Solid forms of macrocyclic compounds as CFTR modulators and their preparation

Abstract

Disclosed are processes and methods for preparing Compound I. Also disclosed are crystalline forms of Compound I, its pharma- ceutically acceptable salts, solvates, hydrates, and cocrystals, pharmaceutical compositions comprising same, methods of using same to treat cystic fibrosis, and methods of making same. Disclosed herein are crystalline and amorphous solid forms of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, pharmaceutical compositions thereof, methods of using any of the foregoing to treat cystic fibrosis, and processes for making the crystalline and amorphous forms.

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 342,392, filed May 16, 2022, and U.S. Provisional Application No. 63 / 342,408, filed May 16, 2022, the contents of which are incorporated by reference in their entireties. [Background technology]

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

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

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

[0005] Sequence analysis of the CFTR gene has revealed a variety of disease-causing mutations (Cutting, 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) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, over 2000 CF gene mutations have been identified, and the CFTR2 database currently contains information on at least 322 of these identified mutations, with at least 281 mutations having sufficient evidence to define them as disease-causing. The most common disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, commonly referred to as the F508del mutation. This mutation occurs in many cases of cystic fibrosis and is associated with severe disease.

[0006] CFTR is a cAMP / ATP-mediated anion channel expressed in various cell types, including absorptive and secretory epithelial cells, where it controls the flow of anions across the membrane and also regulates the activity of other ion channels and proteins. In epithelial cells, normal function of CFTR is essential for maintaining electrolyte transport throughout the body, including respiratory and digestive tissues. CFTR is composed of 1480 amino acids that encode a protein consisting of tandem repeats of transmembrane domains, each of which contains six transmembrane helices and a nucleotide-binding domain. The two transmembrane domains are linked via a large, polar regulatory (R) domain to multiple phosphorylation sites that control channel activity and cellular trafficking.

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

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

[0009] Accordingly, one aspect of the disclosure provides a solid form of a CFTR modulating compound, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (Compound I), and pharma- ceutically acceptable salts thereof. Compound I has the following structure: [ka] It can be shown as having:

[0010] Further aspects of the present disclosure provide methods of preparing Compound I, stereoisomers of Compound I, deuterated derivatives of Compound I and stereoisomers thereof, and pharma- ceutically acceptable salts of any of the foregoing.

[0011] Compound I was first disclosed in PCT International Application No. PCT / US2021 / 072475, published as WO2022 / 109573 and incorporated herein by reference in its entirety. Compound I is disclosed in WO2022 / 109573 as crystalline Form A (neat).

[0012] Crystalline forms are of interest in the pharmaceutical industry, where control over the crystalline form of an active ingredient may be desirable or even required. Different crystalline forms may have different properties, so a reproducible process for producing a compound with a particular crystalline form in high purity may be desirable for a compound intended to be used in a pharmaceutical product. For example, different crystalline forms may have different chemical, physical, and / or pharmaceutical properties. In some embodiments, one or more crystalline forms disclosed herein may exhibit higher levels of purity, chemical stability, and / or physical stability. Certain crystalline forms (e.g., crystalline free form, crystalline salt, crystalline salt solvate, and crystalline salt hydrate forms of Compound I (collectively referred to as "crystalline forms") may exhibit lower hygroscopicity. Thus, the crystalline forms of the present disclosure may provide advantages during drug substance manufacturing, storage, and handling. Thus, the pharmaceutically acceptable crystalline forms of Compound I may be particularly useful for the manufacture of drugs for the treatment of CFTR-mediated diseases.

[0013] Amorphous forms of therapeutic compounds may also be of interest in the pharmaceutical industry, where crystalline forms are not particularly bioavailable.Some amorphous forms may improve bioavailability, thereby allowing for the administration of reduced dosages.For some compounds, amorphous forms provide the most biologically accessible form of therapeutic agent.

[0014] In some embodiments, the crystalline form of compound I is a methanol solvate (wet) of compound I. In some embodiments, the crystalline form of compound I is a methanol solvate (dry) of compound I. In some embodiments, the crystalline form of compound I is the p-toluenesulfonic acid salt of compound I.

[0015] In some embodiments, the solid form of Compound I is an amorphous form. In some embodiments, the solid amorphous form of Compound I is a neat amorphous form of Compound I.

[0016] Another aspect of the present invention provides a pharmaceutical composition comprising at least one solid form selected from a solid form of Compound I, a pharma- ceutically acceptable salt thereof, and a deuterated derivative of any of the foregoing, as disclosed herein, which may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0017] In certain embodiments, the pharmaceutical compositions of the present invention comprise compound I in any of the pharma- ceutically acceptable solid forms disclosed herein. In some embodiments, the compositions comprising compound I in any of the pharma- ceutically acceptable crystalline forms disclosed herein may optionally further comprise at least one compound selected from compound II, compound III, compound III-d, compound IV, compound V, compound VI, compound VII, compound VIII, compound IX, compound X, and pharma- ceutically acceptable salts and deuterated derivatives thereof.

[0018] Another aspect of the invention provides a method of treating the CFTR-mediated disease cystic fibrosis, comprising administering to a subject in need thereof compound I in any of the pharma- ceutically acceptable solid forms disclosed herein, optionally as part of a pharmaceutical composition comprising at least one additional component, such as a carrier or additional active agent. In some embodiments, the method of treating the CFTR-mediated disease cystic fibrosis comprises administering compound I in any of the pharma- ceutically acceptable solid forms disclosed herein, optionally comprising administering to a subject in need thereof (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl) Cyclopropanecarboxamide (Compound II), N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound III), or N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound II I-d), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (compound IV), N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3 -carboxamide (compound V), N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (compound VI), (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6-Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound VII), (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ 6 and further administering one or more additional CFTR modulators selected from thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (Compound VIII), N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound IX), and N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound X).

[0019] A further aspect of the present disclosure provides a process for making the solid forms of Compound I disclosed herein.

[0020] Another aspect of the present invention provides solid forms of Compound I, pharma- ceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing, as disclosed herein, for use in any of the methods described herein. [Brief description of the drawings]

[0021] [Figure 1] 1 provides an X-ray powder diffraction (XRPD) pattern of neat Form A of Compound I. [Diagram 2] 1 provides a differential scanning calorimetry (DSC) analysis of neat Form A of Compound I. [Diagram 3] 1 provides an XRPD pattern of crystalline Compound I methanol solvate (wet). [Figure 4]1 provides the 13C SSNMR spectrum of crystalline Compound I methanol solvate (wet). [Diagram 5] 1 provides the 19F SSNMR spectrum of crystalline Compound I methanol solvate (wet). [Figure 6] 1 provides an XRPD pattern of crystalline Compound I methanol solvate (dried). [Figure 7] 1 provides the TGA curve of crystalline Compound I methanol solvate (dry). [Figure 8] 1 provides a DSC analysis of crystalline Compound I methanol solvate (dried). [Figure 9] 1 provides an XRPD pattern of crystalline p-toluenesulfonic acid of Compound I. [Figure 10] 1 provides a DSC analysis of crystalline Compound I p-toluenesulfonic acid. [Figure 11] 1 provides the 13C SSNMR spectrum of crystalline Compound I p-toluenesulfonic acid. [Figure 12] 1 provides the 19F SSNMR spectrum of crystalline Compound I p-toluenesulfonic acid. [Figure 13] 1 provides an XRPD pattern of neat amorphous Compound I. [Figure 14] 1 provides a TGA curve of neat amorphous Compound I. [Figure 15] 1 provides a DSC analysis of neat amorphous Compound I. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] definition As used throughout this disclosure, “Compound I” refers to (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, which can be represented as having the following structure: [ka]

[0023] Compound I can be a racemic mixture or an enantioenriched mixture of isomers (e.g., greater than 90% ee, greater than 95% ee, greater than 98% ee). Compound I can be in the form of a pharmaceutically acceptable salt, solvate, and / or hydrate. Compound I and methods of making and using Compound I, stereoisomers of Compound I, deuterated derivatives of Compound I and their stereoisomers, and pharmaceutically acceptable salts of any of the foregoing, are disclosed in WO2022 / 109573, which is incorporated herein by reference.

[0024] As used herein, “Compound II” refers to (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, which can be represented by the following structure: [ka] Compound II may be in the form of a pharma- ceutically acceptable salt. Compound II and methods of making and using Compound II are disclosed in WO2010 / 053471, WO2011 / 119984, WO2011 / 133751, WO2011 / 133951, and WO2015 / 160787, each of which is incorporated herein by reference.

[0025] As used throughout this disclosure, “compound III” refers to N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide and is represented by the following structure: [ka] Compound III may also be in the form of a pharma- ceutically acceptable salt.Compound III and methods of making and using Compound III are disclosed in WO2006 / 002421, WO2007 / 079139, WO2010 / 108162, and WO2010 / 019239, each of which is incorporated herein by reference.

[0026] In some embodiments, a deuterated derivative of compound III (compound III-d) is used in the compositions and methods disclosed herein. The chemical name of compound III-d is N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide and is represented by the following structure: [ka] Compound III-d can be in the form of a pharma-ceutically acceptable salt. Compound III-d and methods of making and using compound III-d are disclosed in WO2012 / 158885, WO2014 / 078842, and U.S. Patent No. 8,865,902, which are incorporated herein by reference.

[0027] As used herein, "compound IV" refers to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, and is represented by the following chemical structure: [ka] Compound IV can be in the form of a pharma-ceutically acceptable salt. Compound IV and methods of making and using Compound IV are disclosed in WO2007 / 056341, WO2009 / 073757, and WO2009 / 076142, which are incorporated herein by reference.

[0028] As used herein, "Compound V" refers to N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, represented by the following chemical structure: [ka] Compound V may be in the form of a pharma- ceutically acceptable salt. Compound V and methods of making and using Compound V are disclosed in WO2018 / 107100 and WO2019 / 113476, which are incorporated herein by reference.

[0029] As used herein, “Compound VI” refers to N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, and is represented by the following chemical structure: [ka] Compound VI can be in the form of a pharma- ceutically acceptable salt. Compound VI and methods of making and using Compound VI are disclosed in WO2018 / 064632, which is incorporated herein by reference.

[0030] As used herein, "Compound VII" refers to (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione, represented by the following chemical structure: [ka] Compound VII can be in the form of a pharma- ceutically acceptable salt. Compound VII and methods of making and using Compound VII are disclosed in WO2019 / 161078, WO2020 / 102346, and PCT Application No. PCT / US2020 / 046116, which are incorporated herein by reference.

[0031] As used herein, "compound VIII" refers to (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ 6 -Thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, represented by the following chemical structure: [ka] Compound VIII can be in the form of a pharma- ceutically acceptable salt. Compound VIII and methods of making and using compound VIII are disclosed in WO2020 / 206080, which is incorporated herein by reference.

[0032] As used herein, "compound IX" refers to N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, and is represented by the following chemical structure: [ka] Compound IX may be in the form of a pharma- ceutically acceptable salt. Compound IX and methods of making and using compound IX are disclosed in WO2016 / 057572, which is incorporated herein by reference.

[0033] As used herein, "Compound X" refers to N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, represented by the following chemical structure: [ka] Compound X may be in the form of a pharma- ceutically acceptable salt. Compound X and methods of making and using Compound X are disclosed in WO2016 / 057572, which is incorporated herein by reference.

[0034] As used herein, "CFTR" means cystic fibrosis transmembrane conductance regulator.

[0035] As used herein, the terms "CFTR modulator" and "CFTR-modulating compound" refer interchangeably to compounds that directly or indirectly increase the activity of CFTR. Increased activity resulting from a CFTR modulator includes, but is not limited to, compounds that correct, enhance, stabilize, and / or amplify CFTR.

[0036] As used herein, the term "CFTR corrector" refers to a compound that enhances the processing and trafficking of CFTR, thereby increasing the amount of CFTR at the cell surface.

[0037] As used herein, the term "CFTR potentiator" refers to a compound that increases the channel activity of the CFTR protein located on the cell surface, resulting in enhanced ion transport.

[0038] As used herein, the terms "CFTR potentiator potentiators," "CFTR potentiators," and "CFTR co-potentiators" are used interchangeably and refer to compounds that increase CFTR potentiation.

[0039] As used herein, the term "active pharmaceutical ingredient" ("API") or "therapeutic agent" refers to a biologically active compound.

[0040] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0041] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of a compound that produces a desired effect (e.g., amelioration of CF or symptoms of CF, or lessening the severity of CF or symptoms of CF) when the compound is administered. The exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0042] As used herein, the terms "treatment", "treating" and the like generally refer to an improvement in CF or one or more of its symptoms, or a reduction in the severity of CF or one or more of its symptoms in a subject. As used herein, "treatment" includes, but is not limited to, the following: increasing the subject's growth, increasing weight gain, reducing mucus in the lungs, improving pancreatic and / or liver function, reducing chest infections, and / or reducing coughing or shortness of breath. Improvement in or a reduction in the severity of any of these symptoms can be readily assessed according to standard methods and techniques known in the art.

[0043] As used herein, the term "in combination with" when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means that the two or more compounds, agents, or active pharmaceutical ingredients are administered to a patient before or after each other, or simultaneously with each other.

[0044] As used herein, "mutation" can refer to a mutation in the CFTR gene or CFTR protein. A "CFTR gene mutation" refers to a mutation in the CFTR gene, and a "CFTR protein mutation" refers to a mutation in the CFTR protein. Generally, a genetic defect or mutation, or a nucleotide change in a gene, results in a mutation, or frameshift, in the CFTR protein translated from that gene.

[0045] As used herein, the term "F508del" refers to a mutant CFTR protein lacking the amino acid phenylalanine at position 508, or a mutant CFTR gene encoding a CFTR protein lacking the amino acid phenylalanine at position 508.

[0046] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0047] As used herein, the term "alkyl" refers to a saturated or partially saturated branched or unbranched aliphatic hydrocarbon having carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, etc.) in which one or more adjacent carbon atoms are interrupted by a double bond (alkenyl) or triple bond (alkynyl). An alkyl group can be substituted or unsubstituted.

[0048] The term "aliphatic" or "aliphatic group," as used herein, refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or to a monocyclic or bicyclic hydrocarbon (also referred to herein as "alicyclic," "carbocyclic," or "cycloalkyl") that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-20 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-10 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-8 aliphatic carbon atoms. In yet other embodiments, an aliphatic group contains 1-6 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C ring that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the remainder of the molecule. 3-8 Hydrocarbon, or bicyclic or tricyclic C 8-14 It refers to a hydrocarbon, with any individual ring in the bicyclic ring system having 3-7 members. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrid groups thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, and (cycloalkyl)alkenyl. Suitable alicyclic groups include cycloalkyl, bicyclic cycloalkyl (e.g., decalin), bridged bicycloalkyl, such as norbornyl or [2.2.2]bicyclo-octyl, and bridged tricyclic, such as adamantyl.

[0049] As used herein, the term “halogen” or “halo” means F, Cl, Br, or I.

[0050] The term "alkoxy" as used herein refers to an alkyl or cycloalkyl covalently linked to an oxygen atom. An alkoxy group can be substituted or unsubstituted.

[0051] As used herein, "cycloalkyl group" refers to a cyclic non-aromatic hydrocarbon group containing 3 to 12 carbons in the ring (e.g., 3 to 10 carbons, etc.). Cycloalkyl groups include monocyclic, bicyclic, tricyclic, bridged, fused, and spirocyclic rings, including monospiro and dispiro rings. Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, spiro[2.2]pentane, and dispiro[2.0.2.1]heptane. Cycloalkyl groups can be substituted or unsubstituted.

[0052] The term "heteroatom" refers to any atom of oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocycle, such as N (such as 3,4-dihydro-2H-pyrrolyl), NH (such as pyrrolidinyl), or NR + (including a substitutable nitrogen of a heterocyclic ring which is, for example, N-substituted pyrrolidinyl).

[0053] As used herein, the terms "heterocyclyl," "heterocycle," or "heterocyclic" refer to non-aromatic monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused, and spiro ring systems (including monospiro and dispiro ring systems) in which one or more ring members are independently selected heteroatoms. In some embodiments, a "heterocycle," "heterocyclyl," or "heterocyclic" group has 3 to 14 ring members in which one or more ring members are heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus, and each ring in the system contains 3 to 7 ring members.

[0054] As used herein, the term "aryl" refers to a functional group or substituent derived from an aromatic ring, including monocyclic aromatic rings, as well as bicyclic, tricyclic and fused ring systems in which at least one ring in the system is aromatic. Aryl groups may be optionally substituted with one or more substituents. Non-limiting examples of aryl groups include phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthalenyl.

[0055] As used herein, the term "heteroaryl" refers to an aromatic ring containing at least one ring atom that is a heteroatom such as O, N, or S. Heteroaryl groups encompass monocyclic, bicyclic, and tricyclic ring systems having a total of 5-14 ring members, where at least one ring in the system is aromatic, where at least one ring in the system contains one or more heteroatoms, and where each ring in the system contains 3-7 ring members. Non-limiting examples of heteroaryl rings include pyridine, quinoline, indole, and indoline. Heteroaryl groups may be optionally substituted with one or more substituents. In certain embodiments, the term "heteroaryl ring" encompasses heteroaryl rings in various oxidation states, such as heteroaryl rings containing N-oxides and sulfoxides. Non-limiting examples of such heteroaryl rings include pyrimidine N-oxides, quinoline N-oxides, thiophene S-oxides, and pyrimidine N-oxides.

[0056] "Tert" and "t-" are used interchangeably and refer to tertiary.

[0057] The term "stable" as used herein refers to compounds that do not substantially change when subjected to conditions that allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.

[0058] "Selected" and "chosen" are used interchangeably herein.

[0059] As used herein, the term "solvent" refers to any liquid in which the product is at least partially soluble (solubility of product >1 g / L).

[0060] Non-limiting examples of suitable solvents that may be used in the present disclosure include, for example, water (H 2 O), methanol (MeOH), methylene chloride or dichloromethane (DCM; CH 2 Cl 2 ), acetonitrile (MeCN;CH 3 CN), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et 2 O), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0061] The term "protecting group," as used herein, refers to any chemical group that is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction.

[0062] Methods for adding (a process commonly referred to as "protecting") and removing (a process commonly referred to as "deprotecting") protecting groups are well known in the art and are described, for example, in PJ Kocienski, Protecting Groups, 3 rd edition (Thieme, 2005), and Greene and Wuts, Protective Groups in Organic Synthesis, 4th edition (John Wiley & Sons, New York, 2007), both of which are incorporated by reference in their entireties.

[0063] Non-limiting examples of useful protecting groups for amines that can be used in the present disclosure include monovalent protecting groups such as, for example, t-butyloxycarbonyl (Boc), benzyl (Bn), β-methoxyethoxytrityl (MEM), tetrahydropyranyl (THP), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts), as well as protecting groups such as, for example, benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloylamine, N-dithiazide, N-phenylethylamine ... Divalent protecting groups such as succinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetramethyldisilylazacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilisoindoline (Benzostabase, BSB), N-diphenylsilyldiethylene, N-5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, N-5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, and 1,3,5-dioxazine.

[0064] Non-limiting examples of useful protecting groups for alcohols that can be used in the present disclosure include, for example, acetyl (Ac), benzoyl (Bz), benzyl (Bn), β-Methoxyethoxymethyl (MEM), dimethoxytrityl (DMT), methoxymethyl (MOM), methoxytrityl (MMT), p-methoxybenzyl (PMB), pivaloyl (Piv), tetrahydropyranyl (THP), trityl (Tr), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), and t-butyldiphenylsilyl (TBDPS).

[0065] Non-limiting examples of useful protecting groups for carboxylic acids that can be used in the present disclosure include, for example, methyl or ethyl esters, substituted alkyl esters such as 9-fluorenylmethyl, methoxymethyl (MOM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl, β-methoxyethoxymethyl (MEM), 2-(trimethylsilyl)ethoxymethyl (SEM), benzyloxymethyl (BOM), pivaloyloxymethyl (POM), phenylacetoxymethyl, and cyanomethyl, acetyl (Ac), phenacyl, substituted phenacyl esters, 2,2,2-trichloroethyl, 2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, t-butyl, 3-methyl-3-pentyl, dicyclopropylmethyl, cyclopentyl, cyclohexyl, allyl, methallyl, cinnamyl, phenyl (Ph), silyl esters, benzyl, and substituted benzyl, 2,6-dialkylphenyl, and pentafluorophenyl (PFP).

[0066] Non-limiting examples of amine bases that may be used in the present disclosure include, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine (NMM), triethylamine (Et 3 N;TEA), diisopropylethylamine (i-Pr 2 EtN; DIPEA), pyridine, 2,2,6,6-tetramethylpiperidine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), t-Bu-tetramethylguanidine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and potassium bis(trimethylsilyl)amide (KHMDS).

[0067] Non-limiting examples of carbonate bases that may be used in the present disclosure include, for example, sodium carbonate (Na 2 CO 3 ), potassium carbonate (K 2CO 3 ), Cesium carbonate (Cs 2 CO 3 ), lithium carbonate (Li 2 CO 3 ), sodium bicarbonate (NaHCO 3 ), and potassium bicarbonate (KHCO 3 ) are mentioned.

[0068] Non-limiting examples of alkoxide bases that can be used in the present disclosure include, for example, t-AmOLi (lithium t-amylate), t-AmONa (sodium t-amylate), t-AmOK (potassium t-amylate), sodium tert-butoxide (NaOtBu), potassium tert-butoxide (KOtBu), and sodium methoxide (NaOMe; NaOCH 3 ) are mentioned.

[0069] Non-limiting examples of hydroxide bases that may be used in the present disclosure include, for example, lithium hydroxide (LiOH), sodium hydroxide (NaOH), and potassium hydroxide.

[0070] Non-limiting examples of phosphate groups that may be used in the present disclosure include, for example, trisodium phosphate (Na 3 PO 4 ), tripotassium phosphate (K 3 PO 4 ), dipotassium phosphate (K 2 HPO 4 ), and monopotassium phosphate (KH 2 PO 4 ) are mentioned.

[0071] Non-limiting examples of acids that may be used in the present disclosure include, for example, trifluoroacetic acid (TFA), hydrochloric acid (HCl), methanesulfonic acid (MsOH), phosphoric acid (H 3 PO 4 ), and sulfuric acid (H 2 SO 4 ) are mentioned.

[0072] As used herein, the terms "reductant" and "reducing agent" are used interchangeably. As used herein, the terms "reducing conditions" and "reducing reaction conditions" are used interchangeably to refer to reaction conditions involving the use of a reducing agent. Non-limiting examples of reducing agents and reducing conditions that may be used in the present disclosure include, for example, H 2 and palladium on carbon, H 2 and palladium alumina, sodium dithionite (Na 2 S 2 O 4 ), iron (Fe) and acetic acid (AcOH), and iron (Fe) and ammonium chloride (NH 4 Cl).

[0073] As used herein, the term "sulfonyl chloride" refers to a sulfonyl group (-SO 2 -) is single-bonded to a chlorine atom (e.g., RSO 2 A non-limiting example of a sulfonyl chloride is methanesulfonyl chloride (MeSO 2 Cl), trifluoromethanesulfonyl chloride (F 3 CSO 2 Cl) Benzenesulfonyl chloride (PhSO 2 Cl), p-Toluenesulfonyl chloride (4-MeC 6 H 4 SO 2 Cl or TsCl), 2-nitrobenzylsulfonyl chloride (2-NO 2 C 6 H 4 SO 2 Cl or 2-NsCl), and 4-nitrobenzylsulfonyl chloride (4-NO 2 C 6 H 4 SO 2 Examples include 4-NsCl or 4-NsCl.

[0074] Suitable sulfonate esters -OSO that may be used in the present disclosure 2 Non-limiting examples of R include methanesulfonyl (R = Me), trifluoromethanesulfonyl (R = CF3 ) benzenesulfonyl (R=Ph), p-toluenesulfonyl (R=4-MeC 6 H 4 -), 2-nitrobenzylsulfonyl (R = 2-NO 2 C 6 H 4 -), and 4-nitrobenzylsulfonyl (R = 4-NO 2 C 6 H 4 -) are mentioned.

[0075] The term "compound," when referring to a compound of the present disclosure, refers to a collection of molecules having identical chemical structure except that isotopic variations may exist among the constituent atoms of the molecule.

[0076] The compounds described herein may be optionally substituted with one or more substituents, as outlined above, or as illustrated by the particular classes, subclasses, and species of the present disclosure. The phrase "optionally substituted" is understood to be used interchangeably with the phrase "substituted or unsubstituted". In general, the term "substituted", whether preceded by the term "optionally", indicates that at least one hydrogen of the "substituted" group is replaced with a substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a particular group, the substituents may be the same or different at each position. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds.

[0077] As used herein, the term "stable compound" refers to compounds that are sufficiently stable to permit their manufacture and maintain their compound integrity for a period of time sufficient to be useful for the purposes detailed herein (e.g., as a therapeutic agent, an intermediate for use in the manufacture of a therapeutic compound, formulation into an intermediate that can be isolated or stored, and / or treatment of a disease or condition that is responsive to a therapeutic agent).

[0078] As used herein, the term "stereoisomer" refers to both enantiomers and diastereomers.

[0079] It is to be understood that certain compounds of the present invention may exist as separate stereoisomers or enantiomers and / or as mixtures of such stereoisomers or enantiomers. As used in the chemical structures disclosed herein, the "wedge line" ( [ka] ) or "Hash Line" ( [ka] ) bond indicates a chiral center of known absolute stereochemistry (i.e., one stereoisomer). As used in the chemical structures disclosed herein, the "wavy line" bond ( [ka] ) indicates a chiral center of unknown absolute stereochemistry (i.e., one stereoisomer). As used in the chemical structures disclosed herein, the "wavy line" bond ( [ka] ) indicates a mixture of E / Z isomers. [ka] ("straight") bonds indicate the presence of a mixture (e.g., a racemate or concentrate). [ka] A ("straight") bond indicates that the double bond has E / Z stereochemistry as depicted. As used in the chemical structures disclosed herein, [ka] (i.e., a "wavy" line perpendicular to the "straight" bond to group "A") indicates that group "A" is a substituent whose point of attachment is the terminus of the bond that terminates in the "wavy" line.

[0080] Certain compounds disclosed herein may exist as tautomers, and both tautomeric forms are intended, even if only a single tautomeric structure is depicted. For example, a description of compound A is understood to include its tautomeric form, compound B, and vice versa, as well as mixtures thereof. [ka] Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0081] Unless otherwise specified, structures depicted herein are also meant to include all isomeric forms of the structure, for example, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, mixtures of geometric and conformational isomers of the compounds of the present disclosure are within the scope of the present disclosure.

[0082] As used herein, the term "pharmaceutically acceptable solid form" refers to a solid form of Compound I of the present disclosure, which solid forms of Compound I (e.g., crystalline free form, crystalline salts, crystalline salt solvates, crystalline salt hydrates, and amorphous forms) are non-toxic and suitable for use in pharmaceutical compositions.

[0083] The terms "about" and "approximately", when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, include a particular dose, amount, or weight percent value, or range of doses, amounts, or weight percents, recognized by one of ordinary skill in the art, that provides an equivalent pharmacological effect as that provided by the particular dose, amount, or weight percent. As used herein, the terms "about" and "approximately", when used in connection with amounts, volumes, reaction times, reaction temperatures, and the like in methods and processes, refer to an acceptable error for a particular value as determined by one of ordinary skill in the art, depending in part on how the value is measured or determined. In some embodiments, the terms "about" and "approximately" refer to within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms "about" and "approximately" refer to within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range. In some embodiments, the terms "about" and "approximately" mean within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range. In some embodiments, the terms "about" and "approximately" mean within 15% of a given value. In some embodiments, the terms "about" and "approximately" mean within 10% of a given value. As used herein, the symbol "~" appearing immediately before a numerical value has the same meaning as the terms "about" and "approximately".

[0084] As used herein, the term "amorphous" refers to a solid material that does not have long-range order in the position of its molecules. Amorphous solids are generally glasses or supercooled liquids in which the molecules are randomly arranged such that there is no well-defined arrangement, e.g., no molecular packing, and no long-range order. Amorphous solids are generally rather isotropic, i.e., they exhibit similar properties in all directions, and do not have a distinct melting point. Instead, they typically exhibit a glass transition temperature that indicates a transition from a glassy amorphous state to a supercooled liquid amorphous state upon heating. For example, an amorphous material is a solid material that does not have sharp characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., it is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) are seen in its XRPD pattern. Broad peaks are characteristic of amorphous solids. For a comparison of XRPD of amorphous and crystalline materials, see US2004 / 0006237. In some embodiments, a solid material may include an amorphous compound, for example, the solid material may be characterized by a lack of sharp characteristic crystalline peaks in its XRPD spectrum (i.e., the material is not crystalline but is amorphous as determined by XRPD). Instead, one or several broad peaks (e.g., halos) may be seen in the XRPD pattern of the material. For a representative comparison of XRPD of amorphous and crystalline materials, see US2004 / 0006237. A solid material including an amorphous compound may be characterized by, for example, a broader temperature range of melting of the solid material compared to the range of melting of a pure crystalline solid. Other techniques, such as, for example, solid-state NMR, may also be used to characterize crystalline or amorphous forms.

[0085] As used herein, the terms "crystalline form," "crystalline form," and "form" refer interchangeably to a crystal structure (or polymorph) having a particular molecular packing arrangement within a crystal lattice. Crystalline forms can be identified using, for example, powder X-ray diffraction (XRPD), single crystal X-ray diffraction, and solid-state nuclear magnetic resonance (e.g., 13 C. 19 F,15 N, and 31 The crystalline Forms can be identified and distinguished from one another by one or more characterization techniques, including, for example, XRPD, single crystal X-ray diffraction, and SSNMR. Thus, as used herein, the terms "crystalline Form A of Compound (I)" and "crystalline p-toluenesulfonic acid of Compound (I)" refer to crystalline Form A of Compound (I) by one or more characterization techniques, including, for example, XRPD, single crystal X-ray diffraction, and SSNMR. 13 It refers to unique crystalline forms that can be identified and distinguished from one another by one or more characterization techniques, including C SSNMR. In some embodiments, the novel crystalline forms are characterized by a powder X-ray diffractogram having one or more signals at one or more specified degrees 2 theta (°2θ) values.

[0086] As used herein, the term "free form" refers to the non-ionized form of a compound in the solid state. Examples of free forms include free bases and free acids.

[0087] As used herein, the term "neat form" refers to the unsolvated, unhydrated free form of a compound in the solid state.

[0088] As used herein, the term "solvate" refers to a crystal form that contains one or more molecules of a compound of the present disclosure and one or more molecules of a solvent, in a stoichiometric or non-stoichiometric amount, incorporated into the crystal lattice. When the solvent is water, the solvate is referred to as a "hydrate."

[0089] In some embodiments, the solid material may include a mixture of crystalline solids and amorphous solids. The solid material containing the amorphous compound may also include, for example, up to 30% crystalline solids. In some embodiments, the solid material prepared to include the amorphous compound may also include, for example, up to 25%, 20%, 15%, 10%, 5%, or 2% crystalline solids. In embodiments where the solid material includes a mixture of crystalline solids and amorphous solids, the characterization data, such as XRPD, may include indications of both crystalline solids and amorphous solids. In some embodiments, the crystalline forms of the present disclosure may contain up to 30% amorphous compounds. In some embodiments, the crystalline preparations of Compound I may contain up to 25%, 20%, 15%, 10%, 5%, or 2% amorphous solids.

[0090] As used herein, the term "substantially amorphous" refers to a solid material that has little or no long-range order at the molecular level. For example, a substantially amorphous material has less than 15% crystallinity (e.g., less than 10% crystallinity, or less than 5% crystallinity, or less than 2% crystallinity). It is noted that the term "substantially amorphous" also includes the descriptor "amorphous," which refers to a material that has no (0%) crystallinity.

[0091] As used herein, the term "substantially crystalline" refers to a solid material that has few or no amorphous molecules. For example, a substantially crystalline material has less than 15% amorphous molecules (e.g., less than 10% amorphous molecules, less than 5% amorphous molecules, or less than 2% amorphous molecules). It is also noted that the term "substantially crystalline" includes the descriptor "crystalline," which refers to a material that is 100% crystalline in form.

[0092] As used herein, the term "ambient conditions" refers to room temperature, open air conditions, and uncontrolled humidity conditions. As used herein, the terms "room temperature" and "ambient temperature" refer to temperatures between 15° C. and 30° C.

[0093] As used herein, the terms "X-ray powder diffractogram", "X-ray powder diffraction pattern", "XRPD pattern", and "XRPD spectrum" refer interchangeably to an experimentally obtained pattern that plots signal position (on the abscissa) against signal intensity (on the ordinate).

[0094] "Signal" or "peak," as used herein, refers to a point on an XRPD pattern where there is a maximum in intensity, measured in counts. An XRPD peak is identified by its angular value, measured in degrees two-theta (°2θ), shown on the abscissa of the powder X-ray diffractogram, which may be expressed, for example, as "a signal at . . . degrees two-theta," "a signal with a 2-theta value of . . .," and / or "a signal with a 2-theta value that is at least . . . selected from . . .."

[0095] The repeatability of the measured angle values ​​is within a range of ±0.2° 2θ, i.e. the angle value can be the recited angle value +0.2 degrees 2-theta, the angle value -0.2 degrees 2-theta, or any value between those two end points (between the angle value +0.2 degrees 2-theta and the angle value -0.2 degrees 2-theta).

[0096] One of skill in the art will recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may not be apparent, for example, to the naked eye. Indeed, one of skill in the art will recognize that some art-recognized methods are capable and suitable for determining whether a signal is present by pattern analysis, such as, for example, Rietveld refinement.

[0097] The terms "signal intensity" and "peak intensity" refer interchangeably to relative signal intensities within a given powder X-ray diffractogram. Factors that can affect relative signal intensity or peak intensity include sample thickness and preferred orientation (e.g., crystalline particles are not randomly distributed).

[0098] As used herein, a powder X-ray diffractogram is "substantially similar to that in [a particular] figure" if at least 90%, e.g., at least 95%, at least 98%, or at least 99% of the signals in the two diffractograms overlap. In determining "substantially similar," one of skill in the art will understand that there may be variations in intensity and / or signal position in an XRPD diffractogram even for the same crystalline form. Thus, one of skill in the art will understand that the maximum value of a signal in an XRPD diffractogram (in degrees 2-theta units) generally means that the value is specified as ±0.2 degrees 2-theta of that reported value, which is an art-recognized variance.

[0099] As used herein, the term "TGA" refers to thermogravimetric analysis and "TGA / DSC" refers to thermogravimetric analysis and differential scanning calorimetry.

[0100] As used herein, the term "DSC" refers to the analytical method of Differential Scanning Calorimetry.

[0101] As used herein, the term "glass transition temperature" or "Tg" refers to the temperature above which a hard, brittle "glassy" amorphous solid becomes viscous or rubbery.

[0102] As used herein, "melting temperature," "melting point," or "Tm" refers to the temperature at which a substance transitions from a solid to a liquid phase.

[0103] As used herein, the term "dispersion" refers to a disperse system in which one substance, the dispersed phase, is distributed in discrete units throughout a second substance (the continuous phase or vehicle). The size of the dispersed phase can vary widely (e.g., colloidal particles from nanometer dimensions to a few microns in size). In general, the dispersed phase can be a solid, liquid, or gas. In the case of a solid dispersion, the dispersed phase and the continuous phase are both solids. In pharmaceutical applications, the solid dispersion may include, among others, a crystalline drug in an amorphous polymer, an amorphous drug in an amorphous polymer, an amorphous drug dispersed in an amorphous drug, or alternatively, an amorphous drug dispersed in one or more excipients. In some embodiments, the solid dispersion includes a polymer that constitutes the dispersed phase and the drug that constitutes the continuous phase. Alternatively, the solid dispersion includes a drug that constitutes the dispersed phase and a polymer that constitutes the continuous phase.

[0104] The present disclosure also provides processes for preparing salts of the compounds of the present disclosure.

[0105] A salt of a compound of the present disclosure is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group. In some embodiments, the salt is a pharma- ceutically acceptable salt.

[0106] As used herein, the term "pharmaceutically acceptable salt" refers to any non-toxic salt that is capable of providing a compound of the present disclosure, either directly or indirectly, upon administration to a recipient. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. A "pharmaceutically acceptable counterion" is an ionic portion of the salt that is not toxic when released from the salt upon administration to a recipient. Those skilled in the art will recognize that when an amount of "a compound or a pharmaceutically acceptable salt thereof" is disclosed, the amount of the pharmaceutically acceptable salt form of the compound is the amount that corresponds to the concentration of the free base of the compound.

[0107] The "free base" form of a compound does not include ionic salts.Please note that the disclosed amounts of compounds or their pharmaceutically acceptable salts herein are based on their free base forms.For example, "10 mg of at least one compound selected from compound I and its pharmaceutically acceptable salts" includes the concentration of 10 mg of compound I and the pharmaceutically acceptable salts of compound I that correspond to 10 mg of compound I.

[0108] Suitable pharma- ceutically acceptable salts include, for example, those disclosed in S. M. Berge, et al. J. Pharm. Sci., 1977, 66, 1-19, which provides, for example, in Table 1, the following pharma- ceutically acceptable salts: [Table 1]

[0109] Non-limiting examples of pharma- ceutically acceptable salts derived from appropriate acids include salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids; salts formed with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids; and salts formed by using other methods used in the art, such as ion exchange. Non-limiting examples of pharma-ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts. Non-limiting examples of pharma- ceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-butyl salts. + (C 1-4 Alkyl) 4The present disclosure also contemplates the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Suitable non-limiting examples of alkali metal salts and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0110] In some embodiments, the present disclosure is also directed to processes for preparing isotopically labeled compounds of the foregoing compounds or pharma- ceutically acceptable salts thereof, wherein the formulas and variables of such compounds and salts are each, and independently, as described above or as described in any other embodiment above, except that one or more atoms therein are replaced (isotopically labeled) with an atom having an atomic mass or mass number different from the atomic mass or mass number of the atom that is normally found in nature. Examples of isotopes that are commercially available and suitable for the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Examples include Cl.

[0111] In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition.

[0112] As used herein, the term "derivative" refers to a collection of molecules that have the same chemical structure as the disclosed compounds, except that one or more atoms of the molecule may be replaced with another atom. In addition, unless otherwise specified, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the substitution of carbon at C, are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, probes in biological assays, or compounds with improved therapeutic profiles.

[0113] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as a reference compound, in which one or more hydrogen atoms are replaced with deuterium atoms. In some embodiments, one or more hydrogens replaced with deuterium are part of an alkyl group. In some embodiments, one or more hydrogens replaced with deuterium are part of a methyl group. In the chemical structure, deuterium can be represented by "D".

[0114] As used herein, the phrase "deuterated derivatives of [a compound] and its stereoisomers, and pharma- ceutically acceptable salts of any of the foregoing" is intended to include the deuterated derivatives of the specified compound, the deuterated derivatives of any stereoisomers of that compound, and pharma- ceutically acceptable salts of the particular compound, pharma-ceutically acceptable salts of any of the stereoisomers of that compound, and pharma-ceutically acceptable salts of the deuterated derivatives of the particular compound or of its stereoisomers.

[0115] In some embodiments, the derivative is a silicon derivative, and at least one carbon atom in the disclosed compound is replaced by silicon.In some embodiments, the at least one carbon atom that is replaced by silicon can be a non-aromatic carbon.In some embodiments, the at least one carbon atom that is replaced by silicon can be an aromatic carbon.In certain embodiments, the silicon derivative of the present invention can also have one or more hydrogen atoms that are replaced by deuterium and / or germanium.

[0116] In other embodiments, the derivatives are germanium derivatives, in which at least one carbon atom in the disclosed compounds is replaced with germanium. In certain embodiments, the germanium derivatives of the present invention may also have one or more hydrogen atoms replaced with deuterium and / or silicon.

[0117] Because the general properties of silicon and germanium are similar to those of carbon, the substitution of silicon or germanium for carbon can result in compounds with similar biological activity as the original carbon-containing compound.

[0118] solid form Another aspect of the disclosure provides solid forms (e.g., crystalline forms, amorphous forms, solvates) of Compound I that can be used in the therapeutic methods and pharmaceutical compositions described herein. In some embodiments, the invention provides neat amorphous forms of Compound I. In some embodiments, the invention provides neat crystalline forms of Compound I. In some embodiments, the invention provides solvate crystalline forms of Compound I.

[0119] A. Methanol solvate of compound I (wet) In some embodiments, the present invention provides a methanol solvate (wet) of crystalline Compound I. Figure 3 provides a powder X-ray diffractogram of the methanol solvate (wet) of crystalline Compound I.

[0120] In some embodiments, the crystalline methanol solvate (wet) of Compound I is substantially pure. In some embodiments, the crystalline methanol solvate (wet) of Compound I is substantially crystalline. In some embodiments, the crystalline methanol solvate (wet) of Compound I is characterized by an X-ray powder diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0121] In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by a powder X-ray diffractogram having a signal at 25.5±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by a powder X-ray diffractogram having a signal at 21.0±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by a powder X-ray diffractogram having a signal at 20.5±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by a powder X-ray diffractogram having a signal at 19.0±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by a powder X-ray diffractogram having a signal at 18.9±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by a powder X-ray diffractogram having a signal at 18.6±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by a powder X-ray diffractogram having a signal at 16.9±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by a powder X-ray diffractogram having a signal at 15.0±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by a powder X-ray diffractogram having a signal at 14.6±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by a powder X-ray diffractogram having a signal at 8.4±0.2 degrees 2-theta.

[0122] In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by an X-ray powder diffractogram having signals at two or more of 25.5±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 19.0±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 18.6±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, 15.0±0.2 degrees 2-theta, 14.6±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate (wet) of Compound I is characterized by an X-ray powder diffractogram having signals at three or more of 25.5±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 19.0±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 18.6±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, 15.0±0.2 degrees 2-theta, 14.6±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate (wet) of Compound I is characterized by an X-ray powder diffractogram having signals at four or more of 25.5±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 19.0±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 18.6±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, 15.0±0.2 degrees 2-theta, 14.6±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate (wet) of Compound I is characterized by an X-ray powder diffractogram having signals at five or more of 25.5±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 19.0±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 18.6±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, 15.0±0.2 degrees 2-theta, 14.6±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta.In some embodiments, the crystalline methanol solvate (wet) of Compound I is characterized by an X-ray powder diffractogram having signals at six or more of 25.5±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 19.0±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 18.6±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, 15.0±0.2 degrees 2-theta, 14.6±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta.

[0123] In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by a powder X-ray diffractogram having signals at 25.5±0.2 degrees 2-theta and 8.4±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by a powder X-ray diffractogram having signals at 20.5±0.2 degrees 2-theta and 8.4±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by a powder X-ray diffractogram having signals at 20.5±0.2 degrees 2-theta and 16.9±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by a powder X-ray diffractogram having signals at 25.5±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by a powder X-ray diffractogram having signals at 20.5±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by a powder X-ray diffractogram having signals at 25.5±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta.

[0124] In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized by a powder X-ray diffractogram having signals at 25.5±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 19.0±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 18.6±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, 15.0±0.2 degrees 2-theta, 14.6±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta.

[0125] In some embodiments, the crystalline methanol solvate (wet) of Compound I is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0126] In some embodiments, the methanol solvate (wet) is monoclinic, P2 1 Space group, and Cu K α It is characterized by the following unit cell dimensions measured at 100 K using a Rigaku diffractometer equipped with 400 nm radiation (λ=1.54178 Å): [Table 2]

[0127] In some embodiments, the methanol solvate (wet) of the crystalline compound has a peak at 164.2±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the methanol solvate (wet) of the crystalline compound has a peak at 162.8±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline methanol solvate (wet) of Compound I has a signal at 145.6±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the methanol solvate (wet) of the crystalline compound has a peak at 132.5±0.2 ppm. 13C SSNMR spectrum. In some embodiments, the methanol solvate (wet) of the crystalline compound has a peak at 124.5±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the methanol solvate (wet) of the crystalline compound has a peak at 122.1±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the methanol solvate (wet) of the crystalline compound has a peak at 120.6±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline methanol solvate (wet) of Compound I has a signal at 113.1±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline methanol solvate (wet) of Compound I has a signal at 73.5±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline methanol solvate (wet) of Compound I has a signal at 55.9±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the methanol solvate (wet) of the crystalline compound has a peak at 49.7±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline methanol solvate (wet) of Compound I has a signal at 35.2±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline methanol solvate (wet) of Compound I has a signal at 31.1±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline methanol solvate (wet) of Compound I has a signal at 30.5±0.2 ppm. 13C SSNMR spectrum. In some embodiments, the methanol solvate (wet) of the crystalline compound has a peak at 29.3±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the methanol solvate (wet) of the crystalline compound has a peak at 27.4±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline methanol solvate (wet) of Compound I has a signal at 24.8±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the methanol solvate (wet) of the crystalline compound has a peak at 21.0±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline methanol solvate (wet) of Compound I has a signal at 19.0±0.2 ppm. 13 It is characterized as having a C SSNMR spectrum.

[0128] In some embodiments, the crystalline methanol solvate of Compound I (wet) has one or more signals selected from 164.2±0.2 ppm, 162.8±0.2 ppm, 145.6±0.2 ppm, 132.5±0.2 ppm, 124.5±0.2 ppm, 122.1±0.2 ppm, 120.6±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 49.7±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 29.3±0.2 ppm, 27.4±0.2 ppm, 24.8±0.2 ppm, 21.0±0.2 ppm, and 19.0±0.2 ppm. 13It is characterized as having a C SSNMR spectrum. In some embodiments, the crystalline methanol solvate of Compound I (wet) has two or more signals selected from 164.2±0.2 ppm, 162.8±0.2 ppm, 145.6±0.2 ppm, 132.5±0.2 ppm, 124.5±0.2 ppm, 122.1±0.2 ppm, 120.6±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 49.7±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 29.3±0.2 ppm, 27.4±0.2 ppm, 24.8±0.2 ppm, 21.0±0.2 ppm, and 19.0±0.2 ppm. 13 It is characterized as having a C SSNMR spectrum. In some embodiments, the crystalline methanol solvate of Compound I (wet) has three or more signals selected from 164.2±0.2 ppm, 162.8±0.2 ppm, 145.6±0.2 ppm, 132.5±0.2 ppm, 124.5±0.2 ppm, 122.1±0.2 ppm, 120.6±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 49.7±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 29.3±0.2 ppm, 27.4±0.2 ppm, 24.8±0.2 ppm, 21.0±0.2 ppm, and 19.0±0.2 ppm. 13 It is characterized as having a C SSNMR spectrum. In some embodiments, the crystalline methanol solvate of Compound I (wet) has four or more signals at 164.2±0.2 ppm, 162.8±0.2 ppm, 145.6±0.2 ppm, 132.5±0.2 ppm, 124.5±0.2 ppm, 122.1±0.2 ppm, 120.6±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 49.7±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 29.3±0.2 ppm, 27.4±0.2 ppm, 24.8±0.2 ppm, 21.0±0.2 ppm, and 19.0±0.2 ppm. 13It is characterized as having a C SSNMR spectrum. In some embodiments, the crystalline methanol solvate of Compound I (wet) has five or more signals selected from 164.2±0.2 ppm, 162.8±0.2 ppm, 145.6±0.2 ppm, 132.5±0.2 ppm, 124.5±0.2 ppm, 122.1±0.2 ppm, 120.6±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 49.7±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 29.3±0.2 ppm, 27.4±0.2 ppm, 24.8±0.2 ppm, 21.0±0.2 ppm, and 19.0±0.2 ppm. 13 It is characterized as having a C SSNMR spectrum. In some embodiments, the crystalline methanol solvate of Compound I (wet) has six or more signals selected from 164.2±0.2 ppm, 162.8±0.2 ppm, 145.6±0.2 ppm, 132.5±0.2 ppm, 124.5±0.2 ppm, 122.1±0.2 ppm, 120.6±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 49.7±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 29.3±0.2 ppm, 27.4±0.2 ppm, 24.8±0.2 ppm, 21.0±0.2 ppm, and 19.0±0.2 ppm. 13 It is characterized as having a C SSNMR spectrum. In some embodiments, the crystalline methanol solvate of Compound I (wet) has seven or more signals selected from 164.2±0.2 ppm, 162.8±0.2 ppm, 145.6±0.2 ppm, 132.5±0.2 ppm, 124.5±0.2 ppm, 122.1±0.2 ppm, 120.6±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 49.7±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 29.3±0.2 ppm, 27.4±0.2 ppm, 24.8±0.2 ppm, 21.0±0.2 ppm, and 19.0±0.2 ppm. 13It is characterized as having a C SSNMR spectrum. In some embodiments, the crystalline methanol solvate of Compound I (wet) has eight or more signals selected from 164.2±0.2 ppm, 162.8±0.2 ppm, 145.6±0.2 ppm, 132.5±0.2 ppm, 124.5±0.2 ppm, 122.1±0.2 ppm, 120.6±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 49.7±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 29.3±0.2 ppm, 27.4±0.2 ppm, 24.8±0.2 ppm, 21.0±0.2 ppm, and 19.0±0.2 ppm. 13 It is characterized as having a C SSNMR spectrum.

[0129] In some embodiments, the crystalline methanol solvate of Compound I (wet) has signals at 164.2±0.2 ppm, 162.8±0.2 ppm, 145.6±0.2 ppm, 132.5±0.2 ppm, 124.5±0.2 ppm, 122.1±0.2 ppm, 120.6±0.2 ppm, and 113.1±0.2 ppm. 13 In some embodiments, the crystalline methanol solvate (wet) of Compound I is characterized as having a C SSNMR spectrum: 13 The C SSNMR spectrum is characterized as having signals at 164.2±0.2 ppm, 162.8±0.2 ppm, 145.6±0.2 ppm, 132.5±0.2 ppm, 124.5±0.2 ppm, 122.1±0.2 ppm, 120.6±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 49.7±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 29.3±0.2 ppm, 27.4±0.2 ppm, 24.8±0.2 ppm, 21.0±0.2 ppm, and 19.0±0.2 ppm.

[0130] In some embodiments, the crystalline methanol solvate of Compound I (wet) has two or more signals selected from 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 24.8±0.2 ppm, and 19.0±0.2 ppm. 13 In some embodiments, the crystalline methanol solvate (wet) of Compound I is characterized as having a C SSNMR spectrum of three or more signals selected from 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 24.8±0.2 ppm, and 19.0±0.2 ppm. 13 In some embodiments, the crystalline methanol solvate (wet) of Compound I is characterized as having a C SSNMR spectrum of four or more signals selected from 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 24.8±0.2 ppm, and 19.0±0.2 ppm. 13 In some embodiments, the crystalline methanol solvate (wet) of Compound I is characterized as having a C SSNMR spectrum of five or more signals selected from 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 24.8±0.2 ppm, and 19.0±0.2 ppm. 13In some embodiments, the crystalline methanol solvate (wet) of Compound I is characterized as having a C SSNMR spectrum of six or more signals selected from 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 24.8±0.2 ppm, and 19.0±0.2 ppm. 13 In some embodiments, the crystalline methanol solvate (wet) of Compound I is characterized as having a C SSNMR spectrum of seven or more signals selected from 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 24.8±0.2 ppm, and 19.0±0.2 ppm. 13 In some embodiments, the crystalline methanol solvate (wet) of Compound I is characterized as having a C SSNMR spectrum of 8 or more signals selected from 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 24.8±0.2 ppm, and 19.0±0.2 ppm. 13 In some embodiments, the crystalline methanol solvate (wet) of Compound I is characterized as having a C SSNMR spectrum of 9 or more signals selected from 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 24.8±0.2 ppm, and 19.0±0.2 ppm. 13 It is characterized as having a C SSNMR spectrum.

[0131] In some embodiments, the crystalline methanol solvate of Compound I (wet) has signals at 145.6±0.2 ppm and 132.5±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline methanol solvate (wet) of Compound I has signals at 145.6±0.2 ppm, 132.5±0.2 ppm, and 113.1±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline methanol solvate (wet) of Compound I has signals at 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, and 73.5±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline methanol solvate (wet) of Compound I has signals at 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, and 55.9±0.2 ppm. 13 In some embodiments, the crystalline methanol solvate (wet) of Compound I has signals at 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, and 35.2±0.2 ppm. 13 It is characterized as having a C SSNMR spectrum.

[0132] In some embodiments, the crystalline methanol solvate of Compound I (wet) has signals at 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 24.8±0.2 ppm, and 19.0±0.2 ppm. 13 It is characterized as having a C SSNMR spectrum.

[0133] In some embodiments, the crystalline methanol solvate (wet) of Compound I has a structure substantially similar to that shown in FIG. 13 Characterized by C SSNMR spectrum.

[0134] In some embodiments, the crystalline methanol solvate (wet) of Compound I has a pH of -63.9±0.2 ppm. 19 In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized as having a F MAS signal at -76.6±0.2 ppm. 19 In some embodiments, the crystalline methanol solvate of Compound I (wet) is characterized as having a F MAS signal at -79.7±0.2 ppm. 19 F MAS signal.

[0135] In some embodiments, the crystalline methanol solvate (wet) of Compound I has two signals selected from -63.9±0.2 ppm, -76.6±0.2 ppm, and -79.7±0.2 ppm. 19 In some embodiments, the crystalline methanol solvate of Compound I (wet) has signals at -63.9±0.2 ppm, -76.6±0.2 ppm, and -79.7±0.2 ppm. 19 F MAS.

[0136] In some embodiments, the crystalline methanol solvate (wet) of Compound I has a structure substantially similar to that shown in FIG. 19 Characterized by F MAS.

[0137] Another aspect of the present invention provides a method for making a methanol solvate (wet) of crystalline Compound I. In some embodiments, the method for making a methanol solvate (wet) of crystalline Compound I includes (i) combining neat Form A of Compound I, water, and methanol in a sealed vial, (ii) heating to 65° C. and stirring until a homogenous slurry is formed, and (iii) cooling the slurry without stirring and allowing it to stand at room temperature for 3 days to obtain a methanol solvate (wet) of crystalline Compound I.

[0138] B. Methanol solvate of compound I (dried) In some embodiments, the present invention provides a methanol solvate (dried) of crystalline Compound I. Figure 6 provides a powder X-ray diffractogram of the methanol solvate (dried) of crystalline Compound I.

[0139] In some embodiments, the crystalline methanol solvate (dry) of Compound I is substantially pure. In some embodiments, the crystalline methanol solvate (dry) of Compound I is substantially crystalline. In some embodiments, the crystalline methanol solvate (dry) of Compound I is characterized by an X-ray powder diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0140] In some embodiments, the crystalline methanol solvate of Compound I (dry) is characterized by a powder X-ray diffractogram having a signal at 27.2±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (dry) is characterized by a powder X-ray diffractogram having a signal at 26.4±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (dry) is characterized by a powder X-ray diffractogram having a signal at 25.9±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (dry) is characterized by a powder X-ray diffractogram having a signal at 21.4±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (dry) is characterized by a powder X-ray diffractogram having a signal at 19.3±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (dry) is characterized by a powder X-ray diffractogram having a signal at 18.1±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (dry) is characterized by a powder X-ray diffractogram having a signal at 15.4±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (dry) is characterized by a powder X-ray diffractogram having a signal at 14.2±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (dry) is characterized by a powder X-ray diffractogram having a signal at 7.4±0.2 degrees 2-theta.

[0141] In some embodiments, the crystalline methanol solvate of Compound I (dried) is characterized by an X-ray powder diffractogram having signals at two or more of 27.2±0.2 degrees 2-theta, 26.4±0.2 degrees 2-theta, 25.9±0.2 degrees 2-theta, 21.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, and 7.4±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (dried) is characterized by an X-ray powder diffractogram having signals at three or more of 27.2±0.2 degrees 2-theta, 26.4±0.2 degrees 2-theta, 25.9±0.2 degrees 2-theta, 21.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, and 7.4±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (dried) is characterized by an X-ray powder diffractogram having signals at four or more of 27.2±0.2 degrees 2-theta, 26.4±0.2 degrees 2-theta, 25.9±0.2 degrees 2-theta, 21.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, and 7.4±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (dried) is characterized by an X-ray powder diffractogram having signals at five or more of 27.2±0.2 degrees 2-theta, 26.4±0.2 degrees 2-theta, 25.9±0.2 degrees 2-theta, 21.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, and 7.4±0.2 degrees 2-theta.In some embodiments, the crystalline methanol solvate of Compound I (dried) is characterized by an X-ray powder diffractogram having signals at six or more of 27.2±0.2 degrees 2-theta, 26.4±0.2 degrees 2-theta, 25.9±0.2 degrees 2-theta, 21.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, and 7.4±0.2 degrees 2-theta.

[0142] In some embodiments, the crystalline methanol solvate of Compound I (dry) is characterized by a powder X-ray diffractogram having signals at 25.9±0.2 degrees 2-theta and 19.3±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (dry) is characterized by a powder X-ray diffractogram having signals at 19.3±0.2 degrees 2-theta and 15.4±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (dry) is characterized by a powder X-ray diffractogram having signals at 25.9±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, and 15.4±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (dry) is characterized by an X-ray powder diffractogram having signals at 19.3±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, and 15.4±0.2 degrees 2-theta. In some embodiments, the crystalline methanol solvate of Compound I (dry) is characterized by an X-ray powder diffractogram having signals at 25.9±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, and 15.4±0.2 degrees 2-theta.

[0143] In some embodiments, the crystalline methanol solvate of Compound I (dried) is characterized by a powder X-ray diffractogram having signals at 27.2±0.2 degrees 2-theta, 26.4±0.2 degrees 2-theta, 25.9±0.2 degrees 2-theta, 21.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, and 7.4±0.2 degrees 2-theta.

[0144] In some embodiments, the crystalline methanol solvate of Compound I (dried) is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0145] In some embodiments, the methanol solvate of Compound I (dry) is characterized by a TGA thermogram exhibiting approximately a 1.2% loss from ambient temperature up to about 182° C. In some embodiments, the methanol solvate of Compound I (dry) is characterized by a TGA thermogram substantially similar to FIG.

[0146] In some embodiments, the methanol solvate of Compound I (dry) is characterized by a DSC thermogram exhibiting endotherms at about 175° C. and about 186° C. In some embodiments, the methanol solvate of Compound I (dry) is characterized by a DSC thermogram substantially similar to FIG.

[0147] Another aspect of the present invention provides a method for making a methanol solvate (dried) of crystalline Compound I. In some embodiments, the method for making a methanol solvate (dried) of crystalline Compound I includes (i) combining neat Form A of Compound I, water, and methanol in a sealed vial, (ii) heating to 65° C. and stirring until a homogenous slurry is formed, (iii) cooling the slurry without stirring and allowing it to stand at room temperature for 3 days, and (iv) drying overnight in a vacuum drying oven at 60° C. to obtain a methanol solvate (dried) of crystalline Compound I.

[0148] C. Crystalline Compound I p-Toluenesulfonic Acid In some embodiments, the present invention provides a crystalline p-toluenesulfonic acid salt of Compound I. Figure 9 provides a powder X-ray diffractogram of the crystalline p-toluenesulfonic acid salt of Compound I.

[0149] In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is substantially pure. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is substantially crystalline. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by an X-ray powder diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation.

[0150] In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by a powder X-ray diffractogram having a signal at 5.7±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by a powder X-ray diffractogram having a signal at 5.8±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by a powder X-ray diffractogram having a signal at 7.4±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by a powder X-ray diffractogram having a signal at 10.1±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by a powder X-ray diffractogram having a signal at 11.5±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by a powder X-ray diffractogram having a signal at 11.9±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by a powder X-ray diffractogram having a signal at 14.9±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by a powder X-ray diffractogram having a signal at 15.9±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by a powder X-ray diffractogram having a signal at 16.2±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by a powder X-ray diffractogram having a signal at 18.3±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by an X-ray powder diffractogram having a signal at 20.4±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by an X-ray powder diffractogram having a signal at 21.0±0.2 degrees 2-theta.In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by a powder X-ray diffractogram having a signal at 21.6±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I C is characterized by a powder X-ray diffractogram having a signal at 22.8±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by a powder X-ray diffractogram having a signal at 23.2±0.2 degrees 2-theta.

[0151] In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by an X-ray powder diffractogram having signals at two or more of 5.7±0.2 degrees 2-theta, 5.8±0.2 degrees 2-theta, 7.4±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 11.5±0.2 degrees 2-theta, 11.9±0.2 degrees 2-theta, 14.9±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 16.2±0.2 degrees 2-theta, 18.3±0.2 degrees 2-theta, 20.4±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 21.6±0.2 degrees 2-theta, 22.8±0.2 degrees 2-theta, and 23.2±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by an X-ray powder diffractogram having signals at three or more of 5.7±0.2 degrees 2-theta, 5.8±0.2 degrees 2-theta, 7.4±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 11.5±0.2 degrees 2-theta, 11.9±0.2 degrees 2-theta, 14.9±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 16.2±0.2 degrees 2-theta, 18.3±0.2 degrees 2-theta, 20.4±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 21.6±0.2 degrees 2-theta, 22.8±0.2 degrees 2-theta, and 23.2±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by an X-ray powder diffractogram having signals at four or more of 5.7±0.2 degrees 2-theta, 5.8±0.2 degrees 2-theta, 7.4±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 11.5±0.2 degrees 2-theta, 11.9±0.2 degrees 2-theta, 14.9±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 16.2±0.2 degrees 2-theta, 18.3±0.2 degrees 2-theta, 20.4±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 21.6±0.2 degrees 2-theta, 22.8±0.2 degrees 2-theta, and 23.2±0.2 degrees 2-theta.In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by an X-ray powder diffractogram having signals at five or more of 5.7±0.2 degrees 2-theta, 5.8±0.2 degrees 2-theta, 7.4±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 11.5±0.2 degrees 2-theta, 11.9±0.2 degrees 2-theta, 14.9±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 16.2±0.2 degrees 2-theta, 18.3±0.2 degrees 2-theta, 20.4±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 21.6±0.2 degrees 2-theta, 22.8±0.2 degrees 2-theta, and 23.2±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by an X-ray powder diffractogram having signals at six or more of 5.7±0.2 degrees 2-theta, 5.8±0.2 degrees 2-theta, 7.4±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 11.5±0.2 degrees 2-theta, 11.9±0.2 degrees 2-theta, 14.9±0.2 degrees 2-theta, 15.9±0.2 degrees 2-theta, 16.2±0.2 degrees 2-theta, 18.3±0.2 degrees 2-theta, 20.4±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 21.6±0.2 degrees 2-theta, 22.8±0.2 degrees 2-theta, and 23.2±0.2 degrees 2-theta.

[0152] In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by a powder X-ray diffractogram having signals at 5.7±0.2 degrees 2-theta and 5.8±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by a powder X-ray diffractogram having signals at 5.7±0.2 degrees 2-theta, 5.8±0.2 degrees 2-theta, and 7.4±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by a powder X-ray diffractogram having signals at 5.7±0.2 degrees 2-theta, 5.8±0.2 degrees 2-theta, 7.4±0.2 degrees 2-theta, and 10.1±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by an X-ray powder diffractogram having signals at 5.7±0.2 degrees 2-theta, 5.8±0.2 degrees 2-theta, 7.4±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, and 11.5±0.2 degrees 2-theta. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized by an X-ray powder diffractogram having signals at 5.7±0.2 degrees 2-theta, 5.8±0.2 degrees 2-theta, 7.4±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 11.5±0.2 degrees 2-theta, and 11.9±0.2 degrees 2-theta.

[0153] In some embodiments, the crystalline p-toluenesulfonic acid salt of Compound I is characterized by a powder X-ray diffractogram substantially similar to that in FIG.

[0154] In some embodiments, the p-toluenesulfonic acid of Compound I is characterized by a DSC thermogram exhibiting endotherms at about 48° C. and about 115° C. In some embodiments, the p-toluenesulfonic acid of Compound I is characterized by a DSC thermogram substantially similar to FIG.

[0155] In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 163.8±0.2 ppm.13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 161.8±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 160.9±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 152.9±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 146.1±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 141.0±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 139.3±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 138.0±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 136.7±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 132.5±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 130.6±0.2 ppm. 13C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 127.8±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 126.7±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 124.7±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 122.1±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 114.5±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 113.1±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 110.3±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 75.5±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 57.0±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 48.6±0.2 ppm. 13C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 35.0±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 32.5±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 31.0±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 29.8±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 28.3±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 26.2±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 25.0±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 23.0±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a signal at 19.5±0.2 ppm. 13 It is characterized as having a C SSNMR spectrum.

[0156] In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has two or more signals selected from 141.0±0.2 ppm, 126.7±0.2 ppm, 57.0±0.2 ppm, 31.0±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a C SSNMR spectrum having three or more signals selected from 141.0±0.2 ppm, 126.7±0.2 ppm, 57.0±0.2 ppm, 31.0±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a C SSNMR spectrum having four or more signals selected from 141.0±0.2 ppm, 126.7±0.2 ppm, 57.0±0.2 ppm, 31.0±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a C SSNMR spectrum having five or more signals selected from 141.0±0.2 ppm, 126.7±0.2 ppm, 57.0±0.2 ppm, 31.0±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a C SSNMR spectrum having six or more signals selected from 141.0±0.2 ppm, 126.7±0.2 ppm, 57.0±0.2 ppm, 31.0±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13 It is characterized as having a C SSNMR spectrum.

[0157] In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has signals at 141.0±0.2 ppm and 19.5±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has signals at 141.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has signals at 141.0±0.2 ppm, 57.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has signals at 141.0±0.2 ppm, 57.0±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has signals at 141.0±0.2 ppm, 57.0±0.2 ppm, 31.0±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has signals at 141.0±0.2 ppm, 126.7±0.2 ppm, 57.0±0.2 ppm, 31.0±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13 It is characterized as having a C SSNMR spectrum.

[0158] In some embodiments, the p-toluenesulfonic acid of crystalline Compound I is 163.8±0.2 ppm, 161.8±0.2 ppm, 160.9±0.2 ppm, 152.9±0.2 ppm, 146.1±0.2 ppm, 141.0±0.2 ppm, 139.3±0.2 ppm, 138.0±0.2 ppm, 136.7±0.2 ppm, 132.5±0.2 ppm, 130.6±0.2 ppm, 127.8±0.2 ppm, 126.7±0.2 ppm, 124.7±0.2 ppm, having one or more signals selected from 122.1±0.2 ppm, 114.5±0.2 ppm, 113.1±0.2 ppm, 110.3±0.2 ppm, 75.5±0.2 ppm, 57.0±0.2 ppm, 48.6±0.2 ppm, 35.0±0.2 ppm, 32.5±0.2 ppm, 31.0±0.2 ppm, 29.8±0.2 ppm, 28.3±0.2 ppm, 26.2±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a C SSNMR spectrum of 163.8±0.2 ppm, 161.8±0.2 ppm, 160.9±0.2 ppm, 152.9±0.2 ppm, 146.1±0.2 ppm, 141.0±0.2 ppm, 139.3±0.2 ppm, 138.0±0.2 ppm, 136.7±0.2 ppm, 132.5±0.2 ppm, 130.6±0.2 ppm, 127.8±0.2 ppm, 126.7±0.2 ppm, 124.7±0.2 ppm, having two or more signals selected from 122.1±0.2 ppm, 114.5±0.2 ppm, 113.1±0.2 ppm, 110.3±0.2 ppm, 75.5±0.2 ppm, 57.0±0.2 ppm, 48.6±0.2 ppm, 35.0±0.2 ppm, 32.5±0.2 ppm, 31.0±0.2 ppm, 29.8±0.2 ppm, 28.3±0.2 ppm, 26.2±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm 13In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a C SSNMR spectrum of 163.8±0.2 ppm, 161.8±0.2 ppm, 160.9±0.2 ppm, 152.9±0.2 ppm, 146.1±0.2 ppm, 141.0±0.2 ppm, 139.3±0.2 ppm, 138.0±0.2 ppm, 136.7±0.2 ppm, 132.5±0.2 ppm, 130.6±0.2 ppm, 127.8±0.2 ppm, 126.7±0.2 ppm, 124.7±0.2 ppm, and 31.0±0.2 ppm, 29.8±0.2 ppm, 28.3±0.2 ppm, 26.2±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a C SSNMR spectrum of 163.8±0.2 ppm, 161.8±0.2 ppm, 160.9±0.2 ppm, 152.9±0.2 ppm, 146.1±0.2 ppm, 141.0±0.2 ppm, 139.3±0.2 ppm, 138.0±0.2 ppm, 136.7±0.2 ppm, 132.5±0.2 ppm, 130.6±0.2 ppm, 127.8±0.2 ppm, 126.7±0.2 ppm, 124.7±0.2 ppm, and 4 or more signals selected from 122.1±0.2 ppm, 114.5±0.2 ppm, 113.1±0.2 ppm, 110.3±0.2 ppm, 75.5±0.2 ppm, 57.0±0.2 ppm, 48.6±0.2 ppm, 35.0±0.2 ppm, 32.5±0.2 ppm, 31.0±0.2 ppm, 29.8±0.2 ppm, 28.3±0.2 ppm, 26.2±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a C SSNMR spectrum of 163.8±0.2 ppm, 161.8±0.2 ppm, 160.9±0.2 ppm, 152.9±0.2 ppm, 146.1±0.2 ppm, 141.0±0.2 ppm, 139.3±0.2 ppm, 138.0±0.2 ppm, 136.7±0.2 ppm, 132.5±0.2 ppm, 130.6±0.2 ppm, 127.8±0.2 ppm, 126.7±0.2 ppm, 124.7±0.2 ppm, 5 or more signals selected from 122.1±0.2 ppm, 114.5±0.2 ppm, 113.1±0.2 ppm, 110.3±0.2 ppm, 75.5±0.2 ppm, 57.0±0.2 ppm, 48.6±0.2 ppm, 35.0±0.2 ppm, 32.5±0.2 ppm, 31.0±0.2 ppm, 29.8±0.2 ppm, 28.3±0.2 ppm, 26.2±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a C SSNMR spectrum of 163.8±0.2 ppm, 161.8±0.2 ppm, 160.9±0.2 ppm, 152.9±0.2 ppm, 146.1±0.2 ppm, 141.0±0.2 ppm, 139.3±0.2 ppm, 138.0±0.2 ppm, 136.7±0.2 ppm, 132.5±0.2 ppm, 130.6±0.2 ppm, 127.8±0.2 ppm, 126.7±0.2 ppm, 124.7±0.2 ppm, having six or more signals selected from 122.1±0.2 ppm, 114.5±0.2 ppm, 113.1±0.2 ppm, 110.3±0.2 ppm, 75.5±0.2 ppm, 57.0±0.2 ppm, 48.6±0.2 ppm, 35.0±0.2 ppm, 32.5±0.2 ppm, 31.0±0.2 ppm, 29.8±0.2 ppm, 28.3±0.2 ppm, 26.2±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm 13In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a C SSNMR spectrum of 163.8±0.2 ppm, 161.8±0.2 ppm, 160.9±0.2 ppm, 152.9±0.2 ppm, 146.1±0.2 ppm, 141.0±0.2 ppm, 139.3±0.2 ppm, 138.0±0.2 ppm, 136.7±0.2 ppm, 132.5±0.2 ppm, 130.6±0.2 ppm, 127.8±0.2 ppm, 126.7±0.2 ppm, 124.7±0.2 ppm, and 7 or more signals selected from 122.1±0.2 ppm, 114.5±0.2 ppm, 113.1±0.2 ppm, 110.3±0.2 ppm, 75.5±0.2 ppm, 57.0±0.2 ppm, 48.6±0.2 ppm, 35.0±0.2 ppm, 32.5±0.2 ppm, 31.0±0.2 ppm, 29.8±0.2 ppm, 28.3±0.2 ppm, 26.2±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a C SSNMR spectrum of 163.8±0.2 ppm, 161.8±0.2 ppm, 160.9±0.2 ppm, 152.9±0.2 ppm, 146.1±0.2 ppm, 141.0±0.2 ppm, 139.3±0.2 ppm, 138.0±0.2 ppm, 136.7±0.2 ppm, 132.5±0.2 ppm, 130.6±0.2 ppm, 127.8±0.2 ppm, 126.7±0.2 ppm, 124.7±0.2 ppm, having eight or more signals selected from 122.1±0.2 ppm, 114.5±0.2 ppm, 113.1±0.2 ppm, 110.3±0.2 ppm, 75.5±0.2 ppm, 57.0±0.2 ppm, 48.6±0.2 ppm, 35.0±0.2 ppm, 32.5±0.2 ppm, 31.0±0.2 ppm, 29.8±0.2 ppm, 28.3±0.2 ppm, 26.2±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm; 13 It is characterized as having a C SSNMR spectrum.

[0159] In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has three or more signals selected from 163.8±0.2 ppm, 161.8±0.2 ppm, 160.9±0.2 ppm, 152.9±0.2 ppm, 146.1±0.2 ppm, 141.0±0.2 ppm, 139.3±0.2 ppm, 138.0±0.2 ppm, 136.7±0.2 ppm, 132.5±0.2 ppm, 130.6±0.2 ppm, 127.8±0.2 ppm, 126.7±0.2 ppm, 124.7±0.2 ppm, 122.1±0.2 ppm, 114.5±0.2 ppm, 113.1±0.2 ppm, and 110.3±0.2 ppm. 13 It is characterized as having a C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has four or more signals selected from 163.8±0.2 ppm, 161.8±0.2 ppm, 160.9±0.2 ppm, 152.9±0.2 ppm, 146.1±0.2 ppm, 141.0±0.2 ppm, 139.3±0.2 ppm, 138.0±0.2 ppm, 136.7±0.2 ppm, 132.5±0.2 ppm, 130.6±0.2 ppm, 127.8±0.2 ppm, 126.7±0.2 ppm, 124.7±0.2 ppm, 122.1±0.2 ppm, 114.5±0.2 ppm, 113.1±0.2 ppm, and 110.3±0.2 ppm. 13 It is characterized as having a C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has five or more signals selected from 163.8±0.2 ppm, 161.8±0.2 ppm, 160.9±0.2 ppm, 152.9±0.2 ppm, 146.1±0.2 ppm, 141.0±0.2 ppm, 139.3±0.2 ppm, 138.0±0.2 ppm, 136.7±0.2 ppm, 132.5±0.2 ppm, 130.6±0.2 ppm, 127.8±0.2 ppm, 126.7±0.2 ppm, 124.7±0.2 ppm, 122.1±0.2 ppm, 114.5±0.2 ppm, 113.1±0.2 ppm, and 110.3±0.2 ppm. 13It is characterized as having a C SSNMR spectrum. In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has six or more signals selected from 163.8±0.2 ppm, 161.8±0.2 ppm, 160.9±0.2 ppm, 152.9±0.2 ppm, 146.1±0.2 ppm, 141.0±0.2 ppm, 139.3±0.2 ppm, 138.0±0.2 ppm, 136.7±0.2 ppm, 132.5±0.2 ppm, 130.6±0.2 ppm, 127.8±0.2 ppm, 126.7±0.2 ppm, 124.7±0.2 ppm, 122.1±0.2 ppm, 114.5±0.2 ppm, 113.1±0.2 ppm, and 110.3±0.2 ppm. 13 It is characterized as having a C SSNMR spectrum.

[0160] In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has signals at 163.8±0.2 ppm, 161.8±0.2 ppm, 160.9±0.2 ppm, 152.9±0.2 ppm, 146.1±0.2 ppm, 141.0±0.2 ppm, 139.3±0.2 ppm, 138.0±0.2 ppm, 136.7±0.2 ppm, 132.5±0.2 ppm, 130.6±0.2 ppm, 127.8±0.2 ppm, 126.7±0.2 ppm, 124.7±0.2 ppm, 122.1±0.2 ppm, 114.5±0.2 ppm, 113.1±0.2 ppm, and 110.3±0.2 ppm. 13In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a C SSNMR spectrum of 163.8±0.2 ppm, 161.8±0.2 ppm, 160.9±0.2 ppm, 152.9±0.2 ppm, 146.1±0.2 ppm, 141.0±0.2 ppm, 139.3±0.2 ppm, 138.0±0.2 ppm, 136.7±0.2 ppm, 132.5±0.2 ppm, 130.6±0.2 ppm, 127.8±0.2 ppm, 126.7±0.2 ppm, 124.7±0. 2 ppm, 122.1 ± 0.2 ppm, 114.5 ± 0.2 ppm, 113.1 ± 0.2 ppm, 110.3 ± 0.2 ppm, 75.5 ± 0.2 ppm, 57.0 ± 0.2 ppm, 48.6 ± 0.2 ppm, 35.0 ± 0.2 ppm, 32.5 ± 0.2 ppm, 31.0 ± 0.2 ppm, 29.8 ± 0.2 ppm, 28.3 ± 0.2 ppm, 26.2 ± 0.2 ppm, 25.0 ± 0.2 ppm, 23.0 ± 0.2 ppm, and 19.5 ± 0.2 ppm. 13 It is characterized as having a C SSNMR spectrum.

[0161] In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a structure substantially similar to that shown in FIG. 13 Characterized by C SSNMR spectrum.

[0162] In some embodiments, the p-toluenesulfonic acid of crystalline Compound I is at -62.5±0.2 ppm. 19 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a F MAS signal at -64.2±0.2 ppm. 19 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a F MAS signal at -64.6±0.2 ppm. 19 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a F MAS signal at -65.4±0.2 ppm. 19In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a F MAS signal at -66.1±0.2 ppm. 19 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a F MAS signal at -77.4±0.2 ppm. 19 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a F MAS signal at -78.1±0.2 ppm. 19 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a F MAS signal at -79.7±0.2 ppm. 19 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I is characterized as having a F MAS signal at -80.1±0.2 ppm. 19 F MAS signal.

[0163] In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has two or more signals selected from -62.5±0.2 ppm, -64.2±0.2 ppm, -64.6±0.2 ppm, -65.4±0.2 ppm, -66.1±0.2 ppm, -77.4±0.2 ppm, -78.1±0.2 ppm, -79.7±0.2 ppm, -80.1±0.2 ppm. 19 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has three or more signals selected from -62.5±0.2 ppm, -64.2±0.2 ppm, -64.6±0.2 ppm, -65.4±0.2 ppm, -66.1±0.2 ppm, -77.4±0.2 ppm, -78.1±0.2 ppm, -79.7±0.2 ppm, and -80.1±0.2 ppm. 19In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has four or more signals selected from -62.5±0.2 ppm, -64.2±0.2 ppm, -64.6±0.2 ppm, -65.4±0.2 ppm, -66.1±0.2 ppm, -77.4±0.2 ppm, -78.1±0.2 ppm, -79.7±0.2 ppm, and -80.1±0.2 ppm. 19 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has five or more signals selected from -62.5±0.2 ppm, -64.2±0.2 ppm, -64.6±0.2 ppm, -65.4±0.2 ppm, -66.1±0.2 ppm, -77.4±0.2 ppm, -78.1±0.2 ppm, -79.7±0.2 ppm, and -80.1±0.2 ppm. 19 In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has six or more signals selected from -62.5±0.2 ppm, -64.2±0.2 ppm, -64.6±0.2 ppm, -65.4±0.2 ppm, -66.1±0.2 ppm, -77.4±0.2 ppm, -78.1±0.2 ppm, -79.7±0.2 ppm, and -80.1±0.2 ppm. 19 F MAS.

[0164] In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has signals at -62.5±0.2 ppm, -64.2±0.2 ppm, -64.6±0.2 ppm, -65.4±0.2 ppm, -66.1±0.2 ppm, -77.4±0.2 ppm, -78.1±0.2 ppm, -79.7±0.2 ppm, -80.1±0.2 ppm. 19 F MAS.

[0165] In some embodiments, the crystalline p-toluenesulfonic acid of Compound I has a structure substantially similar to that shown in FIG. 19 Characterized by F MAS.

[0166] Another aspect of the present invention provides a method for making crystalline p-toluenesulfonic acid of Compound I. In some embodiments, the method for making crystalline p-toluenesulfonic acid of Compound I includes (i) adding p-toluenesulfonic acid to neat Form A of Compound I in a ball mill tube, (ii) adding methanol and water (60:40 v / v), (iii) ball milling at 7500 rpm for three cycles of 60 seconds with a 10 second pause to obtain crystalline p-toluenesulfonic acid of Compound I, and (iv) drying the resulting material in a vacuum drying oven at 40°C.

[0167] D. Neat amorphous Compound I In some embodiments, the present invention provides neat amorphous Compound I. In some embodiments, the neat amorphous Compound I is substantially pure. In some embodiments, the neat amorphous Compound I is substantially amorphous.

[0168] In some embodiments, neat amorphous Compound I is characterized by a powder X-ray diffractogram generated by powder X-ray diffraction analysis using an incident beam of Cu Kα radiation. In some embodiments, neat amorphous Compound I is characterized by a powder X-ray diffractogram substantially similar to FIG.

[0169] In some embodiments, the TGA thermogram of neat amorphous Compound I exhibits negligible weight loss from ambient temperature to thermal decomposition. In some embodiments, the TGA thermogram of neat amorphous Compound I is substantially similar to FIG.

[0170] In some embodiments, the glass transition temperature of neat amorphous Compound I is measured using DSC. In some embodiments, the glass transition of neat amorphous Compound I is 64.8° C. In some embodiments, recrystallization of Compound I occurs at 110.2° C. and melting occurs at 181.1° C. In some embodiments, the DSC thermogram of neat amorphous Compound I is substantially similar to FIG. 15.

[0171] Another aspect of the present invention provides a method of making neat amorphous Compound I. In some embodiments, the method of making neat amorphous Compound I comprises (i) heating neat Form A of crystalline Compound I to 200° C., and (ii) cooling the resulting material to 10° C. to obtain neat amorphous Compound I.

[0172] Another aspect of the present invention provides a method of making neat amorphous Compound I. In some embodiments, the method of making neat amorphous Compound I comprises (i) heating neat Form A of crystalline Compound I to 200° C. at a rate of 10° C. per minute to obtain neat amorphous Compound I, and (ii) cooling the resulting material to 10° C. Synthetic Processes and Intermediates

[0173] In some embodiments, compound I is prepared using a compound of the present disclosure.

[0174] In some embodiments, compound I is a compound of formula I, formula II, or formula III: [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, -R a is selected from an alcohol protecting group, The compound of formula I, II or III is N'-[(2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide, (6R)-6-benzyloxy-12,12-dimethyl-17-nitro-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,8,14,16-hexane (E / Z mixture), N'-[(2R)-2-benzyl oxy-2-(trifluoromethyl)hex-5-enoyl]-6-[1,1-bis(trideuteriomethyl)but-3-enylamino]-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide, (6R)-6-benzyloxy-17-nitro-12,12-bis(trideuteriomethyl)-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexane (E / Z mixture), and pharma- ceutically acceptable salts thereof.

[0175] In some embodiments of Formula I, Formula II, and / or Formula III, R a is selected from acetyl (Ac), benzoyl (Bz), benzyl (Bn), β-methoxyethoxymethyl (MEM), dimethoxytrityl (DMT), methoxymethyl (MOM), methoxytrityl (MMT), p-methoxybenzyl (PMB), pivaloyl (Piv), tetrahydropyranyl (THP), trityl (Tr), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), and t-butyldiphenylsilyl (TBDPS). In some embodiments of Formula I, Formula II, and / or Formula III, R a is Bn.

[0176] In some embodiments, compound I is compound 6, [ka] or a pharma- ceutically acceptable salt thereof.

[0177] In some embodiments, compound I is [ka] or a pharma- ceutically acceptable salt thereof.

[0178] In some embodiments, compound I is [ka] or a pharma- ceutically acceptable salt thereof, wherein R a is selected from an alcohol protecting group, R 1 is -N(Boc) 2 , -NHBoc, -N(Phth), -NH(Cbz), and -NO 2 is selected from.

[0179] In some embodiments of Formula XI, Formula XII, and / or Formula XIII, R a is selected from acetyl (Ac), benzoyl (Bz), benzyl (Bn), β-methoxyethoxymethyl (MEM), dimethoxytrityl (DMT), methoxymethyl (MOM), methoxytrityl (MMT), p-methoxybenzyl (PMB), pivaloyl (Piv), tetrahydropyranyl (THP), trityl (Tr), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), and t-butyldiphenylsilyl (TBDPS). In some embodiments of Formula XI, Formula XII, and / or Formula XIII, R a is Bn.

[0180] In some embodiments, compound I is [ka] or a pharma- ceutically acceptable salt thereof.

[0181] In some embodiments, the compounds of the present disclosure are compounds of formula I, formula II, or formula III: [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, -R a is selected from an alcohol protecting group, The compound of formula I, II or III is N'-[(2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide, (6R)-6-benzyloxy-12,12-dimethyl-17-nitro-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,8,14,16-hexane (E / Z mixture), N'-[(2R)-2-benzyl oxy-2-(trifluoromethyl)hex-5-enoyl]-6-[1,1-bis(trideuteriomethyl)but-3-enylamino]-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide, (6R)-6-benzyloxy-17-nitro-12,12-bis(trideuteriomethyl)-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexane (E / Z mixture), and pharma- ceutically acceptable salts thereof.

[0182] In some embodiments of Formula I, Formula II, and / or Formula III, Ra is selected from acetyl (Ac), benzoyl (Bz), benzyl (Bn), β-methoxyethoxymethyl (MEM), dimethoxytrityl (DMT), methoxymethyl (MOM), methoxytrityl (MMT), p-methoxybenzyl (PMB), pivaloyl (Piv), tetrahydropyranyl (THP), trityl (Tr), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), and t-butyldiphenylsilyl (TBDPS). In some embodiments of Formula I, Formula II, and / or Formula III, R a is Bn.

[0183] In some embodiments, the compounds of the present disclosure are compounds of formula I: [ka] or a pharma- ceutically acceptable salt thereof, wherein R a is selected from alcohol protecting groups. In some embodiments of Formula I, R a is selected from acetyl (Ac), benzoyl (Bz), benzyl (Bn), β-methoxyethoxymethyl (MEM), dimethoxytrityl (DMT), methoxymethyl (MOM), methoxytrityl (MMT), p-methoxybenzyl (PMB), pivaloyl (Piv), tetrahydropyranyl (THP), trityl (Tr), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), and t-butyldiphenylsilyl (TBDPS). a is Bn.

[0184] In some embodiments, the compound of the present disclosure is compound 6, [ka] or a pharma- ceutically acceptable salt thereof.

[0185] In some embodiments, the compounds of the present disclosure are [ka] or a pharma- ceutically acceptable salt thereof, wherein: R a is selected from an alcohol protecting group, R 1 is -N(Boc) 2 , -NHBoc, -N(Phth), -NH(Cbz), and -NO 2 is selected from.

[0186] In some embodiments of Formula XI, Formula XII, and / or Formula XIII, R a is selected from acetyl (Ac), benzoyl (Bz), benzyl (Bn), β-methoxyethoxymethyl (MEM), dimethoxytrityl (DMT), methoxymethyl (MOM), methoxytrityl (MMT), p-methoxybenzyl (PMB), pivaloyl (Piv), tetrahydropyranyl (THP), trityl (Tr), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), and t-butyldiphenylsilyl (TBDPS). In some embodiments of Formula XI, Formula XII, and / or Formula XIII, R a is Bn.

[0187] In some embodiments, the compounds of the present disclosure are [ka] or a pharma- ceutically acceptable salt thereof.

[0188] Treatment method Compound I, in any one of the pharma- ceutically acceptable solid forms disclosed herein, acts as a CFTR modulator, i.e., it regulates CFTR activity in the body. Individuals suffering from mutations in the gene encoding CFTR may benefit from receiving a CFTR modulator. CFTR mutations may affect CFTR mass, i.e., the number of CFTR channels on the cell surface, or CFTR function, i.e., the functional ability of each channel to open and transport ions. Mutations that affect CFTR mass include mutations that cause synthesis defects (class I defects), mutations that cause processing and trafficking defects (class II defects), mutations that cause reduced synthesis of CFTR (class V defects), and mutations that reduce the surface stability of CFTR (class VI defects). Mutations that affect CFTR function include mutations that cause gating defects (class III defects) and mutations that cause conductance defects (class IV defects). Some CFTR mutations exhibit characteristics of more than one class. Certain mutations in the CFTR gene lead to cystic fibrosis.

[0189] Thus, in some embodiments, the present invention provides a method for treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient an effective amount of any one of the pharma- ceutically acceptable crystalline and amorphous forms of compound I disclosed herein, alone or in combination with another active ingredient, such as another CFTR modulator. In some embodiments, the patient has an F508del / minimal function (MF) genotype, an F508del / F508del genotype (homozygous for F508del mutation), an F508del / gating genotype, or an F508del / residual function (RF) genotype. In some embodiments, the patient is heterozygous and has one F508del mutation. In some embodiments, the patient is homozygous and has two F508del mutations. In some embodiments, the patient is homozygous for N1303K mutation.

[0190] In some embodiments, the patient is heterozygous and carries an F508del mutation in one allele and a mutation selected from the table below in the other allele. [Table 3-1] [Table 3-2]

[0191] In some embodiments, the present invention provides a method for treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient, the method comprising administering to the patient an effective amount of Compound I in any one of the pharma- ceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, the pharma-ceutically acceptable solid form of Compound I is a substantially amorphous form. In some embodiments, the pharma-ceutically acceptable solid form of Compound I is a substantially crystalline form.

[0192] In some embodiments, a method for treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering to the patient an effective amount of compound I in any one of the pharma- ceutically acceptable crystalline forms disclosed herein. In some embodiments, the pharma-ceutically acceptable crystalline form of compound I is a methanol solvate (wet) of compound I. In some embodiments, the pharma-ceutically acceptable crystalline form of compound I is a methanol solvate (dry) of compound I. In some embodiments, the pharma-ceutically acceptable crystalline form of compound I is the p-toluenesulfonic acid salt of compound I.

[0193] In some embodiments, a method of treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering to the patient an effective amount of Compound I in a pharma- ceutically acceptable amorphous form as disclosed herein. In some embodiments, the pharma- ceutically acceptable crystalline form of Compound I is neat amorphous Compound I.

[0194] In some embodiments, a method for treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering to the patient an effective amount of Compound I in any one of the pharma- ceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein in combination with at least one additional active pharmaceutical ingredient. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR modulator. 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 potentiator.

[0195] In some embodiments, a method of treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering to the patient an effective amount of Compound I in any one of the pharma- ceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharma- ceutically acceptable salts and deuterated derivatives thereof.

[0196] In some embodiments, a method of treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering an effective amount of Compound I as a solid form selected from a methanol solvate of Compound I (wet), a methanol solvate of Compound I (dry), a p-toluenesulfonic acid of Compound I, and neat amorphous Compound I, in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharma- ceutically acceptable salts and deuterated derivatives thereof.

[0197] In some embodiments, a method of treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering an effective amount of Compound I as a solid crystalline form selected from a methanol solvate of Compound I (wet), a methanol solvate of Compound I (dry), a p-toluenesulfonic acid of Compound I, and neat amorphous Compound I, in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharma- ceutically acceptable salts and deuterated derivatives thereof.

[0198] In some embodiments, a method of treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering to the patient an effective amount of Compound I as a solid amorphous form that is neat amorphous Compound I, in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharma- ceutically acceptable salts and deuterated derivatives thereof.

[0199] Pharmaceutical Compositions Another aspect of the present invention provides pharmaceutical compositions comprising Compound I in any one of the pharma- ceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, the pharmaceutical compositions comprise Compound I in a solid form selected from a methanol solvate of Compound I (wet), a methanol solvate of Compound I (dry), and a p-toluenesulfonic acid of Compound I. In some embodiments, the pharmaceutical compositions comprise neat amorphous Compound I.

[0200] In some embodiments, the present invention provides a pharmaceutical composition comprising compound I in any one of the pharma- ceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR corrector. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR potentiator. In some embodiments, the pharmaceutical composition comprises compound I in any one of the pharma- ceutically acceptable crystalline forms disclosed herein and at least two additional active pharmaceutical ingredients, one of which is a CFTR corrector and one of which is a CFTR potentiator. In some embodiments, the at least one additional active pharmaceutical ingredient is compound II, compound III, compound III-d, compound IV, compound V, compound VI, compound VII, compound VIII, compound IX, compound X, and pharma- ceutically acceptable salts and deuterated derivatives thereof.

[0201] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective, and an anti-inflammatory agent.

[0202] In some embodiments, the present invention provides pharmaceutical compositions comprising: (a) Compound I, in any one of the pharma- ceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein; and (b) at least one pharma- ceutically acceptable carrier.

[0203] In some embodiments, the present invention provides pharmaceutical compositions comprising: (a) Compound I, in any one of the pharma- ceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein, and at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharma- ceutically acceptable salts and deuterated derivatives thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0204] In some embodiments, the present invention provides pharmaceutical compositions comprising: (a) a solid form of Compound I selected from a methanol solvate of Compound I (wet), a methanol solvate of Compound I (dry), a p-toluenesulfonic acid of Compound I, and neat amorphous Compound I; (b) at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharma- ceutically acceptable salts and deuterated derivatives thereof; and (c) at least one pharma- ceutically acceptable carrier.

[0205] The pharmaceutical compositions described herein are useful for the treatment of cystic fibrosis and other CFTR-mediated diseases.

[0206] As mentioned above, the pharmaceutical composition disclosed herein may optionally further comprise at least one pharma- ceutically acceptable carrier. The at least one pharma- ceutically acceptable carrier may be selected from adjuvants and vehicles. As used herein, at least one pharma- ceutically acceptable carrier includes any and all solvents, diluents, other liquid vehicles, dispersing aids, suspending aids, surfactants, isotonicity agents, thickening agents, emulsifiers, preservatives, solid binders, and lubricants suitable for the specific dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York disclose various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, such as by producing any undesirable biological effects or otherwise interacting in a deleterious manner with any other components of the pharmaceutical composition, use of any conventional carrier is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharma- ceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), saturated vegetable fatty acids, partial glyceride mixtures of water, salts and electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., carboxymethylcellulose, cellulose acetate, cellulose esters ... Examples of suitable additives include, but are not limited to, sodium stearate, ethylcellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository wax), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants.

[0207] Non-limiting exemplary embodiments A. Set 1 1. Compound I, [ka] Compound I as a neat amorphous form of substantially amorphous Compound I (i.e., less than 15% of Compound I is in crystalline form, less than 10% of Compound I is in crystalline form, less than 5% of Compound I is in crystalline form). 2. The neat amorphous form of substantially amorphous Compound I according to embodiment 1, wherein Compound I is 100% amorphous. 3. A neat amorphous form of substantially amorphous Compound I according to embodiment 1 or embodiment 2, characterized by a powder X-ray diffractogram substantially similar to that in FIG. 13. 4. A neat amorphous form of substantially amorphous Compound I according to any one of embodiments 1-3, characterized by a TGA thermogram showing negligible weight loss from ambient temperature to thermal decomposition. 5. A neat amorphous form of substantially amorphous Compound I according to any one of embodiments 1-4, characterized by a TGA thermogram substantially similar to FIG. 14. 6. The neat amorphous form of substantially amorphous Compound I according to any one of embodiments 1 to 5, characterized by a glass transition temperature of 64.8° C. 7. A neat amorphous form of substantially amorphous Compound I according to any one of embodiments 1-6, characterized by a DSC thermogram substantially similar to FIG. 15. 8. The neat amorphous form of substantially amorphous Compound I according to any one of embodiments 1-7, prepared by (i) heating crystalline Compound I Form A to 200° C., and (ii) cooling the resulting material to 10° C. to obtain neat amorphous Compound I. 9. Substantially amorphous methanol solvate (wet) of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 10. The substantially crystalline methanol solvate (wet) of Compound I according to embodiment 9, wherein the methanol solvate (wet) of Compound I is 100% crystalline. 11. The methanol solvate (wet) of the substantially crystalline Compound I of embodiment 9 or embodiment 10, characterized by an X-ray powder diffractogram having signals at one or more of 25.5±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 19.0±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 18.6±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, 15.0±0.2 degrees 2-theta, 14.6±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta. 12. The methanol solvate (wet) of the substantially crystalline Compound I according to any one of embodiments 9 to 11, characterized by an X-ray powder diffractogram having signals at two or more of 25.5±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 19.0±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 18.6±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, 15.0±0.2 degrees 2-theta, 14.6±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta. 13. The methanol solvate (wet) of the substantially crystalline Compound I of any one of embodiments 9-12, characterized by an X-ray powder diffractogram having signals at three or more of 25.5±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 19.0±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 18.6±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, 15.0±0.2 degrees 2-theta, 14.6±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta. 14. The methanol solvate (wet) of the substantially crystalline Compound I of any one of embodiments 9-13, characterized by a powder X-ray diffractogram having signals at four or more of 25.5±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 19.0±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 18.6±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, 15.0±0.2 degrees 2-theta, 14.6±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta. The methanol solvate (wet) of the substantially crystalline Compound I of any one of embodiments 9-14, characterized by an X-ray powder diffractogram having signals at five or more of 15.25.5±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 19.0±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 18.6±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, 15.0±0.2 degrees 2-theta, 14.6±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta. The methanol solvate (wet) of the substantially crystalline Compound I of any one of embodiments 9-15, characterized by an X-ray powder diffractogram having signals at six or more of 16.25.5±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 19.0±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 18.6±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, 15.0±0.2 degrees 2-theta, 14.6±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta. A methanol solvate (wet) of substantially crystalline Compound I according to any one of embodiments 9 to 16, characterized by a powder X-ray diffractogram having signals at 17.25.5±0.2 degrees 2-theta and 8.4±0.2 degrees 2-theta. 18. A methanol solvate (wet) of the substantially crystalline Compound I according to any one of embodiments 9 to 16, characterized by a powder X-ray diffractogram having signals at 20.5±0.2 degrees 2-theta and 8.4±0.2 degrees 2-theta. 19. A methanol solvate (wet) of substantially crystalline Compound I according to any one of embodiments 9 to 16, characterized by a powder X-ray diffractogram having signals at 20.5±0.2 degrees 2-theta and 16.9±0.2 degrees 2-theta. A methanol solvate (wet) of substantially crystalline Compound I according to any one of embodiments 9 to 16, characterized by a powder X-ray diffractogram having signals at 20.25.5±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta. 21. A methanol solvate (wet) of the substantially crystalline Compound I according to any one of embodiments 9 to 16, characterized by a powder X-ray diffractogram having signals at 20.5±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta. 22. A methanol solvate (wet) of substantially crystalline Compound I according to any one of embodiments 9 to 16, characterized by a powder X-ray diffractogram having signals at 25.5±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta. 23. The methanol solvate (wet) of the substantially crystalline Compound I according to any one of embodiments 9 to 16, characterized by a powder X-ray diffractogram having signals at 25.5±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, 20.5±0.2 degrees 2-theta, 19.0±0.2 degrees 2-theta, 18.9±0.2 degrees 2-theta, 18.6±0.2 degrees 2-theta, 16.9±0.2 degrees 2-theta, 15.0±0.2 degrees 2-theta, 14.6±0.2 degrees 2-theta, and 8.4±0.2 degrees 2-theta. 24. A substantially crystalline methanol solvate (wet) of compound I according to any one of embodiments 9 to 23, characterized by a powder X-ray diffractogram substantially similar to that in FIG. 3. 25.Monoclinic system, P2 1 Space group, and Cu K α A methanol solvate (wet) of the substantially crystalline Compound I according to any one of embodiments 9 to 24, characterized by the following unit cell dimensions measured at 100K using a Rigaku diffractometer with radiation (λ=1.54178 Å): [Table 4] 26. Having one or more signals selected from 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 24.8±0.2 ppm, and 19.0±0.2 ppm. 13 A substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 25, characterized by a C SSNMR spectrum. 27. Having two or more signals selected from 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 24.8±0.2 ppm, and 19.0±0.2 ppm. 13 A substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 26, characterized by a C SSNMR spectrum. 28. Having three or more signals selected from 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 24.8±0.2 ppm, and 19.0±0.2 ppm. 13 A substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 27, characterized by a C SSNMR spectrum. 29. Having four or more signals selected from 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 24.8±0.2 ppm, and 19.0±0.2 ppm. 13 A substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 28, characterized by a C SSNMR spectrum. 30. Five or more signals selected from 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 24.8±0.2 ppm, and 19.0±0.2 ppm. 13 A substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 29, characterized by a C SSNMR spectrum. 31. Six or more signals selected from 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 24.8±0.2 ppm, and 19.0±0.2 ppm. 13 A substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 30, characterized by a C SSNMR spectrum. 32. Has signals at 145.6±0.2 ppm and 132.5±0.2 ppm 13 A substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 31, characterized by a C SSNMR spectrum. 33. Has signals at 145.6±0.2 ppm, 132.5±0.2 ppm, and 113.1±0.2 ppm 13 A substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 31, characterized by a C SSNMR spectrum. 34. Has signals at 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, and 73.5±0.2 ppm 13 A substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 31, characterized by a C SSNMR spectrum. 35.1 has signals at 45.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, and 55.9±0.2 ppm 13 A substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 31, characterized by a C SSNMR spectrum. 36.1 has signals at 45.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, and 35.2±0.2 ppm 13 A substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 31, characterized by a C SSNMR spectrum. 37.7 with signals at 3.5±0.2 ppm and 55.9±0.2 ppm 13 A substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 31, characterized by a C SSNMR spectrum. 38.7 with signals at 3.5±0.2 ppm, 55.9±0.2 ppm, and 24.8±0.2 ppm 13 A substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 31, characterized by a C SSNMR spectrum. 39.1 has signals at 32.5±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, and 24.8±0.2 ppm 13 A substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 31, characterized by a C SSNMR spectrum. 40.1 has signals at 32.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, and 24.8±0.2 ppm 13 A substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 31, characterized by a C SSNMR spectrum. 41. Has signals at 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 24.8±0.2 ppm, and 19.0±0.2 ppm. 13 A substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 40, characterized by a C SSNMR spectrum. 42. A method substantially similar to that shown in FIG. 13 A substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 41, characterized by a C SSNMR spectrum. 43. Having one or more signals selected from -63.9±0.2 ppm, -76.6±0.2 ppm, and -79.7±0.2 ppm 19 A methanol solvate (wet) of substantially crystalline Compound I according to any one of embodiments 9 to 42, characterized by F MAS. 44. Having two or more signals selected from -63.9±0.2 ppm, -76.6±0.2 ppm, and -79.7±0.2 ppm 19 A methanol solvate (wet) of substantially crystalline Compound I according to any one of embodiments 9 to 43, characterized by F MAS. 45. Has signals at -63.9±0.2 ppm, -76.6±0.2 ppm, and -79.7±0.2 ppm 19 A methanol solvate (wet) of substantially crystalline Compound I according to any one of embodiments 9 to 44, characterized by F MAS. 46. ​​A method substantially similar to that shown in FIG. 19 A methanol solvate (wet) of the substantially crystalline Compound I according to any one of embodiments 9 to 45, characterized by F MAS. 47. The substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 9 to 46, prepared by (i) combining neat Form A of Compound I, water, and methanol in a sealed vial, (ii) heating to 65° C. and stirring until a homogeneous slurry is formed, and (iii) cooling the slurry without stirring and allowing it to stand at room temperature for 3 days to obtain the crystalline methanol solvate (wet) of Compound I. 48. Substantially amorphous methanol solvate of Compound I (dry) (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 49. The substantially crystalline methanol solvate (dry) of Compound I according to embodiment 48, wherein the methanol solvate (dry) of Compound I is 100% crystalline. The methanol solvate (dried) of the substantially crystalline Compound I of embodiment 48 or embodiment 49, characterized by an X-ray powder diffractogram having signals at one or more of 50.27.2±0.2 degrees 2-theta, 26.4±0.2 degrees 2-theta, 25.9±0.2 degrees 2-theta, 21.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, and 7.4±0.2 degrees 2-theta. 51. The methanol solvate (dried) of the substantially crystalline Compound I according to any one of embodiments 48 to 50, characterized by an X-ray powder diffractogram having signals at two or more of 27.2±0.2 degrees 2-theta, 26.4±0.2 degrees 2-theta, 25.9±0.2 degrees 2-theta, 21.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, and 7.4±0.2 degrees 2-theta. 52. The substantially crystalline methanol solvate of Compound I according to any one of embodiments 48 to 51, characterized by a powder X-ray diffractogram having signals at three or more of 27.2±0.2 degrees 2-theta, 26.4±0.2 degrees 2-theta, 25.9±0.2 degrees 2-theta, 21.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, and 7.4±0.2 degrees 2-theta (dried). 53. The substantially crystalline methanol solvate of Compound I according to any one of embodiments 48-52, characterized by an X-ray powder diffractogram having signals at four or more of 27.2±0.2 degrees 2-theta, 26.4±0.2 degrees 2-theta, 25.9±0.2 degrees 2-theta, 21.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, and 7.4±0.2 degrees 2-theta (dried). 54. The substantially crystalline methanol solvate of Compound I according to any one of embodiments 48-53, characterized by an X-ray powder diffractogram having signals at five or more of 27.2±0.2 degrees 2-theta, 26.4±0.2 degrees 2-theta, 25.9±0.2 degrees 2-theta, 21.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, and 7.4±0.2 degrees 2-theta (dried). 55. The substantially crystalline methanol solvate of Compound I according to any one of embodiments 48-54, characterized by an X-ray powder diffractogram having signals at six or more of 27.2±0.2 degrees 2-theta, 26.4±0.2 degrees 2-theta, 25.9±0.2 degrees 2-theta, 21.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, and 7.4±0.2 degrees 2-theta (dried). A substantially crystalline methanol solvate of Compound I according to any one of embodiments 48 to 55, characterized by a powder X-ray diffractogram having signals at 56.25.9±0.2 degrees 2-theta and 19.3±0.2 degrees 2-theta (dried). 57. A substantially crystalline methanol solvate of Compound I (dried) according to any one of embodiments 48 to 56, characterized by a powder X-ray diffractogram having signals at 19.3±0.2 degrees 2-theta and 15.4±0.2 degrees 2-theta. 58. A substantially crystalline methanol solvate of Compound I (dried) according to any one of embodiments 48 to 57, characterized by a powder X-ray diffractogram having signals at 25.9±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, and 15.4±0.2 degrees 2-theta. 59. A substantially crystalline methanol solvate of Compound I (dried) according to any one of embodiments 48 to 57, characterized by a powder X-ray diffractogram having signals at 19.3±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, and 15.4±0.2 degrees 2-theta. A methanol solvate (dried) of substantially crystalline Compound I according to any one of embodiments 48 to 57, characterized by a powder X-ray diffractogram having signals at 60.25.9±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, and 15.4±0.2 degrees 2-theta. 61. The methanol solvate (dried) of substantially crystalline Compound I according to any one of embodiments 48 to 57, characterized by a powder X-ray diffractogram having signals at 27.2±0.2 degrees 2-theta, 26.4±0.2 degrees 2-theta, 25.9±0.2 degrees 2-theta, 21.4±0.2 degrees 2-theta, 19.3±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 15.4±0.2 degrees 2-theta, 14.2±0.2 degrees 2-theta, and 7.4±0.2 degrees 2-theta. 62. A substantially crystalline methanol solvate of compound I according to any one of embodiments 48-61, characterized by a powder X-ray diffractogram substantially similar to that in FIG. 6 (dried). 63. The substantially crystalline methanol solvate (dried) of Compound I according to any one of embodiments 48-62, prepared by: (i) combining neat Form A of Compound I, water, and methanol in a sealed vial; (ii) heating to 65° C. and stirring until a homogeneous slurry is formed; (iii) cooling the slurry without stirring and allowing it to stand at room temperature for 3 days; and (iv) drying in a vacuum oven at 60° C. overnight to obtain a crystalline methanol solvate (dried) of Compound I. 64. A substantially amorphous p-toluenesulfonic acid salt of Compound I (i.e., less than 15% of Compound I is in amorphous form, less than 10% of Compound I is in amorphous form, less than 5% of Compound I is in amorphous form). 65. The substantially crystalline p-toluenesulfonic acid of Compound I according to embodiment 64, wherein the p-toluenesulfonic acid of Compound I is 100% crystalline. 66.5.7±0.2 degrees 2theta, 5.8±0.2 degrees 2theta, 7.4±0.2 degrees 2theta, 10.1±0.2 degrees 2theta, 11.5±0.2 degrees 2theta, 11.9±0.2 degrees 2theta, 14.9±0.2 degrees 2theta, 15.9±0.2 degrees 2theta, 16.2±0.2 degrees 2theta, 18.3±0.2 degrees 2theta, 20.4±0.2 degrees 2theta, 21.0±0.2 degrees 2theta, 21.6±0.2 degrees 2theta, 22.8±0.2 degrees 2theta, and 23.2±0.2 degrees The substantially crystalline p-toluenesulfonic acid salt of compound I according to embodiment 64 or embodiment 65, characterized by an X-ray powder diffractogram having signals at one or more of 2 theta. 67.5.7±0.2 degrees 2theta, 5.8±0.2 degrees 2theta, 7.4±0.2 degrees 2theta, 10.1±0.2 degrees 2theta, 11.5±0.2 degrees 2theta, 11.9±0.2 degrees 2theta, 14.9±0.2 degrees 2theta, 15.9±0.2 degrees 2theta, 16.2±0.2 degrees 2theta, 18.3±0.2 degrees 2theta, 20.4±0.2 degrees 2theta, 21.0±0.2 degrees 2theta, 21.6±0.2 degrees 2theta, 22.8±0.2 degrees 2theta, and 23.2±0.2 degrees The substantially crystalline p-toluenesulfonic acid of compound I according to any one of embodiments 64 to 66, characterized by a powder X-ray diffractogram having signals at two or more of 2 theta. 68.5.7±0.2 degrees 2theta, 5.8±0.2 degrees 2theta, 7.4±0.2 degrees 2theta, 10.1±0.2 degrees 2theta, 11.5±0.2 degrees 2theta, 11.9±0.2 degrees 2theta, 14.9±0.2 degrees 2theta, 15.9±0.2 degrees 2theta, 16.2±0.2 degrees 2theta, 18.3±0.2 degrees 2theta, 20.4±0.2 degrees 2theta, 21.0±0.2 degrees 2theta, 21.6±0.2 degrees 2theta, 22.8±0.2 degrees 2theta, and 23.2±0.2 degrees The substantially crystalline p-toluenesulfonic acid salt of compound I according to any one of embodiments 64 to 67, characterized by a powder X-ray diffractogram having signals at 3 or more of 2 theta. 69.5.7±0.2 degrees 2theta, 5.8±0.2 degrees 2theta, 7.4±0.2 degrees 2theta, 10.1±0.2 degrees 2theta, 11.5±0.2 degrees 2theta, 11.9±0.2 degrees 2theta, 14.9±0.2 degrees 2theta, 15.9±0.2 degrees 2theta, 16.2±0.2 degrees 2theta, 18.3±0.2 degrees 2theta, 20.4±0.2 degrees 2theta, 21.0±0.2 degrees 2theta, 21.6±0.2 degrees 2theta, 22.8±0.2 degrees 2theta, and 23.2±0.2 degrees The substantially crystalline p-toluenesulfonic acid salt of compound I according to any one of embodiments 64 to 68, characterized by an X-ray powder diffractogram having signals at 4 or more of 2 theta. 70.5.7±0.2 degrees 2theta, 5.8±0.2 degrees 2theta, 7.4±0.2 degrees 2theta, 10.1±0.2 degrees 2theta, 11.5±0.2 degrees 2theta, 11.9±0.2 degrees 2theta, 14.9±0.2 degrees 2theta, 15.9±0.2 degrees 2theta, 16.2±0.2 degrees 2theta, 18.3±0.2 degrees 2theta, 20.4±0.2 degrees 2theta, 21.0±0.2 degrees 2theta, 21.6±0.2 degrees 2theta, 22.8±0.2 degrees 2theta, and 23.2±0.2 degrees The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 69, characterized by a powder X-ray diffractogram having signals at 5 or more of 2 theta. 71.5.7±0.2 degrees 2theta, 5.8±0.2 degrees 2theta, 7.4±0.2 degrees 2theta, 10.1±0.2 degrees 2theta, 11.5±0.2 degrees 2theta, 11.9±0.2 degrees 2theta, 14.9±0.2 degrees 2theta, 15.9±0.2 degrees 2theta, 16.2±0.2 degrees 2theta, 18.3±0.2 degrees 2theta, 20.4±0.2 degrees 2theta, 21.0±0.2 degrees 2theta, 21.6±0.2 degrees 2theta, 22.8±0.2 degrees 2theta, and 23.2±0.2 degrees The substantially crystalline p-toluenesulfonic acid salt of compound I according to any one of embodiments 64 to 70, characterized by a powder X-ray diffractogram having signals at 6 or more of 2 theta. 72. The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 71, characterized by a powder X-ray diffractogram having signals at 5.7±0.2 degrees 2-theta and 5.8±0.2 degrees 2-theta. 73. The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 71, characterized by a powder X-ray diffractogram having signals at 5.7±0.2 degrees 2-theta, 5.8±0.2 degrees 2-theta, and 7.4±0.2 degrees 2-theta. The substantially crystalline p-toluenesulfonic acid salt of compound I according to any one of embodiments 64 to 71, characterized by a powder X-ray diffractogram having signals at 74.7±0.2 degrees 2-theta, 5.8±0.2 degrees 2-theta, 7.4±0.2 degrees 2-theta, and 10.1±0.2 degrees 2-theta. 75. The substantially crystalline p-toluenesulfonic acid salt of Compound I of any one of embodiments 64 to 71, characterized by a powder X-ray diffractogram having signals at 5.7±0.2 degrees 2-theta, 5.8±0.2 degrees 2-theta, 7.4±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, and 11.5±0.2 degrees 2-theta. 76. The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 71, characterized by a powder X-ray diffractogram having signals at 5.7±0.2 degrees 2-theta, 5.8±0.2 degrees 2-theta, 7.4±0.2 degrees 2-theta, 10.1±0.2 degrees 2-theta, 11.5±0.2 degrees 2-theta, and 11.9±0.2 degrees 2-theta. 77. A substantially crystalline p-toluenesulfonic acid salt of compound I according to any one of embodiments 64-76, characterized by a powder X-ray diffractogram substantially similar to that in FIG. 9. 78. Having one or more signals selected from 141.0±0.2 ppm, 126.7±0.2 ppm, 57.0±0.2 ppm, 31.0±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm 13 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 77, characterized by a C SSNMR spectrum. 79. Having two or more signals selected from 141.0±0.2 ppm, 126.7±0.2 ppm, 57.0±0.2 ppm, 31.0±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm 13 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 78, characterized by a C SSNMR spectrum. 80.Having three or more signals selected from 141.0±0.2 ppm, 126.7±0.2 ppm, 57.0±0.2 ppm, 31.0±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm 13 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 79, characterized by a C SSNMR spectrum. 81. Having four or more signals selected from 141.0±0.2 ppm, 126.7±0.2 ppm, 57.0±0.2 ppm, 31.0±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm 13 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 80, characterized by a C SSNMR spectrum. 82.Having five or more signals selected from 141.0±0.2 ppm, 126.7±0.2 ppm, 57.0±0.2 ppm, 31.0±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm 13 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 81, characterized by a C SSNMR spectrum. 83. Six or more signals selected from 141.0±0.2 ppm, 126.7±0.2 ppm, 57.0±0.2 ppm, 31.0±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 82, characterized by a C SSNMR spectrum. 84.14 has signals at 1.0±0.2 ppm and 19.5±0.2 ppm 13 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 83, characterized by a C SSNMR spectrum. 85.14 has 1.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm 13 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 82, characterized by a C SSNMR spectrum. 86.14 has 1.0±0.2 ppm, 57.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 82, characterized by a C SSNMR spectrum. 87.14 1.0±0.2 ppm, 57.0±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm 13 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 82, characterized by a C SSNMR spectrum. 88.14 1.0±0.2 ppm, 57.0±0.2 ppm, 31.0±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm 13 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 82, characterized by a C SSNMR spectrum. 89.141.0±0.2ppm, 126.7±0.2ppm, 57.0±0.2ppm, 31.0±0.2ppm, 25.0±0.2ppm, 23.0±0.2ppm, and 19.5±0.2ppm 13 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 82, characterized by a C SSNMR spectrum. 90. A substantially similar 13 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 89, characterized by a C SSNMR spectrum. 91. Having one or more signals selected from -62.5±0.2ppm, -64.2±0.2ppm, -64.6±0.2ppm, -65.4±0.2ppm, -66.1±0.2ppm, -77.4±0.2ppm, -78.1±0.2ppm, -79.7±0.2ppm, -80.1±0.2ppm 19 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 90, characterized as having F MAS. 92. Two or more signals selected from -62.5±0.2ppm, -64.2±0.2ppm, -64.6±0.2ppm, -65.4±0.2ppm, -66.1±0.2ppm, -77.4±0.2ppm, -78.1±0.2ppm, -79.7±0.2ppm, -80.1±0.2ppm 19 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 90, characterized as having F MAS. 93. Three or more signals selected from -62.5±0.2ppm, -64.2±0.2ppm, -64.6±0.2ppm, -65.4±0.2ppm, -66.1±0.2ppm, -77.4±0.2ppm, -78.1±0.2ppm, -79.7±0.2ppm, -80.1±0.2ppm 19 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 90, characterized as having F MAS. 94. Has four or more signals selected from -62.5±0.2ppm, -64.2±0.2ppm, -64.6±0.2ppm, -65.4±0.2ppm, -66.1±0.2ppm, -77.4±0.2ppm, -78.1±0.2ppm, -79.7±0.2ppm, -80.1±0.2ppm 19 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 90, characterized as having F MAS. 95. Five or more signals selected from -62.5±0.2ppm, -64.2±0.2ppm, -64.6±0.2ppm, -65.4±0.2ppm, -66.1±0.2ppm, -77.4±0.2ppm, -78.1±0.2ppm, -79.7±0.2ppm, -80.1±0.2ppm 19 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 90, characterized as having F MAS. 96. Six or more signals selected from -62.5±0.2ppm, -64.2±0.2ppm, -64.6±0.2ppm, -65.4±0.2ppm, -66.1±0.2ppm, -77.4±0.2ppm, -78.1±0.2ppm, -79.7±0.2ppm, -80.1±0.2ppm 19 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 90, characterized as having F MAS. 97. Has signals at -62.5±0.2ppm, -64.2±0.2ppm, -64.6±0.2ppm, -65.4±0.2ppm, -66.1±0.2ppm, -77.4±0.2ppm, -78.1±0.2ppm, -79.7±0.2ppm, -80.1±0.2ppm 19 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 90, characterized as having F MAS. 98. A method substantially similar to that shown in FIG. 19 The substantially crystalline p-toluenesulfonic acid salt of Compound I according to any one of embodiments 64 to 97, characterized by F MAS. 99. The substantially crystalline methanol solvate (wet) of Compound I according to any one of embodiments 64 to 98, prepared by: (i) adding p-toluenesulfonic acid to neat Form A of Compound I in a ball mill tube; (ii) adding methanol and water (60:40 v / v); (iii) ball milling at 7500 rpm for 3 cycles of 60 seconds with a pause of 10 seconds to obtain crystalline p-toluenesulfonic acid of Compound I; and (iv) drying the resulting material in a vacuum drying oven at 40°C. 100. A pharmaceutical composition comprising a compound I according to any one of embodiments 1 to 99 and a pharma- ceutically acceptable carrier. 101. The pharmaceutical composition of embodiment 100, further comprising one or more additional therapeutic agents. 102. The pharmaceutical composition according to embodiment 101, wherein the pharmaceutical composition comprises one or more additional CFTR modulating compounds. 103. The pharmaceutical composition according to embodiment 101 or embodiment 102, wherein the pharmaceutical composition comprises one or more compounds selected from compound II, compound III, compound III-d, compound IV, compound V, compound VI, compound VII, compound VIII, compound IX, compound X, and pharma- ceutically acceptable salts and deuterated derivatives thereof. 104. Compound I according to any one of embodiments 1 to 99 or a pharmaceutical composition according to any one of embodiments 100 to 103, for use in the treatment of cystic fibrosis. 105. The use of compound I as defined in any one of embodiments 1 to 99 or a pharmaceutical composition as defined in any one of embodiments 100 to 103 in the manufacture of a medicament for the treatment of cystic fibrosis. 106. A method for treating cystic fibrosis, comprising administering to a subject in need thereof a compound I as described in any one of embodiments 1-99 or a pharmaceutical composition as described in any one of embodiments 101-103.

[0208] B. Set 2 1. Compound I, [ka] or a stereoisomer of compound I, or a deuterated derivative of compound I or a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, the method comprising: [ka] or a stereoisomer of a compound of formula I, or a deuterated derivative of a compound of formula I or a stereoisomer thereof, or a salt of any of the foregoing, to compound I, or a stereoisomer thereof, or a deuterated derivative of compound I or a stereoisomer thereof, or a salt of any of the foregoing, wherein R a is selected from alcohol protecting groups. 2.R a 2. The method of embodiment 1, wherein is benzyl (Bn). 3. Compound I, [ka] or a stereoisomer of compound I, or a deuterated derivative of compound I or a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, the method comprising: [ka] or a stereoisomer of a compound of formula II, or a deuterated derivative of a compound of formula II or a stereoisomer thereof, or a salt of any of the foregoing, to compound I, or a stereoisomer thereof, or a deuterated derivative of compound I or a stereoisomer thereof, or a salt of any of the foregoing, wherein R a is selected from alcohol protecting groups, where R a is not benzyl (Bn). 4.R a The method of embodiment 3, wherein is selected from naphthylmethyl, biphenylmethyl, acetyl (Ac), trifluoroacetyl, and benzoyl (Bz). 5. The method of embodiment 3 or 4, wherein converting the compound of formula II, or a stereoisomer of the compound of formula II, or a deuterated derivative or stereoisomer thereof of the compound of formula II, or a salt of any of the foregoing, to compound I, or a stereoisomer thereof, or a deuterated derivative or stereoisomer thereof of compound I, or a salt of any of the foregoing, is carried out in the presence of reduction reaction conditions. 6. The reduction conditions are hydrogen gas (H 2 ), palladium on carbon (Pd / C), and methanolic ammonia (NH 3 / MeOH); hydrogen gas (H 2 ), palladium on carbon (Pd / C), ethanolic ammonia (NH 3 / EtOH); Hydrogen gas (H 2 ), palladium alumina (Pd / Al), and methanolic ammonia (NH 3 / MeOH); hydrogen gas (H 2 ), palladium alumina (Pd / Al), and methanolic ammonia (NH 3 / EtOH); Hydrogen gas (H 2 ), platinum on carbon (Pt / C), and methanolic ammonia (NH 3 / MeOH); hydrogen gas (H 2 ), platinum on carbon (Pt / C), and ethanolic ammonia (NH 3 / EtOH); Hydrogen gas (H 2 ), platinum alumina (Pt / Al), and methanolic ammonia (NH 3 / MeOH); hydrogen gas (H 2 ), platinum alumina (Pt / Al), and methanolic ammonia (NH 3 / EtOH); Hydrogen gas (H 2 ), ruthenium on carbon (Ru / C), and methanolic ammonia (NH 3 / MeOH); hydrogen gas (H 2 ), ruthenium on carbon (Ru / C), and ethanolic ammonia (NH 3 / EtOH); Hydrogen gas (H 2 ), ruthenium alumina (Ru / Al), and methanolic ammonia (NH 3 / MeOH); and hydrogen gas (H2 ), ruthenium alumina (Ru / Al), and methanolic ammonia (NH 3 6. The method of embodiment 5, wherein the aqueous solution is selected from the group consisting of ethanol, ethyl alcohol, ethyl acetate, ethyl ether, ethyl glycerol, ethyl ether ... 7. The reduction conditions are hydrogen gas (H 2 ), palladium on carbon (Pd / C), and methanolic ammonia (NH 3 7. The method of embodiment 5 or 6, wherein the aryl ether is 0.1 to 0.5 wt %. 8. The method comprises the step of: [ka] or a stereoisomer of a compound of formula I, or a deuterated derivative of a compound of formula I or a stereoisomer thereof, or a salt of any of the foregoing, to a compound of formula II, or a stereoisomer thereof, or a deuterated derivative of a compound of formula II or a stereoisomer thereof, or a salt of any of the foregoing, wherein R a The method of any one of the preceding embodiments, wherein is selected from an alcohol protecting group. 9.R a The method of embodiment 8, wherein is benzyl (Bn). 10. The method according to embodiment 8 or 9, wherein the conversion of the compound of formula I, or a stereoisomer of the compound of formula I, or a deuterated derivative or stereoisomer thereof, or a salt of any of the foregoing, to the compound of formula II, or a stereoisomer thereof, or a deuterated derivative or stereoisomer of the compound of formula II, or a salt of any of the foregoing, is carried out in the presence of a dehydrating reagent and a base. 11. The method of embodiment 10, wherein the dehydrating reagent is selected from 2-chloro-1,3-dimethylimidazolinium chloride (DMC), p-toluenesulfonyl chloride (p-TsCl), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), propylphosphonic anhydride (T3P), 1,1'-carbonyldiimidazole (CDI), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU). 12. The method of embodiment 10 or 11, wherein the dehydrating reagent is 2-chloro-1,3-dimethylimidazolinium chloride (DMC). 13. The base is 1,4-diazabicyclo[2.2.2]octane (DABCO), triethylamine (Et 3 13. The method of any one of embodiments 10 to 12, wherein the aryl amine is selected from the group consisting of N,N-diisopropylethylamine (DIPEA), N-methylmorpholine (NMM), pyridine, and DIPEA (N,N-diisopropylethylamine). 14. The method of any one of embodiments 10 to 13, wherein the base is 1,4-diazabicyclo[2.2.2]octane (DABCO). 15. The method of any one of embodiments 10-14, wherein the dehydrating reagent is 2-chloro-1,3-dimethylimidazolinium chloride (DMC) and the base is 1,4-diazabicyclo[2.2.2]octane (DABCO). 16. The method comprises: [ka] or a stereoisomer of a compound of formula III, or a deuterated derivative of a compound of formula III or a stereoisomer thereof, or a salt of any of the foregoing, to a compound of formula I, or a stereoisomer thereof, or a deuterated derivative of a compound of formula I or a stereoisomer thereof, or a salt of any of the foregoing, wherein R a The method of any one of embodiments 8 to 15, wherein is selected from an alcohol protecting group. 17.R a The method of embodiment 16, wherein is benzyl (Bn). 18. The method according to embodiment 16 or 17, wherein the conversion of the compound of formula III, or a stereoisomer of the compound of formula III, or a deuterated derivative or stereoisomer thereof, or a salt of any of the foregoing, to the compound of formula I, or a stereoisomer thereof, or a deuterated derivative or stereoisomer thereof, or a salt of any of the foregoing, is carried out in the presence of a ruthenium catalyst. 19. Ruthenium catalysts include dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II) (Zahn 1B catalyst), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), dichloro[1,3-bis(2,6-isopropylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II);(1,3-dimesitylimidazolidin-2-ylidene)dichloro(2-isopropoxy-5-nitrobenzylidene)ruthenium(II), dichloro 19. The method of embodiment 18, wherein the cation exchanger is selected from (3-phenyl-1H-inden-1-ylidene)bis(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](3-phenyl-1H-inden-1-ylidene)(tricyclohexylphosphine)ruthenium(II), and dichloro(2-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium(II). 20. The method of embodiment 18 or 19, wherein the ruthenium catalyst is dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II) (Zahn 1B catalyst). 21. The method comprises: [ka] or a deuterated derivative of compound 2, or a salt of any of the foregoing, with a compound of formula IV, [ka] or a stereoisomer of a compound of formula IV, or a deuterated derivative of a compound of formula IV or a stereoisomer thereof, or a salt of any of the foregoing, to produce a compound of formula III, or a stereoisomer thereof, or a deuterated derivative of a compound of formula III or a stereoisomer thereof, or a salt of any of the foregoing, wherein R a The method of any one of embodiments 16 to 20, wherein is selected from an alcohol protecting group. twenty two. R 22. The method of embodiment 21, wherein a is benzyl (Bn). 23. The method of embodiment 21 or 22, wherein reacting compound 2, or a deuterated derivative of compound 2, or a salt of any of the foregoing, with a compound of formula IV, or a stereoisomer of a compound of formula IV, or a deuterated derivative of a compound of formula IV or a stereoisomer thereof, or a salt of any of the foregoing, is carried out in the presence of a peptide coupling agent and a base. 24. The method of embodiment 23, wherein the peptide coupling agent is selected from 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 1,1-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide (CMPI), 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholinomethylene)]methanaminium hexafluorophosphate (COMU), isobutyl chloroformate (IBCF), and propanephosphonic anhydride (T3P). 25. The method of embodiment 23 or 24, wherein the peptide coupling agent is 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT). 26. The base is N-methylmorpholine (NMM), 1-methylimidazole, triethylamine (Et 3 N), N,N,-diisopropylethylamine (DIPEA), and pyridine. 27. The method of any one of embodiments 23-26, wherein the base is N-methylmorpholine (NMM). 28. The method of any one of embodiments 23-27, wherein the dehydrating reagent is 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and the base is N-methylmorpholine (NMM). 29. The method comprises the step of: [ka] or a salt of any of the foregoing, to compound 2, or a deuterated derivative of compound 2, or a salt of any of the foregoing, wherein R b The method of any one of embodiments 21-28, wherein is selected from methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (i-Pr), and tert-butyl (t-Bu). 30.R b is methyl (Me). 31. The method of embodiment 29 or 30, wherein the conversion of the compound of formula V, or the deuterated derivative of the compound of formula V, or a salt of any of the foregoing, to compound 2, or the deuterated derivative of compound 2, or a salt of any of the foregoing, is carried out in the presence of an aqueous solution of a hydroxide base. 32. The method of embodiment 31, wherein the hydroxide base is selected from aqueous lithium hydroxide (LiOH), aqueous sodium hydroxide (NaOH), aqueous potassium hydroxide (KOH), and cesium hydroxide (CsOH). 33. The method of embodiment 31 or 32, wherein the base is sodium hydroxide (NaOH). 34. The method comprises reacting a compound of formula VI, [ka] or a deuterated derivative of a compound of formula VI, or a salt of any of the foregoing, [ka] or a deuterated derivative of a compound of formula VI, or a salt of any of the foregoing, to produce a compound of formula V, or a deuterated derivative of a compound of formula V, or a salt of any of the foregoing; During the ceremony, -R b is selected from methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (i-Pr), and tert-butyl (t-Bu); The method of any one of embodiments 29-33, wherein -X is selected from Cl and Br. 35.R b 35. The method of embodiment 34, wherein is methyl (Me) and X is Cl. 36. The method of embodiment 34 or 35, wherein reacting the compound of formula VI, or the deuterated derivative of the compound of formula IV, or a salt of any of the foregoing, with compound 3, or the deuterated derivative of compound 3, or a salt of any of the foregoing, is carried out in the presence of a base. 37. The base is sodium carbonate (NaHCO 3 ), N,N,-diisopropylethylamine (DIPEA), N-methylmorpholine (NMM), sodium bicarbonate (NaHCO 3 ), potassium bicarbonate (KHCO 3 ), potassium carbonate (K 2 CO 3 ), and dibasic potassium phosphate (K 2 HPO 4 37. The method of embodiment 36, wherein said first and second aryl groups are selected from the group consisting of aryl, aryl- ... 38. A base is The method of embodiment 36 or 37, wherein N,N-diisopropylethylamine (DIPEA). 39. The method comprises reacting a compound of formula VII: [ka] or a deuterated derivative of a compound of formula VII, or a salt of any of the foregoing, to compound 3, or a deuterated derivative of compound 3, or a salt of any of the foregoing, wherein R cThe method of any one of embodiments 34-38, wherein is selected from an amine protecting group. 40.R c 40. The method of embodiment 39, wherein is tert-butyloxycarbonyl (Boc). 41. The method of embodiment 39 or 40, wherein the conversion of the compound of formula VII, or the deuterated derivative of the compound of formula VII, or a salt of any of the foregoing, to compound 3, or the deuterated derivative of compound 3, or a salt of any of the foregoing, is carried out in the presence of a protic acid. 42. The method of embodiment 41, wherein the protic acid is selected from hydrochloric acid (HCl), trifluoroacetic acid (TFA), p-toluenesulfonic acid (pTsOH), and methanesulfonic acid (MsOH). 43. The method of embodiment 41 or 42, wherein the protic acid is hydrochloric acid (HCl). 44. The method comprises: [ka] or converting a deuterated derivative of a compound of formula VIII to a compound of formula VII, or a deuterated derivative of a compound of formula VII, or a salt of any of the foregoing, wherein R c The method of any one of embodiments 39-43, wherein is selected from an amine protecting group. 45.R c 45. The method of embodiment 44, wherein is tert-butyloxycarbonyl (Boc). 46. ​​The method of embodiment 44 or 45, wherein the conversion of the compound of formula VIII, or the deuterated derivative of the compound of formula VIII, to the compound of formula VII, or the deuterated derivative of the compound of formula VII, or a salt of any of the foregoing, is carried out in the presence of an allylmagnesium halide and a copper(I) halide. 47. The method of embodiment 46, wherein the allylmagnesium halide is selected from allylmagnesium chloride and allylmagnesium bromide. 48. The method of embodiment 46 or 47, wherein the allylmagnesium halide is allylmagnesium chloride. 49. The method of any one of embodiments 46-48, wherein the copper(I) halide is selected from copper(I) chloride, copper(I) bromide, copper(I) bromide dimethylsulfide complex, and copper(I) iodide. 50. The method of any one of embodiments 46-49, wherein the copper(I) halide is copper(I) bromide dimethylsulfide complex. 51. The method of any one of embodiments 46-50, wherein the allylmagnesium halide is allylmagnesium chloride and the copper(I) halide is copper(I) bromide dimethylsulfide complex. 52. The method comprises the step of: [ka] or a deuterated derivative of a compound of formula IX, or a salt of any of the foregoing, to a compound of formula VIII, or a deuterated derivative of a compound of formula VIII, or a salt of any of the foregoing, wherein R c The method of any one of embodiments 44-51, wherein is selected from an amine protecting group. 53.R c 53. The method of embodiment 52, wherein is tert-butyloxycarbonyl (Boc). 54. The method according to embodiment 52 or 53, wherein the conversion of the compound of formula IX, or the deuterated derivative of the compound of formula IX, or a salt of any of the foregoing, to the compound of formula VIII, or the deuterated derivative of the compound of formula VIII, or a salt of any of the foregoing, is carried out in the presence of a sulfonyl halide and a base. 55. The method of embodiment 54, wherein the sulfonyl halide is selected from p-toluenesulfonyl chloride (p-TsCl), benzenesulfonyl chloride, and methanesulfonyl chloride (MsCl). 56. The method of embodiment 54 or 55, wherein the sulfonyl halide is p-toluenesulfonyl chloride (p-TsCl). 57. The method of any one of embodiments 54-56, wherein the base is selected from aqueous sodium hydroxide (NaOH), aqueous potassium hydroxide (KOH), and aqueous lithium hydroxide (LiOH). 58. The method of any one of embodiments 54-57, wherein the base is potassium hydroxide (KOH). 59. The method of any one of embodiments 54-58, wherein the sulfonyl halide is p-toluenesulfonyl chloride (p-TsCl) and the base is potassium hydroxide (KOH). 60. The method comprises the step of: [ka] or a deuterated derivative of a compound of formula X, or a salt of any of the foregoing, to compound 3, or a deuterated derivative of compound 3, or a salt of any of the foregoing, wherein X 1 The method of any one of embodiments 52-59, wherein is selected from F, Cl, and Br. 61.X 1 The method of embodiment 60, wherein is Cl. 62. The method according to embodiment 60 or 61, wherein the conversion of the compound of formula X, or the deuterated derivative of the compound of formula X, or a salt of any of the foregoing, to compound 3, or the deuterated derivative of compound 3, or a salt of any of the foregoing, is carried out in the presence of thiourea and a protic acid. 63. The protic acids hydrochloric acid (HCl), acetic acid (AcOH), and sulfuric acid (H 2 SO 4 63. The method of embodiment 62, wherein said compound is selected from the group consisting of 64. The method of embodiment 62 or 63, wherein the protic acid is hydrochloric acid (HCl). 65. The method comprises the steps of: [ka] or a deuterated derivative of hex-5-en-2-one, or a salt of any of the foregoing, to a compound of formula X, or a deuterated derivative of a compound of formula X, or a salt of any of the foregoing, wherein X 1 The method of any one of embodiments 60-64, wherein is selected from F, Cl, and Br. 66. A process for converting hex-5-en-2-one, or a deuterated derivative of hex-5-en-2-one, or a salt of any of the foregoing, to a compound of formula X, or a deuterated derivative of a compound of formula X, or a salt of any of the foregoing, comprising the steps of: (i) reacting hex-5-en-2-one, or a deuterated derivative of hex-5-en-2-one, or a salt of any of the foregoing, with a methylmagnesium halide, or a deuterated derivative of a methylmagnesium halide, or a salt of any of the foregoing; (ii) reacting the product of step (i) with 2-haloacetonitrile or a deuterated derivative of 2-haloacetonitrile, forming a compound of formula X, or a salt of any of the foregoing, wherein X 1 66. The method of embodiment 65, wherein is selected from F, Cl, and Br. 67. The method of embodiment 66, wherein the methylmagnesium halide is selected from methylmagnesium chloride (MeMgCl), methylmagnesium bromide (MeMgBr), and methylmagnesium iodide (MeMgI). 68. The method of embodiment 66 or 67, wherein the methylmagnesium halide is methylmagnesium chloride (MeMgCl). 69. The method of any one of embodiments 66-68, wherein the 2-haloacetonitrile is selected from 2-fluoroacetonitrile, 2-chloroacetonitrile, and 2-bromoacetonitrile. 70.X 1 The method of any one of embodiments 66-69, wherein is Cl and the 2-haloacetonitrile is 2-chloroacetonitrile. 71.X 1The method of any one of embodiments 66-70, wherein is Cl, the methylmagnesium halide is methylmagnesium chloride (MeMgCl), and the 2-haloacetonitrile is 2-chloroacetonitrile. 72. Compound I, [ka] or a stereoisomer of compound I, or a deuterated derivative of compound I or a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, the method comprising: reacting a compound of formula I, formula II, or formula III: [ka] or a stereoisomer of a compound, or a deuterated derivative of a compound or a stereoisomer thereof, or a salt of any of the foregoing, to Compound I, or a stereoisomer of Compound I, or a deuterated derivative of Compound I or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -R a is selected from alcohol protecting groups; The compound of formula I, formula II or formula III is N'-[(2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide, (6R)-6-benzyloxy-12,12-dimethyl-17-nitro-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,8,14,16-hexane (E / Z mixture), N'-[(2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide, 12,12-bis(trideuteriomethyl)-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexane (E / Z mixture), and pharma- ceutically acceptable salts thereof. 73.R a The method of embodiment 72, wherein is benzyl (Bn). 74. A compound selected from the following formulas: [ka] or a stereoisomer of the compound, or a deuterated derivative of the compound or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, -R a is selected from alcohol protecting groups; the compound of formula I, II or III is N'-[(2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide, (6R)-6-benzyloxy-12,12-dimethyl-17-nitro-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,8,14,16-hexane (E / Z mixture), N'-[(2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]-6-[1,1-bis(trideuteriomethyl)but-3-enylamino]-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide, (6R)-6-benzyloxy-17-nitro-12,12-bis(trideuteriomethyl)-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexane (E / Z mixture), and a pharma- ceutically acceptable salt thereof, or a stereoisomer of the compound, or a deuterated derivative of the compound or a stereoisomer thereof, or a salt of any of the foregoing. 75. A compound selected from the following formulas: [ka] or a stereoisomer of the compound, or a deuterated derivative of the compound or a stereoisomer thereof, or a salt of any of the foregoing, wherein R a is selected from an alcohol protecting group, or a stereoisomer of the compound, or a deuterated derivative of the compound or a stereoisomer thereof, or a salt of any of the foregoing. 76.R a The compound according to embodiment 74 or 75, wherein is benzyl (Bn). 77. A compound having the formula: [ka] or a stereoisomer of the compound, or a deuterated derivative of the compound or a stereoisomer thereof, or a salt of any of the foregoing. 78. Compound I, [ka] or a stereoisomer of compound I, or a deuterated derivative of compound I or a stereoisomer thereof, or a pharma- ceutically acceptable salt of any of the foregoing, the method comprising: [ka] or a stereoisomer of a compound of formula XI, or a deuterated derivative of a compound of formula XI or a stereoisomer thereof, or a salt of any of the foregoing, into compound I, or a stereoisomer thereof, or a deuterated derivative of compound I or a stereoisomer thereof, or a salt of any of the foregoing, During the ceremony, R a is selected from alcohol protecting groups; R 1 But -N(Boc) 2 , -NHBoc, -N(Phth), -NH(Cbz), and -NO 2 A method selected from the group consisting of 79.R a The method of embodiment 78, wherein is benzyl (Bn). 80. The method according to embodiment 78 or 79, wherein converting the compound of formula XI, or a stereoisomer of the compound of formula XI, or a deuterated derivative or stereoisomer thereof, or a salt of any of the foregoing, to compound I, or a stereoisomer thereof, or a deuterated derivative or stereoisomer of compound I, or a salt of any of the foregoing, comprises a reaction carried out in the presence of reducing reaction conditions. 81. The reduction conditions are hydrogen gas (H 2 ), palladium on carbon (Pd / C), and methanolic ammonia (NH 3 / MeOH); hydrogen gas (H 2 ), palladium on carbon (Pd / C), and ethanolic ammonia (NH 3 / EtOH); Hydrogen gas (H 2 ), palladium alumina (Pd / Al), and methanolic ammonia (NH 3 / MeOH); hydrogen gas (H 2 ), palladium alumina (Pd / Al), and methanolic ammonia (NH 3 / EtOH); Hydrogen gas (H 2 ), platinum on carbon (Pt / C), and methanolic ammonia (NH 3 / MeOH); hydrogen gas (H 2 ), platinum on carbon (Pt / C), and ethanolic ammonia (NH 3 / EtOH); Hydrogen gas (H 2 ), platinum alumina (Pt / Al), and methanolic ammonia (NH 3 / MeOH); hydrogen gas (H 2 ), platinum alumina (Pt / Al), and methanolic ammonia (NH 3 / EtOH); Hydrogen gas (H 2 ), ruthenium on carbon (Ru / C), and methanolic ammonia (NH 3 / MeOH); hydrogen gas (H 2 ), ruthenium on carbon (Ru / C), and ethanolic ammonia (NH 3 / EtOH); Hydrogen gas (H 2 ), ruthenium alumina (Ru / Al), and methanolic ammonia (NH 3 / MeOH); and hydrogen gas (H 2 ), ruthenium alumina (Ru / Al), and methanolic ammonia (NH 3 81. The method of embodiment 80, wherein the aqueous solution is selected from the group consisting of ethanol, ethyl alcohol, ethyl acetate, ethyl ether, ethyl glycerol, ethyl ether ... 82. The reduction conditions are hydrogen gas (H 2 ), palladium on carbon (Pd / C), and methanolic ammonia (NH 3 82. The method of embodiment 80 or 81, wherein the aryl ether is 0.1 to 0.5 wt %. 83. The method of any one of embodiments 78-82, wherein converting the compound of formula XI, or a stereoisomer of the compound of formula XI, or a deuterated derivative of the compound of formula XI or a stereoisomer thereof, or a salt of any of the foregoing, to compound I, or a stereoisomer thereof, or a deuterated derivative of compound I or a stereoisomer thereof, or a salt of any of the foregoing, further comprises a reaction carried out in the presence of an acid. 84. The acids are trifluoroacetic acid (TFA), hydrochloric acid (HCl), methanesulfonic acid (MsOH), phosphoric acid (H 3 PO 4 ), and sulfuric acid (H 2 SO 4 84. The method of embodiment 83, wherein said compound is selected from the group consisting of 85. The method of embodiment 83 or 84, wherein the acid is trifluoroacetic acid (TFA). 86. The method comprises the step of: [ka] or a stereoisomer of a compound of formula XII, or a deuterated derivative of a compound of formula XII or a stereoisomer thereof, or a salt of any of the foregoing, to a compound of formula XI, or a stereoisomer thereof, or a deuterated derivative of a compound of formula XI or a stereoisomer thereof, or a salt of any of the foregoing, wherein R a is selected from alcohol protecting groups; R 1 But -N(Boc) 2 , -NHBoc, -N(Phth), -NH(Cbz), and -NO 2 The method according to any one of embodiments 78 to 85, wherein the method is selected from the group consisting of: 87.R a The method of embodiment 86, wherein is benzyl (Bn). 88. The method according to embodiment 86 or 87, wherein converting the compound of formula XII, or a stereoisomer of the compound of formula XII, or a deuterated derivative or stereoisomer thereof, or a salt of any of the foregoing, into a compound of formula XI, or a stereoisomer thereof, or a deuterated derivative or stereoisomer of the compound of formula XI, or a salt of any of the foregoing, comprises a reaction carried out in the presence of a ruthenium catalyst. 89. Ruthenium catalysts include dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II) (Zahn 1B catalyst), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), dichloro[1,3-bis(2,6-isopropylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II);(1,3-dimesitylimidazolidin-2-ylidene)dichloro(2-isopropoxy-5-nitrobenzylidene)ruthenium(II), dichloro 89. The method of embodiment 88, wherein the cation exchanger is selected from (3-phenyl-1H-inden-1-ylidene)bis(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](3-phenyl-1H-inden-1-ylidene)(tricyclohexylphosphine)ruthenium(II), and dichloro(2-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium(II). 90. The method of embodiment 88 or 89, wherein the ruthenium catalyst is dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II) (Zahn 1B catalyst). 91. The method comprises the step of: [ka] or a deuterated derivative of compound 2, or a salt of any of the foregoing, with a compound of formula IV, [ka] or a stereoisomer of a compound of formula IV, or a deuterated derivative of a compound of formula IV or a stereoisomer thereof, or a salt of any of the foregoing, to produce a compound of formula III, or a stereoisomer thereof, or a deuterated derivative of a compound of formula III or a stereoisomer thereof, or a salt of any of the foregoing, wherein R a is selected from alcohol protecting groups; R 1 But -N(Boc) 2 , -NHBoc, -N(Phth), -NH(Cbz), and -NO 2 The method according to any one of embodiments 78 to 90, wherein the method is selected from the group consisting of: 92.R a The method of embodiment 91, wherein is benzyl (Bn). 93. The method according to embodiment 91 or 92, wherein reacting the compound of formula XIII, or the deuterated derivative of formula XIII, or a salt of any of the foregoing, with the compound of formula IV, or a stereoisomer of the compound of formula IV, or the deuterated derivative of the compound of formula IV or a stereoisomer thereof, or a salt of any of the foregoing, is carried out in the presence of a peptide coupling agent and a base. 94. The method of embodiment 93, wherein the peptide coupling agent is selected from 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 1,1-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide (CMPI), 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholinomethylene)]methanaminium hexafluorophosphate (COMU), isobutyl chloroformate (IBCF), and propanephosphonic anhydride (T3P). 95. The method of embodiment 93 or 94, wherein the peptide coupling agent is propylphosphonic anhydride (T3P). EXAMPLES

[0209] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] General Solid-State NMR (SSNMR) Methods A Bruker-Biospin 400 MHz wideband spectrometer equipped with a Bruker-Biospin 4 mm HFX probe was used. Samples were prepared using a 4 mm ZrO 2 The rotor was loaded and spun under magic angle spinning (MAS) conditions with the spinning speed typically set at 12.5 kHz. 13 To set the characteristic recycle delay for a C cross-polarization (CP) MAS experiment, the proton relaxation time is 1 H MAS T 1 Measured using saturation recovery relaxation experiments. 19 To set the characteristic recycle delay for the F MAS experiment, the fluorine relaxation time is 19 F MAS T 1 Measurements were made using a saturation recovery relaxation experiment. The CP contact time for the carbon CPMAS experiment was set to 2 milliseconds (ms). CP proton pulses with a linear ramp (50%-100%) were used. The Hartmann-Hahn match at carbon was optimized with an external reference sample (glycine). Both carbon and fluorine spectra were recorded with proton decoupling using a TPPM15 decoupling sequence at a field strength of approximately 100 kHz.

[0210] General Thermogravimetric Analysis (TGA) Methods TGA was used to investigate the presence of residual solvents in the characterized lots and to identify the temperature at which sample decomposition occurs. Unless otherwise provided in the following examples, TGA data was collected on a TA instrument Discovery series equipped with a TRIOS system. TGA data for neat amorphous Compound I was collected on a Mettler Toledo TGA / DSC 3+STARe system. General Differential Scanning Calorimetry (DSC) Methods

[0211] Unless otherwise provided in the following examples, the melting point or glass transition point of the material was measured using a Mettler Toledo TGA / DSC 3+STARe system. DSC data of Compound I methanol solvate (dry) and Compound I p-toluenesulfonic acid were collected on a TA instrument Discovery series equipped with a TRIOS system.

[0212] Example 1: Preparation of (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (Compound I) [ka] Step 1: Methyl 6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate [ka] 2-Methylhex-5-en-2-amine (hydrochloride salt) (69.4 g, 463.7 mmol) was suspended in acetonitrile (960 mL) and treated with DIEA (220 mL, 1.263 mol). To the formed brown solution was added methyl 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (120 g, 421.7 mmol) in one portion. The orange solution was slowly heated to 65° C. over 2.5 hours (Note: the reaction is exothermic on heating). The deep orange solution was evaporated at 40° C. and to the residue was added MTBE (1 L) and water (1 L) and the layers were separated. The deep orange organic phase was washed with saturated aqueous NH 4 After washing with a 1:1 solution of Cl / water mixture (2×600 mL) and once with brine (400 mL), the organic phase was dried, filtered and evaporated to give methyl 6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (152.7 g, 100%). ESI-MS m / z calculated 361.12494, found 362.0 (M+1). + ; Retention time: 3.02 minutes (LC method D).

[0213] Step 2: 6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid [ka] Methyl 6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (152.4 g, 421.7 mmol) was dissolved in methanol (750 mL) and treated with NaOH (750 mL of 2M, 1.500 mol) with stirring (added all at once, resulting in a slight exotherm of 30°C to 40°C). The solution was stirred at room temperature for 18 h. The deep red solution was concentrated under reduced pressure at 42°C and the resulting orange-red solution was treated with toluene (1 L). The emulsion was stirred in an ice bath and acidified to pH = 1 by addition of HCl (260 mL 6M, 1.560 mol) while keeping the internal temperature below 15°C. The phases were separated and the organic phase was washed twice with water (2 x 500 mL) and once with brine (400 mL). The organic phase was washed twice with water (2 x 500 mL) and once with brine (400 mL). The organic phase was washed twice with MgSO 4 The mixture was dried at rt, filtered, evaporated, and dried under vacuum to give 137 g of a deep orange solid mass. This material was evaporated from acetonitrile (ca. 1 L, to remove residual toluene), dissolved in acetonitrile (600 mL) and warmed to ca. 60° C. To the deep red hot solution was added N-cyclohexylcyclohexanamine (79 mL, 396.5 mmol) with stirring (an exotherm was observed at 60° C.-70° C.) and the hot solution was seeded with crystals. The material became a solid mass at an internal temperature of ca. 60° C., which could be magnetically stirred after breaking down. The thick suspension was stirred overnight in a cold warm water bath and then in an ice bath for 3 h. The solid was collected by filtration, washed with cold acetonitrile until the filtrate was colorless, and dried over the weekend to give 6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid (dicyclohexylamine salt) (172 g, 77%) as a yellow solid. This salt was suspended in MTBE (1 L) and treated with citric acid (1.2 L of 1 M, 1.200 mol). The mixture was stirred and the phases separated. The organic phase was washed twice more with 1 M citric acid (2 x 400 mL) and 0.5 M KHSO. 4(4×400 mL) four times. The organic phase was then washed once with brine (200 mL), dried, filtered and evaporated to give 6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid (113.4 g, 77%) as a yellow-orange oil that crystallized on standing. 1 H NMR(400MHz,DMSO-d6)δ 14.21(s,1H),8.46(s,1H),6.20-6.00(m,1H),5.82-5.57(m,1H),5.13-4.74(m,2H),1.97(d,J=2.9Hz,4H),1.45(s,6H)ppm.ESI-MS m / z Calculated value 347.10928, actual value 348.0 (M+1) + ; Retention time: 2.49 minutes (LC method D).

[0214] Step 3: N'-[(2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide [ka] 6-(1,1-Dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid (100 g, 285.1 mmol) and (2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (86.3 g, 299.4 mmol) were dissolved in DMF (600 mL) and cooled in an ice bath. At an internal temperature of 3.1 °C, HATU (114 g, 299.8 mmol) was added in one portion (no exotherm was observed). DIEA (100 mL, 574.1 mmol) was then added slowly over 0.5 h, keeping the internal temperature at 3-10 °C (exothermic). After addition, the ice bath was removed and the reaction was stirred for an additional 0.5 h, allowing it to warm to room temperature. The orange solution was added to a stirred solution of ice and water (3 L) and MTBE (1 L). The mixture was stirred for 10 min and the phases were separated. The organic phase was washed twice with water (2×1 L) and 0.2 M KHSO 4(3×1 L) and once with brine (250 mL). The organic phase was dried, filtered and evaporated to give N′-[(2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide (181 g, quantitative yield) as an orange mass. ESI-MS m / z calculated 617.2073, found 618.0 (M+1). + retention time: 3.25 min (LC Method D). This material was used directly in the next step.

[0215] Step 4: 6-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-N-(1,1-dimethylpent-4-enyl)-5-nitro-3-(trifluoromethyl)pyridin-2-amine [ka] N'-[(2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide (176.1 g, 285.2 mmol) was dissolved in acetonitrile (1.4 L) and heated to 55° C. The yellow-orange solution was treated with DIEA (124 mL, 711.9 mmol) followed by the addition of tosyl chloride (54.4 g, 285.3 mmol) in portions over 15 min (exothermic, removed heating mantel and kept internal temperature between 55° C. and 60° C. by slow addition) and the reaction stirred at 55° C. for 45 min. The reaction solution was concentrated under reduced pressure at 40° C. and the residue was extracted with 1:1 MTBE / heptane (1.4 L) and water (1.4 L). The organic phase was washed once more with water (1.5 L) and 0.2 M KHSO 4The mixture was washed twice with hexane (2×1 L) and once with brine (0.5 L). The organic phase was dried, filtered and evaporated to give 172 g of an orange oil, which was dissolved in 100 mL of toluene and 300 mL of heptane. The solution was loaded onto a 3 kg silica column (column volume=4800 mL, flow rate=900 mL / min). Eluted with 100% hexane for 1 min, with an initial gradient of 0% to 10% ethyl acetate in hexane over 106 min (2 column volumes). The product begins to elute at approximately 4% ethyl acetate and isocratically held at 4.3% ethyl acetate until the product has ceased elution to give 6-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-N-(1,1-dimethylpent-4-enyl)-5-nitro-3-(trifluoromethyl)pyridin-2-amine (139.1 g, 80%). 1 H NMR(400MHz,chloroform-d)δ 8.51(s,1H),7.40-7.27(m,5H),6.03-5.87(m,1H),5.80-5.66(m,1H),5.58(s,1H),5.31-5.16(m,2H),5.03-4.95(m,1H),4.95-4.89(m ,1H),4.81(d,J=10.5Hz,1H),4.64(d,J=10.5Hz,1H),3.28-3.13(m,2H),2.08-1.99(m,2H),1.99-1.89(m,2H),1.47(s,6H)ppm.ESI-MS m / z Calculated value 599.1967, measured value 600.0 (M+1) + ; Retention time: 3.71 minutes (LC method D).

[0216] Step 5: (6R)-6-Benzyloxy-12,12-dimethyl-17-nitro-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,8,14,16-hexaene (E / Z mixture) [ka] The reaction was carried out in parallel in three 46.3 g batches, each in a 12 L three-neck round bottom flask. The following experiment describes one of these batches.

[0217] A sparging tube reflux condenser equipped with a gas bleeder and overhead stirrer was attached to a 12 L vessel placed in a heat blanket. 6-[5-[(1R)-1-benzyloxy-1-(trifluoromethyl)but-3-enyl]-1,3,4-oxadiazol-2-yl]-N-(1,1-dimethylpent-4-enyl)-5-nitro-3-(trifluoromethyl)pyridin-2-amine (46.3 g, 76.22 mmol) was dissolved in DCE (8.23 L). The system was sparged with a strong stream of nitrogen gas. The heat blanket was set at 50° C. When the vessel reached 53° C., dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II) (Zhan catalyst-1B, 11.2 g, 15.26 mmol) was added all at once. The catalyst vessel was rinsed with DCE and the rinse was added to the reaction. Upon completion of catalyst addition, the blanket temperature was increased to 73° C. When the internal temperature reached 72° C., stirring was continued for 2 hours 28 minutes and then the heat blanket temperature was reduced to 45° C. After 2 hours 27 minutes, the internal temperature reached 50° C. After 15 minutes, solid 2-sulfanylpyridine-3-carboxylic acid (12 g, 77.33 mmol) and triethylamine (11 mL, 78.92 mmol) were added. Stir for 12 hours and then allow the mixture to cool to room temperature. 2and 10 g of activated charcoal (20-40 mesh, granular) were added to the reaction. Stirred for 1 hour, then filtered over Celite and the filtrate was evaporated to give a crude product mixture. The material from all three parallel reactions was combined to give 71.2 g of crude product mixture. This material was purified on two separate 3 kg silica gel columns using a gradient of 100% hexane to 10% ethyl acetate in hexane over 110 minutes, followed by a gradient of 10% ethyl acetate in hexane to 100% ethyl acetate over 10 minutes. After combining the two separate purified batches, (6R)-6-benzyloxy-12,12-dimethyl-17-nitro-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,8,14,16-hexaene (E / Z mixture) (51.88 g, 40%) was obtained. 1 H NMR(400MHz,DMSO-d6)δ 8.55(d,J=0.8Hz,1H),7.49-7.21(m,5H),6.58(s,1H),5.79(dt,J=13.7,6 .5Hz,1H),5.58(ddd,J=15.0,8.8,5.6Hz,1H),4.83(d,J=11.1Hz,1H),4.5 5(d,J=11.1Hz,1H),3.13(dd,J=14.2,5.4Hz,1H),2.77(dd,J=14.3,8.8Hz ,1H),2.38-2.24(m,1H),2.14-1.93(m,3H),1.58-1.32(m,6H)ppm.ESI-MS m / z Calculated value 571.1654, measured value 572.1 (M+1) + retention times: 3.46 min and 3.49 min (LC Method D). The product was formed as a 3:1 mixture of double bond isomers.

[0218] Step 6: (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (compound I) and its enantiomers [ka] (6R)-6-Benzyloxy-12,12-dimethyl-17-nitro-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,8,14,16-hexaene (E / Z mixture) (50.8 g, 88.89 mmol) was dissolved in 250 mL of ethanol, partially concentrated by rotary evaporation using a 28° C. water bath to remove any residual solvent, and then dissolved in additional ethanol (720 mL) in a 5 L flask. The solution was degassed using five cycles of house vacuum with backfilling of nitrogen gas. Dihydroxypalladium (15.2 g of 10% w / w, 10.824 mmol) was added to the substrate solution under nitrogen. The nitrogen atmosphere was replaced with hydrogen by repeating the house vacuum with backfilling of hydrogen for six cycles. Finally, a balloon was used to keep the vessel under 1 atmosphere of hydrogen. The mixture was vigorously stirred overnight with a magnetic stirrer, and then the hydrogen balloon was removed. The mixture was filtered through 70 g of Celite on a center fritted funnel. The green filtrate solution was concentrated by rotary evaporation using a 28° C. water bath. 42.65 g of crude product was obtained as a yellow solid, of which 41.5 g was purified by reverse phase chromatography (dissolved in 125 mL of methanol and 2.55 mL of DMF (2% DMF / methanol solution) and concentrated with 3.8 kg C 18The column was loaded (column volume = 3.3 L, flow rate = 375 mL / min). An initial gradient of 40% to 70% acetonitrile in water over 176 min was programmed (20 column volumes), then the eluent was 100% acetonitrile over the next approximately 20 min). Mixed and pure fractions were isolated from the column. The pure fractions were concentrated to give (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (28.17 g, 70%) as a yellow solid. This material was combined with several smaller batches (80 mg, 340 mg, 360 mg, 1.46 g, and 1.63 g) made by a similar method as a solution in acetonitrile, which was then concentrated to give a yellow solid. This solid was dissolved in dichloromethane, heptane was added, and the solution was then concentrated overnight at 40° C. under vacuum in the dark to give 31.95 g of (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12.5]nonadeca-1(18),2,4,14,16-pentaen-6-ol. 1 H NMR (400MHz, DMSO-d 6 )δ 7.61(s,1H),7.59(s,1H),5.96(s,2H),4.64(s,1H),2.90-2.71(m,1H),2.30-2.15(m,1H),2.15-1.9 8(m,1H),1.91-1.74(m,1H),1.73-1.57(m,1H),1.56-1.38(m,5H),1.36(s,3H),1.31(s,3H).ESI-MS m / z calculated value 453.15994, measured value 454.2(M+1) + ; Retention time: 3.03 minutes (LC method D).

[0219] One mixed fraction from the reverse phase purification described above contained an impurity that exhibited a mass one unit greater than the intended product described above. This fraction was concentrated and the residue was dissolved in 3.6 mL of methanol and then purified using a gradient of 1-99% acetonitrile in water (+HCl modifier). 18 Purification by reverse phase preparative HPLC through a column afforded (6R)-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12.5]nonadeca-1(18),2,4,14,16-pentaene-6,17-diol (105 mg, 0.003%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 10.43(s,1H),7.64(s,1H),7.57(s,1H),4.85(s,1H),2.91-2.74(m,1H),2.30-2.15(m,1H),2.10-1.96 (m,1H),1.85-1.68(m,1H),1.68-1.54(m,1H),1.53-1.37(m,5H),1.36(s,3H),1.31(s,3H)ppm.ESI-MS m / z calculated value 454.14395, actual value 455.2(M+1) + ; Retention time: 2.87 minutes (LC method D).

[0220] Step 7: Solid-state morphological characterization of crystalline Compound I Form A (neat) A. Powder X-ray Diffraction The XRPD diffractogram of crystalline Compound I Form A (neat) produced by Step 6 and recrystallized from EtOH was obtained using conventional X-ray powder diffraction (XRPD) methods. The XRPD diffractogram of crystalline Compound I Form A (neat) is provided in Figure 1 and the XRPD data is summarized below. [Table 6]

[0221] B. Differential Scanning Calorimetry Analysis DSC data was collected at a 10.00° C. / min ramp to 250.00° C. A DSC thermogram of crystalline Compound I Form A (neat) produced by step 6 is provided in FIG. 2. The thermogram shows a Tm onset of 180.8° C. with a Tm peak at 183.18° C., 62.32 J / g.

[0222] Example 2: Biological activity of Compound I Ussing chamber assay of CFTR-mediated short-circuit current Ussing chamber experiments were performed using human bronchial epithelial (HBE) cells derived from CF subjects heterozygous for F508del and minimally functional CFTR mutations (F508del / MF-HBE) and cultured as previously described (Neuberger T, Burton B, Clark H, Van Goor F Methods Mol Biol 2011:741:39-54). After 4 days, the apical media was removed and cells were grown at an air-liquid interface for >14 days before use. This resulted in a monolayer of ciliated, well-differentiated columnar cells, a characteristic feature of human bronchial airway epithelium.

[0223] CFTR-mediated short circuit (I SC ) To isolate electrical current, F508del / MF-HBE grown on Costar® Snapwell™ cell culture inserts were mounted in an Ussing chamber and transepithelial I SC Voltage clamp recording conditions (V hold = 0 mV) at 37°C. The basolateral solution was 145 mM NaCl, 0.83 mM K 2 HPO 4 , 3.3 mM KH 2 PO 4 , 1.2 mM MgCl 2 , 1.2 mM CaCl 2 The apical membrane solution contained 145 mM NaGluconate, 1.2 mM MgCl 2 , 1.2 mM CaCl 2The medium contained 10 mM glucose, 10 mM HEPES (pH adjusted to 7.4 with NaOH), and 30 μM amiloride to block epithelial sodium channels. Forskolin (20 μM) was added to the apical membrane to activate CFTR, and then a CFTR inhibitor cocktail consisting of BPO, GlyH-101, and CFTR inhibitor 172 (final assay concentration of 20 μM each) was added to the apical membrane to specifically insulate CFTR currents. CFTR-mediated I SC (μA / cm 2 ) was determined from the peak forskolin response to steady-state current after inhibition.

[0224] Identification of potentiator compounds CFTR-mediated I SC The activity of CFTR potentiator compounds against CFTR was determined in the Ussing chamber assay described above. F508del / MF-HBE cell cultures were cultured with 10 μM (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6 The cells were incubated with a range of concentrations of potentiator compounds in combination with -thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione in the presence of 20% human serum for 18-24 hours at 37°C. The potentiator compounds and (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ-(2-methyl-1H-pyrazole)-1H-pyrazole ... 6 -Thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione concentrations in CFTR-mediated I SCwas kept constant throughout the Ussing chamber measurements to ensure compound presence throughout the experiment. The potency and efficacy of the putative F508del potentiator was compared to that of the known Vertex potentiator, Ivacaftor (N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide).

[0225] The CFTR modulating activity of Compound I using the assay described in this Example was found to be <500 nM EC 50 had.

[0226] Example 3: Crystalline forms of Compound I 1. Methanol solvate of compound I (wet) A. Synthesis Procedure A 30 mL vial with a magnetic stir bar was charged with neat Form A of Compound I (0.15 g), water (1.1 mL), and methanol (3.3 mL). The sealed vial was heated to 65° C. When the slurry solution became homogeneous, the heating block was turned off and stirring was stopped. The solution was allowed to cool naturally without stirring. The solution self-nucleated within 1 hour and the unstirred solution was kept cooled and left at room temperature for 3 days.

[0227] B. Powder X-ray diffraction X-ray powder diffraction (XRPD) diffractograms of the methanol solvate (wet) powder of Compound I were acquired in transmission mode at room temperature using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel 1D Medipix-3 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X-ray generator was operated with copper radiation (1.54060 Å) at a voltage of 45 kV and a current of 40 mA. Powder samples were placed on a 96-well sample holder with mylar film and loaded into the instrument. Samples were scanned over the range of about 3° to about 40° 2θ with a step size of 0.0131303° and 49 seconds per step. The results are shown in FIG. 3 and summarized in the table below. [Table 7]

[0228] C. Single crystal analysis Single crystals of compound I were obtained with the methanol solvate (wet) structure. X-ray diffraction data were obtained using Cu K α The results were obtained using a Rigaku diffractometer equipped with radiation (λ = 1.54178 Å) and a CMOS detector at 100 K. The structure was solved and refined using the SHELX program (Sheldrick, GM, ActaCryst., (2008) A64, 112-122), and the results are summarized below. [Table 8]

[0229] D. Solid-State NMR 13 The results of C CPMAS SSNMR are shown in Figure 4. 19 The F MAS SSNMR results are shown in Figure 5 and summarized below. [Table 9] [Table 10]

[0230] 2. Methanol solvate of compound I (dried) A. Synthesis Procedure A 30 mL vial with a magnetic stir bar was charged with neat Form A of Compound I (0.15 g), water (1.1 mL), and methanol (3.3 mL). The sealed vial was heated to 65° C. When the slurry solution became homogeneous, the heating block was turned off and stirring was stopped. The solution was allowed to cool naturally without stirring. The solution self-nucleated within 1 hour, and the unstirred solution was continued to cool and stand at room temperature for 3 days. The sample was then placed in a vacuum drying oven at 60° C. overnight.

[0231] B. Powder X-ray diffraction X-ray powder diffraction (XRPD) diffractograms of the methanol solvate (dried) powder of Compound I were acquired in transmission mode at room temperature using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel 1D Medipix-3 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X-ray generator was operated with copper radiation (1.54060 Å) at a voltage of 45 kV and a current of 40 mA. Powder samples were placed on a 96-well sample holder with mylar film and loaded into the instrument. Samples were scanned over the range of about 3° to about 40° 2θ with a step size of 0.0131303° and 49 seconds per step. The results are shown in FIG. 6 and summarized in the table below. [Table 11]

[0232] C. Thermogravimetric analysis Thermogravimetric analysis of the methanol solvate (dry) of Compound I was measured using a TA5500 Discovery TGA. The TGA thermogram (FIG. 7) shows a weight loss of about 1.2% from ambient temperature to about 182° C.

[0233] D. Differential Scanning Calorimetry Analysis The melting point of the methanol solvate (dry) of Compound I was measured using a TA Instruments Q2000 DSC. The thermogram (Figure 8) showed endotherms at about 175°C and about 186°C.

[0234] 3. Compound I p-Toluenesulfonic Acid A. Synthesis Procedure Compound I neat form A (approximately 45.3 mg) and approximately 17.2 mg of p-toluenesulfonic acid were weighed into a Prisse ball mill (2 mL) tube. A methanol:water mixture (60:40 v / v) (10 μl) was added to the tube. The mixture was ball milled at 7500 rpm for three cycles (60 seconds, 10 seconds pause). The material was then vacuum dried in a vacuum drying oven at 40° C.

[0235] B. Powder X-ray diffraction X-ray powder diffraction (XRPD) diffractograms of the p-toluenesulfonic acid powder of compound I were acquired in transmission mode at room temperature using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel 1D Medipix-3 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X-ray generator was operated with copper radiation (1.54060 Å) at a voltage of 45 kV and a current of 40 mA. Powder samples were placed on a 96-well sample holder with mylar film and loaded into the instrument. Samples were scanned over the range of about 3° to about 40° 2θ with a step size of 0.0131303° and 49 seconds per step. The results are shown in FIG. 9 and summarized in the table below. [Table 12]

[0236] C. Differential Scanning Calorimetry Analysis The melting point of the p-toluenesulfonic acid of Compound I was measured using a TA Instruments Q2000 DSC. The thermogram (FIG. 10) showed endotherms at about 175° C. and about 186° C.

[0237] D. Solid-State NMR Regarding compound I, p-toluenesulfonic acid, 13 The results of C CPMAS SSNMR are shown in FIG. 19 The F MAS SSNMR is shown in Figure 12 and summarized below. [Table 13] [Table 14]

[0238] 4. Neat Amorphous Compound I A. Synthesis Procedure Neat amorphous material of Compound I was prepared using a Mettler Toledo TGA / DSC 3+STARe system. Approximately 8 mg of neat Compound I Form A was weighed in triplicate onto the DSC pan. The temperature was increased to 200° C. at a rate of 10° C. per minute and then cooled to 10° C. The amorphous material was collected from the DSC pan.

[0239] B. Powder X-ray diffraction XRPD patterns were recorded at room temperature in continuous mode using a PANalytical Empyrean X-ray diffractometer (Almelo, The Netherlands). X-rays were generated using a Cu tube operated at 45 kV and 40 mA. A Pixel 1d detector was used with anti-scatter slit P8. The divergence optics was a Bragg Brentano type High Definition (BBHD) with a 10 mm mask, 1 / 8 divergence slit, and 1 / 2 anti-scatter slit. The continuous scan mode integrated over a range of 4 to 40 degrees 2-theta using a step size of 0.0131 degrees and a count time of 13.77 seconds per step. Powder samples were placed on the scored area in a zero background holder and flattened with a glass slide. The results are shown in Figure 13.

[0240] C. Thermogravimetric analysis TGA data for neat amorphous Compound I was collected on a Mettler Toledo TGA / DSC 3+STARe system. The thermogram (FIG. 14) showed negligible weight loss from ambient temperature to thermal decomposition.

[0241] D. Differential Scanning Calorimetry Analysis The glass transition temperature of neat amorphous Compound I was measured using the DSC heating / cooling / reheating method. Neat amorphous material of Compound I was made using a Mettler Toledo TGA / DSC 3+STARe system. Approximately 3.5 mg of Compound I Form A was weighed onto the DSC pan. The temperature was increased to 200°C at a rate of 10°C per minute and then cooled to -20°C to produce neat amorphous material. It was then reheated to 200°C to detect the glass transition temperature. The glass transition of neat amorphous Compound I was observed at 64.8°C, and then recrystallization occurred at 110.2°C, resulting in melting at 181.1°C. The DSC thermogram is shown in Figure 15.

[0242] Example 4: Synthesis of bisamide precursors Intermediate 1: Preparation of 2-methylhex-5-en-2-amine hydrochloride (compound 3·HCl) [ka] Step 1: 2-Methylhex-5-en-2-ol (Compound 7) [ka] The reactor was then filled with Et 2 O (1.822 kg, 5.094 L, 15.28 mol, 1.0 equiv.) and Et 2 The reaction mixture was charged with 3.0 M MeMgBr in 20 (9 L). The mixture was cooled to 0° C. with an ice / salt bath. To the reaction mixture was added hex-5-en-2-one (CAS#109-49-9, 1,500 g, 1.77 L, 15.28 mol) dropwise. The addition time was about 4.5 h. After the addition was complete, the ice / salt bath was removed and the mixture was stirred at about 0° C. for 15 min. The reaction mixture was stirred overnight and allowed to warm to room temperature. The reaction mixture was cooled with an ice / water bath while saturated NH 4 The reaction was quenched with aqueous Cl (5 L). The first 2-2.5 L added was exothermic. 2 L of saturated NH 4Aqueous Cl was added to the mixture, causing it to solidify into an unstirrable mass, which became stirrable again upon further addition. MTBE (3 L) was added to the mixture. The organic phase was separated and the aqueous phase (still cloudy with some solids) was diluted with water (3 L) and saturated NH 4 The mixture was diluted with aqueous Cl and mixed with MTBE (5 L) to give an emulsion which was filtered over diatomaceous earth. The filter cake was rinsed with MTBE (5 L). The clear phases were then separated and the aqueous phase was extracted once more with MTBE (3 L). The combined organic phases were washed with brine (5 L) and diluted with Na 2 SO 4 The mixture was dried at rt and filtered. The solvent was removed under reduced pressure (55° C. water bath, reduced to 20 mbar) to give 1,631 g (14.28 mol, 93.5%) as a yellow oil.

[0243] Step 2: 2-Chloro-N-(2-methylhex-5-en-2-yl)acetamide (compound 8) [ka] The reactor was charged with 2-methylhex-5-en-2-ol (4,822.8 g, 42.235 mol) and 2-chloroacetonitrile (17,995 g, 238.3 mol, 5.64 equiv). The mixture was cooled to 2-0°C (thermostat was at 0°C) and sulfuric acid (4,305 g, 42.23 mol, 1 equiv) was added in a small stream. The mixture then began to warm and the internal temperature rose to 58.4°C (thermostat was set at -5°C). When the internal temperature dropped to 38°C, the addition of sulfuric acid was continued (thermostat was set at 20°C). The total addition took 1 hour 45 minutes. The now dark brown mixture was stirred at 24-28°C for an additional hour. The mixture was cooled to 15-17°C and 34.5 L of water was added followed by 30% aqueous NaOH (approximately 8.5 L) until pH 10.2, maintaining the internal temperature below 28°C. The mixture turned beige in color. The mixture was added to MTBE (40 L) with stirring. Phase separation was allowed to slow (approximately 2 hours). The phases were separated and the aqueous phase was extracted with MTBE (20 L). The combined organics were washed with water (5 L) but the phase separation was very slow so 5 L of brine was added resulting in a faster separation. The aqueous phase had a pH of 7-8. The organic phase was washed with 5 L of brine and diluted with Na 2 SO 4 After filtration (combined Na 2 SO 4 The cake was washed with 3 x 3 L of MTBE. 、 The solvent was removed in the reactor under reduced pressure (thermostat set at 60° C., pressure at 180 mbar). Approximately 65 L of solvent was removed. The heat was then set at 70° C. and the less volatile liquids were distilled (down to 15 mbar). When the distillation stopped, the dark red residue was co-evaporated with 2×10.8 L of toluene. The first half of the second batch of toluene collected by distillation was then removed. 1 The second half of the second batch of toluene collected by distillation was sampled for H-NMR, which showed that there was about 1.2% w / w 2-chloroacetonitrile present. 1Sampled for H-NMR, which showed approximately 0.3% w / w 2-chloroacetonitrile was present. Distillation was continued at 70° C. and 15 mbar for another hour, with some crystals appearing on the inside of the glass surface. The reactor was cooled to room temperature under nitrogen. The product (7,834 g) was collected by filtration.

[0244] Step 3: 2-Methylhex-5-en-2-amine hydrochloride (Compound 3 HCl) [ka] A reactor was charged with 2-chloro-N-(2-methylhex-5-en-2-yl)acetamide (3,910 g, 96.8% pure, obtained as 3,785 g, 19.95 mol) and ethanol (43 L). To the stirred red-brown solution was added thiourea (1,825.5 g, 23.98 mol, 1.202 equiv). The red-brown solution was heated to reflux (thermostat set at 100° C.). After 2 h of reflux, IPC-1 indicated nearly complete consumption of starting material. After 2 h 45 min of reflux, IPC-2 indicated complete conversion. The mixture was cooled to 50° C. (done by forced reflux under reduced pressure with thermostat set at 50° C., which took 15 min). To the red-brown solution, acetic acid (3,324 g, 55.35 mol, 2.77 equiv.) was added over 10-15 min, no temperature change was observed. The mixture was refluxed overnight (thermostat set at 100 °C). Reflux was reached after 30-40 min, with a reflux temperature of 82.1 °C. After another 30 min, a white solid precipitated. The mixture was refluxed overnight. An orange suspension was obtained. The mixture was cooled to 15-20 °C (this was done by setting the thermostat at 15 °C and forced reflux under reduced pressure, which took 30 min to reach 28 °C). The suspension was filtered, and the filter cake was rinsed with EtOH (5 × 1 L). The combined filtrate (approximately 57 L) was concentrated under reduced pressure. A red-brown solid mass was obtained, yielding 4,005 g as crude acetate salt.

[0245] The solid mass was dissolved in hot water (9 L) and charged to the reactor, and the flask was rinsed with an additional 1 L of water. DCM (22 L) was added and Na 2 CO 3 (3,355 g) was added in small portions. Up to 1.7-1.8 Kg was added and the mixture remained clear, with further addition giving a beige emulsion. The emulsion was diluted with DCM (22 L), stirred for 30 min and allowed to settle overnight. The mixture was filtered over a pad of diatomaceous earth (approximately 5 cm thick) covered with a layer of sand (approximately 5 cm thick). The liquid was siphoned off the bottom of the reactor and although the organic phase appeared to be well separated already, there was a thick layer of emulsion on top which still contained some organic phase. The wet filter cake was rinsed with 3 L of DCM and this filtrate was used to extract the aqueous phase. The combined organic phase (approximately 49-50 L) was diluted with Na 2 SO 4 The mixture was filtered and the removed solid was washed with 5 L of DCM. Approximately 50 L of the product solution was charged to the reactor (set jacket temperature at -5°C). To the product solution was added 6M HCl in isopropanol (5 L, 30 mol, 1.5 eq) dropwise (internal temperature at start of addition: 2°C). 70 min after addition was complete, the internal temperature was maintained at <6°C. After stirring overnight at 10°C, the solvent was evaporated using a rotary evaporator (water bath at 50°C). The salts started to crash out of solution at 240 mbar. Evaporation was stopped at 50 mbar and the contents of the flask were mixed with MTBE (22 L) and transferred to the reactor. Stirred for 18 h. The product was collected by filtration and washed with MTBE (2 x 2 L) to give a cream-coloured solid. The solid was dried at room temperature under reduced pressure (17 mbar) for 18 h. Yield: 1,833 g (12.25 mol, 61.4%). 1 H NMR(500MHz,DMSO-d6)δ 8.08(s,3H),5.92-5.64(m,1H),5.15-4.87(m,2H),2.21-1.96(m,2H),1.72-1.49(m,2H),1.23(s,6H)ppm.ESI-MS m / z Calculated value 113.1204, actual value 114.5 (M+1) + .

[0246] Intermediate 1: Alternative preparation of 2-methylhex-5-en-2-amine hydrochloride (compound 3·HCl) [ka] Step 1: tert-Butyl 2,2-dimethylaziridine-1-carboxylate (compound 10) [ka] To a solution of tert-butyl N-(2-hydroxy-1,1-dimethyl-ethyl)carbamate (30 g, 155.35 mmol) in diethyl ether (750 mL) was added p-TsCl (35.6 g, 186.73 mmol) and powdered KOH (103 g, 1.5605 mol) at 0° C. The reaction temperature was raised to reflux and stirred for 16 h. Another portion of KOH (17 g, 303 mmol) was added and the reaction was refluxed for an additional 2 h. The reaction was cooled to room temperature and diluted with diethyl ether (500 mL). The solid that formed was removed by filtration through a fritted glass funnel and washed with additional diethyl ether (100 mL). The combined ether filtrates were washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl 2,2-dimethylaziridine-1-carboxylate (24.602 g, 88%) as a clear oil. 1 H NMR (500 MHz, chloroform-d) δ 2.04(s,2H), 1.46(s,9H), 1.28(s,6H) ppm.

[0247] Step 2: tert-Butyl N-(1,1-dimethylpent-4-enyl)carbamate (compound 11) [ka] A reaction flask was charged with THF (205 mL, 2 M, 410 mmol) and allyl(chloro)magnesium in anhydrous THF (200 mL). The solution was cooled to -30°C and copper(I) bromide (dimethylsulfide complex) (28 g, 136.2 mmol) was added. The reaction mixture was stirred at the same temperature for 30 min and then cooled to -78°C. A solution of tert-butyl 2,2-dimethylaziridine-1-carboxylate (24.602 g, 136.49 mmol) in anhydrous THF (200 mL) was added dropwise to the reaction mixture. The reaction was stirred at the same temperature for 30 min and then transferred to a -20°C freezer and stored for 3 h. The reaction was quenched with saturated aqueous ammonium solution (200 mL) at 0°C. The reaction was stirred at room temperature for 10 min and then diluted with diethyl ether (200 mL). The solution was filtered through a pad of Celite and washed with ethanol (100 mL). The two layers were separated and the aqueous layer was extracted with diethyl ether (2×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography using a gradient of 0% to 10% diethyl ether in hexanes to provide tert-butyl N-(1,1-dimethylpent-4-enyl)carbamate (18.6 g, 61%) as a pale yellow liquid. 1 H NMR (500 MHz, chloroform-d) δ 5.82 (ddt, J = 16.8, 10.2, 6.6, 6.6 Hz, 1H), 5.09-4.87 (m, 2H), 4.38 (s, 1H), 2.11-1.98 (m, 2H), 1.79-1.64 (m, 2H), 1.43 (s, 9H), 1.26 (s, 6H) ppm.

[0248] Step 3: 2-Methylhex-5-en-2-amine hydrochloride (compound 3·HCl) [ka] A solution of tert-butyl N-(1,1-dimethylpent-4-enyl)carbamate (26.6 g, 124.7 mmol) and HCl in diethyl ether (350 mL, 2 M, 700 mmol) was stirred at room temperature for 2 days. The solvent was removed and the residue was triturated with hexane to provide 2-methylhex-5-en-2-amine (hydrochloride salt) (15.198 g, 77%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ 8.08(s,3H),5.92-5.64(m,1H),5.15-4.87(m,2H),2.21-1.96(m,2H),1.72-1.49(m,2H),1.23(s,6H)ppm.

[0249] Intermediate 2: 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate methyl (compound 16) [ka] Step 1: Methyl 1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate (compound 13) [ka] Urea hydrogen peroxide (62.7 g, 646.53 mmol) was added in portions to a stirred solution of methyl 5-(trifluoromethyl)pyridine-2-carboxylate (40 g, 191.09 mmol) in 1,2-dichloromethane (300 mL) at 0° C. Trifluoroacetic anhydride (107.70 g, 72 mL, 507.65 mmol) was then added in a cooling bath (CO 2 / acetone bath) at a temperature of -10°C over 30 minutes. The reaction mixture was then stirred at a temperature of 0°C for an additional 30 minutes and then at ambient temperature for 1 hour. The reaction mixture was then poured into cooled ice water (600 mL). The mixture was diluted with dichloromethane (300 mL) and then separated into layers. The aqueous phase was extracted with dichloromethane (2 x 200 mL). The combined organic phase was washed with water (2 x 300 mL) and brine (1 x 200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate (47.6 g, 90%) as a pale yellow solid. 1 H NMR(300MHz,DMSO-d6)δ 8.89(s,1H),8.02-7.90(m,1H),7.86-7.72(m,1H),3.89(s,3H)ppm. 19 F NMR(282MHz,DMSO-d6)δ-62.00(s,3F)ppm.ESI-MS m / z Calculated value 221.02998, Actual value 222.1(M+1) + ; Retention time: 1.24 minutes (LC method A).

[0250] Step 2: Methyl 6-hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate (compound 14) [ka] Trifluoroacetic anhydride (291.62 g, 193 mL, 1.3885 mol) was added dropwise to a mixture of methyl 1-oxide-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate (51.058 g, 230.66 mmol) in DMF (305 mL) at 0° C. The mixture was then stirred at room temperature overnight. The mixture was concentrated under reduced pressure to remove excess trifluoroacetic acid. The remaining DMF solution was poured dropwise into a stirred volume of water (1000 mL) cooled to 0° C. The precipitated solid was collected by filtration and then washed with water (300 mL). The solid was dried under vacuum to give methyl 6-hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate (45.24 g, 86%) as a white solid. 1H NMR (300 MHz, CDCl 3 )δ 7.90(d,J=7.2Hz,1H),7.03(d,J=7.2Hz,1H),4.02(s,3H)ppm. 1 Not a single exchangeable proton was observed in the 1 H NMR. 19 F NMR (282MHz, CDCl 3 ) δ-66.39(s,3F)ppm. ESI-MS m / z calculated 221.03, found 222.1(M+1) + ; Retention time: 1.43 minutes (LC method A).

[0251] Step 3: Methyl 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (compound 15) [ka] To an ice-cold solution of methyl 6-hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate (33.04 g, 149.41 mmol) in sulfuric acid (200 mL at 18.4 M, 3.6800 mol) was added nitric acid (13 mL at 15.8 M, 205.40 mmol) dropwise. After 5 min, the ice bath was removed and the reaction mixture was stirred at 38° C. overnight. As the reaction was not complete, nitric acid (3 mL at 15.8 M, 47.400 mmol) was added dropwise at room temperature and the reaction was heated at 38° C. for 4.5 h. The reaction was slowly poured onto ice-cold water (900 mL) and the mixture was cooled at 0° C. for 15 min. The resulting solid was then isolated by filtration and washed with water (600 mL). The solid was dried under vacuum overnight to give methyl 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (39.49 g, 99%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 8.54(s,1H),3.95(s,3H)ppm. 1 Not a single exchangeable proton was observed in the 1 H NMR. 19 F NMR(282MHz,DMSO-d6)δ-64.56(s,3F)ppm.ESI-MS m / z Calculated value 266.0151, Actual value 267.1(M+1)+ ; Retention time: 1.64 minutes (LC method A).

[0252] Step 4: Methyl 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (compound 16) [ka] A mixture of methyl 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (10 g, 37.575 mmol) and phenyl dichlorophosphate (48.008 g, 34 mL, 227.55 mmol) was heated at 170 °C for 90 min. After cooling to room temperature, the mixture was diluted with ethyl acetate (400 mL) and washed with brine (2 x 200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0% to 15% ethyl acetate in heptane) afforded methyl 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (5.45 g, 50%) as a yellow solid. 1 H NMR (300 MHz, CDCl 3 ) δ 8.75(s,1H),4.07(s,3H)ppm. 19 F NMR (282MHz, CDCl 3 ) δ-64.12 (s, 3F) ppm. ESI-MS m / z calculated 283.9812, found 285.0 (M+1) + ; Retention time: 1.95 minutes (LC method A).

[0253] Intermediate 3: Preparation of 2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (hydrochloride) (compound 22·HCl) [ka] Step 1: Ethyl 2-hydroxy-2-(trifluoromethyl)pent-4-enoate (compound 18) [ka] To a solution of ethyl 3,3,3-trifluoro-2-oxo-propanoate (30 g, 176.38 mmol) in diethyl ether (300 mL) at −78° C., allyl(bromo)magnesium (185 mL of 1 M, 185.00 mmol) was added dropwise over a period of 3 h (internal temperature: −74° C. to −76° C.). The mixture was stirred at −78° C. for 45 min. The dry ice-acetone bath was removed. The mixture was allowed to warm to about 10° C. over a period of 1 h and added to a mixture of 1 M aqueous HCl (210 mL) and crushed ice (400 g) (pH 4). The mixture was extracted with EtOAc and diluted with 5% aqueous NaHCO 3 , washed with brine, and then washed with anhydrous Na 2 SO 4 The mixture was filtered, concentrated, and co-evaporated with hexane to give ethyl 2-hydroxy-2-(trifluoromethyl)pent-4-enoate (42.2 g, 90%) as a pale yellow oil. 1 H NMR (300 MHz, CDCl 3 )δ 1.33(t,J=7.1Hz,3H),2.60-2.79(m,2H),3.84(br.s.,1H),4.24-4.48(m,2H),5.09-5.33(m,2H),5.59-5.82(m,1H)ppm. 19 F NMR (282MHz, CDCl 3 )δ-78.5(s,3F)ppm.

[0254] Step 2: Ethyl 2-benzyloxy-2-(trifluoromethyl)pent-4-enoate (compound 19) [ka] To a solution of ethyl 2-hydroxy-2-(trifluoromethyl)pent-4-enoate (18.56 g, 83.105 mmol) in DMF (100 mL) was added NaH (5.3 g, 60% w / w, 132.51 mmol) at 0° C. The reaction was stirred for 15 min and benzyl bromide (21.14 g, 15 mL, 121.12 mol) and tetrabutylammonium iodide (8.5 g, 23.012 mmol) were added. The mixture was stirred overnight at room temperature. The reaction was quenched with water (300 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine (500 mL) and dried over sodium sulfate. Purification by silica gel chromatography (20% to 60% DCM in hexanes) gave ethyl 2-benzyloxy-2-(trifluoromethyl)pent-4-enoate (22.01 g, 70%) as a colorless oil. 1 H NMR (250 MHz, CDCl 3 )δ 7.55-7.25(m,5H),6.00-5.80(m,1H),5.30-5.10(m,2H),4.86(d,J=10.5Hz,1H),4.68(d,J= 10.5Hz,1H),4.33(q,J=7.0Hz,2H),2.81(d,J=7.0Hz,2H),1.34(t,J=7.1Hz,3H)ppm.ESI-MS m / z calculated value 302.113, actual value 303.5(M+1) + ; Retention time: 4.14 minutes (LC method B).

[0255] Step 3: Ethyl 2-benzyloxy-2-(trifluoromethyl)pent-4-enoate (compound 20) [ka] To a solution of ethyl 2-benzyloxy-2-(trifluoromethyl)pent-4-enoate (28.99 g, 95.902 mmol) in methanol (150 mL) was added a solution of NaOH (7.6714 g, 191.80 mmol) in water (50 mL). The reaction mixture was stirred at 40° C. for 3 h. The reaction mixture was concentrated in vacuo and the residue was diluted with water (200 mL) and washed with diethyl ether (200 mL). The aqueous layer was acidified to pH 1 with concentrated HCl and extracted with diethyl ether (3×200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to provide 2-benzyloxy-2-(trifluoromethyl)pent-4-enoic acid (28.04 g, 99%) as a pale yellow liquid. 1 H NMR (250 MHz, CDCl 3 )δ 7.55-7.28(m,5H),5.97-5.69(m,1H),5.33-5.17(m,2H),4.95-4.66(m,2H),2.91(d,J=7.1Hz,2H)ppm. 1 Not a single exchangeable proton was observed in the 1 H NMR.

[0256] Step 4: tert-Butyl N-[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamate (compound 21) [ka] To a solution of 2-benzyloxy-2-(trifluoromethyl)pent-4-enoic acid (300 g, 1.094 mol) in DMF (2 L) was added HATU (530 g, 1.394 mol) and DIEA (400 mL, 2.296 mol) and the mixture was stirred at ambient temperature for 10 min. To the mixture was added tert-butyl N-aminocarbamate (152 g, 1.150 mol) and the mixture was stirred at ambient temperature for 36 h. The reaction was quenched with cold water (4 L) and the mixture was extracted with EtOAc (2×2 L). The organic phase was washed with brine and diluted with MgSO 4It was dried over ice, filtered, and concentrated in vacuo. Purification by silica gel chromatography (0% to 40% EtOAc / hexanes) afforded tert-butyl N-[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamate (386.49 g, 91%) as an oil which slowly crystallized to an off-white solid. 1 H NMR(400MHz,DMSO)δ 10.00(d,J=37.9Hz,1H),8.93(s,1H),7.46-7.39(m,2H),7.38-7.29(m,3H),6.01-5.64(m,1H),5.32(d,J=17. 1Hz,1H),5.17(d,J=10.1Hz,1H),4.77(s,2H),2.96(qd,J=15.4,6.8Hz,2H),1.39(d,J=17.3Hz,9H)ppm.ESI-MS m / z calculated value 388.16098, actual value 389.0(M+1) + ; Retention time: 2.51 minutes (LC method C).

[0257] Step 5: 2-Benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (hydrochloride) (compound 22·HCl) [ka] To a solution of tert-butyl N-[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamate (98.5 g, 240.94 mmol) in DCM (400 mL) was added a solution of HCl in dioxane (200 mL of 4 M, 800.00 mmol). The mixture was stirred at room temperature for 2 h, concentrated, and coevaporated with DCM and hexane to give 2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (hydrochloride salt) (81.15 g, 97%) as an off-white solid. 1H NMR(500MHz,DMSO-d6)δ 11.07(s,1H),7.70-7.16(m,5H),5.87-5.61(m,1H),5.45-5.09(m,2H),4.7 9(s,2H),3.6-3.4(m,2H),3.23-3.07(m,1H),3.04-2.87(m,1H)ppm.ESI-MS m / z calculated value 288.10855, actual value 289.2(M+1) + ; Retention time: 2.0 minutes (LC method D).

[0258] Intermediate 4: Preparation of (2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (compound 23a) [ka] Step 1: 2-Benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (compound 22) [ka] tert-Butyl N-[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamate (386.49 g, 995.1 mmol) was dissolved in DCM (1.25 L) and toluene (250 mL) and treated with HCl (750 mL of 4 M, 3.000 mol) at room temperature and the yellow solution was stirred at room temperature for 18 h. The mixture was concentrated in vacuo and diluted with EtOAc (2 L). The mixture was treated with NaOH (600 mL of 2 M, 1.200 mol) and stirred at ambient temperature for 10 min. The organic phase was separated, washed with 1 L of brine and diluted with MgSO 4 Dry on a kettle, filter and concentrate in vacuo. 2-Benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (286 g, 100%) was used directly in the subsequent step (trace amounts of toluene present). 1H NMR(400MHz,DMSO)δ 9.34(s,1H),7.40-7.22(m,5H),5.69(ddt,J=17.1,10.3,6.9Hz,1H),5.33-5.23(m,1H) ,5.15(dd,J=10.3,1.8Hz,1H),4.73(s,2H),4.51(s,2H),3.05-2.87(m,2H)ppm.ESI-MS m / z calculated value 288.10855, actual value 289.0(M+1) + ; Retention time: 1.32 minutes (LC method E).

[0259] Step 2: (2R)-2-Benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (compound 23a) [ka] 7% MeOH (+20 mM NH) at a flow rate of 70 mL / min 3 ) / 93%CO 2 Racemic 2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (5.0 g, 17.35 mmol) was separated by chiral SFC using a ChiralPak IG column (250 × 21.2 mm, 5 μm) at 40 °C using a mobile phase of 2, the sample concentration was 111 mg / mL in methanol (no modifier), injection volume = 160 μL at 136 bar outlet pressure, detection wavelength of 210 nm to provide two enantiomeric products.

[0260] The first enantiomer to elute was isolated as (2S)-2-benzyloxy-2-(trifluoromethyl)pent-4-ene hydrazide (compound 23a, 1.79 g, 72%). 1H NMR(400MHz,DMSO-d6)δ 9.31(s,1H),7.45-7.39(m,2H),7.38-7.26(m,3H),5.77-5.62(m,1H),5.28(dq,J=17.1,1.6Hz,1H),5.15(dq,J=10.2 ,1.3Hz,1H),4.72(s,2H),4.44(d,J=4.2Hz,2H),2.99(dd,J=7.4,1.3Hz,1H),2.91(dd,J=15.4,6.4Hz,1H)ppm.ESI-MS m / z calculated value 288.10855, actual value 289.2(M+1) + ; Retention time: 1.28 minutes (LC method F).

[0261] The second enantiomer eluting was isolated as a white solid, (2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enehydrazide (compound 23b, 1.7 g, 68%). 1 H NMR(400MHz,DMSO-d6)δ 9.31(s,1H),7.48-7.39(m,2H),7.39-7.25(m,3H),5.77-5.62(m,1H),5.28(dq,J=17.1,1.6Hz,1H),5.15(dq,J=1 0.2,1.5Hz,1H),4.73(s,2H),4.51(s,2H),3.00(dd,J=15.3,7.5Hz,1H),2.91(dd,J=15.3,6.4Hz,1H)ppm.ESI-MS m / z calculated value 288.10855, actual value 289.2(M+1) + ; Retention time: 1.28 minutes (LC method F).

[0262] Example 5: Synthesis of (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (Compound I) [ka] Step 1: Methyl 6-((2-methylhex-5-en-2-yl)amino)-3-nitro-5-(trifluoromethyl)picolinate (compound 24) [ka] NaHCO 3 (88.6 g, 1.05 mol, 3 eq.) was added to a mixture of compound 16 (100 g, 0.35 mol, 1 eq.) and the HCl salt of compound 3 (57.9 g, 0.39 mol, 1.1 eq.) in 2-MeTHF (800 mL, 8 volumes). The mixture was heated to 75° C. (reaction mixture temperature). After completion of the reaction by LC analysis, the mixture was allowed to cool to ambient temperature. At ambient temperature, 700 mL of water was added. After stirring, the phases were separated. The organic layer was washed with 400 mL of water and diluted with Na 2 SO 4 The crude product was dried under vacuum and used directly in the next step. ESI-MS m / z calculated 361.12, found 362 (M+1). + . 1 H NMR(400MHz,chloroform-d)δ 8.45(d,J=0.8Hz,1H),5.77(ddt,J=16.8,10.2,6.3Hz,1H),5.51(s,1H),5.01(dq,J=17.1,1.6Hz,1 H),4.98-4.92(m,1H),4.01(s,3H),2.11-2.00(m,2H),2.01-1.92(m,2H),1.88(s,1H),1.49(s,6H). 19 F NMR (376 MHz, CDCl 3 )δ-64.47.

[0263] Step 2: 6-((2-methylhex-5-en-2-yl)amino)-3-nitro-5-(trifluoromethyl)picolinic acid (compound 2) [ka] To a solution of compound 24 (54 g, 149.454 mmol, 1 equiv) in EtOH (216 mL, 0.692 M, 4 vol) was added 6M NaOH (32.382 mL, 194.29 mmol, 1.3 equiv) dropwise via addition funnel over 10 min, maintaining the temperature at <30° C. The mixture was stirred at ambient temperature until the reaction was complete by LC analysis. (If the reaction has not been further converted, add additional 6M NaOH (2.491 mL, 14.945 mmol, 0.1 equiv) until the reaction was complete.) The mixture was concentrated to remove EtOH. The mixture was concentrated and IPAc (420 mL, 8 vol) was added. The mixture was acidified by adding 6M HCl (38.609 mL, 231.653 mmol, 1.55 equiv) dropwise via addition funnel, maintaining the temperature at <30° C. Stirred for 10 minutes and allowed to separate the phases. 26 g silica gel and 26 g activated charcoal were added to the organic layer and stirred at ambient temperature for several hours. The mixture was filtered over a pad of diatomaceous earth and washed twice with 25 mL IPAc. The filtrate was concentrated to give an oil. 140 mL heptane was added, concentrated, then repeated. 220 mL heptane was added to give a slurry that was allowed to stir for 2 more hours. The solid was collected by filtration and washed three times with 25 mL heptane. The solid was dried under vacuum to give compound 2 (42.3 g, 81.5%) as a light yellow solid. ESI-MS m / z calculated 347.11, found 348 (M+1) + . 1 H NMR(400MHz,chloroform-d)δ 8.47(d,J=0.8Hz,1H),7.89(s,2H),5.78(ddt,J=16.6,10.2,6.2Hz,1H),5.56(s,1H),5.12-4.89(m,2H),2.15-1.93(m,4H),1.53(s,6H). 19 F NMR (376 MHz, CDCl 3 )δ-64.45.

[0264] Step 3: (R)-N'-(2-(benzyloxy)-2-(trifluoromethyl)pent-4-enoyl)-6-((2-methylhex-5-en-2-yl)amino)-3-nitro-5-(trifluoromethyl)picolinohydrazide (compound 4) [ka] Compound 2 (900 g, 2591.496 mmol, 1 equiv) was added to the reactor followed by N,N-dimethylformamide (2700 mL, 0.96 M, 3 volumes). The mixture was stirred at ambient temperature and 4-methylmorpholine (NMM, 288.34 g, 313.413 mL, 0.92 g / mL, 2850.646 mmol, 1.1 equiv) was added dropwise. After the addition was complete, the mixture was stirred at ambient temperature for 15 minutes. CDMT (500.488 g, 2850.646 mmol, 1.1 equiv) was added as a slurry in N,N-dimethylformamide (900 mL, 2.879 M, 1 volume). After the addition, the mixture was stirred for 1 h, then compound 23a (784.391 g, 2721.071 mmol, 1.05 equiv) in N,N-dimethylformamide (900 mL, 2.879 M, 1 volume) was added to the mixture over 1.5 h. The mixture was stirred at ambient temperature until LC analysis confirmed the reaction was complete. 2 L of water was slowly added to quench the reaction, then MTBE (12 L, 0.288 M, 13 volumes) was added. Additional H 2 HO (14400 mL, 0.18 M, 16 vol) was added. After stirring, the phases were separated. The organic layer was washed with 0.5 M NaOH (5400 mL, 6 vol), 0.5 M HCl (5400 mL, 6 vol), and 5% w / v aqueous NaCl (5400 mL, 6 vol). The organic layer was washed with Na 2 SO 4 The mixture was dried over hexane, filtered and concentrated by rotary evaporation (40° C., 20 mbar). 2 L of ethyl acetate was added to chase MTBE and concentrated on a rotary evaporator at 50° C. to give crude compound 4 (1551 g, 91.9%), which was used directly in the next step. ESI-MS m / z calculated 617.21, found 618 (M+1). + . 1H NMR(400MHz,chloroform-d)δ 9.26(s,1H),8.84(d,J=4.6Hz,1H),8.33-8.26(m,1H),7.47-7.29(m,6H ),5.81(dddd,J=27.2,12.3,10.2,6.7Hz,2H),5.45(s,1H),5.38-5.27( m,2H),5.01(dq,J=17.2,1.6Hz,1H),4.95(dt,J=10.2,1.4Hz,1H),4.85 (s,2H),3.19-2.95(m,2H),2.12-1.95(m,4H),1.61(s,5H),1.51(s,6H). 19 F NMR (376 MHz, CDCl 3 )δ-64.53,-73.76.

[0265] Step 4: (R)-9-(benzyloxy)-3,3-dimethyl-1 5 -Nitro-1 3 ,9-Bis(trifluoromethyl)-2,11,12-triaza-1(2,6)-pyridinacyclotridecaphane-6-ene-10,13-dione (compound 6) [ka] A solution of compound 4 (517 g, 837.181 mmol, 1 equiv) in EtOAc (77.55 L, 0.011 M, 150 vol) was stirred at ambient temperature with subsurface N 2 Sparging was started. After 30 min of sparging, dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II) (Zhan Catalyst-1B, 61.428 g, 83.718 mmol, 0.1 equiv.) was added and the mixture was immersed in subsurface N 2The mixture was heated to 40° C. with continued sparging. After the reaction was complete by LC analysis, the mixture was cooled to ambient temperature. 2-mercaptonicotinic acid (64.954 g, 418.59 mmol, 0.5 eq.) was then charged to the reactor followed by TEA (42.357 g, 58.829 mL, 0.72 g / mL, 418.59 mmol, 0.5 eq.) and the mixture was stirred overnight. Silica gel (1265.817 g, 5023.083 mmol, 6 eq.) was added to the mixture and stirred for at least 1 h. The mixture was filtered through a glass filter with a layer of silica gel (2 kg) and a thin layer of diatomaceous earth and the solid was washed with EtOAc (20.68 L, 0.04 M, 40 vol.). The solvent was distilled from the filtrate via a rotary evaporator. The final weight of crude material was 397 g with an area percent purity of 79.71% by LC analysis.

[0266] A slurry of the combined crude material (compound 4, 1551 g, 2383.955 mmol, 1 equiv) in MTBE (6.204 L, 0.384 M, 4 vol) was heated to 55° C. and stirred for 1 h. MTBE (1.241 L, 1.921 M, 0.8 vol) and heptane (4963.2 mL, 0.48 M, 3.2 vol) were added over 15 min. The mixture was stirred for an additional 30 min, then cooled to 10° C. over 2 h, followed by stirring at 10° C. overnight.

[0267] The mixture was then filtered and the filter cake was washed first with MTBE (310.2 mL, 0.2 vol) and then with heptane (3×413 mL, 0.8 vol). The filter cake was dried for 1 h and then transferred to a rotary evaporator and dried at 50° C. for 4 h to give compound 6 (1119 g, 78.4%). ESI-MS m / z calculated 589.18, found 590 (M+1). + . 1H NMR (400MHz, chloroform-d) δ 8.51 (d, J = 8.9Hz, 1H), 7.90 (s, 1H), 7.51 (s, 1H), 7.48-7.39 (m, 1H), 7.39-7.29 (m, 2H), 7.13-6.97 (m, 2H), 5.67 (ddd, J = 14.9, 10.8, 3.9Hz, 1H), 5.42-5.32 (m, 1H), 4.76-4.5 5(m,2H),4.43(d,J=9.9Hz,1H),2.90-2.72(m,2H),2.55(t,J=12.6Hz,1H),2.19-2.06 (m,1H),2.05(s,1H),1.59(s,5H),1.52(s,4H),1.47-1.39(m,1H),1.32-1.19(m,4H). 19 F NMR (376 MHz, CDCl 3 )δ-64.25,-64.62,-73.96,-74.27.

[0268] Step 5: (R)-10-(benzyloxy)-4,4-dimethyl-2 3 -Nitro-2 5 ,10-Bis(trifluoromethyl)-3-aza-1(2,5)-oxadiazola-2(2,6)-pyridinacyclodecaphan-7-ene (compound 5) [ka] A solution of compound 6 (20.0 g, 33.9 mmol, 1 equiv.) and 1,4-diazabicyclo[2.2.2]octane (DABCO; 5.71 g, 50.9 mmol, 1.5 equiv.) in DCM (160 mL, 8 vol. equiv.) was stirred at room temperature when 25 w / v % 2-chloro-1,3-dimethylimidazolinium chloride (DMC; 6.23 g, 24.9 mL, 37.3 mmol, 1.1 equiv.) was added over 5 min while maintaining the reaction temperature between 15 and 30 °C. Immediately after the addition of DMC was complete, the reaction suspension was diluted with PhMe (40 mL, 2 vol. equiv.) and concentrated to remove most of the DCM. The concentrate was diluted again with a total volume of PhMe (160 mL, 8 vol. equiv.). The suspension was heated at 100 °C. The reaction temperature was maintained at 100-105 °C for 5-6 h until completion was confirmed by LC analysis. The suspension was cooled to room temperature and the solids (DABCO·HCl and N,N-dimethylimidazolidinone) were removed by filtration. The filter cake was washed twice with MTBE (40 mL, 2 vol). The filtrate and washes were combined and washed successively first with water (60 mL, 3 vol eq), then with 0.5 M HCl (67.9 mL, 33.9 mmol, 1 eq), and then with water (60 mL, 3 vol eq). The mixture was then concentrated to give crude compound 5 (20.9 g, 108% theory).

[0269] Crude compound 5 was dissolved in hot (75° C.) EtOH (40 mL) and cooled to room temperature over 1 h. The solid was collected by filtration and the filter cake was washed with EtOH (2×10 mL) and then air-dried to give compound 5 (14.0 g, 72%) as a yellow solid. ESI-MS m / z calculated 571.17, found 572 (M+1). + . 1H NMR (400MHz, chloroform-d) δ 8.47(d,J=0.9Hz,1H),7.41-7.21(m,7H),5.76-5.58(m,2H),5.56-5.47(m,1H) ,4.85(dd,J=11.2,1.5Hz,1H),4.52(d,J=11.0Hz,1H),3.14-3.03(m,1H),2.69 (dd,J=14.3,8.5Hz,1H),2.52(td,J=9.9,9.5,5.6Hz,1H),2.14(ddd,J=12.0,1 0.0,5.4Hz,1H),1.99(ddt,J=14.7,8.0,4.0Hz,2H),1.45(s,3H),1.42(s,3H). 19 F NMR (376 MHz, CDCl 3 )δ-64.13,-72.99.

[0270] Step 6: (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (compound I) [ka] EtOH (210 mL, 15 volume equivalents), EtOAc (70 mL, 5 volume equivalents), and 7M NH 3 A suspension of compound 5 (14.0 g, 24.5 mmol, 1 equiv.) and 10 wt.% palladium on activated carbon (Evonik Nobylst P1173; 2.6 g, 50 w / w%, 0.5 equiv.) in MeOH / MeOH (3.5 mL, 24.5 mmol, 1 equiv.) was evacuated and heated with N 2 The reaction vessel was evacuated and refilled with H 2 (balloon pressure) and stirred rapidly at room temperature for 16 h. The reaction vessel was evacuated / N 2Recharges at 0.5 to 1000 rpm were performed three times and the mixture was analyzed by LC for reaction completion. A portion of diatomaceous earth (2 g) was added to the reaction mixture and the suspension was filtered through a 1 cm bed of packed diatomaceous earth to remove the catalyst. The flask / filter bed was washed with EtOH (3×10 mL) and the washings were combined with the filtrate and concentrated (45° C. / 20 Torr) to give compound I (11.5 g, 104% theory) as a light yellow foam.

[0271] The foam was dissolved in DCM (98 mL, 7 volume equivalents) and SiO 2 The mixture was filtered through a packed bed (14 g; 1 g / g). The filter bed was washed with DCM (80 mL) and then with 20% EtOAc / DCM (2×100 mL). Each subsequent wash was colorless, with the final wash being nearly colorless. The filtrate and washes were combined and concentrated to give compound I (11.1 g) as an orange solid. The solid was dissolved in warm (30° C.) DCM (98 mL, 7 vol eq) and diluted with heptane (98 mL, 7 vol eq) with rapid mixing. The solution was concentrated (45° C. / 360 Torr) to remove most of the DCM, and the resulting suspension was then recharged with an additional portion of heptane (98 mL, 7 vol). The suspension was partially concentrated again (to remove residual DCM) and cooled to room temperature. The solid was collected by filtration, and the filter cake was washed with heptane (2×10 mL) and air-dried to give compound I (10.7 g, 96%) as a light yellow granular solid. ESI-MS m / z calculated 453.16, found 454 (M+1). + . 1 H NMR (400MHz, DMSO-d 6 )δ 7.62(s,1H),7.59(s,1H),5.96(s,2H),4.64(s,1H),2.81(p,J=7.2,6.8Hz,1H),2.28-2.15(m,1H),2.06(t,J=12.4 Hz,1H),1.82(dt,J=12.1,7.5Hz,1H),1.65(d,J=13.7Hz,1H),1.44(q,J=8.7,8.0Hz,5H),1.36(s,3H),1.31(s,3H). 19 F NMR(376MHz,DMSO)δ-62.34,-78.23.

[0272] Example 6: (R)-10-(benzyloxy)-4,4-dimethyl-2 3 -Nitro-2 5 Alternative synthesis of 1,10-bis(trifluoromethyl)-3-aza-1(2,5)-oxadiazola-2(2,6)-pyridinacyclodecaphan-7-ene (compound 5) [ka] Step 1: (R)-6-(5-(2-(benzyloxy)-1,1,1-trifluoropent-4-en-2-yl)-1,3,4-oxadiazol-2-yl)-N-(2-methylhex-5-en-2-yl)-5-nitro-3-(trifluoromethyl)pyridin-2-amine (compound 25) [ka] (R)-6-(5-(2-(benzyloxy)-1,1,1-trifluoropent-4-en-2-yl)-1,3,4-oxadiazol-2-yl)-N-(2-methylhex-5-en-2-yl)-5-nitro-3-(trifluoromethyl)pyridin-2-amine (compound 25) can be synthesized using a procedure similar to that reported in: ·Li,C.;Dickson,HDTett.Lett.2009,50,6435. ·Augustine,JK;Vairaperumal,V.;Narasimhan,S.;Alagarsamy,P.;Radhakrishnan,A.Tetrahedron,2009,65,9989.

[0273] A suitable vessel equipped with an overhead stirrer and nitrogen inlet is charged with 6-((2-methylhex-5-en-2-yl)amino)-3-nitro-5-(trifluoromethyl)picolinic acid (14.9 mmol, 1 eq), (R)-2-(benzyloxy)-2-(trifluoromethyl)pent-4-enehydrazide (15.6 mmol, 1.05 eq), and acetonitrile (34.8 mL, 6 vol). The mixture is stirred and T3P (33.1 g, 50 w / w% as a solution, 52.0 mmol, 3.5 eq) and DIPEA (89.2 mmol, 6 eq) are charged to the reactor. The mixture is heated to an internal temperature of 78° C. and monitored by HPLC until the desired reaction conversion is observed. The temperature is reduced to 25° C. and water (29 mL, 5 vol) is charged to the reactor and the mixture is stirred for 10 min. Charge MTBE (46.4 mL, 8 vol), stir for 10 min, allow to settle, then separate. Isolate the organic layer and wash successively with 5% citric acid (29 mL, 5 vol), saturated sodium bicarbonate (29 mL, 5 vol), and water (29 mL, 5 vol). Concentrate the organic layer to an oil and use as is in further workup.

[0274] Step 2: (R)-10-(benzyloxy)-4,4-dimethyl-2 3 -Nitro-2 5 ,10-Bis(trifluoromethyl)-3-aza-1(2,5)-oxadiazola-2(2,6)-pyridinacyclodecaphan-7-ene (compound 5) [ka] Compound 5 can be produced from compound 25 by using a method similar to that described in step 4 of Example 5.

[0275] Example 7: Alternative synthesis of (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (compound I) [ka] Step 1: (R)-(2-(5-(2-(benzyloxy)-1,1,1-trifluoropent-4-en-2-yl)-1,3,4-oxadiazol-2-yl)-6-((2-methylhex-5-en-2-yl)amino)-5-(trifluoromethyl)pyridin-3-yl) tert-butyl carbamate (compound 27) [ka] (R)-(tert-butyl 2-(5-(2-(benzyloxy)-1,1,1-trifluoropent-4-en-2-yl)-1,3,4-oxadiazol-2-yl)-6-((2-methylhex-5-en-2-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)carbamate (compound 27) can be synthesized using a procedure similar to that reported in: ·Li,C.;Dickson,HDTett.Lett.2009,50,6435. ·Augustine,JK;Vairaperumal,V.;Narasimhan,S.;Alagarsamy,P.;Radhakrishnan,A.Tetrahedron,2009,65,9989.

[0276] A suitable vessel equipped with an overhead stirrer and nitrogen inlet is charged with 3-((tert-butoxycarbonyl)amino)-6-((2-methylhex-5-en-2-yl)amino)-5-(trifluoromethyl)picolinic acid (compound 26) (14.9 mmol, 1 equiv.; prepared according to Example 90, step 3 of WO2022 / 109573A1), (R)-2-(benzyloxy)-2-(trifluoromethyl)pent-4-enehydrazide (15.6 mmol, 1.05 equiv.), and acetonitrile (34.8 mL, 6 volumes). The mixture is stirred and T3P (33.1 g, 50 w / w% as a solution, 52.0 mmol, 3.5 equiv.) and DIPEA (89.2 mmol, 6 equiv.) are charged to the reactor. The mixture is heated to an internal temperature of 78° C. and monitored by HPLC until the desired reaction conversion is observed. The temperature is reduced to 25° C. and water (29 mL, 5 volumes) is charged to the reactor and the mixture is stirred for 10 minutes. MTBE (46.4 mL, 8 volumes) is charged and stirred for 10 minutes, allowed to settle, and then separated. The organic layer is isolated and washed successively with 5% citric acid (29 mL, 5 volumes), saturated sodium bicarbonate (29 mL, 5 volumes), and water (29 mL, 5 volumes). The organic layer is concentrated to an oil and used as is in further workup.

[0277] Step 2: (R)-(10-(benzyloxy)-4,4-dimethyl-2 5 ,10-Bis(trifluoromethyl)-3-aza-1(2,5)-oxadiazola-2(2,6)-pyridinacyclodecaphan-7-ene-2 3 -yl) tert-butyl carbamate (compound 28) [ka] Compound 28 can be produced from compound 27 by using a method similar to that described in step 4 of Example 5. Step 3: (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (compound I) [ka]

[0278] Compound I can be produced from compound 28 by using a method similar to that described in step 6 of Example 5. Other embodiments

[0279] All publications and patents mentioned in this disclosure are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. In the event that the meaning of a term in any of the patents or publications incorporated by reference conflicts with the meaning of the term used in this disclosure, the meaning of the term defined in this disclosure is intended to control.

[0280] The foregoing discussion discloses and describes merely exemplary embodiments of the present disclosure. Those skilled in the art will readily recognize from such discussion and the accompanying drawings and claims that various changes, modifications, and variations can be made therein without departing from the spirit and scope of the present disclosure, as defined in the following claims.

Claims

1. Compound I, selected from amorphous compound I, methanol solvate of crystalline compound I (wet), methanol solvate of crystalline compound I (dry), and p-toluenesulfonic acid of crystalline compound I. 【Chemistry 101】 The solid form.

2. The solid form of compound I according to claim 1, wherein the solid form of compound I is substantially amorphous.

3. A methanol solvate (wet) of crystalline compound I according to claim 1, characterized by a powder X-ray diffractogram having a signal at one or more of the following: 25.5±0.2°C 2-theta, 21.0±0.2°C 2-theta, 20.5±0.2°C 2-theta, 19.0±0.2°C 2-theta, 18.9±0.2°C 2-theta, 18.6±0.2°C 2-theta, 16.9±0.2°C 2-theta, 15.0±0.2°C 2-theta, 14.6±0.2°C 2-theta, and 8.4±0.2°C 2-theta.

4. Having one or more signals selected from 145.6±0.2 ppm, 132.5±0.2 ppm, 113.1±0.2 ppm, 73.5±0.2 ppm, 55.9±0.2 ppm, 35.2±0.2 ppm, 31.1±0.2 ppm, 30.5±0.2 ppm, 24.8±0.2 ppm, and 19.0±0.2 ppm. １３ A methanol solvate (wet) of the crystalline compound I according to claim 1, characterized by a C SSN NMR spectrum.

5. A methanol solvate (dried) of the crystalline compound I according to claim 1, characterized by a powder X-ray diffractogram having signals at one or more of the following: 27.2±0.2°C 2-theta, 26.4±0.2°C 2-theta, 25.9±0.2°C 2-theta, 21.4±0.2°C 2-theta, 19.3±0.2°C 2-theta, 18.1±0.2°C 2-theta, 15.4±0.2°C 2-theta, 14.2±0.2°C 2-theta, and 7.4±0.2°C 2-theta.

6. The p-toluenesulfonic acid of crystalline compound I according to claim 1, characterized by a powder X-ray diffractogram having a signal at one or more of the following: 5.7±0.2° 2-theta, 5.8±0.2° 2-theta, 7.4±0.2° 2-theta, 10.1±0.2° 2-theta, 11.5±0.2° 2-theta, 11.9±0.2° 2-theta, 14.9±0.2° 2-theta, 15.9±0.2° 2-theta, 16.2±0.2° 2-theta, 18.3±0.2° 2-theta, 20.4±0.2° 2-theta, 21.0±0.2° 2-theta, 21.6±0.2° 2-theta, 22.8±0.2° 2-theta, and 23.2±0.2° 2-theta.

7. Having one or more signals selected from 141.0±0.2 ppm, 126.7±0.2 ppm, 57.0±0.2 ppm, 31.0±0.2 ppm, 25.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. １３ p-toluenesulfonic acid of crystalline compound I according to claim 1, characterized by a C SSN NMR spectrum.

8. A pharmaceutical composition comprising compound I according to claim 1 and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to claim 8, further comprising one or more additional therapeutic agents.

10. The aforementioned pharmaceutical composition 【Chemical Engineering 201】 【Chemical Engineering 202】 The pharmaceutical composition according to claim 9, comprising one or more compounds selected from the pharmaceutically acceptable salts thereof and any deuterated derivatives of the foregoing.

11. A pharmaceutical composition according to any one of claims 8 to 10, for use in the treatment of cystic fibrosis. 【Request Item 12】 【Chemistry 120】 A compound selected from, or a stereoisomer of said compound, or a deuterated derivative of said compound or a stereoisomer thereof, or a salt of any of the above, During the ceremony, -R ａ However, selected from alcohol protecting groups, - The compound of formula I, formula II, or formula III is N'-[(2R)-2-benzyloxy-2-(trifluoromethyl)penta-4-enoyl]-6-(1,1-dimethylpenta-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide, (6R)-6-benzyloxy-12,12-dimethyl-17-nitro-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,8,14,16-hexane(E / Z mixture) , N'-[(2R)-2-benzyloxy-2-(trifluoromethyl)hexa-5-enoyl]-6-[1,1-bis(triduteriomethyl)buta-3-enylamino]-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide, (6R)-6-benzyloxy-17-nitro-12,12-bis(triduteriomethyl)-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexane(E / Z mixture), A compound other than a compound selected from the pharmaceutically acceptable salts thereof, or a stereoisomer of the said compound, or a deuterated derivative of the said compound or a stereoisomer thereof, or a salt of any of the foregoing.

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