Combinations of macrocyclic CFTR modulators with CFTR correctors and / or CFTR potentiators

Abstract

The present invention is 1 , R 2 , R 3 , R 4 , X, Ar 1 and Ar 2 The present invention relates to compounds of formula (I), wherein X is as described herein, and their use in the treatment of CFTR-related diseases and disorders, particularly in the treatment of cystic fibrosis, in combination with one or more therapeutically active ingredients that act as CFTR modulators, where the CFTR modulators are one or more CFTR correctors and / or CFTR potentiators. The present invention further relates to pharmaceutical compositions comprising compounds of formula (I) in combination with one or more therapeutically active ingredients that act as CFTR modulators, where the CFTR modulators are one or more CFTR correctors and / or CFTR potentiators. [Formula 1] TIFF2025530377000024.tif81161

Description

[Technical Field]

[0001] The present invention relates to a compound of formula (I)

[0002] [ka]

[0003] and their use in combination with one or more therapeutically active ingredients acting as CFTR modulators, in the treatment of CFTR-related diseases and disorders, where the CFTR modulators are one or more CFTR correctors (in particular, type I correctors and / or type II correctors and / or type III correctors) and / or CFTR potentiators, in the prevention and / or treatment of CFTR-related diseases and disorders; such CFTR-related diseases are in particular cystic fibrosis. The present invention further relates to pharmaceutical compositions comprising a compound of formula (I) in combination with one or more therapeutically active ingredients acting as CFTR modulators, where the CFTR modulators are one or more CFTR correctors (in particular, type I correctors and / or type II correctors and / or type III correctors) and / or CFTR potentiators. [Background technology]

[0004] Certain compounds of formula (I) are disclosed in PCT / EP2021 / 069292 as modulators of CFTR and are believed to be useful in the treatment of CFTR-related diseases and disorders, in particular cystic fibrosis, or other 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-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 disorders such as pseudo-Hurler; mucopolysaccharidoses; Sandhoff / Tay-Sachs disease; osteogenesis imperfecta; Fabry disease; Sjogren's disease; osteoporosis; osteopenia; bone healing and growth (including bone repair, bone regeneration, decreased bone resorption, and increased bone deposition); chlorhydria such as congenital myotonia (Thomson and Becker forms). chloride channelopathies; Bartter's syndrome type 3; epilepsy; lysosomal storage diseases; primary ciliary dyskinesia (PCD) - a term for genetic disorders of ciliary structure and / or function (including PCD with situs inversus, also known as Kartagener syndrome, PCD without situs inversus, and ciliary aplasia); generalized epilepsy with febrile seizures plus (GEFS+); generalized epilepsy with febrile and afebrile seizures; myotonia; paramyotonia congenita; potassium-aggravated myotonia; hyperkalemic periodic paralysis; long QT syndrome (LQTS); LQTS / Brugada syndrome; autosomal dominant LQTS with hearing loss; autosomal recessive LQTS; LQTS with atypical features dysmorphic features); congenital and acquired LQTS; dilated cardiomyopathy; autosomal dominant LQTS; osteopetrosis; and Bartter syndrome type 3.

[0005] Cystic fibrosis (CF; mucoviscidosis, also known as fibrocystic disease of pancreas or pancreatic fibrosis) is an autosomal recessive genetic disease caused by dysfunction of an 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 and cause 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 frequent disease-causing mutation by far is a deletion of phenylalanine at position 508 (F508del; allele frequency 0.697 in the CFTR2 database), which causes channel misfolding during synthesis in the endoplasmic reticulum, degradation of the misfolded protein, and consequently, significantly reduced 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; thus, F508del-CFTR also contains a gating defect (Dalemans, 1991). Approximately 40% of all CF patients are homozygous for the F508del mutation, while another ~40% of patients are heterozygous for the F508del mutation and have another disease-causing mutation in class I, II, III, IV, V, VI, or VII. Such disease-causing mutations are quite 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.

[0006] 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).

[0007] 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), such as the nucleotide-binding domain 1 (NBD1) stabilizer SION-638 (currently in Phase 1) and its follow-on molecule, NBD1-A, are still in the exploratory stage (G. Hurlbut, oral presentation at the North American Cystic Fibrosis Conference 2022). 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), as well as in non-CF disorders such as acute respiratory distress syndrome (ARDS) (Erfinanda L, Sci Transl Med. 2022, 14(674):eabg8577).

[0008] 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.

[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. Macrocyclic tetrapeptides (12 or 13 members), such as the compound Apicidin (CAS: 183506-66-3), have been proposed as potential agents 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 C Communications 2022, 13:3586). Non-macrocyclic CFTR correctors and / or potentiators of CFTR are 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.Furthermore, specific macrocyclic compounds in which an unsubstituted phenylene group is a part of the macrocyclic compound in contrast to the 8- to 10-membered bicyclic heteroarylene of the compound of formula (I) of the present invention can be found as screening compounds (CAS registration 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-2213101-10-7, CAS-2213101-11-1, CAS-2213101-12-1, CAS-2213101-13-2, CAS-2213101-14-3, CAS-2213101-15-4, CAS-2213101-16-5, CAS-2213101-17-6, CAS-2213101-18-7, CAS-2213101-19-8, CAS-2213101-20-1, CAS-2213101-21-1, CAS-2213101-22-1, CAS-2213101-23-1, CAS-2213101-24-1, CAS-2213101-25-2, CAS-2213101-26-3, CAS-2213101-27-4, CAS-2213101-28-5, CAS-2213101-29- 101-09-6, 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-2215789-20-9, 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-2215947-6 4-9, 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-22163 42-86-6, CAS-2216343-03-0, CAS-2216343-09-6, CAS-2216343-14-3, CAS-2216343-18-7, CAS-2216343-24-5, CAS-2216343-32-5, CAS-2 216343-38-1, CAS-2216343-45-0, CAS-2216343-53-0, CAS-2216343-59-6, CAS-2216343-64-3, CAS-2216343-74-5, CAS-2216343-76-7).

[0010] CFTR modulators can be further subdivided into CFTR correctors and CFTR potentiators. CFTR correctors improve CFTR folding and cell surface trafficking, particularly for CFTR with class II (folding and trafficking) mutations, thereby increasing cell surface expression of CFTR. CFTR potentiators increase the onset probability of cell-surface CFTR, particularly for CFTR with gating defects, including corrector-rescued class II mutants, and can thus activate CFTR additively / synergistically with CFTR correctors. Thus, potentiators and correctors are used in combination in clinical settings to treat patients with CFTR class II mutations. Many CFTR correctors have been described in literature and patents. Some of these correctors, such as VX-809 (lumacaftor), VX-661 (tezacaftor), ABBV-2222 (galicaftor), VX-445 (elexacaftor), VX-659 (bamocaftor), VX-440 (olacaftor), VX-121 (vanzacaftor), the ABBV-C2 correctors ABBV-119 and ABBV-567, as well as PTI-801, have been used in clinical trials in CF patients, alone and / or in combination with other CFTR modulators. Similarly, many potentiators have been described in the literature and in patents. Some of these potentiators, such as VX-770 (ivacaftor), VX- 561 (deutivacaftor), GLPG-1837, GLPG-2451, ABBV-3067 (navocaftor), and QBW-251 (icenticaftor), alone and / or in combination with other CFTR modulators, are being used in clinical trials in patients with CF.

[0011] CFTR correctors can be further subdivided with regard to their mechanisms: it is well established that correctors that exhibit additive or synergistic behavior must have distinct, i.e., complementary, mechanisms of action, likely resulting from different binding sites on the CFTR protein. Conversely, correctors that exhibit competitive behavior are likely to share the same CFTR binding site (Okiyoneda, 2013; Veit, 2018; Veit, 2020; Fiedorczuk 2022; Marchesin 2023). Thus, the structurally related correctors VX-809 (lumacaftor), VX-661 (tezacaftor), and ABBV-2222 (galicaftor) are classified as type I correctors, corrector 4a and related compounds are classified as type II correctors, while VX-445 (elexacaftor) is classified as a type III corrector, as are the structurally related correctors VX-440 (olacaftor), VX-659 (vamocaftor), and VX-121 (banzacaftor). The ABBV-C2 corrector, ABBV-119, and ABBV-567 are likely type III correctors. PTI-801 is likely another type III corrector. Due to the additive nature of their effects, correctors with different mechanisms are often combined in clinical settings to achieve greater correction efficacy with potentiators.

[0012] VX-770 (ivacaftor, KALYDECO, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, CAS 873054-44-5, e.g., WO2006 / 002421, WO2011 / 072241, WO2007 / 079139, WO2007 / 134279, WO2010 / 019239, WO2013 / 130669) is a CFTR potentiator and has been reported clinically and / or in vivo. Based on in vitro assay data, VX-770 is the first CFTR modulator approved (US and EU: initial approval in 2012) for the treatment of CF patients aged 4 months and older who have a single mutation in the CFTR gene that responds to KALYDEKO. The current USPI for VX-770 (as of December 2020) lists 97 eligible CFTR mutations. VX-770 is also part of ORKAMBI (a combination of VX-809 and VX-770), SYMDEKO / SYMKEVI (a combination of VX-661 and VX-770), and TRIKAFTA / KAFTRIO (a combination of VX-661, VX-445, and VX-770), which are described below.

[0013] The efficacy of KALYDECO in CF patients with the G551D mutation in the CFTR gene was evaluated in two Phase III clinical trials involving 213 CF patients. Study 1 (NCT00909532) evaluated patients aged 12 years and older, while Study 2 (NCT00909727) evaluated patients aged 6 to 11 years. Patients were randomized (1:1) and were randomly assigned to receive prescribed CF medications (e.g., tobramycin, dornase alfa). alfa) and given KALYDECO or placebo with a fat-containing meal for 48 weeks. The primary endpoint was improvement in lung function, measured by the mean absolute change from baseline in percent predicted pre-dose FEV1 over 24 weeks of treatment. FEV1 stands for "forced expiratory volume in 1 second," and is commonly used as the primary endpoint for assessing lung function in clinical trials for CF. Both studies In this study, treatment with KALYDECO resulted in a significant absolute change of at least 10% in percent-predicted FEV1 (ppFEV1) compared with placebo. Several secondary endpoints, including risk of pulmonary exacerbation (Study 1: relative risk reduction of 0.4 vs. placebo), body weight (+approximately 2 kg vs. placebo), and the pharmacodynamic biomarker sweat chloride (-approximately 50 mM vs. placebo), were also favorably affected by KALYDECO after 48 weeks of treatment. Another small Phase 3 study tested KALYDECO in CF patients aged 6 years and older with rare mutations predictive of response, using change from baseline in absolute ppFEV1 as the primary endpoint. Furthermore, KALYDECO was evaluated in CF patients aged 4 months to 5 years without evaluating efficacy by FEV1 measurement; however, KALYDECO exposure and sweat chloride reductions were similar to those seen in studies with older patients. The recommended dose of KALYDECO for adults and pediatric patients 6 years of age and older is one 150 mg tablet taken orally every 12 hours (bid). The recommended dose of KALYDECO (oral granules) for patients 4 months to less than 6 years of age is based on body weight: 25 mg bid for patients 4-6 months of age (if weighing >5 kg); 25 mg bid for patients 6 months to less than 6 years of age (if weighing 5-7 kg), 50 mg bid for patients 7-14 kg, and 75 mg bid for patients 6 months to less than 6 years of age. bid (for patients weighing 14-25 kg). The FDA recommends that for patients 6 months of age and older with moderate hepatic impairment (Child-Pugh class B), the KALYDECO dosage be reduced to one tablet or one packet of oral granules once daily. For patients 6 months of age and older with severe hepatic impairment (Child-Pugh class C), KALYDECO should be used cautiously at a dose of one tablet or one packet of oral granules once daily or less frequently. Use is not recommended for patients under 6 months of age with hepatic impairment. KALYDECO is available as a light blue, film-coated capsule tablet for oral administration containing 150 mg of ivacaftor. Each KALYDECO tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coat contains carnauba wax, FD&C Blue #2, PEG 3350, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac.

[0014] KALYDECO is also available as white to off-white oral granules (sweetened but unflavored) packaged in unit dose packets containing 25 mg, 50 mg, or 75 mg of ivacaflut. Each unit dose packet of KALYDECO oral granules additionally contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, mannitol, sucralose, and sodium lauryl sulfate.

[0015] The overall safety profile of KALYDECO is based on pooled data from three placebo-controlled clinical trials (NCT00909532, NCT00909727, NCT00953706) conducted in 353 CF patients aged 6 years and older who had the G551D mutation in the CFTR gene or were homozygous for the F508del mutation. 221 patients received KALYDECO and 132 patients received placebo for 16 to 48 weeks. Serious adverse reactions that occurred more frequently in KALYDECO-treated patients, regardless of whether they were considered drug-related by the investigator, included abdominal pain, elevated liver enzymes, and hypoglycemia. Transaminase elevations have been reported in CF patients receiving KALYDECO. The FDA recommends that ALT and AST be assessed before initiating KALYDECO treatment, every 3 months during the first year of treatment, and annually thereafter. Treatment should be discontinued in patients with ALT or AST levels greater than 5 times the upper limit of normal (ULN). After the transaminase elevations resolved, the FDA We recommend considering the benefits and risks of restarting KALYDECO. Non-congenital lens opacities / cataracts have been reported in pediatric patients treated with KALYDECO. FDA recommends baseline and follow-up examinations for pediatric patients initiating KALYDECO treatment.

[0016] VX-809 (lumacaftor, 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, CAS 936727-05-8, e.g., WO2007 / 056341, WO2009 / 073757, WO2009 / 076141, WO2010 / 037066, WO2011 / 127241) is a Type I As part of ORKAMBI, a combination product with the CFTR corrector and CFTR potentiator lumacaftor, ivacaftor, it was approved in the US (2014) and EU (2015) for the treatment of patients aged 2 years and older with cystic fibrosis (CF) who are homozygous for the F508del mutation in the CFTR gene.

[0017] The efficacy of ORKAMBI was evaluated in CF patients homozygous for the F508del mutation in two Phase 3 clinical trials (NCT01807923, NCT01807949) involving a total of 1,108 patients aged 12 years or older. Of these, 369 patients received ORKAMBI (lumacaftor 400 mg / ivacaftor 250 mg, bid) for 24 weeks in addition to their prescribed CF medications (e.g., bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline). The primary efficacy endpoint was change in lung function, as measured by absolute change from baseline in ppFEV1 at week 24. ORKAMBI treatment resulted in statistically significant increases of 2.6% and 3.0% in absolute ppFEV1 compared with placebo treatment. The secondary endpoint of risk of pulmonary exacerbations was also favorable with ORKAMBI (relative risk reduction of 0.3-0.4 vs. placebo). A small, open-label, Phase 3 study tested ORKAMBI in CF patients aged 6 to 11 years who were homozygous for the F508del mutation, measuring sweat chloride concentration as a marker of CFTR function. The mean absolute change from baseline in sweat chloride was -20.4 mM at Day 15 and -24.8 mM at Week 24. After a two-week washout period, mean absolute sweat chloride concentrations increased by 21.3 mM. Similarly, in CF patients aged 2 to 5 years who were homozygous for F508del-CFTR, the mean absolute change from baseline in sweat chloride was -31.7 mM at Week 24, followed by an increase of 33 mM after a two-week washout period. These data demonstrate improvement in CFTR function. The efficacy of ORKAMBI in children 2 to 11 years of age was extrapolated from efficacy in patients 12 years of age and older who are homozygous for the F508del mutation, and is supported by population pharmacokinetic analyses showing similar drug exposure levels in patients 12 years of age and older and children 2 to 11 years of age. The recommended dose of ORKAMBI for adults and pediatric patients 12 years of age and older is two tablets (each tablet contains 200 mg lumacaftor / 125 mg ivacaftor) taken orally every 12 hours, for a total of 800 mg lumacaftor / 500 mg ivacaftor daily.The recommended dose of ORKAMBI for patients 6 to 11 years of age is two tablets (each containing 100 mg lumacaftor / 125 mg ivacaftor) taken orally bid, for a total of 400 mg lumacaftor / 500 mg ivacaftor per day. For patients 2 to 5 years of age, the dose of ORKAMBI depends on body weight. For children over 14 kg, one granule packet (containing 150 mg lumacaftor / 188 mg ivacaftor) is recommended for oral administration bid. For children under 14 kg, one granule packet (containing 100 mg lumacaftor / 125 mg ivacaftor) is recommended for oral administration bid. The FDA recommends that ORKAMBI be used in children with moderate hepatic impairment (Child-related liver damage). The recommended dosage for ORKAMBI is two tablets in the morning and one tablet in the evening for patients 6 years of age and older with hepatic impairment (Child-Pugh class B), and one packet of granules daily for patients 2 to 5 years of age with moderate hepatic impairment (Child-Pugh class C). In patients with severe hepatic impairment (Child-Pugh class C), ORKAMBI should be used with caution, at the maximum dose, with one tablet in the morning and one tablet in the evening or less frequently, or one packet of oral granules once daily or less frequently. ORKAMBI is available as pink, oval, film-coated fixed-dose tablets containing 100 mg lumacaftor and 125 mg ivacaftor, or 200 mg lumacaftor and 125 mg ivacaftor. Additionally, the following inactive ingredients are present: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; magnesium stearate; povidone; and sodium lauryl sulfate. The tablet film coat contains carmine, FD&C Blue No. 1, FD&C Blue No. 2, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, triferric oxide, propylene glycol, and shellac. ORKAMBI is also available as oral granules in unit-dose packets containing 100 mg lumacaftor / 125 mg ivacaftor or 150 mg lumacaftor / 188 mg ivacaftor per packet. Additionally, the following inactive ingredients are present: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; povidone; and sodium lauryl sulfate. The overall safety profile of ORKAMBI is based on pooled data from 1,108 CF patients aged 12 years and older who are homozygous for the F508del mutation and received at least one dose of study drug in two double-blind, placebo-controlled Phase 3 clinical trials, both involving 24 weeks of treatment. 369 patients received ORKAMBI bid and 370 patients received placebo. Serious adverse reactions that occurred more frequently in ORKAMBI-treated patients, regardless of whether they were considered drug-related by the investigator, were pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and increased transaminases. These occurred in 1% or less of patients.Elevated transaminases (ALT / AST) have been observed in some cases in association with elevated bilirubin. The FDA recommends measuring serum transaminases and bilirubin before initiating ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. Treatment should be interrupted in patients with ALT or AST >5x the upper limit of normal (ULN), or in patients with ALT or AST >3x ULN and bilirubin >2x ULN. After resolution, the FDA recommends considering the benefits and risks of resuming ORKAMBI. Furthermore, respiratory side effects (chest discomfort, dyspnea, and breathing abnormalities) are more common at the time of ORKAMBI initiation and in patients with ppFEV1 <40%, and additional monitoring is recommended during treatment initiation. Elevated blood pressure has also been observed in some patients, and the FDA recommends periodic monitoring of blood pressure in all patients. Noncongenital lens opacities / cataracts have been reported in pediatric patients treated with ORKAMBI. The FDA recommends baseline and follow-up testing for pediatric patients initiating ORKAMBI treatment.

[0018] VX-661 (tezacaftor, 1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1Hindol-5-yl}cyclopropane-1-carboxamide), CAS 1152311-62-0 (e.g., WO2007 / 117715, WO2011 / 119984, WO2014 / 014841) is a type I CFTR corrector approved in the US (2018) as part of SYMDEKO and in the EU (2018) as part of SYMKEVI. SYMDEKO / SYMKEVI is homozygous for the F508del mutation in the CFTR gene. It is a combination product of tezacaftor and the CFTR potentiator ivacaftor for the treatment of cystic fibrosis (CF) in patients 6 years of age and older who have at least one mutation in the CFTR gene that is responsive to tezacaftor / ivacaftor based on in vitro data and / or clinical evidence. The current SYMDEKO USPI (June 2022) lists 154 active CFTR mutations.

[0019] The efficacy of SYMDEKO in CF patients aged 12 years and older was evaluated in three double-blind, placebo-controlled trials (Studies 1, 2, and 3). In all trials, patients continued their standard-of-care CF medications (e.g., bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline). Study 1 (NCT02347657) evaluated 504 patients homozygous for the F508del-CFTR mutation. Patients were randomized 1:1 to receive SYMDEKO or placebo with a fat-containing diet. The primary efficacy outcome was improvement in lung function as measured by the mean absolute change from baseline in ppFEV1 over 24 weeks of treatment. Treatment with SYMDEKO resulted in a significant 4% absolute change in ppFEV1 compared with placebo. Several secondary endpoints also showed favorable changes with SYMDEKO after 24 weeks of treatment, including risk of pulmonary exacerbations (relative risk reduction of 0.35 vs. placebo), absolute change from baseline to week 24 in CFQ-R Respiratory Domain Score (a measure of respiratory symptoms relevant to CF patients, such as cough, sputum, and dyspnea: +5.1), and absolute change from baseline in sweat chloride to week 24 (-10.1 mM vs. placebo).

[0020] Study 2 (NCT02392234), a crossover study, evaluated 244 patients (146 patients with a splice mutation and 98 patients with a missense mutation as the second allele) who were heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor / ivacaftor. The primary efficacy outcome measure was improvement in lung function as measured by the mean absolute change from baseline in ppFEV1 averaged over weeks 4 and 8 of treatment. Treatment with SYMDEKO resulted in a significant 6.8% absolute change in ppFEV1 compared with placebo. SYMDEKO also significantly improved several secondary endpoints, including absolute change from baseline in CFQ-R Respiratory Domain Score (+11.1 vs. placebo) and sweat chloride (-9.5 mM), a biomarker of CFTR function. Study 3 (NCT02516410) evaluated SYMDEKO in 168 patients heterozygous for the F508del mutation and a second mutation not predicted to respond to tezacaftor / ivacaftor. No significant changes from baseline in absolute ppFEV1 were observed in the SYMDEKO group by week 12 when compared with the placebo group.

[0021] The efficacy of SYMDEKO in patients 6 to <12 years of age was extrapolated from patients 12 years of age and older, and this is supported by population pharmacokinetic analyses showing similar exposure levels of tezacaftor and ivacaftor in patients 6 to <12 years of age (Study 4; (NCT02953314), an open-label study in 70 patients) and patients 12 years of age and older (Studies 1 and 2). Additionally, in Study 4, a change in sweat chloride of -14.5 mM from baseline to Week 24 was observed, indicating improved CFTR function.

[0022] The recommended dose of SYMDEKO for patients 12 years of age and older and pediatric patients 6 years of age and older is one tablet (containing 100 mg tezacaftor / 150 mg ivacaftor) in the morning and one tablet (containing 150 mg ivacaftor) in the evening, for a total of 100 mg tezacaftor / 300 mg ivacaftor per day, if weighing 30 kg or more. The recommended dose of SYMDEKO for patients 6 to 11 years of age is one tablet (containing 50 mg tezacaftor / 75 mg ivacaftor) in the morning and one tablet (containing 75 mg ivacaftor) in the evening, for a total of 100 mg tezacaftor / 300 mg ivacaftor per day, if weighing less than 30 kg. The SYMDEKO dosage is 50 mg tezacaftor / 150 mg ivacaftor. The FDA recommends that patients with moderate hepatic impairment (Child-Pugh class B) have their SYMDEKO dose reduced to one morning tablet and the evening ivacaftor dose omitted. In patients with severe hepatic impairment (Child-Pugh class C), SYMDEKO should be used with caution, with a maximum dose of one morning tablet.

[0023] SYMDEKO is available as a white capsule-type tezacaftor / ivacaftor fixed-dose combination tablet packaged with a light blue capsule-type ivacaftor tablet. It is available in 50 mg tezacaftor / 75 mg ivacaftor + 75 mg ivacaftor and 100 mg tezacaftor / 150 mg ivacaftor + 150 mg ivacaftor packages. The following inactive ingredients are present in the tezacaftor / ivacaftor combination tablet: croscarmellose sodium, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coat contains HPMC / hypromellose 2910, hydroxypropyl cellulose, talc, and titanium dioxide. Ivacaftor tablets contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coat contains carnauba wax, FD&C Blue No. 2, PEG 3350, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide, propylene glycol, and shellac.

[0024] The overall safety profile of SYMDEKO is based on data from 1,001 CF patients in three double-blind, placebo-controlled clinical trials: two 12-week and 24-week parallel-group studies (NCT02347657, NCT02516410) and one 8-week crossover study (NCT02392234). Eligible patients were also eligible to participate in an open-label extension safety study (up to 96 weeks of SYMDEKO). A total of 496 CF patients aged 12 years and older received at least one dose of SYMDEKO in the three placebo-controlled trials. Serious adverse reactions that occurred more frequently in SYMDEKO-treated patients compared with placebo, regardless of whether they were considered drug-related by the investigator, included distal intestinal obstruction syndrome (3 (0.6%) SYMDEKO-treated patients vs. 0 placebo-treated patients). Transaminase elevations (ALT / AST) were observed in SYMDEKO-treated patients. The FDA recommends measuring serum transaminases before starting SYMDEKO, every 3 months during the first year of treatment, and annually thereafter. Treatment should be interrupted in patients with ALT or AST >5x the upper limit of normal (ULN), or in patients with ALT or AST >3x ULN and bilirubin >2x ULN. After resolution, the FDA recommends considering the benefits and risks of restarting SYMDEKO. Non-congenital lens opacities / cataracts have been reported in pediatric patients treated with SYMDEKO. The FDA recommends baseline and follow-up testing for pediatric patients initiating SYMDEKO treatment.

[0025] VX-445 (elexacaftor, N-(1,3-dimethyl-1H-pyrazole-4-sulfonyl)-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyridin-1-yl]pyridine-3-carboxamide 2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide), CAS2216712-66-0, e.g., WO2016 / 057572, WO2018 / 107100, WO2019 / 152940), is a type III CFTR corrector and part of TRIKAFTA. TRIKAFTA / KAFTRIO was approved in the US as a combination product of elexacaftor and benzocaine-3000 (as of 2019) and in the EU as part of KAFTRIO in 2020. TRIKAFTA / KAFTRIO is a combination product of elexacaftor and benzocaine-3000 (as of 2020) for the treatment of cystic fibrosis (CF) in patients 6 years of age and older with at least one F508del mutation in the CFTR gene or a CFTR gene mutation that is responsive based on in vitro data. It is a combination product of the CFTR corrector tezacaftor and the CFTR potentiator ivacaftor. The current TRIKAFTA USPI (October 2021) lists 178 valid CFTR mutations.

[0026] The efficacy of TRIKAFTA in patients with CF aged 12 years and older was evaluated in two double-blind, placebo-controlled studies (Studies 1 and 2). Patients discontinued their previous CFTR modulator therapy but continued other standard-of-care CF medications (e.g., bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline). Study 1 (NCT03525444) evaluated 403 patients (200 TRIKAFTA, 203 placebo). These patients had an F508del mutation in one allele and a mutation in the second allele resulting in a CFTR protein that was either null or unresponsive to ivacaftor and tezacaftor / ivacaftor. The primary efficacy outcome measure was improvement in lung function, as measured by the mean absolute change from baseline in ppFEV1 over 4 weeks of treatment at an interim analysis point. The treatment difference between TRIKAFTA and placebo was 13.8%. Risk of pulmonary exacerbation (relative risk reduction of 0.63 vs. placebo), absolute change from baseline in CFQ-R Respiratory Domain Score (+20.2 vs. placebo), and absolute change from baseline in body mass index (BMI) (+1.04 kg / m vs. placebo) 2 TRIKAFTA also demonstrated favorable changes in key secondary endpoints measured at 24 weeks of treatment, including absolute change from baseline in sweat chloride (-41.8 mM vs. placebo) and sweat chloride (-41.8 mM vs. placebo).

[0027] Study 2 (NCT03525548) evaluated 107 CF patients aged 12 years or older who were homozygous for the F508del mutation. After a 4-week open-label run-in period with tezacaftor / ivacaftor, patients were randomized to TRIKAFTA or continued tezacaftor / ivacaftor for 4 weeks. The primary endpoint was the mean absolute change from baseline in ppFEV1 at week 4 of the double-blind treatment period. Treatment with TRIKAFTA resulted in a statistically significant 10.0% improvement in ppFEV1 compared with tezacaftor / ivacaftor. Key secondary endpoints at week 4, including absolute change from baseline in CFQ-R Respiratory Domain Score (+17.4) and sweat chloride, a CFTR functional biomarker (-45.1 mM), also showed favorable changes with TRIKAFTA compared with tezacaftor / ivacaftor.

[0028] Study 3 (NCT03691779) was an open-label study evaluating TRIKAFTA in 66 children 6 to <12 years of age who were homozygous for the F508del mutation or heterozygous for the F508del mutation and had a mutation on the second allele that resulted in a CFTR protein that was either null or unresponsive to ivacaftor and tezacaftor / ivacaftor. The mean absolute change from baseline in sweat chloride to week 24 was -60.9 mmol / L. The efficacy of TRIKAFTA in patients 6 to <12 years of age was extrapolated from patients 12 years of age and older, and this is supported by population pharmacokinetic analyses showing that exposure levels of elexacaftor, tezacaftor, and ivacaftor in patients 6 to <12 years of age were within the range of exposure observed in patients 12 years of age and older (Studies 1 and 2).

[0029] The recommended dose of TRIKAFTA for patients 12 years of age and older and children 6 years of age and older is 2 tablets in the morning (each tablet contains 100 mg elexacaftor and 100 mg tezacaftor) if weighing 30 kg or more. The recommended dose of TRIKAFTA for patients 6 to 11 years of age weighing less than 30 kg is two tablets (each containing elexacaftor 50 mg / tezacaftor 25 mg / ivacaftor 37.5 mg) in the morning and one tablet (each containing ivacaftor 75 mg) in the evening, for a total of elexacaftor 200 mg / tezacaftor 100 mg / ivacaftor 300 mg per day. The FDA does not recommend the use of TRIKAFTA in patients with moderate hepatic impairment (Child-Pugh class B). However, if used, the TRIKAFTA dose should be reduced by alternating one and two tablets daily in the morning only.

[0030] TRIKAFTA is a co-packaged fixed-dose combination tablet of elexacaftor, tezacaftor, and ivacaftor with ivacaftor tablets. Both tablets are for oral administration. The elexacaftor, tezacaftor, and ivacaftor fixed-dose combination tablets are orange, capsule-shaped, film-coated tablets containing 100 mg elexacaftor, 50 mg tezacaftor, and 75 mg ivacaftor, or light orange, capsule-shaped, film-coated tablets containing 50 mg elexacaftor, 25 mg tezacaftor, and 37.5 mg ivacaftor. The following inactive ingredients are present: hypromellose, hypromellose acetate succinate, sodium lauryl sulfate, croscarmellose sodium, microcrystalline cellulose, and magnesium stearate. The tablet film coating contains hypromellose, hydroxypropyl cellulose, titanium dioxide, talc, iron oxide yellow, and iron oxide red. Ivacaftor tablets are available as light blue film-coated capsules containing 150 mg or 75 mg of ivacaftor and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coating contains carnauba wax, FD&C Blue No. 2, PEG 3350, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, triferric oxide, propylene glycol, and shellac.

[0031] The safety profile of TRIKAFTA is based on data from 510 CF patients aged 12 years and older in two double-blind, controlled studies (Studies 1 and 2) with 24-week and 4-week treatment periods. Eligible patients were also eligible to participate in an open-label extension safety study (up to 96 weeks of TRIKAFTA). A total of 257 CF patients aged 12 years and older received at least one dose of TRIKAFTA in the two controlled studies. In Study 1, serious adverse reactions that occurred more frequently in patients treated with TRIKAFTA compared with placebo were rash (1% vs. <1%) and influenza (1% vs. 0%). The most common adverse drug reactions with TRIKAFTA (occurring in ≥ 5% of patients and ≥ 1% more frequently than placebo) were headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, increased alanine aminotransferase, nasal congestion, increased blood creatine phosphokinase, increased aspartate aminotransferase, epistaxis, rhinitis, influenza, sinusitis, and increased blood bilirubin.

[0032] In Study 1, the incidence of adverse reactions of transaminase elevations (AST and / or ALT) was 11% in TRIKAFTA-treated patients and 4% in placebo-treated patients. The incidence of maximum total bilirubin elevations >2 × ULN was 4% in TRIKAFTA-treated patients and <1% in placebo-treated patients. Liver failure leading to transplantation while receiving TRIKAFTA has been reported in patients with cirrhosis and portal hypertension. The FDA recommends avoiding the use of TRIKAFTA in patients with pre-existing advanced liver disease unless the benefits are expected to outweigh the risks. If used in these patients, close monitoring is required after initiation of treatment. The FDA recommends that patients undergoing treatment with TRIKAFTA undergo a follow-up period of 1 year or more prior to initiation of TRIKAFTA. Liver function tests (ALT, AST, and bilirubin) are recommended for all patients every 3 months for the first year and annually thereafter. If liver function test values ​​are significantly elevated, e.g., ALT or AST >5x upper limit of normal (ULN), or ALT or AST >3x ULN and bilirubin >2x ULN, treatment should be interrupted and laboratory values ​​followed closely until the abnormalities resolve. After resolution, the FDA recommends considering the benefits and risks of resuming TRIKAFTA.

[0033] Non-congenital lens opacities / cataracts have been reported in pediatric patients treated with ivacaftor-containing regimens. The FDA recommends baseline and follow-up examinations for pediatric patients initiating TRIKAFTA treatment. Additional potential side effects of TRIKAFTA have been reported, including rash (Study 1, 10% with TRIKAFTA vs. 5% with placebo) and elevated blood pressure. The maximum increase from baseline in mean systolic and diastolic blood pressure was 3.5 mmHg and 1.9 mmHg, respectively, in TRIKAFTA-treated patients (baseline: systolic 113 mmHg, diastolic 69 mmHg) and 0.9 mmHg and 0.5 mmHg, respectively, in placebo-treated patients (baseline: systolic 114 mmHg, diastolic 70 mmHg).

[0034] ABBV-2222 (GLPG-2222, gallicaftor, 4-[(2R,4R)-4-({[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid; CAS 1918143-53-9, e.g., WO2016 / 069757) is a Type I It is a CFTR corrector and is currently being tested in combination with the CFTR potentiator ABBV-3067 (see below) in an open-label Phase II trial (NCT03969888) in 78 CF patients aged 18 years or older who are homozygous for the F508del-CFTR mutation. The primary endpoint is absolute change from baseline in ppFEV1 at day 29, and secondary endpoints include absolute change from baseline in sweat chloride at day 29 and change in forced vital capacity (the total amount of air exhaled during forced expiratory volume test, pulmonary function tests). Several undisclosed dosing regimens of galicaftor and navocaftor are being tested. Additionally, gallicaftor was tested as part of a triple combination of CFTR modulators in an open-label Phase II study (NCT04853368), in which one cohort of patients with homozygous F508del-CFTR was treated with a fixed dose of gallicaftor and the potentiator, navocaftor, for 28 days, followed by 28 days of treatment with the triple combination of gallicaftor / navocaftor and the CFTR corrector, ABBV-119. ABBV-119 has a different mechanism of action than gallicaftor.An interim analysis after the dual treatment phase showed efficacy of the galicaftor / navocaftor dual combination on ppFEV1 ("favorable results"), but the addition of ABBV-119 did not provide any additional benefit, and the trial was discontinued (Abbvie's oral presentation at a press conference on April 29, 2022). Gallicaftor was previously tested as a single agent in a placebo-controlled Phase IIa study (NCT03119649). 59 CF patients aged 18 years or older who were homozygous for the F508del-CFTR mutation were treated for 4 weeks at doses of 50, 100, 200, and 400 mg once daily. The primary endpoint was the number of participants experiencing treatment-emergent adverse events by Day 43. Key secondary endpoints were change from baseline in ppFEV1 at Day 29, change from baseline in CFQ-R at Day 29, and change from baseline in sweat chloride concentration at Day 29. Gallicaftor was well tolerated and safe. No significant changes were observed in ppFEV1 and CFQ-R scores compared to placebo. The change in sweat chloride was significant in the 200 mg dose group (-15.8 mM vs. placebo). These data indicate that gallicaftor, as monotherapy, does not affect lung function in patients with homozygous F508del-CFTR CF at the doses tested. Gallicaftor demonstrated high efficacy (EC ) in electrophysiological recordings (transepithelial current clamp) in vitro in the presence of the potentiator GLPG1837 using differentiated human bronchial epithelial cells from homozygous F508del-CFTR donors. 50= 5 nM) (Wang, 2018). Additionally, galicaftor was tested in a fixed-dose combination with another potentiator, GLPG-2451, in a Phase 1b open-label study (NCT03540524). Ten CF patients homozygous for the F508del-CFTR mutation were treated with the galicaftor / GLPG-2451 combination for 2 weeks, followed by the addition of another CFTR modulator (GLPG-2737). An interim analysis at week 2 of treatment with gallicaftor and GLPG-2451 showed that the combination was well tolerated and safe during the 2-week treatment phase. Furthermore, key secondary endpoints improved versus baseline: ppFEV1 (+3%) and sweat chloride (-25mM) (Press Release Galapagos, October 24, 2018), demonstrating that galicaftor can partially correct F508del-CFTR function when used in combination with a potentiator.

[0035] PTI-801 (posenacaftor, CAS2095064-05-2; compound of Example 2 in WO2019 / 071078) can be classified as a type III CFTR corrector according to the examples in this application. PTI-801 was most recently tested in combination with a CFTR potentiator, PTI-808, and a CFTR amplifier, PTI-428, in a Phase 1 / 2 randomized, double-blind, placebo-controlled trial (NCT03500263). Thirty-one CF patients aged 18 years or older who carried at least one F508del-CFTR allele were randomized to receive the triple therapy combination or placebo. The triple combination was administered daily in fixed doses of PTI-428 (30 mg) plus low-dose PTI-801 (200 mg) and high-dose-tested PTI-808 (300 mg), or high-dose-tested PTI-801 (600 mg) and medium-dose PTI-808 (150 mg). Patients were first treated with PTI-808 or placebo for 7 days, followed by a 14-day triple combination treatment period, followed by a 7-day washout period during which no treatment was administered. Patients receiving combination therapy with high-dose PTI-801 experienced significant improvements in pulmonary function, with a 5% increase in mean absolute ppFEV1 at day 14 compared to pretreatment. These patients also experienced significant decreases in sweat chloride levels, with a 19 mM decrease at day 14 compared to pretreatment and a 24 mM decrease compared to placebo. Positive effects were also reported in patients who would not be enrolled in other CFTR modulator combination trials due to their propensity for rapid lung function decline: When treated with the combination regimen with 600 mg of PTI-801, these patients experienced a 6% improvement in ppFEV1 compared to baseline and an 8% improvement compared to placebo.

[0036] ABBV-3067 (navocaftor, GLPG-3067, (5-(3-Amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methanol), CAS 2159103-66-7, e.g., WO 2017 / 208115), as mentioned above, is a CFTR potentiator currently being analyzed in combination with gallicaftor in a Phase II trial (NCT03969888). Previously, a Phase I study was conducted in healthy volunteers, also in combination with gallicaftor, consisting of a single ascending dose part with single oral doses of navocaftor ranging from 15 to 1000 mg and a multiple ascending dose part with oral doses starting at 45 mg once daily for 14 days (NCT03128606). Navocaftor was generally well tolerated in healthy subjects at single doses up to 1000 mg and at doses up to 500 mg bid for 14 days. Navocaftor exposure was not significantly altered in the presence of gallicaftor, and gallicaftor exposure was similar in the presence of two different doses of navocaftor (Poster #36, North American Cystic Fibrosis Conference 2017, Indianapolis).

[0037] QBW-251 (Icenticaftor, 3-Amino-6-methoxy-N-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5-(trifluoromethyl)pyridine-2-carboxamide, CAS 1334546-77-8, see e.g., WO 2011 / 113894), is a CFTR potentiator that was tested in a placebo-controlled Phase I / II study in a cohort of CF patients aged 18 years or older with a monoallelic CFTR class III / IV CFTR mutation, i.e., a mutation that places CFTR on the cell surface and can benefit from potentiation (NCT02190604). One of the primary endpoints was the change from baseline in the lung clearance index (LCI) after 14 days of treatment. The lung clearance index (LCI) is an index of ventilation inhomogeneity obtained from a multiple-breath washout test. 2.5 A mean change from baseline in LCI of more than 1 unit indicates improvement. Other efficacy endpoints were absolute change from baseline in ppFEV1 and change from baseline in sweat chloride concentration after 14 days of treatment. Patients treated with 450 mg isenticaftor (bid) had a mean change from baseline in LCI of more than 1 unit. 2.5The study demonstrated an improvement in CFTR target engagement and clinically meaningful improvements in lung function, including an improvement in FEV1 (-1.13 vs. placebo), a 6.5% increase vs. placebo, and a reduction in sweat chloride concentration (-8.4 mM vs. placebo). In the same study, and in contrast, treatment of a cohort of patients homozygous for the F508del-CFTR mutation with isenticaftor (450 mg bid) did not result in a reduction in sweat chloride or improvement in lung function, indicating the need for concomitant use with a CFTR corrector in this patient population (Kazani, 2021). In healthy volunteers, isenticaftor was well tolerated at all doses tested, up to 1000 mg bid at the SAD and 750 mg bid at the MAD. Icenticaftor 150 mg and 450 mg bid doses (across all patient subgroups) were well tolerated by CF patients with no unexpected events, deaths, or discontinuations (Kazani 2021).

[0038] Additionally, a placebo-controlled Phase II study (NCT02449018) evaluated isenticaftor in 92 patients aged 18-75 years with moderate to severe COPD and chronic bronchitis symptoms. Patients received 300 mg bid isenticaftor (N=64) or placebo (N=28) for 4 weeks in addition to their background COPD treatment. The primary endpoint was LCI after 4 weeks of treatment. 2.5 The primary secondary endpoint was the change from baseline in FEV1 after 4 weeks of treatment. The primary exploratory endpoints included the change from baseline in sweat chloride and plasma fibrinogen concentrations (markers of inflammation) after 4 weeks of treatment. Icenticaftor treatment significantly reduced LCI compared with placebo treatment. 2.5However, isenticaftor treatment improved FEV1 compared with placebo (+0.05-0.06 L, mean baseline 1.4-1.5 L), sweat chloride (-5.04 mM, mean baseline 23 mM), and plasma fibrinogen (-0.39 g / L, mean baseline 3.2 g / L), suggesting that isenticaftor treatment, compared with placebo, improved several areas of COPD lung disease. Improvements in bronchiectasis have been suggested (NCT02449018; Rowe, 2020). Currently, isenticaftor is undergoing a placebo-controlled Phase II clinical trial (NCT04396366) in subjects aged 18 years and older with bronchiectasis, at an oral dose of 300 mg bid and for a 12-week treatment period. An estimated 72 patients will be randomized 1:1 to drug or placebo treatment. The primary endpoint is the change from baseline in the bacterial load of potentially pathogenic microorganisms in sputum, measured as colony-forming units (CFU / mL), after 1 week of treatment. Key secondary endpoints measured after 12 weeks of treatment include change from baseline scores on the Quality of Life Questionnaire for Bronchiectasis, Respiratory Domain Only (QOL-B, a disease-specific questionnaire developed for non-cystic fibrosis bronchiectasis), change from baseline in fibrinogen plasma concentration, and rescue medication. These included change in (non-fatal) medication use (salbutamol / albuterol), change from baseline in FEV1, change from baseline in airway lumen measured by high-resolution computed tomography (HRCT), and change from baseline in global and regional airway air trapping severity measured by HRCT.

[0039] VX-121 (Vanzacaptor, (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-l-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracoza-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione [17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione), CAS 2374124-49-7 (e.g., WO2019 / 161078, WO2021 / 030552), is a type III CFTR corrector currently being studied in two active-controlled, double-blind, randomized phase III clinical trials in CF patients as part of a new triple combination therapy that also includes banzacaftor, the type I corrector, tezacaftor, and the CFTR potentiator, VX-561 (deuterated version of ivacaftor). In Study 1 (NCT05033080), the new triple combination will be compared with TRIKAFTA in an estimated 400 CF patients aged 12 years or older who are heterozygous for the F508del-CFTR mutation and have a minimal function mutation on the other allele. After a 4-week TRIKAFTA run-in period, patients will be randomized 1:1 to either continuing TRIKAFTA or receiving a once-daily combination of banzacaftor, tezacaftor, and dutivacaftor (20 mg / 100 mg / 250 mg) for 48 weeks. The primary efficacy endpoint is improvement in lung function, as measured by the mean absolute change from baseline in ppFEV1, over 24 weeks of treatment.Key secondary endpoints, assessed at 24 weeks of treatment, include absolute change from baseline in sweat chloride, the proportion of participants with sweat chloride <60 mM and <30 mM (from baseline) by week 24. In Study 2 (NCT05076149), the new triple combination will be compared with TRIKAFTA in a blinded study in an estimated 550 CF patients aged 12 years or older who are homozygous for F508del-CFTR, heterozygous for F508del-CFTR and a gating or residual function CFTR mutation, or have at least one other TRIKAFTA-responsive CFTR mutation and no F508del-CFTR mutation. After a 4-week TRIKAFTA run-in period, patients will be randomized 1:1 to continue TRIKAFTA or receive a once-daily combination of banzacaftor, tezacaftor, and dutivacaftor (20 mg / 100 mg / 250 mg) for 48 weeks. The primary efficacy outcome was pulmonary function as measured by the mean absolute change from baseline in ppFEV1 through 24 weeks of treatment. Key secondary endpoints measured at 24 weeks of treatment were absolute change from baseline in sweat chloride, proportion of participants with sweat chloride <60 mM and <30 mM (from baseline) by week 24.

[0040] The efficacy and safety of the new triple combination, banzacaftor / tezacaftor / dutivacaftor, have previously been studied in a phase II trial in CF patients heterozygous for the F508del and minimal-function mutations in the CFTR gene (NCT03912233) or homozygous for the F508del-CFTR mutation. Heterozygous patients (N=58) received a triple combination of banzacaftor (5, 10, or 20 mg), tezacaftor 100 mg, and dutivacaftor 150 mg once daily for 4 weeks compared with placebo treatment, followed by an 18-day washout period from the triple combination to the tezacaftor / dutivacaftor dual combination. The primary efficacy outcome measure was improvement in lung function, as measured by the mean absolute change from baseline in ppFEV1, over 4 weeks of treatment. The ppFEV1 treatment differences between the new triple combination and placebo were +2.7% / +12.3% / +7.9% for the 5 mg / 10 mg / 20 mg banzacaftor groups. The key secondary endpoint, absolute change from baseline in sweat chloride over 4 weeks of treatment, was favorable for the new triple combination, with differences vs. placebo of -45.1 mM / -48.1 mM / -51.8 mM for the 5 mg / 10 mg / 20 mg banzacaftor groups. Homozygous patients (N=28) were randomized to either continue tezacaftor / ivacaftor (SYMKEVI) after a 4-week run-in period or receive the new triple combination of banzacaftor 20 mg / tezacaftor 100 mg / dutivacaftor 150 mg once daily for 4 weeks, followed by a 28-day washout period to the tezacaftor / ivacaftor dual combination. The primary efficacy outcome was improvement in pulmonary function as measured by the mean absolute change from baseline in ppFEV1 over 4 weeks of treatment. The ppFEV1 treatment difference between the new triple combination and the dual combination was +16.0%. The key secondary endpoint, absolute change from baseline in sweat chloride over 4 weeks of treatment, was favorable for the new triple combination, with a difference of + / -42.9 mM compared to the dual combination.The new triple combination was generally well tolerated (Vertex press release, July 28, 2021).

[0041] VX-561 (ivacaftor, N-[2-tert-butyl-4-[1,1,1,3,3,3-hexadeuterio-2-(trideuteriomethyl)propan-2-yl]-5-hydroxyphenyl]-4-oxo-1H-quinoline-3-carboxamide), CTP-656, CAS 1413431-07-8, e.g., WO2019 / 109021, WO2019 / 018395) is a deuterated form of ivacaftor for once-daily administration. This phase II study (NCT03911713) compared different doses of ivacaftor with the standard ivacaftor dose (150 mg bid = Kalydeco) in CF patients aged 18 years or older who harbored one of the following ivacaftor-responsive CFTR mutations in at least one allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D and were already taking ivacaftor. Patients (N=77) were randomized to either continue ivacaftor (150 mg bid) or receive 12 weeks of once-daily treatment with 25, 50, 150, or 250 mg of ivacaftor. The primary efficacy outcome was improvement in lung function, as measured by the mean absolute change from baseline in ppFEV1, over 12 weeks of treatment. The therapeutic difference in ppFEV1 of dutyvacaftor compared with ivacaftor was 150 mg / 250 mg once daily. The absolute change from baseline in sweat chloride over 12 weeks of treatment, a key secondary endpoint, was measured as +2.4 mM and -7.4 mM in the ivacaftor 150 mg / 250 mg once-daily groups compared with ivacaftor 150 mg bid. The mean c trough Plasma concentration (Mean c trough Plasma concentrations were 458 ng / mL and 1100 ng / mL for the 150 mg and 250 mg doses, compared with 952 ng / mL for the ivacaftor 150 mg bid dose.

[0042] CFTR correctors, including lumacaftor, tezacaftor, gallicaftor, Corr4a, elexacaftor, and vamocaftor, have been studied in vivo for their ability to restore folding of mutant CFTR (especially F508del-CFTR) and its trafficking to the cell surface. Trafficking to the cell surface can be analyzed by various assay techniques, including anti-CFTR immunoblotting (the CFTR "C band" represents transported mature CFTR), anti-CFTR cell surface ELISA, enzyme fragment complementation techniques, or CFTR-HRP fusion protein in recombinant cell lines expressing mutant CFTR proteins or primary cells from CF patients. Importantly, the combined use of collectors with different types of collector mechanisms showed additive effects on increasing cell surface expression of F508del-CFTR. This has been shown, for example, for elexacaftor + / - tezacaftor (type III corrector + / - type I corrector; Keating, 2018; Veit, 2020) or vamocaftor + / - tezacaftor (type III corrector + / - type I corrector; Davies, 2018) or type I + type II + type III corrector (Veit, 2018).

[0043] Mutant CFTR transported to the cell surface may still have impaired gating, and the addition of potentiators has been shown to significantly enhance the function of cell-surface F508del-CFTR. Various functional assays are available for analyzing CFTR function. For example, cellular expression of halide-sensitive yellow fluorescent protein can be used to measure iodide influx through functional CFTR (Galietta, 2001). Furthermore, Ussing chambers and electrophysiological measurements using recombinant epithelial cells or reconstituted bronchial epithelia from CF patients can be used to characterize the effects of CFTR modulators on CFTR function. For example, the addition of the potentiator ivacaftor to lumacaftor-corrected F508del-CFTR was shown to enhance CFTR function by nearly twofold in reconstituted bronchial epithelia from CF patients (van Goor, 2011), consistent with clinical trial data demonstrating improved FEV1 with ivacaftor addition in lumacaftor-treated patients (Boyle, 2014). Similarly, again using Ussing chamber data, we demonstrated the additivity of the type I corrector tezacaftor and the type III corrector elexacaftor in correcting F508del-CFTR function in reconstituted CF bronchial epithelium, and further demonstrated a two-fold enhancement of function with the addition of the potentiator ivacaftor. We also demonstrated an additive effect of the type III corrector elexacaftor on F508del-CFTR function compared with the combination of the type I corrector tezacaftor and the potentiator ivacaftor (Keating, 2018). This latter comparison is consistent with clinical trial data in patients homozygous for F508del-CFTR, in which the addition of elexacaftor to a baseline treatment of tezacaftor plus ivacaftor (SYMDEKO) resulted in a 10% increase in ppFEV1 (Keating, 2018). The FDA recognizes the predictive power of in vitro tests regarding clinical efficacy of CFTR modulators and has not recommended any drug for rare CFTR mutations based solely on in vitro evidence. CFTR modulators have been approved for this purpose (Ussing chamber assays in Fisher rat thyroid epithelial cells recombinantly expressing mutant CFTR; uspi SYMDEKO, uspi KALYDEKO, uspi TRIKAFTA).

[0044] Despite the availability of a variety of CFTR modulators with mechanisms complementary to many of the common mutations, patients have not fully restored CFTR function (as indicated by persistently elevated sweat chloride levels), nor has their lung function. These findings highlight the need for novel, additional CFTR corrector mechanisms with high efficacy that could be used alone or in addition to currently available or future background therapies (i.e., SYMDEKO or ORKAMBI or TRIKAFTA or [gallicaftor + navocaftor], and any additional background therapies) to enhance the efficacy of such CFTR modulator treatments.

[0045] CFTR correctors of novel mechanisms (i.e., not type I, not type II, not type III correctors) with potential in the prevention and treatment of CFTR-related diseases and disorders, in particular cystic fibrosis, in particular CFTR correctors such as compounds of formula (I) as defined below, including type I correctors (lumacaftor, tezacaftor, gallicaftor) and / or type II correctors (corrector 4a) and / or type III correctors (elexacaftor, vamo It has been found that when used in combination with CFTR correctors of other mechanisms, such as ivacaftor, navocaftor, isenticaftor, dutivacaftor, GLPG-1837, and GLPG-2451 (also known as CFTR potentiators), the compounds appear to have complementary, and even synergistic, effects in the treatment of CFTR-related diseases and disorders, particularly cystic fibrosis. Therefore, such combinations are considered particularly useful in the treatment of cystic fibrosis. The compounds of formula (I) can restore CFTR function in the absence and presence of potentiators, as measured by Ussing chamber assays in reconstituted tissue from CF patients with the F508del-CFTR mutation.

[0046] In addition, CFTR correctors, such as compounds of formula (I), particularly according to any one of embodiments 1) to 15), when used in combination with CFTR stabilizers, such as SION-638 or NBD1-A, are believed to have complementary and even synergistic effects in the treatment of CFTR-related diseases and disorders, particularly cystic fibrosis. Thus, such combinations are believed to be particularly useful in the treatment of cystic fibrosis. [Brief explanation of the drawings]

[0047] [Figure 1] FIG. 1 shows the effect of Example Compound 3 on F508del-CFTR cell surface expression when given in addition to basal treatment with type I or type II or type III or [type I + type III] CFTR corrector. [Figure 2] FIG. 2 shows the effect of Example Compound 3 on F508del-CFTR function (YFP quenching assay) when given in addition to basal treatment with the type I CFTR corrector, gallicaftor and / or the CFTR potentiator, navocaftor. [Figure 3] FIG. 3 shows the effect of Example Compound 3 on F508del-CFTR function (YFP quenching assay) when given in addition to basal treatment with the type I CFTR corrector, tezacaftor and / or the CFTR potentiator, ivacaftor. [Figure 4] FIG. 4 shows the effect of example compound 3 on F508del-CFTR function (YFP quenching assay) when given in addition to basal treatment with the type II CFTR corrector, corrector 4a, and / or the CFTR potentiator, navocaftor. [Figure 5] FIG. 5 shows the effect of Example Compound 3 on F508del-CFTR function (YFP quenching assay) when given in addition to basal treatment with the type III CFTR corrector, elexacaftor and / or the CFTR potentiator, ivacaftor. [Figure 6] Figure 6 shows the effect of Example Compound 3 on F508del-CFTR cell surface expression when given in addition to baseline treatment with the type III CFTR correctors, elexacaftor or the compound of Example 2 of WO 2019 / 071078 (PTI-801). Additionally, the effect of adding one type III corrector (elexacaftor) to another type III corrector (PTI-801) is shown. Summary of the Invention

[0048] Detailed Description of the Invention 1) A first aspect relates to a pharmaceutical composition comprising, as an active ingredient, a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more therapeutically active ingredients acting as CFTR modulators, wherein the CFTR modulators are one or more CFTR correctors (in particular type I correctors and / or type II correctors and / or type III correctors) and / or CFTR potentiators; or pharmaceutically acceptable salts thereof; and further comprising at least one pharmaceutically acceptable excipient:

[0049] [ka]

[0050] (In the formula, X is -CR X1 R X2 represents R X1 represents hydrogen, and R X2 teeth, -C 1-6 - alkyl (especially methyl, ethyl, isopropyl, isobutyl); -C 1-4 -fluoroalkyl (especially 2,2,2-trifluoroethyl, 2,2-difluoroethyl); or -C 3-6 -cycloalkyl (especially cyclopentyl); represents; R 1 is C 1-4 - represents alkyl (especially methyl); R 2 is C 1-4 - represents alkyl (especially methyl); R 3 is C 1-6 - represents alkyl (especially isobutyl); R 4 represents a 5-membered heteroaryl (especially oxadiazolyl), which is independently unsubstituted or substituted by 1 or 2 substituents, said substituents being selected from the group consisting of C 1-4 -Alkyl (especially methyl), C 1-4 -alkoxy (especially methoxy), C1-3 -fluoroalkyl, C 1-3 -fluoroalkoxy, C 3-6 independently selected from cycloalkyl (especially cyclopropyl) or halogen (especially fluoro); Ar 1 represents an 8- to 10-membered bicyclic heteroarylene (particularly a 10-membered bicyclic heteroarylene), which bicyclic heteroarylene is independently unsubstituted or contains one C 1-4 - substituted by alkyl (especially methyl) or halogen (especially fluoro); Ar 2 represents phenyl, which is unsubstituted or substituted by one or two substituents, said substituents being C 1-4 -Alkyl, C 1-3 -Fluoroalkyl, halogen, C 1-6 -alkoxy and C 1-3 -fluoroalkoxy).

[0051] The pharmaceutical composition according to embodiment 1) can be used as a medicament, for example, in the form of a pharmaceutical composition for enteral (especially oral) or parenteral administration (including topical application or inhalation). Such 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 active ingredient combination of the present invention, optionally with other therapeutically valuable substances, with suitable non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if necessary, conventional pharmaceutical adjuvants, to form a pharmaceutical dosage form. Pharmaceutical compositions for oral administration may, in particular, be in the form of capsules or tablets.

[0052] 2) A second aspect is that the compound of formula (I) is E ) is a compound of the formula:

[0053] [ka]

[0054] 3) A further aspect is where X is -CR X1 R X2 represents R X1 is hydrogen and R X2 C 1-4 -fluoroalkyl (in particular 2,2,2-trifluoroethyl, 2,2-difluoroethyl).

[0055] 4) A further aspect is where X is -CR X1 R X2 represents R X1 is hydrogen and R X2 is 2,2,2-trifluoroethyl.

[0056] 5) A further aspect is R 1 represents methyl.

[0057] 6) A further aspect is R 2 represents methyl.

[0058] 7) A further aspect is R 3 is isobutyl.

[0059] 8) A further aspect is R 4 represents a 5-membered heteroaryl (particularly oxadiazolyl), and the 5-membered heteroaryl is independently selected from one C 1-4 -Alkyl (especially methyl), C 1-4 -alkoxy (especially methoxy), C 1-3 -fluoroalkyl, C 1-3- substituted by fluoroalkoxy or halogen (especially fluoro).

[0060] 9) A further aspect is R 4 represents a 5-membered heteroaryl (particularly oxadiazolyl), and the 5-membered heteroaryl is independently selected from one C 1-4 -substituted by alkoxy (in particular methoxy).

[0061] 10) A further aspect is R 4 represents oxadiazolyl, and the 5-membered heteroaryl independently contains one C 1-4 -substituted by alkoxy (in particular methoxy).

[0062] 11) A further embodiment is Ar 1 represents an 8- to 10-membered bicyclic heteroarylene (particularly a 10-membered bicyclic heteroarylene), and the bicyclic heteroarylene is independently substituted by one halogen (particularly fluoro).

[0063] 12) A further embodiment is Ar 1 represents a 10-membered bicyclic heteroarylene (especially quinoline-diyl), which bicyclic heteroarylene is substituted by one halogen (especially fluoro).

[0064] 13) A further embodiment is Ar 2 represents unsubstituted phenyl.

[0065] 14) A further embodiment relates to a pharmaceutical composition according to embodiment 1), in which the compound of formula (I) is selected from the following compounds: (3S,7S,10R,13R)-13-benzyl-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (3S,7S,10S,13R)-13-benzyl-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (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,10S,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-7-isobutyl-10-isopropyl-6,9-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[17,16-c]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-7,10-diisobutyl-6,9-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[17,16-c]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-7-isobutyl-6,9,10-trimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[17,16-c]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-7-isobutyl-6,9,10-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[17,16-c]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-10-(2,2-difluoroethyl)-7-isobutyl-6,9-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[17,16-c]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,10-trimethyl-1,5,8,11-tetraoxo-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-N-(2-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)ethyl)-20-fluoro-7-isobutyl-6,9,10-trimethyl-1,5,8,11-tetraoxo-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-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,10-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydroimidazo[1',2':1,6]pyrido[2,3-p][1]oxa[4,7,10,14]tetraazacycloheptadecine-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-6,9,10-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydroimidazo[1',2':1,6]pyrido[2,3-p][1]oxa[4,7,10,14]tetraazacycloheptadecine-3-carboxamide (isoxazol-5-yl)ethyl)-7-isobutyl-6,9,10-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydroimidazo[1',2':1,6]pyrido[2,3-p][1]oxa[4,7,10,14]tetraazacycloheptadecine-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-20-fluoro-7-isobutyl-6,9,10-trimethyl-1,5,8,11-tetraoxo-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-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-20-fluoro-7-isobutyl-6,9,10-trimethyl-1,5,8,11-tetraoxo- 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-N-(2-(5-cyclopropyl-1,2,4-oxadiazole- 3-yl)ethyl)-20-fluoro-7-isobutyl-6,9,10-trimethyl-1,5,8,11-tetraoxo-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-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-20-fluoro-7-isobutyl-6,9,10-trimethyl-1,5,8,11-tetraoxo-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-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-10-(2,2-difluoroethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-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,10S,13R)-13-benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-10-(2,2-difluoroethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-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-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-10-ethyl-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-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-10-(2,2-difluoroethyl)-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-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-7-isobutyl-6,9,10,20-tetramethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,10,20-tetramethyl-1,5,8,11-tetraoxo-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-7-isobutyl-6,9,10,20-tetramethyl-1,5,8,11-tetraoxo-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-10-(2,2-difluoroethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-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-10-(2,2-difluoroethyl)-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,20-trimethyl-1,5,8,11-tetraoxo-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-10-(2,2-difluoroethyl)-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9,20-trimethyl-1,5,8,11-tetraoxo-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-10-(2,2-difluoroethyl)-7-isobutyl-6,9,20-trimethyl-1,5,8,11-tetraoxo-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-10-(2,2-difluoroethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-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-10-(2,2-difluoroethyl)-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo -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-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-7-isobutyl-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-7-isobutyl-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-7-isobutyl-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-7-isobutyl-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-7-isobutyl-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)-7-isobutyl-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-10-(2,2-difluoroethyl)-20-fluoro-N-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-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-10-(2,2-difluoroethyl)-N-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)-7-isobutyl-6,9,20-trimethyl-1,5,8,11-tetraoxo-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9,17-trimethyl-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; (8R,11RS,14S,18S)-8-benzyl-14-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-2,12,15-trimethyl-10,13,16,20-tetraoxo-11-(2,2,2-trifluoroethyl)-7,8,9,10,11,12,13,14,15,16,17,18,19,20-tetradecahydrooxazolo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacycloheptadecine-18-carboxamide; (8R,11R,14S,18S)-8-benzyl-14-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-2,12,15-trimethyl-10,13,16,20-tetraoxo-11-(2,2,2-trifluoroethyl)-7,8,9,10,11,12,13,14,15,16,17,18,19,20-tetradecahydrooxazolo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacycloheptadecine-18-carboxamide; (8R,11RS,14S,18S)-8-benzyl-14-isobutyl-2,11,12,15-tetramethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-10,13,16,20-tetraoxo-7,8,9,10,11,12,13,14,15,16,17,18,19,20-tetradecahydrobenzofuro[7,6-p][1]oxa[4,7,10,14]tetraazacycloheptadecine-18-carboxamide; (3S,7S,10R,13R)-13-benzyl-10-cyclopentyl-7-isobutyl-6,9-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[17,16-c]quinoline-3-carboxamide; and (3S,7S,10R,13R)-13-Benzyl-10-cyclopentyl-20-fluoro-7-isobutyl-6,9-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[17,16-c]quinoline-3-carboxamide.

[0066] 15) A further embodiment is where the compound of formula (I) is (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-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]tetraazacycloheptadecino[16,17-f]quinoline-3-carboxamide).

[0067] The corresponding structures of the compounds described in embodiments 14) and 15) along with their chemical names are shown in Table S, but in case of doubt the structures shown shall prevail.

[0068] Thus, for example, the compound of Example 43: (8R,11RS,14S,18S)-8-benzyl-14-isobutyl-2,11,12,15-tetramethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-10,13,16,20-tetraoxo-7,8,9,10,11,12,13,14,15,16,17,18,19,20-tetradecahydrobenzofuro[7,6-p][1]oxa[4,7,10,14]tetraazacycloheptadecine-18-carboxamide has the structure shown in Table S, where, with respect to the chiral centers at carbons 8, 14, and 18, the compound has the absolute configuration shown; with respect to the chiral center at carbon 11 (labeled &1), the absolute configuration of that chiral center can be either (R) or (S):

[0069] [ka] and any mixtures thereof.

[0070] 16) A further embodiment is one in which the one or more therapeutically active ingredients acting as CFTR modulators are selected from lumacaftor, tezacaftor, and gallicaftor; and / or a type II corrector which is corrector 4a; and / or a type I corrector selected from elexacaftor, vamocaftor, oracaftor, and banzacaftor. II corrector; and / or a CFTR potentiator selected from ivacaftor, navocaftor, isenticaftor, dutivacaftor, GLPG-1837, and GLPG2451; or a pharmaceutically acceptable salt thereof.

[0071] 17) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 16), wherein the one or more therapeutically active ingredients acting as CFTR modulators are a Type I corrector selected from lumacaftor, tezacaftor, and gallicaftor; and / or a Type II corrector that is collector 4a; and / or a Type III corrector selected from elexacaftor and banzacaftor; and / or a CFTR potentiator selected from ivacaftor, navocaftor, isenticaftor, and dutivacaftor; or a pharmaceutically acceptable salt thereof.

[0072] 18) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 16), in which the CFTR corrector is a type I corrector selected from lumacaftor, tezacaftor and gallicaftor.

[0073] 19) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 16) or 18), in which the CFTR corrector is a type II corrector, which is corrector 4a.

[0074] 20) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 16), 18) or 19), wherein the CFTR corrector is a type III corrector selected from elexacaftor, vamocaftor, oracaftor and banzacaftor.

[0075] 21) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 16) or 18) to 20), wherein the CFTR potentiator is selected from ivacaftor, navocaftor, isenticaftor, and dutivacaftor.

[0076] 22) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 17), wherein the composition comprises a compound of Formula (I) and one therapeutically active ingredient that acts as a CFTR modulator, and the CFTR modulator is a CFTR potentiator; or a pharmaceutically acceptable salt thereof.

[0077] 23) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 17) or 22), wherein the composition comprises a compound of Formula (I) and one therapeutically active ingredient that acts as a CFTR modulator, wherein the CFTR modulator is a CFTR potentiator selected from ivacaftor, isenticaftor, and dutivacaftor; or a pharmaceutically acceptable salt thereof.

[0078] 24) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 17), wherein the composition comprises a compound of formula (I) and one therapeutically active ingredient that acts as a CFTR modulator, and the CFTR modulator is a type I corrector.

[0079] 25) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 17), wherein the composition comprises a compound of formula (I) and one therapeutically active ingredient that acts as a CFTR modulator, and the CFTR modulator is a type II corrector.

[0080] 26) A further embodiment is a composition comprising a compound of formula (I) and one therapeutically active ingredient that acts as a CFTR modulator, wherein the CFTR modulator is a type III corrector. The present invention relates to a pharmaceutical composition according to any one of aspects 1) to 17), which is a target.

[0081] 27) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 17), wherein the composition has a compound of Formula (I) and two therapeutically active ingredients that act as CFTR modulators, one of the CFTR modulators being a CFTR potentiator or a pharmaceutically acceptable salt thereof, and the second CFTR modulator being a CFTR corrector or a pharmaceutically acceptable salt thereof.

[0082] 28) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 17) or 27), wherein the composition has a compound of Formula (I) and two therapeutically active ingredients that act as CFTR modulators, one of the CFTR modulators being a CFTR potentiator or a pharmaceutically acceptable salt thereof, and a second CFTR modulator being a type I corrector or a pharmaceutically acceptable salt thereof.

[0083] 29) A further embodiment is the composition comprising a compound of formula (I), and ivacaftor and tezacaftor, or pharmaceutically acceptable salts thereof; or - ivacaftor and lumacaftor, or pharmaceutically acceptable salts thereof; or - navocaftor and gallicaftor, or their pharmaceutically acceptable salts; The present invention relates to a pharmaceutical composition according to any one of aspects 1) to 17), 27) or 28), having the following structure:

[0084] 30) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 17) or 27) to 29), wherein the composition comprises the compounds of formula (I), navocaftor and gallicaftor, or pharmaceutically acceptable salts thereof.

[0085] 31) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 17) or 27) to 29), wherein the composition comprises the compounds of formula (I), ivacaftor, and tezacaftor; or a pharmaceutically acceptable salt thereof.

[0086] 32) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 17), wherein the composition comprises a compound of Formula (I) and three therapeutically active ingredients that act as CFTR modulators, wherein one of the CFTR modulators is a CFTR potentiator or a pharmaceutically acceptable salt thereof, a second CFTR modulator is a type I corrector or a pharmaceutically acceptable salt thereof, and a third CFTR modulator is a type III corrector or a pharmaceutically acceptable salt thereof.

[0087] 33) A further embodiment is the composition comprising a compound of formula (I), and - ivacaftor, tezacaftor and elexacaftor, or pharmaceutically acceptable salts thereof; or - dutivacaftor, tezacaftor and banzacaftor, or their pharmaceutically acceptable salts; 32) relates to a pharmaceutical composition according to embodiment 32), which has

[0088] 34) A further aspect is - ivacaftor or a pharmaceutically acceptable salt thereof in a pharmaceutical unit dosage suitable for oral administration of ivacaftor, wherein ivacaftor or a pharmaceutically acceptable salt thereof is in a pharmaceutical unit dosage suitable for oral administration of a total of about 300 mg or less of ivacaftor per day; and - tezacaftor or a pharmaceutically acceptable salt thereof in a pharmaceutical unit dose suitable for oral administration of tezacaftor, and The pharmaceutical composition according to embodiment 31) has about 100 mg or less of tezacaftor in a pharmaceutical unit dose suitable for oral administration.

[0089] Such combination pharmaceutical compositions according to aspects 1) to 34) are particularly useful for the prevention or treatment of a CFTR-related disorder as defined herein, in particular cystic fibrosis; and in a method for the prevention or treatment of a CFTR-related disorder as defined herein, in particular cystic fibrosis, comprising administering a pharmaceutically effective dose of such combination pharmaceutical composition to a subject (in particular a human) in need thereof.

[0090] Thus, the compounds of formula (I) or pharmaceutically acceptable salts thereof as defined in any one of embodiments 1) to 15) according to the present invention are intended to be used in combination (or combination therapy) with said further pharmaceutically active ingredient, as defined herein, which is a CFTR modulator (CFTR corrector and / or CFTR potentiator).

[0091] The definitions set forth herein apply uniformly to all of Embodiments 1) through 43) and apply mutatis mutandis throughout the specification and claims, unless a broader or narrower definition is given by a specific definition. It should be understood that any definition or preferred definition of a term may independently (and together with) define and replace the respective term in any or all other terms or preferred definitions defined herein.

[0092] 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 / or a CFTR potentiator that - alone and / or in combination - has demonstrated the potential for therapeutic use (tested in in vitro and / or in vivo models, in particular in clinical trials) and / or is indicated for such therapeutic use; such therapeutic use is for CFTR-related diseases (in particular cystic fibrosis). Examples are, in particular, CFTR potentiators: ivacaftor, navocaftor, isenticaftor, dutivacaftor, GLPG-1837 and GLPG-2451; and CFTR correctors: type I correctors (lumacaftor, tezacaftor, gallicaftor), type II corrector (corrector 4a) and type III correctors (elexacaftor, vamocaftor, oracaftor, banzacaftor; and also ABBV-119, ABBV-567; and also PTI-801).

[0093] Accordingly, in a sub-embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1) to 15) for use in the prevention or treatment of a CFTR-related disease as defined herein, in particular cystic fibrosis; said compound of formula (I) is intended to be / is administered in combination with a CFTR potentiator, such as ivacaftor, navocaftor, isenticaftor or dutivacaftor, or a pharmaceutically acceptable salt thereof; optionally in further combination with a CFTR corrector, such as lumacaftor, tezacaftor, gallicaftor, elexacaftor or banzacaftor, or a pharmaceutically acceptable salt thereof, in particular.

[0094] Additionally, the present invention relates to pharmaceutical compositions having as an active ingredient a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined according to any one of aspects 1) to 15), in combination with one or more therapeutically active ingredients acting as CFTR modulators; and at least one pharmaceutically acceptable excipient, wherein the one or more CFTR modulators are CFTR stabilizers, such as SION-638 or NBD1-A, or pharmaceutically acceptable salts thereof. CFTR stabilizers, such as SION-638 or NBD1-A, can additionally be used as CFTR modulators in aspects 16) to 43), mutatis mutandis. You may.

[0095] The term "subject" means a mammal, particularly a human.

[0096] The combination treatment (or concomitant treatment) may in particular be simultaneous (fixed or non-fixed dose).

[0097] "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 a non-fixed dose combination, where such a non-fixed dose combination may be equivalent to a fixed dose combination (e.g., by using two or more different pharmaceutical compositions to be administered at near-simultaneous times by the same route of administration), or in a non-fixed dose combination using two or more different routes or regimens of administration; in each case, the administration will result in the subject being exposed essentially simultaneously to the two or more active ingredients and / or treatments being combined. An example of the simultaneous administration of a non-fixed dose combination using two different pharmaceutical compositions to be administered at approximately the same time by the same administration route is a non-fixed dose combination in which a compound of Formula (I) as defined in any one of embodiments 1)-15) is administered bid and each CFTR modulating agent is administered bid. Another example of the simultaneous administration of a non-fixed dose combination using two different administration routes is a non-fixed dose combination in which a compound of Formula (I) as defined in any one of embodiments 1)-15) is administered once daily or bid and each CFTR modulating agent is administered tid. Another example of the simultaneous administration of a non-fixed dose combination using two different administration routes is a non-fixed dose combination in which a compound of Formula (I) as defined in any one of embodiments 1)-15) is administered once daily and each CFTR modulating agent is administered bid. Another example of simultaneous administration of a non-fixed dose combination using two different routes of administration is a non-fixed dose combination in which a compound of Formula (I) as defined in any one of embodiments 1) to 15) is administered bid and each CFTR modulator is administered once daily.

[0098] "Fixed-dose combination", when referring to a dosage form, means in the present application that the relevant dosage form is the administration of one single pharmaceutical composition having two or more active ingredients, in particular the pharmaceutical composition of any one of embodiments 1) to 34).

[0099] 35) Another aspect of the invention relates to a compound of formula (I) as defined in any one of aspects 1) to 15) or a pharmaceutically acceptable salt thereof for use in the treatment of CFTR-related diseases and disorders, in particular cystic fibrosis, wherein the compound is intended to be used / intended to be administered / administered in combination with one or more therapeutically active ingredients that act as CFTR modulators; the CFTR modulators being one or more CFTR correctors (in particular type I correctors and / or type II correctors and / or type III correctors) and / or CFTR potentiators.

[0100] 36) Another embodiment according to embodiment 35) relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1), 2) or 15) for use in the treatment of CFTR-related diseases and disorders, in particular cystic fibrosis, wherein the compound is intended to be used / intended to be administered / administered in combination with one or more therapeutically active ingredients that act as CFTR modulators; the CFTR modulators are one or more CFTR correctors (in particular type I correctors and / or type II correctors and / or type III correctors) and / or CFTR potentiators.

[0101] 37) In another embodiment, the CFTR modulator is a compound according to any one of embodiments 22), 28), 29), and 30). 31) or 33) for use according to embodiment 35) or 36), or a pharmaceutically acceptable salt thereof.

[0102] 38) Another embodiment relates to a compound of formula (I) as defined in embodiment 15) for use according to embodiment 35) or 36), wherein the CFTR modulator is defined in any one of embodiments 22), 28), 29), 30), 31) or 33).

[0103] 39) Another embodiment relates to a compound of formula (I) as defined in embodiment 15) for use according to embodiment 35) or 36), wherein the CFTR modulator is as defined in embodiment 29).

[0104] 40) Another embodiment relates to a compound of Formula (I) that is (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, or a pharmaceutically acceptable salt thereof, for use according to embodiment 35) or 36), wherein the CFTR modulator is navocaftor or gallicaftor.

[0105] 41) Another embodiment relates to a compound of Formula (I) that is (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, or a pharmaceutically acceptable salt thereof, for use according to embodiment 35) or 36), wherein the CFTR modulator is ivacaftor or tezacaftor.

[0106] 42) Another aspect of the present invention is - a pharmaceutical composition as defined in any one of aspects 1) to 34); - and instructions for use of said pharmaceutical composition for the treatment of CFTR-related diseases and disorders, in particular cystic fibrosis; The present invention relates to a kit comprising:

[0107] 43) Another aspect is - a pharmaceutical composition comprising a compound of formula (I) as defined in any one of embodiments 1) to 15); - one or more pharmaceutical compositions comprising one or more CFTR modulators as defined in any one of aspects 16) to 34); - and instructions for using said pharmaceutical compositions in combination for the treatment of CFTR-related diseases and disorders, in particular cystic fibrosis; The present invention relates to a kit comprising:

[0108] A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of aspects 1) to 15) for use in combination in the treatment of a CFTR-related disease (particularly cystic fibrosis) as defined herein; wherein said compound of formula (I) is intended to be / is administered in combination with one or more CFTR modulators; wherein said CFTR modulators are CFTR correctors (particularly type I, type II, type III correctors) and / or CFTR potentiators or pharmaceutically acceptable salts thereof; wherein said one or more CFTR modulators are in particular as defined in any one of aspects 16) to 34); wherein said compound of formula (I) or a pharmaceutically acceptable salt thereof is / are intended to be / are administered in combination with one or more CFTR modulators; wherein said one or more CFTR modulators are in particular as defined in any one of aspects 16) to 34); Any embodiment relating to a compound of formula I) or a pharmaceutically acceptable salt thereof may also include - a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1) to 15) for use in combination in the treatment of a CFTR-related disease (in particular cystic fibrosis) as defined herein; wherein the compound of formula (I) is intended to be / is administered in combination with one or more CFTR modulators; a compound of formula (I) or a pharmaceutically acceptable salt thereof; - the CFTR modulator or a pharmaceutically acceptable salt thereof, which is a CFTR corrector and / or a CFTR potentiator, for use in the treatment of the CFTR-related disease (in particular cystic fibrosis); the CFTR modulator or a pharmaceutically acceptable salt thereof, which is a CFTR corrector and / or a CFTR potentiator, is (intended to be) administered in combination with the compound of formula (I); the CFTR modulator or a pharmaceutically acceptable salt thereof; - use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament / pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and the CFTR modulator or a pharmaceutically acceptable salt thereof, which is a CFTR corrector and / or a CFTR potentiator, for use in the treatment of the CFTR-related disease (in particular cystic fibrosis); - use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament / pharmaceutical composition having the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient for use in the treatment of a CFTR-related disease (in particular cystic fibrosis), wherein the medicament / pharmaceutical composition is (intended to be) used in combination with the CFTR modulator or a pharmaceutically acceptable salt thereof, which is a CFTR corrector and / or a CFTR potentiator; - the use of the CFTR modulator, which is a CFTR corrector and / or a CFTR potentiator, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament / pharmaceutical composition having as an active ingredient the CFTR modulator, which is a CFTR corrector and / or a CFTR potentiator, or a pharmaceutically acceptable salt thereof, for use in the treatment of the CFTR-related disease, in particular cystic fibrosis; wherein the medicament / pharmaceutical composition is (intended to be) used (concomitantly) with the compound of formula (I) or a pharmaceutically acceptable salt thereof; - use of a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and the CFTR modulator or a pharmaceutically acceptable salt thereof, which is a CFTR corrector and / or a CFTR potentiator, for the treatment of the CFTR-related disease (in particular cystic fibrosis); - a medicament for use in the prevention or treatment of said CFTR-related disease (in particular cystic fibrosis), comprising said compound of formula (I) or a pharmaceutically acceptable salt thereof, and intended to be administered in combination with said CFTR modulator or a pharmaceutically acceptable salt thereof, which is a CFTR corrector and / or a CFTR potentiator; - a method for the prevention or treatment of a CFTR-related disease (particularly cystic fibrosis), comprising administering to a subject (preferably a human) in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein the compound of formula (I) is administered in combination with an effective amount of a CFTR modulator, or a pharmaceutically acceptable salt thereof, which is a CFTR corrector and / or a CFTR potentiator; and wherein the combined administration may be performed as a fixed dose combination or a non-fixed dose combination; - a method for preventing or treating the CFTR-related disease (particularly cystic fibrosis), comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and the CFTR modulator or a pharmaceutically acceptable salt thereof, which is a CFTR corrector and / or a CFTR potentiator; and - A method for preventing or treating a CFTR-related disease (particularly cystic fibrosis), comprising administering to a subject (preferably a human) in need thereof an effective amount of a CFTR modulator or a pharmaceutically acceptable salt thereof, which is a CFTR corrector and / or a CFTR potentiator. a method for preventing or treating a disease, wherein the anti-CFTR modulator, which is a CFTR corrector and / or a CFTR potentiator, is administered in combination with an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof; and the combined administration may be in the form of a fixed dose combination or a non-fixed dose combination; It is understood that this also relates to

[0109] 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.

[0110] 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.

[0111] The term "cystic fibrosis" refers to any form of cystic fibrosis, particularly cystic fibrosis associated with one or more genetic mutations. Preferably, the cystic fibrosis is associated with impaired CFTR trafficking (Class II mutations) or reduced CFTR stability (Class VI mutations) [particularly impaired CFTR trafficking / Class II mutations], where the impaired CFTR trafficking or reduced CFTR stability may be associated with another disease-causing mutation of the same or any other class. Such additional disease-causing CFTR genetic mutations include Class I mutations (loss of functional CFTR protein), (additional) Class II mutations (impaired CFTR trafficking), Class III mutations (impaired CFTR regulation), Class IV mutations (impaired CFTR conductance), Class V mutations (reduced CFTR protein due to impaired splicing), 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; particularly 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. Further CFTR genetic mutations (particularly class III and / or IV mutations) include G551D, R117H, D1152H, A455E, S549N, and the like. , R347H, S945L and R117C.

[0112] 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.

[0113] 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.

[0114] When the plural is used for compounds, salts, pharmaceutical compositions, diseases, etc., it is intended to refer to the singular compound, salt, etc. as well.

[0115] Any reference to a compound will be understood to refer, where appropriate and appropriate, to the salts (particularly the pharmaceutically acceptable salts) of such a compound.

[0116] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesired toxic effects. Such salts include inorganic or organic acid and / or base addition salts, depending on the presence of basic and / or acidic groups in the subject compound. References include, for example, "Handbook of Pharmaceutical Salts. Properties, Selection and Use.", P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and "Pharmaceutical Salts and Co-crystals," Johan Wouters and Luc See Quere (Eds.), RSC Publishing, 2012.

[0117] The definitions described herein are for Formula (I) / Formula (I) as defined in any one of Embodiments 1) to 15). E) and apply mutatis mutandis throughout the specification and claims unless a broader or narrower definition is given by a specific definition. It is to be understood that any definition or preferred definition of a term may independently (and together with) define and replace each term in any or all other terms or preferred definitions defined herein.

[0118] Whenever a substituent is described as optional, such substituent may be absent (i.e., the respective residue is unsubstituted with respect to such optional substituent), in which case all sites having a free valence (e.g., in an aromatic ring, ring carbon atoms and / or ring nitrogen atoms having a free valence to which such optional substituent may be attached) are intended to be replaced with hydrogen, as appropriate. Similarly, when the term "optionally" is used with respect to (ring) heteroatoms, this term means that each optional heteroatom, etc. is absent (i.e., a group has no heteroatoms / is a carbocyclic ring / etc.) or that each optional heteroatom, etc. is present as explicitly defined.

[0119] The term "halogen" means fluorine / fluoro, chlorine / chloro or bromine / bromo; preferably fluorine / fluoro.

[0120] The term "alkyl," used alone or in combination, means a straight- or branched-chain saturated hydrocarbon group having 1 to 6 carbon atoms. x- y The term "-alkyl" (x and y are each integers) refers to an alkyl group as defined above having x to y carbon atoms. For example, C 1-6-Alkyl groups have 1 to 6 carbon atoms. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, 3-methyl-butyl, 2,2-dimethyl-propyl and 3,3-dimethyl-butyl. For the avoidance of any doubt, when a group is described as, for example, propyl or butyl, it is meant to be n-propyl or n-butyl, respectively. R 1 C 1-4 When referring to an alkyl group, the term specifically refers to methyl. 1-4 -R representing alkyl 2 For R, the term specifically refers to methyl. 3 Ga-C 1-6 When referring to -alkyl, the term especially refers to isobutyl.

[0121] The term "alkoxy", used alone or in combination, means an alkyl-O- group, wherein the alkyl group is as previously defined. x-y The term "-alkoxy" (x and y are each integers) refers to an alkoxy group as defined above having x to y carbon atoms. For example, C 1-4 -alkoxy group is "C 1-4 -alkyl" has the meaning previously described; 1-4 -alkyl-O- group. Representative examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

[0122] The term "fluoroalkyl," used alone or in combination, refers to an alkyl group, as defined above, having 1 to 3 carbon atoms, in which one or more (and in some cases all) hydrogen atoms have been replaced with fluorine. x-y The term "fluoroalkyl" (x and y are each integers) refers to a fluoroalkyl group as defined above having x to y carbon atoms. For example, C 1-3-fluoroalkyl groups have 1 to 3 carbon atoms in which 1 to 7 hydrogen atoms have been replaced by fluorine. Representative examples of fluoroalkyl groups include C1-fluoroalkyl groups, such as trifluoromethyl and difluoromethyl, as well as 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. R X2 C 1-4 When -fluoroalkyl is represented, this term especially denotes 2,2-difluoroethyl or 2,2,2-trifluoroethyl.

[0123] The term "fluoroalkoxy", used alone or in combination, means an alkoxy group, as defined above, having 1 to 3 carbon atoms in which one or more (and in some cases all) hydrogen atoms have been replaced by fluorine. x-y The term "fluoroalkoxy" (x and y are each integers) refers to a fluoroalkoxy group as defined above having x to y carbon atoms. For example, C 1-3 A fluoroalkoxy group has 1 to 3 carbon atoms, and 1 to 7 hydrogen atoms are replaced by fluorine atoms. Representative examples of the fluoroalkoxy group include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy. Preferred are (C1) fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy.

[0124] The term "cycloalkyl," used alone or in combination, specifically refers to a saturated monocyclic hydrocarbon ring having 3 to 6 carbon atoms. x-y The term "-cycloalkyl" (x and y are each integers) refers to a cycloalkyl group as defined above having x to y carbon atoms. For example, C 3-6 - cycloalkyl groups have 3 to 6 carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0125] The term "heteroaryl," whether used alone or in combination, unless a broader or narrower definition is explicitly stated, refers to a 5- to 10-membered monocyclic or bicyclic aromatic ring having from 1 to 4 heteroatoms, each independently selected from oxygen, nitrogen, and sulfur. Representative examples of such heteroaryl groups include 5-membered heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl; 6-membered heteroaryl groups such as pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl; and 6-membered heteroaryl groups such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, and benzoyl. and 8-10 membered bicyclic heteroaryl groups such as benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyridazinyl, and imidazothiazolyl. The above heteroaryl groups are unsubstituted or substituted as expressly defined.

[0126] Substituent R representing "5-membered heteroaryl" 4 For R, this term especially means isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl; especially isoxazol-3-yl, isoxazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 2H-[1,2,3]triazol-2-yl, 2H-tetrazol-2-yl; especially 1,2,4-oxadiazol-5-yl. 4 Groups are unsubstituted or substituted as expressly defined.

[0127] Substituent Ar representing "8-10 membered bicyclic heteroarylene" 1 For Ar, this term means in particular benzofuran-diyl, benzoxazole-diyl, imidazopyridine-diyl, quinoline-diyl, isoquinoline-diyl; especially benzofuran-6,7-diyl, benzo[d]oxazole-6,7-diyl, imidazo[1,2-a]pyridine-5,6-diyl, quinoline-3,4-diyl, quinoline-5,6-diyl, isoquinoline-5,6-diyl; especially quinoline-5,6-diyl. 1 Groups are unsubstituted or substituted as expressly defined.

[0128] The compounds of formula (I) have at least three stereogenic or asymmetric centers that exist in either the (R)- or (S)-configuration, as defined in each embodiment defining such compounds of formula (I). In addition, compounds of formula (I) may have one or more additional stereogenic or asymmetric centers, such as one or more additional asymmetric carbon atoms. Thus, compounds of formula (I) may exist as a mixture of stereoisomers or, preferably, as pure stereoisomers. Mixtures of stereoisomers may be separated by methods known to those skilled in the art. When a given chemical name describes any stereogenic or asymmetric center as being in the (RS)-configuration, this means that such stereogenic or asymmetric center in such compounds may exist in the (R)-configuration, the (S)-configuration, or any mixture of epimers about such center.

[0129] Thus, for example, the compound (8R,11RS,14S,18S)-8-benzyl-14-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-2,12,15-trimethyl-10,13,16,20-tetraoxo-11-(2,2,2-trifluoroethyl)-7,8,9,10,11,12,13,14,15,16,17,18,19,20-tetradecahydrooxazolo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacycloheptadecine-18-carboxamide is (8R,11R,14S,18S)-8-benzyl-14-isobutyl 1,2-Dimethyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-2,12,15-trimethyl-10,13,16,20-tetraoxo-11-(2,2,2-trifluoroethyl)-7,8,9,10,11,12,13,14,15,16,17,18,19,20-tetradecahydrooxazolo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacycloheptadecine-18-carboxamide; compound, (8R,11S,14S,18S)-8-benzo and mixtures thereof. Similarly, in a chemical structure (as in Table S), a stereogenic or asymmetric center designated "abs" represents that center in the (R)- or (S)-configuration. A stereo or chiral center designated "&1" represents that stereo or chiral center in its respective (RS)-configuration, i.e., encompasses the respective (R)- or (S)-configuration or any mixture of epimers at such center.

[0130] When not used in reference to temperature, the term "about" placed before a numerical value "X" in this application denotes between 10% of XX and 10% of X+X, preferably between 5% of XX and 5% of X+X. In the specific case of temperatures, the term "about" placed before a temperature "Y" in this application denotes between temperatures 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.

[0131] Whenever the words "between" or "to" are used to describe a numerical range, it is understood that the endpoints of the stated range are expressly included in that range. This means, for example, that when a temperature range is stated to be between 40°C and 80°C (or 40°C to 80°C), 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 means that the variable is the integer 1, 2, 3, or 4.

[0132] The term "essentially," in the context of the present invention, is understood to particularly mean that each amount / purity / time, etc., is at least 90 percent, particularly at least 95 percent, and especially at least 99 percent of the respective total. For example, when used in the term "essentially simultaneous exposure," in cases where chronic / steady-state exposure to pharmaceutically active ingredients is intended, it is understood to particularly mean that each exposure results in simultaneous exposure of pharmaceutically effective amounts of all combined active ingredients for at least 90 percent, particularly at least 95 percent, and especially at least 99 percent of the relevant time, i.e., relevant days.

[0133] Certain aspects of the present invention are described in the following examples, which serve to more fully illustrate the present invention and are not intended to limit its scope in any way.

[0134] Experimental section I. Chemistry All temperatures are in °C. Commercially available starting materials were used as received without further purification. All reactions were carried out in oven-dried glassware under a nitrogen atmosphere unless otherwise stated. Compounds were purified by flash column chromatography on silica gel or by preparative HPLC. The compounds described in this invention were identified based on LC-MS data (retention time t R are given in min; molecular weights obtained from mass spectrometry are given in g / mol.) using the conditions described below. When the compounds of the invention appear as a mixture of conformational isomers, especially when visible in their LC-MS spectra, the retention time of the most abundant isomer is given.

[0135] Analytical LC-MS equipment: HPLC pump: Binary gradient pump, Agilent G4220A or equivalent Autosampler: Gilson (with Gilson 845z injector) LH215 or equivalent Column compartment: Dionex TCC-3000RS or equivalent Gas removal machine: Dionex SRD-3200 or equivalent Make-up pump: Dionex HPG-3200SD or equivalent DAD detector: Agilent G4212A or equivalent MS detector: Single quadrupole mass spectrometer, Thermo Finnigan MSQPlus or equivalent ELS detector: Sedere SEDEX 90 or equivalent LC-MS under acidic conditions Method A: Column: Waters Atlantis T3 (3.0 μm, 2.1 x 50 mm). Conditions: MeCN + 0.1% formic acid [eluent A]; water + 0.1% formic acid [eluent B]. Gradient: 95% B to 2% B in 5 min (flow rate: 0.8 mL / min). Detection: UV / Vis + MS.

[0136] Method B: 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.

[0137] Method C: Column: Waters XSelect CSH C18 (3.5 μm, 2.1 x 30 mm). Conditions: MeCN + 0.1% formic acid [eluent A]; water + 0.1% formic acid [eluent B]. Gradient: 95% B to 2% B in 1.6 min (flow rate: 1 mL / min). Detection: UV / Vis + MS.

[0138] Method D: Column: Waters BEH C18 (2.1 x 50 mm, 2.5 μm). 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.

[0139] Method E: Waters Acquity Binary, Solvent Manager; MS: Waters SQ Detector or Xevo TQD or SYNAPT G2 MS; DAD: Acquity UPLC PDA Detector; ELSD: Acquity UPLC ELSD. Column: Waters ACQUITY thermostated at 60°C in an Acquity UPLC Column Manager. UPLC CSH C18 1.7 μm 2.1 x 50 mm. Eluent: A: H2O + 0.05% formic acid; B: MeCN + 0.045% formic acid. Method: Gradient: 2% B to 98% B in 2.0 min. Flow rate: 1.0 mL / min. Detection: UV 214 nm and ELSD and MS. Ris written in min.

[0140] LC-MS under basic conditions Method F: Column: Waters BEH C18 (2.5 μm, 2.1 x 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.

[0141] Method G: 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.

[0142] Preparative HPLC equipment: Gilson LH215, Gilson 333 / 334 HPLC pump with Dionex SRD-3200 degasser, Dionex ISO-3100A Make-up Pump, Dionex DAD-3000 DAD Detector, Single Quadrupole Mass Spectrometer MS Detector, Thermo Finnigan MSQ Plus, MRA100-000 Flow Splitter, Polymer Laboratories PL-ELS1000 ELS Detector Preparative HPLC under basic conditions Column: Waters XBridge (10 μm, 75 × 30 mm). Conditions: MeCN [eluent A]; water + 0.5% NH4OH (25% aqueous solution) [eluent B]; gradient: see Table 1 (flow rate: 75 mL / min). The percentage of eluent A at the start (x) is determined depending on the polarity of the compound to be purified. Detection: UV / Vis + MS.

[0143] [Table 1]

[0144] Preparative HPLC under acidic conditions Column: Waters Atlantis T3 (10 μm, 75 × 30 mm). Conditions: MeCN [eluent A]; water + 0.5% HCOH [eluent B]; gradient: see Table 2 (flow rate: 75 mL / min). The percentage of eluent A at the start (x) is determined depending on the polarity of the compound to be purified. Detection: UV / Vis + MS.

[0145] [Table 2]

[0146] Preparative HPLC for chiral separations In most cases, the desired diastereomer can be isolated or purified by standard preparative-scale HPLC according to standard methods well known to those skilled in the art. In some cases, the use of chiral chromatography columns is recommended to separate complex mixtures of diastereomers. Best results are obtained when using chiral stationary phase columns, such as Chiralpak IA, IB, or IC columns based on immobilized amylose or cellulose chiral phases, with an isocratic elution based on mixtures of MeCN with EtOH or MeOH in ratios varying from 9:1 to 1:9. To compensate for the presence of ionizable functional groups in the compounds to be purified, modifiers such as 0.1% diethylamine for basic derivatives or 0.1% formic acid for acidic derivatives can be added to the solvent mixture. In some cases, supercritical fluid chromatography was used using the same chiral stationary phase columns described above with an isocratic elution consisting of 50% to 90% supercritical carbon dioxide with EtOH, MeOH, or a 1:1 EtOH:MeCN mixture. Detection: UV / Vis.

[0147] Abbreviations (used above and below): AcOH acetic acid aq. aqueous solution ATM atmosphere BnBr benzyl bromide Boc tert-butoxycarbonyl Boc2O Di-tert-butyl dicarbonate nBuLi n-butyllithium CHCl3Chloroform d day DCM dichloromethane DIAD Diisopropyl azodicarboxylate DIPEA Diisopropyl-ethylamine, Huenig's base DMF Dimethylformamide DMSO dimethyl sulfoxide DPPA Diphenylphosphoryl azide dppf 1,1'-bis(diphenylphosphino)ferrocene Et Ethyl Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol Evaporated Evaporated under vacuum Example: Example FC Silica gel flash chromatography Fmoc 9-Fluorenylmethoxycarbonyl h time HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate hept Heptane hex hexane HPLC High Performance Liquid Chromatography HV high vacuum conditions LC-MS Liquid Chromatography-Mass Spectrometry Lit. Literature M mol / l Me methyl MeCN acetonitrile MeI iodomethane Meldrum's Acid 2,2-Dimethyl-1,3-dioxane-4,6-dione MeOH Methanol mL milliliter min mix. mixture MOM methoxymethyl MW Microwave NaBH(OAc)3 Sodium triacetoxyborohydride NCS N-chlorosuccinimide NMP N-methyl-2-pyrrolidone OAc acetate org.organic Pd( t Bu3P)2 Bis(tri-tert-butylphosphine)palladium(0) Pd(OAc)2 Palladium(II) Acetate Pd / C Palladium on activated carbon Pd(OH)2 / C Palladium hydroxide on activated carbon (Pearlman catalyst) Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0)Ph Phenyl PhMe Toluene PPh3 Triphenylphosphine prep. for preparative preparation PyClop Chlorotripyrrolidinophosphonium Hexafluorophosphate rac racemic RM reaction mixture RT room temperature s seconds sat. saturation Selectfluor 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) SM starting material soln. solution tBu tert-butyl = tertiary butyl TEA Triethylamine Tf Trifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran T3P n-propylphosphonic anhydride t R retention time μM micromolar XPhos 2-Dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl

[0148] Preparation of precursors and intermediates Amine: Commercially available amines are listed in Table AM.

[0149] [Table 3]

[0150] Non-commercially available amines are synthesized as follows.

[0151] 2-(3-cyclopropylisoxazol-5-yl)ethan-1-amine hydrochloride (AM5) Step 1: A solution of DIAD (61.7 mL, 318 mmol) in THF (350 mL) is added dropwise to a solution of but-3-yn-1-ol (22.9 mL, 318 mmol), isoindoline-1,3-dione (44.5 g, 302 mmol), and PPh3 (83 g, 318 mmol) in THF (1500 mL) at 0 °C, and the RM is stirred for 1 h. The RM is concentrated in vacuo, and the residue is dissolved in hot PhMe (370 mL), followed by slow addition of MeOH (210 mL). The RM is cooled to RT, and MeOH is added until a white solid precipitates. After partial concentration of the RM, the solid is collected by filtration, washing with cold PhMe, and then air-dried to give 2-(but-3-yn-1-yl)isoindoline-1,3-dione. LC-MS C:t R =1.81 min; non-ionized.

[0152] Step 2: Na2CO3 (22.7 g, 214 mmol) is carefully added to a solution of hydroxylamine.HCl (37.2 g, 535 mmol) in HO (125 mL) at RT, followed by the slow addition of a solution of cyclopropanecarbaldehyde (26.7 mL, 357 mmol) in EtOH (100 mL). The RM is stirred for 1 h, then partitioned and extracted between HO and EtOAc. The layers are separated, and the aqueous phase is re-extracted with EtOAc (2x). The combined organic layers are washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo to give the crude product, which is recrystallized from n-hept to give E / Z-cyclopropanecarbaldehyde oxime as a white solid. LC-MS C:t R = 2.13 and 2.30 min; non-ionized.

[0153] Step 3: NCS (34.3 g, 257 mmol) is added portionwise to a solution of cyclopropanecarbaldehyde oxime (19.3 g, 226 mmol) and pyridine (0.83 mL, 10.3 mmol) in DMF (100 mL) at 0 °C, and the RM is stirred for 3 h. A solution of 2-(but-3-yn-1-yl)isoindoline-1,3-dione (21.0 g, 103 mmol) in DMF (100 mL) is added, followed by TEA (28.7 mL, 206 mmol), and the RM is stirred for 3 h. The RM is partitioned between HO and DCM and extracted. The layers are separated, and the aqueous phase is re-extracted with DCM (2x). The combined organic layers are washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the crude product, which is triturated with MeOH to give 2-(2-(3-cyclopropylisoxazol-5-yl)ethyl)isoindoline-1,3-dione as a white solid. LC-MS G:t R = 1.91 min; [M+H] + =283.1.

[0154] Step 4: Hydrazine.H2O (9.44 mL, 194 mmol) is added to a suspension of 2-(2-(3-cyclopropylisoxazol-5-yl)ethyl)isoindoline-1,3-dione (28.0 g, 97 mmol) in EtOH (100 mL) at RT and the RM is heated to 80 °C for 5 h. The RM is cooled to RT and filtered, washing with EtOH. The filtrate is concentrated under vacuum. The mixture is concentrated under reduced pressure, the residue is suspended in Et2O and refiltered and washed with Et2O. After partial concentration of the filtrate, 100 mL of 1 M HCl in Et2O is added and the precipitate is filtered and dried under vacuum to give the title compound as a white solid. LC-MS G:t R = 1.42 min; [M+H] + =153.1.

[0155] 2-(5-cyclopropyl-2H-tetrazol-2-yl)ethan-1-amine hydrochloride (AM6) Step 1: tert-Butyl N-(2-bromoethyl)carbamate (2.22 g, 9.7 mmol) is added to a suspension of 5-cyclopropyl-2H-1,2,3,4-tetrazole (1.00 g, 8.81 mmol) and K2CO3 (1.46 g, 10.6 mmol) in MeCN (20 mL) at RT, and the RM is heated to 50 °C for 4 h. The RM is cooled to RT, and then MeCN is evaporated, followed by addition of water and EtOAc. The layers are separated, and the aqueous phase is re-extracted with EtOAc (2x). The combined organic layers are dried (MgSO4), filtered, and evaporated. Purification by FC (eluting with 20% to 80% EtOAc in hept) gives tert-butyl (2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)carbamate (1.21 g, 55%) as a colorless oil. LC-MS F:t R =0.80min;[M+H] + =254.35.

[0156] Step 2: 4M HCl in dioxane (12 mL, 48.1 mmol) is added to a solution of tert-butyl (2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)carbamate (1.21 g, 4.81 mmol) in dioxane (26 mL) at RT, and the RM is stirred at RT for 46 h. The RM is concentrated and co-evaporated with EtO under vacuum to give the title compound (0.92 g, 100%) as a white solid. LC-MS F:t R =0.44 min; [M+H] + =154.25.

[0157] 2-(3-Methoxy-1,2,4-oxadiazol-5-yl)ethan-1-amine hydrochloride (AM7) 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 at RT for 1.5 h. Water and EtOAc are added to the RM, then the two layers are separated and the inorganic layer is extracted with EtOAc (2x). The combined organic layers 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 F:t R =0.64 min; [M+H] + =246.36.

[0158] 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 HO, saturated aqueous NaHCO, and brine, and then 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 F:t R =0.75min; [M+H] + =244.33.

[0159] Step 3: 4M HCl in dioxane (0.62 mL, 2.47 mmol) is added to a solution of tert-butyl (2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)carbamate (150 mg, 0.62 mmol) in DCM (2 mL) at RT, and the RM is stirred at RT for 4 days and then at 50° C. for 6 h. The mixture is evaporated to give the title compound (79 mg, 71%) as a white solid. LC-MS F:t R =0.35min;[M+H] + =144.21.

[0160] 2-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)ethan-1-amine hydrochloride (AM8) Step 1: Pd(OAc)2 (17.1 mg, 0.076 mmol) is added to a solution of tert-butyl N-[2-(4-bromo-2H-1,2,3-triazol-2-yl)ethyl]carbamate (291 mg, 1 mmol), cyclopropylboronic acid (112 mg, 1.3 mmol), potassium phosphate tribasic acid (758 mg, 3.5 mmol), and tricyclohexylphosphine (45.1 mg, 0.156 mmol) in toluene (22 mL) and HO (0.22 mL) at RT. This mixture is heated to 100 °C for 18 h. The RM is cooled to RT, then the mixture is filtered and the filtrate is concentrated. FC (eluting with 5% to 40% EtOAc in hept / EtOAc 7:3) is added to the RM. f =0.27) to give tert-butyl (2-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)ethyl)carbamate (194 mg, 77%) as a yellow oil. LC-MS B:t R =0.82 min; [M+H] + =253.34.

[0161] Step 2: 4M HCl in dioxane (4.9 mL, 19.6 mmol) is added to a solution of tert-butyl (2-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)ethyl)carbamate (550 mg, 1.96 mmol) in DCM (3.4 mL) at RT. The RM is stirred at RT for 30 min, and then the RM is concentrated to give the title compound (432 mg, 98%) as a white solid, which is used directly in the next step. LC-MS B:t R =0.37 min; [M+H] + =153.11.

[0162] 2-(3-Methoxyisoxazol-5-yl)ethan-1-amine hydrochloride (AM9) Step 1: DPPA (1.32 mL, 6.1 mmol) is added dropwise to a solution of 3-(3-methoxyisoxazol-5-yl)propanoic acid (1.0 g, 5.55 mmol) and TEA (0.93 mL, 6.66 mmol) in PhMe (25 mL) at RT, and the RM is heated to 100 °C for 1.5 h. 2-Methylpropan-2-ol (1.06 mL, 11.1 mmol) is added, and the RM is heated under reflux for 16 h. The RM is cooled to RT, partitioned between saturated aqueous NaHCO3 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 over Na2SO4, filtered, and evaporated in vacuo. The crude product is purified by FC (eluting with 0% to 100% EtOAc in hept) to give tert-butyl (2-(3-methoxyisoxazol-5-yl)ethyl)carbamate as a colorless oil. LC-MS C:t R = 1.80 min; [M+H] + =243.1.

[0163] Step 2: The title compound is prepared from tert-butyl (2-(3-methoxyisoxazol-5-yl)ethyl)carbamate analogously to the procedure described for AM8, step 2. LC-MS B:t R =0.28min;[M+H] + =143.09.

[0164] 2-(4-Fluoro-3-methoxyisoxazol-5-yl)ethan-1-amine hydrochloride (AM10) Step 1: In a microwave tube, phthalic anhydride (354 mg, 2.36 mmol) was added to A A suspension of M9 (402 mg, 2.25 mmol) and DIPEA (0.47 mL, 2.7 mmol) in dioxane (12 mL) was added at RT. The tube was sealed and heated to 100 °C for 48 h. Water was added to RM, the mixture was acidified with 1 M HCl, and the product was extracted with EtOAc, dried (MgSO), filtered, and concentrated to give 2-(2-(3-methoxyisoxazol-5-yl)ethyl)isoindoline-1,3-dione (718 mg) as a white solid, which was used directly in the next step. LC-MS B:t R =0.85min;[M+H] + =273.09.

[0165] Step 2: Selectfluor (1.07 g, 2.87 mmol) is added to a solution of 2-(2-(3-methoxyisoxazol-5-yl)ethyl)isoindoline-1,3-dione (710 mg, 2.61 mmol) in tetramethylene sulfone (21.7 mL, 226 mmol) at 40 °C, and the RM is heated to 120 °C for 18 h. The resulting dark brown solution is cooled to near 50 °C, and the RM is then poured into pre-stirred HO (30 mL) followed by EtOAc (10 mL). The two layers are separated, and the inorganic layer is extracted with EtOAc (5 mL). The combined organic layers are washed with brine, dried (NaSO), filtered, and concentrated. Purification by prep HPLC (acidic) affords 2-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)isoindoline-1,3-dione (89 mg) as a colorless oil. LC-MS B:t R =0.90min;[M+H] + =291.02.

[0166] Step 3: Hydrazine monohydrate (0.222 mL, 2.93 mmol) is added to a solution of 2-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)isoindoline-1,3-dione (85 mg, 0.293 mmol) in EtOH (3 mL) at RT and the RM is heated to 80° C. for 1 h. The RM is cooled to RT and a white precipitate forms. Ether is added and the solid is triturated, then filtered. The filtrate is concentrated to give the title compound (40 mg) as a colorless oil, which is used directly in the next step. LC-MS B:t R =0.33 min; [M+H] + =161.08.

[0167] Fabrication of Component A tert-Butyl (S)-3-amino-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoate (A1) Step 1: HATU (11.10 g, 29.2 mmol) is added to a solution of Fmoc-L-aspartic acid beta-tert-butyl ester (12.26 g, 29.20 mmol) and DIPEA (7.5 mL, 43.8 mmol) in DMF (100 mL) at RT. After stirring for 5 min at RT, a solution of 2-(3-methylisoxazol-5-yl)ethan-1-amine hydrochloride (AM4, 5.00 g, 29.2 mmol) and DIPEA (7.5 mL, 43.8 mmol) in DMF (100 mL) is added and stirring is continued for 30 min. The RM is partitioned between HO and EtOAc and the layers are separated. The aqueous layer is re-extracted with EtOAc (2x) and the combined organic layers are washed with brine, dried (MgSO4), filtered and evaporated to give tert-butyl (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoate as a yellow oil which is used directly in the next step. LC-MS F:t R = 1.10 min; [M+H] + =520.26.

[0168] Step 2: Piperidine (15.0 mL, 150.0 mmol) is added to a solution of tert-butyl (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoate (17.9 g, max. 29.2 mmol) in DCM (200 mL) at RT and the RM is stirred for 30 min. The RM is concentrated and the residue is diluted with (DCM:MeOH:N Purify directly by FC (eluting with H3 100:2:0.5) to give the title compound (4.02 g) as a yellowish solid. LC-MS F:t R =0.64 min; [M+H] + =298.26.

[0169] Table A below lists components A that were prepared similarly to the two-step sequence described above for A1.

[0170] [Table 4]

[0171] Allyl (S)-3-amino-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoate hydrochloride (A11) Step 1: HATU (6.80 g, 17.9 mmol) is added to a solution of Boc-L-aspartic acid-beta-allyl ester (4.80 g, 17 mmol), 2-(3-methyl-1,2-oxazol-5-yl)ethan-1-amine hydrochloride (AM4, 3.00 g, 17.5 mmol) and DIPEA (11.7 mL, 43.8 mmol) in a DMF / DCM (1 / 1) mixture (20 mL) at RT and the RM is stirred for 18 h. The mixture is concentrated and the crude product is purified by FC (100% DCM to DCM / MeOH 9 / 1) and then by prep. HPLC (acidic) to give allyl (S)-3-((tert-butoxycarbonyl)amino)-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoate (3.76 g). LC-MS B:t R=0.83 min; [M+H] + =382.41.

[0172] Step 2: 4M HCl in dioxane (4.87 mL, 39.5 mmol) was added to allyl To a solution of (S)-3-((tert-butoxycarbonyl)amino)-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoate (3.76 g) in DCM (15 mL) is added and the RM is stirred at RT for 2 h. The volatiles are removed in vacuo and the residue is triturated with EtO to give the title compound as a white solid. LC-MS F:t R =0.57 min; [M+H] + =282.21.

[0173] Manufacture of component B Benzyl (R)-3-(2-amino-3-phenylpropoxy)quinoline-4-carboxylate dihydrochloride (B1) Step 1: KHCO3 (5.88 g, 58.1 mmol) and BnBr (7.69 mL, 63.4 mmol) are added to a solution of 3-hydroxyquinoline-4-carboxylic acid (10.0 g, 52.9 mmol) in DMF (100 mL) and the RM is stirred for 16 h. The RM is filtered and the filtrate is concentrated in vacuo. The residue is partitioned between HO and EtOAc. The layers are separated and the aqueous layer is re-extracted with EtOAc (2x). The combined organic layers are washed with brine, dried (MgSO4), filtered and evaporated. The crude product is purified by FC (eluting with 20% to 80% EtOAc in hept) to give benzyl 3-hydroxyquinoline-4-carboxylate (6.97 g) as a white solid. LC-MS B:t R =0.95min;[M+H] + =280.19.

[0174] Step 2: DIAD (1.9 mL, 9.47 mmol) was added to benzyl 3-hydroxyquinoline-4-carboxylate (1.47 g, 5.26 mmol), tert-butyl A mixture of (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate (2.02 g, 7.89 mmol) and PPh3 (2.51 g, 9.47 mmol) in THF (22 mL) was added at 0 °C, and the RM was stirred at RT for 16 h. The mixture was concentrated, and the residue was directly purified by FC (eluting with 20% to 50% EtOAc in hept) to give benzyl 4-bromo-2-methylpropan-2-yl. (R)-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)quinoline-4-carboxylate (2.55 g) is obtained as a white solid. LC-MS B:t R = 1.17 min; [M+H] + =513.06.

[0175] Step 3: 4M HCl in dioxane (12.5 mL, 49.8 mmol) is added to a solution of benzyl (R)-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)quinoline-4-carboxylate (2.55 g, 4.98 mmol) in dioxane (11.5 mL) and the RM is stirred at 50° C. for 1 h. The volatiles are removed in vacuo and the residue is triturated with EtO (3×) to give the title compound as a yellowish solid. LC-MS B:t R =0.83 min; [M+H] + =413.34.

[0176] Methyl (R)-6-(2-amino-3-phenylpropoxy)-2-methylbenzo[d]oxazole-7-carboxylate hydrochloride (B2) Step 1: Nitric acid (0.36 mL, 6.0 mmol) is carefully added to a solution of methyl 2,6-dihydroxybenzoate (1.0 g, 6.0 mmol) in acetic acid (10 mL) at 0 °C, and the RM is warmed to RT and stirred for 1 h. The RM is poured into cold water, and the precipitate is collected by filtration, washed with more cold water, and then dried under vacuum to give methyl 2,6-dihydroxy-3-nitrobenzoate as a pink solid. LC-MS B:t R =0.75min; non-ionized. 1H NMR (DMSO) δ: 11.73 (s, 1H), 10.94 (s, 1H), 8.05 (d, J=9.4Hz, 1H), 6.60 (d, J=9.4Hz, 1H), 3.81 (s, 3H).

[0177] Step 2: 4M HCl in dioxane (1.45 mL, 5.8 mmol) was added to methyl To a suspension of 2,6-dihydroxy-3-nitrobenzoate (500 mg, 2.3 mmol) in triethyl orthoacetate (13.5 mL, 72 mmol) was added, and the RM was evacuated / purged with N (3x), followed by addition of 10% Pd / C (173 mg, 7 mol%). The RM was evacuated / purged with H (3x) and stirred under an H atmosphere for 16 h. The RM was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give methyl 6-hydroxy-2-methylbenzo[d]oxazole-7-carboxylate as a yellow solid. LC-MS B:t R =0.78 min; [M+H] + =208.32. 1 H NMR (DMSO) δ:10.69(s, 1H), 7.76(d, J=8.7Hz, 1H), 6.96(d, J=8.7Hz, 1H), 3.97(s, 3H), 2.60(s, 3H).

[0178] Step 3-4: The title compound is prepared from methyl 6-hydroxy-2-methylbenzo[d]oxazole-7-carboxylate according to the reaction sequence described for B1, Step 2 and Step 3. LC-MS B:t R =0.69 min; [M+H] + =341.35. Note: The title compound is unstable and should not be stored for long periods of time.

[0179] Methyl (R)-6-(2-amino-3-phenylpropoxy)imidazo[1,2-a]pyridine-5-carboxylate dihydrochloride (B-3) Step 1: Br2 (0.81 mL, 15.7 mmol) is added dropwise to a solution of methyl-3-hydroxypicolinate (2.41 g, 15.7 mmol) in water (110 mL) at 0 °C, and the RM is allowed to warm to RT and stirred overnight. The RM is quenched with 40% aqueous sodium bisulfite and extracted with DCM (2x). The combined organic extracts are washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo to give methyl 6-bromo-3-hydroxypicolinate as a white solid. LC-MS A:t R = 3.19 min; [M+H] + =231.9.

[0180] Step 2: Methyl (R)-6-bromo-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinate is prepared from methyl 6-bromo-3-hydroxypicolinate and tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in analogy to the procedure described for B-1.1 Step 2. LC-MS C:t R = 2.16 min; [M + H - t Bu] + =409.0.

[0181] Step 3: Pd2(dba)3 (483 mg, 0.53 mmol) and XPhos (201 mg, 0.42 mmol) are added to a mixture of methyl (R)-6-bromo-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinate (5.0 g, 10.5 mmol), benzyl carbamate (1.67 g, 11.1 mmol) and Cs2CO3 (5.15 g, 15.8 mmol) in dioxane (130 mL) at RT, and the RM is heated to 95 °C and stirred for 48 h. The RM is cooled to RT, filtered and the filtrate concentrated in vacuo and then purified by FC (eluting with 0% to 40% EtOAc in hept) to give methyl (R)-6-(((benzyloxy)carbonyl)amino)-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinate as an orange solid. LC-MS C:t R= 2.24 min; [M+H] + =536.2.

[0182] Step 4: A solution of methyl (R)-6-(((benzyloxy)carbonyl)amino)-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinate (1.43 g, 2.19 mmol) in EtOH (20 mL) is purged with N2 / vacuum (3x) before adding 10% Pd / C (70 mg, 0.07 mmol). After three additional inactivations, a H2 balloon is attached and the RM is stirred at 55 °C for 1 h. The mixture is filtered through a plug of Celite, rinsing with EtOH. The filtrate is concentrated to give methyl (R)-6-amino-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinate is obtained as a yellow oil. LC-MS G:t R = 2.00 min; [M+H] + =402.2.

[0183] Step 5: A 50% aqueous solution of 2-chloroacetaldehyde (0.475 mL, 3.74 mmol) is added to a mixture of methyl (R)-6-amino-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinate (0.50 g, 1.25 mmol) and NaHCO3 (209 mg, 2.49 mmol) in EtOH (15 mL), and the RM is heated to 70 °C and stirred for 5 h. The RM is concentrated in vacuo, and the residue is partitioned between water and EtOAc and extracted. The layers are separated, and the aqueous phase is re-extracted with EtOAc (2x). The combined organic extracts are washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product is purified by FC (eluting with 50% to 100% EtOAc in hept) to give methyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)imidazo[1,2-a]pyridine-5-carboxylate as a white solid. LC-MS F:t R = 1.01 min; [M+H] + =426.52.

[0184] Step 6: The title compound is prepared analogously to the procedure described for B1, step 3. LC-MS G:t R = 1.83 min; [M+H] + =326.2.

[0185] Benzyl (R)-6-(2-amino-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylate dihydrochloride (B4) 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 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 G:t R = 1.38 min; [M+H] + =239.9.

[0186] 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 G:t R = 2.03 min; non-ionized.

[0187] Step 3: nBuLi (1.6 M in hex, 0.98 mL, 1.57 mmol) is added dropwise to a solution of 5-bromo-3-fluoro-6-(methoxymethoxy)quinoline (300 mg, 1.05 mmol) in THF (18 mL) at −78° C., 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 heated at 60° C. for 10 min. The RM is cooled to RT and partitioned between saturated aqueous NaHCO and EtOAc. The layers are separated, and the aqueous layer is re-extracted with EtOAc (2×). Combine the organic extracts 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 G:t R = 2.08 min; [M+H] + =342.10.

[0188] 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 at RT 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 slightly brownish oil. LC-MS G:t R =2.06min;[MH] - =298.1.

[0189] 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 G:t R = 2.39 min; [M-Boc+H] + =531.2.

[0190] Step 6: 4M HCl in dioxane (0.44 mL, 1.77 mmol) is added to a solution of benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylate (94 mg, 0.18 mmol) in dioxane (3 mL) 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 as a white solid. LC-MS G:t R = 2.10 min; [M+H] + =431.2.

[0191] Benzyl (R)-6-(2-amino-3-phenylpropoxy)-8-methylquinoline-5-carboxylate (B5) Step 1: Meldrum's acid (6.04 g, 41.1 mmol) and triethyl orthoformate (6.06 mL, 35.7 mmol) are added to a solution of 4-methoxy-2-methylaniline (5.0 g, 35.7 mmol) in EtOH (50 mL) at RT and the RM is heated to 80° C. for 2 h. The RM is cooled to RT and the precipitate is collected by filtration washing with EtOH and dried under HV to give 5-(((4-methoxy-2-methylphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione as a white solid. LC-MS B:t R =0.90min;[M+H] + =292.13.

[0192] Step 2: 5-(((4-Methoxy-2-methylphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.19 g, 28.1 mmol) is dissolved in Dowtherm A (50 mL) and heated to 250° C. for 5 min. The RM is cooled to RT, diluted with EtO, and the precipitate is collected by filtration, washed with EtO, and then dried under HV to give 6-methoxy-8-methylquinolin-4-ol as a brown solid. LC-MS B:t R =0.58min;[M+H] + =190.21.

[0193] Step 3: Phosphorus tribromide (2.16 mL, 22.7 mmol) was added to 6-methoxy-8-methyl- A solution of thylquinolin-4-ol (3.91 g, 20.7 mmol) in DMF (75 mL) is added at RT and the RM is heated to 45 °C for 1 h. The RM is cooled to RT, diluted with water and the pH is adjusted to 8 by addition of saturated aqueous NaHCO3. The precipitate is collected by filtration, dissolved in EtOAc, washed with brine, dried over Na2SO4, filtered and evaporated under vacuum. The crude product is purified by FC (eluting with 10% EtOAc in hept) to give 4-bromo-6-methoxy-8-methylquinoline as a white solid. LC-MS B:t R =0.82 min; [M+H] + =254.03.

[0194] Step 4: nBuLi (1.6 M in hex, 35.7 mL, 57.1 mmol) is added dropwise to a solution of 4-bromo-6-methoxy-8-methylquinoline (7.2 g, 28.5 mmol) in THF at -78 °C and the RM is stirred for 30 min. The reaction is quenched with saturated aqueous NH4Cl and extracted with EtOAc (3x). The combined organic extracts are washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product is purified by FC (eluting with 20% EtOAc in hept) to give 6-methoxy-8-methylquinoline as a yellow oil. LC-MS B:t R =0.49 min; [M+H] + =174.26.

[0195] Step 5: Br2 (1.45 mL, 28.2 mmol) is added to a solution of 6-methoxy-8-methylquinoline (2.44 g, 14.1 mmol) and NaOAc (1.39 g, 16.9 mmol) in AcOH (18.3 mL) at RT, and the RM is stirred for 10 min. The RM is quenched with saturated aqueous NaHSO3 and extracted with EtOAc (2x). The combined organic extracts are dried (MgSO4), filtered, and concentrated in vacuo. The residue is taken up in PhMe and concentrated in vacuo (2x) to give 5-bromo-6-methoxy-8-methylquinoline as a green solid. LC-MS B:t R =0.74 min; [M+H] + =252.09.

[0196] Step 6: BBr3 (1 M in DCM, 42.5 mL, 42.5 mmol) is added dropwise to a solution of 5-bromo-6-methoxy-8-methylquinoline (3.57 g, 14.2 mmol) in DCM (70 mL) at 0 °C. The cooling bath is removed and the RM is stirred at RT for 2 h. The RM is carefully quenched into cold MeOH and concentrated in vacuo. The residue is co-evaporated with PhMe, EtOAc, and DCM to give 5-bromo-8-methylquinolin-6-ol as a yellow solid. LC-MS B:t R =0.55min;[M+H] + =238.01.

[0197] Step 7: tert-butyl (R)-(1-((5-bromo-8-methylquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamate is prepared from 5-bromo-8-methylquinolin-6-ol and tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in analogy to the procedure described for B1 step 2. LC-MS B:t R = 1.10 min; [M+H] + =472.94.

[0198] Step 8: nBuLi (1.6 M in hex, 0.54 mL, 0.86 mmol) is added dropwise to a solution of tert-butyl (R)-(1-((5-bromo-8-methylquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamate (185 mg, 0.39 mmol) in THF (2 mL) at −78° C., and the RM is stirred for 30 min before benzyl chloroformate (0.058 mL, 0.41 mmol) is added dropwise. The RM is warmed to RT, quenched by the addition of saturated aqueous NaHCO3 solution, and extracted with EtOAc. The layers are separated, the aqueous phase is re-extracted with EtOAc (2×), and the combined organic layers are washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by prep. HPLC (acidic) to give benzyl (R)-6-(2-((tert-butoxycarbonyl) (amino)-3-phenylpropoxy)-8-methylquinoline-5-carboxylate is obtained as a white solid. LC-MS B:t R = 1.11 min; [M+H] + =527.33.

[0199] Step 9: TFA (4.0 mL, 52.2 mmol) is added to a solution of benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-8-methylquinoline-5-carboxylate (550 mg, 1.04 mmol) in DCM (5 mL) at RT and the RM is stirred for 1 h. The RM is concentrated in vacuo and the residue is co-evaporated with DCM (2x) before being purified by prep. HPLC (basic) to give the title compound as a yellow oil. LC-MS B:t R =0.78 min; [M+H] + =427.23.

[0200] Methyl (R)-6-(2-amino-3-phenylpropoxy)-2-methylbenzofuran-7-carboxylate hydrochloride (B6) Step 1: DMAP (120 mg, 0.99 mmol) is added to a solution of 2,6-dihydroxybenzoic acid (3.0 g, 19.7 mmol) in 1,2-dimethoxyethane (15 mL) at 0 °C, followed by dropwise addition of acetone (1.9 mL, 25.8 mmol) and thionyl chloride (1.85 mL, 25.2 mmol). The RM is stirred for 30 min, then warmed to RT and stirred for 16 h. The RM is quenched by the addition of saturated aqueous NaHCO3 and extracted with Et2O (4x). The combined organic extracts are washed with brine, dried over Na2SO4, filtered, and evaporated. The crude product is purified by FC (eluting with 0% to 50% EtOAc in hept) to give 5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one as a white solid. LC-MS C:t R = 1.93 min; [M+H] + =195.1.

[0201] Step 2: K2CO3 (2.38 g, 17.2 mmol) and 3-bromopropyne (1.67 mL of an 80% solution in PhMe, 15.5 mmol) are added to a solution of 5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (3.0 g, 15.4 mmol) in acetone (60 mL) at RT, and the RM is heated to 55 °C for 21 h. The mixture is concentrated, and the residue is partitioned between water 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 over Na2SO4, filtered, and evaporated in vacuo. The crude product is purified by FC (eluting with 5% to 35% EtOAc in hept) to give 2,2-dimethyl-5-(prop-2-yn-1-yloxy)-4H-benzo[d][1,3]dioxin-4-one as a white solid. LC-MS G:t R = 1.83 min; [M+H] + =233.1.

[0202] Step 3: NaOMe (30% solution in MeOH, 1.9 mL, 10.1 mmol) is added to a solution of 2,2-dimethyl-5-(prop-2-yn-1-yloxy)-4H-benzo[d][1,3]dioxin-4-one (1.53 g, 6.6 mmol) in DMF (15 mL) at 0 °C, and the RM is warmed to RT and stirred for 1 h. The RM is quenched with 1 M aqueous HCl and extracted with EtOAc (3x). The combined organic extracts are washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo to give methyl 2-hydroxy-6-(prop-2-yn-1-yloxy)benzoate as a beige solid. LC-MS G:t R = 1.79 min; [M+H] + =207.0.

[0203] Step 4: A mixture of methyl 2-hydroxy-6-(prop-2-yn-1-yloxy)benzoate (1.33 g, 6.5 mmol), CsF (1.5 g, 9.9 mmol) and diethylaniline (18 mL) is purged with N2 and then irradiated in a MW oven at 200 °C for 55 min. The RM is diluted with EtOAc and washed with 1 M aqueous HCl. The aqueous phase is extracted with EtOAc (2x) and the combined organic extracts are washed with 1 M HCl, brine. The crude product is purified by FC (eluting with 1% to 15% EtOAc in hept) to give methyl 6-hydroxy-2-methylbenzofuran-7-carboxylate as a white solid. LC-MS C:t R = 1.98 min; [M+H] + =207.0.

[0204] Steps 5-6: The title compound is prepared from methyl 6-hydroxy-2-methylbenzofuran-7-carboxylate analogously to the procedure described for B1 steps 2 and 3. LC-MS G:t R = 1.98 min; [M+H] + =340.1.

[0205] Benzyl (R)-6-(2-amino-3-phenylpropoxy)-3-methylisoquinoline-5-carboxylate dihydrochloride (B7) Step 1: Trifluoromethanesulfonic anhydride (26.2 mL, 158 mmol) is added dropwise to a solution of 2-hydroxy-4-methoxybenzaldehyde (16 g, 105 mmol) and pyridine (42.5 mL, 526 mmol) in DCM (70 mL) at −10° C., and the RM is stirred for 30 min. The RM is quenched with ice water, acidified with 1 M aqueous HCl, and then extracted with EtOAc (2×). The combined organic extracts are washed with brine, dried over NaSO, filtered, and evaporated in vacuo to give 2-formyl-5-methoxyphenyl trifluoromethanesulfonate as a yellow oil. 1H NMR (400MHz, CDCl3) δ 10.13(s, 1H), 7.95(d, J=8.8Hz, 1H), 7.03(dd, J=8.7, 2.3Hz, 1H), 6.88(d, J=2.3Hz, 1H), 3.93(s, 3H).

[0206] Step 2: A solution of 2-formyl-5-methoxyphenyl trifluoromethanesulfonate (19.6 g, 66.4 mmol) and TEA (93 mL, 664 mmol) in DMF (400 mL) at RT was purged with Ar for 30 min. Prop-1-yne (1 M in DMF, 133 mL, 133 mmol), CuI (1.27 g, 6.64 mmol), and Pd(PPh3)4 (5.0 g, 4.33 mmol) were added sequentially, and the RM was stirred sealed for 2 h. The RM was filtered through a pad of Celite, and the filtrate was partially concentrated in vacuo, then diluted with EtOAc, washed sequentially with 1 M KHSO4 solution and brine, and concentrated in vacuo. The crude product is purified by FC (eluting with 0% to 30% EtOAc in hept) to give 4-methoxy-2-(prop-1-yn-1-yl)benzaldehyde as a yellow solid. LC-MS G:t R = 1.80 min; [M+H] + =175.1.

[0207] Step 3: A solution of 4-methoxy-2-(prop-1-yn-1-yl)benzaldehyde (10.3 g, 58.8 mmol) in MeOH (350 mL) at RT is purged with Ar in an autoclave for 5 min. NH3 7M in MeOH (150 mL, 1050 mmol) is added and the RM is heated to 65 °C for 4 h under a pressure reaching 2 bar. The RM is concentrated in vacuo and the residue is co-evaporated with DCM (2x) to give 6-methoxy-3-methylisoquinoline as a brown solid. LC-MS G:t R = 1.81 min; [M+H] + =174.1.

[0208] Step 4: BBr3 (1 M in DCM, 55.4 mL, 55.4 mmol) is added dropwise to a solution of 6-methoxy-3-methylisoquinoline (5.0 g, 27.7 mmol) in DCM (100 mL) at -78 °C. The cooling bath is removed and the RM is stirred at RT for 30 h. The RM is carefully quenched into cold MeOH and concentrated in vacuo. The residue is co-evaporated with PhMe, EtOAc, and DCM to give 3-methylisoquinolin-6-ol as a brown solid. LC-MS G:t R = 1.10 min; [M+H] + =160.1.

[0209] Step 5: Br2 (1.3 mL, 25.3 mmol) was added dropwise to a suspension of 3-methylisoquinolin-6-ol (4.67 g, 19.4 mmol) in CHCl3 (75 mL). and the RM is stirred for 2 h. EtOAc is added and the solid is collected by filtration, washed with EtOAc and hept. The filter residue is neutralized by suspending in saturated aqueous NaHCO3, re-filtered and then washed with H2O and hept. The filter residue is suspended in MeCN and evaporated to give 5-bromo-3-methylisoquinolin-6-ol as a brown solid. LC-MS G:t R = 1.02 min; [M+H] + =238.0.

[0210] Step 6: tert-butyl (R)-(1-((5-bromo-3-methylisoquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamate is prepared from 5-bromo-3-methylisoquinolin-6-ol and tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in analogy to the procedure described for B1 step 2. LC-MS G:t R = 2.21 min; [M+H] + =471.1.

[0211] Step 7: A solution of tert-butyl (R)-(1-((5-bromo-3-methylisoquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamate (2.5 g, 5.30 mmol), benzyl alcohol (2.76 mL, 26.5 mmol), and DIPEA (2.78 mL, 15.9 mmol) in PhMe (20 mL) at RT is purged with Ar for 10 min. The RM is then purged with CO and heated to 88 °C under a CO atmosphere before addition of Pd( t A solution of (Bu3P)2 (271 mg, 0.53 mmol) in PhMe (5.5 mL) is added via syringe pump (3 mL / h). The temperature is raised to 95 °C and the RM is stirred under CO atmosphere for 24 h. The RM is cooled to RT and concentrated in vacuo, and the residue is partitioned between saturated aqueous NaHCO3 and EtOAc and extracted. The layers are separated, the aqueous phase is re-extracted with EtOAc (1x), the organic layers are combined, washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product is purified by FC (eluting with 5%-65% EtOAc in hept) to give benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-3-methylisoquinoline-5-carboxylate as a colorless oil. LC-MS G:t R = 2.19 min; [M+H] + =527.2.

[0212] Step 8: The title compound is prepared from benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-3-methylisoquinoline-5-carboxylate analogously to the procedure described for B1, step 3. LC-MS G:t R = 1.95 min; [M+H] + =427.2.

[0213] Benzyl (R)-3-(2-amino-3-phenylpropoxy)-6-fluoroquinoline-4-carboxylate dihydrochloride (B8) The title compound is prepared from 6-fluoro-3-hydroxyquinoline-4-carboxylic acid analogously to the procedure described for B1, steps 1-3. LC-MS F:tR = 1.12 min; [M+H] + =431.24.

[0214] Manufacture of component C N-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-methyl-D-alanine (C1) Step 1: MeI (1.0 mL, 16.06 mmol) is added to a solution of (tert-butoxycarbonyl)-D-alanine (2.01 g, 10.62 mmol) in THF (10 mL) at 0 °C, followed by the addition of NaH (1.08 g, 27.1 mmol). After 30 min at 0 °C, the RM is warmed to RT and stirring is continued for 3 h. The mixture is quenched with H2O and acidified (pH 2) with 0.5 M KHSO4. The layers are separated and the aqueous layer is extracted with EtOAc (3 x 20 mL). The combined organic layers are washed with brine, dried (Na2SO4), filtered, and Evaporation gives N-(tert-butoxycarbonyl)-N-methyl-D-alanine as a brown oil which is used directly in the next step.

[0215] Step 2: K2CO3 (2.84 g, 20.5 mmol) was added to a solution of N-(tert-butoxycarbonyl)-N-methyl-D-alanine (2.16 g, 10.6 mmol) in acetone (6 mL) at RT, followed by dropwise addition of BnBr (1.4 mL, 11.8 mmol). The resulting mixture was heated to 50 °C and stirred for 2.5 h. The mixture was cooled to RT, filtered, and the filtrate was concentrated to give benzyl N-(tert-butoxycarbonyl)-N-methyl-D-alaninate, which was used directly in the next step. LC-MS G:t R = 2.19 min; [M+H] + = non-ionized.

[0216] Step 3: 4M HCl in dioxane (0.56 mL, 12.0 mmol) is added to a solution of benzyl N-(tert-butoxycarbonyl)-N-methyl-D-alaninate (11.0 g, 34.2 mmol) in DCM (3 mL) at RT, and the resulting mixture is stirred for 18 h. The suspension is filtered and washed with EtO (2x) to give benzyl methyl-D-alaninate HCl as a white solid. LC-MS G:t R = 1.80 min; [M+H] + =194.2.

[0217] Step 4: Benzyl methyl-D-alaninate. A solution of HCl (0.82 g, 3.6 mmol) and DIPEA (1.0 mL, 5.75 mmol) in DMF (1 mL) was added to a pre-stirred solution of Boc-N-methyl-L-leucine (0.90 mg, 3.7 mmol), HATU (1.39 g, 3.7 mmol), and DIPEA (1.0 mL, 5.75 mmol) in DMF (6 mL) at RT, and the resulting mixture was stirred for 18 h. The mixture was concentrated, and the residue was partitioned between HO and EtOAc. The layers were separated, and the aqueous layer was re-extracted with EtOAc (2x). The combined organic extracts are washed with brine, dried (MgSO), filtered and evaporated to give the crude product which is triturated with EtO to give benzyl N-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-methyl-D-alaninate as a colorless oil. LC-MS F:t R = 2.33 min; [M+H] + =421.2.

[0218] Step 5: A solution of benzyl N-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-methyl-D-alaninate (1.32 g, 3.13 mmol) in EtOH (20 mL) is purged with N2 / vacuum (3x) before adding 10% Pd / C (333 mg, 10 mol%). The RM is evacuated / purged with H2 (3x) and stirred under an H2 atmosphere for 2 h. The mixture is concentrated and filtered through a plug of Celite, rinsing with EtOH. The filtrate is concentrated to give the title compound as a colorless oil. LC-MS C:t R= 1.98 min; [M+H] + =331.20. 1 H NMR (400MHz, DMSO) δ 5.03-4.46(m, 2H), 2.95-2.83(m, 2H), 2.75-2.54(m, 4H), 1.58-1.44(m, 2H) ), 1.41(s, 10H), 1.31-1.23(m, 3H), 1.23-1.17(m, 1H), 0.94-0.84(m, 6H).

[0219] 2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanamido)-4,4,4-trifluorobutanoic acid (C2) 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 RT, and the resulting mixture was stirred at RT 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 HO 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 rac-methyl (R)-2-(benzylamino)-4,4,4-trifluorobutanoate as a brown oil which was used directly in the next step. LC-MS F:t R =0.96 min; [M+H] + =262.37.

[0220] 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 rac-methyl (R)-2-(benzylamino)-4,4,4-trifluorobutanoate (8.07 g, 30.9 mmol) in MeOH (100 mL) at room temperature, and the resulting mixture was stirred at room temperature 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 room temperature for an additional 2 h. The mixture is evaporated to dryness, partitioned between H2O and DCM, and the layers are separated. The aqueous layer is re-extracted with DCM, and the combined organic extracts are dried (Na2SO4), filtered, and evaporated to give rac-methyl (R)-2-(benzyl(methyl)amino)-4,4,4-trifluorobutanoate as a brown oil, which is used directly in the next step. LC-MS F:t R =0.96 min; [M+H] + =262.37.

[0221] Step 3: A solution of rac-methyl (R)-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 the solid is rinsed with MeOH. 4 M HCl (5.89 mL, 23.5 mmol) is added and the mixture is evaporated to dryness to give rac-methyl (R)-4,4,4-trifluoro-2-(methylamino)butanoate hydrochloride as an off-white solid, which is used directly in the next step. LC-MS F:t R =0.6 min; [M+H] + =186.37.

[0222] 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), rac-methyl (R)-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 yellowish oil. LC-MS B:t R = 1.06 min; [M+H] + =413.29.

[0223] 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 and then extracted with DCM (3x). The organic layers are combined, dried (Na2SO4), filtered and evaporated to give the title compound as a white solid. LC-MS B:t R =0.86 min; [M+H] + =359.49. LC-MS B:t R =0.96 min; [M+H] + =399.27.

[0224] (R)-2-((S)-2-((allyloxy)carbonyl)(methyl)amino)-N,4-dimethylpentanamido)-2-cyclopentylacetic acid (C3) Step 1: 4M HCl in dioxane (11 mL, 44 mmol) is added to a solution of Boc-N-Me-L-leucine (2.78 g, 11 mmol) in DCM (20 mL) at RT. The mixture is stirred at RT for 2 h. The RM is concentrated to give (S)-4-methyl-2-methylamino-pentanoic acid (2.14 g), which is used directly in the next step.

[0225] Step 2: Allyl chloroformate (1.27 mL, 11.6 mmol) is added to (S)-4-methyl-2-methylamino-pentanoic acid (1.59 g, 11 mmol) and Na2CO3 (4.08 g, 38.5 mmol) in dioxane / HO 3 / 5 (48 mL). The mixture is stirred overnight at RT, then the RM is diluted with EtOAc and acidified to pH 2 with 2 M aqueous HCl. The layers are separated and the aqueous layer is extracted with EtOAc (2x). The combined organic layers are dried (Na2SO4), filtered, and concentrated to give N-((allyloxy)carbonyl)-N-methyl-L-leucine (2.5 g, 99%), which is used directly in the next step. LC-MS B:t R =0.80min;[M+H] + =230.43.

[0226] Step 3: NaH (60% dispersion in mineral oil, 265 mg, 6.92 mmol) is added to a solution of methyl (R)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylacetate (420 mg, 1.73 mmol) in DMF (8 mL) at 0 °C, followed by MeI (0.87 mL, 13.8 mmol) and allowing the RM to warm to RT overnight. The solvent is evaporated and the crude product is purified by FC to give methyl (R)-2-((tert-butoxycarbonyl)(methyl)amino)-2-cyclopentylacetate. LC-MS B:t R = 1.03 min; [M+H] + =272.28.

[0227] Step 4: 4M HCl in dioxane (0.32 mL, 1.29 mmol) was added to methyl (R)-2-((tert-butoxycarbonyl)(methyl)amino)-2-cyclopentyl acetate (350 mg, 1.29 mmol) is added to a solution of DCM (3 mL) at 0° C., and the mixture is stirred at RT for 2 h. N-((allyloxy)carbonyl)-N-methyl-L-leucine (from Step 2, 296 mg, 1.29 mmol), DIPEA (0.68 mL, 3.87 mmol), and PyCloP (666 mg, 1.55 mmol) are added to the RM at RT, and the mixture is then heated to 40° C. for 2 h. Water is added to the RM, and the product is extracted with DCM (2×). The combined organic layers are dried (MgSO4), filtered, and concentrated. Purification by FC gives methyl (R)-2-((S)-2-((allyloxy)carbonyl)(methyl)amino)-N,4-dimethylpentanamido)-2-cyclopentylacetate. LC-MS B:t R = 1.08 min; [M+H] + =383.24.

[0228] Step 5: LiOH.HO (37.5 mg, 0.89 mmol) is added to a solution of methyl (R)-2-((S)-2-(((allyloxy)carbonyl)(methyl)amino)-N,4-dimethylpentanamido)-2-cyclopentylacetate (171 mg, 0.45 mmol) in a 3 / 1 MeOH / HO solvent mixture (2.5 mL) at RT and the RM is heated to 100 °C for 15 h. MeOH is evaporated and the residue is acidified to pH 1 with 2 M HCl, then extracted with EtOAc (3x). The organic layers are combined, dried (MgSO), filtered and evaporated to give the title compound, which is used directly in the next step. LC-MS B:t R =0.96 min; [M+H] + =369.13.

[0229] (R)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanamido)-4,4-difluorobutanoic acid (C4) Step 1: 1M aqueous NaOH (13.5 mL, 13.5 mmol) is added to a suspension of (R)-2-amino-4,4-difluorobutanoic acid (1.0 g, 7.19 mmol) in dioxane (20 mL) at RT. BocO (1.64 g, 7.42 mmol) is added to RM and stirred at RT for 24 h. The mixture is concentrated, and the residue is acidified with 4M aqueous potassium hydrogen sulfate and extracted with DCM. The combined organic extracts are dried (MgSO), filtered, and concentrated. The crude residue is redissolved in MeCN, washed with hept, and then coevaporated with EtO to give (R)-2-((tert-butoxycarbonyl)amino)-4,4-difluorobutanoic acid as a colorless oil, which is used directly in the next step. LC-MS B:t R =0.70 min; [M+H] + =240.26.

[0230] Step 2: A 60% dispersion of NaH in mineral oil (0.46 g, 12.1 mmol) is added to a suspension of (R)-2-((tert-butoxycarbonyl)amino)-4,4-difluorobutanoic acid (1.41 g, 5.89 mmol) in DMF (23 mL) at 0 °C. The RM is stirred at 0 °C for 10 min and then at RT for an additional 10 min. The RM is recooled to 0 °C, and then MeI (0.76 mL, 12.1 mmol) is added dropwise, and the RM is allowed to warm to RT overnight. Water and EtOAc are added, then the two layers are separated, and the aqueous layer is further extracted with EtOAc (2x). The organic layers are combined, dried (NaSO), filtered, and concentrated to give methyl (R)-2-((tert-butoxycarbonyl)(methyl)amino)-4,4-difluorobutanoate as a yellow oil, which is used directly in the next step. LC-MS B:t R =0.88min;[M+H] + =268.17.

[0231] Step 3: TFA (4.51 mL, 58.9 mmol) is added to a solution of methyl (R)-2-((tert-butoxycarbonyl)(methyl)amino)-4,4-difluorobutanoate (1.57 g, 5.89 mmol) in DCM (40 mL) at RT, and the RM is stirred at RT for 2 h. The volatiles are removed in vacuo, and the residue is co-evaporated with DCM (3x) to give methyl (R)-4,4-difluoro-2-(methylamino)butanoate 2,2,2-trifluoroacetate, which is used directly in the next step. LC-MS B: t R =0.24 min; [M+H] + =168.05.

[0232] Steps 4 and 5: The title compound is prepared from methyl (R)-4,4-difluoro-2-(methylamino)butanoate 2,2,2-trifluoroacetate and Boc-N-methyl-L-leucine according to the reaction sequence described for C2, steps 4 and 5. LC-MS B:t R =0.93 min; [M+H] + =381.26.

[0233] Table C below lists building blocks C prepared from Boc-N-methyl-L-leucine and the corresponding SM in a similar four-step sequence to that described above for C4 (steps 2-5). Alternatively, in step 3, Boc deprotection can be performed in the presence of 4M HCl in dioxane instead of TFA.

[0234] [Table 5]

[0235] Synthesis of Compounds of Formula (I) (3S,7S,10R,13R)-13-benzyl-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9,20-trimethyl-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]isoquinoline-3-carboxamide (Example 1) Step 1: HATU (829 mg, 2.12 mmol) is added to a solution of B7 (1.50 g, 2.01 mmol), C2 (803 mg, 2.01 mmol), and DIPEA (1.38 mL, 8.06 mmol) in DMF (25 mL) at RT, and the RM is stirred for 2.5 h. The RM is partitioned between HO and EtOAc. The layers are separated, and the aqueous layer is re-extracted with EtOAc (2x). The combined organic layers are washed with saturated aqueous NaHCO, 1 M aqueous citric acid, HO, and brine, dried (NaSO), filtered, and evaporated. The crude product was 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-methylisoquinoline-5-carboxylate (779 mg) (LC-MS F:t R = 1.40 min; [M+H] + =808.04) and 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-methylisoquinoline-5-carboxylate (296 mg) (LC-MS F:t R = 1.37 min; [M+H] + =808.03).

[0236] 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-methylisoquinoline-5-carboxylate (779 mg, 0.965 mmol) in EtOH (10 mL) is evacuated / purged with N (3x) before adding 10% Pd / C (51.4 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 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-methylisoquinoline-5-carboxylic acid as a white solid. LC-MS F:t R =0.69 min; [M+H] + =717.90.

[0237] Step 3: HATU (27.9 mg, 0.07 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-methylisoquinoline-5-carboxylic acid (50 mg, 0.07 mmol), A7 (27.4 mg, 0.07 mmol) and DIPEA (0.037 μL, 0.21 mmol) in DMF (1.5 mL) at RT and the RM is stirred for 10 min. The RM is directly purified by prep. HPLC (basic) 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-methylisoquinoline-5-carboxamido)-4-((2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoate as a white solid. LC-MS F:t R = 1.28 min; [M+H] + =1014.33.

[0238] Step 4: TFA (0.40 mL, 5.0 mmol) is added to a solution of 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-methylisoquinoline-5-carboxamido)-4-((2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoate (32 mg, 0.03 mmol) in DCM (1.5 mL) at RT, and the RM is stirred for 1.5 h. The RM is concentrated, and the residue is redissolved in DCM and concentrated again (2x). The residue is dissolved in DMF (1.5 mL), then DIPEA (0.04 mL, 0.25 mmol) and HATU (14.4 mg, 0.04 mmol) are added and the RM is stirred for 5 min. The RM is directly purified by prep. HPLC (basic) to give the title compound as a white solid. LC-MS E:t R =0.84 min; [M+H] + =839.4.

[0239] Note: If the product of Step 1 above is a methyl or ethyl ester instead of the benzyl ester described (e.g., Example 41 below), basic hydrolysis is performed using 10 eq. of 2M aqueous NaOH in MeOH at RT or with heating up to 80°C. The subsequent reaction sequence then remains the same as that described for Example 1. In some cases, chiral chromatography is used to obtain the desired product as a pure stereoisomer. In some cases, the product of Step 1 is maintained as a mixture of stereoisomers and the synthetic sequence is performed on the mixture, resulting in the final example being a mixture of epimers. In some cases, the mixture of stereoisomers is separated by chiral chromatography.

[0240] Table MC-1 below lists compounds of general formula (I) prepared from the corresponding building blocks A, B and C in a manner similar to the synthesis described for Example 1.

[0241] [Table 6]

[0242] [Table 7]

[0243] * indicates example compounds isolated during synthesis, in most cases as minor epimers due to epimerization of chiral centers, and isolated by prep. HPLC purification of the final synthetic step. In certain cases, enantiomerically or diastereomerically pure components undergo epimerization during synthesis, and example compounds are isolated as mixtures of epimers.

[0244] (3S,7S,10R,13R)-13-Benzyl-10-cyclopentyl-7-isobutyl-6,9-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[17,16-c]quinoline-3-carboxamide (Ex 44) Step 1: T3P (50% in DMF, 0.50 mL, 0.82 mmol) is added to a solution of C3 (152 mg, 0.41 mmol), B1 (200 mg, 0.41 mmol), and DIPEA (0.22 mL, 1.24 mmol) in DCM (1 mL) at RT, and the RM is stirred at elevated temperature for 2 h. HO is added, and the mixture is extracted with DCM. The organic layer is concentrated, and the crude residue is purified by FC to give benzyl 3-(((2R,5R,8R)-2-benzyl-5-cyclopentyl-8-isobutyl-6,9-dimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)quinoline-4-carboxylate.

[0245] Step 2: LiOH.HO (19.3 mg, 0.456 mmol) is added to a solution of benzyl 3-(((2R,5R,8R)-2-benzyl-5-cyclopentyl-8-isobutyl-6,9-dimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)quinoline-4-carboxylate (174 mg, 0.23 mmol) in a 2 / 1 THF / HO solvent mixture (1.0 mL) at RT, and the RM is heated to 50 °C for 3 d. The THF is evaporated, and the residue is acidified to pH 3 with 2 M HCl, then extracted with DCM (3x). The organic layers are combined, dried (MgSO4), filtered and evaporated to give 3-(((2R,5R,8R)-2-benzyl-5-cyclopentyl-8-isobutyl-6,9-dimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)quinoline-4-carboxylic acid, which is used directly in the next step. LC-MS B:t R = 1.09 min; [M+H] + =673.09.

[0246] Step 3: HATU (95.1 mg, 0.25 mmol) is added to a solution of 3-(((2R,5R,8R)-2-benzyl-5-cyclopentyl-8-isobutyl-6,9-dimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)quinoline-4-carboxylic acid (150 mg, 0.22 mmol), A11 (70.8 mg, 0.0.22 mmol) and DIPEA (0.153 mL, 0.989 mmol) in DCM (2 mL) at RT and the RM is stirred at RT for 3 h. Purification by FC gave allyl (S)-3-(3-(((2R,5R,8S)-2-benzyl)-2-benzoate. to obtain benzyl-5-cyclopentyl-8-isobutyl-6,9-dimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)quinoline-4-carboxamido)-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoate.

[0247] Step 4: Pd(Ph3)4 (20.2 mg, 0.017 mmol) was added to a solution of allyl (S)-3-(3-(((2R,5R,8S)-2-benzyl-5-cyclopentyl-8-isobutyl-6,9-dimethyl-4,7,10-trioxo-11-oxa-3,6,9-triazatetradec-13-en-1-yl)oxy)quinoline-4-carboxamido)-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoate (160 mg, 0.171 mmol) and 1,3-dimethylbarbituric acid (53.9 mg, 0.342 mmol) in DCM (2 mL) at RT and the RM was stirred at RT for 1 h. The RM is concentrated to give (S)-3-(3-((R)-2-((R)-2-cyclopentyl-2-((S)-N,4-dimethyl-2-(methylamino)pentanamido)acetamido)-3-phenylpropoxy)quinoline-4-carboxamido)-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoic acid, which is used directly in the next step.

[0248] Step 5: HATU (66.3 mg, 0.171 mmol) is added to a solution of (S)-3-(3-((R)-2-((R)-2-cyclopentyl-2-((S)-N,4-dimethyl-2-(methylamino)pentanamido)acetamido)-3-phenylpropoxy)quinoline-4-carboxamido)-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoic acid (up to 0.171 mmol) and DIPEA (90 μL, 0.51 mmol) in DCM (2 mL) at RT and the RM is stirred at RT for 30 min. Purification by prep. HPLC (basic) gives the title compound. LC-MS E:t R = 1.27 min; [M+H] + =794.6.

[0249] Table MC-2 below lists compounds of general formula (I) that were prepared from the corresponding building blocks A, B, and C in a manner similar to the synthesis described for Example 44.

[0250] [Table 8]

[0251] The following table of examples lists example compounds of formula (I) prepared according to the above methods. The configuration at stereocenters not mentioned in the compound names is unknown, but only one epimer exists.

[0252] [Table 9]

[0253] [Table 10]

[0254] [Table 11]

[0255] [Table 12]

[0256] Table S: Structures of compounds of Examples 1 to 45

[0257] [Table 13]

[0258] [Table 14]

[0259] In Table S above, stereogenic or asymmetric centers designated "abs" in the structures represent such centers in the enantiomerically enriched absolute (R)- or (S)-configuration, respectively, as shown. Steric or asymmetric centers designated "&1" in the structures represent such centers in the respective (RS)-configuration, i.e., including the respective enantiomerically enriched (R)-configuration or the enantiomerically enriched (S)-configuration, or any mixture of epimers at such centers.

[0260] II. Biological Testing The compounds of the present invention may be further characterized for their general pharmacokinetic and pharmacological properties, for example, for their bioavailability in different species (such as rats or dogs), using conventional assays well known in the art; or for their properties with respect to drug safety and / or toxicological properties, for example, cytochrome P450 enzyme inhibition and time-dependent inhibition, pregnane X receptor (PXR) activation, glutathione binding, or phototoxic behavior, using conventional assays well known in the art.

[0261] Biological in vitro assays EC of the compound 50 and E max Value evaluation The corrector activity of compounds of formula (I) for CFTR is determined according to the following experimental method, which measures the effect of overnight incubation with compounds on F508del-CFTR cell surface expression in a recombinant U2OS cell line (DiscoveRx, #93-0987C3), which contains (i) human F508del-CFTR tagged with Prolink (PK = short β-galactosidase fragment) and (ii) The β-galactosidase enzyme (Enzyme Acceptor; EA) is co-expressed with the remaining portion of the enzyme, which is localized to the plasma membrane. Upon incubation with a compound that increases the PK-tagged F508del-CFTR in the plasma membrane, the EA fragment is complemented to form functional β-galactosidase enzyme, which is quantified by a chemiluminescent reaction.

[0262] 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 compound dilution series (5x working stock solution in complete medium) is added. The final DMSO concentration in the assay is 0.2 The cells are incubated with the compounds in an incubator at 37°C and 5% CO2 for 16 h. The next day, the cell plates are incubated in the dark at RT for 2 h. 10 μl / well of Flash detection reagent (DiscoverX, #93-0247) is then added, the plates are incubated in the dark at RT for an additional 30 min, and chemiluminescence is measured. Concentration-response curves are generated using the compound-specific maximum effect as the upper plateau, and compound-specific EC20 values ​​are determined from these CRCs. 50 Determine the E value of the corrector lumacaftor max Compound-specific E max Calculate the value (E max Lumacaftor = 100%).

[0263] 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. maxValues ​​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.

[0264] [Table 15]

[0265] [Table 16]

[0266] Example of Restoration of Cell Surface F508del-CFTR Expression by Compounds of Formula (I) in Combination with CFTR Correctors with Different Mechanisms Restoration of F508del-CFTR cell surface expression by Example Compound 3 in combination with a CFTR corrector with a different mechanism can be determined in vitro using the DiscoveRx enzyme fragment complementation assay.

[0267] Combination effect experiment: Restoration of F508del-CFTR cell surface expression in recombinant U2OS cell lines This assay uses the above-mentioned U2OS cells (DiscoveRx, #93-0987C3) expressing the human F508del-CFTR chloride channel. Cells are seeded at 3500 cells / well in 20 μl of complete medium (McCoy's 5a (#36600-021, Gibco) + 10% FBS Gibco + penicillin / streptomycin) in a 384-well low-volume plate (Corning, #3826). After incubating the cells for 5 h in an incubator, 5 μl / well of compound dilutions (5x working stock solution in complete medium) are added to achieve the indicated concentrations. The final DMSO concentration in the assay is 0.34%. Cells are incubated with compounds for 16 h at 37°C, 5% CO2. The next day, cell plates are incubated for 2 h at RT in the dark. Then, 10 μl / well of Flash detection reagent (DiscoverX, #93-0247) was added, the plate was incubated for an additional 30 min at RT in the dark, and chemiluminescence was measured. Measurements were expressed as fold-change relative to baseline values ​​(no CFTR corrector = vehicle treatment).

[0268] The results of the combined effect experiment are shown in Figure 1.

[0269] Figure 1 shows an analysis of F508del-CFTR cell surface expression following treatment with 200 nM Example Compound 3 when added to a basal treatment of CFTR correctors with different mechanisms, such as 2 μM tezacaftor or 0.2 μM gallicaftor (both type I correctors), or 5 μM corrector 4a (type II corrector), or 2 μM elexacaftor (type III corrector), or the combination of [2 μM tezacaftor + 2 μM elexacaftor] (type I corrector + type III corrector). Example Compound 3 enhances F508del-CFTR surface expression relative to all basal treatments. Error bars represent the standard error of the mean.

[0270] FIG. 6 shows an analysis of F508del-CFTR cell surface expression as a result of treatment with 200 nM of Example Compound 3 when added to a baseline treatment of CFTR correctors of the type III corrector mechanism, such as 2 μM elexacaftor or 5 μM of the compound of Example 2 of WO 2019 / 071078 (PTI-801). Example Compound 3 enhances F508del-CFTR surface expression relative to these baseline treatments. The effect of one type III corrector (elexacaftor; 2 μM) on another type III corrector (PTI-801; 5 μM) is significant. ) does not lead to an additive effect. Error bars represent the standard error of the mean.

[0271] Example of restoration of F508del-CFTR function by compounds of formula (I) in combination with CFTR correctors and CFTR potentiators with different mechanisms Restoration of F508del-CFTR function by Example Compound 3 in combination with CFTR correctors and CFTR potentiators with different mechanisms can be determined in vitro using a YFP quenching assay.

[0272] Combination Effect Experiment: Restoration of F508del-CFTR Function in Recombinant U2OS Cell Line This assay uses U2OS cells (DiscoveRx, #93-0987C3) expressing the human F508del-CFTR chloride channel and a halide-sensitive mutant of yellow fluorescent protein (YFP Topaz F46L / H148Q / I152L; US2006 / 0257934A1), which reports the influx of exogenously added iodide (a surrogate ion) through functional surface CFTR, based on the property of YFP to bind iodide and quench its fluorescence.

[0273] Cells are seeded at 20,000 cells / well in 384-well 384w black clear-bottom plates in 40 μl / well of growth medium (McCoy's 5a (#36600-021, Gibco) + 10% FBS Gibco + penicillin / streptomycin) containing various CFTR collectors at the indicated concentrations. The final DMSO concentration in the assay is 0.1%. Cells are incubated with compounds for 24 h at 37°C, 5% CO2. The following day, plates are resuspended in 55 μL / well of PBS + (0.9 mM Ca 2+ and 0.5 mM Mg 2+ Wash the cells twice with 15 μL of PBS+. Remove the PBS+ completely and replenish the cells with 15 μL of PBS+. Then, add 5 μL of a 4x concentrated stock solution of potentiator or vehicle in dilution buffer (PBS+, 0.4 μM forskolin, 0.2% bovine serum albumin (fatty acid-free), pH 7.4) and incubate for 30 min in the dark. The final DMSO concentration in the assay is 0.5%. The plate was then transferred to a FLIPR Tetra (Fluorescence Imaging Plate Reader, Molecular Devices: excitation 470–495 nm; emission: 526–585 nm) and a baseline fluorescence reading of the YFP signal was taken for 6 seconds (10 x 0.6 s intervals). 25 µL of iodide buffer (137 mM NaI; 2.7 mM KCl; 1.5 mM KH2PO4; 8.1 mM Na2HPO4, 1 mM CaCl2; 0.5 mM MgCl2, pH 7.4) was then added and fluorescence readings continued for 70 seconds (50 x 0.6 s intervals; 20 x 2 s intervals) to assess YFP quenching due to CFTR-mediated iodide influx. For analysis, fluorescence traces were aligned and normalized to the last time point before iodide addition (normalized fluorescence = 1). Normalized fluorescence values ​​obtained 14 seconds after iodide addition are used to assess the degree of YFP quenching and thus CFTR function.

[0274] The results of the combined effect experiment are shown in Figures 2 to 5.

[0275] Figure 2 shows an analysis of F508del-CFTR function (YFP quenching assay) following treatment with 400 nM Example Compound 3 when added to a basal treatment with the type I CFTR corrector, gallicaftor (1 μM) and / or the CFTR potentiator, navocaftor (50 nM). Example Compound 3 enhances F508del-CFTR function relative to all basal treatments. Error bars represent the standard error of the mean.

[0276] Figure 3 shows an analysis of F508del-CFTR function (YFP quenching assay) following treatment with 400 nM Example Compound 3 when added to a basal treatment of the type I CFTR corrector, tezacaftor (2 μM) and / or the CFTR potentiator, ivacaftor (2 nM). Example Compound 3 enhances F508del-CFTR function relative to all basal treatments. Error bars represent the standard error of the mean.

[0277] Figure 4 shows an analysis of F508del-CFTR function (YFP quenching assay) following treatment with 400 nM of Example Compound 3 when added to a basal treatment of type II CFTR corrector, corrector 4a (5 μM) and / or the CFTR potentiator, navocaftor (50 nM). Example Compound 3 enhances F508del-CFTR function relative to all basal treatments. Error bars represent the standard error of the mean.

[0278] Figure 5 shows an analysis of F508del-CFTR function (YFP quenching assay) following treatment with 400 nM Example Compound 3 when added to a basal treatment of the type III CFTR corrector, elexacaftor (2 μM) and / or the CFTR potentiator, ivacaftor (2 nM). Example Compound 3 enhances F508del-CFTR function relative to all basal treatments. Error bars represent the standard error of the mean.

[0279] reference Boyle MP et al. (2014). Lancet Respir Med 2(7):527–538.

[0280] Dalemans W (1991) Nature 354:526~528.

[0281] Davies JC (2018) N Engl J Med 379(17):1599~1611 de Boeck K(2020) Acta Paediatr 109(5):893~895 Elborn JS(2016) Lancet 388:2519~2531.

[0282] Fiedorczuk K (2022) Cell 185(1):158~168.

[0283] Flowers AM (2016) FASEB J 30(5):1789~1797.

[0284] Am J Physiol Cell Physiol 281(5):C1734~1742.

[0285] Hutt DM (2011) ACS Med Chem Lett 2(9):703~707.

[0286] Kazani S (2021) J Cyst Fibers 20(2):250~256.

[0287] Keating D (2018) N Engl J Med 379(17):1612~1620.

[0288] The Big D (2021) J Med Chem 64(11):7241~7260.

[0289] Marchesin V (2023). Okiyoneda T et al. (2013). Nat Chem Biol 9(7):444~454.

[0290] Patel SD et al. (2020). Eur Respir Rev 29(156):190068.

[0291] Rowe SM et al. (2020). Int J Chron Obstruct Pulmon Dis 15:2399~2409.

[0292] Stevers LM et al. (2022). Nat Commun 13:3586.

[0293] Van Goor F et al. (2011). Proc Natl Acad Sci USA 108(46):18843~18848.

[0294] Veit G et al. (2018). Nat Med 24(11):1732~1742.

[0295] Veit G et al. (2020). JCI Insight 5(18):e139983.

[0296] Wang X et al. (2018). J Med Chem 61(4):1436~1449.

Claims

1. A pharmaceutical composition having as an active ingredient a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more therapeutically active ingredients that act as CFTR modulators, wherein the CFTR modulators are one or more CFTR correctors and / or CFTR potentiators; or pharmaceutically acceptable salts thereof; and further comprising at least one pharmaceutically acceptable excipient: 【Chemical 1】 (In the formula, X is -CR Ｘ１ R Ｘ２ represents R Ｘ１ represents hydrogen, R Ｘ２ teeth, - C １－６ - alkyl; - C １－４ -fluoroalkyl; or - C ３－６ -cycloalkyl; represents; R １ is C １－４ represents alkyl; R ２ is C １－４ represents alkyl; R ３ is C １－６ represents alkyl; R ４ represents a 5-membered heteroaryl, which is independently unsubstituted or substituted by 1 or 2 substituents, said substituents being selected from the group consisting of C １－４ -Alkyl, C １－４ -alkoxy, C １－３ -fluoroalkyl, C １－３ -fluoroalkoxy, C ３－６ - independently selected from cycloalkyl or halogen; Ar １ represents an 8- to 10-membered bicyclic heteroarylene, which is independently unsubstituted or contains one C １－４ - substituted by alkyl or halogen; Ar ２ represents phenyl, which is unsubstituted or substituted by one or two substituents, said substituents being C １－４ -Alkyl, C １－３ -fluoroalkyl, halogen, C １－６ -alkoxy and C １－３ -fluoroalkoxy.

2. The compound of formula (I) Ｅ 2. The pharmaceutical composition of claim 1, wherein the compound is 【Chemistry 2】

3. X is -CR Ｘ１ R Ｘ２ represents R Ｘ１ is hydrogen, and R Ｘ２ The pharmaceutical composition according to claim 1 or 2, wherein is 2,2,2-trifluoroethyl.

4. R ４ represents oxadiazolyl, and the 5-membered heteroaryl independently represents one C １－４ The pharmaceutical composition according to any one of claims 1 to 3, wherein the substituted aryl group is -alkoxy.

5. Ar １ The pharmaceutical composition according to any one of claims 1 to 4, wherein represents a 10-membered bicyclic heteroarylene, and the bicyclic heteroarylene is substituted with one halogen.

6. Ar ２ The pharmaceutical composition according to any one of claims 1 to 5, wherein represents unsubstituted phenyl.

7. When the compound of formula (I) is: (3S,7S,10R,13R)-13-benzyl-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (3S,7S,10S,13R)-13-benzyl-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (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,10S,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-trifluoroethylene) (ethyl)-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-7-isobutyl-10-isopropyl-6,9-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[17,16-c]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-7,10-diisobutyl-6,9-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[17,16-c]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-7-isobutyl-6,9,10-trimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[17,16-c]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-7-isobutyl-6,9,10-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[17,16-c]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-10-(2,2-difluoroethyl)-7-isobutyl-6,9-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[17,16-c]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,10-trimethyl-1,5,8,11-tetraoxo-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-N-(2-(4-cyclopropyl-2H-1,2,3-triazol-2-yl)ethyl)-20-fluoro-7-isobutyl-6,9,10-trimethyl-1,5,8,11-tetraoxo-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-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,10-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydroimidazo[1',2':1,6]pyrido[2,3-p][1]oxa[4,7,10,14]tetraazacycloheptadecine-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-7-isobutyl-6,9,10-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydroimidazo[1',2':1,6]pyrido[2,3-p][1]oxa[4,7,10,14]tetraazacycloheptadecene-3-carboxamide Mido; (3S,7S,10R,13R)-13-benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-20-fluoro-7-isobutyl-6,9,10-trimethyl-1,5,8,11-tetraoxo-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-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-20-fluoro-7-isobutyl-6,9,10-trimethyl-1,5,8,11-tetraoxo- 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-N-(2-(5-cyclopropyl-1,2,4-oxadiazole- 3-yl)ethyl)-20-fluoro-7-isobutyl-6,9,10-trimethyl-1,5,8,11-tetraoxo-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-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-20-fluoro-7-isobutyl-6,9,10-trimethyl-1,5,8,11-tetraoxo-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-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-10-(2,2-difluoroethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-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,10S,13R)-13-benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-10-(2,2-difluoroethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-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-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethyl)-10-ethyl-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-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-10-(2,2-difluoroethyl)-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-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-7-isobutyl-6,9,10,20-tetramethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,1 2,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[16,17-f]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,10,20-tetramethyl-1,5,8,11-tetraoxo-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-7-isobutyl-6,9,10,20-tetramethyl-1,5,8,11-tetraoxo-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-10-(2,2-difluoroethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-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-10-(2,2-difluoroethyl)-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,20-trimethyl-1,5,8,11-tetraoxo-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-10-(2,2-difluoroethyl)-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9,20-trimethyl-1,5,8,11-tetraoxo-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-10-(2,2-difluoroethyl)-7-isobutyl-6,9,20-trimethyl-1,5,8,11-tetraoxo-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-10-(2,2-difluoroethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-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-10-(2,2-difluoroethyl)-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-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-N-(2-(5-cyclopropyl- 1,2,4-oxadiazol-3-yl)ethyl)-7-isobutyl-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)ethyl)-7-isobutyl-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(3-cyclopropylisoxazol-5-yl)ethyl)-7-isobutyl-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(5-cyclopropylisoxazol-3-yl)ethyl)-7-isobutyl-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-7-isobutyl-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)-7-isobutyl-6,9,20-trimethyl-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-10-(2,2-difluoroethyl)-20-fluoro-N-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-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-10-(2,2-difluoroethyl)-N-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)-7-isobutyl-6,9,20-trimethyl-1,5,8,11-tetraoxo-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]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9,17-trimethyl-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; (8R,11RS,14S,18S)-8-benzyl-14-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-2,12,15-trimethyl-10,13,16,20-tetraoxo-11-(2,2,2-trifluoroethyl)-7,8,9,10,11,12,13,14,15,16,17,18,19,20-tetradecahydrooxazolo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacycloheptadecine-18-carboxamide; (8R,11R,14S,18S)-8-benzyl-14-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-2,12,15-trimethyl-10,13,16,20-tetraoxo-11-(2,2,2-trifluoroethyl)-7,8,9,10,11,12,13,14,15,16,17,18,19,20-tetradecahydrooxazolo[4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacycloheptadecine-18-carboxamide; (8R,11RS,14S,18S)-8-benzyl-14-isobutyl-2,11,12,15-tetramethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-10,13,16,20-tetraoxo-7,8,9,10,11,12,13,14,15,16,17,18,19,20-tetradecahydrobenzofuro[7,6-p][1]oxa[4,7,10,14]tetraazacycloheptadecine-18-carboxamide; (3S,7S,10R,13R)-13-benzyl-10-cyclopentyl-7-isobutyl-6,9-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[17,16-c]quinoline-3-carboxamide; Or, (3S,7S,10R,13R)-13-benzyl-10-cyclopentyl-20-fluoro-7-isobutyl-6,9-dimethyl-N-(2-(3-methylisoxazol-5-yl)ethyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecyno[17,16-c]quinoline-3-carboxamide; or a pharmaceutically acceptable salt thereof.

8. 2. The pharmaceutical composition of claim 1, wherein the compound of formula (I) is (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; or a pharmaceutically acceptable salt thereof.

9. The one or more therapeutically active ingredients acting as CFTR modulators are selected from lumacaftor, tezacaftor, and gallicaftor; and / or a type I corrector.

9. The pharmaceutical composition according to claim 1, wherein the compound is a type II corrector selected from the group consisting of elexacaftor and banzacaftor; a type III corrector selected from the group consisting of ivacaftor, navocaftor, isenticaftor, and dutivacaftor; or a pharmaceutically acceptable salt thereof.

10. 9. The pharmaceutical composition of any one of claims 1 to 8, wherein the composition comprises a compound of formula (I) and one therapeutically active ingredient that acts as a CFTR modulator, the CFTR modulator being a CFTR potentiator; or a pharmaceutically acceptable salt thereof.

11. 9. The pharmaceutical composition of any one of claims 1 to 8, wherein the composition comprises a compound of formula (I) and two therapeutically active ingredients that act as CFTR modulators, one of the CFTR modulators being a CFTR potentiator or a pharmaceutically acceptable salt thereof, and the second CFTR modulator being a CFTR corrector or a pharmaceutically acceptable salt thereof.

12. The composition comprises a compound of formula (I), and ivacaftor and tezacaftor, or pharmaceutically acceptable salts thereof; or ivacaftor and lumacaftor, or pharmaceutically acceptable salts thereof; or - navocaftor and gallicaftor, or pharmaceutically acceptable salts thereof; The pharmaceutical composition according to any one of claims 1 to 8, comprising:

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 8 for use in the treatment of cystic fibrosis; wherein the compound is intended to be used / administered in combination with one or more therapeutically active ingredients that act as CFTR modulators; and the CFTR modulators are one or more CFTR correctors and / or CFTR potentiators; a compound of formula (I) or a pharmaceutically acceptable salt thereof.

14. A compound of formula (I) as defined in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for use in the treatment of cystic fibrosis; wherein the compound is intended to be used / administered in combination with one or more therapeutically active ingredients which act as CFTR modulators; and wherein the CFTR modulators are ivacaftor and tezacaftor, or pharmaceutically acceptable salts thereof; or ivacaftor and lumacaftor, or pharmaceutically acceptable salts thereof; or - navocaftor and gallicaftor, or pharmaceutically acceptable salts thereof; or a pharmaceutically acceptable salt thereof.

15. A method for treating cystic fibrosis, comprising administering a pharmaceutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in combination with one or more therapeutically active ingredients which act as CFTR modulators; wherein the CFTR modulator is - ivacaftor and tezacaftor, or pharmaceutically acceptable salts thereof; Or, - ivacaftor and lumacaftor, or pharmaceutically acceptable salts thereof; Or, - navocaftor and gallicaftor, or pharmaceutically acceptable salts thereof; The method is as follows:

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