorphic form of the compound of Formula (A-1) as described herein. In some embodiments, provided herein are methods for treating or preventing a disease or condition in an individual, the methods comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable salt form of a compound of Formula (A-1) described herein.

[0263] In some embodiments, the disease or condition is mediated by KIF18A. In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is a cell proliferation disorder, including loss of cell growth control, abnormalities in cell cycle regulation, centrosome abnormalities (structure and / or number, fragmentation), solid tumors, hematopoietic cancers, and hyperproliferative disorders, such as thyroid hyperplasia (particularly Graves' disease) and cysts (such as the hypervascularization of the ovarian stroma characteristic of polycystic ovary syndrome (Stein-Leventhal syndrome)). Solid tumors and hematologically driven tumors (such as carcinomas) include, but are not limited to, cancers of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, urothelium, liver, lung (including squamous cell carcinoma and small cell lung carcinoma), pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gallbladder, ovary, testis, germ cell, uterus, pancreas, stomach, cervix, thyroid, prostate, salivary gland, and skin (including squamous cell carcinoma); hematopoietic malignancies of the lymphoid system (including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma); hematopoietic malignancies of the myeloid system (including acute and chronic myeloid leukemia); tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma, and schwannoma), tumors of neuroendocrine origin, tumors of endocrine origin, small cell tumors, tumors of unknown primary origin, other tumors (including retinoblastoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, Ewing's sarcoma, Kaposi's sarcoma), and other cancer-related disorders that are a consequence of the presence or progression of cancer (such as tumor-induced pleural or pericardial effusion and malignant ascites). In some embodiments, the disease or condition is cancer, and the cancer is selected from the group consisting of advanced solid tumors, high-grade serous adenocarcinoma of the 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 the bladder, head and neck squamous cell carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, uterine serous adenocarcinoma, and endometrial carcinoma.In some embodiments, the disease or condition (eg, cancer) is associated with chromosomal instability.

[0264] In some embodiments, methods of treating or preventing cancer in an individual are provided, the methods 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) described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, methods of treating or preventing cancer in an individual are provided, the methods comprising administering to an individual in need thereof a therapeutically effective amount of a polymorphic form of the compound of Formula (A-1) described herein to the subject. In some embodiments, methods of treating or preventing cancer in an individual are provided, the methods comprising administering to an individual in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt form of the compound of Formula (A-1) described herein to the subject. In some embodiments, methods of treating or preventing cancer in a subject in need thereof are provided, the methods comprising administering to the subject a therapeutically effective amount of at least one chemical entity described herein. Also provided herein is the use of a solid formulation comprising a compound of Formula (A), Formula (B), Formula (C), Formula (A-1), Formula (A-2), or Formula (A-3) described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease in a subject. Also provided herein is the use of a polymorphic form of the compound of Formula (A-1) described herein in the manufacture of a medicament for the treatment of a disease in a subject. Also provided herein is the use of a pharmaceutically acceptable salt form of the compound of Formula (A-1) described herein in the manufacture of a medicament for the treatment of a disease in a subject. In some embodiments of the foregoing, the cancer is selected from the group consisting of advanced solid tumors, high-grade serous adenocarcinoma of the 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 the bladder, head and neck squamous cell carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, uterine serous adenocarcinoma, endometrial carcinoma, and uterine carcinoma. In some embodiments, the disease or condition (e.g., cancer) is associated with chromosomal instability.

[0265] In some embodiments, provided herein are methods of treating cancer, the methods 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) described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of treating cancer, the methods comprising administering to an individual in need thereof a polymorphic form of the compound of Formula (A-1) described herein, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a solid formulation comprising a compound of Formula (A), Formula (B), Formula (C), Formula (A-1), Formula (A-2), or Formula (A-3) described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. Also provided herein is the use of a polymorphic form of the compound of Formula (A-1) described herein, in the manufacture of a medicament for the treatment of cancer. Also provided herein is the use of a pharmaceutically acceptable salt form of a compound of Formula (A-1) described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[0266] In some embodiments, provided herein is a method of treating a disease or condition mediated by KIF18A in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a formulation or polymorphic form described herein.

[0267] In some embodiments, provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a solid formulation comprising a compound of Formula (A) or a pharmaceutically acceptable salt thereof, a polymorphic form of the compound of Formula (A-1), or a pharmaceutically acceptable salt form of the compound of Formula (A-1), as described herein. In some embodiments, the cancer is selected from the group consisting of carcinoma, 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, gallbladder, ovary, testis, 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, tumors of neuroendocrine origin, tumors of endocrine origin, small cell tumors, tumors of unknown primary, other tumors (including retinoblastoma, melanoma, seminoma, teratocarcinoma, osteosarcoma), and other cancer-related disorders that are a result of the presence or progression of cancer. In some embodiments, the cancer is selected from the group consisting of advanced solid tumors, high-grade serous adenocarcinoma of the 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 the bladder, head and neck squamous cell carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, uterine serous adenocarcinoma, and endometrial carcinoma. In some embodiments, the disease or condition (e.g., cancer) is associated with chromosomal instability.

[0268] Administration of the compounds and formulations described herein can be via any mode of administration acceptable for the therapeutic agent, including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, pulmonary, vaginal, rectal, or ocular administration. In some embodiments, the compound or formulation is administered orally or intravenously. In some embodiments, the compound or formulation described herein is administered orally.

[0269] In some embodiments, the compounds and formulations described herein are administered periodically. In some embodiments, the compounds or formulations are administered daily. In some embodiments, the compounds or formulations are 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 compounds or formulations are administered every 28 days. In some embodiments, administration of the compound or formulation is separated by 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. In some embodiments, administration of the compound or formulation is separated by at least 28 days. In some embodiments, the compound or formulation is administered in a 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 cycle. In some embodiments, the compound or formulation is administered in a 28 day cycle. In some embodiments, the compound or formulation is administered orally in a 28 day cycle.

[0270] Vb. Kit Also provided are articles of manufacture and kits containing any of the compounds of Formula (A) or pharmaceutically acceptable salts thereof described herein, polymorphic forms of the compounds of Formula (A-1), or solid formulations comprising a pharmaceutically acceptable salt form of the compounds of Formula (A-1). The articles of manufacture may include a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The container 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 to prevent, treat, or suppress a condition described herein, and may also indicate instructions for either in vivo or in vitro use.

[0271] In one aspect, provided herein is a kit comprising a solid formulation comprising a compound of Formula (A) or a polymorphic form of a compound of Formula (A-1) described herein and instructions for use. The kit may also include instructions for use in treating any of the diseases or conditions described herein in an individual in need of such treatment. The kit may additionally contain any materials or equipment that may be used in administering the compound or composition, such as vials, syringes, or IV bags. The kit may also include sterile packaging.

[0272] Vc. Combination A solid formulation comprising a compound of Formula (A) or a pharmaceutically acceptable salt thereof, a polymorphic form of the compound of Formula (A-1), or a pharmaceutically acceptable salt form of the 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.

[0273] A solid formulation comprising a compound of Formula (A) or a pharmaceutically acceptable salt thereof, a polymorphic form of the compound of Formula (A-1), or a pharmaceutically acceptable salt form of the compound of Formula (A-1) described herein may be combined with one or more other therapies to treat a disease or condition described herein. In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is a cell proliferation disorder, including loss of cell growth control, abnormalities in cell cycle regulation, centrosome abnormalities (structure and / or number, fragmentation), solid tumors, hematopoietic cancers, and hyperproliferative disorders, such as thyroid hyperplasia (particularly Graves' disease) and cysts, such as the hypervascularization of the ovarian stroma characteristic of polycystic ovary syndrome (Stein-Leventhal syndrome)). Solid tumors and hematologically driven tumors (such as carcinomas) include, but are not limited to, cancers of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, urothelium, liver, lung (including squamous cell carcinoma and small cell lung carcinoma), pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gallbladder, ovary, testis, germ cell, uterus, pancreas, stomach, cervix, thyroid, prostate, salivary gland, and skin (including squamous cell carcinoma); hematopoietic malignancies of the lymphoid system (including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma); hematopoietic malignancies of the myeloid system (including acute and chronic myeloid leukemia); tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma, and schwannoma), tumors of neuroendocrine origin, tumors of endocrine origin, small cell tumors, tumors of unknown primary origin, other tumors (including retinoblastoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, Ewing's sarcoma, Kaposi's sarcoma), and other cancer-related disorders that are a consequence of the presence or progression of cancer (such as tumor-induced pleural or pericardial effusion and malignant ascites).In some embodiments, the cancer is selected from the group consisting of advanced solid tumors, high-grade serous adenocarcinoma of the 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 the bladder, head and neck squamous cell carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, uterine serous adenocarcinoma, and endometrial carcinoma. In some embodiments, the disease or condition (e.g., cancer) is associated with chromosomal instability. [Example]

[0274] Example 1. Materials, Methods, and Abbreviations Differential scanning calorimetry (DSC) DSC was performed using a TA Instruments Discovery DSC2500 Differential Scanning Calorimeter equipped with a TA Instruments Refrigerated Cooling System 90 in either temperature modulated or constant rate variable temperature mode. DSC was used to measure the thermodynamic properties of the SDIs prepared herein, including the glass transition temperature (T g ) (defined as the temperature at which an amorphous material transitions from a less fluid, glassy state to a more fluid, rubbery state), cold crystallization temperature (T c (defined as a crystallization event below the melting temperature), and the melting temperature (T m ) The system was purged with a nitrogen flow at 50 mL / min to ensure an inert atmosphere throughout the measurement process.

[0275] The spray-dried samples were placed in non-hermetic aluminum pans and heated at a constant rate of 2.0°C / min. Table 1-1 provides a summary of the DSC parameters. [Table 15]

[0276] X-ray powder diffraction (XRPD) For characterization of the solid formulations, XRPD was performed using a Rigaku Miniflex 6G X-ray diffractometer to assess the crystallinity of the bulk compound and SDD. Amorphous materials give an "amorphous halo" diffraction pattern, lacking the discrete peaks seen in crystalline materials. Samples were irradiated with monochromated Cu Kα radiation and analyzed in continuous scan mode over a range of 5° to 40°. Samples were rotated during analysis to minimize preferred orientation effects. Table 1-2 lists the XRPD parameters. [Table 16]

[0277] For characterization of the polymorphic forms, both transmission and reflection geometry were used.

[0278] In transmission geometry, XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer or an Empyrean diffractometer, using an incident beam of Cu radiation generated using an Optix long microfocus source. An elliptically tilted multilayer mirror was used to collect Cu Kα X-rays through the sample onto the detector. Prior to analysis, a silicon sample (NIST SRM 640f) was analyzed to verify that the observed position of the Si111 peak matched the NIST-certified position. Samples were sandwiched between 3 μm-thick films and analyzed in transmission geometry. A beam stopper, a short anti-scatter extension, and an anti-scatter knife edge were used to minimize background caused by air. Soller slits for the incident and diffracted beams were used to minimize spread from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the sample and data acquisition software v.5.5.

[0279] In reflection geometry, XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer with an incident beam of Cu Kα radiation generated using a long, microfocus source and a nickel filter. The diffractometer was configured using a symmetric Bragg-Brentano geometry. Prior to analysis, a silicon specimen (NIST SRM 640f) was analyzed to verify that the observed position of the Si111 peak matched the NIST-certified position. The sample specimen was prepared as a thin, circular layer centered on a silicon zero-background substrate. Anti-scatter slits (SS) were used to minimize background caused by air. Soller slits for the incident and diffracted beams were used to minimize spread from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the sample and data acquisition software v.5.5.

[0280] 1 H NMR Proton solution NMR spectra were obtained on a Bruker AVANCE 600 MHz spectrometer using DMSO-d6.

[0281] Polarized Light Microscopy (PLM) Optical microscopy was performed using a Leica MZ12.5 stereo microscope. Samples were observed using a 0.8–10x objective with crossed polarizers and a primary red compensator. Samples were observed either in situ or in a drop of mineral oil. PLM images of the polymorphic form were acquired using a Leica DM LP microscope equipped with an Infinity2 color camera. Crossed polarizers were used with a primary red compensator and Köhler illumination. Samples were placed on glass microscope slides. A 1½-inch coverslip was placed over the sample. Mineral oil was then added to the edge of the coverslip to coat the sample by capillary action. Images were acquired at ambient temperature using Teledyne Lumenera INFINITY ANALYZE software version 7.1.0.1215. The camera was white balanced according to the software's default camera settings.

[0282] Particle morphology by scanning electron microscopy (SEM) SEM samples were prepared by dispersing the powder on an adhesive carbon-coated stage and coating it with a thin conductive layer of gold-palladium using a Cressington 108 Auto. Samples were analyzed using a Phenom XL operated in high vacuum mode and equipped with an Everhart-Thornley (secondary electron) detector or a backscatter detector. Micrographs were taken at various magnifications for qualitative particle morphology analysis. Experimental parameters were varied for each sample to obtain the best imaging conditions. These experimental parameters are described in the description of each micrograph.

[0283] Particle Size Distribution (PSD) by Light Diffraction The particle size distribution of the SDI samples was determined by laser diffraction using a Mastersizer 3000 equipped with an Aero S unit (Malvern Instruments). Tables 1-3 show the parameters. The particle size distribution description includes Dv 10 Diameter, Dv 50 diameter and Dv 90 For example, Dv 50 The diameter is the diameter at which 50% of the sample volume is made up of smaller particles. [Table 17]

[0284] Assay and impurities by high performance liquid chromatography (HPLC) Assay and impurities of SDI samples were evaluated using an HPLC method provided by the client. Parameters are shown in Tables 1-4. The method was demonstrated to meet system suitability criteria for early development work, including but not limited to reproducibility, standard agreement, injector precision, tailing, and signal-to-noise ratio. [Table 18]

[0285] Residual Solvents by Gas Chromatography - Headspace Sampling The residual solvent content of SDI was measured by GC-HS after secondary drying. Measurements were performed using an HP6890 series GC equipped with an Agilent 7697A headspace sampler. A 30 m x 0.32 mm x 1.8 μm capillary column (Agilent GC column PN: 123-1334) containing 6% cyanopropylphenyl and 94% dimethylpolysiloxane was used for the test. GC samples were prepared by dissolving approximately 100 mg of sample in 4 mL of dimethyl sulfoxide (DMSO). Tables 1-5, 1-6, and 1-7 provide a summary of the GC method parameters. [Table 19] [Table 20] [Table 21]

[0286] Combined TGA / DSC analysis Combined TGA / DSC analysis was 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. The balance was verified with calcium oxalate. Samples were placed in aluminum pans. The pans were sealed and the lids were pierced before the pans were 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.

[0287] Dynamic Vapor Sorption and Desorption (DVS) Moisture sorption / desorption data were collected using a Surface Measurement System DVS Intrinsic instrument. Samples were not dried prior to analysis. Adsorption and desorption data were collected over a RH range of 5% to 95% in 10% RH increments. The analytical equilibrium criterion was a weight change of less than 0.0100% over 5 minutes, with a maximum equilibration time of 3 hours.

[0288] Temperature Modulated Differential Scanning Calorimetry (TMDSC) Temperature-modulated DSC (TMDSC) was performed using a Mettler Toledo DSC3+ differential scanning calorimeter. Temperature calibration was performed using octane, phenyl salicylate, indium, tin, and zinc. The sample was placed in a sealed aluminum DSC pan, the weight was accurately recorded, and the sample was inserted into the DSC cell. A pre-weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The pan lid was pierced prior to sample analysis. Samples were analyzed from -50°C to 250°C at 2°C / min with a pulse height of 0.5°C. [Table 22-1] [Table 22-2] [Table 22-3]

[0289] Example S-1. Synthesis of Compound of Formula (A) General synthesis method The 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 the following exemplary synthetic schemes for their general preparation, followed by specific examples. In obtaining the various compounds herein, one skilled in the art will recognize that starting materials can be suitably selected to carry the ultimately desired substituents through the reaction scheme, with or without protection as necessary, to yield the desired product. Alternatively, it may be necessary or desirable to employ, in place of the ultimately desired substituent, a suitable group that will carry through the reaction scheme and that may be replaced with the desired substituent, as appropriate. Furthermore, one skilled in the art will recognize that protecting groups can 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, where appropriate. Unless otherwise specified, variables are as defined above with respect to Formula (A), Formula (B), Formula (C), Formula (A-1), Formula (A-2), or Formula (A-3).

[0290] If it is desired to obtain a specific enantiomer of a compound, this can be achieved from the corresponding enantiomeric mixture by using any conventional procedure suitable for separating or resolving enantiomers.Thus, for example, diastereomeric derivatives can be produced by reacting a mixture of enantiomers, for example, a racemate, with a suitable chiral compound.The diastereomers can then be separated by any convenient means, for example, crystallization, and the desired enantiomer can be recovered.In another resolution process, chiral high performance liquid chromatography can be used to separate the racemate.Alternatively, if necessary, a specific enantiomer can be obtained by using a suitable chiral intermediate in one of the processes described.

[0291] Where it is desired to obtain a particular isomer of a compound or to otherwise purify the product of a reaction, chromatography, recrystallization, and other conventional separation procedures may be used on intermediates or final products.

[0292] General methods for preparing the compounds described herein are shown in the following exemplary methods. The variables in the schemes provided herein are as defined 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 can be prepared by similar methods.

[0293] In some embodiments, the compounds provided herein can be synthesized according to Scheme 1, Scheme 2, Scheme 3, and / or Scheme 4. The rings A, B, Y shown in Schemes 1-4 below are 1 , Y 2 , Y 3 , Y 4 , m, R B , and R C is as defined for compounds of formula I.

[0294] Scheme 1. [ka] Scheme 1 outlines an exemplary synthetic route to compounds of general formula I. Compounds of formula I are prepared by reacting a carboxylic acid of formula A (e.g., X=OH) with an indoline of formula B in the presence of a coupling reagent (e.g., HATU in combination with a base (e.g., iPrNEt) or EDCI in combination with HOBt or DMAP). Alternatively, an acid halide of formula A (e.g., X=Cl or F) is reacted directly with a compound of formula B along with an acid scavenger (e.g., EtN).

[0295] Scheme 2. [ka] The indoline intermediate of formula B can be prepared via the Fischer indole synthesis described in Scheme 2. Aryl hydrazines of formula C (e.g., formulas Ci, C-ii, and C-iii) are reacted with ring B-substituted carbaldehydes of formula D in the presence of an acid, followed by a reducing agent (such as NaBH, Pd / C, and H gas, or EtSiH). Aryl hydrazines of formula Ci (monosubstituted at the para position) provide indolines of formula Bi, while hydrazines of formula C-ii (containing at least one meta substituent and no ortho substitution) provide a mixture of indolines of formula B-ii-a and B-ii-b. Aryl hydrazines of formula C-iii (substituted at one ortho position) provide indolines of formula B-iii.

[0296] Scheme 3. [ka] Indolines of Formula B can also be prepared via the 3,3-dialkylation method described in Scheme 3. Indoles of Formula D are reacted with optionally substituted 3-6 atom aliphatic and heteroaliphatic linear chains (Formula E) bearing two terminal leaving groups "LG." LG can be Cl, Br, I, or a sulfonate ester, or another suitable group displaceable by a nucleophile. This transformation can be mediated by a trialkylboron such as EtB and a base such as potassium t-butoxide. The spirocyclization reaction is followed by reaction with a reducing agent such as NaBH, Pd / C and H gas, or EtSiH.

[0297] Scheme 4. [ka] Indolines of formula B can also be prepared via alkylation of the enolate 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 (formula E) bearing two terminal leaving groups "LG." LG can be Cl, Br, I, or a sulfonate ester, or another suitable group displaceable by a nucleophile. This reaction may be mediated by an additive such as tetramethyldiaminoethane or hexamethylphosphorus triamide. The spirocyclization reaction is followed by reaction with a reducing agent (such as LiAlH or borane).

[0298] Synthesis of intermediates Synthesis of 3-(piperidin-1-ylsulfonyl)benzoic acid (A-01) [ka] Step 1. A mixture of piperidine (0.25 mL, 2.6 mmol), CHCl (5.0 mL), iPrNEt (1.3 mL, 7.7 mmol), and methyl 3-chlorosulfonylbenzoate (900 mg, 3.84 mmol, 1.5 equiv) was stirred for 2 h, concentrated, poured into HO (20 mL), and extracted with EtOAc (2 × 10 mL). The extracts were combined, washed with brine (10.0 mL), dried over NaSO, filtered, and concentrated to give methyl 3-(1-piperidylsulfonyl)benzoate (0.95 g).

[0299] Step 2. A mixture of methyl 3-(1-piperidylsulfonyl)benzoate (0.90 g, 3.2 mmol), THF (6.0 mL), HO (2.0 mL), and LiOH HO (0.67 g, 16 mmol) was stirred for 2 h and then concentrated. The mixture was treated with HCl (4 N) to pH 3, poured into HO (10 mL), and extracted with EtOAc (2 × 10 mL). The extracts were combined, washed with brine (10 mL), dried over NaSO, filtered, and concentrated to give 3-(1-piperidylsulfonyl)benzoic acid (A-01, 0.72 g). ESI MS m / z: 270.0 (M+H). + .

[0300] Compounds A-03 and A-04 were prepared in the same manner as A-01 from the sulfonyl chlorides and amines shown in Table S-1 below. [Table 23]

[0301] Synthesis of 5''-nitrodispiro[cyclopropane-1,1'-cyclohexane-4',3''-indoline] (B-01) [ka] Step 1. To a mixture of ZnEt (1 M in hexane, 180 mL) and CHCl (200 mL) at 0 °C under N, CHCl (26 mL, 320 mmol) in CHCl (60 mL) was slowly added. The mixture was stirred at 0 °C for 30 min, and ethyl 4-methylenecyclohexanecarboxylate (12 g, 71 mmol) in CHCl (50 mL) was slowly added. The mixture was stirred at 20 °C for 12 h, cooled to 0 °C, and saturated NHCl (100 mL) was added. The organic phase was separated, washed with water (50 mL × 2), brine (50 mL), dried over NaSO, filtered, concentrated, and purified by silica chromatography (1–10% CHCl in petroleum ether) to give the compound ethyl spiro[2.5]octane-6-carboxylate (10 g).

[0302] Step 2. To a mixture of ethyl spiro[2.5]octane-6-carboxylate (10 g, 55 mmol) and THF (300 mL) under N2 was added LiAlH4 (3.1 g, 81 mmol) in portions at 0 °C. The mixture was stirred at 0 °C for 1 h and then at 22 °C for an additional 1 h. To the stirring mixture was slowly added 2 M aqueous NaOH (3.0 mL), followed by Na2SO4 (30 g). The suspension was filtered, and the filtrate was concentrated to give spiro[2.5]octan-6-ylmethanol (7.5 g). 1 H NMR (DMSO-d 6 , 400 MHz) δ 3.51 (d, J = 6.38 Hz, 2H), 1.82-1.68 (m, 4H), 1.53 (tdt, J = 14.71, 6.38, 3.24 Hz, 1H), 1.40-1.29 (m, 1H), 1.12-1.07 (m, 2H), 0.96-0.84 (m, 2H), 0.35-0.24 (m, 2H), 0.23-0.12 (m, 2H).

[0303] Step 3. To a mixture of spiro[2.5]octan-6-ylmethanol (7.5 g, 54 mmol) and CHCl (250 mL) was added Dess-Martin periodinane (28 g, 66 mmol) at 0 °C. The mixture was stirred for 5 h while the temperature was raised to 25 °C. The mixture was filtered through Celite, and the filter cake was washed with CHCl (50 mL × 3). The filtrate was concentrated and purified by silica chromatography (0–10% EtOAc in petroleum ether) to give spiro[2.5]octane-6-carbaldehyde (7.30 g). 1 H NMR (DMSO-d 6 , 400 MHz) δ 9.68 (d, J = 1.25 Hz, 1H), 2.35-2.23 (m, 1H), 1.97-1.85 (m, 2H), 1.70-1.51 (m, 4H), 1.12-1.03 (m, 2H), 0.35-0.27 (m, 2H), 0.26-0.18 (m, 2H).

[0304] Step 4.a) A mixture of (4-nitrophenyl)hydrazine (1.8 g, 12 mmol), TFA (4.5 mL, 61 mmol), CHCl (40 mL), and spiro[2.5]octane-6-carbaldehyde (2.0 g, 15 mmol) was stirred at 40 °C for 15 h. b) Additional TFA (6.3 mL, 85 mmol), CHCl, and EtSiH (6.3 mL, 4.6 mmol) were added at 0 °C, and the mixture was stirred at 25 °C for 2 h, then concentrated and purified by silica chromatography (0–15% [1:1 Me-THF in EtOAc] in petroleum ether) to give 5′-nitrodispiro[cyclopropane-1,1′-cyclohexane-4′,3′-indoline] (B-01, 0.88 g).

[0305] Synthesis of dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline] (B-06) [ka] Step 1. 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.

[0306] 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 NaBHCN (0.90 g, 14 mmol) in portions. The mixture was stirred at 20 °C for 12 h, then NaBHCN (0.50 g) and THF (15 mL) were added, and the mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated and purified by chromatography (silica, 0–15% [1:1 THF / EtOAc] in petroleum ether) to give dispiro[cyclopropane-1,1'-cyclohexane-4',3"-indoline] (B-06, 0.64 g).

[0307] Example S-2. Synthesis of Compound 1, Compound 2, and Compound 9 [ka] A mixture of 3-[(4,4-difluoro-1-piperidyl)sulfonyl]benzoic acid (88 mg, 0.28 mmol), DMF (1.5 mL), EtN (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. The resulting mixture was stirred at 20 °C for 3.5 h, concentrated, and purified by preparative HPLC (45-75% MeCN in HO [10 mM NHHCO]) to give (3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)(4'-fluorospiro[cyclopentane-1,3'-indoline]-1'-yl)methanone (compound 1) (35 mg). ESI MS m / z: 479.2 (M+H).

[0308] Compounds 2 and 9 were prepared from the carboxylic acid and indoline analogs shown by the method described above for the synthesis of compound 1. The carboxylic acid and indoline intermediates used in the synthesis of compounds 2 and 9 are shown in Table S-2. [Table 24]

[0309] Example S-3. Synthesis of Compound of Formula (A-1) [ka] Compound 9 (1.0 g, 1.9 mmol), ethanesulfonamide (0.60 g, 5.5 mmol), CuI (0.37 g, 1.9 mmol), KPO (1.3 g, 6.0 mmol), N 1 ,N 2A degassed mixture of N-dimethylcyclohexane-1,2-diamine (0.27 g, 1.9 mmol) and DMF (14 mL) was stirred at 150 °C for 3 h. The mixture was combined with HO (40 mL). The resulting precipitate was filtered, washed with HO (5 mL × 3), dissolved in EtOAc (50 mL), washed with water (20 mL × 2), dried over NaSO, concentrated, and purified by preparative HPLC (50–20% HO in MeCN [0.1% formic acid]) to give N-(tert-butyl)-3-(5′-(ethylsulfonamido)dispiro[cyclopropane-1,1′-cyclohexane-4′,3′-indoline]-1′-carbonyl)benzenesulfonamide (compound of formula (A-1), 1.3 g).

[0310] Example S-4. Synthesis of Comp...

Claims

1. (1) Formula (A): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein Ring A is independently halo, —OH, C １－６ Alkyl, 3-10 membered heterocycloalkyl, —NR ａ１ C(O)NR ａ２ R ａ３ , -NR ａ４ C(O)OR ａ５ , -NR ａ６ R ａ７ , -N=S(O)R ａ８ R ａ９ , -OR ａ１０ , -S(O)R ａ１１ , -S(O)(NR ａ１２ ) R ａ１３ , -S(O) ２ NR ａ１４ R ａ１５ , -S(O) ２ R ａ１６ , -(CR ａ１７ R ａ１８ ) ０－１ C(O)NR ａ１９ R ａ２０ , -SR ａ２１ , -C(O)R ａ２２ , as well as —OH, cyano, C ３－１０ C substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo. １－６ C optionally substituted with one or more substituents independently selected from the group consisting of alkyl ６－１４ aryl or 5-12 membered heteroaryl; R ａ１ -R ａ２２ are each independently hydrogen, or each independently halo, cyano, —OH, —O(C １－６ alkyl), C ２－６ Alkenyl, C ３－１０ Cycloalkyl, -S(C １－６ alkyl), =CR １ａ１ R １ａ２ , and halo, —OH, and —O(C １－６ C optionally substituted with one or more substituents independently selected from the group consisting of alkyl １－６ C optionally substituted with one or more substituents independently selected from the group consisting of alkyl １－６ Alkyl, C ２－６ Alkenyl, C ３－１０ Cycloalkyl, C ３－１０ Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C ６－１４ aryl, or 5-12 membered heteroaryl, wherein R １ａ１ and R １ａ２ are each independently hydrogen or C １－６ is alkyl; Ring B is C ５－７ Cycloalkyl, C ５－７ cycloalkenyl, or 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; m is 2; Two R's Ｂ The groups are bonded to the same carbon atom on ring B and together with the carbon atom to which they are bonded form C ３－７ Forming a cycloalkyl; Y １ is N or CR Ｃ１ and Y ２ is N or CR Ｃ２ and Y ３ is N or CR Ｃ３ and Y ４ is N or CR Ｃ４ and In the formula, Y １ , Y ２ , Y ３ and Y ４ of which 3 or less are N; R Ｃ１ -R Ｃ４ each independently represents hydrogen, halo, cyano, —OH, or —NO ２ , —C(O)NR ｃ１ R ｃ２ , -NR ｃ３ R ｃ４ , -NR ｃ５ S (O) ２ R ｃ６ , -P(O)R ｃ７ R ｃ８ , -N=S(O)R ｃ９ R ｃ１０ , -S(O)(NR ｃ１１ ) R ｃ１２ , -S(O) ２ R ｃ１３ , -NR ｃ１４ C(O)OR ｃ１５ , -NR ｃ１６ S (O) ２ (CH ２ ) １－６ NR ｃ１７ C(O)R ｃ１８ or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH １－６ is alkyl; R ｃ１ -R ｃ１８ are each independently hydrogen, C ３－１０ C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; １－６ The compound of formula (A) or a pharmaceutically acceptable salt thereof, wherein R is alkyl; (2) a pharmaceutically acceptable polymer.

2. 2. The formulation of claim 1, wherein the pharmaceutically acceptable polymer comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC), or methacrylic acid-ethyl acrylate copolymer, or any combination thereof.

3. 3. The formulation of claim 1 or claim 2, wherein the pharmaceutically acceptable polymer comprises HPMCAS.

4. 4. The formulation of claim 3, wherein the HPMCAS is HPMCAS-M.

5. 3. The formulation of claim 1 or claim 2, wherein the pharmaceutically acceptable polymer comprises HPMCP.

6. 6. The formulation of claim 5, wherein the HPMCP is HPMCP-HP55.

7. 3. The formulation of claim 1 or claim 2, wherein the pharmaceutically acceptable polymer comprises HPMC.

8. 8. The formulation of claim 7, wherein the HPMC is HPMC E3LV.

9. 3. The formulation of claim 1 or claim 2, wherein the pharmaceutically acceptable polymer comprises a methacrylic acid-ethyl acrylate copolymer.

10. 10. The formulation of claim 9, wherein the methacrylic acid-ethyl acrylate copolymer is methacrylic acid-ethyl acrylate copolymer (1:1).

11. The formulation according to any one of claims 1 to 10, wherein the weight ratio of the compound of formula (A) or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer in the formulation is from about 20:80 to about 90:

10.

12. The formulation according to any one of claims 1 to 11, wherein the weight ratio of the compound of formula (A) or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer in the formulation is from about 25:75 to about 70:

30.

13. The formulation according to any one of claims 1 to 12, wherein the weight ratio of the compound of formula (A) or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer in the formulation is about 25:

75.

14. The formulation according to any one of claims 1 to 12, wherein the weight ratio of the compound of formula (A) or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer in the formulation is about 40:

60.

15. The formulation according to any one of claims 1 to 12, wherein the weight ratio of the compound of formula (A) or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer in the formulation is about 50:

50.

16. The formulation according to any one of claims 1 to 12, wherein the weight ratio of the compound of formula (A) or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer in the formulation is about 60:

40.

17. The formulation according to any one of claims 1 to 12, wherein the weight ratio of the compound of formula (A) or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable polymer in the formulation is about 70:

30.

18. The formulation of any one of claims 1 to 2, 5 to 6, and 11 to 13, wherein the formulation comprises the compound of formula (A) or a pharmaceutically acceptable salt thereof and HPMCP-HP55 in a weight ratio of about 25:

75.

19. 15. The formulation of any one of claims 1 to 2, 5 to 6, 11, 12, and 14, wherein the formulation comprises the compound of formula (A) or a pharmaceutically acceptable salt thereof and HPMCP-HP55 in a weight ratio of about 40:

60.

20. 16. The formulation of any one of claims 1-2, 5-6, 11, 12, and 15, wherein the formulation comprises the compound of formula (A) or a pharmaceutically acceptable salt thereof and HPMCP-HP55 in a weight ratio of about 50:

50.

21. 17. The formulation of any one of claims 1-2, 5-6, 11, 12, and 16, wherein the formulation comprises the compound of formula (A) or a pharmaceutically acceptable salt thereof and HPMCP-HP55 in a weight ratio of about 60:

40.

22. 18. The formulation of any one of claims 1-2, 5-6, 11, 12, and 17, wherein the formulation comprises the compound of formula (A) or a pharmaceutically acceptable salt thereof and HPMCP-HP55 in a weight ratio of about 70:

30.

23. 14. The formulation of any one of claims 1 to 2, 9 to 10, and 11 to 13, wherein the formulation comprises the compound of formula (A) or a pharmaceutically acceptable salt thereof and methacrylic acid-ethyl acrylate copolymer (1:1) in a weight ratio of about 25:

75.

24. 15. The formulation of any one of claims 1 to 2, 9 to 10, 11, 12, and 14, wherein the formulation comprises the compound of formula (A) or a pharmaceutically acceptable salt thereof and methacrylic acid-ethyl acrylate copolymer (1:1) in a weight ratio of about 40:

60.

25. 16. The formulation of any one of claims 1-2, 9-10, 11, 12, and 15, wherein the formulation comprises the compound of formula (A) or a pharmaceutically acceptable salt thereof and methacrylic acid-ethyl acrylate copolymer (1:1) in a weight ratio of about 50:

50.

26. 17. The formulation of any one of claims 1 to 2, 9 to 10, 11, 12, and 16, wherein the formulation comprises the compound of formula (A) or a pharmaceutically acceptable salt thereof and methacrylic acid-ethyl acrylate copolymer (1:1) in a weight ratio of about 60:

40.

27. 18. The formulation of any one of claims 1-2, 9-10, 11, 12, and 17, wherein the formulation comprises the compound of formula (A) or a pharmaceutically acceptable salt thereof and methacrylic acid-ethyl acrylate copolymer (1:1) in a weight ratio of about 70:

30.

28. 14. The formulation of any one of claims 1-4 or 11-13, wherein the formulation comprises the compound of formula (A) or a pharmaceutically acceptable salt thereof and HPMCAS in a weight ratio of about 25:

75.

29. 15. The formulation of any one of claims 1 to 4, 11, 12, and 14, wherein the formulation comprises the compound of formula (A) or a pharmaceutically acceptable salt thereof and HPMCAS in a weight ratio of about 40:

60.

30. 16. The formulation of any one of claims 1 to 4, 11, 12, and 15, wherein the formulation comprises the compound of formula (A) or a pharmaceutically acceptable salt thereof and HPMCAS in a weight ratio of about 50:

50.

31. 17. The formulation of any one of claims 1 to 4, 11, 12, and 16, wherein the formulation comprises the compound of formula (A) or a pharmaceutically acceptable salt thereof and HPMCAS in a weight ratio of about 60:

40.

32. 18. The formulation of any one of claims 1 to 4, 11, 12, and 17, wherein the formulation comprises the compound of formula (A) or a pharmaceutically acceptable salt thereof and HPMCAS in a weight ratio of about 70:

30.

33. 33. The formulation of any one of claims 1 to 32, wherein Ring B is cyclohexyl.

34. The two R Ｂ 34. The formulation of any one of claims 1 to 33, wherein the groups are attached to the same carbon atom on Ring B and together with the carbon atom to which they are attached form a cyclopropyl.

35. Ring A is one -S(O) ２ NR ａ１４ R ａ１５ C substituted with a group ６－１４ The formulation of any one of claims 1 to 34, wherein the compound is aryl.

36. Y ２ But, CR Ｃ２ and CR Ｃ２ But, -NR ｃ５ S (O) ２ R ｃ６ The formulation according to any one of claims 1 to 35, wherein

37. Ring A is one -S(O) ２ NR ａ１４ R ａ１５ C substituted with a group ６－１４ aryl, and Y ２ But, CR Ｃ２ and CR Ｃ２ But, -NR ｃ５ S (O) ２ R ｃ６ The formulation according to any one of claims 1 to 36, wherein

38. Ring A is one -S(O) ２ NR ａ１４ R ａ１５ C substituted with a group ６－１４ aryl, and R ａ１４ is H and R ａ１５ But C １－６ is alkyl, and Y ２ But, CR Ｃ２ and CR Ｃ２ But, -NR ｃ５ S (O) ２ R ｃ６ and R ｃ６ C optionally substituted with one —OH １－６ 38. The formulation of any one of claims 1 to 37, wherein the alkyl group is alkyl.

39. The compound of formula (A) is represented by formula (A-1): 【Chemistry 2】 The formulation according to any one of claims 1 to 38, wherein the compound is

40. The compound of formula (A) is represented by formula (A-2): 【Transformation 3】 The formulation according to any one of claims 1 to 38, wherein the compound is

41. The compound of formula (A) is represented by formula (A-3): 【Chemistry 4】 The formulation according to any one of claims 1 to 38, wherein the compound is

42. 42. The formulation of any one of claims 1 to 41, wherein the compound of formula (A) is in substantially amorphous form.

43. Formula (A): 【Transformation 5】 or a pharmaceutically acceptable salt thereof, wherein Ring A is independently halo, —OH, C １－６ Alkyl, 3-10 membered heterocycloalkyl, —NR ａ１ C(O)NR ａ２ R ａ３ , -NR ａ４ C(O)OR ａ５ , -NR ａ６ R ａ７ , -N=S(O)R ａ８ R ａ９ , -OR ａ１０ , -S(O)R ａ１１ , -S(O)(NR ａ１２ ) R ａ１３ , -S(O) ２ NR ａ１４ R ａ１５ , -S(O) ２ R ａ１６ , -(CR ａ１７ R ａ１８ ) ０－１ C(O)NR ａ１９ R ａ２０ , -SR ａ２１ , -C(O)R ａ２２ , as well as —OH, cyano, C ３－１０ C substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo. １－６ C optionally substituted with one or more substituents independently selected from the group consisting of alkyl ６－１４ aryl or 5-12 membered heteroaryl; R ａ１ -R ａ２２ are each independently hydrogen, or each independently halo, cyano, —OH, —O(C １－６ alkyl), C ２－６ Alkenyl, C ３－１０ Cycloalkyl, -S(C １－６ alkyl), =CR １ａ１ R １ａ２ , and halo, —OH, and —O(C １－６ C optionally substituted with one or more substituents independently selected from the group consisting of alkyl １－６ C optionally substituted with one or more substituents independently selected from the group consisting of alkyl １－６ Alkyl, C ２－６ Alkenyl, C ３－１０ Cycloalkyl, C ３－１０ Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C ６－１４ aryl, or 5-12 membered heteroaryl, wherein R １ａ１ and R １ａ２ are each independently hydrogen or C １－６ is alkyl; Ring B is C ５－７ Cycloalkyl, C ５－７ cycloalkenyl, or 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; m is 2; Two R's Ｂ The groups are bonded to the same carbon atom on ring B and together with the carbon atom to which they are bonded form C ３－７ Forming a cycloalkyl; Y １ is N or CR Ｃ１ and Y ２ is N or CR Ｃ２ and Y ３ is N or CR Ｃ３ and Y ４ is N or CR Ｃ４ and In the formula, Y １ , Y ２ , Y ３ and Y ４ of which 3 or less are N; R Ｃ１ -R Ｃ４ each independently represents hydrogen, halo, cyano, —OH, or —NO ２ , —C(O)NR ｃ１ R ｃ２ , -NR ｃ３ R ｃ４ , -NR ｃ５ S (O) ２ R ｃ６ , -P(O)R ｃ７ R ｃ８ , -N=S(O)R ｃ９ R ｃ１０ , -S(O)(NR ｃ１１ ) R ｃ１２ , -S(O) ２ R ｃ１３ , -NR ｃ１４ C(O)OR ｃ１５ , -NR ｃ１６ S (O) ２ (CH ２ ) １－６ NR ｃ１７ C(O)R ｃ１８ or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH １－６ is alkyl; R ｃ１ -R ｃ１８ are each independently hydrogen, C ３－１０ C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; １－６ is alkyl, The formulations may be administered to human subjects to achieve a maximum plasma concentration (C ｍａｘ ) to about 1.5 μmol / mL to about 5.0 μmol / mL.

44. The formulation is effective to reduce the area under the plasma concentration-time curve (AUC) of the compound of formula (A) in a human subject. ０－２４ 44. The formulation of claim 43, wherein the formulation is effective to achieve a vasoconstriction of the vasoconstrictor ...

45. The compound of formula (A) or a pharmaceutically acceptable salt thereof is represented by formula (A-1): 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

46. The compound of formula (A) or a pharmaceutically acceptable salt thereof is represented by formula (A-2): 【Transformation 7】 or a pharmaceutically acceptable salt thereof.

47. The compound of formula (A) or a pharmaceutically acceptable salt thereof is represented by formula (A-3): 【Transformation 8】 or a pharmaceutically acceptable salt thereof.

48. 48. The formulation of any one of claims 43 to 47, wherein the formulation is administered to the subject without food.

49. 49. The formulation of any one of claims 1 to 48, wherein the formulation is a spray-dried dispersion.

50. Formula (A-1): 【Chemistry 9】 or a crystalline form of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

51. 51. The crystalline form of claim 50, characterized in that it has an XRPD pattern comprising peaks at 13.54±0.20, 17.89±0.20, 18.39±0.20, 19.39±0.20, and 19.73±0.20 degrees 2θ angles.

52. 52. The crystalline form of claim 51, characterized in that it has an XRPD pattern containing additional peaks at 15.46±0.20 and 17.29±0.20 degrees 2θ angles.

53. 53. The crystalline form of claim 51 or 52, characterized in that it has an XRPD pattern containing additional peaks at 8.61±0.20 and 15.04±0.20 degrees 2θ angles.

54. 54. A crystalline form according to any one of claims 50 to 53, characterized in that it has an XRPD pattern substantially as shown in Figure 2.

55. 55. The crystalline form of any one of claims 50 to 54, characterized by an endothermic onset at 188±2°C as determined by DSC.

56. 56. The crystalline form of any one of claims 50 to 55, characterized by having an endothermic peak at 194±2°C as determined by DSC.

57. 57. A crystalline form according to any one of claims 50 to 56, characterized in that it has a DSC graph substantially as shown in Figure 3.

58. 58. The crystalline form of any one of claims 50 to 57, characterized in that it has a weight loss of 0.01±0.005% between 52 and 150°C as determined by TGA.

59. 59. The crystalline form of any one of claims 50 to 58, characterized in that it has an apparent decomposition at 316±5°C as determined by TGA.

60. 60. A crystalline form according to any one of claims 50 to 59, characterized in that it has a TGA graph substantially as shown in Figure 3.

61. 61. The crystalline form of any one of claims 50 to 60, characterized in that it has a weight gain from 5% RH to 95% RH of 0.095±0.005% as determined by DVS.

62. 62. The crystalline form of any one of claims 50 to 61, characterized in that it has a weight loss from 95% RH to 5% RH of 0.097±0.005% as determined by DVS.

63. 63. The crystalline form of any one of claims 50 to 62, characterized in that it has a DVS graph substantially as shown in Figure 4.

64. 51. The crystalline form of claim 50, characterized in that it has an XRPD pattern comprising peaks at 15.62±0.20, 16.60±0.20, 19.87±0.20, 20.11±0.20, and 25.76±0.20 degrees 2θ angles.

65. 65. The crystalline form of claim 64, characterized in that it has an XRPD pattern containing additional peaks at 17.50±0.20 and 21.13±0.20 degrees 2θ angles.

66. 66. The crystalline form of claim 64 or 65, characterized in that it has an XRPD pattern containing additional peaks at 8.23±0.20 and 11.72±0.20 degrees 2θ angles.

67. 67. The crystalline form of any one of claims 50 or 64-66, characterized in that it has an XRPD pattern substantially as shown in Figure 10.

68. 68. The crystalline form of any one of claims 50 or 64-67, characterized by an endothermic onset at 196±2°C as determined by DSC.

69. 69. The crystalline form of any one of claims 50 or 64-68, characterized by having an endothermic peak at 197±2°C as determined by DSC.

70. 70. The crystalline form of any one of claims 50 or 64-69, characterized in that it has a DSC graph substantially as shown in Figure 11.

71. 71. The crystalline form of any one of claims 50 or 64-70, characterized in that it has a weight loss of 0.05±0.01% between 25 and 100°C as determined by TGA.

72. 72. The crystalline form of any one of claims 50 or 64-71, characterized in that it has a weight loss of 0.10±0.05% between 100 and 180°C as determined by TGA.

73. 73. The crystalline form of any one of claims 50 or 64-72, characterized in that it has a TGA graph substantially as shown in Figure 12.

74. 74. The crystalline form of any one of claims 50 or 64-73, characterized in that it has a weight gain from 0.1% RH to 95% RH of 0.030%±0.005% as determined by DVS.

75. 75. The crystalline form of any one of claims 50 or 64-74, characterized in that it has a weight loss from 95% RH to 0.1% RH of 0.050%±0.005% as determined by DVS.

76. 13. The crystalline form of any one of claims 50 or 64-75, characterized in that it has a DVS graph substantially as shown in Figure 13.

77. The crystalline form of any one of claims 50 to 76, comprising a compound of formula (A-1).

78. 51. The crystalline form of claim 50, comprising the monosodium salt of the compound of formula (A-1).

79. 79. The crystalline form of claim 78, characterized in that it has an XRPD pattern comprising peaks at 7.66±0.20, 8.45±0.20, 11.64±0.20, 17.92±0.20, and 22.82±0.20 degrees 2θ angles.

80. 80. The crystalline form of claim 79, characterized in that it has an XRPD pattern containing additional peaks at 16.91±0.20 and 17.13±0.20 degrees 2θ angles.

81. 80. The crystalline form of claim 78 or 79, characterized in that it has an XRPD pattern containing additional peaks at 13.60±0.20 and 18.34±0.20 degrees 2θ angles.

82. 82. The crystalline form of any one of claims 50 or 78-81, characterized in that it has an XRPD pattern substantially as shown in Figure 14.

83. 83. The crystalline form of any one of claims 50 or 78-82, characterized by an endothermic onset at 186±2°C as determined by DSC.

84. 84. The crystalline form of any one of claims 50 or 78-83, characterized by having an endothermic peak at 190±2°C as determined by DSC.

85. 15. The crystalline form of any one of claims 50 or 78-84, characterized in that it has a DSC graph substantially as shown in Figure 15.

86. 86. The crystalline form of any one of claims 50 or 78-85, characterized in that it has a weight loss of 0.7%±0.1% between 25°C and 170°C as determined by TGA.

87. 16. The crystalline form of any one of claims 50 or 78-86, characterized in that it has a TGA graph substantially as shown in Figure 16.

88. 79. The crystalline form of claim 78, characterized in that it has an XRPD pattern comprising peaks at 14.19±0.20, 17.44±0.20, 17.70±0.20, and 18.14±0.20 degrees 2θ angles.

89. 90. The crystalline form of claim 88, characterized in that it has an XRPD pattern containing additional peaks at 18.61±0.20 and 27.38±0.20 degrees 2θ angles.

90. 90. The crystalline form of claim 88 or 89, characterized in that it has an XRPD pattern containing additional peaks at 16.87±0.20 and 21.64±0.20 degrees 2θ angles.

91. 38. The crystalline form of any one of claims 50, 78, or 88-90, characterized by having an XRPD pattern substantially as shown in Figure 38.

92. 92. The crystalline form of any one of claims 50, 78, or 88-91, characterized by having an endothermic peak at 166±2°C as determined by DSC.

93. 93. The crystalline form of any one of claims 50, 78, or 88-92, characterized by having an endothermic peak at 192±2°C as determined by DSC.

94. 94. The crystalline form of any one of claims 50, 78, or 88-93, characterized by having an endothermic peak at 208±2°C as determined by DSC.

95. 39. The crystalline form of any one of claims 50, 78, or 88-94, characterized in that it has a DSC graph substantially as shown in Figure 39.

96. 96. The crystalline form of any one of claims 50, 78, or 88-95, characterized in that it has a weight loss of 0.3%±0.1% between 25°C and 80°C as determined by TGA.

97. 97. The crystalline form of any one of claims 50, 78, or 88-96, characterized in that it has a weight loss of 7.3%±0.1% between 80°C and 190°C as determined by TGA.

98. 40. The crystalline form of any one of claims 50, 78, or 88-97, characterized in that it has a TGA graph substantially as shown in Figure 40.

99. 79. The crystalline form of claim 78, characterized in that it has an XRPD pattern comprising peaks at 6.85±0.20, 11.74±0.20, 17.14±0.20, and 18.92±0.20 degrees 2θ angles.

100. 100. The crystalline form of claim 99, characterized in that it has an XRPD pattern containing additional peaks at 18.51±0.20 and 20.95±0.20 degrees 2θ angles.

101. 101. The crystalline form of claim 99 or 100, characterized in that it has an XRPD pattern containing additional peaks at 16.64±0.20 and 24.73±0.20 degrees 2θ angles.

102. 49. The crystalline form of any one of claims 50, 78, or 99-101, characterized by having an XRPD pattern substantially as shown in Figure 49.

103. 103. The crystalline form of any one of claims 50, 78, or 99-102, characterized by having an endothermic peak at 183±2°C as determined by DSC.

104. 50. The crystalline form of any one of claims 50, 78, or 99-103, characterized in that it has a DSC graph substantially as shown in Figure 50.

105. 105. The crystalline form of any one of claims 50, 78, or 99-104, characterized in that it has a weight loss of 0.7%±0.1% between 30°C and 120°C as determined by TGA.

106. 106. The crystalline form of any one of claims 50, 78, or 99-105, characterized by having a weight loss of 8.0%±0.1% between 120°C and 180°C as determined by TGA.

107. 107. The crystalline form of any one of claims 50, 78, or 99-106, characterized by having a weight loss of 4.2%±0.1% between 180°C and 230°C as determined by TGA.

108. 51. The crystalline form of any one of claims 50, 78, or 99-107, characterized in that it has a TGA graph substantially as shown in Figure 51.

109. 51. The crystalline form of claim 50, comprising the disodium salt of the compound of formula (A-1).

110. 110. The crystalline form of claim 50 or 109, characterized in that it has an XRPD pattern comprising peaks at 6.39±0.20, 6.89±0.20, 16.32±0.20, 17.01±0.20, and 22.82±0.20 degrees 2θ angles.

111. 111. The crystalline form of claim 110, characterized in that it has an XRPD pattern containing additional peaks at 12.50±0.20 and 16.52±0.20 degrees 2θ angles.

112. 112. The crystalline form of claim 100 or 111, characterized in that it has an XRPD pattern containing additional peaks at 13.48±0.20 and 14.34±0.20 degrees 2θ angles.

113. 113. A crystalline form according to any one of claims 50 or 109 to 112, characterized in that it has an XRPD pattern substantially as shown in Figure 17.

114. 114. The crystalline form of any one of claims 50 or 109-113, characterized by having an endothermic peak at 60±2°C as determined by DSC.

115. 115. The crystalline form of any one of claims 50 or 109-114, characterized by having an endothermic peak at 212±2°C as determined by DSC.

116. 116. A crystalline form according to any one of claims 50 or 109 to 115, characterized in that it has a DSC graph substantially as shown in Figure 18.

117. 117. The crystalline form of any one of claims 50 or 109-116, characterized in that it has a weight loss of 3.3%±0.5% between 25°C and 48°C as determined by TGA.

118. 118. The crystalline form of any one of claims 50 or 109-117, characterized in that it has a weight loss of 2.1%±0.5% between 48°C and 100°C as determined by TGA.

119. 119. A crystalline form according to any one of claims 50 or 109 to 118, characterized in that it has a TGA graph substantially as shown in Figure 19.

120. 110. The crystalline form of claim 50 or 109, characterized in that it has an XRPD pattern comprising peaks at 5.26±0.50, 8.80±0.50, 16.75±0.50, and 17.72±0.50 degrees 2θ angles.

121. 121. The crystalline form of claim 120, characterized in that it has an XRPD pattern containing additional peaks at 9.28±0.50 and 10.47±0.50 degrees 2θ angles.

122. 122. The crystalline form of claim 120 or 121, characterized in that it has an XRPD pattern containing additional peaks at 8.37±0.50 and 21.32±0.50 degrees 2θ angles.

123. 26. The crystalline form of any one of claims 50, 109, or 120-122, characterized in that it has an XRPD pattern substantially as shown in Figure 26.

124. 27. The crystalline form of any one of claims 50, 109, or 120-123, characterized in that it has a DSC graph substantially as shown in Figure 27.

125. 125. The crystalline form of any one of claims 50, 109, or 120-124, characterized in that it has a weight loss of 5.4%±0.1% between 25°C and 140°C as determined by TGA.

126. 28. The crystalline form of any one of claims 50, 109, or 120-125, characterized in that it has a TGA graph substantially as shown in Figure 28.

127. 110. The crystalline form of claim 50 or 109, characterized in that it has an XRPD pattern comprising peaks at 6.03±0.20, 7.66±0.20, 12.04±0.20, and 18.73±0.20 degrees 2θ angles.

128. 128. The crystalline form of claim 127, characterized in that it has an XRPD pattern containing additional peaks at 12.93±0.20 and 18.97±0.20 degrees 2θ angles.

129. 129. The crystalline form of claim 127 or 128, characterized in that it has an XRPD pattern containing additional peaks at 19.91±0.20 and 24.62±0.20 degrees 2θ angles.

130. 32. The crystalline form of any one of claims 50, 109, or 127-129, characterized by having an XRPD pattern substantially as shown in Figure 32.

131. 131. The crystalline form of any one of claims 50, 109, or 127-130, characterized by having an endothermic peak at 52±2°C as determined by DSC.

132. 132. The crystalline form of any one of claims 50, 109, or 127-131, characterized by having an endothermic peak at 84±2°C as determined by DSC.

133. 133. The crystalline form of any one of claims 50, 109, or 127-132, characterized by having an endothermic peak at 104±2°C as determined by DSC.

134. 134. The crystalline form of any one of claims 50, 109, or 127-133, characterized by having an endothermic peak at 128±2°C as determined by DSC.

135. 33. The crystalline form of any one of claims 50, 109, or 127-134, characterized in that it has a DSC graph substantially as shown in Figure 33.

136. 136. The crystalline form of any one of claims 50, 109, or 127-135, characterized by having a weight loss of 11.9%±3.0% between 30°C and 110°C as determined by TGA.

137. 34. The crystalline form of any one of claims 50, 109, or 127-136, characterized in that it has a TGA graph substantially as shown in Figure 34.

138. 110. The crystalline form of claim 50 or 109, characterized in that it has an XRPD pattern comprising peaks at 6.07±0.20, 6.84±0.20, 12.07±0.20, 18.75±0.20, and 19.96±0.20 degrees 2θ angles.

139. 139. The crystalline form of claim 138, characterized in that it has an XRPD pattern containing additional peaks at 18.10±0.20 and 20.47±0.20 degrees 2θ angles.

140. 140. The crystalline form of claim 138 or 139, characterized in that it has an XRPD pattern containing additional peaks at 7.70±0.20 and 13.63±0.20 degrees 2θ angles.

141. 141. The crystalline form of any one of claims 50, 109, or 138-140, characterized by having an XRPD pattern substantially as shown in Figure 41.

142. 142. The crystalline form of any one of claims 50, 109, or 138-141, characterized by having an endothermic peak at 73±2°C as determined by DSC.

143. 143. The crystalline form of any one of claims 50, 109, or 138-142, characterized by having an endothermic peak at 99±2°C as determined by DSC.

144. 144. The crystalline form of any one of claims 50, 109, or 138-143, characterized by having an endothermic peak at 120±2°C as determined by DSC.

145. 42. The crystalline form of any one of claims 50, 109, or 138-144, characterized in that it has a DSC graph substantially as shown in Figure 42.

146. 146. The crystalline form of any one of claims 50, 109, or 138-145, characterized in that it has a weight loss of 0.6%±0.5% between 30°C and 48°C as determined by TGA.

147. 147. The crystalline form of any one of claims 50, 109, or 138-146, characterized in that it has a weight loss of 4.1%±0.5% between 48°C and 81°C as determined by TGA.

148. 148. The crystalline form of any one of claims 50, 109, or 138-147, characterized by having a weight loss of 2.7%±0.5% between 81°C and 140°C as determined by TGA.

149. 43. The crystalline form of any one of claims 50, 109, or 138-148, characterized in that it has a TGA graph substantially as shown in Figure 43.

150. 150. The crystalline form of any one of claims 50, 109, or 138-149, characterized in that it has a weight gain of 60%±5% from 1% RH to 95% RH as determined by DVS.

151. 151. The crystalline form of any one of claims 50, 109, or 138-150, characterized in that it has a weight loss of 58%±5% from 95% RH to 1% RH as determined by DVS.

152. 44. The crystalline form of any one of claims 50, 109, or 138-150, characterized in that it has a DVS graph substantially as shown in Figure 44.

153. 110. The crystalline form of claim 50 or 109, characterized in that it has an XRPD pattern comprising peaks at 66.93±0.50, 20.10±0.50, 32.35±0.50, and 37.94±0.50 degrees 2θ angles.

154. 154. The crystalline form of claim 153, characterized in that it has an XRPD pattern containing additional peaks at 13.86±0.50 and 17.26±0.50 degrees 2θ angles.

155. 155. The crystalline form of claim 153 or 154, characterized in that it has an XRPD pattern containing additional peaks at 20.80±0.50 and 32.53±0.50 degrees 2θ angles.

156. 35. The crystalline form of any one of claims 50, 109, or 153-155, characterized by having an XRPD pattern substantially as shown in Figure 35.

157. 36. The crystalline form of any one of claims 50, 109, or 153-156, characterized in that it has a DSC graph substantially as shown in Figure 36.

158. 158. The crystalline form of any one of claims 50, 109, or 153-157, characterized in that it has a weight loss of 2.7%±0.1% between 25°C and 64°C as determined by TGA.

159. 159. The crystalline form of any one of claims 50, 109, or 153-158, characterized in that it has a weight loss of 2.4%±0.1% between 65°C and 100°C as determined by TGA.

160. 160. The crystalline form of any one of claims 50, 109, or 153-159, characterized by having a weight loss of 0.9%±0.1% between 100°C and 140°C as determined by TGA.

161. 37. The crystalline form of any one of claims 50, 109, or 153-160, characterized in that it has a TGA graph substantially as shown in Figure 37.

162. 51. The crystalline form of claim 50, comprising the monopotassium salt of the compound of formula (A-1).

163. 163. The crystalline form of claim 50 or 162, characterized in that it has an XRPD pattern comprising peaks at 13.48±0.20, 16.62±0.20, and 16.62±0.20 degrees 2θ angles.

164. 164. The crystalline form of claim 163, characterized in that it has an XRPD pattern containing additional peaks at 12.25±0.20 and 19.69±0.20 degrees 2θ angles.

165. 165. The crystalline form of claim 163 or 164, characterized in that it has an XRPD pattern containing additional peaks at 11.21±0.20 and 24.83±0.20 degrees 2θ angles.

166. 166. A crystalline form according to any one of claims 50 or 162-165, characterized in that it has an XRPD pattern substantially as shown in Figure 20.

167. 167. The crystalline form of any one of claims 50 or 162-166, characterized by having an endothermic peak at 39±5°C as determined by DSC.

168. 168. The crystalline form of any one of claims 50 or 162-167, characterized by having an endothermic peak at 156±5°C as determined by DSC.

169. 21. The crystalline form of any one of claims 50 or 162-168, characterized in that it has a DSC graph substantially as shown in Figure 21.

170. 170. The crystalline form of any one of claims 50 or 162-169, characterized in that it has a weight loss of 3.2%±0.1% between 25°C and 100°C as determined by TGA.

171. 22. The crystalline form of any one of claims 50 or 162-170, characterized in that it has a TGA graph substantially as shown in Figure 22.

172. 51. The crystalline form of claim 50, comprising a dipotassium salt of the compound of formula (A-1).

173. 173. The crystalline form of claim 50 or 172, characterized in that it has an XRPD pattern comprising peaks at 5.84±0.50, 5.91±0.50, 9.21±0.50, and 18.56±0.50 degrees 2θ angles.

174. 174. The crystalline form of claim 173, characterized in that it has an XRPD pattern containing additional peaks at 15.56±0.50 and 19.02±0.50 degrees 2θ angles.

175. 175. The crystalline form of claim 173 or 174, characterized in that it has an XRPD pattern containing additional peaks at 13.56±0.50 and 25.27±0.50 degrees 2θ angles.

176. 23. The crystalline form of any one of claims 50 or 172-175, characterized in that it has an XRPD pattern substantially as shown in Figure 23.

177. 177. The crystalline form of any one of claims 50 or 172-176, characterized by having an endothermic peak at 70±10°C as determined by DSC.

178. 24. The crystalline form of any one of claims 50 or 172-177, characterized in that it has a DSC graph substantially as shown in Figure 24.

179. 179. The crystalline form of any one of claims 50 or 172-178, characterized in that it has a substantially continuous weight loss between 25°C and 300°C as determined by TGA.

180. 28. The crystalline form of any one of claims 50 or 172-179, characterized in that it has a TGA graph substantially as shown in Figure 25.

181. 173. The crystalline form of claim 50 or 172, characterized in that it has an XRPD pattern comprising peaks at 6.66±0.20, 17.43±0.20, 19.31±0.20, and 23.72±0.20 degrees 2θ angles.

182. 182. The crystalline form of claim 181, characterized in that it has an XRPD pattern containing additional peaks at 13.12±0.20 and 19.99±0.20 degrees 2θ angles.

183. 183. The crystalline form of claim 181 or 182, characterized in that it has an XRPD pattern containing additional peaks at 18.82±0.20 and 22.76±0.20 degrees 2θ angles.

184. 29. The crystalline form of any one of claims 50, 172, or 181-183, characterized by having an XRPD pattern substantially as shown in Figure 29.

185. 185. The crystalline form of any one of claims 50, 172, or 181-184, characterized by having an endothermic peak at 83±2°C as determined by DSC.

186. 30. The crystalline form of any one of claims 50, 172, or 181-185, characterized in that it has a DSC graph substantially as shown in Figure 30.

187. 187. The crystalline form of any one of claims 50, 172, or 181-186, characterized by having a weight loss of 0.3%±0.1% between 25°C and 40°C as determined by TGA.

188. 188. The crystalline form of any one of claims 50, 172, or 181-187, characterized by having a weight loss of 2.7%±0.1% between 40°C and 75°C as determined by TGA.

189. 189. The crystalline form of any one of claims 50, 172, or 181-188, characterized by having a weight loss of 3.1%±0.1% between 75°C and 170°C as determined by TGA.

190. 31. The crystalline form of any one of claims 50, 172, or 181-189, characterized in that it has a TGA graph substantially as shown in Figure 31.

191. 173. The crystalline form of claim 50 or 172, characterized in that it has an XRPD pattern comprising peaks at 6.65±0.20, 17.42±0.20, 19.30±0.20, and 23.75±0.20 degrees 2θ angles.

192. 192. The crystalline form of claim 191, characterized in that it has an XRPD pattern containing additional peaks at 20.00±0.20 and 22.78±0.20 degrees 2θ angles.

193. 193. The crystalline form of claim 191 or 192, characterized in that it has an XRPD pattern containing additional peaks at 13.13±0.20 and 18.82±0.20 degrees 2θ angles.

194. 45. The crystalline form of any one of claims 50, 172, or 191-193, characterized by having an XRPD pattern substantially as shown in Figure 45.

195. 195. The crystalline form of any one of claims 50, 172, or 191-194, characterized by having an endothermic peak at 86±2°C as determined by DSC.

196. 46. ​​The crystalline form of any one of claims 50, 172, or 191-195, characterized in that it has a DSC graph substantially as shown in Figure 46.

197. 200. The crystalline form of any one of claims 50, 172, or 191-196, characterized in that it has a weight loss of 0.7% or 0.7%±0.1% between 25°C and 42°C as determined by TGA.

198. 200. The crystalline form of any one of claims 50, 172, or 191-197, characterized in that it has a weight loss of 6.0%±0.1% between 42°C and 94°C as determined by TGA.

199. 47. The crystalline form of any one of claims 50, 172, or 191-198, characterized in that it has a TGA graph substantially as shown in Figure 47.

200. 200. The crystalline form of any one of claims 50, 172, or 191-199, characterized in that it has a weight gain of 62%±5% from 1% RH to 95% RH as determined by DVS.

201. 201. The crystalline form of any one of claims 50, 172, or 191-200, characterized in that it has a weight loss of 70%±5% from 95% RH to 1% RH as determined by DVS.

202. 48. The crystalline form of any one of claims 50, 172, or 191-201, characterized in that it has a DVS graph substantially as shown in Figure 48.

203. 202. A method of inhibiting KIF18A, comprising contacting a cell with an effective amount of (i) a formulation of any one of claims 1-49 or (ii) a crystalline form of any one of claims 50-202.

204. 20. 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 of any one of claims 1-49 or (ii) a crystalline form of any one of claims 50-202.

205. 202. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (i) a formulation of any one of claims 1-49 or (ii) a crystalline form of any one of claims 50-202.

206. 206. The method of claim 205, wherein the cancer is selected from the group consisting of carcinoma, 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, gallbladder, ovary, testis, 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, tumors of neuroendocrine origin, tumors of endocrine origin, small cell tumors, tumors of unknown primary, other tumors (including retinoblastoma, melanoma, seminoma, teratocarcinoma, osteosarcoma), and other cancer-related disorders that are a result of the presence or progression of cancer.

207. 50. A method for preparing the formulation of any one of claims 1 to 49, wherein the process comprises spray drying a solution of the 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.

208. 208. The method of claim 207, wherein the solution of the compound of formula (A) comprises dichloromethane and an alcohol.

209. 209. The method of claim 207 or claim 208, wherein the solution of the compound of formula (A) comprises dichloromethane and methanol.

210. 210. The method of any one of claims 207 to 209, wherein the solution of the compound of formula (A) comprises dichloromethane and an alcohol in a weight ratio of about 87:

13.

211. 203. A method of preparing the crystalline form of any one of claims 50 to 202, 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, isopropanol alcohol, methylcyclohexane, tetrahydrofuran, anisole, methyl isopropyl ketone, dipropyl ether, chloroform, tert-amyl alcohol, and any mixture thereof.

212. Formula (A): 【Chemistry 10】 1. A method for preparing a substantially amorphous form of a compound of formula (I), comprising: (1) forming a mixture of a compound of formula (A) and a solvent selected from the group consisting of N,N-dimethylformamide (DMF), water, and mixtures thereof; (2) isolating a solid from said mixture of (1); (3) washing said solid of (2) with water; and (4) drying said solid of (3) at room temperature, wherein Ring A is independently halo, —OH, C １－６ Alkyl, 3-10 membered heterocycloalkyl, —NR ａ１ C(O)NR ａ２ R ａ３ , -NR ａ４ C(O)OR ａ５ , -NR ａ６ R ａ７ , -N=S(O)R ａ８ R ａ９ , -OR ａ１０ , -S(O)R ａ１１ , -S(O)(NR ａ１２ ) R ａ１３ , -S(O) ２ NR ａ１４ R ａ１５ , -S(O) ２ R ａ１６ , -(CR ａ１７ R ａ１８ ) ０－１ C(O)NR ａ１９ R ａ２０ , -SR ａ２１ , -C(O)R ａ２２ , as well as —OH, cyano, C ３－１０ C substituted with one or more substituents independently selected from the group consisting of cycloalkyl, and 3-10 membered heterocycloalkyl optionally substituted with one or more halo. １－６ C optionally substituted with one or more substituents independently selected from the group consisting of alkyl ６－１４ aryl or 5-12 membered heteroaryl; R ａ１ -R ａ２２ are each independently hydrogen, or each independently halo, cyano, —OH, —O(C １－６ alkyl), C ２－６ Alkenyl, C ３－１０ Cycloalkyl, -S(C １－６ alkyl), =CR １ａ１ R １ａ２ , and halo, —OH, and —O(C １－６ C optionally substituted with one or more substituents independently selected from the group consisting of alkyl １－６ C optionally substituted with one or more substituents independently selected from the group consisting of alkyl １－６ Alkyl, C ２－６ Alkenyl, C ３－１０ Cycloalkyl, C ３－１０ Cycloalkenyl, 3-10 membered heterocycloalkyl, 3-10 membered heterocycloalkenyl, C ６－１４ aryl, or 5-12 membered heteroaryl, wherein R １ａ１ and R １ａ２ are each independently hydrogen or C １－６ is alkyl; Ring B is C ５－７ Cycloalkyl, C ５－７ cycloalkenyl, or 5-7 membered heterocycloalkyl, wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; m is 2; Two R's Ｂ The groups are bonded to the same carbon atom on ring B and together with the carbon atom to which they are bonded form C ３－７ Forming a cycloalkyl; Y １ is N or CR Ｃ１ and Y ２ is N or CR Ｃ２ and Y ３ is N or CR Ｃ３ and Y ４ is N or CR Ｃ４ and In the formula, Y １ , Y ２ , Y ３ and Y ４ of which 3 or less are N; R Ｃ１ -R Ｃ４ each independently represents hydrogen, halo, cyano, —OH, or —NO ２ , —C(O)NR ｃ１ R ｃ２ , -NR ｃ３ R ｃ４ , -NR ｃ５ S (O) ２ R ｃ６ , -P(O)R ｃ７ R ｃ８ , -N=S(O)R ｃ９ R ｃ１０ , -S(O)(NR ｃ１１ ) R ｃ１２ , -S(O) ２ R ｃ１３ , -NR ｃ１４ C(O)OR ｃ１５ , -NR ｃ１６ S (O) ２ (CH ２ ) １－６ NR ｃ１７ C(O)R ｃ１８ or C optionally substituted with one or more substituents independently selected from the group consisting of halo and —OH １－６ is alkyl; R ｃ１ -R ｃ１８ are each independently hydrogen, C ３－１０ C optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halo, and —OH; １－６ The method according to claim 1, wherein the alkyl is alkyl.

213. 213. The method of claim 212, wherein the solvent is a mixture of DMF and water.

214. The compound of formula (A) is represented by formula (A-1): 【Chemistry 11】 The method of claim 212 or 213, wherein the compound is

215. The compound of formula (A) is represented by formula (A-2): 【Chemistry 12】 The method of claim 212 or 213, wherein the compound is

216. The compound of formula (A) is represented by formula (A-3): 【Chemistry 13】 The method of claim 212 or 213, wherein the compound is

217. 207. The method of claim 205 or 206, wherein the cancer is associated with chromosomal instability.

218. The method of claim 205 or 217, wherein the cancer is selected from the group consisting of advanced solid tumors, high-grade serous adenocarcinoma of the ovary, squamous non-small cell lung cancer, triple-negative breast cancer, gastric adenocarcinoma, colorectal adenocarcinoma, esophageal squamous cell carcinoma, esophageal adenocarcinoma, esophagogastric junction adenocarcinoma, transitional cell carcinoma of the bladder, head and neck squamous cell carcinoma, ovarian carcinosarcoma, uterine carcinosarcoma, uterine serous adenocarcinoma, and endometrial carcinoma.

219. 219. The method of any one of claims 205, 206, 217, or 218, wherein (i) the formulation of any one of claims 1-49 or (ii) the crystalline form of any one of claims 50-202 is administered to the subject in a 28 day cycle.

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