Solid forms of macrocyclic compounds as CFTR modulators and their preparation

Abstract

# imgabs0 # discloses a process and a method for preparing the compound I. Also disclosed are crystalline forms, pharmaceutically acceptable salts, solvates, hydrates and co-crystals thereof, pharmaceutical compositions comprising the crystalline forms, pharmaceutically acceptable salts, solvates, hydrates and co-crystals thereof, pharmaceutical compositions comprising the crystalline forms, pharmaceutically acceptable salts, solvates, hydrates and co-crystals thereof, pharmaceutical compositions comprising the crystalline forms, pharmaceutically acceptable salts, solvates, hydrates and co-crystals thereof, pharmaceutical compositions comprising the crystalline forms, pharmaceutically acceptable salts, solvates, hydrates and co-crystals thereof, and pharmaceutical compositions comprising the crystalline forms, pharmaceutically acceptable salts, solvates, hydrates and co-crystals thereof. The present invention relates to crystalline forms, pharmaceutically acceptable salts, solvates, hydrates and co-crystals thereof, methods of treating cystic fibrosis by hydrates and co-crystals, and methods for preparing the crystalline forms, pharmaceutically acceptable salts, solvates, hydrates and co-crystals thereof.

Description

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

[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 preparing crystalline and amorphous forms. Further disclosed herein are processes and methods for preparing CFTR modulators.

[0003] Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 88,000 children and adults worldwide. Despite advances in treatment, CF remains incurable.

[0004] In CF patients, mutations in the endogenously expressed CFTR in the respiratory epithelium lead to reduced apical anion secretion, resulting in an imbalance in ion and fluid transport. The resulting reduction in anion transport leads to increased mucus accumulation in the lungs, and accompanied by microbial infections, ultimately leading to death in CF patients. In addition to respiratory diseases, CF patients often suffer from gastrointestinal problems and pancreatic insufficiency, which can lead to death if not treated. In addition, most men with cystic fibrosis are infertile, and women with cystic fibrosis have reduced fertility.

[0005] Sequence analysis of the CFTR gene has revealed a variety of disease-causing mutations (Cutting, GR et al. (1990) Nature 346:366-369; Dean, M et al. (1990) Cell 61:863:870; and Kerem, BS et al. (1989) Science 245:1073-1080; Kerem, BS et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, more than 2000 mutations in the CF gene have been identified; currently, the CFTR2 database contains information on at least 322 of these identified mutations, with sufficient evidence to define at least 281 mutations as pathogenic. The most common pathogenic mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence and is often referred to as the F508del mutation. This mutation occurs in many cases of cystic fibrosis and is associated with severe disease.

[0006] CFTR is the cAMP / ATP-mediated anion channel expressed in various cell types comprising absorptive and secretory epithelial cells, wherein the CFTR regulates the anion flux across the membrane and the activity of other ion channels and proteins. In epithelial cells, the normal function of CFTR is most important for maintaining the transport of electrolytes throughout the body (comprising respiratory and digestive tissues). CFTR is composed of 1480 amino acids of coded proteins, and the protein is composed of tandem repeats of a transmembrane domain, and each transmembrane domain contains six transmembrane helices and nucleotide binding domains. Two transmembrane domains are connected with multiple phosphorylation sites by large polarity regulation (R) domains, which regulate channel activity and cellular transport.

[0007] Chloride transport is carried out by ENaC (epithelial sodium channel) and CFTR present on the apical membrane and by Na+ expressed on the basolateral surface of the cell. + -K + -ATPase pump and Cl - The secondary active transport of chloride from the luminal side results in the accumulation of intracellular chloride, which can then be transported via Cl - The channel passively leaves the cell, thus enabling mediator transport. + / 2Cl - / K + Co-transporter, Na + -K + -ATPase pump and basolateral membrane K on the basolateral surface + The arrangement of channels and CFTR on the luminal side coordinates the secretion of chloride. Since water itself may not be actively transported, its flow across the epithelium depends on the small transepithelial osmotic gradient created by the bulk flow of sodium and chloride.

[0008] A variety of CFTR modulators have been identified recently. These modulators can be characterized as, for example, potentiators, correctors, potentiator enhancers / co-potentiators, amplifiers, read-through agents, and nucleic acid therapies. CFTR modulators that increase the channel gating activity of mutant and wild-type CFTR at the surface of epithelial cells are called potentiators. Correctors improve erroneous protein processing and the resulting transport to the epithelial surface. Ghelani and Schneider-Futschik (2020) ACS Pharmacol. Transl. Sci. 3: 4-10. The U.S. FDA has approved three CFTR correctors for the treatment of cystic fibrosis. However, monotherapy with some CFTR correctors has not been found to be sufficiently effective, and therefore combination therapy with potentiators is needed 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 the more severe forms of these diseases.

[0009] Thus, one aspect of the present 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-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (Compound I) and a pharmaceutically acceptable salt thereof. Compound I can be depicted as having the following structure:

[0010]

[0011] Additional aspects of the present disclosure provide methods for preparing Compound 1, stereoisomers of Compound 1, deuterated derivatives of Compound 1 and stereoisomers thereof, and pharmaceutically acceptable salts of any of the foregoing.

[0012] Compound 1 was first described in PCT International Application No. PCT / US2021 / 072475, published as WO 2022 / 109573, and the document is incorporated herein by reference in its entirety. Compound 1 is disclosed in WO 2022 / 109573 as crystalline Form A (pure).

[0013] Crystalline forms are of interest in the pharmaceutical industry, where control of the crystalline form of an active ingredient may be desirable or even required. For compounds that are desired to be used in medicines, it may be desirable to produce a reproducible method of a compound with a specific crystalline form in high purity, because different crystalline forms may have different properties. 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 forms, crystalline salts, crystalline salt solvates, and crystalline salt hydrate forms of Compound I (collectively referred to as "crystalline forms")) may exhibit lower hygroscopicity. Therefore, the crystalline forms disclosed herein may provide advantages during drug substance manufacturing, storage, and handling. Therefore, the pharmaceutically acceptable crystalline form of Compound I may be particularly suitable for producing drugs for treating CFTR-mediated diseases.

[0014] Amorphous forms of therapeutic compounds may also be of interest in the pharmaceutical industry where the crystalline form is not particularly bioavailable. Some amorphous forms may improve bioavailability and thus allow for administration of reduced doses. For some compounds, the amorphous form provides the most biologically accessible form of the therapeutic agent.

[0015] In some embodiments, the crystalline form of Compound 1 is Compound 1 Methanol Solvate (Wet). In some embodiments, the crystalline form of Compound 1 is Compound 1 Methanol Solvate (Dry). In some embodiments, the crystalline form of Compound 1 is Compound 1 p-toluenesulfonic acid.

[0016] In some embodiments, the solid form of Compound 1 is an amorphous form. In some embodiments, the solid amorphous form of Compound 1 is pure amorphous form of Compound 1.

[0017] Another aspect of the present invention provides a pharmaceutical composition comprising at least one solid form selected from the following: a solid form of Compound I disclosed herein, a pharmaceutically acceptable salt thereof, and a deuterated derivative of any of the foregoing, which composition may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0018] In certain embodiments, the pharmaceutical compositions of the present invention include Compound I in any of the pharmaceutically acceptable solid forms disclosed herein. In some embodiments, the composition comprising Compound I in any of the pharmaceutically acceptable crystalline forms disclosed herein may optionally further include at least one compound selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof.

[0019] Another aspect of the present invention provides a method for treating CFTR-mediated diseases cystic fibrosis, the method comprising administering to a subject in need thereof a compound I in any of the pharmaceutically acceptable solid forms disclosed herein, optionally as part of a pharmaceutical composition comprising at least one additional component (such as a carrier or an additional active agent). In some embodiments, the method for treating CFTR-mediated diseases cystic fibrosis comprises administering a compound I in any of the pharmaceutically acceptable solid forms disclosed herein, and optionally further administering one or more additional CFTR modulators selected from the following: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methyl ... 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 Amine (Compound III-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-(phenylsulfonyl)-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]hept-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ 6-thia-3,9,11,18,23-pentazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexene-2,2,4-trione (Compound VII), (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hex-5-yl}-9-oxa-2λ 6 -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadecan-1(17),4(19),5,7,14(18),15-hexene-2,2,13-trione (Compound VIII); N-(phenylsulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound IX) and N-[(6-amino-2-pyridinyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide (Compound X).

[0020] Additional aspects of the present disclosure provide methods of preparing solid forms of Compound 1 disclosed herein.

[0021] Another aspect of the invention provides a solid form of Compound I disclosed herein, a pharmaceutically acceptable salt thereof, and a deuterated derivative of any of the foregoing, for use in any of the methods described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 An X-ray powder diffraction (XRPD) pattern of pure Form A of Compound 1 is provided.

[0023] Figure 2 Differential Scanning Calorimetry (DSC) analysis of pure Form A of Compound 1 is provided.

[0024] Figure 3 Provided is an XRPD pattern of crystalline Compound 1 methanol solvate (wet).

[0025] Figure 4 Provided is a crystalline methanol solvate of Compound I (wet) 13 C SSNMR spectrum.

[0026] Figure 5 Provided is a crystalline methanol solvate of Compound I (wet) 19 F SSNMR spectrum.

[0027] Figure 6 An XRPD pattern of crystalline Compound 1 methanol solvate (dry) is provided.

[0028] Figure 7 The TGA curve of crystalline Compound 1 methanol solvate (dry) is provided.

[0029] Figure 8 Provided is the DSC analysis of crystalline Compound 1 methanol solvate (dry).

[0030] Fig. 9 An XRPD pattern of crystalline Compound 1 p-toluenesulfonic acid is provided.

[0031] Fig.10 A DSC analysis of crystalline Compound 1 p-toluenesulfonic acid is provided.

[0032] Fig.11 Provided is a crystalline compound I p-toluenesulfonic acid 13 C SSNMR spectrum.

[0033] Fig.12 Provided is a crystalline compound I p-toluenesulfonic acid 19 F SSNMR spectrum.

[0034] Fig.13 An XRPD pattern of pure amorphous Compound 1 is provided.

[0035] Fig.14 A TGA curve of pure amorphous Compound I is provided.

[0036] Fig.15 A DSC analysis of pure amorphous Compound I is provided.

[0037] definition

[0038] As used throughout this disclosure, "Compound 1" refers to (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, which compound can be depicted as having the following structure:

[0039]

[0040] Compound I can be a racemic mixture or an enantiomerically enriched (e.g., >90% ee, >95% ee, >98% ee) mixture of isomers. Compound I can be in the form of a pharmaceutically acceptable salt, solvate and / or hydrate. Compound I and methods for preparing and using Compound I, stereoisomers of Compound I, deuterated derivatives of Compound I and its stereoisomers, and pharmaceutically acceptable salts of any of the foregoing are disclosed in WO 2022 / 109573, which is incorporated herein by reference.

[0041] 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 depicted by the following structure:

[0042]

[0043] Compound II may be in the form of a pharmaceutically acceptable salt. Compound II and methods of making and using Compound II are disclosed in WO 2010 / 053471, WO 2011 / 119984, WO 2011 / 133751, WO 2011 / 133951 and WO 2015 / 160787, each of which is incorporated herein by reference.

[0044] As used throughout this disclosure, "Compound III" refers to N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, which is depicted by the following structure:

[0045]

[0046] Compound III may also be in the form of a pharmaceutically acceptable salt.Compound III and methods of making and using Compound III are disclosed in WO 2006 / 002421, WO 2007 / 079139, WO 2010 / 108162 and WO 2010 / 019239, each of which is incorporated herein by reference.

[0047] In some embodiments, deuterated derivatives of compound III (compound III-d) are 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, as depicted in the following structure:

[0048]

[0049] Compound III-d may be in the form of a pharmaceutically acceptable salt. Compound III-d and methods of making and using Compound III-d are disclosed in WO 2012 / 158885, WO 2014 / 078842, and U.S. Pat. No. 8,865,902, which are incorporated herein by reference.

[0050] 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, which is depicted by the following chemical structure:

[0051]

[0052] Compound IV may be in the form of a pharmaceutically acceptable salt. Compound IV and methods of making and using Compound IV are disclosed in WO 2007 / 056341, WO 2009 / 073757 and WO 2009 / 076142, which are incorporated herein by reference.

[0053] 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, which is depicted by the following chemical structure:

[0054]

[0055] Compound V may be in the form of a pharmaceutically acceptable salt. Compound V and methods of making and using Compound V are disclosed in WO 2018 / 107100 and WO 2019 / 113476, which are incorporated herein by reference.

[0056] 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, which is depicted by the following chemical structure:

[0057]

[0058] Compound VI may be in the form of a pharmaceutically acceptable salt. Compound VI and methods for preparing and using Compound VI are disclosed in WO 2018 / 064632, which is incorporated herein by reference.

[0059] As used herein, "Compound VII" refers to (14S)-8-[3-(2-{dispiro[2.0.2.1]hept-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]tetracosyl-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione, said compound being depicted by the following chemical structure:

[0060]

[0061] Compound VII may be in the form of a pharmaceutically acceptable salt. Compound VII and methods for preparing and using Compound VII are disclosed in WO 2019 / 161078, WO 2020 / 102346, and PCT Application No. PCT / US2020 / 046116, which are incorporated herein by reference.

[0062] 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]nonadecan-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, said compound being depicted by the following chemical structure:

[0063]

[0064] Compound VIII may be in the form of a pharmaceutically acceptable salt. Compound VIII and methods of preparing and using Compound VIII are disclosed in WO2020 / 206080, which is incorporated herein by reference.

[0065] 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, which is depicted by the following chemical structure:

[0066]

[0067] Compound IX may be in the form of a pharmaceutically acceptable salt. Compound IX and methods of making and using Compound IX are disclosed in WO 2016 / 057572, which is incorporated herein by reference.

[0068] As used herein, "Compound X" refers to N-[(6-amino-2-pyridinyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is depicted by the following chemical structure:

[0069]

[0070] Compound X may be in the form of a pharmaceutically acceptable salt. Compound X and methods of making and using Compound X are disclosed in WO 2016 / 057572, which is incorporated herein by reference.

[0071] As used herein, "CFTR" means cystic fibrosis transmembrane conductance regulator.

[0072] As used herein, the terms "CFTR modulator" and "CFTR modulating compound" interchangeably refer to compounds that directly or indirectly increase the activity of CFTR. The increase in activity caused by a CFTR modulator includes, but is not limited to, compounds that correct, enhance, stabilize and / or amplify CFTR.

[0073] As used herein, the term "CFTR corrector" refers to a compound that promotes the processing and trafficking of CFTR to increase the amount of CFTR at the cell surface.

[0074] As used herein, the term "CFTR potentiator" refers to a compound that increases the channel activity of the CFTR protein located at the cell surface, thereby resulting in enhanced ion transport.

[0075] As used herein, the terms "CFTR potentiator enhancer," "CFTR potentiator enhancer," and "CFTR co-potentiator" are used interchangeably and refer to a compound that enhances CFTR potentiation.

[0076] As used herein, the term "active pharmaceutical ingredient" ("API") or "therapeutic agent" refers to a biologically active compound.

[0077] The terms "patient" and "subject" are used interchangeably and refer to animals including humans.

[0078] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of a compound that produces the desired effect for which the compound is administered (e.g., improving CF or a symptom of CF, or reducing the severity of a symptom of CF). The exact amount of an effective dose will depend on the purpose of the treatment and will be determined by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0079] As used herein, the terms "treatment", "treating" and the like generally mean improving one or more symptoms of CF or its symptoms in a subject or reducing the severity of one or more symptoms of CF or its symptoms. As used herein, "treatment" includes but is not limited to the following: increased growth, increased weight gain, reduced mucus in the lungs, improved pancreatic and / or liver function, reduced chest infection, and / or reduced cough or shortness of breath in a subject. Improvement in any of these symptoms or reduction in their severity can be readily assessed according to standard methods and techniques known in the art.

[0080] As used herein, the term "in combination with" when referring to two or more compounds, agents or additional pharmaceutically active ingredients means that the two or more compounds, agents or pharmaceutically active ingredients are administered to the patient before, simultaneously with or after each other.

[0081] As used herein, "mutation" may refer to a mutation in the CFTR gene or the CFTR protein. "CFTR gene mutation" refers to a mutation in the CFTR gene, and "CFTR protein mutation" refers to a mutation in the CFTR protein. Typically, a genetic defect or mutation or a change in nucleotides in a gene produces a mutation or frameshift in the CFTR protein translated from the gene.

[0082] As used herein, the term "F508del" refers to a mutant CFTR protein lacking the amino acid phenylalanine at position 508, or to a mutant CFTR gene encoding a CFTR protein lacking the amino acid phenylalanine at position 508.

[0083] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0084] As used herein, the term "alkyl" means a saturated or partially saturated, branched or unbranched aliphatic hydrocarbon containing 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) in which one or more adjacent carbon atoms are interrupted by a bis(alkenyl) or tris(alkynyl) bond. The alkyl group may be substituted or unsubstituted.

[0085] As used herein, the term "aliphatic" or "aliphatic group" means a straight chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or an aromatic (also referred to herein as "alicyclic", "carbocycle" or "cycloalkyl") monocyclic or bicyclic hydrocarbon that is completely saturated or contains one or more unsaturated units but is not a single point of connection with the rest 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 still 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, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C alkyl that is completely saturated or contains one or more unsaturated units. 3-8 Hydrocarbon or bicyclic or tricyclic C 8-14 A hydrocarbon, but not aromatic, having a single point of attachment to the rest of the molecule, wherein any individual ring in the bicyclic ring system has 3-7 members. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, and (cycloalkyl)alkenyl. Suitable cycloaliphatic groups include cycloalkyl, bicyclic cycloalkyl (e.g., decalin), bridged bicyclic alkyl (e.g., norbornyl or [2.2.2]bicyclo-octyl), and bridged tricyclic (e.g., adamantyl).

[0086] As used herein, the term "halogen" or "halo" means F, Cl, Br or I.

[0087] As used herein, the term "alkoxy" refers to an alkyl or cycloalkyl group bonded to an oxygen atom. The alkoxy group may be substituted or unsubstituted.

[0088] As used herein, "cycloalkyl" refers to a cyclic non-aromatic hydrocarbon group containing 3-12 carbons (e.g., 3-10 carbons) in the ring. "Cycloalkyl" encompasses monocyclic, bicyclic, tricyclic, bridged rings, fused rings and spirocyclic rings, including monospirocyclic and dispirocyclic rings. Non-limiting examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, spiro [2.2] hexane and dispiro [2.0.2.1] heptane. Cycloalkyl can be substituted or unsubstituted.

[0089] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; any quaternized form of basic nitrogen; or a substituent of a heterocyclic ring, such as nitrogen N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).

[0090] As used herein, the term "heterocyclyl", "heterocycle", or "heterocycle" means non-aromatic monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused and spiro ring systems, including monospiro and bispiro ring systems, in which one or more ring members are independently selected heteroatoms. In some embodiments, a "heterocycle", "heterocyclyl", or "heterocyclic" group has three to fourteen 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 three to seven ring members.

[0091] As used herein, the term "aryl" is a functional group or substituent derived from an aromatic ring and encompasses monocyclic aromatic rings and bicyclic, tricyclic and fused ring systems, wherein at least one ring in the system is aromatic. Aryl can be optionally substituted with one or more substituents. Non-limiting examples of aryl include phenyl, naphthyl and 1,2,3,4-tetrahydronaphthyl.

[0092] As used herein, the term "heteroaryl" refers to an aromatic ring including at least one ring atom, wherein the at least one ring atom is a heteroatom, such as O, N or S. Heteroaryl encompasses monocyclic, bicyclic and tricyclic systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains three to seven ring members. Non-limiting examples of heteroaryl rings include pyridine, quinoline, indole and dihydroindole. Heteroaryl can be optionally substituted with one or more substituents. In certain embodiments, the term "heteroaryl ring" encompasses heteroaryl rings with 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.

[0093] "Tert" and "t-" are used interchangeably and mean tertiary.

[0094] As used herein, the term "stable" refers to a compound that is not substantially altered when subjected to conditions that allow for its production, detection, and preferably its recovery, purification, and use for one or more of the purposes disclosed herein.

[0095] "Selected from" and "chosen from" are used interchangeably herein.

[0096] As used herein, the term "solvent" refers to any liquid in which the product is at least partially soluble (solubility of the product > 1 g / L).

[0097] Non-limiting examples of suitable solvents that can be used in the present disclosure include, for example, water (H 2 O), methanol (MeOH), 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-butyl alcohol, diethyl ether (Et 2 O), methyl tert-butyl ether (MTBE), 1,4-dioxane and N-methylpyrrolidone (NMP).

[0098] As used herein, the term "protecting group" refers to any chemical group introduced into a molecule by chemical modification of a functional group in order to obtain chemical selectivity in a subsequent chemical reaction.

[0099] Methods for adding (commonly referred to as "protection") and removing (commonly referred to as "deprotection") protecting groups are well known in the art and are available in, for example, PJ Kocienski, Protecting Groups, 3rd Edition (Thieme, 2005) and Greene and Wuts, Protective Groups in Organic Synthesis, 4th Edition (John Wiley & Sons, New York, 2007), both of which are incorporated herein by reference in their entirety.

[0100] Non-limiting examples of useful protecting groups for the amines useful in the present disclosure include monovalent protecting groups such as tert-butoxycarbonyl (Boc), benzyl (Bn), β-methoxyethoxytrityl (MEM), tetrahydropyranyl (THP), 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), formyl, acetyl (Ac), trifluoroacetyl (TFA), trityl (Tr), and p-toluenesulfonyl (Ts); and divalent protecting groups such as benzylidene, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycolamine, N-dithiosuccinyl imine, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole (BIPSOP), N-1,1,4,4-tetramethyldisilazacyclopentane (STABASE), N-1,1,3,3-tetramethyl-1,3-disilaindoline (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.

[0101] Non-limiting examples of useful protecting groups for alcohols useful 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 (TMS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), and tert-butyldiphenylsilyl (TBDPS).

[0102] Non-limiting examples of useful protecting groups for carboxylic acids useful 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 cyano. methyl, acetyl (Ac), phenacyl, substituted phenacyl esters, 2,2,2-trichloroethyl, 2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, tert-butyl, 3-methyl-3-pentyl, dicyclopropylmethyl, cyclopentyl, cyclohexyl, allyl, methallyl, cinnamoyl, phenyl (Ph), silyl esters, benzyl and substituted benzyl esters, 2,6-dialkylphenyl, and pentafluorophenyl (PFP).

[0103] Non-limiting examples of amine bases that can be used in the present disclosure include, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine (NMM), triethylamine (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).

[0104] Non-limiting examples of carbonate bases that can be used in the present disclosure include, for example, sodium carbonate (Na 2 CO 3 ), potassium carbonate (K 2 CO 3 ), cesium carbonate (Cs2 CO 3 )、Lithium carbonate (Li 2 CO 3 ), sodium bicarbonate (NaHCO 3 ) and potassium bicarbonate (KHCO 3 ).

[0105] Non-limiting examples of alkoxide bases that can be used in the present disclosure include, for example, t-AmOLi (lithium tert-amylate), t-AmONa (sodium tert-amylate), t-AmOK (potassium tert-amylate), sodium tert-butoxide (NaOtBu), potassium tert-butoxide (KOtBu), and sodium methoxide (NaOMe; NaOCH 3 ).

[0106] 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.

[0107] Non-limiting examples of phosphate bases that can be used in the present disclosure include, for example, trisodium phosphate (Na3PO 4 ), tripotassium phosphate (K 3 PO 4 ), potassium dihydrogen phosphate (K 2 HPO 4 ) and potassium dihydrogen phosphate (KH 2 PO 4 ).

[0108] Non-limiting examples of acids that can be used in the present disclosure include, for example, trifluoroacetic acid (TFA), hydrochloric acid (HCl), methanesulfonic acid (MsOH), phosphoric acid (H 3 PO 4 ) and sulfuric acid (H 2 SO 4 ).

[0109] 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 can be used in the present disclosure include, for example, H 2 and palladium on carbon; H 2 and palladium on alumina; sodium dithionite (Na 2 S 2 O 4 ); iron (Fe) and acetic acid (AcOH); and iron (Fe) and ammonium chloride (NH 4 Cl).

[0110] As used herein, the term "sulfonyl chloride" refers to a 2 -) with chlorine atoms (e.g., RSO 2 Cl) alone. Non-limiting examples of sulfonyl chlorides include, for example, methanesulfonyl chloride (MeSO 2 Cl), trifluoromethanesulfonyl chloride (F 3 CSO 2 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 Cl or 4-NsCl).

[0111] Suitable sulfonate-OSO that can be used in the present disclosure 2 Non-limiting examples of R include, for example, methanesulfonyl (R = Me), trifluoromethanesulfonyl (R = CF 3 )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 -).

[0112] When referring to compounds of the present disclosure, the term "compound" refers to a collection of molecules having the same chemical structure except for possible isotopic variations among the constituent atoms of the molecules.

[0113] The compounds described herein may be optionally substituted with one or more substituents, as generally shown above, or as exemplified by specific classes, subclasses and species of the present disclosure. It should be understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". Typically, the term "substituted", whether preceded by the term "optionally", indicates that at least one hydrogen in the "substituted" group is replaced by a substituent. Unless otherwise indicated, the "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 by more than one substituent selected from a specified group, the substituent at each position may be the same or different. The combination of substituents contemplated by the present disclosure is preferably a combination of substituents that results in the formation of a stable or chemically feasible compound.

[0114] As used herein, the term "stable compound" refers to a compound that has sufficient stability to allow its manufacture and is capable of maintaining the integrity of the compound for a sufficient period of time so that it can be used for the purposes detailed herein (e.g., formulation into a therapeutic product, an intermediate for producing a therapeutic compound, an isolatable or storable intermediate, and / or treating a disease or condition responsive to a therapeutic agent).

[0115] As used herein, the term "stereoisomer" refers to both enantiomers and diastereomers.

[0116] It should be understood that certain compounds of the present invention may exist as individual stereoisomers or enantiomers and / or mixtures of those stereoisomers or enantiomers. As used in the chemical structures disclosed herein, the "wedge" with respect to stereogenic atoms is or "hash" A bond indicates a chiral center of known absolute stereochemistry (ie, a stereoisomer). As used in the chemical structures disclosed herein, a "wavy" bond to a stereogenic atom indicates a chiral center of unknown absolute stereochemistry (ie, one stereoisomer). As used in the chemical structures disclosed herein, a "wavy" bond to a double-bonded carbon indicates a mixture of E / Z isomers. As used in the chemical structures disclosed herein, the ("straight") bonds indicate that a mixture (e.g., a racemate or an enrichment) is present. As used herein, the two carbon atoms of a double bond are ("straight") bonds indicate that the double bond has the E / Z stereochemistry as drawn. As used in the chemical structures disclosed herein, (ie, a "wavy" line perpendicular to the "straight" bond of group "A") indicates that group "A" is a substituent whose point of attachment is at the end of the bond terminating at the "wavy" line.

[0117] Certain compounds disclosed herein may exist as tautomers, and both tautomeric forms are contemplated, even if only a single tautomeric structure is depicted. For example, a description of compound A should be understood to include its tautomer compound B, and vice versa, as well as mixtures thereof:

[0118]

[0119] Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0120] Unless otherwise indicated, structures depicted herein are also meant to encompass all isomeric forms of the structure, e.g., geometric (or conformational), such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, geometric and conformational mixtures of the disclosed compounds are within the scope of the present disclosure.

[0121] As used herein, the term "pharmaceutically acceptable solid form" refers to a solid form of Compound 1 of the present disclosure, wherein the solid form of Compound 1 (e.g., crystalline free form, crystalline salt, crystalline salt solvate, crystalline salt hydrate, and amorphous form) is non-toxic and suitable for pharmaceutical compositions.

[0122] When used in combination with the dosage, amount or weight percentage of the ingredients of the composition or dosage form, the terms "about" and "approximately" include the value of the specified dosage, amount or weight percentage or the range of the dosage, amount or weight percentage that is considered by those of ordinary skill in the art to provide a pharmacological effect equivalent to the pharmacological effect obtained from the specified dosage, amount or weight percentage. As used herein, when used in combination with amount, volume, reaction time, reaction temperature, etc. in a method or process, the terms "about" and "approximately" may refer to the acceptable error of a specific value as determined by those skilled in the art, which depends in part on how to measure or determine the value. In some embodiments, the terms "about" or "approximately" mean within 1, 2, 3 or 4 standard deviations. In certain embodiments, the terms "about" and "approximately" mean 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 "~" that appears immediately before a value has the same meaning as the terms "about" and "approximately".

[0123] As used herein, the term "amorphous" refers to a solid material that does not have a long-range order in the position of its molecules. Amorphous solids are generally glasses or supercooled liquids in which molecules are arranged in a random manner so that there is no clear arrangement (e.g., molecular stacking) and there is no long-range order. Amorphous solids are generally isotropic, that is, they show similar properties in all directions and do not have a definite melting point. On the contrary, they generally show a glass transition temperature, which marks the transition from a vitrified amorphous state to a supercooled liquid amorphous state when heated. For example, an amorphous material is a solid material that does not have a sharp characteristic crystalline peak in its X-ray powder diffraction (XRPD) diagram (i.e., not crystalline as determined by XRPD). On the contrary, one or more broad peaks (e.g., halo) appear in its XRPD diagram. Broad peaks are the characteristics of amorphous solids. For a comparison of the XRPD of amorphous materials and crystalline materials, see US2004 / 0006237. In some embodiments, the solid material may include an amorphous compound, and the material may be characterized, for example, by the lack of sharp characteristic crystalline peaks in its XRPD spectrum (i.e., the material is not crystalline but amorphous as determined by XRPD). In contrast, one or several broad peaks (e.g., halos) may appear in the XRPD pattern of the material. For a representative comparison of the XRPD of amorphous and crystalline materials, see US2004 / 0006237. A solid material comprising an amorphous compound may be characterized, for example, by the wider melting temperature range of the solid material compared to the melting range of a pure crystalline solid. Other techniques such as solid-state NMR may also be used to characterize crystalline or amorphous forms.

[0124] As used herein, the terms "crystalline form", "crystalline form" and "form" refer interchangeably to a crystalline structure (or polymorph) having a specific molecular packing arrangement in the crystal lattice. The crystalline form can be characterized by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, and solid-state nuclear magnetic resonance (e.g., 13 C. 19 F. 15 N and 31 Thus, as used herein, the terms "crystalline Form A of Compound (I)" and "crystalline p-toluenesulfonate salt of Compound (I)" refer to crystalline Form A of Compound (I) that can be characterized by one or more characterization techniques, including, for example, XRPD, single crystal X-ray diffraction, and 13 Unique crystalline forms are identified and distinguished from one another by C SSNMR.In some embodiments, the novel crystalline form is characterized by an X-ray powder diffraction pattern having one or more signals at one or more specified degree 2θ values ​​(°2θ).

[0125] As used herein, the term "free form" refers to a non-ionized version of a compound in a solid state. Examples of free forms include free bases and free acids.

[0126] As used herein, the term "pure form" refers to the unsolvated and unhydrated free-form version of a compound in a solid state.

[0127] As used herein, the term "solvate" refers to a crystalline form comprising one or more molecules of a compound of the present disclosure and one or more molecules of a stoichiometric or non-stoichiometric amount of one or more solvents incorporated into the crystal lattice. When the solvent is water, the solvate is referred to as a "hydrate."

[0128] In some embodiments, the solid material may include a mixture of crystalline solids and amorphous solids. A solid material including an amorphous compound may also, for example, contain up to 30% crystalline solids. In some embodiments, a solid material prepared to include an amorphous compound may also, for example, contain up to 25%, 20%, 15%, 10%, 5% or 2% crystalline solids. In embodiments where the solid material contains a mixture of crystalline solids and amorphous solids, characterization data such as XRPD may contain indicators of both crystalline solids and amorphous solids. In some embodiments, the crystalline form of the present disclosure may contain up to 30% amorphous compounds. In some embodiments, a crystalline formulation of Compound I may contain up to 25%, 20%, 15%, 10%, 5% or 2% amorphous solids.

[0129] As used herein, the term "substantially amorphous" refers to a solid material that has little or no long-range order in the positions of its molecules. For example, a substantially amorphous material has less than 15% crystallinity (e.g., less than 10% crystallinity, less than 5% crystallinity, or less than 2% crystallinity). It should also be noted that the term "substantially amorphous" encompasses the descriptor "amorphous," which refers to a material with no (0%) crystallinity.

[0130] 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 should also be noted that the term "substantially crystalline" includes the descriptor "crystalline," which refers to a material that is in 100% crystalline form.

[0131] As used herein, the term "ambient conditions" means room temperature, open air conditions, and uncontrolled humidity conditions. As used herein, the term "room temperature" or "ambient temperature" means 15°C to 30°C.

[0132] As used herein, the terms "X-ray powder diffractogram", "X-ray powder diffraction pattern", "XRPD pattern", "XRPD spectrum" refer interchangeably to an experimentally obtained graph that plots signal position (on the abscissa) versus signal intensity (on the ordinate).

[0133] As used herein, "signal" or "peak" refers to a point in an XRPD pattern where the intensity, as measured in counts, is at a local maximum. An XRPD peak is identified by its angle value measured in degrees 2θ (°2θ) depicted on the abscissa of the X-ray powder diffraction pattern, which angle value may be expressed, for example, as "signal at ... degrees 2θ", "signal at [a] 2θ value of ...", and / or "signal at at least ... 2θ values ​​selected from ...".

[0134] The repeatability of the measured angle values ​​is within the range of ±0.2° 2θ, i.e., the angle value can be at the listed angle value +0.2 degrees 2θ, at the angle value -0.2 degrees 2θ, or at any value between these two end points (angle value +0.2 degrees 2θ and angle value -0.2 degrees 2θ).

[0135] One of ordinary 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. In fact, one of ordinary skill in the art will recognize that some industry-recognized methods are capable of and are suitable for determining whether a signal is present in a pattern, such as Rietveld refinement.

[0136] The terms "signal intensity" and "peak intensity" refer interchangeably to the relative signal intensity within a given X-ray powder diffraction pattern. Factors that may affect the relative signal or peak intensity include sample thickness and preferred orientation (e.g., crystalline particles are not randomly distributed).

[0137] As used herein, an X-ray powder diffraction pattern is "substantially similar to that in a [particular] pattern" when at least 90% (e.g., at least 95%, at least 98%, or at least 99%) of the signals in the two diffraction patterns overlap. In determining "substantial similarity," one of ordinary skill in the art will understand that even for the same crystalline form, there may be variations in the intensity and / or signal positions in an XRPD diffraction pattern. Thus, one of ordinary skill in the art will understand that a signal maximum (in degrees 2θ) in an XRPD diffraction pattern generally means that the value is identified as ±0.2 degrees 2θ of the reported value, which is a variance recognized in the industry.

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

[0139] As used herein, the term "DSC" refers to the analytical method of Differential Scanning Calorimetry.

[0140] As used herein, the term "glass transition temperature" or "Tg" refers to the temperature above which a hard and brittle "glassy" amorphous solid becomes sticky or rubbery.

[0141] As used herein, the term "melting temperature," "melting point," or "Tm" refers to the temperature at which a material transitions from a solid phase to a liquid phase.

[0142] As used herein, the term "dispersion" refers to a dispersed system in which one substance (i.e., the dispersed phase) is distributed in discrete units throughout a second substance (continuous phase or medium). The size of the dispersed phase can vary significantly (e.g., colloidal particles ranging in size from nanometers to several microns). Typically, the dispersed phase can be solid, liquid, or gas. In the case of a solid dispersion, both the dispersed phase and the continuous phase are solid. In pharmaceutical applications, solid dispersions may include, in particular, crystalline drugs in the form of amorphous polymers; amorphous drugs in the form of amorphous polymers; amorphous drugs dispersed in amorphous drugs; or alternatively amorphous drugs dispersed in one or more excipients. In some embodiments, the solid dispersion comprises a polymer constituting the dispersed phase and a drug constituting the continuous phase. Alternatively, the solid dispersion comprises a drug constituting the dispersed phase and a polymer constituting the continuous phase.

[0143] The present disclosure also provides methods for preparing salts of the compounds of the present disclosure.

[0144] Salts of the compounds of the present disclosure are formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. In some embodiments, the salt is a pharmaceutically acceptable salt.

[0145] As used herein, the term "pharmaceutically acceptable salt" means any non-toxic salt that is capable of providing, directly or indirectly, a compound of the present disclosure when administered to a recipient. Pharmaceutically acceptable salts of the compounds of the present disclosure include salts derived from suitable inorganic and organic acids and bases. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is non-toxic when released from the salt when administered to a recipient. One of ordinary skill in the art will recognize that when disclosing an amount of a "compound or a pharmaceutically acceptable salt thereof," the amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound.

[0146] For example, a "free base" form of a compound does not contain an ionically bonded salt. It should be noted that the disclosed amounts of a compound or a pharmaceutically acceptable salt thereof herein are based on its free base form. For example, "10 mg of at least one compound selected from Compound 1 and a pharmaceutically acceptable salt thereof" includes 10 mg of Compound 1 and a pharmaceutically acceptable salt of Compound 1 in a concentration equivalent to 10 mg of Compound 1.

[0147] Suitable pharmaceutically acceptable salts are, for example, those disclosed in SM Berge et al., Journal of Pharmaceutical Sciences (J. Pharm. Sci.), 1977, 66, 1-19. For example, Table 1 of the article provides the following pharmaceutically acceptable salts:

[0148] Table of pharmaceutically acceptable salts

[0149]

[0150]

[0151] Non-limiting examples of pharmaceutically acceptable salts derived from appropriate acids include: salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid; salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; and salts formed by using other methods used in the art such as ion exchange. Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbic acid, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfuric acid, 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. Non-limiting examples of pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4Salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium and magnesium. Additional 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 benzenesulfonates and glucosamine salts.

[0152] In some embodiments, the present disclosure also relates to methods for preparing isotopically labeled compounds of the aforementioned compounds or pharmaceutically acceptable salts thereof, wherein the formulas and variables of such compounds and salts are each and independently as described above or in any other embodiment above, with the proviso that one or more atoms are replaced by one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the atoms that normally occur in nature (isotopically labeled). Examples of commercially available isotopes suitable for the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, respectively 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl.

[0153] 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 indicated, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen in its natural abundance isotopic composition.

[0154] As used herein, the term "derivative" refers to a collection of molecules having the same chemical structure as the compounds of the present disclosure, except that one or more atoms of the molecule may have been replaced by another atom. In addition, unless otherwise specified, the structures described herein are also intended to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium or replacing 13 C or 14 Compounds having the present structures except for the substitution of C for carbon are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as compounds with improved therapeutic properties.

[0155] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as a reference compound and having one or more hydrogen atoms replaced by a deuterium atom. In some embodiments, the one or more hydrogens replaced by deuterium are part of an alkyl group. In some embodiments, the one or more hydrogens replaced by deuterium are part of a methyl group. In chemical structures, deuterium can be represented as "D".

[0156] As used herein, the phrase "deuterated derivatives of [compound] and stereoisomers thereof and pharmaceutically acceptable salts of any of the foregoing" is intended to include deuterated derivatives of a particular compound, deuterated derivatives of any stereoisomer of that compound, and pharmaceutically acceptable salts of a particular compound, pharmaceutically acceptable salts of any of the stereoisomers of that compound, and pharmaceutically acceptable salts of a deuterated derivative of a particular compound or its stereoisomers.

[0157] In some embodiments, the derivative is a silicon derivative, wherein at least one carbon atom in the disclosed compound has been replaced by silicon. In some embodiments, the at least one carbon atom replaced by silicon can be a non-aromatic carbon. In some embodiments, the at least one carbon atom replaced by silicon can be an aromatic carbon. In certain embodiments, the silicon derivatives of the present invention can also have one or more hydrogen atoms replaced by deuterium and / or germanium.

[0158] In other embodiments, the derivatives are germanium derivatives, wherein at least one carbon atom in the disclosed compounds has been 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.

[0159] Since the general properties of silicon and germanium are similar to those of carbon, replacing carbon with silicon or germanium can produce compounds with similar biological activities as the original compounds containing carbon. DETAILED DESCRIPTION

[0160] Solid form

[0161] Another aspect of the present disclosure provides solid forms (e.g., crystalline forms, amorphous forms, solvates) of Compound 1, which can be used in the methods of treatment and pharmaceutical compositions described herein. In some embodiments, the present invention provides a pure amorphous form of Compound 1. In some embodiments, the present invention provides a pure crystalline form of Compound 1. In some embodiments, the present invention provides a solvate crystalline form of Compound 1.

[0162] A. Compound I methanol solvate (wet)

[0163] In some embodiments, the present invention provides crystalline Compound 1 Methanol Solvate (wet). Figure 3An X-ray powder diffraction pattern of crystalline Compound 1 methanol solvate (wet) is provided.

[0164] In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is substantially pure. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is substantially crystalline. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by an X-ray powder diffraction pattern generated by X-ray powder diffraction analysis with an incident beam of Cu Ka radiation.

[0165] In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by an X-ray powder diffraction pattern having a signal at 25.5±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by an X-ray powder diffraction pattern having a signal at 21.0±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by an X-ray powder diffraction pattern having a signal at 20.5±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by an X-ray powder diffraction pattern having a signal at 19.0±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by an X-ray powder diffraction pattern having a signal at 18.9±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by an X-ray powder diffraction pattern having a signal at 18.6±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by an X-ray powder diffraction pattern having a signal at 16.9±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by an X-ray powder diffraction pattern having a signal at 15.0±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by an X-ray powder diffraction pattern having a signal at 14.6±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by an X-ray powder diffraction pattern having a signal at 8.4±0.2 degrees 2θ.

[0166] In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by an X-ray powder diffraction pattern having signals at two or more of 25.5±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, 19.0±0.2 degrees 2θ, 18.9±0.2 degrees 2θ, 18.6±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, 15.0±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by an X-ray powder diffraction pattern having signals at three or more of 25.5±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, 19.0±0.2 degrees 2θ, 18.9±0.2 degrees 2θ, 18.6±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, 15.0±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by an X-ray powder diffraction pattern having signals at four or more of 25.5±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, 19.0±0.2 degrees 2θ, 18.9±0.2 degrees 2θ, 18.6±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, 15.0±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by an X-ray powder diffraction pattern having signals at five or more of 25.5±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, 19.0±0.2 degrees 2θ, 18.9±0.2 degrees 2θ, 18.6±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, 15.0±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by an X-ray powder diffraction pattern having signals at six or more of 25.5±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, 19.0±0.2 degrees 2θ, 18.9±0.2 degrees 2θ, 18.6±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, 15.0±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ.

[0167] In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by an X-ray powder diffraction pattern having signals at 25.5±0.2 degrees 2θ and 8.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by an X-ray powder diffraction pattern having signals at 20.5±0.2 degrees 2θ and 8.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by an X-ray powder diffraction pattern having signals at 20.5±0.2 degrees 2θ and 16.9±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by an X-ray powder diffraction pattern having signals at 25.5±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by an X-ray powder diffraction pattern having signals at 20.5±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by an X-ray powder diffraction pattern having signals at 25.5±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ.

[0168] In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by an X-ray powder diffraction pattern having signals at 25.5±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, 19.0±0.2 degrees 2θ, 18.9±0.2 degrees 2θ, 18.6±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, 15.0±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ.

[0169] In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by being substantially similar to Figure 3 X-ray powder diffraction pattern of .

[0170] In some embodiments, the methanol solvate (wet) is characterized by a monoclinic crystal system, namely P2 1 space group, and in the case of Cu K α radiation The following unit cell dimensions were measured on a Rigaku diffractometer at 100 K:

[0171] a α90°

[0172] b β92.1±0.1°

[0173] c γ90°.

[0174] In some embodiments, the crystalline Compound Methanol Solvate (wet) is characterized as having a peak at 164.2±0.2 ppm 13 C SSNMR Spectrum. In some embodiments, the crystalline Compound methanol solvate (wet) is characterized by having a peak at 162.8±0.2 ppm 13 C SSNMR spectrum. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by having a signal at 145.6±0.2 ppm. 13 C SSNMR Spectrum. In some embodiments, the crystalline Compound methanol solvate (wet) is characterized by having a peak at 132.5±0.2 ppm 13 C SSNMR Spectrum. In some embodiments, the crystalline Compound methanol solvate (wet) is characterized by having a peak at 124.5±0.2 ppm 13 C SSNMR spectrum. In some embodiments, the crystalline Compound methanol solvate (wet) is characterized by having a peak at 122.1±0.2 ppm 13 C SSNMR spectrum. In some embodiments, the crystalline Compound methanol solvate (wet) is characterized by having a peak at 120.6±0.2 ppm 13 C SSNMR spectrum. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by having a signal at 113.1 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by having a signal at 73.5±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by having a signal at 55.9±0.2 ppm. 13 C SSNMR Spectrum. In some embodiments, the crystalline Compound methanol solvate (wet) is characterized by having a peak at 49.7±0.2 ppm 13 C SSNMR spectrum. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by having a signal at 35.2±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by having a signal at 31.1 ± 0.2 ppm. 13CSS NMR spectrum. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by having a CSS NMR spectrum containing a signal at 30.5 ± 0.2 ppm. 13 C SSNMR Spectrum. In some embodiments, the crystalline Compound methanol solvate (wet) is characterized by having a peak at 29.3±0.2 ppm. 13 C SSNMR Spectrum. In some embodiments, the crystalline Compound methanol solvate (wet) is characterized by having a peak at 27.4±0.2 ppm 13 C SSNMR spectrum. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by having a signal at 24.8±0.2 ppm. 13 C SSNMR Spectrum. In some embodiments, the crystalline Compound methanol solvate (wet) is characterized by having a peak at 21.0±0.2 ppm 13 C SSNMR spectrum. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by having a signal at 19.0±0.2 ppm. 13 C SSNMR spectrum.

[0175] In some embodiments, the crystalline Compound 1 Methanol Solvate (Wet) is characterized by having a signal containing one or more selected from the group consisting of 13 C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by having a signal comprising two or more selected from 13CSS NMR spectrum: 164.2±0.2ppm, 162.8±0.2ppm, 145.6±0.2ppm, 132.5±0.2ppm, 124.5±0.2ppm, 122.1±0.2ppm, 120.6±0.2ppm, 113.1±0.2ppm, 73.5±0.2ppm, 55.9±0.2ppm, 49.7±0.2ppm, 35.2±0.2ppm, 31.1±0.2ppm, 30.5±0.2ppm, 29.3±0.2ppm, 27.4±0.2ppm, 24.8±0.2ppm, 21.0±0.2ppm, and 19.0±0.2ppm. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by having a signal containing three or more selected from 13 C SSNMR spectrum: 164.2±0.2ppm, 162.8±0.2ppm, 145.6±0.2ppm, 132.5±0.2ppm, 124.5±0.2ppm, 122.1±0.2ppm, 120.6±0.2ppm, 113.1±0.2ppm, 73.5±0.2pp m. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized as having a crystal structure containing four or more signals 164.2±0.2ppm, 162.8±0.2ppm, 145.6±0.2ppm, 132.5±0.2ppm, 124.5±0.2ppm, 122.1±0.2ppm, 120.6±0.2ppm, 113.1±0.2ppm, 73.5±0.2ppm, 55.9±0.2ppm, 49.7±0.2ppm, 35.2±0.2ppm, 31.1±0.2ppm, 30.5±0.2ppm, 29.3±0.2ppm, 27.4±0.2ppm, 24.8±0.2ppm, 21.0±0.2ppm, and 19.0±0.2ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by having a spectrum containing five or more signals selected from the following: 13C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by having a signal containing six or more selected from 13 C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by having a signal comprising seven or more selected from the group consisting of 13 C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by having a signal containing eight or more selected from the group consisting of 13C SSNMR spectrum: 164.2±0.2ppm, 162.8±0.2ppm, 145.6±0.2ppm, 132.5±0.2ppm, 124.5±0.2ppm, 122.1±0.2ppm, 120.6±0.2ppm, 113.1±0.2ppm, 73.5±0.2pp m.

[0176] In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized as having a crystal structure containing 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 C SSNMR spectrum. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized as having a spectral distribution containing 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. 13 CSS NMR spectrum.

[0177] In some embodiments, the crystalline Compound 1 Methanol Solvate (Wet) is characterized by having a signal comprising two or more selected from the group consisting of 13 C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by having a signal containing three or more selected from the group consisting of13 C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by having a signal containing four or more selected from the group consisting of 13 C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by having a signal containing five or more selected from the group consisting of 13 C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by having a signal containing six or more selected from the following: 13 C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by having a signal containing seven or more selected from the following: 13 C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by having eight or more signals selected from the group consisting of 13C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by having a signal containing nine or more selected from the following: 13 CSSNMR spectrum: 145.6±0.2ppm, 132.5±0.2ppm, 113.1±0.2ppm, 73.5±0.2ppm, 55.9±0.2ppm, 35.2±0.2ppm, 31.1±0.2ppm, 30.5±0.2ppm, 24.8±0.2ppm and 19.0±0.2ppm.

[0178] In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized as having a chromatogram containing signals at 145.6±0.2 ppm and 132.5±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by having a spectral distribution containing 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 Compound 1 methanol solvate (wet) is characterized by having a spectral distribution containing 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 Compound 1 methanol solvate (wet) is characterized by having a spectral distribution containing 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 C SSNMR spectrum. In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by having a spectral distribution containing 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 C SSNMR spectrum.

[0179] In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized as having a crystal structure containing 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 C SSNMR spectrum.

[0180] In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by being substantially similar to Figure 4 of 13 C SSNMR spectrum.

[0181] In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by having a pH of -63.9 ± 0.2 ppm. 19 F MAS signal. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by having a F MAS signal at -76.6 ± 0.2 ppm. 19 F MAS signal. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by having a F MAS signal at -79.7 ± 0.2 ppm. 19 F MAS signal.

[0182] In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by having a signal containing two signals selected from -63.9 ± 0.2 ppm, -76.6 ± 0.2 ppm, and -79.7 ± 0.2 ppm. 19 F MAS. In some embodiments, the crystalline Compound 1 methanol solvate (wet) is characterized by having peaks at -63.9 ± 0.2 ppm, -76.6 ± 0.2 ppm, and -79.7 ± 0.2 ppm. 19 F MAS signal.

[0183] In some embodiments, the crystalline Compound 1 Methanol Solvate (wet) is characterized by being substantially similar to Figure 5 of 19 F MAS.

[0184] Another aspect of the present invention provides a method for preparing a crystalline Compound I methanol solvate (wet). In some embodiments, the method for preparing a crystalline Compound I methanol solvate (wet) comprises: (i) combining Compound I pure Form A, 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 to stand at room temperature for more than 3 days to produce a crystalline Compound I methanol solvate (wet).

[0185] B. Compound I methanol solvate (dry)

[0186] In some embodiments, the present invention provides crystalline Compound 1 Methanol Solvate (Dry). Figure 6 An X-ray powder diffraction pattern of crystalline Compound 1 methanol solvate (dry) is provided.

[0187] In some embodiments, the crystalline Compound 1 Methanol Solvate (Dry) is substantially pure. In some embodiments, the crystalline Compound 1 Methanol Solvate (Dry) is substantially crystalline. In some embodiments, the crystalline Compound 1 Methanol Solvate (Dry) is characterized by an X-ray powder diffraction pattern generated by X-ray powder diffraction analysis with an incident beam of Cu Ka radiation.

[0188] In some embodiments, the crystalline Compound 1 methanol solvate (dry) is characterized by an X-ray powder diffraction pattern having a signal at 27.2±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (dry) is characterized by an X-ray powder diffraction pattern having a signal at 26.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (dry) is characterized by an X-ray powder diffraction pattern having a signal at 25.9±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (dry) is characterized by an X-ray powder diffraction pattern having a signal at 21.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (dry) is characterized by an X-ray powder diffraction pattern having a signal at 19.3±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (dry) is characterized by an X-ray powder diffraction pattern having a signal at 18.1±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 Methanol Solvate (dry) is characterized by an X-ray powder diffraction pattern having a signal at 15.4 ± 0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 Methanol Solvate (dry) is characterized by an X-ray powder diffraction pattern having a signal at 14.2 ± 0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 Methanol Solvate (dry) is characterized by an X-ray powder diffraction pattern having a signal at 7.4 ± 0.2 degrees 2θ.

[0189] In some embodiments, the crystalline Compound 1 Methanol Solvate (dry) is characterized by an X-ray powder diffraction pattern having signals at two or more of 27.2±0.2 degrees 2θ, 26.4±0.2 degrees 2θ, 25.9±0.2 degrees 2θ, 21.4±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, 15.4±0.2 degrees 2θ, 14.2±0.2 degrees 2θ, and 7.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 Methanol Solvate (dry) is characterized by an X-ray powder diffraction pattern having signals at three or more of 27.2±0.2 degrees 2θ, 26.4±0.2 degrees 2θ, 25.9±0.2 degrees 2θ, 21.4±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, 15.4±0.2 degrees 2θ, 14.2±0.2 degrees 2θ, and 7.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 Methanol Solvate (dry) is characterized by an X-ray powder diffraction pattern having signals at four or more of 27.2±0.2 degrees 2θ, 26.4±0.2 degrees 2θ, 25.9±0.2 degrees 2θ, 21.4±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, 15.4±0.2 degrees 2θ, 14.2±0.2 degrees 2θ, and 7.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 Methanol Solvate (dry) is characterized by an X-ray powder diffraction pattern having signals at five or more of 27.2±0.2 degrees 2θ, 26.4±0.2 degrees 2θ, 25.9±0.2 degrees 2θ, 21.4±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, 15.4±0.2 degrees 2θ, 14.2±0.2 degrees 2θ, and 7.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 Methanol Solvate (dry) is characterized by an X-ray powder diffraction pattern having signals at six or more of 27.2±0.2 degrees 2θ, 26.4±0.2 degrees 2θ, 25.9±0.2 degrees 2θ, 21.4±0.2 degrees 2θ, 19.3±0.2 degrees 2γ, 18.1±0.2 degrees 2θ, 15.4±0.2 degrees 2θ, 14.2±0.2 degrees 2θ, and 7.4±0.2 degrees 2θ.

[0190] In some embodiments, the crystalline Compound 1 methanol solvate (dry) is characterized by an X-ray powder diffraction pattern having signals at 25.9±0.2 degrees 2θ and 19.3±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (dry) is characterized by an X-ray powder diffraction pattern having signals at 19.3±0.2 degrees 2θ and 15.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (dry) is characterized by an X-ray powder diffraction pattern having signals at 25.9±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, and 15.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 methanol solvate (dry) is characterized by an X-ray powder diffraction pattern having signals at 19.3±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, and 15.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 Methanol Solvate (dry) is characterized by an X-ray powder diffraction pattern having signals at 25.9±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, and 15.4±0.2 degrees 2θ.

[0191] In some embodiments, the crystalline Compound 1 Methanol Solvate (dry) is characterized by an X-ray powder diffraction pattern having signals at 27.2±0.2 degrees 2θ, 26.4±0.2 degrees 2θ, 25.9±0.2 degrees 2θ, 21.4±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, 15.4±0.2 degrees 2θ, 14.2±0.2 degrees 2θ, and 7.4±0.2 degrees 2θ.

[0192] In some embodiments, the crystalline Compound 1 Methanol Solvate (Dry) is characterized by being substantially similar to Figure 6 X-ray powder diffraction pattern of .

[0193] In some embodiments, Compound 1 Methanol Solvate (Dry) is characterized by a TGA thermogram showing a loss of approximately 1.2% from ambient temperature to about 182° C. In some embodiments, Compound 1 Methanol Solvate (Dry) is characterized by being substantially similar to Figure 7 TGA thermogram of .

[0194] In some embodiments, Compound 1 Methanol Solvate (Dry) is characterized by a DSC thermogram showing endotherms at about 175° C. and about 186° C. In some embodiments, Compound 1 Methanol Solvate (Dry) is characterized by being substantially similar to Figure 8 DSC thermogram of .

[0195] Another aspect of the present invention provides a method for preparing a crystalline Compound I methanol solvate (dry). In some embodiments, the method for preparing a crystalline Compound I methanol solvate (dry) comprises: (i) combining Compound I pure Form A, 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 more than 3 days, and (iv) drying in a vacuum oven at 60° C. overnight to produce a crystalline Compound I methanol solvate (dry).

[0196] C. Crystallized Compound I p-toluenesulfonic acid

[0197] In some embodiments, the present invention provides crystalline Compound 1 p-toluenesulfonic acid. Fig. 9 An X-ray powder diffraction pattern of crystalline Compound 1 p-toluenesulfonic acid is provided.

[0198] In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is substantially pure. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is substantially crystalline. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern generated by X-ray powder diffraction analysis with an incident beam of Cu Ka radiation.

[0199] In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having a signal at 5.7±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having a signal at 5.8±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having a signal at 7.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having a signal at 10.1±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having a signal at 11.5±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having a signal at 11.9±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having a signal at 14.9±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having a signal at 15.9 ± 0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having a signal at 16.2 ± 0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having a signal at 18.3 ± 0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having a signal at 20.4 ± 0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having a signal at 21.0 ± 0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having a signal at 21.6 ± 0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid C is characterized by an X-ray powder diffraction pattern having a signal at 22.8 ± 0.2 degrees 2θ. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having a signal at 23.2 ± 0.2 degrees 2θ.

[0200] In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having signals at two or more of 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, 10.1±0.2 degrees 2θ, 11.5±0.2 degrees 2θ, 11.9±0.2 degrees 2θ, 14.9±0.2 degrees 2θ, 15.9±0.2 degrees 2θ, 16.2±0.2 degrees 2θ, 18.3±0.2 degrees 2θ, 20.4±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 21.6±0.2 degrees 2θ, 22.8±0.2 degrees 2θ, and 23.2±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having signals at three or more of 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, 10.1±0.2 degrees 2θ, 11.5±0.2 degrees 2θ, 11.9±0.2 degrees 2θ, 14.9±0.2 degrees 2θ, 15.9±0.2 degrees 2θ, 16.2±0.2 degrees 2θ, 18.3±0.2 degrees 2θ, 20.4±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 21.6±0.2 degrees 2θ, 22.8±0.2 degrees 2θ, and 23.2±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having signals at four or more of 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, 10.1±0.2 degrees 2θ, 11.5±0.2 degrees 2θ, 11.9±0.2 degrees 2θ, 14.9±0.2 degrees 2θ, 15.9±0.2 degrees 2θ, 16.2±0.2 degrees 2θ, 18.3±0.2 degrees 2θ, 20.4±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 21.6±0.2 degrees 2θ, 22.8±0.2 degrees 2θ, and 23.2±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having signals at five or more of 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, 10.1±0.2 degrees 2θ, 11.5±0.2 degrees 2θ, 11.9±0.2 degrees 2θ, 14.9±0.2 degrees 2θ, 15.9±0.2 degrees 2θ, 16.2±0.2 degrees 2θ, 18.3±0.2 degrees 2θ, 20.4±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 21.6±0.2 degrees 2θ, 22.8±0.2 degrees 2θ, and 23.2±0.2 degrees 2θ.In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having signals at six or more of 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, 10.1±0.2 degrees 2θ, 11.5±0.2 degrees 2θ, 11.9±0.2 degrees 2θ, 14.9±0.2 degrees 2θ, 15.9±0.2 degrees 2θ, 16.2±0.2 degrees 2θ, 18.3±0.2 degrees 2θ, 20.4±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 21.6±0.2 degrees 2θ, 22.8±0.2 degrees 2θ, and 23.2±0.2 degrees 2θ.

[0201] In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having signals at 5.7±0.2 degrees 2θ and 5.8±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having signals at 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, and 7.4±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having signals at 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, and 10.1±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having signals at 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, 10.1±0.2 degrees 2θ, and 11.5±0.2 degrees 2θ. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by an X-ray powder diffraction pattern having signals at 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, 10.1±0.2 degrees 2θ, 11.5±0.2 degrees 2θ, and 11.9±0.2 degrees 2θ.

[0202] In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by being substantially similar to Fig. 9 X-ray powder diffraction pattern of .

[0203] In some embodiments, Compound 1 p-toluenesulfonic acid is characterized by a DSC thermogram showing endotherms at about 48° C. and about 115° C. In some embodiments, Compound 1 p-toluenesulfonic acid is characterized by being substantially similar to Fig.10 DSC thermogram of .

[0204] In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized as having a signal at 163.8 ± 0.2 ppm 13C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 161.8 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 160.9 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 152.9 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 146.1 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 141.0 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 139.3 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 138.0±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 136.7 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 132.5 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 130.6 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 127.8 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 126.7 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 124.7 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 122.1 ± 0.2 ppm. 13C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 114.5 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 113.1 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 110.3 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 75.5 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 57.0 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 48.6 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 35.0 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 32.5 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 31.0 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 29.8 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 28.3 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 26.2±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 25.0 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 23.0 ± 0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal at 19.5 ± 0.2 ppm.13 C SSNMR spectrum.

[0205] In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal comprising two or more selected from the group consisting of 13 C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal containing three or more selected from the group consisting of 13 C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal containing four or more selected from the group consisting of 13 C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal containing five or more selected from the group consisting of 13 C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having six or more signals selected from the group consisting of 13 C SSNMR spectrum: 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.

[0206] In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized as having a signal at 141.0±0.2 ppm and 19.5±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a spectrum containing signals at 141.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13C SSNMR spectrum. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a spectrum containing signals at 141.0±0.2 ppm, 57.0±0.2 ppm, 23.0±0.2 ppm, and 19.5±0.2 ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a spectrum containing 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 C SSNMR spectrum. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a spectrum containing 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 C SSNMR spectrum. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a spectrum containing 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 C SSNMR spectrum.

[0207] In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal containing one or more selected from the group consisting of 13C SSNMR spectrum: 163.8±0.2ppm, 161.8±0.2ppm, 160.9±0.2ppm, 152.9±0.2ppm, 146.1±0.2ppm, 141.0±0.2ppm, 139.3±0.2pp m, 138.0±0.2ppm, 136.7±0.2ppm, 132.5±0.2ppm, 130.6±0.2ppm, 127.8±0.2ppm, 126.7±0.2ppm, 124.7±0.2ppm, 122 .1±0.2ppm, 114.5±0.2ppm, 113.1±0.2ppm, 110.3±0.2ppm, 75.5±0.2ppm, 57.0±0.2ppm, 48.6±0.2ppm, 35.0±0.2ppm, 32.5±0.2ppm, 31.0±0.2ppm, 29.8±0.2ppm, 28.3±0.2ppm, 26.2±0.2ppm, 25.0±0.2ppm, 23.0±0.2ppm, and 19.5±0.2ppm. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal comprising two or more selected from 13 C SSNMR spectrum: 163.8±0.2ppm, 161.8±0.2ppm, 160.9±0.2ppm, 152.9±0.2ppm, 146.1±0.2ppm, 141.0±0.2ppm, 139.3±0.2pp m, 138.0±0.2ppm, 136.7±0.2ppm, 132.5±0.2ppm, 130.6±0.2ppm, 127.8±0.2ppm, 126.7±0.2ppm, 124.7±0.2ppm, 122 .1±0.2ppm, 114.5±0.2ppm, 113.1±0.2ppm, 110.3±0.2ppm, 75.5±0.2ppm, 57.0±0.2ppm, 48.6±0.2ppm, 35.0±0.2ppm, 32.5±0.2ppm, 31.0±0.2ppm, 29.8±0.2ppm, 28.3±0.2ppm, 26.2±0.2ppm, 25.0±0.2ppm, 23.0±0.2ppm, and 19.5±0.2ppm. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal containing three or more selected from 13C SSNMR spectrum: 163.8±0.2ppm, 161.8±0.2ppm, 160.9±0.2ppm, 152.9±0.2ppm, 146.1±0.2ppm, 141.0±0.2ppm, 139.3±0.2pp m, 138.0±0.2ppm, 136.7±0.2ppm, 132.5±0.2ppm, 130.6±0.2ppm, 127.8±0.2ppm, 126.7±0.2ppm, 124.7±0.2ppm, 122 .1±0.2ppm, 114.5±0.2ppm, 113.1±0.2ppm, 110.3±0.2ppm, 75.5±0.2ppm, 57.0±0.2ppm, 48.6±0.2ppm, 35.0±0.2ppm, 32.5±0.2ppm, 31.0±0.2ppm, 29.8±0.2ppm, 28.3±0.2ppm, 26.2±0.2ppm, 25.0±0.2ppm, 23.0±0.2ppm, and 19.5±0.2ppm. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal containing four or more selected from the group consisting of 13 C SSNMR spectrum: 163.8±0.2ppm, 161.8±0.2ppm, 160.9±0.2ppm, 152.9±0.2ppm, 146.1±0.2ppm, 141.0±0.2ppm, 139.3±0.2pp m, 138.0±0.2ppm, 136.7±0.2ppm, 132.5±0.2ppm, 130.6±0.2ppm, 127.8±0.2ppm, 126.7±0.2ppm, 124.7±0.2ppm, 122 .1±0.2ppm, 114.5±0.2ppm, 113.1±0.2ppm, 110.3±0.2ppm, 75.5±0.2ppm, 57.0±0.2ppm, 48.6±0.2ppm, 35.0±0.2ppm, 32.5±0.2ppm, 31.0±0.2ppm, 29.8±0.2ppm, 28.3±0.2ppm, 26.2±0.2ppm, 25.0±0.2ppm, 23.0±0.2ppm, and 19.5±0.2ppm. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal containing five or more selected from the group consisting of 13C SSNMR spectrum: 163.8±0.2ppm, 161.8±0.2ppm, 160.9±0.2ppm, 152.9±0.2ppm, 146.1±0.2ppm, 141.0±0.2ppm, 139.3±0.2pp m, 138.0±0.2ppm, 136.7±0.2ppm, 132.5±0.2ppm, 130.6±0.2ppm, 127.8±0.2ppm, 126.7±0.2ppm, 124.7±0.2ppm, 122 .1±0.2ppm, 114.5±0.2ppm, 113.1±0.2ppm, 110.3±0.2ppm, 75.5±0.2ppm, 57.0±0.2ppm, 48.6±0.2ppm, 35.0±0.2ppm, 32.5±0.2ppm, 31.0±0.2ppm, 29.8±0.2ppm, 28.3±0.2ppm, 26.2±0.2ppm, 25.0±0.2ppm, 23.0±0.2ppm, and 19.5±0.2ppm. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal containing six or more selected from the group consisting of 13 C SSNMR spectrum: 163.8±0.2ppm, 161.8±0.2ppm, 160.9±0.2ppm, 152.9±0.2ppm, 146.1±0.2ppm, 141.0±0.2ppm, 139.3±0.2pp m, 138.0±0.2ppm, 136.7±0.2ppm, 132.5±0.2ppm, 130.6±0.2ppm, 127.8±0.2ppm, 126.7±0.2ppm, 124.7±0.2ppm, 122 .1±0.2ppm, 114.5±0.2ppm, 113.1±0.2ppm, 110.3±0.2ppm, 75.5±0.2ppm, 57.0±0.2ppm, 48.6±0.2ppm, 35.0±0.2ppm, 32.5±0.2ppm, 31.0±0.2ppm, 29.8±0.2ppm, 28.3±0.2ppm, 26.2±0.2ppm, 25.0±0.2ppm, 23.0±0.2ppm, and 19.5±0.2ppm. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal containing seven or more selected from the group consisting of 13C SSNMR spectrum: 163.8±0.2ppm, 161.8±0.2ppm, 160.9±0.2ppm, 152.9±0.2ppm, 146.1±0.2ppm, 141.0±0.2ppm, 139.3±0.2pp m, 138.0±0.2ppm, 136.7±0.2ppm, 132.5±0.2ppm, 130.6±0.2ppm, 127.8±0.2ppm, 126.7±0.2ppm, 124.7±0.2ppm, 122 .1±0.2ppm, 114.5±0.2ppm, 113.1±0.2ppm, 110.3±0.2ppm, 75.5±0.2ppm, 57.0±0.2ppm, 48.6±0.2ppm, 35.0±0.2ppm, 32.5±0.2ppm, 31.0±0.2ppm, 29.8±0.2ppm, 28.3±0.2ppm, 26.2±0.2ppm, 25.0±0.2ppm, 23.0±0.2ppm, and 19.5±0.2ppm. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having eight or more signals selected from the group consisting of 13 C SSNMR spectrum: 163.8±0.2ppm, 161.8±0.2ppm, 160.9±0.2ppm, 152.9±0.2ppm, 146.1±0.2ppm, 141.0±0.2ppm, 139.3±0.2pp m, 138.0±0.2ppm, 136.7±0.2ppm, 132.5±0.2ppm, 130.6±0.2ppm, 127.8±0.2ppm, 126.7±0.2ppm, 124.7±0.2ppm, 122 .1±0.2ppm, 114.5±0.2ppm, 113.1±0.2ppm, 110.3±0.2ppm, 75.5±0.2ppm, 57.0±0.2ppm, 48.6±0.2ppm, 35.0±0.2ppm , 32.5±0.2ppm, 31.0±0.2ppm, 29.8±0.2ppm, 28.3±0.2ppm, 26.2±0.2ppm, 25.0±0.2ppm, 23.0±0.2ppm and 19.5±0.2ppm.

[0208] In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal comprising three or more selected from the group consisting of 13C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal comprising four or more selected from the group consisting of 13 C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal containing five or more selected from the group consisting of 13 C SSNMR spectrum: 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. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal containing six or more selected from the group consisting of 13C SSNMR spectrum: 163.8±0.2ppm, 161.8±0.2ppm, 160.9±0.2ppm, 152.9±0.2ppm, 146.1±0.2ppm, 141.0±0.2ppm, 139.3±0.2ppm, 138.0±0.2ppm, 136.7±0.2 ppm, 132.5±0.2ppm, 130.6±0.2ppm, 127.8±0.2ppm, 126.7±0.2ppm, 124.7±0.2ppm, 122.1±0.2ppm, 114.5±0.2ppm, 113.1±0.2ppm and 110.3±0.2ppm.

[0209] In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized as having a signal at 163.8±0.2ppm, 161.8±0.2ppm, 160.9±0.2ppm, 152.9±0.2ppm, 146.1±0.2ppm, 141.0±0.2ppm, 139.3±0.2ppm, 138.0±0.2ppm, 136.7±0.2ppm, 132.5±0.2ppm, 130.6±0.2ppm, 127.8±0.2ppm, 126.7±0.2ppm, 124.7±0.2ppm, 122.1±0.2ppm, 114.5±0.2ppm, 113.1±0.2ppm, and 110.3±0.2ppm. 13 C SSNMR spectrum. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a peak 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. 0.2ppm, 122.1±0.2ppm, 114.5±0.2ppm, 113.1±0.2ppm, 110.3±0.2ppm, 75.5±0.2ppm, 57.0±0.2ppm, 48.6±0.2ppm, 35.0±0.2ppm, 32.5±0.2ppm, 31.0±0.2ppm, 29.8±0.2ppm, 28.3±0.2ppm, 26.2±0.2ppm, 25.0±0.2ppm, 23.0±0.2ppm and 19.5±0.2ppm 13 C SSNMR spectrum.

[0210] In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by being substantially similar to Fig.11 of 13 CSS NMR spectrum.

[0211] In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a 19 F MAS signal. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a peak at -64.2 ± 0.2 ppm. 19 F MAS signal. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a peak at -64.6 ± 0.2 ppm. 19 F MAS signal. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a peak at -65.4 ± 0.2 ppm. 19 F MAS signal. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a peak at -66.1 ± 0.2 ppm. 19 F MAS signal. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a peak at -77.4 ± 0.2 ppm. 19 F MAS signal. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a peak at -78.1 ± 0.2 ppm. 19 F MAS signal. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a peak at -79.7 ± 0.2 ppm. 19 F MAS signal. In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by having a peak at -80.1 ± 0.2 ppm. 19 F MAS signal.

[0212] In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal comprising two or more selected from the group consisting of 19 F MAS: -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. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal containing three or more selected from the group consisting of 19F MAS: -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. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal comprising four or more selected from the group consisting of 19 FMAS: -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. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a signal containing five or more selected from the following: 19 F MAS: -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. In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having six or more signals selected from the group consisting of 19 F MAS: -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.

[0213] In some embodiments, the crystalline Compound 1 p-toluenesulfonic acid is characterized by having a temperature of -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 signal.

[0214] In some embodiments, crystalline Compound 1 p-toluenesulfonic acid is characterized by being substantially similar to Fig.12 of 19 FMAS.

[0215] Another aspect of the present invention provides a method for preparing crystalline p-toluenesulfonic acid of Compound I. In some embodiments, the method for preparing p-toluenesulfonic acid of Compound I comprises: (i) adding p-toluenesulfonic acid to pure Form A of Compound I in a grinding ball 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, and (iv) drying the resulting material in a vacuum drying oven at 40° C. to produce crystalline p-toluenesulfonic acid of Compound I.

[0216] D. Pure amorphous compound I

[0217] In some embodiments, the present invention provides pure amorphous Compound 1. In some embodiments, pure amorphous Compound 1 is substantially pure. In some embodiments, pure amorphous Compound 1 is substantially amorphous.

[0218] In some embodiments, pure amorphous Compound 1 is characterized by an X-ray powder diffraction pattern generated by X-ray powder diffraction analysis using an incident beam of Cu Ka radiation. In some embodiments, pure amorphous Compound 1 is characterized by a pattern substantially similar to Fig.13 X-ray powder diffraction pattern of .

[0219] In some embodiments, the TGA thermogram of pure amorphous Compound 1 shows negligible weight loss from ambient temperature until thermal degradation. In some embodiments, the TGA thermogram of pure amorphous Compound 1 is substantially similar to Fig.14 .

[0220] In some embodiments, the glass transition point of pure amorphous Compound I is measured using DSC. In some embodiments, the glass transition of pure 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 pure amorphous Compound I is substantially similar to Fig.15 .

[0221] Another aspect of the present invention provides a method for preparing pure amorphous Compound I. In some embodiments, the method for preparing pure amorphous Compound I comprises: (i) heating crystallized Compound I pure Form A to 200° C., and (ii) cooling the resulting material to 10° C. to produce pure amorphous Compound I.

[0222] Another aspect of the present invention provides a method for preparing pure amorphous Compound I. In some embodiments, the method for preparing pure amorphous Compound I comprises: (i) heating crystallized Compound I pure Form A to 200° C., and (ii) cooling the resulting material to 10° C. at a rate of 10° C. / min to produce pure amorphous Compound I.

[0223] Synthesis process and intermediates

[0224] In some embodiments, Compound 1 is prepared using a compound of the present disclosure.

[0225] In some embodiments, Compound I is prepared using a compound of Formula I, Formula II, or Formula III:

[0226]

[0227] or a pharmaceutically acceptable salt thereof,

[0228] in:

[0229] -R a is selected from alcohol protecting groups; and

[0230] - the compound of formula I, II or III is not selected from the following compounds: 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-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,8,14,16-hexaene (E / Z mixed) mixture); N′-[(2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]-6-[1,1-bis(trideuteromethyl)but-3-enylamino]-3-nitro-5-(trifluoromethane)pyridine-2-carbohydrazide; (6R)-6-benzyloxy-17-nitro-12,12-bis(trideuteromethyl)-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaene (E / Z mixture); and pharmaceutically acceptable salts thereof.

[0231] In some embodiments of Formula I, Formula II and / or Formula III, R ais 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 (TMS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) and tert-butyldiphenylsilyl (TBDPS). In some embodiments of Formula I, Formula II and / or Formula III, R a It's Bn.

[0232] In some embodiments, Compound 1 is prepared using Compound 6:

[0233]

[0234] or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, Compound 1 is prepared using a compound selected from:

[0236]

[0237] or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, Compound 1 is prepared using a compound selected from:

[0239]

[0240] or a pharmaceutically acceptable salt thereof, wherein:

[0241] R a is selected from alcohol protecting groups, and

[0242] R 1 Selected from -N(Boc) 2 , -NHBoc, -N(Phth), -NH(Cbz) and -NO 2 .

[0243] In some embodiments of Formula XI, Formula XII and / or Formula XIII, R ais 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 (TMS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) and tert-butyldiphenylsilyl (TBDPS). In some embodiments of Formula XI, Formula XII and / or Formula XIII, R a It's Bn.

[0244] In some embodiments, Compound 1 is prepared using a compound selected from:

[0245]

[0246] or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the compounds of the present disclosure are compounds of Formula I, Formula II, or Formula III:

[0248]

[0249] or a pharmaceutically acceptable salt thereof,

[0250] in:

[0251] -R a is selected from alcohol protecting groups; and

[0252] - the compound of formula I, II or III is not selected from the following compounds: 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-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,8,14,16-hexaene (E / Z mixed) mixture); N′-[(2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]-6-[1,1-bis(trideuteromethyl)but-3-enylamino]-3-nitro-5-(trifluoromethane)pyridine-2-carbohydrazide; (6R)-6-benzyloxy-17-nitro-12,12-bis(trideuteromethyl)-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaene (E / Z mixture); and pharmaceutically acceptable salts thereof.

[0253] 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 (TMS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) and tert-butyldiphenylsilyl (TBDPS). In some embodiments of Formula I, Formula II and / or Formula III, R a It's Bn.

[0254] In some embodiments, the compounds of the present disclosure are compounds of Formula I:

[0255]

[0256] or a pharmaceutically acceptable salt thereof, wherein R a In some embodiments of Formula I, R ais 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 (TMS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) and tert-butyldiphenylsilyl (TBDPS). In some embodiments of Formula I, R a It's Bn.

[0257] In some embodiments, the compound of the present disclosure is Compound 6:

[0258]

[0259] or a pharmaceutically acceptable salt thereof.

[0260] In some embodiments, the compounds of the present disclosure are

[0261]

[0262] or a pharmaceutically acceptable salt thereof, wherein:

[0263] R a is selected from alcohol protecting groups, and

[0264] R 1 Selected from -N(Boc) 2 , -NHBoc, -N(Phth), -NH(Cbz) and -NO 2 .

[0265] 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 (TMS), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) and tert-butyldiphenylsilyl (TBDPS). In some embodiments of Formula XI, Formula XII and / or Formula XIII, R a It's Bn.

[0266] In some embodiments, the compounds of the present disclosure are:

[0267]

[0268] or a pharmaceutically acceptable salt thereof.

[0269] Treatment

[0270] Compound I in any of the pharmaceutically acceptable solid forms disclosed herein acts as a CFTR regulator, that is, it regulates the CFTR activity in vivo. Individuals mutated in the gene encoding CFTR can benefit from receiving CFTR regulators. CFTR mutations may affect CFTR amount, i.e., the number of CFTR channels at the cell surface, or the mutations may affect CFTR function, i.e., the functional ability of each channel to open and transport ions. The mutations affecting the amount of CFTR include mutations that cause synthesis defects (class I defects), mutations that cause processing and transport defects (class II defects), mutations that cause CFTR synthesis to reduce (class V defects), and mutations that reduce the surface stability of CFTR (class VI defects). The mutations that affect CFTR function include mutations that cause gating defects (class III defects) and mutations that cause conduction defects (class IV defects). Some CFTR mutations show the characteristics of multiple categories. Some mutations in the CFTR gene cause cystic fibrosis.

[0271] Thus, in some embodiments, the present invention provides a method for treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient, the method comprising administering to the patient an effective amount of any of the pharmaceutically 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 a F508del / minimal function (MF) genotype, a F508del / F508del genotype (homozygous for the F508del mutation), a F508del / gating genotype, or a 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 the N1303K mutation.

[0272] In some embodiments, the patient is heterozygous and has a F508del mutation on one allele and a mutation on the other allele selected from the following table:

[0273] CFTR mutation table

[0274]

[0275]

[0276]

[0277] In some embodiments, the present invention provides a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient, the method comprising administering to the patient an effective amount of Compound 1 in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, the pharmaceutically acceptable solid form of Compound 1 is a substantially amorphous form. In some embodiments, the pharmaceutically acceptable solid form of Compound 1 is a substantially crystalline form.

[0278] In some embodiments, a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering to the patient an effective amount of Compound 1 in any one of the pharmaceutically acceptable crystalline forms disclosed herein. In some embodiments, the pharmaceutically acceptable crystalline form of Compound 1 is Compound 1 methanol solvate (wet). In some embodiments, the pharmaceutically acceptable crystalline form of Compound 1 is Compound 1 methanol solvate (dry). In some embodiments, the pharmaceutically acceptable crystalline form of Compound 1 is Compound 1 p-toluenesulfonic acid.

[0279] In some embodiments, a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering to the patient an effective amount of a pharmaceutically acceptable amorphous form of Compound 1 disclosed herein. In some embodiments, the pharmaceutically acceptable form of Compound 1 is pure amorphous Compound 1.

[0280] In some embodiments, the method of treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering to the patient an effective amount of any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms of Compound 1 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.

[0281] In some embodiments, the method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering to the patient an effective amount of any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof.

[0282] In some embodiments, the method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering to the patient an effective amount of Compound 1 in a solid form selected from Compound 1 methanol solvate (wet), Compound 1 methanol solvate (dry), Compound 1 p-toluenesulfonic acid, and pure amorphous Compound 1 in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof.

[0283] In some embodiments, the method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering to the patient an effective amount of Compound I in a solid crystalline form selected from Compound I methanol solvate (wet), Compound I methanol solvate (dry), Compound I p-toluenesulfonic acid, and pure 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 pharmaceutically acceptable salts and deuterated derivatives thereof.

[0284] In some embodiments, the method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprises administering to the patient an effective amount of Compound I in solid amorphous form, i.e., pure 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 pharmaceutically acceptable salts and deuterated derivatives thereof.

[0285] Pharmaceutical composition

[0286] Another aspect of the present invention provides a pharmaceutical composition comprising Compound 1 in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein. In some embodiments, the pharmaceutical composition comprises Compound 1 in a solid form selected from Compound 1 methanol solvate (wet), Compound 1 methanol solvate (dry), and Compound 1 p-toluenesulfonic acid. In some embodiments, the pharmaceutical composition comprises pure amorphous Compound 1.

[0287] In some embodiments, the present invention provides a pharmaceutical composition comprising any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein in Compound I and 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 any one of the pharmaceutically acceptable crystalline forms disclosed herein in Compound I 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, at least one additional active pharmaceutical ingredient is Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof.

[0288] In some embodiments, the at least one additional active pharmaceutical ingredient is selected from mucolytics, bronchodilators, antibiotics, anti-infective agents, and anti-inflammatory agents.

[0289] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) Compound I in any of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein; (b) and at least one pharmaceutically acceptable carrier.

[0290] In some embodiments, the present invention provides a pharmaceutical composition comprising: (a) Compound I in any one of the pharmaceutically acceptable solid (e.g., crystalline or amorphous) forms disclosed herein; (b) at least one compound selected from the group consisting of Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof; and (c) at least one pharmaceutically acceptable carrier.

[0291] In some embodiments, the present invention provides a pharmaceutical composition comprising (a) Compound I in a solid form selected from Compound I methanol solvate (wet), Compound I methanol solvate (dry), Compound I p-toluenesulfonic acid and pure 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 pharmaceutically acceptable salts and deuterated derivatives thereof, and (c) at least one pharmaceutically acceptable carrier.

[0292] The pharmaceutical compositions described herein are useful for treating cystic fibrosis and other CFTR-mediated diseases.

[0293] As described above, the pharmaceutical composition disclosed herein may optionally further include at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles. As used herein, the at least one pharmaceutically acceptable carrier comprises any and all solvents, diluents, other liquid vehicles, dispersing aids, suspension aids, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders and lubricants suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, disclose various carriers for formulating pharmaceutical compositions and known techniques for preparing the same. Unless any conventional carrier is incompatible with the compounds of the present disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component of the pharmaceutical composition, its use is contemplated to be within the scope of the present disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars (such as lactose, glucose and sucrose ), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, phosphate buffer solution, non-toxic compatible lubricants (such as sodium laurate sulfate and magnesium stearate), coloring agents, release agents, encapsulating agents, sweeteners, flavoring agents, fragrances, preservatives and antioxidants.

[0294] Restricted demonstration and implementation of

[0295] A. Collection 1

[0296] 1. A compound I

[0297]

[0298] It is in the form of a substantially amorphous pure amorphous form of Compound I (ie, wherein less than 15% of Compound I is in crystalline form, wherein less than 10% of Compound I is in crystalline form, wherein less than 5% of Compound I is in crystalline form).

[0299] 2. The substantially amorphous pure amorphous form of Compound I according to Example 1, wherein Compound I is 100% amorphous.

[0300] 3. A substantially amorphous pure amorphous form of Compound I according to Example 1 or Example 2, characterized in that it is substantially similar to Fig.13 X-ray powder diffraction pattern of .

[0301] 4. The substantially amorphous pure amorphous form of Compound I according to any one of Embodiments 1 to 3, characterized by a TGA thermogram showing negligible weight loss upon warming from ambient temperature until thermal degradation.

[0302] 5. The substantially amorphous pure amorphous form of Compound I according to any one of Embodiments 1 to 4, characterized in that it is substantially similar to Fig.14 TGA thermogram of .

[0303] 6. The substantially amorphous pure amorphous form of Compound I according to any one of Embodiments 1 to 5, characterized by a glass transition temperature of 64.8°C.

[0304] 7. The substantially amorphous pure amorphous form of Compound I according to any one of Embodiments 1 to 6, characterized in that it is substantially similar to Fig.15 DSC thermogram of .

[0305] 8. A substantially amorphous pure amorphous form of Compound I according to any one of Embodiments 1 to 7, prepared by: (i) heating crystalline Compound I Form A to 200°C, and (ii) cooling the resulting material to 10°C to produce pure amorphous Compound I.

[0306] 9. A substantially crystalline Compound 1 methanol solvate (wet) (i.e., wherein less than 15% of Compound 1 is in amorphous form, wherein less than 10% of Compound 1 is in amorphous form, wherein less than 5% of Compound 1 is in amorphous form).

[0307] 10. The substantially crystalline Compound 1 Methanol Solvate (wet) of Embodiment 9, wherein the Compound 1 Methanol Solvate (wet) is 100% crystalline.

[0308] 11. The substantially crystalline Compound 1 methanol solvate (wet) of Embodiment 9 or Embodiment 10, characterized by an X-ray powder diffraction pattern having signals at one or more of 25.5±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, 19.0±0.2 degrees 2θ, 18.9±0.2 degrees 2θ, 18.6±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, 15.0±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ.

[0309] 12. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 11, characterized by having an X-ray powder diffraction pattern having signals at two or more of 25.5±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, 19.0±0.2 degrees 2θ, 18.9±0.2 degrees 2θ, 18.6±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, 15.0±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ.

[0310] 13. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 12, characterized by having an X-ray powder diffraction pattern having signals at three or more of 25.5±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, 19.0±0.2 degrees 2θ, 18.9±0.2 degrees 2θ, 18.6±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, 15.0±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ.

[0311] 14. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 13, characterized by having an X-ray powder diffraction pattern having signals at four or more of 25.5±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, 19.0±0.2 degrees 2θ, 18.9±0.2 degrees 2θ, 18.6±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, 15.0±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ.

[0312] 15. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 14, characterized by having an X-ray powder diffraction pattern having signals at five or more of 25.5±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, 19.0±0.2 degrees 2θ, 18.9±0.2 degrees 2θ, 18.6±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, 15.0±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ.

[0313] 16. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 15, characterized by having an X-ray powder diffraction pattern having signals at six or more of 25.5±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, 19.0±0.2 degrees 2θ, 18.9±0.2 degrees 2θ, 18.6±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, 15.0±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ.

[0314] 17. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 16, characterized by having an X-ray powder diffraction pattern having signals at 25.5±0.2 degrees 2θ and 8.4±0.2 degrees 2θ.

[0315] 18. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 16, characterized by having an X-ray powder diffraction pattern having signals at 20.5±0.2 degrees 2θ and 8.4±0.2 degrees 2θ.

[0316] 19. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 16, characterized by having an X-ray powder diffraction pattern having signals at 20.5±0.2 degrees 2θ and 16.9±0.2 degrees 2θ.

[0317] 20. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 16, characterized by having an X-ray powder diffraction pattern having signals at 25.5±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ.

[0318] 21. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 16, characterized by having an X-ray powder diffraction pattern having signals at 20.5±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ.

[0319] 22. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 16, characterized by having an X-ray powder diffraction pattern having signals at 25.5±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ.

[0320] 23. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 16, characterized by having an X-ray powder diffraction pattern having signals at 25.5±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, 19.0±0.2 degrees 2θ, 18.9±0.2 degrees 2θ, 18.6±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, 15.0±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ.

[0321] 24. The substantially crystalline Compound 1 methanol solvate (wet) of any one of Embodiments 9 to 23, characterized in that it is substantially similar to Figure 3 X-ray powder diffraction pattern of .

[0322] 25. The substantially crystalline Compound 1 methanol solvate (wet) of any one of Embodiments 9 to 24, characterized by a monoclinic crystal system, i.e., P21 space group, and in a Cu K Alpha radiation The following unit cell dimensions were measured on a Rigaku diffractometer at 100 K:

[0323] a α90°

[0324] b β92.1±0.1°

[0325] C γ90°.

[0326] 26. The substantially crystalline Compound 1 methanol solvate (wet) of any one of Embodiments 9 to 25, characterized by having one or more signals selected from the group consisting of 13 C SSNMR spectrum: 145.6±0.2ppm, 132.5±0.2ppm, 113.1±0.2ppm, 73.5±0.2ppm, 55.9±0.2ppm, 35.2±0.2ppm, 31.1±0.2ppm, 30.5±0.2ppm, 24.8±0.2ppm and 19.0±0.2ppm.

[0327] 27. The substantially crystalline Compound 1 methanol solvate (wet) of any one of Embodiments 9 to 26, characterized by having two or more signals selected from the group consisting of 13 C SSNMR spectrum: 145.6±0.2ppm, 132.5±0.2ppm, 113.1±0.2ppm, 73.5±0.2ppm, 55.9±0.2ppm, 35.2±0.2ppm, 31.1±0.2ppm, 30.5±0.2ppm, 24.8±0.2ppm and 19.0±0.2ppm.

[0328] 28. The substantially crystalline Compound 1 methanol solvate (wet) of any one of Embodiments 9 to 27, characterized by having three or more signals selected from the group consisting of 13 C SSNMR spectrum: 145.6±0.2ppm, 132.5±0.2ppm, 113.1±0.2ppm, 73.5±0.2ppm, 55.9±0.2ppm, 35.2±0.2ppm, 31.1±0.2ppm, 30.5±0.2ppm, 24.8±0.2ppm and 19.0±0.2ppm.

[0329] 29. The substantially crystalline Compound 1 methanol solvate (wet) of any one of Embodiments 9 to 28, characterized by having four or more signals selected from the following: 13 C SSNMR spectrum: 145.6±0.2ppm, 132.5±0.2ppm, 113.1±0.2ppm, 73.5±0.2ppm, 55.9±0.2ppm, 35.2±0.2ppm, 31.1±0.2ppm, 30.5±0.2ppm, 24.8±0.2ppm and 19.0±0.2ppm.

[0330] 30. The substantially crystalline Compound 1 methanol solvate (wet) of any one of claims 9 to 29, characterized by having five or more signals selected from the group consisting of 13C SSNMR spectrum: 145.6±0.2ppm, 132.5±0.2ppm, 113.1±0.2ppm, 73.5±0.2ppm, 55.9±0.2ppm, 35.2±0.2ppm, 31.1±0.2ppm, 30.5±0.2ppm, 24.8±0.2ppm and 19.0±0.2ppm.

[0331] 31. The substantially crystalline Compound 1 methanol solvate (wet) of any one of Embodiments 9 to 30, characterized by having six or more signals selected from the following: 13 C SSNMR spectrum: 145.6±0.2ppm, 132.5±0.2ppm, 113.1±0.2ppm, 73.5±0.2ppm, 55.9±0.2ppm, 35.2±0.2ppm, 31.1±0.2ppm, 30.5±0.2ppm, 24.8±0.2ppm and 19.0±0.2ppm.

[0332] 32. The substantially crystalline Compound 1 methanol solvate (wet) of any one of Examples 9 to 31, characterized by having signals at 145.6±0.2 ppm and 132.5±0.2 ppm. 13 C SSNMR spectrum.

[0333] 33. The substantially crystalline Compound 1 methanol solvate (wet) of any one of Examples 9 to 31, characterized by having signals at 145.6 ± 0.2 ppm, 132.5 ± 0.2 ppm, and 113.1 ± 0.2 ppm. 13 C SSNMR spectrum.

[0334] 34. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 31, characterized by having 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.

[0335] 35. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 31, characterized by having 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 C SSNMR spectrum.

[0336] 36. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 31, characterized by having 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 C SSNMR spectrum.

[0337] 37. The substantially crystalline Compound 1 methanol solvate (wet) of any one of Examples 9 to 31, characterized by having signals at 73.5 ± 0.2 ppm and 55.9 ± 0.2 ppm. 13 C SSNMR spectrum.

[0338] 38. The substantially crystalline Compound 1 methanol solvate (wet) of any one of Examples 9 to 31, characterized by having signals at 73.5 ± 0.2 ppm, 55.9 ± 0.2 ppm, and 24.8 ± 0.2 ppm. 13 C SSNMR spectrum.

[0339] 39. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 31, characterized by having signals at 132.5 ± 0.2 ppm, 73.5 ± 0.2 ppm, 55.9 ± 0.2 ppm, and 24.8 ± 0.2 ppm. 13 C SSNMR spectrum.

[0340] 40. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 31, characterized by having signals at 132.5 ± 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 C SSNMR spectrum.

[0341] 41. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 40, characterized by having 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 C SSNMR spectrum.

[0342] 42. The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 41, characterized in that it is substantially similar to Figure 4 of 13 C SSNMR spectrum.

[0343] 43. The substantially crystalline Compound 1 methanol solvate (wet) of any one of Embodiments 9 to 42, characterized by having one or more signals selected from -63.9 ± 0.2 ppm, -76.6 ± 0.2 ppm, and -79.7 ± 0.2 ppm. 19 F MAS.

[0344] 44. The substantially crystalline Compound 1 methanol solvate (wet) of any one of Embodiments 9 to 43, characterized by having two or more signals selected from -63.9 ± 0.2 ppm, -76.6 ± 0.2 ppm, and -79.7 ± 0.2 ppm. 19 F MAS.

[0345] 45. The substantially crystalline Compound 1 methanol solvate (wet) of any one of Examples 9 to 44, characterized by having signals at -63.9 ± 0.2 ppm, -76.6 ± 0.2 ppm, and -79.7 ± 0.2 ppm. 19 F MAS.

[0346] 46. ​​The substantially crystalline Compound 1 Methanol Solvate (wet) of any one of Embodiments 9 to 45, characterized in that it is substantially similar to Figure 5 of 19 F MAS.

[0347] 47. The substantially crystalline Compound 1 methanol solvate (wet) of any one of Embodiments 9 to 46, prepared by (i) combining Compound 1 pure Form A, 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 to stand at room temperature for more than 3 days to produce crystalline Compound 1 methanol solvate (wet).

[0348] 48. A substantially crystalline Compound 1 Methanol Solvate (Dry) (i.e., wherein less than 15% of Compound 1 is in amorphous form, wherein less than 10% of Compound 1 is in amorphous form, wherein less than 5% of Compound 1 is in amorphous form).

[0349] 49. The substantially crystalline Compound 1 Methanol Solvate (Dry) of Embodiment 48, wherein the Compound 1 Methanol Solvate (Dry) is 100% crystalline.

[0350] 50. The substantially crystalline Compound 1 Methanol Solvate (dry) of Embodiment 48 or Embodiment 49, characterized by an X-ray powder diffraction pattern having signals at one or more of 27.2±0.2 degrees 2θ, 26.4±0.2 degrees 2θ, 25.9±0.2 degrees 2θ, 21.4±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, 15.4±0.2 degrees 2θ, 14.2±0.2 degrees 2θ, and 7.4±0.2 degrees 2θ.

[0351] 51. The substantially crystalline Compound 1 Methanol Solvate (dry) of any one of Embodiments 48 to 50, characterized by having an X-ray powder diffraction pattern having signals at two or more of 27.2±0.2 degrees 2θ, 26.4±0.2 degrees 2θ, 25.9±0.2 degrees 2θ, 21.4±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, 15.4±0.2 degrees 2θ, 14.2±0.2 degrees 2θ, and 7.4±0.2 degrees 2θ.

[0352] 52. The substantially crystalline Compound 1 Methanol Solvate (dry) of any one of Embodiments 48 to 51, characterized by an X-ray powder diffraction pattern having signals at three or more of 27.2±0.2 degrees 2θ, 26.4±0.2 degrees 2θ, 25.9±0.2 degrees 2θ, 21.4±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, 15.4±0.2 degrees 2θ, 14.2±0.2 degrees 2θ, and 7.4±0.2 degrees 2θ.

[0353] 53. The substantially crystalline Compound 1 Methanol Solvate (dry) of any one of Embodiments 48 to 52, characterized by an X-ray powder diffraction pattern having signals at four or more of 27.2±0.2 degrees 2θ, 26.4±0.2 degrees 2θ, 25.9±0.2 degrees 2θ, 21.4±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, 15.4±0.2 degrees 2θ, 14.2±0.2 degrees 2θ, and 7.4±0.2 degrees 2θ.

[0354] 54. The substantially crystalline Compound 1 Methanol Solvate (dry) of any one of Embodiments 48 to 53, characterized by an X-ray powder diffraction pattern having signals at five or more of 27.2±0.2 degrees 2θ, 26.4±0.2 degrees 2θ, 25.9±0.2 degrees 2θ, 21.4±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, 15.4±0.2 degrees 2θ, 14.2±0.2 degrees 2θ, and 7.4±0.2 degrees 2θ.

[0355] 55. The substantially crystalline Compound 1 Methanol Solvate (dry) of any one of Embodiments 48 to 54, characterized by an X-ray powder diffraction pattern having signals at six or more of 27.2±0.2 degrees 2θ, 26.4±0.2 degrees 2θ, 25.9±0.2 degrees 2θ, 21.4±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, 15.4±0.2 degrees 2θ, 14.2±0.2 degrees 2θ, and 7.4±0.2 degrees 2θ.

[0356] 56. The substantially crystalline Compound 1 Methanol Solvate (Dry) of any one of Embodiments 48 to 55, characterized by an X-ray powder diffraction pattern having signals at 25.9±0.2 degrees 2θ and 19.3±0.2 degrees 2θ.

[0357] 57. The substantially crystalline Compound 1 Methanol Solvate (Dry) of any one of Embodiments 48 to 56, characterized by an X-ray powder diffraction pattern having signals at 19.3±0.2 degrees 2θ and 15.4±0.2 degrees 2θ.

[0358] 58. The substantially crystalline Compound 1 Methanol Solvate (dry) of any one of Embodiments 48 to 57, characterized by an X-ray powder diffraction pattern having signals at 25.9±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, and 15.4±0.2 degrees 2θ.

[0359] 59. The substantially crystalline Compound 1 Methanol Solvate (dry) of any one of Embodiments 48 to 57, characterized by an X-ray powder diffraction pattern having signals at 19.3±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, and 15.4±0.2 degrees 2θ.

[0360] 60. The substantially crystalline Compound 1 Methanol Solvate (dry) of any one of Embodiments 48 to 57, characterized by an X-ray powder diffraction pattern having signals at 25.9±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, and 15.4±0.2 degrees 2θ.

[0361] 61. The substantially crystalline Compound 1 Methanol Solvate (dry) of any one of Embodiments 48 to 57, characterized by an X-ray powder diffraction pattern having signals at 27.2±0.2 degrees 2θ, 26.4±0.2 degrees 2θ, 25.9±0.2 degrees 2θ, 21.4±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, 15.4±0.2 degrees 2θ, 14.2±0.2 degrees 2θ, and 7.4±0.2 degrees 2θ.

[0362] 62. The substantially crystalline Compound 1 Methanol Solvate (Dry) of any one of Embodiments 48 to 61, characterized in that it is substantially similar to Figure 6 X-ray powder diffraction pattern of .

[0363] 63. The substantially crystalline Compound 1 methanol solvate (dry) of any one of Embodiments 48 to 62, prepared by (i) combining pure Form A of Compound 1, 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 more than 3 days, and (iv) drying in a vacuum oven at 60° C. overnight to produce crystalline Compound 1 methanol solvate (dry).

[0364] 64. A substantially crystalline Compound 1 p-toluenesulfonic acid (ie, wherein less than 15% of Compound 1 is in amorphous form, wherein less than 10% of Compound 1 is in amorphous form, wherein less than 5% of Compound 1 is in amorphous form).

[0365] 65. The substantially crystalline Compound 1 p-toluenesulfonic acid of Embodiment 64, wherein the Compound 1 p-toluenesulfonic acid is 100% crystalline.

[0366] 66. The substantially crystalline Compound 1 p-toluenesulfonic acid of Embodiment 64 or Embodiment 65, characterized by an X-ray powder diffraction pattern having signals at one or more of 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, 10.1±0.2 degrees 2θ, 11.5±0.2 degrees 2θ, 11.9±0.2 degrees 2θ, 14.9±0.2 degrees 2θ, 15.9±0.2 degrees 2θ, 16.2±0.2 degrees 2θ, 18.3±0.2 degrees 2θ, 20.4±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 21.6±0.2 degrees 2θ, 22.8±0.2 degrees 2θ, and 23.2±0.2 degrees 2θ.

[0367] 67. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 66, characterized by an X-ray powder diffraction pattern having signals at two or more of 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, 10.1±0.2 degrees 2θ, 11.5±0.2 degrees 2θ, 11.9±0.2 degrees 2θ, 14.9±0.2 degrees 2θ, 15.9±0.2 degrees 2θ, 16.2±0.2 degrees 2θ, 18.3±0.2 degrees 2θ, 20.4±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 21.6±0.2 degrees 2θ, 22.8±0.2 degrees 2θ, and 23.2±0.2 degrees 2θ.

[0368] 68. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 67, characterized by an X-ray powder diffraction pattern having signals at three or more of 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, 10.1±0.2 degrees 2θ, 11.5±0.2 degrees 2θ, 11.9±0.2 degrees 2θ, 14.9±0.2 degrees 2θ, 15.9±0.2 degrees 2θ, 16.2±0.2 degrees 2θ, 18.3±0.2 degrees 2θ, 20.4±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 21.6±0.2 degrees 2θ, 22.8±0.2 degrees 2θ, and 23.2±0.2 degrees 2θ.

[0369] 69. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 68, characterized by an X-ray powder diffraction pattern having signals at four or more of 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, 10.1±0.2 degrees 2θ, 11.5±0.2 degrees 2θ, 11.9±0.2 degrees 2θ, 14.9±0.2 degrees 2θ, 15.9±0.2 degrees 2θ, 16.2±0.2 degrees 2θ, 18.3±0.2 degrees 2θ, 20.4±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 21.6±0.2 degrees 2θ, 22.8±0.2 degrees 2θ, and 23.2±0.2 degrees 2θ.

[0370] 70. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 69, characterized by an X-ray powder diffraction pattern having signals at five or more of 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, 10.1±0.2 degrees 2θ, 11.5±0.2 degrees 2θ, 11.9±0.2 degrees 2θ, 14.9±0.2 degrees 2θ, 15.9±0.2 degrees 2θ, 16.2±0.2 degrees 2θ, 18.3±0.2 degrees 2θ, 20.4±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 21.6±0.2 degrees 2θ, 22.8±0.2 degrees 2θ, and 23.2±0.2 degrees 2θ.

[0371] 71. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 70, characterized by an X-ray powder diffraction pattern having signals at six or more of 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, 10.1±0.2 degrees 2θ, 11.5±0.2 degrees 2γ, 11.9±0.2 degrees 2θ, 14.9±0.2 degrees 2θ, 15.9±0.2 degrees 2θ, 16.2±0.2 degrees 2θ, 18.3±0.2 degrees 2θ, 20.4±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 21.6±0.2 degrees 2θ, 22.8±0.2 degrees 2θ, and 23.2±0.2 degrees 2θ.

[0372] 72. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 71, characterized by an X-ray powder diffraction pattern having signals at 5.7±0.2 degrees 2θ and 5.8±0.2 degrees 2θ.

[0373] 73. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 71, characterized by an X-ray powder diffraction pattern having signals at 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, and 7.4±0.2 degrees 2θ.

[0374] 74. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 71, characterized by an X-ray powder diffraction pattern having signals at 0.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, and 10.1±0.2 degrees 2θ.

[0375] 75. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 71, characterized by an X-ray powder diffraction pattern having signals at 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, 10.1±0.2 degrees 2θ, and 11.5±0.2 degrees 2θ.

[0376] 76. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64-71, characterized by an X-ray powder diffraction pattern having signals at 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, 10.1±0.2 degrees 2θ, 11.5±0.2 degrees 2θ, and 11.9±0.2 degrees 2θ.

[0377] 77. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 76, characterized in that it is substantially similar to Fig. 9 X-ray powder diffraction pattern of .

[0378] 78. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 77, characterized by having one or more signals selected from the group consisting of 13 C SSNMR spectrum: 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.

[0379] 79. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 78, characterized by having two or more signals selected from the group consisting of 13 C SSNMR spectrum: 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.

[0380] 80. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 79, characterized by having three or more signals selected from the group consisting of 13 C SSNMR spectrum: 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.

[0381] 81. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 80, characterized by having four or more signals selected from the group consisting of 13C SSNMR spectrum: 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.

[0382] 82. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 81, characterized by having five or more signals selected from the group consisting of 13 C SSNMR spectrum: 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.

[0383] 83. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 82, characterized by having six or more signals selected from the group consisting of 13 C SSNMR spectrum: 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.

[0384] 84. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 83, characterized by having signals at 141.0 ± 0.2 ppm and 19.5 ± 0.2 ppm. 13 C SSNMR spectrum.

[0385] 85. The substantially crystalline compound I p-toluenesulfonic acid of any one of embodiments 64 to 82, characterized in that it has 141.0 ± 0.2 ppm, 23.0 ± 0.2 ppm and 19.5 ± 0.2 ppm. 13 C SSNMR spectrum.

[0386] 86. The substantially crystalline compound I p-toluenesulfonic acid of any one of embodiments 64 to 82, characterized in that it has 141.0±0.2 ppm, 57.0±0.2 ppm, 23.0±0.2 ppm and 19.5±0.2 ppm. 13 C SSNMR spectrum.

[0387] 87. The substantially crystalline Compound I p-toluenesulfonic acid of any one of Embodiments 64 to 82, characterized in that the p-toluenesulfonic acid has 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 C SSNMR spectrum.

[0388] 88. The substantially crystalline Compound I p-toluenesulfonic acid of any one of Embodiments 64 to 82, characterized by having 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 C SSNMR spectrum.

[0389] 89. The substantially crystalline Compound I p-toluenesulfonic acid of any one of Embodiments 64 to 82, characterized by having 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 C SSNMR spectrum.

[0390] 90. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 89, characterized in that it is substantially similar to Fig.11 of 13 C SSNMR spectrum.

[0391] 91. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 90, characterized by having a signal containing one or more signals selected from the group consisting of 19 F MAS: -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.

[0392] 92. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 90, characterized in that it has a signal having two or more selected from the group consisting of 19 F MAS: -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.

[0393] 93. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 90, characterized in that it has a signal having three or more selected from the group consisting of19 F MAS: -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.

[0394] 94. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 90, characterized by having a signal having four or more selected from the group consisting of 19 F MAS: -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.

[0395] 95. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 90, characterized by having a signal having five or more selected from the group consisting of 19 F MAS: -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.

[0396] 96. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 90, characterized by having a signal having six or more selected from the group consisting of 19 F MAS: -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.

[0397] 97. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 90, characterized in that it has a crystalline phase containing 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. 19FMAS.

[0398] 98. The substantially crystalline Compound 1 p-toluenesulfonic acid of any one of Embodiments 64 to 97, characterized in that it is substantially similar to Fig.12 of 19 F MAS.

[0399] 99. A substantially crystalline Compound I methanol solvate (wet) according to any one of Examples 64 to 98, prepared by: (i) adding p-toluenesulfonic acid to Compound I pure Form A in a grinding ball 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, and (iv) drying the resulting material in a vacuum drying oven at 40°C to produce crystalline Compound I p-toluenesulfonic acid.

[0400] 100. A pharmaceutical composition comprising Compound I according to any one of Embodiments 1 to 99 and a pharmaceutically acceptable carrier.

[0401] 101. The pharmaceutical composition of embodiment 100, further comprising one or more additional therapeutic agents.

[0402] 102. The pharmaceutical composition of embodiment 101, wherein the pharmaceutical composition comprises one or more additional CFTR modulating compounds.

[0403] 103. A pharmaceutical composition according to Embodiment 101 or Embodiment 102, wherein the pharmaceutical composition comprises one or more compounds selected from the following: Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof.

[0404] 104. Compound I according to any one of Embodiments 1 to 99 or the pharmaceutical composition according to any one of Embodiments 100 to 103 for use in the treatment of cystic fibrosis.

[0405] 105. Use of 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 the preparation of a medicament for the treatment of cystic fibrosis.

[0406] 106. A method of treating cystic fibrosis, the method comprising administering Compound I according to any one of Embodiments 1 to 99 or the pharmaceutical composition according to any one of Embodiments 101 to 103 to a subject in need thereof.

[0407] B. Collection 2

[0408] 1. A method for preparing compound I:

[0409]

[0410] or a stereoisomer of Compound I, or a deuterated derivative of Compound I or a stereoisomer of Compound I, or a pharmaceutically acceptable salt of any one of the foregoing, wherein the method comprises treating a compound of Formula I:

[0411]

[0412] or a stereoisomer of the compound of formula I, or a deuterated derivative of the compound of formula I or its stereoisomer, or a salt of any of the foregoing, is converted into compound I, or a stereoisomer thereof, or a deuterated derivative of compound I or its stereoisomer, or a salt of any of the foregoing, wherein R a is selected from alcohol protecting groups.

[0413] 2. The method according to embodiment 1, wherein R a It is benzyl (Bn).

[0414] 3. A method for preparing compound I:

[0415]

[0416] or a stereoisomer of Compound I, or a deuterated derivative of Compound I or a stereoisomer of Compound I, or a pharmaceutically acceptable salt of any of the foregoing, wherein the method comprises treating a compound of Formula II:

[0417]

[0418]

[0419] or the stereoisomer of the compound of formula II, or the deuterated derivative of the compound of formula II or its stereoisomer, or a salt of any of the foregoing is converted into compound I, or its stereoisomer, or the deuterated derivative of compound I or its stereoisomer, or a salt of any of the foregoing, wherein R a is selected from alcohol protecting groups, and provided that R a Not benzyl (Bn).

[0420] 4. The method according to embodiment 3, wherein R a Selected from naphthylmethyl, biphenylmethyl, acetyl (Ac), trifluoroacetyl and benzoyl (Bz).

[0421] 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 of the compound of formula II 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 is carried out in the presence of reducing reaction conditions.

[0422] 6. The method according to embodiment 5, wherein the reducing condition is selected from hydrogen (H 2 ), palladium / carbon (Pd / C) and methanolic ammonia (NH 3 / MeOH); Hydrogen (H 2 ), palladium / carbon (Pd / C) and ethanolamine (NH 3 / EtOH); hydrogen (H 2 ), palladium / alumina (Pd / A1) and methanolic ammonia (NH 3 / MeOH); Hydrogen (H 2 ), palladium / alumina (Pd / A1) and methanolic ammonia (NH 3 / EtOH); hydrogen (H 2 ), platinum / carbon (Pt / C) and methanol / ammonia (NH 3 / MeOH); Hydrogen (H 2 ), platinum / carbon (Pt / C) and ethanolamine (NH 3 / EtOH); hydrogen (H 2 ), platinum / alumina (Pt / A1) and methanol ammonia (NH 3 / MeOH); Hydrogen (H 2 ), platinum / alumina (Pt / Al) and methanol ammonia (NH 3 / EtOH); hydrogen (H 2 ), ruthenium / carbon (Ru / C) and methanol ammonia (NH 3 / MeOH); Hydrogen (H 2 ), ruthenium / carbon (Ru / C) and ethanolamine (NH 3 / EtOH); hydrogen (H 2 ), ruthenium / alumina (Ru / Al) and methanol ammonia (NH 3 / MeOH); and hydrogen (H 2 ), ruthenium / alumina (Ru / Al) and methanol ammonia (NH 3 / EtOH).

[0423] 7. The method according to embodiment 5 or 6, wherein the reducing condition is hydrogen (H 2 ), palladium / carbon (Pd / C) and methanolic ammonia (NH 3 / MeOH).

[0424] 8. The method according to any one of embodiments 1 to 7, wherein the method comprises treating the compound of formula I:

[0425]

[0426] or the stereoisomer of the compound of formula I, or the deuterated derivative of the compound of formula I or its stereoisomer, or a salt of any one of the foregoing is converted into the compound of formula II, or its stereoisomer, or the deuterated derivative of the compound of formula II or its stereoisomer, or a salt of any one of the foregoing, wherein R a is selected from alcohol protecting groups.

[0427] 9. The method according to embodiment 8, wherein R a It is benzyl (Bn).

[0428] 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 of the compound of formula I or its stereoisomer, or a salt of any of the foregoing into the compound of formula II, or a stereoisomer thereof, or a deuterated derivative of the compound of formula II or its stereoisomer, or a salt of any of the foregoing is carried out in the presence of a dehydrating agent and a base.

[0429] 11. A method according to embodiment 10, wherein the dehydrating agent is selected from 2-chloro-1,3-dimethylimidazolium 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]pyridine 3-hexafluorophosphate oxide (HATU).

[0430] 12. The method of embodiment 10 or 11, wherein the dehydrating agent is 2-chloro-1,3-dimethylimidazolium chloride (DMC).

[0431] 13. The method of any one of embodiments 10 to 12, wherein the base is selected from 1,4-diazabicyclo[2.2.2]octane (DABCO), triethylamine (Et 3 N), N-methylmorpholine (NMM), pyridine and DIPEA (N,N-diisopropylethylamine).

[0432] 14. The method of any one of embodiments 10 to 13, wherein the base is 1,4-diazabicyclo[2.2.2]octane (DABCO).

[0433] 15. The method of any one of embodiments 10 to 14, wherein the dehydrating agent is 2-chloro-1,3-dimethylimidazolium chloride (DMC) and the base is 1,4-diazabicyclo[2.2.2]octane (DABCO).

[0434] 16. The method of any one of embodiments 8 to 15, wherein the method comprises reacting a compound of formula III:

[0435]

[0436] or the stereoisomer of the compound of formula III, or the deuterated derivative of the compound of formula III or its stereoisomer, or a salt of any one of the foregoing is converted into the compound of formula I, or its stereoisomer, or the deuterated derivative of the compound of formula I or its stereoisomer, or a salt of any one of the foregoing, wherein R a is selected from alcohol protecting groups.

[0437] 17. The method according to embodiment 16, wherein R a It is benzyl (Bn).

[0438] 18. The method of embodiment 16 or 17, wherein converting the compound of formula III, or a stereoisomer of the compound of formula III, or a deuterated derivative of the compound of formula III or a stereoisomer thereof, or a salt of any of the foregoing into the compound of formula I, or a stereoisomer thereof, or a deuterated derivative of the compound of formula I or a stereoisomer thereof, or a salt of any of the foregoing is carried out in the presence of a ruthenium catalyst.

[0439] 19. A method according to embodiment 18, wherein the ruthenium catalyst is selected from dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II) (Jane's 1B catalyst); dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl](2-isopropyloxyphenylmethylene)ruthenium(II); dichloro[1,3-bis(2,6-isopropylphenyl)-2-imidazolidinyl] 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).

[0440] 20. A method according to embodiment 18 or 19, wherein the ruthenium catalyst is dichloro[1,3-bis(2,4,6-trimethylphenyl)2-imidazolidinyl][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II) (Jane 1B catalyst).

[0441] 21. The method of any one of embodiments 16 to 20, wherein the method comprises allowing Compound 2 to:

[0442]

[0443] Or a deuterated derivative of compound 2, or a salt of any of the foregoing and a compound of formula IV:

[0444]

[0445] or a stereoisomer of the compound of formula IV, or a deuterated derivative of the compound of formula IV or a stereoisomer thereof, or a salt of any of the foregoing, to produce the compound of formula III, or a stereoisomer thereof, or a deuterated derivative of the 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.

[0446] 22. The method according to embodiment 21, wherein R a It is benzyl (Bn).

[0447] 23. A method according to 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 the compound of formula IV, or a deuterated derivative of the compound of formula IV or its stereoisomer, or a salt of any of the foregoing is carried out in the presence of a peptide coupling agent and a base.

[0448] 24. A method according to 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-oxyethyleneiminooxy)dimethylamino-morpholinomethylene)]tetramethylammonium hexafluorophosphate (COMU), isobutyl chloroformate (IBCF) and propanephosphonic anhydride (T3P).

[0449] 25. The method of embodiment 23 or 24, wherein the peptide coupling agent is 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT).

[0450] 26. The method of any one of embodiments 23 to 25, wherein the base is selected from N-methylmorpholine (NMM), 1-methylimidazole, triethylamine (Et 3 N), N,N,-isopropylethylamine (DIPEA) and pyridine.

[0451] 27. The method of any one of embodiments 23 to 26, wherein the base is N-methylmorpholine (NMM).

[0452] 28. The method of any one of embodiments 23 to 27, wherein the dehydrating agent is 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and the amine base is N-methylmorpholine (NMM).

[0453] 29. The method of any one of embodiments 21 to 28, wherein the method comprises treating a compound of formula V:

[0454]

[0455] or the deuterated derivative of the compound of formula V, or a salt of any of the foregoing, is converted into compound 2, a deuterated derivative of compound 2, or a salt of any of the foregoing, wherein R b Selected from methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (i-Pr) and tert-butyl (t-Bu).

[0456] 30. The method of embodiment 29, wherein R b It is methyl (Me).

[0457] 31. The method of embodiment 29 or 30, wherein converting the compound of formula V, or a deuterated derivative of the compound of formula V, 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 is carried out in the presence of an aqueous hydroxide base solution.

[0458] 32. The method of embodiment 31, wherein the hydroxide base is selected from lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), and cesium hydroxide (CsOH).

[0459] 33. The method of embodiment 31 or 32, wherein the base is sodium hydroxide (NaOH).

[0460] 34. The method of any one of embodiments 29 to 33, wherein the method comprises treating a compound of formula VI:

[0461]

[0462] or a deuterated derivative of a compound of formula VI, or a salt of any of the foregoing and compound 3:

[0463]

[0464] or a deuterated derivative of a compound of formula VI, or a salt of any of the foregoing, to produce the compound of formula V, or a deuterated derivative of the compound of formula V, or a salt of any of the foregoing, wherein:

[0465] -R b is selected from the group consisting of methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (i-Pr) and tert-butyl (t-Bu); and

[0466] -X is selected from Cl and Br.

[0467] 35. The method of embodiment 34, wherein R b is methyl (Me) and X is Cl.

[0468] 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 a deuterated derivative of compound 3, or a salt of any of the foregoing, is carried out in the presence of a base.

[0469] 37. The method according to embodiment 36, wherein the base is selected from 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 potassium dihydrogen phosphate (K 2 HPO 4 ).

[0470] 38. The method of any one of embodiments 36 or 37, wherein the base is N,N,-diisopropylethylamine (DIPEA).

[0471] 39. The method of any one of embodiments 34 to 38, wherein the method comprises reacting a compound of formula VII:

[0472]

[0473] or a deuterated derivative of the compound of formula VII, or a salt of any of the foregoing, is converted into compound 3, or a deuterated derivative of compound 3, or a salt of any of the foregoing, wherein R c is selected from amine protecting groups.

[0474] 40. The method of embodiment 39, wherein R c It is tert-butoxycarbonyl (Boc).

[0475] 41. The method of embodiment 39 or 40, wherein converting the compound of formula VII, or a deuterated derivative of the compound of formula VII, or a salt of any of the foregoing, into compound 3, or a deuterated derivative of compound 3, or a salt of any of the foregoing is carried out in the presence of a protic acid.

[0476] 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).

[0477] 43. The method of embodiment 41 or 42, wherein the protic acid is hydrochloric acid (HCl).

[0478] 44. The method of any one of embodiments 39 to 43, wherein the method comprises treating a compound of formula VIII:

[0479]

[0480] or the deuterated derivative of the compound of formula VIII is converted into the compound of formula VII, or the deuterated derivative of the compound of formula VII, or a salt of any one of the foregoing, wherein R c is selected from amine protecting groups.

[0481] 45. The method according to embodiment 44, wherein R c It is tert-butoxycarbonyl (Boc).

[0482] 46. ​​The method of embodiment 44 or 45, wherein converting 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 allylmagnesium halide and copper(I) halide.

[0483] 47. The method of embodiment 46, wherein the allylmagnesium halide is selected from allylmagnesium chloride and allylmagnesium bromide.

[0484] 48. The method of embodiment 46 or 47, wherein the allylmagnesium halide is allylmagnesium chloride.

[0485] 49. The method of any one of embodiments 46 to 48, wherein the copper (I) halide is selected from copper (I) chloride, copper (I) bromide, copper (I) bromide dimethyl sulfide complex, and copper (I) iodide.

[0486] 50. The method of any one of embodiments 46 to 49, wherein the copper (I) halide is copper (I) bromide dimethyl sulfide complex.

[0487] 51. The method of any one of embodiments 46 to 50, wherein the allylmagnesium halide is allylmagnesium chloride and the copper(I) halide is copper(I) bromide dimethyl sulfide complex.

[0488] 52. The method of any one of embodiments 44 to 51, wherein the method comprises treating a compound of formula IX:

[0489]

[0490] or a deuterated derivative of the compound of formula IX, or a salt of any one of the foregoing, is converted into the compound of formula VIII, or a deuterated derivative of the compound of formula VIII, or a salt of any one of the foregoing, wherein R c is selected from amine protecting groups.

[0491] 53. The method according to embodiment 52, wherein R c It is tert-butoxycarbonyl (Boc).

[0492] 54. The method of embodiment 52 or 53, wherein converting 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.

[0493] 55. The method of embodiment 54, wherein the sulfonyl halide is selected from p-toluenesulfonyl chloride (p-TsCl), benzenesulfonyl chloride, and methanesulfonyl chloride (MsCl).

[0494] 56. The method of embodiment 54 or 55, wherein the sulfonyl chloride is p-toluenesulfonyl chloride (p-TsCl).

[0495] 57. The method of any one of embodiments 54 to 56, wherein the base is selected from sodium hydroxide (NaOH), potassium hydroxide (KOH), and lithium hydroxide (LiOH).

[0496] 58. The method of any one of embodiments 54 to 57, wherein the base is potassium hydroxide (KOH).

[0497] 59. The method of any one of embodiments 54 to 58, wherein the sulfonyl halide is p-toluenesulfonyl chloride (p-TsCl) and the base is potassium hydroxide (KOH).

[0498] 60. The method according to any one of embodiments 52 to 59, wherein the method comprises reacting a compound of formula X:

[0499]

[0500] or a deuterated derivative of the compound of formula X, or a salt of any of the foregoing, is converted into compound 3, or a deuterated derivative of compound 3, or a salt of any of the foregoing, wherein X 1 Selected from F, Cl and Br.

[0501] 61. The method according to embodiment 60, wherein X 1 It is Cl.

[0502] 62. The method of embodiment 60 or 61, wherein converting the compound of formula X, or a deuterated derivative of the 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 is carried out in the presence of a protic acid.

[0503] 63. The method according to embodiment 62, wherein the protic acid is selected from hydrochloric acid (HCl), acetic acid (AcOH) and sulfuric acid (H 2 SO 4 ).

[0504] 64. The method of embodiment 62 or 63, wherein the protic acid is hydrochloric acid (HCl).

[0505] 65. The method of any one of embodiments 60-64, wherein the method comprises reacting hex-5-en-2-one:

[0506]

[0507] or a deuterated derivative of hex-5-en-2-one, or a salt of any of the foregoing, into the compound of formula X, or a deuterated derivative of the compound of formula X, or a salt of any of the foregoing, wherein X 1 Selected from F, Cl and Br.

[0508] 66. The method of embodiment 65, wherein the method 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 the compound of formula X, or a deuterated derivative of the compound of formula X, or a salt of any of the foregoing comprises:

[0509] (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 methylmagnesium halide, or a deuterated derivative of the methylmagnesium halide, or a salt of any of the foregoing; and

[0510] (ii) reacting the product of step (i) with 2-haloacetonitrile or a deuterated derivative of said 2-haloacetonitrile,

[0511] To produce a compound of formula X or a salt of any of the foregoing, wherein X 1 Selected from F, Cl and Br.

[0512] 67. The method of embodiment 66, wherein the methylmagnesium halide is selected from methylmagnesium chloride (MeMgCl), methylmagnesium bromide (MeMgBr), and methylmagnesium iodide (MeMgI).

[0513] 68. The method of embodiment 66 or 67, wherein the methylmagnesium halide is methylmagnesium chloride (MeMgCl).

[0514] 69. The method of any one of embodiments 66 to 68, wherein the 2-haloacetonitrile is selected from 2-fluoroacetonitrile, 2-chloroacetonitrile, and 2-bromoacetonitrile.

[0515] 70. The method of any one of embodiments 66 to 69, wherein X 1 is Cl and 2-haloacetonitrile is 2-chloroacetonitrile.

[0516] 71. The method of any one of embodiments 66 to 70, wherein X 1 is Cl, the methylmagnesium halide is methylmagnesium chloride (MeMgCl) and the 2-haloacetonitrile is 2-chloroacetonitrile.

[0517] 72. A method for preparing compound I:

[0518]

[0519] or a stereoisomer of Compound I, or a deuterated derivative of Compound I or a stereoisomer of Compound I, or a pharmaceutically acceptable salt of any of the foregoing, wherein the method comprises treating a compound of Formula I, Formula II or Formula III:

[0520]

[0521] or a stereoisomer of the compound, or a deuterated derivative of the compound or its stereoisomer, or a salt of any of the foregoing is converted into Compound I, or a stereoisomer of Compound I, or a deuterated derivative of Compound I or its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing,

[0522] in:

[0523] -R a is selected from alcohol protecting groups; and

[0524] - the compound of formula I, II or III is not selected from the following compounds: 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-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,8,14,16-hexaene (E / Z mixed) mixture); N′-[(2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]-6-[1,1-bis(trideuteromethyl)but-3-enylamino]-3-nitro-5-(trifluoromethane)pyridine-2-carbohydrazide; (6R)-6-benzyloxy-17-nitro-12,12-bis(trideuteromethyl)-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaene (E / Z mixture); and pharmaceutically acceptable salts thereof.

[0525] 73. The method according to embodiment 72, wherein R a It is benzyl (Bn).

[0526] 74. A compound selected from the group consisting of:

[0527]

[0528] or a stereoisomer of said compound, or a deuterated derivative of said compound or its stereoisomer, or a salt of any of the foregoing,

[0529] in:

[0530] -R a is selected from alcohol protecting groups; and

[0531] - the compound of formula I, formula II or formula III is not selected from the following compounds: 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-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,8,14,16-hexa olefins (E / Z mixture); N′-[(2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]-6-[1,1-bis(trideuteromethyl)but-3-enylamino]-3-nitro-5-(trifluoromethane)pyridine-2-carbohydrazide; (6R)-6-benzyloxy-17-nitro-12,12-bis(trideuteromethyl)-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaene (E / Z mixture);

[0532] and pharmaceutically acceptable salts thereof.

[0533] 75. A compound selected from the group consisting of:

[0534]

[0535] or a stereoisomer of the compound, or a deuterated derivative of the compound or its stereoisomer, or a salt of any of the foregoing, wherein R a is selected from alcohol protecting groups.

[0536] 76. The compound according to embodiment 74 or 75, wherein R a It is benzyl (Bn).

[0537] 77. A compound having the formula:

[0538]

[0539] or a stereoisomer of the compound, or a deuterated derivative of the compound or its stereoisomer, or a salt of any of the foregoing.

[0540] 78. A method for preparing compound I:

[0541]

[0542] or a stereoisomer of Compound I, or a deuterated derivative of Compound I or a stereoisomer of Compound I, or a pharmaceutically acceptable salt of any of the foregoing, wherein the method comprises treating a compound of Formula II:

[0543]

[0544] or the stereoisomer of the compound of formula XI, or the deuterated derivative of the compound of formula XI or its stereoisomer, or a salt of any of the foregoing, is converted into compound I, or its stereoisomer, or the deuterated derivative of compound I or its stereoisomer, or a salt of any of the foregoing,

[0545] in:

[0546] R a is selected from alcohol protecting groups, and

[0547] R 1 Selected from -N(Boc) 2 , -NHBoc, -N(Phth), -NH(Cbz) and -NO 2 .

[0548] 79. The method according to embodiment 78, wherein R a It is benzyl (Bn).

[0549] 80. The method of embodiment 78 or 79, wherein converting the compound of formula XI, or the stereoisomer of the compound of formula XI, or the deuterated derivative of the compound of formula XI or its stereoisomer, or a salt of any of the foregoing to compound I, or its stereoisomer, or the deuterated derivative of compound I or its stereoisomer, or a salt of any of the foregoing comprises a reaction performed in the presence of reducing reaction conditions.

[0550] 81. The method according to embodiment 80, wherein the reducing conditions are selected from hydrogen (H 2 ), palladium / carbon (Pd / C) and methanolic ammonia (NH 3 / MeOH); Hydrogen (H 2 ), palladium / carbon (Pd / C) and ethanolamine (NH 3 / EtOH); hydrogen (H 2 ), palladium / alumina (Pd / A1) and methanolic ammonia (NH 3 / MeOH); Hydrogen (H 2 ), palladium / alumina (Pd / A1) and methanolic ammonia (NH 3 / EtOH); hydrogen (H 2 ), platinum / carbon (Pt / C) and methanol / ammonia (NH 3 / MeOH); Hydrogen (H 2 ), platinum / carbon (Pt / C) and ethanolamine (NH 3 / EtOH); hydrogen (H 2), platinum / alumina (Pt / A1) and methanol ammonia (NH 3 / MeOH); Hydrogen (H 2 ), platinum / alumina (Pt / Al) and methanol ammonia (NH 3 / EtOH); hydrogen (H 2 ), ruthenium / carbon (Ru / C) and methanol ammonia (NH 3 / MeOH); Hydrogen (H 2 ), ruthenium / carbon (Ru / C) and ethanolamine (NH 3 / EtOH); hydrogen (H 2 ), ruthenium / alumina (Ru / Al) and methanol ammonia (NH 3 / MeOH); and hydrogen (H 2 ), ruthenium / alumina (Ru / Al) and methanol ammonia (NH 3 / EtOH).

[0551] 82. The method of embodiment 80 or 81, wherein the reducing condition is hydrogen (H 2 ), palladium / carbon (Pd / C) and methanolic ammonia (NH 3 / MeOH).

[0552] 83. The method of any one of embodiments 78 to 82, wherein converting the compound of formula XI, or the stereoisomer of the compound of formula XI, or the deuterated derivative of the compound of formula XI or its stereoisomer, or a salt of any of the foregoing to compound I, or its stereoisomer, or the deuterated derivative of compound I or its stereoisomer, or a salt of any of the foregoing further comprises reacting in the presence of an acid.

[0553] 84. The method according to embodiment 83, wherein the acid is selected from trifluoroacetic acid (TFA), hydrochloric acid (HCl), methanesulfonic acid (MsOH), phosphoric acid (H 3 PO 4 ) and sulfuric acid (H 2 SO 4 ).

[0554] 85. The method of embodiment 83 or 84, wherein the acid is trifluoroacetic acid (TFA).

[0555] 86. The method of any one of embodiments 78 to 85, wherein the method comprises treating the compound of Formula XII:

[0556]

[0557] or a stereoisomer of the compound of formula XII, or a deuterated derivative of the compound of formula XII or a stereoisomer thereof, or a salt of any of the foregoing is converted into the compound of formula XI, or a stereoisomer thereof, or a deuterated derivative of the compound of formula XI or a stereoisomer thereof, or a salt of any of the foregoing, wherein:

[0558] R a is selected from alcohol protecting groups, and

[0559] R 1 Selected from -N(Boc) 2 , -NHBoc, -N(Phth), -NH(Cbz) and -NO 2 .

[0560] 87. The method according to embodiment 86, wherein R a It is benzyl (Bn).

[0561] 88. The method of embodiment 86 or 87, wherein converting the compound of formula XII, or a stereoisomer of the compound of formula XII, or a deuterated derivative of the compound of formula XII or a stereoisomer thereof, or a salt of any of the foregoing into the compound of formula XI, or a stereoisomer thereof, or a deuterated derivative of the compound of formula XI or a stereoisomer thereof, or a salt of any of the foregoing comprises a reaction performed in the presence of a ruthenium catalyst.

[0562] 89. A method according to embodiment 88, wherein the ruthenium catalyst is selected from dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II) (Jane 1B catalyst); dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl](2-isopropyloxyphenylmethylene)ruthenium(II); dichloro[1,3-bis(2,6-isopropylphenyl)-2-imidazolidinyl] dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl](3-phenyl-1H-inden-1-yl)bis(tricyclohexylphosphine)ruthenium(II); and dichloro(2-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium(II).

[0563] 90. A method according to embodiment 88 or 89, wherein the ruthenium catalyst is dichloro[1,3-bis(2,4,6-trimethylphenyl)2-imidazolidinyl][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II) (Jane's 1B catalyst).

[0564] 91. The method of any one of embodiments 78 to 90, wherein the method comprises making Formula XIII:

[0565]

[0566] Or a deuterated derivative of compound 2, or a salt of any of the foregoing and a compound of formula IV:

[0567]

[0568] or a stereoisomer of the compound of formula IV, or a deuterated derivative of the compound of formula IV or a stereoisomer thereof, or a salt of any of the foregoing, to produce the compound of formula III, or a stereoisomer thereof, or a deuterated derivative of the compound of formula III or a stereoisomer thereof, or a salt of any of the foregoing, wherein:

[0569] R a is selected from alcohol protecting groups, and

[0570] R 1 Selected from -N(Boc) 2 , -NHBoc, -N(Phth), -NH(Cbz) and -NO 2 .

[0571] 92. The method according to embodiment 91, wherein R a It is benzyl (Bn).

[0572] 93. A method according to embodiment 91 or 92, wherein reacting a compound of formula XIII, or a deuterated derivative of formula XIII, or a salt of any of the foregoing, with a compound of formula IV, or a stereoisomer of the compound of formula IV, or a deuterated derivative of the compound of formula IV or its stereoisomer, or a salt of any of the foregoing is carried out in the presence of a peptide coupling agent and a base.

[0573] 94. A method according to 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-oxyethyleneiminooxy)dimethylamino-morpholinomethylene)]tetramethylammonium hexafluorophosphate (COMU), isobutyl chloroformate (IBCF) and propanephosphonic anhydride (T3P).

[0574] 95. The method of embodiment 93 or 94, wherein the peptide coupling agent is propanephosphonic anhydride (T3P).

[0575] Real

[0576] Abbreviations

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584] General Solid-State NMR (SSNMR) Methods

[0585] A Bruker-Biospin 400 MHz wide aperture spectrometer equipped with a Bruker-Biospin 4 mm HFX probe was used. The sample was loaded into a 4 mm ZrO 2 The rotor is spun under magic angle spinning (MAS) conditions at a rotation speed typically set at 12.5 kHz. 1 H MAS T 1 Saturation recovery relaxation experiments measure proton relaxation times to set 13 C Cross-polarization (CP) MAS experiments using appropriate cycle delays. 19 F MAS T 1 The saturation recovery relaxation experiment measures the fluorine relaxation time to set 19Appropriate cycle delay for F MAS experiment. CP contact time for carbon CPMAS experiment was set to 2 milliseconds. CP proton pulse with linear ramp (50% to 100%) was used. Carbon Hartmann-Hahn match was optimized on external reference sample (glycine). Both carbon and fluorine spectra were recorded with proton decoupling using TPPM15 decoupling sequence at a field strength of about 100 kHz.

[0586] General Thermogravimetric Analysis (TGA) Methods

[0587] TGA was used to investigate the presence of residual solvents in the characterized batches and to identify the temperature at which the samples decomposed. Unless otherwise provided in the following examples, TGA data were collected on a TA Instruments Discovery series with a TRIOS system. TGA data for pure amorphous Compound I were collected on a Mettler Toledo TGA / DSC 3+STARe system.

[0588] Universal Differential Scanning Calorimetry (DSC)

[0589] Unless otherwise provided in the examples below, the melting points or glass transition points of the materials were measured using a Mettler Toledo TGA / DSC 3+STARe system.DSC data for Compound 1 methanol solvate (dry) and Compound 1 p-toluenesulfonic acid were collected on a TA Instruments Discovery Series with a TRIOS system.

[0590] Example 1: Preparation of (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (Compound I)

[0591]

[0592] Step 1: 6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid methyl ester

[0593]

[0594] 2-Methylhex-5-en-2-amine (hydrochloride) (69.4 g, 463.7 mmol) was suspended in acetonitrile (960 mL) and treated with DIEA (220 mL, 1.263 mol). To the resulting brown solution was added 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid methyl ester (120 g, 421.7 mmol) in one go. The orange solution was slowly heated to 65 °C over 2.5 hours (note: the reaction shows an exotherm when heated). The dark orange solution was evaporated at 40 °C, and MTBE (1 L) and water (1 L) were added to the residue, and the layers were separated. The dark orange organic phase was washed with saturated NH 4 The mixture was washed with a 1:1 solution of aqueous Cl / water mixture (2X 600 mL), washed once with brine (400 mL), and the organic phase was dried, filtered and evaporated to give methyl 6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)picolinate (152.7 g, 100%). ESI-MS m / z calculated value 361.12494, found value 362.0 (M+1) + ; Retention time: 3.02 minutes (LC method D).

[0595] Step 2: 6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid

[0596]

[0597] 6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid methyl ester (152.4 g, 421.7 mmol) was dissolved in methanol (750 mL) and treated with NaOH (750 mL of 2M, 1.500 mol) under stirring (added simultaneously to give a slight temperature rise of 30°C to 40°C). The solution was stirred at room temperature for 18 hours. The dark 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 adding HCl (260 mL of 6M, 1.560 mol) to keep the internal temperature below 15°C. The phases were separated and the organic phase was washed twice with water (2X 500 mL) and once with brine (400 mL). The organic phase was purified by MgS0 4Dry, filter, evaporate and dry under vacuum to give 137 g of a dark orange solid block. This material was evaporated from acetonitrile (about 1 L to remove residual toluene) and dissolved in acetonitrile (600 mL) and warmed to about 60° C. N-cyclohexylcyclohexylamine (79 mL, 396.5 mmol) was added to the dark red hot solution under stirring (note the temperature rise of 60° C. to 70° C.), and the hot solution was spread. The material becomes a solid block at an internal temperature of about 60° C., which can be stirred magnetically after fragmentation. The dense suspension was stirred overnight in a cooling hot water bath and then stirred in an ice bath for 3 hours. 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. The 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 were separated. The organic phase was washed twice more with 1 M citric acid (2 x 400 mL) and washed with 0.5 M KHSO 4 The organic phase was then washed 4 times with brine (200 mL), dried, filtered and evaporated to give 6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)picolinic acid (113.4 g, 77%) as a yellow-orange oil which crystallized upon standing. 1 HNMR (400MHz, DMSO-d6) δ14.21 (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=2.9 Hz, 4H), 1.45 (s, 6H) ppm. ESI-MS m / z calculated value 347.10928, found value 348.0 (M+1) + ; Retention time: 2.49 minutes (LC method D).

[0598] Step 3: N′-[(2R)-2-Benzyloxy-2-(trifluoromethyl)pent-4-enoyl]-6-(1,1-dimethylpent-4-enylamino)-3-nitro-5-(trifluoromethyl)pyridine-2-carbohydrazide

[0599]

[0600] 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-enoylhydrazide (86.3 g, 299.4 mmol) were dissolved in DMF (600 mL) and cooled in an ice bath. HATU (114 g, 299.8 mmol) was added in one portion at an internal temperature of 3.1° C. (no exotherm was observed). DIEA (100 mL, 574.1 mmol) was then added slowly over 0.5 h (exotherm) maintaining the internal temperature between 3 and 10° C. After the 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 minutes and the phases were separated. The organic phase was washed with water (2X 1 L), 0.2 M KHSO 4 The mixture was washed twice with 4% paraformaldehyde (3X 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 block. ESI-MS m / z calculated value 617.2073, found value 618.0 (M+1) + ; Retention time: 3.25 min (LC method D). This material was used directly in the next step.

[0601] 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

[0602]

[0603] 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 portionwise addition of tosyl chloride (54.4 g, 285.3 mmol) over 15 min (exotherm, internal temperature maintained between 55 and 60°C by removing the hot mantel and adding slowly) and the reaction was stirred at 55-60°C for 45 min. The reaction solution was concentrated under reduced pressure at 40°C and the residue was extracted with MTBE / heptane 1:1 (1.4 L) and water (1.4 L). The organic phase was washed once more with water (1.5 L) and washed with 0.2 M KHSO 4 The 1% ethyl acetate (0.5 L) was washed twice with 1% ethyl acetate (2 x 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). Elution was performed with 100% hexanes for 1 minute, then an initial gradient of 0% to 10% ethyl acetate / hexanes was programmed over 106 minutes (2 column volumes). The product began eluting at about 4% ethyl acetate and was maintained isocratic at 4.3% ethyl acetate until the product had finished eluting 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) δ8.51 (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, found value 600.0 (M+1) + ; Retention time: 3.71 minutes (LC method D).

[0604] Step 5: (6R)-6-Benzyloxy-12,12-dimethyl-17-nitro-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,8,14,16-hexaene (E / Z mixture)

[0605]

[0606] This reaction was run in parallel in three 46.3 g batches, each in a 12 L 3-neck round bottom flask. The following experiment describes one of these batches.

[0607] A sparge, reflux condenser and aerator, as well as an overhead stirrer, were attached to a 12 L vessel placed in a hot bed. 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 copious amounts of nitrogen. The hot bed was set to 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) (Jane's catalyst 1B, 11.2 g, 15.26 mmol) was added simultaneously. The catalyst vessel was rinsed with DCE and the rinse was added to the reaction. Once the catalyst addition was complete, the layer temperature was increased to 73°C. Once the internal temperature reached 72°C, stirring was continued for 2 hours and 28 minutes, and then the hot layer temperature was reduced to 45°C. After 2 hours and 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 the mixture was cooled to room temperature. 100 g of SiO2 was added to the reaction. 2and 10 g of activated carbon (20-40 mesh, granular). Stir for 1 hour, then filter through diatomaceous earth, and evaporate the filtrate to obtain a crude product mixture. The materials from all three parallel reactions are combined to obtain 71.2 g of a crude product mixture. This material is purified on two separate 3 kg silica gel columns using a gradient of 100% hexanes to 10% ethyl acetate / hexanes in 110 minutes, followed by a gradient of 10% ethyl acetate / hexanes to 100% ethyl acetate in 10 minutes. After combining the two separate purification batches, (6R)-6-benzyloxy-12,12-dimethyl-17-nitro-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]19-carbon-1(18),2,4,8,14,16-hexaene (E / Z mixture) (51.88 g, 40%) is obtained. 1 HNMR (400MHz, DMSO-d6) δ8.55 (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), 4.55 (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, found value 572.1 (M+1) + ; Retention time: 3.46 min and 3.49 min (LC method D). The product was formed as a 3:1 mixture of double bond isomers.

[0608] Step 6: (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (Compound I) and its enantiomers

[0609]

[0610] (6R)-6-Benzyloxy-12,12-dimethyl-17-nitro-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[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 and partially concentrated by rotary evaporation and 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 5 cycles of internal vacuum and nitrogen backfill. Dihydroxypalladium (15.2 g of 10% w / w, 10.824 mmol) was added to the substrate solution under nitrogen. The internal vacuum was repeated for 6 cycles with hydrogen backfill to replace the nitrogen atmosphere with hydrogen. Finally, a balloon was used to keep the container under 1 atmosphere of hydrogen. The mixture was stirred vigorously overnight with a magnetic stirrer, and then the hydrogen balloon was removed. The mixture was filtered through 70 g of diatomaceous earth on a medium sintered funnel. The green filtrate solution was concentrated by rotary evaporation and a 28°C water bath. 42.65 g of the crude product was obtained as a yellow solid, 41.5 g of which was obtained by reverse phase chromatography (dissolved in 125 mL of methanol and 2.55 mL of DMF (2% DMF / methanol solution), and loaded on 3.8 kg C 18 The 1-hydroxy-2-nitro-1-yl-2-nitro-4-ol (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (28.17 g, 70%) was purified on a 5% column (column volume = 3.3 L, flow rate = 375 ml / min). An initial gradient of 40% to 70% acetonitrile / water (20 column volumes) was programmed over 176 minutes, followed by bringing the eluent to 100% acetonitrile after approximately 20 minutes. Mixed and pure fractions were separated 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-tetraazatricyclo[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) prepared by a similar method as solution in acetonitrile, which was then concentrated to give a yellow solid. This solid was dissolved in dichloromethane, and heptane was added, and the solution was then concentrated under vacuum at 40° C. in the dark overnight to give 31.95 g of (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol. 1 H NMR (400 MHz, DMSO-d 6)δ7.61(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), 2.15-1.98(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, found value 454.2(M+1) + ; Retention time: 3.03 minutes (LC method D).

[0611] A mixed fraction from the above reverse phase purification contained an impurity that showed one mass unit greater than the expected product. This fraction was concentrated and the residue was dissolved in 3.6 mL of methanol and purified by reverse phase preparative HPLC via C 18 Column purification using a 1 to 99% acetonitrile / water (+ HCl modifier) ​​gradient afforded (6R)-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[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 (400 MHz, 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, found value 455.2 (M+1) + ; Retention time: 2.87 minutes (LC method D).

[0612] Step 7: Solid Form Characterization of Crystallized Compound 1 Form A (Pure)

[0613] AX-ray powder diffraction

[0614] The XRPD diffraction pattern of crystalline Compound 1 Form A (pure) produced by Step 6 and recrystallized from EtOH was obtained using a general X-ray powder diffraction (XRPD) method. The XRPD diffraction pattern of crystalline Compound 1 Form A (pure) is provided at Figure 1 , and the XRPD data are summarized below.

[0615] XRPD signals of crystalline Compound 1 Form A (pure)

[0616] XRPD signal number Angle (2θ degrees ± 0.2) strength% 1 7.4271 100 2 8.4377 7.56 3 14.1039 4.84 4 14.5744 2.53 5 14.962 7.2 6 16.9424 2.49 7 19.0503 5.71 8 19.9711 2.4 9 22.4778 2.31 10 25.5622 2.19 11 25.7502 3.64

[0617] B. Differential Scanning Calorimetry Analysis

[0618] DSC data were collected and ramped to 250.00°C at 10.00°C / min. The DSC thermogram of the crystalline Compound I Form A (pure) produced from Step 6 is provided at Figure 2 The thermogram shows an onset Tm of 180.8°C with a Tm peak at 183.18°C, 62.32 J / g.

[0619] Example 2: Biological Activity of Compound I

[0620] Ussing chamber measurement of CFTR-mediated short-circuit current

[0621] Ussing chamber experiments were performed using human bronchial epithelial (HBE) cells heterozygous for F508del and minimal functional CFTR mutations (F508del / MF-HBE) derived from CF subjects and cultured as previously described (Neuberger T, Burton B, Clark H, Van Goor F Methods Mol Biol 2011: 741: 39-54). After four days, the apical medium was removed and cells were grown at an air-liquid interface for >14 days before use. This resulted in a monolayer of ciliated, fully differentiated columnar cells that are characteristic of human bronchial airway epithelium.

[0622] To isolate the CFTR-mediated short circuit (I SC ) current, Snapwell TM F508del / MF-HBE grown on cell culture inserts were mounted in Ussing chambers and recorded under voltage clamp conditions (V 保持 =0 mV) at 37°C and transepithelial I SC The basolateral solution contained (in mM) 145 NaCl, 0.83 K 2 HPO 4 , 3.3KH 2 PO 4 、1.2MgCl 2 , 1.2CaCl 2 , 10 glucose, 10 HEPES (pH adjusted to 7.4 with NaOH), and the apical solution contained (in mM) 145 sodium gluconate, 1.2 MgCl 2 , 1.2CaCl2 , 10 glucose, 10 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 surface to activate CFTR, followed by the apical addition of a CFTR inhibitor cocktail consisting of BPO, GlyH-101, and CFTR inhibitor 172 (each at a final assay concentration of 20 μM) to specifically isolate CFTR currents. The CFTR-mediated I under each condition was determined based on the forskolin peak response to the steady-state current after inhibition. SC (μA / cm 2 ).

[0623] Identification of synergist compounds

[0624] The effects of CFTR potentiator compounds on CFTR-mediated I SC F508del / MF-HBE cell cultures were treated with a range of concentrations of potentiator compounds and 10 μM (14S)-8-[3-(2-{dispiro[2.0.2.1]hept-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ at 37°C in the presence of 20% human serum. 6 -thia-3,9,11,18,23-pentazatetracyclo[17.3.1.111,14.05,10]triacontac-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione were combined and incubated for 18-24 hours. The concentration of the potentiator compound and the (14S)-8-[3-(2-{dispiro[2.0.2.1]hept-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ were used during the 18-24 hour incubation. 6 -Thia-3,9,11,18,23-pentazatetracyclo[17.3.1.111,14.05,10]tetracosyl-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione plays a key role in the regulation of CFTR-mediated I SC The Ussing chamber was kept constant during the measurement to ensure compound presence throughout the experiment. The efficacy and potency of putative F508del potentiators were compared to those of a known apex potentiator, ivacaftor (N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide).

[0625] The EC values ​​for the CFTR modulating activity of Compound I were determined using the assay described in this Example. 50 <500nM.

[0626] Example 3: Crystalline Form of Compound 1

[0627] 1. Compound I methanol solvate (wet)

[0628] A. Synthesis Procedure

[0629] A 30 mL vial with a magnetic stir bar was charged with Compound 1 pure Form A (0.15 g), water (1.1 mL) and methanol (3.3 mL). The sealed vial was heated to 65 °C. When the slurry solution was homogenized, the heating block was turned off and stirring was stopped. The solution was allowed to cool naturally without stirring. The solution self-nucleated within one hour, and the unstirred solution continued to cool and was allowed to stand at room temperature for more than 3 days.

[0630] BX-ray powder diffraction

[0631] Powder X-ray powder diffraction (XRPD) diffraction patterns of Compound I methanol solvate (wet) were acquired in transmission mode at room temperature using a PANalytical Empyrean system (Malvem PANalytical Inc, Westborough, Massachusetts) equipped with a sealed tube source and a PIXcel 1D Medipix-3 detector. The X-ray generator was operated at a voltage of 45 kV and a current of 40 mA. The powder sample was placed in a 96-well sample holder with Mylar membrane and loaded into the instrument. The sample was scanned in the range of about 3° to about 40° 2γ with a step size of 0.0131303° and 49 seconds per step. The results are shown in Figure 3 and are summarized in the following table:

[0632] XRPD results of Compound I methanol solvate (wet)

[0633] XRPD Signal Angle (2θ degrees ± 0.2) strength% 1 25.5 100.0 2 8.4 66.6 3 20.5 61.4 4 16.9 51.8 5 14.6 24.9 6 18.6 21.1 7 19.0 15.7 8 21.0 12.7 9 15.0 12.5 10 18.9 11.7

[0634] C. Single Crystal Analysis

[0635] Single crystals with the structure of Compound I methanol solvate (wet) were obtained. α radiation X-ray diffraction data were acquired on a Rigaku diffractometer with a CMOS detector at 100 K. The structure was solved and refined using the SHELX program (Sheldrick, GM, Acta Cryst., (2008) A64, 112-122), and the results are summarized below.

[0636] Single crystal elucidation of Compound I methanol solvate (wet)

[0637]

[0638]

[0639] D. Solid-state NMR

[0640] 13 The results of CPMAS SSNMR are shown in Figure 4 In, and 19 F MAS SSNMR is shown in Figure 5 and are summarized as follows.

[0641] Compound I methanol solvate (wet) 13 C CPMAS SSNMR results

[0642] Signal Chemical shift [ppm] Intensity [relative] 1 164.2 58.6 2 162.8 59.5 3 145.6 71.6 4 132.5 79.3 5 124.5 48.4 6 122.1 28.1 7 120.6 56.6 8 113.1 78.9 9 73.5 91.8 10 55.9 100.0 11 49.7 19.2 12 35.2 66.1 13 31.1 63.6 14 30.5 68.7 15 29.3 57.5 16 27.4 56.4 17 24.8 85.6 18 21.0 50.4 19 19.0 62.1

[0643] Compound I methanol solvate (wet) 19 F MAS SSNMR results

[0644] Signal Chemical shift [ppm] Intensity [relative] 1 -63.9 12.5 2 -76.6 1.6 3 -79.7 2.9

[0645] 2. Compound I methanol solvate (dry)

[0646] A. Synthesis Procedure

[0647] Compound I pure Form A (0.15 g), water (1.1 mL) and methanol (3.3 mL) were loaded into a 30 mL vial with a magnetic stirring bar. The sealed vial was heated to 65 ° C. When the slurry solution was homogenized, the heating block was turned off and stirring was stopped. The solution was allowed to cool naturally without stirring. The solution self-nucleated within one hour, and the unstirred solution continued to cool and was allowed to stand at room temperature for more than 3 days. The sample was then placed in a vacuum drying oven at 60 ° C overnight.

[0648] BX-ray powder diffraction

[0649] Powder X-ray powder diffraction (XRPD) diffraction patterns of Compound I methanol solvate (dry) were acquired in transmission mode at room temperature using a PANalytical Empyrean system (Malvern Panalytical, Westborough, MA) equipped with a sealed tube source and a PIXcel 1D Medipix-3 detector. The X-ray generator was operated at a voltage of 45 kV and a current of 40 mA. The powder sample was placed in a 96-well sample holder with Mylar membrane and loaded into the instrument. The sample was scanned in the range of about 3° to about 40° 2γ with a step size of 0.0131303° and 49 seconds per step. The results are shown in Figure 6 and summarized in the table below.

[0650] XRPD results of Compound I methanol solvate (dry)

[0651] XRPD Signal Angle (2θ degrees ± 0.2) strength% 1 19.3 100.0 2 25.9 79.4 3 15.4 64.9 4 18.1 48.7 5 7.4 32.7 6 21.4 24.1 7 14.2 19.7 8 27.2 18.9 9 26.4 13.9

[0652] C. Thermogravimetric analysis

[0653] Thermogravimetric analysis of Compound I methanol solvate (dry) was measured using TA5500 Discovery TGA. TGA thermogram ( Figure 7 ) shows a weight loss of about 1.2% from ambient temperature up to about 182°C.

[0654] D. Differential Scanning Calorimetry Analysis

[0655] The melting point of crystalline Compound I methanol solvate (dry) was measured using a TA Instruments Q2000 DSC. Thermogram ( Figure 8 ) shows endotherms at about 175°C and about 186°C.

[0656] 3. Compound I p-toluenesulfonic acid

[0657] A. Synthesis Procedure

[0658] Compound I pure Form A (about 45.3 mg) and about 17.2 mg of p-toluenesulfonic acid were weighed into a precellys ball mill (2 mL) tube. Methanol: water mixture (60: 40 v / v) (10 μl) was added to the tube. The mixture was ball milled at 7500 rpm in 3 cycles (60 seconds with a 10 second pause). The material was then vacuum dried in a vacuum drying oven at 40°C.

[0659] BX-ray powder diffraction

[0660] Powder X-ray powder diffraction (XRPD) diffraction patterns of Compound I p-toluenesulfonic acid were acquired in transmission mode at room temperature using a PANalytical Empyrean system (Malvern Panalytical, Westborough, MA) equipped with a sealed tube source and a PIXcel 1D Medipix-3 detector. The X-ray generator was operated at a voltage of 45 kV and a current of 40 mA. The powder sample was placed in a 96-well sample holder with Mylar membrane and loaded into the instrument. The sample was scanned in 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.

[0661] XRPD results of compound I p-toluenesulfonic acid

[0662] XRPD Signal Angle (2θ degrees ± 0.2) strength% 1 5.7 100.0 2 5.8 61.0 3 7.4 30.7 4 10.1 29.8 5 11.5 19.5 6 11.9 17.3 7 15.9 17.1 8 23.2 14.0 9 14.9 13.5 10 20.4 13.3 11 16.2 12.6 12 21.6 12.1 13 22.8 11.5 14 21.0 11.2 15 18.3 10.4

[0663] C. Differential Scanning Calorimetry Analysis

[0664] The melting point of p-toluenesulfonic acid of Compound I was measured using a TA Instruments Q2000 DSC. Thermogram ( Fig.10 ) shows endotherms at about 175°C and about 186°C.

[0665] D. Solid-state NMR

[0666] p-Toluenesulfonic acid of compound I 13 The results of CPMAS SSNMR are shown in Fig.11 In, and 19 The results of F MASSSNMR are shown in Fig.12 and are summarized as follows.

[0667] Compound I p-toluenesulfonic acid 13 C CPMAS Results

[0668] Signal Chemical shift [ppm] Intensity [relative] 1 163.8 30.2 2 161.8 6.4 3 160.9 5.9 4 152.9 30.3 5 146.1 4.8 6 141.0 100.0 7 139.3 27.8 8 138.0 13.8 9 136.7 26.0 10 132.5 20.0 11 130.6 21.0 12 127.8 45.9 13 126.7 51.7 14 124.7 40.6 15 122.1 18.8 16 114.5 26.3 17 113.1 21.9 18 110.3 25.9 19 75.5 49.7 20 57.0 55.3 21 48.6 9.1 22 35.0 20.9 23 32.5 34.5 24 31.0 52.0 25 29.8 43.1 26 28.3 38.5 27 26.2 37.0 28 25.0 55.2 29 23.0 60.5 30 19.5 71.2

[0669] Compound I p-toluenesulfonic acid 19 F MAS Results

[0670]

[0671]

[0672] 4. Pure amorphous compound I

[0673] A. Synthesis Procedure

[0674] Pure amorphous material of Compound 1 was prepared using a Mettler Toledo TGA / DSC 3+STARe system. Approximately 8 mg of pure Form A of Compound 1 was weighed in triplicate on a 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 recovered from the DSC pan.

[0675] BX-ray powder diffraction

[0676] XRPD patterns were recorded in continuous mode at room temperature 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 an anti-scatter slit P8. The divergent optics were Bragg Brentano 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 2θ using a 0.0131 degree step size and a counting time of 13.77 seconds per step. The powder sample was placed in a recessed area within a zero background holder and flattened with a glass slide. The results are shown in Fig.13 middle.

[0677] C. Thermogravimetric analysis

[0678] TGA data of pure amorphous Compound I were collected on a Mettler Toledo TGA / DSC 3+STARe system. Thermogram ( Fig.14 ) shows negligible weight loss from ambient temperature until thermal degradation.

[0679] D. Differential Scanning Calorimetry Analysis

[0680] The glass transition point of pure amorphous Compound I was measured using the DSC heating / cooling / reheating method. Pure amorphous material of Compound I was prepared using the Mettler Toledo TGA / DSC 3+STARe system. About 3.5 mg of Compound I Form A was weighed on 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 a pure amorphous material. It was then reheated to 200°C to detect the glass transition point. The glass transition of pure amorphous Compound I was observed at 64.8°C, and then recrystallized at 110.2°C, resulting in melting at 181.1°C. The DSC thermogram is shown in Fig.15 Place.

[0681] Example 4: Synthesis of bisamide precursor

[0682] Intermediate 1: Preparation of 2-methylhex-5-en-2-amine hydrochloride (Compound 3·HCl)

[0683]

[0684] Step 1: 2-Methylhex-5-en-2-ol (Compound 7)

[0685]

[0686] The reactor was charged with 3.0 M MeMgBr in Et 2 O (1.822 kg, 5.094 L, 15.28 mol, 1.0 equiv) and Et 2 O (9L). The mixture was cooled to 0°C with an ice / salt bath. Hex-5-en-2-one (CAS#109-49-9, 1,500g, 1.77L, 15.28mol) was added dropwise to the reaction mixture. The addition time was about 4.5 hours. After the addition was complete, the ice / salt bath was removed and the mixture was stirred at about 0°C for 15 minutes. The reaction mixture was stirred overnight and allowed to warm to room temperature. The reaction mixture was washed with saturated NH 4 The solution was quenched with aqueous Cl solution (5 L) while cooling in an ice / water bath. The first 2-2.5 L of addition was exothermic. When 2 L of saturated NH 4 When aqueous Cl solution was added to the mixture, it coagulated 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 washed with water (3 L) and saturated NH 4 The aqueous Cl solution was diluted and mixed with MTBE (5 L) to give an emulsion which was filtered through celite. The filter cake was rinsed with MTBE (5 L). The now clear phases were separated and the aqueous phase was extracted again with MTBE (3 L). The combined organic phases were washed with brine (5 L) and purified by evaporation with NaSO 4 Dry and filter.Remove the solvent under reduced pressure (water bath at 55°C, down to 20 mbar) to yield a yellow oil, 1,631 g (14.28 mol, 93.5%).

[0687] Step 2: 2-Chloro-N-(2-methylhex-5-en-2-yl)acetamide (Compound 8)

[0688]

[0689] 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 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 up and the internal temperature rose to 58.4°C (thermostat set at -5°C). When the internal temperature dropped to 38°C, sulfuric acid was continued to be added (thermostat set at 20°C). The total addition took 1 hour and 45 minutes. The now dark brown mixture was stirred at 24-28°C for another hour. The mixture was cooled to 15-17°C and 34.5 L of water was added, followed by 30% aqueous NaOH (about 8.5 L) until pH 10.2, keeping the internal temperature below 28°C. The mixture turned beige. The mixture was added to MTBE (40 L) while stirring. The phases separated slowly (about 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 rapid separation. The aqueous phase had a pH of 7-8. The organic phase was washed with 5 L of brine and filtered through Na 2 SO 4 After filtration (the combined Na 2 SO 4 The filter cake was washed with 3×3 L of MTBE) and the solvent was removed under reduced pressure in the reactor (the thermostat was set at 60° C. and the pressure was set to 180 mbar). About 65 L of solvent were removed. The heating was then set at 70° C. and the low volatility liquid was 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 crop of toluene collected by distillation was subjected to 1 H-NMR sampling showed the presence of about 1.2% w / w 2-chloroacetonitrile. The second half of the second crop of toluene collected by distillation was subjected to 1 H-NMR sampling showed the presence of about 0.3% w / w of 2-chloroacetonitrile. Distillation was continued at 70°C and 15 mbar for more than 1 hour, and some crystals appeared 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.

[0690] Step 3: 2-Methylhex-5-en-2-amine hydrochloride (Compound 3·HCl)

[0691]

[0692] The reactor was charged with 2-chloro-N-(2-methylhex-5-en-2-yl)acetamide (3,910 g, taken as 96.8% purity, 3,785 g, 19.95 mol) and ethanol (43 L). Thiourea (1,825.5 g, 23.98 mol, 1.202 equiv) was added to the stirred red-brown solution. The red-brown solution was heated to reflux (the thermostat was set at 100° C.). After reflux for 2 hours, IPC-1 showed that the starting material was almost completely consumed. After reflux for 2 hours and 45 minutes, IPC-2 showed complete conversion. The mixture was cooled to 50° C. (by setting the thermostat at 50° C. and forcing reflux under reduced pressure, which took 15 minutes). Over the course of 10-15 minutes, acetic acid (3,324 g, 55.35 mol, 2.77 equiv) was added to the red-brown solution, and no temperature change was observed. The mixture was refluxed overnight (the thermostat was set at 100°C). After 30-40 minutes, reflux was reached, reflux temperature = 82.1°C. After another 30 minutes, a white solid was precipitated. The mixture was refluxed overnight. An orange suspension was obtained. The mixture was cooled to 15-20°C (by setting the thermostat at 15°C and forcing reflux under reduced pressure, which took 30 minutes to reach 28°C). The suspension was filtered, and the filter cake was rinsed with EtOH (5×1L). The combined filtrate (about 57L) was concentrated under reduced pressure. A reddish-brown solid was obtained with a yield of 4,005g crude acetate.

[0693] The solid material was dissolved in hot water (9 L) and loaded into the reactor; the flask was rinsed with another 1 L of water. DCM (22 L) was added and Na 2 CO 3 (3,355g). Add up to 1.7-1.8Kg, the mixture remains clear, further addition produces a beige emulsion. The emulsion is diluted with DCM (22L), stirred for 30 minutes and allowed to settle overnight. The mixture is filtered on a diatomaceous earth pad (about 5cm thickness) topped with a layer of sand (about 5cm thickness). The liquid is siphoned from the bottom of the reactor, and it seems that the organic phase has been very separated, but there is a thick emulsion layer at the top, which still contains some organic phase. The wet cake is rinsed with 3L of DCM, and the filtrate from this is used to extract the aqueous phase. The combined organic phase (about 49-50L) is filtered through Na 2 SO 4Dry. The mixture was filtered and the removed solid was washed with 5L DCM. About 50L of the product solution was loaded into a reactor (set at -5°C jacket temperature). Isopropanol (5L, 30mol, 1.5 equivalents) containing 6M HCl was added dropwise to the product solution (internal temperature at the beginning of addition: 2°C). After 70 minutes, the addition was complete and the internal temperature was kept <6°C. After stirring overnight at 10°C, the solvent was evaporated using a rotary evaporator (water bath at 50°C). Salt began to precipitate from the solution at 240mbar. At 50mbar, evaporation was stopped, and the contents of the flask were mixed with MTBE (22L) and transferred to the reactor. Stir for 18 hours. The product was collected by filtration and washed with MTBE (2×2L) to obtain a cream-colored solid. The solid was dried at room temperature under reduced pressure (17mbar) for 18 hours. Yield: 1,833g (12.25mol, 61.4%). 1 HNMR (500MHz, DMSO-d6) δ8.08 (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, found value 114.5 (M+1) + .

[0694] Intermediate 1: Alternative preparation of 2-methylhex-5-en-2-amine hydrochloride (Compound 3·HCl)

[0695]

[0696] Step 1: tert-Butyl 2,2-dimethylaziridine-1-carboxylate (Compound 10)

[0697]

[0698] At 0 ℃, p-TsCl (35.6 g, 186.73 mmol) and powdered KOH (103 g, 1.5605 mol) were added to a solution of tert-butyl N-(2-hydroxy-1,1-dimethyl-ethyl)carbamate (30 g, 155.35 mmol) in diethyl ether (750 mL). The reaction temperature was raised to reflux temperature and stirred for 16 hours. Another portion of KOH (17 g, 303 mmol) was added and the reaction was refluxed for another 2 hours. The reaction was cooled to room temperature and diluted with diethyl ether (500 mL). The solid formed was removed by filtration through a glass sintered funnel and washed with more diethyl ether (100 mL). The combined ethereal filtrates were washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 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.

[0699] Step 2: tert-Butyl N-(1,1-dimethylpent-4-enyl)carbamate (Compound 11)

[0700]

[0701] Allyl (chloro) magnesium in THF (205mL, 2M, 410mmol) and anhydrous THF (200mL) was loaded into the reaction flask. The solution was cooled to -30 ° C, and copper (I) bromide (dimethyl sulfide complex) (28g, 136.2mmol) was added. The reaction mixture was stirred at the same temperature for 30 minutes and then cooled to -78 ° C. A solution of 2,2-dimethylaziridine-1-formic acid tert-butyl ester (24.602g, 136.49mmol) in anhydrous THF (200mL) was added dropwise to the reaction mixture. The reaction was stirred at the same temperature for 30 minutes, and then moved to -20 ° C freezer and stored for 3 hours. At 0 ° C, the reaction was quenched with saturated aqueous ammonium chloride solution (200mL). The reaction was stirred at room temperature for 10 minutes, then diluted with diethyl ether (200mL). The solution was filtered through a diatomaceous earth pad and washed with ether (100mL). The two layers were separated and the aqueous layer was extracted with diethyl ether (2 x 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 0% to 10% diethyl ether / hexanes gradient to give tert-butyl N-(1,1-dimethylpent-4-enyl)carbamate (18.6 g, 61%) as a light yellow liquid. 1H 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.

[0702] Step 3: 2-Methylhex-5-en-2-amine hydrochloride (Compound 3·HCl)

[0703]

[0704] 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, 2M, 700 mmol) was stirred at room temperature for 2 days. The solvent was removed and the residue was triturated with hexanes to give 2-methylhex-5-en-2-amine (hydrochloride) (15.198 g, 77%) as a white solid. 1 H NMR (500MHz, DMSO-d6) 68.08 (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.

[0705] Intermediate 2: 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid methyl ester (Compound 16)

[0706]

[0707] Step 1: 1-oxo-5-(trifluoromethyl)pyridin-1-ium-2-carboxylic acid methyl ester (Compound 13)

[0708]

[0709] Urea hydroperoxide (62.7 g, 646.53 mmol) was added portionwise to a stirred solution of methyl 5-(trifluoromethyl)pyridine-2-carboxylate (40 g, 191.09 mmol) in 1,2-dichloroethane (300 mL) at 0°C. The mixture was then stirred at -10°C with a cooling bath (CO 2The mixture was stirred at 0 ° C for another 30 minutes in 4% acetone bath (107.70 g, 72 mL, 507.65 mmol). The reaction mixture was then stirred at a temperature of 0 ° C for another 30 minutes, and then stirred at ambient temperature for 1 hour. The reaction mixture was then poured into cold ice water (600 mL). The mixture was diluted with dichloromethane (300 mL), and then the layers were separated. The aqueous phase was extracted with dichloromethane (2 × 200 mL). The combined organic phases were washed with water (2 × 300 mL) and brine (1 × 200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 1-oxo-5-(trifluoromethyl)pyridine-1-ium-2-methylformate (47.6 g, 90%) as a pale yellow solid. 1 H NMR (300MHz, DMSO-d6) 68.89 (s, 1H), 8.02-7.90 (m, 1H), 7.86-7.72 (m, 1H), 3.89 (s, 3H)ppm. 19 F NMR (282 MHz, DMSO-dS) δ -62.00 (s, 3F) ppm. ESI-MS m / z calculated value 221.02998, found value 222.1 (M+1) + ; Retention time: 1.24 min (LC method A).

[0710] Step 2: 6-Hydroxy-5-(trifluoromethyl)pyridine-2-carboxylic acid methyl ester (Compound 14)

[0711]

[0712] At 0 ° C, trifluoroacetic anhydride (291.62g, 193mL, 1.3885mol) is added dropwise to a mixture of 1-oxo-5-(trifluoromethyl)pyridine-1-ium-2-formic acid methyl esters (51.058g, 230.66mmol) in DMF (305mL). The mixture is then stirred at room temperature overnight. The mixture is concentrated under reduced pressure to remove excess trifluoroacetic acid. The remaining DMF solution is poured dropwise into 0 ° C of cooling and stirring water volume (1000mL). The precipitated solid is collected by filtration, and then washed with water (300mL). The solid is dried under vacuum to obtain 6-hydroxy-5-(trifluoromethyl)pyridine-2-formic acid methyl esters (45.24g, 86%) as a white solid. 1 H NMR (300 MHz, CDCl 3 )δ7.90(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 H NMR. 19F NMR (282 MHz, CDCl 3 )δ-66.39 (s, 3F) ppm. ESI-MS m / z calculated value 221.03, found value 222.1 (M+1) + ; Retention time: 1.43 minutes (LC method A).

[0713] Step 3: 6-Hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid methyl ester (Compound 15)

[0714]

[0715] Nitric acid (13mL of 15.8M, 205.40mmol) was added dropwise to an ice-cold solution of 6-hydroxy-5-(trifluoromethyl)pyridine-2-formic acid methyl ester (33.04g, 149.41mmol) in sulfuric acid (200mL of 18.4M, 3.6800mol). After 5 minutes, the ice bath was removed and the reaction mixture was stirred overnight at 38°C. The reaction was not completed, nitric acid (3mL of 15.8M, 47.400mmol) was added dropwise at room temperature, and the reaction was heated at 38°C for 4.5 hours. The reaction was slowly poured onto ice-cold water (900mL), and the mixture was cooled at 0°C for 15 minutes. The resulting solid was then separated by filtration and washed with water (600mL). The solid was dried under vacuum overnight to give methyl 6-hydroxy-3-nitro-5-(trifluoromethyl)picolinate (39.49 g, 99%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 3.95 (s, 3H) ppm. 1 Not a single exchangeable proton was observed in HNMR. 19 F NMR (282 MHz, DMSO-d6) δ -64.56 (s, 3F) ppm. ESI-MS m / z calculated value 266.0151, found value 267.1 (M+1) + ; Retention time: 1.64 min (LC method A).

[0716] Step 4: 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid methyl ester (Compound 16)

[0717]

[0718] A mixture of 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid methyl ester (10 g, 37.575 mmol) and phenyl dichlorophosphate (48.008 g, 34 mL, 227.55 mmol) was heated at 170 ° C for 90 minutes. After cooling to room temperature, the mixture was diluted with ethyl acetate (400 mL) and washed with brine (2X 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 / heptane) produced 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid methyl ester (5.45 g, 50%) as a yellow solid. 1 H NMR (300 MHz, CDCl 3 )δ8.75(s, 1H), 4.07(s, 3H)ppm. 19 F NMR (282 MHz, CDCl 3 )δ-64.12 (s, 3F) ppm. ESI-MS m / z calculated value 283.9812, found value 285.0 (M+1) + ; Retention time: 1.95 min (LC method A).

[0719] Intermediate 3: Preparation of 2-benzyloxy-2-(trifluoromethyl)pent-4-enoylhydrazide (hydrochloride) (Compound 22·HCl)

[0720]

[0721] Step 1: 2-Hydroxy-2-(trifluoromethyl)pent-4-enoic acid ethyl ester (Compound 18)

[0722]

[0723] To a solution of 3,3,3-trifluoro-2-oxo-propionic acid ethyl ester (30 g, 176.38 mmol) in diethyl ether (300 mL) at -78 ° C over a 3-hour period, allyl (bromine) magnesium (185 mL of 1M, 185.00 mmol) (internal temperature: -74 ° C - 76 ° C) was added dropwise. The mixture was stirred at -78 ° C for 45 minutes. The dry ice-acetone bath was removed. The mixture was warmed to about 10 ° C over a 1-hour period and added to a mixture (pH 4) of 1M HCl aqueous solution (210 mL) and crushed ice (400 g). The mixture was extracted with EtOAc and purged with 5% NaHCO 3 aqueous solution, brine, and washed with anhydrous Na 2 SO 4The mixture was filtered, concentrated, and co-evaporated with hexanes to give ethyl 2-hydroxy-2-(trifluoromethyl)pent-4-enoate (42.2 g, 90%) as a light yellow oil. 1 H NMR (300 MHz, CDCl 3 ) δ1.33 (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 (282 MHz, CDCl 3 )δ-78.5(s,3F)ppm.

[0724] Step 2: 2-Benzyloxy-2-(trifluoromethyl)pent-4-enoic acid ethyl ester (Compound 19)

[0725]

[0726] To a solution of ethyl 2-hydroxy-2-(trifluoromethyl)pent-4-enoate (18.56 g, 83.105 mmol) in DMF (100 mL) at 0°C was added NaHH (5.3 g, 60% w / w, 132.51 mmol). The reaction was stirred for 15 minutes, 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 at room temperature overnight. 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 / 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 )δ7.55-7.25 (m, 5H), 6.00-5.80 (m, 1H), 5.30-5.10 (m, 2H), 4.86 (d, J = 10.5 Hz, 1H), 4.68 (d, J = 10.5 Hz, 1H), 4.33 (q, J = 7.0 Hz, 2H), 2.81 (d, J = 7.0 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m / z calculated value 302.113, found value 303.5 (M+1) + ; Retention time: 4.14 minutes (LC method B).

[0727] Step 3: 2-Benzyloxy-2-(trifluoromethyl)pent-4-enoic acid (Compound 20)

[0728]

[0729] 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 hours. The reaction mixture was concentrated under vacuum, 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 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 2-benzyloxy-2-(trifluoromethyl)pent-4-enoic acid (28.04 g, 99%) as a light yellow liquid. 1 H NMR (250 MHz, CDCl 3 ) δ7.55-7.28 (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. exist 1 Not a single exchangeable proton was observed in H NMR.

[0730] Step 4: tert-Butyl N-[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamate (Compound 21)

[0731]

[0732] 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 minutes. To the mixture was added tert-butyl N-aminocarbamate (152 g, 1.150 mol), and the mixture was stirred at ambient temperature for 36 hours. 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 purified by MgSO 4 Dry, filter and concentrate in vacuo. Purification by silica gel chromatography (0% to 40% EtOAc / hexanes) gave tert-butyl N-[[2-benzyloxy-2-(trifluoromethyl)pent-4-enoyl]amino]carbamate (386.49 g, 91%) as an oil that slowly crystallized to an off-white solid.1 H NMR (400 MHz, DMSO) δ 10.00 (d, J = 37.9 Hz, 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 = 17.1 Hz, 1H), 5.17 (d, J = 10.1 Hz, 1H), 4.77 (s, 2H), 2.96 (qd, J = 15.4, 6.8 Hz, 2H), 1.39 (d, J = 17.3 Hz, 9H) ppm. ESI-MS m / z calculated value 388.16098, found value 389.0 (M+1) + ; Retention time: 2.51 min (LC method C).

[0733] Step 5: 2-Benzyloxy-2-(trifluoromethyl)pent-4-enoylhydrazide (hydrochloride) (Compound 22·HCl)

[0734]

[0735] 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 HCl in dioxane (200 mL of 4M, 800.00 mmol). The mixture was stirred at room temperature for 2 h, concentrated and co-evaporated with DCM and hexanes to give 2-benzyloxy-2-(trifluoromethyl)pent-4-enoylhydrazide (hydrochloride) (81.15 g, 97%) as an off-white solid. 1 H NMR (500 MHz, 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), 4.79 (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, found value 289.2 (M+1) + ; Retention time: 2.0 min (LC method D).

[0736] Intermediate 4: Preparation of (2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoylhydrazide (Compound 23a)

[0737]

[0738] Step 1: 2-Benzyloxy-2-(trifluoromethyl)pent-4-enoylhydrazide (Compound 22)

[0739]

[0740] 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 hours. 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 minutes. The organic phase was separated, washed with 1 L of brine, and filtered through MgSO 4 Dried, filtered and concentrated in vacuo and used directly in the next step (trace toluene present), 2-benzyloxy-2-(trifluoromethyl)pent-4-enoylhydrazide (286 g, 100%). 1 H NMR (400 MHz, DMSO) δ 9.34 (s, 1H), 7.40-7.22 (m, 5H), 5.69 (ddt, J = 17.1, 10.3, 6.9 Hz, 1H), 5.33-5.23 (m, 1H), 5.15 (dd, J = 10.3, 1.8 Hz, 1H), 4.73 (s, 2H), 4.51 (s, 2H), 3.05-2.87 (m, 2H) ppm. ESI-MS m / z calculated value 288.10855, found value 289.0 (M+1) + ; Retention time: 1.32 min (LC method E).

[0741] Step 2: (2R)-2-Benzyloxy-2-(trifluoromethyl)pent-4-enoylhydrazide (Compound 23a)

[0742]

[0743] The chiral SFC was performed using a ChiralPak IG column (250 x 21.2 mm; 5 μm) at 40 °C with 7% MeOH (plus 20 mM NH 3 ) / 93%CO 2 The mobile phase was 500 μL, with a flow rate of 70 mL / min for separation of racemic 2-benzyloxy-2-(trifluoromethyl)pent-4-enoylhydrazide (5.0 g, 17.35 mmol), and the sample concentration was 111 mg / mL / methanol (without modifier), injection volume = 160 μL, outlet pressure was 136 bar, and detection wavelength was 210 nm), resulting in two single enantiomer products:

[0744] The first enantiomer to elute was isolated as (2S)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoylhydrazide (compound 23a, 1.79 g, 72%). 1 H NMR (400 MHz, 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, 1.6 Hz, 1H), 5.15 (dq, J = 10.2, 1.3 Hz, 1H), 4.72 (s, 2H), 4.44 (d, J = 4.2 Hz, 2H), 2.99 (dd, J = 7.4, 1.3 Hz, 1H), 2.91 (dd, J = 15.4, 6.4 Hz, 1H) ppm. ESI-MS m / z calculated value 288.10855, found value 289.2 (M+1) + ; Retention time: 1.28 min (LC method F).

[0745] The second enantiomer to elute was isolated as (2R)-2-benzyloxy-2-(trifluoromethyl)pent-4-enoylhydrazide (compound 23b, 1.7 g, 68%) as a white solid. 1 H NMR (400 MHz, 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, 1.6 Hz, 1H), 5.15 (dq, J = 10.2, 1.5 Hz, 1H), 4.73 (s, 2H), 4.51 (s, 2H), 3.00 (dd, J = 15.3, 7.5 Hz, 1H), 2.91 (dd, J = 15.3, 6.4 Hz, 1H) ppm. ESI-MS m / z calculated value 288.10855, found value 289.2 (M+1) + ; Retention time: 1.28 min (LC method F).

[0746] Example 5: Synthesis of (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (Compound I)

[0747]

[0748] Step 1: 6-((2-methylhex-5-en-2-yl)amino)-3-nitro-5-(trifluoromethyl)picolinic acid methyl ester (Compound 24)

[0749]

[0750] 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 compound 3 HCl salt (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 the reaction was complete by LC analysis, the mixture was allowed to reach 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 washed with Na 2 SO 4 Dry, filter and concentrate. The crude product was dried under vacuum and used as is in the next step. ESI-MS m / z calculated 361.12, found 362 (M+1) + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.45 (d, J = 0.8 Hz, 1H), 5.77 (ddt, J = 16.8, 10.2, 6.3 Hz, 1H), 5.51 (s, 1H), 5.01 (dq, J = 17.1, 1.6 Hz, 1H), 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.

[0751] Step 2: 6-((2-methylhex-5-en-2-yl)amino)-3-nitro-5-(trifluoromethyl)picolinic acid (Compound 2)

[0752]

[0753] To a solution of compound 24 (54 g, 149.454 mmol, 1 eq) in EtOH (216 mL, 0.692 M, 4 vols) was added 6 M NaOH (32.382 mL, 194.29 mmol, 1.3 eq) dropwise via an addition funnel over 10 min, maintaining the temperature at <30 °C. The mixture was stirred at ambient temperature until complete reaction by LC analysis. (If the reaction did not convert further, additional 6 M NaOH (2.491 mL, 14.945 mmol, 0.1 eq) was added until the reaction was complete.) The mixture was concentrated to remove EtOH. The mixture was concentrated and IPAc (420 mL, 8 vols) was added. The mixture was acidified by dropwise addition of 6 M HCl (38.609 mL, 231.653 mmol, 1.55 eq) via an addition funnel, maintaining the temperature at <30 °C. Stir for 10 min and allow the phases to separate. 26 g of silica gel and 26 g of activated carbon were added to the organic layer and stirred for several hours at ambient temperature. The mixture was filtered through a celite pad and washed twice with 25 mL of IPAc. The filtrate was concentrated to an oil. 140 mL of heptane was added and concentrated, and then repeated. 220 mL of heptane was added to obtain a slurry, which was stirred for NLT 2 hours. The solid was collected by filtration and washed three times with 25 mL of heptane. The solid was dried under vacuum to obtain compound 2 (42.3 g, 81.5%) as a light yellow solid. ESI-MS m / z calculated value 347.11, found value 348 (M+1) + . 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.47 (d, J = 0.8 Hz, 1H), 7.89 (s, 2H), 5.78 (ddt, J = 16.6, 10.2, 6.2 Hz, 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.

[0754] 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)

[0755]

[0756] Compound 2 (900 g, 2591.496 mmol, 1 eq) 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 eq) 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 eq) was added as a slurry in N,N-dimethylformamide (900 mL, 2.879 M, 1 volume). The mixture was stirred for 1 hour after the addition, and 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 hours. The mixture was stirred at ambient temperature until the reaction was confirmed to be complete by LC analysis. 2 L of water was slowly added to quench the reaction, and then MTBE (12 L, 0.288 M, 13 volumes) was added. Additional H 2 O (14400 mL, 0.18 M, 16 volumes). After stirring, the phases were separated. The organic layer was washed with 0.5 M NaOH (5400 mL, 6 volumes), 0.5 M HCl (5400 mL, 6 volumes) and 5% w / v NaCl aqueous solution (5400 mL, 6 volumes). The organic layer was washed with Na 2 SO 4 Dry, filter and concentrate by rotary evaporation (40 °C, 20 mbar). Add 2 L of ethyl acetate to chase MTBE and concentrate 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 value 617.21, found value 618 (M+1) + . 1 H NMR (400 MHz, chloroform-d) δ 9.26 (s, 1H), 8.84 (d, J = 4.6 Hz, 1H), 8.33-8.26 (m, 1H), 7.47-7.29 (m, 6H), 5.81 (dddd, J = 27.2, 12.3, 10.2, 6.7 Hz, 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). 19F NMR (376 MHz, CDCl 3 )δ-64.53, -73.76.

[0757] Step 4: (R)-9-(Benzyloxy)-3,3-dimethyl-1 5 -Nitro-1 3 ,9-bis(trifluoromethyl)-2,11,12-triaza-1(2,6)-pyridylcyclotrichloropropane-6-ene-10,13-dione (Compound 6)

[0758]

[0759] A solution of compound 4 (517 g, 837.181 mmol, 1 eq) in EtOAc (77.55 L, 0.011 M, 150 vol) was stirred at ambient temperature and subsurface N 2 After sparging for 30 minutes, dichloro[1,3-bis(2,4,6-trimethylphenyl)2-imidazolidinylidene][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II) (Jen's catalyst 1B, 61.428 g, 83.718 mmol, 0.1 eq) was added and the mixture was heated to 40°C while continuing to N 2 Spray.After completing the reaction by LC analysis, the mixture is cooled to ambient temperature.Then 2-mercaptonicotinic acid (64.954g, 418.59mmol, 0.5 equivalent) is loaded into the reactor, TEA (42.357g, 58.829mL, 0.72g / mL, 418.59mmol, 0.5 equivalent) is subsequently loaded, and the mixture is stirred overnight.Silica gel (1265.817g, 5023.083mmol, 6 equivalents) is added to the mixture and stirred for at least one hour.The mixture is filtered through a glass filter, and the glass filter has a silica gel layer (2kg) and a diatomaceous earth thin layer, and solids are washed with EtOAc (20.68L, 0.04M, 40 volumes).Solvent is distilled out from the filtrate by a rotary evaporator.Analyzed by LC, the final weight of the crude material is 397g, and the purity is 79.71% area percentage.

[0760] A slurry of the combined crude material (compound 4, 1551 g, 2383.955 mmol, 1 eq) in MTBE (6.204 L, 0.384 M, 4 vol) was heated to 55 °C and stirred for 1 hour. 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 minutes. The mixture was stirred for an additional 30 minutes and then cooled to 10 °C over 2 hours and then stirred at 10 °C overnight.

[0761] 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 x 413 mL, 0.8 vol). The filter cake was pulled dry for 1 hour, then transferred to a rotary evaporator to dry at 50 °C for 4 hours to give compound 6 (1119 g, 78.4%). ESI-MS m / z calculated value 589.18, found value 590 (M+1) + . 1 H NMR (400 MHz, chloroform-d) δ 8.51 (d, J = 8.9 Hz, 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, 3.9 Hz, 1H), 5.42-5.32 (m, 1H) , 4.76-4.55 (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.

[0762] Step 5: (R)-10-(Benzyloxy)-4,4-dimethyl-2 3 -Nitro-2 5 ,10-bis(trifluoromethyl)-3-aza-1(2,5)-oxadiazole-2(2,6)-pyridinecyclodecane-7-ene (Compound 5)

[0763]

[0764] A solution of compound 6 (20.0 g, 33.9 mmol, 1 eq) and 1,4-diazabicyclo[2.2.2]octane (DABCO; 5.71 g, 50.9 mmol, 1.5 eq) in DCM (160 mL, 8 Vol Eq) was stirred at room temperature while the reaction temperature was maintained between 15-30°C while adding 25 w / v% 2-chloro-1,3-dimethylimidazolium chloride (DMC; 6.23 g, 24.9 mL, 37.3 mmol, 1.1 eq) over 5 minutes. Immediately after complete addition of DMC, the reaction suspension was diluted with PhMe (40 mL, 2 Vol Eq) and concentrated to remove most of the DCM. The concentrate was diluted again with PhMe (160 mL, 8 Vol Eq) total volume. The suspension was heated at 100°C. The reaction temperature was maintained at 100-105°C for 5-6 hours until the reaction was confirmed to be complete by LC analysis. The suspension was cooled to room temperature, and the solid (DABCO HCl and N, N-dimethylimidazolinone) was removed by filtration. The filter cake was washed twice with MTBE (40mL, 2 volumes). The filtrate and washings were combined and washed successively, first with water (60mL, 3VolEq), then with 0.5M HCl (67.9mL, 33.9mmol, 1 equivalent), and then with water (60mL, 3VolEq). The mixture was then concentrated to obtain crude compound 5 (20.9g; 108% theory).

[0765] The crude compound 5 was dissolved in hot (75°C) EtOH (40 mL) and cooled to room temperature within 1 hour. The solid was collected by filtration, and the filter cake was washed with EtOH (2 x 10-mL) and then air-dried to give compound 5 (14.0 g; 72%) as a yellow solid. ESI-MS m / z calculated value 571.17, found value 572 (M+1) + . 1 H NMR (400MHz, chloroform-d) δ8.47 (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=1 2.0, 10.0, 5.4Hz, 1H), 1.99 (ddt, J=14.7, 8.0, 4.0Hz, 2H), 1.45 (s, 3H), 1.42 (s, 3H). 19F NMR (376 MHz, CDCl 3 )δ-64.13, -72.99.

[0766] Step 6: (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (Compound I)

[0767]

[0768] Compound 5 (14.0 g, 24.5 mmol, 1 eq) and 10 wt% palladium / activated carbon (Evonik Nobylst P1173; 2.6 g, 50 w / w%, 0.5 eq) were dissolved in EtOH (210 mL, 15 VolEq), EtOAc (70 mL, 5 VolEq) and 7 M NH 3 / MeOH (3.5 mL, 24.5 mmol, 1 eq) was evacuated and heated with N 2 The reaction vessel was evacuated and filled with H 2 The reaction vessel was backfilled with N 2 Backfill three times, and the reaction of the mixture was analyzed by LC to be complete. A portion of diatomaceous earth (2 g) was added to the reaction mixture, and the suspension was filtered through a 1-cm diatomaceous earth packed bed to remove the catalyst. The flask / filter bed was washed with EtOH (3 x 10 mL), and the washings were combined with the filtrate and concentrated (45 ° C / 20 Torr), to obtain Compound I (11.5 g; 104% theory) as a bright yellow foam.

[0769] The foam was dissolved in DCM (98 mL, 7 VolEq) and filtered through SiO 2The packed bed (14g; 1g / g) was filtered. The filter bed was washed with DCM (80mL), and then washed with 20% EtOAc / DCM (2x 100mL). The color of each subsequent washing became lighter, and the final washing was almost colorless. The filtrate and washings were combined and concentrated to obtain compound I (11.1g) as an orange solid. The resulting product was dissolved in warm (30°C) DCM (98mL, 7VolEq) and quickly mixed and diluted with heptane (98mL, 7VolEq). The solution was concentrated (45°C / 360 Torr) to remove most of the DCM, and then the resulting suspension was backfilled with another portion of heptane (98mL, 7 volumes). 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 (2x 10-mL) and air-dried to obtain compound I (10.7g; 96%) as a bright yellow granular solid. ESI-MS m / z calculated value 453.16, found value 454 (M+1) + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.62 (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. 4Hz, 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) delta -62.34, -78.23.

[0770] Example 6: (R)-10-(Benzyloxy)-4,4-dimethyl-2 3 -Nitro-2 5 Alternative Synthesis of 10-Bis(trifluoromethyl)-3-aza-1(2,5)-oxadiazole-2(2,6)-pyridinecyclodecane-7-ene (Compound 5)

[0771]

[0772] 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)

[0773]

[0774] (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:

[0775] Li, C.; Dickson, HD. Tetrahedron Lett., 2009, 50, 6435.

[0776] ·Augustine, JK; Vairaperumal, V.; Narasimhan, S.; Alagarsamy, P.; Radhakrishnan, A. "Tetrahedron", 2009, 65, 9989.

[0777] A suitable vessel with overhead stirring and nitrogen inlet was 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-enoylhydrazide (15.6 mmol, 1.05 eq) and acetonitrile (34.8 mL, 6 vols). The mixture was stirred and T3P (33.1 g as a 50 w / w% solution, 52.0 mmol, 3.5 eq) and DIPEA (89.2 mmol, 6 eq) were charged to the reactor. The mixture was heated to an internal temperature of 78°C and monitored by HPLC until the desired reaction conversion was observed. The temperature was reduced to 25°C and water (29 mL, 5 vols) was charged to the reactor and the mixture was stirred for 10 minutes. MTBE (46.4 mL, 8 volumes) was charged, stirred for 10 minutes, allowed to settle and then separated. The organic layer was separated and subsequently washed with 5% citric acid (29 mL, 5 volumes), saturated sodium bicarbonate (29 mL, 5 volumes) and water (29 mL, 5 volumes). The organic layer was concentrated to an oil and used as is in subsequent processing.

[0778] Step 2: (R)-10-(Benzyloxy)-4,4-dimethyl-2 3 -Nitro-2 5 ,10-bis(trifluoromethyl)-3-aza-1(2,5)-oxadiazole-2(2,6)-pyridinecyclodecane-7-ene (Compound 5)

[0779]

[0780] Compound 5 can be prepared from Compound 25 by using a procedure similar to that described in Example 5, Step 4.

[0781] Example 7: Alternative Synthesis of (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (Compound I)

[0782]

[0783] Step 1: (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)

[0784]

[0785] (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:

[0786] Li, C.; Dickson, HD. Tetrahedron Letters, 2009, 50, 6435.

[0787] ·Augustine, JK; Vairaperumal, V.; Narasimhan, S.; Alagarsamy, P.; Radhakrishnan, A. "Tetrahedron", 2009, 65, 9989.

[0788] A suitable vessel with overhead stirring and nitrogen inlet was charged with 3-((tert-butoxycarbonyl)amino)-6-((2-methylhex-5-en-2-yl)amino)-5-(trifluoromethyl)picolinic acid (Compound 26) (14.9 mmol; 1 eq; prepared according to Example 90, Step 3 of WO2022 / 109573 A1), (R)-2-(benzyloxy)-2-(trifluoromethyl)pent-4-enoylhydrazide (15.6 mmol, 1.05 eq) and acetonitrile (34.8 mL, 6 volumes). The mixture was stirred and T3P (33.1 g, as a 50 w / w% solution, 52.0 mmol, 3.5 eq) and DIPEA (89.2 mmol, 6 eq) were charged to the reactor. The mixture was heated to an internal temperature of 78°C and monitored by HPLC until the desired reaction conversion was observed. The temperature was lowered to 25°C and water (29 mL, 5 volumes) was charged to the reactor and the mixture was stirred for 10 minutes. MTBE (46.4 mL, 8 volumes) was charged, stirred for 10 minutes, allowed to settle and then separated. The organic layer was separated and subsequently washed with 5% citric acid (29 mL, 5 volumes), saturated sodium bicarbonate (29 mL, 5 volumes) and water (29 mL, 5 volumes). The organic layer was concentrated to an oil and used as is in subsequent processing.

[0789] Step 2: (R)-(10-(Benzyloxy)-4,4-dimethyl-2 5 ,10-bis(trifluoromethyl)-3-aza-1(2,5)-oxadiazole-2(2,6)-pyridinecyclodecane-7-ene-2 3 -yl) tert-butyl carbamate (Compound 28)

[0790]

[0791] Compound 28 can be prepared from Compound 27 by using a procedure similar to that described in Example 5, Step 4.

[0792] Step 3: (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (Compound I)

[0793]

[0794] Compound 1 can be prepared from Compound 28 by using a procedure similar to that described in Example 5, Step 6.

[0795] Other embodiments

[0796] All publications and patents mentioned in this disclosure are incorporated herein 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 its entirety. If the meaning of a term in any patent or publication incorporated by reference conflicts with the meaning of a term used in this disclosure, the meaning of the term defined in this disclosure is intended to control.

[0797] The foregoing discussion discloses and describes only exemplary embodiments of the present disclosure. Those skilled in the art will readily recognize from such discussion and from the accompanying drawings and claims that various changes, modifications and variations may be made therein without departing from the spirit and scope of the present disclosure as defined in the following claims.

Claims

1. A compound I It is in the form of Compound 1 which is substantially amorphous.

2. The substantially amorphous Compound I of claim 1, wherein Compound I is 100% amorphous.

3. A substantially crystalline Compound 1 methanol solvate (wet).

4. The substantially crystalline Compound 1 Methanol Solvate (wet) of claim 3, wherein the Compound 1 Methanol Solvate (wet) is 100% crystalline.

5. The substantially crystalline Compound 1 methanol solvate (wet) according to claim 3, characterized in that An X-ray powder diffraction pattern having signals at one or more of 25.5±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 20.5±0.2 degrees 2θ, 19.0±0.2 degrees 2θ, 18.9±0.2 degrees 2θ, 18.6±0.2 degrees 2θ, 16.9±0.2 degrees 2θ, 15.0±0.2 degrees 2θ, 14.6±0.2 degrees 2θ, and 8.4±0.2 degrees 2θ.

6. The substantially crystalline Compound 1 methanol solvate (wet) according to claim 3, characterized in that An X-ray powder diffraction pattern substantially similar to that of FIG. 3 .

7. The substantially crystalline Compound 1 methanol solvate (wet) according to claim 3, characterized in that The monoclinic crystal system, i.e., P21 space group, and in the presence of Cu K α radiation The following unit cell dimensions were measured on a Rigaku diffractometer at 100 K:

8. The substantially crystalline Compound 1 methanol solvate (wet) according to claim 3, characterized in that Having one or more signals selected from the following 13 C SSNMR spectrum: 145.6±0.2ppm, 132.5±0.2ppm, 113.1±0.2ppm, 73.5±0.2ppm, 55.9±0.2ppm, 35.2±0.2ppm, 31.1±0.2ppm, 30.5±0.2ppm, 24.8±0.2ppm and 19.0±0.2ppm.

9. The substantially crystalline Compound 1 methanol solvate (wet) according to claim 3, characterized in that Basically similar to Figure 4 13 C SSNMR spectrum.

10. The substantially crystalline Compound 1 methanol solvate (wet) according to claim 3, characterized in that Having one or more signals selected from -63.9 ± 0.2 ppm, -76.6 ± 0.2 ppm and -79.7 ± 0.2 ppm 19 F MAS.

11. The substantially crystalline Compound 1 methanol solvate (wet) according to claim 3, characterized in that Basically similar to Figure 5 19 F MAS.

12. The substantially crystalline Compound 1 methanol solvate (wet) of claim 3, prepared by: (i) combining Compound 1 pure Form A, 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 to stand at room temperature for more than 3 days to produce crystalline Compound 1 methanol solvate (wet).

13. A substantially crystalline Compound 1 methanol solvate (dry).

14. The substantially crystalline Compound 1 Methanol Solvate (Dry) of claim 13, wherein the Compound 1 Methanol Solvate (Dry) is 100% crystalline.

15. The substantially crystalline Compound 1 methanol solvate (dry) according to claim 13, characterized in that An X-ray powder diffraction pattern having signals at one or more of 27.2±0.2 degrees 2θ, 26.4±0.2 degrees 2θ, 25.9±0.2 degrees 2θ, 21.4±0.2 degrees 2θ, 19.3±0.2 degrees 2θ, 18.1±0.2 degrees 2θ, 15.4±0.2 degrees 2θ, 14.2±0.2 degrees 2θ, and 7.4±0.2 degrees 2θ.

16. The substantially crystalline Compound 1 methanol solvate (dry) according to claim 13, characterized in that An X-ray powder diffraction pattern substantially similar to that of FIG. 6 .

17. The substantially crystalline Compound 1 methanol solvate (dry) of claim 13, prepared by: (i) combining Compound 1 pure Form A, 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 more than 3 days, and (iv) drying in a vacuum oven at 60°C overnight to produce a crystalline Compound 1 methanol solvate (dry).

18. A substantially crystalline compound I p-toluenesulfonic acid.

19. The substantially crystalline Compound I p-toluenesulfonic acid of claim 18, wherein Compound I p-toluenesulfonic acid is 100% crystalline.

20. The substantially crystalline compound I p-toluenesulfonic acid of claim 18, characterized in that An X-ray powder diffraction pattern having signals at one or more of 5.7±0.2 degrees 2θ, 5.8±0.2 degrees 2θ, 7.4±0.2 degrees 2θ, 10.1±0.2 degrees 2θ, 11.5±0.2 degrees 2θ, 11.9±0.2 degrees 2θ, 14.9±0.2 degrees 2θ, 15.9±0.2 degrees 2θ, 16.2±0.2 degrees 2θ, 18.3±0.2 degrees 2θ, 20.4±0.2 degrees 2θ, 21.0±0.2 degrees 2θ, 21.6±0.2 degrees 2θ, 22.8±0.2 degrees 2θ, and 23.2±0.2 degrees 2θ.

21. The substantially crystalline compound I p-toluenesulfonic acid of claim 18, characterized in that An X-ray powder diffraction pattern substantially similar to that of FIG. 9 .

22. The substantially crystalline compound I p-toluenesulfonic acid of claim 18, characterized in that Having one or more signals selected from the following 13 C SSNMR spectrum: 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.

23. The substantially crystalline compound I p-toluenesulfonic acid of claim 18, characterized in that Basically similar to Figure 11 13 C SSNMR spectrum.

24. The substantially crystalline Compound 1 p-toluenesulfonic acid of claim 18, characterized by having a signal comprising one or more signals selected from the group consisting of 19 F MAS: -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.

25. The substantially crystalline compound I p-toluenesulfonic acid of claim 18, characterized in that Basically similar to Figure 12 19 F MAS.

26. The substantially crystalline Compound 1 methanol solvate (wet) of claim 18, prepared by (i) adding p-toluenesulfonic acid to Compound 1 pure Form A in a grinding ball 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, and (iv) drying the resulting material in a vacuum drying oven at 40°C to produce crystalline Compound 1 p-toluenesulfonic acid.

27. A pharmaceutical composition comprising Compound I according to any one of claims 1 to 26 and a pharmaceutically acceptable carrier.

28. The pharmaceutical composition of claim 27, further comprising one or more additional therapeutic agents.

29. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition comprises one or more additional CFTR modulating compounds.

30. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition comprises one or more compounds selected from the group consisting of Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof.

31. Compound I according to any one of claims 1 to 26 or a pharmaceutical composition according to any one of claims 27 to 30 for use in the treatment of cystic fibrosis.

32. Use of Compound I according to any one of claims 1 to 26 or a pharmaceutical composition according to any one of claims 27 to 30 for the preparation of a medicament for the treatment of cystic fibrosis.

33. A method of treating cystic fibrosis, the method comprising administering Compound I according to any one of claims 1 to 26 or a pharmaceutical composition according to any one of claims 27 to 30 to a subject in need thereof.

34. A method for preparing compound I: or a stereoisomer of Compound I, or a deuterated derivative of Compound I or a stereoisomer of Compound I, or a pharmaceutically acceptable salt of any one of the foregoing, wherein the method comprises treating a compound of Formula I: or a stereoisomer of the compound of formula I, or a deuterated derivative of the compound of formula I or its stereoisomer, or a salt of any of the foregoing, is converted into compound I, or a stereoisomer thereof, or a deuterated derivative of compound I or its stereoisomer, or a salt of any of the foregoing, wherein R a is selected from alcohol protecting groups.

35. A method for preparing compound I: or a stereoisomer of Compound I, or a deuterated derivative of Compound I or a stereoisomer of Compound I, or a pharmaceutically acceptable salt of any of the foregoing, wherein the method comprises treating a compound of Formula II: or the stereoisomer of the compound of formula II, or the deuterated derivative of the compound of formula II or its stereoisomer, or a salt of any of the foregoing is converted into compound I, or its stereoisomer, or the deuterated derivative of compound I or its stereoisomer, or a salt of any of the foregoing, wherein R a is selected from alcohol protecting groups, and provided that R a Not benzyl (Bn).

36. The method of claim 34 or 35, wherein converting the compound of formula II, or a stereoisomer of the compound of formula II, or a deuterated derivative of the compound of formula II 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 is carried out in the presence of reducing reaction conditions.

37. The method according to any one of claims 34 to 36, wherein the method comprises treating the compound of formula I: or the stereoisomer of the compound of formula I, or the deuterated derivative of the compound of formula I or its stereoisomer, or a salt of any one of the foregoing is converted into the compound of formula II, or its stereoisomer, or the deuterated derivative of the compound of formula II or its stereoisomer, or a salt of any one of the foregoing, wherein R a is selected from alcohol protecting groups.

38. The method of claim 37, wherein converting the compound of formula I, or a stereoisomer of the compound of formula I, or a deuterated derivative of the compound of formula I or a stereoisomer thereof, or a salt of any of the foregoing into the compound of formula II, or a stereoisomer thereof, or a deuterated derivative of the compound of formula II or a stereoisomer thereof, or a salt of any of the foregoing is carried out in the presence of a dehydrating agent and a base.

39. The method according to any one of claims 34 to 38, wherein the method comprises reacting a compound of formula III: or the stereoisomer of the compound of formula III, or the deuterated derivative of the compound of formula III or its stereoisomer, or a salt of any one of the foregoing is converted into the compound of formula I, or its stereoisomer, or the deuterated derivative of the compound of formula I or its stereoisomer, or a salt of any one of the foregoing, wherein R a is selected from alcohol protecting groups.

40. The method of claim 39, wherein converting the compound of formula III, or a stereoisomer of the compound of formula III, or a deuterated derivative of the compound of formula III or a stereoisomer thereof, or a salt of any of the foregoing into the compound of formula I, or a stereoisomer thereof, or a deuterated derivative of the compound of formula I or a stereoisomer thereof, or a salt of any of the foregoing is carried out in the presence of a ruthenium catalyst.

41. The method according to any one of claims 39 or 40, wherein the method comprises making compound 2: Or a deuterated derivative of compound 2, or a salt of any of the foregoing and a compound of formula IV: or a stereoisomer of the compound of formula IV, or a deuterated derivative of the compound of formula IV or a stereoisomer thereof, or a salt of any of the foregoing, to produce the compound of formula III, or a stereoisomer thereof, or a deuterated derivative of the 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.

42. The method of claim 41, 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 the compound of Formula IV, or a deuterated derivative of the compound of Formula IV or its stereoisomer, or a salt of any of the foregoing is carried out in the presence of a peptide coupling agent and a base.

43. The method according to claim 41 or 42, wherein the method comprises treating a compound of formula V: or the deuterated derivative of the compound of formula V, or a salt of any of the foregoing, is converted into compound 2, a deuterated derivative of compound 2, or a salt of any of the foregoing, wherein R b Selected from methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (i-Pr) and tert-butyl (t-Bu).

44. The method of claim 43, wherein converting the compound of formula V, or a deuterated derivative of the compound of formula V, or a salt of any of the foregoing, into compound 2, or a deuterated derivative of compound 2, or a salt of any of the foregoing is carried out in the presence of an aqueous hydroxide base solution.

45. The method according to 43 or 44, wherein the method comprises making a compound of formula VI: or a deuterated derivative of a compound of formula VI, or a salt of any of the foregoing and compound 3: or a deuterated derivative of a compound of formula VI, or a salt of any of the foregoing, to produce the compound of formula V, or a deuterated derivative of the compound of formula V, or a salt of any of the foregoing, wherein: -R b is selected from the group consisting of methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (i-Pr) and tert-butyl (t-Bu); and -X is selected from Cl and Br.

46. ​​The method of claim 45, 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 a deuterated derivative of compound 3, or a salt of any of the foregoing is carried out in the presence of a base.

47. The method according to claim 45 or 46, wherein the method comprises treating a compound of formula VII: or a deuterated derivative of the compound of formula VII, or a salt of any of the foregoing, is converted into compound 3, or a deuterated derivative of compound 3, or a salt of any of the foregoing, wherein R c is selected from amine protecting groups.

48. The method of claim 47, wherein converting the compound of formula VII, or a deuterated derivative of the compound of formula VII, or a salt of any of the foregoing, into compound 3, or a deuterated derivative of compound 3, or a salt of any of the foregoing is carried out in the presence of a protic acid.

49. The method of claim 47 or 48, wherein the method comprises treating a compound of formula VIII: or the deuterated derivative of the compound of formula VIII is converted into the compound of formula VII, or the deuterated derivative of the compound of formula VII, or a salt of any one of the foregoing, wherein R c is selected from amine protecting groups.

50. The process of claim 49, wherein converting the compound of formula VIII, or a deuterated derivative of the compound of formula VIII, to the compound of formula VII, or a 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.

51. The method of claim 49 or 50, wherein the method comprises treating a compound of formula IX: or a deuterated derivative of the compound of formula IX, or a salt of any one of the foregoing, is converted into the compound of formula VIII, or a deuterated derivative of the compound of formula VIII, or a salt of any one of the foregoing, wherein R c is selected from amine protecting groups.

52. The method of claim 51, wherein converting the compound of formula IX, or a deuterated derivative of the compound of formula IX, or a salt of any of the foregoing, into the compound of formula VIII, or a 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.

53. The method of claim 45 or 46, wherein the method comprises treating a compound of formula X: or a deuterated derivative of the compound of formula X, or a salt of any of the foregoing, is converted into compound 3, or a deuterated derivative of compound 3, or a salt of any of the foregoing, wherein X 1 Selected from F, Cl and Br.

54. The method of claim 53, wherein converting the compound of formula X, or a deuterated derivative of the compound of formula X, or a salt of any of the foregoing, into compound 3, or a 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.

55. The method of claim 53 or 54, wherein the method comprises reacting hex-5-en-2-one: or a deuterated derivative of hex-5-en-2-one, or a salt of any of the foregoing, into the compound of formula X, or a deuterated derivative of the compound of formula X, or a salt of any of the foregoing, wherein X 1 Selected from F, Cl and Br.

56. The method of claim 55, wherein the method 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, into the compound of formula X, or a deuterated derivative of the compound of formula X, or a salt of any of the foregoing comprises: (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 methylmagnesium halide, or a deuterated derivative of the methylmagnesium halide, or a salt of any of the foregoing; and (ii) reacting the product of step (i) with 2-haloacetonitrile or a deuterated derivative of said 2-haloacetonitrile, To produce a compound of formula X or a salt of any of the foregoing, wherein X 1 Selected from F, Cl and Br.

57. A method for preparing compound I: or a stereoisomer of Compound I, or a deuterated derivative of Compound I or a stereoisomer of Compound I, or a pharmaceutically acceptable salt of any of the foregoing, wherein the method comprises treating a compound of Formula I, Formula II or Formula III: or a stereoisomer of the compound, or a deuterated derivative of the compound or its stereoisomer, or a salt of any of the foregoing is converted into Compound I, or a stereoisomer of Compound I, or a deuterated derivative of Compound I or its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing, in: -R a is selected from alcohol protecting groups; and - the compound of formula I, II or III is not selected from the following compounds: 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-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,8,14,16-hexaene (E / Z mixed) mixture); N′-[(2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]-6-[1,1-bis(trideuteromethyl)but-3-enylamino]-3-nitro-5-(trifluoromethane)pyridine-2-carbohydrazide; (6R)-6-benzyloxy-17-nitro-12,12-bis(trideuteromethyl)-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaene (E / Z mixture); and pharmaceutically acceptable salts thereof.

58. A compound selected from the group consisting of: or a stereoisomer of said compound, or a deuterated derivative of said compound or its stereoisomer, or a salt of any of the foregoing, in: -R a is selected from alcohol protecting groups; and - the compound of formula I, formula II or formula III is not selected from the following compounds: 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-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,8,14,16-hexa olefins (E / Z mixture); N′-[(2R)-2-benzyloxy-2-(trifluoromethyl)hex-5-enoyl]-6-[1,1-bis(trideuteromethyl)but-3-enylamino]-3-nitro-5-(trifluoromethane)pyridine-2-carbohydrazide; (6R)-6-benzyloxy-17-nitro-12,12-bis(trideuteromethyl)-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetraazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,9,14,16-hexaene (E / Z mixture); and pharmaceutically acceptable salts thereof.

59. A compound selected from the group consisting of: or a stereoisomer of the compound, or a deuterated derivative of the compound or its stereoisomer, or a salt of any of the foregoing, wherein R a is selected from alcohol protecting groups.

60. A compound having the formula: or a stereoisomer of the compound, or a deuterated derivative of the compound or its stereoisomer, or a salt of any of the foregoing.

61. A method for preparing compound I: or a stereoisomer of Compound I, or a deuterated derivative of Compound I or a stereoisomer of Compound I, or a pharmaceutically acceptable salt of any of the foregoing, wherein the method comprises treating a compound of Formula II: or the stereoisomer of the compound of formula XI, or the deuterated derivative of the compound of formula XI or its stereoisomer, or a salt of any of the foregoing, is converted into compound I, or its stereoisomer, or the deuterated derivative of compound I or its stereoisomer, or a salt of any of the foregoing, in: R a is selected from alcohol protecting groups, and R 1 Selected from -N(Boc)2, -NHBoc, -N(Phth), -NH(Cbz) and -NO2.

62. The method of claim 62, 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 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 comprises a reaction performed in the presence of reducing reaction conditions.

63. The method of claim 62 or 63, wherein converting the compound of formula XI, or the stereoisomer of the compound of formula XI, or the deuterated derivative of the compound of formula XI or its stereoisomer, or a salt of any of the foregoing into compound I, or its stereoisomer, or the deuterated derivative of compound I or its stereoisomer, or a salt of any of the foregoing further comprises reacting in the presence of an acid.

64. The method according to any one of claims 61 to 63, wherein the method comprises treating the compound of formula XII: or a stereoisomer of the compound of formula XII, or a deuterated derivative of the compound of formula XII or a stereoisomer thereof, or a salt of any of the foregoing is converted into the compound of formula XI, or a stereoisomer thereof, or a deuterated derivative of the 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, and R 1 Selected from -N(Boc)2, -NHBoc, -N(Phth), -NH(Cbz) and -NO2.

65. The method of claim 64, wherein converting the compound of formula XII, or a stereoisomer of the compound of formula XII, or a deuterated derivative of the compound of formula XII or a stereoisomer thereof, or a salt of any of the foregoing to the compound of formula XI, or a stereoisomer thereof, or a deuterated derivative of the compound of formula XI or a stereoisomer thereof, or a salt of any of the foregoing comprises a reaction performed in the presence of a ruthenium catalyst.

66. The method of claim 64 or 65, wherein the method comprises making Formula XIII: Or a deuterated derivative of compound 2, or a salt of any of the foregoing and a compound of formula IV: or a stereoisomer of the compound of formula IV, or a deuterated derivative of the compound of formula IV or a stereoisomer thereof, or a salt of any of the foregoing, to produce the compound of formula XII, or a stereoisomer thereof, or a deuterated derivative of the compound of formula XII or a stereoisomer thereof, or a salt of any of the foregoing, wherein: R a is selected from alcohol protecting groups, and R 1 Selected from -N(Boc)2, -NHBoc, -N(Phth), -NH(Cbz) and -NO2.

67. The method of claim 66, wherein reacting a compound of formula XIII, or a deuterated derivative of formula XIII, or a salt of any of the foregoing, with a compound of formula IV, or a stereoisomer of the compound of formula IV, or a deuterated derivative of the compound of formula IV or a stereoisomer of the compound of formula IV, or a salt of any of the foregoing is carried out in the presence of a peptide coupling agent and a base.

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