Crystalline form of (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide

Abstract

The present invention relates to crystalline forms of (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide; methods for their preparation, pharmaceutical compositions comprising such crystalline forms, pharmaceutical compositions prepared from such crystalline forms, and their use as pharmaceuticals, particularly as CFTR modulators.

Description

[Technical Field]

[0001] The present invention relates to (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide ((3S,7S,10R,13R)-13-benzyl-20-fl uoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecino[16,17-f]quinoline-3-carboxamide) (hereinafter also referred to as "compound"):

[0002] [ka]

[0003] The present invention relates to novel crystalline forms of the compound of formula (I), methods for their preparation, pharmaceutical compositions comprising the crystalline forms, pharmaceutical compositions prepared from such crystalline forms, and their use as CFTR modulators, particularly as CFTR modulators for the treatment of cystic fibrosis. The present invention further relates to the crystalline forms as medicaments in combination with one or more therapeutically active ingredients that act as CFTR modulators. [Background technology]

[0004] Cystic fibrosis (CF; mucoviscidosis, which is a fibrocystic disease of the pancreas or pancreatic fibrosis) Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by dysfunction of the epithelial chloride / bicarbonate channel called the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). CFTR dysfunction causes dysregulation of chloride, bicarbonate, and water transport at the surface of secretory epithelia, leading to the accumulation of thick mucus in organs including the lungs, pancreas, liver, and intestine, resulting in multiple organ failure. Today, the most debilitating effects of CF are observed in the lungs, where—due to abnormal hydration of airway surface fluid, mucus plugging, impaired mucociliary clearance, chronic inflammation, and infection—the lungs eventually lose their function, leading to death from respiratory failure (Elborn, 2016). Human CFTR is a multidomain protein with 1,480 amino acids. Many different mutations causing CFTR dysfunction have been found in CF patients, including loss of functional CFTR protein (class I mutations), CFTR trafficking defects (class II mutations), CFTR regulation defects (also known as gating defects; class III mutations), CFTR conductance defects (class IV mutations), reduced CFTR protein due to splicing defects (class V mutations) or reduced CFTR stability (class VI mutations), and loss of CFTR protein due to mRNA destabilization (class VII mutations) (de Boeck, Acta Paediatr. 2020, 109(5):893-895). The CFTR2 database (http: / / cftr2.org; data as of 22.08.2022) currently contains information on 401 disease-causing mutations.The most common disease-causing mutation by far is a deletion of phenylalanine at position 508 (F508del; allele frequency 0.697 in the CFTR2 database), which causes misfolding of the channel during synthesis in the endoplasmic reticulum, degradation of the misfolded protein, and consequently a marked reduction in transport to the cell surface (Class II mutation). The remaining F508del-CFTR that traffics to the cell surface is functional, but less functional than wild-type CFTR; i.e., F508del-CFTR also contains a gating defect (Dalemans, 1991). Approximately 40% of all CF patients are homozygous for the F508del mutation, while another ~40% are heterozygous for the F508del mutation and carry another disease-causing mutation in Class I, II, III, IV, V, VI, or VII. Such disease-causing mutations are fairly rare, with class III G551D mutations (allele frequency 0.0210) and class I G542X mutations (allele frequency 0.0254) and class II. The N1303K mutation (allele frequency 0.0158) is the next most common.

[0005] Currently, CF is treated with a wide range of medications for various organ symptoms and disorders. Intestinal and pancreatic disorders are treated, once diagnosed, with the addition of pancreatic digestive enzymes to the diet. Pulmonary symptoms are primarily treated with inhaled hypertonic saline, mucolytics, anti-inflammatory agents, bronchodilators, and antibiotics (Elborn, 2016).

[0006] In addition to symptomatic treatments, CFTR modulators have been developed and approved for patients with specific CFTR mutations. These compounds either directly improve CFTR folding and CFTR trafficking to the cell surface (CFTR correctors) or improve CFTR function at the cell surface (CFTR potentiators). Other types of modulators, such as compounds that increase (mutated) CFTR mRNA levels (CFTR amplifiers) and compounds that increase the plasma membrane stability of mutated CFTR (CFTR stabilizers), are still in the exploratory stage. CFTR modulators can also enhance the function of non-mutated (i.e., wild-type) CFTR and are therefore being studied in disorders where increasing wild-type CFTR function may have beneficial effects, such as chronic bronchitis / COPD / bronchiectasis (Le Grand, J Med Chem. 2021, 64(11):7241-7260. Patel, Eur Respir Rev. 2020, 29(156):190068) and dry eye disease (Flores, FASEB J. 2016, 30(5):1789-1797).

[0007] CFTR modulators and combinations thereof can be discovered and optimized by assessing their ability to promote mutant CFTR trafficking and function in in vitro cultured recombinant and primary cell lines, with activity in such systems predictive of activity in CF patients.

[0008] The crystalline CFTR modulators of the present invention, alone or in combination, are believed to be useful in the treatment of CFTR-related diseases and disorders, particularly cystic fibrosis, or other CFTR-related diseases and disorders selected from the following: - chronic bronchitis; sinusitis; constipation; pancreatitis; pancreatic insufficiency; male infertility caused by congenital bilateral absence of the vas deferens (CBAVD); mild lung disease; allergic bronchopulmonary aspergillosis (ABPA); liver disease; coagulation-fibrinolysis deficiencies such as protein C deficiency; and diabetes; - asthma; COPD; smoking-induced COPD; and dry eye disease; and - idiopathic pancreatitis; hereditary emphysema; hereditary hemochromatosis; especially I-cell disease; lysosomal storage diseases such as pseudo-Hurler; mucopolysaccharidoses; Sandhoff / Tay-Sachs; osteogenesis imperfecta; Fabry disease; Sjogren's disease; osteoporosis; osteopenia; bone healing and growth (including bone repair, bone regeneration, decreased bone resorption, and increasing bone deposition); chloride channelopathies such as myotonia congenita (Thomson and Becker forms); Bartter's syndrome type 3; epilepsy; lysosomal storage diseases; primary ciliary dyskinesia (PCD) - a term for genetic disorders of cilia structure and / or function (Kartagener syndrome). These include PCD with situs inversus, PCD without situs inversus, and ciliary aplasia, also known as situs inversus syndrome; generalized epilepsy with febrile seizures plus (GEFS+); generalized epilepsy with febrile and afebrile seizures; myotonia; congenital paramyotonia; potassium-aggravated myotonia; hyperkalemic periodic paralysis; long QT syndrome (LQTS); LQTS / Brugada syndrome; autosomal dominant LQTS with hearing loss; autosomal recessive LQTS; LQTS with dysmorphic features; congenital and acquired LQTS; dilated cardiomyopathy; autosomal dominant LQTS; osteopetrosis; and Bartter syndrome type 3.

[0009] WO2019 / 161078 discloses macrocycles as modulators of cystic fibrosis, generally 15-membered macrocycles having a (pyridine-carbonyl)-sulfamoyl moiety linked to an additional aromatic group. Further macrocycles are disclosed in WO2022 / 109573 (macrocycles having a 1,3,4-oxadiazole ring), WO2022 / 076625, WO2022 / 076626, WO2022 / 076624, WO2022 / 076621, WO2022 / 076620, WO2022 / 076618, WO2021 / 030556, and WO2021 / 030555. The compound, Apicidin (CAS:18 Macrocyclic tetrapeptides (12 or 13 members) such as 3506-66-3 have been proposed as potential drugs for the treatment of CF (Hutt DM et al., ACS Med Chem Lett. 2011;2(9):703-707. doi:10.1021 / ml200136e). WO2020 / 128925 discloses macrocyclic compounds capable of modulating the activity of CFTR, the macrocyclic compounds having an optionally substituted bivalent N-(pyridin-2-yl)pyridinyl-sulfonamide moiety. Other macrocyclic compounds have been described to stabilize the chloride channel CFTR (Stevers LM et al., Nature Communications 2022, 13:3586). Non-macrocyclic CFTR correctors and / or potentiators of CFTR have been disclosed, for example, in WO2011 / 119984, WO2014 / 015841, WO2007 / 134279, WO2010 / 019239, WO2011 / 019413, WO2012 / 027731, WO2013 / 130669, WO2014 / 078842 and WO2018 / 227049, WO2010 / 037066, WO2011 / 127241, WO2013 / 112804, WO2014 / 071122 and WO2020 / 128768.Additionally, specific macrocyclic compounds can be found as screening compounds (CAS Registry Numbers: CAS-2213100-89-9, CAS-2213100-96-8, CAS-2213100-99-1, CAS-2213101-02-9, CAS-2213101-04-1, CAS-2213101-06-3, CAS-2213101-08-5, CAS-2213101-09-6, CAS-2213101-19-8, CAS-2213101-24-5). , CAS-2215788-95-5, CAS-2215788-98-8, CAS-2215789-01-6, CAS-2215789-02-7, CAS-2215789-09-4, CAS-2215789-15-2, CAS-2 215789-20-9, CAS-2215789-24-3, CAS-2215789-35-6, CAS-2215789-37-8, CAS-2215946-94-2, CAS-2215947-04-7, CAS-2215947 -13-8, CAS-2215947-24-1, CAS-2215947-34-3, CAS-2215947-44-5, CAS-2215947-51-4, CAS-2215947-64-9, CAS-2215947-68-3, CAS-2215947-78-5, CAS-2215947-91-2, CAS-2215954-57-5, CAS-2216342-34-4, CAS-2216342-78-6, CAS-2216342-86-6, CAS-22 16343-03-0, CAS-2216343-09-6, CAS-2216343-14-3, CAS-2216343-18-7, CAS-2216343-24-5, CAS-2216343-32-5, CAS-2216343- 38-1, CAS-2216343-45-0, CAS-2216343-53-0, CAS-2216343-59-6, CAS-2216343-64-3, CAS-2216343-74-5, CAS-2216343-76-7). Summary of the Invention

[0010] The present invention provides a novel crystalline form of (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide, which is a CFTR modulator and is useful for the prevention or treatment of diseases responsive to CFTR activation, particularly cystic fibrosis. In the treatment of cystic fibrosis, the crystalline forms may be used in combination with one or more CFTR modulating agents known in the art. [Brief explanation of the drawings]

[0011] [Figure 1] Figure 1 shows the powder X-ray diffraction diagram of crystalline form 1 of "Compound" obtained in Example 8. The X-ray diffractogram measured using Method 1 shows characteristic peaks at the following angles 2θ (relative peak intensities are given in parentheses): 5.1° (100%), 8.0° (29%), 10.3° (18%), 12.4° (16%), 18.3° (24%), 18.8° (39%), 19.0° (21%), 19.6° (21%), 21.2° (23%), 22.0° (25%). [Figure 2] FIG. 2 shows the TGA curve of crystalline form 1 of the “compound” obtained in Example 8. [Figure 3] FIG. 3 shows the DSC curve of crystalline form 1 of the “compound” obtained in Example 8. [Figure 4] FIG. 4 shows the moisture sorption isotherm of a sample of crystalline Form 1 of the Compound from Example 6.

[0012] For the avoidance of any doubt, the above peaks describe the experimental results of the powder X-ray diffraction shown in Figure 1. In contrast to the above list of peaks, it should be understood that only selected characteristic peaks are necessary to completely and unambiguously characterize each crystalline form of the Compound of the present invention.

[0013] In the powder X-ray diffraction diagram of FIG. 1, the refraction angle 2 theta (2θ) is plotted on the horizontal axis and the counts are plotted on the vertical axis.

[0014] Detailed Description of the Invention 1) A first aspect of the present invention relates to the compound ((3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide:

[0015] [ka]

[0016] wherein the crystalline form is characterized by the presence of at least four, or at least six, or at least eight peaks in a powder X-ray diffraction diagram at refraction angles 2θ selected from 5.1°, 8.0°, 10.3°, 12.4°, 18.3°, 18.8°, 19.0°, 19.6°, 21.2°, and 22.0°.

[0017] The crystalline form of the "Compound" according to embodiment 1) is intended to encompass the crystalline form of the "Compound" as a free base (i.e., not in the form of a salt). The crystalline form may have a non-coordinating and / or a coordinating solvent. Coordinating solvent is used herein as a term for a crystalline solvate. Similarly, non-coordinating solvent is used herein as a term for a physically adsorbed or physically trapped solvent (as defined in Polymorphism in the Pharmaceutical Industry (Ed. R. Hilfiker, VCH, 2006), Chapter 8: UJ Griesser: The Importance of Solvates). The crystalline form of the "Compound" may in particular encompass isomorphic, non-stoichiometric hydrates, i.e., having 0 to 1 equivalent of coordinated water. The crystalline form of the "Compound" may in particular encompass isomorphic solvates, i.e., having a coordinating solvent such as isopropanol, methanol, ethanol, and / or water.

[0018] 2) Another embodiment relates to a crystalline form of the Compound according to embodiment 1), characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffraction diagram: 5.1°, 8.0°, 18.8°.

[0019] 3) Another embodiment relates to a crystalline form of the Compound according to embodiment 1) or 2), characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffraction diagram: 5.1°, 8.0°, 10.3°, 18.8°, 19.6°.

[0020] 4) Another embodiment relates to a crystalline form of the Compound according to any one of embodiments 1) to 3), characterized by the presence of peaks at the following refraction angles 2θ in a powder X-ray diffraction diagram: 5.1°, 8.0°, 10.3°, 12.4°, 18.3°, 18.8°, 19.0°, 19.6°, 21.2°, 22.0°.

[0021] 5) Another embodiment relates to a crystalline form of the Compound according to any one of embodiments 1) to 4), which exhibits essentially the powder X-ray diffraction pattern shown in FIG.

[0022] 6) Another embodiment relates to a crystalline form of the Compound according to embodiment 1), characterized by the presence of peaks at the following refraction angles 2θ: 5.1°, 8.0°, and 18.8° in a powder X-ray diffraction diagram; or such a crystalline form according to any one of embodiments 1) to 5), which exhibits an endothermic event at about 198°C as determined by differential scanning calorimetry (e.g., by using a method described herein).

[0023] For the avoidance of doubt, whenever one of the above embodiments refers to "peaks at the following refraction angles 2θ in a powder X-ray diffraction diagram," it is to be understood that the powder X-ray diffraction diagram was obtained using combined Cu Kα1 and Kα2 radiation without removing Kα2; and the accuracy of the 2θ values ​​provided herein is within the range of + / −0.1 to 0.2°. In particular, when specifying a refraction angle 2θ for a peak in the embodiments and claims of the present invention, the stated 2θ value should be understood to be between −0.2° and +0.2° (2θ + / −0.2°); and preferably between −0.1° and +0.1° (2θ + / −0.1°).

[0024] Thus, structures are said to be isomorphic if the peak positions in the powder X-ray diffractograms differ by within + / - 0.2 degrees in 2θ.

[0025] When the plural is used for compounds, solids, pharmaceutical compositions, diseases, etc., it is intended to refer to the singular compound, solid, etc. as well.

[0026] The term "enantiomerically enriched" is understood in the context of the present invention to specifically mean that at least 90, preferably at least 95, and most preferably at least 99 percent by weight of the "compound" is present in the form of one enantiomer of the "compound." The "compound" is understood to exist in the enantiomerically enriched absolute (3S,7S,10R,13R)-configuration.

[0027] The term "essentially pure" is understood in the context of the present invention to mean in particular that at least 90, preferably at least 95, and most preferably at least 99 weight percent of the crystals of the "compound" are present in the crystalline form of the present invention, in particular in the single crystalline form of the present invention.

[0028] For example, when defining the presence of a peak in an X-ray powder diffraction diagram, a common way is to do this in terms of the S / N ratio (S=signal, N=noise). According to this definition, when stating that a peak must be present in an X-ray powder diffraction diagram, it is understood that the peak in the X-ray powder diffraction diagram is defined by having an S / N ratio (S=signal, N=noise) greater than x (x is a number greater than 1), usually greater than 2, in particular greater than 3.

[0029] In the context of the statement that a crystalline form essentially exhibits the powder X-ray diffraction pattern shown in Figure 1, the term "essentially" means that at least the main peaks of the diagram shown in said figure, i.e., peaks having a relative intensity of more than 10%, in particular more than 20%, compared to the most intense peak in the diagram, must be present. However, those skilled in the art of powder X-ray diffraction will recognize that the relative intensities of powder X-ray diffraction diagrams can be subject to strong intensity variations due to preferred orientation effects.

[0030] When not used in reference to temperature, the term "about" placed before a numerical value "X" in this application means between 10% of XX and 10% of X+X, preferably between 5% of XX and 5% of X+X. In the specific case of temperature, the term "about" placed before a temperature "Y" in this application means between a temperature Y-10°C and Y+10°C, preferably between Y-5°C and Y+5°C, in particular between Y-3°C and Y+3°C. Room temperature means a temperature of about 25°C. When the term n equivalents (n is a number) is used in this application, it is intended that within the scope of this application n means about n, preferably n means exactly n.

[0031] Whenever the words "between" or "to" are used to describe a numerical range, the endpoints of the stated range are expressly included in that range. For example: when a temperature range is stated to be between 40°C and 80°C (or 40°C to 80°C), it is meant that the endpoints 40°C and 80°C are included in the range; or when a variable is defined as an integer between 1 and 4 (or 1 to 4), it is meant that the variable is the integer 1, 2, 3, or 4.

[0032] The expression %w / w means weight percentage relative to the total weight of the composition under consideration. Similarly, the expression v / v means the volume ratio of two components under consideration. The expression "vol" means volume (e.g., L of solvent) per weight (e.g., kg of reactant). For example, 7 vol means 7 liters (of solvent) per kg (of reactant).

[0033] The crystalline forms, in particular essentially pure crystalline forms, of the Compound according to any one of the aspects 1) to 6) can be used as a medicament, for example in the form of a pharmaceutical composition for enteral or parenteral administration.

[0034] 7) Accordingly, another embodiment relates to a crystalline form of the Compound according to any one of embodiments 1) to 6), (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide, for use as a medicament.

[0035] The crystalline solid, in particular the essentially pure crystalline solid, of the Compound according to any one of embodiments 1) to 6) may be used as the sole component or as a mixture with other crystalline or amorphous forms of the Compound.

[0036] Pharmaceutical compositions can be produced in a manner well known to anyone skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by combining the crystalline form of the present invention, optionally with other therapeutically valuable substances, with suitable non-toxic, inert, pharmaceutically acceptable solid or liquid carrier materials and, if necessary, conventional pharmaceutical adjuvants to form a pharmaceutical dosage form.

[0037] 8) A further aspect of the present invention relates to a pharmaceutical composition having as an active ingredient a crystalline form of the Compound according to any one of aspects 1) to 6), (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide, and further comprising at least one pharmaceutically acceptable carrier material.

[0038] Such pharmaceutical compositions according to embodiment 8) are particularly useful for the prevention or treatment of CFTR-related diseases or disorders, in particular cystic fibrosis.

[0039] 9) A further embodiment of the invention relates to a pharmaceutical composition according to embodiment 8) in the form of a tablet.

[0040] 10) A further embodiment of the invention relates to a pharmaceutical composition according to embodiment 8), which is in the form of a capsule.

[0041] 11) A further embodiment of the invention relates to a pharmaceutical composition according to embodiment 8), which is in liquid form.

[0042] 12) A further aspect of the present invention relates to the use of a "compound" according to any one of aspects 1) to 6), (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-( Regarding the use of a crystalline form of (2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide, the pharmaceutical composition is "the compound", (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-o- The active ingredient in the composition is 1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide, and the active ingredient ....

[0043] For the avoidance of any doubt, embodiment 12) particularly relates to a crystalline form according to any one of embodiments 1) to 6), which is suitable / used as a final isolation step of the Compound (e.g., to meet purity requirements for pharmaceutical manufacture), but which the final pharmaceutical composition according to embodiment 12) may or may not comprise (e.g., because said original crystalline form of the Compound is further transformed during the manufacturing process and / or dissolved in a pharmaceutically acceptable carrier material; i.e., in the final pharmaceutical composition the Compound may be present in amorphous form, in another crystalline form, in a dissolved form, etc.).

[0044] 13) Thus, a further aspect of the present invention relates to a pharmaceutical composition having as an active ingredient the compound (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide, which is a compound according to aspect 1). to 6), a crystalline form of (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide, and at least one pharmaceutically acceptable carrier material.

[0045] 14) A further embodiment of the invention relates to a pharmaceutical composition according to embodiment 13) in capsule, tablet or liquid form.

[0046] 15) A further embodiment of the present invention relates to a "compound" according to any one of embodiments 1) to 6), a crystalline form of ((3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide, for use in the prevention or treatment of a CFTR-related disease or disorder, in particular cystic fibrosis.

[0047] 16) A further aspect of the present invention relates to a compound according to any one of aspects 1) to 6), (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazole-5- This relates to a crystalline form of (methyl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide.

[0048] 17) A further embodiment of the present invention relates to a method for treating a CFTR-related disease, in particular cystic fibrosis, comprising administering to a patient an effective amount of a compound according to any one of embodiments 1) to 6), a crystalline form of ((3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide.

[0049] The crystalline forms of the Compounds defined in any one of aspects 1) to 6) are useful for the treatment of CFTR-related diseases or disorders, in particular cystic fibrosis.

[0050] CFTR-related diseases and disorders may be defined to include in particular cystic fibrosis and further CFTR-related diseases and disorders selected from: - Chronic bronchitis, sinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild lung disease, allergic bronchopulmonary aspergillosis (ABPA), liver disease, coagulation and fibrinolysis defects such as protein C deficiency, and diabetes. - Asthma; COPD; smoking-induced COPD; and dry eye disease; and - Idiopathic pancreatitis; hereditary emphysema; hereditary hemochromatosis; especially I-cell disease; lysosomal storage diseases such as pseudo-Hurler; mucopolysaccharidoses; Sandhoff / Tay-Sachs disease; osteogenesis imperfecta; Fabry disease; Sjögren's disease; osteoporosis; osteopenia; bone healing and growth (including bone repair, bone regeneration, decreased bone resorption, and increased bone deposition); chloride channelopathies such as myotonia congenita (Thomsen and Becker types); Bartter syndrome type 3; epilepsy; lysosomal storage diseases; primary ciliary dyskinesia (PCD) - cilia structure and or terms for genetic disorders of function (including PCD with situs inversus, also known as Kartagener syndrome, PCD without situs inversus, and ciliary dysplasia); generalized epilepsy with febrile seizures plus (GEFS+); generalized epilepsy with febrile and afebrile seizures; myotonia; paramyotonia congenita; potassium-induced myotonia; hyperkalemic periodic paralysis; long QT syndrome (LQTS); LQTS / Brugada syndrome; autosomal dominant LQTS with hearing loss; autosomal recessive LQTS; LQTS with dysmorphic features; congenital and acquired LQTS; dilated cardiomyopathy; autosomal dominant LQTS; osteopetrosis; and Bartter syndrome type 3.

[0051] The term "treatment of cystic fibrosis" means any treatment for cystic fibrosis and particularly includes treatment that reduces the severity of cystic fibrosis and / or reduces the symptoms of cystic fibrosis.

[0052] The term "cystic fibrosis" refers to any form of cystic fibrosis, in particular cystic fibrosis associated with one or more genetic mutations. Preferably, such cystic fibrosis is associated with impaired CFTR trafficking (Class II mutations) or reduced CFTR stability (Class VI mutations) [in particular impaired CFTR trafficking / Class II mutations], where such impaired CFTR trafficking or reduced CFTR stability may be associated with further disease-causing mutations of the same or any other class. Such further disease-causing CFTR genetic mutations include Class I mutations (loss of functional CFTR protein), (further) Class II mutations (impaired CFTR trafficking), Class III mutations (impaired CFTR regulation), Class IV mutations These include Class V mutations (CFTR conductance impairment), Class V mutations (reduced CFTR protein due to splicing defects), and / or (additional) Class VI mutations (reduced CFTR protein due to reduced CFTR stability). The one or more genetic mutations may include, for example, F508del, A561E, and N1303K, and at least one mutation selected from I507del, R560T, R1066C, and V520F; in particular, F508del. In addition to the above, further CFTR genetic mutations include, for example, G85E, R347P, L206W, and M1101K. The genetic mutations may be heterozygous, homozygous, or compound heterozygous. In particular, the genetic mutation is heterozygous with one F508del mutation. Additional CFTR gene mutations (particularly those that are class III and / or IV mutations) include G551D, R117H, D1152H, A455E, S549N, R347H, S945L, and R117C.

[0053] The severity of a particular cystic fibrosis / cystic fibrosis-associated genetic mutation and the effectiveness of its correction may generally be measured by examining chloride transport carried out by CFTR. For example, a patient's average sweat chloride content may be used for such an assessment.

[0054] The term "cystic fibrosis symptoms" specifically refers to elevated chloride levels in sweat; cystic fibrosis symptoms may further include chronic bronchitis; sinusitis; constipation; pancreatitis; pancreatic insufficiency; male infertility caused by congenital bilateral absence of the vas deferens (CBAVD); mild lung disease; allergic bronchopulmonary aspergillosis (ABPA); liver disease; coagulation and fibrinolysis defects such as protein C deficiency; and / or diabetes.

[0055] The crystalline form of the Compound defined in any one of embodiments 1) to 6) is believed to be particularly useful as a therapeutic agent for the prevention or treatment of CFTR-related diseases and disorders, particularly cystic fibrosis. It can be used as the sole therapeutic agent or in combination with one or more therapeutically active ingredients that act as CFTR modulators, where the one or more CFTR modulators are CFTR correctors and / or CFTR potentiators. Such combination therapy may be performed simultaneously at fixed or non-fixed doses.

[0056] Thus, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier material and: - a crystalline form of the "compound" defined in any one of aspects 1) to 6); - and one or more therapeutically active ingredients that act as CFTR modulators, wherein the CFTR modulators are CFTR correctors and / or CFTR potentiators; The present invention also relates to a pharmaceutical composition comprising:

[0057] The term "therapeutically active ingredient acting as a CFTR modulator" means a CFTR corrector (in particular a type I, type II or type III corrector) and a CFTR potentiator that - alone and / or in combination - have demonstrated the potential for therapeutic use (tested in in vitro and / or in vivo models, in particular in clinical trials) and / or are indicated for such therapeutic use; such therapeutic use is for CFTR-related diseases (in particular cystic fibrosis). Examples include, inter alia, CFTR potentiators: ivacaftor, navocaftor, isenticaftor, deutivacaftor, GLPG-1837, and GLPG-2451; and CFTR correctors: type I correctors (lumacaftor, tezacaftor, galicaftor), type II corrector (corrector 4a), and type III correctors (elexacaftor). ), bamocaftor, olacaftor, and vanzacaftor.

[0058] Preferably, the pharmaceutical composition comprises a crystalline form of the "compound" defined in any one of Aspects 1) to 6), further comprising navocaftor and gallicaftor. Another preferred pharmaceutical composition comprises a crystalline form of the "compound" defined in any one of Aspects 1) to 6), ivacaftor, and tezacaftor.

[0059] "Concurrently," when referring to a dosage form, means in this application that the dosage form involved is the near-simultaneous administration of two or more active ingredients and / or treatments; by simultaneous administration, it is understood that the subject will be exposed to the two or more active ingredients and / or treatments at the same time. When administered simultaneously, the two or more active ingredients may be administered in a fixed dose combination, or in an equivalent non-fixed dose combination (e.g., by using two or more different pharmaceutical compositions to be administered at about the same time by the same route of administration), or in a non-fixed dose combination using two or more different routes of administration; by such administration, the subject will be exposed to the two or more active ingredients and / or treatments essentially at the same time.

[0060] "Fixed dose combination", when referring to a dosage form, means in this application that the relevant dosage form is the administration of one single pharmaceutical composition having two or more active ingredients.

[0061] The present invention also relates to methods for preparing enantiomerically enriched forms of the Compound, and to methods for preparing and characterizing crystalline forms of the Compound according to any one of embodiments 1) to 6), which are described in the procedures in the Experimental section below. [Example]

[0062] Testing Procedure: All temperatures are given in °C. Commercially available starting materials are used as received without further purification. Unless otherwise noted, all reactions are carried out in oven-dried glassware under a nitrogen or argon atmosphere. Compounds are purified by flash column chromatography on silica gel or preparative HPLC. The compounds described in this invention are characterized by LC-MS data (retention time t R(The values ​​are given in min; the molecular weights obtained from mass spectrometry are given in g / mol.) When the compounds of the present invention are mixtures of conformational isomers, especially when the isomers appear in the LC-MS spectrum, the retention time of the most abundant isomer is given.

[0063] LC-MS for quality control (QC) analysis: Equipment and conditions: Pump: Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector, DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD. Column: Waters Acquity UPLC CSH C18 1.7μm 2.1x50mm or Acquity UPLC HSS T3 C18 1.8μm 2.1x50mm, thermostated at 60℃ in an Acquity UPLC Column Manager. Eluent: A1: H2O + 0.05% FA; B1: AcCN + 0.045% FA. Method: Gradient: 2% B to 98% B in 2.0 min. Flow rate: 1.0 mL / min. Detection: UV 214nm, ELSD, and MS. tR is in min.

[0064] Analytical LC-MS device: Binary gradient pump, Agilent G4220A or equivalent, equipped with a mass spectrometer detector (single quadrupole mass spectrometer, Thermo Finnigan MSQPlus or equivalent).

[0065] conditions: Method B (acidic): Column: Zorbax RRHD SB-aq (1.8 μm, 2.1 x 50 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 95% B to 5% B in 2.0 min (flow rate: 0.8 mL / min). Detection: UV / Vis + MS.

[0066] Method I (basic): Column: Waters BEH C18 (2.5 μm, 2.1 × 50 mm). Conditions: Water / NH3 [c(NH3) = 13 mmol / L] [eluent A]; MeCN [eluent B]. Gradient: 5% B to 95% B in 2 min (flow rate 0.8 mL / min). Detection: UV / Vis + MS.

[0067] Method J (basic): Column: Waters XSelect CSH C18 (3.5 μm, 2.1 × 30 mm). Conditions: 95% MeCN + 5% water / NH4HCO3 [c(NH4HCO3) = 10 mmol / L] [eluent A]; water / NH4HCO3 [c(NH4HCO3) = 10 mmol / L] [eluent B]. Gradient: 95% B to 2% B in 1.6 min (flow rate 1 mL / min). Detection: UV / Vis + MS.

[0068] Preparative LC-MS device: Binary gradient pump, Gilson 333 / 334 or equivalent, equipped with a mass spectrometer detector (single quadrupole mass spectrometer, Thermo Finnigan MSQPlus or equivalent).

[0069] conditions: Basic conditions: Column: Waters XBridge C18 (10 μm, 30 × 75 mm); Conditions: MeCN [Eluent A]; Water + 0.5% NH4OH (25% aq.) [Eluent B]; Gradient: 95% B to 5% B in 6.5 min (Flow rate: 75 mL / min). Detection: UV / Vis + MS.

[0070] Chiral analytical chromatography device: HPLC: Dionex HPG-3200SD pump with Dionex DAD-3000UV detector.

[0071] SFC: CO2 supply: Aurora Fusion A5 Evolution; pump: Agilent G4302A; UV detector: Agilent G1315C.

[0072] conditions: HPLC: Column: ChiralPak AY-H, 5 μm, 250×4.6 mm or Regis® Whelk-O1 250×4.6 mm, 5 μm; Eluent: A: Hept, 0.05% DEA, B: Ethanol, 0.05% DEA, flow rate 0.8 to 1.2 mL / min.

[0073] SFC column: Regis(R,R) Whelk-O1, 4.6x250mm, 5μM; Eluent: A: 60% CO2, B: 40% DCM / EtOH / DEA 50:50:0.1.

[0074] Chiral Preparative Chromatography device: HPLC: 2 Varian SD1 pumps with Dionex DAD-3000UV detector.

[0075] SFC: CO2 supply: Maximator DLE15-GG-C; Pump: 2 SSI HF CP 300; UV detector: Dionex DAD-3000.

[0076] conditions: HPLC: Column: ChiralPak IA, IB, IC, IE or IF, 5 μm, 20 x 250 mm or Regis® Whelk-O1, 21.1 x 250 mm, 5 μm; Eluent: appropriate mixture of A (0% to 90% Hept) and B (10% to 100% EtOH, 0.1% DEA); Flow rate: appropriate flow rates of 16, 23 or 34 mL / min.

[0077] SFC: Column: Regis® Whelk-O1, 30x250mm, 5µm or ChiralPak IC, 30x250mm, 5µm; Eluent: appropriate mixture of A (60% to 80% CO2) and B (30% to 40% DCM / EtOH / DEA 50:50:0.1), flow rate 160mL / min.

[0078] X-ray powder diffraction analysis (XRPD) XRPD (method 1): Powder X-ray diffraction patterns were collected on a Bruker D8 Advance X-ray diffractometer equipped with a Cu Kα X-ray tube scanned at 40 kV / 40 mA and a Lynxeye linear detector. The instrument was operated in reflectance mode (coupled 2θ / theta) with a step size of 0.02° (2θ) and a step time of 76.8 seconds over a 2θ scan range of 3 to 50°. The divergence slit was set to a variable slit open at all angles for full sample irradiation, and the antiscatter slit on the detector side was set to maximum opening. The powder was packed into the cavity of a 25 mm diameter and 0.5 mm deep silicon single crystal sample holder and flattened with a glass slide. The sample was rotated in its own plane during the measurement. Diffraction data are reported using coupled Cu Kα1 and Kα2 radiation without Kα2 removal. As is typical for previously recorded powder X-ray diffraction patterns, the 2θ values ​​provided herein are accurate to within + / −0.2°.

[0079] XRPD (method 2): Powder X-ray diffraction patterns were collected on a Bruker D8 GADDS-HTS diffractometer equipped with an automated XYZ stage, a laser video microscope for sample positioning, a Vantec-500 detector, and a Cu Kα X-ray tube scanned at 40 kV / 40 mA. The instrument was operated in reflection mode, and the X-ray optics consisted of a single Göbel multilayer mirror coupled to a 0.5 mm pinhole collimator. Typically, a single frame was recorded over 180 s with goniometer positions of 4° theta 1 and 16° theta 2 and a sample-to-detector distance of 20 cm. The frame was integrated over a 2θ range of 5–35°. Samples were measured under ambient conditions and prepared as slab samples using the as-received powder without grinding. Approximately 5–10 mg of sample was lightly pressed onto a glass slide to obtain a flat surface. The sample was not moved during the measurement. Diffraction data were reported using combined Cu Kα1 and Kα2 radiation without Kα2 removal. Recorded so far As is typical for powder X-ray diffraction patterns, the accuracy of the 2θ values ​​provided herein is within + / −0.2°.

[0080] Gravimetric Vapor Sorption (GVS) Analysis Measurements are performed on a multisample instrument SPS-100n (Projekt Messtechnik, Ulm, Germany) operating in stepping mode at 25°C. Approximately 20 mg of sample is equilibrated at 40% RH before starting a predefined humidity program (40-0-95-0-95-40% RH, applying 5% ΔRH steps, with a maximum equilibration time of 24 hours after each step). Hygroscopicity is classified according to the European Pharmacopea Technical Guide (1999, p. 86), e.g., non-hygroscopic: mass increase of less than 0.2% mass / mass; slightly hygroscopic: mass increase of less than 2% and more than 0.2% mass / mass; hygroscopic: mass increase of less than 15% and more than 2% mass / mass. For this classification, the mass change between 40% and 80% RH is evaluated in the first adsorption scan.

[0081] Differential scanning calorimetry (DSC) DSC data is available from STAR e Mettler Toledo DSC 3 with software version 16.00 + STAR e The system is equilibrated for energy and temperature using indium standards. Typically, a 1-5 mg sample is placed in an automatically drilled aluminum pan and then heated at 10°C for 1 min. -1 Heat from -20°C to 250°C at a rate of 20 mL min. Apply a nitrogen purge over the sample at 20 mL min. -1 Report the peak temperature for the melting point.

[0082] Thermogravimetric analysis (TGA) TGA data was obtained using a Mettler Toledo TGA / DSC 3 + STAR eTypically, approximately 5 mg of sample is placed in an automatically drilled aluminum pan and incubated at 10 °C min under a constant flow of nitrogen. -1 The mixture is heated at 30° C. to 350° C. The off-gases are analyzed on a Pfeiffer ThermoStar quadrupole mass spectrometer.

[0083] Abbreviations (used above or below): aq. aqueous solution Boc butyloxycarbonyl d day DCM dichloromethane DEA Diethylamine DIPEA Diisopropyl-ethylamine, Huenig's base, ethyl-diisopropylamine DMF Dimethylformamide DMSO dimethyl sulfoxide Et Ethyl EtOAc ethyl acetate EtOH ethanol FC flash chromatography h time HATU 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate Hept Heptane HPLC High-Performance Liquid Chromatography HV high vacuum conditions LC-MS Liquid Chromatography-Mass Spectrometry Me methyl MeCN acetonitrile MeOH Methanol mL milliliter min mp melting peak Ph phenyl prep. for preparative preparation rpm revolutions per minute RT room temperature RH Relative Humidity s seconds sat. saturation SEM Scanning Electron Microscope SFC Supercritical Fluid Chromatography tBME tert.-butyl methyl ether tBu tert-butyl = tertiary butyl TFA trifluoroacetic acid THF tetrahydrofuran t R retention time

[0084] Synthesis of Reference Example 1: Building Block Synthesis tert-Butyl (S)-3-amino-4-((2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoate (A-1) Step 1: HATU (11.82 g, 31.1 mmol) is added to a solution of boc-beta-Ala-OH (5.0 g, 25.9 mmol), o-methylisourea bisulfate (4.5 g, 25.9 mmol), and DIPEA (18.1 mL, 104 mmol) in DMF (150 mL) at RT, and the RM is stirred for 1.5 h. Water and EtOAc are added to the RM, then the two layers are separated and the aqueous layer is extracted with EtOAc (2x). The combined organic extracts are washed with brine, dried (Na2SO4), filtered, and concentrated to give the crude product, which is purified by FC (eluting with 20% to 100% EtOAc in hept) to give tert-butyl (3-((imino(methoxy)methyl)amino)-3-oxopropyl)carbamate as a white solid. LC-MS I:t R =0.64 min; [M+H] + =246.36.

[0085] Step 2: 1,8-diazabicyclo[5.4.0]undec-7-ene (8.96 mL, 59.3 mmol) is added to a solution of tert-butyl (3-((imino(methoxy)methyl)amino)-3-oxopropyl)carbamate (6.19 g, 24.7 mmol) and NBS (10.56 g, 59.3 mmol) in EtOAc (120 mL) at RT, and the RM is stirred for 5 h. Additional 1,8-diazabicyclo[5.4.0]undec-7-ene (1.85 mL, 12.4 mmol) and NBS (2.2 g, 12.4 mmol) are added, and stirring is continued for 16 h. The suspension is filtered, and the filtrate is washed with water, saturated aqueous NaHCO3, and brine, before being evaporated to dryness. The crude product is purified by FC (eluting with 20% to 100% EtOAc in hept) to give tert-butyl (2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)carbamate as a colorless oil. LC-MS I:t R =0.75min;[M+H] + =244.33.

[0086] Step 3: 4M HCl in dioxane (0.62 mL, 2.47 mmol) was added to ter To a solution of t-butyl (2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)carbamate (150 mg, 0.62 mmol) in DCM (2 mL) at RT is added and the RM is stirred at RT for 4 days and then at 50° C. for 6 h. The mixture is evaporated to give 2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethan-1-amine hydrochloride as a white solid. LC-MS I:t R =0.35min;[M+H] + =144.21.

[0087] Step 4: HATU (7.36 g, 19.4 mmol) is added to a solution of Fmoc-L-aspartic acid beta-tert-butyl ester (7.74 g, 18.4 mmol), 2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethan-1-amine hydrochloride (3.31 g, 18.4 mmol), and DIPEA (9.47 mL, 55.3 mmol) in DMF (121 mL) at RT, and the RM is stirred for 1 h. The RM is partitioned between water and EtOAc, and the layers are separated. The aqueous phase is re-extracted with EtOAc (2x) and the combined organic extracts are washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and evaporated to give tert-butyl (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoate as a white solid. LC-MS I:t R = 1.08 min; [M+H] + =537.66.

[0088] Step 5: Piperidine (9.38 mL, 93.9 mmol) is added to a solution of tert-butyl (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoate (10.39 g, 18.8 mmol) in DCM (170 mL) at RT and the RM is stirred for 16 h. The RM is concentrated and the residue is triturated with MeCN at 0° C., then filtered. The filtrate is washed with heptane (2×), concentrated and purified by FC (eluting with 10% MeOH in DCM) to give the title compound A-1 as a white solid. LC-MS I:t R =0.63 min; [M+H] + =315.39.

[0089] Benzyl (R)-6-(2-amino-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylate dihydrochloride (B-1) Step 1: A solution of Br2 (0.17 mL, 3.37 mmol) in AcOH (8.0 mL) is added to a solution of 3-fluoroquinolin-6-ol (0.50 g, 3.06 mmol) and NaOAc (0.30 g, 3.68 mmol) in AcOH (20 mL) at RT, and the RM is stirred for 30 min. The RM is concentrated to dryness, and the residue is partitioned and extracted between saturated aqueous NaHCO3 and EtOAc. The layers are separated, and the aqueous layer is re-extracted with EtOAc (2x). The combined organic extracts are washed with brine, dried (Na2SO4), filtered, and evaporated to give 5-bromo-3-fluoroquinolin-6-ol as a brown solid. LC-MS J:t R = 1.38 min; [M+H] + =239.9.

[0090] Step 2: A solution of 5-bromo-3-fluoroquinolin-6-ol (0.74 g, 3.06 mmol) in THF (15 mL) is added dropwise to a suspension of NaH (0.17 g, 4.29 mmol) in THF (15 mL) at RT. The resulting mixture is stirred for 15 min, after which methoxymethyl bromide (0.3 mL, 3.67 mmol) is added dropwise at 0 °C. After stirring at 0 °C for 1.5 h, the RM is quenched by the addition of HO and extracted with EtOAc. The organic layer is washed with NaHCO , brine, dried (Na SO ), filtered, and evaporated. The crude product is purified by FC (eluting with 2% to 30% EtOAc in hept) to give 5-bromo-3-fluoro-6-(methoxymethoxy)quinoline as a colorless oil. LC-MS J:t R = 2.03 min; non-ionized.

[0091] Step 3: nBuLi (1.6M in hex, 0.98mL, 1.57mmol) was added to the 5- To a solution of bromo-3-fluoro-6-(methoxymethoxy)quinoline (300 mg, 1.05 mmol) in THF (18 mL) at −78 °C is added dropwise, and the RM is stirred for 30 min. The RM is quenched with freshly crushed dry ice (1.0 g, 22.7 mmol), then warmed to RT and stirred for 30 min. The RM is concentrated in vacuo, and the intermediate lithium carboxylate is dissolved in DMF (4 mL), followed by addition of KHCO (31.5 mg, 0.315 mmol) and BnBr (0.15 mL, 1.26 mmol), and the RM is stirred at RT for 16 h. The RM is partitioned between saturated aqueous NaHCO and EtOAc and extracted. The layers are separated, and the aqueous layer is re-extracted with EtOAc (2×). The combined organic extracts are washed with brine, dried (NaSO), filtered, and evaporated. The crude product is purified by prep. HPLC (basic) to give benzyl 3-fluoro-6-(methoxymethoxy)quinoline-5-carboxylate as a yellow oil. LC-MS J:t R = 2.08 min; [M+H] + =342.10.

[0092] Step 4: TFA (0.24 mL, 3.13 mmol) is added to a solution of benzyl 3-fluoro-6-(methoxymethoxy)quinoline-5-carboxylate (107 mg, 0.31 mmol) in DCM (3 mL) at RT, and the resulting mixture is stirred for 2 h. The RM is concentrated in vacuo, and the residue is dissolved in EtOAc and extracted with saturated aqueous NaHCO3. The aqueous layer is extracted with EtOAc, and the combined organic layers are washed with brine, dried (NaSO4), filtered, and concentrated to give benzyl 3-fluoro-6-hydroxyquinoline-5-carboxylate as a light brown oil. LC-MS J:t R =2.06min;[MH] + =298.1.

[0093] Step 5: DIAD (0.064 mL, 0.33 mmol) is added to a mixture of benzyl 3-fluoro-6-hydroxyquinoline-5-carboxylate (93.8 mg, 0.31 mmol), tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate (82 mg, 0.33 mmol), and PPh3 (86 mg, 0.33 mmol) in THF (2 mL) at 0 °C, and the RM is stirred at RT for 16 h. The mixture is concentrated, and the residue is directly purified by FC (eluting with 20% to 60% EtOAc in hept) to give benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylate as a colorless oil. LC-MS J:t R = 2.39 min; [M+H] + =531.2.

[0094] Step 6: 4M HCl in dioxane (0.44 mL, 1.77 mmol) was added to benzyl A solution of (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylate (94 mg, 0.18 mmol) in dioxane (3 mL) is added and the RM is stirred at RT for 24 h. The volatiles are removed in vacuo and the residue is triturated with EtO (3x) to give the title compound B-1 as a white solid. LC-MS J:t R = 2.10 min; [M+H] + =431.2.

[0095] 2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanamido)-4,4,4-trifluorobutanoic acid (C-1) Step 1: NaOAc (12.78 g, 0.156 mol), TFA (2.41 mL, 31.1 mmol) and benzaldehyde (3.34 mL, 32.7 mmol) were added to methyl A solution of 2-amino-4,4,4-trifluorobutanoate hydrochloride (6.81 g, 31.1 mmol) in MeOH (20 mL) was added at room temperature, and the resulting mixture was stirred for 1 h. NaBHCN (2.27 g, 34.3 mmol) was then added, and stirring was continued for 45 min. The mixture was evaporated to dryness, then partitioned between H2O and DCM, and the layers were separated. The aqueous layer was extracted with DCM, and the combined organic extracts were dried (Na2SO4), filtered, and evaporated to give methyl-2-(benzylamino)-4,4,4-trifluorobutanoate as a brown oil, which was used directly in the next step. LC-MS I:t R =0.96m in;[M+H] + =262.37.

[0096] Step 2: NaOAc (12.67 g, 155 mmol), TFA (2.39 mL, 30.9 mmol), and formaldehyde (37% in HO, 2.53 mL, 34 mmol) were added to a solution of methyl-2-(benzylamino)-4,4,4-trifluorobutanoate (8.07 g, 30.9 mmol) in MeOH (100 mL) at RT, and the resulting mixture was stirred at RT for 1 h. NaBHCN (2.25 g, 34.0 mmol) was then added, and stirring was continued. After 1.5 h, formaldehyde (37% in HO, 0.46 mL, 6.18 mmol) and NaBHCN (409 mg, 6.18 mmol) were added, and the mixture was stirred at RT for an additional 2 h. The mixture was evaporated to dryness, partitioned between HO and DCM, and the layers were separated. The aqueous layer is re-extracted with DCM and the combined organic extracts are dried (Na2SO4), filtered and evaporated to give methyl-2-(benzyl(methyl)amino)-4,4,4-trifluorobutanoate as a brown oil which is used directly in the next step. LC-MS I:t R = 1.13 min; [M+H] + =276.45.

[0097] Step 3: A solution of methyl-2-(benzyl(methyl)amino)-4,4,4-trifluorobutanoate (6.48 g, 23.5 mmol) in EtOH (200 mL) is evacuated / purged with Ar (3x) before adding Pd / C (1.25 g, 5 mol%). The RM is evacuated / purged with H2 (3x) and stirred under an H2 atmosphere for 2.5 h. The mixture is filtered and rinsed with MeOH. 4 M HCl (5.89 mL, 23.5 mmol) is added and the mixture is evaporated to dryness to give methyl-4,4,4-trifluoro-2-(methylamino)butanoate hydrochloride as an off-white solid, which is used directly in the next step. LC-MS I:t R =0.60min;[M+H] + =186.37.

[0098] Step 4: HATU (11.26 g, 29.6 mmol) is added portionwise to a solution of Boc-N-methyl-L-leucine (6.24 g, 24.7 mmol), methyl-4,4,4-trifluoro-2-(methylamino)butanoate hydrochloride (5.47 g, 24.7 mmol), and DIPEA (16.9 mL, 98.7 mmol) in DMF (80 mL) at RT, and the resulting mixture is stirred for 1 h. Water is added, and the mixture is extracted with EtOAc (3x). The combined organic extracts are washed successively with saturated aqueous NaHCO3, HO, and brine, dried (Na2SO4), filtered, and concentrated. Purification by FC (eluting with 15% EtOAc in hept) gives methyl-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanamido)-4,4,4-trifluorobutanoate as a yellow oil. LC-MS B:t R = 1.06 min; [M+H] + =413.29.

[0099] Step 5: 2M aqueous NaOH (6.9 mL, 13.8 mmol) is added to a solution of methyl-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanamido)-4,4,4-trifluorobutanoate (2.84 g, 6.88 mmol) in MeOH (10 mL) at RT, and the mixture is stirred at RT for 1.5 h. The volatiles are removed in vacuo, and the aqueous residue is neutralized with 2M aqueous HCl, then extracted with DCM (3x). The combined organic layers are dried (Na2SO4), filtered, and evaporated to give the title compound C-1 as a white solid. LC-MS B:t R =0.96 min; [M+H] + =399.29.

[0100] Reference Example 1: (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacyclo Heptadecino[16,17-f]quinoline-3-carboxamide Step 1: HATU (1.03 g, 2.58 mmol) is added to a solution of B-1 (1.24 g, 2.46 mmol), C-1 (980 mg, 2.46 mmol), and DIPEA (1.26 mL, 7.38 mmol) in DMF (20 mL) at RT, and the RM is stirred for 30 min. The RM is partitioned between water and EtOAc, and the layers are separated. The aqueous phase is re-extracted with EtOAc (2x), and the combined organic extracts are washed with brine, dried (Na2SO4), filtered, and evaporated. The crude product is purified by prep. HPLC (basic) to give benzyl 6-(((6S,9R,12R)-12-benzyl-6-isobutyl-2,2,5,8-tetramethyl-4,7,10-trioxo-9-(2,2,2-trifluoroethyl)-3-oxa-5,8,11-triazatridecan-13-yl)oxy)-3-fluoroquinoline-5-carboxylate as a white solid. LC-MS I:tR = 1.45 min; [M+H] + =811.73. Note: The second stereoisomer, benzyl 6-(((6S,9S,12R)-12-benzyl-6-isobutyl-2,2,5,8-tetramethyl-4,7,10-trioxo-9-(2,2,2-trifluoroethyl)-3-oxa-5,8,11-triazatridecan-13-yl)oxy)-3-fluoroquinoline-5-carboxylate, is also isolated as a white solid. LC-MS I:t R = 1.43 min; [M+H] + =811.66.

[0101] Step 2: A solution of benzyl 6-(((6S,9R,12R)-12-benzyl-6-isobutyl-2,2,5,8-tetramethyl-4,7,10-trioxo-9-(2,2,2-trifluoroethyl)-3-oxa-5,8,11-triazatridecan-13-yl)oxy)-3-fluoroquinoline-5-carboxylate (519 mg, 0.61 mmol) in EtOH (10 mL) is evacuated / purged with N (3x) before adding 10% Pd / C (32 mg, 5 mol%). The RM is evacuated / purged with H (3x) and stirred under an atmosphere of H for 2 h. The RM is filtered through a pad of Celite and the filtrate is concentrated in vacuo to give 6-(((6S,9R,12R)-12-benzyl-6-isobutyl-2,2,5,8-tetramethyl-4,7,10-trioxo-9-(2,2,2-trifluoroethyl)-3-oxa-5,8,11-triazatridecan-13-yl)oxy)-3-fluoroquinoline-5-carboxylic acid as a white solid. LC-MS I:t R =0.73 min; [M+H] + =721.58.

[0102] Step 3: HATU (417 mg, 1.09 mmol) is added to a solution of 6-(((6S,9R,12R)-12-benzyl-6-isobutyl-2,2,5,8-tetramethyl-4,7,10-trioxo-9-(2,2,2-trifluoroethyl)-3-oxa-5,8,11-triazatridecan-13-yl)oxy)-3-fluoroquinoline-5-carboxylic acid (759 mg, 1.04 mmol), A-1 (390 mg, 1.04 mmol) and DIPEA (0.55 mL, 3.13 mmol) in DMF (13 mL) at RT and the RM is stirred for 1 h. The RM is partitioned between water and EtOAc and the layers are separated. The aqueous phase is re-extracted with EtOAc (2x) and the combined organic extracts are washed successively with saturated aqueous NaHCO3, 1M aqueous citric acid, water, and brine. The organic extract is dried (Na2SO4), filtered, and evaporated to give tert-butyl (S)-3-(6-(((6S,9R,12R)-12-benzyl-6-isobutyl-2,2,5,8-tetramethyl-4,7,10-trioxo-9-(2,2,2-trifluoroethyl)-3-oxa-5,8,11-triazatridecan-13-yl)oxy)-3-fluoroquinoline-5-carboxamido)-4-((2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoate as a white solid. LC-MS I:t R = 1.32 min; [M+H] + =1018.01.

[0103] Step 4: TFA (3.3 mL, 42.8 mmol) was treated with tert-butyl (S)-3-(6-(((6S,9R,12R)-12-benzyl-6-isobutyl-2,2,5, A solution of 8-tetramethyl-4,7,10-trioxo-9-(2,2,2-trifluoroethyl)-3-oxa-5,8,11-triazatridecan-13-yl)oxy)-3-fluoroquinoline-5-carboxamido)-4-((2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoate (1.19 g, 1.1 mmol) in DCM (35 mL) at RT was added and the RM was stirred for 3 h. The RM was concentrated in vacuo, and the residue was redissolved in DCM and concentrated again in vacuo (2x). The residue was dissolved in DMF (18 mL), then DIPEA (1.51 mL, 8.8 mmol) and HATU (502 mg, 1.32 mmol) were added and the RM was stirred for 15 min. The RM was partitioned between water and EtOAc and the layers were separated. The aqueous phase is re-extracted with EtOAc (2x) and the combined organic extracts are washed with brine, dried (Na2SO4), filtered and evaporated. The crude product is purified by prep. HPLC (basic) to give the title compound as a white solid. LC-MS I:t R = 1.05 min; [M+H] + =843.68.

[0104] II. Biological Assays In vitro assay The corrector activity of compounds of formula (I) for CFTR is determined according to the following experimental method. This method measures the effect of overnight incubation with compounds on F508del-CFTR cell surface expression in a recombinant U2OS cell line (DiscoveRx, #93-0987C3). This cell line is designed to simultaneously express (i) human F508del-CFTR tagged with Prolink (PK = short β-galactosidase fragment) and (ii) the remaining portion of the β-galactosidase enzyme (Enzyme Acceptor; EA) localized to the plasma membrane. Incubation with compounds that increase PK-tagged F508del-CFTR in the plasma membrane complements the EA fragment to form functional β-galactosidase enzyme, which is quantified by a chemiluminescent reaction.

[0105] Briefly, cells are seeded at 3500 cells / well in 20 μl of full medium (McCoy's 5a (#36600-021, Gibco) + 10% FBS Gibco + penicillin / streptomycin) in 384-well low volume plates (Corning, #3826). After incubating the cells for 5 h in an incubator, 5 μl / well of a compound dilution series (5x working stock solution in complete medium) is added. The final DMSO concentration in the test is 0.25%. Cells are incubated with compounds for 16 h in an incubator at 37°C and 5% CO2. The next day, cell plates are incubated in the dark at RT for 2 h. Then, 10 μl / well of Flash detection reagent (DiscoverX, #93-0247) is added, and the plates are incubated in the dark at RT for an additional 30 min, and chemiluminescence is measured. Concentration-response curves were constructed using the compound-specific maximum effect as the upper plateau, and compound-specific EC 50 Determine the E value of the corrector lumacaftor max Compound-specific E max Calculate the value (E max Lumacaftor = 100%).

[0106] EC to be calculated 50 Values ​​may vary with each day's assay run. This type of variation is known to those skilled in the art. EC values ​​obtained from several measurements 50 The values ​​are reported as geometric mean values. max Values ​​may vary with each day's assay run. This type of variation is known to those skilled in the art. E obtained from several measurements max Values ​​are reported as arithmetic means.

[0107] The compound of Reference Example 1 was tested and had an EC 50 and 460% E max It has.

[0108] reference Elborn JS. (2016) Cystic fibrosis. Lancet 388:2519~2531. Dalemans W, Barbry P, Champigny G, Jallat S, Dott K, Dreyer D, Crystal RG, Pavirani A, Lecocq JP, Lazdunski M (1991). Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation.Nature 354:526~8.

[0109] III. Working Example Example 1: Crystallization from an EtOH-based formulation 241 mg of amorphous Compound was dissolved in 3 mL of a mixture of ethanol, glyceryl monolinoleate, propylene glycol, and glycerol polyethylene glycol oxystearate (10% / 36% / 9% / 45% by weight). The solution was stirred overnight at room temperature and turned into a suspension. The solid was filtered and analyzed by XRPD (Method 2), which confirmed the presence of crystalline material. The diffractogram was assigned to crystalline Form 1 of Compound.

[0110] Example 2: Crystallization from EtOH 10 mg of amorphous Compound was suspended in 20 μL of EtOH. The sample was stored in a sealed vial at ambient temperature for 2 weeks. The solvent was then evaporated and the remaining solid was analyzed by XRPD (Method 2), which confirmed the presence of crystalline Form 1 of Compound.

[0111] Example 3: Crystallization from toluene 10 mg of amorphous Compound was dissolved in 20 μL of toluene. The sample was stored in a sealed vial at ambient temperature for 2 weeks. A solid then precipitated, which was analyzed by XRPD (Method 2) to confirm the presence of crystalline Form 1 of Compound.

[0112] Example 4: Crystallization from tBME using seeds 10 mg of amorphous Compound was dissolved in 50 μL of tBME. Seeds of the product of Example 1 were added and the mixture was stirred at room temperature. After 5 days, a white solid formed. XRPD (Method 2) confirmed that it consisted of crystalline Form 1 of Compound. TGA of the sample showed a water loss of 1.5% over the temperature range of 50°C to 160°C.

[0113] Example 5: Seeded crystallization from heptane 10 mg of amorphous Compound was suspended in 50 μL of heptane. Seeds of the product of Example 1 were added, and the mixture was stirred at room temperature. After 12 days, a white solid formed. XRPD (Method 2) confirmed that it consisted of crystalline Form 1 of Compound. TGA of the sample showed a water loss of 1.2% over the temperature range of 50°C to 150°C.

[0114] Example 6: Crystallization from EtOH 0.5 mL of EtOH was added to 100 mg of amorphous Compound. While the original solid was still dissolving, a new solid formed, which was filtered the same day and dried under vacuum for 10 min to yield 70 mg of solid. XRPD (Method 1) confirmed that the solid consisted of crystalline Form 1 of Compound. TGA showed a loss of 2.5% (0.5 equiv.) of EtOH between approximately 50 and 140 °C. DSC showed an initial broad endotherm between approximately 40 and 140 °C, attributed to solvent loss. This was followed by a sharp peak at 198 °C with an enthalpy of 41 J / g. SEM showed the presence of small needles and prisms with a maximum length of less than 100 μm. GVS showed a nearly linear change at 2% water content between 0 and 95% RH. The temperature changes with a small hysteresis observed between about 50% and 85% RH (see Figure 4). A maximum water content of 2% corresponds to about 1 equivalent of water. After the GVS measurement, no residual EtOH was detected in the sample by TGA.

[0115] Example 7: Crystallization from MeOH A solution of 114 mg of "compound" in 1 mL of MeOH was allowed to evaporate at ambient conditions. Hexagonal platelets with dimensions up to a few mm crystallized. Single-crystal X-ray structure determination at 301 K revealed a Hermann-Mauguin space group of P 212121 and the following unit cell parameters: a = 14.4261(4) Å, b = 22.1403(7) Å, c = 27.0500(10) Å, α = 90°, β = 90°, γ = 90°, V = 8639.7(5) Å. 3 , Z=8; an orthorhombic crystal system was revealed. Crystal structure analysis showed that one position in the crystal was partially occupied by methanol and water. The powder X-ray pattern calculated from the single crystal data is in good agreement with the experimentally determined pattern of crystalline form 1.

[0116] Example 8: Seeded crystallization from EtOH / tBME 7 g of amorphous Compound was dissolved in 35 mL of EtOH. Seeds of Form 1 were added, resulting in a thick suspension within 3 h. 25 mL of tBME was added, and stirring was continued for 1 h, after which the mixture was cooled to 5°C. After 30 min, the solid was filtered, washed with 5 mL of tBME, and dried on the filter under normal atmosphere. 6.2 g of a white powder was obtained. XRPD (Method 1) confirmed the crystallization of Form 1 of Compound (see Figure 1). A weight loss of 2.1% EtOH (corresponding to approximately 0.4 equivalents) was observed by TGA between 40°C and 140°C. DSC showed a mp of 198°C with an enthalpy of 45 J / g. HPLC indicated a purity of 99.85% a / a.

Claims

1. (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-( ... 2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide: 【Chemical 1】 Crystalline form of.

2. 2. The crystalline form of (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide according to claim 1, characterized by the presence of peaks at the following refraction angles 2θ: 5.1°, 8.0°, and 18.8° in a powder X-ray diffraction diagram.

3. 2. The compound of claim 1, wherein the crystalline form of (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide is characterized by the presence of peaks at the following refraction angles 2θ: 5.1°, 8.0°, 10.3°, 18.8°, and 19.6° in a powder X-ray diffraction diagram.

4. The compound according to claim 1, characterized by the presence of peaks in the powder X-ray diffraction diagram at the following refraction angles 2θ: 5.1°, 8.0°, 10.3°, 12.4°, 18.3°, 18.8°, 19.0°, 19.6°, 21.2°, 22.0°. A crystalline form of (S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide.

5. 5. A crystalline form of the compound of any one of claims 1 to 4, (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide, exhibiting essentially the powder X-ray diffraction pattern shown in FIG.

6. 6. The compound of any one of claims 1 to 5, wherein the crystalline form of (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide exhibits an endothermic event at about 198°C as determined by differential scanning calorimetry.

7. A crystalline form of the compound of any one of claims 1 to 6, (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide, for use as a pharmaceutical.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, in the form of (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide, as an active ingredient, and at least one pharmaceutically acceptable carrier.

9. A compound according to any one of claims 1 to 6, (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10 ...

1. Use of a crystalline form of 1,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide, wherein the pharmaceutical composition comprises the compound, (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9 1. Use of a composition comprising 1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide as an active ingredient, and further comprising at least one pharmaceutically acceptable carrier material.

10. 10. The compound of claim 1, wherein the crystalline form of (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide is a compound of formula (I) for use in the prevention or treatment of CFTR-related diseases and disorders.

11. 10. A crystalline form of the compound of any one of claims 1 to 6, (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide, for use in the treatment of cystic fibrosis.

12. Use of a crystalline form of the compound of any one of claims 1 to 6, (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide, for the manufacture of a medicament for the prevention or treatment of CFTR-related diseases and disorders.

13. Use of a crystalline form of the compound of any one of claims 1 to 6, (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide, for the manufacture of a medicament for the treatment of cystic fibrosis.

14. 10. A method for treating CFTR-related diseases and disorders, comprising administering to a patient an effective amount of the compound of any one of claims 1 to 6, the crystalline form of ((3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide.

15. The compound according to any one of claims 1 to 6, ((3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4 1. A method for treating cystic fibrosis, comprising administering to a patient an effective amount of a crystalline form of (1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]quinoline-3-carboxamide.

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