Solid forms of modulators of cystic fibrosis transmembrane conductance regulators

Abstract

Disclosed are crystalline forms of Compound I, pharmaceutically acceptable salts, solvates, hydrates, and co-crystals thereof. Also disclosed are pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods of preparing the same.

Description

Summary of the Invention

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 587,829, filed October 4, 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] This article discloses crystalline and amorphous solid forms of cystic fibrosis transmembrane conduction regulator (CFTR) modulators, pharmaceutical compositions thereof, methods for treating cystic fibrosis using any of the foregoing, and methods for preparing crystalline and amorphous forms.

[0003] Cystic fibrosis (CF) is a recessive genetic disorder that affects approximately 83,000 children and adults worldwide. Despite some progress in treatment, there is still no cure for CF.

[0004] In patients with cystic fibrosis (CF), endogenously expressed CFTR mutations in the respiratory epithelium lead to reduced apical anion secretion, resulting in an imbalance of ion and fluid transport. This reduced anion transport causes increased mucus accumulation in the lungs, accompanied by microbial infections, ultimately leading to death in CF patients. In addition to respiratory problems, CF patients often suffer from gastrointestinal issues and pancreatic insufficiency, which can also be fatal if left untreated. Furthermore, most men with cystic fibrosis are infertile, and women with cystic fibrosis experience reduced fertility.

[0005] Sequence analysis of the CFTR gene has revealed a variety of disease-causing mutations (Cutting, GR et al. (1990), Nature 346:366-369; Dean, M et al. (1990), Cell 61:863:870; and Kerem, BS et al. (1989), Science 245:1073-1080; Kerem, BS et al. (1990), Proceedings of the National Academy of Sciences of the United States of America 87:8447-8451). To date, more than 2,000 mutations in the CF gene have been identified; currently, the CFTR2 database contains information on only 322 of these identified mutations, and there is sufficient evidence to define 281 mutations as pathogenic. The most common pathogenic mutation is the deletion of phenylalanine at position 508 of the CFTR amino acid sequence, commonly known as the F508del mutation. This mutation occurs in approximately 70% of cystic fibrosis cases and is associated with severe disease.

[0006] The deletion of residue 508 in CFTR prevents the nascent protein from folding correctly. This causes the mutant protein to be unable to leave the endoplasmic reticulum (ER) and be transported to the plasma membrane. Consequently, the number of CFTR channels in the membrane for anion transport is significantly lower than that observed in cells expressing wild-type CFTR, i.e., cells without the mutant CFTR. In addition to impaired transport, the mutation results in defective channel gating. The reduced number of channels in the membrane, along with the defective gating, leads to reduced anion and fluid transport across the epithelium. (Quinton, PM (1990), FASEB J. 4: 2709-2727). Channels defective due to the F508del mutation remain functional, although less so than wild-type CFTR channels. (Dalemans et al. (1991), Nature London. 354: 526-528; Pasyk and Foskett (1995), Journal of Cell Biochem. 270: 12347-50). Besides F508del, other pathogenic mutations in CFTR that lead to defective transport, synthesis, and / or channel gating can be upregulated or downregulated to alter anion secretion and thus disease progression and / or severity.

[0007] CFTR is a cAMP / ATP-mediated anion channel expressed in various cell types, including absorptive and secretory epithelial cells, where it regulates transmembrane anion flux as well as the activity of other ion channels and proteins. In epithelial cells, normal CFTR function is crucial for maintaining electrolyte transport throughout the body, including respiratory and digestive tissues. CFTR consists of approximately 1480 amino acids encoding a protein composed of tandem repeats of transmembrane domains, each containing six transmembrane helices and a nucleotide-binding domain. Two transmembrane domains are linked to multiple phosphorylation sites via a large polarity regulation (R) domain, thereby regulating channel activity and cellular transport.

[0008] Chloride ion transport is facilitated by ENaC and CFTR present on the apical membrane and Na+ expressed on the outer surface of the cell basolateral surface. + -K + The coordinated activity of the ATPase pump and Cl- channel occurs. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then be transported via Cl- channels. - The channel passively leaves the cell, thus causing mediator transport. Na + / 2Cl - / K + Cotransporter protein, Na + -K +-ATPase pump and basolateral membrane on the basolateral surface K + The channels and the arrangement of CFTRs on the luminal side coordinate chloride ion secretion via the CFTRs on the luminal side. Since water itself may not be able to be actively transported, its transepithelial flow depends on the small transepithelial osmotic gradient generated by the large flow of sodium and chloride.

[0009] Several CFTR-regulating compounds have recently been identified. However, there is still a need for compounds that can treat cystic fibrosis and other CFTR-mediated diseases (and specifically, more severe forms of these diseases) or reduce their severity.

[0010] Solid forms of pharmaceutical compounds have attracted industry attention due to their ease of manufacture, storage, and administration. Depending on their chemical and physical properties, a variety of different solid forms of a particular compound can be envisioned.

[0011] Crystallization form is of interest in the pharmaceutical industry, where control over the crystalline form of an active ingredient may be desirable or even necessary. For compounds intended for use in pharmaceuticals, reproducible methods for producing compounds with a specific crystalline form at high purity are desirable, as different crystalline forms can have different properties. For example, different crystalline forms can have different chemical, physical, and / or pharmaceutical properties. In some embodiments, one or more crystalline forms disclosed herein may exhibit higher levels of purity, chemical stability, and / or physical stability. Certain crystalline forms (e.g., the crystalline free form, crystalline salt, crystalline salt solvate, and crystalline salt hydrate form of Compound I (collectively, the “crystalline forms”)) may exhibit lower hygroscopicity. Therefore, the crystalline forms of this disclosure can provide advantages during the preparation, storage, and handling of pharmaceutical substances. Thus, pharmaceutically acceptable crystalline forms of Compound I may be particularly suitable for producing medicaments for treating CFTR-mediated diseases.

[0012] The amorphous forms of therapeutic compounds may also be of interest in the pharmaceutical industry, where the crystalline form is not particularly bioavailable. Some amorphous forms can improve bioavailability and thus allow for the administration of reduced doses. For some compounds, the amorphous form provides the most biologically accessible form of the therapeutic agent.

[0013] Therefore, one aspect of this disclosure provides the CFTR-regulating compound (R)-7-(bicyclo[1.1.1]pent-1-ylmethyl)-6-((6-(tert-butyl)furano[2,3-b]pyrazin-2-yl)methyl)-16-(2,6-dimethylphenyl)-9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidinia-4(1,3)-benzerocyclononadenosine-5-one 3,3-dioxide (compound I) and its pharmaceutically acceptable salts in solid form (crystalline and amorphous). Compound I can be described as having the following structure:

[0014] I.

[0015] In some embodiments, compound I is in its pure crystalline form A. In some embodiments, compound I is in its pure crystalline form B. In some embodiments, compound I is in its pure crystalline form C. In some embodiments, compound I is in its pure crystalline form D. In some embodiments, compound I is in its pure crystalline form E. In some embodiments, compound I is in its compressed crystalline form A. In some embodiments, compound I is in its compressed crystalline form E. In some embodiments, compound I is in its crystalline form as a solvate of EtOH (compound I). In some embodiments, compound I is in its crystalline form as a solvate of IMeOH (compound IMeOH). In some embodiments, compound I is in its crystalline form as a solvate of NPA (compound I). In some embodiments, compound I is in its crystalline form as a solvate of MeOAc (compound IMeOAc). In some embodiments, compound I is in its crystalline form as a solvate of IMeOAc (compound IMeOAc). In some embodiments, compound I is in its crystalline form as a solvate of IMeOAc (compound IMeOAc). In some embodiments, compound I is in its crystalline form as a solvate of IMeOAc (compound IMeOAc). In some embodiments, compound I is in its crystalline form as a hydrated crystalline form A. In some embodiments, compound I is in its crystalline form as a hydrated crystalline form B. In some embodiments, compound I is in the crystalline form of compound I hydrate form C. In some embodiments, compound I is in the crystalline form of compound I EtOH solvate hydrate. In some embodiments, compound I is in the crystalline form of compound I MeOH solvate hydrate. In some embodiments, compound I is in the crystalline form of compound I IPA solvate hydrate. In some embodiments, compound I is in the crystalline form of compound I MeOAc solvate hydrate.

[0016] In some embodiments, compound I is in an amorphous solid form.

[0017] In some embodiments, compound I is formulated as a solid (e.g., spray-dried) dispersion.

[0018] Other aspects of this disclosure provide pharmaceutical compositions comprising Compound I in any of the pharmaceutically acceptable crystalline forms disclosed herein, said compositions may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier. Still other aspects of this disclosure are methods for treating CFTR-mediated cystic fibrosis, said methods comprising administering to a subject of need Compound I in any of the pharmaceutically acceptable solid forms disclosed herein, optionally as part of a pharmaceutical composition comprising at least one additional component (such as a carrier or another active agent). Further aspects of this disclosure provide methods for preparing a solid form of Compound I disclosed herein.

[0019] Pharmaceutical compositions comprising compound I in solid form as described herein, or amorphous compound I formulated into a solid (e.g., spray-dried) dispersion, and (R)-1-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropyl-2-yl)-1H-indol-5-yl)cyclopropaneformamide (compound II) and / or a pharmaceutically acceptable salt thereof.

[0020] II

[0021] And / or with N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (compound III)

[0022] III

[0023] Or a combination of N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propyl-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (compound III-d).

[0024] III-d.

[0025] Methods for treating cystic fibrosis using compound I in solid form or formulated as a solid (e.g., spray-dried) dispersion, as described herein, are also disclosed. In some embodiments, compound I in solid form or formulated as a solid (e.g., spray-dried) dispersion, as disclosed herein, is administered together with compound II and / or compound III or compound III-d in a single pharmaceutical composition or in multiple compositions to treat cystic fibrosis. In some embodiments, amorphous compound I, as described herein, in solid form or formulated as a solid (e.g., spray-dried) dispersion, in combination with (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol (compound IV), a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, is used to treat cystic fibrosis. In some embodiments, amorphous compound I, as described herein, in solid form or formulated as a solid (e.g., spray-dried) dispersion, in combination with (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol (compound V), a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, is used to treat cystic fibrosis.

[0026] Another aspect of this disclosure provides a method for preparing compound I disclosed herein in solid form.

[0027] Another aspect of the invention provides compound I in solid form or formulated as a solid (e.g., spray-dried) dispersion for use in any of the methods described herein. Attached Figure Description

[0028] Figure 1 The XRPD spectrum of compound I in its pure form A is provided.

[0029] Figure 2 TGA curves for pure form A of crystalline compound I are provided.

[0030] Figure 3 DSC analysis of compound I in its pure form A is provided.

[0031] Figure 4 Provides compound I in pure form A 13 CssNMR spectrum.

[0032] Figure 5The XRPD spectrum of compound I in its pure form B is provided.

[0033] Figure 6 Provided compound I in pure form B 13 CssNMR spectrum.

[0034] Figure 7 The XRPD spectrum of compound I in its pure form C is provided.

[0035] Figure 8 Provides the TGA curves for compound I in its pure form, C.

[0036] Figure 9 DSC analysis of compound I in its pure form C is provided.

[0037] Figure 10 Provides compound I in pure form C 13 CssNMR spectrum.

[0038] Figure 11 Provided compound I in pure form D 13 CssNMR spectrum.

[0039] Figure 12 XRPD spectra of compound I in its pure form E are provided.

[0040] Figure 13 TGA curves for compound I in its pure form E are provided.

[0041] Figure 14 DSC analysis of compound I in its pure form E is provided.

[0042] Figure 15 Provides compound I in pure form E 13 CssNMR spectrum.

[0043] Figure 16 XRPD spectra of compound I in its compressed form E are provided.

[0044] Figure 17 Provides the compressed form E of compound I 13 CssNMR spectrum.

[0045] Figure 18 The XRPD spectrum of compound I in compressed form A is provided.

[0046] Figure 19 Provides the compressed form A of compound I 13 CssNMR spectrum.

[0047] Figure 20 XRPD spectra of compound I, EtOH solvate form B, are provided.

[0048] Figure 21 TGA curves for compound I, EtOH solvate form B, are provided.

[0049] Figure 22 DSC analysis of compound I in its EtOH solvate form B is provided.

[0050] Figure 23 Provided compound I EtOH solvate form B 13 CssNMR spectrum.

[0051] Figure 24 XRPD spectra of compound I MeOH solvate are provided.

[0052] Figure 25 Provides compound I MeOH solvate 13 CssNMR spectrum.

[0053] Figure 26 XRPD spectra of the solvate of compound I NPA are provided.

[0054] Figure 27 Provides the solvation of compound I NPA 13 CssNMR spectrum.

[0055] Figure 28 XRPD spectra of compound I MeOAc solvate form A are provided.

[0056] Figure 29 TGA curves for compound I MeOAc solvate form A are provided.

[0057] Figure 30 DSC analysis of compound I MeOAc solvate form A is provided.

[0058] Figure 31 Provides the solvate form A of compound I MeOAc 13 CssNMR spectrum.

[0059] Figure 32 XRPD spectra of compound I MeOAc solvate form B are provided.

[0060] Figure 33 TGA curves for compound I MeOAc solvate form B are provided.

[0061] Figure 34 DSC analysis of compound I MeOAc solvate form B is provided.

[0062] Figure 35 Provided the solvate form B of compound I MeOAc 13 CssNMR spectrum.

[0063] Figure 36 XRPD spectra of compound I MeOAc solvate form C are provided.

[0064] Figure 37 Provides the solvate form of compound I MeOAc C 13 CssNMR spectrum.

[0065] Figure 38 XRPD spectra of compound I in hydrate form A are provided.

[0066] Figure 39 Provided the hydrate form A of compound I 13 CssNMR spectrum.

[0067] Figure 40 XRPD spectra of compound I in hydrate form B are provided.

[0068] Figure 41 Provided the hydrated form of compound I, B. 13 CssNMR spectrum.

[0069] Figure 42 XRPD spectra of compound I in its hydrated form C are provided.

[0070] Figure 43 Provided the hydrate form of compound I, C 13 CssNMR spectrum.

[0071] Figure 44 XRPD spectra of the solvate hydrate of compound I EtOH are provided.

[0072] Figure 45 Provided the solvate hydrate of compound I EtOH 13 CssNMR spectrum.

[0073] Figure 46 XRPD spectra of the solvate hydrate of compound I MeOH are provided.

[0074] Figure 47 Provides the solvate hydrate of compound I MeOH 13 CssNMR spectrum.

[0075] Figure 48 XRPD spectra of compound I IPA solvate hydrate are provided.

[0076] Figure 49 Provided the solvate hydrate of compound I IPA 13 C CPMAS spectrum.

[0077] Figure 50 XRPD spectra of the solvate hydrate of compound I MeOAc are provided.

[0078] Figure 51 Provided the solvate hydrate of compound I MeOAc 13 CssNMR spectrum.

[0079] Figure 52 The XRPD spectrum of amorphous compound I is provided.

[0080] Figure 53 Provided amorphous compound I 13 CssNMR spectrum.

[0081] Figure 54 The XRPD spectrum of compound I SDD 1A is provided.

[0082] Figure 55 Provided compound I SDD 1A 13 CssNMR spectrum.

[0083] Figure 56 DSC analysis of compound I SDD 1A is provided.

[0084] Figure 57 The XRPD spectrum of compound I SDD 1B is provided.

[0085] Figure 58 DSC analysis of compound ISDD 1B is provided.

[0086] Figure 59 The XRPD spectrum of compound I SDD 1C is provided.

[0087] Figure 60 DSC analysis of compound I SDD 1C is provided.

[0088] Figure 61 The XRPD spectrum of compound I SDD 1D is provided.

[0089] Figure 62 DSC analysis of compound I SDD 1D is provided.

[0090] Figure 63 The XRPD spectrum of compound I SDD 1E is provided.

[0091] Figure 64DSC analysis of compound I SDD 1E is provided.

[0092] definition

[0093] As used throughout this disclosure, “Compound I” refers to CFTR corrector (R)-7-(bicyclo[1.1.1]pent-1-ylmethyl)-6-((6-(tert-butyl)furano[2,3-b]pyrazin-2-yl)methyl)-16-(2,6-dimethylphenyl)-9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidinia-4(1,3)benzylcyclononano-5-one 3,3-dioxide, which can be described as having the following structure:

[0094] I.

[0095] Compound I and methods for preparing and using compound I are disclosed in PCT / US2023 / 017627 (incorporated herein by reference).

[0096] As used throughout this disclosure, "compound II" refers to (R)-1-(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropyl-2-yl)-1H-indol-5-yl)cyclopropaneformamide, which can be described as having the following structure:

[0097] II.

[0098] Compound II may be in the form of a pharmaceutically acceptable salt. Compound II and methods for preparing and using Compound II are disclosed in WO 2010 / 053471, WO 2011 / 119984 and WO 2015 / 160787, each of which is incorporated herein by reference.

[0099] As used throughout this disclosure, "compound III" refers to N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (also known as N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide), which can be described as having the following structure:

[0100] III.

[0101] Compound III may also be in the form of a pharmaceutically acceptable salt. Compound III and methods for preparing and using Compound III are disclosed in WO 2006 / 002421, WO 2007 / 079139 and WO 2010 / 019239, each of which is incorporated herein by reference.

[0102] In some embodiments, the 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) 3 (propane-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide, the compound can be described as having the following structure:

[0103] III-d.

[0104] Compound III-d can be in the form of a pharmaceutically acceptable salt. Compound III-d and methods for its preparation and use are disclosed in WO 2012 / 158885 and WO 2014 / 078842, which are incorporated herein by reference.

[0105] As used throughout this disclosure, “compound IV” refers to (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol. Compound IV may also be in the form of deuterated derivatives or pharmaceutically acceptable salts. Methods for preparing and using compound IV, its deuterated derivatives, and pharmaceutically acceptable salts are described in WO 2022 / 032068, which is incorporated herein by reference.

[0106] As used throughout this disclosure, “compound V” refers to (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadecan-1(18),2,4,14,16-pentaen-6-ol. Compound V may also be in the form of deuterated derivatives or pharmaceutically acceptable salts. Methods for preparing and using compound V, its deuterated derivatives, and pharmaceutically acceptable salts are described in WO 2022 / 109573, which is incorporated herein by reference.

[0107] As used in this article, "CFTR" refers to the transmembrane conduction regulator of cystic fibrosis.

[0108] As used herein, the terms “CFTR modulator” and “CFTR-regulating compound” are interchangeable terms for compounds that increase the activity of CFTR. Increased activity caused by CFTR modulators includes, but is not limited to, compounds that correct, enhance, stabilize, and / or amplify CFTR.

[0109] As used herein, the term "CFTR corrector" refers to a compound that promotes the processing and transport of CFTR to increase the amount of CFTR at the cell surface. Compounds I and II disclosed herein are CFTR correctors.

[0110] As used herein, the term "CFTR enhancer" refers to a compound that increases the channel activity of CFTR proteins located on the cell surface, thereby enhancing ion transport. Compounds III, III-d, IV, and V disclosed herein are CFTR enhancers. It should be understood that when this document provides a description of a combination of compound I with other specified CFTR regulators, references to "compound III or III-d" in connection with said combination mean either compound III or compound III-d, and not both, included in said combination.

[0111] As used herein, the terms “active pharmaceutical ingredient” (“API”) or “therapeutic agent” refer to bioactive compounds.

[0112] It should be understood that certain compounds of the present invention may exist as individual stereoisomers or enantiomers and / or mixtures of those stereoisomers or enantiomers. As used in the chemical structures disclosed herein, the "wedge" shape of the stereo atoms ( ) or "hash" The ) bond indicates the chiral center of known absolute stereochemistry (i.e., a stereoisomer). As used in the chemical structures disclosed herein, the "wavy" bond with the stereoatom ( ) indicates the chiral center of unknown absolute stereochemistry (i.e., a stereoisomer). As used in the chemical structures disclosed herein, the "wavy" bond with the double-bonded carbon ( () indicates a mixture of E / Z isomers. As used in the chemical structures disclosed herein, with respect to stereoatoms. (“straight”) bonds indicate the presence of mixtures (e.g., racemates or enrichments). As used herein, with two carbon atoms in a double bond... ("Straight") bonds indicate that double bonds have the E / Z stereochemistry as shown in the diagram. As used in the chemical structures disclosed herein, (That is, the "wavy" line perpendicular to the "straight" bond of group "A") indicates that group "A" is a substituent whose attachment point is located at the end of the bond that terminates at the "wavy" line.

[0113] As used herein, the term "pharmaceutically acceptable solid form" refers to the solid form of Compound I of this disclosure, including crystalline forms of Compound I (e.g., free crystalline form, crystalline salt, crystalline salt solvate, and crystalline salt hydrate), which are non-toxic and suitable for use in pharmaceutical compositions. As used herein, the term "pharmaceutically acceptable solid form" also refers to the amorphous form of Compound I and solid dispersions comprising said amorphous form.

[0114] The terms “patient” and “subject” are used interchangeably and refer to animals including humans.

[0115] The terms “effective dose” and “effective amount” are used interchangeably herein and refer to the amount of compound that produces the desired effect of administering the compound (e.g., improving symptoms of CF or CF, or reducing the severity of symptoms of CF or CF). The exact amount of effective dose will depend on the therapeutic purpose and will be determined by someone skilled in the art using known techniques (see, for example, Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0116] As used herein, the terms “treatment”, “treating,” etc., generally refer to improvement of a subject’s CF or one or more of its symptoms, or reduction of the severity of CF or one or more of its symptoms. As used herein, “treatment” includes, but is not limited to, the following: increased growth in the subject, increased weight gain, reduced pulmonary mucus, improved pancreatic and / or liver function, relief of chest infection, and / or relief of cough or shortness of breath. Improvement in any of these symptoms or reduction in their severity can be readily assessed using standard methods and techniques known in the art.

[0117] As used herein, when referring to two or more compounds, agents or other active pharmaceutical ingredients, the term “in combination with” means that the two or more compounds, agents or active pharmaceutical ingredients are administered to the patient before, at the same time as or after each other.

[0118] When used in conjunction with the dosage, amount, or weight percentage of an ingredient in a composition or dosage form, the terms "about" and "approximately" include a specified dosage, amount, or weight percentage, or a range of said dosage, amount, or weight percentage, that would be considered by a person of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dosage, amount, or weight percentage. The terms "about" and "approximately" may refer to an acceptable error in a particular value as determined by a person of ordinary skill in the art, depending in part on how said value is measured or determined. 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 or range. In some embodiments, the terms "about" and "approximately" mean within 10% of a given value or range.

[0119] As used herein, the term "amorphous" refers to a solid material that does not possess long-range order in the positions of its molecules. Amorphous solids are typically in which molecules are arranged in a random manner, such that there is no definite arrangement (e.g., molecular packing) and no long-range order, unlike glasses or supercooled liquids. Amorphous solids are typically isotropic, i.e., exhibiting similar properties in all directions, and do not have a definite melting point. Instead, they typically exhibit a glass transition temperature, which marks the transition from a glassy amorphous state to a supercooled liquid amorphous state upon heating. In some embodiments, the solid material may comprise an amorphous compound, and said material may, for example, be characterized by the lack of sharp characteristic crystalline peaks in its XRPD spectrum (i.e., as determined by XRPD, said material is not crystalline but amorphous). Instead, one or more broad peaks (e.g., halos) may appear in the XRPD spectrum of said material. Broad peaks are a characteristic of amorphous solids. For a comparison of the XRPDs of amorphous and crystalline materials, see US 2004 / 0006237. Other techniques, such as solid-state NMR, can also be used to characterize crystalline or amorphous forms.

[0120] As used herein, the terms “crystalline form,” “crystallinity,” and “form” are used interchangeably to refer to a crystal structure (or polymorph) having a specific molecular packing arrangement in a crystal lattice. Crystallinity can be determined by the presence or absence of a specific salt, solvate, or hydrate, and by one or more characterization techniques, including, for example, X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, and... 13 C solid-state nuclear magnetic resonance (C 13X-ray powder diffraction (XPD) can be used to identify and distinguish these crystalline forms from each other. Therefore, as used herein, the terms "crystalline form A of compound I" and "crystalline potassium salt form A of compound I" refer to unique crystalline forms that can be identified and distinguished from each other by the presence or absence of potassium alone and by other characterization techniques. In some embodiments, the novel crystalline form is characterized by an X-ray powder diffraction pattern having one or more signals at a specified 2θ value (º2θ).

[0121] As used herein, the term "free form" refers to the non-ionized version of a compound as a solid. Examples of free forms include free bases and free acids.

[0122] As used herein, the term "pure form" refers to the unsolvated and unhydrated free form of a compound in a solid state.

[0123] As used herein, the term "compressed form" refers to a crystalline form that has been mechanically compressed to become a different crystalline form.

[0124] As used herein, the term "solvent" refers to a crystalline form comprising one or more molecules of a compound of the present disclosure and one or more molecules of one or more solvents incorporated into the crystal lattice in stoichiometric or non-stoichiometric amounts. When the solvent is water, the solvate is referred to as a "hydrate". Other non-limiting examples of solvate forms include solvate forms derived from ethanol ("EtOH solvate"), methanol ("MeOH solvate"), n-propanol ("NPA solvate"), methyl acetate ("MeOAc solvate"), and isopropanol ("IPA solvate").

[0125] In some embodiments, the solid material may comprise a mixture of crystalline solids and amorphous solids. Solid materials comprising amorphous compounds may also contain, for example, up to 30% crystalline solids. In some embodiments, solid materials prepared to comprise amorphous compounds may also contain, for example, up to 25%, 20%, 15%, 10%, 5%, or 2% crystalline solids. In embodiments where the solid material comprises a mixture of crystalline and amorphous solids, characterization data such as XRPD and ssNMR may include indicators for both crystalline and amorphous solids. In some embodiments, the crystalline form of this disclosure may contain up to 30% amorphous compound. In some embodiments, the crystalline formulation of compound I may contain up to 25%, 20%, 15%, 10%, 5%, or 2% amorphous solids.

[0126] As used herein, the term "substantially amorphous" refers to a solid material having little or no long-range order in the positions of its molecules. For example, a substantially amorphous material has less than 15% crystallinity (e.g., less than 10%, less than 5%, or less than 2%). It should also be noted that the term "substantially amorphous" includes the descriptive term "amorphous," which refers to a material that does not have (0%) crystallinity.

[0127] 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%, less than 5%, or less than 2%). It should also be noted that the term "substantially crystalline" includes the descriptive term "crystalline," which refers to a material that is 100% crystalline.

[0128] As used herein, a crystalline form is considered "substantially pure" when it constitutes, by weight, 90% or more of the total amount of all solid forms of a given compound in a sample, as determined by a method according to this technique (e.g., quantitative XRPD). In some embodiments, a solid form is considered "substantially pure" when it constitutes, by weight, 95% or more of the total amount of all solid forms in a sample. In some embodiments, a solid form is considered "substantially pure" when it constitutes, by weight, 99% or more of the total amount of all solid forms in a sample.

[0129] As used herein, the term "XRPD" refers to the analytical characterization method of X-ray powder diffraction. The XRPD patterns disclosed herein are recorded under ambient conditions using a diffractometer with transmission or reflection geometry.

[0130] As used herein, the term “ambient conditions” refers to room temperature, outdoor conditions, and uncontrolled humidity conditions. The terms “room temperature” and “ambient temperature” refer to 15°C to 30°C.

[0131] As used herein, the terms “X-ray powder diffraction pattern,” “X-ray powder diffraction spectrum,” and “XRPD spectrum” are interchangeable to refer to experimentally obtained spectra plotting the position of the signal (on the x-axis) relative to the signal intensity (on the y-axis).

[0132] As used herein, “signal” or “peak” refers to a point in an XRPD spectrum where the intensity, if measured in count, is at a local maximum. An XRPD peak is identified by the angle value measured in degrees 2θ (° 2θ) that it is plotted on the x-axis of the X-ray powder diffraction pattern, which may be expressed, for example, as “signal at… degrees 2θ”, “signal at [one] 2θ value of…” and / or “signal selected from at least… 2θ values ​​of…”.

[0133] The repeatability of the measured angle values ​​is within ±0.2° 2θ, that is, the angle values ​​can be at the listed angle values ​​+0.2 degrees 2θ, at the angle values ​​-0.2 degrees 2θ, or at any value between these two endpoints (angle values ​​+0.2 degrees 2θ and angle values ​​-0.2 degrees 2θ).

[0134] Those skilled in the art will recognize that one or more signals (or peaks) in an XRPD spectrum may overlap and may not be apparent to the naked eye, for example. In fact, those skilled in the art will recognize that several industry-recognized methods are capable of and suitable for determining the presence of a signal in the spectrum, such as Rietveld refinement.

[0135] The terms “signal intensity” and “peak intensity” are used interchangeably to refer to the relative signal intensity within a given X-ray powder diffraction pattern. Factors that can affect the relative signal or peak intensity include sample thickness and preferred orientation (e.g., non-random distribution of crystalline particles).

[0136] As used herein, an X-ray powder diffraction pattern is “substantially similar to the pattern in [specific] pattern” when at least 90% (e.g., at least 95%, at least 98%, or at least 99%) of the signal overlaps in two diffraction patterns. In determining “substantially similar,” those skilled in the art will understand that even for the same crystalline form, the intensity and / or signal position in an XRPD diffraction pattern can vary. Therefore, those skilled in the art will understand that the maximum signal value (in degrees 2θ) in an XRPD diffraction pattern generally means that the value was identified as ± 0.2 degrees 2θ of the reported value, which is an industry-recognized variance.

[0137] As used herein, the term “X-ray powder diffraction pattern with signal at a 2θ value” refers to an XRPD pattern containing X-ray reflection positions (degrees 2θ) as measured and observed in an X-ray powder diffraction experiment.

[0138] As used herein, the term "TGA" refers to thermogravimetric analysis, and "TGA / DSC" refers to thermogravimetric analysis and differential scanning calorimetry.

[0139] As used herein, the term "DSC" refers to the analytical method of differential scanning calorimetry.

[0140] As used herein, the term "ssNMR" refers to the analytical method of solid-state nuclear magnetic resonance (NMR).

[0141] As used in this article, the term "CPMAS" refers to Cross-Polarized Magic Angle Rotation NMR.

[0142] As used herein, the term "solvent" means any liquid that is at least partially soluble in the product (product solubility > 1 g / L).

[0143] As used herein, the term "glass transition temperature" or "T" refers to... g "" refers to a temperature above which a hard and brittle "glassy" amorphous solid becomes sticky or rubbery.

[0144] As used herein, the terms "melting temperature," "melting point," or "T" are used interchangeably. m "" refers to the temperature at which the solid and liquid states of a material are in equilibrium.

[0145] As used herein, the term "dispersion" refers to a dispersion system in which one substance (i.e., the dispersed phase) is distributed in discrete units throughout a second substance (the continuous phase or medium). The size of the dispersed phase can vary significantly (e.g., from nanometer-sized to several micrometer-sized colloidal particles). Typically, the dispersed phase can be a solid, liquid, or gas. In the case of a solid dispersion, both the dispersed phase and the continuous phase are solids. In pharmaceutical applications, solid dispersions may in particular include crystalline drugs in amorphous polymers; amorphous drugs in amorphous polymers; amorphous drugs dispersed in amorphous drugs; or alternatively, amorphous drugs dispersed in one or more excipients. In some embodiments, a solid dispersion comprises a polymer constituting the dispersed phase and a drug constituting the continuous phase. Alternatively, a solid dispersion comprises a drug constituting the dispersed phase and a polymer constituting the continuous phase.

[0146] Treatment

[0147] Compound I, present in any of the pharmaceutically acceptable crystalline forms disclosed herein, acts as a CFTR regulator, i.e., it regulates CFTR activity in vivo. Individuals with mutations in the gene encoding CFTR may benefit from receiving a CFTR regulator. CFTR mutations may affect the amount of CFTR, i.e., the number of CFTR channels at the cell surface, or said mutations may affect CFTR function, i.e., the functional ability of each channel to open and transport ions. Mutations affecting the amount of CFTR include those causing defects in synthesis (Class I defects), those causing defects in processing and transport (Class II defects), those causing reduced CFTR synthesis (Class V defects), and those reducing the surface stability of CFTR (Class VI defects). Mutations affecting CFTR function include those causing defects in gating (Class III defects) and those causing defects in conduction (Class IV defects). Some CFTR mutations exhibit characteristics of multiple classes. Certain mutations in the CFTR gene lead to cystic fibrosis.

[0148] Therefore, in some embodiments, the present invention provides a method for treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms, the method comprising administering to the patient an effective amount of Compound I in any of the pharmaceutically acceptable solid forms disclosed herein, alone or in combination with another active ingredient, such as another CFTR modulator. In some embodiments, the patient has an F508del / minimum function (MF) genotype, an F508del / F508del genotype (homozygous for the F508del mutation), an F508del / gated genotype, or an F508del / residual function (RF) genotype. In some embodiments, the patient is heterozygous and has an F508del mutation. In some embodiments, the patient is homozygous for the N1303K mutation.

[0149] In some embodiments, the present invention provides a method for treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms, the method comprising administering to the patient an effective amount of compound I in its pure form A of crystalline compound I.

[0150] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I in its pure form B of crystalline compound I.

[0151] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I in its pure crystalline form C.

[0152] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I in its pure form D of crystalline compound I.

[0153] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I in its pure form E of crystalline compound I.

[0154] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I in compressed form A of crystalline compound I.

[0155] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I in compressed form E of crystalline compound I.

[0156] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I in the form of a crystalline compound I EtOH solvate B.

[0157] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I, a crystalline compound I MeOH solvate.

[0158] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I, a crystalline compound I NPA solvate.

[0159] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I in the form of a crystalline compound I MeOAc solvate A.

[0160] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I in the form of a crystalline compound I MeOAc solvate B.

[0161] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I in the form of a crystalline compound I MeOAc solvate C.

[0162] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I in the hydrated form of crystalline compound I.

[0163] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I in the hydrated form of crystalline compound I.

[0164] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I in the hydrated form of crystalline compound I C.

[0165] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I, which is a crystalline compound I EtOH solvate hydrate.

[0166] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I, which is a crystalline compound I, a MeOH solvate hydrate.

[0167] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I, which is a crystalline compound I, a solvate hydrate of compound I.

[0168] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I, which is a crystalline compound I MeOAc solvate hydrate.

[0169] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms includes administering to the patient an effective amount of compound I, which is amorphous.

[0170] In some embodiments, a method of treating a patient with cystic fibrosis, reducing its severity, or treating its symptoms comprises administering to the patient an effective amount of compound I in the form of a solid (e.g., spray-dried) dispersion.

[0171] Combination therapy

[0172] One aspect disclosed herein provides a method for treating cystic fibrosis and other CFTR-mediated diseases in combination with compound I, which is any of the pharmaceutically acceptable solid forms disclosed herein, or amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, and other pharmaceutically active agents, including CFTR modifiers. In some embodiments, compound I, which is any of the pharmaceutically acceptable solid forms disclosed herein, or amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, may be administered in combination with at least one additional active pharmaceutical ingredient (such as a CFTR modifier). In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR corrector. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR enhancer. In some embodiments, the method of treating cystic fibrosis and other CFTR-mediated diseases with compound I, which is any of the pharmaceutically acceptable solid forms disclosed herein, includes combination with at least two additional active pharmaceutical ingredients, one of which is a CFTR corrector and the other of which is a CFTR enhancer.

[0173] In some embodiments, at least one additional active agent is selected from mucolytics, bronchodilators, antibiotics, anti-infectives, and anti-inflammatory agents.

[0174] In some embodiments, at least one additional active agent is selected from (a) compound IV or compound V, deuterated derivatives of compound IV or compound V, and pharmaceutically acceptable salts of compound IV, compound V, and their deuterated derivatives; and optionally (b) compound II and its pharmaceutically acceptable salts. Thus, in some embodiments, the combination therapy provided herein comprises compound I in any of the pharmaceutically acceptable crystalline forms disclosed herein, or amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, and an additional active agent selected from compound IV or V, their deuterated derivatives, and pharmaceutically acceptable salts. In some embodiments, the combination optionally includes compound II. In some embodiments, the combination therapy provided herein comprises at least one compound I selected in any of the pharmaceutically acceptable solid forms disclosed herein, or amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, and at least one compound selected from compound IV or compound V and their pharmaceutically acceptable salts, and at least one compound selected from compound II and its pharmaceutically acceptable salts.

[0175] In some embodiments, at least one additional active pharmaceutical ingredient is selected from (a) compound II and its pharmaceutically acceptable salts; and (b) compound III or compound III-d and its pharmaceutically acceptable salts. Therefore, in some embodiments, the combination therapy provided herein comprises compound I in any of the pharmaceutically acceptable crystalline forms disclosed herein, or amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, and at least one compound selected from compound II, (compound III or III-d), and its pharmaceutically acceptable salts. In some embodiments, the combination therapy provided herein comprises at least one compound I in any of the pharmaceutically acceptable solid forms disclosed herein, or amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, and at least one compound selected from compound III or III-d and / or its pharmaceutically acceptable salts.

[0176] In some embodiments, at least one compound I selected from any of the pharmaceutically acceptable solid forms disclosed herein, or a compound I formulated as a solid (e.g., spray-dried) dispersion, is administered in combination with at least one compound selected from compound II and its pharmaceutically acceptable salts. In some embodiments, at least one compound I selected from any of the pharmaceutically acceptable solid forms disclosed herein, or a compound I formulated as a solid (e.g., spray-dried) dispersion, is administered in combination with at least one compound selected from compound III and its pharmaceutically acceptable salts. In some embodiments, at least one compound I selected from any of the pharmaceutically acceptable solid forms disclosed herein, or a compound I formulated as a solid (e.g., spray-dried) dispersion, is administered in combination with at least one compound selected from compound III-d and its pharmaceutically acceptable salts. In some embodiments, at least one compound I selected from any of the pharmaceutically acceptable solid forms disclosed herein, or a compound I formulated as a solid (e.g., spray-dried) dispersion, is administered in combination with compound II or its pharmaceutically acceptable salts and at least one compound selected from compound III and its pharmaceutically acceptable salts. In some embodiments, at least one compound I selected from any of the pharmaceutically acceptable solid forms disclosed herein, or an amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, is administered in combination with at least one compound selected from compound II and its pharmaceutically acceptable salt, and at least one compound selected from compound III-d and its pharmaceutically acceptable salt.

[0177] In some embodiments, at least one compound I selected from any of the pharmaceutically acceptable solid forms disclosed herein, or an amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, is administered in an amount from 2 mg to 1000 mg.

[0178] In some embodiments, at least one compound I selected from any of the pharmaceutically acceptable solid forms disclosed herein, or an amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, is administered in a first pharmaceutical composition; at least one compound selected from compound II and its pharmaceutically acceptable salts is administered in a second pharmaceutical composition; and at least one compound selected from compound III, compound III-d, compound IV, compound V, and pharmaceutically acceptable salts of compounds III, III-d, IV, and V is administered in a third pharmaceutical composition.

[0179] In some embodiments, at least one compound I selected from any of the pharmaceutically acceptable solid forms disclosed herein, or an amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, is administered in the first pharmaceutical composition; at least one compound selected from compounds IV or V and their pharmaceutically acceptable salts is administered in the second pharmaceutical composition.

[0180] In some embodiments, at least one compound selected from any of the pharmaceutically acceptable solid forms disclosed herein, or an amorphous compound I formulated as a solid dispersion, is administered in the first pharmaceutical composition; at least one compound selected from compound III or III-d and their pharmaceutically acceptable salts is administered in the second pharmaceutical composition.

[0181] In some embodiments, at least one compound I selected from any of the pharmaceutically acceptable solid forms disclosed herein, or an amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, is administered in a first pharmaceutical composition; and at least one compound selected from compounds IV or V and their pharmaceutically acceptable salts, and optionally at least one compound selected from compounds II and their pharmaceutically acceptable salts, is administered in a second pharmaceutical composition. In some embodiments, at least one compound I selected from any of the pharmaceutically acceptable solid forms disclosed herein, or an amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, is administered in a first pharmaceutical composition; and (a) at least one compound selected from compounds IV, V and their pharmaceutically acceptable salts, and (b) at least one compound selected from compounds II and their pharmaceutically acceptable salts, is administered in a second pharmaceutical composition.

[0182] In some embodiments, at least one compound I selected from any of the pharmaceutically acceptable solid forms disclosed herein, or an amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, is administered in a first pharmaceutical composition; and at least one compound selected from compound II and its pharmaceutically acceptable salts, and at least one compound selected from compound III or III-d and its pharmaceutically acceptable salts, is administered in a second pharmaceutical composition. In some embodiments, the second pharmaceutical composition comprises half a daily dose of the at least one compound selected from compound III, III-d, and its pharmaceutically acceptable salts, and the other half of the at least one compound selected from compound III, III-d, and its pharmaceutically acceptable salts is administered in a third pharmaceutical composition.

[0183] Any suitable pharmaceutical formulation may be used for compound I (either in the pharmaceutically acceptable solid form disclosed herein or formulated as a solid (e.g., spray-dried) dispersion), compound II, compound III, compound III-d, and their pharmaceutically acceptable salts. Some exemplary pharmaceutical compositions for compound II and its pharmaceutically acceptable salts are found in WO 2011 / 119984 and WO 2014 / 014841, which are incorporated herein by reference. Exemplary pharmaceutical compositions for compound III and its pharmaceutically acceptable salts are found in WO 2007 / 134279, WO2010 / 019239, WO 2011 / 019413, WO 2012 / 027731, and WO 2013 / 130669, and exemplary pharmaceutical compositions for compound III-d and its pharmaceutically acceptable salts are found in US 8,865,902, US 9,181,192, US 9,512,079, WO 2017 / 053455, and WO 2018 / 080591, all of which are incorporated herein by reference. Exemplary formulations of compounds IV and V, their deuterated derivatives, and pharmaceutically acceptable salts are found in WO2022 / 032068 and WO 2022 / 109573, both of which are incorporated herein by reference.

[0184] In some embodiments, the solid form of compound I used in the combination therapy of the present invention is compound I in its pure form A.

[0185] In some embodiments, the solid form of compound I used in the combination therapy of the present invention is compound I in its pure form B.

[0186] In some embodiments, the solid form of compound I used in the combination therapy of the present invention is the pure form C of compound I.

[0187] In some embodiments, the solid form of compound I used in the combination therapy of the present invention is compound I in its pure form D.

[0188] In some embodiments, the solid form of compound I used in the combination therapy of the present invention is the pure form E of compound I.

[0189] In some embodiments, the solid form of compound I used in the combination therapy of the present invention is compound I compressed form A.

[0190] In some embodiments, the solid form of compound I used in the combination therapy of the present invention is compound I compressed form E.

[0191] In some embodiments, the solid form of compound I in the combination therapy of the present invention is compound IEtOH solvate form B. In some embodiments, the solid form of compound I in the combination therapy of the present invention is compound I MeOH solvate. In some embodiments, the solid form of compound I in the combination therapy of the present invention is compound I NPA solvate. In some embodiments, the solid form of compound I in the combination therapy of the present invention is compound I MeOAc solvate form A. In some embodiments, the solid form of compound I in the combination therapy of the present invention is compound I MeOAc solvate form B. In some embodiments, the solid form of compound I in the combination therapy of the present invention is compound I MeOAc solvate form C. In some embodiments, the solid form of compound I in the combination therapy of the present invention is compound I hydrate form A. In some embodiments, the solid form of compound I in the combination therapy of the present invention is compound I hydrate form B. In some embodiments, the solid form of compound I in the combination therapy of the present invention is compound I hydrate form C. In some embodiments, the solid form of compound I in the combination therapy of the present invention is compound I EtOH solvate hydrate. In some embodiments, the solid form of compound I in the combination therapy of the present invention is compound I MeOH solvate hydrate. In some embodiments, the solid form of compound I used in the combination therapy of the present invention is compound I IPA solvate hydrate. In some embodiments, the solid form of compound I used in the combination therapy of the present invention is compound I MeOAc solvate hydrate. In some embodiments, the solid form of compound I used in the combination therapy of the present invention is amorphous compound I.

[0192] In some embodiments, compound I used in the combination therapy of the present invention is in the form of a solid (e.g., spray-dried) dispersion.

[0193] Pharmaceutical Composition

[0194] Another aspect of the present invention provides a pharmaceutical composition comprising compound I in any of the pharmaceutically acceptable solid forms disclosed herein, or an amorphous compound I formulated as a solid (e.g., spray-dried) dispersion. In some embodiments, the present invention provides a pharmaceutical composition comprising compound I in any of the pharmaceutically acceptable solid forms disclosed herein, or an amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, and at least one additional active pharmaceutical agent. In some embodiments, the at least one additional active pharmaceutical agent is a CFTR modifier. In some embodiments, the at least one additional active pharmaceutical agent is a CFTR corrector. In some embodiments, the at least one additional active pharmaceutical agent is a CFTR enhancer. In some embodiments, the pharmaceutical composition comprises compound I in any of the pharmaceutically acceptable crystalline forms disclosed herein, or an amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, and at least two additional active pharmaceutical agents, one of which is a CFTR corrector and the other of which is a CFTR enhancer.

[0195] In some embodiments, at least one additional active agent is selected from mucolytics, bronchodilators, antibiotics, anti-infectives, and anti-inflammatory agents.

[0196] In some embodiments, the present invention provides a pharmaceutical composition comprising at least one compound I selected from any of the pharmaceutically acceptable crystalline forms disclosed herein, or an amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, and at least one pharmaceutically acceptable carrier.

[0197] In some embodiments, the present invention provides a pharmaceutical composition comprising (a) compound I in any of the pharmaceutically acceptable solid forms disclosed herein or an amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, (b) at least one compound selected from compound IV, compound V, their deuterated derivatives and pharmaceutically acceptable salts thereof, and (c) at least one pharmaceutically acceptable carrier.

[0198] In some embodiments, this disclosure provides a pharmaceutical composition comprising (a) a compound I in any of the pharmaceutically acceptable solid forms disclosed herein or an amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, (b) at least one compound selected from compounds III, III-d and their pharmaceutically acceptable salts, and (c) at least one pharmaceutically acceptable carrier.

[0199] In some embodiments, this disclosure provides a pharmaceutical composition comprising (a) a compound I in any of the pharmaceutically acceptable solid forms disclosed herein or an amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, (b) at least one compound selected from compound II and its pharmaceutically acceptable salts, (c) at least one compound selected from compounds III, III-d, VI and V and their pharmaceutically acceptable salts, and (d) at least one pharmaceutically acceptable carrier.

[0200] In some embodiments, this disclosure provides a pharmaceutical composition comprising (a) a compound I in any of the pharmaceutically acceptable solid forms disclosed herein or an amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, (b) at least one compound selected from compound II and its pharmaceutically acceptable salts, (c) at least one compound selected from compound IV and its pharmaceutically acceptable salts, and (d) at least one pharmaceutically acceptable carrier.

[0201] In some embodiments, this disclosure provides a pharmaceutical composition comprising (a) a compound I in any of the pharmaceutically acceptable solid forms disclosed herein or an amorphous compound I formulated as a solid (e.g., spray-dried) dispersion, (b) at least one compound selected from compound II and its pharmaceutically acceptable salts, (c) at least one compound selected from compound V and its pharmaceutically acceptable salts, and (d) at least one pharmaceutically acceptable carrier.

[0202] Any pharmaceutical composition disclosed herein may comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from pharmaceutically acceptable mediators and pharmaceutically acceptable adjuvants. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0203] In some embodiments, the solid form of compound I used in the pharmaceutical composition of the present invention is compound I in its pure form A.

[0204] In some embodiments, the crystalline form of compound I in the pharmaceutical composition of the present invention is compound I in its pure form B.

[0205] In some embodiments, the solid form of compound I used in the pharmaceutical composition of the present invention is compound I in its pure form C.

[0206] In some embodiments, the solid form of compound I used in the pharmaceutical composition of the present invention is compound I in its pure form D.

[0207] In some embodiments, the solid form of compound I used in the pharmaceutical composition of the present invention is the pure form E of compound I.

[0208] In some embodiments, the solid form of compound I used in the pharmaceutical composition of the present invention is compound I compressed form A.

[0209] In some embodiments, the solid form of compound I used in the pharmaceutical composition of the present invention is the compressed form E of compound I.

[0210] In some embodiments, the solid form of compound I in the pharmaceutical composition of the present invention is compound IEtOH solvate form B. In some embodiments, the solid form of compound I in the pharmaceutical composition of the present invention is compound I MeOH solvate. In some embodiments, the solid form of compound I in the pharmaceutical composition of the present invention is compound I NPA solvate. In some embodiments, the solid form of compound I in the pharmaceutical composition of the present invention is compound I MeOAc solvate form A. In some embodiments, the solid form of compound I in the pharmaceutical composition of the present invention is compound I MeOAc solvate form B. In some embodiments, the solid form of compound I in the pharmaceutical composition of the present invention is compound I MeOAc solvate form C. In some embodiments, the solid form of compound I in the pharmaceutical composition of the present invention is compound I hydrate form A. In some embodiments, the solid form of compound I in the pharmaceutical composition of the present invention is compound I hydrate form B. In some embodiments, the solid form of compound I in the pharmaceutical composition of the present invention is compound I hydrate form C. In some embodiments, the solid form of compound I in the pharmaceutical composition of the present invention is compound I EtOH solvate hydrate. In some embodiments, the solid form of compound I in the pharmaceutical composition of the present invention is compound I MeOH solvate hydrate. In some embodiments, the solid form of compound I in the pharmaceutical composition of the present invention is compound IIPA solvate hydrate. In some embodiments, the solid form of compound I in the pharmaceutical composition of the present invention is compound I MeOAc solvate hydrate. In some embodiments, the solid form of compound I in the pharmaceutical composition of the present invention is amorphous compound I.

[0211] In some embodiments, compound I used in the pharmaceutical composition of the present invention is in the form of a solid (e.g., spray-dried) dispersion.

[0212] The pharmaceutical compositions described herein may be used to treat cystic fibrosis and other CFTR-mediated diseases.

[0213] 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 mediators. As used herein, the at least one pharmaceutically acceptable carrier includes any and all solvents, diluents, other liquid mediators, dispersants, suspending agents, surfactants, isotonic 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, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JC Boylan, 1988–1999, Marcel Dekker, New York, disclose various carriers for the formulation of pharmaceutical compositions and known techniques for their preparation. Unless any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effects or otherwise interacting in a harmful manner with any other component of the pharmaceutical composition, its use is contemplated within the scope of this disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffers (such as phosphates, glycine, sorbic acid, and potassium sorbate), mixtures of metaglycerides of saturated vegetable fatty acids, water, salts and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, and sugars (such as lactose, glucose, and sucrose). Starch (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth gum, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, phosphate buffer, non-toxic compatible lubricants (such as sodium laurate sulfate and magnesium stearate), colorants, release agents, encapsulating agents, sweeteners, flavoring agents, aroma agents, preservatives and antioxidants.

[0214] Non-limiting list of exemplary embodiments

[0215] 1. Compound I

[0216]

[0217] (Compound I)

[0218] As a basically crystalline compound I in pure form A (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form).

[0219] 2. Compound I according to Example 1, wherein compound I is 100% crystalline compound I in pure form A.

[0220] 3. Basically, pure compound I is pure form A.

[0221] 4. Compound I in pure form A according to any one of Examples 1 to 3, characterized in that it has the following X-ray powder diffraction patterns: signals at (a) 9.2 ± 0.2 degrees 2θ, 14.1 ± 0.2 degrees 2θ and (b) 15.9 ± 0.2 degrees 2θ and / or 26.2 ± 0.2 degrees 2θ.

[0222] 5. Compound I in pure form A according to any one of Examples 1 to 3, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 9.2 ± 0.2 degrees 2θ, 14.1 ± 0.2 degrees 2θ and 15.9 ± 0.2 degrees 2θ and (b) one or more 2θ values ​​selected from 16.6 ± 0.2 degrees 2θ, 13.0 ± 0.2 degrees 2θ, 18.4 ± 0.2 degrees 2θ, 10.3 ± 0.2 degrees 2θ and 22.6 ± 0.2 degrees 2θ.

[0223] 6. Compound I in pure form A according to any one of Examples 1 to 3, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 9.2 ± 0.2 degrees 2θ, 14.1 ± 0.2 degrees 2θ and 15.9 ± 0.2 degrees 2θ and (b) two or more 2θ values ​​selected from 16.6 ± 0.2 degrees 2θ, 13.0 ± 0.2 degrees 2θ, 18.4 ± 0.2 degrees 2θ, 10.3 ± 0.2 degrees 2θ and 22.6 ± 0.2 degrees 2θ.

[0224] 7. Compound I in pure form A according to any one of Examples 1 to 3, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 9.2 ± 0.2 degrees 2θ, 14.1 ± 0.2 degrees 2θ and 15.9 ± 0.2 degrees 2θ and (b) three or more 2θ values ​​selected from 16.6 ± 0.2 degrees 2θ, 13.0 ± 0.2 degrees 2θ, 18.4 ± 0.2 degrees 2θ, 10.3 ± 0.2 degrees 2θ and 22.6 ± 0.2 degrees 2θ.

[0225] 8. Compound I in pure form A according to any one of Examples 1 to 3, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 9.2 ± 0.2 degrees 2θ, 14.1 ± 0.2 degrees 2θ and 15.9 ± 0.2 degrees 2θ and (b) four or more 2θ values ​​selected from 16.6 ± 0.2 degrees 2θ, 13.0 ± 0.2 degrees 2θ, 18.4 ± 0.2 degrees 2θ, 10.3 ± 0.2 degrees 2θ and 22.6 ± 0.2 degrees 2θ.

[0226] 9. Compound I in pure form A according to any one of Examples 1 to 3, characterized in that it has the following X-ray powder diffraction patterns: signals at 9.2 ± 0.2 degrees 2θ, 14.1 ± 0.2 degrees 2θ, 15.9 ± 0.2 degrees 2θ, 16.6 ± 0.2 degrees 2θ, 13.0 ± 0.2 degrees 2θ, 18.4 ± 0.2 degrees 2θ, 10.3 ± 0.2 degrees 2θ, and 22.6 ± 0.2 degrees 2θ.

[0227] 10. Compound I in pure form A according to any one of Examples 1 to 3, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 9.2 ± 0.2 degrees 2θ, 14.1 ± 0.2 degrees 2θ and 26.2 ± 0.2 degrees 2θ and (b) one or more 2θ values ​​selected from 16.6 ± 0.2 degrees 2θ, 13.0 ± 0.2 degrees 2θ, 18.4 ± 0.2 degrees 2θ, 10.3 ± 0.2 degrees 2θ and 22.6 ± 0.2 degrees 2θ.

[0228] 11. Compound I in pure form A according to any one of Examples 1 to 3, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 9.2 ± 0.2 degrees 2θ, 14.1 ± 0.2 degrees 2θ and 26.2 ± 0.2 degrees 2θ and (b) two or more 2θ values ​​selected from 16.6 ± 0.2 degrees 2θ, 13.0 ± 0.2 degrees 2θ, 18.4 ± 0.2 degrees 2θ, 10.3 ± 0.2 degrees 2θ and 22.6 ± 0.2 degrees 2θ.

[0229] 12. Compound I in pure form A according to any one of Examples 1 to 3, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 9.2 ± 0.2 degrees 2θ, 14.1 ± 0.2 degrees 2θ and 26.2 ± 0.2 degrees 2θ and (b) three or more 2θ values ​​selected from 16.6 ± 0.2 degrees 2θ, 13.0 ± 0.2 degrees 2θ, 18.4 ± 0.2 degrees 2θ, 10.3 ± 0.2 degrees 2θ and 22.6 ± 0.2 degrees 2θ.

[0230] 13. Compound I in pure form A according to any one of Examples 1 to 3, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 9.2 ± 0.2 degrees 2θ, 14.1 ± 0.2 degrees 2θ and 26.2 ± 0.2 degrees 2θ and (b) four or more 2θ values ​​selected from 16.6 ± 0.2 degrees 2θ, 13.0 ± 0.2 degrees 2θ, 18.4 ± 0.2 degrees 2θ, 10.3 ± 0.2 degrees 2θ and 22.6 ± 0.2 degrees 2θ.

[0231] 14. Compound I, pure form A, according to any one of Examples 1 to 3, is characterized by having the following X-ray powder diffraction patterns: signals at 9.2 ± 0.2 degrees 2θ, 14.1 ± 0.2 degrees 2θ, 26.2 ± 0.2 degrees 2θ, 16.6 ± 0.2 degrees 2θ, 13.0 ± 0.2 degrees 2θ, 18.4 ± 0.2 degrees 2θ, 10.3 ± 0.2 degrees 2θ, and 22.6 ± 0.2 degrees 2θ.

[0232] 15. Compound I in pure form A according to any one of Examples 1 to 14, characterized in that it is substantially similar to... Figure 1 X-ray powder diffraction pattern.

[0233] 16. Compound I in pure form A according to any one of Examples 1 to 15, characterized by TGA showing negligible weight loss from ambient temperature to up to about 200°C.

[0234] 17. Compound I in pure form A according to any one of Examples 1 to 16, characterized in that it is substantially similar to... Figure 2 TGA data.

[0235] 18. Compound I in pure form A according to any one of Examples 1 to 17, characterized by DSC analysis showing an endothermic peak at about 198°C.

[0236] 19. Compound I in pure form A according to any one of Examples 1 to 18, characterized in that it is substantially similar to... Figure 3 DSC analysis.

[0237] 20. Compound I, pure form A, according to any one of Examples 1 to 19, characterized in that it has the following... 13 C ss NMR spectrum: (a) peak at 126.0 ± 0.2 ppm and (b) one or more peaks selected from 26.6 ± 0.2 ppm, 128.4 ± 0.2 ppm, 20.0 ± 0.2 ppm, 43.7 ± 0.2 ppm, 140.2 ± 0.2 ppm, 168.7 ± 0.2 ppm and 133.3 ± 0.2 ppm.

[0238] 21. Compound I, pure form A, according to any one of Examples 1 to 19, characterized in that it has the following... 13C ss NMR spectra: (a) a peak at 126.0 ± 0.2 ppm and (b) two or more peaks selected from 26.6 ± 0.2 ppm, 128.4 ± 0.2 ppm, 20.0 ± 0.2 ppm, 43.7 ± 0.2 ppm, 140.2 ± 0.2 ppm, 168.7 ± 0.2 ppm and 133.3 ± 0.2 ppm.

[0239] 22. Compound I, pure form A, according to any one of Examples 1 to 19, is characterized by having the following... 13 C ss NMR spectrum: (a) peak at 126.0 ± 0.2 ppm and (b) three or more peaks selected from 26.6 ± 0.2 ppm, 128.4 ± 0.2 ppm, 20.0 ± 0.2 ppm, 43.7 ± 0.2 ppm, 140.2 ± 0.2 ppm, 168.7 ± 0.2 ppm and 133.3 ± 0.2 ppm.

[0240] 23. Compound I, pure form A, according to any one of Examples 1 to 19, is characterized by having the following... 13 C ss NMR spectra: (a) a peak at 126.0 ± 0.2 ppm and (b) four or more peaks selected from 26.6 ± 0.2 ppm, 128.4 ± 0.2 ppm, 20.0 ± 0.2 ppm, 43.7 ± 0.2 ppm, 140.2 ± 0.2 ppm, 168.7 ± 0.2 ppm and 133.3 ± 0.2 ppm.

[0241] 24. Compound I, pure form A, according to any one of Examples 1 to 19, characterized in that it has the following... 13 C ss NMR spectra: (a) a peak at 126.0 ± 0.2 ppm and (b) five or more peaks selected from 26.6 ± 0.2 ppm, 128.4 ± 0.2 ppm, 20.0 ± 0.2 ppm, 43.7 ± 0.2 ppm, 140.2 ± 0.2 ppm, 168.7 ± 0.2 ppm and 133.3 ± 0.2 ppm.

[0242] 25. Compound I, pure form A, according to any one of Examples 1 to 19, characterized in that it has the following... 13C ss NMR spectra: (a) a peak at 126.0 ± 0.2 ppm and (b) six or more peaks selected from 26.6 ± 0.2 ppm, 128.4 ± 0.2 ppm, 20.0 ± 0.2 ppm, 43.7 ± 0.2 ppm, 140.2 ± 0.2 ppm, 168.7 ± 0.2 ppm and 133.3 ± 0.2 ppm.

[0243] 26. Compound I, pure form A, according to any one of Examples 1 to 19, characterized in that it has the following... 13 C ss NMR spectrum: peaks at 126.0 ± 0.2 ppm, 26.6 ± 0.2 ppm, 128.4 ± 0.2 ppm, 20.0 ± 0.2 ppm, 43.7 ± 0.2 ppm, 140.2 ± 0.2 ppm, 168.7 ± 0.2 ppm and 133.3 ± 0.2 ppm.

[0244] 27. Compound I, pure form A, according to any one of Examples 1 to 26, is characterized by being substantially similar to F. Figure 4 of 13 CssNMR spectrum.

[0245] 28. Compound I in pure form A according to any one of Examples 1 to 27, characterized in that it has a monoclinic crystal system, space group P212121, and unit cell size, wherein it is equipped with Cu K α Radiation (λ = 1.54178 Å) was measured at 100 K on a Rigaku diffractometer with an HPAD detector:

[0246]

[0247] 29. Compound I in pure form A according to any one of Examples 1 to 28, which is prepared by a method comprising: (i) dissolving amorphous compound I in ethanol, (ii) increasing the temperature to about 73°C, (iii) decreasing the temperature to about 20°C, (iv) separating the solid by filtration, and (v) drying the solid at 50°C.

[0248] 30. Compound I is in essentially crystalline pure form B (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form).

[0249] 31. Compound I according to Example 30, wherein compound I is 100% crystalline compound I in pure form B.

[0250] 32. Basically, pure compound I is pure form B.

[0251] 33. Compound I in pure form B according to any one of Examples 30 to 32, characterized in that it has the following X-ray powder diffraction patterns: (a) a signal at 26.3 degrees 2θ and (b) a signal at one or more 2θ values ​​selected from the following: 11.1 degrees 2θ, 19.6 degrees 2θ and 7.2 degrees 2θ.

[0252] 34. Compound I in pure form B according to any one of Examples 30 to 32, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 26.3 ± 0.2 degrees 2θ and (b) signals at two or more 2θ values ​​selected from the following: 11.1 ± 0.2 degrees 2θ, 19.6 ± 0.2 degrees 2θ and 7.2 ± 0.2 degrees 2θ.

[0253] 35. Compound I in pure form B according to any one of Examples 30 to 32, characterized in that it has the following X-ray powder diffraction patterns: signals at 2θ values ​​of 26.3 ± 0.2 degrees 2θ, 11.1 ± 0.2 degrees 2θ, 19.6 ± 0.2 degrees 2θ and 7.2 ± 0.2 degrees 2θ.

[0254] 36. Compound I in pure form B according to any one of Examples 30 to 32, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 2θ values ​​of 26.3 ± 0.2 degrees 2θ, 11.1 ± 0.2 degrees 2θ, 19.6 ± 0.2 degrees 2θ and 7.2 ± 0.2 degrees 2θ and (b) signals at one or more 2θ values ​​selected from the following: 18.5 ± 0.2 degrees 2θ, 20.8 ± 0.2 degrees 2θ, 14.3 ± 0.2 degrees 2θ and 17.1 ± 0.2 degrees 2θ.

[0255] 37. Compound I in pure form B according to any one of Examples 30 to 32, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 2θ values ​​of 26.3 ± 0.2 degrees 2θ, 11.1 ± 0.2 degrees 2θ, 19.6 ± 0.2 degrees 2θ and 7.2 ± 0.2 degrees 2θ and (b) signals at two or more 2θ values ​​selected from the following: 18.5 ± 0.2 degrees 2θ, 20.8 ± 0.2 degrees 2θ, 14.3 ± 0.2 degrees 2θ and 17.1 ± 0.2 degrees 2θ.

[0256] 38. Compound I in pure form B according to any one of Examples 30 to 32, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 2θ values ​​of 26.3 ± 0.2 degrees 2θ, 11.1 ± 0.2 degrees 2θ, 19.6 ± 0.2 degrees 2θ and 7.2 ± 0.2 degrees 2θ and (b) signals at three or more 2θ values ​​selected from the following: 18.5 ± 0.2 degrees 2θ, 20.8 ± 0.2 degrees 2θ, 14.3 ± 0.2 degrees 2θ and 17.1 ± 0.2 degrees 2θ.

[0257] 39. Compound I in pure form B according to any one of Examples 30 to 32, characterized in that it has the following X-ray powder diffraction patterns: signals at 2θ values ​​of 26.3 ± 0.2 degrees 2θ, 11.1 ± 0.2 degrees 2θ, 19.6 ± 0.2 degrees 2θ, 7.2 ± 0.2 degrees 2θ, 18.5 ± 0.2 degrees 2θ, 20.8 ± 0.2 degrees 2θ, 14.3 ± 0.2 degrees 2θ, and 17.1 ± 0.2 degrees 2θ.

[0258] 40. Compound I in pure form B according to any one of Examples 30 to 39, characterized in that it is substantially similar to... Figure 5 X-ray powder diffraction pattern.

[0259] 41. Compound I, pure form B, according to any one of Examples 30 to 40, characterized by having a peak at 142.6 ± 0.2 ppm. 13 CssNMR spectrum.

[0260] 42. Compound I in pure form B according to any one of Examples 30 to 40, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 142.6 ± 0.2 ppm and (b) one or more peaks selected from the following: 27.1 ± 0.2 ppm, 18.4 ± 0.2 ppm, 134.9 ± 0.2 ppm, 132.4 ± 0.2 ppm, 128.2 ± 0.2 ppm, 126.6 ± 0.2 ppm and 133.4 ± 0.2 ppm.

[0261] 43. Compound I in pure form B according to any one of Examples 30 to 40, characterized in that it has the following 13C ss NMR spectra: (a) the peak at 142.6 ± 0.2 ppm and (b) two or more peaks selected from the following: 27.1 ± 0.2 ppm, 18.4 ± 0.2 ppm, 134.9 ± 0.2 ppm, 132.4 ± 0.2 ppm, 128.2 ± 0.2 ppm, 126.6 ± 0.2 ppm and 133.4 ± 0.2 ppm.

[0262] 44. Compound I in pure form B according to any one of Examples 30 to 40, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 142.6 ± 0.2 ppm and (b) three or more peaks selected from the following: 27.1 ± 0.2 ppm, 18.4 ± 0.2 ppm, 134.9 ± 0.2 ppm, 132.4 ± 0.2 ppm, 128.2 ± 0.2 ppm, 126.6 ± 0.2 ppm and 133.4 ± 0.2 ppm.

[0263] 45. Compound I, pure form B, according to any one of Examples 30 to 40, characterized in that it has the following... 13 C ss NMR spectra: (a) the peak at 142.6 ± 0.2 ppm and (b) four or more peaks selected from the following: 27.1 ± 0.2 ppm, 18.4 ± 0.2 ppm, 134.9 ± 0.2 ppm, 132.4 ± 0.2 ppm, 128.2 ± 0.2 ppm, 126.6 ± 0.2 ppm and 133.4 ± 0.2 ppm.

[0264] 46. ​​Compound I, pure form B, according to any one of Examples 30 to 40, characterized in that it has the following... 13 C ss NMR spectra: (a) the peak at 142.6 ± 0.2 ppm and (b) five or more peaks selected from the following: 27.1 ± 0.2 ppm, 18.4 ± 0.2 ppm, 134.9 ± 0.2 ppm, 132.4 ± 0.2 ppm, 128.2 ± 0.2 ppm, 126.6 ± 0.2 ppm and 133.4 ± 0.2 ppm.

[0265] 47. Compound I in pure form B according to any one of Examples 30 to 40, characterized in that it has the following 13C ss NMR spectra: (a) the peak at 142.6 ± 0.2 ppm and (b) six or more peaks selected from the following: 27.1 ± 0.2 ppm, 18.4 ± 0.2 ppm, 134.9 ± 0.2 ppm, 132.4 ± 0.2 ppm, 128.2 ± 0.2 ppm, 126.6 ± 0.2 ppm and 133.4 ± 0.2 ppm.

[0266] 48. Compound I, pure form B, according to any one of Examples 30 to 40, characterized in that it has the following... 13 C ss NMR spectrum: peaks at 142.6 ± 0.2 ppm, 27.1 ± 0.2 ppm, 18.4 ± 0.2 ppm, 134.9 ± 0.2 ppm, 132.4 ± 0.2 ppm, 128.2 ± 0.2 ppm, 126.6 ± 0.2 ppm and 133.4 ± 0.2 ppm.

[0267] 49. Compound I in pure form B according to any one of Examples 30 to 48, characterized in that it is substantially similar to Figure 6 of 13 CssNMR spectrum.

[0268] 50. Compound I in pure form B according to any one of Examples 30 to 49, which is prepared by a method comprising exposing compound I in hydrate form A to about 3% humidity.

[0269] 51. Compound I is in essentially crystalline pure form C (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form).

[0270] 52. Compound I according to Example 51, wherein compound I is 100% crystalline compound I in pure form C.

[0271] 53. Basically, pure compound I is pure form C.

[0272] 54. Compound I in pure form C according to any one of Examples 51 to 53, characterized in that it has an X-ray powder diffraction pattern with a signal at 5.4 ± 0.2 degrees 2θ.

[0273] 55. Compound I in pure form C according to any one of Examples 51 to 53, characterized in that it has the following X-ray powder diffraction pattern: signals at one or more of (a) 5.4 ± 0.2 degrees 2θ and (b) 10.2 ± 0.2 degrees 2θ, 15.2 ± 0.2 degrees 2θ, 12.6 ± 0.2 degrees 2θ, 16.7 ± 0.2 degrees 2θ, 11.7 ± 0.2 degrees 2θ, 23.0 ± 0.2 degrees 2θ and 7.6 ± 0.2 degrees 2θ.

[0274] 56. Compound I in pure form C according to any one of Examples 51 to 53, characterized in that it has the following X-ray powder diffraction pattern: signals at two or more of (a) 5.4 ± 0.2 degrees 2θ and (b) 10.2 ± 0.2 degrees 2θ, 15.2 ± 0.2 degrees 2θ, 12.6 ± 0.2 degrees 2θ, 16.7 ± 0.2 degrees 2θ, 11.7 ± 0.2 degrees 2θ, 23.0 ± 0.2 degrees 2θ and 7.6 ± 0.2 degrees 2θ.

[0275] 57. Compound I in pure form C according to any one of Examples 51 to 53, characterized in that it has the following X-ray powder diffraction pattern: signals at three or more of the following locations: (a) 5.4 ± 0.2 degrees 2θ and (b) 10.2 ± 0.2 degrees 2θ, 15.2 ± 0.2 degrees 2θ, 12.6 ± 0.2 degrees 2θ, 16.7 ± 0.2 degrees 2θ, 11.7 ± 0.2 degrees 2θ, 23.0 ± 0.2 degrees 2θ and 7.6 ± 0.2 degrees 2θ.

[0276] 58. Compound I in pure form C according to any one of Examples 51 to 53, characterized in that it has the following X-ray powder diffraction pattern: signals at four or more of the following locations: (a) 5.4 ± 0.2 degrees 2θ and (b) 10.2 ± 0.2 degrees 2θ, 15.2 ± 0.2 degrees 2θ, 12.6 ± 0.2 degrees 2θ, 16.7 ± 0.2 degrees 2θ, 11.7 ± 0.2 degrees 2θ, 23.0 ± 0.2 degrees 2θ and 7.6 ± 0.2 degrees 2θ.

[0277] 59. Compound I in pure form C according to any one of Examples 51 to 53, characterized in that it has the following X-ray powder diffraction pattern: signals at five or more of the following locations: (a) 5.4 ± 0.2 degrees 2θ and (b) 10.2 ± 0.2 degrees 2θ, 15.2 ± 0.2 degrees 2θ, 12.6 ± 0.2 degrees 2θ, 16.7 ± 0.2 degrees 2θ, 11.7 ± 0.2 degrees 2θ, 23.0 ± 0.2 degrees 2θ and 7.6 ± 0.2 degrees 2θ.

[0278] 60. Compound I in pure form C according to any one of Examples 51 to 53, characterized in that it has the following X-ray powder diffraction pattern: signals at six or more of the following locations: (a) 5.4 ± 0.2 degrees 2θ and (b) 10.2 ± 0.2 degrees 2θ, 15.2 ± 0.2 degrees 2θ, 12.6 ± 0.2 degrees 2θ, 16.7 ± 0.2 degrees 2θ, 11.7 ± 0.2 degrees 2θ, 23.0 ± 0.2 degrees 2θ and 7.6 ± 0.2 degrees 2θ.

[0279] 61. Compound I in pure form C according to any one of Examples 51 to 53, characterized in that it has the following X-ray powder diffraction patterns: signals at 5.4 ± 0.2 degrees 2θ, 10.2 ± 0.2 degrees 2θ, 15.2 ± 0.2 degrees 2θ, 12.6 ± 0.2 degrees 2θ, 16.7 ± 0.2 degrees 2θ, 11.7 ± 0.2 degrees 2θ, 23.0 ± 0.2 degrees 2θ and 7.6 ± 0.2 degrees 2θ.

[0280] 62. Compound I in pure form C according to any one of Examples 51 to 61, characterized in that it is substantially similar to Figure 7 X-ray powder diffraction pattern.

[0281] 63. Compound I in pure form C according to any one of Examples 51 to 62, characterized by TGA showing negligible weight loss from ambient temperature to up to about 40°C and about 0.16% weight loss from 40°C to 240°C.

[0282] 64. Compound I in pure form C according to any one of Examples 51 to 63, characterized in that it is substantially similar to... Figure 8 TGA data.

[0283] 65. Compound I in pure form C according to any one of Examples 51 to 64, characterized by DSC analysis showing an endothermic peak at about 237°C.

[0284] 66. Compound I in pure form C according to any one of Examples 51 to 65, characterized in that it is substantially similar to... Figure 9 DSC analysis.

[0285] 67. Compound I, pure form C, according to any one of Examples 51 to 66, characterized by having peaks at 43.8 ± 0.2 ppm and 132.3 ± 0.2 ppm. 13 CssNMR spectrum.

[0286] 68. Compound I, pure form C, according to any one of Examples 51 to 67, characterized in that it has the following... 13 C ss NMR spectra: (a) peaks at 43.8 ± 0.2 ppm and 132.3 ± 0.2 ppm and (b) one or more peaks selected from 28.4 ± 0.2 ppm, 29.4 ± 0.2 ppm, 129.1 ± 0.2 ppm, 135.1 ± 0.2 ppm, 139.6 ± 0.2 ppm and 28.2 ± 0.2 ppm.

[0287] 69. Compound I, pure form C, according to any one of Examples 51 to 68, characterized in that it has the following... 13 C ss NMR spectra: (a) peaks at 43.8 ± 0.2 ppm and 132.3 ± 0.2 ppm and (b) two or more peaks selected from 28.4 ± 0.2 ppm, 29.4 ± 0.2 ppm, 129.1 ± 0.2 ppm, 135.1 ± 0.2 ppm, 139.6 ± 0.2 ppm and 28.2 ± 0.2 ppm.

[0288] 70. Compound I, pure form C, according to any one of Examples 51 to 69, characterized in that it has the following... 13 C ss NMR spectra: (a) peaks at 43.8 ± 0.2 ppm and 132.3 ± 0.2 ppm and (b) three or more peaks selected from 28.4 ± 0.2 ppm, 29.4 ± 0.2 ppm, 129.1 ± 0.2 ppm, 135.1 ± 0.2 ppm, 139.6 ± 0.2 ppm and 28.2 ± 0.2 ppm.

[0289] 71. Compound I, pure form C, according to any one of Examples 51 to 70, characterized in that it has the following... 13 C ss NMR spectra: (a) peaks at 43.8 ± 0.2 ppm and 132.3 ± 0.2 ppm and (b) four or more peaks selected from 28.4 ± 0.2 ppm, 29.4 ± 0.2 ppm, 129.1 ± 0.2 ppm, 135.1 ± 0.2 ppm, 139.6 ± 0.2 ppm and 28.2 ± 0.2 ppm.

[0290] 72. Compound I, pure form C, according to any one of Examples 51 to 71, characterized in that it has the following... 13C ss NMR spectra: (a) peaks at 43.8 ± 0.2 ppm and 132.3 ± 0.2 ppm and (b) five or more peaks selected from 28.4 ± 0.2 ppm, 29.4 ± 0.2 ppm, 129.1 ± 0.2 ppm, 135.1 ± 0.2 ppm, 139.6 ± 0.2 ppm and 28.2 ± 0.2 ppm.

[0291] 73. Compound I, pure form C, according to any one of Examples 51 to 72, is characterized by having the following... 13 C ss NMR spectrum: peaks at 43.8 ± 0.2 ppm, 132.3 ± 0.2 ppm, 28.4 ± 0.2 ppm, 29.4 ± 0.2 ppm, 129.1 ± 0.2 ppm, 135.1 ± 0.2 ppm, 139.6 ± 0.2 ppm and 28.2 ± 0.2 ppm.

[0292] 74. Compound I in pure form C according to any one of Examples 51 to 73, characterized in that it is substantially similar to... Figure 10 of 13 CssNMR spectrum.

[0293] 75. Compound I in pure form C according to any one of Examples 51 to 74, which is prepared by a method comprising: (i) stirring compound I in hexadecane at about 80°C, and (ii) centrifuging and drying the resulting solid.

[0294] 76. Compound I is in essentially crystalline pure form D (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form).

[0295] 77. Compound I according to Example 76, wherein compound I is 100% crystalline compound I in pure form D.

[0296] 78. Basically, pure compound I is pure form D.

[0297] 79. Compound I, pure form D, according to any one of Examples 76 to 78, characterized by having a peak at 50.8 ± 0.2 ppm. 13 CssNMR spectrum.

[0298] 80. Compound I in pure form D according to any one of Examples 76 to 78, characterized in that it has the following 13C ss NMR spectra: (a) the peak at 50.8 ± 0.2 ppm and (b) one or more peaks selected from 28.3 ± 0.2 ppm, 127.2 ± 0.2 ppm, 129.8 ± 0.2 ppm, and 170.6 ± 0.2 ppm.

[0299] 81. Compound I in pure form D according to any one of Examples 76 to 78, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 50.8 ± 0.2 ppm and (b) two or more peaks selected from 28.3 ± 0.2 ppm, 127.2 ± 0.2 ppm, 129.8 ± 0.2 ppm, and 170.6 ± 0.2 ppm.

[0300] 82. Compound I in pure form D according to any one of Examples 76 to 78, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 50.8 ± 0.2 ppm and (b) three or more peaks selected from 28.3 ± 0.2 ppm, 127.2 ± 0.2 ppm, 129.8 ± 0.2 ppm, and 170.6 ± 0.2 ppm.

[0301] 83. Compound I in pure form D according to any one of Examples 76 to 78, characterized in that it has the following 13 C ss NMR spectrum: peaks at 50.8 ± 0.2 ppm, 28.3 ± 0.2 ppm, 127.2 ± 0.2 ppm, 129.8 ± 0.2 ppm, and 170.6 ± 0.2 ppm.

[0302] 84. Compound I in pure form D according to any one of Examples 76 to 78, characterized in that it has the following 13 C ss NMR spectra: (a) peaks at 50.8 ± 0.2 ppm, 28.3 ± 0.2 ppm, 127.2 ± 0.2 ppm, 129.8 ± 0.2 ppm and 170.6 ± 0.2 ppm and (b) one or more peaks selected from 135.3 ± 0.2 ppm, 136.8 ± 0.2 ppm and 129.2 ± 0.2 ppm.

[0303] 85. Compound I in pure form D according to any one of Examples 76 to 78, characterized in that it has the following 13C ss NMR spectra: (a) peaks at 50.8 ± 0.2 ppm, 28.3 ± 0.2 ppm, 127.2 ± 0.2 ppm, 129.8 ± 0.2 ppm and 170.6 ± 0.2 ppm and (b) two or more peaks selected from 135.3 ± 0.2 ppm, 136.8 ± 0.2 ppm and 129.2 ± 0.2 ppm.

[0304] 86. Compound I in pure form D according to any one of Examples 76 to 78, characterized in that it has the following 13 C ss NMR spectrum: peaks at 50.8 ± 0.2 ppm, 28.3 ± 0.2 ppm, 127.2 ± 0.2 ppm, 129.8 ± 0.2 ppm, 170.6 ± 0.2 ppm, 135.3 ± 0.2 ppm, 136.8 ± 0.2 ppm and 129.2 ± 0.2 ppm.

[0305] 87. Compound I in pure form D according to any one of Examples 76 to 86, characterized in that it is substantially similar to... Figure 11 of 13 CssNMR spectrum.

[0306] 88. Compound I in pure form D according to any one of Examples 76 to 87, which is prepared by a method comprising drying compound I hydrate C at about 80°C.

[0307] 89. Compound I in pure form D according to any one of Examples 76 to 87, which is prepared by a method comprising: (i) stirring compound I in pure form A in an IPA, and (ii) separating the solid by filtration, and (iii) drying the solid at about 125°C.

[0308] 90. Compound I is in essentially crystalline pure form E (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form).

[0309] 91. Compound I according to Example 90, wherein compound I is 100% crystalline compound I in pure form D.

[0310] 92. Basically, pure compound I is pure form E.

[0311] 93. Compound I in pure form E according to any one of Examples 90 to 92, characterized in that it has the following X-ray powder diffraction patterns: (a) a signal at 13.4 ± 0.2 degrees 2θ and (b) a signal at 14.7 ± 0.2 degrees 2θ or 19.6 ± 0.2 degrees 2θ.

[0312] 94. Compound I in pure form E according to any one of Examples 90 to 92, characterized by having X-ray powder diffraction patterns with signals at 13.4 ± 0.2 degrees 2θ, 14.7 ± 0.2 degrees 2θ, and 19.6 ± 0.2 degrees 2θ.

[0313] 95. Compound I in pure form E according to any one of Examples 90 to 92, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 13.4 ± 0.2 degrees 2θ, 14.7 ± 0.2 degrees 2θ and 19.6 ± 0.2 degrees 2θ and (b) one or more 2θ values ​​selected from 10.3 degrees 2θ, 8.5 degrees 2θ, 16.0 degrees 2θ, 16.2 degrees 2θ and 21.4 degrees 2θ.

[0314] 96. Compound I in pure form E according to any one of Examples 90 to 92, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 13.4 ± 0.2 degrees 2θ, 14.7 ± 0.2 degrees 2θ and 19.6 ± 0.2 degrees 2θ and (b) two or more 2θ values ​​selected from 10.3 degrees 2θ, 8.5 degrees 2θ, 16.0 degrees 2θ, 16.2 degrees 2θ and 21.4 degrees 2θ.

[0315] 97. Compound I in pure form E according to any one of Examples 90 to 92, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 2θ values ​​of 13.4 ± 0.2 degrees, 14.7 ± 0.2 degrees, and 19.6 ± 0.2 degrees and (b) three or more signals selected from 2θ values ​​of 10.3 degrees, 8.5 degrees, 16.0 degrees, 16.2 degrees, and 21.4 degrees.

[0316] 98. Compound I in pure form E according to any one of Examples 90 to 92, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 13.4 ± 0.2 degrees 2θ, 14.7 ± 0.2 degrees 2θ and 19.6 ± 0.2 degrees 2θ and (b) four or more 2θ values ​​selected from 10.3 degrees 2θ, 8.5 degrees 2θ, 16.0 degrees 2θ, 16.2 degrees 2θ and 21.4 degrees 2θ.

[0317] 99. Compound I in pure form E according to any one of Examples 90 to 92, characterized in that it has the following X-ray powder diffraction pattern: signals at 13.4 ± 0.2 degrees 2θ, 14.7 ± 0.2 degrees 2θ, 19.6 ± 0.2 degrees 2θ, 10.3 degrees 2θ, 8.5 degrees 2θ, 16.0 degrees 2θ, 16.2 degrees 2θ, and 21.4 degrees 2θ.

[0318] 100. Compound I in pure form E according to any one of Examples 90 to 99, characterized in that it is substantially similar to... Figure 12 X-ray powder diffraction pattern.

[0319] 101. Compound I in pure form E according to any one of Examples 90 to 100, characterized by TGA showing negligible weight loss from 30°C to 120°C.

[0320] 102. Compound I in pure form E according to any one of Examples 90 to 101, characterized in that it is substantially similar to... Figure 13 TGA data.

[0321] 103. Compound I in pure form E according to any one of Examples 90 to 102, characterized by DSC analysis showing an endothermic peak at about 212°C.

[0322] 104. Compound I in pure form E according to any one of Examples 90 to 103, characterized in that it is substantially similar to Figure 14 DSC analysis.

[0323] 105. Compound I in pure form E according to any one of Examples 90 to 104, characterized by having peaks at 20.5 ± 0.2 ppm and 43.6 ± 0.2 ppm. 13 CssNMR spectrum.

[0324] 106. Compound I in pure form E according to any one of Examples 90 to 104, characterized in that it has the following 13 C ss NMR spectra: (a) peaks at 20.5 ± 0.2 ppm and 43.6 ± 0.2 ppm and (b) one or more peaks selected from 28.3 ± 0.2 ppm, 43.6 ± 0.2 ppm, 20.5 ± 0.2 ppm, 135.0 ± 0.2 ppm, 128.2 ± 0.2 ppm and 139.6 ± 0.2 ppm.

[0325] 107. Compound I in pure form E according to any one of Examples 90 to 104, characterized in that it has the following13 C ss NMR spectra: (a) peaks at 20.5 ± 0.2 ppm and 43.6 ± 0.2 ppm and (b) two or more peaks selected from 28.3 ± 0.2 ppm, 43.6 ± 0.2 ppm, 20.5 ± 0.2 ppm, 135.0 ± 0.2 ppm, 128.2 ± 0.2 ppm and 139.6 ± 0.2 ppm.

[0326] 108. Compound I in pure form E according to any one of Examples 90 to 104, characterized in that it has the following 13 C ss NMR spectra: (a) peaks at 20.5 ± 0.2 ppm and 43.6 ± 0.2 ppm and (b) three or more peaks selected from 28.3 ± 0.2 ppm, 43.6 ± 0.2 ppm, 20.5 ± 0.2 ppm, 135.0 ± 0.2 ppm, 128.2 ± 0.2 ppm and 139.6 ± 0.2 ppm.

[0327] 109. Compound I in pure form E according to any one of Examples 90 to 104, characterized in that it has the following 13 C ss NMR spectra: (a) peaks at 20.5 ± 0.2 ppm and 43.6 ± 0.2 ppm and (b) four or more peaks selected from 28.3 ± 0.2 ppm, 43.6 ± 0.2 ppm, 20.5 ± 0.2 ppm, 135.0 ± 0.2 ppm, 128.2 ± 0.2 ppm and 139.6 ± 0.2 ppm.

[0328] 110. Compound I in pure form E according to any one of Examples 90 to 104, characterized in that it has the following 13 C ss NMR spectra: (a) peaks at 20.5 ± 0.2 ppm and 43.6 ± 0.2 ppm and (b) five or more peaks selected from 28.3 ± 0.2 ppm, 43.6 ± 0.2 ppm, 20.5 ± 0.2 ppm, 135.0 ± 0.2 ppm, 128.2 ± 0.2 ppm and 139.6 ± 0.2 ppm.

[0329] 111. Compound I in pure form E according to any one of Examples 90 to 104, characterized in that it has the following 13C ss NMR spectrum: peaks at 20.5 ± 0.2 ppm, 43.6 ± 0.2 ppm, 28.3 ± 0.2 ppm, 43.6 ± 0.2 ppm, 20.5 ± 0.2 ppm, 135.0 ± 0.2 ppm, 128.2 ± 0.2 ppm and 139.6 ± 0.2 ppm.

[0330] 112. Compound I in pure form E according to any one of Examples 90 to 111, characterized in that it is substantially similar to Figure 14 of 13 C ss NMR spectrum.

[0331] 113. Compound I in pure form E according to any one of Examples 90 to 112, characterized in that it has the following orthorhombic crystal system, space group P212121, and unit cell size, wherein it is equipped with Cu K α Radiation (λ = 1.54178 Å) and measurements at 100 K on a Rigaku diffractometer with an HPAD detector:

[0332]

[0333] 114. Compound I in pure form E according to any one of Examples 90 to 113, which is prepared by a method comprising: (i) stirring compound I in pure form A in MeOAc, and (ii) separating the solid by centrifugation, and (iii) drying the solid at about 50°C.

[0334] 115. Compound I is in essentially crystalline compressed form E (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form).

[0335] 116. Compound I according to Example 115, wherein compound I is 100% crystalline compound I in compressed form E.

[0336] 117. Basically pure compound I in compressed form E.

[0337] 118. Compound I in compressed form E according to any one of Examples 115 to 117, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 2θ values ​​of 7.5 ± 0.2 degrees 2θ and 20.8 ± 0.2 degrees 2θ and (b) signals at 16.1 ± 0.2 degrees 2θ and / or 8.6 ± 0.2 degrees 2θ.

[0338] 119. Compound I in compressed form E according to any one of Examples 115 to 117, characterized in that it has the following X-ray powder diffraction patterns: signals at 2θ values ​​of 7.5 ± 0.2 degrees 2θ, 20.8 ± 0.2 degrees 2θ, 16.1 ± 0.2 degrees 2θ and 8.6 ± 0.2 degrees 2θ.

[0339] 120. Compound I in compressed form E according to any one of Examples 115 to 117, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 2θ values ​​of 7.5 ± 0.2 degrees 2θ, 20.8 ± 0.2 degrees 2θ, 16.1 ± 0.2 degrees 2θ and 8.6 ± 0.2 degrees 2θ and (b) signals at one or more 2θ values ​​selected from the following: 18.4 ± 0.2 degrees 2θ, 20.1 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ and 23.1 ± 0.2 degrees 2θ.

[0340] 121. Compound I in compressed form E according to any one of Examples 115 to 117, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 2θ values ​​of 7.5 ± 0.2 degrees 2θ, 20.8 ± 0.2 degrees 2θ, 16.1 ± 0.2 degrees 2θ and 8.6 ± 0.2 degrees 2θ and (b) signals at two or more 2θ values ​​selected from the following: 18.4 ± 0.2 degrees 2θ, 20.1 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ and 23.1 ± 0.2 degrees 2θ.

[0341] 122. Compound I in compressed form E according to any one of Examples 115 to 117, characterized in that it has the following X-ray powder diffraction patterns: (a) signals at 2θ values ​​of 7.5 ± 0.2 degrees 2θ, 20.8 ± 0.2 degrees 2θ, 16.1 ± 0.2 degrees 2θ and 8.6 ± 0.2 degrees 2θ and (b) signals at three or more 2θ values ​​selected from the following: 18.4 ± 0.2 degrees 2θ, 20.1 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ and 23.1 ± 0.2 degrees 2θ.

[0342] 123. Compound I in compressed form E according to any one of Examples 115 to 117, characterized in that it has the following X-ray powder diffraction patterns: signals at 2θ values ​​of 7.5 ± 0.2 degrees 2θ, 20.8 ± 0.2 degrees 2θ, 16.1 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 18.4 ± 0.2 degrees 2θ, 20.1 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, and 23.1 ± 0.2 degrees 2θ.

[0343] 124. The compressed form E of compound I according to any one of Examples 115 to 123, characterized in that it is substantially similar to Figure 16 X-ray powder diffraction pattern.

[0344] 125. Compound I in compressed form E according to any one of Examples 115 to 124, characterized in that it has peaks at 41.8 ± 0.2 ppm and 135.7 ± 0.2 ppm. 13 CssNMR spectrum.

[0345] 126. The compressed form E of compound I according to any one of Examples 115 to 124, characterized in that it has the following 13 C ss NMR spectra: (a) peaks at 41.8 ± 0.2 ppm and 135.7 ± 0.2 ppm and (b) one or more peaks selected from 28.2 ± 0.2 ppm, 22.0 ± 0.2 ppm, 129.8 ± 0.2 ppm, 136.2 ± 0.2 ppm and 141.1 ± 0.2 ppm.

[0346] 127. The compressed form E of compound I according to any one of Examples 115 to 124, characterized in that it has the following 13 C ss NMR spectra: (a) peaks at 41.8 ± 0.2 ppm and 135.7 ± 0.2 ppm and (b) two or more peaks selected from 28.2 ± 0.2 ppm, 22.0 ± 0.2 ppm, 129.8 ± 0.2 ppm, 136.2 ± 0.2 ppm and 141.1 ± 0.2 ppm.

[0347] 128. The compressed form E of compound I according to any one of Examples 115 to 124, characterized in that it has the following 13 C ss NMR spectra: (a) peaks at 41.8 ± 0.2 ppm and 135.7 ± 0.2 ppm and (b) three or more peaks selected from 28.2 ± 0.2 ppm, 22.0 ± 0.2 ppm, 129.8 ± 0.2 ppm, 136.2 ± 0.2 ppm and 141.1 ± 0.2 ppm.

[0348] 129. The compressed form E of compound I according to any one of Examples 115 to 124, characterized in that it has the following 13C ss NMR spectra: (a) peaks at 41.8 ± 0.2 ppm and 135.7 ± 0.2 ppm and (b) four or more peaks selected from 28.2 ± 0.2 ppm, 22.0 ± 0.2 ppm, 129.8 ± 0.2 ppm, 136.2 ± 0.2 ppm and 141.1 ± 0.2 ppm.

[0349] 130. The compressed form E of compound I according to any one of Examples 115 to 124, characterized in that it has the following 13 C ss NMR spectrum: peaks at 41.8 ± 0.2 ppm, 135.7 ± 0.2 ppm, 28.2 ± 0.2 ppm, 22.0 ± 0.2 ppm, 129.8 ± 0.2 ppm, 136.2 ± 0.2 ppm and 141.1 ± 0.2 ppm.

[0350] 131. The compressed form E of compound I according to any one of Examples 115 to 124, characterized in that it has the following... 13 C ss NMR spectrum: peaks at 41.8 ± 0.2 ppm, 135.7 ± 0.2 ppm, 28.2 ± 0.2 ppm, 22.0 ± 0.2 ppm, 129.8 ± 0.2 ppm, 136.2 ± 0.2 ppm, 141.1 ± 0.2 ppm and 127.3 ± 0.2 ppm.

[0351] 132. The compressed form E of compound I according to any one of Examples 115 to 131, characterized in that it is substantially similar to Figure 17 of 13 CssNMR spectrum.

[0352] 133. The compressed form E of compound I according to any one of Examples 115 to 132, which is prepared by a method comprising mechanically compressing the pure form E of compound I.

[0353] 134. Compound I is in essentially crystalline compressed form A (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form).

[0354] 135. Compound I according to Example 134, wherein compound I is 100% crystalline compound I in compressed form A.

[0355] 136. Basically pure compound I is compressed into form A.

[0356] 137. Compound I in compressed form A according to any one of Examples 134 to 136, characterized in that it has the following X-ray powder diffraction pattern: signals at (a) 8.9 ± 0.2 degrees 2θ, 15.2 ± 0.2 degrees 2θ, 15.8 ± 0.2 degrees 2θ and (b) selected from one or more of 18.2 ± 0.2 degrees 2θ, 20.9 ± 0.2 degrees 2θ and 16.7 ± 0.2 degrees 2θ.

[0357] 138. Compound I in compressed form A according to any one of Examples 134 to 136, characterized in that it has the following X-ray powder diffraction pattern: signals at (a) 8.9 ± 0.2 degrees 2θ, 15.2 ± 0.2 degrees 2θ, 15.8 ± 0.2 degrees 2θ and (b) selected from two or more of 18.2 ± 0.2 degrees 2θ, 20.9 ± 0.2 degrees 2θ and 16.7 ± 0.2 degrees 2θ.

[0358] 139. Compound I in compressed form A according to any one of Examples 134 to 136, characterized in that it has the following X-ray powder diffraction patterns: signals at 8.9 ± 0.2 degrees 2θ, 15.2 ± 0.2 degrees 2θ, 15.8 ± 0.2 degrees 2θ, 18.2 ± 0.2 degrees 2θ, 20.9 ± 0.2 degrees 2θ and 16.7 ± 0.2 degrees 2θ.

[0359] 140. Compound I in compressed form A according to any one of Examples 134 to 136, characterized in that it has the following X-ray powder diffraction patterns: signals at (a) 8.9 ± 0.2 degrees 2θ, 15.2 ± 0.2 degrees 2θ, 15.8 ± 0.2 degrees 2θ, 18.2 ± 0.2 degrees 2θ, 20.9 ± 0.2 degrees 2θ and 16.7 ± 0.2 degrees 2θ and (b) 21.5 ± 0.2 degrees 2θ or 23.0 ± 0.2 degrees 2θ.

[0360] 141. Compound I in compressed form A according to any one of Examples 134 to 136, characterized in that it has the following X-ray powder diffraction patterns: signals at 8.9 ± 0.2 degrees 2θ, 15.2 ± 0.2 degrees 2θ, 15.8 ± 0.2 degrees 2θ, 18.2 ± 0.2 degrees 2θ, 20.9 ± 0.2 degrees 2θ, 16.7 ± 0.2 degrees 2θ, 21.5 ± 0.2 degrees 2θ, and 23.0 ± 0.2 degrees 2θ.

[0361] 142. The compressed form A of compound I according to any one of Examples 134 to 141, characterized in that it is substantially similar to Figure 18X-ray powder diffraction pattern.

[0362] 143. The compression form A according to any one of embodiments 134 to 142, characterized in that it has the following 13 CssNMR spectra: (a) the peak at 28.9 ± 0.2 ppm and (b) one or more peaks selected from 41.9 ± 0.2 ppm, 21.6 ± 0.2 ppm, 132.9 ± 0.2 ppm and 127.5 ± 0.2 ppm.

[0363] 144. The compressed form A of compound I according to any one of Examples 134 to 142, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 28.9 ± 0.2 ppm and (b) two or more peaks selected from 41.9 ± 0.2 ppm, 21.6 ± 0.2 ppm, 132.9 ± 0.2 ppm and 127.5 ± 0.2 ppm.

[0364] 145. Compound I in compressed form A according to any one of Examples 134 to 142, characterized in that it has the following... 13 C ss NMR spectra: (a) the peak at 28.9 ± 0.2 ppm and (b) three or more peaks selected from 41.9 ± 0.2 ppm, 21.6 ± 0.2 ppm, 132.9 ± 0.2 ppm and 127.5 ± 0.2 ppm.

[0365] 146. Compound I in compressed form A according to any one of Examples 134 to 142, characterized in that it has the following 13 C ss NMR spectrum: peaks at 28.9 ± 0.2 ppm, 41.9 ± 0.2 ppm, 21.6 ± 0.2 ppm, 132.9 ± 0.2 ppm and 127.5 ± 0.2 ppm.

[0366] 147. Compound I in compressed form A according to any one of Examples 134 to 142, characterized in that it has the following 13 C ss NMR spectra: peaks at (a) 28.9 ± 0.2 ppm, 41.9 ± 0.2 ppm, 21.6 ± 0.2 ppm, 132.9 ± 0.2 ppm and 127.5 ± 0.2 ppm and (b) selected from one or more of 130.7 ± 0.2 ppm, 133.7 ± 0.2 ppm and 22.5 ± 0.2 ppm.

[0367] 148. Compound I in compressed form A according to any one of Examples 134 to 142, characterized in that it has the following 13 C ss NMR spectra: peaks at (a) 28.9 ± 0.2 ppm, 41.9 ± 0.2 ppm, 21.6 ± 0.2 ppm, 132.9 ± 0.2 ppm and 127.5 ± 0.2 ppm and (b) selected from two or more of 130.7 ± 0.2 ppm, 133.7 ± 0.2 ppm and 22.5 ± 0.2 ppm.

[0368] 149. Compound I in compressed form A according to any one of Examples 134 to 142, characterized in that it has the following 13 C ss NMR spectrum: peaks at 28.9 ± 0.2 ppm, 41.9 ± 0.2 ppm, 21.6 ± 0.2 ppm, 132.9 ± 0.2 ppm, 127.5 ± 0.2 ppm, 130.7 ± 0.2 ppm, 133.7 ± 0.2 ppm and 22.5 ± 0.2 ppm.

[0369] 150. Compound I in compressed form A according to any one of Examples 134 to 149, characterized in that it is substantially similar to Figure 18 of 13 C ss NMR spectrum.

[0370] 151. The compressed form A of compound I according to any one of Examples 134 to 150, which is prepared by a method comprising mechanically compressing the pure form A of compound I.

[0371] 152. Compound I is in the essentially crystalline EtOH solvate form B (i.e., less than 15% of compound I is in the amorphous form, less than 10% of compound I is in the amorphous form, and less than 5% of compound I is in the amorphous form).

[0372] 153. Compound I according to Example 152, wherein compound I is 100% crystalline compound I in EtOH solvate form B.

[0373] 154. Basically pure compound I is in solvate form B of EtOH.

[0374] 155. Compound I EtOH solvate form B according to any one of Examples 152 to 154, characterized in that it has the following X-ray powder diffraction pattern: a signal at one or more selected from the following 2θ values: 6.4 ± 0.2 degrees 2θ, 10.8 ± 0.2 degrees 2θ, 7.1 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 10.2 ± 0.2 degrees 2θ, 17.5 ± 0.2 degrees 2θ and 19.5 ± 0.2 degrees 2θ.

[0375] 156. Compound I EtOH solvate form B according to any one of Examples 152 to 155, characterized in that it has the following X-ray powder diffraction pattern: signals at two or more 2θ values ​​selected from the following: 6.4 ± 0.2 degrees 2θ, 10.8 ± 0.2 degrees 2θ, 7.1 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 10.2 ± 0.2 degrees 2θ, 17.5 ± 0.2 degrees 2θ and 19.5 ± 0.2 degrees 2θ.

[0376] 157. Compound I EtOH solvate form B according to any one of Examples 152 to 156, characterized in that it has the following X-ray powder diffraction pattern: signals at three or more 2θ values ​​selected from the following: 6.4 ± 0.2 degrees 2θ, 10.8 ± 0.2 degrees 2θ, 7.1 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 10.2 ± 0.2 degrees 2θ, 17.5 ± 0.2 degrees 2θ and 19.5 ± 0.2 degrees 2θ.

[0377] 158. Compound I EtOH solvate form B according to any one of Examples 152 to 157, characterized in that it has the following X-ray powder diffraction pattern: signals at four or more 2θ values ​​selected from the following: 6.4 ± 0.2 degrees 2θ, 10.8 ± 0.2 degrees 2θ, 7.1 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 10.2 ± 0.2 degrees 2θ, 17.5 ± 0.2 degrees 2θ and 19.5 ± 0.2 degrees 2θ.

[0378] 159. Compound I EtOH solvate form B according to any one of Examples 152 to 158, characterized in that it has the following X-ray powder diffraction pattern: signals at five or more 2θ values ​​selected from the following: 6.4 ± 0.2 degrees 2θ, 10.8 ± 0.2 degrees 2θ, 7.1 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 10.2 ± 0.2 degrees 2θ, 17.5 ± 0.2 degrees 2θ and 19.5 ± 0.2 degrees 2θ.

[0379] 160. Compound I EtOH solvate form B according to any one of Examples 152 to 159, characterized in that it has the following X-ray powder diffraction pattern: signals at six or more 2θ values ​​selected from the following: 6.4 ± 0.2 degrees 2θ, 10.8 ± 0.2 degrees 2θ, 7.1 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 10.2 ± 0.2 degrees 2θ, 17.5 ± 0.2 degrees 2θ and 19.5 ± 0.2 degrees 2θ.

[0380] 161. Compound I EtOH solvate form B according to any one of Examples 152 to 160, characterized in that it has the following X-ray powder diffraction pattern: signals at seven or more 2θ values ​​selected from the following: 6.4 ± 0.2 degrees 2θ, 10.8 ± 0.2 degrees 2θ, 7.1 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 10.2 ± 0.2 degrees 2θ, 17.5 ± 0.2 degrees 2θ and 19.5 ± 0.2 degrees 2θ.

[0381] 162. Compound I EtOH solvate form B according to any one of Examples 152 to 161, characterized in that it has the following X-ray powder diffraction pattern: signals at 2θ values ​​of 6.4 ± 0.2 degrees 2θ, 10.8 ± 0.2 degrees 2θ, 7.1 ± 0.2 degrees 2θ, 14.2 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 10.2 ± 0.2 degrees 2θ, 17.5 ± 0.2 degrees 2θ and 19.5 ± 0.2 degrees 2θ.

[0382] 163. Compound I EtOH solvate form B according to any one of Examples 152 to 162, characterized in that it is substantially similar to Figure 20 X-ray powder diffraction pattern.

[0383] 164. Compound I EtOH solvate form B according to any one of Examples 152 to 163, characterized in that it exhibits a TGA loss of about 5.29% by weight from ambient temperature to up to about 90°C.

[0384] 165. Compound I EtOH solvate form B according to any one of Examples 152 to 164, characterized in that it is substantially similar to Figure 21 TGA data.

[0385] 166. Compound I EtOH solvate form B according to any one of Examples 152 to 165, characterized by DSC analysis showing endothermic peaks at about 109°C and about 197°C.

[0386] 167. Compound I EtOH solvate form B according to any one of Examples 152 to 166, characterized in that it is substantially similar to Figure 22 DSC analysis.

[0387] 168. Compound I EtOH solvate form B according to any one of Examples 152 to 167, characterized in that it has one or more peaks selected from the group consisting of 13 Css NMR spectra: 28.1 ± 0.2 ppm, 18.7 ± 0.2 ppm, 44.1 ± 0.2 ppm, 128.9 ± 0.2 ppm, 21.6 ± 0.2 ppm, 142.8 ± 0.2 ppm, 132.0 ± 0.2 ppm and 130.4.

[0388] 169. Compound I, EtOH solvate form B according to any one of Examples 152 to 168, characterized in that it has two or more peaks selected from the group consisting of 13 Css NMR spectra: 28.1 ± 0.2 ppm, 18.7 ± 0.2 ppm, 44.1 ± 0.2 ppm, 128.9 ± 0.2 ppm, 21.6 ± 0.2 ppm, 142.8 ± 0.2 ppm, 132.0 ± 0.2 ppm and 130.4.

[0389] 170. Compound I, EtOH solvate form B according to any one of Examples 152 to 169, characterized in that it has three or more peaks selected from the group consisting of 13Css NMR spectra: 28.1 ± 0.2 ppm, 18.7 ± 0.2 ppm, 44.1 ± 0.2 ppm, 128.9 ± 0.2 ppm, 21.6 ± 0.2 ppm, 142.8 ± 0.2 ppm, 132.0 ± 0.2 ppm and 130.4.

[0390] 171. Compound I EtOH solvate form B according to any one of Examples 152 to 170, characterized in that it has four or more peaks selected from the group consisting of 13 Css NMR spectra: 28.1 ± 0.2 ppm, 18.7 ± 0.2 ppm, 44.1 ± 0.2 ppm, 128.9 ± 0.2 ppm, 21.6 ± 0.2 ppm, 142.8 ± 0.2 ppm, 132.0 ± 0.2 ppm and 130.4.

[0391] 172. Compound I, EtOH solvate form B according to any one of Examples 152 to 171, is characterized by having five or more peaks selected from the group consisting of... 13 Css NMR spectra: 28.1 ± 0.2 ppm, 18.7 ± 0.2 ppm, 44.1 ± 0.2 ppm, 128.9 ± 0.2 ppm, 21.6 ± 0.2 ppm, 142.8 ± 0.2 ppm, 132.0 ± 0.2 ppm and 130.4.

[0392] 173. Compound I EtOH solvate form B according to any one of Examples 152 to 172, characterized in that it has six or more peaks selected from the group consisting of 13 Css NMR spectra: 28.1 ± 0.2 ppm, 18.7 ± 0.2 ppm, 44.1 ± 0.2 ppm, 128.9 ± 0.2 ppm, 21.6 ± 0.2 ppm, 142.8 ± 0.2 ppm, 132.0 ± 0.2 ppm and 130.4.

[0393] 174. Compound I, EtOH solvate form B according to any one of Examples 152 to 173, is characterized by having seven or more peaks selected from the group consisting of... 13Css NMR spectra: 28.1 ± 0.2 ppm, 18.7 ± 0.2 ppm, 44.1 ± 0.2 ppm, 128.9 ± 0.2 ppm, 21.6 ± 0.2 ppm, 142.8 ± 0.2 ppm, 132.0 ± 0.2 ppm and 130.4.

[0394] 175. Compound I EtOH solvate form B according to any one of Examples 152 to 174, characterized in that it has the following 13 C ss NMR spectrum: peaks at 28.1 ± 0.2 ppm, 18.7 ± 0.2 ppm, 44.1 ± 0.2 ppm, 128.9 ± 0.2 ppm, 21.6 ± 0.2 ppm, 142.8 ± 0.2 ppm, 132.0 ± 0.2 ppm and 130.4 ppm.

[0395] 176. Compound I EtOH solvate form B according to any one of Examples 152 to 175, characterized in that it is substantially similar to Figure 23 of 13 CssNMR spectrum.

[0396] 177. Compound I EtOH solvate form B according to any one of Examples 152 to 176, characterized in that it has the following monoclinic crystal system, space group P212121, and unit cell size, wherein it is equipped with Cu K α Radiation (λ = 1.54178 Å) and measurements at 100 K on a Bruker diffractometer with a CPAD detector:

[0397]

[0398] 178. Compound I in EtOH solvate form B according to any one of Examples 152 to 177, which is prepared by a method comprising: (i) stirring compound I in ethanol, and (ii) separating the solid by centrifugation or vacuum filtration.

[0399] 179. Compound I is a substantially crystalline MeOH solvate (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form).

[0400] 180. Compound I according to Example 179, wherein Compound I is a 100% crystalline compound I MeOH solvate.

[0401] 181. Basically pure compound I MeOH solvate.

[0402] 182. The compound I MeOH solvate according to any one of Examples 179 to 181, characterized in that it has the following X-ray powder diffraction pattern: a signal at one or more selected from the following 2θ values: 26.1 ± 0.2 degrees 2θ, 12.2 ± 0.2 degrees 2θ, 22.8 ± 0.2 degrees 2θ and 21.1 ± 0.2 degrees 2θ.

[0403] 183. The MeOH solvate of compound I according to any one of Examples 179 to 182, characterized in that it has the following X-ray powder diffraction pattern: signals at two or more 2θ values ​​selected from the following: 26.1 ± 0.2 degrees 2θ, 12.2 ± 0.2 degrees 2θ, 22.8 ± 0.2 degrees 2θ and 21.1 ± 0.2 degrees 2θ.

[0404] 184. The MeOH solvate of compound I according to any one of Examples 179 to 183, characterized in that it has the following X-ray powder diffraction pattern: signals at three or more 2θ values ​​selected from the following: 26.1 ± 0.2 degrees 2θ, 12.2 ± 0.2 degrees 2θ, 22.8 ± 0.2 degrees 2θ and 21.1 ± 0.2 degrees 2θ.

[0405] 185. The compound I MeOH solvate according to any one of Examples 179 to 184, characterized in that it has the following X-ray powder diffraction patterns: signals at 26.1 ± 0.2 degrees 2θ, 12.2 ± 0.2 degrees 2θ, 22.8 ± 0.2 degrees 2θ and 21.1 ± 0.2 degrees 2θ.

[0406] 186. The MeOH solvate of compound I according to any one of Examples 179 to 185, characterized in that it is substantially similar to Figure 24 X-ray powder diffraction pattern.

[0407] 187. The MeOH solvate of compound I according to any one of Examples 179 to 186, characterized in that it has one or more peaks selected from the group consisting of 13 C ssNMR spectrum: 129.1 ± 0.2 ppm, 136.6 ± 0.2 ppm, 136.5 ± 0.2 ppm, 129.6 ± 0.2 ppm, 142.6 ± 0.2 ppm, 130.5 ± 0.2 ppm, 128.2 ± 0.2 ppm and 130.0 ± 0.2 ppm.

[0408] 188. The MeOH solvate of compound I according to any one of Examples 179 to 187, characterized in that it has two or more peaks selected from the group consisting of 13 C ssNMR spectrum: 129.1 ± 0.2 ppm, 136.6 ± 0.2 ppm, 136.5 ± 0.2 ppm, 129.6 ± 0.2 ppm, 142.6 ± 0.2 ppm, 130.5 ± 0.2 ppm, 128.2 ± 0.2 ppm and 130.0 ± 0.2 ppm.

[0409] 189. The MeOH solvate of compound I according to any one of Examples 179 to 188, characterized in that it has three or more peaks selected from the group consisting of 13 C ssNMR spectrum: 129.1 ± 0.2 ppm, 136.6 ± 0.2 ppm, 136.5 ± 0.2 ppm, 129.6 ± 0.2 ppm, 142.6 ± 0.2 ppm, 130.5 ± 0.2 ppm, 128.2 ± 0.2 ppm and 130.0 ± 0.2 ppm.

[0410] 190. The MeOH solvate of compound I according to any one of Examples 179 to 189, characterized in that it has four or more peaks selected from the group consisting of 13 C ssNMR spectrum: 129.1 ± 0.2 ppm, 136.6 ± 0.2 ppm, 136.5 ± 0.2 ppm, 129.6 ± 0.2 ppm, 142.6 ± 0.2 ppm, 130.5 ± 0.2 ppm, 128.2 ± 0.2 ppm and 130.0 ± 0.2 ppm.

[0411] 191. The MeOH solvate of compound I according to any one of Examples 179 to 190, characterized in that it has five or more peaks selected from the following, expressed in ppm ± 0.2. 13 C ssNMR spectrum: 129.1 ± 0.2 ppm, 136.6 ± 0.2 ppm, 136.5 ± 0.2 ppm, 129.6 ± 0.2 ppm, 142.6 ± 0.2 ppm, 130.5 ± 0.2 ppm, 128.2 ± 0.2 ppm, 130.0 ± 0.2 ppm.

[0412] 192. The MeOH solvate of compound I according to any one of Examples 179 to 191, characterized in that it has six or more peaks selected from the group consisting of 13 C ssNMR spectrum: 129.1 ± 0.2 ppm, 136.6 ± 0.2 ppm, 136.5 ± 0.2 ppm, 129.6 ± 0.2 ppm, 142.6 ± 0.2 ppm, 130.5 ± 0.2 ppm, 128.2 ± 0.2 ppm and 130.0 ± 0.2 ppm.

[0413] 193. The MeOH solvate of compound I according to any one of Examples 179 to 192, characterized in that it has seven or more peaks selected from the group consisting of 13 C ssNMR spectrum: 129.1 ± 0.2 ppm, 136.6 ± 0.2 ppm, 136.5 ± 0.2 ppm, 129.6 ± 0.2 ppm, 142.6 ± 0.2 ppm, 130.5 ± 0.2 ppm, 128.2 ± 0.2 ppm and 130.0 ± 0.2 ppm.

[0414] 194. The MeOH solvate of compound I according to any one of Examples 179 to 193, characterized in that it has the following 13 C ss NMR spectrum: peaks at 129.1 ± 0.2 ppm, 136.6 ± 0.2 ppm, 136.5 ± 0.2 ppm, 129.6 ± 0.2 ppm, 142.6 ± 0.2 ppm, 130.5 ± 0.2 ppm, 128.2 ± 0.2 ppm and 130.0 ± 0.2 ppm.

[0415] 195. The MeOH solvate of compound I according to any one of Examples 179 to 194, characterized in that it is substantially similar to Figure 25 of 13 CssNMR spectrum.

[0416] 196. The MeOH solvate of compound I according to any one of Examples 179 to 195, characterized in that it has the following monoclinic crystal system, space group P212121, and unit cell size, wherein it is equipped with Cu K α Radiation (λ = 1.54178 Å) and measurements at 100 K on a Bruker diffractometer with a CPAD detector:

[0417]

[0418] 197. The compound I MeOH solvate according to any one of Examples 179 to 196, which is prepared by a method comprising: (i) dissolving compound I in MeOH and increasing the temperature to about 62°C, (ii) cooling the solution to about 10°C, and (iii) separating the solid by centrifugation.

[0419] 198. Compound I is a substantially crystalline NPA solvate (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form).

[0420] 199. Compound I according to Example 198, wherein Compound I is a 100% crystalline compound I NPA solvate.

[0421] 200. Basically pure compound I NPA solvate.

[0422] 201. The compound I NPA solvate according to any one of Examples 198 to 200, characterized in that it has the following X-ray powder diffraction pattern: a signal at one or more selected from the following 2θ values: 10.6 ± 0.2 degrees 2θ, 6.3 ± 0.2 degrees 2θ, 19.1 ± 0.2 degrees 2θ, 19.6 ± 0.2 degrees 2θ, 17.3 ± 0.2 degrees 2θ, 17.2 ± 0.2 degrees 2θ, 10.0 ± 0.2 degrees 2θ and 14.0 ± 0.2 degrees 2θ.

[0423] 202. The compound I NPA solvate according to any one of Examples 198 to 201, characterized in that it has the following X-ray powder diffraction pattern: signals at two or more 2θ values ​​selected from the following: 10.6 ± 0.2 degrees 2θ, 6.3 ± 0.2 degrees 2θ, 19.1 ± 0.2 degrees 2θ, 19.6 ± 0.2 degrees 2θ, 17.3 ± 0.2 degrees 2θ, 17.2 ± 0.2 degrees 2θ, 10.0 ± 0.2 degrees 2θ and 14.0 ± 0.2 degrees 2θ.

[0424] 203. The compound I NPA solvate according to any one of Examples 198 to 202, characterized in that it has the following X-ray powder diffraction pattern: signals at three or more 2θ values ​​selected from the following: 10.6 ± 0.2 degrees 2θ, 6.3 ± 0.2 degrees 2θ, 19.1 ± 0.2 degrees 2θ, 19.6 ± 0.2 degrees 2θ, 17.3 ± 0.2 degrees 2θ, 17.2 ± 0.2 degrees 2θ, 10.0 ± 0.2 degrees 2θ and 14.0 ± 0.2 degrees 2θ.

[0425] 204. The compound I NPA solvate according to any one of Examples 198 to 203, characterized in that it has the following X-ray powder diffraction pattern: signals at four or more 2θ values ​​selected from the following: 10.6 ± 0.2 degrees 2θ, 6.3 ± 0.2 degrees 2θ, 19.1 ± 0.2 degrees 2θ, 19.6 ± 0.2 degrees 2θ, 17.3 ± 0.2 degrees 2θ, 17.2 ± 0.2 degrees 2θ, 10.0 ± 0.2 degrees 2θ and 14.0 ± 0.2 degrees 2θ.

[0426] 205. The compound I NPA solvate according to any one of Examples 198 to 204, characterized in that it has the following X-ray powder diffraction pattern: signals at five or more 2θ values ​​selected from the following: 10.6 ± 0.2 degrees 2θ, 6.3 ± 0.2 degrees 2θ, 19.1 ± 0.2 degrees 2θ, 19.6 ± 0.2 degrees 2θ, 17.3 ± 0.2 degrees 2θ, 17.2 ± 0.2 degrees 2θ, 10.0 ± 0.2 degrees 2θ, and 14.0 ± 0.2 degrees 2θ.

[0427] 206. The compound I NPA solvate according to any one of Examples 198 to 205, characterized in that it has the following X-ray powder diffraction pattern: signals at six or more 2θ values ​​selected from the following: 10.6 ± 0.2 degrees 2θ, 6.3 ± 0.2 degrees 2θ, 19.1 ± 0.2 degrees 2θ, 19.6 ± 0.2 degrees 2θ, 17.3 ± 0.2 degrees 2θ, 17.2 ± 0.2 degrees 2θ, 10.0 ± 0.2 degrees 2θ, and 14.0 ± 0.2 degrees 2θ.

[0428] 207. The compound I NPA solvate according to any one of Examples 198 to 206, characterized in that it has the following X-ray powder diffraction pattern: signals at seven or more 2θ values ​​selected from the following: 10.6 ± 0.2 degrees 2θ, 6.3 ± 0.2 degrees 2θ, 19.1 ± 0.2 degrees 2θ, 19.6 ± 0.2 degrees 2θ, 17.3 ± 0.2 degrees 2θ, 17.2 ± 0.2 degrees 2θ, 10.0 ± 0.2 degrees 2θ, and 14.0 ± 0.2 degrees 2θ.

[0429] 208. The compound I NPA solvate according to any one of Examples 198 to 207, characterized in that it has the following X-ray powder diffraction patterns: signals at 10.6 ± 0.2 degrees 2θ, 6.3 ± 0.2 degrees 2θ, 19.1 ± 0.2 degrees 2θ, 19.6 ± 0.2 degrees 2θ, 17.3 ± 0.2 degrees 2θ, 17.2 ± 0.2 degrees 2θ, 10.0 ± 0.2 degrees 2θ and 14.0 ± 0.2 degrees 2θ.

[0430] 209. The NPA solvate of compound I according to any one of Examples 198 to 208, characterized in that it is substantially similar to Figure 26 X-ray powder diffraction pattern.

[0431] 210. The NPA solvate of compound I according to any one of Examples 198 to 209, characterized in that it has one or more peaks selected from the group consisting of 13 C ssNMR spectrum: 28.0 ± 0.2 ppm, 30.0 ± 0.2 ppm, 128.7 ± 0.2 ppm, 44.0 ± 0.2 ppm, 130.0 ± 0.2 ppm, 131.0 ± 0.2 ppm, 12.7 ± 0.2 ppm and 10.8 ± 0.2 ppm.

[0432] 211. The NPA solvate of compound I according to any one of Examples 198 to 210, characterized in that it has two or more peaks selected from the group consisting of 13 C ssNMR spectrum: 28.0 ± 0.2 ppm, 30.0 ± 0.2 ppm, 128.7 ± 0.2 ppm, 44.0 ± 0.2 ppm, 130.0 ± 0.2 ppm, 131.0 ± 0.2 ppm, 12.7 ± 0.2 ppm and 10.8 ± 0.2 ppm.

[0433] 212. The NPA solvate of compound I according to any one of Examples 198 to 211, characterized in that it has three or more peaks selected from the group consisting of 13 C ssNMR spectrum: 28.0 ± 0.2 ppm, 30.0 ± 0.2 ppm, 128.7 ± 0.2 ppm, 44.0 ± 0.2 ppm, 130.0 ± 0.2 ppm, 131.0 ± 0.2 ppm, 12.7 ± 0.2 ppm and 10.8 ± 0.2 ppm.

[0434] 213. The NPA solvate of compound I according to any one of Examples 198 to 212, characterized in that it has four or more peaks selected from the group consisting of 13 C ssNMR spectrum: 28.0 ± 0.2 ppm, 30.0 ± 0.2 ppm, 128.7 ± 0.2 ppm, 44.0 ± 0.2 ppm, 130.0 ± 0.2 ppm, 131.0 ± 0.2 ppm, 12.7 ± 0.2 ppm and 10.8 ± 0.2 ppm.

[0435] 214. The NPA solvate of compound I according to any one of Examples 198 to 213, characterized in that it has five or more peaks selected from the group consisting of 13 C ssNMR spectrum: 28.0 ± 0.2 ppm, 30.0 ± 0.2 ppm, 128.7 ± 0.2 ppm, 44.0 ± 0.2 ppm, 130.0 ± 0.2 ppm, 131.0 ± 0.2 ppm, 12.7 ± 0.2 ppm and 10.8 ± 0.2 ppm.

[0436] 215. The NPA solvate of compound I according to any one of Examples 198 to 214, characterized in that it has six or more peaks selected from the group consisting of 13 C ssNMR spectrum: 28.0 ± 0.2 ppm, 30.0 ± 0.2 ppm, 128.7 ± 0.2 ppm, 44.0 ± 0.2 ppm, 130.0 ± 0.2 ppm, 131.0 ± 0.2 ppm, 12.7 ± 0.2 ppm and 10.8 ± 0.2 ppm.

[0437] 216. The NPA solvate of compound I according to any one of Examples 198 to 215, characterized in that it has seven or more peaks selected from the group consisting of 13 C ssNMR spectrum: 28.0 ± 0.2 ppm, 30.0 ± 0.2 ppm, 128.7 ± 0.2 ppm, 44.0 ± 0.2 ppm, 130.0 ± 0.2 ppm, 131.0 ± 0.2 ppm, 12.7 ± 0.2 ppm and 10.8 ± 0.2 ppm.

[0438] 217. The NPA solvate of compound I according to any one of Examples 198 to 216, characterized in that it has the following 13C ss NMR spectrum: peaks at 28.0 ± 0.2 ppm, 30.0 ± 0.2 ppm, 128.7 ± 0.2 ppm, 44.0 ± 0.2 ppm, 130.0 ± 0.2 ppm, 131.0 ± 0.2 ppm, 12.7 ± 0.2 ppm and 10.8 ± 0.2 ppm.

[0439] 218. The NPA solvate of compound I according to any one of Examples 198 to 217, characterized in that it is substantially similar to Figure 27 of 13 CssNMR spectrum.

[0440] 219. The NPA solvate of compound I according to any one of Examples 198 to 218, which is prepared by a method comprising: (i) stirring compound I in NPA, and (ii) separating the solid by centrifugation.

[0441] 220. Compound I is in the form of a substantially crystalline MeOAc solvate A (i.e., less than 15% of compound I is in the amorphous form, less than 10% of compound I is in the amorphous form, and less than 5% of compound I is in the amorphous form).

[0442] 221. Compound I according to Example 220, wherein Compound I is 100% crystalline Compound I in MeOAc solvate form A.

[0443] 222. Basically, the pure compound I MeOAc is in solvate form A.

[0444] 223. Compound I MeOAc solvate form A according to any one of Examples 220 to 222, characterized in that it has the following X-ray powder diffraction patterns: (a) a signal at 8.5 ± 0.2 degrees 2θ and (b) a signal at one or more 2θ values ​​selected from the following: 19.9 ± 0.2 degrees 2θ, 21.3 ± 0.2 degrees 2θ and 10.1 ± 0.2 degrees 2θ.

[0445] 224. Compound I MeOAc solvate form A according to any one of Examples 220 to 222, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 8.5 ± 0.2 degrees 2θ and (b) signals at two or more 2θ values ​​selected from the following: 19.9 ± 0.2 degrees 2θ, 21.3 ± 0.2 degrees 2θ and 10.1 ± 0.2 degrees 2θ.

[0446] 225. Compound I MeOAc solvate form A according to any one of Examples 220 to 222, characterized in that it has the following X-ray powder diffraction patterns: signals at 8.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 21.3 ± 0.2 degrees 2θ and 10.1 ± 0.2 degrees 2θ.

[0447] 226. Compound I MeOAc solvate form A according to any one of Examples 220 to 222, characterized in that it has an X-ray powder diffraction pattern with the following signals: (a) signals at 8.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 21.3 ± 0.2 degrees 2θ and 10.1 ± 0.2 degrees 2θ and (b) signals at 15.9 ± 0.2 degrees 2θ and / or 13.2 ± 0.2 degrees 2θ.

[0448] 227. Compound I MeOAc solvate form A according to any one of Examples 220 to 222, characterized in that it has the following X-ray powder diffraction patterns: signals at 8.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 21.3 ± 0.2 degrees 2θ, 10.1 ± 0.2 degrees 2θ, 15.9 ± 0.2 degrees 2θ, and 13.2 ± 0.2 degrees 2θ.

[0449] 228. Compound I MeOAc solvate form A according to any one of Examples 220 to 222, characterized in that it has the following X-ray powder diffraction pattern: signals at 8.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 21.3 ± 0.2 degrees 2θ and 10.1 ± 0.2 degrees 2θ, 15.9 ± 0.2 degrees 2θ, 13.2 ± 0.2 degrees 2θ, 16.0 ± 0.2 degrees 2θ and 19.4 ± 0.2 degrees 2θ.

[0450] 229. Compound I MeOAc solvate form A according to any one of Examples 220 to 228, characterized in that it is substantially similar to... Figure 28 X-ray powder diffraction pattern.

[0451] 230. Compound I MeOAc solvate form A according to any one of Examples 220 to 229, characterized in that it exhibits a TGA with a weight loss of 1.68% from 30°C to 120°C.

[0452] 231. Compound I MeOAc solvate form A according to any one of Examples 220 to 230, characterized in that it is substantially similar to Figure 29 TGA data.

[0453] 232. The solvate form A of compound I MeOAc according to any one of Examples 220 to 231, characterized by DSC analysis showing endothermic peaks at about 100°C and about 216°C.

[0454] 233. Compound I MeOAc solvate form A according to any one of Examples 220 to 232, characterized in that it is substantially similar to... Figure 30 DSC analysis.

[0455] 234. Compound I MeOAc solvate form A according to any one of Examples 220 to 233, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 129.3 ± 0.2 ppm and (b) one or more peaks selected from the following: 43.3 ± 0.2 ppm, 29.8 ± 0.2 ppm, 33.2 ± 0.2 ppm, 171.5 ± 0.2 ppm and 45.1 ± 0.2 ppm.

[0456] 235. Compound I MeOAc solvate form A according to any one of Examples 220 to 233, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 129.3 ± 0.2 ppm and (b) two or more peaks selected from the following: 43.3 ± 0.2 ppm, 29.8 ± 0.2 ppm, 33.2 ± 0.2 ppm, 171.5 ± 0.2 ppm and 45.1 ± 0.2 ppm.

[0457] 236. Compound I MeOAc solvate form A according to any one of Examples 220 to 233, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 129.3 ± 0.2 ppm and (b) three or more peaks selected from the following: 43.3 ± 0.2 ppm, 29.8 ± 0.2 ppm, 33.2 ± 0.2 ppm, 171.5 ± 0.2 ppm and 45.1 ± 0.2 ppm.

[0458] 237. Compound I MeOAc solvate form A according to any one of Examples 220 to 233, characterized in that it has the following 13C ss NMR spectra: (a) the peak at 129.3 ± 0.2 ppm and (b) four or more peaks selected from the following: 43.3 ± 0.2 ppm, 29.8 ± 0.2 ppm, 33.2 ± 0.2 ppm, 171.5 ± 0.2 ppm and 45.1 ± 0.2 ppm.

[0459] 238. Compound I MeOAc solvate form A according to any one of Examples 220 to 233, characterized in that it has the following 13 C ss NMR spectrum: peaks at 129.3 ± 0.2 ppm, 43.3 ± 0.2 ppm, 29.8 ± 0.2 ppm, 33.2 ± 0.2 ppm, 171.5 ± 0.2 ppm and 45.1 ± 0.2 ppm.

[0460] 239. Compound I MeOAc solvate form A according to any one of Examples 220 to 233, characterized in that it has the following 13 C ss NMR spectra: (a) peaks at 129.3 ± 0.2 ppm, 43.3 ± 0.2 ppm, 29.8 ± 0.2 ppm, 33.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, and 45.1 ± 0.2 ppm and (b) peaks at 27.7 ± 0.2 ppm and / or 129.7 ± 0.2 ppm.

[0461] 240. Compound I MeOAc solvate form A according to any one of Examples 220 to 233, characterized in that it has the following 13 C ss NMR spectrum: peaks at 129.3 ± 0.2 ppm, 43.3 ± 0.2 ppm, 29.8 ± 0.2 ppm, 33.2 ± 0.2 ppm, 171.5 ± 0.2 ppm, 45.1 ± 0.2 ppm, 51.3 ± 0.2 ppm, 27.7 ± 0.2 ppm and 129.7 ± 0.2 ppm.

[0462] 241. Compound I MeOAc solvate form A according to any one of Examples 220 to 240, characterized in that it is substantially similar to Figure 31 of 13 CssNMR spectrum.

[0463] 242. Compound I in MeOAc solvate form A according to any one of Examples 220 to 241, which is prepared by a method comprising: (i) stirring compound I in pure form A in MeOAc, and (ii) separating the solid by filtration.

[0464] 243. Compound I is in the form of a substantially crystalline MeOAc solvate B (i.e., less than 15% of compound I is in the amorphous form, less than 10% of compound I is in the amorphous form, and less than 5% of compound I is in the amorphous form).

[0465] 244. Compound I according to Example 243, wherein compound I is 100% crystalline compound I in the form of MeOAc B.

[0466] 245. Basically pure compound I MeOAc solvate form B.

[0467] 246. Compound I MeOAc solvate form B according to any one of Examples 243 to 245, characterized in that it has the following X-ray powder diffraction pattern: a signal at 4.6 ± 0.2 degrees 2θ and / or a signal at 7.7 ± 0.2 degrees 2θ.

[0468] 247. Compound I MeOAc solvate form B according to any one of Examples 243 to 246, characterized in that it has the following X-ray powder diffraction patterns: signals at 4.6 ± 0.2 degrees 2θ and 7.7 ± 0.2 degrees 2θ.

[0469] 248. Compound I MeOAc solvate form B according to any one of Examples 243 to 247, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 4.6 ± 0.2 degrees 2θ and / or a signal at 7.7 ± 0.2 degrees 2θ, and (b) a signal at one or more 2θ values ​​selected from the following: 8.6 ± 0.2 degrees 2θ, 8.2 ± 0.2 degrees 2θ, 5.9 ± 0.2 degrees 2θ, 15.7 ± 0.2 degrees 2θ, 12.0 ± 0.2 degrees 2θ and 12.5 ± 0.2 degrees 2θ.

[0470] 249. Compound I MeOAc solvate form B according to any one of Examples 243 to 247, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 4.6 ± 0.2 degrees 2θ and / or a signal at 7.7 ± 0.2 degrees 2θ, and (b) a signal at two or more 2θ values ​​selected from the following: 8.6 ± 0.2 degrees 2θ, 8.2 ± 0.2 degrees 2θ, 5.9 ± 0.2 degrees 2θ, 15.7 ± 0.2 degrees 2θ, 12.0 ± 0.2 degrees 2θ and 12.5 ± 0.2 degrees 2θ.

[0471] 250. Compound I MeOAc solvate form B according to any one of Examples 243 to 247, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 4.6 ± 0.2 degrees 2θ and / or a signal at 7.7 ± 0.2 degrees 2θ, and (b) signals at three or more 2θ values ​​selected from the following: 8.6 ± 0.2 degrees 2θ, 8.2 ± 0.2 degrees 2θ, 5.9 ± 0.2 degrees 2θ, 15.7 ± 0.2 degrees 2θ, 12.0 ± 0.2 degrees 2θ and 12.5 ± 0.2 degrees 2θ.

[0472] 251. Compound I MeOAc solvate form B according to any one of Examples 243 to 247, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 4.6 ± 0.2 degrees 2θ and / or a signal at 7.7 ± 0.2 degrees 2θ, and (b) a signal at four or more 2θ values ​​selected from the following: 8.6 ± 0.2 degrees 2θ, 8.2 ± 0.2 degrees 2θ, 5.9 ± 0.2 degrees 2θ, 15.7 ± 0.2 degrees 2θ, 12.0 ± 0.2 degrees 2θ and 12.5 ± 0.2 degrees 2θ.

[0473] 252. Compound I MeOAc solvate form B according to any one of Examples 243 to 247, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 4.6 ± 0.2 degrees 2θ and / or a signal at 7.7 ± 0.2 degrees 2θ, and (b) signals at five or more 2θ values ​​selected from the following: 8.6 ± 0.2 degrees 2θ, 8.2 ± 0.2 degrees 2θ, 5.9 ± 0.2 degrees 2θ, 15.7 ± 0.2 degrees 2θ, 12.0 ± 0.2 degrees 2θ and 12.5 ± 0.2 degrees 2θ.

[0474] 253. Compound I MeOAc solvate form B according to any one of Examples 243 to 247, characterized in that it has the following X-ray powder diffraction patterns: signals at 4.6 ± 0.2 degrees 2θ, 7.7 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 8.2 ± 0.2 degrees 2θ, 5.9 ± 0.2 degrees 2θ, 15.7 ± 0.2 degrees 2θ, 12.0 ± 0.2 degrees 2θ, and 12.5 ± 0.2 degrees 2θ.

[0475] 254. Compound I MeOAc solvate form B according to any one of Examples 243 to 253, characterized in that it is substantially similar to... Figure 32 X-ray powder diffraction pattern.

[0476] 255. Compound I MeOAc solvate form B according to any one of Examples 243 to 254, characterized by a TGA showing a weight loss of about 1.39% from 30°C to 60°C and a weight loss of about 0.20% from 60°C to 190°C.

[0477] 256. Compound I MeOAc solvate form B according to any one of Examples 243 to 255, characterized in that it is substantially similar to... Figure 33 TGA data.

[0478] 257. Compound I MeOAc solvate form B according to any one of Examples 243 to 256, characterized by DSC analysis showing endothermic peaks at about 51°C and about 187°C.

[0479] 258. Compound I MeOAc solvate form B according to any one of Examples 243 to 257, characterized in that it is substantially similar to... Figure 34 DSC analysis.

[0480] 259. Compound I MeOAc solvate form B according to any one of Examples 243 to 258, characterized in that it has a peak at 50.4 ± 0.2 ppm. 13 CssNMR spectrum.

[0481] 260. Compound I MeOAc solvate form B according to any one of Examples 243 to 258, characterized in that it has the following 13C ss NMR spectra: (a) the peak at 50.4 ± 0.2 ppm and (b) one or more peaks selected from the following: 51.4 ± 0.2 ppm, 27.8 ± 0.2 ppm, 43.4 ± 0.2 ppm, 130.5 ± 0.2 ppm, 130.0 ± 0.2 ppm, 128.8 ± 0.2 ppm and 127.6 ± 0.2 ppm.

[0482] 261. Compound I MeOAc solvate form B according to any one of Examples 243 to 258, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 50.4 ± 0.2 ppm and (b) two or more peaks selected from the following: 51.4 ± 0.2 ppm, 27.8 ± 0.2 ppm, 43.4 ± 0.2 ppm, 130.5 ± 0.2 ppm, 130.0 ± 0.2 ppm, 128.8 ± 0.2 ppm and 127.6 ± 0.2 ppm.

[0483] 262. Compound I MeOAc solvate form B according to any one of Examples 243 to 258, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 50.4 ± 0.2 ppm and (b) three or more peaks selected from the following: 51.4 ± 0.2 ppm, 27.8 ± 0.2 ppm, 43.4 ± 0.2 ppm, 130.5 ± 0.2 ppm, 130.0 ± 0.2 ppm, 128.8 ± 0.2 ppm and 127.6 ± 0.2 ppm.

[0484] 263. Compound I MeOAc solvate form B according to any one of Examples 243 to 258, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 50.4 ± 0.2 ppm and (b) four or more peaks selected from the following: 51.4 ± 0.2 ppm, 27.8 ± 0.2 ppm, 43.4 ± 0.2 ppm, 130.5 ± 0.2 ppm, 130.0 ± 0.2 ppm, 128.8 ± 0.2 ppm and 127.6 ± 0.2 ppm.

[0485] 264. Compound I MeOAc solvate form B according to any one of Examples 243 to 258, characterized in that it has the following 13C ss NMR spectra: (a) the peak at 50.4 ± 0.2 ppm and (b) five or more peaks selected from the following: 51.4 ± 0.2 ppm, 27.8 ± 0.2 ppm, 43.4 ± 0.2 ppm, 130.5 ± 0.2 ppm, 130.0 ± 0.2 ppm, 128.8 ± 0.2 ppm and 127.6 ± 0.2 ppm.

[0486] 265. Compound I MeOAc solvate form B according to any one of Examples 243 to 258, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 50.4 ± 0.2 ppm and (b) six or more peaks selected from the following: 51.4 ± 0.2 ppm, 27.8 ± 0.2 ppm, 43.4 ± 0.2 ppm, 130.5 ± 0.2 ppm, 130.0 ± 0.2 ppm, 128.8 ± 0.2 ppm and 127.6 ± 0.2 ppm.

[0487] 266. Compound I MeOAc solvate form B according to any one of Examples 243 to 258, characterized in that it has the following 13 C ss NMR spectrum: peaks at 50.4 ± 0.2 ppm, 51.4 ± 0.2 ppm, 27.8 ± 0.2 ppm, 43.4 ± 0.2 ppm, 130.5 ± 0.2 ppm, 130.0 ± 0.2 ppm, 128.8 ± 0.2 ppm and 127.6 ± 0.2 ppm.

[0488] 267. Compound I MeOAc solvate form B according to any one of Examples 243 to 258, characterized in that it is substantially similar to... Figure 35 of 13 CssNMR spectrum.

[0489] 268. Compound I in MeOAc solvate form B according to any one of Examples 243 to 267, which is prepared by a method comprising: (i) stirring compound I in pure form A in MeOAc at about 5°C, (ii) separating the solid by centrifugation, and (iii) drying the solid at room temperature.

[0490] 269. Compound I is in the form of a substantially crystalline MeOAc solvate C (i.e., less than 15% of compound I is in the amorphous form, less than 10% of compound I is in the amorphous form, and less than 5% of compound I is in the amorphous form).

[0491] 270. Compound I according to Example 269, wherein compound I is 100% crystalline compound I in the form of MeOAc C.

[0492] 271. Basically pure compound I MeOAc solvate form C.

[0493] 272. The compound I MeOAc solvate form C according to any one of Examples 269 to 271, characterized in that it has the following X-ray powder diffraction pattern: signal at 6.4 ± 0.2 degrees 2θ.

[0494] 273. Compound I MeOAc solvate form C according to any one of Examples 269 to 271, characterized in that it has the following X-ray powder diffraction patterns: (a) a signal at 6.4 ± 0.2 degrees 2θ and (b) a signal at one or more 2θ values ​​selected from the following: 18.7 ± 0.2 degrees 2θ, 18.9 ± 0.2 degrees 2θ and 19.8 ± 0.2 degrees 2θ.

[0495] 274. Compound I MeOAc solvate form C according to any one of Examples 269 to 271, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 6.4 ± 0.2 degrees 2θ and (b) signals at two or more 2θ values ​​selected from the following: 18.7 ± 0.2 degrees 2θ, 18.9 ± 0.2 degrees 2θ and 19.8 ± 0.2 degrees 2θ.

[0496] 275. Compound I MeOAc solvate form C according to any one of Examples 269 to 271, characterized in that it has an X-ray powder diffraction pattern having the following signals: (a) a signal at 6.4 ± 0.2 degrees 2θ and (b) signals at three or more 2θ values ​​selected from the following: 18.7 ± 0.2 degrees 2θ, 18.9 ± 0.2 degrees 2θ and 19.8 ± 0.2 degrees 2θ.

[0497] 276. The compound I MeOAc solvate form C according to any one of Examples 269 to 271, characterized in that it has the following X-ray powder diffraction patterns: signals at 6.4 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ, 18.9 ± 0.2 degrees 2θ and 19.8 ± 0.2 degrees 2θ.

[0498] 277. Compound I MeOAc solvate form C according to any one of Examples 269 to 271, characterized in that it has an X-ray powder diffraction pattern with the following signals: (a) signals at 6.4 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ, 18.9 ± 0.2 degrees 2θ and 19.8 ± 0.2 degrees 2θ and (b) signals at one or more 2θ values ​​selected from the following: 16.8 ± 0.2 degrees 2θ, 19.0 ± 0.2 degrees 2θ, 12.9 ± 0.2 degrees 2θ and 14.1 ± 0.2 degrees 2θ.

[0499] 278. Compound I MeOAc solvate form C according to any one of Examples 269 to 271, characterized in that it has an X-ray powder diffraction pattern having the following signals: (a) signals at 6.4 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ, 18.9 ± 0.2 degrees 2θ and 19.8 ± 0.2 degrees 2θ and (b) signals at two or more 2θ values ​​selected from the following: 16.8 ± 0.2 degrees 2θ, 19.0 ± 0.2 degrees 2θ, 12.9 ± 0.2 degrees 2θ and 14.1 ± 0.2 degrees 2θ.

[0500] 279. Compound I MeOAc solvate form C according to any one of Examples 269 to 271, characterized in that it has an X-ray powder diffraction pattern having the following signals: (a) signals at 6.4 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ, 18.9 ± 0.2 degrees 2θ and 19.8 ± 0.2 degrees 2θ and (b) signals at three or more 2θ values ​​selected from the following: 16.8 ± 0.2 degrees 2θ, 19.0 ± 0.2 degrees 2θ, 14.1 ± 0.2 degrees 2θ and 19.2 ± 0.2 degrees 2θ.

[0501] 280. Compound I MeOAc solvate form C according to any one of Examples 269 to 271, characterized in that it has the following X-ray powder diffraction patterns: signals at 6.4 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ, 18.9 ± 0.2 degrees 2θ, 19.8 ± 0.2 degrees 2θ, 16.8 ± 0.2 degrees 2θ, 19.0 ± 0.2 degrees 2θ, 14.1 ± 0.2 degrees 2θ and 19.2 ± 0.2 degrees 2θ.

[0502] 281. Compound I MeOAc solvate form C according to any one of Examples 269 to 279, characterized in that it is substantially similar to... Figure 36 X-ray powder diffraction pattern.

[0503] 282. Compound I MeOAc solvate form C according to any one of Examples 269 to 281, characterized in that it has one or more peaks selected from the following 13 Css NMR spectra: 28.3 ± 0.2 ppm, 49.6 ± 0.2 ppm and 150.1 ± 0.2 ppm.

[0504] 283. Compound I MeOAc solvate form C according to any one of Examples 269 to 282, characterized in that it has two or more peaks selected from the group consisting of 13 Css NMR spectra: 28.3 ± 0.2 ppm, 49.6 ± 0.2 ppm and 150.1 ± 0.2 ppm.

[0505] 284. Compound I MeOAc solvate form C according to any one of Examples 269 to 283, characterized in that it has the following 13 C ss NMR spectrum: peaks at 28.3 ± 0.2 ppm, 49.6 ± 0.2 ppm and 150.1 ± 0.2 ppm.

[0506] 285. Compound I MeOAc solvate form C according to any one of Examples 269 to 284, characterized in that it has the following 13 C ss NMR spectra: (a) peaks at 28.3 ± 0.2 ppm, 49.6 ± 0.2 ppm and 150.1 ± 0.2 ppm and (b) one or more peaks selected from the following: 28.9 ± 0.2 ppm, 51.4 ± 0.2 ppm, 129.9 ± 0.2 ppm, 51.8 ± 0.2 ppm and 42.4 ± 0.2 ppm.

[0507] 286. Compound I MeOAc solvate form C according to any one of Examples 269 to 285, characterized in that it has the following 13 C ss NMR spectra: (a) peaks at 28.3 ± 0.2 ppm, 49.6 ± 0.2 ppm and 150.1 ± 0.2 ppm and (b) two or more peaks selected from the following: 28.9 ± 0.2 ppm, 51.4 ± 0.2 ppm, 129.9 ± 0.2 ppm, 51.8 ± 0.2 ppm and 42.4 ± 0.2 ppm.

[0508] 287. Compound I MeOAc solvate form C according to any one of Examples 269 to 286, characterized in that it has the following 13 C ss NMR spectra: (a) peaks at 28.3 ± 0.2 ppm, 49.6 ± 0.2 ppm and 150.1 ± 0.2 ppm and (b) three or more peaks selected from the following: 28.9 ± 0.2 ppm, 51.4 ± 0.2 ppm, 129.9 ± 0.2 ppm, 51.8 ± 0.2 ppm and 42.4 ± 0.2 ppm.

[0509] 288. Compound I MeOAc solvate form C according to any one of Examples 269 to 287, characterized in that it has the following 13 C ss NMR spectra: (a) peaks at 28.3 ± 0.2 ppm, 49.6 ± 0.2 ppm and 150.1 ± 0.2 ppm and (b) four or more peaks selected from the following: 28.9 ± 0.2 ppm, 51.4 ± 0.2 ppm, 129.9 ± 0.2 ppm, 51.8 ± 0.2 ppm and 42.4 ± 0.2 ppm.

[0510] 289. Compound I MeOAc solvate form C according to any one of Examples 269 to 288, characterized in that it has the following 13 C ss NMR spectrum: peaks at 28.3 ± 0.2 ppm, 49.6 ± 0.2 ppm, 150.1 ± 0.2 ppm, 28.9 ± 0.2 ppm, 51.4 ± 0.2 ppm, 129.9 ± 0.2 ppm, 51.8 ± 0.2 ppm and 42.4 ± 0.2 ppm.

[0511] 290. Compound I MeOAc solvate form C according to any one of Examples 269 to 289, characterized in that it is substantially similar to... Figure 37 of 13 CssNMR spectrum.

[0512] 291. Compound I in MeOAc solvate form C according to any one of Examples 269 to 290, which is prepared by a method comprising: (i) stirring compound I in pure form A in MeOAc at about 5°C, and (ii) separating the solid by filtration.

[0513] 292. Compound I is in essentially crystalline hydrate form A (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form).

[0514] 293. Compound I according to Example 292, wherein compound I is 100% crystalline compound I hydrate form A.

[0515] 294. Basically pure compound I is in hydrate form A.

[0516] 295. Compound I in hydrate form A according to any one of Examples 292 to 294, characterized in that it has the following X-ray powder diffraction pattern: signal at 21.4 ± 0.2 degrees 2θ.

[0517] 296. Compound I in hydrate form A according to any one of Examples 292 to 295, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 21.4 ± 0.2 degrees 2θ, and (b) a signal at one or more 2θ values ​​selected from the following: 14.0 ± 0.2 degrees 2θ, 19.5 ± 0.2 degrees 2θ, 7.0 ± 0.2 degrees 2θ, 18.6 ± 0.2 degrees 2θ, 11.0 ± 0.2 degrees 2θ, 18.2 ± 0.2 degrees 2θ, and 20.5 ± 0.2 degrees 2θ.

[0518] 297. Compound I in hydrate form A according to any one of Examples 292 to 295, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 21.4 ± 0.2 degrees 2θ, and (b) signals at two or more 2θ values ​​selected from the following: 14.0 ± 0.2 degrees 2θ, 19.5 ± 0.2 degrees 2θ, 7.0 ± 0.2 degrees 2θ, 18.6 ± 0.2 degrees 2θ, 11.0 ± 0.2 degrees 2θ, 18.2 ± 0.2 degrees 2θ, and 20.5 ± 0.2 degrees 2θ.

[0519] 298. Compound I in hydrate form A according to any one of Examples 292 to 295, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 21.4 ± 0.2 degrees 2θ, and (b) signals at three or more 2θ values ​​selected from the following: 14.0 ± 0.2 degrees 2θ, 19.5 ± 0.2 degrees 2θ, 7.0 ± 0.2 degrees 2θ, 18.6 ± 0.2 degrees 2θ, 11.0 ± 0.2 degrees 2θ, 18.2 ± 0.2 degrees 2θ and 20.5 ± 0.2 degrees 2θ.

[0520] 299. Compound I in hydrate form A according to any one of Examples 292 to 295, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 21.4 ± 0.2 degrees 2θ, and (b) signals at four or more 2θ values ​​selected from the following: 14.0 ± 0.2 degrees 2θ, 19.5 ± 0.2 degrees 2θ, 7.0 ± 0.2 degrees 2θ, 18.6 ± 0.2 degrees 2θ, 11.0 ± 0.2 degrees 2θ, 18.2 ± 0.2 degrees 2θ, and 20.5 ± 0.2 degrees 2θ.

[0521] 300. Compound I in hydrate form A according to any one of Examples 292 to 295, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 21.4 ± 0.2 degrees 2θ, and (b) signals at five or more 2θ values ​​selected from the following: 14.0 ± 0.2 degrees 2θ, 19.5 ± 0.2 degrees 2θ, 7.0 ± 0.2 degrees 2θ, 18.6 ± 0.2 degrees 2θ, 11.0 ± 0.2 degrees 2θ, 18.2 ± 0.2 degrees 2θ, and 20.5 ± 0.2 degrees 2θ.

[0522] 301. Compound I in hydrate form A according to any one of Examples 292 to 295, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 21.4 ± 0.2 degrees 2θ, and (b) signals at six or more 2θ values ​​selected from the following: 14.0 ± 0.2 degrees 2θ, 19.5 ± 0.2 degrees 2θ, 7.0 ± 0.2 degrees 2θ, 18.6 ± 0.2 degrees 2θ, 11.0 ± 0.2 degrees 2θ, 18.2 ± 0.2 degrees 2θ, and 20.5 ± 0.2 degrees 2θ.

[0523] 302. Compound I in hydrate form A according to any one of Examples 292 to 295, characterized in that it has the following X-ray powder diffraction patterns: signals at 21.4 ± 0.2 degrees 2θ, 14.0 ± 0.2 degrees 2θ, 19.5 ± 0.2 degrees 2θ, 7.0 ± 0.2 degrees 2θ, 18.6 ± 0.2 degrees 2θ, 11.0 ± 0.2 degrees 2θ, 18.2 ± 0.2 degrees 2θ and 20.5 ± 0.2 degrees 2θ.

[0524] 303. Compound I in hydrate form A according to any one of Examples 292 to 302, characterized in that it is substantially similar to Figure 38 X-ray powder diffraction pattern.

[0525] 304. Compound I in hydrate form A according to any one of Examples 292 to 303, characterized in that it has one or more peaks selected from the group consisting of 13 Css NMR spectra: 26.8 ± 0.2 ppm, 18.3 ± 0.2 ppm and 126.5 ± 0.2 ppm.

[0526] 305. Compound I in hydrate form A according to any one of Examples 292 to 304, characterized in that it has two or more peaks selected from the group consisting of 13 C ss NMR spectra: 26.8 ± 0.2 ppm, 18.3 ± 0.2 ppm and 126.5 ± 0.2 ppm.

[0527] 306. Compound I in hydrate form A according to any one of Examples 292 to 305, characterized in that it has the following 13 C ss NMR spectrum: peaks at 26.8 ± 0.2 ppm, 18.3 ± 0.2 ppm and 126.5 ± 0.2 ppm.

[0528] 307. Compound I in hydrate form A according to any one of Examples 292 to 306, characterized in that it has the following 13 C ss NMR spectra: (a) peaks at 26.8 ± 0.2 ppm, 18.3 ± 0.2 ppm and 126.5 ± 0.2 ppm and (b) one or more peaks selected from the following: 131.5 ± 0.2 ppm, 135.0 ± 0.2 ppm, 20.0 ± 0.2 ppm, 142.9 ± 0.2 ppm and 128.3 ± 0.2 ppm.

[0529] 308. Compound I in hydrate form A according to any one of Examples 292 to 307, characterized in that it has the following 13 C ss NMR spectra: (a) peaks at 26.8 ± 0.2 ppm, 18.3 ± 0.2 ppm and 126.5 ± 0.2 ppm and (b) two or more peaks selected from the following: 131.5 ± 0.2 ppm, 135.0 ± 0.2 ppm, 20.0 ± 0.2 ppm, 142.9 ± 0.2 ppm and 128.3 ± 0.2 ppm.

[0530] 309. Compound I in hydrate form A according to any one of Examples 292 to 308, characterized in that it has the following 13C ss NMR spectra: (a) peaks at 26.8 ± 0.2 ppm, 18.3 ± 0.2 ppm and 126.5 ± 0.2 ppm and (b) three or more peaks selected from the following: 131.5 ± 0.2 ppm, 135.0 ± 0.2 ppm, 20.0 ± 0.2 ppm, 142.9 ± 0.2 ppm and 128.3 ± 0.2 ppm.

[0531] 310. Compound I in hydrate form A according to any one of Examples 292 to 309, characterized in that it has the following 13 C ss NMR spectra: (a) peaks at 26.8 ± 0.2 ppm, 18.3 ± 0.2 ppm and 126.5 ± 0.2 ppm and (b) four or more peaks selected from the following: 131.5 ± 0.2 ppm, 135.0 ± 0.2 ppm, 20.0 ± 0.2 ppm, 142.9 ± 0.2 ppm and 128.3 ± 0.2 ppm.

[0532] 311. Compound I in hydrate form A according to any one of Examples 292 to 310, characterized in that it has the following 13 C ss NMR spectrum: peaks at 26.8 ± 0.2 ppm, 18.3 ± 0.2 ppm, 126.5 ± 0.2 ppm, 131.5 ± 0.2 ppm, 135.0 ± 0.2 ppm, 20.0 ± 0.2 ppm, 142.9 ± 0.2 ppm and 128.3 ± 0.2 ppm.

[0533] 312. Compound I in hydrate form A according to any one of Examples 292 to 311, characterized in that it is substantially similar to Figure 39 of 13 CssNMR spectrum.

[0534] 313. Compound I hydrate form A according to any one of Examples 292 to 312, characterized in that it has the following monoclinic crystal system, space group P212121, and unit cell size, wherein it is equipped with Cu K α Radiation (λ = 1.54178 Å) and measurements at 100 K on a Bruker diffractometer with a CPAD detector:

[0535]

[0536] 314. Compound I in hydrate form A according to any one of Examples 292 to 313, which is prepared by a method comprising: (i) stirring compound I in water in EtOH solvate form B, and (ii) separating the solid by filtration and air drying.

[0537] 315. Compound I is in essentially crystalline hydrate form B (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form).

[0538] 316. Compound I according to Example 315, wherein compound I is 100% crystalline compound I hydrate form B.

[0539] 317. Basically pure compound I in hydrate form B.

[0540] 318. Compound I in hydrate form B according to any one of Examples 315 to 317, characterized in that it has the following X-ray powder diffraction pattern: signal at 24.5 ± 0.2 degrees 2θ.

[0541] 319. Compound I in hydrate form B according to any one of Examples 315 to 317, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 24.5 ± 0.2 degrees 2θ, and (b) a signal at one or more 2θ values ​​selected from the following: 7.0 ± 0.2 degrees 2θ, 19.3 ± 0.2 degrees 2θ, 19.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 13.9 ± 0.2 degrees 2θ, 10.9 ± 0.2 degrees 2θ, and 19.7 ± 0.2 degrees 2θ.

[0542] 320. Compound I in hydrate form B according to any one of Examples 315 to 317, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 24.5 ± 0.2 degrees 2θ, and (b) signals at two or more 2θ values ​​selected from the following: 7.0 ± 0.2 degrees 2θ, 19.3 ± 0.2 degrees 2θ, 19.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 13.9 ± 0.2 degrees 2θ, 10.9 ± 0.2 degrees 2θ, and 19.7 ± 0.2 degrees 2θ.

[0543] 321. Compound I in hydrate form B according to any one of Examples 315 to 317, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 24.5 ± 0.2 degrees 2θ, and (b) signals at three or more 2θ values ​​selected from the following: 7.0 ± 0.2 degrees 2θ, 19.3 ± 0.2 degrees 2θ, 19.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 13.9 ± 0.2 degrees 2θ, 10.9 ± 0.2 degrees 2θ and 19.7 ± 0.2 degrees 2θ.

[0544] 322. Compound I in hydrate form B according to any one of Examples 315 to 317, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 24.5 ± 0.2 degrees 2θ, and (b) signals at four or more 2θ values ​​selected from the following: 7.0 ± 0.2 degrees 2θ, 19.3 ± 0.2 degrees 2θ, 19.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 13.9 ± 0.2 degrees 2θ, 10.9 ± 0.2 degrees 2θ and 19.7 ± 0.2 degrees 2θ.

[0545] 323. Compound I in hydrate form B according to any one of Examples 315 to 317, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 24.5 ± 0.2 degrees 2θ, and (b) signals at five or more 2θ values ​​selected from the following: 7.0 ± 0.2 degrees 2θ, 19.3 ± 0.2 degrees 2θ, 19.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 13.9 ± 0.2 degrees 2θ, 10.9 ± 0.2 degrees 2θ, and 19.7 ± 0.2 degrees 2θ.

[0546] 324. Compound I in hydrate form B according to any one of Examples 315 to 317, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 24.5 ± 0.2 degrees 2θ, and (b) signals at six or more 2θ values ​​selected from the following: 7.0 ± 0.2 degrees 2θ, 19.3 ± 0.2 degrees 2θ, 19.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 13.9 ± 0.2 degrees 2θ, 10.9 ± 0.2 degrees 2θ, and 19.7 ± 0.2 degrees 2θ.

[0547] 325. Compound I in hydrate form B according to any one of Examples 315 to 317, characterized in that it has the following X-ray powder diffraction patterns: signals at 24.5 ± 0.2 degrees 2θ, 7.0 ± 0.2 degrees 2θ, 19.3 ± 0.2 degrees 2θ, 19.4 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 13.9 ± 0.2 degrees 2θ, 10.9 ± 0.2 degrees 2θ and 19.7 ± 0.2 degrees 2θ.

[0548] 326. Compound I in hydrate form B according to any one of Examples 315 to 325, characterized in that it is substantially similar to Figure 40 X-ray powder diffraction pattern.

[0549] 327. Compound I in hydrate form B according to any one of Examples 315 to 326, characterized by having a peak at 19.3 ± 0.2 ppm. 13 CssNMR spectrum.

[0550] 328. Compound I in hydrate form B according to any one of Examples 315 to 327, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 19.3 ± 0.2 ppm and (b) one or more peaks selected from the following: 29.4 ± 0.2 ppm, 128.6 ± 0.2 ppm, 130.3 ± 0.2 ppm, 42.3 ± 0.2 ppm, 128.9 ± 0.2 ppm, 134.6 ± 0.2 ppm and 136.4 ± 0.2 ppm.

[0551] 329. Compound I in hydrate form B according to any one of Examples 315 to 328, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 19.3 ± 0.2 ppm and (b) two or more peaks selected from the following: 29.4 ± 0.2 ppm, 128.6 ± 0.2 ppm, 130.3 ± 0.2 ppm, 42.3 ± 0.2 ppm, 128.9 ± 0.2 ppm, 134.6 ± 0.2 ppm and 136.4 ± 0.2 ppm.

[0552] 330. Compound I in hydrate form B according to any one of Examples 315 to 329, characterized in that it has the following 13C ss NMR spectra: (a) the peak at 19.3 ± 0.2 ppm and (b) three or more peaks selected from the following: 29.4 ± 0.2 ppm, 128.6 ± 0.2 ppm, 130.3 ± 0.2 ppm, 42.3 ± 0.2 ppm, 128.9 ± 0.2 ppm, 134.6 ± 0.2 ppm and 136.4 ± 0.2 ppm.

[0553] 331. Compound I in hydrate form B according to any one of Examples 315 to 330, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 19.3 ± 0.2 ppm and (b) four or more peaks selected from the following: 29.4 ± 0.2 ppm, 128.6 ± 0.2 ppm, 130.3 ± 0.2 ppm, 42.3 ± 0.2 ppm, 128.9 ± 0.2 ppm, 134.6 ± 0.2 ppm and 136.4 ± 0.2 ppm.

[0554] 332. Compound I in hydrate form B according to any one of Examples 315 to 331, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 19.3 ± 0.2 ppm and (b) five or more peaks selected from the following: 29.4 ± 0.2 ppm, 128.6 ± 0.2 ppm, 130.3 ± 0.2 ppm, 42.3 ± 0.2 ppm, 128.9 ± 0.2 ppm, 134.6 ± 0.2 ppm and 136.4 ± 0.2 ppm.

[0555] 333. Compound I in hydrate form B according to any one of Examples 315 to 332, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 19.3 ± 0.2 ppm and (b) six or more peaks selected from the following: 29.4 ± 0.2 ppm, 128.6 ± 0.2 ppm, 130.3 ± 0.2 ppm, 42.3 ± 0.2 ppm, 128.9 ± 0.2 ppm, 134.6 ± 0.2 ppm and 136.4 ± 0.2 ppm.

[0556] 334. Compound I in hydrate form B according to any one of Examples 315 to 333, characterized in that it has the following 13C ss NMR spectrum: peaks at 19.3 ± 0.2 ppm, 29.4 ± 0.2 ppm, 128.6 ± 0.2 ppm, 130.3 ± 0.2 ppm, 42.3 ± 0.2 ppm, 128.9 ± 0.2 ppm, 134.6 ± 0.2 ppm and 136.4 ± 0.2 ppm.

[0557] 335. Compound I in hydrate form B according to any one of Examples 315 to 334, characterized in that it is substantially similar to Figure 41 of 13 CssNMR spectrum.

[0558] 336. Compound I hydrate form B according to any one of Examples 315 to 335, characterized in that it has the following monoclinic crystal system, space group P212121, and unit cell size, wherein it is equipped with Cu K α Radiation (λ = 1.54178 Å) and measurements at 100 K on a Bruker diffractometer with a CPAD detector:

[0559]

[0560] 337. Compound I in hydrate form B according to any one of Examples 315 to 336, which is prepared by a method comprising: (i) stirring compound I in a MeOH / water mixture at about 80°C, (ii) separating the solid by filtration, and (iii) exposing the solid to about 11% humidity.

[0561] 338. Compound I is in essentially crystalline hydrate form C (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form).

[0562] 339. Compound I according to Example 338, wherein compound I is 100% crystalline compound I hydrate form C.

[0563] 340. Basically pure compound I in hydrate form C.

[0564] 341. Compound I in hydrate form C according to any one of Examples 338 to 340, characterized in that it has the following X-ray powder diffraction pattern: signal at 16.1 ± 0.2 degrees 2θ.

[0565] 342. Compound I in hydrate form C according to any one of Examples 338 to 340, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 16.1 ± 0.2 degrees 2θ, and (b) a signal at one or more 2θ values ​​selected from the following: 7.0 ± 0.2 degrees 2θ, 21.9 ± 0.2 degrees 2θ, 11.2 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 14.9 ± 0.2 degrees 2θ, 15.4 ± 0.2 degrees 2θ, and 18.2 ± 0.2 degrees 2θ.

[0566] 343. Compound I in hydrate form C according to any one of Examples 338 to 340, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 16.1 ± 0.2 degrees 2θ, and (b) signals at two or more 2θ values ​​selected from the following: 7.0 ± 0.2 degrees 2θ, 21.9 ± 0.2 degrees 2θ, 11.2 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 14.9 ± 0.2 degrees 2θ, 15.4 ± 0.2 degrees 2θ, and 18.2 ± 0.2 degrees 2θ.

[0567] 344. Compound I in hydrate form C according to any one of Examples 338 to 340, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 16.1 ± 0.2 degrees 2θ, and (b) signals at three or more 2θ values ​​selected from the following: 7.0 ± 0.2 degrees 2θ, 21.9 ± 0.2 degrees 2θ, 11.2 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 14.9 ± 0.2 degrees 2θ, 15.4 ± 0.2 degrees 2θ, and 18.2 ± 0.2 degrees 2θ.

[0568] 345. Compound I in hydrate form C according to any one of Examples 338 to 340, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 16.1 ± 0.2 degrees 2θ, and (b) signals at four or more 2θ values ​​selected from the following: 7.0 ± 0.2 degrees 2θ, 21.9 ± 0.2 degrees 2θ, 11.2 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 14.9 ± 0.2 degrees 2θ, 15.4 ± 0.2 degrees 2θ, and 18.2 ± 0.2 degrees 2θ.

[0569] 346. Compound I in hydrate form C according to any one of Examples 338 to 340, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 16.1 ± 0.2 degrees 2θ, and (b) signals at five or more 2θ values ​​selected from the following: 7.0 ± 0.2 degrees 2θ, 21.9 ± 0.2 degrees 2θ, 11.2 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 14.9 ± 0.2 degrees 2θ, 15.4 ± 0.2 degrees 2θ, and 18.2 ± 0.2 degrees 2θ.

[0570] 347. Compound I in hydrate form C according to any one of Examples 338 to 340, characterized in that it has the following X-ray powder diffraction pattern: (a) a signal at 16.1 ± 0.2 degrees 2θ, and (b) signals at six or more 2θ values ​​selected from the following: 7.0 ± 0.2 degrees 2θ, 21.9 ± 0.2 degrees 2θ, 11.2 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 14.9 ± 0.2 degrees 2θ, 15.4 ± 0.2 degrees 2θ, and 18.2 ± 0.2 degrees 2θ.

[0571] 348. Compound I in hydrate form C according to any one of Examples 338 to 340, characterized in that it has the following X-ray powder diffraction patterns: signals at 16.1 ± 0.2 degrees 2θ, 7.0 ± 0.2 degrees 2θ, 21.9 ± 0.2 degrees 2θ, 11.2 ± 0.2 degrees 2θ, 15.1 ± 0.2 degrees 2θ, 14.9 ± 0.2 degrees 2θ, 15.4 ± 0.2 degrees 2θ and 18.2 ± 0.2 degrees 2θ.

[0572] 349. Compound I in hydrate form C according to any one of Examples 338 to 348, characterized in that it is substantially similar to Figure 42 X-ray powder diffraction pattern.

[0573] 350. Compound I in hydrate form C according to any one of Examples 338 to 349, characterized by having a peak at 127.7 ± 0.2 ppm. 13 C ss NMR spectrum.

[0574] 351. Compound I in hydrate form C according to any one of Examples 338 to 350, characterized in that it has the following 13C ss NMR spectra: (a) the peak at 127.7 ± 0.2 ppm and (b) one or more peaks selected from the following: 51.6 ± 0.2 ppm, 29.6 ± 0.2 ppm, 42.2 ± 0.2 ppm, 102.4 ± 0.2 ppm, 130.5 ± 0.2 ppm, 19.9 ± 0.2 ppm, 142.7 ± 0.2 ppm.

[0575] 352. Compound I in hydrate form C according to any one of Examples 338 to 351, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 127.7 ± 0.2 ppm and (b) two or more peaks selected from the following: 51.6 ± 0.2 ppm, 29.6 ± 0.2 ppm, 42.2 ± 0.2 ppm, 102.4 ± 0.2 ppm, 130.5 ± 0.2 ppm, 19.9 ± 0.2 ppm, 142.7 ± 0.2 ppm.

[0576] 353. Compound I in hydrate form C according to any one of Examples 338 to 352, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 127.7 ± 0.2 ppm and (b) three or more peaks selected from the following: 51.6 ± 0.2 ppm, 29.6 ± 0.2 ppm, 42.2 ± 0.2 ppm, 102.4 ± 0.2 ppm, 130.5 ± 0.2 ppm, 19.9 ± 0.2 ppm, 142.7 ± 0.2 ppm.

[0577] 354. Compound I in hydrate form C according to any one of Examples 338 to 353, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 127.7 ± 0.2 ppm and (b) four or more peaks selected from the following: 51.6 ± 0.2 ppm, 29.6 ± 0.2 ppm, 42.2 ± 0.2 ppm, 102.4 ± 0.2 ppm, 130.5 ± 0.2 ppm, 19.9 ± 0.2 ppm, 142.7 ± 0.2 ppm.

[0578] 355. Compound I in hydrate form C according to any one of Examples 338 to 354, characterized in that it has the following 13C ss NMR spectra: (a) the peak at 127.7 ± 0.2 ppm and (b) five or more peaks selected from the following: 51.6 ± 0.2 ppm, 29.6 ± 0.2 ppm, 42.2 ± 0.2 ppm, 102.4 ± 0.2 ppm, 130.5 ± 0.2 ppm, 19.9 ± 0.2 ppm, 142.7 ± 0.2 ppm.

[0579] 356. Compound I in hydrate form C according to any one of Examples 338 to 355, characterized in that it has the following 13 C ss NMR spectra: (a) the peak at 127.7 ± 0.2 ppm and (b) six or more peaks selected from the following: 51.6 ± 0.2 ppm, 29.6 ± 0.2 ppm, 42.2 ± 0.2 ppm, 102.4 ± 0.2 ppm, 130.5 ± 0.2 ppm, 19.9 ± 0.2 ppm, 142.7 ± 0.2 ppm.

[0580] 357. Compound I in hydrate form C according to any one of Examples 338 to 356, characterized in that it has the following 13 C ss NMR spectrum: peaks at 127.7 ± 0.2 ppm, 51.6 ± 0.2 ppm, 29.6 ± 0.2 ppm, 42.2 ± 0.2 ppm, 102.4 ± 0.2 ppm, 130.5 ± 0.2 ppm, 19.9 ± 0.2 ppm, and 142.7 ± 0.2 ppm.

[0581] 358. Compound I in hydrate form C according to any one of Examples 338 to 357, characterized in that it is substantially similar to Figure 43 of 13 CssNMR spectrum.

[0582] 359. Compound I in hydrate form C according to any one of Examples 338 to 358, characterized in that it has a monoclinic crystal system, space group P212121, and unit cell size, wherein it is equipped with Cu K α Radiation (λ = 1.54178 Å) and measurements at 100 K on a Bruker diffractometer with a CPAD detector:

[0583]

[0584] 360. Compound I in hydrate form C according to any one of Examples 338 to 359, which is prepared by a method comprising: (i) stirring compound I in a MeOH / water mixture at about 80°C, (ii) separating the solid by filtration, and (iii) exposing the solid to about 75% humidity.

[0585] 361. Compound I is a substantially crystalline EtOH solvate hydrate (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form).

[0586] 362. Compound I according to Example 361, wherein Compound I is 100% crystalline Compound I EtOH solvate hydrate.

[0587] 363. Basically pure compound I EtOH solvate hydrate.

[0588] 364. The compound I EtOH solvate hydrate according to any one of Examples 361 to 363, characterized in that it has the following X-ray powder diffraction pattern: a signal at one or more selected from the following 2θ values: 6.7 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 14.7 ± 0.2 degrees 2θ, 20.0 ± 0.2 degrees 2θ, 11.3 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ and 19.1 ± 0.2 degrees 2θ.

[0589] 365. The compound I EtOH solvate hydrate according to any one of Examples 361 to 364, characterized in that it has the following X-ray powder diffraction pattern: signals at two or more 2θ values ​​selected from the following: 6.7 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 14.7 ± 0.2 degrees 2θ, 20.0 ± 0.2 degrees 2θ, 11.3 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ and 19.1 ± 0.2 degrees 2θ.

[0590] 366. The compound I EtOH solvate hydrate according to any one of Examples 361 to 365, characterized in that it has the following X-ray powder diffraction pattern: signals at three or more 2θ values ​​selected from the following: 6.7 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 14.7 ± 0.2 degrees 2θ, 20.0 ± 0.2 degrees 2θ, 11.3 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ and 19.1 ± 0.2 degrees 2θ.

[0591] 367. The compound I EtOH solvate hydrate according to any one of Examples 361 to 366, characterized in that it has the following X-ray powder diffraction pattern: signals at four or more 2θ values ​​selected from the following: 6.7 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 14.7 ± 0.2 degrees 2θ, 20.0 ± 0.2 degrees 2θ, 11.3 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ and 19.1 ± 0.2 degrees 2θ.

[0592] 368. The compound I EtOH solvate hydrate according to any one of Examples 361 to 367, characterized in that it has the following X-ray powder diffraction pattern: signals at five or more 2θ values ​​selected from the following: 6.7 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 14.7 ± 0.2 degrees 2θ, 20.0 ± 0.2 degrees 2θ, 11.3 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ and 19.1 ± 0.2 degrees 2θ.

[0593] 369. The compound I EtOH solvate hydrate according to any one of Examples 361 to 368, characterized in that it has the following X-ray powder diffraction pattern: signals at six or more 2θ values ​​selected from the following: 6.7 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 14.7 ± 0.2 degrees 2θ, 20.0 ± 0.2 degrees 2θ, 11.3 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ and 19.1 ± 0.2 degrees 2θ.

[0594] 370. The compound I EtOH solvate hydrate according to any one of Examples 361 to 369, characterized in that it has the following X-ray powder diffraction pattern: signals at seven or more 2θ values ​​selected from the following: 6.7 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 14.7 ± 0.2 degrees 2θ, 20.0 ± 0.2 degrees 2θ, 11.3 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ and 19.1 ± 0.2 degrees 2θ.

[0595] 371. The compound I EtOH solvate hydrate according to any one of Examples 361 to 370, characterized in that it has the following X-ray powder diffraction patterns: signals at 6.7 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 14.7 ± 0.2 degrees 2θ, 20.0 ± 0.2 degrees 2θ, 11.3 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ and 19.1 ± 0.2 degrees 2θ.

[0596] 372. The compound I EtOH solvate hydrate according to any one of Examples 361 to 371, characterized in that it is substantially similar to Figure 44 X-ray powder diffraction pattern.

[0597] 373. The compound I EtOH solvate hydrate according to any one of Examples 361 to 372, characterized in that it has one or more peaks selected from the group consisting of 13 C ssNMR spectrum: 29.8 ± 0.2 ppm, 127.0 ± 0.2 ppm, 17.9 ± 0.2 ppm, 42.9 ± 0.2 ppm, 18.0 ± 0.2 ppm, 20.9 ± 0.2 ppm, 135.7 ± 0.2 ppm and 129.1 ± 0.2 ppm.

[0598] 374. The compound I EtOH solvate hydrate according to any one of Examples 361 to 373, characterized in that it has two or more peaks selected from the group consisting of 13 C ssNMR spectrum: 29.8 ± 0.2 ppm, 127.0 ± 0.2 ppm, 17.9 ± 0.2 ppm, 42.9 ± 0.2 ppm, 18.0 ± 0.2 ppm, 20.9 ± 0.2 ppm, 135.7 ± 0.2 ppm and 129.1 ± 0.2 ppm.

[0599] 375. The compound I EtOH solvate hydrate according to any one of Examples 361 to 374, characterized in that it has three or more peaks selected from the group consisting of 13 C ssNMR spectrum: 29.8 ± 0.2 ppm, 127.0 ± 0.2 ppm, 17.9 ± 0.2 ppm, 42.9 ± 0.2 ppm, 18.0 ± 0.2 ppm, 20.9 ± 0.2 ppm, 135.7 ± 0.2 ppm and 129.1 ± 0.2 ppm.

[0600] 376. The compound I EtOH solvate hydrate according to any one of Examples 361 to 375, characterized in that it has four or more peaks selected from the group consisting of 13 C ssNMR spectrum: 29.8 ± 0.2 ppm, 127.0 ± 0.2 ppm, 17.9 ± 0.2 ppm, 42.9 ± 0.2 ppm, 18.0 ± 0.2 ppm, 20.9 ± 0.2 ppm, 135.7 ± 0.2 ppm and 129.1 ± 0.2 ppm.

[0601] 377. The compound I EtOH solvate hydrate according to any one of Examples 361 to 376, characterized in that it has five or more peaks selected from the group consisting of 13 C ssNMR spectrum: 29.8 ± 0.2 ppm, 127.0 ± 0.2 ppm, 17.9 ± 0.2 ppm, 42.9 ± 0.2 ppm, 18.0 ± 0.2 ppm, 20.9 ± 0.2 ppm, 135.7 ± 0.2 ppm and 129.1 ± 0.2 ppm.

[0602] 378. The compound I EtOH solvate hydrate according to any one of Examples 361 to 377, characterized in that it has six or more peaks selected from the group consisting of 13 ssNMR spectrum: 29.8 ± 0.2 ppm, 127.0 ± 0.2 ppm, 17.9 ± 0.2 ppm, 42.9 ± 0.2 ppm, 18.0 ± 0.2 ppm, 20.9 ± 0.2 ppm, 135.7 ± 0.2 ppm and 129.1 ± 0.2 ppm.

[0603] 379. The compound I EtOH solvate hydrate according to any one of Examples 361 to 378, characterized in that it has seven or more peaks selected from the group consisting of 13 C ssNMR spectrum: 29.8 ± 0.2 ppm, 127.0 ± 0.2 ppm, 17.9 ± 0.2 ppm, 42.9 ± 0.2 ppm, 18.0 ± 0.2 ppm, 20.9 ± 0.2 ppm, 135.7 ± 0.2 ppm and 129.1 ± 0.2 ppm.

[0604] 380. The compound I EtOH solvate hydrate according to any one of Examples 361 to 379, characterized in that it has the following 13C ss NMR spectrum: peaks at 29.8 ± 0.2 ppm, 127.0 ± 0.2 ppm, 17.9 ± 0.2 ppm, 42.9 ± 0.2 ppm, 18.0 ± 0.2 ppm, 20.9 ± 0.2 ppm, 135.7 ± 0.2 ppm and 129.1 ± 0.2 ppm.

[0605] 381. The compound I EtOH solvate hydrate according to any one of Examples 361 to 380, characterized in that it is substantially similar to Figure 45 of 13 CssNMR spectrum.

[0606] 382. The compound I EtOH solvate hydrate according to any one of Examples 361 to 381, characterized in that it has the following monoclinic crystal system, space group P212121, and unit cell size, wherein it is equipped with Cu K α Radiation (λ = 1.54178 Å) and measurements at 100 K on a Bruker diffractometer with a CPAD detector:

[0607]

[0608] 383. Compound I EtOH solvate hydrate according to any one of Examples 361 to 382, ​​which is prepared by a method comprising: (i) stirring Compound I in an EtOH / water mixture at about 60°C, and (ii) separating the solid by centrifugation.

[0609] 384. Compound I is a substantially crystalline MeOH solvate hydrate (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form).

[0610] 385. Compound I according to Example 384, wherein Compound I is 100% crystalline Compound I MeOH hydrate.

[0611] 386. Basically pure compound I MeOH solvate hydrate.

[0612] 387. The compound I MeOH solvate hydrate according to any one of Examples 384 to 386, characterized in that it has the following X-ray powder diffraction pattern: a signal at one or more selected from the following 2θ values: 8.6 ± 0.2 degrees 2θ, 6.7 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 14.8 ± 0.2 degrees 2θ, 19.2 ± 0.2 degrees 2θ, 18.8 ± 0.2 degrees 2θ and 19.2 ± 0.2 degrees 2θ.

[0613] 388. The compound I MeOH solvate hydrate according to any one of Examples 384 to 387, characterized in that it has the following X-ray powder diffraction pattern: signals at two or more 2θ values ​​selected from the following: 8.6 ± 0.2 degrees 2θ, 6.7 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 14.8 ± 0.2 degrees 2θ, 19.2 ± 0.2 degrees 2θ, 18.8 ± 0.2 degrees 2θ and 19.2 ± 0.2 degrees 2θ.

[0614] 389. The compound I MeOH solvate hydrate according to any one of Examples 384 to 388, characterized in that it has the following X-ray powder diffraction pattern: signals at three or more 2θ values ​​selected from the following: 8.6 ± 0.2 degrees 2θ, 6.7 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 14.8 ± 0.2 degrees 2θ, 19.2 ± 0.2 degrees 2θ, 18.8 ± 0.2 degrees 2θ and 19.2 ± 0.2 degrees 2θ.

[0615] 390. The compound I MeOH solvate hydrate according to any one of Examples 384 to 389, characterized in that it has the following X-ray powder diffraction pattern: signals at four or more 2θ values ​​selected from the following: 8.6 ± 0.2 degrees 2θ, 6.7 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 14.8 ± 0.2 degrees 2θ, 19.2 ± 0.2 degrees 2θ, 18.8 ± 0.2 degrees 2θ and 19.2 ± 0.2 degrees 2θ.

[0616] 391. The compound I MeOH solvate hydrate according to any one of Examples 384 to 390, characterized in that it has the following X-ray powder diffraction pattern: signals at five or more 2θ values ​​selected from the following: 8.6 ± 0.2 degrees 2θ, 6.7 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 14.8 ± 0.2 degrees 2θ, 19.2 ± 0.2 degrees 2θ, 18.8 ± 0.2 degrees 2θ and 19.2 ± 0.2 degrees 2θ.

[0617] 392. The compound I MeOH solvate hydrate according to any one of Examples 384 to 391, characterized in that it has the following X-ray powder diffraction pattern: signals at six or more 2θ values ​​selected from the following: 8.6 ± 0.2 degrees 2θ, 6.7 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 14.8 ± 0.2 degrees 2θ, 19.2 ± 0.2 degrees 2θ, 18.8 ± 0.2 degrees 2θ and 19.2 ± 0.2 degrees 2θ.

[0618] 393. The compound I MeOH solvate hydrate according to any one of Examples 384 to 392, characterized in that it has the following X-ray powder diffraction pattern: signals at seven or more 2θ values ​​selected from the following: 8.6 ± 0.2 degrees 2θ, 6.7 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 14.8 ± 0.2 degrees 2θ, 19.2 ± 0.2 degrees 2θ, 18.8 ± 0.2 degrees 2θ and 19.2 ± 0.2 degrees 2θ.

[0619] 394. The compound I MeOH solvate hydrate according to any one of Examples 384 to 393, characterized in that it has the following X-ray powder diffraction patterns: signals at 8.6 ± 0.2 degrees 2θ, 6.7 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 14.8 ± 0.2 degrees 2θ, 19.2 ± 0.2 degrees 2θ, 18.8 ± 0.2 degrees 2θ and 19.2 ± 0.2 degrees 2θ.

[0620] 395. The MeOH solvate hydrate of compound I according to any one of Examples 384 to 394, characterized in that it is substantially similar to Figure 46 X-ray powder diffraction pattern.

[0621] 396. The compound I MeOH solvate hydrate according to any one of Examples 384 to 395, characterized in that it has one or more peaks selected from the group consisting of 13 C ssNMR spectrum: 29.3 ± 0.2 ppm, 126.9 ± 0.2 ppm, 43.1 ± 0.2 ppm, 20.9 ± 0.2 ppm, 17.2 ± 0.2 ppm, 127.8 ± 0.2 ppm, 29.6 ± 0.2 ppm and 135.7 ± 0.2 ppm.

[0622] 397. The compound I MeOH solvate hydrate according to any one of Examples 384 to 396, characterized in that it has two or more peaks selected from the group consisting of 13 C ssNMR spectrum: 29.3 ± 0.2 ppm, 126.9 ± 0.2 ppm, 43.1 ± 0.2 ppm, 20.9 ± 0.2 ppm, 17.2 ± 0.2 ppm, 127.8 ± 0.2 ppm, 29.6 ± 0.2 ppm and 135.7 ± 0.2 ppm.

[0623] 398. The compound I MeOH solvate hydrate according to any one of Examples 384 to 397, characterized in that it has three or more peaks selected from the group consisting of 13 C ssNMR spectrum: 29.3 ± 0.2 ppm, 126.9 ± 0.2 ppm, 43.1 ± 0.2 ppm, 20.9 ± 0.2 ppm, 17.2 ± 0.2 ppm, 127.8 ± 0.2 ppm, 29.6 ± 0.2 ppm and 135.7 ± 0.2 ppm.

[0624] 399. The compound I MeOH solvate hydrate according to any one of Examples 384 to 398, characterized in that it has four or more peaks selected from the group consisting of 13 C ssNMR spectrum: 29.3 ± 0.2 ppm, 126.9 ± 0.2 ppm, 43.1 ± 0.2 ppm, 20.9 ± 0.2 ppm, 17.2 ± 0.2 ppm, 127.8 ± 0.2 ppm, 29.6 ± 0.2 ppm and 135.7 ± 0.2 ppm.

[0625] 400. The compound I MeOH solvate hydrate according to any one of Examples 384 to 399, characterized in that it has five or more peaks selected from the group consisting of 13C ssNMR spectrum: 29.3 ± 0.2 ppm, 126.9 ± 0.2 ppm, 43.1 ± 0.2 ppm, 20.9 ± 0.2 ppm, 17.2 ± 0.2 ppm, 127.8 ± 0.2 ppm, 29.6 ± 0.2 ppm and 135.7 ± 0.2 ppm.

[0626] 401. The compound I MeOH solvate hydrate according to any one of Examples 384 to 400, characterized in that it has six or more peaks selected from the group consisting of 13 C ssNMR spectrum: 29.3 ± 0.2 ppm, 126.9 ± 0.2 ppm, 43.1 ± 0.2 ppm, 20.9 ± 0.2 ppm, 17.2 ± 0.2 ppm, 127.8 ± 0.2 ppm, 29.6 ± 0.2 ppm and 135.7 ± 0.2 ppm.

[0627] 402. The compound I MeOH solvate hydrate according to any one of Examples 384 to 401, characterized in that it has seven or more peaks selected from the group consisting of 13 C ssNMR spectrum: 29.3 ± 0.2 ppm, 126.9 ± 0.2 ppm, 43.1 ± 0.2 ppm, 20.9 ± 0.2 ppm, 17.2 ± 0.2 ppm, 127.8 ± 0.2 ppm, 29.6 ± 0.2 ppm and 135.7 ± 0.2 ppm.

[0628] 403. The compound I MeOH solvate hydrate according to any one of Examples 384 to 402, characterized in that it has the following 13 C ss NMR spectrum: peaks at 29.3 ± 0.2 ppm, 126.9 ± 0.2 ppm, 43.1 ± 0.2 ppm, 20.9 ± 0.2 ppm, 17.2 ± 0.2 ppm, 127.8 ± 0.2 ppm, 29.6 ± 0.2 ppm and 135.7 ± 0.2 ppm.

[0629] 404. The compound I MeOH solvate hydrate according to any one of Examples 384 to 403, characterized in that it is substantially similar to Figure 47 of 13 CssNMR spectrum.

[0630] 405. Compound I MeOH solvate hydrate according to any one of Examples 384 to 404, which is prepared by a method comprising: (i) stirring compound I in a MeOH / water mixture at about 80°C, and (ii) separating the solid by centrifugation.

[0631] 406. Compound I is a substantially crystalline IPA solvate hydrate (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form).

[0632] 407. Compound I according to Example 406, wherein Compound I is 100% crystalline Compound I IPA solvate hydrate.

[0633] 408. Basically pure compound I IPA solvate hydrate.

[0634] 409. The compound I IPA solvate hydrate according to any one of Examples 406 to 408, characterized in that it has the following X-ray powder diffraction pattern: a signal at one or more selected from the following 2θ values: 6.7 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 14.8 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ, 17.7 ± 0.2 degrees 2θ and 17.3 ± 0.2 degrees 2θ.

[0635] 410. The compound I IPA solvate hydrate according to any one of Examples 406 to 409, characterized in that it has the following X-ray powder diffraction pattern: signals at two or more 2θ values ​​selected from the following: 6.7 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 14.8 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ, 17.7 ± 0.2 degrees 2θ and 17.3 ± 0.2 degrees 2θ.

[0636] 411. The compound I IPA solvate hydrate according to any one of Examples 406 to 410, characterized in that it has the following X-ray powder diffraction pattern: signals at three or more 2θ values ​​selected from the following: 6.7 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 14.8 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ, 17.7 ± 0.2 degrees 2θ and 17.3 ± 0.2 degrees 2θ.

[0637] 412. The compound I IPA solvate hydrate according to any one of Examples 406 to 411, characterized in that it has the following X-ray powder diffraction pattern: signals at four or more 2θ values ​​selected from the following: 6.7 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 14.8 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ, 17.7 ± 0.2 degrees 2θ and 17.3 ± 0.2 degrees 2θ.

[0638] 413. The compound I IPA solvate hydrate according to any one of Examples 406 to 412, characterized in that it has the following X-ray powder diffraction pattern: signals at five or more 2θ values ​​selected from the following: 6.7 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 14.8 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ, 17.7 ± 0.2 degrees 2θ and 17.3 ± 0.2 degrees 2θ.

[0639] 414. The compound I IPA solvate hydrate according to any one of Examples 406 to 413, characterized in that it has the following X-ray powder diffraction pattern: signals at six or more 2θ values ​​selected from the following: 6.7 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 14.8 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ, 17.7 ± 0.2 degrees 2θ and 17.3 ± 0.2 degrees 2θ.

[0640] 415. The compound I IPA solvate hydrate according to any one of Examples 406 to 414, characterized in that it has the following X-ray powder diffraction pattern: signals at seven or more 2θ values ​​selected from the following: 6.7 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 14.8 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ, 17.7 ± 0.2 degrees 2θ and 17.3 ± 0.2 degrees 2θ.

[0641] 416. The compound I IPA solvate hydrate according to any one of Examples 406 to 415, characterized in that it has the following X-ray powder diffraction patterns: signals at 6.7 ± 0.2 degrees 2θ, 8.6 ± 0.2 degrees 2θ, 11.5 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 14.8 ± 0.2 degrees 2θ, 18.7 ± 0.2 degrees 2θ, 17.7 ± 0.2 degrees 2θ and 17.3 ± 0.2 degrees 2θ.

[0642] 417. The compound I IPA solvate hydrate according to any one of Examples 406 to 416, characterized in that it is substantially similar to Figure 48 X-ray powder diffraction pattern.

[0643] 418. The compound I IPA solvate hydrate according to any one of Examples 406 to 417, characterized in that it has one or more peaks selected from the group consisting of 13 C ssNMR spectrum: 30.0 ± 0.2 ppm, 127.4 ± 0.2 ppm, 24.9 ± 0.2 ppm, 18.6 ± 0.2 ppm, 24.2 ± 0.2 ppm, 20.3 ± 0.2 ppm, 136.8 ± 0.2 ppm and 42.7 ± 0.2 ppm.

[0644] 419. The compound I IPA solvate hydrate according to any one of Examples 406 to 418, characterized in that it has two or more peaks selected from the group consisting of 13 C ssNMR spectrum: 30.0 ± 0.2 ppm, 127.4 ± 0.2 ppm, 24.9 ± 0.2 ppm, 18.6 ± 0.2 ppm, 24.2 ± 0.2 ppm, 20.3 ± 0.2 ppm, 136.8 ± 0.2 ppm and 42.7 ± 0.2 ppm.

[0645] 420. The compound I IPA solvate hydrate according to any one of Examples 406 to 419, characterized in that it has three or more peaks selected from the group consisting of 13 C ssNMR spectrum: 30.0 ± 0.2 ppm, 127.4 ± 0.2 ppm, 24.9 ± 0.2 ppm, 18.6 ± 0.2 ppm, 24.2 ± 0.2 ppm, 20.3 ± 0.2 ppm, 136.8 ± 0.2 ppm and 42.7 ± 0.2 ppm.

[0646] 421. The compound I IPA solvate hydrate according to any one of Examples 406 to 420, characterized in that it has four or more peaks selected from the group consisting of 13 C ssNMR spectrum: 30.0 ± 0.2 ppm, 127.4 ± 0.2 ppm, 24.9 ± 0.2 ppm, 18.6 ± 0.2 ppm, 24.2 ± 0.2 ppm, 20.3 ± 0.2 ppm, 136.8 ± 0.2 ppm and 42.7 ± 0.2 ppm.

[0647] 422. The compound I IPA solvate hydrate according to any one of Examples 406 to 421, characterized in that it has five or more peaks selected from the group consisting of 13 C ssNMR spectrum: 30.0 ± 0.2 ppm, 127.4 ± 0.2 ppm, 24.9 ± 0.2 ppm, 18.6 ± 0.2 ppm, 24.2 ± 0.2 ppm, 20.3 ± 0.2 ppm, 136.8 ± 0.2 ppm and 42.7 ± 0.2 ppm.

[0648] 423. The compound I IPA solvate hydrate according to any one of Examples 406 to 422, characterized in that it has six or more peaks selected from the group consisting of 13 C ssNMR spectrum: 30.0 ± 0.2 ppm, 127.4 ± 0.2 ppm, 24.9 ± 0.2 ppm, 18.6 ± 0.2 ppm, 24.2 ± 0.2 ppm, 20.3 ± 0.2 ppm, 136.8 ± 0.2 ppm and 42.7 ± 0.2 ppm.

[0649] 424. The compound I IPA solvate hydrate according to any one of Examples 406 to 423, characterized in that it has seven or more peaks selected from the group consisting of 13 C ssNMR spectrum: 30.0 ± 0.2 ppm, 127.4 ± 0.2 ppm, 24.9 ± 0.2 ppm, 18.6 ± 0.2 ppm, 24.2 ± 0.2 ppm, 20.3 ± 0.2 ppm, 136.8 ± 0.2 ppm and 42.7 ± 0.2 ppm.

[0650] 425. The compound I IPA solvate hydrate according to any one of Examples 406 to 424, characterized in that it has the following 13C ss NMR spectrum: peaks at 30.0 ± 0.2 ppm, 127.4 ± 0.2 ppm, 24.9 ± 0.2 ppm, 18.6 ± 0.2 ppm, 24.2 ± 0.2 ppm, 20.3 ± 0.2 ppm, 136.8 ± 0.2 ppm and 42.7 ± 0.2 ppm.

[0651] 426. The compound I IPA solvate hydrate according to any one of Examples 406 to 425, characterized in that it is substantially similar to Figure 49 of 13 C ss NMR spectrum.

[0652] 427. Compound I IPA solvate hydrate according to any one of Examples 406 to 426, characterized in that it has the following monoclinic crystal system, space group P212121, and unit cell size, wherein it is equipped with Cu K α Radiation (λ = 1.54178 Å) and measurements at 100 K on a Bruker diffractometer with a CPAD detector:

[0653]

[0654] 428. Compound I IPA solvate hydrate according to any one of Examples 406 to 427, which is prepared by a method comprising: (i) stirring Compound I in an IPA / water mixture, and (ii) separating the solid by centrifugation.

[0655] 429. Compound I is a substantially crystalline MeOAc solvate hydrate (i.e., less than 15% of compound I is in amorphous form, less than 10% of compound I is in amorphous form, and less than 5% of compound I is in amorphous form).

[0656] 430. Compound I according to Example 429, wherein Compound I is 100% crystalline Compound I MeOAc hydrate.

[0657] 431. Essentially pure compound I MeOAc solvate hydrate.

[0658] 432. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 431, characterized in that it has the following X-ray powder diffraction pattern: a signal at one or more selected from the following 2θ values: 6.5 ± 0.2 degrees 2θ, 10.7 ± 0.2 degrees 2θ, 14.3 ± 0.2 degrees 2θ, 17.5 ± 0.2 degrees 2θ, 7.1 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 19.5 ± 0.2 degrees 2θ and 14.2 ± 0.2 degrees 2θ.

[0659] 433. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 432, characterized in that it has the following X-ray powder diffraction pattern: signals at two or more 2θ values ​​selected from the following: 6.5 ± 0.2 degrees 2θ, 10.7 ± 0.2 degrees 2θ, 14.3 ± 0.2 degrees 2θ, 17.5 ± 0.2 degrees 2θ, 7.1 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 19.5 ± 0.2 degrees 2θ and 14.2 ± 0.2 degrees 2θ.

[0660] 434. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 433, characterized in that it has the following X-ray powder diffraction pattern: signals at three or more 2θ values ​​selected from the following: 6.5 ± 0.2 degrees 2θ, 10.7 ± 0.2 degrees 2θ, 14.3 ± 0.2 degrees 2θ, 17.5 ± 0.2 degrees 2θ, 7.1 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 19.5 ± 0.2 degrees 2θ and 14.2 ± 0.2 degrees 2θ.

[0661] 435. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 434, characterized in that it has the following X-ray powder diffraction pattern: signals at four or more 2θ values ​​selected from the following: 6.5 ± 0.2 degrees 2θ, 10.7 ± 0.2 degrees 2θ, 14.3 ± 0.2 degrees 2θ, 17.5 ± 0.2 degrees 2θ, 7.1 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 19.5 ± 0.2 degrees 2θ and 14.2 ± 0.2 degrees 2θ.

[0662] 436. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 435, characterized in that it has the following X-ray powder diffraction pattern: signals at five or more 2θ values ​​selected from the following: 6.5 ± 0.2 degrees 2θ, 10.7 ± 0.2 degrees 2θ, 14.3 ± 0.2 degrees 2θ, 17.5 ± 0.2 degrees 2θ, 7.1 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 19.5 ± 0.2 degrees 2θ and 14.2 ± 0.2 degrees 2θ.

[0663] 437. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 436, characterized in that it has the following X-ray powder diffraction pattern: signals at six or more 2θ values ​​selected from the following: 6.5 ± 0.2 degrees 2θ, 10.7 ± 0.2 degrees 2θ, 14.3 ± 0.2 degrees 2θ, 17.5 ± 0.2 degrees 2θ, 7.1 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 19.5 ± 0.2 degrees 2θ and 14.2 ± 0.2 degrees 2θ.

[0664] 438. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 437, characterized in that it has the following X-ray powder diffraction pattern: signals at seven or more 2θ values ​​selected from the following: 6.5 ± 0.2 degrees 2θ, 10.7 ± 0.2 degrees 2θ, 14.3 ± 0.2 degrees 2θ, 17.5 ± 0.2 degrees 2θ, 7.1 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 19.5 ± 0.2 degrees 2θ and 14.2 ± 0.2 degrees 2θ.

[0665] 439. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 438, characterized in that it has the following X-ray powder diffraction patterns: signals at 6.5 ± 0.2 degrees 2θ, 10.7 ± 0.2 degrees 2θ, 14.3 ± 0.2 degrees 2θ, 17.5 ± 0.2 degrees 2θ, 7.1 ± 0.2 degrees 2θ, 19.9 ± 0.2 degrees 2θ, 19.5 ± 0.2 degrees 2θ and 14.2 ± 0.2 degrees 2θ.

[0666] 440. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 439, characterized in that it is substantially similar to Figure 50 X-ray powder diffraction pattern.

[0667] 441. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 440, characterized in that it has one or more peaks selected from the group consisting of 13 C ssNMR spectrum: 28.1 ± 0.2 ppm, 43.6 ± 0.2 ppm, 130.5 ± 0.2 ppm, 21.4 ± 0.2 ppm, 20.7 ± 0.2 ppm, 19.0 ± 0.2 ppm, 135.9 ± 0.2 ppm and 143.4 ± 0.2 ppm.

[0668] 442. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 441, characterized in that it has two or more peaks selected from the group consisting of 13 C ssNMR spectrum: 28.1 ± 0.2 ppm, 43.6 ± 0.2 ppm, 130.5 ± 0.2 ppm, 21.4 ± 0.2 ppm, 20.7 ± 0.2 ppm, 19.0 ± 0.2 ppm, 135.9 ± 0.2 ppm and 143.4 ± 0.2 ppm.

[0669] 443. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 442, characterized in that it has three or more peaks selected from the group consisting of 13 C ssNMR spectrum: 28.1 ± 0.2 ppm, 43.6 ± 0.2 ppm, 130.5 ± 0.2 ppm, 21.4 ± 0.2 ppm, 20.7 ± 0.2 ppm, 19.0 ± 0.2 ppm, 135.9 ± 0.2 ppm and 143.4 ± 0.2 ppm.

[0670] 444. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 443, characterized in that it has four or more peaks selected from the group consisting of 13 C ssNMR spectrum: 28.1 ± 0.2 ppm, 43.6 ± 0.2 ppm, 130.5 ± 0.2 ppm, 21.4 ± 0.2 ppm, 20.7 ± 0.2 ppm, 19.0 ± 0.2 ppm, 135.9 ± 0.2 ppm and 143.4 ± 0.2 ppm.

[0671] 445. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 444, characterized in that it has five or more peaks selected from the group consisting of 13C ssNMR spectrum: 28.1 ± 0.2 ppm, 43.6 ± 0.2 ppm, 130.5 ± 0.2 ppm, 21.4 ± 0.2 ppm, 20.7 ± 0.2 ppm, 19.0 ± 0.2 ppm, 135.9 ± 0.2 ppm and 143.4 ± 0.2 ppm.

[0672] 446. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 445, characterized in that it has six or more peaks selected from the group consisting of 13 C ssNMR spectrum: 28.1 ± 0.2 ppm, 43.6 ± 0.2 ppm, 130.5 ± 0.2 ppm, 21.4 ± 0.2 ppm, 20.7 ± 0.2 ppm, 19.0 ± 0.2 ppm, 135.9 ± 0.2 ppm and 143.4 ± 0.2 ppm.

[0673] 447. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 446, characterized in that it has seven or more peaks selected from the group consisting of 13 C ssNMR spectrum: 28.1 ± 0.2 ppm, 43.6 ± 0.2 ppm, 130.5 ± 0.2 ppm, 21.4 ± 0.2 ppm, 20.7 ± 0.2 ppm, 19.0 ± 0.2 ppm, 135.9 ± 0.2 ppm and 143.4 ± 0.2 ppm.

[0674] 448. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 447, characterized in that it has the following 13 C ss NMR spectrum: peaks at 28.1 ± 0.2 ppm, 43.6 ± 0.2 ppm, 130.5 ± 0.2 ppm, 21.4 ± 0.2 ppm, 20.7 ± 0.2 ppm, 19.0 ± 0.2 ppm, 135.9 ± 0.2 ppm and 143.4 ± 0.2 ppm.

[0675] 449. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 448, characterized in that it is substantially similar to Figure 51 of 13 CssNMR spectrum.

[0676] 450. The compound I MeOAc solvate hydrate according to any one of Examples 429 to 449, which is prepared by a method comprising (i) stirring an amorphous compound I in a MeOAc / water mixture, (ii) adding compound IMeOAc form A, compound I MeOAc form B, compound I MeOAc form C, compound I pure form E, compound I hydrate form A and compound I hydrate form B, (iii) further stirring, and (iv) separating the solid by centrifugation.

[0677] 451. Compound I is essentially amorphous (i.e., less than 15% of compound I is in crystalline form, less than 10% of compound I is in crystalline form, and less than 5% of compound I is in crystalline form).

[0678] 452. The substantially amorphous compound I according to Example 451, wherein compound I is 100% amorphous.

[0679] 453. The amorphous compound I according to Example 451 or Example 452, characterized in that it is substantially similar to Figure 52 X-ray powder diffraction pattern.

[0680] 454. The amorphous compound I according to any one of Examples 451 to 453, characterized in that it is substantially similar to Figure 53 of 13 C ss NMR spectrum.

[0681] 455. The amorphous compound I according to any one of Examples 451 to 454, which is prepared by a method comprising: (i) purifying compound I by column chromatography, (ii) dissolving the solid in DCM, (iii) removing the solvent, and (iv) drying the solid under high vacuum.

[0682] 456. Compound I, formulated as a solid dispersion.

[0683] 457. Compound I according to Example 456, wherein the solid dispersion is a spray-dried dispersion.

[0684] 458. Compound I formulated as a spray-dried dispersion according to Example 456 or Example 457, wherein the spray-dried dispersion comprises a polymer.

[0685] 459. Compound I, formulated as a spray-dried dispersion according to Example 458, wherein the polymer is HPMCAS-H.

[0686] 460. Compound I, formulated as a spray-dried dispersion according to Example 458, wherein the polymer is HPMC-E15.

[0687] 461. Compound I formulated as a spray-dried dispersion according to Example 459 or Example 460, wherein the w / w ratio of compound I to polymer is 50 / 50.

[0688] 462. Compound I formulated as a spray-dried dispersion according to Example 459 or Example 460, wherein the w / w ratio of compound I to polymer is 80 / 20.

[0689] 463. Compound I, formulated as a spray-dried dispersion according to any one of Examples 456 to 462, is prepared by a method comprising: (i) preparing a solution of Compound I and a polymer in a DCM / MeOH mixture, and (ii) spray-drying the resulting solution using a spray dryer.

[0690] 464. Compound I, formulated as a spray-dried dispersion according to Example 463, wherein the w / w ratio of the DCM / MeOH mixture is 50 / 50.

[0691] 465. Compound I, formulated as a spray-dried dispersion according to Example 463, wherein the w / w ratio of the DCM / MeOH mixture is 63 / 37.

[0692] 466. A pharmaceutical composition comprising compound I according to any one of Examples 1 to 465 and a pharmaceutically acceptable carrier.

[0693] 467. The pharmaceutical composition according to Example 466 further comprises one or more additional therapeutic agents.

[0694] 468. The pharmaceutical composition according to Example 467, wherein the pharmaceutical composition comprises one or more additional CFTR regulating compounds.

[0695] 469. The pharmaceutical composition according to Example 467 or Example 468, wherein the pharmaceutical composition comprises one or more compounds selected from: compound II, compound III, compound III-d, compound IV and compound V, and pharmaceutically acceptable salts and deuterated derivatives of any of the foregoing.

[0696] 470. Compound I according to any one of Examples 1 to 463 or the pharmaceutical composition according to any one of Examples 466 to 469, for the treatment of cystic fibrosis.

[0697] 471. The compound to be used according to Example 470, wherein the compound is administered in combination with one or more compounds selected from: compound II, compound III, compound III-d, compound IV and compound V, and pharmaceutically acceptable salts and deuterated derivatives of any of the foregoing.

[0698] 472. Use of a compound I according to any one of Examples 1 to 463 or a pharmaceutical composition according to any one of Examples 466 to 469 for the preparation of a medicament for the treatment of cystic fibrosis.

[0699] 473. The use according to Example 472, wherein the drug is formulated for administration in combination with one or more compounds selected from: compound II, compound III, compound III-d, compound IV, and pharmaceutically acceptable salts and deuterated derivatives of any of the foregoing.

[0700] 474. A method for treating cystic fibrosis, the method comprising administering to a subject in need compound I according to any one of Examples 1 to 463 or a pharmaceutical composition according to any one of Examples 466 to 469.

[0701] 475. The treatment method according to Example 474, wherein the method further comprises administering one or more compounds selected from: compound II, compound III, compound III-d, compound IV, and pharmaceutically acceptable salts and deuterated derivatives of any of the foregoing.

[0702] 476. A method for preparing pure form A of compound I according to any one of Examples 1 to 28, the method comprising: (i) dissolving amorphous compound I in ethanol, (ii) increasing the temperature to about 73°C, (iii) decreasing the temperature to about 20°C, (iv) separating the solid by filtration, and (v) drying the solid at 50°C.

[0703] 477. A method for preparing pure form B of compound I according to any one of Examples 30 to 49, the method comprising exposing compound I in hydrate form A to about 3% humidity.

[0704] 478. A method for preparing compound I in pure form C according to any one of Examples 51 to 74, the method comprising (i) stirring compound I in hexadecane at about 80°C, and (ii) centrifuging and drying the resulting solid.

[0705] 479. A method for preparing pure form D of compound I according to any one of Examples 76 to 87, said method comprising drying compound I hydrate C at about 80°C.

[0706] 480. A method for preparing pure form D of compound I according to any one of Examples 76 to 87, the method comprising (i) stirring pure form A of compound I in an IPA, (ii) separating the solid by filtration, and (iii) drying the solid at about 125°C.

[0707] 481. A method for preparing pure form E of compound I according to any one of Examples 90 to 112, the method comprising (i) stirring pure form A of compound I in MeOAc, (ii) separating the solid by centrifugation, and (iii) drying the solid at about 50°C.

[0708] 482. A method for preparing compound I in EtOH solvate form B according to any one of Examples 152 to 177, the method comprising (i) stirring compound I in ethanol, and (ii) separating the solid by centrifugation.

[0709] 483. A method for preparing a MeOH solvate of compound I according to any one of Examples 179 to 196, the method comprising (i) dissolving compound I in MeOH and increasing the temperature to about 62°C, (ii) cooling the solution to about 10°C, and (iii) separating the solid by centrifugation.

[0710] 484. A method for preparing a solvate of compound I NPA according to any one of Examples 198 to 218, the method comprising (i) stirring compound I in NPA, and (ii) separating the solid by centrifugation.

[0711] 485. A method for preparing compound I in solvate form A according to any one of Examples 220 to 241, the method comprising (i) stirring compound I in pure form A in MeOAc, and (ii) separating the solid by filtration.

[0712] 486. A method for preparing compound I in solvate form B of MeOAc according to any one of Examples 243 to 258, the method comprising (i) stirring compound I in pure form A in MeOAc at about 5°C, (ii) separating the solid by centrifugation, and (iii) drying the solid at room temperature.

[0713] 487. A method for preparing compound I in solvate form C of MeOAc according to any one of Examples 269 to 281, the method comprising (i) stirring compound I in pure form A in MeOAc at about 5°C, and (ii) separating the solid by filtration.

[0714] 488. A method for preparing compound I in hydrate form A according to any one of Examples 292 to 313, the method comprising (i) stirring compound I in water in solvate form B (EtOH), and (ii) separating the solid by filtration and air drying.

[0715] 489. A method for preparing compound I in hydrate form B according to any one of Examples 315 to 336, the method comprising (i) stirring compound I in a MeOH / water mixture at about 80°C, (ii) separating the solid by filtration, and (iii) exposing the solid to about 11% humidity.

[0716] 490. A method for preparing compound I in hydrate form C according to any one of Examples 338 to 359, the method comprising (i) stirring compound I in a MeOH / water mixture at about 80°C, (ii) separating the solid by filtration, and (iii) exposing the solid to about 75% humidity.

[0717] 491. A method for preparing compound I EtOH solvate hydrate according to any one of Examples 361 to 382, ​​the method comprising (i) stirring compound I in an EtOH / water mixture at about 60°C, and (ii) separating the solid by centrifugation.

[0718] 492. A method for preparing compound I MeOH solvate hydrate according to any one of Examples 384 to 404, the method comprising (i) stirring compound I in a MeOH / water mixture at about 80°C, and (ii) separating the solid by centrifugation.

[0719] 493. A method for preparing compound I IPA solvate hydrate according to any one of Examples 406 to 427, the method comprising (i) stirring compound I in an IPA / water mixture, and (ii) separating the solid by centrifugation.

[0720] 494. A method for preparing compound I MeOAc solvate hydrate according to any one of Examples 429 to 449, the method comprising (i) stirring amorphous compound I in a MeOAc / water mixture, (ii) adding compound I in MeOAc form A, compound I in MeOAc form B, compound I in MeOAc form C, compound I in pure form E, compound I in hydrate form A and compound I in hydrate form B, (iii) further stirring, and (iv) separating the solid by centrifugation.

[0721] 495. A method for preparing amorphous compound I according to any one of Examples 451 to 454, the method comprising (i) purifying compound I by column chromatography, (ii) dissolving the solid in DCM, (iii) removing the solvent, and (iv) drying the solid under high vacuum.

[0722] 496. A method for preparing an amorphous compound I formulated as a spray-dried dispersion according to any one of Examples 456 to 462, the method comprising (i) preparing a solution of compound I and a polymer in a DCM / MeOH mixture, and (ii) spray-drying the resulting solution using a spray dryer.

[0723] Methods for preparing compound I and compound I in solid form

[0724] General Experimental Procedure

[0725] Compounds II, III, III-d and IV can be prepared by any suitable method in the art, such as PCT Publications WO 2011 / 133751, WO 2011 / 133951, WO 2015 / 160787 and U.S. Patent No. 8,865,902.

[0726] Unless otherwise stated, reagents and starting materials should be obtained from commercial sources and used without purification.

[0727] At 400 and 100 MHz respectively 1 H and 13 Solution-phase proton and carbon NMR spectra were obtained on a Bruker Biospin DRX 400 MHz FTNMR spectrometer operating at the C resonance frequency or on a 300 MHz NMR spectrometer. One-dimensional proton and carbon spectra were acquired at digital resolutions of 0.1834 and 0.9083 Hz / Pt, respectively, using a broadband observe (BBFO) probe with sample rotation at 20 Hz. All proton and carbon spectra were acquired under temperature control at 30 °C using standard, previously published pulse sequences and conventional processing parameters.

[0728] Furthermore, using a Varian Mercury NMR instrument with a 45-degree pulse angle, a spectral width of 4800 Hz, and 28860 acquisition points, data were recorded at 300 MHz. 1 Solution-phase NMR spectra of H. The FID was zero-filled to 32 k points, and a 0.3 Hz line broadening was applied before the Fourier transform.

[0729] Also, using a Bruker Avance III HD NMR instrument with a 30-degree pulse angle, an 8000 Hz spectral width, and a 128 k acquisition point, recording was performed at 400 MHz. 1 Solution-phase NMR spectra of H. The FID was zero-filled to 256 k points, and a 0.3 Hz line broadening was applied before the Fourier transform.

[0730] Solution-phase NMR spectra were also recorded on a Bruker AC 250 MHz instrument equipped with a 5 mm QNP (H1 / C13 / F19 / P31) probe (type: 250-SB, s#23055 / 0020) or a Varian 500 MHz instrument equipped with an ID PFG, 5 mm, 50-202 / 500 MHz probe (model / part number 99337300).

[0731] General UPLC / HPLC analytical methods

[0732] LC Method A: Using Acquity UPLC BEH C manufactured by Waters 18 A dual-gradient analytical reversed-phase UPLC was used, with a column (50 × 2.1 mm, 1.7 μm particles) (pn: 186002350) and a flow rate of 1%–99% mobile phase B over 3.0 min. Mobile phase A: H₂O (0.05% CF₃CO₂H). Mobile phase B: CH₃CN (0.035% CF₃CO₂H). Flow rate: 1.2 mL / min, injection volume: 1.5 μL, and column temperature: 60 °C.

[0733] LC Method C: Using Acquity UPLC BEH C manufactured by Waters Corporation 18 A reversed-phase UPLC with a column (50 × 2.1 mm, 1.7 μm particles) (pn: 186002350) and a dual gradient running from 30% to 99% mobile phase B over 2.9 min. Mobile phase A: H₂O (0.05% CF₃CO₂H). Mobile phase B: CH₃CN (0.035% CF₃CO₂H). Flow rate: 1.2 mL / min, injection volume: 1.5 μL, and column temperature: 60 °C.

[0734] LC Method I: UPLC Luna C 18 (2) 50 x 3 mm 3 μm. Run: 2.5 min. Mobile phase: Initial 95% H2O 0.1% FA / 5% MeCN 0.1% FA, linear gradient to 95% MeCN 0.1% FA over 1.3 min, hold for 1.2 min at 95% CH3CN 0.1% FA, T: 45°C, flow rate: 1.5 mL / min.

[0735] LC Method J: UPLC SunFire C 18 75 × 4.6 mm 3.5 μm, run time: 6 minutes. Mobile phase conditions: initial 95% H2O + 0.1% FA / 5% CH3CN + 0.1% FA, linear gradient to 95% CH3CN for 4 minutes, hold at 95% CH3CN for 2 minutes. T: 45℃, flow rate: 1.5 mL / min.

[0736] LC method L: Luna C 18 3.0 × 50 mm, 3.0 μM, temperature: 45℃, flow rate: 2.0 mL / min, run time: 3 minutes. Mobile phase: initial 95% H2O (0.1% formic acid) and 5% CH3CN (0.1% FA), linear gradient to 95% CH3CN (0.1% FA) for 2.0 minutes, then held at 95% CH3CN (0.1% FA) for 1.0 minute.

[0737] Unless otherwise stated, the following procedure is used to analyze all solid forms.

[0738] X-ray powder diffraction

[0739] X-ray powder diffraction (XRPD) spectra were recorded in transmission mode at room temperature (25 ± 2 °C) using a PANalytical system (Malvern PANalytical Inc, Westborough, Massachusetts) equipped with a sealed tube source and a PIXcel 1D Medipix-3 detector. The X-ray generator was operated at 45 kV and 40 mA using copper radiation (1.54060 Å). The powder sample was placed on a 96-well sample holder with a Mylar membrane and loaded into the instrument. The sample was scanned in the range of approximately 3 to approximately 40 °2θ, with a step size of 0.0131303 °2θ and a step time of 49 seconds.

[0740] Solid-state NMR

[0741] A Bruker-Biospin 400 MHz wide-aperture spectrometer equipped with a Bruker-Biospin 4 mm HFX probe was used. The sample was loaded into a 4 mm ZrO2 rotor and rotated under magic angle rotation (MAS) conditions at a rotational speed typically set to 12.5 kHz. 1 H MAS T1 saturation recovery relaxation experiment measures proton relaxation time to set 13 Appropriate cycling delay was applied to the C cross-polarized (CP) MAS experiment. The CP contact time for the carbon CPMAS experiment was set to 2 ms. A CP proton pulse with a linear ramp (50% to 100%) was used. The carbon Hartmann-Hahn matching was optimized on an external reference sample (glycine). All carbon spectra were recorded using proton decoupling at a field strength of approximately 100 kHz using a TPPM15 decoupling sequence.

[0742] Thermogravimetric analysis

[0743] Thermogravimetric analysis was performed using a TA5500 Discovery TGA instrument. Samples of approximately 1–10 mg were scanned at a heating rate of 10 °C / min under nitrogen purging from room temperature to 300 °C.

[0744] Differential scanning calorimetry

[0745] Differential scanning calorimetry was performed using a TA5500 Discovery DSC instrument. Samples of approximately 1–10 mg were scanned from room temperature to 300 °C at a heating rate of 10 °C / min.

[0746] Example

[0747] abbreviation

[0748] Boc = tert-butoxycarbonyl

[0749] CDMT = 2-chloro-4,6-dimethoxy-1,3,5-triazine

[0750] DCM = dichloromethane

[0751] DIEA = N,N-diisopropylethylamine

[0752] DMAP = 4-Dimethylaminopyridine

[0753] DME = dimethoxyethane

[0754] DMF = dimethylformamide

[0755] DMSO = dimethyl sulfoxide

[0756] Dppf = 1,1'-bis(diphenylphosphino)ferrocene

[0757] EtOAc = Ethyl acetate

[0758] EtOH = ethanol

[0759] ESI = Electro-injection ionization

[0760] HPLC = High Performance Liquid Chromatography

[0761] HPMCAS = Hydroxypropyl methylcellulose succinate

[0762] LC = Liquid Chromatography

[0763] MeOH = methanol

[0764] MeTHF = 2-Methyltetrahydrofuran

[0765] MS = Mass Spectrometry

[0766] THF = Tetrahydrofuran

[0767] UPLC = Ultra-high performance liquid chromatography

[0768] Example 1: Synthesis of (R)-16-(2,6-dimethylphenyl)-7-isobutyl-6-(spiro[2,3]hexane-5-yl)-9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidin-4(1,3)-benzanecyclononadenosine-5-one 3,3-dioxide (compound I)

[0769] Part A: Preparation of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[0770]

[0771] Step 1: N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate tert-butyl ester

[0772]

[0773] Boc₂O (838 g, 3.840 mol) was added to a solution of 300 g (1.829 mol) of 4,6-dichloropyrimidine-2-amine in DCM (2.1 L), followed by the addition of DMAP (5.6 g, 45.84 mmol). The mixture was stirred at ambient temperature for 6 hours. Additional DMAP (5.6 g, 45.84 mmol) was added, and the reaction mixture was stirred at ambient temperature for another 24 hours. The mixture was diluted with water (2.1 L) and the organic phase was separated. The organic phase was washed with water (2.1 L) and 2.1 L of brine, dried over magnesium sulfate, filtered through diatomaceous earth, and concentrated under vacuum to obtain a light orange oil with sludge. The mixture was diluted with approximately 500 mL of heptane and filtered using an M filter. The precipitate was washed with 250 mL of heptane. The filtrate was concentrated under vacuum to obtain a thick orange oil, which was inoculated with a previously tested solid and allowed to crystallize to obtain a light orange hard solid. N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate tert-butyl ester (645 g, 97%). 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 8.07 (s, 1H), 1.44 (s, 18H). ESI-MS m / z calculated value 363.07526, experimental value 364.1 (M+1). + Retention time: 2.12 minutes (LC method A).

[0774] Step 2: N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]carbamate tert-butyl ester

[0775]

[0776] All solvents were degassed before use. To a slurry of N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate (88 g, 241.6 mmol), DME (704 mL) containing (2,6-dimethylphenyl)boronic acid (approx. 36.24 g, 241.6 mmol), Cs₂CO₃ (approx. 196.8 g, 604.0 mmol) and water (176 mL) were added. Pd(dppf)Cl₂ (approx. 8.839 g, 12.08 mmol) was added, and the mixture was vigorously stirred under nitrogen at 80 °C (reflux) for 1 hour (with no starting material residue). The reaction mixture was cooled to ambient temperature and diluted with water (704 mL). The aqueous phase was separated and extracted with EtOAc (704 mL). The organic phase was washed with 700 mL of brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was subjected to chromatographic analysis on a 1500 g silica gel column, eluted with 0-30% EtOAc / hexane. The product fractions (eluted with 15% EtOAc) were combined and concentrated under vacuum to give a clear oil product, which was then allowed to crystallize. N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]carbamate tert-butyl ester (81.3 g, 78%). 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 7.88 (s, 1H), 7.30 (dd, J = 8.2, 7.0 Hz, 1H), 7.21–7.16 (m, 2H), 2.03 (s, 6H), 1.38 (s, 18H). ESI-MS calculated m / z 433.17682, experimental value 434.1 (M+1). + Retention time: 2.32 minutes (LC method A).

[0777] Step 3: 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (hydrochloride)

[0778]

[0779] N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]carbamate tert-butyl ester (514.8 g, 915.9 mmol) was dissolved in dichloromethane (4 L). 1,4-dioxane containing hydrogen chloride (1 L, 4 mol) was added, and the mixture was stirred overnight at room temperature. The resulting precipitate was collected by vacuum filtration and dried under vacuum to give 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine hydrochloride (213.5 g, 64%) (213.5 g, 82%) as a white solid. 1¹H NMR (250 MHz, DMSO-d⁶) δ 7.45–6.91 (m, 3H), 6.73 (s, 1H), 2.08 (s, 6H). ESI-MS m / z calculated value 233.072, experimental value 234.1 (M+1). + Retention time: 2.1 minutes (LC method C).

[0780] Step 4: 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine

[0781]

[0782] 4-Chloro-6-(2,6-dimethylphenyl)pyrimidine-2-amine (hydrochloride) (166 g, 614.5 mmol) and 4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-amine (hydrochloride) (30 g, 111.0 mmol) were suspended in DCM (2.5 L), treated with NaOH (725 mL, 1 M, 725.0 mmol) and stirred at room temperature for 1 hour. The mixture was transferred to a separatory funnel and allowed to stand overnight. The DCM phase was separated, and the aqueous phase containing insoluble material was extracted twice or more with DCM (2 x 500 mL). The combined brown DCM phases were stirred with magnesium sulfate and charcoal for 1 hour, filtered, and the yellow solution was concentrated to approximately 500 mL. The solution was diluted with heptane (750 mL), and the DCM was removed under reduced pressure at 60 °C to give a cream-colored suspension. The suspension was stirred at room temperature for 1 hour, filtered, washed with cold heptane and dried to give 4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-amine (157 g, 91%) as a cream-colored solid. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 7.28–7.14 (m, 3H), 7.10 (d, J = 7.5 Hz, 2H), 6.63 (s, 1H), 2.06 (s, 6H). ESI-MS calculated m / z 233.07198, experimental 234.0 (M+1). + Retention time: 1.45 minutes (LC method A).

[0783] Step 5: 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[0784]

[0785] 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (235 g, 985.5 mmol) was dissolved in MeTHF (2.3 L) under stirring and nitrogen atmosphere and cooled in an ice bath. Methyl 3-chlorosulfonylbenzoate (347 g, 1.479 mol) was added to the cold solution in a single addition (appearing slightly endothermic), followed by dropwise addition of a solution of lithium 2-methylbutane-2-ol (in heptane, 875 mL, 3.1 M, 2.712 mol) over 1.25 hours (exothermic, internal temperature 0 to 10 °C). The ice bath was removed, and the green solution was stirred at room temperature for 4 hours. Cold HCl (2 L, 1.5 M, 3.000 mol) was added to the green solution to separate the phases, and the organic phase was washed once with water (1 L) and once with brine (500 mL). The aqueous phase was back-extracted once with MeTHF (350 mL), and the organic phases were combined. This yellow MeTHF solution of methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoate (ESI-MS m / z calculated 431.07065, experimental 432.0 (M+1)) was analyzed. + (Retention time: 1.81 min) The sample was treated with NaOH (2.3 L, 2 M, 4.600 mol) and stirred at room temperature for 1 hour. The phases were separated, and the NaOH phase was washed twice with MeTHF (2 x 500 mL), and the combined organic phases were extracted once with 2 M NaOH (1 x 250 mL). The combined NaOH phases were combined, stirred in an ice bath, and slowly acidified by adding an aqueous HCl solution (416 mL, 36% w / w, 4.929 mol) while maintaining the internal temperature between 10 and 20 °C. At the end of the addition (pH approximately 5-6), the final pH was adjusted to 2-3 by adding solid citric acid. The resulting yellow viscous suspension was stirred overnight at room temperature to obtain a creamy, brittle suspension. The solids were collected by filtration, washed with plenty of water, and blotted dry for 3 hours. The solids were dried under reduced pressure at 45-50 °C under nitrogen venting for 120 hours. 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (395 g, 96%) was isolated as a creamy white solid. 1¹H NMR (400 MHz, DMSO-d⁶) δ 13.44 (s, 1H), 12.46 (s, 1H), 8.48–8.39 (m, 1H), 8.25–8.15 (m, 1H), 8.15–8.08 (m, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.31 (s, 1H), 7.28–7.18 (m, 1H), 7.10 (d, J = 7.6 Hz, 2H), 1.84 (s, 6H). ESI-MS calculated m / z 417.055, experimental 418.0 (M+1). + Retention time: 1.56 minutes. (LC Method A).

[0786] Part B: Preparation of (2R)-2-amino-3-(1-bicyclo[1.1.1]pentyl)prop-1-ol

[0787]

[0788] Step 1: Tricyclic [1.1.1.01,3]pentane

[0789]

[0790] Over one hour, MeLi (48 mL, 1.6 M, 76.800 mmol) was slowly added to a solution of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane (10 g, 33.691 mmol) in diethyl ether (25 mL) while maintaining the internal reaction temperature between -50 and -60 °C. The reaction mixture was then warmed to 0 °C and stirred at this temperature for 30 minutes. The reaction flask was attached to a bent tube and a receiving flask equipped with a vacuum adapter. The system was placed under vacuum using a water vacuum pump, and the reaction mixture was distilled into the receiving flask, cooled with liquid nitrogen, while the distillation flask was maintained at approximately 0 °C in a water-ice bath to provide a clear distillate containing approximately 3.5% tricyclo[1.1.1.01,3]pentane (53 g, 83%). 1 ¹H NMR (400 MHz, CDCl₃) δ 1.96 (s, 6H). This solution can be used directly for the next reaction without further purification.

[0791] Step 2: Methyl (2R)-2-(tert-butoxycarbonylamino)-3-(3-iodo-1-bicyclo[1.1.1]pentyl)propionate

[0792]

[0793] Methyl (2S)-2-(tert-butoxycarbonylamino)-3-iodopropionate (3 g, 9.1149 mmol) was dissolved in a solution of tricyclo[1.1.1.01,3]pentane (53 g, 28.063 mmol in DCM) from a previous experiment, and then triethylborane (1.1 mL, 1 M, 1.1000 mmol in hexane) was added. This reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was analyzed by reversed-phase chromatography at 50 g C. 18 Purification was performed on a RediSep Rf gold column using a 5-100% gradient of acetonitrile / pure water to obtain a clarified oil of (2R)-2-(tert-butoxycarbonylamino)-3-(3-iodo-1-bicyclo[1.1.1]pentyl)propionate (1.64 g, 45%), which was then allowed to stand to crystallize. 1 ¹H NMR (400MHz, CDCl₃) δ 4.98 (d, J = 7.3 Hz, 1H), 4.37–4.23 (m, 1H), 3.74 (s, 3H), 2.31–2.21 (m, 6H), 2.19–2.08 (m, 1H), 1.88 (dd, J = 14.7, 7.6 Hz, 1H), 1.45 (s, 9H). ESI-MS m / z calculated value 395.0594, experimental value 296.0 (M⁻⁹⁹). + Retention time: 1.95 minutes, with a sample of (2R)-2-(tert-butoxycarbonylamino)-3-(3-iodo-1-bicyclo[1.1.1]pentyl)propionate (1.63 g, 35%) yellow oil of lower purity, which was allowed to stand to crystallize. 1 ¹H NMR (400 MHz, CDCl₃) δ 4.98 (d, J = 7.8 Hz, 1H), 4.36–4.25 (m, 1H), 3.74 (s, 3H), 2.31–2.19 (m, 6H), 2.16–2.10 (m, 1H), 1.88 (dd, J = 14.4, 7.6 Hz, 1H), 1.45 (s, 9H). ESI-MS m / z calculated value 395.0594, experimental value 296.0 (M⁻⁹⁹). + Retention time: 1.96 minutes; LC method I.

[0794] Step 3: Methyl (2R)-3-(1-bicyclo[1.1.1]pentyl)-2-(tert-butoxycarbonylamino)propionate

[0795]

[0796] Triethylborane (in hexane) (0.5 mL, 1 M, 0.5000 mmol) was added dropwise to a solution of (2R)-2-(tert-butoxycarbonylamino)-3-(3-iodo-1-bicyclo[1.1.1]pentyl)propionate (1.64 g, 4.1287 mmol), 2,6-dimethylpyridine (1.288 g, 1.4 mL, 12.020 mmol) and tris(trimethylsilyl)silane (3.0628 g, 3.8 mL, 12.317 mmol) in anhydrous THF (9 mL), and stirred at room temperature over the entire weekend. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified on silica gel using a 40 g column with a 0-50% ethyl acetate / heptane gradient to give methyl (2R)-3-(1-bicyclo[1.1.1]pentyl)-2-(tert-butoxycarbonylamino)propionate (766 mg, 65%) as a pale yellow powder. 1 ¹H NMR (400 MHz, CDCl₃) δ 4.94 (d, J = 7.3 Hz, 1H), 4.35–4.25 (m, 1H), 3.73 (s, 3H), 2.45 (s, 1H), 2.04–1.91 (m, 1H), 1.83–1.69 (m, 7H), 1.45 (s, 9H). ESI-MS m / z calculated value 269.16272, experimental value 170.2 (M⁻⁹)⁺; retention time: 1.91 min; LC method L.

[0797] Step 4: N-[(1R)-1-(1-bicyclo[1.1.1]pentylmethyl)-2-hydroxy-ethyl] tert-butyl carbamate

[0798]

[0799] LiBH4 (350 mg, 16.067 mmol) was added to a solution of methyl (2R)-3-(1-bicyclo[1.1.1]pentyl)-2-(tert-butoxycarbonylamino)propionate (1.46 g, 5.1497 mmol) in THF (15 mL) and maintained at 0 °C in an ice-water bath. The reaction mixture was kept at this temperature for 30 min and then warmed and stirred at room temperature for 2 h. The reaction mixture was then cooled to 0 °C and quenched by adding a saturated aqueous solution of ammonium chloride (15 mL). The biphase mixture was stirred at 0 °C for 20 min, and the layers were separated. The aqueous layer was extracted with ethyl acetate (4 x 25 mL). The combined organic layers were washed with brine (150 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude and partially quenched material. The sample of this material, N-[(1R)-1-(1-bicyclo[1.1.1]pentylmethyl)-2-hydroxy-ethyl] tert-butyl carbamate (100 mg, 7%) (white powder), was retained and set aside. ESI-MS calculated m / z value: 241.1678; experimental value: 264.2 (M+23). + Retention time: 1.73 minutes. The remaining portion of the crude material was dissolved back into DCM (50 mL) and washed with 0.2 M HCl aqueous solution (50 mL) until hydrogen escaping ceased. The aqueous phase was separated and washed with DCM (50 mL). The organic phases were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give N-[(1R)-1-(1-bicyclo[1.1.1]pentylmethyl)-2-hydroxyethyl] tert-butyl carbamate (1.15 g, 88%) as a white solid. 1 ¹H NMR (400 MHz, CDCl₃) δ 4.55 (br.s., 1H), 3.75–3.58 (m, 2H), 3.56–3.47 (m, 1H), 2.59–2.34 (m, 2H), 1.78–1.70 (m, 6H), 1.65 (dd, J = 14.7, 4.9 Hz, 1H), 1.53 (dd, J = 14.7, 8.6 Hz, 1H), 1.46 (s, 9H). ESI-MS m / z calculated value 241.1678, experimental value 264.2 (M+23)+; zero value (M-)+; retention time: 1.73 min; LC method J.

[0800] Step 5: (2R)-2-amino-3-(1-bicyclo[1.1.1]pentyl)prop-1-ol

[0801]

[0802] N-[(1R)-1-(1-bicyclo[1.1.1]pentylmethyl)-2-hydroxyethyl]carbamate tert-butyl ester (1.15 g, 4.4794 mmol) was added in small amounts to a solution of HCl (in dioxane, 40 mL, 4 M, 160.00 mmol), stirred at ambient temperature, and then maintained at this temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was ground in anhydrous THF (20 mL), filtered, and washed with more THF (2 x 5 mL). The resulting solid was dried under high vacuum for 1 hour to give (2R)-2-amino-3-(1-bicyclo[1.1.1]pentyl)prop-1-ol (hydrochloride) (730 mg, 87%) as a white powder. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 7.91 (br. s., 3H), 5.31 (t, J = 5.1 Hz, 1H), 3.62 (dt, J = 11.7, 3.7 Hz, 1H), 3.39 (dt, J = 11.7, 6.0 Hz, 1H), 3.07 -2.96 (m, 1H), 2.45 (s, 1H), 1.78 - 1.61 (m, 8H). ESI-MS m / z calculated value 141.11537, experimental value 142.2 (M+1) + Retention time: 0.57 minutes; LC method I.

[0803] Part C: Preparation of (R)-16-(2,6-dimethylphenyl)-7-isobutyl-6-(spiro[2,3]hexane-5-yl)-9-oxa-3-thia-2,6-diaza-1(2,4)-pyrimidin-4(1,3)-benzanecyclononadenosine-5-one 3,3-dioxide (Compound I)

[0804]

[0805] Step 1: 3-[[4-[(2R)-2-amino-3-(1-bicyclo[1.1.1]pentyl)propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[0806]

[0807] Under a nitrogen atmosphere, (2R)-2-amino-3-(1-bicyclo[1.1.1]pentyl)prop-1-ol (hydrochloride) (505 mg, 2.7002 mmol), 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (1.3 g, 3.1110 mmol), DMF (5.8 mL), and MeTHF (58 mL) were added to a flame-dried flask. This suspension was cooled to 0 °C, and sodium tert-butoxide (1.5 g, 15.608 mmol) was added, and the mixture was stirred at this temperature for 5 minutes. The reaction mixture was then warmed to ambient temperature and stirred for 30 minutes. The mixture was then cooled to 0 °C and diluted with MeTHF (50 mL), quenched with ice-cold 1 NHCl (100 mL), and stirred vigorously. The aqueous phase was separated and extracted with MeTHF (3 x 50 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to reversed-phase chromatography at 100 g C. 18 Purification was performed on an aqueous RediSep Rf gold column using a 5-100% gradient of acetonitrile / acidic water (0.1% HCl) to obtain 3-[[4-[(2R)-2-amino-3-(1-bicyclo[1.1.1]pentyl)propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (hydrochloride) (1.254 g, 82%) as a white powder. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 13.07 (br. s, 1H), 8.46 (t, J = 1.7 Hz, 1H), 8.25 (br. s, 3H), 8.14 (dd, J = 14.1, 7.7 Hz, 2H), 7.71 (t, J = 7.7 Hz, 1H), 7.31 - 7.21 (m, 1H), 7.18 - 7.07 (m, 2H), 6.30 (br. s, 1H), 4.35 (dd, J = 11.7, 2.2 Hz, 1H), 4.16 (dd, J = 12.0, 6.6 Hz, 1H), 3.49 - 3.45 (m, 1H, overlapping with water). 2.46 (s, 1H), 2.07 (s, 1H), 2.01 (br. s, 6H), 1.83 (d, J = 6.8 Hz, 2H), 1.75, 1.70 (ABq. JAB = 9.5 Hz, 6H). ESI-MS calculated m / z: 522.19366; experimental value: 523.2 (M+1). + Retention time: 2.48 minutes; LC method J.

[0808] Step 2: 3-[[4-[(2R)-3-(1-bicyclo[1.1.1]pentyl)-2-[(6-tert-butylfurano[2,3-b]pyrazin-2-yl)methylamino]propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid

[0809]

[0810] Under nitrogen atmosphere, 3-[[4-[(2R)-2-amino-3-(1-bicyclo[1.1.1]pentyl)propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (hydrochloride) (83 mg, 0.1476 mmol), 6-tert-butylfurano[2,3-b]pyrazin-2-carboxaldehyde (31.6 mg, 0.1547 mmol), anhydrous DCM (3.0 mL), acetic acid (20 µL, 0.3517 mmol), and DIEA (95 µL, 0.5454 mmol) were added to a 20 mL vial. The mixture was cooled in an ice bath, sodium triacetoxyborohydride (110 mg, 0.5190 mmol) was added, and the reaction mixture was stirred for 4 hours while being warmed to ambient temperature. The reactants were quenched with 1 M HCl aqueous solution (1 mL), MeOH (0.5 mL), and DMSO (0.5 mL), filtered, and purified by reversed-phase HPLC (1-99% acetonitrile / 5 mM HCl aqueous solution over 30 min) to give 3-[[4-[(2R)-3-(1-bicyclo[1.1.1]pentyl)-2-[(6-tert-butylfurano[2,3-b]pyrazin-2-yl)methylamino]propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (hydrochloride) (68.3 mg, 62%) as a white solid. ESI-MS calculated m / z 710.28864, experimental 711.2 (M+1). + Retention time: 1.61 minutes. LC method A.

[0811] Step 3: (11R)-11-(1-bicyclo[1.1.1]pentylmethyl)-12-[(6-tert-butylfurano[2,3-b]pyrazin-2-yl)methyl]-6-(2,6-dimethylphenyl)-2,2-dioxo-9-oxa-2λ6-thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadecan-1(18),4(19),5,7,14,16-hexen-13-one (Compound I)

[0812]

[0813] Under nitrogen atmosphere, 3-[[4-[(2R)-3-(1-bicyclo[1.1.1]pentyl)-2-[(6-tert-butylfurano[2,3-b]pyrazin-2-yl)methylamino]propoxy]-6-(2,6-dimethylphenyl)pyrimidin-2-yl]aminosulfonyl]benzoic acid (hydrochloride) (67 mg, 0.08966 mmol) was combined with CDMT (43 mg, 0.2449 mmol) and DMF (3.0 mL). The solution was stirred at 0 °C. 4-Methylmorpholine (65 µL, 0.5912 mmol) was added, and the mixture was stirred in a cooling bath and warmed to ambient temperature. After 16 hours, the reactants were filtered and purified by reversed-phase HPLC (1-99% acetonitrile / 5 mM HCl aqueous solution over 30 minutes) to give (11R)-11-(1-bicyclo[1.1.1]pentylmethyl)-12-[(6-tert-butylfurano[2,3-b]pyrazin-2-yl)methyl]-6-(2,6-dimethylphenyl)-2,2-dioxo-9-oxa-2λ as a white solid. 6 -Thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadecan-1(18),4(19),5,7,14,16-hexen-13-one (33.6 mg, 54%). 1 H NMR (400 MHz, chloroform-d) δ 9.06 (s, 1H), 8.72 (t, J = 1.8 Hz, 1H), 8.41 (s, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.89 (dt, J = 7.7, 1.4 Hz, 1H), 7.67(t, J = 7.8 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 7.6 Hz, 2H), 6.61(s, 1H), 6.20 (s, 1H), 5.40 (dd, J = 11.4, 4.0 Hz, 1H), 5.36 - 5.29 (m, 1H),4.29 - 4.18 (m, 2H), 4.09 - 4.00 (m, 1H), 2.45 (s, 1H), 2.09 - 1.96 (m, 7H), 1.81 (dd, J = 15.5, 3.3 Hz, 1H), 1.62 - 1.56 (m, 6H), 1.42 (s, 9H). ESI-MS calculated m / z value: 692.2781, experimental value: 693.2 (M+1). + Retention time: 2.3 minutes. LC method A.

[0814] Example 2: Compound I in pure form A

[0815] 1. Synthesis Procedure

[0816] 3.5 g of amorphous compound I was loaded into a 100 mL reactor (Mettler Toledo Easy Max 102), followed by 50 mL of EtOH. The temperature was increased to 73 °C as quickly as possible and maintained at 73 °C for 1.5 hours.

[0817] Once the material dissolved, the temperature was reduced to 20°C within 5.083 hours. The resulting crystals of compound I in solvate form B were filtered under a nitrogen stream. The separated material was then placed in a vacuum oven at 50°C under nitrogen purging for 3 days to form compound I in pure form A. The crystalline phase was confirmed using XRPD analysis.

[0818] 2. X-ray powder diffraction

[0819] X-ray powder diffraction (XRPD) results are shown in Figure 1 And in the table below.

[0820] Table 1. XRPD signals of compound I in pure form A

[0821]

[0822] 3. Thermogravimetric analysis

[0823] Thermograph ( Figure 2 The readings show a weight loss of 0.04% from 30°C to 200°C.

[0824] 4. Differential Scanning Calorimetry Analysis

[0825] Thermograph ( Figure 3 It shows an endothermic peak at approximately 198°C, with a heat of fusion of 17 J / g.

[0826] 5. Solid-state NMR

[0827] Compound I in pure form A 13 C CPMAS spectrum is shown in Figure 4 And in the table below.

[0828] Table 2. Compound I in pure form A 13 C CPMAS

[0829]

[0830] 6. Single Crystal Elucidation

[0831] Single crystals of compound I in its pure form A were obtained by desolvation of the solvate of compound I EtOH. α X-ray diffraction data were acquired at 100 K using a Rigaku diffractometer with radiation (λ = 1.54178 Å) and an HPAD detector. The structure was analyzed and refined using the SHELX program (Sheldrick, GM, Acta Crystallographica Sinica, (2008) A64, 112-122), and the results are summarized in the table below.

[0832] Table 3. Single-crystal elucidation of compound I in pure form A

[0833]

[0834] Example 3: Compound I in pure form B

[0835] 1. Synthesis Procedure

[0836] The pure form B of compound I was prepared by exposing the hydrate form A of compound I to 3% humidity for 3 hours using an Anton Paar CHC+ chamber (humidity XRD).

[0837] In another procedure, pure form B of compound I was prepared by placing the hydrated form A of compound I in an ssNMR rotor in an oven at 125°C for 3 hours.

[0838] 2. X-ray powder diffraction

[0839] The X-ray powder diffraction (XRPD) spectrum of compound I in pure form B is shown in Figure 5 And in the table below.

[0840] Table 4. XRPD signals of compound I in pure form B

[0841]

[0842] 3. Solid-state NMR

[0843] Compound I in pure form B 13 C CPMAS spectrum is shown in Figure 6 And in the table below.

[0844] Table 5. Compound I in pure form B 13 C CPMAS

[0845]

[0846] Example 4: Compound I in pure form C

[0847] 1. Synthesis Procedure

[0848] Approximately 60 mg of compound I was added to a 2 mL HPLC vial, followed by 250 μL of hexadecane. The vial was slurried at 80 °C for 19 days. The slurry was then centrifuged and dried under reduced pressure at 50 °C overnight.

[0849] 2. X-ray powder diffraction

[0850] X-ray powder diffraction (XRPD) results are shown in Figure 7 And in the table below.

[0851] Table 6. XRPD signals of compound I in pure form C

[0852]

[0853] 3. Thermogravimetric analysis

[0854] Thermograph ( Figure 8 The data shows a weight loss of 0.05% from 30°C to 40°C and a weight loss of 0.16% from 40°C to 240°C.

[0855] 4. Differential Scanning Calorimetry Analysis

[0856] Thermograph ( Figure 9 It shows an endothermic peak at approximately 237°C, with a heat of fusion of 42 J / g.

[0857] 5. Solid-state NMR

[0858] Compound I in pure form C 13 C CPMAS spectrum is shown in Figure 10 And in the table below.

[0859] Table 7. Compound I in pure form C 13 C CPMAS

[0860]

[0861] Example 5: Compound I in pure form D

[0862] 1. Synthesis Procedure

[0863] Compound I in pure form D was prepared by vacuum drying compound I in hydrate form C overnight at 80 °C.

[0864] In a separate procedure, pure form D of compound I was prepared by slurrying 150 mg of compound I in pure form A in 3 mL of IPA overnight. After filtration, the solid was placed in an oven at 125°C for 3 hours.

[0865] 3. Solid-state NMR

[0866] Compound I in pure form D 13 C CPMAS spectrum is shown in Figure 11 And in the table below.

[0867] Table 8. Compound I in pure form D 13 C CPMAS

[0868]

[0869] Example 6: Compound I in pure form E

[0870] 1. Synthesis Procedure

[0871] 100 mg of compound I, pure form A, was added to an HPLC vial, followed by 0.5 mL of MeOAc. The mixture was stirred with a magnetic stir bar for 4 days. The slurry was then centrifuged, and the resulting solid was dried under vacuum at 50 °C to obtain compound I, pure form E.

[0872] 2. X-ray powder diffraction

[0873] X-ray powder diffraction (XRPD) results are shown in Figure 12 And in the table below.

[0874] Table 9. XRPD signals of compound I in pure form E

[0875]

[0876] 3. Thermogravimetric analysis

[0877] Thermograph ( Figure 13 The readings show a weight loss of 0.08% from 30°C to 120°C.

[0878] 4. Differential Scanning Calorimetry (DSC) Analysis

[0879] Thermograph ( Figure 14 It shows an endothermic peak at approximately 212°C, with a heat of fusion of 30 J / g.

[0880] 5. Solid-state NMR

[0881] Compound I in pure form E 13 C CPMAS spectrum is shown in Figure 15 And in the table below.

[0882] Table 10. Compound I in pure form E 13 C CPMAS

[0883]

[0884] 6. Single Crystal Elucidation

[0885] Single crystals of compound I in pure form E were grown by dissolving compound I in pure form A in methyl acetate and crystallizing upon the addition of heptane. Once separated, this material was vacuum-dried at 50°C for 2 days. [The text then abruptly shifts to a seemingly unrelated topic:] ...equipped with Cu K... α X-ray diffraction data were acquired at 100 K using a Rigaku diffractometer with radiation (λ=1.54178Å) and an HPAD detector. The structure was analyzed and refined using the SHELX program (Sheldrick, GM, Acta Crystallographica Sinica, (2008) A64, 112-122), and the results are summarized in the table below.

[0886] Table 11. Single-crystal elucidation of compound I in pure form E

[0887]

[0888] Example 7: Compressed form E of compound I

[0889] 1. Synthesis Procedure

[0890] 100 mg of compound I in pure form E was compressed using a Material Transfer System (MTS) and a 5 mm circular flat surface, Natoli #99307. The MTS was equipped with work tools. The powder was manually weighed and filled into the mold. Compression was performed at 100 mm / min, reaching a target force of 21.6 kN, and held for 10 seconds. The blister was compressed 10 times, with the blister removed and crushed with a scraper after each compression. After crushing, the same material was placed back into the mold for compression again until a total of 10 compressions were completed to obtain compound I in compressed form E.

[0891] 2. X-ray powder diffraction

[0892] X-ray powder diffraction (XRPD) results are shown in Figure 16 And in the table below.

[0893] Table 12. XRPD signals of compound I in compressed form E

[0894]

[0895] 5. Solid-state NMR

[0896] The compressed form of compound I, E 13 C CPMAS spectrum is shown in Figure 17 And in the table below.

[0897] Table 13. Compressed form E of compound I 13 C CPMAS

[0898]

[0899] Example 8: Compressed form A of compound I

[0900] 1. Synthesis Procedure

[0901] 100 mg of compound I in pure form A was compressed using an MTS and a 5 mm circular flat surface of Natoli #99307. The MTS was equipped with the work tool. The powder was weighed manually and filled into the mold. Compression was performed at 100 mm / min, reaching a target force of 21.6 kN, and held for 10 seconds. The blister was compressed 10 times, with the blister removed and crushed with a scraper after each compression. After crushing, the same material was placed back into the mold for compression again until a total of 10 compressions were completed to obtain compound I in compressed form A.

[0902] 2. X-ray powder diffraction

[0903] X-ray powder diffraction (XRPD) results are shown in Figure 18 And in the table below.

[0904] Table 14. XRPD signals of compound I in compressed form A

[0905]

[0906] 5. Solid-state NMR

[0907] The compressed form of compound I, A 13 C CPMAS spectrum is shown in Figure 19 And in the table below.

[0908] Table 15. Compressed form A of compound I 13 C CPMAS

[0909]

[0910] Example 9: Compound I EtOH solvate form B

[0911] 1. Synthesis Procedure

[0912] 1000 mg of compound I, pure form A, was added to a 20 mL scintillation vial, followed by 10 mL of EtOH. The contents of the vial were stirred with a magnetic stir bar at room temperature for 5 days. The slurry was centrifuged to obtain compound I, EtOH solvate form B.

[0913] 2. X-ray powder diffraction

[0914] X-ray powder diffraction (XRPD) results are shown in Figure 20 And in the table below.

[0915] Table 16. XRPD signals of compound I EtOH solvate form B

[0916]

[0917] 3. Thermogravimetric analysis

[0918] Thermograph ( Figure 21 The results show a 5.29% weight loss from 30°C to 90°C.

[0919] 4. Differential Scanning Calorimetry Analysis

[0920] Thermograph ( Figure 22 The results show an endothermic peak at approximately 109°C with a heat of fusion of 43 J / g, followed by a second endothermic peak at approximately 197°C with a heat of fusion of 13 J / g.

[0921] 5. Solid-state NMR

[0922] Compound I EtOH solvate form B 13 C CPMAS spectrum is shown in Figure 23 And in the table below.

[0923] Table 17. Solvate form B of compound I EtOH 13 C CPMAS

[0924]

[0925] 6. Single Crystal Elucidation

[0926] Single crystals of compound I, in its solvate form B, were obtained from EtOH. X-ray diffraction data were acquired at 100 K using a Bruker diffractometer equipped with Cu Kα radiation (λ = 1.54178 Å) and a CPAD detector. The structures were resolved and refined using the SHELX program (Sheldrick, GM, Acta Crystallographica Sinica, (2008) A64, 112-122), and the results are summarized in the table below.

[0927] Table 18. Single-crystal elucidation of compound I, EtOH solvate form B

[0928]

[0929] Example 10: Compound I MeOH solvate

[0930] 1. Synthesis Procedure

[0931] 600 mg of compound I in pure form A was loaded into a reaction vessel. 30 mL of MeOH was added to the reactor, and the temperature was increased to 62 °C as quickly as possible. The vessel was then cooled to 10 °C over 5 hours. The slurry was then centrifuged, and the solvate of compound IMeOH was separated into a wet cake.

[0932] 2. X-ray powder diffraction

[0933] X-ray powder diffraction (XRPD) results are shown in Figure 24 And in the table below.

[0934] Table 19. XRPD signals of compound I MeOH solvate

[0935]

[0936] 3. Solid-state NMR

[0937] Compound I MeOH solvate 13 C CPMAS spectrum is shown in Figure 25 And in the table below.

[0938] Table 20. Solvates of Compound I (MeOH) 13 C CPMAS

[0939]

[0940] 4. Single Crystal Elucidation

[0941] Single crystals of the solvate of compound I, MeOH, were obtained from MeOH. X-ray diffraction data were acquired at 100 K using a Bruker diffractometer equipped with Cu Kα radiation (λ = 1.54178 Å) and a CPAD detector. The structure was resolved and refined using the SHELX program (Sheldrick, GM, Acta Crystallographica Sinica, (2008) A64, 112-122), and the results are summarized in the table below.

[0942] Table 21. Single-crystal elucidation of the solvate of compound I MeOH

[0943]

[0944] Example 11: Compound I NPA solvate

[0945] 1. Synthesis Procedure

[0946] Approximately 50 mg of pure form A of compound I was added to an HPLC vial, followed by 1 mL of NPA and a magnetic stir bar. The vial was stirred at room temperature for 2 hours. The solid was separated by centrifugation to obtain the solvate of compound I NPA.

[0947] 2. X-ray powder diffraction

[0948] X-ray powder diffraction (XRPD) results are shown in Figure 26 And in the table below.

[0949] Table 22. XRPD signals of compound I NPA solvates

[0950]

[0951] 3. Solid-state NMR

[0952] Compound I NPA solvates 13 C CPMAS spectrum is shown in Figure 27 And in the table below.

[0953] Table 23. Solvates of Compound I NPA 13 C CPMAS

[0954]

[0955] Example 12: Compound I MeOAc solvate form A

[0956] 1. Synthesis Procedure

[0957] 1000 mg of compound I, pure form A, was weighed in an HPLC vial, and then 0.5 mL of MeOAc was added. After stirring at room temperature for 3 days, the slurry was filtered, and the resulting compound I, MeOAc solvate form A, was separated into a wet cake.

[0958] 2. X-ray powder diffraction

[0959] X-ray powder diffraction (XRPD) results are shown in Figure 28 And in the table below.

[0960] Table 24. XRPD signals of compound I MeOAc solvate form A

[0961]

[0962] 3. Thermogravimetric analysis

[0963] Thermograph ( Figure 29 The results show a 1.68% weight loss from 30°C to 120°C.

[0964] 4. Differential Scanning Calorimetry Analysis

[0965] Thermograph ( Figure 30 The figure shows an endothermic peak at approximately 100°C, with a heat of fusion of 91 J / g, followed by a second endothermic peak at approximately 216°C, with a heat of fusion of 33 J / g.

[0966] 5. Solid-state NMR

[0967] Compound I MeOAc solvate form A 13 C CPMAS spectrum is shown in Figure 31 And in the table below.

[0968] Table 25. Solvate form A of compound I MeOAc 13 C CPMAS

[0969]

[0970] Example 13: Compound I MeOAc solvate form B

[0971] 1. Synthesis Procedure

[0972] 1000 mg of compound I, pure form A, was weighed in an HPLC vial, and then 0.5 mL of MeOAc was added. After stirring at 5 °C for 5 days, the slurry was centrifuged, and the solid was vacuum dried overnight at room temperature.

[0973] 2. X-ray powder diffraction

[0974] X-ray powder diffraction (XRPD) results are shown in Figure 32 And in the table below.

[0975] Table 26. XRPD signals of compound I MeOAc solvate form B

[0976]

[0977] 3. Thermogravimetric analysis

[0978] Thermograph ( Figure 33 The results show a weight loss of 0.39% from 30°C to 60°C and a weight loss of 0.20% from 60°C to 190°C.

[0979] 4. Differential Scanning Calorimetry Analysis

[0980] Thermograph ( Figure 34 The results show an endothermic peak at approximately 51°C with a heat of fusion of 8 J / g, followed by a second endothermic peak at approximately 187°C with a heat of fusion of 10.5 J / g.

[0981] 5. Solid-state NMR

[0982] Compound I MeOAc solvate form B 13 C CPMAS spectrum is shown in Figure 35 And in the table below.

[0983] Table 27. Solvates of Compound I (MeOAc) in Form B 13 C CPMAS

[0984]

[0985] Example 14: Compound I MeOAc solvate form C

[0986] 1. Synthesis Procedure

[0987] 1000 mg of compound I, pure form A, was weighed in an HPLC vial, and then 0.5 mL of MeOAc was added. After stirring at 5°C for 6 days, the slurry was filtered to obtain a wet cake, yielding compound I, MeOAc, solvated form C.

[0988] 2. X-ray powder diffraction

[0989] X-ray powder diffraction (XRPD) results are shown in Figure 36 And in the table below.

[0990] Table 28. XRPD signals of compound I MeOAc solvate form C

[0991]

[0992] 3. Solid-state NMR

[0993] Compound I MeOAc solvate form C 13 C CPMAS spectrum is shown in Figure 37 And in the table below.

[0994] Table 29. Solvate form C of compound I MeOAc 13 C CPMAS

[0995]

[0996] Example 15: Compound I in hydrate form A

[0997] 1. Synthesis Procedure

[0998] A 400 mL reaction vessel contained 16.5 g of compound I (EtOH solvate form B) and 250 mL of water. The solution was stirred at 25 °C for 4 hours. The slurry was then filtered, and the resulting solid was air-dried overnight.

[0999] 2. X-ray powder diffraction

[1000] X-ray powder diffraction (XRPD) results are shown in Figure 38 And in the table below.

[1001] Table 30. XRPD signals of compound I in hydrate form A

[1002]

[1003] 3. Solid-state NMR

[1004] Compound I in hydrate form A 13 C CPMAS spectrum is shown in Figure 39 And in the table below.

[1005] Table 31. Hydrolysate form A of compound I 13 C CPMAS

[1006]

[1007] 4. Single Crystal Elucidation

[1008] Single crystals of compound I hydrate form A were obtained by solvent exchange of compound I EtOH solvate with water. X-ray diffraction data were acquired at 100 K using a Bruker diffractometer equipped with Cu Kα radiation (λ = 1.54178 Å) and a CPAD detector. The structure was resolved and refined using the SHELX program (Sheldrick, GM, Acta Crystallographica Sinica, (2008) A64, 112-122), and the results are summarized in the table below.

[1009] Table 32. Single-crystal elucidation of compound I in hydrate form A

[1010]

[1011] Example 16: Compound I in hydrate form B

[1012] 1. Synthesis Procedure

[1013] 200 mg of amorphous compound I was added to an HPLC vial containing 1.5 mL of 50:50 MeOH / water. The vial was placed in a shaker block at 80 °C for 2 days. The slurry was centrifuged and vacuum dried overnight at 80 °C. The sample was then exposed to 11% RH for 3 days.

[1014] 2. X-ray powder diffraction

[1015] X-ray powder diffraction (XRPD) results are shown in Figure 40 And in the table below.

[1016] Table 33. XRPD signals of compound I in hydrate form B

[1017]

[1018] 3. Solid-state NMR

[1019] Compound I in hydrate form B 13 C CPMAS spectrum is shown in Figure 41 And in the table below.

[1020] Table 34. Hydrolysate form B of compound I 13 C CPMAS

[1021]

[1022] 4. Single Crystal Elucidation

[1023] Single crystals of compound I hydrate form B were obtained by solvent exchange between the solvate hydrate of compound I (EtOH) and water. This was achieved using Cu K... α X-ray diffraction data were acquired at 100 K using a Bruker diffractometer with radiation (λ=1.54178 Å) and a CPAD detector. The structure was analyzed and refined using the SHELX program (Sheldrick, GM, Acta Crystallographica Sinica, (2008) A64, 112-122), and the results are summarized in the table below.

[1024] Table 35. Single-crystal elucidation of compound I in hydrate form B

[1025]

[1026] Example 17: Compound I in hydrate form C

[1027] 1. Synthesis Procedure

[1028] 100 mg of amorphous compound I was dissolved in 1 mL of 50:50 MeOH / water. The solution was placed in a shaker block at 80 °C. After shaking for 5 days, the slurry was centrifuged and vacuum dried overnight at 80 °C. The dried sample was then exposed to 75% RH for 20 days.

[1029] 2. X-ray powder diffraction

[1030] X-ray powder diffraction (XRPD) results are shown in Figure 42 And in the table below.

[1031] Table 36. XRPD signals of compound I in hydrate form C

[1032]

[1033] 3. Solid-state NMR

[1034] Compound I in hydrate form C 13 C CPMAS spectrum is shown in Figure 43 And in the table below.

[1035] Table 37. Hydrolysate form C of compound I 13 C CPMAS

[1036]

[1037] 4. Single Crystal Elucidation

[1038] Single crystals of compound I in hydrate form C were obtained by solvent exchange between the solvate hydrate of compound I (EtOH) and water. This was achieved using Cu K... α X-ray diffraction data were acquired at 100 K using a Bruker diffractometer with radiation (λ=1.54178 Å) and a CPAD detector. The structure was analyzed and refined using the SHELX program (Sheldrick, GM, Acta Crystallographica Sinica, (2008) A64, 112-122), and the results are summarized in the table below.

[1039] Table 38. Single-crystal elucidation of compound I in hydrate form C

[1040]

[1041] Example 18: Compound I EtOH solvate hydrate

[1042] 1. Synthesis Procedure

[1043] 400 mg of compound I, pure form A, was added to a scintillation vial. 2 mL of EtOH, 2 mL of water, and a magnetic stir bar were added to the vial. The contents of the vial were stirred overnight at 60°C. The resulting solid was separated by centrifugation to obtain the compound I EtOH solvate hydrate.

[1044] 2. X-ray powder diffraction

[1045] X-ray powder diffraction (XRPD) results are shown in Figure 44 And in the table below.

[1046] Table 39. XRPD signals of compound I EtOH solvate hydrate

[1047]

[1048] 3. Solid-state NMR

[1049] Compound I EtOH solvate hydrate 13 C CPMAS spectrum is shown in Figure 45 And in the table below.

[1050] Table 40. Hydroxides of Compound I EtOH solvates 13 C CPMAS

[1051]

[1052] 4. Single Crystal Elucidation

[1053] Single crystals of compound I EtOH solvate hydrate were obtained from a slurry of compound I in an 80 / 20 mixture of EtOH and water. This was achieved using Cu K... α X-ray diffraction data were acquired at 100 K on a Bruker diffractometer with radiation (λ=1.54178 Å) and a CPAD detector. The structure was analyzed and refined using the SHELX program (Sheldrick, GM, Acta Crystallographica Sinica, (2008) A64, 112-122), and the results are summarized in the table below.

[1054] Table 41. Single-crystal elucidation of the solvate hydrate of compound I EtOH

[1055]

[1056] Example 19: Compound I MeOH solvate hydrate

[1057] 1. Synthesis Procedure

[1058] 150 mg of amorphous compound I was dissolved in 1 mL of 50:50 MeOH / water. The solution was slurried overnight in a shaker block at 80 °C. The solid was separated by centrifugation to obtain compound I MeOH solvate hydrate.

[1059] 2. X-ray powder diffraction

[1060] X-ray powder diffraction (XRPD) results are shown in Figure 46 And in the table below.

[1061] Table 42. XRPD signal of compound I MeOH solvate hydrate

[1062]

[1063] 3. Solid-state NMR

[1064] Compound I MeOH solvate hydrate 13 C CPMAS spectrum is shown in Figure 47 And in the table below.

[1065] Table 43. Hydroxides of Compound I MeOH solvate 13 C CPMAS

[1066]

[1067] Example 20: Compound I IPA solvate hydrate

[1068] 1. Synthesis Procedure

[1069] 100 mg of amorphous compound I was dissolved in 2 mL of IPA and 1 mL of water. The solution was sonicated for 1 hour. The sample was then slurried for 3 months. The resulting solid was separated by centrifugation to obtain the compound I IPA solvate hydrate.

[1070] 2. X-ray powder diffraction

[1071] X-ray powder diffraction (XRPD) results are shown in Figure 48 And in the table below.

[1072] Table 44. XRPD signal of compound I IPA solvate hydrate

[1073]

[1074] 3. Solid-state NMR

[1075] Compound I IPA solvate hydrate 13 C CPMAS spectrum is shown in Figure 49 And in the table below.

[1076] Table 45. Compound I IPA solvate hydrate 13 C CPMAS

[1077]

[1078] 4. Single Crystal Elucidation

[1079] Single crystals of compound I, IPA solvate hydrate, were obtained from IPA and water. (The text abruptly ends here, likely due to an incomplete sentence or missing information.) αX-ray diffraction data were acquired at 100 K using a Bruker diffractometer with radiation (λ=1.54178 Å) and a CPAD detector. The structure was analyzed and refined using the SHELX program (Sheldrick, GM, Acta Crystallographica Sinica, (2008) A64, 112-122), and the results are summarized in the table below.

[1080] Table 46. Single-crystal elucidation of the solvate hydrate of compound I IPA

[1081]

[1082] Example 21: Compound I MeOAc solvate hydrate

[1083] 1. Synthesis Procedure

[1084] 100 mg of amorphous compound I was added to an HPLC vial, followed by 0.5 mL of 95:5 MeOAc:water. The vial was then placed in a shaker block at room temperature for 1 day. Next, compound I in MeOAc form A, compound I in MeOAc form B, compound I in MeOAc form C, compound I in pure form E, compound I in hydrated form A, and compound I in hydrated form B were added to the vial. The slurry was then shaken at room temperature for another 4 days. The mixture was then centrifuged to obtain a wet cake of compound I MeOAc solvate hydrate.

[1085] 2. X-ray powder diffraction

[1086] X-ray powder diffraction (XRPD) results are shown in Figure 50 And in the table below.

[1087] Table 47. XRPD signals of compound I MeOAc solvate hydrate

[1088]

[1089] 3. Solid-state NMR

[1090] Compound I MeOAc solvate hydrate 13 C CPMAS spectrum is shown in Figure 51 And in the table below.

[1091] Table 48. Hydroxides of Compound I MeOAc solvates 13 C CPMAS

[1092]

[1093] Example 22: Amorphous compound I

[1094] 1. Synthesis Procedure

[1095] 147 g of crude compound I was dissolved in 440 mL of DCM and 10 mL of toluene, and purified by column chromatography (3 kg silica) using a gradient of 15% to 50% EtOAc / hexane. The combined fractions were concentrated under reduced pressure. The concentrated product was dissolved in DCM and concentrated four times under reduced pressure. After drying under high vacuum, 108.35 g of amorphous compound I (98.84% purity) was obtained.

[1096] 2. X-ray powder diffraction

[1097] X-ray powder diffraction (XRPD) results are shown in Figure 52 middle.

[1098] 3. Solid-state NMR

[1099] amorphous compound I 13 C CPMAS spectrum is shown in Figure 53 And in the table below.

[1100] Table 49. Amorphous compound I 13 C CPMAS

[1101]

[1102] Example 23: Solid dispersion of compound I

[1103] Unless otherwise specified, the following procedure is used to analyze all solid dispersions.

[1104] X-ray powder diffraction

[1105] X-ray powder diffraction (XRPD) spectra of compound I spray-dried dispersion (SDD) 1A were recorded in transmission mode at room temperature using a PANalytical system (Malvern PANalytical Inc, Almelo, The Netherlands) equipped with a sealed tube source and a PIXcel1D detector. The X-ray generator was operated at 45 kV and 40 mA using copper radiation (1.540598 Å). The powder sample was placed in a recessed region within a zero-background holder, flattened with a glass slide, and then loaded into the instrument. The sample was scanned in the range of approximately 4° to approximately 40° 2θ, with a step size of 0.0131° and a step duration of 14 seconds.

[1106] XRPD spectra of compound 1 SDD 1B-1E were recorded in reflectance mode at room temperature using a Panaco X-ray system (Malvin Panaco, Westborough, MA) equipped with a sealed tube source and a PIXcel1D Medipix3 detector. The X-ray generator was operated at 45 kV and 40 mA using copper radiation (1.540598 Å). The powder sample was laid flat on the sample holder after use and loaded into the instrument. The sample was scanned in the range of approximately 3° to approximately 40° 2θ, with a step size of 0.0131° and a step time of 48 seconds.

[1107] Solid-state NMR

[1108] A Bruker-Biospin 400 MHz wide-aperture spectrometer equipped with a Bruker-Biospin 4 mm HFX probe was used. The sample was loaded into a 4 mm ZrO2 rotor and rotated under magic angle rotation (MAS) conditions at a rotational speed typically set to 12.5 kHz. 1 H MAS T1 saturation recovery relaxation experiment measures proton relaxation time to set 13 C and 31 Appropriate cyclic delay for P-cross-polarized (CP) MAS experiments. 19 F MAS T1 saturation recovery relaxation experiment to measure fluorine relaxation time to set 19 Appropriate cycling delays were applied to the F MAS experiments. The CP contact time for the carbon and phosphorus CPMAS experiments was set to 2 ms. CP proton pulses with a linear ramp (50% to 100%) were used. Hartmann-Hahn matching for carbon was optimized on an external reference sample (glycine), while Hartmann-Hahn matching for phosphorus was optimized on the actual sample. All carbon, phosphorus, and fluorine spectra were recorded using a TPPM15 decoupling sequence at a field strength of approximately 100 kHz with proton decoupling.

[1109] Differential scanning calorimetry

[1110] Modulated differential scanning calorimetry (mDSC) analysis of compound I SDD 1A was performed using a Mettler Toledo DSC 3. Approximately 3 mg of sample was weighed into an aluminum crimped-edge sealed dish with a pinhole. The sample was equilibrated at -20°C and then heated to 250°C at a rate of 2°C / min (modulation amplitude ± 0.32°C, modulation period 60 seconds). Upon completion of the run, the data were analyzed using STARe thermal analysis software (Mettler Toledo, Columbus, OH, Ohio). Glass transition was obtained from reverse heat flow.

[1111] MDSC analysis of compound 1 SDD 1B-1E was performed using a Mettler Toledo DSC 3+ instrument. Samples weighing 5–8 mg were weighed into 40 µL aluminum crimp-sealed trays with pinhole caps. The trays were placed on the autosampler tray, with an empty tray used as a reference. The samples were heated from 25 °C to 200 °C at a rate of 2 °C / min (modulation amplitude ± 0.32 °C, modulation period 60 s). Upon completion of the run, the data were analyzed using STARe thermal analysis software (Mettler Toledo, Columbus, Ohio). Glass transition temperatures were obtained from reverse heat flow.

[1112] Residual solvent analysis:

[1113] Residual solvents were determined by headspace gas chromatography using an Agilent Technologies system (GC 6890N, headspace unit 7967A or equivalent). Sample material (50 or 100 mg ± 10%) was dissolved in 1.0 mL of dimethylacetamide inside a 10 mL headspace vial. The vial was then capped. The column used for analysis was a DB-624, 30 m x 0.32 mm id, 1.8 μm film thickness (manufacturer J & W). Residual solvents were detected by flame ionization detection (FID).

[1114] A. SDD 1A: 50% amorphous compound I and 50% polymer solvent: DCM / MeOH (50 / 50 %w / w) polymer: HPMCAS-H

[1115] 1. Synthesis Procedure

[1116] Weigh 15 g of compound I and 15 g of HPMCAS-H polymer separately. Dissolve compound I in 270 g of 1:1 DCM:MeOH, and then add the polymer to the solution. Stir the solution continuously with a magnetic stirrer for 30 minutes to obtain a light pink clear solution with 50% drug loading and 10% solid loading.

[1117] The resulting 300 g solution was then spray-dried using a Buchi B290 spray dryer at a 50 mm nozzle gas rotor flow meter, 90% suction, 78°C inlet temperature, 48°C outlet temperature, 20% pump setting (6 g / min) and 2 pulse settings, -5°C condenser temperature and -50 mbar filter pressure. The spray drying run time was 60 minutes. 23.33 g of wet solids was collected and dried a second time at 40°C for 48 hours. 22.77 g of the dried 1:1 spray-dried dispersion of Compound I with the polymer was recovered, representing a yield of approximately 76%.

[1118] 2. X-ray powder diffraction

[1119] X-ray powder diffraction (XRPD) results are shown in Figure 54 middle.

[1120] 3. Solid-state NMR

[1121] Compound I SDD 1A 13 C CPMAS spectrum is shown in Figure 55 And in the table below.

[1122] Table 50. Compound I SDD 1A 13 C CPMAS

[1123]

[1124] 4. Differential Scanning Calorimetry Analysis

[1125] Modulated differential scanning calorimetry (mDSC) analysis of compound I SDD1A was performed using a Mettler Toledo DSC 3. The thermogram shows a glass transition temperature of 145 °C in reverse heat flow, as shown in the figure. Figure 56 As shown in the image.

[1126] 5. Residual solvent

[1127] The residual solvent (ppm) detected in the final spray-dried dispersion of compound I SDD 1A after secondary drying at 40°C under vacuum is as follows:

[1128]

[1129] B. SDD 1B: 50% Compound I and 50% Polymer Solvent: DCM / MeOH (63 / 37% w / w) Polymer: HPMCAS-H

[1130] 1. Synthesis Procedure

[1131] Weigh 621 g of compound form I A and 621 g of HPMCAS-H separately. Mix 7042.14 g of DCM with 4135.86 g of MeOH. Add compound form I A to this DCM:MeOH mixture and stir using a magnetic stir plate under sufficient vortex. Stir the solution until it becomes clear. Add HPMCAS-H to this solution and stir continuously to obtain a clear solution.

[1132] The resulting solution was then spray-dried using an Anhydro MS-35 spray dryer at the following spray drying parameters. The resulting wet SDD 1B was dried in an oven under vacuum at 40°C until the residual solvent standard was met.

[1133] MS-35 Specifications

[1134]

[1135] 2. X-ray powder diffraction

[1136] X-ray powder diffraction (XRPD) data of compound I SDD 1B were recorded in transmission mode at room temperature using a Panacore imaging system and are shown below. Figure 57 middle.

[1137] 3. Differential Scanning Calorimetry (DSC) Analysis

[1138] Modulated differential scanning calorimetry (mDSC) analysis of compound I SDD1B was performed using a Mettler Toledo DSC 3+. The thermogram shows a glass transition temperature of 142 °C in reverse heat flow, as shown in the figure. Figure 58 As shown in the image.

[1139] 4. Residual solvent

[1140] The residual solvent (ppm) detected in the final spray-dried dispersion of compound I SDD 1B after secondary drying at 40°C under vacuum is as follows:

[1141]

[1142] C. SDD 1C: 80% Compound I and 20% Polymer Solvent: DCM / MeOH (63 / 37% w / w) Polymer: HPMCAS-H

[1143] 1. Synthesis Procedure

[1144] Weigh 15 g of compound form I A and 3.75 g of HPMCAS-H separately. Mix 106.31 g of DCM with 62.44 g of MeOH in a glass bottle. Add compound form I A to this DCM:MeOH mixture and stir using a magnetic stir plate under sufficient vortex. Stir the solution until it becomes clear. Add HPMCAS-H to this solution and stir continuously for about 1 hour to obtain a clear solution.

[1145] The resulting solution was then spray-dried using a Buqi B290 spray dryer at a 50 mm nozzle gas rotor flow meter, 85% suction, 94°C inlet temperature, 52°C outlet temperature, 20% pump setting and 2-pulse setting, -10°C condenser temperature and -80 mbar filter pressure. 16.07 g of wet solids were collected and secondary dried at 40°C for 72 hours. After the secondary drying, 15.11 g of dry SDD 1C was recovered.

[1146] 2. X-ray powder diffraction

[1147] X-ray powder diffraction (XRPD) data of compound I SDD 1C were recorded in transmission mode at room temperature using a Panacore imaging system and are shown below. Figure 59 middle.

[1148] 3. Differential Scanning Calorimetry (DSC) Analysis

[1149] Modulated differential scanning calorimetry (mDSC) analysis of compound I SDD1C was performed using a Mettler Toledo DSC 3+. The thermogram shows a glass transition temperature of 162 °C in reverse heat flow, as shown in the figure. Figure 60 As shown in the image.

[1150] 4. Residual solvent

[1151] The sample results (ppm) of residual solvent detected in the compound I SDD 1C sample after a second drying in the bottle for 48 hours (T48) and an additional 24 hours of drying under vacuum at 40°C (T72) are as follows:

[1152]

[1153] D. SDD 1D: 50% Compound I and 50% Polymer Solvent: DCM / MeOH (63 / 37 w / w) Polymer: HPMC-E15

[1154] 1. Synthesis Procedure

[1155] Weigh 9.0 g of compound form I A and 9.0 g of HPMC-E15 separately. Mix 102.06 g of DCM with 59.94 g of MeOH in a glass bottle. Add compound form I A to this DCM:MeOH mixture and stir using a magnetic stir plate under sufficient vortexing until the solution becomes clear. Add HPMC-E15 to this solution and stir continuously for about 1 hour to obtain a clear solution.

[1156] The resulting 180.0 g of solution was then spray-dried using a Buqi B290 spray dryer at a 50 mm nozzle gas rotor flow meter, 85% suction, 88°C inlet temperature, 49°C outlet temperature, 20% pump setting and 2-pulse setting, -10°C condenser temperature and -80 mbar filter pressure. 12.0 g of wet solids was collected and secondary dried at 40°C for 72 hours. 11.8 g of dry SDD 1D was recovered, representing a dry yield of approximately 67.4%.

[1157] 2. X-ray powder diffraction

[1158] X-ray powder diffraction (XRPD) data of compound I SDD 1D were collected in transmission mode at room temperature using a Panacore imaging system and are shown below. Figure 61 middle.

[1159] 3. Differential scanning calorimetry

[1160] Modulated differential scanning calorimetry (mDSC) analysis of compound I SDD1D was performed using a Mettler Toledo DSC 3+. The thermogram shows a glass transition temperature of 157 °C in reverse heat flow, as shown in the figure. Figure 62 As shown in the image.

[1161] 4. Residual solvent

[1162] The sample results (ppm) of residual solvent detected in the compound I SDD 1D sample after secondary drying in the bottle for 48 hours (T48) and further drying in a tray at 40°C under vacuum for 24 hours (T72) are as follows:

[1163]

[1164] E. SDD 1E: 80% Compound I and 20% Polymer Solvent: DCM / MeOH (63 / 37 w / w) Polymer: HPMC-E15

[1165] 1. Synthesis Procedure

[1166] Weigh 15.0 g of compound form I A and 3.75 g of HPMC-E15 separately. Mix 106.31 g of DCM with 62.44 g of MeOH in a glass bottle. Add compound form I A to this DCM:MeOH mixture and stir magnetically until the solution becomes clear. Add HPMC-E15 to this solution and stir continuously for about 1 hour.

[1167] The solution was then spray-dried using a Buqi B290 spray dryer at a 50 mm nozzle gas rotor flow meter, 85% suction, 101°C inlet temperature, 51°C outlet temperature, 20% pump setting and 2-pulse setting, -10°C condenser temperature and -80 mbar filter pressure. 15.3 g of wet solids were collected and secondary dried at 40°C for 72 hours. After the secondary drying, 14.4 g of dry SDD 1E was recovered.

[1168] 4. X-ray powder diffraction

[1169] X-ray powder diffraction (XRPD) data of compound I SDD 1E were collected in transmission mode at room temperature using a Panacore imaging system and are shown below. Figure 63 middle.

[1170] 3. Differential scanning calorimetry

[1171] Modulated differential scanning calorimetry (mDSC) analysis of compound I SDD1E was performed using a Mettler Toledo DSC 3+. The thermogram shows a glass transition temperature of 168 °C in reverse heat flow, as shown in the figure. Figure 64 As shown in the image.

[1172] 4. Residual solvent

[1173] The sample results (ppm) of residual solvent detected in the compound I SDD 1E sample after secondary drying in the bottle for 48 hours (T48) and further drying in a tray at 40°C under vacuum for 24 hours (T72) are as follows:

[1174]

Claims

1. A solid form selected from the following compounds I: pure form A, pure form B, pure form C, pure form D, pure form E, compressed form A, compressed form E, solvate form B of compound I EtOH, solvate form MeOH of compound I, solvate form NPA of compound I, solvate form A of compound I MeOAc, solvate form B of MeOAc of compound I, solvate form C of compound I MeOAc, hydrate form A of compound I, hydrate form B of compound I, hydrate form C of compound I MeOAc, solvate hydrate of compound I EtOH, solvate hydrate of compound I MeOH, solvate hydrate of compound I IPA, and solvate hydrate of compound I MeOAc.

2. A compound I formulated as a spray-dried dispersion.

3. A pharmaceutical composition comprising compound I according to claim 1 or claim 2 and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to claim 3, further comprising one or more additional therapeutic agents.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition comprises one or more additional CFTR regulating compounds.

6. The pharmaceutical composition according to claim 4 or claim 5, wherein the pharmaceutical composition comprises one or more compounds selected from: compound II, compound IV, compound V, and pharmaceutically acceptable salts and deuterated derivatives of any of the foregoing.

7. The compound I according to claim 1 or claim 2, or the pharmaceutical composition according to any one of claims 3 to 6, for the treatment of cystic fibrosis.

8. The compound for use according to claim 7, wherein the compound is administered in combination with one or more compounds selected from: compound II, compound IV and compound V, and pharmaceutically acceptable salts and deuterated derivatives of any of the foregoing.

9. Use of a compound I according to claim 1 or claim 2, or a pharmaceutical composition according to any one of claims 3 to 6, for the preparation of a medicament for the treatment of cystic fibrosis.

10. The use according to claim 9, wherein the drug is formulated for administration in combination with one or more compounds selected from: compound II, compound IV and compound V, and pharmaceutically acceptable salts and deuterated derivatives of any of the foregoing.

11. A method for treating cystic fibrosis, the method comprising administering to a subject in need compound I according to claim 1 or claim 2, or a pharmaceutical composition according to any one of claims 3 to 6.

12. The treatment method according to claim 11, wherein the method further comprises administering one or more compounds selected from: compound II, compound IV, compound V, and pharmaceutically acceptable salts and deuterated derivatives of any of the foregoing.

13. A method for preparing compound I in pure form A according to claim 1, the method comprising (i) dissolving amorphous compound I in ethanol, (ii) increasing the temperature to about 73°C, (iii) decreasing the temperature to about 20°C, (iv) separating the solid by filtration, and (v) drying the solid at 50°C.

14. A method for preparing compound I in pure form B according to claim 1, the method comprising exposing compound I in hydrate form A to about 3% humidity.

15. A method for preparing compound I in pure form C according to claim 1, the method comprising (i) stirring compound I in hexadecane at about 80°C, and (ii) centrifuging and drying the resulting solid.

16. A method for preparing compound I in pure form D according to claim 1, said method comprising drying compound I hydrate C at about 80°C.

17. A method for preparing compound I in pure form D according to claim 1, the method comprising (i) stirring compound I in pure form A in an IPA, (ii) separating the solid by filtration, and (iii) drying the solid at about 125°C.

18. A method for preparing compound I in pure form E according to claim 1, the method comprising (i) stirring compound I in pure form A in MeOAc, (ii) separating the solid by centrifugation, and (iii) drying the solid at about 50°C.

19. A method for preparing the compressed form E of compound I according to claim 1, the method comprising mechanically compressing the pure form E of compound I.

20. A method for preparing a compressed form A of compound I according to claim 1, the method comprising mechanically compressing the pure form A of compound I.

21. A method for preparing compound I in EtOH solvate form B according to claim 1, the method comprising (i) stirring compound I in ethanol, and (ii) separating the solid by centrifugation.

22. A method for preparing the compound I MeOH solvate according to claim 1, the method comprising (i) dissolving compound I in MeOH and increasing the temperature to about 62°C, (ii) cooling the solution to about 10°C, and (iii) separating the solid by centrifugation.

23. A method for preparing a solvate of compound I NPA according to claim 1, the method comprising (i) stirring compound I in NPA, and (ii) separating the solid by centrifugation.

24. A method for preparing compound I in solvate form A of MeOAc according to claim 1, the method comprising (i) stirring compound I in pure form A in MeOAc, and (ii) separating the solid by filtration.

25. A method for preparing compound I in solvate form B of MeOAc according to claim 1, the method comprising (i) stirring compound I in pure form A in MeOAc at about 5°C, (ii) separating the solid by centrifugation, and (iii) drying the solid at room temperature.

26. A method for preparing compound I in solvate form C of MeOAc according to claim 1, the method comprising (i) stirring compound I in pure form A in MeOAc at about 5°C, and (ii) separating the solid by filtration.

27. A method for preparing compound I in hydrate form A according to claim 1, the method comprising (i) stirring compound I in water in solvate form B (EtOH), and (ii) separating the solid by filtration and air drying.

28. A method for preparing compound I in hydrate form B according to claim 1, the method comprising (i) stirring compound I in a MeOH / water mixture at about 80°C, (ii) separating the solid by filtration, and (iii) exposing the solid to about 11% humidity.

29. A method for preparing the hydrated form C of compound I according to claim 1, the method comprising (i) stirring compound I in a MeOH / water mixture at about 80°C, (ii) separating the solid by filtration, and (iii) exposing the solid to about 75% humidity.

30. A method for preparing compound I EtOH solvate hydrate according to claim 1, the method comprising (i) stirring compound I in an EtOH / water mixture at about 60°C, and (ii) separating the solid.

31. A method for preparing compound I MeOH solvate hydrate according to claim 1, the method comprising (i) stirring compound I in a MeOH / water mixture at about 80°C, and (ii) separating the solid by centrifugation.

32. A method for preparing the IPA solvate hydrate of compound I according to claim 1, the method comprising (i) stirring compound I in an IPA / water mixture, and (ii) separating the solid by centrifugation.

33. A method for preparing compound I MeOAc solvate hydrate according to claim 1, the method comprising (i) stirring amorphous compound I in a MeOAc / water mixture, (ii) adding compound I in MeOAc form A, compound I MeOAc form B, compound I MeOAc form C, compound I in pure form E, compound I in hydrate form A and compound I in hydrate form B, (iii) further stirring, and (iv) separating the solid by centrifugation.

34. A method for preparing a spray-dried dispersion of compound I according to claim 2, the method comprising (i) preparing a solution of compound I and a polymer in a DCM / MeOH mixture, and (ii) spray-drying the resulting solution using a spray dryer.

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