Preparation method and crystal form of (6A,12A)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol

Abstract

Disclosed are processes and methods for preparing Compound (I). Also disclosed are crystalline forms of Compound (I), its pharmaceutically acceptable salts, solvates, hydrates, and co-crystals, pharmaceutical compositions containing same, methods of using same to treat cystic fibrosis, and methods of making same. JPEG2025505577000510.jpg4460

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 306,443, filed February 3, 2022, and U.S. Provisional Application No. 63 / 308,456, filed February 9, 2022, the contents of which are incorporated by reference in their entirety.

[0002] Disclosed herein are modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), processes and methods for preparing crystalline and amorphous solid forms of CFTR modulators, pharmaceutical compositions thereof, methods of treating cystic fibrosis using any of the foregoing, and processes for making the crystalline and amorphous forms. [Background technology]

[0003] Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 88,000 children and adults worldwide. Despite advances in CF treatment, there is no cure.

[0004] In patients with CF, mutations in endogenously expressed CFTR in respiratory epithelia result in reduced apical membrane anion secretion, leading to an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to increased mucus accumulation in the lungs, accompanied by microbial infections that ultimately lead to death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal disorders and pancreatic insufficiency, which can be fatal if left untreated. Additionally, the majority of men with cystic fibrosis are infertile, and fertility is reduced in women with cystic fibrosis.

[0005] Sequence analysis of the CFTR gene has revealed a variety of disease-causing mutations (Cutting, G.R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B.S. et al. (1989) Science 245:1073-1080; Kerem, B.S. et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, over 2,000 CF gene mutations have been identified, and the CFTR2 database currently contains information on at least 322 of these identified mutations, with sufficient evidence to define at least 281 mutations as disease-causing. The most common disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, commonly referred to as the F508del mutation. This mutation occurs in many cases of cystic fibrosis and is associated with severe disease.

[0006] CFTR is a cAMP / ATP-mediated anion channel expressed in various cell types, including absorptive and secretory epithelial cells, where it controls the flow of anions across the membrane and also regulates the activity of other ion channels and proteins. In epithelial cells, normal CFTR function is essential for maintaining electrolyte transport throughout the body, including respiratory and digestive tissues. CFTR is a 1,480-amino acid protein that encodes a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide-binding domain. The two transmembrane domains are linked via large, polar regulatory (R) domains to multiple phosphorylation sites that control channel activity and cellular trafficking.

[0007] Chloride transport occurs through the coordinated activity of ENaC (epithelial sodium channel) and CFTR present on the apical membrane, and the Na+-K+-ATPase pump and Cl- channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to intracellular chloride accumulation, after which chloride can passively leave the cell via Cl- channels, resulting in vectorial transport. The location of the Na+ / 2Cl- / K+ cotransporter, the Na+-K+-ATPase pump, and the basolateral membrane K+ channels on the basolateral surface, as well as CFTR on the luminal side, regulates chloride secretion. Presumably because water itself is not actively transported, its flow across the epithelium depends on the slight transepithelial osmotic gradient generated by the bulk flow of sodium and chloride. Recently, several CFTR modulators have been identified. These modulators are considered, for example, potentiators, correctors, potentiator enhancers / copotentiators, amplifiers, read-through drugs, and nucleic acid therapies. CFTR modulators that increase the channel gating activity of mutant and wild-type CFTR at the epithelial cell surface are known as potentiators. Correctors improve defective protein processing, resulting in trafficking to the epithelial surface. Ghelani and Schneider-Futschik (2020) ACS Pharmacol. Transl. Sci. 3:4-10. Three CFTR correctors have been approved by the US Food and Drug Administration for the treatment of cystic fibrosis. However, monotherapy with some CFTR correctors has proven ineffective, and as a result, combination therapy with potentiators is required to enhance CFTR activity. Currently, only one CFTR potentiator is approved for the treatment of cystic fibrosis. Thus, while the treatment of cystic fibrosis has been transformed by these new small molecule CFTR modulators, new and better modulators are needed to prevent disease progression, reduce the severity of cystic fibrosis and other CFTR-mediated diseases, and treat more severe forms of these diseases. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Cutting, GRet al. (1990) Nature 346:366-369 [Non-patent document 2] Dean, M. et al. (1990) Cell 61:863:870 [Non-patent document 3] Kerem, BS. et al. (1989) Science 245:1073-1080 [Non-patent document 4] Kerem, BS. et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451 [Non-patent document 5] Ghelani and Schneider-Futschik(2020)ACS Pharmacol.Transl.Sci.3:4-10 Summary of the Invention [Means for solving the problem]

[0009] The compound (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (Compound I) is a modulator of CFTR activity and is therefore useful in the treatment of CFTR-mediated diseases such as CF. Compound I has the following structure: [ka] Compound I is disclosed in PCT International Application No. PCT / US2021 / 044895, published as WO 2022 / 032068 and incorporated herein by reference in its entirety. However, there remains a need for an efficient process for the synthesis of Compound I that provides this compound or a pharmaceutically acceptable salt thereof in higher yield, higher selectivity, or higher purity, for example, compared to known processes.

[0010] Accordingly, one aspect of the present disclosure provides methods for preparing Compound I, stereoisomers of Compound I, deuterated derivatives of Compound I and stereoisomers thereof, and pharmaceutically acceptable salts of any of the foregoing.

[0011] A further aspect of the present disclosure provides solid forms and pharmaceutically acceptable salts thereof of Compound I. Compound I was first described in WO 2022 / 032068 as a heptane solvate.

[0012] Crystalline forms are of interest in the pharmaceutical industry, where control over the crystalline form of an active ingredient may be desirable or even required. Because different crystalline forms may have different properties, a reproducible process for producing a compound with a specific crystalline form in high purity may be desirable for compounds intended for use in pharmaceuticals. For example, different crystalline forms may have different chemical, physical, and / or pharmaceutical properties. In some embodiments, one or more crystalline forms disclosed herein may exhibit a higher level of purity, chemical stability, and / or physical stability compared to the form produced in WO 2022 / 032068. Certain crystalline forms (e.g., the crystalline free form, crystalline salts, crystalline salt solvates, and crystalline salt hydrate forms of Compound I (collectively referred to as "crystalline forms") may exhibit lower hygroscopicity than the forms produced in WO 2022 / 032068. Thus, the crystalline forms of the present disclosure may offer advantages during drug substance manufacturing, storage, and handling over the amorphous forms produced in WO 2022 / 032068. Thus, pharmaceutically acceptable crystalline forms of Compound I may be particularly useful in the manufacture of medicaments for the treatment of CFTR-mediated diseases.

[0013] In some embodiments, the crystalline form of compound I is neat crystalline form A of compound I. In some embodiments, the crystalline form of compound I is neat crystalline form B of compound I. In some embodiments, the crystalline form of compound I is hemihydrate crystalline form C of compound I. In some embodiments, the crystalline form of compound I is neat crystalline form D of compound I. In some embodiments, the crystalline form of compound I is neat crystalline form E of compound I. In some embodiments, the crystalline form of compound I is an acetic acid solvate of compound I. In some embodiments, the crystalline form of compound I is heptane solvate crystalline form B of compound I. In some embodiments, the crystalline form of compound I is heptane solvate crystalline form C of compound I. In some embodiments, the crystalline form of compound I is an octane solvate of compound I. In some embodiments, the crystalline form of compound I is cyclohexane solvate crystalline form A of compound I. In some embodiments, the crystalline form of compound I is cyclohexane solvate crystalline form B of compound I. In some embodiments, the crystalline form of Compound I is cyclohexane solvate crystalline form C of Compound I. In some embodiments, the crystalline form of Compound I is an ethanol solvate of Compound I. In some embodiments, the crystalline form of Compound I is a solvate / hydrate (dry) of Compound I. In some embodiments, the crystalline form of Compound I is a solvate / hydrate (wet) of Compound I. In some embodiments, the crystalline form of Compound I is an L-lysine co-crystal of Compound I. In some embodiments, the crystalline form of Compound I is an L-arginine co-crystal of Compound I. In some embodiments, the crystalline form of Compound I is an L-phenylalanine co-crystal of Compound I. In some embodiments, the crystalline form of Compound I is a succinic acid co-crystal (wet) of Compound I. In some embodiments, the crystalline form of Compound I is a succinic acid co-crystal (dry) of Compound I. In some embodiments, the crystalline form of Compound I is a methanol solvate / hydrate of Compound I.

[0014] In some embodiments, the solid form of Compound I is an amorphous form. In some embodiments, the solid amorphous form of Compound I is a neat amorphous form of Compound I.

[0015] Another aspect of the present invention provides pharmaceutical compositions comprising at least one solid form selected from the solid forms of Compound I disclosed herein, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing, which may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0016] In certain embodiments, pharmaceutical compositions of the present invention comprise Compound I in any of the pharmaceutically acceptable solid forms disclosed herein. In some embodiments, compositions comprising Compound I in any of the pharmaceutically acceptable crystalline forms disclosed herein may optionally further comprise at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts, and deuterated derivatives thereof.

[0017] Another aspect of the present invention provides methods of treating the CFTR-mediated disease cystic fibrosis, comprising administering Compound I in any of the pharmaceutically acceptable solid forms disclosed herein to a subject in need of such treatment, optionally as part of a pharmaceutical composition containing at least one additional component (such as a carrier or an additional active agent). In some embodiments, a method of treating the CFTR-mediated disease cystic fibrosis comprises administering Compound I in any of the pharmaceutically acceptable solid forms disclosed herein, and optionally administering (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide. N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound III), or N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound III-d), 3-(6-(1-(2,2-difluoromethyl)phenyl)-4-oxoquinoline-3-carboxamide) N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound V), N-(benzenesulfonyl)-6-[3 -[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (compound VI), (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (Compound VII), (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ6-thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (Compound VIII), N and further administering one or more additional CFTR modulators selected from N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound IX), and N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound X).

[0018] A further aspect of the present disclosure provides a process for making the solid forms of Compound I disclosed herein.

[0019] Another aspect of the present invention provides solid forms of Compound I, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing, as disclosed herein, for use in any of the methods described herein. [Brief explanation of the drawings]

[0020] [Figure 1] FIG. 1 provides the powder X-ray diffraction (XRPD) pattern of the neat amorphous form of Compound I.

[0021] [Figure 2] FIG. 2 provides a thermogravimetric analysis (TGA) curve of the neat amorphous form of Compound I.

[0022] [Figure 3]FIG. 3 provides a differential scanning calorimetry (DSC) analysis of the neat amorphous form of Compound I.

[0023] [Figure 4] FIG. 4 provides the 13C-solid state NMR (SSNMR) spectrum of the neat amorphous form of Compound I.

[0024] [Figure 5] FIG. 5 provides the 19F-SS NMR spectrum of the neat amorphous form of Compound I.

[0025] [Figure 6] FIG. 6 provides the XRPD pattern of neat crystalline Form A of crystalline Compound I.

[0026] [Figure 7] FIG. 7 provides the TGA curve of neat crystalline Form A of crystalline Compound I.

[0027] [Figure 8] FIG. 8 provides a DSC analysis of neat crystalline Form A of crystalline Compound I.

[0028] [Figure 9] FIG. 9 provides the XRPD pattern of neat crystalline Form B of crystalline Compound I.

[0029] [Figure 10] FIG. 10 provides the TGA curve of neat crystalline Form B of crystalline Compound I.

[0030] [Figure 11] FIG. 11 provides a DSC analysis of neat crystalline Form B of crystalline Compound I.

[0031] [Figure 12] FIG. 12 provides the 13C-SS NMR spectrum of neat crystalline Form B of crystalline Compound I.

[0032] [Figure 13] FIG. 13 provides the 19F-SSNMR spectrum of neat crystalline Form B of crystalline Compound I.

[0033] [Figure 14] FIG. 14 provides the XRPD pattern of crystalline Compound I hemihydrate Form C.

[0034] [Figure 15] FIG. 15 provides the TGA curve of crystalline Compound I hemihydrate crystal form C.

[0035] [Figure 16] FIG. 16 provides a DSC analysis of crystalline Compound I hemihydrate Form C.

[0036] [Figure 17] FIG. 17 provides the 13C-SS NMR spectrum of crystalline Compound I hemihydrate Form C.

[0037] [Figure 18] FIG. 18 provides the 19F-SS NMR spectrum of crystalline Compound I hemihydrate Form C.

[0038] [Figure 19] FIG. 19 provides the XRPD pattern of neat crystalline Form D of crystalline Compound I.

[0039] [Figure 20] FIG. 20 provides the TGA curve of neat crystalline Form D of crystalline Compound I.

[0040] [Figure 21] FIG. 21 provides a DSC analysis of neat crystalline Form D of crystalline Compound I.

[0041] [Figure 22] FIG. 22 provides the 13C-SS NMR spectrum of neat crystalline Form D of crystalline Compound I.

[0042] [Figure 23] FIG. 23 provides the 19F-SSNMR spectrum of neat crystalline Form D of crystalline Compound I.

[0043] [Figure 24] FIG. 24 provides a DSC analysis of neat crystalline Form E of crystalline Compound I.

[0044] [Figure 25] FIG. 25 provides the XRPD pattern of the crystalline Compound I acetic acid solvate.

[0045] [Figure 26] FIG. 26 provides a DSC analysis of the crystalline Compound I acetic acid solvate.

[0046] [Figure 27] FIG. 27 provides the XRPD pattern of crystalline Compound I heptane solvate crystal form B.

[0047] [Figure 28] FIG. 28 provides a DSC analysis of crystalline Compound I heptane solvate crystal form B.

[0048] [Figure 29] FIG. 29 provides the 13C-SS NMR spectrum of crystalline Compound I heptane solvate crystal form B.

[0049] [Figure 30] FIG. 30 provides the 19F-SSNMR spectrum of crystalline Compound I heptane solvate crystal form B.

[0050] [Figure 31] FIG. 31 provides the XRPD pattern of crystalline Compound I heptane solvate crystal form C.

[0051] [Figure 32]FIG. 32 provides the TGA curve of crystalline Compound I heptane solvate crystal form C.

[0052] [Figure 33] FIG. 33 provides a DSC analysis of crystalline Compound I heptane solvate crystal form C.

[0053] [Figure 34] FIG. 34 provides the 13C-SS NMR spectrum of crystalline Compound I heptane solvate crystal form C.

[0054] [Figure 35] FIG. 35 provides the XRPD pattern of the crystalline Compound I octane solvate.

[0055] [Figure 36] FIG. 36 provides the 13C-SS NMR spectrum of the crystalline Compound I octane solvate.

[0056] [Figure 37] FIG. 37 provides the 19F-SSNMR spectrum of the crystalline Compound I octane solvate.

[0057] [Figure 38] FIG. 38 provides the XRPD pattern of crystalline Compound I cyclohexane solvate crystal form A.

[0058] [Figure 39] FIG. 39 provides the 13C-SS NMR spectrum of crystalline Compound I cyclohexane solvate crystal form A.

[0059] [Figure 40] FIG. 40 provides the 19F-SS NMR spectrum of crystalline Compound I cyclohexane solvate crystal form A.

[0060] [Figure 41]FIG. 41 provides the XRPD pattern of crystalline Compound I cyclohexane solvate crystal form B.

[0061] [Figure 42] FIG. 42 provides a DSC analysis of crystalline Compound I cyclohexane solvate crystal form B.

[0062] [Figure 43] FIG. 43 provides the 13C-SS NMR spectrum of crystalline Compound I cyclohexane solvate crystal form B.

[0063] [Figure 44] FIG. 44 provides the 19F-SSNMR spectrum of crystalline Compound I cyclohexane solvate crystal form B.

[0064] [Figure 45] FIG. 45 provides the XRPD pattern of crystalline Compound I cyclohexane solvate crystal form C.

[0065] [Figure 46] FIG. 46 provides the XRPD pattern of the crystalline Compound I ethanol solvate.

[0066] [Figure 47] FIG. 47 provides the 13C-SS NMR spectrum of the crystalline Compound I ethanol solvate.

[0067] [Figure 48] FIG. 48 provides the 19F-SSNMR spectrum of the crystalline Compound I ethanol solvate.

[0068] [Figure 49] FIG. 49 provides the XRPD pattern of crystalline Compound I solvate / hydrate (dry).

[0069] [Figure 50]FIG. 50 provides the TGA curve of crystalline Compound I solvate / hydrate (dry).

[0070] [Figure 51] FIG. 51 provides a DSC analysis of crystalline Compound I solvates / hydrates (dry).

[0071] [Figure 52] FIG. 52 provides the XRPD pattern of crystalline Compound I solvate / hydrate (wet).

[0072] [Figure 53] FIG. 53 provides the 13C-SS NMR spectrum of crystalline Compound I solvate / hydrate (wet).

[0073] [Figure 54] FIG. 54 provides the 19F-SSNMR spectrum of crystalline Compound I solvate / hydrate (wet).

[0074] [Figure 55] FIG. 55 provides the XRPD pattern of crystalline Compound I L-lysine co-crystal.

[0075] [Figure 56] FIG. 56 provides the TGA curve of crystalline Compound I L-lysine co-crystal.

[0076] [Figure 57] FIG. 57 provides a DSC analysis of crystalline Compound I L-lysine co-crystal.

[0077] [Figure 58] FIG. 58 provides the 13C-SS NMR spectrum of crystalline Compound I L-lysine co-crystal.

[0078] [Figure 59] FIG. 59 provides the XRPD pattern of crystalline Compound I L-arginine co-crystal.

[0079] [Figure 60] FIG. 60 provides the TGA curve of crystalline Compound I L-arginine co-crystal.

[0080] [Figure 61] FIG. 61 provides a DSC analysis of crystalline Compound I L-arginine co-crystal.

[0081] [Figure 62] FIG. 62 provides the XRPD pattern of crystalline Compound I L-phenylalanine co-crystal.

[0082] [Figure 63] FIG. 63 provides a DSC analysis of crystalline Compound I L-phenylalanine co-crystal.

[0083] [Figure 64] FIG. 64 provides the XRPD pattern of crystalline Compound I succinic acid co-crystal (wet).

[0084] [Figure 65] FIG. 65 provides the XRPD pattern of crystalline Compound I succinic acid co-crystal (dry).

[0085] [Figure 66] FIG. 66 provides a DSC analysis of crystalline Compound I succinic acid co-crystal (dry).

[0086] [Figure 67] FIG. 67 provides the XRPD pattern of the crystalline Compound I methanol solvate / hydrate.

[0087] [Figure 68] FIG. 68 provides the 13C-SS NMR spectrum of the crystalline Compound I methanol solvate / hydrate.

[0088] [Figure 69]FIG. 69 provides the 19F-SSNMR spectrum of the crystalline Compound I methanol solvate / hydrate.

[0089] [Figure 70] FIG. 70 provides the powder X-ray diffraction (XRPD) pattern of crystalline Compound I heptane solvate crystal form A.

[0090] [Figure 71] FIG. 71 provides XRPD patterns of crystalline Compound I heptane solvate Form A prepared under three different drying conditions.

[0091] [Figure 72] FIG. 72 provides a DSC analysis of crystalline Compound I heptane solvate Form A.

[0092] [Figure 73] FIG. 73 provides the 13C-SS NMR spectrum of crystalline Compound I heptane solvate crystal form A.

[0093] [Figure 74] FIG. 74 provides the 19F-SSNMR of crystalline Compound I heptane solvate crystal form A.

[0094] [Figure 75] FIG. 75 provides the TGA curve of crystalline Compound I heptane solvate crystal form A (drying condition 1).

[0095] [Figure 76] FIG. 76 provides the TGA curve of crystalline Compound I heptane solvate crystal form A (drying condition 2).

[0096] [Figure 77] FIG. 77 provides the TGA curve of crystalline Compound I heptane solvate crystal form A (drying condition 3). DETAILED DESCRIPTION OF THE INVENTION

[0097] definition As used throughout this disclosure, “Compound I” refers to (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, which can be represented as having the following structure: [ka]

[0098] Compound I can be a racemic mixture or an enantiomerically enriched (e.g., greater than 90% ee, greater than 95% ee, greater than 98% ee) mixture of isomers. Compound I can be in the form of a pharmaceutically acceptable salt, solvate, and / or hydrate. Compound I and methods of making and using Compound I, stereoisomers of Compound I, deuterated derivatives of Compound I and stereoisomers thereof, and pharmaceutically acceptable salts of any of the foregoing, are disclosed in WO 2022 / 032068, which is incorporated herein by reference.

[0099] As used herein, "Compound II" refers to (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, which can be represented by the following structure: [ka] Compound II can be in the form of a pharmaceutically acceptable salt.Compound II and methods for making and using Compound II are disclosed in WO 2010 / 053471, WO 2011 / 119984, WO 2011 / 133751, WO 2011 / 133951 and WO 2015 / 160787, each of which is incorporated herein by reference.

[0100] As used throughout this disclosure, "Compound III" refers to N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, and is represented by the following structure: [ka] Compound III can also be in the form of a pharmaceutically acceptable salt. Compound III and methods of making and using Compound III are disclosed in WO 2006 / 002421, WO 2007 / 079139, WO 2010 / 108162, and WO 2010 / 019239, each of which is incorporated herein by reference.

[0101] In some embodiments, a deuterated derivative of Compound III (Compound III-d) is used in the compositions and methods disclosed herein. The chemical name of Compound III-d is N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d)propan-2-yl-1,1,1,3,3,3-d)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide and is represented by the following structure: [ka] Compound III-d can be in the form of a pharmaceutically acceptable salt. Compound III-d and methods of making and using compound III-d are disclosed in WO 2012 / 158885, WO 2014 / 078842, and U.S. Pat. No. 8,865,902, which are incorporated herein by reference.

[0102] As used herein, "Compound IV" refers to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, represented by the following chemical structure: [ka] Compound IV can be in the form of a pharmaceutically acceptable salt. Compound IV and methods of making and using Compound IV are disclosed in WO 2007 / 056341, WO 2009 / 073757, and WO 2009 / 076142, which are incorporated herein by reference.

[0103] As used herein, "Compound V" refers to N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, and is represented by the following chemical structure: [ka] Compound V can be in the form of a pharmaceutically acceptable salt. Compound V and methods of making and using Compound V are disclosed in WO 2018 / 107100 and WO 2019 / 113476, which are incorporated herein by reference.

[0104] As used herein, "Compound VI" refers to N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, and is represented by the following chemical structure: [ka] Compound VI can be in the form of a pharmaceutically acceptable salt. Compound VI and methods of making and using Compound VI are disclosed in WO 2018 / 064632, which is incorporated herein by reference.

[0105] As used herein, "Compound VII" refers to (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione, and is represented by the following chemical structure: [ka] Compound VII can be in the form of a pharmaceutically acceptable salt. Compound VII and methods for making and using Compound VII are disclosed in International Publication No. WO 2019 / 161078, International Publication No. WO 2020 / 102346, and PCT Application No. PCT / US2020 / 046116, which are incorporated herein by reference.

[0106] As used herein, "compound VIII" refers to (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ6-thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, and is represented by the following chemical structure: [ka] Compound VIII can be in the form of a pharmaceutically acceptable salt. Compound VIII and methods for making and using Compound VIII are disclosed in International Publication No. WO 2020 / 206080, which is incorporated herein by reference.

[0107] As used herein, "compound IX" refers to N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, represented by the following chemical structure: [ka] Compound IX can be in the form of a pharmaceutically acceptable salt. Compound IX and methods of making and using Compound IX are disclosed in WO 2016 / 057572, which is incorporated herein by reference.

[0108] As used herein, "Compound X" refers to N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, and is represented by the following chemical structure: [ka] Compound X can be in the form of a pharmaceutically acceptable salt. Compound X and methods of making and using Compound X are disclosed in WO 2016 / 057572, which is incorporated herein by reference.

[0109] As used herein, "CFTR" means cystic fibrosis transmembrane conductance regulator.

[0110] As used herein, the terms "CFTR modulator" and "CFTR-modulating compound" refer interchangeably to compounds that directly or indirectly increase the activity of CFTR. Increased activity resulting from a CFTR modulator includes, but is not limited to, compounds that correct, enhance, stabilize, and / or amplify CFTR.

[0111] As used herein, the term "CFTR corrector" refers to a compound that promotes the processing and trafficking of CFTR, increasing the amount of CFTR at the cell surface.

[0112] As used herein, the term "CFTR potentiator" refers to a compound that increases the channel activity of the CFTR protein located on the cell surface, resulting in enhanced ion transport.

[0113] As used herein, the terms "CFTR potentiator potentiator," "CFTR potentiator," and "CFTR co-potentiator" are used interchangeably and refer to compounds that increase CFTR potentiation.

[0114] As used herein, the term "active pharmaceutical ingredient" ("API") or "therapeutic agent" refers to a biologically active compound.

[0115] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0116] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of a compound that, when administered, produces a desired effect (e.g., amelioration of CF or symptoms of CF, or a reduction in the severity of CF or symptoms of CF). The exact amount of an effective dose will depend on the purpose of the treatment, and will be ascertainable by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0117] As used herein, the terms "treatment," "treating," and the like generally refer to an improvement in CF or one or more of its symptoms, or a reduction in the severity of CF or one or more of its symptoms in a subject. As used herein, "treatment" includes, but is not limited to, increasing the subject's growth, increasing weight gain, reducing mucus in the lungs, improving pancreatic and / or liver function, reducing chest infections, and / or reducing coughing or shortness of breath. Improvement in or a reduction in the severity of any of these symptoms can be readily assessed according to standard methods and techniques known in the art.

[0118] As used herein, the term "in combination with," when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means that the two or more compounds, agents, or active pharmaceutical ingredients are administered to a patient either before or after each other, or simultaneously with each other.

[0119] As used herein, "mutation" can refer to a mutation in the CFTR gene or CFTR protein. A "CFTR gene mutation" refers to a mutation in the CFTR gene, and a "CFTR protein mutation" refers to a mutation in the CFTR protein. Generally, a genetic defect or mutation, or a nucleotide change in a gene, results in a mutation or frameshift in the CFTR protein translated from that gene.

[0120] As used herein, the term "F508del" refers to a mutant CFTR protein lacking the amino acid phenylalanine at position 508, or a mutant CFTR gene encoding a CFTR protein lacking the amino acid phenylalanine at position 508.

[0121] As used herein, the term "alkyl" means a saturated or partially saturated, branched or straight-chain aliphatic hydrocarbon having carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, etc.), where one or more adjacent carbon atoms are interrupted by a double bond (alkenyl) or triple bond (alkynyl). An alkyl group can be substituted or unsubstituted.

[0122] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0123] As used herein, the term "π bond" refers to a covalent bond formed by p orbitals of adjacent atoms. A π bond exists when there is a multiple bond, i.e., a double or triple bond, between two atoms. For example, a carbon-carbon double bond consists of one π bond, and a carbon-carbon triple bond consists of two π bonds.

[0124] The terms "aliphatic" or "aliphatic group," as used herein, refer to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation; or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule (referred to herein as "alicyclic," "carbocyclic," or "cycloalkyl"). Unless otherwise specified, an aliphatic group contains 1-20 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-10 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-8 aliphatic carbon atoms. In yet other embodiments, an aliphatic group contains 1-6 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-8 hydrocarbon or a bicyclic or tricyclic C8-14 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule, and any individual ring within the bicyclic ring system has 3 to 7 members. Suitable aliphatic groups include, but are not limited to, straight-chain or branched-chain, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrid groups thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, and (cycloalkyl)alkenyl. Suitable alicyclic groups include cycloalkyl, bicyclic cycloalkyl (e.g., decalin), bridged bicycloalkyls such as norbornyl or [2.2.2]bicyclo-octyl, and bridged tricyclics such as adamantyl.

[0125] As used herein, the term "halogen" or "halo" means F, Cl, Br, or I.

[0126] As used herein, the term "haloalkyl group" refers to an alkyl group substituted with one or more halogen atoms, such as fluoroalkyl, which refers to an alkyl group substituted with one or more fluorine atoms.

[0127] As used herein, the term "alkoxy" refers to an alkyl or cycloalkyl covalently linked to an oxygen atom. An alkoxy group can be substituted or unsubstituted.

[0128] As used herein, the terms "haloalicyclic" and "haloalkoxy" mean an alicyclic or alkoxy, optionally substituted with one or more halo atoms. Examples of haloalicyclics include -CHF, -CHF, -CF, -CF-, and perhaloalkyls, such as -CFCF.

[0129] As used herein, "cycloalkyl group" refers to a cyclic, non-aromatic hydrocarbon group containing 3 to 12 carbons in the ring (e.g., 3 to 10 carbons). Cycloalkyl groups include monocyclic, bicyclic, tricyclic, bridged, fused, and spirocyclic groups, including monospiro and dispiro rings. Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, spiro[2.2]pentane, and dispiro[2.0.2.1]heptane. Cycloalkyl groups can be substituted or unsubstituted.

[0130] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocyclic ring, for example, a substitutable nitrogen of a heterocyclic ring that is N (such as 3,4-dihydro-2H-pyrrolyl), NH (such as pyrrolidinyl), or NR (such as N-substituted pyrrolidinyl)).

[0131] The term "heteroaliphatic," as used herein, refers to an aliphatic group in which one or two carbon atoms are independently replaced with one or more heteroatoms, such as oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups can be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocycle," "heterocyclyl," "heterocycloaliphatic," and "heterocyclic" groups.

[0132] As used herein, the terms "heterocycle," "heterocyclyl," "heterocycloaliphatic," or "heterocyclic ring" refer to non-aromatic monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused, and spirocyclic ring systems, including monospiro and dispiro ring systems, in which one or more ring members are independently selected heteroatoms. In some embodiments, a "heterocycle," "heterocyclyl," "heteroaliphatic," or "heterocyclic" group has three to fourteen ring members, one or more of which are heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and each ring in the system contains three to seven ring members.

[0133] As used herein, the term "aryl" refers to a functional group or substituent derived from an aromatic ring, including monocyclic aromatic rings, as well as bicyclic, tricyclic, and fused ring systems in which at least one ring in the system is aromatic. Aryl groups may be optionally substituted with one or more substituents. Non-limiting examples of aryl groups include phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthalenyl.

[0134] As used herein, the term "heteroaryl" refers to an aromatic ring containing at least one ring atom that is a heteroatom, such as O, N, or S. Heteroaryl groups encompass monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, where at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in the system contains three to seven ring members. Non-limiting examples of heteroaryl rings include pyridine, quinoline, indole, and indoline. Heteroaryl groups may be optionally substituted with one or more substituents. In certain embodiments, the term "heteroaryl ring" encompasses heteroaryl rings in various oxidation states, including heteroaryl rings containing N-oxides and sulfoxides. Non-limiting examples of such heteroaryl rings include pyrimidine N-oxide, quinoline N-oxide, thiophene S-oxide, and pyrimidine N-oxide.

[0135] The term "stable," as used herein, refers to compounds that do not substantially change when subjected to conditions that allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.

[0136] The term "chemically stable," as used herein, means that a solid form of Compound I does not decompose into one or more different compounds when subjected to specified conditions, such as 40°C / 75% relative humidity, for a specified period of time, e.g., 1 day, 2 days, 3 days, 1 week, 2 weeks, or more. In some embodiments, less than 25% of the solid form of Compound I decomposes. In some embodiments, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1%, or less than about 0.5% of the solid form of Compound I decomposes under specified conditions. In some embodiments, a detectable amount of the solid form of Compound I does not decompose.

[0137] The term "physically stable," as used herein, means that a solid form of Compound I does not change into one or more different physical forms of Compound I (e.g., different solid forms as measured by XRPD, DSC, etc.) when subjected to specified conditions, such as, for example, 40°C / 75% relative humidity, for a specified period of time, e.g., 1 day, 2 days, 3 days, 1 week, 2 weeks, or more. In some embodiments, less than 25% of the solid form of Compound I changes into one or more different physical forms when subjected to the specified conditions. In some embodiments, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, less than about 1%, or less than about 0.5% of the solid form of Compound I changes into one or more different physical forms of Compound I when subjected to the specified conditions. In some embodiments, no detectable amount of the solid form of Compound I changes into one or more physically different solid forms of Compound I.

[0138] In this specification, "selected" and "chosen" are used interchangeably.

[0139] As used herein, the term "ambient conditions" refers to room temperature, open air conditions, and uncontrolled humidity conditions. As used herein, the terms "room temperature" and "ambient temperature" refer to temperatures between 15°C and 30°C.

[0140] As used herein, the term "solvent" refers to any liquid in which the product is at least partially soluble (product solubility >1 g / L).

[0141] Non-limiting examples of suitable solvents that can be used in the present disclosure include, for example, water (HO), methanol (MeOH), methylene chloride or dichloromethane (DCM; CHCl), acetonitrile (MeCN; CHCN), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0142] The term "protecting group," as used herein, refers to any chemical group that is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction.

[0143] Methods for adding (a process commonly referred to as "protecting") and removing (a process commonly referred to as "deprotecting") protecting groups are well known in the art and are available, for example, in P.J. Kocienski, Protecting Groups, 3rd edition (Thieme, 2005), and Greene and Wuts, Protective Groups in Organic Synthesis, 4th edition (John Wiley & Sons, New York, 2007), both of which are incorporated herein by reference in their entireties.

[0144] Non-limiting examples of useful protecting groups for amines that can be used in the present disclosure include monovalent protecting groups such as t-butyloxycarbonyl (Boc), benzyl (Bn), β-methoxyethoxytrityl (MEM), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts), as well as protecting groups such as benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloylamine, N-dithiazolinone, and the like. Examples of divalent protecting groups include succinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilisoindoline (Benzostabase, BSB), N-diphenylsilyldiethylene, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

[0145] Non-limiting examples of useful protecting groups for alcohols that can be used in the present disclosure include, for example, acetyl (Ac), benzoyl (Bz), benzyl (Bn), β-methoxyethoxymethyl (MEM), dimethoxytrityl (DMT), methoxymethyl (MOM), methoxytrityl (MMT), p-methoxybenzyl (PMB), pivaloyl (Piv), tetrahydropyranyl (THP), trityl (Tr), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), and t-butyldiphenylsilyl (TBDPS).

[0146] Non-limiting examples of useful protecting groups for carboxylic acids that can be used in the present disclosure include, for example, methyl or ethyl esters, substituted alkyl esters such as 9-fluorenylmethyl, methoxymethyl (MOM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl, β-methoxyethoxymethyl (MEM), 2-(trimethylsilyl)ethoxymethyl (SEM), benzyloxymethyl (BOM), pivaloyloxymethyl (POM), phenylacetoxymethyl, and cyanomethyl, acetyl (Ac), phenacyl, substituted phenacyl esters, 2,2,2-trichloroethyl, 2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, t-butyl, 3-methyl-3-pentyl, dicyclopropylmethyl, cyclopentyl, cyclohexyl, allyl, methallyl, cinnamyl, phenyl (Ph), silyl esters, benzyl, and substituted benzyl, 2,6-dialkylphenyl, and pentafluorophenyl (PFP).

[0147] Non-limiting examples of amine bases that can be used in the present disclosure include, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine (NMM), triethylamine (EtN; TEA), diisopropylethylamine (i-PrEtN; DIPEA), pyridine, 2,2,6,6-tetramethylpiperidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), t-Bu-tetramethylguanidine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and potassium bis(trimethylsilyl)amide (KHMDS).

[0148] Non-limiting examples of carbonate bases that can be used in the present disclosure include, for example, sodium carbonate (Na2CO3), potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), lithium carbonate (Li2CO3), sodium bicarbonate (NaHCO3), and potassium bicarbonate (KHCO3).

[0149] Non-limiting examples of alkoxide bases that can be used in the present disclosure include, for example, t-AmOLi (lithium t-amylate), t-AmONa (sodium t-amylate), t-AmOK (potassium t-amylate), sodium tert-butoxide (NaOtBu), potassium tert-butoxide (KOtBu), and sodium methoxide (NaOMe; NaOCH).

[0150] Non-limiting examples of hydroxide bases that may be used in the present disclosure include, for example, lithium hydroxide (LiOH), sodium hydroxide (NaOH), and potassium hydroxide.

[0151] Non-limiting examples of phosphate groups that can be used in the present disclosure include, for example, trisodium phosphate (NaPO), tripotassium phosphate (KPO), dipotassium phosphate (KHPO), and monopotassium phosphate (KHPO).

[0152] Non-limiting examples of acids that can be used in the present disclosure include, for example, trifluoroacetic acid (TFA), hydrochloric acid (HCl), methanesulfonic acid (MsOH), phosphoric acid (H3PO4), and sulfuric acid (H2SO4).

[0153] As used herein, the terms "reductant" and "reducing agent" are used interchangeably. Non-limiting examples of reducing agents and conditions that may be used in the present disclosure include, for example, H and palladium on carbon, H and palladium on alumina, sodium dithionite (NaSO), iron (Fe) and acetic acid (AcOH), and iron (Fe) and ammonium chloride (NHCl).

[0154] As used herein, the terms "oxidant" and "oxidizing agent" are used interchangeably. Non-limiting examples of oxidizing agents and oxidizing conditions that may be used in the present disclosure include, for example, manganese dioxide (MnO), ruthenium(III) chloride (RuCl), sodium periodate (NaIO) and water (HO), and osmium tetroxide (OsO) and sodium periodate (NaIO).

[0155] As used herein, the term "halogenating agent" refers to a reagent that introduces one or more halogens into a compound by converting a specific functional group to a halide. In some embodiments, the halogenating agent converts an alkene or alkyne to a halide. In some embodiments, the halogenating agent converts a hydroxyl group to a halide. Non-limiting examples of halogenating agents that can be used in the present disclosure include, for example, bromine (Br), iodine (I), and pyridinium tribromide.

[0156] As used herein, the terms "alkyl halide" and "haloalkane" are used interchangeably. An alkyl halide is a compound in which one or more hydrogen atoms in an unsubstituted or substituted alkane have been replaced with one or more halogen atoms. Non-limiting examples of alkyl halides include, for example, 1-halopropane and benzyl halides (e.g., benzyl bromide).

[0157] As used herein, the term "alkyl triflate" refers to a compound in which one or more hydrogen atoms in an unsubstituted or substituted alkane have been replaced with one or more triflate groups (e.g., -OSOCF). Non-limiting examples of alkyl triflates include, for example, 1-propyl triflate, allyl triflate, and benzyl triflate.

[0158] As used herein, the term "alkyl tosylate" refers to a compound in which one or more hydrogen atoms in an unsubstituted or substituted alkane are replaced with one or more tosyl groups (e.g., 4-MeC6H4SO2O-). Non-limiting examples of alkyl tosylates include, for example, 1-propyl tosylate, allyl tosylate, and benzyl tosylate.

[0159] As used herein, the term "sulfonyl chloride" refers to a compound in which a sulfonyl group (-SO-) is single-bonded to a chlorine atom (e.g., RSOCl). Non-limiting examples of sulfonyl chlorides include, for example, methanesulfonyl chloride (MeSOCl), trifluoromethanesulfonyl chloride (FCSOCl), benzenesulfonyl chloride (PhSOCl), p-toluenesulfonyl chloride (4-MeC6H4SO2Cl or TsCl), 2-nitrobenzylsulfonyl chloride (2-NO2C6H4SO2Cl or 2-NsCl), and 4-nitrobenzylsulfonyl chloride (4-NO2C6H4SO2Cl or 4-NsCl).

[0160] Non-limiting examples of suitable sulfonate esters -OSO2R that can be used in the present disclosure include, for example, methanesulfonyl (R=Me), trifluoromethanesulfonyl (R=CF3), benzenesulfonyl (R=Ph), p-toluenesulfonyl (R=4-MeC6H4-), 2-nitrobenzylsulfonyl (R=2-NO2C6H4-), and 4-nitrobenzylsulfonyl (R=4-NO2C6H4-).

[0161] The term "compound," when referring to a compound of the present disclosure, refers to a collection of molecules having identical chemical structure except that isotopic variations may exist among the constituent atoms of the molecules.

[0162] The compounds described herein can be optionally substituted with one or more substituents, as generally indicated above or as exemplified by the specific classes, subclasses, and species of the present disclosure. It should be understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted," whether preceded by the term "optionally," indicates that at least one hydrogen of the "substituted" group is replaced with a substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when multiple positions in any given structure may be substituted with multiple substituents selected from a specified group, the substituents may be the same or different at each position. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds.

[0163] As used herein, the term "stable compound" refers to a compound that is sufficiently stable to permit its manufacture and maintains its integrity for a period of time sufficient to be useful for the purposes detailed herein (e.g., as a therapeutic agent, an intermediate for use in the manufacture of a therapeutic compound, formulation into an intermediate that can be isolated or stored, and / or treatment of a disease or condition that responds to a therapeutic agent).

[0164] As used herein, the term "stereoisomer" refers to both enantiomers and diastereomers.

[0165] It is to be understood that certain compounds of the present invention may exist as separate stereoisomers or enantiomers and / or as mixtures of such stereoisomers or enantiomers. As used in the chemical structures disclosed herein, the "wedge" to the asymmetric central atom [ka] or "hash lines" [ka] The bond denotes a chiral center of known absolute stereochemistry (i.e., one stereoisomer). As used in the chemical structures disclosed herein, the "wavy line" bond to the chiral center atom [ka] indicates a chiral center of unknown absolute stereochemistry (i.e., one stereoisomer). As used in the chemical structures disclosed herein, the "wavy line" attachment to the double bond carbon [ka] indicates a mixture of E / Z isomers. When used in the chemical structures disclosed herein, [ka] A ("straight") bond indicates that a mixture (e.g., a racemate or concentrate) is present. As used herein, two bonds to a double bond carbon [ka] A ("straight") bond indicates that the double bond has E / Z stereochemistry as drawn. As used in the chemical structures disclosed herein, [ka] (i.e., a "wavy" line perpendicular to the "straight" bond to group "A") indicates that group "A" is a substituent, the point of attachment of which is the terminus of the bond that terminates at the "wavy" line.

[0166] The terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, include a specific dose, amount, or weight percent value, or range of doses, amounts, or weight percents, recognized by one of ordinary skill in the art, that provides the equivalent pharmacological effect as that provided by the specific dose, amount, or weight percent. As used herein, the terms "about" and "approximately," when used in connection with amounts, volumes, reaction times, reaction temperatures, and the like in methods and processes, refer to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In some embodiments, the terms "about" and "approximately" refer to within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms "about" and "approximately" refer to within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range. In some embodiments, the terms "about" and "approximately" mean within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range. In some embodiments, the terms "about" and "approximately" mean within 15% of a given value. In some embodiments, the terms "about" and "approximately" mean within 10% of a given value. As used herein, the symbol "~" appearing immediately before a numerical value has the same meaning as the terms "about" and "approximately."

[0167] Certain compounds disclosed herein may exist as tautomers, and both tautomeric forms are intended, even if only a single tautomeric structure is shown. For example, a description of compound A is understood to include its tautomeric form, compound B, and vice versa, as well as mixtures thereof. [ka] Unless otherwise specified, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0168] Unless otherwise specified, structures depicted herein are also meant to include all isomeric forms of the structure, for example, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, mixtures of geometric and conformational isomers of the compounds of the present disclosure are within the scope of the present disclosure.

[0169] "Tert" and "t-" are used interchangeably and mean tertiary.

[0170] The present disclosure also provides processes for preparing salts of the compounds of the present disclosure.

[0171] A salt of a compound of the present disclosure is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group. In some embodiments, the salt is a pharmaceutically acceptable salt.

[0172] As used herein, the term "pharmaceutically acceptable salt" refers to any non-toxic salt that is capable of providing a compound of the present disclosure, either directly or indirectly, upon administration to a recipient. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. A "pharmaceutically acceptable counterion" is an ionic portion of the salt that is not toxic when released from the salt upon administration to a recipient. One of ordinary skill in the art will recognize that when an amount of "a compound or a pharmaceutically acceptable salt thereof" is disclosed, the amount of the pharmaceutically acceptable salt form of the compound is the amount corresponding to the concentration of the free base of the compound.

[0173] The "free base" form of a compound does not include ion-bonded salts. It should be noted that the amounts of compounds or their pharmaceutically acceptable salts disclosed herein are based on their free base form. For example, "10 mg of at least one compound selected from Compound I and its pharmaceutically acceptable salts" includes 10 mg of Compound I and the concentration of a pharmaceutically acceptable salt of Compound I equivalent to 10 mg of Compound I.

[0174] Suitable pharmaceutically acceptable salts include, for example, those disclosed in S. M. Berge, et al. J. Pharm. Sci., 1977, 66, 1-19, which provides, for example, in Table 1, the following pharmaceutically acceptable salts: [Table 1-1]

[0175] Non-limiting examples of pharmaceutically acceptable salts derived from appropriate acids include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid; salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; and salts formed by using other methods used in the art, such as ion exchange. Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- Pharmaceutically acceptable salts include ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts. Non-limiting examples of pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N(C1-4 alkyl)4 salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Suitable, non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0176] In some embodiments, the present disclosure is also directed to processes for preparing isotopically labeled compounds of the foregoing compounds or pharmaceutically acceptable salts thereof, wherein the formulas and variables of such compounds and salts are each and independently as described above or as described in any other embodiment above, except that one or more atoms therein are replaced (isotopically labeled) with an atom having an atomic mass or mass number different from the atomic mass or mass number of the atom normally occurring in nature. Examples of isotopes that are commercially available and suitable for the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., H, C, C, N, O, O, P, P, S, F, and Cl, respectively.

[0177] In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition.

[0178] As used herein, the term "derivative" refers to a collection of molecules having the same chemical structure as a compound of the present disclosure, except that one or more atoms of the molecule may be replaced with another atom. In addition, unless otherwise specified, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen with deuterium or tritium, or the replacement of carbon with 13C or 14C, are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools, probes in biological assays, or compounds with improved therapeutic profiles.

[0179] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as a reference compound, in which one or more hydrogen atoms have been replaced with deuterium atoms. In some embodiments, the one or more hydrogens replaced with deuterium are part of an alkyl group. In some embodiments, the one or more hydrogens replaced with deuterium are part of a methyl group. In a chemical structure, deuterium may be represented by "D."

[0180] As used herein, the phrase "deuterated derivatives of [a compound] and stereoisomers thereof, and pharmaceutically acceptable salts of any of the foregoing" is intended to include deuterated derivatives of the specified compound, deuterated derivatives of any stereoisomers of that compound, and pharmaceutically acceptable salts of the particular compound, pharmaceutically acceptable salts of any of the stereoisomers of that compound, and pharmaceutically acceptable salts of the deuterated derivatives of the particular compound or of its stereoisomers.

[0181] In some embodiments, the derivative is a silicon derivative, in which at least one carbon atom in the disclosed compound is replaced with silicon. In some embodiments, the at least one carbon atom replaced with silicon can be a non-aromatic carbon. In some embodiments, the at least one carbon atom replaced with silicon can be an aromatic carbon. In certain embodiments, the silicon derivative of the present invention can also have one or more hydrogen atoms replaced with deuterium and / or germanium.

[0182] In other embodiments, the derivatives are germanium derivatives, in which at least one carbon atom in the disclosed compounds is substituted with germanium. In certain embodiments, the germanium derivatives of the present invention may also have one or more hydrogen atoms substituted with deuterium and / or silicon.

[0183] Because the general properties of silicon and germanium are similar to those of carbon, the substitution of silicon or germanium for carbon can result in compounds with similar biological activity to the original carbon-containing compound.

[0184] As used herein, the term "pharmaceutically acceptable crystalline form" refers to a solid form of Compound I of the present disclosure, which solid forms of Compound I (e.g., crystalline free form, crystalline salt, crystalline salt solvate, crystalline salt hydrate, and amorphous form) are non-toxic and suitable for use in pharmaceutical compositions.

[0185] As used herein, the term "amorphous" refers to a solid material that lacks long-range order in the position of its molecules. An amorphous solid is generally a supercooled liquid in which the molecules are randomly arranged, with no well-defined arrangement, e.g., molecular packing, and no long-range order. An amorphous solid is generally isotropic, i.e., exhibits similar properties in all directions, and does not have a distinct melting point. For example, an amorphous material is a solid material that does not have sharp, characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) are observed in its XRPD pattern. Broad peaks are characteristic of amorphous solids. For a comparison of XRPD of amorphous and crystalline materials, see U.S. Patent Application Publication No. 2004 / 0006237. In some embodiments, a solid material may comprise an amorphous compound; for example, the solid material may be characterized by a lack of sharp, characteristic crystalline peaks in its XRPD spectrum (i.e., the solid material is amorphous, but not crystalline, as determined by XRPD). Instead, one or more broad peaks (e.g., halos) may be observed in the XRPD pattern of the solid material. See U.S. Patent Application Publication No. 2004 / 0006237 for a comparison of XRPD of amorphous and crystalline materials. A solid material comprising an amorphous compound may be characterized, for example, by a broader melting temperature range of the solid material compared to the melting temperature range of a pure crystalline solid. Other techniques, such as, for example, solid-state NMR, may also be used to characterize crystalline or amorphous forms.

[0186] As used herein, the terms "crystalline form," "crystalline form," and "form" refer interchangeably to a crystalline structure (or polymorph) having a particular molecular packing arrangement within a crystal lattice. Crystalline forms can be identified and distinguished from one another by one or more characterization techniques, including, for example, powder X-ray diffraction (XRPD), single crystal X-ray diffraction, and C solid-state nuclear magnetic resonance (C-SSNMR). Thus, as used herein, the terms "crystalline Form [X] of Compound (I)" and "crystalline Form [C] of Compound (I) potassium salt" refer to unique crystalline forms that can be identified and distinguished from one another by one or more characterization techniques, including, for example, XRPD, single crystal X-ray diffraction, and C-SSNMR. In some embodiments, novel crystalline forms are characterized by a powder X-ray diffractogram having one or more signals at one or more specified degrees two-theta (°2θ) values.

[0187] As used herein, the term "free form" refers to the non-ionized form of a compound in the solid state. Examples of free forms include the free base and the free acid.

[0188] As used herein, the term "neat form" refers to the unsolvated and unhydrated free form of a compound in the solid state.

[0189] As used herein, the term "solvate" refers to a crystalline form that contains one or more molecules of a compound of the present disclosure and one or more molecules of a solvent incorporated into the crystal lattice, in stoichiometric or non-stoichiometric amounts. When the solvent is water, the solvate is referred to as a "hydrate."

[0190] In some embodiments, the solid material may comprise a mixture of crystalline solids and amorphous solids. A solid material comprising an amorphous compound may also comprise, for example, up to 30% crystalline solids. In some embodiments, a solid material prepared to comprise an amorphous compound may also comprise, for example, up to 25%, 20%, 15%, 10%, 5%, or 2% crystalline solids. In embodiments where the solid material comprises a mixture of crystalline solids and amorphous solids, characterization data such as XRPD may include indicators of both crystalline solids and amorphous solids. In some embodiments, the crystalline forms of the present disclosure may contain up to 30% amorphous compound. In some embodiments, crystalline preparations of Compound I may contain up to 25%, 20%, 15%, 10%, 5%, or 2% amorphous solids.

[0191] As used herein, the term "substantially amorphous" refers to a solid material that has little or no long-range order at the molecular level. For example, a substantially amorphous material has less than 15% crystallinity (e.g., less than 10% crystallinity, or less than 5% crystallinity, or less than 2% crystallinity). Note that the term "substantially amorphous" also includes the descriptor "amorphous," which refers to a material that has no crystallinity (0%).

[0192] As used herein, the term "substantially crystalline" refers to a solid material having few or no amorphous molecules. For example, a substantially crystalline material has less than 15% amorphous molecules (e.g., less than 10% amorphous molecules, less than 5% amorphous molecules, or less than 2% amorphous molecules). Note that the term "substantially crystalline" also includes the descriptor "crystalline," which refers to a material that is 100% crystalline in form.

[0193] As used herein, a crystalline form is "substantially pure" when it accounts for 90% or more by weight of the sum of all solid forms in a sample, as determined by methods according to the art, such as quantitative XRPD. In some embodiments, a solid form is "substantially pure" when it accounts for 95% or more by weight of the sum of all solid forms in a sample. In some embodiments, a solid form is "substantially pure" when it accounts for 99% or more by weight of the sum of all solid forms in a sample.

[0194] As used herein, the terms "X-ray powder diffractogram," "X-ray powder diffraction pattern," "XRPD pattern," and "XRPD spectrum" refer interchangeably to an experimentally obtained pattern that plots signal position (on the abscissa) against signal intensity (on the ordinate).

[0195] "Signal" or "peak," as used herein, refers to a point on an XRPD pattern where there is a maximum intensity, measured in counts. An XRPD peak is identified by its angular value, measured in degrees two-theta (°2θ), shown on the abscissa of an X-ray powder diffractogram, which may be expressed, for example, as "a signal at . . . degrees two-theta," "a signal with a two-theta value . . .," and / or "a signal with a two-theta value that is at least . . . selected from . . . ."

[0196] The repeatability of the measured angle values ​​is within a range of ±0.2° 2θ, i.e., the angle value can be the recited angle value +0.2 degrees 2-theta, the angle value -0.2 degrees 2-theta, or any value between those two endpoints (between the angle value +0.2 degrees 2-theta and the angle value -0.2 degrees 2-theta).

[0197] Those skilled in the art will recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may not be apparent to the naked eye, for example. Indeed, those skilled in the art will recognize that several art-recognized methods are capable of and suitable for determining whether a signal is present by pattern analysis, such as Rietveld refinement.

[0198] The terms "signal intensity" and "peak intensity" refer interchangeably to relative signal intensities within a given powder X-ray diffractogram. Factors that can affect relative signal intensity or peak intensity include sample thickness and preferred orientation (e.g., crystalline particles are not randomly distributed).

[0199] As used herein, a powder X-ray diffractogram is "substantially similar to that in [a particular] figure" if at least 90%, e.g., at least 95%, at least 98%, or at least 99% of the signals in the two diffractograms overlap. In determining "substantially similar," one of skill in the art will understand that even for the same crystalline form, there may be variations in intensity and / or signal position in XRPD diffractograms. Thus, one of skill in the art will understand that, generally, the maximum value of a signal (in units of ∼degrees 2-theta) in an XRPD diffractogram means that the value is specified as ±0.2 degrees 2-theta of that reported value, which is an art-recognized variance.

[0200] As used herein, the term "TGA" refers to thermogravimetric analysis and "TGA / DSC" refers to thermogravimetric analysis and differential scanning calorimetry.

[0201] As used herein, the term "DSC" refers to the analytical method of differential scanning calorimetry.

[0202] As used herein, the term "glass transition temperature" or "Tg" refers to the temperature above which a hard, brittle "glassy" amorphous solid becomes viscous or rubbery.

[0203] As used herein, "melting temperature," "melting point," or "Tm" refers to the temperature at which a substance transitions from a solid to a liquid phase.

[0204] As used herein, the term "dispersion" refers to a disperse system in which one entity, the dispersed phase, is distributed in dispersed units throughout a second entity (the continuous phase or vehicle). The size of the dispersed phase can vary greatly (e.g., colloidal particles from nanometer dimensions to several microns in size). Generally, the dispersed phase can be a solid, liquid, or gas. In solid dispersions, the dispersed and continuous phases are both solids. In pharmaceutical applications, a solid dispersion can contain a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase), or alternatively, an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase). In some embodiments, a solid dispersion contains a polymer that constitutes the dispersed phase and the drug that constitutes the continuous phase. Alternatively, a solid dispersion contains a drug that constitutes the dispersed phase and a polymer that constitutes the continuous phase. (Mode for Carrying Out the Invention)

[0205] Another aspect of the present disclosure provides solid forms (e.g., crystalline forms, amorphous forms, solvates, hydrates, co-crystals) of Compound I that can be used in the therapeutic methods and pharmaceutical compositions described herein. In some embodiments, the present invention provides a neat amorphous form of Compound I. In some embodiments, the present invention provides a neat crystalline form of Compound I. In some embodiments, the present invention provides a solvated crystalline form of Compound I. In some embodiments, the present invention provides a hydrate crystalline form of Compound I. In some embodiments, the present invention provides a hemihydrate crystalline form of Compound I. In some embodiments, the present invention provides a solvate / hydrate crystalline form of Compound I. In some embodiments, the present invention provides a co-crystal crystalline form of Compound I.

[0206] A. Neat amorphous form of Compound I In some embodiments, the present invention provides a neat amorphous form of Compound I. In some embodiments, the present invention provides a neat amorphous form of Compound I. Figure 1 provides a powder X-ray diffractogram of the neat amorphous form of Compound I at room temperature.

[0207] In some embodiments, the neat amorphous form of Compound I is substantially pure. In some embodiments, the neat amorphous form of Compound I is substantially amorphous. In some embodiments, the neat amorphous form of Compound I is characterized by a powder X-ray diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0208] In some embodiments, the neat amorphous form of Compound I is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0209] In some embodiments, the neat amorphous form of Compound I is characterized by a C-SS NMR spectrum with a peak at 163.8±0.2 ppm. In some embodiments, the neat amorphous form of Compound I is characterized by a C-SS NMR spectrum with a peak at 151.9±0.2 ppm. In some embodiments, the neat amorphous form of Compound I is characterized by a C-SS NMR spectrum with a peak at 137.6±0.2 ppm. In some embodiments, the neat amorphous form of Compound I is characterized by a C-SS NMR spectrum with a peak at 125.8±0.2 ppm. In some embodiments, the neat amorphous form of Compound I is characterized by a C-SS NMR spectrum with a peak at 120.8±0.2 ppm. In some embodiments, the neat amorphous form of Compound I is characterized by a C-SS NMR spectrum with a peak at 117.8±0.2 ppm. In some embodiments, the neat amorphous form of Compound I is characterized by a C-SS NMR spectrum with a peak at 77.3±0.2 ppm. In some embodiments, the neat amorphous form of Compound I is characterized by a C-SS NMR spectrum with a peak at 73.6±0.2 ppm. In some embodiments, the neat amorphous form of Compound I is characterized by a C-SS NMR spectrum with a peak at 34.5±0.2 ppm. In some embodiments, the neat amorphous form of Compound I is characterized by a C-SS NMR spectrum with a peak at 31.4±0.2 ppm. In some embodiments, the neat amorphous form of Compound I is characterized by a C-SS NMR spectrum with a peak at 26.3±0.2 ppm. In some embodiments, the neat amorphous form of Compound I is characterized by a C-SS NMR spectrum with a peak at 22.5±0.2 ppm. In some embodiments, the neat amorphous form of Compound I is characterized by a 13C-SS NMR spectrum having a peak at 19.5±0.2 ppm.

[0210] In some embodiments, the neat amorphous form of Compound I is characterized by a C-SS NMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 163.8±0.2 ppm, 151.9±0.2 ppm, 137.6±0.2 ppm, 125.8±0.2 ppm, 120.8±0.2 ppm, 117.8±0.2 ppm, 77.3±0.2 ppm, 73.6±0.2 ppm, 34.5±0.2 ppm, 31.4±0.2 ppm, 26.3±0.2 ppm, 22.5±0.2 ppm, and 19.5±0.2 ppm. In some embodiments, the neat amorphous form of Compound I is characterized by a C-SS NMR spectrum having peaks at 163.8±0.2 ppm, 151.9±0.2 ppm, 137.6±0.2 ppm, 125.8±0.2 ppm, 120.8±0.2 ppm, 117.8±0.2 ppm, 77.3±0.2 ppm, 73.6±0.2 ppm, 34.5±0.2 ppm, 31.4±0.2 ppm, 26.3±0.2 ppm, 22.5±0.2 ppm, and 19.5±0.2 ppm.

[0211] In some embodiments, the neat amorphous form of Compound I is characterized by a 13C-SS NMR spectrum substantially similar to that of FIG.

[0212] In some embodiments, the neat amorphous form of Compound I is characterized by a 19F-SS NMR spectrum having a peak at -64.6±0.2 ppm. In some embodiments, the neat amorphous form of Compound I is characterized by a 19F-SS NMR spectrum having a peak at -77.4±0.2 ppm.

[0213] In some embodiments, neat amorphous Form C of Compound I is characterized by a 19F-SS NMR spectrum having one or two peaks selected from −64.6±0.2 ppm and −77.4±0.2 ppm.

[0214] In some embodiments, the neat amorphous form of Compound I is characterized by a 19F-SSNMR spectrum substantially similar to that of FIG.

[0215] Another aspect of the present invention provides a method for making a neat amorphous form of Compound I. In some embodiments, the method for making a neat amorphous form of Compound I includes (i) dissolving tert-butyl N-[(6R,12R)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]-N-tert-butoxycarbonyl-carbamate in ethanol, (ii) adding 10% Pd / C, (iii) stirring under hydrogen at room temperature, and (iv) dissolving the liquid phase in a crystalline form. (v) redissolving in dichloromethane; (vi) cooling the solution in an ice bath and treating with trifluoroacetic acid; (viii) stirring at room temperature for 2 hours; (ix) diluting the solution with heptane and evaporating and drying to obtain a solid; (x) dissolving the solid in dichloromethane and diluting with heptane; (xi) stirring the suspension at room temperature; (xii) removing the solid by filtration; and (xiii) concentrating the mother liquor and purifying the resulting solid by reverse phase chromatography to obtain the neat amorphous form of Compound I.

[0216] B. Neat crystalline form A of crystalline Compound I

[0217] In some embodiments, the present invention provides a neat crystalline form of Compound I. In some embodiments, the present invention provides a neat crystalline form A of crystalline Compound I. Figure 6 provides a powder X-ray diffractogram of neat crystalline form A of crystalline Compound I.

[0218] In some embodiments, neat crystalline Form A of crystalline Compound I is substantially pure. In some embodiments, neat crystalline Form A of crystalline Compound I is substantially crystalline. In some embodiments, neat crystalline Form A of crystalline Compound I is characterized by a powder X-ray diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0219] In some embodiments, neat crystalline Form A of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 4.6±0.2 degrees 2-theta. In some embodiments, neat crystalline Form A of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 20.8±0.2 degrees 2-theta.

[0220] In some embodiments, neat crystalline Form A of crystalline Compound I is characterized by a powder X-ray diffractogram having signals at 4.6±0.2 degrees two-theta and 20.8±0.2 degrees two-theta.

[0221] In some embodiments, neat crystalline Form A of crystalline Compound I is characterized by an X-ray powder diffractogram having (a) signals at one or two of 4.6±0.2 degrees 2-theta and 20.8±0.2 degrees 2-theta, and (b) signals at one or two of 9.2±0.2 degrees 2-theta and 18.4±0.2 degrees 2-theta.

[0222] In some embodiments, neat crystalline Form A of crystalline Compound I is characterized by an X-ray powder diffractogram having signals at two, three, or four of the following positions: 4.6±0.2 degrees 2-theta, 9.2±0.2 degrees 2-theta, 18.4±0.2 degrees 2-theta, and 20.8±0.2 degrees 2-theta.

[0223] In some embodiments, neat crystalline Form A of crystalline Compound I is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0224] Another aspect of the present invention provides a method for making neat crystalline Form A of crystalline Compound I. In some embodiments, the method for making neat crystalline Form A of crystalline Compound I includes (i) dissolving heptane solvate crystalline Form A of Compound I in methanol, (ii) adding water, (iii) stirring at room temperature for five days, and (iv) collecting the solid and drying it under reduced pressure at 40° C. for 24 hours to obtain neat crystalline Form A of crystalline Compound I.

[0225] C. Neat crystalline form B of crystalline Compound I In some embodiments, the present invention provides neat crystalline Form B of crystalline Compound I. Figure 9 provides a powder X-ray diffractogram of neat crystalline Form B of crystalline Compound I.

[0226] In some embodiments, neat crystalline Form B of crystalline Compound I is substantially pure. In some embodiments, neat crystalline Form B of crystalline Compound I is substantially crystalline. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a powder X-ray diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0227] In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 5.7±0.2 degrees 2-theta. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 6.1±0.2 degrees 2-theta. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 7.6±0.2 degrees 2-theta. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 10.3±0.2 degrees 2-theta. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 10.6±0.2 degrees 2-theta. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 12.3±0.2 degrees 2-theta.

[0228] In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a powder X-ray diffractogram having signals at one, two, three, four, five, or six of the following: 5.7±0.2 degrees 2-theta, 6.1±0.2 degrees 2-theta, 7.6±0.2 degrees 2-theta, 10.3±0.2 degrees 2-theta, 10.6±0.2 degrees 2-theta, and 12.3±0.2 degrees 2-theta.

[0229] In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a powder X-ray diffractogram having (a) signals at one, two, three, four, five, or six of 5.7±0.2 degrees two-theta, 6.1±0.2 degrees two-theta, 7.6±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, 10.6±0.2 degrees two-theta, and 12.3±0.2 degrees two-theta, and (b) signals at one or two of 9.3±0.2 degrees two-theta and 16.1±0.2 degrees two-theta.

[0230] In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by an X-ray powder diffractogram having signals at two, three, four, five, six, seven, or eight of the following angles: 5.7±0.2 degrees 2-theta, 6.1±0.2 degrees 2-theta, 7.6±0.2 degrees 2-theta, 9.3±0.2 degrees 2-theta, 10.3±0.2 degrees 2-theta, 10.6±0.2 degrees 2-theta, 12.3±0.2 degrees 2-theta, and 16.1±0.2 degrees 2-theta.

[0231] In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a powder X-ray diffractogram with signals at 5.7±0.2 degrees 2-theta, 6.1±0.2 degrees 2-theta, 7.6±0.2 degrees 2-theta, 9.3±0.2 degrees 2-theta, 10.3±0.2 degrees 2-theta, 10.6±0.2 degrees 2-theta, 12.3±0.2 degrees 2-theta, and 16.1±0.2 degrees 2-theta.

[0232] In some embodiments, the neat crystalline Form B of crystalline Compound I is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0233] In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 165.8±0.2 ppm. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 154.2±0.2 ppm. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 151.8±0.2 ppm. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 140.1±0.2 ppm. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 138.1±0.2 ppm. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 136.2±0.2 ppm. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 134.9±0.2 ppm. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 131.7±0.2 ppm. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 129.4±0.2 ppm. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 125.5±0.2 ppm. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 123.0±0.2 ppm. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 120.2±0.2 ppm. In some embodiments, the neat crystalline form B of crystalline Compound I is characterized by a 13C-SS NMR spectrum with a peak at 117.5±0.2 ppm.In some embodiments, neat crystalline form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 78.3±0.2 ppm. In some embodiments, neat crystalline form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 73.6±0.2 ppm. In some embodiments, neat crystalline form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 37.6±0.2 ppm. In some embodiments, neat crystalline form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 34.0±0.2 ppm. In some embodiments, neat crystalline form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 29.9±0.2 ppm. In some embodiments, neat crystalline form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 27.3±0.2 ppm. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 22.7±0.2 ppm. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 21.1±0.2 ppm. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 18.9±0.2 ppm.

[0234] In some embodiments, the neat crystalline Form B of crystalline Compound I has an NA of 165.8±0.2 ppm, 154.2±0.2 ppm, 151.8±0.2 ppm, 140.1±0.2 ppm, 138.1±0.2 ppm, 136.2±0.2 ppm, 134.9±0.2 ppm, 131.7±0.2 ppm, 129.4±0.2 ppm, 125.5±0.2 ppm, 123.0±0.2 ppm, 120.2±0.2 ppm, 11 The C-SS NMR spectrum is characterized by having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 7.5±0.2 ppm, 78.3±0.2 ppm, 73.6±0.2 ppm, 37.6±0.2 ppm, 34.0±0.2 ppm, 29.9±0.2 ppm, 27.3±0.2 ppm, 22.7±0.2 ppm, 21.1±0.2 ppm, and 18.9±0.2 ppm. In some embodiments, the neat crystalline Form B of crystalline Compound I has an NA of 165.8±0.2 ppm, 154.2±0.2 ppm, 151.8±0.2 ppm, 140.1±0.2 ppm, 138.1±0.2 ppm, 136.2±0.2 ppm, 134.9±0.2 ppm, 131.7±0.2 ppm, 129.4±0.2 ppm, 125.5±0.2 ppm, 123.0±0.2 ppm , 120.2±0.2 ppm, 117.5±0.2 ppm, 78.3±0.2 ppm, 73.6±0.2 ppm, 37.6±0.2 ppm, 34.0±0.2 ppm, 29.9±0.2 ppm, 27.3±0.2 ppm, 22.7±0.2 ppm, 21.1±0.2 ppm, and 18.9±0.2 ppm.

[0235] In some embodiments, the neat crystalline Form B of crystalline Compound I has a densitometric value of (a) 165.8±0.2 ppm, 154.2±0.2 ppm, 151.8±0.2 ppm, 140.1±0.2 ppm, 138.1±0.2 ppm, 136.2±0.2 ppm, 134.9±0.2 ppm, 131.7±0.2 ppm, 129.4±0.2 ppm, 125.5±0.2 ppm, 123.0±0.2 ppm, 120.2±0.2 ppm, 117.5±0.2 ppm, 78.3±0.2 ppm, 73.6±0.2 ppm, ppm, 37.6±0.2 ppm, 34.0±0.2 ppm, 29.9±0.2 ppm, 27.3±0.2 ppm, 22.7±0.2 ppm, 21.1±0.2 ppm, and 18.9±0.2 ppm; and (b) one, two, or three peaks selected from 164.7±0.2 ppm, 163.8±0.2 ppm, and 74.4±0.2 ppm.

[0236] In some embodiments, the neat crystalline Form B of crystalline Compound I has an NA of 165.8±0.2 ppm, 164.7±0.2 ppm, 163.8±0.2 ppm, 154.2±0.2 ppm, 151.8±0.2 ppm, 140.1±0.2 ppm, 138.1±0.2 ppm, 136.2±0.2 ppm, 134.9±0.2 ppm, 131.7±0.2 ppm, 129.4±0.2 ppm, 125.5±0.2 ppm, 123.0±0.2 ppm, 120.2 and 18.9±0.2 ppm.

[0237] In some embodiments, the neat crystalline Form B of crystalline Compound I has an ADP of 165.8±0.2 ppm, 164.7±0.2 ppm, 163.8±0.2 ppm, 154.2±0.2 ppm, 151.8±0.2 ppm, 140.1±0.2 ppm, 138.1±0.2 ppm, 136.2±0.2 ppm, 134.9±0.2 ppm, 131.7±0.2 ppm, 129.4±0.2 ppm, 125.5±0.2 ppm, 123.0 ... ±0.2 ppm, 120.2±0.2 ppm, 117.5±0.2 ppm, 78.3±0.2 ppm, 74.4±0.2 ppm, 73.6±0.2 ppm, 37.6±0.2 ppm, 34.0±0.2 ppm, 29.9±0.2 ppm, 27.3±0.2 ppm, 22.7±0.2 ppm, 21.1±0.2 ppm, and 18.9±0.2 ppm.

[0238] In some embodiments, the neat crystalline Form B of crystalline Compound I is characterized by a 13C-SS NMR spectrum substantially similar to that of FIG.

[0239] In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a F-SS NMR spectrum with a peak at -64.3±0.2 ppm. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a F-SS NMR spectrum with a peak at -65.9±0.2 ppm. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by a F-SS NMR spectrum with a peak at -76.5±0.2 ppm.

[0240] In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by having a F-SS NMR spectrum with one or two peaks selected from -64.3±0.2 ppm, -65.9±0.2 ppm, and -76.5±0.2 ppm. In some embodiments, neat crystalline Form B of crystalline Compound I is characterized by having a F-SS NMR spectrum with peaks at -64.3±0.2 ppm, -65.9±0.2 ppm, and -76.5±0.2 ppm.

[0241] In some embodiments, the neat crystalline Form B of crystalline Compound I is characterized by a 19F-SSNMR spectrum substantially similar to that of FIG.

[0242] Another aspect of the present invention provides a method for making neat crystalline Form B of crystalline Compound I. In some embodiments, the method for making neat crystalline Form B of crystalline Compound I comprises (i) dissolving heptane solvate crystalline Form A of Compound I in dichloromethane at room temperature, and (ii) slowly evaporating the dichloromethane at room temperature to obtain neat crystalline Form B of crystalline Compound I.

[0243] D. Crystalline Compound I Hemihydrate Form C In some embodiments, the present invention provides crystalline hemihydrate Form C of Compound I. Figure 14 provides a powder X-ray diffractogram of crystalline hemihydrate Form C of Compound I.

[0244] In some embodiments, the crystalline hemihydrate Form C of Compound I is substantially pure. In some embodiments, the crystalline hemihydrate Form C of Compound I is substantially crystalline. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0245] In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 4.8±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 8.2±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 9.3±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 11.2±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 12.5±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 13.1±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 16.4±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 18.4±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 19.3±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 19.6±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 21.1±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 21.6±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 22.8±0.2 degrees 2-theta.In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 23.5±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 24±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 24.6±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 25.8±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a powder X-ray diffractogram having a signal at 27.1±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by an X-ray powder diffractogram having a signal at 29.6±0.2 degrees two-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by an X-ray powder diffractogram having a signal at 33.4±0.2 degrees two-theta.

[0246] In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by an X-ray powder diffractogram having signals at one, two, three, or four of the following: 4.8±0.2 degrees two-theta, 16.4±0.2 degrees two-theta, 19.3±0.2 degrees two-theta, and 21.1±0.2 degrees two-theta.

[0247] In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by an X-ray powder diffractogram having signals at one, two, three, four, or five of the following angles: 13.1±0.2 degrees 2-theta, 16.4±0.2 degrees 2-theta, 18.4±0.2 degrees 2-theta, 19.6±0.2 degrees 2-theta, and 21.1±0.2 degrees 2-theta.

[0248] In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by an X-ray powder diffractogram having signals at one, two, three, four, five, six, seven, eight, nine, or ten of 4.8±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 16.4±0.2 degrees 2-theta, 18.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 19.6±0.2 degrees 2-theta, 21.1±0.2 degrees 2-theta, 24.0±0.2 degrees 2-theta, 24.6±0.2 degrees 2-theta, and 27.1±0.2 degrees 2-theta.

[0249] In some embodiments, the crystalline hemihydrate Form C of Compound I has a viscosity of 4.8±0.2 degrees 2-theta, 8.2±0.2 degrees 2-theta, 9.3±0.2 degrees 2-theta, 11.2±0.2 degrees 2-theta, 12.5±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 16.4±0.2 degrees 2-theta, 18.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 19.6±0.2 degrees 2-theta, 21.1±0.2 degrees 2-theta, 21.6±0.2 degrees 2-theta, 22.8±0.2 degrees 2-theta, 23.5±0.2 degrees 2-theta, 24.0±0.2 degrees 2-theta, 24.6±0.2 degrees The powder is characterized by an X-ray powder diffractogram having signals at one, two, three, four, five, six, seven, eight, nine, ten, or more of 25.8±0.2 degrees 2-theta, 27.1±0.2 degrees 2-theta, 29.6±0.2 degrees 2-theta, and 33.4±0.2 degrees 2-theta. In some embodiments, the crystalline hemihydrate Form C of Compound I has a viscosity of 4.8±0.2 degrees 2-theta, 8.2±0.2 degrees 2-theta, 9.3±0.2 degrees 2-theta, 11.2±0.2 degrees 2-theta, 12.5±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 16.4±0.2 degrees 2-theta, 18.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 19.6±0.2 degrees 2-theta, 21.1±0.2 degrees 2-theta, 21.6±0.2 degrees 2-theta, 22.8±0.2 degrees 2-theta, 23.5±0.2 degrees 2-theta, 24±0.2 degrees 2-theta, 24.6±0.2 degrees 2-theta, 25.8±0.2 degrees It is characterized by a powder X-ray diffractogram with signals at 2-theta, 27.1±0.2 degrees 2-theta, 29.6±0.2 degrees 2-theta, and 33.4±0.2 degrees 2-theta.

[0250] In some embodiments, the crystalline hemihydrate crystal form C of Compound I is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0251] In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a C-SS NMR spectrum with a peak at 163.8±0.2 ppm. In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a C-SS NMR spectrum with a peak at 151.3±0.2 ppm. In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a C-SS NMR spectrum with a peak at 139.1±0.2 ppm. In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a C-SS NMR spectrum with a peak at 137.7±0.2 ppm. In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a C-SS NMR spectrum with a peak at 127.2±0.2 ppm. In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a C-SS NMR spectrum with a peak at 125.8±0.2 ppm. In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a C-SS NMR spectrum with a peak at 119.9±0.2 ppm. In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a C-SS NMR spectrum with a peak at 118.4±0.2 ppm. In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a C-SS NMR spectrum with a peak at 75.6±0.2 ppm. In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a C-SS NMR spectrum with a peak at 73.6±0.2 ppm. In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a C-SS NMR spectrum with a peak at 35.8±0.2 ppm. In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a C-SS NMR spectrum with a peak at 32.2±0.2 ppm. In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a 13C-SS NMR spectrum with a peak at 29.6±0.2 ppm.In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a C-SS NMR spectrum with a peak at 24.6±0.2 ppm. In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a C-SS NMR spectrum with a peak at 22.1±0.2 ppm. In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a C-SS NMR spectrum with a peak at 19.2±0.2 ppm.

[0252] In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a C-SS NMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 163.8±0.2 ppm, 151.3±0.2 ppm, 139.1±0.2 ppm, 137.7±0.2 ppm, 127.2±0.2 ppm, 125.8±0.2 ppm, 119.9±0.2 ppm, 118.4±0.2 ppm, 75.6±0.2 ppm, 73.6±0.2 ppm, 35.8±0.2 ppm, 32.2±0.2 ppm, 29.6±0.2 ppm, 24.6±0.2 ppm, 22.1±0.2 ppm, and 19.2±0.2 ppm. In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a C-SS NMR spectrum with peaks at 163.8±0.2 ppm, 151.3±0.2 ppm, 139.1±0.2 ppm, 137.7±0.2 ppm, 127.2±0.2 ppm, 125.8±0.2 ppm, 119.9±0.2 ppm, 118.4±0.2 ppm, 75.6±0.2 ppm, 73.6±0.2 ppm, 35.8±0.2 ppm, 32.2±0.2 ppm, 29.6±0.2 ppm, 24.6±0.2 ppm, 22.1±0.2 ppm, and 19.2±0.2 ppm.

[0253] In some embodiments, the crystalline hemihydrate crystal form C of Compound I is characterized by a 13C-SS NMR spectrum substantially similar to that of FIG.

[0254] In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a F-SS NMR spectrum with a peak at -65.5±0.2 ppm. In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a F-SS NMR spectrum with a peak at -77.4±0.2 ppm. In some embodiments, the crystalline hemihydrate form C of Compound I is characterized by a F-SS NMR spectrum with peaks at -65.5±0.2 ppm and -77.4±0.2 ppm.

[0255] In some embodiments, the crystalline hemihydrate crystal form C of Compound I is characterized by a 19F-SSNMR spectrum substantially similar to that of FIG.

[0256] In some embodiments, the crystalline hemihydrate Form C of Compound I is characterized by a monoclinic system, a P21 space group, and the following unit cell dimensions measured at 100 K on a Bruker diffractometer using Cu Kα radiation (λ=1.54178 Å): [Table 57]

[0257] Another aspect of the present invention provides a method for making crystalline hemihydrate Form C of Compound I. In some embodiments, the method for making crystalline hemihydrate Form C of Compound I includes: (i) dissolving Compound I in ethanol at 25° C.; (ii) adding water (ethanol to water ratio of about 1:4 v / v) over 10-12 hours; (iii) heating the slurry to 60° C. for 4 hours; (iv) cooling the slurry to 20° C. over 3 hours; (v) stirring for at least 2 hours; (vi) filtering the solid and washing with an ethanol / water solution (1:4 v / v); and (vii) drying the solid in a vacuum oven at 50° C. with a slight nitrogen bleed to obtain crystalline hemihydrate Form C of Compound I.

[0258] E. Neat crystalline form D of crystalline Compound I In some embodiments, the present invention provides neat crystalline Form D of crystalline Compound I. Figure 19 provides a powder X-ray diffractogram of neat crystalline Form D of crystalline Compound I.

[0259] In some embodiments, neat crystalline Form D of crystalline Compound I is substantially pure. In some embodiments, neat crystalline Form D of crystalline Compound I is substantially crystalline. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0260] In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 8.4±0.2 degrees 2-theta. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 8.8±0.2 degrees 2-theta. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 14.3±0.2 degrees 2-theta. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 14.8±0.2 degrees 2-theta. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 15.4±0.2 degrees 2-theta. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 16.77±0.2 degrees 2-theta. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 16.85±0.2 degrees 2-theta. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 19.6±0.2 degrees 2-theta. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 20.0±0.2 degrees 2-theta. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 20.3±0.2 degrees 2-theta. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 21.7±0.2 degrees 2-theta. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 22.5±0.2 degrees 2-theta. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 24.7±0.2 degrees 2-theta. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 25.2±0.2 degrees 2-theta.In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 26.2±0.2 degrees 2-theta. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 26.45±0.2 degrees 2-theta. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 26.52±0.2 degrees 2-theta. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 27.8±0.2 degrees 2-theta. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram having a signal at 28.8±0.2 degrees 2-theta.

[0261] In some embodiments, the neat crystalline Form D of crystalline Compound I has a β-α value of 8.4±0.2 degrees 2-theta, 8.8±0.2 degrees 2-theta, 14.3±0.2 degrees 2-theta, 14.8±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 16.77±0.2 degrees 2-theta, 16.85±0.2 degrees 2-theta, 19.6±0.2 degrees 2-theta, 20.0±0.2 degrees 2-theta, 20.3±0.2 degrees 2-theta, 21.7±0.2 degrees 2-theta, 22.5±0.2 degrees 2-theta, 24.7±0.2 degrees 2-theta, 25.2±0.2 degrees 2-theta, 26.2±0.2 degrees 2-theta, 26.45±0.2 degrees The powder is characterized by an X-ray powder diffractogram having signals at one, two, three, four, five, six, seven, eight, nine, ten, or more of 2-theta, 26.52±0.2 degrees 2-theta, 27.8±0.2 degrees 2-theta, and 28.8±0.2 degrees 2-theta.

[0262] In some embodiments, neat crystalline Form D of crystalline Compound I has (a) 8.4±0.2 degrees 2-theta, 8.8±0.2 degrees 2-theta, 14.3±0.2 degrees 2-theta, 14.8±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 16.77±0.2 degrees 2-theta, 16.85±0.2 degrees 2-theta, 19.6±0.2 degrees 2-theta, 20.0±0.2 degrees 2-theta, 20.3±0.2 degrees 2-theta, 21.7±0.2 degrees 2-theta, 22.5±0.2 degrees 2-theta, 24.7±0.2 degrees 2-theta, 25.2±0.2 degrees 2-theta, 26.2±0.2 degrees 2-theta, 26.45±0.2 degrees 2-theta, 26.52±0.2 degrees 2-theta, 27.8±0.2 degrees 2-theta, and 28.8±0.2 degrees 2-theta, and (b) signals at one, two, or three of 16.0±0.2 degrees 2-theta, 18.55±0.2 degrees 2-theta, and 18.64±0.2 degrees 2-theta.

[0263] In some embodiments, the neat crystalline Form D of crystalline Compound I has a solubility of 8.4±0.2 degrees 2-theta, 8.8±0.2 degrees 2-theta, 14.3±0.2 degrees 2-theta, 14.8±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 16.0±0.2 degrees 2-theta, 16.77±0.2 degrees 2-theta, 16.85±0.2 degrees 2-theta, 18.55±0.2 degrees 2-theta, 18.64±0.2 degrees 2-theta, 19.6±0.2 degrees 2-theta, 20.0±0.2 degrees 2-theta, 20.3±0.2 degrees 2-theta, 21.7±0.2 degrees 2-theta, 22.5±0.2 degrees 2-theta, 24.7±0.2 degrees 2-theta, 25.2±0.2 degrees; 2-theta, 26.2±0.2 degrees; 2-theta, 26.45±0.2 degrees; 2-theta, 26.52±0.2 degrees; 2-theta, 27.8±0.2 degrees; 2-theta, and 28.8±0.2 degrees; characterized by a powder X-ray diffractogram having signals at three, four, five, six, seven, eight, nine, ten, or more positions within the following: 2-theta, 25.2±0.2 degrees; 2-theta, 26.2±0.2 degrees; 2-theta, 26.45±0.2 degrees; 2-theta, 26.52±0.2 degrees; 2-theta, 27.8±0.2 degrees; 2-theta, and 28.8±0.2 degrees;

[0264] In some embodiments, the neat crystalline Form D of crystalline Compound I has a solubility of 8.4±0.2 degrees 2-theta, 8.8±0.2 degrees 2-theta, 14.3±0.2 degrees 2-theta, 14.8±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 16.0±0.2 degrees 2-theta, 16.77±0.2 degrees 2-theta, 16.85±0.2 degrees 2-theta, 18.55±0.2 degrees 2-theta, 18.64±0.2 degrees 2-theta, 19.6±0.2 degrees 2-theta, 20.0±0.2 degrees 2-theta, 20.3±0.2 degrees 2-theta, 21.7±0.2 degrees 2-theta, 22.5±0.2 degrees 2-theta, 24.7±0.2 degrees It is characterized by a powder X-ray diffractogram with signals at 25.2±0.2 degrees 2-theta, 26.2±0.2 degrees 2-theta, 26.45±0.2 degrees 2-theta, 26.52±0.2 degrees 2-theta, 27.8±0.2 degrees 2-theta, and 28.8±0.2 degrees 2-theta.

[0265] In some embodiments, the neat crystalline Form D of crystalline Compound I is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0266] In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 152.2±0.2 ppm. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 137.7±0.2 ppm. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 127.3±0.2 ppm. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 120.8±0.2 ppm. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 118.1±0.2 ppm. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 75.7±0.2 ppm. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 35.9±0.2 ppm. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 30.4±0.2 ppm. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 22.1±0.2 ppm. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a C-SS NMR spectrum with a peak at 17.7±0.2 ppm.

[0267] In some embodiments, the neat crystalline Form D of crystalline Compound I is characterized by a C-SS NMR spectrum having one, two, three, four, five, six, seven, eight, or nine peaks selected from 152.2±0.2 ppm, 137.7±0.2 ppm, 127.3±0.2 ppm, 120.8±0.2 ppm, 118.1±0.2 ppm, 75.7±0.2 ppm, 35.9±0.2 ppm, 30.4±0.2 ppm, 22.1±0.2 ppm, and 17.7±0.2 ppm.

[0268] In some embodiments, the neat crystalline Form D of crystalline Compound I is characterized by a C-SS NMR spectrum having (a) one, two, three, four, five, six, seven, eight, nine, or ten peaks selected from 152.2±0.2 ppm, 137.7±0.2 ppm, 127.3±0.2 ppm, 120.8±0.2 ppm, 118.1±0.2 ppm, 75.7±0.2 ppm, 35.9±0.2 ppm, 30.4±0.2 ppm, 22.1±0.2 ppm, and 17.7±0.2 ppm, and (b) one, two, or three peaks selected from 164.6±0.2 ppm, 163.8±0.2 ppm, and 74.2±0.2 ppm.

[0269] In some embodiments, the neat crystalline Form D of crystalline Compound I is characterized by a C-SS NMR spectrum having four, five, six, seven, eight, nine, ten, or more peaks selected from 164.6±0.2 ppm, 163.8±0.2 ppm, 152.2±0.2 ppm, 137.7±0.2 ppm, 127.3±0.2 ppm, 120.8±0.2 ppm, 118.1±0.2 ppm, 75.7±0.2 ppm, 74.2±0.2 ppm, 35.9±0.2 ppm, 30.4±0.2 ppm, 22.1±0.2 ppm, and 17.7±0.2 ppm.

[0270] In some embodiments, the neat crystalline form D of crystalline Compound I is characterized by a C-SS NMR spectrum with peaks at 164.6±0.2 ppm, 163.8±0.2 ppm, 152.2±0.2 ppm, 137.7±0.2 ppm, 127.3±0.2 ppm, 120.8±0.2 ppm, 118.1±0.2 ppm, 75.7±0.2 ppm, 74.2±0.2 ppm, 35.9±0.2 ppm, 30.4±0.2 ppm, 22.1±0.2 ppm, and 17.7±0.2 ppm.

[0271] In some embodiments, the neat crystalline Form D of crystalline Compound I is characterized by a 13C-SS NMR spectrum substantially similar to that of FIG.

[0272] In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a F-SS NMR spectrum with a peak at -62.4±0.2 ppm. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a F-SS NMR spectrum with a peak at -77.2±0.2 ppm. In some embodiments, neat crystalline Form D of crystalline Compound I is characterized by a F-SS NMR spectrum with peaks at -62.4±0.2 ppm and -77.2±0.2 ppm.

[0273] In some embodiments, the neat crystalline Form D of crystalline Compound I is characterized by a 19F-SSNMR spectrum substantially similar to that of FIG.

[0274] In some embodiments, the neat crystalline form D of crystalline Compound I is characterized by a monoclinic system, a P21 space group, and the following unit cell dimensions measured at 250 K on a Bruker diffractometer using Cu Kα radiation (λ=1.54178 Å): [Table 58]

[0275] Another aspect of the present invention provides a method for making neat crystalline Form D of crystalline Compound I. In some embodiments, the method for making neat crystalline Form D of crystalline Compound I comprises: (i) dissolving hemihydrate Form C of crystalline Compound I in ethanol; (ii) placing the solution under nitrogen for 30 minutes; and (iii) placing the solution in an oven at 80° C. for about 5 days to obtain neat crystalline Form D of crystalline Compound I. In some embodiments, a method for making neat crystalline Form D of crystalline Compound I includes: (i) slurrying hemihydrate Form C of Compound I in n-heptane; (ii) heating the slurry to 85° C.; (iii) seeding with neat crystalline Form D of crystalline Compound I; (iv) holding the slurry at 85±5° C.; (v) cooling the slurry to 65° C. over 4 hours; (vi) collecting the solid and washing the solid with n-heptane; and (vii) drying the solid in a vacuum oven at 50° C. with a slight nitrogen bleed to obtain neat crystalline Form D of crystalline Compound I.

[0276] F. Neat crystalline form E of crystalline Compound I In some embodiments, the present invention provides neat crystalline Form E of Compound I.

[0277] In some embodiments, the neat crystalline Form E of crystalline Compound I is characterized by an orthorhombic crystal system, a P 212121 space group, and the following unit cell dimensions measured at 100 K on a Bruker diffractometer using Cu Kα radiation (λ=1.54178 Å): [Table 59]

[0278] Another aspect of the present invention provides a method for making neat crystalline form E of crystalline Compound I. In some embodiments, the method for making neat crystalline form E of crystalline Compound I comprises cooling neat crystalline form D of crystalline Compound I to a temperature below −40° C. to obtain neat crystalline form E of crystalline Compound I.

[0279] G. Crystalline Compound I Acetic Acid Solvate In some embodiments, the present invention provides a crystalline acetic acid solvate of Compound I. Figure 25 provides a powder X-ray diffractogram of crystalline Compound I acetic acid solvate.

[0280] In some embodiments, the crystalline acetic acid solvate of Compound I is substantially pure. In some embodiments, the crystalline acetic acid solvate of Compound I is substantially crystalline. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0281] In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 5.4±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 8.3±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 10.2±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 10.4±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 10.9±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 11.7±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 13.1±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 13.2±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 13.8±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 14.2±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 15.9±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 16.7±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 17.5±0.2 degrees two-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 18.0±0.2 degrees two-theta.In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 18.5±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 18.9±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 19.5±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 19.8±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 20.2±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 20.6±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 21.6±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 22.5±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 25.0±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 25.3±0.2 degrees 2-theta. In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 26.3±0.2 degrees 2-theta.

[0282] In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by an X-ray powder diffractogram having signals at one, two, three, four, or five of the following: 5.4±0.2 degrees 2-theta, 10.2±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, and 20.2±0.2 degrees 2-theta.

[0283] In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram having signals at one, two, three, four, five, six, seven, eight, nine, or ten of 5.4±0.2 degrees 2-theta, 10.2±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 18.5±0.2 degrees 2-theta, 19.5±0.2 degrees 2-theta, 19.8±0.2 degrees 2-theta, 20.2±0.2 degrees 2-theta, 20.6±0.2 degrees 2-theta, and 21.6±0.2 degrees 2-theta.

[0284] In some embodiments, the crystalline acetic acid solvate of Compound I has a crystalline acetic acid solvate of Compound I at 5.4±0.2 degrees 2-theta, 8.3±0.2 degrees 2-theta, 10.2±0.2 degrees 2-theta, 10.4±0.2 degrees 2-theta, 10.9±0.2 degrees 2-theta, 11.7±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 13.2±0.2 degrees 2-theta, 13.8±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 16.7±0.2 degrees 2-theta, 17.5±0.2 degrees 2-theta, 18.0±0.2 degrees 2-theta, 18.5±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 19.5±0.2 degrees 2-theta, 19.8±0.2 degrees; 2-theta, 20.2±0.2 degrees; 2-theta, 20.6±0.2 degrees; 2-theta, 21.6±0.2 degrees; 2-theta, 22.5±0.2 degrees; 2-theta, 25.0±0.2 degrees; 2-theta, 25.3±0.2 degrees; 2-theta, and 26.3±0.2 degrees; characterized by a powder X-ray diffractogram having signals at one, two, three, four, five, six, seven, eight, nine, ten, or more positions within the range of 2-theta, 19.8±0.2 degrees; 2-theta, 20.2±0.2 degrees; 2-theta, 20.6±0.2 degrees; 2-theta, 21.6±0.2 degrees; 2-theta, 22.5±0.2 degrees; 2-theta, 25.0±0.2 degrees; 2-theta, 25.3±0.2 degrees; 2-theta, and 26.3±0.2 degrees; In some embodiments, the crystalline acetic acid solvate of Compound I has a crystalline acetic acid solvate of Compound I at 5.4±0.2 degrees 2-theta, 8.3±0.2 degrees 2-theta, 10.2±0.2 degrees 2-theta, 10.4±0.2 degrees 2-theta, 10.9±0.2 degrees 2-theta, 11.7±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 13.2±0.2 degrees 2-theta, 13.8±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 16.7±0.2 degrees 2-theta, 17.5±0.2 degrees 2-theta, 18.0±0.2 degrees 2-theta, 18.5±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 19.5±0.2 degrees It is characterized by a powder X-ray diffractogram with signals at 2-theta, 19.8±0.2 degrees 2-theta, 20.2±0.2 degrees 2-theta, 20.6±0.2 degrees 2-theta, 21.6±0.2 degrees 2-theta, 22.5±0.2 degrees 2-theta, 25.0±0.2 degrees 2-theta, 25.3±0.2 degrees 2-theta, and 26.3±0.2 degrees 2-theta.

[0285] In some embodiments, the crystalline acetic acid solvate of Compound I is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0286] Another aspect of the present invention provides a method for making a crystalline acetic acid solvate of Compound I. In some embodiments, the method for making a crystalline acetic acid solvate of Compound I comprises (i) combining hemihydrate crystalline Form C of Compound I and acetic acid, and (ii) ball milling at 7500 rpm for two cycles of 10 seconds each, with a 60-second pause after each cycle, to obtain a crystalline acetic acid solvate of Compound I.

[0287] H. Crystalline Heptane Solvate of Compound I, Form B In some embodiments, the present invention provides crystalline heptane solvate crystal form B of Compound I. Figure 27 provides a powder X-ray diffractogram of crystalline heptane solvate crystal form B of Compound I.

[0288] In some embodiments, the crystalline heptane solvate Form B of Compound I is substantially pure. In some embodiments, the crystalline heptane solvate Form B of Compound I is substantially crystalline. In some embodiments, the crystalline heptane solvate Form B of Compound I is characterized by a powder X-ray diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0289] In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a powder X-ray diffractogram having a signal at 4.4±0.2 degrees two-theta. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a powder X-ray diffractogram having a signal at 7.3±0.2 degrees two-theta. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a powder X-ray diffractogram having a signal at 8.9±0.2 degrees two-theta. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a powder X-ray diffractogram having a signal at 10.9±0.2 degrees two-theta. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a powder X-ray diffractogram having a signal at 11.1±0.2 degrees two-theta. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a powder X-ray diffractogram having a signal at 14.4±0.2 degrees two-theta. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a powder X-ray diffractogram having a signal at 14.7±0.2 degrees two-theta. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a powder X-ray diffractogram having a signal at 18.8±0.2 degrees two-theta. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a powder X-ray diffractogram having a signal at 21.9±0.2 degrees two-theta. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a powder X-ray diffractogram having a signal at 23.2±0.2 degrees two-theta. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a powder X-ray diffractogram having a signal at 23.8±0.2 degrees two-theta. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a powder X-ray diffractogram having a signal at 24.5±0.2 degrees two-theta. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a powder X-ray diffractogram having a signal at 25.6±0.2 degrees two-theta.

[0290] In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by an X-ray powder diffractogram having signals at one, two, three, four, five, six, seven, eight, nine, ten, or more of 4.4±0.2 degrees 2-theta, 7.3±0.2 degrees 2-theta, 8.9±0.2 degrees 2-theta, 10.9±0.2 degrees 2-theta, 11.1±0.2 degrees 2-theta, 14.4±0.2 degrees 2-theta, 14.7±0.2 degrees 2-theta, 18.8±0.2 degrees 2-theta, 21.9±0.2 degrees 2-theta, 23.2±0.2 degrees 2-theta, 23.8±0.2 degrees 2-theta, 24.5±0.2 degrees 2-theta, and 25.6±0.2 degrees 2-theta.

[0291] In some embodiments, the crystalline heptane solvate Form B of Compound I has a crystalline α-asymmetric ... It is characterized by a powder X-ray diffractogram having signals at one, two, three, or four of the following: 2-theta, 10.1±0.2 degrees 2-theta, 17.9±0.2 degrees 2-theta, and 20.4±0.2 degrees 2-theta.

[0292] In some embodiments, the crystalline heptane solvate Form B of Compound I has a viscosity of 4.4±0.2 degrees 2-theta, 7.3±0.2 degrees 2-theta, 8.1±0.2 degrees 2-theta, 8.9±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 10.9±0.2 degrees 2-theta, 11.1±0.2 degrees 2-theta, 14.4±0.2 degrees 2-theta, 14.7±0.2 degrees 2-theta, 17.9±0.2 degrees 2-theta, 18.8±0.2 degrees 2-theta, 20.4±0.2 degrees 2-theta, 21.9±0.2 degrees 2-theta, 23.2±0.2 degrees 2-theta, 23.8±0.2 degrees 2-theta, 24.5±0.2 degrees 2-theta, and characterized by a powder X-ray diffractogram having signals at four, five, six, seven, eight, nine, ten, or more positions within 25.6±0.2 degrees 2-theta.

[0293] In some embodiments, the crystalline heptane solvate Form B of Compound I has a viscosity of 4.4±0.2 degrees 2-theta, 7.3±0.2 degrees 2-theta, 8.1±0.2 degrees 2-theta, 8.9±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 10.9±0.2 degrees 2-theta, 11.1±0.2 degrees 2-theta, 14.4±0.2 degrees 2-theta, 14.7±0.2 degrees 2-theta, 17.9±0.2 degrees 2-theta, 18.8±0.2 degrees 2-theta, 20.4±0.2 degrees 2-theta, 21.9±0.2 degrees 2-theta, 23.2±0.2 degrees 2-theta, 23.8±0.2 degrees 2-theta, 24.5±0.2 degrees It is characterized by a powder X-ray diffractogram with signals at 25.6±0.2 degrees 2-theta and 25.6±0.2 degrees 2-theta.

[0294] In some embodiments, the crystalline heptane solvate crystal form B of Compound I is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0295] In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a C-SS NMR spectrum with a peak at 137.5±0.2 ppm. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a C-SS NMR spectrum with a peak at 117.4±0.2 ppm. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a C-SS NMR spectrum with a peak at 126.3±0.2 ppm. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a C-SS NMR spectrum with a peak at 75.5±0.2 ppm. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a C-SS NMR spectrum with a peak at 34.2±0.2 ppm.

[0296] In some embodiments, the crystalline heptane solvate Form B of Compound I is characterized by a C-SS NMR spectrum having one, two, three, four, or five peaks selected from 137.5±0.2 ppm, 126.3±0.2 ppm, 117.4±0.2 ppm, 75.5±0.2 ppm, and 34.2±0.2 ppm.

[0297] In some embodiments, the crystalline heptane solvate crystalline Form B of Compound I has one, two, three, four, or five peaks selected from (a) 137.5±0.2 ppm, 126.3±0.2 ppm, 117.4±0.2 ppm, 75.5±0.2 ppm, and 34.2±0.2 ppm, and (b) 164.4±0.2 ppm, 163.0±0.2 ppm, 151.0±0.2 ppm, 139.5±0.2 ppm, 120.8±0.2 ppm. m, 120.0±0.2 ppm, 74.7±0.2 ppm, 74.1±0.2 ppm, 73.0±0.2 ppm, 31.1±0.2 ppm, 28.2±0.2 ppm, 22.4±0.2 ppm, 20.8±0.2 ppm, 19.5±0.2 ppm, and 13.8±0.2 ppm.

[0298] In some embodiments, the crystalline heptane solvate crystalline Form B of Compound I has the following NAs: 164.4±0.2 ppm, 163.0±0.2 ppm, 151.0±0.2 ppm, 139.5±0.2 ppm, 137.5±0.2 ppm, 126.3±0.2 ppm, 120.8±0.2 ppm, 120.0±0.2 ppm, 117.4±0.2 ppm, 75.5±0.2 ppm, 74.7 ... and 13.8±0.2 ppm.

[0299] In some embodiments, the crystalline heptane solvate of Compound I, Form B, has the following concentrations: 164.4±0.2 ppm, 163.0±0.2 ppm, 151.0±0.2 ppm, 139.5±0.2 ppm, 137.5±0.2 ppm, 126.3±0.2 ppm, 120.8±0.2 ppm, 120.0±0.2 ppm, 117.4±0.2 ppm, 75.5±0.2 ppm ppm, 74.7±0.2 ppm, 74.1±0.2 ppm, 73.0±0.2 ppm, 34.2±0.2 ppm, 31.1±0.2 ppm, 28.2±0.2 ppm, 22.4±0.2 ppm, 20.8±0.2 ppm, 19.5±0.2 ppm, and 13.8±0.2 ppm.

[0300] In some embodiments, the crystalline heptane solvate crystal form B of Compound I is characterized by a 13C-SS NMR spectrum substantially similar to that of FIG.

[0301] In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a F-SS NMR spectrum with a peak at -78.4±0.2 ppm. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a F-SS NMR spectrum with a peak at -64.2±0.2 ppm. In some embodiments, the crystalline heptane solvate of Compound I, Form B, is characterized by a F-SS NMR spectrum with (a) one or two peaks selected from -78.4±0.2 ppm and -64.2±0.2 ppm, and (b) one or two peaks selected from -63.4±0.2 ppm and -77.4±0.2 ppm.

[0302] In some embodiments, the crystalline heptane solvate Form B of Compound I is characterized by a F-SS NMR spectrum having three or four peaks selected from −78.4±0.2 ppm, −77.4±0.2 ppm, −64.2±0.2 ppm, and −63.4±0.2 ppm.

[0303] In some embodiments, the crystalline heptane solvate crystal form B of Compound I is characterized by a 19F-SSNMR spectrum substantially similar to that of FIG.

[0304] Another aspect of the present invention provides a method for making crystalline heptane solvate Form B of Compound I. In some embodiments, the method for making crystalline heptane solvate Form B of Compound I comprises: (i) adding 1-butanol / heptane (75% heptane by volume) to neat crystalline Form D of crystalline Compound I; and (ii) shaking the mixture at 25° C. for 2 days to obtain crystalline heptane solvate Form B of Compound I.

[0305] I. Crystalline Heptane Solvate of Compound I, Form C In some embodiments, the present invention provides crystalline heptane solvate crystal form C of Compound I. Figure 31 provides a powder X-ray diffractogram of crystalline heptane solvate crystal form C of Compound I.

[0306] In some embodiments, the crystalline heptane solvate Form C of Compound I is substantially pure. In some embodiments, the crystalline heptane solvate Form C of Compound I is substantially crystalline. In some embodiments, the crystalline heptane solvate Form C of Compound I is characterized by a powder X-ray diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0307] In some embodiments, the crystalline heptane solvate of Compound I, Form C, is characterized by a powder X-ray diffractogram having a signal at 9.3±0.2 degrees two-theta. In some embodiments, the crystalline heptane solvate of Compound I, Form C, is characterized by a powder X-ray diffractogram having a signal at 13.1±0.2 degrees two-theta. In some embodiments, the crystalline heptane solvate of Compound I, Form C, is characterized by a powder X-ray diffractogram having a signal at 32.3±0.2 degrees two-theta.

[0308] In some embodiments, the crystalline heptane solvate of Compound I, Form C, is characterized by an X-ray powder diffractogram having signals at one or two of 9.3±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, and 32.3±0.2 degrees 2-theta. In some embodiments, the crystalline heptane solvate of Compound I, Form C, is characterized by an X-ray powder diffractogram having signals at 9.3±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, and 32.3±0.2 degrees 2-theta.

[0309] In some embodiments, the crystalline heptane solvate of Compound I, Form C, is characterized by an X-ray powder diffractogram having signals at (a) one, two, or three of 9.3±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, and 32.3±0.2 degrees 2-theta, and (b) one, two, three, four, or five of 5.5±0.2 degrees 2-theta, 8.0±0.2 degrees 2-theta, 8.2±0.2 degrees 2-theta, 11.6±0.2 degrees 2-theta, and 20.4±0.2 degrees 2-theta.

[0310] In some embodiments, the crystalline heptane solvate of Compound I, Form C, is characterized by an X-ray powder diffractogram having signals at five or six of the following angles: 5.5±0.2 degrees 2-theta, 8.0±0.2 degrees 2-theta, 8.2±0.2 degrees 2-theta, 9.3±0.2 degrees 2-theta, 11.6±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 20.4±0.2 degrees 2-theta, and 32.3±0.2 degrees 2-theta.

[0311] In some embodiments, the crystalline heptane solvate of Compound I, Form C, is characterized by an X-ray powder diffractogram with signals at 5.5±0.2 degrees 2-theta, 8.0±0.2 degrees 2-theta, 8.2±0.2 degrees 2-theta, 9.3±0.2 degrees 2-theta, 11.6±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 20.4±0.2 degrees 2-theta, and 32.3±0.2 degrees 2-theta.

[0312] In some embodiments, the crystalline heptane solvate crystal form C of Compound I is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0313] In some embodiments, the crystalline heptane solvate of Compound I, Form C, is characterized by a C-SS NMR spectrum with a peak at 126.9±0.2 ppm. In some embodiments, the crystalline heptane solvate of Compound I, Form C, is characterized by a C-SS NMR spectrum with a peak at 124.1±0.2 ppm. In some embodiments, the crystalline heptane solvate of Compound I, Form C, is characterized by a C-SS NMR spectrum with a peak at 121.5±0.2 ppm. In some embodiments, the crystalline heptane solvate of Compound I, Form C, is characterized by a C-SS NMR spectrum with a peak at 118.8±0.2 ppm. In some embodiments, the crystalline heptane solvate of Compound I, Form C, is characterized by a C-SS NMR spectrum with a peak at 71.5±0.2 ppm. In some embodiments, the crystalline heptane solvate of Compound I, Form C, is characterized by a C-SS NMR spectrum with a peak at 36.1±0.2 ppm. In some embodiments, the crystalline heptane solvate of Compound I, Form C, is characterized by a C-SS NMR spectrum with a peak at 24.3±0.2 ppm. In some embodiments, the crystalline heptane solvate of Compound I, Form C, is characterized by a C-SS NMR spectrum with a peak at 14.2±0.2 ppm.

[0314] In some embodiments, the crystalline heptane solvate of Compound I, Form C, is characterized by a C-SS NMR spectrum having one, two, three, four, five, six, seven, or eight peaks selected from 126.9±0.2 ppm, 124.1±0.2 ppm, 121.5±0.2 ppm, 118.8±0.2 ppm, 71.5±0.2 ppm, 36.1±0.2 ppm, 24.3±0.2 ppm, and 14.2±0.2 ppm.

[0315] In some embodiments, the crystalline heptane solvate of Compound I, Form C, exhibits (a) one, two, three, four, five, six, seven, or eight peaks selected from 126.9±0.2 ppm, 124.1±0.2 ppm, 121.5±0.2 ppm, 118.8±0.2 ppm, 71.5±0.2 ppm, 36.1±0.2 ppm, 24.3±0.2 ppm, and 14.2±0.2 ppm; and (b) one, two, three, four, five, six, seven, or eight peaks selected from 126.9±0.2 ppm, 124.1±0.2 ppm, 121.5±0.2 ppm, 118.8±0.2 ppm, 71.5±0.2 ppm, 36.1±0.2 ppm, 24.3±0.2 ppm, and 14.2±0.2 ppm. The C-SS NMR spectrum is characterized by having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 9.4±0.2 ppm, 128.3±0.2 ppm, 117.9±0.2 ppm, 76.1±0.2 ppm, 73.6±0.2 ppm, 37.0±0.2 ppm, 33.6±0.2 ppm, 30.9±0.2 ppm, 27.9±0.2 ppm, 23.3±0.2 ppm, 21.0±0.2 ppm, 20.0±0.2 ppm, and 18.1±0.2 ppm.

[0316] In some embodiments, the crystalline heptane solvate of Compound I, Form C, has the following NAs: 164.4±0.2 ppm, 163.6±0.2 ppm, 163.1±0.2 ppm, 151.1±0.2 ppm, 139.4±0.2 ppm, 128.3±0.2 ppm, 126.9±0.2 ppm, 124.1±0.2 ppm, 121.5±0.2 ppm, 118.8±0.2 ppm, 117.9±0.2 ppm, 76.1±0.2 ppm, 73.6±0.2 ppm The C-SS NMR spectrum is characterized by having seventeen or more peaks selected from the following: pm, 71.5±0.2 ppm, 37.0±0.2 ppm, 36.1±0.2 ppm, 33.6±0.2 ppm, 30.9±0.2 ppm, 27.9±0.2 ppm, 24.3±0.2 ppm, 23.3±0.2 ppm, 21.0±0.2 ppm, 20.0±0.2 ppm, 18.1±0.2 ppm, and 14.2±0.2 ppm.

[0317] In some embodiments, the crystalline heptane solvate of Compound I, Form C, has an NA of 164.4±0.2 ppm, 163.6±0.2 ppm, 163.1±0.2 ppm, 151.1±0.2 ppm, 139.4±0.2 ppm, 128.3±0.2 ppm, 126.9±0.2 ppm, 124.1±0.2 ppm, 121.5±0.2 ppm, 118.8±0.2 ppm, 117.9±0.2 ppm, 76.1±0.2 ppm, 77.1±0.2 ppm, 78.1±0.2 ppm, 79.1±0.2 ppm, 80.1±0.2 ppm, 81.1±0.2 ppm, 82.1±0.2 ppm, 83.1±0.2 ppm, 84.1±0.2 ppm, 85.1±0.2 ppm, 86.1±0.2 ppm, 87.1±0.2 ppm, 88.1±0.2 ppm, 89.1±0.2 ppm, 89.1±0.2 ppm, 90.1±0.2 ppm, 91.1±0.2 ppm, 92.1±0.2 ppm, 93.1±0.2 ppm, 94.1±0.2 ppm, 95.1±0.2 ppm, 96.1±0.2 ppm, 97.1±0.2 ppm, 98.1±0.2 ppm, 9 ... It is characterized by a C-SS NMR spectrum having peaks at 3.6±0.2 ppm, 71.5±0.2 ppm, 37.0±0.2 ppm, 36.1±0.2 ppm, 33.6±0.2 ppm, 30.9±0.2 ppm, 27.9±0.2 ppm, 24.3±0.2 ppm, 23.3±0.2 ppm, 21.0±0.2 ppm, 20.0±0.2 ppm, 18.1±0.2 ppm, and 14.2±0.2 ppm.

[0318] In some embodiments, the crystalline heptane solvate crystal form C of Compound I is characterized by a 13C-SS NMR spectrum substantially similar to that of FIG.

[0319] Another aspect of the present invention provides a method for making crystalline heptane solvate crystalline Form C of Compound I. In some embodiments, the method for making crystalline heptane solvate crystalline Form C of Compound I comprises (i) adding ethyl acetate / heptane (25% by volume heptane) to neat crystalline Form D of crystalline Compound I, and (ii) shaking at 25° C. for 2 days to obtain crystalline heptane solvate crystalline Form C of Compound I.

[0320] J. Crystalline Compound I Octane Solvate In some embodiments, the present invention provides an octane solvate of crystalline Compound I. Figure 35 provides a powder X-ray diffractogram of crystalline Compound I octane solvate.

[0321] In some embodiments, the crystalline octane solvate of Compound I is substantially pure. In some embodiments, the crystalline octane solvate of Compound I is substantially crystalline. In some embodiments, the crystalline octane solvate of Compound I is characterized by a powder X-ray diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0322] In some embodiments, the crystalline octane solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 5.6±0.2 degrees two-theta. In some embodiments, the crystalline octane solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 5.9±0.2 degrees two-theta. In some embodiments, the crystalline octane solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 10.2±0.2 degrees two-theta. In some embodiments, the crystalline octane solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 11.7±0.2 degrees two-theta. In some embodiments, the crystalline octane solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 18.2±0.2 degrees two-theta. In some embodiments, the crystalline octane solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 18.5±0.2 degrees two-theta. In some embodiments, the crystalline octane solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 20.5±0.2 degrees two-theta.

[0323] In some embodiments, the crystalline octane solvate of Compound I is characterized by an X-ray powder diffractogram having signals at one, two, three, four, or five of the following: 5.6±0.2 degrees 2-theta, 5.9±0.2 degrees 2-theta, 10.2±0.2 degrees 2-theta, 11.7±0.2 degrees 2-theta, and 18.2±0.2 degrees 2-theta.

[0324] In some embodiments, the crystalline octane solvate of Compound I is characterized by an X-ray powder diffractogram having signals at one, two, three, four, five, six, or seven of the following: 5.6±0.2 degrees 2-theta, 5.9±0.2 degrees 2-theta, 10.2±0.2 degrees 2-theta, 11.7±0.2 degrees 2-theta, 18.2±0.2 degrees 2-theta, 18.5±0.2 degrees 2-theta, and 20.5±0.2 degrees 2-theta.

[0325] In some embodiments, the crystalline octane solvate of Compound I is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0326] In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 166.3±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 164.6±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 164.1±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 153.8±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 152.2±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 151.7±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 140.4±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 137.6±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 135.3±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 134.8±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 131.1±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 130.2±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a 13C-SS NMR spectrum with a peak at 127.3±0.2 ppm.In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 125.5±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 122.7±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 120.8±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 120.1±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 118.1±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 75.7±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 74.4±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 73.8±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 40.2±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 37.5±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 36.1±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 32.0±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a 13C-SS NMR spectrum with a peak at 29.9±0.2 ppm.In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 28.5±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 27.0±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 25.1±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 22.4±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 20.0±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 17.7±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 14.1±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 13.5±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 12.6±0.2 ppm.

[0327] In some embodiments, the crystalline octane solvate of Compound I has a RI of 166.3±0.2 ppm, 164.6±0.2 ppm, 164.1±0.2 ppm, 153.8±0.2 ppm, 152.2±0.2 ppm, 151.7±0.2 ppm, 140.4±0.2 ppm, 137.6±0.2 ppm, 135.3±0.2 ppm, 134.8±0.2 ppm, 131.1±0.2 ppm, 130.2±0.2 ppm, 127.3±0.2 ppm, 125.5±0.2 ppm, 122.7±0.2 ppm, 120.8±0.2 ppm, 120.1±0.2 ppm, 118.1±0.2 ppm, 75.7 ±0.2 ppm, 74.4±0.2 ppm, 73.8±0.2 ppm, 40.2±0.2 ppm, 37.5±0.2 ppm, 36.1±0.2 ppm, 32.0±0.2 ppm, 29.9±0.2 ppm, 28.5±0.2 ppm, 27.0±0.2 ppm, 25.1±0.2 ppm, 22.4±0.2 ppm, 20.0±0.2 ppm, 17.7±0.2 ppm, 14.1±0.2 ppm, 13.5±0.2 ppm, and 12.6±0.2 ppm.In some embodiments, the crystalline octane solvate of Compound I has a saturation concentration of 166.3±0.2 ppm, 164.6±0.2 ppm, 164.1±0.2 ppm, 153.8±0.2 ppm, 152.2±0.2 ppm, 151.7±0.2 ppm, 140.4±0.2 ppm, 137.6±0.2 ppm, 135.3±0.2 ppm, 134.8±0.2 ppm, 131.1±0.2 ppm, 130.2±0.2 ppm, 127.3±0.2 ppm, 125.5±0.2 ppm, 122.7±0.2 ppm, 120.8±0.2 ppm, 120.1±0.2 ppm, 1 It is characterized by a C-SS NMR spectrum having peaks at 18.1±0.2 ppm, 75.7±0.2 ppm, 74.4±0.2 ppm, 73.8±0.2 ppm, 40.2±0.2 ppm, 37.5±0.2 ppm, 36.1±0.2 ppm, 32.0±0.2 ppm, 29.9±0.2 ppm, 28.5±0.2 ppm, 27.0±0.2 ppm, 25.1±0.2 ppm, 22.4±0.2 ppm, 20.0±0.2 ppm, 17.7±0.2 ppm, 14.1±0.2 ppm, 13.5±0.2 ppm, and 12.6±0.2 ppm.

[0328] In some embodiments, the crystalline octane solvate of Compound I is characterized by a 13C-SS NMR spectrum substantially similar to that of FIG.

[0329] In some embodiments, the crystalline octane solvate of Compound I is characterized by a F-SS NMR spectrum with a peak at -62.5±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a F-SS NMR spectrum with a peak at -65.0±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a F-SS NMR spectrum with a peak at -65.6±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a F-SS NMR spectrum with a peak at -66.2±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a F-SS NMR spectrum with a peak at -67.1±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a F-SS NMR spectrum with a peak at -75.1±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a F-SS NMR spectrum with a peak at -76.5±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a F-SS NMR spectrum with a peak at -77.2±0.2 ppm.

[0330] In some embodiments, the crystalline octane solvate of Compound I is characterized by a F-SSNMR spectrum having one, two, three, four, five, six, seven, or more peaks selected from -62.5±0.2 ppm, -65.0±0.2 ppm, -65.6±0.2 ppm, -66.2±0.2 ppm, -67.1±0.2 ppm, -75.1±0.2 ppm, -76.5±0.2 ppm, and -77.2±0.2 ppm. In some embodiments, the crystalline octane solvate of Compound I is characterized by a F-SS NMR spectrum having peaks at -62.5±0.2 ppm, -65.0±0.2 ppm, -65.6±0.2 ppm, -66.2±0.2 ppm, -67.1±0.2 ppm, -75.1±0.2 ppm, -76.5±0.2 ppm, and -77.2±0.2 ppm.

[0331] In some embodiments, the crystalline octane solvate of Compound I is characterized by a 19F-SSNMR spectrum substantially similar to that of FIG.

[0332] Another aspect of the present invention provides a method for making the octane solvate of crystalline Compound I. In some embodiments, the method for making the octane solvate of crystalline Compound I comprises shaking crystalline hemihydrate Form C of Compound I in octane at 35° C. for about 1 week to obtain the octane solvate of crystalline Compound I.

[0333] K. Crystalline Cyclohexane Solvate of Compound I, Form A In some embodiments, the present invention provides crystalline cyclohexane solvate Form A of Compound I. Figure 38 provides a powder X-ray diffractogram of crystalline cyclohexane solvate Form A of Compound I.

[0334] In some embodiments, the crystalline cyclohexane solvate Form A of Compound I is substantially pure. In some embodiments, the crystalline cyclohexane solvate Form A of Compound I is substantially crystalline. In some embodiments, the crystalline cyclohexane solvate Form A of Compound I is characterized by an X-ray powder diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0335] In some embodiments, the crystalline cyclohexane solvate of Compound I, Form A, is characterized by a powder X-ray diffractogram having a signal at 5.1±0.2 degrees two-theta. In some embodiments, the crystalline cyclohexane solvate of Compound I, Form A, is characterized by a powder X-ray diffractogram having a signal at 16.0±0.2 degrees two-theta. In some embodiments, the crystalline cyclohexane solvate of Compound I, Form A, is characterized by a powder X-ray diffractogram having a signal at 33.6±0.2 degrees two-theta.

[0336] In some embodiments, the crystalline cyclohexane solvate of Compound I, Form A, is characterized by an X-ray powder diffractogram having signals at one or two of 5.1±0.2 degrees 2-theta, 16.0±0.2 degrees 2-theta, and 33.6±0.2 degrees 2-theta. In some embodiments, the crystalline cyclohexane solvate of Compound I, Form A, is characterized by an X-ray powder diffractogram having signals at 5.1±0.2 degrees 2-theta, 16.0±0.2 degrees 2-theta, and 33.6±0.2 degrees 2-theta.

[0337] In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by an X-ray powder diffractogram having signals at (a) one, two, or three of 5.1±0.2 degrees 2-theta, 16.0±0.2 degrees 2-theta, and 33.6±0.2 degrees 2-theta, and (b) one, two, three, four, or five of 5.6±0.2 degrees 2-theta, 16.7±0.2 degrees 2-theta, 18.5±0.2 degrees 2-theta, 19.9±0.2 degrees 2-theta, and 21.6±0.2 degrees 2-theta.

[0338] In some embodiments, the crystalline cyclohexane solvate of Compound I, Form A, is characterized by an X-ray powder diffractogram having signals at five, six, seven, or more of the following angles: 5.1±0.2 degrees 2-theta, 5.6±0.2 degrees 2-theta, 16.0±0.2 degrees 2-theta, 16.7±0.2 degrees 2-theta, 18.5±0.2 degrees 2-theta, 19.9±0.2 degrees 2-theta, 21.6±0.2 degrees 2-theta, and 33.6±0.2 degrees 2-theta.

[0339] In some embodiments, the crystalline cyclohexane solvate of Compound I, Form A, is characterized by an X-ray powder diffractogram with signals at 5.1±0.2 degrees 2-theta, 5.6±0.2 degrees 2-theta, 16.0±0.2 degrees 2-theta, 16.7±0.2 degrees 2-theta, 18.5±0.2 degrees 2-theta, 19.9±0.2 degrees 2-theta, 21.6±0.2 degrees 2-theta, and 33.6±0.2 degrees 2-theta.

[0340] In some embodiments, the crystalline cyclohexane solvate crystal Form A of Compound I is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0341] In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a C-SS NMR spectrum with a peak at 166.6±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a C-SS NMR spectrum with a peak at 152.1±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a C-SS NMR spectrum with a peak at 150.8±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a C-SS NMR spectrum with a peak at 140.4±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a C-SS NMR spectrum with a peak at 137.6±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a C-SS NMR spectrum with a peak at 135.4±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a C-SS NMR spectrum with a peak at 127.3±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a C-SS NMR spectrum with a peak at 125.5±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a C-SS NMR spectrum with a peak at 123.4±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a C-SS NMR spectrum with a peak at 119.7±0.2 ppm. In some embodiments, the crystalline cyclohexane solvate of Compound I, Form A, is characterized by a C-SS NMR spectrum with a peak at 74.3±0.2 ppm. In some embodiments, the crystalline cyclohexane solvate of Compound I, Form A, is characterized by a C-SS NMR spectrum with a peak at 37.4±0.2 ppm.In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a C-SS NMR spectrum with a peak at 36.2±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a C-SS NMR spectrum with a peak at 30.6±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a C-SS NMR spectrum with a peak at 27.4±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a C-SS NMR spectrum with a peak at 17.7±0.2 ppm.

[0342] In some embodiments, the crystalline cyclohexane solvate of Compound I, Form A, is characterized by a C-SS NMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 166.6±0.2 ppm, 152.1±0.2 ppm, 150.8±0.2 ppm, 140.4±0.2 ppm, 137.6±0.2 ppm, 135.4±0.2 ppm, 127.3±0.2 ppm, 125.5±0.2 ppm, 123.4±0.2 ppm, 119.7±0.2 ppm, 74.3±0.2 ppm, 37.4±0.2 ppm, 36.2±0.2 ppm, 30.6±0.2 ppm, 27.4±0.2 ppm, and 17.7±0.2 ppm. In some embodiments, the crystalline cyclohexane solvate of Compound I, Form A, is characterized by a C-SS NMR spectrum with peaks at 166.6±0.2 ppm, 152.1±0.2 ppm, 150.8±0.2 ppm, 140.4±0.2 ppm, 137.6±0.2 ppm, 135.4±0.2 ppm, 127.3±0.2 ppm, 125.5±0.2 ppm, 123.4±0.2 ppm, 119.7±0.2 ppm, 74.3±0.2 ppm, 37.4±0.2 ppm, 36.2±0.2 ppm, 30.6±0.2 ppm, 27.4±0.2 ppm, and 17.7±0.2 ppm.

[0343] In some embodiments, the crystalline cyclohexane solvate Form A of Compound I has a NA of: (a) NA selected from 166.6±0.2 ppm, 152.1±0.2 ppm, 150.8±0.2 ppm, 140.4±0.2 ppm, 137.6±0.2 ppm, 135.4±0.2 ppm, 127.3±0.2 ppm, 125.5±0.2 ppm, 123.4±0.2 ppm, 119.7±0.2 ppm, 74.3±0.2 ppm, 37.4±0.2 ppm, 36.2±0.2 ppm, 30.6±0.2 ppm, 27.4±0.2 ppm, and 17.7±0.2 ppm. and (b) one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 164.7±0.2 ppm, 163.7±0.2 ppm, 154.4±0.2 ppm, 138.8±0.2 ppm, 131.5±0.2 ppm, 120.7±0.2 ppm, 118.1±0.2 ppm, 75.7±0.2 ppm, 73.4±0.2 ppm, 21.9±0.2 ppm, and 19.4±0.2 ppm.

[0344] In some embodiments, the crystalline cyclohexane solvate of Compound I, Form A, has the following concentrations: 166.6±0.2 ppm, 164.7±0.2 ppm, 163.7±0.2 ppm, 154.4±0.2 ppm, 152.1±0.2 ppm, 150.8±0.2 ppm, 140.4±0.2 ppm, 138.8±0.2 ppm, 137.6±0.2 ppm, 135.4±0.2 ppm, 131.5±0.2 ppm, 127.3±0.2 ppm, 125.5±0.2 ppm, 123.4±0.2 ppm. ppm, 120.7±0.2 ppm, 119.7±0.2 ppm, 118.1±0.2 ppm, 75.7±0.2 ppm, 74.3±0.2 ppm, 73.4±0.2 ppm, 37.4±0.2 ppm, 36.2±0.2 ppm, 30.6±0.2 ppm, 27.4±0.2 ppm, 21.9±0.2 ppm, 19.4±0.2 ppm, and 17.7±0.2 ppm.

[0345] In some embodiments, the crystalline cyclohexane solvate of Compound I, Form A, has the following concentrations: 166.6±0.2 ppm, 164.7±0.2 ppm, 163.7±0.2 ppm, 154.4±0.2 ppm, 152.1±0.2 ppm, 150.8±0.2 ppm, 140.4±0.2 ppm, 138.8±0.2 ppm, 137.6±0.2 ppm, 135.4±0.2 ppm, 131.5±0.2 ppm, 127.3±0.2 ppm, 125.5±0.2 ppm, 1 It is characterized by a C-SS NMR spectrum having peaks at 23.4±0.2 ppm, 120.7±0.2 ppm, 119.7±0.2 ppm, 118.1±0.2 ppm, 75.7±0.2 ppm, 74.3±0.2 ppm, 73.4±0.2 ppm, 37.4±0.2 ppm, 36.2±0.2 ppm, 30.6±0.2 ppm, 27.4±0.2 ppm, 21.9±0.2 ppm, 19.4±0.2 ppm, and 17.7±0.2 ppm.

[0346] In some embodiments, the crystalline cyclohexane solvate crystal form A of Compound I is characterized by a 13C-SS NMR spectrum substantially similar to that of FIG.

[0347] In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a peak in the F-SS NMR spectrum at -62.6±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a peak in the F-SS NMR spectrum at -65.9±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a peak in the F-SS NMR spectrum at -66.8±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a peak in the F-SS NMR spectrum at -75.4±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form A of Compound I is characterized by a peak in the F-SS NMR spectrum at -77.6±0.2 ppm.

[0348] In some embodiments, the crystalline cyclohexane solvate of Compound I, Form A, is characterized by a F-SS NMR spectrum having one, two, three, or four peaks selected from -62.6±0.2 ppm, -65.9±0.2 ppm, -66.8±0.2 ppm, -75.4±0.2 ppm, and -77.6±0.2 ppm. In some embodiments, the crystalline cyclohexane solvate of Compound I, Form A, is characterized by a F-SS NMR spectrum having peaks at -62.6±0.2 ppm, -65.9±0.2 ppm, -66.8±0.2 ppm, -75.4±0.2 ppm, and -77.6±0.2 ppm.

[0349] In some embodiments, the crystalline cyclohexane solvate Form A of Compound I is characterized by a F-SS NMR spectrum having (a) one, two, three, four, or five peaks selected from −62.6±0.2 ppm, −65.9±0.2 ppm, −66.8±0.2 ppm, −75.4±0.2 ppm, and −77.6±0.2 ppm, and (b) one or two peaks selected from −64.5±0.2 ppm and −76.6±0.2 ppm.

[0350] In some embodiments, the crystalline cyclohexane solvate of Compound I, Form A, is characterized by a F-SS NMR spectrum having three, four, five, six, or seven peaks selected from −62.6±0.2 ppm, −64.5±0.2 ppm, −65.9±0.2 ppm, −66.8±0.2 ppm, −75.4±0.2 ppm, −76.6±0.2 ppm, and −77.6±0.2 ppm.

[0351] In some embodiments, the crystalline cyclohexane solvate of Compound I, Form A, is characterized by a F-SS NMR spectrum with peaks at -62.6±0.2 ppm, -64.5±0.2 ppm, -65.9±0.2 ppm, -66.8±0.2 ppm, -75.4±0.2 ppm, -76.6±0.2 ppm, and -77.6±0.2 ppm.

[0352] In some embodiments, the crystalline cyclohexane solvate crystal Form A of Compound I is characterized by a 19F-SSNMR spectrum substantially similar to that of FIG.

[0353] Another aspect of the present invention provides a method for making crystalline cyclohexane solvate Form A of Compound I. In some embodiments, the method for making crystalline cyclohexane solvate Form A of Compound I comprises (i) adding cyclohexane to neat crystalline Form D of crystalline Compound I, and (ii) shaking the mixture at 25° C. for 3 days to obtain crystalline cyclohexane solvate Form A of Compound I.

[0354] L. Crystalline Cyclohexane Solvate of Compound I, Form B In some embodiments, the present invention provides crystalline cyclohexane solvate crystal form B of Compound I. Figure 41 provides a powder X-ray diffractogram of crystalline cyclohexane solvate crystal form B of Compound I.

[0355] In some embodiments, the crystalline cyclohexane solvate Form B of Compound I is substantially pure. In some embodiments, the crystalline cyclohexane solvate Form B of Compound I is substantially crystalline. In some embodiments, the crystalline cyclohexane solvate Form B of Compound I is characterized by an X-ray powder diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0356] In some embodiments, crystalline cyclohexane solvate Form B of Compound I is characterized by a powder X-ray diffractogram having a signal at 15.5±0.2 degrees two-theta. In some embodiments, crystalline cyclohexane solvate Form B of Compound I is characterized by a powder X-ray diffractogram having a signal at 20.8±0.2 degrees two-theta. In some embodiments, crystalline cyclohexane solvate Form B of Compound I is characterized by a powder X-ray diffractogram having a signal at 23.4±0.2 degrees two-theta. In some embodiments, crystalline cyclohexane solvate Form B of Compound I is characterized by a powder X-ray diffractogram having a signal at 26.7±0.2 degrees two-theta.

[0357] In some embodiments, the crystalline cyclohexane solvate of Compound I, Form B, is characterized by an X-ray powder diffractogram having signals at one, two, or three of the following: 15.5±0.2 degrees 2-theta, 20.8±0.2 degrees 2-theta, 23.4±0.2 degrees 2-theta, and 26.7±0.2 degrees 2-theta. In some embodiments, the crystalline cyclohexane solvate of Compound I, Form B, is characterized by an X-ray powder diffractogram having signals at 15.5±0.2 degrees 2-theta, 20.8±0.2 degrees 2-theta, 23.4±0.2 degrees 2-theta, and 26.7±0.2 degrees 2-theta.

[0358] In some embodiments, crystalline cyclohexane solvate Form B of Compound I is characterized by a powder X-ray diffractogram having signals at (a) one, two, three, or four of 15.5±0.2 degrees 2-theta, 20.8±0.2 degrees 2-theta, 23.4±0.2 degrees 2-theta, and 26.7±0.2 degrees 2-theta, and (b) one, two, three, four, five, six, or seven of 7.8±0.2 degrees 2-theta, 11.8±0.2 degrees 2-theta, 13.8±0.2 degrees 2-theta, 16.6±0.2 degrees 2-theta, 18.4±0.2 degrees 2-theta, 19.9±0.2 degrees 2-theta, and 21.6±0.2 degrees 2-theta.

[0359] In some embodiments, crystalline cyclohexane solvate Form B of Compound I is characterized by an X-ray powder diffractogram having signals at five, six, seven, eight, nine, ten, or more of the following angles: 7.8±0.2 degrees 2-theta, 11.8±0.2 degrees 2-theta, 13.8±0.2 degrees 2-theta, 15.5±0.2 degrees 2-theta, 16.6±0.2 degrees 2-theta, 18.4±0.2 degrees 2-theta, 19.9±0.2 degrees 2-theta, 20.8±0.2 degrees 2-theta, 21.6±0.2 degrees 2-theta, 23.4±0.2 degrees 2-theta, and 26.7±0.2 degrees 2-theta.

[0360] In some embodiments, the crystalline cyclohexane solvate of Compound I, Form B, is characterized by an X-ray powder diffractogram with signals at 7.8±0.2 degrees 2-theta, 11.8±0.2 degrees 2-theta, 13.8±0.2 degrees 2-theta, 15.5±0.2 degrees 2-theta, 16.6±0.2 degrees 2-theta, 18.4±0.2 degrees 2-theta, 19.9±0.2 degrees 2-theta, 20.8±0.2 degrees 2-theta, 21.6±0.2 degrees 2-theta, 23.4±0.2 degrees 2-theta, and 26.7±0.2 degrees 2-theta.

[0361] In some embodiments, the crystalline cyclohexane solvate crystal form B of Compound I is characterized by a powder X-ray diffractogram substantially similar to that shown in FIG.

[0362] In some embodiments, crystalline cyclohexane solvate Form B of Compound I is characterized by a C-SS NMR spectrum with a peak at 128.0±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form B of Compound I is characterized by a C-SS NMR spectrum with a peak at 34.7±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form B of Compound I is characterized by a C-SS NMR spectrum with a peak at 31.5±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form B of Compound I is characterized by a C-SS NMR spectrum with a peak at 26.5±0.2 ppm. In some embodiments, crystalline cyclohexane solvate Form B of Compound I is characterized by a C-SS NMR spectrum with a peak at 19.0±0.2 ppm.

[0363] In some embodiments, the crystalline cyclohexane solvate Form B of Compound I is characterized by a C-SS NMR spectrum having one, two, three, four, or five peaks selected from 128.0±0.2 ppm, 34.7±0.2 ppm, 31.5±0.2 ppm, 26.5±0.2 ppm, and 19.0±0.2 ppm.

[0364] In some embodiments, the crystalline cyclohexane solvate Form B of Compound I is characterized by a C-SS NMR spectrum having (a) one, two, three, four, or five peaks selected from 128.0±0.2 ppm, 34.7±0.2 ppm, 31.5±0.2 ppm, 26.5±0.2 ppm, and 19.0±0.2 ppm, and (b) one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 164.7±0.2 ppm, 150.9±0.2 ppm, 138.7±0.2 ppm, 118.2±0.2 ppm, 75.6±0.2 ppm, 73.6±0.2 ppm, 36.5±0.2 ppm, and 19.5±0.2 ppm.

[0365] In some embodiments, the crystalline cyclohexane solvate Form B of Compound I is characterized by a C-SS NMR spectrum having nine, ten, or more peaks selected from 164.7±0.2 ppm, 150.9±0.2 ppm, 138.7±0.2 ppm, 128.0±0.2 ppm, 118.2±0.2 ppm, 75.6±0.2 ppm, 73.6±0.2 ppm, 36.5±0.2 ppm, 34.7±0.2 ppm, 31.5±0.2 ppm, 26.5±0.2 ppm, 19.5±0.2 ppm, and 19.0±0.2 ppm.

[0366] In some embodiments, the crystalline cyclohexane solvate Form B of Compound I is characterized by a C-SS NMR spectrum with peaks at 164.7±0.2 ppm, 150.9±0.2 ppm, 138.7±0.2 ppm, 128.0±0.2 ppm, 118.2±0.2 ppm, 75.6±0.2 ppm, 73.6±0.2 ppm, 36.5±0.2 ppm, 34.7±0.2 ppm, 31.5±0.2 ppm, 26.5±0.2 ppm, 19.5±0.2 ppm, and 19.0±0.2 ppm.

[0367] In some embodiments, the crystalline cyclohexane solvate crystal form B of Compound I is characterized by a 13C-SS NMR spectrum substantially similar to that of FIG.

[0368] In some embodiments, the crystalline cyclohexane solvate Form B of Compound I is characterized by a 19F-SSNMR spectrum with a peak at −75.0±0.2 ppm.

[0369] In some embodiments, the crystalline cyclohexane solvate Form B of Compound I is characterized by a 19F-SS NMR spectrum with peaks at −64.3±0.2 ppm and −75.0±0.2 ppm.

[0370] In some embodiments, the crystalline cyclohexane solvate crystal form B of Compound I is characterized by a 19F-SSNMR spectrum substantially similar to that of FIG.

[0371] Another aspect of the present invention provides a method for making crystalline cyclohexane solvate Form B of Compound I. In some embodiments, the method for making crystalline cyclohexane solvate Form B of Compound I comprises (i) adding cyclohexane to crystalline hemihydrate Form C of Compound I and (ii) shaking the mixture at 80° C. for 3 days to obtain crystalline cyclohexane solvate Form B of Compound I.

[0372] M. Crystalline cyclohexane solvate of Compound I, Form C In some embodiments, the present invention provides crystalline cyclohexane solvate crystal form C of Compound I. Figure 45 provides a powder X-ray diffractogram of crystalline cyclohexane solvate crystal form C of Compound I.

[0373] In some embodiments, the crystalline cyclohexane solvate Form C of Compound I is substantially pure. In some embodiments, the crystalline cyclohexane solvate Form C of Compound I is substantially crystalline. In some embodiments, the crystalline cyclohexane solvate Form C of Compound I is characterized by an X-ray powder diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0374] In some embodiments, the crystalline cyclohexane solvate of Compound I, Form C, is characterized by a powder X-ray diffractogram having a signal at 10.0±0.2 degrees two-theta.

[0375] In some embodiments, the crystalline cyclohexane solvate of Compound I, Form C, is characterized by an X-ray powder diffractogram having (a) a signal at 10.0±0.2 degrees two-theta, and (b) signals at one, two, three, four, or five of 5.8±0.2 degrees two-theta, 7.8±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 13.9±0.2 degrees two-theta, and 19.9±0.2 degrees two-theta.

[0376] In some embodiments, the crystalline cyclohexane solvate of Compound I, Form C, is characterized by an X-ray powder diffractogram with signals at 5.8±0.2 degrees 2-theta, 7.8±0.2 degrees 2-theta, 10.0±0.2 degrees 2-theta, 11.8±0.2 degrees 2-theta, 13.9±0.2 degrees 2-theta, and 19.9±0.2 degrees 2-theta.

[0377] In some embodiments, the crystalline cyclohexane solvate crystal form C of Compound I is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0378] Another aspect of the present invention provides a method of making crystalline cyclohexane solvate Form C of Compound I. In some embodiments, the method of making crystalline cyclohexane solvate Form C of Compound I comprises (i) adding cyclohexane to crystalline hemihydrate Form C of Compound I and (ii) shaking the mixture at 60° C. for one week to obtain crystalline cyclohexane solvate Form C of Compound I.

[0379] N. Crystalline Compound I Ethanol Solvate In some embodiments, the present invention provides a crystalline ethanol solvate of Compound I. Figure 46 provides a powder X-ray diffractogram of the crystalline ethanol solvate of Compound I.

[0380] In some embodiments, the crystalline ethanol solvate of Compound I is substantially pure. In some embodiments, the crystalline ethanol solvate of Compound I is substantially crystalline. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a powder X-ray diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0381] In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 6.2±0.2 degrees two-theta. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 7.8±0.2 degrees two-theta. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a powder X-ray diffractogram having a signal at 13.3±0.2 degrees two-theta.

[0382] In some embodiments, the crystalline ethanol solvate of Compound I is characterized by an X-ray powder diffractogram having signals at one, two, or three of 6.2±0.2 degrees two-theta, 7.8±0.2 degrees two-theta, and 13.3±0.2 degrees two-theta.

[0383] In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0384] In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 162.8±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 151.7±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 150.7±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 139.1±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 138.0±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 127.4±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 126.9±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 124.3±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 120.4±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 117.7±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 78.7±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 77.9±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a 13C-SS NMR spectrum with a peak at 72.6±0.2 ppm.In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 33.4±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 25.9±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 21.7±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 20.0±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 18.8±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a C-SS NMR spectrum with a peak at 17.9±0.2 ppm.

[0385] In some embodiments, the crystalline ethanol solvate of Compound I has an NA of 162.8±0.2 ppm, 151.7±0.2 ppm, 150.7±0.2 ppm, 139.1±0.2 ppm, 138.0±0.2 ppm, 127.4±0.2 ppm, 126.9±0.2 ppm, 124.3±0.2 ppm, 120.4±0.2 ppm, 117.7±0.2 ppm, 78 ...8.0±0.2 ppm, 138.0±0.2 ppm, 138.0±0.2 ppm, 138.0±0.2 ppm, 138.0±0.2 ppm, 138.0±0.2 ppm, 13 ppm, 77.9±0.2 ppm, 72.6±0.2 ppm, 33.4±0.2 ppm, 25.9±0.2 ppm, 21.7±0.2 ppm, 20.0±0.2 ppm, 18.8±0.2 ppm, and 17.9±0.2 ppm.

[0386] In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a 13C-SS NMR spectrum substantially similar to that of FIG.

[0387] In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a F-SS NMR spectrum with a peak at -63.1±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a F-SS NMR spectrum with a peak at -64.2±0.2 ppm. In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a F-SS NMR spectrum with a peak at -78.0±0.2 ppm.

[0388] In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a F-SS NMR spectrum having one, two, or three peaks selected from -63.1±0.2 ppm, -64.2±0.2 ppm, and -78.0±0.2 ppm.

[0389] In some embodiments, the crystalline ethanol solvate of Compound I is characterized by a 19F-SSNMR spectrum substantially similar to that of FIG.

[0390] Another aspect of the present invention provides a method for making an ethanol solvate of crystalline Compound I. In some embodiments, the method for making an ethanol solvate of crystalline Compound I comprises stirring hemihydrate crystal form C of crystalline Compound I in ethanol at −20° C. to obtain the ethanol solvate of crystalline Compound I.

[0391] O. Crystalline Compound I Solvate / Hydrate (Dry) In some embodiments, the present invention provides a crystalline solvate / hydrate (dry) of Compound I. Figure 49 provides a powder X-ray diffractogram of a crystalline solvate / hydrate (dry) of Compound I.

[0392] In some embodiments, the crystalline solvate / hydrate (dry) of Compound I is substantially pure. In some embodiments, the crystalline solvate / hydrate (dry) of Compound I is substantially crystalline. In some embodiments, the crystalline solvate / hydrate (dry) of Compound I is characterized by a powder X-ray diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0393] In some embodiments, the crystalline solvate / hydrate (dry) of Compound I exhibits (a) a signal at 22.7±0.2 degrees 2-theta, and (b) signals at 4.4±0.2 degrees 2-theta, 8.8±0.2 degrees 2-theta, 10.3±0.2 degrees 2-theta, 11.3±0.2 degrees 2-theta, 11.7±0.2 degrees 2-theta, 13.4±0.2 degrees 2-theta, 14.1±0.2 degrees 2-theta, 15.1±0.2 degrees 2-theta, 17.7±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 20.6±0.2 degrees 2-theta, 21.2±0.2 degrees 2-theta, 22.3±0.2 degrees 2-theta, and 22.9±0.2 degrees 2-theta. The powder is characterized by an X-ray powder diffractogram having signals at one, two, three, four, five, six, seven, eight, nine, ten, or more of 23.3±0.2 degrees 2-theta, 27.0±0.2 degrees 2-theta, and 28.3±0.2 degrees 2-theta.

[0394] In some embodiments, the crystalline Compound I solvate / hydrate (dry) has a viscosity of 4.4±0.2 degrees 2-theta, 8.8±0.2 degrees 2-theta, 10.3±0.2 degrees 2-theta, 11.3±0.2 degrees 2-theta, 11.7±0.2 degrees 2-theta, 13.4±0.2 degrees 2-theta, 14.1±0.2 degrees 2-theta, 15.1±0.2 degrees 2-theta, 17.7±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 20.6±0.2 degrees 2-theta, 21.2±0.2 degrees 2-theta, 22.3±0.2 degrees 2-theta, 22.7±0.2 degrees 2-theta, 22.9±0.2 degrees It is characterized by a powder X-ray diffractogram with signals at 2-theta, 23.3±0.2 degrees 2-theta, 27.0±0.2 degrees 2-theta, and 28.3±0.2 degrees 2-theta.

[0395] In some embodiments, the crystalline Compound I solvate / hydrate (dried) is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0396] Another aspect of the present invention provides a method for preparing a crystalline solvate / hydrate (dried) of Compound I. In some embodiments, the method for preparing a crystalline solvate / hydrate (dried) of Compound I comprises: (i) stirring crystalline heptane solvate Form A of Compound I in water at room temperature for two weeks; (ii) filtering the solid; and (iii) air-drying the solid to obtain a crystalline solvate / hydrate (dried) of Compound I. In some embodiments, the method for preparing a crystalline solvate / hydrate (dried) of Compound I comprises: (i) dissolving crystalline heptane solvate Form A of Compound I in ethanol; (i) adding water (water / ethanol = 1.23 to 3.15); (iii) stirring at 60°C for three days; (iv) filtering the solid; and (v) air-drying the solid to obtain a crystalline solvate / hydrate (dried) of Compound I.

[0397] P. Crystalline Compound I Solvates / Hydrates (Wet) In some embodiments, the present invention provides a solvate / hydrate (wet) of crystalline Compound I. Figure 52 provides a powder X-ray diffractogram of a solvate / hydrate (wet) of crystalline Compound I.

[0398] In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is substantially pure. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is substantially crystalline. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by an X-ray powder diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0399] In some embodiments, the crystalline solvate / hydrate (wet) of Compound I exhibits (a) a signal at 26.4±0.2 degrees 2-theta, and (b) a signal at 4.4±0.2 degrees 2-theta, 8.7±0.2 degrees 2-theta, 10.2±0.2 degrees 2-theta, 11.3±0.2 degrees 2-theta, 11.7±0.2 degrees 2-theta, 13.4±0.2 degrees 2-theta, 14.1±0.2 degrees 2-theta, 15.0±0.2 degrees 2-theta, 17.6±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 18.8±0.2 degrees 2-theta, 19.0±0.2 degrees 2-theta, 20.4±0.2 degrees 2-theta, 20.9±0.2 degrees 2-theta, 21.1±0.2 degrees 2-theta. 2-theta, 22.1±0.2 degrees 2-theta, 22.3±0.2 degrees 2-theta, 23.0±0.2 degrees 2-theta, 27.0±0.2 degrees 2-theta, and 28.3±0.2 degrees 2-theta.

[0400] In some embodiments, the solvate / hydrate (wet) of crystalline Compound I has a viscosity of 4.4±0.2 degrees 2-theta, 8.7±0.2 degrees 2-theta, 10.2±0.2 degrees 2-theta, 11.3±0.2 degrees 2-theta, 11.7±0.2 degrees 2-theta, 13.4±0.2 degrees 2-theta, 14.1±0.2 degrees 2-theta, 15.0±0.2 degrees 2-theta, 17.6±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 18.8±0.2 degrees 2-theta, 19.0±0.2 degrees 2-theta, 20.4±0.2 degrees 2-theta, 20.9±0.2 degrees 2-theta, 21.1±0.2 degrees 2-theta, 22.1±0.2 degrees It is characterized by a powder X-ray diffractogram with signals at 2-theta, 22.3±0.2 degrees 2-theta, 23.0±0.2 degrees 2-theta, 26.4±0.2 degrees 2-theta, 27.0±0.2 degrees 2-theta, and 28.3±0.2 degrees 2-theta.

[0401] In some embodiments, the crystalline Compound I solvate / hydrate (wet) is characterized by a powder X-ray diffractogram substantially similar to FIG.

[0402] In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 163.5±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 162.4±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 151.7±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 139.2±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 137.8±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 128.3±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 126.4±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 124.4±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 122.2±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 118.4±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 116.8±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 77.8±0.2 ppm.In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 77.6±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 72.9±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 72.5±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 36.9±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 35.6±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 33.9±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 25.6±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 25.2±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 22.5±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 21.0±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 20.0±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a C-SS NMR spectrum with a peak at 17.2±0.2 ppm.

[0403] In some embodiments, the solvate / hydrate (wet) of crystalline Compound I has a NA of 163.5±0.2 ppm, 162.4±0.2 ppm, 151.7±0.2 ppm, 139.2±0.2 ppm, 137.8±0.2 ppm, 128.3±0.2 ppm, 126.4±0.2 ppm, 124.4±0.2 ppm, 122.2±0.2 ppm, 118.4±0.2 ppm, 116.8±0.2 ppm, 77.8±0.2 ppm, 77.6±0.2 ppm, The C-SS NMR spectrum is characterized by having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 72.9±0.2 ppm, 72.5±0.2 ppm, 36.9±0.2 ppm, 35.6±0.2 ppm, 33.9±0.2 ppm, 25.6±0.2 ppm, 25.2±0.2 ppm, 22.5±0.2 ppm, 21.0±0.2 ppm, 20.0±0.2 ppm, and 17.2±0.2 ppm.

[0404] In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a 13C-SS NMR spectrum substantially similar to that of FIG.

[0405] In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a 19F-SS NMR spectrum with a peak at -62.3±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a 19F-SS NMR spectrum with a peak at -64.5±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a 19F-SS NMR spectrum with a peak at -76.1±0.2 ppm. In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a 19F-SS NMR spectrum with a peak at -78.2±0.2 ppm.

[0406] In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a F-SS NMR spectrum having one, two, three, or four peaks at -62.3±0.2 ppm, -64.5±0.2 ppm, -76.1±0.2 ppm, and -78.2±0.2 ppm.

[0407] In some embodiments, the crystalline solvate / hydrate (wet) of Compound I is characterized by a 19F-SSNMR spectrum substantially similar to that of FIG.

[0408] Another aspect of the present invention provides a method for making a solvate / hydrate (wet) of crystalline Compound I. In some embodiments, the method for making a solvate / hydrate (wet) of crystalline Compound I comprises (i) adding 50:50 (v / v %) ethanol / water to crystalline hemihydrate Form C of Compound I, and (ii) stirring at 5° C. to obtain a solvate / hydrate (wet) of crystalline Compound I.

[0409] Q. Crystalline Compound I L-Lysine Cocrystal In some embodiments, the present invention provides a crystalline L-lysine co-crystal of Compound I. Figure 55 provides a powder X-ray diffractogram of the crystalline L-lysine co-crystal of Compound I.

[0410] In some embodiments, the crystalline L-lysine cocrystal of Compound I is substantially pure. In some embodiments, the crystalline L-lysine cocrystal of Compound I is substantially crystalline. In some embodiments, the crystalline L-lysine cocrystal of Compound I is characterized by a powder X-ray diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0411] In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 3.9±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 7.9±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 8.9±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 9.5±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 10.5±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 11.4±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 11.8±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 13.3±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 13.4±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 13.8±0.2 degrees 2-theta. In some embodiments, the crystalline L-lysine cocrystal of Compound I is characterized by a powder X-ray diffractogram having a signal at 15.4±0.2 degrees 2-theta. In some embodiments, the crystalline L-lysine cocrystal of Compound I is characterized by a powder X-ray diffractogram having a signal at 15.9±0.2 degrees 2-theta. In some embodiments, the crystalline L-lysine cocrystal of Compound I is characterized by a powder X-ray diffractogram having a signal at 16.4±0.2 degrees 2-theta.In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 17.5±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 17.8±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 18.2±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 18.6±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 19.2±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 19.9±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 20.8±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 21.1±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 21.6±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 22.3±0.2 degrees 2-theta. In some embodiments, the crystalline L-lysine cocrystal of Compound I is characterized by a powder X-ray diffractogram having a signal at 22.9±0.2 degrees 2-theta. In some embodiments, the crystalline L-lysine cocrystal of Compound I is characterized by a powder X-ray diffractogram having a signal at 23.6±0.2 degrees 2-theta. In some embodiments, the crystalline L-lysine cocrystal of Compound I is characterized by a powder X-ray diffractogram having a signal at 26.3±0.2 degrees 2-theta.In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 26.6±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 27.0±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 27.5±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 29.2±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having a signal at 29.7±0.2 degrees 2-theta.

[0412] In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by an X-ray powder diffractogram having signals at one, two, three, four, or five of the following: 7.9±0.2 degrees 2-theta, 10.5±0.2 degrees 2-theta, 19.9±0.2 degrees 2-theta, 21.1±0.2 degrees 2-theta, and 21.6±0.2 degrees 2-theta.

[0413] In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a powder X-ray diffractogram having signals at one, two, three, four, five, six, seven, eight, nine, or ten of 7.9±0.2 degrees 2-theta, 9.5±0.2 degrees 2-theta, 10.5±0.2 degrees 2-theta, 11.4±0.2 degrees 2-theta, 17.8±0.2 degrees 2-theta, 19.9±0.2 degrees 2-theta, 20.8±0.2 degrees 2-theta, 21.1±0.2 degrees 2-theta, 21.6±0.2 degrees 2-theta, and 22.9±0.2 degrees 2-theta.

[0414] In some embodiments, the crystalline Compound I L-lysine cocrystal has a viscosity of 3.9±0.2 degrees 2-theta, 7.9±0.2 degrees 2-theta, 8.9±0.2 degrees 2-theta, 9.5±0.2 degrees 2-theta, 10.5±0.2 degrees 2-theta, 11.4±0.2 degrees 2-theta, 11.8±0.2 degrees 2-theta, 13.3±0.2 degrees 2-theta, 13.4±0.2 degrees 2-theta, 13.8±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 16.4±0.2 degrees 2-theta, 17.5±0.2 degrees 2-theta, 17.8±0.2 degrees 2-theta, 18.2±0.2 degrees 2-theta, 18.6±0.2 degrees 2-theta, 19.2±0.2 degrees; 2-theta, 19.9±0.2 degrees; 2-theta, 20.8±0.2 degrees; 2-theta, 21.1±0.2 degrees; 2-theta, 21.6±0.2 degrees; 2-theta, 22.3±0.2 degrees; 2-theta, 22.9±0.2 degrees; 2-theta, 23.6±0.2 degrees; 2-theta, 26.3±0.2 degrees; 2-theta, 26.6±0.2 degrees; 2-theta, 27.0±0.2 degrees; 2-theta, 27.5±0.2 degrees; 2-theta, 29.2±0.2 degrees; 2-theta, and 29.7±0.2 degrees; characterized by a powder X-ray diffractogram having signals at one, two, three, four, five, six, seven, eight, nine, ten, or more positions within the range of 2-theta, 19.2±0.2 degrees; 2-theta, 19.9±0.2 degrees; 2-theta, 20.8±0.2 degrees; 2-theta, 21.1±0.2 degrees; 2-theta, 21.6±0.2 degrees; 2-theta, 22.3±0.2 degrees; 2-theta, 22.9±0.2 degrees; 2-theta, 23.6±0.2 degrees; 2-theta, 26.3±0.2 degrees; 2-theta, 26.6±0.2 degrees; 2-theta, 27.0±0.2 degrees; 2-theta, 27.5±0.2 degrees; 2-theta, 29.2±0.2 degrees;In some embodiments, the crystalline Compound I L-lysine cocrystal has a viscosity of 3.9±0.2 degrees 2-theta, 7.9±0.2 degrees 2-theta, 8.9±0.2 degrees 2-theta, 9.5±0.2 degrees 2-theta, 10.5±0.2 degrees 2-theta, 11.4±0.2 degrees 2-theta, 11.8±0.2 degrees 2-theta, 13.3±0.2 degrees 2-theta, 13.4±0.2 degrees 2-theta, 13.8±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 16.4±0.2 degrees 2-theta, 17.5±0.2 degrees 2-theta, 17.8±0.2 degrees 2-theta, 18.2±0.2 degrees 2-theta, 18.6±0.2 degrees 2-theta, 19.2±0.2 degrees 2-theta, 19.9±0.2 degrees 2-theta, 20.8±0.2 degrees 2-theta, 21.1±0.2 degrees 2-theta, 21.6±0.2 degrees 2-theta, 22.3±0.2 degrees 2-theta, 22.9±0.2 degrees 2-theta, 23.6±0.2 degrees 2-theta, 26.3±0.2 degrees 2-theta, 26.6±0.2 degrees 2-theta, 27.0±0.2 degrees 2-theta, 27.5±0.2 degrees 2-theta, 29.2±0.2 degrees 2-theta, and 29.7±0.2 degrees 2-theta.

[0415] In some embodiments, the crystalline Compound I L-lysine co-crystal is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0416] In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 181.6±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 180.9±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 177.5±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 165.4±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 164.4±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 163.7±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 162.7±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 151.9±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 150.7±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 138.9±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 138.2±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 127.6±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine co-crystal is characterized by a 13C-SS NMR spectrum with a peak at 126.8±0.2 ppm.In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 125.8±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 124.1±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 121.4±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 119.6±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 118.0±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 78.4±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 77.1±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 75.9±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 73.1±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 56.8±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 54.9±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 45.1±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine co-crystal is characterized by a 13C-SS NMR spectrum with a peak at 43.6±0.2 ppm.In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 41.4±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 39.6±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 38.8±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 37.0±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 34.3±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 33.4±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 32.2±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 31.6±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 30.6±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 29.2±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 27.4±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 25.8±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine co-crystal is characterized by a 13C-SS NMR spectrum with a peak at 25.1±0.2 ppm.In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 22.9±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 22.5±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 21.7±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 20.5±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 19.4±0.2 ppm. In some embodiments, the crystalline Compound I L-lysine cocrystal is characterized by a C-SS NMR spectrum with a peak at 18.6±0.2 ppm.

[0417] In some embodiments, the crystalline Compound I L-lysine cocrystal has an NA of 181.6±0.2 ppm, 180.9±0.2 ppm, 177.5±0.2 ppm, 165.4±0.2 ppm, 164.4±0.2 ppm, 163.7±0.2 ppm, 162.7±0.2 ppm, 151.9±0.2 ppm, 150.7±0.2 ppm, 138.9±0.2 ppm, 138. 2±0.2ppm, 127.6±0.2ppm, 126.8±0.2ppm, 125.8±0.2ppm, 124.1±0.2ppm, 121.4±0.2ppm, 119.6±0. 2ppm, 118.0±0.2ppm, 78.4±0.2ppm, 77.1±0.2ppm, 75.9±0.2ppm, 73.1±0.2ppm, 56.8±0.2ppm, 54.9 ±0.2ppm, 45.1±0.2ppm, 43.6±0.2ppm, 41.4±0.2ppm, 39.6±0.2ppm, 38.8±0.2ppm, 37.0±0.2ppm, 34 .3±0.2ppm, 33.4±0.2ppm, 32.2±0.2ppm, 31.6±0.2ppm, 30.6±0.2ppm, 29.2±0.2ppm, 27.4±0.2ppm, The C-SS NMR spectrum is characterized by having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 25.8±0.2 ppm, 25.1±0.2 ppm, 22.9±0.2 ppm, 22.5±0.2 ppm, 21.7±0.2 ppm, 20.5±0.2 ppm, 19.4±0.2 ppm, and 18.6±0.2 ppm.In some embodiments, the crystalline Compound I L-lysine cocrystal has a NA of 181.6±0.2 ppm, 180.9±0.2 ppm, 177.5±0.2 ppm, 165.4±0.2 ppm, 164.4±0.2 ppm, 163.7±0.2 ppm, 162.7±0.2 ppm, 151.9±0.2 ppm, 150.7±0.2 ppm, 138.9±0.2 ppm, ppm, 138.2±0.2ppm, 127.6±0.2ppm, 126.8±0.2ppm, 125.8±0.2ppm, 124.1±0.2ppm, 121.4±0.2 ppm, 119.6±0.2ppm, 118.0±0.2ppm, 78.4±0.2ppm, 77.1±0.2ppm, 75.9±0.2ppm, 73.1±0.2ppm, 56.8±0.2ppm, 54.9±0.2ppm, 45.1±0.2ppm, 43.6±0.2ppm, 41.4±0.2ppm, 39.6±0.2ppm, 38.8± 0.2ppm, 37.0±0.2ppm, 34.3±0.2ppm, 33.4±0.2ppm, 32.2±0.2ppm, 31.6±0.2ppm, 30.6±0.2ppm , 29.2±0.2 ppm, 27.4±0.2 ppm, 25.8±0.2 ppm, 25.1±0.2 ppm, 22.9±0.2 ppm, 22.5±0.2 ppm, 21.7±0.2 ppm, 20.5±0.2 ppm, 19.4±0.2 ppm, and 18.6±0.2 ppm.

[0418] In some embodiments, the crystalline Compound I L-lysine co-crystal is characterized by a 13C-SS NMR spectrum substantially similar to that of FIG.

[0419] Another aspect of the present invention provides a method for making an L-lysine co-crystal of crystalline Compound I. In some embodiments, the method for making an L-lysine co-crystal of crystalline Compound I includes (i) mixing ethanol and water in a ratio of 30.8% to 69.2% by volume, (ii) saturating the ethanol / water mixture with anhydrous L-lysine, (iii) saturating the mixture with crystalline hemihydrate Form C of Compound I, (iv) adding crystalline hemihydrate Form C of Compound I to L-lysine to make a 1:1 molar ratio slurry of Compound I and L-lysine, (v) mixing the slurry for 2 days, (vi) sonicating for an additional 3 hours, and (viii) isolating the solid to obtain the L-lysine co-crystal of crystalline Compound I.

[0420] R. Crystalline Compound I Cocrystal with L-Arginine In some embodiments, the present invention provides a crystalline L-arginine co-crystal of Compound I. Figure 59 provides a powder X-ray diffractogram of the crystalline L-arginine co-crystal of Compound I.

[0421] In some embodiments, the crystalline L-arginine cocrystal of Compound I is substantially pure. In some embodiments, the crystalline L-arginine cocrystal of Compound I is substantially crystalline. In some embodiments, the crystalline L-arginine cocrystal of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0422] In some embodiments, the crystalline Compound I cocrystal with L-arginine is characterized by a powder X-ray diffractogram having a signal at 7.5±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-arginine is characterized by a powder X-ray diffractogram having a signal at 9.0±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-arginine is characterized by a powder X-ray diffractogram having a signal at 10.5±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-arginine is characterized by a powder X-ray diffractogram having a signal at 13.4±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-arginine is characterized by a powder X-ray diffractogram having a signal at 15.9±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-arginine is characterized by a powder X-ray diffractogram having a signal at 18.3±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-arginine is characterized by a powder X-ray diffractogram having a signal at 19.1±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-arginine is characterized by a powder X-ray diffractogram having a signal at 19.4±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-arginine is characterized by a powder X-ray diffractogram having a signal at 21.0±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-arginine is characterized by a powder X-ray diffractogram having a signal at 21.9±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-arginine cocrystal is characterized by an X-ray powder diffractogram having a signal at 23.1±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-arginine cocrystal is characterized by an X-ray powder diffractogram having a signal at 27.4±0.2 degrees 2-theta.

[0423] In some embodiments, the crystalline Compound I L-arginine co-crystal is characterized by an X-ray powder diffractogram having signals at one, two, three, four, or five of the following angles: 7.5±0.2 degrees 2-theta, 18.3±0.2 degrees 2-theta, 19.1±0.2 degrees 2-theta, 19.4±0.2 degrees 2-theta, and 23.1±0.2 degrees 2-theta.

[0424] In some embodiments, the crystalline Compound I L-arginine co-crystal is characterized by a powder X-ray diffractogram having signals at one, two, three, four, five, six, seven, eight, nine, or ten of 7.5±0.2 degrees 2-theta, 9.0±0.2 degrees 2-theta, 10.5±0.2 degrees 2-theta, 18.3±0.2 degrees 2-theta, 19.1±0.2 degrees 2-theta, 19.4±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 21.9±0.2 degrees 2-theta, 23.1±0.2 degrees 2-theta, and 27.4±0.2 degrees 2-theta.

[0425] In some embodiments, the crystalline Compound I L-arginine co-crystal is characterized by a powder X-ray diffractogram having signals at one, two, three, four, five, six, seven, eight, nine, ten, or more of 7.5±0.2 degrees 2-theta, 9.0±0.2 degrees 2-theta, 10.5±0.2 degrees 2-theta, 13.4±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 18.3±0.2 degrees 2-theta, 19.1±0.2 degrees 2-theta, 19.4±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 21.9±0.2 degrees 2-theta, 23.1±0.2 degrees 2-theta, and 27.4±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-arginine co-crystal is characterized by a powder X-ray diffractogram having signals at 7.5±0.2 degrees 2-theta, 9.0±0.2 degrees 2-theta, 10.5±0.2 degrees 2-theta, 13.4±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 18.3±0.2 degrees 2-theta, 19.1±0.2 degrees 2-theta, 19.4±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 21.9±0.2 degrees 2-theta, 23.1±0.2 degrees 2-theta, and 27.4±0.2 degrees 2-theta.

[0426] In some embodiments, the crystalline Compound I L-arginine co-crystal is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0427] Another aspect of the present invention provides a method for making a crystalline L-arginine co-crystal of Compound I. In some embodiments, the method for making a crystalline L-arginine co-crystal of Compound I includes: (i) preparing crystalline hemihydrate crystal Form C of Compound I and L-arginine in a 1:1 molar ratio; (ii) adding ethanol / water (30.8% by volume to 69.2% by volume of ethanol:water); (iii) ball milling the mixture at 7500 RPM for five cycles of 60 seconds with a 10-second pause; and (iv) drying the solid at 45° C. in a vacuum oven overnight to obtain a crystalline L-arginine co-crystal of Compound I.

[0428] S. Crystalline Compound I Cocrystal with L-Phenylalanine In some embodiments, the present invention provides a crystalline L-phenylalanine co-crystal of Compound I. Figure 62 provides a powder X-ray diffractogram of the crystalline L-phenylalanine co-crystal of Compound I.

[0429] In some embodiments, the crystalline L-phenylalanine co-crystal of Compound I is substantially pure. In some embodiments, the crystalline L-phenylalanine co-crystal of Compound I is substantially crystalline. In some embodiments, the crystalline L-phenylalanine co-crystal of Compound I is characterized by an X-ray powder diffractogram generated by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation.

[0430] In some embodiments, the crystalline Compound I cocrystal with L-phenylalanine is characterized by a powder X-ray diffractogram having a signal at 4.9±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-phenylalanine is characterized by a powder X-ray diffractogram having a signal at 6.5±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-phenylalanine is characterized by a powder X-ray diffractogram having a signal at 7.4±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-phenylalanine is characterized by a powder X-ray diffractogram having a signal at 9.0±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-phenylalanine is characterized by a powder X-ray diffractogram having a signal at 10.1±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-phenylalanine is characterized by a powder X-ray diffractogram having a signal at 11.1±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-phenylalanine is characterized by a powder X-ray diffractogram having a signal at 14.8±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-phenylalanine is characterized by a powder X-ray diffractogram having a signal at 15.3±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-phenylalanine is characterized by a powder X-ray diffractogram having a signal at 16.2±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-phenylalanine is characterized by a powder X-ray diffractogram having a signal at 17.6±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-phenylalanine cocrystal is characterized by a powder X-ray diffractogram having a signal at 18.4±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-phenylalanine cocrystal is characterized by a powder X-ray diffractogram having a signal at 19.8±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-phenylalanine cocrystal is characterized by a powder X-ray diffractogram having a signal at 20.5±0.2 degrees 2-theta.In some embodiments, the crystalline Compound I cocrystal with L-phenylalanine is characterized by a powder X-ray diffractogram having a signal at 21.4±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-phenylalanine is characterized by a powder X-ray diffractogram having a signal at 22.2±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-phenylalanine is characterized by a powder X-ray diffractogram having a signal at 22.9±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-phenylalanine is characterized by a powder X-ray diffractogram having a signal at 23.9±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I cocrystal with L-phenylalanine is characterized by a powder X-ray diffractogram having a signal at 26.3±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-phenylalanine co-crystal is characterized by a powder X-ray diffractogram having a signal at 27.9±0.2 degrees 2-theta.

[0431] In some embodiments, the crystalline Compound I L-phenylalanine co-crystal is characterized by an X-ray powder diffractogram having signals at one, two, three, four, or five of the following: 6.5±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 11.1±0.2 degrees 2-theta, 17.6±0.2 degrees 2-theta, and 20.5±0.2 degrees 2-theta.

[0432] In some embodiments, the crystalline Compound I L-phenylalanine co-crystal is characterized by a powder X-ray diffractogram having signals at one, two, three, four, five, six, seven, eight, nine, or ten of 6.5±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 11.1±0.2 degrees 2-theta, 14.8±0.2 degrees 2-theta, 15.3±0.2 degrees 2-theta, 17.6±0.2 degrees 2-theta, 18.4±0.2 degrees 2-theta, 19.8±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, and 21.4±0.2 degrees 2-theta.

[0433] In some embodiments, the crystalline Compound I L-phenylalanine co-crystal has a viscosity of 4.9±0.2 degrees 2-theta, 6.5±0.2 degrees 2-theta, 7.4±0.2 degrees 2-theta, 9.0±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 11.1±0.2 degrees 2-theta, 14.8±0.2 degrees 2-theta, 15.3±0.2 degrees 2-theta, 16.2±0.2 degrees 2-theta, 17.6±0.2 degrees 2-theta, 18.4±0.2 degrees 2-theta, 19.8±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 21.4±0.2 degrees 2-theta, 22.2±0.2 degrees 2-theta, 22.9±0.2 degrees 2-theta, 23.9±0.2 degrees The powder is characterized by an X-ray powder diffractogram having signals at one, two, three, four, five, six, seven, eight, nine, ten, or more of 2-theta, 26.3±0.2 degrees 2-theta, and 27.9±0.2 degrees 2-theta. In some embodiments, the crystalline Compound I L-phenylalanine co-crystal has a viscosity of 4.9±0.2 degrees 2-theta, 6.5±0.2 degrees 2-theta, 7.4±0.2 degrees 2-theta, 9.0±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 11.1±0.2 degrees 2-theta, 14.8±0.2 degrees 2-theta, 15.3±0.2 degrees 2-theta, 16.2±0.2 degrees 2-theta, 17.6±0.2 degrees 2-theta, 18.4±0.2 degrees 2-theta, 19.8±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 21.4±0.2 degrees 2-theta, 22.2±0.2 degrees 2-theta, 22.9±0.2 degrees 2-theta, 23.9±0.2 degrees It is characterized by a powder X-ray diffractogram with signals at 2-theta, 26.3±0.2 degrees 2-theta, and 27.9±0.2 degrees 2-theta.

[0434] In some embodiments, the crystalline Compound I L-phenylalanine co-crystal is characterized by a powder X-ray diffractogram substantially similar to FIG.

[0435] Another aspect of the present invention provides a method for making a crystalline L-phenylalanine co-crystal of Compound I. In some embodiments, the method for making a crystalline L-phenylalanine co-crystal of Compound I includes: (i) preparing crystalline hemihydrate crystal Form C of Compound I and L-phenylalanine in a 1:1 molar ratio; (ii) adding ethanol / water (30.8% by volume to 69.2% by volume of ethanol:water); (iii) ball milling the mixture at 7500 RPM for 60 seconds with a 10-second pause for five cycles; and (iv) drying the solid at 45° C. in a vacuum oven overnight to obtain a crystalline L-phenylalanine co-crystal of Compound I.

[0436] T. Crystalline Compound I cocrystal with succinic acid (wet) In some embodiments, the present invention provides a crystalline succinic acid co-crystal (wet) of Compound I. Figure 64 provides a powder X-ray diffractogram of a crystalline succinic acid co-crystal (wet) of Compound I.

[0437] In some embodiments, the crystalline Compound I succinic acid co-crystal (wet) is substantially pure. In some embodiments, the crystalline Compound I succinic acid co-crystal (wet) is substantially crystalline. In some embodiments, the crystalline Compound I succinic acid co-crystal (wet) is characterized by a powder X-ray diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0438] In some embodiments, the crystalline Compound I succinic acid co-crystal (wet) exhibits (a) a signal at 22.7±0.2 degrees 2-theta, and (b) a signal at 4.0±0.2 degrees 2-theta, 8.1±0.2 degrees 2-theta, 8.9±0.2 degrees 2-theta, 9.1±0.2 degrees 2-theta, 9.8±0.2 degrees 2-theta, 12.1±0.2 degrees 2-theta, 13.5±0.2 degrees 2-theta, 14.4±0.2 degrees 2-theta, 16.8±0.2 degrees 2-theta, 17.9±0.2 degrees 2-theta, 20.1±0.2 degrees 2-theta, 20.4±0.2 degrees 2-theta, 21.7±0.2 degrees 2-theta, 22.0±0.2 degrees 2-theta, 26.1±0.2 degrees 2-theta. The powder is characterized by an X-ray powder diffractogram having signals at one, two, three, four, five, six, seven, eight, nine, ten, or more of 27.1±0.2 degrees two-theta, 27.1±0.2 degrees two-theta, and 28.0±0.2 degrees two-theta.

[0439] In some embodiments, the crystalline Compound I succinic acid co-crystal (wet) has a viscosity of 4.0±0.2 degrees 2-theta, 8.1±0.2 degrees 2-theta, 8.9±0.2 degrees 2-theta, 9.1±0.2 degrees 2-theta, 9.8±0.2 degrees 2-theta, 12.1±0.2 degrees 2-theta, 13.5±0.2 degrees 2-theta, 14.4±0.2 degrees 2-theta, 16.8±0.2 degrees 2-theta, 17.9±0.2 degrees 2-theta, 20.1±0.2 degrees 2-theta, 20.4±0.2 degrees 2-theta, 21.7±0.2 degrees 2-theta, 22.0±0.2 degrees 2-theta, 26.1±0.2 degrees 2-theta, 27.1±0.2 degrees It is characterized by a powder X-ray diffractogram with signals at 28.0±0.2 degrees 2-theta and 28.0±0.2 degrees 2-theta.

[0440] In some embodiments, the crystalline Compound I succinic acid co-crystal (wet) is characterized by a powder X-ray diffractogram substantially similar to that in FIG. 64.

[0441] Another aspect of the present invention provides a method for making crystalline wet succinic acid co-crystal of Compound I. In some embodiments, the method for making crystalline wet succinic acid co-crystal of Compound I includes (i) preparing crystalline hemihydrate crystal Form C of Compound I and succinic acid in a 1:1 molar ratio, (ii) adding ethanol / water (30.8% by volume to 69.2% by volume ethanol:water), (iii) ball milling the mixture at 7500 RPM for 60 seconds with a 10-second pause for five cycles, (iv) drying the solid in a vacuum oven at 45°C overnight, and (v) placing the solid in a humidity chamber at 40°C and 75% relative humidity to obtain crystalline wet succinic acid co-crystal hydrate of Compound I.

[0442] U. Crystalline Compound I succinic acid cocrystal (dry) In some embodiments, the present invention provides a crystalline succinic acid co-crystal (dried) of Compound I. Figure 65 provides a powder X-ray diffractogram of a crystalline succinic acid co-crystal (dried) of Compound I.

[0443] In some embodiments, the crystalline succinic acid co-crystal (dry) of Compound I is substantially pure. In some embodiments, the crystalline succinic acid co-crystal (dry) of Compound I is substantially crystalline. In some embodiments, the crystalline succinic acid co-crystal (dry) of Compound I is characterized by a powder X-ray diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0444] In some embodiments, the crystalline Compound I succinic acid co-crystal (dried) is characterized by an X-ray powder diffractogram having (a) a signal at 25.5±0.2 degrees 2-theta, and (b) signals at one, two, three, four, five, six, seven, eight, nine, ten, or more of 4.1±0.2 degrees 2-theta, 8.2±0.2 degrees 2-theta, 20.0±0.2 degrees 2-theta, 22.0±0.2 degrees 2-theta, 26.1±0.2 degrees 2-theta, and 27.1±0.2 degrees 2-theta.

[0445] In some embodiments, the crystalline Compound I succinic acid co-crystal (dry) is characterized by an X-ray powder diffractogram with signals at 4.1±0.2 degrees 2-theta, 8.2±0.2 degrees 2-theta, 20.0±0.2 degrees 2-theta, 22.0±0.2 degrees 2-theta, 25.5±0.2 degrees 2-theta, 26.1±0.2 degrees 2-theta, and 27.1±0.2 degrees 2-theta.

[0446] In some embodiments, the crystalline Compound I succinic acid co-crystal (dried) is characterized by a powder X-ray diffractogram substantially similar to that in FIG. 65.

[0447] Another aspect of the present invention provides a method for making crystalline dried succinic acid co-crystal of Compound I. In some embodiments, the method for making dried succinic acid co-crystal of Compound I includes (i) preparing crystalline hemihydrate crystal Form C of Compound I and succinic acid in a 1:1 molar ratio, (ii) adding ethanol / water (30.8% by volume to 69.2% by volume ethanol:water), (iii) ball milling the mixture at 7500 RPM for 60 seconds with a 10-second pause for five cycles, and (iv) drying the solid at 45°C in a vacuum oven overnight to obtain dried succinic acid co-crystal of crystalline Compound I.

[0448] V. Crystalline Compound I Methanol Solvate / Hydrate In some embodiments, the present invention provides a methanol solvate / hydrate of crystalline Compound I. Figure 67 provides a powder X-ray diffractogram of the methanol solvate / hydrate of crystalline Compound I.

[0449] In some embodiments, the crystalline methanol solvate / hydrate (wet) of Compound I is substantially pure. In some embodiments, the crystalline methanol solvate / hydrate (wet) of Compound I is substantially crystalline. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a powder X-ray diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0450] In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a powder X-ray diffractogram having a signal at 8.2±0.2 degrees two-theta. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a powder X-ray diffractogram having a signal at 8.8±0.2 degrees two-theta. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a powder X-ray diffractogram having a signal at 10.8±0.2 degrees two-theta. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a powder X-ray diffractogram having a signal at 14.3±0.2 degrees two-theta. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a powder X-ray diffractogram having a signal at 16.4±0.2 degrees two-theta. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a powder X-ray diffractogram having a signal at 17.9±0.2 degrees two-theta. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a powder X-ray diffractogram having a signal at 18.5±0.2 degrees two-theta. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a powder X-ray diffractogram having a signal at 18.7±0.2 degrees two-theta. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a powder X-ray diffractogram having a signal at 20.0±0.2 degrees two-theta. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a powder X-ray diffractogram having a signal at 20.5±0.2 degrees two-theta. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a powder X-ray diffractogram having a signal at 21.5±0.2 degrees two-theta. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a powder X-ray diffractogram having a signal at 26.9±0.2 degrees two-theta.

[0451] In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by an X-ray powder diffractogram having signals at one, two, three, four, or five of the following: 8.2±0.2 degrees 2-theta, 16.4±0.2 degrees 2-theta, 18.7±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, and 21.5±0.2 degrees 2-theta.

[0452] In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by an X-ray powder diffractogram having signals at one, two, three, four, five, six, seven, eight, nine, or ten of 8.2±0.2 degrees 2-theta, 8.8±0.2 degrees 2-theta, 10.8±0.2 degrees 2-theta, 14.3±0.2 degrees 2-theta, 16.4±0.2 degrees 2-theta, 17.9±0.2 degrees 2-theta, 18.5±0.2 degrees 2-theta, 18.7±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, and 21.5±0.2 degrees 2-theta.

[0453] In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a powder X-ray diffractogram having signals at one, two, three, four, five, six, seven, eight, nine, ten, or more of 8.2±0.2 degrees 2-theta, 8.8±0.2 degrees 2-theta, 10.8±0.2 degrees 2-theta, 14.3±0.2 degrees 2-theta, 16.4±0.2 degrees 2-theta, 17.9±0.2 degrees 2-theta, 18.5±0.2 degrees 2-theta, 18.7±0.2 degrees 2-theta, 20.0±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 21.5±0.2 degrees 2-theta, and 26.9±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a powder X-ray diffractogram with signals at 8.2±0.2 degrees 2-theta, 8.8±0.2 degrees 2-theta, 10.8±0.2 degrees 2-theta, 14.3±0.2 degrees 2-theta, 16.4±0.2 degrees 2-theta, 17.9±0.2 degrees 2-theta, 18.5±0.2 degrees 2-theta, 18.7±0.2 degrees 2-theta, 20.0±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 21.5±0.2 degrees 2-theta, and 26.9±0.2 degrees 2-theta.

[0454] In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0455] In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 163.3±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 162.2±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 151.6±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 150.8±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 138.4±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 126.4±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 125.4±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 122.3±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 121.5±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 120.7±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 118.9±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a 13C-SS NMR spectrum with a peak at 118.2±0.2 ppm.In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 117.4±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 77.5±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 73.2±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 49.4±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 36.5±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 35.2±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 34.1±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 33.5±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 32.5±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 25.4±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 22.8±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 22.1±0.2 ppm.In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 21.4±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 20.5±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 20.0±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a C-SS NMR spectrum with a peak at 19.5±0.2 ppm.

[0456] In some embodiments, the crystalline methanol solvate / hydrate of Compound I has a NA of 163.3±0.2 ppm, 162.2±0.2 ppm, 151.6±0.2 ppm, 150.8±0.2 ppm, 138.4±0.2 ppm, 126.4±0.2 ppm, 125.4±0.2 ppm, 122.3±0.2 ppm, 121.5±0.2 ppm, 120.7±0.2 ppm, 118.9±0.2 ppm, 118.2±0.2 ppm, 117.4±0.2 ppm, 77.5±0.2 ppm, 73.2±0.2 ppm m, 49.4±0.2 ppm, 36.5±0.2 ppm, 35.2±0.2 ppm, 34.1±0.2 ppm, 33.5±0.2 ppm, 32.5±0.2 ppm, 25.4±0.2 ppm, 22.8±0.2 ppm, 22.1±0.2 ppm, 21.4±0.2 ppm, 20.5±0.2 ppm, 20.0±0.2 ppm, and 19.5±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I has a NA of 163.3±0.2 ppm, 162.2±0.2 ppm, 151.6±0.2 ppm, 150.8±0.2 ppm, 138.4±0.2 ppm, 126.4±0.2 ppm, 125.4±0.2 ppm, 122.3±0.2 ppm, 121.5±0.2 ppm, 120.7±0.2 ppm, 118.9±0.2 ppm, 118.2±0.2 ppm, 117.4±0.2 ppm, 77.5 ...6.4±0.2 ppm, 126.4±0.2 ppm, 126.4±0.2 ppm, 126.4±0.2 ppm, 126.4±0.2 ppm, 126.4±0.2 ppm, 126.4±0.2 ppm, 126.4±0.2 ppm, It is characterized by a 13C-SS NMR spectrum having peaks at 0.2 ppm, 73.2±0.2 ppm, 49.4±0.2 ppm, 36.5±0.2 ppm, 35.2±0.2 ppm, 34.1±0.2 ppm, 33.5±0.2 ppm, 32.5±0.2 ppm, 25.4±0.2 ppm, 22.8±0.2 ppm, 22.1±0.2 ppm, 21.4±0.2 ppm, 20.5±0.2 ppm, 20.0±0.2 ppm, and 19.5±0.2 ppm.

[0457] In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a 13C-SS NMR spectrum substantially similar to that of Figure 68.

[0458] In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a 19F-SS NMR spectrum with a peak at -64.0±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a 19F-SS NMR spectrum with a peak at -64.6±0.2 ppm. In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a 19F-SS NMR spectrum with a peak at -79.0±0.2 ppm.

[0459] In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a 19F-SS NMR spectrum having one, two, or three peaks at -64.0±0.2 ppm, -64.6±0.2 ppm, and -79.0±0.2 ppm.

[0460] In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a 19F-SSNMR spectrum substantially similar to that of FIG.

[0461] In some embodiments, the crystalline methanol solvate / hydrate of Compound I is characterized by a monoclinic crystal system, a C2 space group, and the following unit cell dimensions measured at 100 K on a Bruker diffractometer using Cu Kα radiation (λ=1.54178 Å): [Table 60]

[0462] Another aspect of the present invention provides a method for making a methanol solvate / hydrate of crystalline Compound I. In some embodiments, the method for making a methanol solvate / hydrate of crystalline Compound I comprises (i) combining crystalline hemihydrate crystal form C of Compound I and methanol, (ii) stirring the mixture, and (iii) isolating the solid to obtain the methanol solvate / hydrate of crystalline Compound I.

[0463] W. Treatment method Compound I, in any one of the pharmaceutically acceptable solid forms disclosed herein, acts as a CFTR modulator, i.e., it regulates CFTR activity in the body. Individuals suffering from mutations in the gene encoding CFTR may benefit from receiving a CFTR modulator. CFTR mutations can affect CFTR abundance, i.e., the number of CFTR channels on the cell surface, or CFTR function, i.e., the functional ability of each channel to open and transport ions. Mutations that affect CFTR abundance include those that cause synthesis defects (Class I defects), processing and trafficking defects (Class II defects), reduced synthesis of CFTR (Class V defects), and reduced surface stability of CFTR (Class VI defects). Mutations that affect CFTR function include those that cause gating defects (Class III defects) and conductance defects (Class IV defects). Some CFTR mutations exhibit characteristics of multiple classes. Specific mutations in the CFTR gene result in cystic fibrosis.

[0464] Thus, in some embodiments, the present invention provides a method for treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient, the method comprising administering to the patient an effective amount of Compound I in any one of the pharmaceutically acceptable crystalline forms disclosed herein, alone or in combination with another active ingredient, such as another CFTR modulator. In some embodiments, the patient has an F508del / minimal function (MF) genotype, an F508del / F508del genotype (homozygous for the F508del mutation), an F508del / gating genotype, or an F508del / residual function (RF) genotype. In some embodiments, the patient is heterozygous and has one F508del mutation. In some embodiments, the patient is homozygous for the N1303K mutation.

[0465] In some embodiments, the patient is heterozygous and carries the F508del mutation in one allele and a mutation selected from Table 1 below in the other allele. [Table 1-2] [Table 1-3]

[0466] In some embodiments, the present invention provides methods for treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient, the methods comprising administering to the patient an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, the pharmaceutically acceptable solid form of Compound I is a substantially amorphous form. In some embodiments, the pharmaceutically acceptable solid form of Compound I is a substantially crystalline form.

[0467] In some embodiments, methods for treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient comprise administering to the patient an effective amount of Compound I in any one of the pharmaceutically acceptable crystalline forms disclosed herein. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is neat crystalline form A of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is neat crystalline form B of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is hemihydrate crystalline form C of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is neat crystalline form D of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is neat crystalline form E of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is the acetic acid solvate of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is the heptane solvate crystalline form B of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is heptane solvate crystalline Form C of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is octane solvate of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is cyclohexane solvate crystalline Form A of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is cyclohexane solvate crystalline Form B of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is cyclohexane solvate crystalline Form C of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is an ethanol solvate of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is a solvate / hydrate (dry) of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is a solvate / hydrate (wet) of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is an L-lysine co-crystal of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is an L-arginine co-crystal of Compound I.In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is an L-phenylalanine co-crystal of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is a succinic acid co-crystal (wet) of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is a succinic acid co-crystal (dry) of Compound I. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is a methanol solvate / hydrate of Compound I.

[0468] In some embodiments, a method for treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering to the patient an effective amount of Compound I in a pharmaceutically acceptable amorphous form disclosed herein. In some embodiments, the pharmaceutically acceptable crystalline form of Compound I is a neat amorphous form of Compound I.

[0469] In some embodiments, a method for treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient comprises administering to the patient an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR corrector. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR potentiator.

[0470] In some embodiments, a method for treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering to the patient an effective amount of Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof.

[0471] In some embodiments, the method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient comprises administering to a patient a crystalline form selected from the group consisting of neat crystalline form A of Compound I, neat crystalline form B of Compound I, hemihydrate crystalline form C of Compound I, neat crystalline form D of Compound I, neat crystalline form E of Compound I, acetic acid solvate of Compound I, heptane solvate crystalline form B of Compound I, heptane solvate crystalline form C of Compound I, octane solvate of Compound I, cyclohexane solvate crystalline form A of Compound I, cyclohexane solvate crystalline form B of Compound I, cyclohexane solvate crystalline form E of Compound I, acetic acid solvate of Compound I, heptane solvate crystalline form B ...octane solvate of Compound I, cyclohexane solvate crystalline form E of Compound I, octane solvate of Compound I, cyclohexane solvate crystalline form E of Compound I, octane solvate of Compound I, cyclohexane solvate crystalline form E of Compound I, octane solvate of The present invention includes administering to a patient an effective amount of Compound I in a solid form selected from hexane solvate crystalline Form C, an ethanol solvate of Compound I, a solvate / hydrate of Compound I (dry), a solvate / hydrate of Compound I (wet), an L-lysine co-crystal of Compound I, an L-arginine co-crystal of Compound I, an L-phenylalanine co-crystal of Compound I, a succinic acid co-crystal of Compound I (wet), a succinic acid co-crystal of Compound I (dry), a methanol solvate / hydrate of Compound I, and a neat amorphous form of Compound I, in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof.

[0472] In some embodiments, the method of treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient comprises administering to a patient a crystalline form selected from the group consisting of neat crystalline form A of Compound I, neat crystalline form B of Compound I, hemihydrate crystalline form C of Compound I, neat crystalline form D of Compound I, neat crystalline form E of Compound I, acetic acid solvate of Compound I, heptane solvate crystalline form B of Compound I, heptane solvate crystalline form C of Compound I, octane solvate of Compound I, cyclohexane solvate crystalline form A of Compound I, cyclohexane solvate crystalline form B of Compound I, acetic acid solvate ... B of Compound I, octane solvate of Compound I, cyclohexane solvate crystalline form A of Compound I, cyclohexane solvate crystalline form B of Compound I, octane solvate of Compound I, octane solvate of Compound I, octane solvate of Compound I, octane solvate of Compound I, octane solvate of Compound I, octane solvate of Compound I, octane solvate of Compound I The present invention includes administering to a patient an effective amount of Compound I in a solid crystalline form selected from cyclohexane solvate crystalline Form C of Compound I, ethanol solvate of Compound I, solvate / hydrate of Compound I (dry), solvate / hydrate of Compound I (wet), L-lysine co-crystal of Compound I, L-arginine co-crystal of Compound I, L-phenylalanine co-crystal of Compound I, succinic acid co-crystal of Compound I (wet), succinic acid co-crystal of Compound I (dry), and methanol solvate / hydrate of Compound I, in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof.

[0473] In some embodiments, a method for treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient comprises administering to the patient an effective amount of Compound I as a solid amorphous form that is a neat amorphous form of Compound I, in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof.

[0474] In some embodiments, a method for treating cystic fibrosis, reducing the severity of cystic fibrosis, or symptomatically treating cystic fibrosis in a patient includes (a) administering to a patient a neat amorphous form of Compound I, neat crystalline Form A of Compound I, neat crystalline Form B of Compound I, hemihydrate crystalline Form C of Compound I, neat crystalline Form D of Compound I, neat crystalline Form E of Compound I, acetic acid solvate of Compound I, heptane solvate crystalline Form B of Compound I, heptane solvate crystalline Form C of Compound I, octane solvate of Compound I, cyclohexane solvate crystalline Form B of Compound I, or a cyclohexane solvate crystalline Form C of Compound I. and (b) an effective amount of Compound I in a solid form selected from Form A, cyclohexane solvate crystalline Form B of Compound I, cyclohexane solvate crystalline Form C of Compound I, ethanol solvate of Compound I, solvate / hydrate of Compound I (dry), solvate / hydrate of Compound I (wet), L-lysine co-crystal of Compound I, L-arginine co-crystal of Compound I, L-phenylalanine co-crystal of Compound I, succinic acid co-crystal of Compound I (wet), succinic acid co-crystal of Compound I (dry), and methanol solvate / hydrate of Compound I; , Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and deuterated derivatives and pharmaceutically acceptable salts thereof; and (c) optionally, at least one compound selected from the group consisting of compounds described in WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 06258 1, WO 2022 / 076618, WO 2022 / 076620, WO 2022 / 076621, WO 2022 / 076622, WO 2022 / 076624, WO 2022 / 076625, WO 2022 / 076626, WO 2022 / 076627, WO 2022 / 076628, WO 2022 / 076629, U.S. Provisional Patent Applications Nos. 63 / 328,097 and 63 / 393,405, Phuan, P.-W. et al. al.J.Cyst.Fibros.2018,17(5),595-606, Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188, Kunzelmann,K.et al.,Front.Pharmacol.2019,10,3, or Son,J.-H.et al.,Eur.J.of Med. Chem. 2020, 112888, in combination with at least one compound selected from the compounds disclosed in.

[0475] X. Pharmaceutical Compositions Another aspect of the present invention provides pharmaceutical compositions comprising Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, the pharmaceutical compositions include neat crystalline Form A of Compound I, neat crystalline Form B of Compound I, hemihydrate crystalline Form C of Compound I, neat crystalline Form D of Compound I, neat crystalline Form E of Compound I, acetic acid solvate of Compound I, heptane solvate crystalline Form B of Compound I, heptane solvate crystalline Form C of Compound I, octane solvate of Compound I, cyclohexane solvate crystalline Form A of Compound I, cyclohexane solvate crystalline Form B of Compound I, cyclohexanone solvate crystalline Form E of Compound I, or the like. and Compound I in a solid form selected from Compound I solvate crystalline form C, ethanol solvate of Compound I, solvate / hydrate of Compound I (dry), solvate / hydrate of Compound I (wet), L-lysine co-crystal of Compound I, L-arginine co-crystal of Compound I, L-phenylalanine co-crystal of Compound I, succinic acid co-crystal (wet), succinic acid co-crystal (dry), methanol solvate / hydrate of Compound I, and neat amorphous form of Compound I. In some embodiments, the pharmaceutical composition comprises neat crystalline form A of Compound I, neat crystalline form B of Compound I, hemihydrate crystalline form C of Compound I, neat crystalline form D of Compound I, neat crystalline form E of Compound I, acetic acid solvate of Compound I, heptane solvate crystalline form B of Compound I, heptane solvate crystalline form C of Compound I, octane solvate of Compound I, cyclohexane solvate crystalline form A of Compound I, cyclohexane solvate crystalline form B of Compound I, acetic acid solvate of Compound I, heptane solvate crystalline form C of Compound I, acetic acid solvate ... The pharmaceutical composition comprises Compound I in a solid crystalline form selected from cyclohexane solvate crystalline form C, ethanol solvate of Compound I, solvate / hydrate of Compound I (dry), solvate / hydrate of Compound I (wet), L-lysine co-crystal of Compound I, L-arginine co-crystal of Compound I, L-phenylalanine co-crystal of Compound I, succinic acid co-crystal of Compound I (wet), succinic acid co-crystal of Compound I (dry), and methanol solvate / hydrate of Compound I. In some embodiments, the pharmaceutical composition comprises Compound I in a solid amorphous form that is a neat amorphous form of Compound I.

[0476] In some embodiments, the present invention provides pharmaceutical compositions comprising Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR corrector. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR potentiator. In some embodiments, the pharmaceutical composition comprises Compound I in any one of the pharmaceutically acceptable crystalline forms disclosed herein and at least two additional active pharmaceutical ingredients, one of which is a CFTR corrector and one of which is a CFTR potentiator. In some embodiments, the at least one additional active pharmaceutical ingredient is Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof.

[0477] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective, and an anti-inflammatory agent.

[0478] In some embodiments, the present invention provides pharmaceutical compositions comprising: (a) Compound I, in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein; and (b) at least one pharmaceutically acceptable carrier.

[0479] In some embodiments, the present invention provides pharmaceutical compositions comprising: (a) Compound I, in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein; (b) at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof; and (c) at least one pharmaceutically acceptable carrier.

[0480] In some embodiments, the present invention provides (a) neat crystalline form A of Compound I, neat crystalline form B of Compound I, hemihydrate crystalline form C of Compound I, neat crystalline form D of Compound I, neat crystalline form E of Compound I, acetic acid solvate of Compound I, heptane solvate crystalline form B of Compound I, heptane solvate crystalline form C of Compound I, octane solvate of Compound I, cyclohexane solvate crystalline form A of Compound I, cyclohexane solvate crystalline form B of Compound I, cyclohexane solvate crystalline form C of Compound I, ethanol solvate of Compound I, solvate / hydrate (dry), solvate / hydrate (wet), Provided is a pharmaceutical composition comprising: Compound I in a solid form selected from L-lysine co-crystal, L-arginine co-crystal of Compound I, L-phenylalanine co-crystal of Compound I, succinic acid co-crystal of Compound I (wet), succinic acid co-crystal of Compound I (dry), and methanol solvate / hydrate of Compound I; (b) at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof; and (c) at least one pharmaceutically acceptable carrier.

[0481] In some embodiments, the present invention provides pharmaceutical compositions comprising: (a) a neat amorphous form of Compound I, neat crystalline Form A of Compound I, neat crystalline Form B of Compound I, hemihydrate crystalline Form C of Compound I, neat crystalline Form D of Compound I, neat crystalline Form E of Compound I, acetic acid solvate of Compound I, heptane solvate crystalline Form B of Compound I, heptane solvate crystalline Form C of Compound I, octane solvate of Compound I, cyclohexane solvate crystalline Form A of Compound I, cyclohexane solvate crystalline Form B of Compound I, cyclohexane solvate crystalline Form E of Compound I, or acetic acid solvate of Compound I; Compound I in a solid form selected from cyclohexane solvate crystalline form C, an ethanol solvate of Compound I, a solvate / hydrate of Compound I (dry), a solvate / hydrate of Compound I (wet), an L-lysine cocrystal of Compound I, an L-arginine cocrystal of Compound I, an L-phenylalanine cocrystal of Compound I, a succinic acid cocrystal of Compound I (wet), a succinic acid cocrystal of Compound I (dry), and a methanol solvate / hydrate of Compound I; (b) Compound II, Compound III, Compound III-d, Compound IV; and (c) at least one compound selected from Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof, and optionally a compound described in WO 2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO 2017 / 009804, WO 2018 / 065921, WO 2017 / 062581, WO 2022 / 076618, WO 2022 / 076620, WO 2022 / 076621, WO 2022 / 076622, WO 2022 / 076624, WO 2022 / 076625, WO 2022 / 076626, WO 2022 / 076627, WO 2022 / 076628, WO 2022 / 076629, U.S. Provisional Patent Applications Nos. 63 / 328,097 and 63 / 393,405, Phuan, P.-W. et al. al.J.Cyst.Fibros.2018,17(5),595-606, Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640, Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32, Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272, Brasell,EJet al.PLoS One 2019,14(12),e0223954;Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188,Kunzelmann,K.et al.,Front.Pharmacol.2019,10,3,orSon,J.-H.et al.,Eur.J.of The present invention provides a pharmaceutical composition comprising at least one compound selected from the group consisting of compounds disclosed in Med. Chem. 2020, 112888, and (d) at least one pharmaceutically acceptable carrier.

[0482] The pharmaceutical compositions described herein are useful for the treatment of cystic fibrosis and other CFTR-mediated diseases.

[0483] As described above, the pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles. As used herein, the at least one pharmaceutically acceptable carrier includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surfactants, isotonicity agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, disclose various carriers used in formulating pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, such as by producing any undesirable biological effects or otherwise interacting in a deleterious manner with any other component of the pharmaceutical composition, use of any conventional carrier is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), saturated vegetable fatty acids, water, partial glyceride mixtures of salts and electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., carboxymethylcellulose), and the like. Examples of suitable additives include, but are not limited to, cellulose acetate, cellulose stearate, maltose, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository wax), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solution, non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants.

[0484] Y. Additional Compounds of the Disclosure In some embodiments, Compound I is prepared using a compound of the present disclosure.

[0485] In some embodiments, Compound I is prepared using a compound selected from the following: [ka]

[0486] In some embodiments, Compound I is prepared using a compound selected from the following: [ka]

[0487] In some embodiments, Compound I is prepared using a compound selected from the following: [ka]

[0488] In some embodiments, Compound I can be prepared using a compound selected from the following: [ka]

[0489] In some embodiments, Compound I can be prepared using a compound selected from the following: [ka]

[0490] In some embodiments, Compound I can be prepared using a compound selected from the following: [ka]

[0491] In some embodiments, Compound I can be prepared using a compound selected from the following: [ka]

[0492] In some embodiments, the compound of the present disclosure is selected from the following: [ka]

[0493] In some embodiments, the compound of the present disclosure is selected from the following: [ka]

[0494] In some embodiments, the compound of the present disclosure is selected from the following: [ka]

[0495] In some embodiments, the compound of the present disclosure is selected from the following: [ka]

[0496] In some embodiments, the compound of the present disclosure is selected from the following: [ka]

[0497] In some embodiments, the compound of the present disclosure is selected from the following: [ka]

[0498] In some embodiments, the compound of the present disclosure is selected from the following: [ka] Non-limiting exemplary embodiments A. Set 1 1. Compound I, [ka] Compound I as a neat amorphous form of substantially amorphous Compound I (i.e., less than 15% of Compound I is in crystalline form, less than 10% of Compound I is in crystalline form, less than 5% of Compound I is in crystalline form). 2. The neat amorphous form of substantially amorphous Compound I according to embodiment 1, wherein Compound I is 100% amorphous. 3. A neat amorphous form of substantially amorphous Compound I according to embodiment 1 or embodiment 2, characterized by a powder X-ray diffractogram substantially similar to that in FIG. 4. The neat amorphous form of substantially amorphous Compound I of any one of embodiments 1 to 3, characterized by a C-SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten, or more peaks selected from 163.8±0.2 ppm, 151.9±0.2 ppm, 137.6±0.2 ppm, 125.8±0.2 ppm, 120.8±0.2 ppm, 117.8±0.2 ppm, 77.3±0.2 ppm, 73.6±0.2 ppm, 34.5±0.2 ppm, 31.4±0.2 ppm, 26.3±0.2 ppm, 22.5±0.2 ppm, and 19.5±0.2 ppm. 5. The neat amorphous form of substantially amorphous Compound I of any one of embodiments 1 to 4, characterized by a C-SS NMR spectrum having peaks at 163.8±0.2 ppm, 151.9±0.2 ppm, 137.6±0.2 ppm, 125.8±0.2 ppm, 120.8±0.2 ppm, 117.8±0.2 ppm, 77.3±0.2 ppm, 73.6±0.2 ppm, 34.5±0.2 ppm, 31.4±0.2 ppm, 26.3±0.2 ppm, 22.5±0.2 ppm, and 19.5±0.2 ppm. 6. The neat amorphous form of substantially amorphous Compound I according to any one of embodiments 1 to 5, characterized by a 13C-SSNMR spectrum substantially similar to that in Figure 4. 7. The neat amorphous form of substantially amorphous Compound I according to any one of embodiments 1 to 6, characterized by a 19F-SSNMR spectrum having one or two peaks selected from -64.6±0.2 ppm and -77.4±0.2 ppm. 8. The neat amorphous form of substantially amorphous Compound I according to any one of embodiments 1 to 7, characterized by a 19F-SSNMR spectrum substantially similar to that in FIG. 5. 9. Neat crystalline Form A of Compound I that is substantially crystalline (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 10. The substantially crystalline neat crystalline form A of Compound I according to embodiment 9, wherein neat crystalline form A of Compound I is 100% crystalline. 11. Neat crystalline form A of substantially crystalline Compound I according to embodiment 9 or embodiment 10, characterized by an X-ray powder diffractogram having one or two signals selected from 4.6±0.2 degrees two-theta and 20.8±0.2 degrees two-theta. 12. Neat crystalline form A of substantially crystalline compound I according to any one of embodiments 9 to 11, characterized by a powder X-ray diffractogram having (a) one or two signals selected from 4.6±0.2 degrees 2-theta and 20.8±0.2 degrees 2-theta, and (b) one or two signals selected from 9.2±0.2 degrees 2-theta and 18.4±0.2 degrees 2-theta. 13. Neat crystalline Form A of substantially crystalline Compound I according to any one of embodiments 9 to 12, characterized by an X-ray powder diffractogram having two, three, or four signals selected from 4.6±0.2 degrees two-theta, 9.2±0.2 degrees two-theta, 18.4±0.2 degrees two-theta, and 20.8±0.2 degrees two-theta. 14. Neat crystalline form A of substantially crystalline Compound I according to any one of embodiments 9 to 13, characterized by a powder X-ray diffractogram substantially similar to that in FIG. 15. Neat crystalline Form B of Compound I that is substantially crystalline (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 16. The substantially crystalline neat crystalline form B of Compound I according to embodiment 15, wherein neat crystalline form B of Compound I is 100% crystalline. 17. Neat crystalline form B of substantially crystalline Compound I according to embodiment 15 or embodiment 16, characterized by an X-ray powder diffractogram having one, two, three, four, five, or six signals selected from 5.7±0.2 degrees two-theta, 6.1±0.2 degrees two-theta, 7.6±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, 10.6±0.2 degrees two-theta, and 12.3±0.2 degrees two-theta. 18. Neat crystalline form B of substantially crystalline Compound I according to any one of embodiments 15 to 17, characterized by an X-ray powder diffractogram having (a) one, two, three, four, five, or six signals selected from 5.7±0.2 degrees 2-theta, 6.1±0.2 degrees 2-theta, 7.6±0.2 degrees 2-theta, 10.3±0.2 degrees 2-theta, 10.6±0.2 degrees 2-theta, and 12.3±0.2 degrees 2-theta, and (b) one or two signals from 9.3±0.2 degrees 2-theta and 16.1±0.2 degrees 2-theta. 19. Neat crystalline form B of substantially crystalline Compound I according to any one of embodiments 15 to 18, characterized by an X-ray powder diffractogram having two, three, four, five, six, seven, or eight signals selected from 5.7±0.2 degrees two-theta, 6.1±0.2 degrees two-theta, 7.6±0.2 degrees two-theta, 9.3±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, 10.6±0.2 degrees two-theta, 12.3±0.2 degrees two-theta, and 16.1±0.2 degrees two-theta. 20. Neat crystalline form B of substantially crystalline Compound I according to any one of embodiments 15 to 19, characterized by an X-ray powder diffractogram having signals at 5.7±0.2 degrees 2-theta, 6.1±0.2 degrees 2-theta, 7.6±0.2 degrees 2-theta, 9.3±0.2 degrees 2-theta, 10.3±0.2 degrees 2-theta, 10.6±0.2 degrees 2-theta, 12.3±0.2 degrees 2-theta, and 16.1±0.2 degrees 2-theta. 21. Neat crystalline form B of substantially crystalline Compound I according to any one of embodiments 15 to 20, characterized by a powder X-ray diffractogram substantially similar to that in FIG. 9. 22.165.8±0.2ppm,154.2±0.2ppm,151.8±0.2ppm,140.1±0.2ppm,138.1±0.2ppm,136.2±0.2ppm,134.9±0.2ppm,131 .7±0.2ppm, 129.4±0.2ppm, 125.5±0.2ppm, 123.0±0.2ppm, 120.2±0.2ppm, 117.5±0.2ppm, 78.3±0.2ppm, 73.6±0.2ppm 22. The neat crystalline form B of substantially crystalline Compound I of any one of embodiments 15 to 21, characterized by a C-SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from: 37.6±0.2 ppm, 34.0±0.2 ppm, 29.9±0.2 ppm, 27.3±0.2 ppm, 22.7±0.2 ppm, 21.1±0.2 ppm, and 18.9±0.2 ppm. 23.165.8±0.2ppm, 154.2±0.2ppm, 151.8±0.2ppm, 140.1±0.2ppm, 138.1±0.2ppm, 136.2±0.2ppm, 134.9±0. 2ppm, 131.7±0.2ppm, 129.4±0.2ppm, 125.5±0.2ppm, 123.0±0.2ppm, 120.2±0.2ppm, 117.5±0.2ppm, 78.3±0 23. Neat crystalline form B of substantially crystalline compound I according to any one of embodiments 15 to 22, characterized by a C-SSNMR spectrum having peaks at 0.2 ppm, 73.6±0.2 ppm, 37.6±0.2 ppm, 34.0±0.2 ppm, 29.9±0.2 ppm, 27.3±0.2 ppm, 22.7±0.2 ppm, 21.1±0.2 ppm, and 18.9±0.2 ppm. 24.(a)165.8±0.2ppm, 154.2±0.2ppm, 151.8±0.2ppm, 140.1±0.2ppm, 138.1±0.2ppm, 136.2±0.2ppm, 134.9±0.2ppm, 131.7±0.2ppm, 129. 4±0.2ppm, 125.5±0.2ppm, 123.0±0.2ppm, 120.2±0.2ppm, 117.5±0.2ppm, 78.3±0.2ppm, 73.6±0.2ppm, 37.6±0.2ppm, 34.0±0.2ppm, 29.9±0 24. The neat crystalline form B of substantially crystalline Compound I according to any one of embodiments 15 to 23, characterized by a C-SSNMR spectrum having (a) one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from 164.7±0.2 ppm, 163.8±0.2 ppm, and 74.4±0.2 ppm, 27.3±0.2 ppm, 22.7±0.2 ppm, 21.1±0.2 ppm, and 18.9±0.2 ppm, and (b) one, two, or three peaks selected from 164.7±0.2 ppm, 163.8±0.2 ppm, and 74.4±0.2 ppm. 25.165.8±0.2ppm, 164.7±0.2ppm, 163.8±0.2ppm, 154.2±0.2ppm, 151.8±0.2ppm, 140.1±0.2ppm, 138.1±0.2ppm, 136.2±0.2pp m, 134.9±0.2ppm, 131.7±0.2ppm, 129.4±0.2ppm, 125.5±0.2ppm, 123.0±0.2ppm, 120.2±0.2ppm, 117.5±0.2ppm, 78.3±0.2ppm, 7 25. The neat crystalline form B of substantially crystalline Compound I according to any one of embodiments 15 to 24, characterized by a C-SSNMR spectrum having four, five, six, seven, eight, nine, ten or more peaks selected from 4.4±0.2 ppm, 73.6±0.2 ppm, 37.6±0.2 ppm, 34.0±0.2 ppm, 29.9±0.2 ppm, 27.3±0.2 ppm, 22.7±0.2 ppm, 21.1±0.2 ppm, and 18.9±0.2 ppm. 26.165.8±0.2ppm, 164.7±0.2ppm, 163.8±0.2ppm, 154.2±0.2ppm, 151.8±0.2ppm, 140.1±0.2ppm, 138.1±0.2ppm, 136. 2±0.2ppm, 134.9±0.2ppm, 131.7±0.2ppm, 129.4±0.2ppm, 125.5±0.2ppm, 123.0±0.2ppm, 120.2±0.2ppm, 117.5±0.2ppm 26. The neat crystalline form B of substantially crystalline Compound I according to any one of embodiments 15 to 25, characterized by a C-SSNMR spectrum having peaks at: 78.3±0.2 ppm, 74.4±0.2 ppm, 73.6±0.2 ppm, 37.6±0.2 ppm, 34.0±0.2 ppm, 29.9±0.2 ppm, 27.3±0.2 ppm, 22.7±0.2 ppm, 21.1±0.2 ppm, and 18.9±0.2 ppm. 27. Neat crystalline form B of substantially crystalline Compound I according to any one of embodiments 15 to 26, characterized by a 13C-SSNMR spectrum substantially similar to that in Figure 12. 28. Neat crystalline form B of substantially crystalline Compound I according to any one of embodiments 15 to 27, characterized by a 19F-SSNMR spectrum having one, two, or three peaks selected from -64.3±0.2 ppm, -65.9±0.2 ppm, and -76.5±0.2 ppm. 29. Neat crystalline form B of substantially crystalline Compound I according to any one of embodiments 15 to 28, characterized by a 19F-SSNMR spectrum substantially similar to that in FIG. 13. 30. A substantially crystalline hemihydrate crystalline form C of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 31. The substantially crystalline hemihydrate crystalline form C of Compound I according to embodiment 30, wherein the hemihydrate crystalline form C of Compound I is 100% crystalline. 32. The substantially crystalline hemihydrate crystalline form C of Compound I according to embodiment 30 or embodiment 31, characterized by an X-ray powder diffractogram having one, two, three, or four signals selected from 4.8±0.2 degrees two-theta, 16.4±0.2 degrees two-theta, 19.3±0.2 degrees two-theta, and 21.1±0.2 degrees two-theta. 33. The substantially crystalline hemihydrate crystalline form C of Compound I according to any one of embodiments 30 to 32, characterized by an X-ray powder diffractogram having one, two, three, four, or five signals selected from 13.1±0.2 degrees two-theta, 16.4±0.2 degrees two-theta, 18.4±0.2 degrees two-theta, 19.6±0.2 degrees two-theta, and 21.1±0.2 degrees two-theta. 34. The substantially crystalline hemihydrate crystalline form C of Compound I according to any one of embodiments 30 to 33, characterized by an X-ray powder diffractogram having one, two, three, four, five, six, seven, eight, nine, or ten signals selected from 4.8±0.2 degrees two-theta, 13.1±0.2 degrees two-theta, 16.4±0.2 degrees two-theta, 18.4±0.2 degrees two-theta, 19.3±0.2 degrees two-theta, 19.6±0.2 degrees two-theta, 21.1±0.2 degrees two-theta, 24.0±0.2 degrees two-theta, 24.6±0.2 degrees two-theta, and 27.1±0.2 degrees two-theta. 35.4.8±0.2 degrees 2-theta, 8.2±0.2 degrees 2-theta, 9.3±0.2 degrees 2-theta, 11.2±0.2 degrees 2-theta, 12.5±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 16.4±0.2 degrees 2-theta, 18.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 19.6±0.2 degrees 2-theta, 21.1±0.2 degrees 2-theta, 21.6±0.2 degrees 2-theta, 22.8±0.2 degrees 2-theta, 23.5±0.2 degrees 2-theta, 24±0.2 degrees 2-theta, 24.6±0.2 degrees 2-theta, 25.8±0.2 degrees 2-theta, 27.1±0.2 degrees 35. The substantially crystalline hemihydrate crystalline form C of Compound I according to any one of embodiments 30 to 34, characterized by an X-ray powder diffractogram having one, two, three, four, five, six, seven, eight, nine, ten or more signals selected from 29.6±0.2 degrees 2-theta, 29.6±0.2 degrees 2-theta, and 33.4±0.2 degrees 2-theta. 36.4.8±0.2 degrees 2-theta, 8.2±0.2 degrees 2-theta, 9.3±0.2 degrees 2-theta, 11.2±0.2 degrees 2-theta, 12.5±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 16.4±0.2 degrees 2-theta, 18.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 19.6±0.2 degrees 2-theta, 21.1±0.2 degrees 2-theta, 21.6±0.2 degrees 2-theta, 22.8±0.2 degrees 2-theta, 23.5±0.2 degrees 2-theta, 24±0.2 degrees 2-theta, 24.6±0.2 degrees 2-theta, 25.8±0.2 degrees 2-theta, 27.1±0.2 degrees 36. The substantially crystalline hemihydrate crystalline form C of Compound I according to any one of embodiments 30 to 35, characterized by an X-ray powder diffractogram with signals at 29.6±0.2 degrees 2-theta, 29.6±0.2 degrees 2-theta, and 33.4±0.2 degrees 2-theta. 37. The substantially crystalline hemihydrate crystalline form C of Compound I according to any one of embodiments 30 to 36, characterized by a powder X-ray diffractogram substantially similar to that in FIG. 14. 38.163.8±0.2ppm, 151.3±0.2ppm, 139.1±0.2ppm, 137.7±0.2ppm, 127.2±0.2ppm, 125.8±0.2p pm, 119.9±0.2ppm, 118.4±0.2ppm, 75.6±0.2ppm, 73.6±0.2ppm, 35.8±0.2ppm, 32.2±0.2ppm, 29 A substantially crystalline hemihydrate crystalline form C of compound I according to any one of embodiments 30 to 37, characterized by a 13C-SSNMR spectrum having one, two, three, four, five, six, seven, eight, nine, ten or more peaks selected from 0.6±0.2 ppm, 24.6±0.2 ppm, 22.1±0.2 ppm, and 19.2±0.2 ppm. 39. The substantially crystalline hemihydrate crystalline form C of Compound I according to any one of embodiments 30 to 38, characterized by a C-SSNMR spectrum having peaks at 163.8±0.2 ppm, 151.3±0.2 ppm, 139.1±0.2 ppm, 137.7±0.2 ppm, 127.2±0.2 ppm, 125.8±0.2 ppm, 119.9±0.2 ppm, 118.4±0.2 ppm, 75.6±0.2 ppm, 73.6±0.2 ppm, 35.8±0.2 ppm, 32.2±0.2 ppm, 29.6±0.2 ppm, 24.6±0.2 ppm, 22.1±0.2 ppm, and 19.2±0.2 ppm. 40. The substantially crystalline hemihydrate crystalline form C of Compound I according to any one of embodiments 30 to 39, characterized by a 13C-SSNMR spectrum substantially similar to that in Figure 17. 41. The substantially crystalline hemihydrate crystalline form C of Compound I according to any one of embodiments 30 to 40, characterized by a F-SSNMR spectrum having one or two peaks selected from -65.5±0.2 ppm and -77.4±0.2 ppm. 42. The substantially crystalline hemihydrate crystalline form C of Compound I according to any one of embodiments 30 to 41, characterized by a 19F-SSNMR spectrum substantially similar to that in FIG. 18. 43. The substantially crystalline hemihydrate crystalline form C of Compound I according to any one of embodiments 30 to 42, characterized by a monoclinic system, a P21 space group, and the following unit cell dimensions measured at 100 K on a Bruker diffractometer using Cu Kα radiation (λ=1.54178 Å): [Table 61] 44. A neat crystalline form D of Compound I that is substantially crystalline (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 45. The substantially crystalline neat crystalline form D of Compound I according to embodiment 44, wherein neat crystalline form D of Compound I is 100% crystalline. 46. ​​Neat crystalline form D of substantially crystalline Compound I according to embodiment 44 or embodiment 45, characterized by an X-ray powder diffractogram having two or three signals selected from 8.4±0.2 degrees two-theta, 14.3±0.2 degrees two-theta, and 20.3±0.2 degrees two-theta. 47.8.4±0.2 degrees 2-theta, 8.8±0.2 degrees 2-theta, 14.3±0.2 degrees 2-theta, 14.8±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 16.77±0.2 degrees 2-theta, 16.85±0.2 degrees 2-theta, 19.6±0.2 degrees 2-theta, 20.0±0.2 degrees 2-theta, 20.3±0.2 degrees 2-theta, 21.7±0.2 degrees 2-theta, 22.5±0.2 degrees 2-theta, 24.7±0.2 degrees 2-theta, 25.2±0.2 degrees 2-theta, 26.2±0.2 degrees 2-theta, 26.45±0.2 degrees 2-theta, 26.52±0.2 degrees 47. Neat crystalline form D of substantially crystalline Compound I according to any one of embodiments 44 to 46, characterized by an X-ray powder diffractogram having one, two, three, four, five, six, seven, eight, nine, ten or more signals selected from 27.8±0.2 degrees 2-theta, 27.8±0.2 degrees 2-theta, and 28.8±0.2 degrees 2-theta. 48.(a) 8.4±0.2 degrees 2-theta, 8.8±0.2 degrees 2-theta, 14.3±0.2 degrees 2-theta, 14.8±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 16.77±0.2 degrees 2-theta, 16.85±0.2 degrees 2-theta, 19.6±0.2 degrees 2-theta, 20.0±0.2 degrees 2-theta, 20.3±0.2 degrees 2-theta, 21.7±0.2 degrees 2-theta, 22.5±0.2 degrees 2-theta, 24.7±0.2 degrees 2-theta, 25.2±0.2 degrees 2-theta, 26.2±0.2 degrees 2-theta, 26.45±0.2 degrees 2-theta, 26.52±0.2 degrees 48. The neat crystalline form D of substantially crystalline Compound I according to any one of embodiments 44 to 47, characterized by an X-ray powder diffractogram having (a) one, two, three, four, five, six, seven, eight, nine, ten or more signals selected from 27.8±0.2 degrees two-theta, 27.8±0.2 degrees two-theta, and 28.8±0.2 degrees two-theta, and (b) one, two, or three signals selected from 16.0±0.2 degrees two-theta, 18.55±0.2 degrees two-theta, and 18.64±0.2 degrees two-theta. 49.8.4±0.2 degrees 2-theta, 8.8±0.2 degrees 2-theta, 14.3±0.2 degrees 2-theta, 14.8±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 16.0±0.2 degrees 2-theta, 16.77±0.2 degrees 2-theta, 16.85±0.2 degrees 2-theta, 18.55±0.2 degrees 2-theta, 18.64±0.2 degrees 2-theta, 19.6±0.2 degrees 2-theta, 20.0±0.2 degrees 2-theta, 20.3±0.2 degrees 2-theta, 21.7±0.2 degrees 2-theta, 22.5±0.2 degrees 2-theta, 24.7±0.2 degrees 2-theta, 25.2±0.2 degrees 49. Neat crystalline form D of substantially crystalline Compound I according to any one of embodiments 44 to 48, characterized by an X-ray powder diffractogram having three, four, five, six, seven, eight, nine, ten or more signals selected from: 26.2±0.2 degrees 2-theta, 26.45±0.2 degrees 2-theta, 26.52±0.2 degrees 2-theta, 27.8±0.2 degrees 2-theta, and 28.8±0.2 degrees 2-theta. 50.8.4±0.2 degrees 2-theta, 8.8±0.2 degrees 2-theta, 14.3±0.2 degrees 2-theta, 14.8±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 16.0±0.2 degrees 2-theta, 16.77±0.2 degrees 2-theta, 16.85±0.2 degrees 2-theta, 18.55±0.2 degrees 2-theta, 18.64±0.2 degrees 2-theta, 19.6±0.2 degrees 2-theta, 20.0±0.2 degrees 2-theta, 20.3±0.2 degrees 2-theta, 21.7±0.2 degrees 2-theta, 22.5±0.2 degrees 2-theta, 24.7±0.2 degrees 2-theta, 25.2±0.2 degrees 50. Neat crystalline form D of substantially crystalline Compound I according to any one of embodiments 44 to 49, characterized by an X-ray powder diffractogram having signals at 26.2±0.2 degrees 2-theta, 26.45±0.2 degrees 2-theta, 26.52±0.2 degrees 2-theta, 27.8±0.2 degrees 2-theta, and 28.8±0.2 degrees 2-theta. 51. Neat crystalline form D of substantially crystalline Compound I according to any one of embodiments 44 to 50, characterized by a powder X-ray diffractogram substantially similar to that in FIG. 19. 52. The neat crystalline form D of substantially crystalline Compound I according to any one of embodiments 44 to 51, characterized by a C-SSNMR spectrum having one, two, three, four, five, six, seven, eight, or nine peaks selected from 52.152.2±0.2 ppm, 137.7±0.2 ppm, 127.3±0.2 ppm, 120.8±0.2 ppm, 118.1±0.2 ppm, 75.7±0.2 ppm, 35.9±0.2 ppm, 30.4±0.2 ppm, 22.1±0.2 ppm, and 17.7±0.2 ppm. 53. Neat crystalline form D of substantially crystalline Compound I according to any one of embodiments 44 to 52, characterized by a C-SSNMR spectrum having (a) one, two, three, four, five, six, seven, eight, nine, or ten peaks selected from 152.2±0.2 ppm, 137.7±0.2 ppm, 127.3±0.2 ppm, 120.8±0.2 ppm, 118.1±0.2 ppm, 75.7±0.2 ppm, 35.9±0.2 ppm, 30.4±0.2 ppm, 22.1±0.2 ppm, and 17.7±0.2 ppm, and (b) one, two, or three peaks selected from 164.6±0.2 ppm, 163.8±0.2 ppm, and 74.2±0.2 ppm. 54. Neat crystalline form D of substantially crystalline Compound I according to any one of embodiments 44 to 53, characterized by a C-SSNMR spectrum having four, five, six, seven, eight, nine, ten or more peaks selected from 164.6±0.2 ppm, 163.8±0.2 ppm, 152.2±0.2 ppm, 137.7±0.2 ppm, 127.3±0.2 ppm, 120.8±0.2 ppm, 118.1±0.2 ppm, 75.7±0.2 ppm, 74.2±0.2 ppm, 35.9±0.2 ppm, 30.4±0.2 ppm, 22.1±0.2 ppm, and 17.7±0.2 ppm. 55. Neat crystalline form D of substantially crystalline Compound I according to any one of embodiments 44 to 54, characterized by a C-SSNMR spectrum having peaks at 164.6±0.2 ppm, 163.8±0.2 ppm, 152.2±0.2 ppm, 137.7±0.2 ppm, 127.3±0.2 ppm, 120.8±0.2 ppm, 118.1±0.2 ppm, 75.7±0.2 ppm, 74.2±0.2 ppm, 35.9±0.2 ppm, 30.4±0.2 ppm, 22.1±0.2 ppm, and 17.7±0.2 ppm. 56. Neat crystalline form D of substantially crystalline Compound I according to any one of embodiments 44 to 55, characterized by a 13C-SSNMR spectrum substantially similar to that in Figure 23. 57. Neat crystalline form D of substantially crystalline Compound I according to any one of embodiments 44 to 56, characterized by a 19F-SSNMR spectrum having one or two peaks selected from: -62.4±0.2 ppm, and -77.2±0.2 ppm. 58. Neat crystalline form D of substantially crystalline Compound I according to any one of embodiments 44 to 57, characterized by a 19F-SSNMR spectrum substantially similar to that in FIG. 24. 59. Neat crystalline form D of the substantially crystalline Compound I according to any one of embodiments 44 to 58, characterized by a monoclinic system, a P21 space group, and the following unit cell dimensions measured at 250 K on a Bruker diffractometer using Cu Kα radiation (λ=1.54178 Å): [Table 62] 60. Neat crystalline Form E of Compound I that is substantially crystalline (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 61. The substantially crystalline neat crystalline form E of Compound I according to embodiment 60, wherein neat crystalline form E of Compound I is 100% crystalline. 62. Neat crystalline form E of substantially crystalline Compound I according to any one of embodiments 60 to 61, characterized by an orthorhombic crystal system, a P 212121 space group, and the following unit cell dimensions measured at 100 K on a Bruker diffractometer using Cu Kα radiation (λ=1.54178 Å): [Table 63] 63. A substantially crystalline acetic acid solvate of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 64. The substantially crystalline acetic acid solvate of Compound I according to embodiment 63, wherein the acetic acid solvate of Compound I is 100% crystalline. 65. The substantially crystalline acetic acid solvate of Compound I, according to embodiment 63 or embodiment 64, characterized by an X-ray powder diffractogram having one, two, three, four, or five signals selected from 5.4±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, 14.2±0.2 degrees two-theta, 15.9±0.2 degrees two-theta, and 20.2±0.2 degrees two-theta. 66. The substantially crystalline acetic acid solvate of Compound I of any one of embodiments 63 to 65, characterized by an X-ray powder diffractogram having one, two, three, four, five, six, seven, eight, nine, or ten signals selected from 5.4±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, 14.2±0.2 degrees two-theta, 15.9±0.2 degrees two-theta, 18.5±0.2 degrees two-theta, 19.5±0.2 degrees two-theta, 19.8±0.2 degrees two-theta, 20.2±0.2 degrees two-theta, 20.6±0.2 degrees two-theta, and 21.6±0.2 degrees two-theta. 67.5.4±0.2 degrees 2-theta, 8.3±0.2 degrees 2-theta, 10.2±0.2 degrees 2-theta, 10.4±0.2 degrees 2-theta, 10.9±0.2 degrees 2-theta, 11.7±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 13.2±0.2 degrees 2-theta, 13.8±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 16.7±0.2 degrees 2-theta, 17.5±0.2 degrees 2-theta, 18.0±0.2 degrees 2-theta, 18.5±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 19.5±0.2 degrees 67. The substantially crystalline acetic acid solvate of Compound I of any one of embodiments 63 to 66, characterized by an X-ray powder diffractogram having one, two, three, four, five, six, seven, eight, nine, ten, or more signals selected from: 19.8±0.2 degrees 2-theta; 20.2±0.2 degrees 2-theta; 20.6±0.2 degrees 2-theta; 21.6±0.2 degrees 2-theta; 22.5±0.2 degrees 2-theta; 25.0±0.2 degrees 2-theta; 25.3±0.2 degrees 2-theta; and 26.3±0.2 degrees 2-theta. 68.5.4±0.2 degrees 2-theta, 8.3±0.2 degrees 2-theta, 10.2±0.2 degrees 2-theta, 10.4±0.2 degrees 2-theta, 10.9±0.2 degrees 2-theta, 11.7±0.2 degrees 2-theta, 13.1±0.2 degrees 2-theta, 13.2±0.2 degrees 2-theta, 13.8±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 16.7±0.2 degrees 2-theta, 17.5±0.2 degrees 2-theta, 18.0±0.2 degrees 2-theta, 18.5±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 19.5±0.2 degrees 68. The substantially crystalline acetic acid solvate of Compound I of any one of embodiments 63 to 67, characterized by an X-ray powder diffractogram having signals at: 19.8±0.2 degrees 2-theta; 20.2±0.2 degrees 2-theta; 20.6±0.2 degrees 2-theta; 21.6±0.2 degrees 2-theta; 22.5±0.2 degrees 2-theta; 25.0±0.2 degrees 2-theta; 25.3±0.2 degrees 2-theta; and 26.3±0.2 degrees 2-theta. 69. The substantially crystalline acetic acid solvate of Compound I, according to any one of embodiments 63 to 68, characterized by a powder X-ray diffractogram substantially similar to that in Figure 25. 70. Substantially the heptane solvate crystalline form B of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 71. The substantially crystalline heptane solvate crystalline form B of Compound I according to embodiment 70, wherein the heptane solvate crystalline form B of Compound I is 100% crystalline. 72. The substantially crystalline heptane solvate crystalline form B of Compound I according to embodiment 70 or embodiment 71, characterized by an X-ray powder diffractogram having one, two, three, four, five, six, seven, eight, nine, ten, or more signals selected from 4.4±0.2 degrees 2-theta, 7.3±0.2 degrees 2-theta, 8.9±0.2 degrees 2-theta, 10.9±0.2 degrees 2-theta, 11.1±0.2 degrees 2-theta, 14.4±0.2 degrees 2-theta, 14.7±0.2 degrees 2-theta, 18.8±0.2 degrees 2-theta, 21.9±0.2 degrees 2-theta, 23.2±0.2 degrees 2-theta, 23.8±0.2 degrees 2-theta, 24.5±0.2 degrees 2-theta, and 25.6±0.2 degrees 2-theta. 73. (a) one, two, three, four, five, six, seven, eight, nine, ten, or more signals selected from 4.4 ± 0.2 degrees 2-theta, 7.3 ± 0.2 degrees 2-theta, 8.9 ± 0.2 degrees 2-theta, 10.9 ± 0.2 degrees 2-theta, 11.1 ± 0.2 degrees 2-theta, 14.4 ± 0.2 degrees 2-theta, 14.7 ± 0.2 degrees 2-theta, 18.8 ± 0.2 degrees 2-theta, 21.9 ± 0.2 degrees 2-theta, 23.2 ± 0.2 degrees 2-theta, 23.8 ± 0.2 degrees 2-theta, 24.5 ± 0.2 degrees 2-theta, and 25.6 ± 0.2 degrees 2-theta; and (b) 8.1 ± 0.2 degrees 2-theta, 10.1 ± 0.2 degrees 73. The substantially crystalline heptane solvate crystalline form B of Compound I according to any one of embodiments 70 to 72, characterized by an X-ray powder diffractogram having one, two, three, or four signals selected from: 17.9±0.2 degrees 2-theta, 17.9±0.2 degrees 2-theta, and 20.4±0.2 degrees 2-theta. 74.4±0.2 degrees 2-theta, 7.3±0.2 degrees 2-theta, 8.1±0.2 degrees 2-theta, 8.9±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 10.9±0.2 degrees 2-theta, 11.1±0.2 degrees 2-theta, 14.4±0.2 degrees 2-theta, 14.7±0.2 degrees 2-theta, 17.9±0.2 degrees 2-theta, 18.8±0.2 degrees 2-theta, 20.4±0.2 degrees 2-theta, 21.9±0.2 degrees 2-theta, 23.2±0.2 degrees 2-theta, 23.8±0.2 degrees 2-theta, 24.5±0.2 degrees 2-theta, 25.6±0.2 degrees The substantially crystalline heptane solvate crystalline form B of Compound I according to any one of embodiments 70 to 73, characterized by an X-ray powder diffractogram having four, five, six, seven, eight, nine, ten or more signals selected from 2-theta. 75.4±0.2 degrees 2-theta, 7.3±0.2 degrees 2-theta, 8.1±0.2 degrees 2-theta, 8.9±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 10.9±0.2 degrees 2-theta, 11.1±0.2 degrees 2-theta, 14.4±0.2 degrees 2-theta, 14.7±0.2 degrees 2-theta, 17.9±0.2 degrees 2-theta, 18.8±0.2 degrees 2-theta, 20.4±0.2 degrees 2-theta, 21.9±0.2 degrees 2-theta, 23.2±0.2 degrees 2-theta, 23.8±0.2 degrees 2-theta, 24.5±0.2 degrees 2-theta, 25.6±0.2 degrees The substantially crystalline heptane solvate crystalline form B of Compound I according to any one of embodiments 70 to 74, characterized by an X-ray powder diffractogram with a signal in 2-theta. 76. The substantially crystalline heptane solvate crystalline form B of Compound I, according to any one of embodiments 70 to 75, characterized by a powder X-ray diffractogram substantially similar to that in FIG. 27. 77. The substantially crystalline heptane solvate crystalline form B of Compound I according to any one of embodiments 70 to 76, characterized by a C-SSNMR spectrum having one, two, three, four, or five peaks selected from 77.137.5±0.2 ppm, 126.3±0.2 ppm, 117.4±0.2 ppm, 75.5±0.2 ppm, and 34.2±0.2 ppm. 78. (a) One, two, three, four, or five peaks selected from 137.5±0.2 ppm, 126.3±0.2 ppm, 117.4±0.2 ppm, 75.5±0.2 ppm, and 34.2±0.2 ppm, and (b) 164.4±0.2 ppm, 163.0±0.2 ppm, 151.0±0.2 ppm, 139.5±0.2 ppm, 120.8±0.2 ppm, 120.0±0.2 ppm, 74.7±0.2 ppm, 74.1±0.2 ppm , 73.0±0.2 ppm, 31.1±0.2 ppm, 28.2±0.2 ppm, 22.4±0.2 ppm, 20.8±0.2 ppm, 19.5±0.2 ppm, and 13.8±0.2 ppm. 79.164.4±0.2ppm, 163.0±0.2ppm, 151.0±0.2ppm, 139.5±0.2ppm, 137.5±0.2ppm, 126.3±0.2ppm, 120.8± 0.2ppm, 120.0±0.2ppm, 117.4±0.2ppm, 75.5±0.2ppm, 74.7±0.2ppm, 74.1±0.2ppm, 73.0±0.2ppm, 34.2±0. 79. The substantially crystalline heptane solvate crystalline form B of Compound I according to any one of embodiments 70 to 78, characterized by a C-SSNMR spectrum having twelve or more peaks selected from: 19.2 ppm, 31.1±0.2 ppm, 28.2±0.2 ppm, 22.4±0.2 ppm, 20.8±0.2 ppm, 19.5±0.2 ppm, and 13.8±0.2 ppm. 80.164.4±0.2ppm, 163.0±0.2ppm, 151.0±0.2ppm, 139.5±0.2ppm, 137.5±0.2ppm, 126.3±0.2ppm, 12 0.8±0.2ppm, 120.0±0.2ppm, 117.4±0.2ppm, 75.5±0.2ppm, 74.7±0.2ppm, 74.1±0.2ppm, 73.0±0.2ppm 80. The substantially crystalline heptane solvate crystalline form B of Compound I according to any one of embodiments 70 to 79, characterized by a C-SSNMR spectrum having peaks at: 34.2±0.2 ppm, 31.1±0.2 ppm, 28.2±0.2 ppm, 22.4±0.2 ppm, 20.8±0.2 ppm, 19.5±0.2 ppm, and 13.8±0.2 ppm. 81. The substantially crystalline heptane solvate crystalline form B of Compound I according to any one of embodiments 70 to 80, characterized by a 13C-SSNMR spectrum substantially similar to that in Figure 29. 82. The substantially crystalline heptane solvate crystalline form B of Compound I according to any one of embodiments 70 to 81, characterized by a F-SSNMR spectrum having: (a) one or two peaks selected from -78.4±0.2 ppm and -64.2±0.2 ppm, and (b) one or two peaks selected from -63.4±0.2 ppm and -77.4±0.2 ppm. 83. The substantially crystalline heptane solvate crystalline form B of Compound I according to any one of embodiments 70 to 82, characterized by a F-SSNMR spectrum having three or four peaks selected from -78.4±0.2 ppm, -77.4±0.2 ppm, -64.2±0.2 ppm, and -63.4±0.2 ppm. 84. The substantially crystalline heptane solvate crystalline form B of Compound I according to any one of embodiments 70 to 83, characterized by a 19F-SSNMR spectrum substantially similar to that in FIG. 30. 85. A substantially crystalline heptane solvate crystalline form C of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 86. The substantially crystalline heptane solvate crystalline form C of Compound I according to embodiment 85, wherein the heptane solvate crystalline form C of Compound I is 100% crystalline. The substantially crystalline heptane solvate crystalline form C of Compound I, according to embodiment 85 or embodiment 86, characterized by an X-ray powder diffractogram having one, two, or three signals selected from 87.9.3±0.2 degrees two-theta, 13.1±0.2 degrees two-theta, and 32.3±0.2 degrees two-theta. 88. The substantially crystalline heptane solvate crystalline form C of Compound I according to...

Claims

1. Substantially crystalline Compound I, 【Chemical 332】 The crystalline Compound I is selected from substantially pure neat crystalline Form A of Compound I, neat crystalline Form B of Compound I, hemihydrate crystalline Form C of Compound I, neat crystalline Form D of Compound I, neat crystalline Form E of Compound I, acetic acid solvate of Compound I, heptane solvate crystalline Form B of Compound I, heptane solvate crystalline Form C of Compound I, octane solvate of Compound I, cyclohexane solvate crystalline Form A of Compound I, cyclohexane solvate crystalline Form B of Compound I, cyclohexane solvate crystalline Form C of Compound I, ethanol solvate of Compound I, solvate / hydrate of Compound I (dry), solvate / hydrate of Compound I (wet), L-lysine co-crystal of Compound I, L-arginine co-crystal of Compound I, L-phenylalanine co-crystal of Compound I, succinic acid co-crystal hydrate of Compound I, succinic acid co-crystal of Compound I, and methanol solvate / hydrate of Compound I.

2. 2. The substantially crystalline Compound I of claim 1, wherein less than 15% of Compound I is in amorphous form.

3. 2. The substantially crystalline Compound I of claim 1, wherein less than 10% of Compound I is in amorphous form.

4. 2. The substantially crystalline Compound I of claim 1, wherein less than 5% of Compound I is in amorphous form.

5. 2. The substantially crystalline compound I of claim 1, wherein 100% of compound I is crystalline.

6. Substantially amorphous Compound I, which is in neat amorphous form.

7. 7. The substantially amorphous Compound I of claim 6, wherein less than 15% of Compound I is in crystalline form.

8. 7. The substantially crystalline Compound I of claim 6, wherein less than 10% of Compound I is in crystalline form.

9. 7. The substantially crystalline Compound I of claim 6, wherein less than 5% of Compound I is in crystalline form.

10. 7. The substantially crystalline Compound I of claim 6, wherein 100% of Compound I is amorphous.

11. 6. The substantially crystalline compound I according to any one of claims 1 to 5, characterized by crystal lattice parameters.

12. 12. The substantially crystalline compound I of any one of claims 1 to 11, characterized by an X-ray powder diffractogram (XRPD).

13. 13. A substantially crystalline compound I according to any one of claims 1 to 12, characterized by a 13C solid-state nuclear magnetic resonance (13C SSNMR) spectrum.

14. A pharmaceutical composition comprising a compound I according to any one of claims 1 to 13.

15. 15. The pharmaceutical composition of claim 14, further comprising one or more additional therapeutic agents.

16. 16. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition comprises one or more additional CFTR modulating compounds.

17. 17. The pharmaceutical composition of claim 16, comprising one or more compounds selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharma- ceutically acceptable salts and deuterated derivatives thereof.

18. A compound I as defined in any one of claims 1 to 13 or a pharmaceutical composition as defined in any one of claims 14 to 17 for use in the treatment of cystic fibrosis.

19. 20. Use of a compound I according to any one of claims 1 to 13 or a pharmaceutical composition according to any one of claims 14 to 17 in the manufacture of a medicament for the treatment of cystic fibrosis.

20. A method for treating cystic fibrosis, comprising administering to a subject in need of such treatment a compound I described in any one of claims 1 to 13 or a pharmaceutical composition described in any one of claims 14 to 17.

21. The compound or composition for use of claim 18, the use of claim 19 or the method of claim 20, wherein the compound I of any one of claims 1 to 13 or the composition of any one of claims 14 to 17 is administered in combination with one or more additional therapeutic agents.

22. 22. The compound or composition for use, use, or method of claim 21 , wherein the one or more additional therapeutic agents comprise one or more additional CFTR modulating compounds.

23. 23. The compound or composition for use, use, or method of claim 21 or claim 22, wherein the one or more additional therapeutic agents comprise one or more compounds selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharma- ceutically acceptable salts and deuterated derivatives thereof.

24. A process for preparing a compound I according to any one of claims 1 to 13, comprising the steps of: (a) (i) dissolving heptane solvate crystalline Form A of Compound I in methanol; (ii) adding water; (iii) stirring at room temperature for five days; and (iv) collecting the solid and drying at 40° C. under reduced pressure for 24 hours to obtain neat crystalline Form A of Compound I. (b) (i) dissolving heptane solvate crystalline Form A of Compound I in dichloromethane at room temperature; and (ii) slowly evaporating the dichloromethane at room temperature to obtain neat crystalline Form B of crystalline Compound I. (c) (i) dissolving Compound I in ethanol at 25° C.; (ii) adding water over 10-12 hours (ethanol to water ratio of about 1:4 v / v); (iii) heating the slurry to 60° C. over 4 hours; (iv) cooling the slurry to 20° C. over 3 hours; (v) stirring for at least 2 hours; (vi) filtering the solid and washing with an ethanol / water solution (1:4 v / v); and (vii) drying the solid in a vacuum oven at 50° C. with a slight nitrogen flow to obtain crystalline hemihydrate crystal form C of Compound I. (d) (i) dissolving crystalline hemihydrate form C of Compound I in ethanol; (ii) placing the solution under nitrogen for 30 minutes; and (iii) placing the solution in an oven at 80° C. for about 5 days to obtain neat form D of crystalline Compound I. (e) (i) slurrying hemihydrate crystalline form C of Compound I in n-heptane; (ii) heating the slurry to 85° C.; (iii) seeding with neat crystalline form D of crystalline Compound I; (iv) holding the slurry at 85+5° C.; (v) cooling the slurry to 65° C. over 4 hours; (vi) collecting the solids and washing the solids with n-heptane; and (vii) drying the solids in a vacuum oven at 50° C. with a slight nitrogen flow to obtain neat crystalline form D of crystalline Compound I. (f) (i) combining hemihydrate crystalline Form C of Compound I with acetic acid; and (ii) ball milling at 7500 rpm for two cycles of 10 seconds each with a pause of 60 seconds after each cycle to obtain crystalline acetic acid solvate of Compound I. (g) (i) adding 1-butanol / heptane (75% by volume of heptane) to neat crystalline Form D of crystalline Compound I; and (ii) shaking the mixture at 25° C. for 2 days to obtain heptane solvate crystalline Form B of crystalline Compound I. (h) (i) adding ethyl acetate / heptane (25% by volume of heptane) to neat crystalline Compound I, Form D, and (ii) shaking at 25° C. for 2 days to obtain crystalline heptane solvate of Compound I, Form C; (i) shaking crystalline hemihydrate form C of Compound I in octane at 35° C. for about one week to obtain crystalline octane solvate of Compound I; (j) (i) adding cyclohexane to neat Form D of crystalline Compound I; and (ii) shaking the mixture at 25° C. for 3 days to obtain crystalline cyclohexane solvate Form A of Compound I. (k) (i) adding cyclohexane to crystalline hemihydrate form C of Compound I; and (ii) shaking the mixture at 80° C. for 3 days to obtain crystalline cyclohexane solvate form B of Compound I. (l) (i) adding cyclohexane to crystalline hemihydrate form C of Compound I; and (ii) shaking the mixture at 60° C. for one week to obtain crystalline cyclohexane solvate form C of Compound I. (m) stirring the hemihydrate crystal form C of crystalline Compound I in ethanol at −20° C. to obtain an ethanol solvate of crystalline Compound I; (n) (i) stirring crystalline heptane solvate crystalline Form A of Compound I in water at room temperature for two weeks; (ii) filtering the solid; and (iii) air-drying the solid to obtain crystalline Compound I solvate / hydrate (dried). (o) (i) dissolving crystalline Compound I heptane solvate crystalline Form A in ethanol; (i) adding water (water / ethanol=1.23-3.15); (iii) stirring at 60° C. for 3 days; (iv) filtering the solid; and (v) air-drying the solid to obtain crystalline Compound I solvate / hydrate (dried). (p) (i) adding ethanol / water 50:50 (vol / vol%) to crystalline hemihydrate crystal form C of Compound I; and (ii) stirring at 5° C. to obtain a solvate / hydrate (wet) of crystalline Compound I; (q) (i) mixing ethanol and water in a ratio of 30.8% to 69.2% by volume; (ii) saturating the ethanol / water mixture with L-lysine anhydrous; (iii) saturating the mixture with crystalline hemihydrate form C of Compound I; (iv) adding crystalline hemihydrate form C of Compound I to L-lysine to make a 1:1 molar ratio slurry of Compound I and L-lysine; (v) mixing the slurry for 2 days; (vi) sonicating for an additional 3 hours; and (viii) isolating the solid to obtain crystalline Compound I L-lysine co-crystals. (r) (i) preparing crystalline hemihydrate crystal form C of Compound I and L-arginine in a 1:1 molar ratio; (ii) adding ethanol / water (30.8% by volume to 69.2% by volume ethanol:water); (iii) ball milling the mixture at 7500 RPM for 60 seconds with a 10 second pause for 5 cycles; and (iv) drying the solid at 45° C. in a vacuum oven overnight to obtain crystalline Compound I co-crystal with L-arginine. (s) (i) preparing crystalline hemihydrate crystal form C of Compound I and L-phenylalanine in a 1:1 molar ratio; (ii) adding ethanol / water (30.8% by volume to 69.2% by volume ethanol:water); (iii) ball milling the mixture at 7500 RPM for 5 cycles for 60 seconds with a 10 second pause; and (iv) drying the solid at 45° C. in a vacuum oven overnight to obtain crystalline Compound I co-crystal with L-phenylalanine. (t) (i) preparing crystalline hemihydrate crystal form C of Compound I and succinic acid in a 1:1 molar ratio; (ii) adding ethanol / water (30.8% by volume to 69.2% by volume ethanol:water); (iii) ball milling the mixture at 7500 RPM for 60 seconds with a 10 second pause for 5 cycles; (iv) drying the solid at 45° C. in a vacuum oven overnight; and (v) placing the solid in a humidity chamber at 40° C. and 75% relative humidity to obtain crystalline Compound I succinic acid co-crystal hydrate. (u) (i) preparing crystalline hemihydrate crystal form C of Compound I and succinic acid in a 1:1 molar ratio; (ii) adding ethanol / water (30.8% by volume to 69.2% by volume ethanol:water); (iii) ball milling the mixture at 7500 RPM for 60 seconds with a 10 second pause for 5 cycles; and (iv) drying the solid at 45° C. in a vacuum oven overnight to obtain crystalline Compound I co-crystal with succinic acid. (v) (i) combining crystalline hemihydrate crystal form C of Compound I and methanol; (ii) stirring the mixture; and (iii) isolating the solid to obtain a crystalline methanol solvate / hydrate of Compound I; or (w) (i) dissolving N-[(6R,12R)-6-benzyloxy-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-17-yl]-N-tert-butoxycarbonyl-tert-butylcarbamate in ethanol, (ii) adding 10% Pd / C, (iii) stirring at room temperature under hydrogen, (iv) isolating and evaporating the liquid phase, and (v) dichloromethane. (vi) cooling the solution in an ice bath and treating with trifluoroacetic acid; (viii) stirring at room temperature for 2 hours; (ix) diluting the solution with heptane, evaporating and drying to obtain a solid; (x) dissolving the solid in dichloromethane and diluting with heptane; (xi) stirring the suspension at room temperature; (xii) removing the solid by filtration; and (xiii) concentrating the mother liquor and purifying the resulting solid by reverse phase chromatography to obtain a neat amorphous form of Compound I.

25. Compound I, 【Chemical 333】 or a stereoisomer of Compound I, or a deuterated derivative of Compound I or a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, the method comprising reacting a compound of formula (1): 【Chemical 334】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (1) or a stereoisomer thereof, or a salt of any of the foregoing, to Compound I, or a stereoisomer thereof, or a deuterated derivative of Compound I or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -X1 is selected from OH, OTs, OMs, ONs, and OTf; each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns), or N(Ra)2 is NO2; The method wherein Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

26. The method includes reacting a compound of formula (2): 【Chemical 335】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (2) or a stereoisomer thereof, or a salt of any of the foregoing, to Compound I, or a stereoisomer thereof, or a deuterated derivative of Compound I or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns), or N(Ra)2 is NO2; 26. The method of claim 25, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

27. The method includes reacting a compound of formula (3): 【Chemical 336】 26. The method of claim 25, comprising converting a compound of formula (3), or a stereoisomer thereof, or a deuterated derivative of compound I, or a stereoisomer thereof, or a salt of any of the foregoing, into compound I, or a stereoisomer thereof, or a deuterated derivative of compound I, or a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, wherein Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns).

28. A compound of the following formula (3): 【Chemical 337】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (3) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (2) 【Chemical 338】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (2) or a stereoisomer thereof, or a salt of any of the foregoing, to a compound of formula (3) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (3) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns), or N(Ra)2 is NO2; 28. The method of claim 27, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

29. A compound of the following formula (2): 【Chemical 339】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (2) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (1) 【Chemistry 340】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (1) or a stereoisomer thereof, or a salt of any of the foregoing, to a compound of formula (2) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (2) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -X1 is selected from OTs, OMs, ONs, and OTf; each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns), or N(Ra)2 is NO2; 29. The method of claim 25 or claim 28, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

30. A compound of the following formula (1): 【Chemical 341】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (1) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (4) 【Chemical 342】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (4) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (1) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (1) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns), or N(Ra)2 is NO2; -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz; Rc is selected from Bn, Me, and allyl; 30. The method of claim 25 or 29, wherein -Rd is selected from Ts, Ms, Ns, and Tf.

31. A compound of the following formula (4): 【Chemical 343】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (4) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (5) 【Chemical 344】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (5) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (4) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (4) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns), or N(Ra)2 is NO2; -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz; Rc is selected from Bn, Me, and allyl; 31. The method of claim 30, wherein -Rd is selected from Ts, Ms, Ns, and Tf.

32. A compound of the following formula (5): 【Chemical 345】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (5) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (6) 【Chemical 346】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (6) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (5) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (5) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, each Ra is independently selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns), or N(Ra)2 is NO2; -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz; 32. The method of claim 31 , wherein -Rc is selected from Bn, Me, and allyl.

33. A compound of the following formula (6): 【Chemical 347】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (6) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (7) 【Chemical 348】 or a deuterated derivative or salt thereof, 【Chemical 349】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (8) or a stereoisomer thereof, or a salt of any of the foregoing, to produce a compound of formula (6) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (6) or a stereoisomer thereof, or a salt of any of the foregoing; During the ceremony, each Ra is independently selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns), or N(Ra)2 is NO2; -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz; Rc is selected from Bn, Me, and allyl; 33. The method of claim 32, wherein -Rd is selected from H, Bn, TBS, and TBDPS.

34. A compound of the following formula (7): 【Chemistry 350】 or a deuterated derivative or salt thereof, the compound having the following formula (9): 【Chemistry 351】 or a deuterated derivative or salt thereof, or a deuterated derivative thereof, or a salt of any of the foregoing, During the ceremony, each Ra is independently selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); Rc is selected from Bn, Me, and allyl; 34. The method of claim 33, wherein -Re is selected from Me, Et, n-Pr, i-Pr, and t-Bu.

35. A compound of the following formula (9): 【Chemical 352】 or a deuterated derivative or salt thereof, the compound having the following formula (11): 【Chemical 352】 or a deuterated derivative or salt thereof to a compound of formula (9) or a deuterated derivative or salt thereof, During the ceremony, Rc is selected from Bn, Me, and allyl; 35. The method of claim 34, wherein -Re is selected from Me, Et, n-Pr, i-Pr, and t-Bu.

36. A compound of the following formula (8): 【Chemical 354】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (8) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (13) 【Chemistry 355】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (13) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (8) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (8) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz; - Rd is selected from H, Bn, TBS, and TBDPS; The method of claim 33, wherein Rf is selected from Me, Et, and Bn.

37. Compound I, 【Chemical 356】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (1) or a stereoisomer thereof, or a salt of any of the foregoing, comprising the steps of: 【Chemical 357】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (18) or a stereoisomer thereof, or a salt of any of the foregoing, into Compound I, or a stereoisomer thereof, or a deuterated derivative of a compound of formula (1) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -X is selected from Cl, Br, I, -OSOR, and -SR; -R is selected from Me, -CF3, Ph, and 4-MePh; -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); The method wherein Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

38. The method includes reacting a compound of formula (2a): 【Chemical 358】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (2a) or a stereoisomer thereof, or a salt of any of the foregoing, into Compound I, or a stereoisomer thereof, or a deuterated derivative of a compound of formula (1) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 38. The method of claim 37, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

39. The method comprises reacting a compound of formula (3a): 【Chemical 359】 39. The method of claim 38, comprising converting compound I, or a stereoisomer thereof, or a deuterated derivative of a compound of formula (3a) or a stereoisomer thereof, or a salt of any of the foregoing, into compound I, or a stereoisomer thereof, or a deuterated derivative of a compound of formula (1) or a stereoisomer thereof, or a salt of any of the foregoing, wherein Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns).

40. A compound of the following formula (3a): 【Hua360】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (3a) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (2a) 【Chemistry 361】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (2a) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (3a) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (3a) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 40. The method of claim 39, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

41. A compound of the following formula (2a): 【Chemical 362】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (2a) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (18) 【Chemistry 363】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (18) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (2a) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (2a) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -X is selected from Cl, Br, I, -OSO2R, and -SO2R; -R is selected from Me, -CF3, Ph, and 4-MePh; -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 41. The method of claim 40, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

42. A compound of the following formula (18): 【Chemistry 364】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (18) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (19) 【Chemistry 365】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (19) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (18) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (18) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -X is selected from Cl, Br, I, -OSO2R, and -SO2R; -R is selected from Me, -CF3, Ph, and 4-MePh; -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz; 42. The method of claim 41, wherein -Rd is selected from H, Bn, TBS, and TBDPS.

43. A compound of the following formula (19): 【Chemistry 366】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (19) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (20) 【Chemical 367】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (20) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (19) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (19) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -X is -SO2R, -R is selected from Me, -CF3, Ph, and 4-MePh; -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz; 43. The method of claim 42, wherein -Rd is selected from H, Bn, TBS, and TBDPS.

44. A compound of the following formula (19): 【Chemistry 368】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (19) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (21) 【Chemical 369】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (21) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (19) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (19) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -X is selected from Cl, Br, I, -OSOR, and -SR; -R is selected from Me, -CF3, Ph, and 4-MePh; -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz; 43. The method of claim 42, wherein -Rd is selected from H, Bn, TBS, and TBDPS.

45. A compound of the following formula (21): 【Hua370】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (21) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (22) 【Chemical 371】 or a deuterated derivative or salt thereof, 【Chemical 372】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (23) or a stereoisomer thereof, or a salt of any of the foregoing, to produce a compound of formula (21) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (21) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -X is selected from Cl, Br, I, -OSOR, and -SR; -R is selected from Me, -CF3, Ph, and 4-MePh; -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz; 45. The method of claim 44, wherein -Rd is selected from H, Bn, TBS, and TBDPS.

46. A compound of the following formula (23): 【Chemical 373】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (23) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (24) 【Chemical 374】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (24) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (23) or a salt thereof: During the ceremony, -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz; - Rd is selected from H, Bn, TBS, and TBDPS; The method of claim 45, wherein Rf is selected from Me, Et, and Bn.

47. Compound I, 【Chemical 375】 or a stereoisomer thereof, or a deuterated derivative of Compound I or a stereoisomer thereof, or a salt of any of the foregoing, comprising a compound of formula (32): 【Chemical 376】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (32) or a stereoisomer thereof, or a salt of any of the foregoing, to compound I, or a stereoisomer thereof, or a deuterated derivative of compound I or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns), or N(Ra)2 is NO2; The method wherein Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

48. The method comprises reacting a compound of formula (33): 【Chemical 377】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (33) or a stereoisomer thereof, or a salt of any of the foregoing, to compound I, or a stereoisomer thereof, or a deuterated derivative of compound I or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 48. The method of claim 47, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

49. A compound of the following formula (33): 【Chemical 378】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (33) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (32) 【Chemical 379】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (32) or a stereoisomer thereof, or a salt of any of the foregoing, to a compound of formula (33) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (33) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 49. The method of claim 48, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

50. A compound of the following formula (32): 【Hua380】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (32) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (34) 【Chemistry 381】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (34) or a stereoisomer thereof, into a compound of formula (32) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (32) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns), or N(Ra)2 is NO2; 50. The method of claim 49, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

51. A compound of the following formula (32): 【Chemical 382】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (32) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (36a) 【Chemical 383】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (36a) or a stereoisomer thereof, into a compound of formula (32) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (32) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns), or NRa2 is NO2; 51. The method of claim 50, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

52. A compound of the following formula (36a): 【Chemical 384】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (36a) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (36b) 【Chemistry 385】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (36b) or a stereoisomer thereof, into a compound of formula (36a) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (36a) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns), or NRa2 is NO2; 52. The method of claim 51, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

53. A compound of the following formula (34): 【Chemistry 386】 or a stereoisomer thereof, or a deuterated derivative of the compound of formula (34) or a stereoisomer thereof, is a compound of the following formula (35): 【Chemical 387】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (35) or a stereoisomer thereof, or a salt of any of the foregoing, to a compound of formula (34) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (34) or a stereoisomer thereof, During the ceremony, each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 51. The method of claim 50, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

54. A compound of the following formula (35): 【Chemistry 388】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (35) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (36) 【Chemical 389】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (36) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (35) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (35) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 54. The method of claim 53, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

55. A compound of the following formula (36): 【Chemical 390】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (36) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (37) 【Chemical 391】 or a deuterated derivative or salt thereof, 【Chemical 392】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (38) or a stereoisomer thereof, or a salt of any of the foregoing, to produce a compound of formula (36) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (36) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 55. The method of claim 54, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

56. A compound of the following formula (34): 【Chemical 393】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (34) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (37a) 【Chemical 394】 or a deuterated derivative or salt thereof, 【Chemical 395】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (38) or a stereoisomer thereof, or a salt of any of the foregoing, to produce a compound of formula (34) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (34) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns), or NRa2 is NO2; 54. The method of claim 50 or 53, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

57. A compound of the following formula (32): 【Chemical 396】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (32) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (42) 【Chemical 397】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (42) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (32) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (32) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -X1 is selected from Cl, Br, and I; each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 50. The method of claim 47 or claim 49, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

58. A compound of the following formula (42): 【Chemical 398】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (42) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (43) 【Chemical 399】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (43) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (42) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (42) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -X1 is selected from Cl, Br, and I; each Ra is independently selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 58. The method of claim 57, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

59. A compound of the following formula (43): 【Chemical 400】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (43) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (44) 【Chemistry 401】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (44) or a stereoisomer thereof, or a salt of any of the foregoing, with a compound of formula (45): 【Chemistry 402】 or a deuterated derivative or salt thereof to produce a compound of formula (43), or a stereoisomer thereof, or a deuterated derivative of a compound of formula (43), or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -X1 is selected from Cl, Br, and I; each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 59. The method of claim 58, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

60. A compound of the following formula (44): 【Chemistry 403】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (44) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (47): 【Chemistry 404】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (47) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (44) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (44) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 60. The method of claim 59, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

61. A compound of the following formula (47): 【Chemistry 405】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (47) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (48) 【Chemistry 406】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (48) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (47) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (47) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, each Ra is independently selected from H, tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 61. The method of claim 60, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

62. A compound of the following formula (48): 【Chemistry 407】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (48) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (49) 【Chemistry 408】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (49) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (48) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (48) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 62. The method of claim 61, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

63. A compound of the following formula (49): 【Chemistry 409】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (49) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (50) 【Chemistry 410】 or a deuterated derivative or salt thereof, 【Chemistry 411】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (38) or a stereoisomer thereof, or a salt of any of the foregoing, to produce a compound of formula (49) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (49) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 63. The method of claim 62, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

64. Compound I, 【Chemistry 412】 or a stereoisomer thereof, or a deuterated derivative of compound I or a stereoisomer thereof, or a salt of any of the foregoing, comprising reacting a compound of formula (51): 【Chemistry 413】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (51) or a stereoisomer thereof, or a salt of any of the foregoing, to compound I, or a stereoisomer thereof, or a deuterated derivative of compound I or a stereoisomer thereof, or a salt of any of the foregoing, wherein Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns).

65. The method includes reacting a compound of formula (52): 【Chemistry 414】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (52) or a stereoisomer thereof, or a salt of any of the foregoing, to compound I, or a stereoisomer thereof, or a deuterated derivative of compound I or a stereoisomer thereof, or a salt of any of the foregoing, -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 65. The method of claim 64, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

66. A compound of the following formula (52): 【Chemistry 415】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (52) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (51) 【Chemistry 416】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (51) or a stereoisomer thereof, or a salt of any of the foregoing, to a compound of formula (52) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (52) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 66. The method of claim 65, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

67. The method includes reacting a compound of formula (3a): 【Chemistry 417】 65. The method of claim 64, comprising converting a compound of formula (3a), or a stereoisomer thereof, or a deuterated derivative of a compound of formula (3b), or a stereoisomer thereof, or a salt of any of the foregoing, to compound I, or a stereoisomer thereof, or a deuterated derivative of compound I, or a stereoisomer thereof, or a salt of any of the foregoing, wherein Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns).

68. A compound of the following formula (3a): 【Chemistry 418】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (3a) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (51): 【Chemistry 419】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (51) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (3a) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (3a) or a stereoisomer thereof, or a salt of any of the foregoing, 68. The method of claim 67, wherein Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns).

69. The method includes reacting a compound of formula (2a): 【Chemistry 420】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (2a) or a stereoisomer thereof, or a salt of any of the foregoing, to compound I, or a stereoisomer thereof, or a deuterated derivative of compound I or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 65. The method of claim 64, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

70. A compound of the following formula (2a): 【Chemistry 421】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (2a) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (51): 【Chemistry 422】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (51) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (2a) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (2a) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 70. The method of claim 69, wherein -Rb is selected from benzyl (Bn), naphthylmethyl (Nap), biphenylmethyl, Ac, TFA, and Bz.

71. A compound of the following formula (51): 【Chemistry 423】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (51) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (53) 【Chemistry 424】 71. The method of claim 70, wherein R is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns).

72. A compound of the following formula (53): 【Chemistry 425】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (53) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (54) 【Chemistry 426】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (54) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (53) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (53) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 72. The method of claim 71, wherein -Re is selected from Me, Et, n-Pr, i-Pr, and t-Bu.

73. A compound of the following formula (54): 【Chemistry 427】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (54) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (55) 【Chemistry 428】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (55) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (54) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (54) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -Ra is selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), phthalimide (Phth), acetyl (Ac), trifluoroacetyl (TFA), pivaloyl (Piv), benzoyl (Bz), carbobenzyloxy (Cbz), methanesulfonyl (Ms), and nitrobenzenesulfonyl (Ns); 73. The method of claim 72, wherein -Re is selected from Me, Et, n-Pr, i-Pr, and t-Bu.

74. A compound of the following formula (55): 【Chemistry 429】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (55) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (56) 【Chemistry 430】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (56) or a stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula (55) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (55) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -Re is selected from Me, Et, n-Pr, i-Pr, and t-Bu; The method of claim 73, wherein Rf is selected from Me, Et, and Bn.

75. A compound of the following formula (56): 【Chemistry 431】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (56) or a stereoisomer thereof, or a salt of any of the foregoing, can be prepared by reacting a compound of formula (12) 【Chemistry 432】 or a deuterated derivative or salt thereof, 【Chemistry 433】 or a stereoisomer thereof, or a deuterated derivative of a compound of formula (57) or a stereoisomer thereof, or a salt of any of the foregoing, to produce a compound of formula (56) or a stereoisomer thereof, or a deuterated derivative of a compound of formula (56) or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -Re is selected from Me, Et, n-Pr, i-Pr, and t-Bu; The method of claim 74, wherein Rf is selected from Me, Et, and Bn. 【Request 76】 【Chemical 434】 A compound selected from a stereoisomer thereof, a deuterated derivative of any of the foregoing, and a salt of any of the foregoing. 【Request 77】 【Chemical 435】 A compound selected from a stereoisomer thereof, a deuterated derivative of any of the foregoing, and a salt of any of the foregoing. 【Request 78】 【Chemical 436】 A compound selected from a stereoisomer thereof, a deuterated derivative of any of the foregoing, and a salt of any of the foregoing.

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