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

Abstract

The present invention relates to compounds # imgabs0 # of formula (I) wherein R1, R2, R3, R4, X, Ar1 and Ar2 are as described in the specification, and their use in combination with one or more therapeutically active ingredients useful as CFTR modulators, which are one or more CFTR correctors and / or CFTR potentiators, for the treatment of diseases and disorders related to CFTR, especially for the treatment of cystic fibrosis. The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) in combination with one or more therapeutically active ingredients useful as CFTR modulators, where the CFTR modulators are one or more CFTR correctors and / or CFTR potentiators.

Description

Technical Field

[0001] The present invention relates to compounds of formula (I) and its use in combination with one or more therapeutically active ingredients used as CFTR modulators for the treatment of CFTR-related diseases and disorders, wherein the CFTR modulator is one or more CFTR correctors (especially type I correctors and / or type II correctors and / or type III correctors) and / or CFTR potentiators; for the prevention and / or treatment of CFTR-related diseases and disorders; wherein such CFTR-related diseases are especially cystic fibrosis. The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) in combination with one or more therapeutically active ingredients used as CFTR modulators, wherein the CFTR modulator is one or more CFTR correctors (especially type I correctors and / or type II correctors and / or type III correctors) and / or CFTR potentiators. Background Art

[0002] PCT / EP2021 / 069292 discloses certain compounds of formula (I) as modulators of CFTR and may be suitable for treating CFTR-related diseases and conditions, in particular cystic fibrosis, or other CFTR-related diseases and conditions selected from the following: Chronic bronchitis; sinusitis; constipation; pancreatitis; pancreatic insufficiency; male infertility due to congenital bilateral absence of the vas deferens (CBAVD); mild lung disease; allergic bronchopulmonary aspergillosis (ABPA); liver disease; coagulation-fibrinolysis defects, such as protein C deficiency; and diabetes mellitus; Asthma; COPD; smoking-induced COPD; and dry eye disease; and Idiopathic pancreatitis; hereditary emphysema; hereditary hemochromatosis; lysosomal storage diseases, especially those such as I-cell disease (pseudo-Hurler); mucopolysaccharidoses; Sandhoff / Tay-Sachs; osteogenesis imperfecta; Fabry disease; Sjogren's disease; osteoporosis; osteopenia; bone healing and growth (including bone repair, bone regeneration, decreased bone resorption, and increased bone deposition); chloride channelopathies, such as myotonia congenita (Thomson and Becker forms); Bartter's syndrome type 3 3); epilepsy; lysosomal storage diseases; primary ciliary dyskinesia (PCD) - a term for inherited disorders of ciliary structure and / or function (including PCD with situs inversus (also known as Kartagener syndrome), PCD without situs inversus, and ciliary dysgenesis); generalized epilepsy with febrile seizures plus (GEFS+); generalized epilepsy with febrile and non-febrile seizures; myotonia; paramyotonia congenita; myotonia potassium-aggravated; hyperkalemic periodic paralysis; long QT syndrome (LQTS); LQTS / Brugada syndrome; autosomal dominant LQTS with deafness; autosomal recessive LQTS; LQTS with dysmorphic features; congenital and acquired LQTS; dilated cardiomyopathy; autosomal dominant LQTS; osteopetrosis; and Bartter syndrome type 3.

[0003] Cystic fibrosis (CF; mucoviscous disease, sometimes also called pancreatic fibrocystic disease or pancreatic fibrosis) is an autosomal recessive disease caused by a dysfunctional epithelial chloride / bicarbonate channel, named Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). CFTR dysfunction leads to dysregulated chloride, bicarbonate, and water transport at the surface of secretory epithelia, resulting in accumulation of viscous mucus in organs including the lungs, pancreas, liver, and intestines and thus multi-organ dysfunction. The most debilitating effects in CF are now observed in the lungs, which lose their functionality over time due to abnormal hydration of airway surface fluid, mucus plugging, impaired mucociliary clearance, chronic inflammation, and infection, leading to death from respiratory failure (Elborn, 2016). Human CFTR is a multidomain protein of 1480 amino acids. Many different mutations that cause CFTR dysfunction have been found in CF patients, such as causing non-functional CFTR protein (class I mutations), CFTR trafficking defects (class II mutations), CFTR regulation defects (also called gating defects; class III mutations), CFTR conduction defects (class IV mutations), reduced CFTR protein due to splicing defects (class V mutations) or due to reduced CFTR stability (class VI mutations), and no CFTR protein due to mRNA instability (class VII mutations) (de Boeck, Acta Paediatr. 2020, 109 (5): 893-895). The CFTR2 database (http: / / cftr2.org; data retrieved on August 22, 2022) currently contains information on 401 pathogenic mutations. To date, the most common pathogenic mutation is the deletion of phenylalanine at position 508 (F508del; allele frequency in the CFTR2 database 0.697), which leads to misfolding of the channel during synthesis at the endoplasmic reticulum, degradation of the misfolded protein, and a significant reduction in the resulting transport to the cell surface (class II mutations). The residual F508del-CFTR transported to the cell surface is functional, but less functional than wild-type CFTR, i.e., F508del-CFTR also has a gating defect (Dalemans, 1991). Approximately 40% of all CF patients are homozygous for the F508del mutation, while another approximately 40% of patients are heterozygous for the F508del mutation and carry another pathogenic mutation from class I, II, III, IV, V, VI or VII. Such pathogenic mutations are significantly rarer, with class III G551D mutations (allele frequency 0.0210) and class I G542X mutations (allele frequency 0.0254) and class II N1303K mutations (allele frequency 0.0158) being the second most common.

[0004] CF is currently treated with a range of medications that address various organ symptoms and dysfunctions. Intestinal and pancreatic dysfunction is treated from the time of diagnosis with food supplements that provide pancreatic digestive enzymes. Pulmonary symptoms are primarily treated with hypertonic saline inhalation, mucolytics, anti-inflammatory drugs, bronchodilators, and antibiotics (Elborn, 2016).

[0005] In addition to symptomatic treatment, CFTR regulators have been developed and approved for patients with some CFTR mutations. These compounds directly improve CFTR folding and transportation to cell surface (CFTR correctors) or improve CFTR function (CFTR potentiators) at cell surface. Other types of regulators are still in the exploratory stage, such as compounds (CFTR potentiators) for increasing the mRNA level of (mutation) CFTR and compounds (CFTR stabilizers) for increasing the plasma membrane stability of mutation CFTR, such as nucleotide binding domain 1 (NBD1) stabilizer SION-638 and its subsequent molecule NBD1-A currently in stage 1 (G.Hurlbut oral report at 2022 North American Cystic Fibrosis Conference (North American Cystic Fibrosis Conference 2022)). CFTR modulators can also enhance the function of non-mutated (i.e. wild-type) CFTR, and therefore increasing wild-type CFTR function is being studied in conditions where it would have beneficial effects on non-CF conditions 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) and acute respiratory distress syndrome (ARDS) (Erfinanda L, Sci Transl Med. 2022, 14(674):eabg8577).

[0006] CFTR modulators and combinations thereof can be discovered and optimized by evaluating their ability to promote the trafficking and function of mutant CFTR in recombinant and primary cell systems cultured in vitro. Activity in such systems predicts activity in CF patients.

[0007] WO2019 / 161078 discloses macrocycles as modulators of cystic fibrosis, wherein the macrocycle is generally a 15-membered macrocycle containing a (pyridine-carbonyl)-sulfamoyl moiety connected to other aromatic groups. Other macrocycles are disclosed in WO2022 / 109573 (a macrocycle containing 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-membered) including the compound Apicidin (CAS: 183506-66-3) have been proposed as potential agents for treating CF (Hutt DM et al., ACS Med Chem Lett. 2011; 2(9): 703-707. doi: 10.1021 / ml200136e). WO2020 / 128925 discloses macrocycles capable of modulating the activity of CFTR, wherein the macrocycle comprises an optionally substituted divalent N-(pyridin-2-yl)pyridinyl-sulfonamide moiety. Other macrocyclic compounds have been described to stabilize chloride channelopathy CFTR (Stevers LM, Nature Communications 2022, 13: 3586). Non-macrocyclic CFTR correctors and / or CFTR potentiators have been disclosed in, for example, 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.In addition, specific macrocycles can be found as screening compounds, in which an unsubstituted phenylene group is a part of the macrocycle compared to the 8- to 10-membered bicyclic heteroaryl group of the compound of formula (I) of the present invention (CAS Registry Numbers: CAS-2213100-89-9, CAS-2213100-96-8, CAS-2213100-99-1, CAS-2213101-02-9, CAS-2213101-04-1, CAS-2213101-06-3, CAS-2213101-08-5, CAS-2213101-09-6, CAS-2213101-1 9-8, 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-2 215789-15-2, 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-2215947-64-9, CAS-221 5947-68-3, CAS-2215947-78-5, CAS-2215947-91-2, CAS-2215954-57-5, CAS-2216342-34-4, CAS-2216342-78-6, CAS-2216342-86-6 , CAS-2216343-03-0, CAS-2216343-09-6, CAS-2216343-14-3, CAS-2216343-18-7, CAS-2216343-24-5, CAS-2216343-32-5, CAS-2216 343-38-1, CAS-2216343-45-0, CAS-2216343-53-0, CAS-2216343-59-6, CAS-2216343-64-3, CAS-2216343-74-5, CAS-2216343-76-7).

[0008] CFTR modulators can be further subdivided into CFTR correctors and CFTR potentiators, etc. CFTR correctors improve the folding of CFTR and its transport to the cell surface, especially CFTR carrying class II (= folding and transport) mutations, and thereby increase CFTR cell surface expression. CFTR potentiators increase the opening probability of cell surface CFTR, especially CFTR carrying gating defects (including class II mutants rescued by correctors), and can therefore activate CFTR in an additive / synergistic manner with CFTR correctors. Therefore, potentiators and correctors have been combined in the clinic to treat patients with CFTR class II mutations. A variety of CFTR correctors have been described in the literature and patents. Some of these correctors (alone and / or in combination with other CFTR modulators) have been used / are being used in clinical trials in CF patients, such as VX-809 (lumacaftor), VX-661 (tezacaftor), ABBV-2222 (galicaftor), VX-445 (elexacaftor), VX-659 (bamocaftor), VX-440 (olacaftor), VX-121 (vanzacaftor), ABBV-C2 correctors - ABBV-119 and ABBV-567, and PTI-801 in addition to those listed previously. Similarly, a variety of potentiators have been described in the literature and patents. Some of these potentiators (alone and / or in combination with other CFTR modulators) have been used / are being used in clinical trials in CF patients, e.g., VX-770 (ivacaftor), VX-561 (deutivacaftor), GLPG-1837, GLPG-2451, ABBV-3067 (navocaftor), QBW-251 (icenticaftor).

[0009] It has been determined that CFTR correctors can be further subdivided based on their mechanism: correctors that act in an additive or synergistic manner must have different (i.e., complementary) mechanisms of action, most likely due to different binding sites on the CFTR protein. Conversely, correctors that act in a competitive manner may share the same CFTR binding site (Okiyoneda, 2013; Veit, 2018; Veit, 2020; Fiedorczuk 2022; Marchesin 2023). Therefore, the structurally related correctors VX-809 (lumakatol), VX-661 (tizacatol) and ABBV-2222 (galicatol) are classified as type I correctors, corrector 4a and related compounds are classified as type II correctors, and VX-445 (eresakatol) and the structurally related correctors VX-440 (orakatol), VX-659 (bamocatol) and VX-121 (wanzacatol) are described as type III correctors. ABBV-C2 correctors ABBV-119 and ABBV-567 may also be type III correctors. PTI-801 may be another type III corrector. Due to the accumulation of their effects, correctors of different mechanisms are combined in the clinic to achieve higher corrective efficacy together with synergists.

[0010] VX-770 (ivacato, 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 the first CFTR modulator ever approved (US and EU: first approved in 2012) for the treatment of CF patients aged 4 months and older who have a mutation in the CFTR gene that is responsive to KALYDEKO based on clinical and / or in vitro assay data. The current VX-770 uspi (December 2020) lists 97 suitable 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), as described below.

[0011] In two Phase III clinical trials in 213 CF patients, KALYDECO was evaluated for the efficacy of CF patients with G551D mutations in the CFTR gene. Trial 1 (NCT00909532) evaluated patients aged at least 12 years old, and Trial 2 (NCT00909727) evaluated patients aged 6 to 11 years old. In addition to receiving prescribed CF therapy (such as tobramycin, deoxyribonuclease α), patients were randomly divided into 1:1 groups to receive KALYDECO or placebo and fat-containing food for 48 weeks. The primary efficacy endpoint is the improvement of lung function, which is measured by the mean absolute change from baseline to the 24th week of treatment of the percentage of the predicted pre-dose FEV1. FEV1 stands for "forced expiratory volume in 1 second" and is the primary endpoint of recording lung function commonly used in CF clinical trials. In both studies, treatment with KALYDECO caused a significant absolute change of at least 10% of the percentage of predicted FEV1 (ppFEV1) compared to placebo. After 48 weeks of treatment with KALYDECO, favorable changes also occurred in some secondary endpoints, such as the risk of pulmonary exacerbations (Trial 1: relative risk reduction of 0.4 compared with placebo), body weight (approximately +2kg compared with placebo), and the pharmacodynamic biomarker sweat chloride (approximately -50mM compared with placebo). In other small Phase III trials, KALYDECO was tested in CF patients at least 6 years old with rarer mutations predicted to respond, using the change from baseline in absolute ppFEV1 as the primary endpoint. In addition, KALYDECO has been evaluated in CF patients between the ages of 4 months and 5 years, but efficacy was not assessed by FEV1 measurement, and KALYDECO exposure and sweat chloride reduction similar to those observed in trials in older patients were achieved. For adults and pediatric patients 6 years of age and older, the recommended dose of KALYDECO is one 150 mg tablet taken orally every 12 hours (twice daily (bid) dosing). Based on weight, the recommended dose of KALYDECO (oral granules) for patients aged 4 months to less than 6 years is: 25 mg bid for patients between 4 and 6 months (if body weight > 5 kg), 25 mg bid for patients between 6 months and less than 6 years (if body weight 5 to 7 kg), 50 mg bid for patients with body weight 7 to 14 kg, and 75 mg bid for patients with body weight 14 to 25 kg. For patients aged 6 months and older with moderate hepatic impairment (Child-Pugh class B), the FDA recommends reducing the dose of KALYDECO to one tablet or one packet of oral granules once daily.In patients aged 6 months and older with severe hepatic impairment (Child-Pugh Class C), KALYDECO should be used with caution at a dose of one tablet or one packet of oral granules once a day or less frequently. It is not recommended for patients with hepatic impairment and under 6 months of age. KALYDECO is available in the form of light blue, capsule-shaped, film-coated tablets for oral administration, which contain 150 mg of ivacaftor. Each KALYDECO tablet contains the following inactive ingredients: colloidal silicon dioxide, cross-linked sodium carboxymethylcellulose, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coating contains carnauba wax, FD&C blue #2, PEG 3350, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, black iron oxide, propylene glycol, and shellac.

[0012] KALYDECO is also available in the form of white to off-white granules for oral administration (sweetened but unflavored) and packaged in unit-dose packets containing 25 mg, 50 mg, or 75 mg of ivacaftor. 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.

[0013] The overall safety profile of KALYDECO is based on pooled data from three placebo-controlled clinical trials in 353 patients aged 6 years and above with CF who have a G551D mutation in the CFTR gene or are homozygous for the F508del mutation (NCT00909532, NCT00909727, NCT00953706). During 16 weeks to 48 weeks, 221 patients received KALYDECO, and 132 patients received placebo. Whether the investigators believe that it is drug-related or not, more frequent serious adverse reactions in patients treated with KALYDECO include abdominal pain, increased liver enzymes, and hypoglycemia. Transaminases in CF patients receiving KALYDECO have been reported to be elevated. The FDA recommends assessing ALT and AST every 3 months and annually thereafter before starting KALYDECO, during the first year of treatment. Dosing should be interrupted in patients with ALT or AST higher than 5 times the upper limit of normal (ULN). After the transaminase elevations resolve, the FDA recommends considering the benefits and risks of resuming KALYDECO. Non-congenital lens opacities / cataracts have been reported in pediatric patients treated with KALYDECO. The FDA recommends baseline and follow-up examinations of pediatric patients who begin treatment with KALYDECO.

[0014] VX-809 (lumacato, 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 CFTR corrector and is approved in the US (2014) and EU (2015) as part of ORKAMBI, a combination product of lumacato and the CFTR potentiator ivacato, for the treatment of cystic fibrosis (CF) in patients 2 years of age and older who are homozygous for the F508del mutation in the CFTR gene.

[0015] The efficacy of ORKAMBI in CF patients homozygous for the F508del mutation was evaluated in two Phase III clinical trials (NCT01807923, NCT01807949) using a total of 1108 patients aged at least 12 years, of which 369 patients received ORKAMBI (400 mg Lumacaftor / 250 mg Ivacaftor, bid) for 24 weeks in addition to their prescribed CF therapy (such as bronchodilators, inhaled antibiotics, deoxyribonuclease alpha and hypertonic saline). The primary efficacy endpoint was the change in lung function, which was measured by the absolute change from baseline in ppFEV1 at week 24, and ORKAMBI treatment caused a statistically significant increase in absolute ppFEV1 of 2.6% and 3.0% compared with placebo treatment. With the use of ORKAMBI, the secondary endpoint (risk of pulmonary exacerbation) also changed favorably (relative risk reduction of 0.3 to 0.4 compared with placebo). In a small open-label Phase III trial, ORKAMBI was tested in CF patients aged 6 to 11 years who were homozygous for the F508del mutation, and sweat chloride concentration was measured as a marker of CFTR function. The mean absolute change from baseline in sweat chloride was -20.4mM on day 15 and -24.8mM at week 24. After a 2-week washout period, the mean absolute sweat chloride concentration increased by 21.3mM. Similarly, in F508del-CFTR homozygous CF patients aged 2 to 5 years, the mean absolute change from baseline in sweat chloride was -31.7mM at week 24, followed by an increase of 33mM after a 2-week washout period. These data indicate an improvement in CFTR function. Based on the support of population pharmacokinetic analyses, the efficacy of ORKAMBI in children aged 2 to 11 years was inferred from the efficacy in patients aged 12 years and older who were homozygous for the F508del mutation, which showed that drug exposure levels in patients aged 12 years and older were similar to those in children aged 2 to 11 years. For adults and pediatric patients 12 years of age and older, the recommended dose of ORKAMBI is two tablets (each containing 200 mg lumacato / 125 mg ivacaftor) taken orally every 12 hours for a total daily dose of 800 mg lumacato / 500 mg ivacaftor. For patients 6 to 11 years of age, the recommended dose of ORKAMBI is two tablets (each containing 100 mg lumacato / 125 mg ivacaftor) taken orally twice daily for a total daily dose of 400 mg lumacato / 500 mg ivacaftor. For patients 2 to 5 years of age, the dose of ORKAMBI is based on body weight. One packet of granules (containing 150 mg lumacato / 188 mg ivacaftor) is recommended for patients over 14 kg taken orally twice daily. One packet of granules (containing 100 mg lumacato / 125 mg ivacaftor) is recommended for patients under 14 kg taken orally twice daily.The FDA recommends reducing the dose of ORKAMBI to two tablets in the morning and one tablet in the evening for patients 6 years of age and older with moderate hepatic impairment (Child-Pugh class B) and to one packet of granules daily for patients 2 to 5 years of age with moderate hepatic impairment. In patients with severe hepatic impairment (Child-Pugh class C), caution is required with the maximum dose of ORKAMBI of 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 combination tablets containing either 100 mg lumacato and 125 mg ivacato or 200 mg lumacato and 125 mg ivacato. In addition, the following inactive ingredients are present: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; magnesium stearate; povidone; and sodium lauryl sulfate. The tablet film coating contains carmine, FD&C Blue #1, FD&C Blue #2, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, black iron oxide, propylene glycol, and shellac. ORKAMBI is also available in the form of oral granules, where each unit dose packet contains either 100 mg lumacator / 125 mg ivacator or 150 mg lumacator / 188 mg ivacator. In addition, the following inactive ingredients are present: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; povidone; sodium lauryl sulfate. The overall safety profile of ORKAMBI is based on pooled data from 1108 patients 12 years and older with CF who were homozygous for the F508del mutation and received at least one dose of study drug in 2 double-blind, placebo-controlled, Phase III clinical trials, each with 24 weeks of treatment. 369 patients received ORKAMBI bid and 370 patients received placebo. Serious adverse reactions that occurred more frequently in patients treated with ORKAMBI, regardless of whether the investigator considered them drug-related, included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and elevated transaminases. These reactions occurred in 1% or fewer patients. Elevations in transaminases (ALT / AST) have been observed in some cases associated with elevated bilirubin. The FDA recommends measuring serum transaminases and bilirubin prior to starting ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. Dosing should be interrupted in patients with ALT or AST >5x upper limit of normal (ULN) or ALT or AST >3x ULN and bilirubin >2x ULN. After resolution, the FDA recommends considering the benefits and risks of resuming ORKAMBI.In addition, respiratory side effects (chest discomfort, dyspnea, and respiratory abnormalities) were observed more commonly during initiation of ORKAMBI and in patients with ppFEV1 <40% and additional monitoring is recommended during initiation of therapy. In addition, increased blood pressure has been observed in some patients and the FDA recommends regular monitoring of blood pressure in all patients. Non-congenital lens opacities / cataracts have been reported in pediatric patients treated with ORKAMBI. The FDA recommends baseline and follow-up examinations for pediatric patients starting ORKAMBI treatment.

[0016] VX-661 (tizacator, 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)-1H indol-5-yl}cyclopropane-1-carboxamide, CAS1152311-62-0, e.g. WO2007 / 117715, WO2011 / 119984, WO2014 / 014841) is a type I CFTR corrector and is approved in the US (2018) as part of SYMDEKO and in the EU (2018) as part of SYMKEVI. SYMDEKO / SYMKEVI is a combination product of tizancator and the CFTR potentiator ivacaftor, which is used to treat cystic fibrosis (CF) in patients 6 years of age and older who are homozygous for the F508del mutation in the CFTR gene or have at least one mutation in the CFTR gene that responds to tizancator / ivacaftor based on in vitro data and / or clinical evidence. The current SYMDEKO uspi (June 2022) lists 154 suitable CFTR mutations.

[0017] The efficacy of SYMDEKO for CF patients aged 12 years and older was evaluated in three double-blind, placebo-controlled trials (Trials 1, 2, and 3). Patients in all trials continued to receive their standard care CF therapy (e.g., bronchodilators, inhaled antibiotics, deoxyribonuclease α, and hypertonic saline). Trial 1 (NCT02347657) evaluated 504 patients who were homozygous for the F508del-CFTR mutation. Patients were randomly divided into 1:1 groups to receive SYMDEKO or placebo and fat-containing foods. The primary efficacy endpoint was the improvement of lung function, which was measured by the mean absolute change in ppFEV1 from baseline to the 24th week of treatment. Compared with placebo, treatment with SYMDEKO caused a significant absolute change of 4% in ppFEV1. After 24 weeks of treatment with SYMDEKO, some secondary endpoints also showed favorable changes, such as the risk of pulmonary exacerbations (relative risk reduction of 0.35 compared with placebo), the absolute change in CFQ-R respiratory domain score (a measure of respiratory symptoms relevant to CF patients such as cough, sputum production and dyspnea: +5.1 from baseline to week 24), and the absolute change in sweat chloride from baseline to week 24 (-10.1 mM compared with placebo).

[0018] The crossover-designed trial 2 (NCT02392234) evaluated 244 patients who were heterozygous for the F508del mutation and carried a second mutation predicted to respond to tezakator / ivacator (146 patients had splicing mutations and 98 patients had missense mutations as the second allele). The primary efficacy endpoint was improvement in lung function, which was measured by the mean absolute change from baseline in ppFEV1 averaged at weeks 4 and 8 of treatment. Treatment with SYMDEKO resulted in a significant absolute change of 6.8% in ppFEV1 compared to placebo. With the use of SYMDEKO, some secondary endpoints also had favorable changes, such as the absolute change from baseline in the CFQ-R respiratory domain score (relative to placebo +11.1) and the absolute change in sweat chloride, a CFTR functional biomarker (-9.5mM). Trial 3 (NCT02516410) evaluated SYMDEKO in 168 patients who were heterozygous for the F508del mutation and carried a second mutation that predicted non-response to tezacaftor / ivacaftor. No significant change in absolute ppFEV1 from baseline to Week 12 was observed in the SYMDEKO group compared with the placebo group.

[0019] The efficacy of SYMDEKO in patients 6 to 12 years of age was extrapolated from patients 12 years of age and older to patients 6 to 12 years of age based on support from population pharmacokinetic analyses showing similar exposure levels of tezacaftor and ivacaftor in patients 6 to 12 years of age (Trial 4; NCT02953314; an open-label study in 70 patients) versus patients 12 years of age and older (Trials 1 and 2). In addition, in Trial 4, a change in sweat chloride of -14.5 mM was observed from baseline to Week 24, indicating improved CFTR function.

[0020] For patients 12 years of age and older and pediatric patients 6 years of age and older (if they weigh at least 30 kg), the recommended dose of SYMDEKO is one tablet in the morning (containing 100 mg tizanto / 150 mg ivacaftor) and one tablet in the evening (containing 150 mg ivacaftor), for a total daily dose of 100 mg tizanto / 300 mg ivacaftor. For patients 6 to 11 years of age (if they weigh less than 30 kg), the recommended dose of SYMDEKO is one tablet in the morning (containing 50 mg tizanto / 75 mg ivacaftor) and one tablet in the evening (containing 75 mg ivacaftor), for a total daily dose of 50 mg tizanto / 150 mg ivacaftor. For patients with moderate hepatic impairment (Child-Pugh class B), the FDA recommends reducing the dose of SYMDEKO to the morning tablet and omitting the ivacaftor dose taken in the evening. In patients with severe hepatic impairment (Child-Pugh class C), SYMDEKO should be used with caution at the maximum dose of 1 morning tablet.

[0021] SYMDEKO is available as white, capsule-shaped, fixed-dose tizacator / ivacator combination tablets co-encapsulated with light blue capsule-shaped ivacaftor tablets. Available in 50 mg tizacator / 75 mg ivacaftor + 75 mg ivacaftor encapsulation and 100 mg tizacator / 150 mg ivacaftor + 150 mg ivacaftor encapsulation. In the tizacator / ivacator combination tablets, the following inactive ingredients are present: croscarmellose sodium, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coating 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 coating contains carnauba wax, FD&C blue #2, PEG 3350, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, black iron oxide, propylene glycol, and shellac.

[0022] 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 trials (NCT02347657, NCT02516410) and an 8-week crossover design trial (NCT02392234). Eligible patients were also able to participate in an open-label extension safety study (up to 96 weeks of SYMDEKO treatment). 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 the investigator considered them to be drug-related, included remote intestinal obstruction syndrome, which occurred in 3 patients (0.6%) treated with SYMDEKO and in 0 patients treated with placebo. Elevated transaminases (ALT / AST) have been observed in patients treated with SYMDEKO. The FDA recommends measuring serum transaminases prior to starting SYMDEKO, every 3 months during the first year of treatment, and annually thereafter. Dosing should be interrupted in patients with ALT or AST > 5x upper limit of normal (ULN) or ALT or AST > 3x ULN and bilirubin > 2x ULN. After resolution, the FDA recommends considering the benefits and risks of resuming SYMDEKO. Non-congenital lens opacities / cataracts have been reported in pediatric patients treated with SYMDEKO. The FDA recommends baseline and follow-up examinations for pediatric patients starting SYMDEKO treatment.

[0023] VX-445 (eresacatol, 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-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, CAS2216712-66-0, e.g. WO2016 / 057572, WO2018 / 107100, WO2019 / 152940) is a type III CFTR corrector and is approved in the US (2019) as part of TRIKAFTA and in the EU (2020) as part of KAFTRIO. TRIKAFTA / KAFTRIO is a combination product of elexacato with the type I CFTR corrector tizancato 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 F508del mutation in the CFTR gene or a mutation in the CFTR gene that is responsive based on in vitro data. The current TRIKAFTA uspi (October 2021) lists 178 suitable CFTR mutations.

[0024] The efficacy of TRIKAFTA in CF patients aged 12 years and older was evaluated in two double-blind, placebo-controlled trials (Trials 1 and 2). Patients interrupted any previous CFTR modulator therapy but continued to receive other standard-of-care CF therapies (e.g., bronchodilators, inhaled antibiotics, deoxyribonuclease α, and hypertonic saline). Trial 1 (NCT03525444) evaluated 403 patients (200 receiving TRIKAFTA and 203 receiving placebo) who had an F508del mutation on one allele and a mutation on the second allele that did not produce CFTR protein or produced CFTR protein that was unresponsive to ivacaftor and tizacaftor / ivacaftor. The primary efficacy endpoint was improvement in lung function, which was measured by the mean absolute change in ppFEV1 from baseline to the fourth week of treatment at the time point of the interim analysis. The treatment difference between TRIKAFTA and placebo was 13.8%. With TRIKAFTA, there were also favorable changes in key secondary endpoints measured at Week 24, such as the risk of pulmonary exacerbations (relative risk reduction of 0.63 compared with placebo), the absolute change from baseline in CFQ-R respiratory domain score (+20.2 compared with placebo), and the absolute change from baseline in body mass index (BMI) (+1.04 kg / m2 compared with placebo). 2 ) and absolute change from baseline in sweat chloride (-41.8 mM compared with placebo).

[0025] Trial 2 (NCT03525548) evaluated 107 CF patients aged 12 years and older who were homozygous for the F508del mutation. After a 4-week open-label trial phase with tizancator / ivacator, patients were randomized to use TRIKAFTA or continue to receive tizancator / ivacator for 4 weeks. The primary endpoint was the mean absolute change from baseline in ppFEV1 at Week 4 of the double-blind treatment period, and treatment with TRIKAFTA resulted in a statistically significant improvement of 10.0% in ppFEV1 compared to tizancator / ivacator. Favorable changes also occurred in key secondary endpoints at Week 4 with TRIKAFTA compared to tizancator / ivacator, such as the absolute change from baseline in the CFQ-R respiratory domain score (+17.4) and the absolute change in sweat chloride, a CFTR functional biomarker (-45.1 mM).

[0026] Trial 3 (NCT03691779) was an open-label trial evaluating TRIKAFTA in 66 children aged 6 to less than 12 years who were homozygous for the F508del mutation or heterozygous for the F508del mutation and had a mutation on the second allele that produced no CFTR protein or produced CFTR protein that was unresponsive to ivacaftor and tizanaftor / ivacaftor. The mean absolute change in sweat chloride from baseline to Week 24 was -60.9 mmol / L. The effectiveness of TRIKAFTA in patients aged 6 to less than 12 years was extrapolated from patients aged 12 years and older based on support from population pharmacokinetic analyses that showed elexacaftor, tizanaftor, and ivacaftor exposure levels in patients aged 6 to less than 12 years were within the range of exposures observed in patients aged 12 years and older (Trials 1 and 2).

[0027] For patients 12 years of age and older and pediatric patients 6 years of age and older (if they weigh at least 30 kg), the recommended dose of TRIKAFTA is two tablets in the morning (each containing 100 mg erexacato / 50 mg tizcato / 75 mg ivacaftor) and one tablet of 150 mg ivacaftor in the evening, for a total daily dose of 200 mg erexacato / 100 mg tizcato / 300 mg ivacaftor. For patients 6 to 11 years of age (if they weigh less than 30 kg), the recommended dose of TRIKAFTA is two tablets in the morning (each containing 50 mg erexacato / 25 mg tizcato / 37.5 mg ivacaftor) and one tablet in the evening (containing 75 mg ivacaftor), for a total daily dose of 100 mg erexacato / 50 mg tizcato / 150 mg ivacaftor. 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 administering only the morning tablet in an alternating schedule of 1 and 2 morning tablets per day.

[0028] TRIKAFTA is a co-encapsulation of elexacato, tizcato and ivacaftor fixed-dose combination tablets and ivacaftor tablets. Both tablets are for oral administration. Elexacato, tizcato and ivacaftor fixed-dose combination tablets are orange, capsule-shaped and film-coated and contain 100 mg elexacato, 50 mg tizcato, 75 mg ivacaftor, or are light orange, capsule-shaped and film-coated and contain 50 mg elexacato, 25 mg tizcato, 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, yellow iron oxide and red iron oxide. Ivacaftor tablets are available as light blue, capsule-shaped, film-coated tablets 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 #2, PEG 3350, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, black iron oxide, propylene glycol, and shellac.

[0029] The safety profile of TRIKAFTA is based on data from 510 patients with CF aged 12 years and older in two double-blind, controlled trials with treatment durations of 24 and 4 weeks (Trials 1 and 2). Eligible patients were also able to participate in an open-label extension safety study (up to 96 weeks of TRIKAFTA treatment). A total of 257 patients aged 12 years and older received at least one dose of TRIKAFTA in two controlled trials. In Trial 1, serious adverse reactions that occurred more frequently in patients treated with TRIKAFTA compared to placebo were rash (1% vs. <1%) and influenza (1% vs. 0). The most common adverse drug reactions to TRIKAFTA (≥5% of patients and incidence ≥1% higher than placebo) were headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, increased alanine aminotransferase, nasal congestion, increased blood creatine phosphokinase, increased aspartate aminotransferase, rhinorrhoea, rhinitis, influenza, sinusitis, and increased blood bilirubin.

[0030] In Trial 1, the adverse reaction of increased transaminases (AST and / or ALT) occurred in 11% of patients treated with TRIKAFTA and in 4% of patients treated with placebo. Maximum total bilirubin elevations >2 times ULN occurred in 4% of patients treated with TRIKAFTA and <1% of patients treated with placebo. Liver failure leading to transplantation has been reported in a patient with cirrhosis and portal hypertension while receiving TRIKAFTA. The FDA recommends avoiding the use of TRIKAFTA in patients with pre-existing advanced liver disease unless the expected benefits outweigh the risks. If used in these patients, these patients should be closely monitored after initiation of treatment. The FDA recommends that liver function tests (ALT, AST, and bilirubin) be assessed in all patients prior to starting TRIKAFTA, every 3 months during the first year of treatment, and annually thereafter. In the presence of significant elevations in liver function tests, such as ALT or AST > 5 times upper limit of normal (ULN) or ALT or AST > 3 times ULN and bilirubin > 2 times ULN, dosing should be interrupted and laboratory testing followed closely until the abnormality resolves. After resolution, the FDA recommends considering the benefits and risks of resuming TRIKAFTA.

[0031] Non-congenital lens opacities / cataracts have been reported in pediatric patients treated with regimens containing ivacaftor. The FDA recommends baseline and follow-up examinations for pediatric patients starting TRIKAFTA treatment. Other potential side effects of TRIKAFTA reported include rash (10% with TRIKFTA vs. 5% with placebo in Trial 1) and increased blood pressure. The maximum increases from baseline in mean systolic and diastolic blood pressure were 3.5 mmHg and 1.9 mmHg, respectively, in patients treated with TRIKAFTA (baseline: systolic 113 mmHg and diastolic 69 mmHg), and 0.9 mmHg and 0.5 mmHg, respectively, in patients treated with placebo (baseline: systolic 114 mmHg and diastolic 70 mmHg).

[0032] ABBV-2222 (GLPG-2222, Gallicatol, 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chroman-2-yl]benzoic acid; CAS1918143-53-9, e.g. WO2016 / 069757) is a type I CFTR corrector that is currently being tested in an open-label Phase II trial (NCT03969888) in combination with the CFTR potentiator ABBV-3067 (see below) in 78 CF patients aged 18 years and older who are homozygous for the F508del-CFTR mutation. The primary endpoint was the absolute change from baseline in ppFEV1 at day 29, and secondary endpoints included the absolute change from baseline in sweat chloride at day 29 and the change in forced vital capacity (the total amount of air exhaled during a forced expiratory volume test, a lung function test). Several undisclosed dosing regimens of Gallicato and Navocato are being tested. Additionally, Gallicato is being tested as part of a triple combination of CFTR modulators in an open-label Phase II trial (NCT04853368), in which one of the cohorts of homozygous F508del-CFTR patients was treated for 28 days with a fixed dose of Gallicato and the potentiator Navocato, followed by 28 days of treatment with a triple combination of Gallicato / Navocato and the CFTR corrector ABBV-119, which has a different mechanism than Gallicato. An interim analysis after the dual treatment phase indicated that the dual combination of Gallicato / Navocato was effective (“performed well”) on ppFEV1, while the addition of ABBV-119 did not add additional efficacy, leading to the interruption of this clinical trial (Abbvie oral communication at a press conference on April 29, 2022). Gallicato has previously been tested as a single agent in a placebo-controlled Phase IIa study (NCT03119649), in which 59 CF patients aged 18 years and older who were homozygous for the F508del-CFTR mutation were treated once daily for 4 weeks at doses of 50, 100, 200 and 400 mg. The primary endpoint was the number of participants with treatment-emergent adverse events up to Day 43, and key secondary endpoints were the change from baseline in ppFEV1 at Day 29, the change from baseline in CFQ-R at Day 29, and the change from baseline in sweat chloride concentration at Day 29. Gallicato was well tolerated and safe. No significant changes were observed in ppFEV1 and CFQ-R scores compared to placebo. In the 200 mg dose group, the change in sweat chloride was significant (-15.8 mM compared to placebo). The data indicate that in a monotherapy mode, the doses of Galicato tested had no effect on lung function in homozygous F508del-CFTR CF patients.In vitro, using differentiated human bronchial epithelial cells from homozygous F508del-CFTR donors, Gallicaretto showed high potency (EC) in electrophysiological recordings (transepithelial current clamp) in the presence of the potentiator GLPG1837. 50 =5nM)(Wang, 2018). In addition, Gallicato has been tested in combination with another potentiator, GLPG-2451, in a fixed-dose combination in a Phase Ib open-label trial (NCT03540524). Ten CF patients homozygous for the F508del-CFTR mutation were treated with the Gallicato / GLPG-2451 combination for 2 weeks before adding another CFTR modulator (GLPG-2737). An interim analysis at 2 weeks of treatment with Gallicato and GLPG-2451 showed that the combination was well tolerated and safe during the 2-week treatment phase. In addition, key secondary endpoints were improved relative to baseline: ppFEV1 (+3%) and sweat chloride (-25mM) (Galapagos press release on October 24, 2018), indicating that Gallicato can partially correct F508del-CFTR function when combined with a potentiator.

[0033] According to the embodiments of the present application, PTI-801 (posenacaftor, CAS2095064-05-2; the compound of Example 2 of WO 2019 / 071078) can be classified as a type III CFTR corrector. Recently, in a phase 1 / 2 randomized, double-blind, placebo-controlled study (NCT03500263), the combination of PTI-801 with the CFTR potentiator PTI-808 and the CFTR enhancer PTI-428 was tested. 31 CF patients aged 18 years and older with at least one F508del-CFTR allele were randomized to receive the triple treatment combination or placebo. The triple combination is a fixed dose of PTI-428 (30 mg) plus a low dose of PTI-801 (200 mg) and a high test dose of PTI-808 (300 mg), or plus a high test dose of PTI-801 (600 mg) and a medium dose of PTI-808 (150 mg) administered daily. Patients were first treated with PTI-808 or placebo for seven days, followed by a 14-day triple combination treatment period, and then a seven-day washout period during which no therapy was received. Patients receiving the therapy combination with a high dose of PTI-801 experienced significant improvements in lung function, with an increase of 5% in the mean absolute ppFEV1 on day 14 compared to before treatment. These patients also showed a significant reduction in sweat chloride levels, with a 19 mM reduction on day 14 compared to before treatment, and a 24 mM reduction compared to placebo. Positive effects have also been reported in patients who are susceptible to rapid lung decline and would not be included in other CFTR modulator combination studies. When treated with the combination regimen with 600 mg PTI-801, these patients had a 6% improvement in ppFEV1 compared to pre-treatment and an 8% improvement compared to placebo.

[0034] ABBV-3067 (navocator, 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. WO2017 / 208115) is a CFTR potentiator that is currently being analyzed in a Phase II trial in combination with gallicator as described above (NCT03969888). Previously, a Phase I study has been conducted in healthy volunteers consisting of a single ascending dose portion of navocator in the range of 15 to 1000 mg in combination with gallicator, and a multiple ascending dose portion of oral doses starting at 45 mg once daily for 14 days in combination with gallicator (NCT03128606). In healthy subjects, Navocato was generally well tolerated when administered in single doses of up to 1000 mg and twice daily for 14 days. Navocato exposure was not significantly altered in the presence of Gallicato, and Gallicato exposure was similar in the presence of two different doses of Navocato (Poster #36, North American Cystic Fibrosis Conference 2017, Indianapolis).

[0035] QBW-251 (Esencato, 3-amino-6-methoxy-N-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5-(trifluoromethyl)pyridine-2-carboxamide, CAS1334546-77-8, e.g., WO2011 / 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 and older carrying CFTR class III, class IV CFTR mutations on one allele (i.e., mutations in which CFTR is on the cell surface and can benefit from potentiation) (NCT02190604). A primary endpoint was the change from baseline in lung clearance index after 14 days of treatment. Lung clearance index (LCI) is a measure of breathing heterogeneity derived from a multiple breath clearance test, and LCI 2.5 A decrease of more than one unit in the mean change from baseline indicated improvement. Other efficacy-related endpoints were the absolute change from baseline in ppFEV1 after 14 days of treatment and the change from baseline in sweat chloride concentration after 14 days of treatment. Patients treated with 450 mg of Esenkator twice daily showed improved LCI 2.5(-1.13 compared to placebo), improved ppFEV1 (6.5% increase compared to placebo), and reduced sweat chloride concentration (-8.4 mM compared to placebo), indicating clinically meaningful improvements in CFTR target engagement and lung function. In the same trial and in contrast, a group of patients homozygous for the F508del-CFTR mutation treated with Esenkato (450 mg, twice daily) did not show a reduction in sweat chloride or an improvement in lung function, indicating that this patient group requires a combination with a CFTR corrector (Kazani, 2021). In healthy volunteers, Esenkato was well tolerated at all exposures tested up to 1000 mg after SAD and up to 750 mg twice daily after MAD. CF patients tolerated Esenkato (in all patient subgroups) at doses of 150 and 450 mg twice daily well, with no unexpected events, deaths, or discontinuations (Kazani 2021).

[0036] In addition, in a placebo-controlled Phase II trial (NCT02449018), esencato was evaluated in 92 patients aged 18 to 75 years with moderate to severe COPD and chronic bronchitis symptoms. In addition to background COPD therapy, patients received esencato 300 mg twice daily (N=64) or placebo (N=28) for 4 weeks. The primary endpoint was LCI after 4 weeks of treatment. 2.5 The key secondary endpoint was the change from baseline in FEV1 after 4 weeks of treatment, and the key exploratory endpoints included the change from baseline in sweat chloride concentration and plasma fibrinogen concentration (a marker of inflammation) after 4 weeks of treatment. Treatment with Esenkato did not change LCI compared with placebo. 2.5. However, treatment with Esenkato resulted in improvements in FEV1 (+0.05-0.06L, mean baseline 1.4-1.5L) as well as sweat chloride (-5.04mM, mean baseline 23mM) and plasma fibrinogen (-0.39g / L, mean baseline 3.2g / L) compared to placebo, indicating that treatment with Esenkato resulted in improvements in several areas of COPD lung disease compared to placebo (NCT02449018; Rowe, 2020). Esenkato is currently being studied in a placebo-controlled Phase II clinical trial in subjects aged 18 years and older with bronchiectasis at an oral dose of 300mg twice daily and a treatment duration of 12 weeks (NCT04396366). An estimated 72 patients will be randomized 1:1 to receive drug and placebo treatment. The primary endpoint was the change from baseline in the bacterial load of potentially pathogenic microorganisms in sputum (measured in colony forming units (CFU / mL)) after 1 week of treatment. Key secondary endpoints measured after 12 weeks of treatment included the change from baseline in the respiratory domain-only score on the Bronchiectasis Quality of Life Questionnaire (QOL-B, a disease-specific questionnaire developed for non-cystic fibrosis bronchiectasis), the change from baseline in fibrinogen plasma concentration, the change in rescue medication use (salbutamol / albuterol), the change from baseline in FEV1, the change from baseline in airway lumen measured by high-resolution computed tomography (HRCT), and the change from baseline in global and regional air retention in the airways measured by HRCT.

[0037] VX-121 (Vanzacatol, (14S)-8-[3-(2-{dispiro[2.0.2.1]hept-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione , CAS2374124-49-7, e.g., WO2019 / 161078, WO2021 / 030552) is a type III CFTR corrector that is currently being tested in CF patients in two active-controlled, double-blind, randomized Phase III clinical trials as part of a new triple combination containing vanacattor, the type I corrector tizacattor, and the CFTR potentiator VX-561 (deuterated tizacattor, a deuterated form of ivacaftor). In trial 1 (NCT05033080), the new triple combination was compared with TRIKAFTA in an estimated 400 CF patients aged 12 years and older who were heterozygous for the F508del-CFTR mutation and carried a minimal functional mutation on the other allele. After a 4-week run-in phase with TRIKAFTA, patients were randomized 1:1 to continue to receive TRIKAFTA or once-daily venzacator, tezcator, and deuterated venzacator (20 mg / 100 mg / 250 mg) for 48 weeks. The primary efficacy endpoint was improvement in lung function as measured by the mean absolute change in ppFEV1 from baseline to Week 24 of treatment. Key secondary endpoints measured at Week 24 of treatment were the absolute change from baseline in sweat chloride, the proportion of participants with sweat chloride <60 mM and <30 mM from baseline to Week 24. In Trial 2 (NCT05076149), the new triple combination was compared with TRIKAFTA in a blinded manner in an estimated 550 CF patients aged 12 years and older who were homozygous for F508del-CFTR, or heterozygous for F508del-CFTR and a gating or residual function CFTR mutation, or had at least 1 other TRIKAFTA-responsive CFTR gene mutation and no F508del-CFTR mutation. After a 4-week run-in phase of dosing with TRIKAFTA, patients were randomized 1:1 to continue receiving TRIKAFTA or once-daily venzacator, tezacator, and deuterated venzacator (20 mg / 100 mg / 250 mg) for 48 weeks. The primary efficacy endpoint was improvement in lung function, as measured by the mean absolute change in ppFEV1 from baseline to Week 24 of treatment. Key secondary endpoints measured at Week 24 of treatment were the absolute change from baseline in sweat chloride, the proportion of participants with sweat chloride <60 mM and <30 mM from baseline to Week 24.

[0038] The efficacy and safety of the new triple combination of wanzacato / tizacato / deuteridecato has previously been tested in a Phase II trial in CF patients who are heterozygous for F508del and minimal functional mutations in the CFTR gene (NCT03912233) or in patients who are homozygous for the F508del-CFTR mutation. In heterozygous patients (N=58), the triple combination of wanzacato (5 or 10 or 20 mg) / 100 mg tizacato / 150 mg deuteridecato was administered once daily for 4 weeks and compared with placebo treatment, followed by a washout period of 18 days from the triple combination to the dual combination of tizacato / deuteridecato. The primary efficacy endpoint was improvement in lung function, which was measured by the mean absolute change in ppFEV1 from baseline to week 4 of treatment. The treatment difference in ppFEV1 between the new triple combination and placebo was +2.7% / +12.3% / +7.9% in the group using the 5mg / 10mg / 20mg dose of Wanzacattor. The key secondary endpoint, the absolute change from baseline to Week 4 of sweat chloride, changed favorably with the new triple combination, with a difference of -45.1mM / -48.1mM / -51.8mM in the group using the 5mg / 10mg / 20mg dose of Wanzacattor compared to placebo. In homozygous patients (N=28), after a 4-week trial phase of tizancator / ivacator (SYMKEVI), randomization was performed to continue to receive tizancator / ivacator or a once-daily dose of the new triple combination of 20 mg tizancator / 100 mg tizancator / 150 mg deuterated tizancator for 4 weeks, followed by a 28-day washout period with the dual combination of tizancator / ivacator. The primary efficacy endpoint was improvement in lung function, as measured by the mean absolute change in ppFEV1 from baseline to week 4 of treatment. The treatment difference in ppFEV1 between the new triple combination and the dual combination was +16.0%. The key secondary endpoint, the absolute change in sweat chloride from baseline to week 4 of treatment, changed favorably with 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).

[0039] VX-561 (deuterated ivacator, N-[2-tert-butyl-4-[1,1,1,3,3,3-hexadeuterated-2-(trideuteriomethyl)propan-2-yl]-5-hydroxyphenyl]-4-oxo-1H-quinoline-3-carboxamide, named CTP-656, CAS1413431-07-8, e.g. WO2019 / 109021, WO2019 / 018395) is a deuterated form of ivacator for once-daily administration. A Phase II study (NCT03911713) compared different doses of deuterated calcitonin to standard doses of ivacaftor (150 mg twice daily = Kalydeco) in CF patients aged 18 years and older who had one of the following ivacaftor-responsive CFTR mutations on at least one allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D, and who were already taking ivacaftor. Patients (N = 77) were randomized to continue receiving ivacaftor (150 mg twice daily) or to receive treatment with 25, 50, 150, or 250 mg of deuterated calcitonin once daily for 12 weeks. The primary efficacy endpoint was improvement in lung function, as measured by the mean absolute change in ppFEV1 from baseline to Week 12 of treatment. In the group using the 150mg / 250mg once-daily dose of deuterated cator, the treatment difference in ppFEV1 for deuterated cator relative to ivacaftor was +3.9% / +3.5%. The key secondary endpoint, absolute change in sweat chloride from baseline to week 12 of treatment, was measured as +2.4mM and -7.4mM for the once-daily 150mg / 250mg deuterated cator groups when compared to ivacaftor 150mg twice-daily. The mean c 谷值 Plasma concentrations were 458 ng / mL and 1100 ng / mL at the 150 mg and 250 mg doses and 952 ng / mL at the 150 mg ivacaftor dose twice daily.

[0040] The ability of the CFTR correctors lumacato, tizcato, galicato, Corr4a, elexacato, bamocato and others to restore the folding of mutant CFTR (particularly F508del-CFTR) and its trafficking to the cell surface has been analyzed in vitro (Van Goor, 2011; Okiyoneda, 2013; Veit, 2018; Keating, 2018; Davies; 2018). Trafficking to the cell surface can be analyzed by different analytical techniques, including anti-CFTR immunoblots (CFTR "C bands" indicate mature, transported CFTR), anti-CFTR cell surface ELISA, enzyme fragment complementation techniques, or CFTR-HRP fusion proteins in recombinant cell lines expressing mutant CFTR-proteins or primary cells from CF patients. Importantly, combinations of correctors with different types of corrector mechanisms show an additive effect on increasing F508del-CFTR cell surface expression. This is demonstrated, for example, in the case of elexacato + / - tezacato (type III calibrator + / - type I calibrator; Keating, 2018; Veit, 2020) or pamoxacoto + / - tezacato (type III calibrator + / - type I calibrator; Davies, 2018) or type I + type II + type III calibrators (Veit, 2018).

[0041] Mutated CFTR transported to the cell surface may still have a gating defect, and it has been demonstrated that the function of cell surface F508del-CFTR is significantly enhanced when a synergist is added. Various functional assays can be used to analyze CFTR function. For example, cell expression of halide-sensitive yellow fluorescent protein can be used to measure iodide influx via functional CFTR (Galietta, 2001). In addition, electrophysiological measurements using Ussing chambers and reconstructed epithelial cells or reconstructed bronchial epithelial cells from CF patients can be used to characterize the effects of CFTR modulators on CFTR function. For example, it has been demonstrated that the administration of the synergist ivacaftor to F508del-CFTR corrected by Lumacaftor can enhance the CFTR function in reconstructed bronchial epithelial cells from CF patients by about two times (van Goor, 2011), which is consistent with clinical trial data on FEV1 improvement after the administration of ivacaftor to patients treated with Lumacaftor (Boyle, 2014). Similarly, again using Ussing chamber readouts, we demonstrated the additive nature of the type I corrector tizakator and the type III corrector eresakator on functional correction of F508del-CFTR in reconstituted CF bronchial epithelial cells, and a further 2-fold enhancement of function by the addition of the potentiator ivacaftor. Furthermore, we demonstrated the additive effect of the type III corrector eresakator on the combination of the type I corrector tizakator and the potentiator ivacaftor on F508del-CFTR function (Keating, 2018). This latter comparison is consistent with clinical trial data in F508del-CFTR homozygous patients, where the addition of eresakator to basal therapy of tizakator + ivacaftor (SYMDEKO) resulted in a 10% increase in ppFEV1 (Keating, 2018). The FDA has recognized the predictive power of in vitro testing for the effects of CFTR modulators in the clinic and has approved CFTR modulators for rare CFTR-mutations based solely on in vitro evidence (Ussing chamber measurements in Fisher rat thyroid epithelial cells recombinantly expressing mutant CFTR; uspi SYMDEKO, uspi KALYDEKO, uspi TRIKAFTA).

[0042] Despite the availability of various CFTR modulators with complementary mechanisms targeting many common mutations, the patient's CFTR function was not fully restored (indicated by the persistence of elevated sweat chloride levels) and his lung function was not fully restored. These results highlight the need for other novel and highly effective CFTR corrector mechanisms that can be used alone or with currently available or future background therapies (i.e., SYMDEKO or ORKAMBI or TRIKAFTA or [galicato + navocato], and optionally other background therapies), and that can combine to increase the efficacy of such CFTR modulator therapies. Summary of the invention

[0043] It has now been discovered that CFTR correctors (particularly compounds of formula (I) such as defined below, which are CFTR correctors with a novel mechanism, i.e., non-type I, non-type II, non-type III correctors, with the potential to prevent and treat CFTR-related diseases and disorders, especially cystic fibrosis) can have complementary or even synergistic effects in treating CFTR-related diseases and disorders, especially cystic fibrosis, when combined with: CFTR correctors with another mechanism, such as type I correctors (lumacato, tizacato, galicato) and / or type II correctors (corrector 4a) and / or type III correctors (eresacato, bamocato, olacato, wanzacato; as well as ABBV-119, ABBV-567, and PTI-801 in addition to those listed previously), and / or CFTR potentiators (ivacato, navacato, esencato, deutecato, GLPG-1837, GLPG2451). Therefore, this combination may be particularly useful in the treatment of cystic fibrosis.Compounds of formula (I) can restore CFTR function in the absence and presence of potentiators as measured by Ussing chamber measurements in reconstructed tissue from CF patients carrying the F508del-CFTR mutation.

[0044] In addition, in the treatment of CFTR-related diseases and disorders (especially cystic fibrosis), CFTR correctors, especially compounds of formula (I) such as any one of embodiments 1) to 15), may have complementary or even synergistic effects when combined with CFTR stabilizers (such as SION-638 or NBD1-A). Therefore, this combination may be particularly suitable for the treatment of cystic fibrosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 The effect of Example Compound 3 on F508del-CFTR cell surface expression when used with basal treatment with type I or type II or type III or [type I + type III] CFTR correctors is shown. Figure 2 Shown are the effects of Example Compound 3 on F508del-CFTR function (YFP quenching assay) when used with basal treatment with the type I CFTR corrector galicator and / or the CFTR potentiator navocator. Figure 3 Shown is the effect of Example Compound 3 on F508del-CFTR function (YFP quenching assay) when used with basal treatment with the type I CFTR corrector tezacator and / or the CFTR potentiator ivacaftor. Figure 4Shown is the effect of Example Compound 3 on F508del-CFTR function (YFP quenching assay) when used with basal treatment with the type II CFTR corrector, Corrector 4a, and / or the CFTR potentiator Navocato. Figure 5 Shown are the effects of Example Compound 3 on F508del-CFTR function (YFP quenching assay) when used with basal treatment with the type III CFTR corrector erexacator and / or the CFTR potentiator ivacaftor. Figure 6 The effect of Example Compound 3 on F508del-CFTR cell surface expression when used with a base treatment with the type III CFTR corrector elexacato or the compound of Example 2 of WO 2019 / 071078 (PTI-801) is shown. In addition, the effect of adding one type III corrector (elexacato) to another type III corrector (PTI-801) is also shown. DETAILED DESCRIPTION

[0046] 1) The first embodiment relates to a pharmaceutical composition comprising as an active ingredient a compound of formula (I): in X stands for -CR X1 R X2 , where R X1 represents hydrogen, and R X2 express ■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); R 1 Represents C 1-4 Alkyl (especially methyl); R 2 Represents C 1-4 Alkyl (especially methyl); R 3 Represents C 1-6 Alkyl (especially isobutyl); R 4 represents a 5-membered heteroaryl (especially oxadiazolyl), wherein the 5-membered heteroaryl is independently unsubstituted, monosubstituted or disubstituted, wherein the substituents are independently selected from C 1-4Alkyl (especially methyl), C 1-4 Alkoxy (especially methoxy), C 1-3 Fluoroalkyl, C 1-3 Fluoroalkoxy, C 3-6 Cycloalkyl (especially cyclopropyl) or halogen (especially fluorine); Ar 1 represents an 8- to 10-membered bicyclic heteroaryl group (especially a 10-membered bicyclic heteroaryl group), wherein the bicyclic heteroaryl group is independently unsubstituted or C 1-4 Alkyl (especially methyl) or halogen (especially fluorine) monosubstituted; Ar 2 represents a phenyl group, wherein the phenyl group is unsubstituted, monosubstituted or disubstituted, wherein the substituents are independently selected from C 1-4 Alkyl, C 1-3 Fluoroalkyl, halogen, C 1-6 Alkoxy and C 1-3 Fluoroalkoxy; or a pharmaceutically acceptable salt thereof; In combination with one or more therapeutically active ingredients used as CFTR modulators; wherein the CFTR modulator is one or more CFTR correctors (especially type I correctors and / or type II correctors and / or type III correctors) and / or CFTR enhancers; or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient.

[0047] As embodiment 1), the pharmaceutical composition can be used as a medicine, for example, in the form of a pharmaceutical composition for enteral (especially such as oral) or parenteral administration (including topical application or inhalation). The production of such pharmaceutical compositions can be in a manner familiar to those 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 forming a galenical administration form in which the combined active ingredients of the present invention (optionally in combination with other therapeutically valuable substances) are formed with suitable non-toxic, inert pharmaceutically acceptable solid or liquid carrier materials and conventional pharmaceutical adjuvants (optionally). Pharmaceutical compositions for oral administration can be in the form of capsules or tablets, in particular.

[0048] 2) The second aspect relates to a pharmaceutical composition according to embodiment 1), wherein the compound of formula (I) is E ) of the compound:

[0049] 3) Another embodiment relates to a pharmaceutical composition according to embodiment 1) or 2), wherein X represents -CR X1 R X2 , where R X1 is hydrogen, and R X2 C 1-4 Fluoroalkyl (especially 2,2,2-trifluoroethyl, 2,2-difluoroethyl).

[0050] 4) Another embodiment relates to a pharmaceutical composition according to embodiment 1) or 2), wherein X represents -CR X1 R X2 , where R X1 is hydrogen, and R X2 It is 2,2,2-trifluoroethyl.

[0051] 5) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 4), wherein R 1 Represents methyl.

[0052] 6) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 5), wherein R 2 Represents methyl.

[0053] 7) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 6), wherein R 3 It is isobutyl.

[0054] 8) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 7), wherein R 4 represents a 5-membered heteroaryl group (especially an oxadiazolyl group), wherein the 5-membered heteroaryl group is independently C 1-4 Alkyl (especially methyl), C 1-4 Alkoxy (especially methoxy), C 1-3 Fluoroalkyl, C 1-3 Fluoroalkoxy or halogen (especially fluorine) monosubstituted.

[0055] 9) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 7), wherein R 4 represents a 5-membered heteroaryl group (especially an oxadiazolyl group), wherein the 5-membered heteroaryl group is independently C 1-4 The alkoxy group (especially the methoxy group) is monosubstituted.

[0056] 10) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 7), wherein R 4 represents an oxadiazolyl group, wherein the 5-membered heteroaryl group is independently C 1-4 The alkoxy group (especially the methoxy group) is monosubstituted.

[0057] 11) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 10), wherein Ar 1 represents 8- to 10-membered bicyclic heteroaryl (especially 10-membered bicyclic heteroaryl), wherein the bicyclic heteroaryl is independently monosubstituted by halogen (especially fluorine).

[0058] 12) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 10), wherein Ar 1 represents a 10-membered bicyclic heteroaryl (especially quinoline-diyl), wherein the bicyclic heteroaryl is monosubstituted by halogen (especially fluorine).

[0059] 13) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 12), wherein Ar 2 represents an unsubstituted phenyl group.

[0060] 14) Another embodiment relates to a pharmaceutical composition according to embodiment 1), wherein 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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecan-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]tetraazacycloheptadecan-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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecan-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]tetraazacycloheptadecan-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]tetraazacycloheptadecan-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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[17,16-c]quinoline-3-carboxamide.

[0061] 15) Another embodiment relates to a pharmaceutical composition according to embodiment 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]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide.

[0062] The corresponding structures of the compounds listed in Embodiments 14) and 15) and their chemical names are shown in Table S, wherein in case of doubt the depicted structures shall prevail.

[0063] 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-tetrahydrobenzofurano[7,6-p][1]oxa[4,7,10,14]tetraazacycloheptadecan-18-carboxamide has the structure depicted in Table S, wherein the compound is in the depicted absolute configuration with respect to the chiral centers at carbons 8, 14, and 18; and with respect to the chiral center at carbon 11, the absolute configuration of the chiral center (labeled &1) may be (R) or (S): These compounds include diastereoisomers: , and any mixture thereof.

[0064] 16) Another embodiment relates to a pharmaceutical composition as in any one of embodiments 1) to 15), wherein the one or more therapeutically active ingredients used as CFTR modulators are type I correctors selected from lumacator, tizacator and galicator; and / or a type II corrector, which is corrector 4a; and / or a type III corrector selected from elexacator, bamocator, olacator and wanzacator; and / or a CFTR potentiator selected from ivacator, navacator, esencator, deuteratedicator, GLPG-1837 and GLPG2451; or a pharmaceutically acceptable salt thereof.

[0065] 17) Another embodiment relates to a pharmaceutical composition as in any one of embodiments 1) to 16), wherein the one or more therapeutically active ingredients used as CFTR modulators are type I correctors selected from lumacator, tizacator and galicator; and / or type II correctors, which are corrector 4a; and / or type III correctors selected from elexacator and wanzacator; and / or CFTR potentiators selected from ivacator, navacator, esencator and deutecator; or pharmaceutically acceptable salts thereof.

[0066] 18) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 16), wherein the CFTR corrector is a type I corrector selected from lumacator, tizacator and galicator.

[0067] 19) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 16) or 18), wherein the CFTR corrector is a type II corrector, which is corrector 4a.

[0068] 20) Another 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 elexacatol, bamocatol, olacatol and wanzacatol.

[0069] 21) Another 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, navacaftor, esencator and deutecator.

[0070] 22) Another embodiment relates to a pharmaceutical composition as in any one of embodiments 1) to 17), wherein the composition comprises the compound of formula (I) and a therapeutically active ingredient used as a CFTR modulator, wherein the CFTR modulator is a CFTR potentiator; or a pharmaceutically acceptable salt thereof.

[0071] 23) Another embodiment relates to a pharmaceutical composition as in any one of embodiments 1) to 17) or 22), wherein the composition comprises the compound of formula (I) and a therapeutically active ingredient used as a CFTR modulator, wherein the CFTR modulator is a CFTR potentiator selected from ivacaftor, esencator and deuteratedicator; or a pharmaceutically acceptable salt thereof.

[0072] 24) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 17), wherein the composition comprises the compound of formula (I) and a therapeutically active ingredient that acts as a CFTR modulator, wherein the CFTR modulator is a type I corrector.

[0073] 25) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 17), wherein the composition comprises the compound of formula (I) and a therapeutically active ingredient that acts as a CFTR modulator, wherein the CFTR modulator is a type II corrector.

[0074] 26) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 17), wherein the composition comprises the compound of formula (I) and a therapeutically active ingredient that acts as a CFTR modulator, wherein the CFTR modulator is a type III corrector.

[0075] 27) Another embodiment relates to a pharmaceutical composition as in any one of embodiments 1) to 17), wherein the composition comprises a compound of formula (I) and two therapeutically active ingredients used as CFTR modulators, wherein one of the CFTR modulators is a CFTR potentiator or a pharmaceutically acceptable salt thereof, and the second CFTR modulator is a CFTR corrector or a pharmaceutically acceptable salt thereof.

[0076] 28) Another embodiment relates to a pharmaceutical composition as in any one of embodiments 1) to 17) or 27), wherein the composition comprises a compound of formula (I) and two therapeutically active ingredients used as CFTR modulators, wherein one of the CFTR modulators is a CFTR potentiator or a pharmaceutically acceptable salt thereof, and the second CFTR modulator is a type I corrector or a pharmaceutically acceptable salt thereof.

[0077] 29) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 17), 27) or 28), wherein the composition comprises a compound of formula (I) and ●Ivacaftor and tizacator or a pharmaceutically acceptable salt thereof; or ●Ivacaftor and Lumacaftor or pharmaceutically acceptable salts thereof; or ●Navocato and Gallicato or pharmaceutically acceptable salts thereof.

[0078] 30) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 17) or 27) to 29), wherein the composition comprises the compound of formula (I), navocato and galicato or a pharmaceutically acceptable salt thereof.

[0079] 31) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 17) or 27) to 29), wherein the composition comprises the compound of formula (I), ivacaftor and tizacaftor; or a pharmaceutically acceptable salt thereof.

[0080] 32) Another embodiment relates to a pharmaceutical composition as in any one of embodiments 1) to 17), wherein the composition comprises a compound of formula (I) and three therapeutically active ingredients used as CFTR modulators, wherein one of the CFTR modulators is a CFTR potentiator or a pharmaceutically acceptable salt thereof, the second CFTR modulator is a type I corrector or a pharmaceutically acceptable salt thereof, and the third CFTR modulator is a type III corrector or a pharmaceutically acceptable salt thereof.

[0081] 33) Another embodiment relates to a pharmaceutical composition as in Example 32), wherein the composition comprises a compound of formula (I) and ● Ivacaftor, tizacaftor and elexacaaftor or a pharmaceutically acceptable salt thereof; or ●Deuteratedicator, tizacator and vanzacator or pharmaceutically acceptable salts thereof.

[0082] 34) Another embodiment relates to a pharmaceutical composition as in Example 31), wherein ivacaftor or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage suitable for oral administration of ivacaftor, wherein ivacaftor or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage suitable for oral administration of a total of about 300 mg / day or less of ivacaftor; and ● Tizacator or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage suitable for oral administration of tizacator, wherein tizacator or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage suitable for oral administration of a total of about 100 mg / day or less of tizacator.

[0083] Such combined pharmaceutical compositions as in embodiments 1) to 34) are particularly suitable for preventing or treating CFTR-related diseases as defined herein (especially cystic fibrosis); and for use in a method for preventing or treating CFTR-related diseases as defined herein (especially cystic fibrosis), the method comprising administering a pharmaceutically effective dose of such combined pharmaceutical composition to a subject (especially a human) in need thereof.

[0084] Therefore, according to the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1) to 15) is used in combination (or in the form of combined therapy) with these other pharmaceutically active ingredients as defined herein, which are CFTR modulators (CFTR correctors and / or CFTR potentiators).

[0085] Unless otherwise expressly set forth a definition provides a broader or narrower definition, the definitions provided herein are intended to apply uniformly to any one of embodiments 1) to 43) and to the entire specification and claims mutatis mutandis in detail. It should be fully understood that a definition or preferred definition of a term is independent of any definition or preferred definition (and combination thereof) of any or all other terms as defined herein to define the corresponding term and can replace the corresponding term.

[0086] The term "therapeutically active ingredient used as a CFTR modulator" refers to any CFTR corrector (especially type I, type II or type III corrector) and / or CFTR potentiator that has (alone and / or in combination) demonstrated potential for therapeutic use (tested in in vitro and / or in vivo models, especially in clinical trials) and / or is indicated for such therapeutic use; wherein such therapeutic use is for CFTR-related diseases (especially cystic fibrosis). Examples are especially CFTR potentiators: ivacaftor, navacaftor, esencaftor, deuteratedicaftor, GLPG-1837 and GLPG-2451; and CFTR correctors: type I correctors (lumacaftor, tizacaftor, galicaftor), type II correctors (corrector 4a) and type III correctors (eresacaftor, bamocaftor, olacaftor, wanzacaftor; and ABBV-119, ABBV-567; and PTI-801).

[0087] Therefore, in a sub-embodiment, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1) to 15), which is used for the prevention / prevention or treatment of a CFTR-related disease as defined herein (especially cystic fibrosis); wherein the compound of formula (I) will (is intended to) be administered in combination with a CFTR potentiator / is administered in combination with a CFTR potentiator, such as in particular ivacaftor, navacaftor, esencato or deutecato or a pharmaceutically acceptable salt thereof; optionally, additionally administered in combination with a CFTR corrector (in particular such as lumacaftor, tizacaftor, galicato, elexacato or wanzacato or a pharmaceutically acceptable salt thereof).

[0088] In addition, the present invention relates to a pharmaceutical composition comprising as an active ingredient a compound of formula (I) as defined in any one of embodiments 1) to 15) or a pharmaceutically acceptable salt thereof, and one or more therapeutically active ingredients used as CFTR modulators; wherein one or more of the CFTR modulators are one or more CFTR stabilizers, such as SION-638 or NBD1-A or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient. One or more stabilizers (such as SION-638 or NBD1-A) may additionally be provided as one or more CFTR modulators in embodiments 16) to 43), mutatis mutandis.

[0089] The term "subject" refers to a mammal, particularly a human.

[0090] The combined treatment (or co-therapy) may in particular be effected simultaneously (either in a fixed dosage form or in a non-fixed dosage form).

[0091] In the present application, when referring to an administration type, "simultaneous" means that the relevant administration type is to administer two or more active ingredients and / or treatments at about the same time; wherein it is understood that simultaneous administration will expose the subject to 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, wherein such a non-fixed combination may be a non-fixed dose combination equivalent to a fixed dose combination (e.g., by using two or more different pharmaceutical compositions administered by the same administration route at about the same time), or a non-fixed dose combination using two or more different administration routes or dosing regimens: wherein in each case, the administration causes the subject to be exposed to the two or more active ingredients and / or treatments combined substantially simultaneously. An example of the simultaneous administration of a non-fixed dose combination using two different pharmaceutical compositions administered by the same administration route at about the same time is the following non-fixed dose combination: wherein the compound of formula (I) as defined in any one of embodiments 1) to 15) is administered twice daily, and the corresponding one or more CFTR modulators are administered twice daily. Another example of a non-fixed dose combination administered simultaneously using two different routes of administration is the following non-fixed dose combination: wherein the compound of formula (I) as defined in any one of Embodiments 1) to 15) is administered once or twice daily, and the corresponding one or more CFTR modulators are administered three times daily. Another example of a non-fixed dose combination administered simultaneously using two different routes of administration is the following non-fixed dose combination: wherein the compound of formula (I) as defined in any one of Embodiments 1) to 15) is administered once daily, and the corresponding one or more CFTR modulators are administered twice daily. Another example of a non-fixed dose combination administered simultaneously using two different routes of administration is the following non-fixed dose combination: wherein the compound of formula (I) as defined in any one of Embodiments 1) to 15) is administered twice daily, and the corresponding one or more CFTR modulators are administered once daily.

[0092] In the present application, "fixed dose combination" when referring to the administration type means that the relevant administration type consists in administering a single pharmaceutical composition comprising two or more active ingredients, in particular a pharmaceutical composition such as any one of embodiments 1) to 34).

[0093] 35) Another aspect of 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), which is used to treat CFTR-related diseases and conditions (especially cystic fibrosis); wherein the compound will be used in combination with one or more therapeutically active ingredients used as CFTR modulators / will be administered in combination with the one or more therapeutically active ingredients / is administered in combination with the one or more therapeutically active ingredients; wherein the CFTR modulator is one or more CFTR correctors (especially type I correctors and / or type II correctors and / or type III correctors) and / or CFTR potentiators.

[0094] 36) Another embodiment of 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), which is used to treat CFTR-related diseases and conditions (especially cystic fibrosis); wherein the compound will be used in combination with one or more therapeutically active ingredients used as CFTR modulators / will be administered in combination with the one or more therapeutically active ingredients / is administered in combination with the one or more therapeutically active ingredients; wherein the CFTR modulator is one or more CFTR correctors (especially type I correctors and / or type II correctors and / or type III correctors) and / or CFTR potentiators.

[0095] 37) Another embodiment relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof as used in embodiment 35) or 36), wherein the one or more CFTR modulators are as defined in any one of embodiments 22), 28), 29), 30), 31) or 33).

[0096] 38) Another embodiment relates to a compound of formula (I) as defined in embodiment 15), as used in embodiment 35) or 36), wherein the one or more CFTR modulators are as defined in any one of embodiments 22), 28), 29), 30), 31) or 33).

[0097] 39) Another embodiment relates to compounds of formula (I) as defined in embodiment 15), used in embodiment 35) or 36), wherein the one or more CFTR modulators are as defined in embodiment 29).

[0098] 40) Another embodiment relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof as used in embodiment 35) or 36), wherein the compound 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]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide, wherein the CFTR modulator is navocato and galicato.

[0099] 41) Another embodiment relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof as used in embodiment 35) or 36), wherein the compound 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]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide, wherein the CFTR modulator is ivacaftor and tizacaftor.

[0100] 42) Another aspect of the present invention relates to a kit comprising ● a pharmaceutical composition as defined in any one of embodiments 1) to 34); ● and instructions on how to use the pharmaceutical composition to treat CFTR-related diseases and disorders, particularly cystic fibrosis.

[0101] 43) Another embodiment relates to a kit comprising ● 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 embodiments 16) to 34); • And instructions on how to use these pharmaceutical compositions in combination to treat CFTR-related diseases and disorders, particularly cystic fibrosis.

[0102] It is to be understood that any embodiment relating to a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1) to 15), wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination for the treatment of a CFTR-related disease as defined herein (especially cystic fibrosis), wherein the compound of formula (I) is to be (intended to be) administered in combination with one or more CFTR modulators / is administered in combination with one or more CFTR modulators, wherein the one or more CFTR modulators are one or more CFTR correctors (especially type I, type II, type III correctors) and / or CFTR potentiators or pharmaceutically acceptable salts thereof, wherein the one or more CFTR modulators are especially as defined in any one of embodiments 16) to 34), also 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 combination with the treatment of a CFTR-related disease as defined herein (particularly cystic fibrosis), wherein the compound of formula (I) is to be (intended to be) administered / is administered in combination with said one or more CFTR modulators; The one or more CFTR modulators, which are one or more CFTR correctors and / or CFTR potentiators, or pharmaceutically acceptable salts thereof, are used to treat the CFTR-related diseases (particularly cystic fibrosis); wherein the one or more CFTR modulators (which are one or more CFTR correctors and / or CFTR potentiators) are (intended to be) administered in combination with the compound of formula (I); ● The use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament / pharmaceutical composition for treating these CFTR-related diseases (especially cystic fibrosis), the medicament / pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the one or more CFTR modulators (which are one or more CFTR correctors and / or CFTR potentiators) or a pharmaceutically acceptable salt thereof; ● The use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament / pharmaceutical composition for treating these CFTR-related diseases (especially cystic fibrosis), the medicament / pharmaceutical composition comprising as an active ingredient the compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein the medicament / pharmaceutical composition is to be (intended to be) used in combination with the one or more CFTR modulators (which are one or more CFTR correctors and / or CFTR potentiators) or a pharmaceutically acceptable salt thereof; ● Use of the one or more CFTR modulators (which are one or more CFTR correctors and / or CFTR potentiators) or pharmaceutically acceptable salts thereof for the manufacture of a medicament / pharmaceutical composition for treating these CFTR-related diseases (especially cystic fibrosis), the medicament / pharmaceutical composition comprising as an active ingredient the one or more CFTR modulators (which are one or more CFTR correctors and / or CFTR potentiators) or pharmaceutically acceptable salts thereof; wherein the medicament / pharmaceutical composition is to be (intended to be) used in combination with the compound of formula (I) or a pharmaceutically acceptable salt thereof; ● Use of a pharmaceutical composition for treating these CFTR-related diseases (especially cystic fibrosis), the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and the one or more CFTR modulators (which are one or more CFTR correctors and / or CFTR potentiators) or a pharmaceutically acceptable salt thereof; ● A medicament for preventing or treating these CFTR-related diseases (especially cystic fibrosis), said medicament comprising said compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein said medicament is to be (intended to be) administered in combination with said one or more CFTR modulators (which are one or more CFTR correctors and / or CFTR potentiators) or a pharmaceutically acceptable salt thereof; ● A method for preventing or treating these CFTR-related diseases (especially cystic fibrosis), the method comprising administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject (preferably a human) in need thereof, wherein the compound of formula (I) is administered in combination with an effective amount of one or more CFTR modulators (which are one or more CFTR correctors and / or CFTR potentiators) or a pharmaceutically acceptable salt thereof; wherein it should be understood that the combined administration may be in the form of a fixed-dose combination or in the form of a non-fixed-dose combination; ● A method for preventing or treating these CFTR-related diseases (especially cystic fibrosis), the method 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 one or more CFTR modulators (which are one or more CFTR correctors and / or CFTR potentiators) or pharmaceutically acceptable salts thereof; and ●A method for preventing or treating these CFTR-related diseases (especially cystic fibrosis), which comprises administering an effective amount of one or more CFTR modulators (which are one or more CFTR correctors and / or CFTR potentiators) or pharmaceutically acceptable salts thereof to a subject in need thereof (preferably a human), wherein the one or more anti-CFTR modulators (which are one or more CFTR correctors and / or CFTR potentiators) are administered in combination with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; it should be understood that the combined administration may be in the form of a fixed-dose combination or in the form of a non-fixed-dose combination.

[0103] CFTR-related diseases and disorders may be defined to include, inter alia, cystic fibrosis and other CFTR-related diseases and disorders selected from: Chronic bronchitis; sinusitis; constipation; pancreatitis; pancreatic insufficiency; male infertility due to congenital bilateral absence of the vas deferens (CBAVD); mild lung disease; allergic bronchopulmonary aspergillosis (ABPA); liver disease; coagulation-fibrinolysis defects, such as protein C deficiency; and diabetes mellitus; Asthma; COPD; smoking-induced COPD; and dry eye disease; and =Idiopathic pancreatitis; hereditary emphysema; hereditary hemochromatosis; lysosomal storage diseases, especially those such as I-cell disease (pseudo-Hurler's disease); mucopolysaccharidoses; Sandohoff / 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 (Thomson and Becker); Bartter syndrome type 3; epilepsy; lysosomal storage diseases; primary ciliary dyskinesia (PCD) - a term for inherited disorders of ciliary structure and / or function (including those with situs inversus). PCD (also known as Kartagner syndrome, PCD without situs inversus, and ciliary dysgenesis); generalized epilepsy with febrile seizures plus (GEFS+); generalized epilepsy with febrile and non-febrile seizures; myotonia; paramyotonia congenita; myotonia aggravated by potassium; hyperkalemic periodic paralysis; long QT syndrome (LQTS); LQTS / Brugada syndrome; autosomal dominant LQTS with deafness; autosomal recessive LQTS; LQTS with dysmorphic features; congenital and acquired LQTS; dilated cardiomyopathy; autosomal dominant LQTS; osteopetrosis; and Bartter syndrome type 3.

[0104] The term "treatment of cystic fibrosis" refers to any treatment of cystic fibrosis and in particular includes treatments that reduce the severity of cystic fibrosis and / or reduce the symptoms of cystic fibrosis.

[0105] The term "cystic fibrosis" refers to any form of cystic fibrosis, especially to cystic fibrosis associated with one or more gene mutations. Preferably, such cystic fibrosis is associated with CFTR transport defects (class II mutations) or reduced CFTR stability (class VI mutations) [specifically, CFTR transport defects / class II mutations], wherein it should be understood that such CFTR transport defects or reduced CFTR stability can be associated with another pathogenic mutation of the same or any other category. Such other pathogenic CFTR gene mutations include class I mutations (non-functional CFTR protein), (another) class II mutations (CFTR transport defects), class III mutations (CFTR regulation defects), class IV mutations (CFTR conduction defects), class V mutations (CFTR proteins reduced due to splicing defects) and / or (another) class VI mutations (CFTR proteins reduced due to reduced CFTR stability). The one or more gene mutations may, for example, include at least one mutation selected from the group consisting of F508del, A561E and N1303K, as well as I507del, R560T, R1066C and V520F; in particular F508del. In addition to those listed above, other CFTR gene mutations include, for example, G85E, R347P, L206W and M1101K. The one or more gene mutations may be heterozygous, homozygous or compound heterozygous. The gene mutation is especially heterozygous, including an F508del mutation. Other CFTR gene mutations (especially class III and / or class IV mutations) include G551D, R117H, D1152H, A455E, S549N, R347H, S945L and R117C.

[0106] The severity of cystic fibrosis / the severity of a certain genetic mutation associated with cystic fibrosis and the efficacy of its correction can generally be measured by testing chloride ion transport by CFTR. For example, in patients, average sweat chloride levels can be used for such assessments.

[0107] The term "symptoms of cystic fibrosis" refers in particular to elevated chloride concentrations in sweat; symptoms of cystic fibrosis further include chronic bronchitis; sinusitis; constipation; pancreatitis; pancreatic insufficiency; male infertility due to congenital bilateral absence of the vas deferens (CBAVD); mild lung disease; allergic bronchopulmonary aspergillosis (ABPA); liver disease; coagulation-fibrinolysis defects, such as protein C deficiency; and / or diabetes mellitus.

[0108] Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to refer also to a single compound, salt or the like.

[0109] Any reference to a compound is to be understood as referring also to (where appropriate and suitable) the salts (and especially pharmaceutically acceptable salts) of such compounds.

[0110] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the compound of the present invention and exhibits minimal undesired toxicological effects. Depending on the presence of basic and / or acidic groups in the compound of the present invention, such salts include inorganic or organic acid and / or base addition salts. See, for example, "Handbook of PhramaceuticalSalts.Properties,Selection and Use.", P.Heinrich Stahl, Camille G.Wermuth (eds.), Wiley-VCH, 2008; and "Pharmaceutical Salts and Co-crystals", Johan Wouters and Luc Quéré (eds.), RSC Publishing, 2012 for reference.

[0111] Unless otherwise expressly set out a definition provides a broader or narrower definition, the definitions provided herein are intended to apply uniformly to formula (I) / formula (I) as defined in any one of embodiments 1) to 15). E ) and apply mutatis mutandis to the entire specification and claims. It is fully understood that a definition or preferred definition of a term is independent of and may replace any definition or preferred definition (and combination thereof) of any or all other terms as defined herein.

[0112] Whenever a substituent is indicated as being optionally selected, it is to be understood that such substituent may be absent (i.e., the corresponding residue is unsubstituted with respect to such optional substituent), in which case all positions with free valences (to which such optional substituent may be attached; such as in an aromatic ring, ring carbon atoms and / or ring nitrogen atoms with free valences) are replaced by hydrogen as appropriate. Similarly, if the term "optionally" is used in the context of one or more (ring) heteroatoms, the term means that the corresponding optional one or more heteroatoms or their analogs are absent (i.e., a certain moiety does not contain one or more heteroatoms / is a carbocyclic ring / or its analogs), or the corresponding optional one or more heteroatoms or their analogs are present as explicitly defined.

[0113] The term "halogen" means fluorine / fluoro, chlorine / chloro or bromine / bromo; preferably fluorine / fluoro.

[0114] The term "alkyl", used alone or in combination, refers to a saturated straight or branched chain hydrocarbon group containing one to six carbon atoms. x-y "alkyl" (x and y are each an integer) refers to an alkyl group as defined previously containing x to y carbon atoms. For example, C 1-6 Alkyl groups contain from one to six 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, where a group is referred to as, for example, propyl or butyl, this means n-propyl, n-butyl, respectively. 1 Represents C 1-4 In the case of alkyl, the term refers in particular to methyl. 1-4 The R of the alkyl 2 , the term refers especially to methyl. 3 Indicates -C 1-6 In the case of alkyl, the term means in particular isobutyl.

[0115] The term "alkoxy", alone or in combination, refers to an alkyl-O- group in which alkyl is as previously defined. x-y "alkoxy" (x and y are each an integer) refers to an alkoxy group as defined above containing x to y carbon atoms. For example, C 1-4 Alkoxy means a compound of formula C 1-4 The term "C 1-4 "Alkyl" has the meaning given previously. Representative examples of alkoxy are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Preferred is methoxy.

[0116] The term "fluoroalkyl", used alone or in combination, refers to an alkyl group as previously defined containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced by fluorine. x-y "fluoroalkyl" (x and y are each an integer) refers to a fluoroalkyl group as defined above containing x to y carbon atoms. For example, C 1-3 Fluoroalkyl contains one to three carbon atoms in which one to seven hydrogen atoms have been replaced by fluorine. Representative examples of fluoroalkyl include, in particular, C1 fluoroalkyl groups such as trifluoromethyl and difluoromethyl as well as 2-fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. X2 Represents C 1-4 In the case of fluoroalkyl, the term means in particular 2,2-difluoroethyl or 2,2,2-trifluoroethyl.

[0117] The term "fluoroalkoxy", used alone or in combination, refers to an alkoxy group as previously defined containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced by fluorine. x-y "fluoroalkoxy" (x and y are each an integer) refers to a fluoroalkoxy group as defined above containing x to y carbon atoms. For example, C 1-3 Fluoroalkoxy contains one to three carbon atoms in which one to seven hydrogen atoms have been replaced by fluorine. Representative examples of fluoroalkoxy include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred are (C1) fluoroalkoxy, such as trifluoromethoxy and difluoromethoxy.

[0118] The term "cycloalkyl", used alone or in combination, refers to a saturated monocyclic hydrocarbon ring containing three to six carbon atoms. x-y "cycloalkyl" (x and y are each an integer) refers to a cycloalkyl group as defined above containing x to y carbon atoms. For example, C 3-6 Cycloalkyl groups contain three to six carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0119] If not specifically defined in a broader or narrower manner, the term "heteroaryl", used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one to a maximum of four heteroatoms, each of which is independently selected from oxygen, nitrogen and sulfur. Representative examples of such heteroaryls are 5-membered heteroaryls such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl; 6-membered heteroaryls such as pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl; and 8- to 10-membered bicyclic heteroaryls such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl , indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridinyl, quinolyl, isoquinolyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, imidazopyridinyl, imidazopyridazinyl and imidazothiazolyl. The above-mentioned heteroaryl radicals are unsubstituted or substituted as explicitly defined.

[0120] For the substituent R representing a "5-membered heteroaryl group" 4, the term means in particular isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl; in particular 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-tetrazolyl; in particular 1,2,4-oxadiazol-5-yl. 4 The radicals are unsubstituted or substituted as explicitly defined.

[0121] For the substituent Ar representing an "8- to 10-membered bicyclic heteroaryl group" 1 , the 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. The Ar 1 The radicals are unsubstituted or substituted as explicitly defined.

[0122] The compound of formula (I) contains at least three stereoisomers or asymmetric centers, which exist in (R)- or (S)-configuration, as defined in the corresponding embodiments of the compounds of such formula (I). In addition, the compound of formula (I) may contain one or more other stereoisomers or asymmetric centers, such as one or more additional asymmetric carbon atoms. Therefore, the compound of formula (I) can exist in the form of a mixture of stereoisomers, or preferably in the form of pure stereoisomers. The mixture of stereoisomers can be separated in a manner known to those skilled in the art. In the case where any stereoisomer or asymmetric center in a given chemical name is expressed as (RS)-configuration, this means that such stereoisomers or asymmetric centers in such compounds can exist in the form of (R)-configuration, in the form of (S)-configuration or in any mixture of diastereomers about such centers.

[0123] 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-tetradecahydrooxazol [4',5':5,6]benzo[1,2-p][1]oxa[4,7,10,14]tetraazacycloheptadecan-18-carboxamide contains (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]tetraazacycloheptadecan-18-carboxamide; Compound (8R,11S,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]tetraazacycloheptadecan-18-carboxamide, and any mixture thereof. Similarly, in a chemical structure (such as in Table S), a stereoisomer or asymmetric center indicated as "abs" represents the stereoisomer or asymmetric center in the corresponding (R)- or (S)-configuration. A stereoisomer or asymmetric center indicated as "&1" means that stereoisomer or asymmetric center in the corresponding (RS)-configuration, ie, any mixture containing the corresponding (R)- or (S)-configuration or diastereomers at such centers.

[0124] Unless used in relation to temperature, the term "about" preceding a numerical value "X" in this application refers to an interval extending from X minus 10% of X to X plus 10% of X and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the specific case of temperature, the term "about" preceding a temperature "Y" in this application refers to an interval extending from temperature Y minus 10°C to Y plus 10°C, preferably to an interval extending from Y minus 5°C to Y plus 5°C, and especially to an interval extending from Y minus 3°C to Y plus 3°C. Room temperature means a temperature of about 25°C. When the term n equivalents (where n is a numerical value) is used in this application, the term means and within the scope of this application that n refers to approximately the numerical value n, preferably n refers to the exact numerical value n.

[0125] Whenever the term "between" or "to" is used to describe a numerical range, it should be understood that the endpoints of the specified range are explicitly included in the range. For example: if a temperature range is described as being between 40°C and 80°C (or 40°C to 80°C), this means that the endpoints 40°C and 80°C are included in the range; or if a variable is defined as an integer between 1 and 4 (or 1 to 4), this means that the variable is an integer of 1, 2, 3 or 4.

[0126] The term "substantially" is to be understood in the context of the present invention as meaning in particular that the corresponding amount / purity / time etc. is at least 90%, in particular at least 95%, and especially at least 99% of the corresponding total amount. For example, when used in the term "substantially simultaneous exposure", it is to be understood as meaning in particular that the corresponding exposure results in simultaneous exposure to the pharmaceutically effective amount of all combined active ingredients during at least 90%, in particular at least 95%, and especially at least 99% of the time (i.e. on the same day) when considering exposure to the pharmaceutical active ingredients in a long-term / steady state.

[0127] Specific embodiments of the invention are described in the following examples, which serve to illustrate the invention in more detail without limiting its scope in any way.

[0128] Experimental Section I. Chemical substances All temperatures are stated in °C. Commercially available starting materials were used as received without further purification. Unless otherwise specified, all reactions were performed in oven-dried glassware under nitrogen atmosphere. Compounds were purified by silica gel flash column chromatography or by preparative HPLC. The compounds described in the present invention are characterized by LC-MS data (retention time t RMolecular weights obtained from mass spectra are given in g / mol). Where compounds of the invention are present as mixtures of conformers, especially where visible in their LC-MS spectra, the retention time of the most abundant conformer is given.

[0129] Analytical LC-MS equipment: HPLC pump: Binary gradient pump, Agilent G4220A or equivalent Autosampler: Gilson LH215 (with Gilson 845z syringe) or equivalent Column compartment: Dionex TCC-3000RS or equivalent Degasser: Dionex SRD-3200 or equivalent Refill Pump: Dionex HPG-3200SD or equivalent DAD detector: Agilent G4212A or equivalent MS detector: Single quadrupole mass analyzer, Thermo Finnigan MSQPlus or equivalent ELS detector: Sedere SEDEX 90 or equivalent

[0130] LC-MS under acidic conditions Method A: Column: Waters Atlantis T3 (3.0 μm, 2.1×50 mm). Conditions: MeCN+0.1% formic acid [eluent A]; water+0.1% formic acid [eluent B]. Gradient: 95% B→2% B in 5 minutes (flow rate 0.8 ml / min). Detection: UV / Vis+MS. Method B: Column: Zorbax RRHD SB-aq (1.8 μm, 2.1×50 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 95% B → 5% B in 2.0 minutes (flow rate: 0.8 ml / min). Detection: UV / Vis + MS. Method C: Column: Waters XSelect CSH C18 (3.5 μm, 2.1×30 mm). Conditions: MeCN+0.1% formic acid [eluent A]; water+0.1% formic acid [eluent B]. Gradient: 95% B→2% B in 1.6 minutes (flow rate 1 ml / min), detection: UV / Vis+MS. Method D: Column: Waters BEH C18 (2.1×50 mm, 2.5 μm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 95% B → 5% B in 2.0 min (flow rate: 0.8 ml / min). Detection: UV / Vis + MS. Method E: Waters Acquity Binary Solvent Manager, MS: Waters SQ Detector or Xevo TQD or SYNAPT G2MS, DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD. Column: ACQUITY UPLC CSH C18 1.7 μm 2.1×50 mm from Waters, thermostated at 60°C in Acquity UPLC Column Manager. Eluent: A: H2O+0.05% formic acid; B: MeCN+0.045% formic acid. Method: Gradient: 2% B→98% B in 2.0 min. Flow rate: 1.0 mL / min. Detection: UV 214 nm and ELSD, and MS, t R Given in minutes.

[0131] LC-MS under alkaline conditions Method F: Column: Waters BEH C18 (2.5 μm, 2.1×50 mm). Conditions: water / NH3 [c(NH3)=13 mmol / l] [eluent A]; MeCN [eluent B]. Gradient: 5% B→95% B in 2 minutes (flow rate 0.8 ml / min). Detection: UV / Vis+MS. 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 → 2% B in 1.6 minutes (flow rate 1 ml / min), detection: UV / Vis + MS.

[0132] Preparative HPLC equipment: Gilson 333 / 334HPLC pump equipped with Gilson LH215, Dionex SRD-3200 degasser, Dionex ISO-3100A replenishment pump, Dionex DAD-3000DAD detector, single quadrupole mass analyzer MS detector, Thermo Finnigan MSQ Plus, MRA100-000 splitter, Polymer Laboratories PL-ELS1000ELS detector

[0133] Preparative HPLC under alkaline 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 for preparative HPLC (flow rate: 75 ml / min), the starting percentage (x) of eluent A depends on the polarity of the compound to be purified. Detection: UV / Vis+MS Preparative HPLC Table 1 Time (minutes) 0 0.01 4.0 6.0 6.2 6.6 Eluent A (%) x x 95 95 x x Eluent B (%) 100-x 100-x 5 5 100-x 100-x

[0134] Preparative HPLC under acidic conditions Column: Waters Atlantis T3 (10 μm, 75×30 mm). Conditions: MeCN [eluent A]; water + 0.5% HCO2H [eluent B]; Gradient see Table 2 for preparative HPLC (flow rate: 75 ml / min), starting percentage (x) of eluent A depends on the polarity of the compound to be purified. Detection: UV / Vis+MS Preparative HPLC Table 2 Time (minutes) 0 0.01 4.0 6.0 6.2 6.6 Eluent A (%) x x 95 95 x x Eluent B (%) 100-x 100-x 5 5 100-x 100-x

[0135] Preparative HPLC for Chiral Separations In most cases, the desired diastereomers can be separated or purified by standard preparative scale HPLC according to standard methods well known to those skilled in the art. In some cases, it is recommended to use a chiral chromatography column to separate complex mixtures of diastereomers. The best results are obtained using a chiral stationary phase column (such as Chiralpak IA, IB or IC columns based on fixed amylose or cellulose chiral phases) and an isocratic eluent based on a mixture of MeCN and EtOH or MeOH varying in ratios ranging from 9:1 to 1:9. To compensate for the presence of ionizable functional groups in the purified compound, a modifier can be added to the solvent mixture, such as 0.1% diethylamine (for basic derivatives) or 0.1% formic acid (for acidic derivatives). In some cases, supercritical fluid chromatography is used, using the same chiral stationary phase column as described above and an isocratic eluent consisting of 50% to 90% supercritical carbon dioxide and EtOH, MeOH or a 1:1 EtOH:MeCN mixture. Detection: UV / Vis.

[0136] Abbreviations (as used above or below): AcOH Acetic acid aq. Aqueous solution atm atmosphere BnBr Toluene bromide Boc tert-Butyloxycarbonyl Boc2O Di-tert-butyl dicarbonate nBuLi n-butyllithium CHCl3 Chloroform d Days DCM Dichloromethane DIAD Diisopropyl azodicarboxylate DIPEA Diisopropyl-ethylamine, Hünig'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 Vacuum evaporation Ex. Example FC Silica gel flash chromatography Fmoc 9-fluorenylmethoxycarbonyl h hour HATU Hexafluorophosphate 3-oxido(1-[bis(dimethylamino)methylene]- 1H-1,2,3-Triazolo[4,5-b]pyridinium hept hex hexane HPLC High Performance Liquid Chromatography HV High Vacuum Conditions LC-MS liquid chromatography-mass spectrometry Lit. M mol / l Me Methyl MeCN Acetonitrile MeI Methyl iodide Meldrum's acid 2,2-dimethyl-1,3-dioxane-4,6-dione MeOH Methanol mL milliliters 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 / Activated Carbon Pd(OH)2 / C palladium hydroxide / activated carbon (Pearlman's catalyst) Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0) Ph Phenyl PhMe Toluene PPh3 Triphenylphosphine prep. Preparation PyClop Chlorotripyrrolidinylphosphonium hexafluorophosphate rac racemic RM reaction mixture RT Room temperature s seconds sat. saturated Selectfluor 1-Chloromethyl-4-fluoro-1,4-diazobicyclo[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 uM micromolar XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0137] Preparation of precursors and intermediates amine: Commercially available amines are depicted in Tables AM. Table AM amine name AM1 2-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)ethan-1-amine.HCl AM2 2-(5-Cyclopropyl-1,2-oxazol-3-yl)ethan-1-amine AM3 2-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)ethan-1-amine.HCl AM4 2-(3-Methyl-1,2-oxazol-5-yl)ethan-1-amine.HCl

[0138] Non-commercially available amines were synthesized as described below.

[0139] 2-(3-Cyclopropylisoxazol-5-yl)ethan-1-amine hydrochloride (AM5) Step 1: To a 0°C 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) was added dropwise a solution of DIAD (61.7 mL, 318 mmol) in THF (350 mL), and the RM was stirred for 1 hour. The RM was concentrated in vacuo, and the residue was dissolved in hot PhMe (370 mL), followed by the slow addition of MeOH (210 mL). The RM was cooled to room temperature, and MeOH was added until a white solid precipitated. The RM was partially concentrated, followed by the collection of the solid by filtration, washing with cold PhMe and then air drying to give 2-(but-3-yn-1-yl)isoindoline-1,3-dione. LC-MS C: t R = 1.81 min; no ionization.

[0140] Step 2: To a room temperature solution of hydroxylamine.HCl (37.2 g, 535 mmol) in H2O (125 mL) was carefully added Na2CO3 (22.7 g, 214 mmol), followed by the slow addition of a solution of cyclopropanecarboxaldehyde (26.7 mL, 357 mmol) in EtOH (100 mL). The RM was stirred for 1 hour and then partitioned between H2O and EtOAc and extracted. The layers were separated and the aqueous phase was re-extracted with EtOAc (2 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the crude product, which was recrystallized from n-heptane to give E / Z-cyclopropanecarboxaldehyde oxime as a white solid. LC-MS C: t R = 2.13 and 2.30 min; no ionization.

[0141] Step 3: To a 0 ° C solution of cyclopropanecarbaldehyde oxime (19.3 g, 226 mmol) and pyridine (0.83 mL, 10.3 mmol) in DMF (100 mL) was added NCS (34.3 g, 257 mmol) portionwise, and the RM was stirred for 3 hours. A solution of 2-(but-3-yn-1-yl)isoindoline-1,3-dione (21.0 g, 103 mmol) in DMF (100 mL) was added, followed by TEA (28.7 mL, 206 mmol), and the RM was stirred for 3 hours. The RM was partitioned between H2O and DCM and extracted. The layers were separated and the aqueous phase was re-extracted with DCM (2 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give a crude product which was 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.

[0142] Step 4: To a room temperature suspension of 2-(2-(3-cyclopropylisoxazol-5-yl)ethyl)isoindoline-1,3-dione (28.0 g, 97 mmol) in EtOH (100 mL) was added hydrazine.H2O (9.44 mL, 194 mmol) and the RM was heated to 80 °C for 5 h. The RM was cooled to room temperature and filtered, washing with EtOH. The filtrate was concentrated in vacuo and the residue was suspended in Et2O and filtered again, washing with Et2O. The filtrate was partially concentrated before adding Et2O (100 mL) containing 1M HCl and the precipitate was filtered and dried in vacuo to give the title compound as a white solid. LC-MS G: t R =1.42 minutes; [M+H] + =153.1.

[0143] 2-(5-Cyclopropyl-2H-tetrazol-2-yl)ethan-1-amine hydrochloride (AM6) Step 1: To a room temperature suspension of 5-cyclopropyl-2H-1,2,3,4-tetrazolyl (1.00 g, 8.81 mmol) and K2CO3 (1.46 g, 10.6 mmol) in MeCN (20 mL) was added tert-butyl N-(2-bromoethyl)carbamate (2.22 g, 9.7 mmol) and the RM was heated to 50 ° C for 4 hours. The RM was allowed to reach room temperature, then MeCN was evaporated, followed by the addition of water and EtOAc. The layers were separated and the aqueous phase was re-extracted with EtOAc (2 times). The combined organic layers were dried (MgSO4), filtered and evaporated. Purification by FC (eluted with heptane containing 20% ​​to 80% EtOAc) gave tert-butyl (2-(5-cyclopropyl-2H-tetrazolyl-2-yl)ethyl)carbamate (1.21 g, 55%) as a colorless oil. LC-MS F: t R = 0.80 min; [M+H] + =254.35.

[0144] Step 2: To a rt solution of tert-butyl (2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)carbamate (1.21 g, 4.81 mmol) in dioxane (26 mL) was added 4M HCl in dioxane (12 mL, 48.1 mmol) and the RM was stirred at rt for 46 h. The RM was concentrated and coevaporated with Et2O in vacuo to afford the title compound as a white solid (0.92 g, 100%). LC-MS F: t R =0.44 min; [M+H] + =154.25.

[0145] 2-(3-Methoxy-1,2,4-oxadiazol-5-yl)ethan-1-amine hydrochloride (AM7) Step 1: To a room temperature solution of boc-β-Ala-OH (5.0 g, 25.9 mmol), o-methylisourea hydrogen sulfate (4.5 g, 25.9 mmol) and DIPEA (18.1 mL, 104 mmol) in DMF (150 mL) was added HATU (11.82 g, 31.1 mmol), and the RM was stirred at room temperature for 1.5 hours. Water and EtOAc were added to the RM, then the two layers were separated, and the organic layer was extracted with EtOAc (2 times). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to give a crude product, which was purified by FC (eluted with 20% to 100% EtOAc in heptane) 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.

[0146] Step 2: To a room temperature 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) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (8.96 mL, 59.3 mmol) and the RM was 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) were added and stirring was continued for 16 h. The suspension was filtered and the filtrate was washed with H2O, saturated aqueous NaHCO3 and brine before being evaporated to dryness. The crude product was purified by FC (eluting with 20% to 100% EtOAc in heptane) to give tert-butyl (2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)carbamate as a colorless oil. LC-MS F: t R = 0.75 min; [M+H] + =244.33.

[0147] Step 3: To a RT solution of tert-butyl (2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)carbamate (150 mg, 0.62 mmol) in DCM (2 ml) was added 4M HCl in dioxane (0.62 mL, 2.47 mmol) and the RM was stirred at RT for 4 days then at 50 °C for 6 h. The mixture was evaporated to give the title compound as a white solid (79 mg, 71%). LC-MS F: t R = 0.35 min; [M+H]+ =144.21.

[0148] 2-(4-Cyclopropyl-2H-1,2,3-triazol-2-yl)ethan-1-amine hydrochloride (AM8) Step 1: To a room temperature 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), tripotassium phosphate (758 mg, 3.5 mmol) and tricyclohexylphosphine (45.1 mg, 0.156 mmol) in toluene (22 mL) and H2O (0.22 mL) was added Pd(OAc)2 (17.1 mg, 0.076 mmol). The mixture was heated to 100 °C for 18 h. The RM was cooled to room temperature, the mixture was then filtered, and the filtrate was concentrated. The residue was purified by FC (eluted with heptane containing 5% to 40% EtOAc, wherein R in heptane / EtOAc 7:3 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.

[0149] Step 2: To a room temperature 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) was added 4M HCl in dioxane (4.9 mL, 19.6 mmol). The RM was stirred at room temperature for 30 min, then the RM was concentrated to give the title compound (432 mg, 98%) as a white solid, which was used as is in the next step. LC-MS B: t R = 0.37 min; [M+H] + =153.11.

[0150] 2-(3-Methoxyisoxazol-5-yl)ethan-1-amine hydrochloride (AM9) Step 1: To a room temperature 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) was added DPPA (1.32 mL, 6.1 mmol) dropwise, and the RM was heated to 100 ° C for 1.5 hours. 2-Methylpropan-2-ol (1.06 mL, 11.1 mmol) was added, and the RM was heated to reflux for 16 hours. The RM was cooled to room temperature and distributed between saturated NaHCO aqueous solution and EtOAc, and the layers were separated. The aqueous phase was re-extracted with EtOAc (2 times) and the combined organic extracts were washed with brine, dried over NaSO, filtered and evaporated in vacuo. The crude product was purified by FC (eluting with 0% to 100% EtOAc in heptane) 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.

[0151] Step 2: The title compound was prepared in an analogous manner to the procedure described for AM8, Step 2 from tert-butyl (2-(3-methoxyisoxazol-5-yl)ethyl)carbamate. LC-MS B: t R = 0.28 min; [M+H] + =143.09.

[0152] 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 room temperature suspension of AM9 (402 mg, 2.25 mmol) and DIPEA (0.47 mL, 2.7 mmol) in dioxane (12 mL). The tube was sealed and heated to 100 ° C for 48 hours. Water was added to RM, and the mixture was acidified with 1M HCl, and the product was extracted with EtOAc, dried (MgSO4), 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 as is in the next step. LC-MS B: t R = 0.85 min; [M+H] + =273.09.

[0153] Step 2: To a 40 °C 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) was added Selectfluor (1.07 g, 2.87 mmol) and the RM was heated to 120 °C for 18 h. The resulting dark brown solution was cooled to about 50 °C and then the RM was poured into pre-stirred H2O (30 mL) and then into EtOAc (10 mL). The two layers were separated and the inorganic layer was extracted with EtOAc (5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by preparative HPLC (acidic) gave 2-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)isoindoline-1,3-dione (89 mg) as a colorless oil. LC-MS B: t R = 0.90 min; [M+H] + =291.02.

[0154] Step 3: To a room temperature solution of 2-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)isoindoline-1,3-dione (85 mg, 0.293 mmol) in EtOH (3 mL) was added hydrazine monohydrate (0.222 mL, 2.93 mmol) and the RM was heated to 80 °C for 1 hour. The RM was cooled to room temperature and a white precipitate formed. Diethyl ether was added and the solid was ground before filtering off. The filtrate was concentrated to give the title compound (40 mg) as a colorless oil, which was used as is in the next step. LC-MS B: t R = 0.33 min; [M+H] + =161.08.

[0155] Preparation of building blocks A (S)-tert-Butyl 3-amino-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoate (A1) Step 1: To a room temperature solution of Fmoc-L-aspartic acid β-tert-butyl ester (12.26 g, 29.20 mmol) and DIPEA (7.5 mL, 43.8 mmol) in DMF (100 mL) was added HATU (11.10 g, 29.2 mmol). After stirring at room temperature for 5 min, a solution of 2-(3-methylisoxazol-5-yl)ethyl-1-amine hydrochloride (AM4, 5.00 g, 29.2 mmol) and DIPEA (7.5 mL, 43.8 mmol) in DMF (100 mL) was added and stirring was continued for 30 min. The RM was partitioned between H2O and EtOAc, and the layers were separated. The aqueous layer was re-extracted with EtOAc (2 times) and the combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to give (S)-tert-butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoate as a yellow oil which was used as is in the next step. LC-MSF: t R = 1.10 min; [M+H] + =520.26.

[0156] Step 2: To a rt solution of (S)-tert-butyl 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) was added piperidine (15.0 mL, 150.0 mmol) and the RM was stirred for 30 min. The RM was concentrated and the residue was directly purified by FC (eluting with 100:2:0.5 DCM:MeOH:NH3) to give the title compound as a pale yellow solid (4.02 g). LC-MS F: t R =0.64 min; [M+H] + =298.26.

[0157] Listed below in Table A are building blocks A, which were prepared in a similar manner to the 2-step sequence described above for A1. Table A

[0158] (S)-3-Amino-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoic acid allyl ester hydrochloride (A11) Step 1: To a room temperature solution of Boc-L-aspartic acid-β-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) was added HATU (6.80 g, 17.9 mmol) and the RM was stirred for 18 h. The mixture was concentrated and the crude product was purified by FC (100% DCM to DCM / MeOH 9 / 1) and then by preparative HPLC (acidic) to give (S)-3-((tert-butoxycarbonyl)amino)-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoic acid allyl ester (3.76 g). LC-MS B: t R =0.83 min; [M+H] + =382.41.

[0159] Step 2: To a solution of (S)-allyl 3-((tert-butoxycarbonyl)amino)-4-((2-(3-methylisoxazol-5-yl)ethyl)amino)-4-oxobutanoate (3.76 g) in DCM (15 mL) was added 4M HCl in dioxane (4.87 mL, 39.5 mmol) and the RM was stirred at rt for 2 h. The volatiles were removed in vacuo and the residue was triturated with Et2O to give the title compound as a white solid. LC-MS F: t R =0.57 min; [M+H] + =282.21.

[0160] Preparation of building block B (R)-3-(2-Amino-3-phenylpropoxy)quinoline-4-carboxylic acid benzyl ester dihydrochloride (B1) Step 1: To a solution of 3-hydroxyquinoline-4-carboxylic acid (10.0 g, 52.9 mmol) in DMF (100 mL) was added KHCO (5.88 g, 58.1 mmol) and BnBr (7.69 mL, 63.4 mmol), and the RM was stirred for 16 hours. The RM was filtered and the filtrate was concentrated in vacuo. The residue was distributed between H2O and EtOAc. The layers were separated and the aqueous layer was re-extracted with EtOAc (2 times). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. The crude product was purified by FC (eluted with heptane containing 20% ​​to 80% EtOAc) to give 3-hydroxyquinoline-4-carboxylic acid benzyl ester (6.97 g) as a white solid. LC-MS B: t R = 0.95 min; [M+H] + =280.19.

[0161] Step 2: To a 0°C mixture of benzyl 3-hydroxyquinoline-4-carboxylate (1.47 g, 5.26 mmol), (R)-tert-butyl (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 DIAD (1.9 mL, 9.47 mmol) 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 heptane) to give benzyl (R)-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)quinoline-4-carboxylate (2.55 g) as a white solid. LC-MS B: t R =1.17 minutes; [M+H] + =513.06.

[0162] Step 3: To a solution of (R)-benzyl 3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)quinoline-4-carboxylate (2.55 g, 4.98 mmol) in dioxane (11.5 mL) was added 4M HCl in dioxane (12.5 mL, 49.8 mmol) and the RM was stirred at 50 °C for 1 h. The volatiles were removed in vacuo and the residue was triturated with Et2O (3 times) to give the title compound as a pale yellow solid. LC-MS B: t R =0.83 min; [M+H] + =413.34.

[0163] (R)-6-(2-amino-3-phenylpropoxy)-2-methylbenzo[d]oxazole-7-carboxylic acid methyl ester hydrochloride (B2) Step 1: To a 0°C solution of methyl 2,6-dihydroxybenzoate (1.0 g, 6.0 mmol) in acetic acid (10 mL) was carefully added nitric acid (0.36 mL, 6.0 mmol), and the RM was warmed to room temperature and stirred for 1 hour. The RM was poured into cold water, and the precipitate was collected by filtration and washed with additional cold water before vacuum drying to give methyl 2,6-dihydroxy-3-nitrobenzoate as a pink solid. LC-MS B: t R = 0.75 min; no ionization. 1 H 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).

[0164] Step 2: To a suspension of methyl 2,6-dihydroxy-3-nitrobenzoate (500 mg, 2.3 mmol) in triethyl orthoacetate (13.5 mL, 72 mmol) was added dioxane (1.45 mL, 5.8 mmol) containing 4M HCl, and the RM was evacuated / purged with N2 (3 times), followed by the addition of 10% Pd / C (173 mg, 7 mol%). The RM was evacuated / purged with H2 (3 times) and stirred under H2 atmosphere for 16 hours. 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).

[0165] Steps 3 to 4: Prepare the title compound from methyl 6-hydroxy-2-methylbenzo[d]oxazole-7-carboxylate following the sequence of reactions described in 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 extended periods of time.

[0166] (R)-6-(2-amino-3-phenylpropoxy)imidazo[1,2-a]pyridine-5-carboxylic acid methyl ester dihydrochloride (B3) Step 1: To a 0°C solution of methyl-3-hydroxypicolinate (2.41 g, 15.7 mmol) in water (110 mL) was added Br2 (0.81 mL, 15.7 mmol) dropwise, and the RM was warmed to room temperature and stirred overnight. The RM was quenched with 40% aqueous sodium bisulfite solution and extracted with DCM (2 times). The combined organic extracts were 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 minutes; [M+H] + =231.9.

[0167] Step 2: (R)-6-bromo-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinic acid methyl ester was prepared from 6-bromo-3-hydroxypicolinic acid methyl ester and (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamic acid tert-butyl ester in a similar manner to the procedure described in B-1.1 Step 2. LC-MS C: tR = 2.16 minutes; [M+H- t Bu] + =409.0.

[0168] Step 3: To a room temperature mixture of (R)-methyl 6-bromo-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinate (5.0 g, 10.5 mmol), benzyl aminocarboxylate (1.67 g, 11.1 mmol) and CsCO (5.15 g, 15.8 mmol) in dioxane (130 mL) was added Pd(dba) (483 mg, 0.53 mmol) and XPhos (201 mg, 0.42 mmol) and the RM was heated to 95 °C and stirred for 48 h. The RM was cooled to rt, filtered and the filtrate concentrated in vacuo then purified by FC (eluting with 0% to 40% EtOAc in heptane) 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 minutes; [M+H] + =536.2.

[0169] Step 4: A solution of (R)-6-(((benzyloxy)carbonyl)amino)-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinic acid methyl ester (1.43 g, 2.19 mmol) in EtOH (20 mL) was purged / evacuated with N2 (3 times) followed by the addition of 10% Pd / C (70 mg, 0.07 mmol). After additional inerting three times, a H2 balloon was connected and the RM was stirred at 55 °C for 1 hour. The mixture was filtered through a plug of celite, rinsed with EtOH. The filtrate was concentrated to give (R)-6-amino-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinic acid methyl ester as a yellow oil. LC-MS G: t R = 2.00 min; [M+H] + =402.2.

[0170] Step 5: To a mixture of (R)-methyl 6-amino-3-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)picolinate (0.50 g, 1.25 mmol) and NaHCO (209 mg, 2.49 mmol) in EtOH (15 mL) was added 50% aqueous 2-chloroacetaldehyde (0.475 mL, 3.74 mmol) and the RM was heated to 70 °C and stirred for 5 hours. The RM was concentrated in vacuo and the residue was partitioned between water and EtOAc and extracted. The layers were separated and the aqueous phase was re-extracted with EtOAc (2 times). The combined organic extracts were washed with brine, dried over NaSO, filtered and evaporated in vacuo. The crude product was purified by FC (eluting with 50% to 100% EtOAc in heptane) to give (R)-methyl 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.

[0171] Step 6: The title compound was prepared in a similar manner to the procedure described in B1, Step 3. LC-MS G: t R =1.83 min; [M+H] + =326.2.

[0172] (R)-6-(2-Amino-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylic acid benzyl ester dihydrochloride (B4) Step 1: To a room temperature solution of 3-fluoroquinoline-6-ol (0.50 g, 3.06 mmol) and NaOAc (0.30 g, 3.68 mmol) in AcOH (20 mL) was added a solution of Br2 (0.17 mL, 3.37 mmol) in AcOH (8.0 mL), and the RM was stirred for 30 minutes. The RM was concentrated to dryness and the residue was distributed between saturated NaHCO3 aqueous solution and EtOAc. The layers were separated and the aqueous layer was re-extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated to give 5-bromo-3-fluoroquinoline-6-ol as a brown solid. LC-MS G: t R =1.38 minutes; [M+H] + =239.9.

[0173] Step 2: To a room temperature suspension of NaH (0.17 g, 4.29 mmol) in THF (15 mL) was added dropwise a solution of 5-bromo-3-fluoroquinoline-6-ol (0.74 g, 3.06 mmol) in THF (15 mL) and the resulting mixture was stirred for 15 minutes, followed by dropwise addition of methoxymethyl bromide (0.3 mL, 3.67 mmol) at 0 ° C. After stirring at 0 ° C for 1.5 hours, the RM was quenched by adding H2O and extracted with EtOAc. The organic layer was washed with NaHCO3, brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by FC (eluted with 2% to 30% EtOAc in heptane) to give 5-bromo-3-fluoro-6-(methoxymethoxy)quinoline as a colorless oil. LC-MS G: t R = 2.03 min; no ionization.

[0174] Step 3: nBuLi (1.6M in hexane, 0.98mL, 1.57mmol) was added dropwise to a -78°C solution of 5-bromo-3-fluoro-6-(methoxymethoxy)quinoline (300mg, 1.05mmol) in THF (18mL), and the RM was stirred for 30 minutes. The RM was quenched with freshly ground dry ice (1.0g, 22.7mmol), and then warmed to room temperature and stirred for 30 minutes. The RM was concentrated in vacuo and the intermediate lithium carboxylate was dissolved in DMF (4mL), followed by the addition of KHCO (31.5mg, 0.315mmol) and BnBr (0.15mL, 1.26mmol), and the RM was heated to 60°C for 10 minutes. The RM was cooled to room temperature and distributed between saturated NaHCO aqueous solution and EtOAc. The layers were separated, and the aqueous layer was extracted again with EtOAc (2 times). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by preparative 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.

[0175] Step 4: TFA (0.24mL, 3.13mmol) was added to a room temperature solution of 3-fluoro-6-(methoxymethoxy)quinoline-5-carboxylic acid benzyl ester (107mg, 0.31mmol) in DCM (3mL), and the resulting mixture was stirred at room temperature for 2 hours. The RM was concentrated in vacuo, the residue was dissolved in EtOAc, and extracted with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with brine, dried (NaSO4), filtered and concentrated to give 3-fluoro-6-hydroxyquinoline-5-carboxylic acid benzyl ester as a light brown oil. LC-MS G: t R =2.06 minutes; [MH] - =298.1.

[0176] Step 5: To a 0°C mixture of benzyl 3-fluoro-6-hydroxyquinoline-5-carboxylate (93.8 mg, 0.31 mmol), (R)-tert-butyl (1-hydroxy-3-phenylpropan-2-yl)carbamate (82 mg, 0.33 mmol) and PPh3 (86 mg, 0.33 mmol) in THF (2 mL) was added DIAD (0.064 mL, 0.33 mmol) 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 60% EtOAc in heptane) 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.

[0177] Step 6: To a solution of (R)-benzyl 6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylate (94 mg, 0.18 mmol) in dioxane (3 mL) was added 4M HCl in dioxane (0.44 mL, 1.77 mmol) and the RM was stirred at rt for 24 h. The volatiles were removed in vacuo and the residue was triturated with Et2O (3 times) to give the title compound as a white solid. LC-MS G: t R =2.10 min; [M+H] + =431.2

[0178] (R)-6-(2-Amino-3-phenylpropoxy)-8-methylquinoline-5-carboxylic acid benzyl ester (B5) Step 1: To a room temperature solution of 4-methoxy-2-methylaniline (5.0 g, 35.7 mmol) in EtOH (50 mL) was added Michaelis acid (6.04 g, 41.1 mmol) and triethyl orthoformate (6.06 mL, 35.7 mmol), and the RM was heated to 80 ° C for 2 hours. The RM was cooled to room temperature and the precipitate was collected by filtration, washed 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 = 0.90 min; [M+H] + =292.13.

[0179] Step 2: 5-(((4-methoxy-2-methylphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.19 g, 28.1 mmol) was dissolved in Dowtherm A (50 mL) and heated to 250 °C for 5 min. The RM was cooled to rt and diluted with Et2O, and the precipitate was collected by filtration and washed with Et2O before drying under HV to give 6-methoxy-8-methylquinolin-4-ol as a brown solid. LC-MS B: t R = 0.58 min; [M+H] + =190.21.

[0180] Step 3: Phosphorus tribromide (2.16 mL, 22.7 mmol) was added to a room temperature solution of 6-methoxy-8-methylquinolin-4-ol (3.91 g, 20.7 mmol) in DMF (75 mL), and the RM was heated to 45 ° C for 1 hour. The RM was cooled to room temperature, diluted with water, and the pH was adjusted to 8 by adding saturated aqueous NaHCO3. The precipitate was collected by filtration and dissolved in EtOAc, washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 10% EtOAc in heptane) to give 4-bromo-6-methoxy-8-methylquinoline as a white solid. LC-MS B: t R = 0.82 min; [M+H] + =254.03.

[0181] Step 4: To a -78 °C solution of 4-bromo-6-methoxy-8-methylquinoline (7.2 g, 28.5 mmol) in THF was added nBuLi (1.6 M in hexanes, 35.7 mL, 57.1 mmol) dropwise and the RM was stirred for 30 min. The reactant was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by FC (eluted with 20% EtOAc in heptane) to give 6-methoxy-8-methylquinoline as a yellow oil. LC-MS B: t R = 0.49 min; [M+H] + =174.26.

[0182] Step 5: To a room temperature 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) was added Br2 (1.45 mL, 28.2 mmol) and the RM was stirred for 10 min. The RM was quenched with saturated NaHSO3 aqueous solution and extracted with EtOAc (2 times). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in PhMe and concentrated in vacuo (2 times) to give 5-bromo-6-methoxy-8-methylquinoline as a green solid. LC-MS B: t R =0.74 min; [M+H] + =252.09.

[0183] Step 6: To a 0°C solution of 5-bromo-6-methoxy-8-methylquinoline (3.57 g, 14.2 mmol) in DCM (70 mL) was added BBr3 (1 M in DCM, 42.5 mL, 42.5 mmol) dropwise. The cooling bath was removed and the RM was stirred at room temperature for 2 hours. The RM was carefully quenched into cold MeOH and concentrated in vacuo. The residue was co-evaporated with PhMe, EtOAc and DCM to give 5-bromo-8-methylquinolin-6-ol as a yellow solid. LC-MS B: t R = 0.55 min; [M+H] + =238.01.

[0184] Step 7: (R)-tert-butyl (1-((5-bromo-8-methylquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamate was prepared from 5-bromo-8-methylquinolin-6-ol and (R)-tert-butyl (1-hydroxy-3-phenylpropan-2-yl)carbamate in an analogous manner to the procedure described for B1, Step 2. LC-MS B: t R = 1.10 min; [M+H]+ =472.94.

[0185] Step 8: To a -78°C solution of (R)-tert-butyl(l-((5-bromo-8-methylquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamate (185 mg, 0.39 mmol) in THF (2 mL) was added nBuLi (1.6 M in hexanes, 0.54 mL, 0.86 mmol) dropwise and the RM was stirred for 30 min before benzyl chlorocarboxylate (0.058 mL, 0.41 mmol) was added dropwise. The RM was warmed to rt and quenched by addition of saturated aqueous NaHCO3 and extracted with EtOAc. The layers were separated and the aqueous phase was re-extracted with EtOAc (2x) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by preparative HPLC (acidic) to give (R)-benzyl 6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-8-methylquinoline-5-carboxylate as a white solid. LC-MS B: t R =1.11 min; [M+H] + =527.33.

[0186] Step 9: To a room temperature solution of (R)-benzyl 6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-8-methylquinoline-5-carboxylate (550 mg, 1.04 mmol) in DCM (5 mL) was added TFA (4.0 mL, 52.2 mmol) and the RM was stirred for 1 h. The RM was concentrated in vacuo and the residue was co-evaporated with DCM (2 times) before purification by preparative HPLC (basic) to give the title compound as a yellow oil. LC-MS B: t R =0.78 min; [M+H] + =427.23.

[0187] (R)-6-(2-amino-3-phenylpropoxy)-2-methylbenzofuran-7-carboxylic acid methyl ester hydrochloride (B6) Step 1: DMAP (120 mg, 0.99 mmol) was added to a 0 ° C solution of 2,6-dihydroxybenzoic acid (3.0 g, 19.7 mmol) in 1,2-dimethoxyethane (15 mL), followed by dropwise addition of acetone (1.9 mL, 25.8 mmol) and thionyl chloride (1.85 mL, 25.2 mmol), and the RM was stirred for 30 minutes, after which the RM was warmed to room temperature and stirred for 16 hours. The RM was quenched by adding saturated aqueous NaHCO3 and extracted with Et2O (4 times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by FC (eluted with heptane containing 0% to 50% EtOAc) 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 minutes; [M+H] + =195.1.

[0188] Step 2: To a room temperature 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) was added KCO (2.38 g, 17.2 mmol) and 3-bromopropyne (80% solution in PhMe, 1.67 mL, 15.5 mmol), and the RM was heated to 55 °C for 21 hours. The mixture was concentrated and the residue was partitioned between water and EtOAc. The layers were separated and the aqueous layer was re-extracted with EtOAc (2 times). The combined organic extracts were washed with brine, dried over NaSO, filtered and evaporated in vacuo. The crude product was purified by FC (eluting with 5% to 35% EtOAc in heptane) 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.

[0189] Step 3: To a 0 °C 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) was added NaOMe (30% solution in MeOH, 1.9 mL, 10.1 mmol) and the RM was warmed to room temperature and stirred for 1 h. The RM was quenched with 1 M aqueous HCl and extracted with EtOAc (3 times). The combined organic extracts were 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 minutes; [M+H] + =207.0.

[0190] 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) was purged with N2 before irradiation in a MW oven at 200 °C for 55 min. The RM was diluted with EtOAc and washed with 1 M aqueous HCl. The aqueous phase was extracted with EtOAc (2 times) and the combined organic extracts were washed with 1 M HCl, brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by FC (eluting with 1% to 15% EtOAc in heptane) to give methyl 6-hydroxy-2-methylbenzofuran-7-carboxylate as a white solid. LC-MS C: t R =1.98 minutes; [M+H] + =207.0.

[0191] Steps 5 to 6: The title compound was prepared from methyl 6-hydroxy-2-methylbenzofuran-7-carboxylate in a similar manner to the procedures described for B1 steps 2 and 3. LC-MS G: t R =1.98 minutes; [M+H] + =340.1.

[0192] (R)-6-(2-Amino-3-phenylpropoxy)-3-methylisoquinoline-5-carboxylic acid benzyl ester dihydrochloride (B7) Step 1: To a -10 °C solution of 2-hydroxy-4-methoxybenzaldehyde (16 g, 105 mmol) and pyridine (42.5 mL, 526 mmol) in DCM (70 mL) was added trifluoromethanesulfonic anhydride (26.2 mL, 158 mmol) dropwise and the RM was stirred for 30 min. The RM was quenched with ice water and acidified with 1 M aqueous HCl before extraction with EtOAc (2 times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give 2-formyl-5-methoxyphenyl trifluoromethanesulfonate as a yellow oil. 1 H NMR (400MHz, CDCl3) δ10.13 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.03 (dd, J = 8.7, 2.3 Hz, 1H), 6.88 (d, J = 2.3 Hz, 1H), 3.93 (s, 3H).

[0193] Step 2: A room temperature solution of 2-formyl-5-methoxyphenyl trifluoromethanesulfonate (19.6 g, 66.4 mmol) and TEA (93 mL, 664 mmol) in DMF (400 mL) was purged with Ar for 30 minutes. Prop-1-yne (1M 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 closed and stirred for 2 hours. The RM was filtered through a diatomaceous earth pad and the filtrate was partially concentrated in vacuo, then diluted with EtOAc, and washed with 1M KHSO4 solution and brine in sequence and concentrated in vacuo. The crude product was purified by FC (eluted with heptane containing 0% to 30% EtOAc) to give 4-methoxy-2-(prop-1-yne-1-yl)benzaldehyde as a yellow solid. LC-MS G: t R =1.80 min; [M+H] + =175.1.

[0194] Step 3: In an autoclave, a room temperature solution of 4-methoxy-2-(prop-1-yn-1-yl)benzaldehyde (10.3 g, 58.8 mmol) in MeOH (350 mL) was purged with Ar for 5 min. NH3 7M in MeOH (150 mL, 1050 mmol) was added and the RM was heated to 65 °C for 4 h with the pressure reaching 2 bar. The RM was concentrated in vacuo and the residue was co-evaporated with DCM (2 times) to give 6-methoxy-3-methylisoquinoline as a brown solid. LC-MS G: t R =1.81 min; [M+H] + =174.1.

[0195] Step 4: To a -78 °C solution of 6-methoxy-3-methylisoquinoline (5.0 g, 27.7 mmol) in DCM (100 mL) was added BBr3 (1 M in DCM, 55.4 mL, 55.4 mmol) dropwise. The cooling bath was removed and the RM was stirred at rt for 30 h. The RM was carefully quenched into cold MeOH and concentrated in vacuo. The residue was 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.

[0196] Step 5: To a suspension of 3-methylisoquinolin-6-ol (4.67 g, 19.4 mmol) in CHCl (75 mL) was added Br (1.3 mL, 25.3 mmol) dropwise and the RM was stirred for 2 h. EtOAc was added and the solid was collected by filtration, washed with EtOAc and heptane. The filtration residue was neutralized by suspending it in saturated aqueous NaHCO and filtered again, then washed with H2O and heptane. The filtration residue was 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.

[0197] Step 6: (R)-tert-butyl (1-((5-bromo-3-methylquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamate was prepared from 5-bromo-3-methylisoquinolin-6-ol and (R)-tert-butyl (1-hydroxy-3-phenylpropan-2-yl)carbamate in an analogous manner to the procedure described for B1, Step 2. LC-MS G: t R =2.21 minutes; [M+H] + =471.1.

[0198] Step 7: A RT solution of (R)-tert-butyl(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) was purged with Ar for 10 min. The RM was then purged with CO and heated to 88 °C under CO atmosphere before Pd( tThe mixture was stirred for 24 h under a CO atmosphere. The RM was cooled to room temperature and concentrated in vacuo, and the residue was partitioned between saturated aqueous NaHCO3 and EtOAc and extracted. The layers were separated and the aqueous phase was re-extracted with EtOAc (1 time), and the combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by FC (eluting with 5% to 65% EtOAc in heptane) to give (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-3-methylisoquinoline-5-carboxylic acid benzyl ester as a colorless oil. LC-MS G: t R =2.19 minutes; [M+H] + =527.2.

[0199] Step 8: The title compound was prepared from (R)-benzyl 6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-3-methylisoquinoline-5-carboxylate in an analogous manner to the procedure described for B1, Step 3. LC-MS G: t R =1.95 min; [M+H] + =427.2.

[0200] (R)-3-(2-Amino-3-phenylpropoxy)-6-fluoroquinoline-4-carboxylic acid benzyl ester dihydrochloride (B8) The title compound was prepared from 6-fluoro-3-hydroxyquinoline-4-carboxylic acid in a similar manner to the procedure described for B1, steps 1 to 3. LC-MS F: t R =1.12 minutes; [M+H] + =431.24.

[0201] Preparation of building block C N-(N-(tert-Butyloxycarbonyl)-N-methyl-L-leucyl)-N-methyl-D-alanine (C1) Step 1: To a 0°C solution of (tert-butoxycarbonyl)-D-alanine (2.01 g, 10.62 mmol) in THF (10 mL) was added MeI (1.0 mL, 16.06 mmol) followed by NaH (1.08 g, 27.1 mmol). After 30 min at 0°C, the RM was warmed to room temperature and stirring was continued for 3 h. The mixture was quenched with H2O and acidified with 0.5 M KHSO4 (pH 2). The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to give N-(tert-butoxycarbonyl)-N-methyl-D-alanine as a brown oil which was used as is in the next step.

[0202] Step 2: To a room temperature solution of N-(tert-butoxycarbonyl)-N-methyl-D-alanine (2.16 g, 10.6 mmol) in acetone (6 mL) was added K2CO3 (2.84 g, 20.5 mmol), 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 hours. The mixture was cooled to room temperature, filtered and the filtrate was concentrated to give N-(tert-butoxycarbonyl)-N-methyl-D-alanine benzyl ester, which was used as is in the next step. LC-MS G: t R =2.19 minutes; [M+H] + = No ionization.

[0203] Step 3: To a room temperature solution of N-(tert-butoxycarbonyl)-N-methyl-D-alanine benzyl ester (11.0 g, 34.2 mmol) in DCM (3 mL) was added 4M HCl in dioxane (0.56 mL, 12.0 mmol) and the resulting mixture was stirred for 18 h. The suspension was filtered and washed with Et2O (2 times) to give methyl-D-alanine benzyl ester HCl as a white solid. LC-MSG: t R =1.80 min; [M+H] + =194.2.

[0204] Step 4: To a pre-stirred room temperature 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) was added methyl-D-alanine benzyl ester hydrochloride (0.82 g, 3.6 mmol) and DIPEA (1.0 mL, 5.75 mmol) in DMF (1 mL), and the resulting mixture was stirred for 18 hours. The mixture was concentrated and the residue was distributed between H2O and EtOAc. The layers were separated and the aqueous layer was re-extracted with EtOAc (2 times). The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated to give a crude product, which was ground with Et2O to give N-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-methyl-D-alanine benzyl ester as a colorless oil. LC-MS F:t R =2.33 minutes; [M+H] + =421.2.

[0205] Step 5: A solution of N-(N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)-N-methyl-D-alanine benzyl ester (1.32 g, 3.13 mmol) in EtOH (20 mL) was purged / evacuated with N2 (3 times) followed by the addition of 10% Pd / C (333 mg, 10 mol%). The RM was evacuated / purged with H2 (3 times) and stirred under H2 atmosphere for 2 h. The mixture was concentrated and filtered through a plug of celite, rinsing with EtOH. The filtrate was concentrated to give the title compound as a colorless oil. LC-MS C: t R =1.98 minutes; [M+H] + =331.20. 1 H NMR(400MHz,DMSO)δ5.03-4.46(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).

[0206] 2-((S)-2-((tert-Butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanamido)-4,4,4-trifluorobutyric 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 a room temperature solution of 2-amino-4,4,4-trifluorobutyric acid methyl ester hydrochloride (6.81 g, 31.1 mmol) in MeOH (20 mL), and the resulting mixture was stirred at room temperature for 1 hour. NaBH3CN (2.27 g, 34.3 mmol) was then added and stirring was continued for 45 minutes. The mixture was evaporated to dryness, then partitioned between H2O and DCM, and the layers were separated. The aqueous layer was extracted with DCM and the combined organic extracts were dried (Na2SO4), filtered and evaporated to give racemic-(R)-2-(benzylamino)-4,4,4-trifluorobutyric acid methyl ester as a brown oil, which was used as is in the next step. LC-MS F: t R = 0.96 min; [M+H] + =262.37.

[0207] Step 2: To a room temperature solution of rac-(R)-methyl 2-(benzylamino)-4,4,4-trifluorobutyrate (8.07 g, 30.9 mmol) in MeOH (100 mL) was added NaOAc (12.67 g, 155 mmol), TFA (2.39 mL, 30.9 mmol) and formaldehyde (37% in H2O, 2.53 mL, 34 mmol) and the resulting mixture was stirred at room temperature for 1 hour. NaBH3CN (2.25 g, 34.0 mmol) was then added and stirring continued. After 1.5 hours, formaldehyde (37% in H2O, 0.46 mL, 6.18 mmol) and NaBH3CN (409 mg, 6.18 mmol) were added and the mixture was stirred at room temperature for another 2 hours. The mixture was evaporated to dryness, partitioned between H2O and DCM, and the layers were separated. The aqueous layer was re-extracted with DCM and the combined organic extracts were dried (Na2SO4), filtered and evaporated to give (R)-2-(benzyl(methyl)amino)-4,4,4-trifluorobutanoic acid rac-methyl ester as a brown oil which was used as such in the next step. LC-MS F: t R = 0.96 min; [M+H] + =262.37.

[0208] Step 3: A solution of rac-(R)-methyl 2-(benzyl(methyl)amino)-4,4,4-trifluorobutyrate (6.48 g, 23.5 mmol) in EtOH (200 mL) was evacuated / purged with Ar (3 times) followed by the addition of Pd / C (1.25 g, 5 mol%). The RM was evacuated / purged with H2 (3 times) and stirred under H2 atmosphere for 2.5 hours. The mixture was filtered and the solids were rinsed with MeOH. 4M HCl (5.89 mL, 23.5 mmol) was added and the mixture was evaporated to dryness to give rac-(R)-methyl 4,4,4-trifluoro-2-(methylamino)butyrate hydrochloride as an off-white solid which was used as is in the next step. LC-MS F: t R = 0.6 min; [M+H] + =186.37.

[0209] Step 4: To a room temperature solution of Boc-N-methyl-L-leucine (6.24 g, 24.7 mmol), rac-(R)-4,4,4-trifluoro-2-(methylamino)butanoic acid methyl ester hydrochloride (5.47 g, 24.7 mmol) and DIPEA (16.9 mL, 98.7 mmol) in DMF (80 mL) was added HATU (11.26 g, 29.6 mmol) portionwise and the resulting mixture was stirred for 1 hour. Water was added and the mixture was extracted with EtOAc (3 times). The combined organic extracts were washed successively with saturated aqueous NaHCO3, H2O and brine, dried (Na2SO4), filtered and concentrated. Purification by FC (eluting with 15% EtOAc in heptane) gave methyl-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanamido)-4,4,4-trifluorobutyrate as a pale yellow oil. LC-MS B: t R =1.06 min; [M+H] + =413.29.

[0210] Step 5: To a room temperature 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) was added 2M aqueous NaOH (6.9 mL, 13.8 mmol) and the mixture was stirred at room temperature for 1.5 hours. The volatiles were removed in vacuo and the residual aqueous solution was neutralized with 2M aqueous HCl before extraction with DCM (3 times). The combined organic layers were 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.

[0211] (R)-2-((S)-2-(((allyloxy)carbonyl)(methyl)amino)-N,4-dimethylpentanamido)-2-cyclopentylacetic acid (C3) Step 1: To a room temperature solution of Boc-N-Me-L-leucine (2.78 g, 11 mmol) in DCM (20 mL) was added 4M HCl in dioxane (11 mL, 44 mmol). The mixture was stirred at room temperature for 2 hours. The RM was concentrated to give (S)-4-methyl-2-methylamino-pentanoic acid (2.14 g) which was used as is in the next step.

[0212] Step 2: To (S)-4-methyl-2-methylamino-pentanoic acid (1.59 g, 11 mmol) and Na2CO3 (4.08 g, 38.5 mmol) in dioxane / H2O 3 / 5 (48 mL) was added allyl chloroformate (1.27 mL, 11.6 mmol). The mixture was stirred at room temperature overnight, then the RM was diluted with EtOAc and acidified to pH 2 using 2M aqueous HCl. The layers were separated and the aqueous layer was extracted with EtOAc (2 times). The combined organic layers were dried (Na2SO4), filtered and concentrated to give N-((allyloxy)carbonyl)-N-methyl-L-leucine (2.5 g, 99%) which was used as is in the next step. LC-MS B: t R = 0.80 min; [M+H] + =230.43.

[0213] Step 3: To a 0 °C solution of (R)-methyl 2-((tert-butoxycarbonyl)amino)-2-cyclopentylacetate (420 mg, 1.73 mmol) in DMF (8 mL) was added NaH (60% dispersion in mineral oil, 265 mg, 6.92 mmol) followed by MeI (0.87 mL, 13.8 mmol) and the RM was warmed to RT overnight. The solvent was evaporated and the crude product was 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.

[0214] Step 4: To a 0 °C solution of (R)-methyl 2-((tert-butoxycarbonyl)(methyl)amino)-2-cyclopentylacetate (350 mg, 1.29 mmol) in DCM (3 mL) was added 4M HCl in dioxane (0.32 mL, 1.29 mmol) and the mixture was 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) were added to the RM at RT and the mixture was then heated to 40 °C for 2 h. Water was added to the RM and the product was extracted with DCM (2 times). The combined organic layers were dried (MgSO4), filtered and concentrated. Purification by FC gave (R)-methyl 2-((S)-2-(((allyloxy)carbonyl)(methyl)amino)-N,4-dimethylpentanamido)-2-cyclopentylacetate. LC-MS B: t R =1.08 min; [M+H] + =383.24.

[0215] Step 5: To a RT solution of methyl (R)-2-((S)-2-(((allyloxy)carbonyl)(methyl)amino)-N,4-dimethylpentanamido)-2-cyclopentylacetate (171 mg, 0.45 mmol) in a solvent mixture of MeOH / H2O3 / 1 (2.5 mL) was added LiOH.H2O (37.5 mg, 0.89 mmol) and the RM was heated to 100 °C for 15 h. MeOH was evaporated and the residue was acidified to pH 1 with 2M HCl then extracted with EtOAc (3 times). The combined organic layers were dried (MgSO4), filtered and evaporated to give the title compound which was used as is in the next step. LC-MS B: t R = 0.96 min; [M+H] + =369.13.

[0216] (R)-2-((S)-2-((tert-Butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanamido)-4,4-difluorobutyric acid (C4) Step 1: To a room temperature suspension of (R)-2-amino-4,4-difluorobutyric acid (1.0 g, 7.19 mmol) in dioxane (20 mL) was added 1 M aqueous NaOH solution (13.5 mL, 13.5 mmol). Boc2O (1.64 g, 7.42 mmol) was added to the RM and stirred at room temperature for 24 hours. The mixture was concentrated and the residue was acidified with 4 M aqueous potassium hydrogen sulfate solution and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude residue was redissolved in MeCN and washed with heptane, then co-evaporated with Et2O to give (R)-2-((tert-butoxycarbonyl)amino)-4,4-difluorobutyric acid as a colorless oil, which was used as is in the next step. LC-MS B: t R = 0.70 min; [M+H] + =240.26

[0217] Step 2: To a 0°C suspension of (R)-2-((tert-butoxycarbonyl)amino)-4,4-difluorobutyric acid (1.41 g, 5.89 mmol) in DMF (23 mL) was added a 60% dispersion of NaH in mineral oil (0.46 g, 12.1 mmol). The RM was stirred at 0°C for 10 min, then stirred at room temperature for an additional 10 min. The RM was cooled back to 0°C, then MeI (0.76 mL, 12.1 mmol) was added dropwise and the RM was returned to room temperature overnight. Water and EtOAc were added, then the two layers were separated and the aqueous layer was further extracted with EtOAc (2 times). The combined organic layers were dried (Na2SO4), filtered and concentrated to give (R)-methyl 2-((tert-butoxycarbonyl)(methyl)amino)-4,4-difluorobutyrate as a yellow oil, which was used as is in the next step. LC-MS B: t R = 0.88 min; [M+H] + =268.17.

[0218] Step 3: To a room temperature solution of (R)-methyl 2-((tert-butoxycarbonyl)(methyl)amino)-4,4-difluorobutanoate (1.57 g, 5.89 mmol) in DCM (40 mL) was added TFA (4.51 mL, 58.9 mmol) and the RM was stirred at room temperature for 2 h. The volatiles were removed in vacuo and the residue was co-evaporated with DCM (3 times) to give (R)-4,4-difluoro-2-(methylamino)butanoic acid methyl ester, which was used as is in the next step. LC-MS B: t R = 0.24 min; [M+H] + =168.05.

[0219] Steps 4 and 5: The title compound was prepared from (R)-4,4-difluoro-2-(methylamino)butanoic acid methyl ester and Boc-N-methyl-L-leucine following the sequence of reactions described for C2, Steps 4 and 5. LC-MS B: t R = 0.93 min; [M+H] + =381.26.

[0220] Listed below in Table C are building blocks C, which were prepared from Boc-N-methyl-L-leucine and the corresponding SM in a 4-step sequence analogous to that described above for C4 (steps 2 to 5). Alternatively, in step 3, Boc deprotection can be performed in the presence of 4M HCl in dioxane instead of TFA. Table C

[0221] 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]tetraazacycloheptadecano[16,17-f]isoquinoline-3-carboxamide (Example 1) Step 1: To a room temperature 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) was added HATU (829 mg, 2.12 mmol) and the RM was stirred for 2.5 h. The RM was partitioned between H2O and EtOAc. The layers were separated and the aqueous layer was re-extracted with EtOAc (2 times). The combined organic layers were washed with saturated NaHCO3 aqueous solution, 1 M aqueous solution, citric acid, H2O and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by preparative 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 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-carboxylic acid benzyl ester (296 mg) (LC-MS F: t R =1.37 minutes; [M+H] + =808.03).

[0222] 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) was evacuated / purged with N2 (3 times) followed by addition of 10% Pd / C (51.4 mg, 5 mol%). The RM was evacuated / purged with H2 (3 times) and stirred under H2 atmosphere for 2 h. The RM was filtered through a pad of celite and the filtrate was 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.

[0223] step 3: To a rt 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) was added HATU (27.9 mg, 0.07 mmol) and the RM was stirred for 10 min. The RM was directly purified by preparative HPLC (basic) to give (S)-tert-butyl 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 minutes; [M+H] + =1014.33.

[0224] Step 4: To a rt solution of (S)-tert-butyl 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) was added TFA (0.40 mL, 5.0 mmol) and the RM was stirred for 1.5 h. The RM was concentrated and the residue was redissolved in DCM and concentrated again (2x). The residue was dissolved in DMF (1.5 mL), then DIPEA (0.04 mL, 0.25 mmol) and HATU (14.4 mg, 0.04 mmol) were added and the RM was stirred for 5 min. The RM was directly purified by preparative HPLC (basic) to give the title compound as a white solid. LC-MS E: t R = 0.84 min; [M+H] + =839.4.

[0225] Note: In the case where the product of step 1 above is a methyl or ethyl ester rather than the described benzyl ester (e.g., Example 41 below), alkaline hydrolysis is performed using 10 equivalents of 2M NaOH aqueous solution in MeOH at room temperature or when heated to 80°C. Then, the subsequent reaction sequence remains the same as described in Example 1. In some cases, chiral chromatography is used to obtain the desired product in the form of pure stereoisomers. In some cases, the product of step 1 remains a mixture of stereoisomers, and the mixture is subjected to the synthesis sequence to obtain the final example, i.e., a mixture of diastereomers. In some cases, the mixture of stereoisomers is separated by chiral chromatography.

[0226] The compounds of general formula (I) listed in the following table MC-1 were prepared in a manner analogous to the synthesis described in Example 1 from the corresponding building blocks A, B and C. Table MC-1 *Denotes an example compound isolated during synthesis that was most often separated into the minor epimer by preparative HPLC purification of the final synthetic step due to epimerization of a chiral center. In some cases, enantiomerically or diastereomerically pure building blocks underwent epimerization during synthesis, and the example compound was isolated as a mixture of epimers.

[0227] (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]tetraazacycloheptadecano[17,16-c]quinoline-3-carboxamide (Example 44) Step 1: T3P (50% in DMF, 0.50 mL, 0.82 mmol) was added to a room temperature 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), and the RM was stirred at elevated temperature for 2 hours. H2O was added and the mixture was extracted with DCM. The organic layer was concentrated and the crude residue was purified by FC 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-ene-1-yl)oxy)quinoline-4-carboxylic acid benzyl ester.

[0228] Step 2: To a rt 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 solvent mixture of THF / H2O 2 / 1 (1.0 mL) was added LiOH.H2O (19.3 mg, 0.456 mmol) and the RM was heated to 50 °C for 3 days. THF was evaporated and the residue was acidified to pH 3 with 2M HCl then extracted with DCM (3 times). The combined organic layers were 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 was used as such in the next step. LC-MS B: t R =1.09 min; [M+H] + =673.09.

[0229] step 3: To a rt 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, 0.22 mmol) and DIPEA (0.153 mL, 0.989 mmol) in DCM (2 mL) was added HATU (95.1 mg, 0.25 mmol) and the RM was stirred at rt for 3 h. Purification by FC gave (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-oxobutanoic acid allyl ester.

[0230] Step 4: To a RT solution of (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-oxobutanoic acid allyl ester (160 mg, 0.171 mmol) and 1,3-dimethylbarbituric acid (53.9 mg, 0.342 mmol) in DCM (2 mL) was added Pd(Ph3)4 (20.2 mg, 0.017 mmol) and the RM was stirred at RT for 1 h. The RM was 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 was used as such in the next step.

[0231] Step 5: To a room temperature 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 (max 0.171 mmol) and DIPEA (90 μL, 0.51 mmol) in DCM (2 mL) was added HATU (66.3 mg, 0.171 mmol) and the RM was stirred at room temperature for 30 min. Purification by preparative HPLC (basic) gave the title compound. LC-MS E: t R =1.27 minutes; [M+H] + =794.6.

[0232] The compounds of general formula (I) listed in the following Table MC-2 were prepared from the corresponding building blocks A, B and C in a manner analogous to the synthesis described in Example 44. Table MC-2

[0233] The table of the examples below lists compounds of formula (I) prepared according to the methods described above. The configuration at stereocenters not mentioned in the compound names is unknown, however only one diastereomer exists. Example Table Table S: Structures of the compounds of Examples 1 to 45

[0234] In Table S above, a stereoisomer or asymmetric center indicated as "abs" in a structure represents that stereoisomer or asymmetric center in the corresponding enantiomerically enriched absolute (R)- or (S)-configuration as depicted. A stereoisomer or asymmetric center indicated as "&1" in a structure represents that stereoisomer or asymmetric center in the corresponding (RS)-configuration (i.e., including the corresponding enantiomerically enriched (R)-configuration or enantiomerically enriched (S)-configuration), or any mixture of diastereomers at such a center.

[0235] II. Biological analysis The compounds of the invention may be further characterized for general pharmacokinetic and pharmacological properties, for example, for their bioavailability in different species (such as rats or dogs), or for their properties with respect to drug safety and / or toxicological properties, for example, for cytochrome P450 enzyme inhibition and time-dependent inhibition, pregnane X receptor (PXR) activation, glutathione binding or phototoxicity, using routine analytical methods well known in the art.

[0236] Biological in vitro assays Compound EC 50 and E max Evaluation of value The corrector activity of compounds of formula (I) on CFTR was determined according to the following experimental method. The method measures the effect of overnight compound incubation on F508del-CFTR cell surface expression in a recombinant U2OS cell line (DiscoveRx, #93-0987C3). This cell line is engineered to co-express (i) Prolink-tagged human F508del-CFTR (PK = short β-galactosidase fragment) and (ii) the rest of the β-galactosidase (enzyme receptor; EA) localized to the plasma membrane. Incubation with compounds that increase PK-tagged F508del-CFTR at the plasma membrane will result in complementation of the EA fragment, thereby forming a functional β-galactosidase, which is quantified by a chemiluminescent reaction.

[0237] Briefly, cells were seeded at 3500 cells / well in 384-well low volume plates (Corning, #3826) in 20 μl complete medium (Mc Coy's 5a (#36600-021, Gibco) + 10% FBS Gibco + penicillin / streptomycin). The cells were incubated in an incubator for 5 hours, followed by the addition of 5 μl / well of compound dilutions listed (5× working stock in complete medium). The final DMSO concentration in the assay was 0.25%. Cells were co-incubated with compounds in an incubator at 37° C., 5% CO2 for 16 hours. The next day, the cell plates were incubated in the dark at room temperature for 2 hours. Next, 10 μl / well of flash detection reagent (DiscoverX, #93-0247) was added, the plates were incubated for another 30 minutes in the dark at room temperature, and chemiluminescence was measured. Concentration-response curves were generated using the compound's intrinsic maximal efficacy as the upper plateau, and from these CRCs, the compound's intrinsic EC 50 Value. Compound specific E max Values ​​are the E of the reference calibrant Lumacato max (E max Lumacator = 100%).

[0238] Calculated EC 50 The values ​​may fluctuate depending on the performance of the daily analysis. Such fluctuations are known to those skilled in the art. EC values ​​from several measurements 50 Values ​​are given as geometric means. max The value of E may fluctuate depending on the performance of the daily analysis. Such fluctuations are known to those skilled in the art. max Values ​​are given as arithmetic means. Biological data table:

[0239] The combination of the compound of formula (I) and a CFTR corrector with a different mechanism can reduce the expression of F508del- Example of Restoration of CFTR Expression The restoration of F508del-CFTR cell surface expression by combinations of Example Compound 3 and CFTR correctors with different mechanisms can be determined in vitro using the DiscoveRx enzyme fragment complementation assay.

[0240] Combination efficacy experiment: Restoration of F508del-CFTR cell surface expression in recombinant U2OS cell line This assay uses U2OS cells expressing human F508del-CFTR chloride channelopathy as mentioned above (DiscoveRx, #93-0987C3). Cells were seeded at 3500 cells / well in 20 μl complete medium (Mc Coy's 5a (#36600-021, Gibco) + 10% FBS Gibco + penicillin / streptomycin) in 384-well low volume plates (Corning, #3826). The cells were incubated in an incubator for 5 hours, followed by the addition of 5 μl / well of compound dilutions (5× working stock in complete medium) to the specified concentration. The final DMSO concentration in the assay was 0.34%. Cells were co-incubated with compounds at 37°C, 5% CO2 for 16 hours. The next day, the cell plates were incubated in the dark at room temperature for 2 hours. Next, 10 μl / well of Flash Detection Reagent (DiscoverX, #93-0247) was added, the plate was incubated for another 30 minutes at room temperature in the dark, and chemiluminescence was measured. The measured values ​​are expressed as fold change relative to baseline values ​​(absence of CFTR calibrator = vehicle treatment).

[0241] The results of the combined efficacy experiment are presented in Figure 1 middle.

[0242] Figure 1 Analysis of F508del-CFTR cell surface expression caused by treatment with 200 nM Example Compound 3 when used with a basal treatment of CFTR correctors with different mechanisms, such as 2 μM Tizacato or 0.2 μM Gallicato (both type I correctors), or 5 μM corrector 4a (type II corrector) or 2 μM Erezacato (type III corrector) or a combination of [2 μM Tizacato + 2 μM Erezacato] (type I corrector + type III corrector) is shown. Example Compound 3 enhances F508del-CFTR surface expression when used with all basal treatments. Error bars represent standard error of the mean.

[0243] Figure 6 Analysis of F508del-CFTR cell surface expression caused by treatment with 200nM Example Compound 3 when used with a basal treatment of a CFTR corrector with a type III corrector mechanism, such as 2μM eresacato or 5μM of the compound of Example 2 of WO 2019 / 071078 (PTI-801) is shown. Example Compound 3 enhances F508del-CFTR surface expression when used with these basal treatments. Adding one type III corrector (eresacato; 2μM) to another type III corrector (PTI-801; 5μm) does not cause an additive effect. Error bars represent standard error of the mean.

[0244] The combination of the compound of formula (I) with a CFTR corrector and a CFTR potentiator having different mechanisms can Example of F508del-CFTR functional restoration The 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.

[0245] Combination efficacy experiment: Restoration of F508del-CFTR function in recombinant U2OS cell line This assay uses U2OS cells expressing human F508del-CFTR chloride channelopathy (DiscoveRx, #93-0987C3) and a halide-sensitive mutant form of yellow fluorescent protein (YFP Topaz F46L / H148Q / I152L; US2006 / 0257934A1). Based on the property of YFP to bind iodide, resulting in quenching of its fluorescence, this mutant YFP reports the entry of exogenously added iodide (the replacement ion) through functional surface CFTR.

[0246] Cells were seeded at 20,000 cells / well in 384-well black clear bottom plates in 40 μl / well of growth medium (Mc Coy's 5a (#36600-021, Gibco) + 10% FBSGibco + penicillin / streptomycin) containing the indicated concentrations of various CFTR calibrants. The final DMSO concentration in the assay was 0.1%. Cells were incubated with compounds at 37°C, 5% CO2 for 24 hours. The next day, the plates were washed with 55 μl / well of PBS + (containing 0.9 mM Ca 2+ and 0.5 mM Mg 2+The cells were washed twice with PBS (0.4 μM forskolin, 0.2% bovine serum albumin (fatty acid-free), pH 7.4) and the cells were incubated in the dark for 30 minutes. The final DMSO concentration in the assay was 0.5%. Subsequently, the plate was transferred to a FLIPR Tetra (fluorescent imaging plate reader, molecular devices: excitation 470-495 nm; emission: 526-585 nm), and a baseline fluorescence reading of the YFP signal was performed for 6 seconds (10×0.6 second intervals), after which 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 added and the fluorescence reading was continued for 70 seconds (50×0.6 second intervals; 20×2 second intervals) to assess YFP quenching caused by iodide influx mediated by CFTR. For analysis, the fluorescence traces were aligned and normalized (normalized fluorescence=1) at the last time point before the addition of iodide. The degree of YFP quenching, i.e., CFTR function, was assessed using the normalized fluorescence value obtained 14 seconds after the addition of iodide.

[0247] The results of the combined efficacy experiment are shown in Figures 2 to 5 middle.

[0248] Figure 2 Analysis of F508del-CFTR function (YFP quenching assay) caused by treatment with 400 nM Example Compound 3 when added to basal treatment with the type I CFTR corrector galicator (1 μM) and / or the CFTR potentiator navocator (50 nM) is shown. Example Compound 3 enhanced F508del-CFTR function when used with all basal treatments. Error bars represent standard error of the mean.

[0249] Figure 3 Analysis of F508del-CFTR function (YFP quenching assay) caused by treatment with 400 nM Example Compound 3 when used with basal treatment of type I CFTR corrector tezcaftor (2 μM) and / or CFTR potentiator ivacaftor (2 nM) is shown. Example Compound 3 enhanced F508del-CFTR function when used with all basal treatments. Error bars represent standard error of the mean.

[0250] Figure 4Shown is an analysis of F508del-CFTR function (YFP quenching assay) caused by treatment with 400 nM Example Compound 3 when used with basal treatment of type II CFTR corrector-corrector 4a (5 μM) and / or CFTR potentiator Navocato (50 nM). Example Compound 3 enhances F508del-CFTR function when used with all basal treatments. Error bars represent standard error of the mean.

[0251] Figure 5 Analysis of F508del-CFTR function (YFP quenching assay) caused by treatment with 400 nM Example Compound 3 when used with basal treatment of the type III CFTR corrector eresacato (2 μM) and / or the CFTR potentiator ivacaftor (2 nM) is shown. Example Compound 3 enhanced F508del-CFTR function when used with all basal treatments. Error bars represent standard error of the mean.

[0252] References Boyle MP et al. (2014). Lancet Respir Med 2(7):527-538. Dalemans W et al. (1991). Nature 354:526-528. Davies JC et al. (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. Fiedorczuk K et al. (2022). Cell 185(1):158-168. Flores AM et al. (2016). FASEB J 30(5):1789-1797. Galietta LV et al. (2001). Am J Physiol Cell Physiol 281(5): C1734-1742. Hutt DM et al. (2011). ACS Med Chem Lett 2(9):703-707. Kazani S et al. (2021). J Cyst Fibros 20(2):250-256. Keating D et al. (2018). N Engl J Med 379(17):1612-1620. Le Grand D et al. (2021). J Med Chem 64(11):7241-7260. Marchesin V et al. (2023). / / doi.org / 10.1101 / 2023.08.15.552928 Okiyoneda T et al. (2013). Nat Chem Biol 9(7):444-454. Patel SD et al. (2020). Eur Respir Rev 29(156):190068. Rowe SM et al. (2020). Int J Chron Obstruct Pulmon Dis 15:2399-2409. Stevers LM et al. (2022). Nat Commun 13:3586. Van Goor F et al (2011). Proc Natl Acad Sci USA 108(46):18843-18848. Veit G et al. (2018). Nat Med 24(11):1732-1742. Veit G et al. (2020). JCI Insight 5(18):e139983. Wang X et al. (2018). J Med Chem 61(4):1436-1449.

Claims

1. A pharmaceutical composition comprising as an active ingredient a compound of formula (I): in X stands for -CR X1 R X2 , where R X1 represents hydrogen, and R X2 express ■C 1-6 alkyl; ■C 1-4 fluoroalkyl; or ■C 3-6 Cycloalkyl; R 1 Represents C 1-4 alkyl; R 2 Represents C 1-4 alkyl; R 3 Represents C 1-6 alkyl; R 4 represents a 5-membered heteroaryl, wherein the 5-membered heteroaryl is independently unsubstituted, monosubstituted or disubstituted, wherein the substituents are independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-3 Fluoroalkyl, C 1-3 Fluoroalkoxy, C 3-6 Cycloalkyl or halogen; Ar 1 represents an 8- to 10-membered bicyclic heteroaryl group, wherein the bicyclic heteroaryl group is independently unsubstituted or C 1-4 Alkyl or halogen monosubstituted; Ar 2 represents a phenyl group, wherein the phenyl group is unsubstituted, monosubstituted or disubstituted, wherein the substituents are independently selected from C 1-4 Alkyl, C 1-3 Fluoroalkyl, halogen, C 1-6 Alkoxy and C 1-3 Fluoroalkoxy; or a pharmaceutically acceptable salt thereof; In combination with one or more therapeutically active ingredients used as CFTR modulators; wherein the CFTR modulators are one or more CFTR correctors and / or CFTR potentiators; or pharmaceutically acceptable salts thereof; and at least one pharmaceutically acceptable excipient.

2. The pharmaceutical composition according to claim 1, wherein the compound of formula (I) is E ) of the compound:

3. The pharmaceutical composition according to any one of claims 1 or 2, wherein X represents -CR X1 R X2 , where R X1 is hydrogen, and R X2 It is 2,2,2-trifluoroethyl.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein R 4 represents an oxadiazolyl group, wherein the 5-membered heteroaryl group is independently C 1-4 Alkoxy monosubstituted.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein Ar 1 represents a 10-membered bicyclic heteroaryl, wherein the bicyclic heteroaryl is monosubstituted by halogen.

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

7. The pharmaceutical composition according to claim 1, wherein 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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecan-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]tetraazacycloheptadecan-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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(5-cyclopropyl-1,2,4-oxadiazol-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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[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]tetraazacycloheptadecan-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]tetraazacycloheptadecan-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]tetraazacycloheptadecan-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]tetraazacycloheptadecano[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]tetraazacycloheptadecano[17,16-c]quinoline-3-carboxamide; or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition according to 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]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the one or more therapeutically active ingredients acting as CFTR modulators are type I correctors selected from lumacaftor, tezacaftor and galicaftor; and / or a type II corrector, which is corrector 4a; and / or a type III corrector selected from elexacaftor and vanzacaftor; and / or a CFTR potentiator selected from ivacaftor, navocaftor, icenticaftor and deutivacaftor; or a pharmaceutically acceptable salt thereof.

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

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

12. A pharmaceutical composition according to any one of claims 1 to 8, wherein the composition comprises a compound of formula (I) and Ivacaftor and tizacator or pharmaceutically acceptable salts thereof; or Ivacato and lumacato or pharmaceutically acceptable salts thereof; or Navocato and Gallicato or pharmaceutically acceptable salts thereof.

13. 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 to be used / administered / is administered in combination with one or more therapeutically active ingredients used as CFTR modulators; wherein the CFTR modulators are one or more CFTR correctors and / or CFTR potentiators.

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 to be used / administered / is administered in combination with one or more therapeutically active ingredients that act as CFTR modulators; wherein the CFTR modulator is ●Ivacaftor and tizacator or pharmaceutically acceptable salts thereof; or ●Ivacato and lumacato or pharmaceutically acceptable salts thereof; or ●Navocato and Gallicato or pharmaceutically acceptable salts thereof.

15. A method for treating cystic fibrosis, the method 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 that act as CFTR modulators; wherein the CFTR modulator is ●Ivacaftor and tizacator or pharmaceutically acceptable salts thereof; or ●Ivacato and lumacato or pharmaceutically acceptable salts thereof; or ●Navocato and Gallicato or pharmaceutically acceptable salts thereof.

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