Macrocyclic CFTR modulators

Abstract

The present invention relates to macrocyclic compounds of Formula (I), wherein Ar1, Ar2, R1, R2, R3, R4, R5, W, and Z are as described in the description, their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of Formula (I), and to their use as modulators of CFTR alone or in combination with one or more therapeutically active ingredients acting as CFTR potentiators or CFTR correctors or CFTR stabilizers.

Description

[0001] Macrocyclic CFTR modulators

[0002] The present invention relates to novel macrocyclic compounds of formula (I) and their use as pharmaceuticals in the treatment of CFTR-related diseases and disorders such as especially cystic fibrosis. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), pharmaceutical compositions containing compounds of formula (I) in combination with one or more therapeutically active ingredients acting as CFTR modulator(s), wherein said CFTR modulator(s) is / are one or more CFTR corrector(s) (especially a type-l corrector, and / or a type-ll corrector, and / or a type-ill corrector), and / or a CFTR potentiator, and / or a CFTR stabilizer; and their use in the treatment of CFTR-related diseases and disorders.

[0003] Cystic Fibrosis (CF; mucoviscidosis, sometimes also called fibrocystic disease of pancreas or pancreatic fibrosis) is an autosomal recessive genetic 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 causing accumulation of sticky mucus in organs including lung, pancreas, liver and intestine and, as a consequence, multi-organ dysfunction. Most debilitating effects in CF are nowadays observed in the lung which - due to abnormal hydration of airway surface liquid, mucus plugging, impaired mucociliary clearance, chronic inflammation and infection - loses its functionality over time leading to death by respiratory failure (Elborn, 2016). Human CFTR is a multidomain protein of 1480 amino acids. Many different mutations causing CFTR dysfunction have been discovered in CF patients leading e.g. to no functional CFTR proteins (class I mutations), CFTR trafficking defects (class II mutations), CFTR regulation defects (also known as gating defects; class III mutations), CFTR conductance defects (class IV mutations), less CFTR protein either due to splicing defects (class V mutations) or due to reduced CFTR stability (class VI mutations), 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 22.08.2022) currently contains information on 401 disease-causing mutations. By far the most common disease-causing mutation is the deletion of phenylalanine at position 508 (F508del; allele frequency 0.697 in the CFTR2 database), that leads to misfolding of the channel during synthesis at the endoplasmic reticulum, degradation of the misfolded protein and a resulting strongly reduced transport to the cell surface (class II mutation). The residual F508del-CFTR that is trafficked to the cell surface is functional, however less than wildtype CFTR, i.e. F508del-CFTR also harbours a gating defect (Dalemans, 1991). Ca 40% of all CF patients are homozygous for the F508del mutation while another -40% of patients are heterozygous for the F508del mutation and carry another disease-causing mutation from class I, II, III, IV, V, VI or VII. Such diseasecausing mutations are considerably rarer with the class III G551 D mutation (allele frequency 0.0210) and the class I G542X mutation (allele frequency 0.0254) and the class II N1303K mutation (allele frequency 0.0158) being the next most prevalent. CF is currently treated by a range of drugs addressing the various organ and dysfunctions. Intestinal and pancreatic dysfunction are treated from diagnosis by food supplementation with pancreatic digestive enzymes. Lung symptoms are mainly treated with hypertonic saline inhalation, mucolytics, anti-inflammatory drugs, bronchiodilators and antibiotics (Elborn, 2016).

[0004] In addition to symptomatic treatments, CFTR modulators have been developed and approved for patients with certain CFTR mutations. These compounds directly improve CFTR folding and trafficking to the cell surface (CFTR correctors) or improve CFTR function at the cell surface (CFTR potentiators). Other types of modulators are still in the exploratory phase such as compounds that increase mRNA levels of (mutated) CFTR (CFTR amplifiers) and compounds that increase the plasma membrane stability of mutated CFTR (CFTR stabilizers)), e.g. the nucleotide binding domain 1 (NBD1) stabilizers SION-638, currently in phase 1 , and its follow-up molecule NBD1-A (oral presentation G. Hurlbut at the North American Cystic Fibrosis Conference 2022) and SION-719 and SION-451 (Pipeline - Sionna Therapeutics (sionnatx.com); accessed Jan 12, 2024). CFTR modulators can also enhance function of non-mutated (i.e. wildtype) CFTR and are therefore being studied in disorders where increasing wildtype CFTR function would have beneficial effects in non-CF disorders such as the use of CFTR potentiators in the treatment of 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; Chen, J Ocul Pharmacol Ther 2020, 36(3): 147-153; Felix, Invest Ophthalmol Vis Sci 2017 5(11):4506-4513), and, in addition, acute respiratory distress syndrome (ARDS) (Erfinanda L, Sci Transl Med. 2022, 14(674):eabg8577). The CFTR potentiator (also referred to as an activator) VSJ-110 (CFTRact-K267) has been shown to be pro-secretory in such models of dry eye disease. Furthermore, an increase in surface expression and function of wildtype CFTR through treatment with correctors has been described (Marchesin 2023) and should lead to similar benefits in the above disorders. A combination of potentiators and correctors can be expected to provide further therapeutic effect in the treatment of disorders benefiting from increasing wildtype CFTR function.

[0005] CFTR modulators and their combinations can be discovered and optimized by assessing their ability to promote trafficking and function of mutated CFTR in in vitro cultivated recombinant and primary cellular systems. Activity in such systems is predictive of activity in CF patients.

[0006] WO2019 / 161078 discloses macrocycles as modulators of cystic fibrosis, wherein said macrocycles generally are 15-membered macrocycles comprising a (pyridine-carbonyl)-sulfamoyl moiety that is linked to a further aromatic group. Further macrocycles are disclosed in WO2022 / 109573 (macrocycles containing a 1 ,3,4-oxadiazole ring), WO2022 / 076625, WO2022 / 076626, WO2022 / 076624, WO2022 / 076621 , W02022 / 076620, WO2022 / 076618, W02021 / 030556, and W02021 / 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 said macrocycles comprise an optionally substituted divalent N-(pyridine- 2-yl)py ridiny l-sulfonamide moiety. Other macrocyclic compounds have been described to stabilize chloride channel CFTR (Stevers L.M., Nature Communications 2022, 13:3586). Non macrocyclic CFTR correctors and / or potentiators of CFTR have been disclosed for example in WO2011 / 119984, WO2014 / 015841 , W02007 / 134279, WO2010 / 019239, WO2011 / 019413, WO2012 / 027731, WO2013 / 130669, WO2014 / 078842 and WO2018 / 227049, WO2010 / 037066, WO2011 / 127241 , WO2013 / 112804, W02014 / 071122, and W02020 / 128768. Furthermore, particular macrocycles can be found as screening compounds, wherein an unsubstituted phenylene group is part of said macrocycles compared to the 8- to 10-membered bicyclic heteroarylene of present compounds of formula (I) (CAS registry number : CAS-2213100-89-9, CAS-2213100-96-8, CAS-2213100-99-1 , CAS-2213101 -02-9, CAS- 2213101-04-1 , CAS-2213101-06-3, CAS-2213101 -08-5, CAS-2213101 -09-6, CAS-2213101-19-8, CAS-2213101- 24-5, CAS-2215788-95-5, CAS-2215788-98-8, CAS-2215789-01 -6, CAS-2215789-02-7, CAS-2215789-09-4, CAS-2215789-15-2, CAS-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-2215947-68-3, CAS-2215947-78-5, CAS-2215947-91 -2, CAS-2215954-57-5, CAS-2216342-34-4, CAS-2216342-78-6, CAS-2216342-86-6, CAS-2216343-03-0, CAS- 2216343-09-6, CAS-2216343-14-3, CAS-2216343-18-7, CAS-2216343-24-5, CAS-2216343-32-5, CAS-2216343- 38-1, CAS-2216343-45-0, CAS-2216343-53-0, CAS-2216343-59-6, CAS-2216343-64-3, CAS-2216343-74-5, CAS-2216343-76-7).

[0007] CFTR modulators can be further subdivided into - among others - CFTR correctors and CFTR potentiators. CFTR correctors improve folding of CFTR and its trafficking to the cell surface, especially of CFTR carrying class II (=folding & trafficking) mutations, and thus increase CFTR cell surface expression. CFTR potentiators increase the opening probability of cell surface CFTR, especially of CFTR carrying gating defects including corrector-rescued class II mutants, and therefore can activate CFTR in an additive / synergistic manner together with CFTR correctors. Thus, potentiators and correctors have been / are being combined in the clinic to treat patients with CFTR class II mutations. A multitude of CFTR correctors have been described in the literature and in patents. Some of these correctors - alone and / or in combination with other CFTR modulators - have been / are being used in clinical trials in CF patients, e.g. 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, in addition, PTI-801 (posenacaftor, CAS 2095064-05-2; compound of example 2 of WO 2019 / 071078). Similarly, a multitude of potentiators has been described in the literature and in patents. Some of these potentiators - alone and / or in combination with other CFTR modulators - have been / 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). The CFTR potentiator / activator VSJ-110 (CFTRact-K267) is being tested in allergic conjunctivitis (phase 2), a disorder characterized by inflammation of the corneal epithelium and thought to benefit from wildtype CFTR activation. It has been established that CFTR correctors can be further subdivided with respect to their mechanism: Correctors behaving in an additive or synergistic way must have different, i.e. complementary, mechanims of action, most likely due to different binding sites on the CFTR protein. Inversely, correctors behaving in a competitive way likely share the same CFTR binding site (Okiyoneda 2013, Veit 2018, Veit 2020, Fiedorczuk 2022; Marchesin 2023). Accordingly, the structurally related correctors VX-809 (lumacaftor), VX-661 (tezacaftor) and ABBV-2222 (galicaftor) have been categorized as type-l correctors, Corrector 4a and related compounds have been categorized as type-ll correctors while VX-445 (elexacaftor) has been described as type-ill corrector, which applies also to the structurally related correctors VX-440 (olacaftor), VX-659 (bamocaftor) and VX-121 (vanzacaftor). ABBV-C2 correctors ABBV-119, ABBV-567 are likely type-ill correctors as well. PTI-801 is likely a further type-ill corrector. Due to their additivity in effect, correctors of different mechanisms are being combined in the clinic to reach - together with a potentiator - higher correction efficacy.

[0008] VX-770 (ivacaftor, KALYDECO, A / -(2, 4-d i-tert-buty l-5-hydroxypheny l)-1 ,4-dihydro-4-oxoquinoline-3-carboxamide, CAS 873054-44-5, e.g. W02006 / 002421, WO2011 / 072241, W02007 / 079139, W02007 / 134279, WO2010 / 019239, WO2013 / 130669), is a CFTR potentiator and the first ever approved CFTR modulator (US and EU: initial approval 2012) for treatment of CF patients aged 4 months and older who have one mutation in the CFTR gene that is responsive to KALYDEKO based on clinical and / or in vitro assay data. The current VX-770 uspi (Dec 2020) lists 97 elegible CFTR mutations. VX-770 is also part of ORKAMBI (combination of VX-809 and VX-770), SYMDEKO / SYMKEVI (combination of VX-661 and VX-770) and TRIKAFTA / KAFTRIO (combination of VX-661 , VX- 445 and VX-770) as described later.

[0009] VX-809 (lumacaftor, 3-[6-({[1 -(2, 2-d if I uoro- 1 , 3-benzodioxol-5-yl)cyclopropyl]carbonyl}am i no)-3-methy I pyridin-2- yl]benzoic acid, CAS 936727-05-8, e.g. W02007 / 056341, W02009 / 073757, W02009 / 076141 , WO2010 / 037066, WO2011 / 127241) is a type-l CFTR corrector, and was approved in the United States (2014) and the EU (2015) as part of ORKAM Bl, which is a combination product of lumacaftor with the CFTR potentiator ivacaftor for the treatment of cystic fibrosis (CF) in patients age 2 years and older who are homozygous for the F508del mutation in the CFTR gene.

[0010] VX-661 (tezacaftor, 1-(2,2-difluoro-2H-1 ,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1- hydroxy-2-methylpropan-2-yl)-1 Hindol-5-yl}cyclopropane-1-carboxamide, CAS 1152311-62-0, e.g. W02007 / 117715, WO2011 / 119984, WO2014 / 014841) is a type-l CFTR corrector, and was approved in the United States (2018) as part of SYMDEKO and in the EU (2018) as part of SYMKEVI. SYMDEKO / SYMKEVI is a combination product of tezacaftor with the CFTR potentiator ivacaftor for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation in the CFTR gene or who have at least one mutation in the CFTR gene that is responsive to tezacaftor / ivacaftor based on in vitro data and / or clinical evidence. The current SYMDEKO uspi (June 2022) lists 154 elegible CFTR mutations. VX-445 (elexacaftor, N-(1,3-dimethyl-1 H-pyrazole-4-sulfonyl)-6-[3-(3,3,3-trifluoro- 2,2-dimethylpropoxy)-1 H- pyrazol-1 -yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, CAS 2216712-66-0, e.g. WO2016 / 057572, W02018 / 107100, WO2019 / 152940) is a type-ill CFTR corrector, and was approved in the United States (2019) as part of TRIKAFTA and in the EU (2020) as part of KAFTRIO. TRIKAFTA / KAFTRIO is a combination product of elexacaftor with the type-l CFTR corrector tezacaftor and the CFTR potentiator ivacaftor for the treatment of cystic fibrosis (CF) in patients age 6 years 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 (Oct 2021) lists 178 elegible CFTR mutations.

[0011] ABBV-2222 (GLPG-2222, galicaftor, 4-[(2R,4R)-4-({[1-(2,2-Difluoro-1 ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic Acid; CAS 1918143-53- 9, e.g. WO2016 / 069757) is a type-l CFTR corrector, that is currently being tested in combination with the CFTR potentiator ABBV-3067 (see later) in an open-label phase-ll trial (NCT03969888) in 78 CF patient aged 18 years and older homozygous for the F508del-CFTR mutation.

[0012] ABBV-3067 (navocaftor, GLPG-3067, (5-(3-Amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)pyrid i n-2-y l)-1 ,3,4- oxadiazol-2-yl)methanol, CAS 2159103-66-7, e.g. WO2017 / 208115) is a CFTR potentiator which is being currently analyzed in a phase-ll trial in combination with galicaftor as described above (NCT03969888).

[0013] QBW-251 (icenticaftor, 3-Amino-6-methoxy-N-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5- (trifluoromethyl)pyridine-2-carboxamide, CAS 1334546-77-8, e.g. WO2011 / 113894) is a CFTR potentiator which was tested in a placebo-controled phase l / ll study in a cohort of CF patients aged 18 years and older carrying CFTR Class class III, IV CFTR mutations on one allele, i.e.mutations where the CFTR is on the cell surface and can profit from potentiation (NCT02190604).

[0014] VX-121 (vanzacaftor, (14S)-8-[3-(2-{Dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1 H-pyrazol-l-yl]-12,12-dimethyl-2A6-thia- 3,9, 11 , 18,23-pentaazatetracyclo [17.3.1.111 , 14.05, 10]tetracosa-1 (22), 5, 7, 9, 19(23), 20-hexaene-2, 2, 4-trione, CAS 2374124-49-7, e.g. WO2019 / 161078, WO2021 / 030552) is a type-ill CFTR corrector, that is currently being tested in two active-cpontroled double-blind, randomized phase-ill linical trials in CF paitnes as part of a new triple combination containing vanzacaftor, the type-l corrector tezacaftor and the CFTR potentiator VX-561 (deutivacaftor, a deuterated version of ivacaftor).

[0015] VX-561 (Deutivacaftor, W-[2-tert-butyl-4-[1 ,1,1 , 3, 3, 3-hexadeu terio-2-(trideu teriomethy I) propan-2-yl]-5- hydroxyphenyl]-4-oxo-1 H-quinoline-3-carboxamide, CTP-656, name, CAS 1413431-07-8, e.g. WO2019 / 109021 , WO2019 / 018395) is a deuterated form of ivacaftor for once-daily application.

[0016] The CFTR correctors lumacaftor, tezacaftor, galicaftor, Corr4a, elexacaftor, bamocaftor and others have been analyzed in vitro for their ability to restore folding of mutated CFTR (especially of F508del-C FTR) and its trafficking to the cell surface (Van Goor 2011 , Okiyoneda 2013, Veit 2018, Keating 2018, Davies 2018). Trafficking to the cell surface can be analyzed by different assay technologies including anti-CFTR immunoblotting (the CFTR “C band” represents the mature trafficked CFTR), anti-CFTR cell surface ELISAs, enzyme fragment complementation techniques or CFTR-HRP fusion proteins in recombinant cell lines expressing the mutated CFTR-protein or in primary cells from CF patients. Importantly, combinations of correctors with different types of corrector mechanism showed additive effects on increasing F508del-CFTR cell surface expression. This was shown for example for elexacaftor + / - tezacaftor (type-ill corrector + / - type-l corrector; Keating 2018, Veit 2020) or bamocaftor + / - tezacaftor (type-l 11 corrector + / - type-l corrector; Davies 2018) or type-l + type-ll + type-ill correctors (Veit, 2018).

[0017] Mutated CFTR trafficked to the cell surface can still have a gating defect, and it has been shown that the function of cell surface F508del-CFTR is markedly augmented when a potentiator is added. Various functional assays are available to analyse CFTR function. For example, cellular expression of halide-sensitive yellow fluorescent protein can be used to measure iodide influx through functional CFTR (Galietta 2001). Furthermore, electrophysiological measurements using the Ussing chamber and either recombinant epithelial cells or reconstituted bronchial epithelium from CF patients can be used to charactize the effects of CFTR modulators on CFTR function. For example, it was shown that the addition of the potentiator ivacaftor to lumacaftor-corrected F508del-CFTR augments CFTR function almost two-fold in reconstituted bronchial epithelium from CF patients (van Goor 2011) in line with clinical trial data on FEV1 improvement upon ivacafor addition in lumacaftor-treated patients (Boyle 2014). Similarly, again using Ussing chamber readouts, the additivity of type-l corrector tezacaftor and type-l 11 corrector elexacaftor on functional correction of F508del-CFTR in reconstituted CF bronchial epithelium was shown as well as the further 2-fold augmentation of function by the addition of potentiator ivacaftor. Also, the additive effect of type-l 11 corrector elexacaftor on a combination of type-l corrector tezacaftor and potentiator ivacaftor on F508del- CFTR function was demonstrated (Keating 2018). The latter comparison is in line with clinical trial data in F508del- CFTR homozygous patients in which adding elexacaftor to a basal treatment of tezacaftor + ivacaftor (SYMDEKO) lead to a ppFEVI increase of 10% (Keating 2018). The FDA has recognized the predictive power of in vitro tests with respect to the effect of CFTR modulators in the clinic, and has approved CFTR modulators for rare CFTR- mutations based on in-vitro evidence only (Ussing chamber measurements in Fisher rat thyroid epithelial cells recombinantly expressing mutated CFTR; uspi SYMDEKO, uspi KALYDEKO, uspi TRIKAFTA).

[0018] Despite the availability of various CFTR modulators with complementary mechanism for many of the common mutations, CFTR function is not fully restored in patients (as indicated by the persistence of elevated sweat chloride levels) neither ist their lung function. These findings highlight the need for additional novel high efficacy CFTR corrector mechanisms that can be used alone or on top of currently available or future background therapy (i.e. SYMDEKO or ORKAMBI or TRIKAFTA or [galicaftor+navocaftor], and optionally further background therapy) and which may, in combination, increase the efficacy of such CFTR modulator therapy.

[0019] It has now been found that CFTR correctors such as especially the compounds of formula (I) as defined below, which are CFTR correctors with a novel mechanism (i.e. not type-l, not type-ll, not type-ill correctors) having potential in the prevention and treatment of CFTR-related diseases and disorders, especially of cystic fibrosis, may have complementary, and even synergistic effect when combined with CFTR correctors with another mechanism such as of type-l correctors (lumacaftor, tezacaftor, galicaftor), and / or type-ll correctors (Corrector4a), and / or type- ill correctors (elexacaftor, bamocaftor, olacaftor, vanzacaftor; and, in addition, ABBV-119, ABBV-567) and / or CFTR potentiators (ivacaftor, navocaftor, icenticaftor, deutivacaftor, GLPG-1837, GLPG2451) in the treatment of CFTR- related diseases and disorders, especially of cystic fibrosis. Such combination may, thus, especially be useful in the treatment of cystic fibrosis. Compounds of formula (I) can restore CFTR function in absence and presence of potentiators when determined by Ussing chamber measurements in reconstituted tissue from CF patients carrying the F508del-CFTR mutation.

[0020] The present invention provides macrocyclic compounds which are modulators of CFTR. The present compounds may, thus, be useful for the treatment of CFTR-related diseases and disorders, especially cystic fibrosis.

[0021] 1) A first aspect of the invention relates to compounds of the Formula (I) wherein

[0022] R1represents Ci.4-alkyl (especially methyl);

[0023] R2represents Ci.4-alkyl (especially methyl);

[0024] R3represents Ci-e-alkyl (especially isobutyl);

[0025] R4represents 5-membered heteroaryl (especially isoxazolyl, oxadiazolyl, tetrazolyl, or triazolyl; in particular isoxazol-5-yl, 1 ,2,4-oxadiazol-5-yl, 2H-tetrazol-2-yl, or 2H-1 ,2,3-triazol-2-yl), wherein said 5-membered heteroaryl is unsubstituted, or mono-, di- or tri-substituted (especially mono- or di-substituted), wherein the substituents are independently selected from Ci.4-alkyl; Ci-4-alkoxy (especially methoxy); Ci-3-fluoroalkyl; Ci-3-fluoroalkoxy; halogen (especially fluoro); cyano; and Cs-e-cycloalkyl (especially cyclopropyl); [in particular R4represents 3-methoxy- isoxazol-5-yl, 4-fluoro-3-methoxy-isoxazol-5-yl, 3-methoxy-1 ,2,4-oxadiazol-5-yl, 5-cyclopropyl-2H-tetrazol-2-yl, or 4-methoxy-2H-1,2,3-triazol-2-yl];

[0026] W represents -CH2- or -CH2-CH2- [in particular W represents -CH2-];

[0027] Z represents -CH2-, -CH2-CH2-, or -CH2-O-*; wherein the asteriks indicates the bond linked to -C-R5; [in particular Z represents -CH2- or -CH2-O-*];

[0028] R5represents halogen (especially fluoro or chloro), Ci-4-alkyl (especially methyl), Ci-4-fluoroalkyl (especially C1- fluoroalkyl; notably trifluoromethyl), or Ci-4-alkoxy (especially methoxy);

[0029] Ar1represents:

[0030] • 6-membered heteroarylene (especially pyridin-3, 4-diyl); wherein said 6-membered heteroarylene is mono- , di- or tri-substituted (especially di-substituted), wherein the substituents are independently selected from Ci-4-alkyl (especially methyl), Ci-4-alkoxy (especially methoxy), C-i-3-fluoroalkyl, Ci-3-fluoroalkoxy, cyano, and halogen; [in particular such Ar1represents 2-methoxy-6-methyl-pyridin-3, 4-diyl]; or

[0031] • 8- to 10-membered bicyclic heteroarylene (especially 10-membered bicyclic heteroarylene; notably isoquinolin-5,6-diyl or quinolin-5,6-diyl); wherein said 8- to 10-membered bicyclic heteroarylene is unsubstituted, or mono- or di-substituted (especially mono-substituted), wherein the substituents are independently selected from Ci.4-alkyl (especially methyl), Ci-3-fluoroalkyl, Ci.4-alkoxy, Ci-3-fluoroalkoxy, cyano, and halogen (especially fluoro); [in particular such Ar1represents 3-methyl-isoquinolin-5,6-diyl or 3-fluoro-quinolin-5,6-diyl];

[0032] [wherein it is understood that in the above groups Ar1the -CO- group and the oxygen (i.e. the groups linking Ar1to the rest of the molecule) are attached in ortho arrangement to aromatic ring carbon atoms of Ar1as depicted in Formula (I)]; and

[0033] Ar2represents phenyl, or 5- or 6-membered heteroaryl (especially pyridinyl or pyrimidinyl; in particular pyridin-2-yl, pyrimidin-2-yl, or pyrimidin-4-yl), wherein said phenyl or 5- or 6-membered heteroaryl is unsubstituted, or mono- or di-substituted (especially unsubstituted or mono-substituted), wherein the substituents are independently selected from Ci-4-alkyl (especially methyl), C-i-3-fluoroalkyl, halogen, cyano, Cs-e-cycloalkyl, Ci-4-alkoxy (especially methoxy), and Ci-3-fluoroalkoxy; [in particular Ar2represents phenyl, 4-methyl-pyridin-2-yl, 4-methoxy-pyridin-2-y I, 6-methoxy-pyridin-2-yl, 4-methoxy-pyrimidin-2-yl, or 6-methoxy-pyrimidin-4-yl].

[0034] The compounds of formula (I) contain at least four stereogenic or asymmetric centers, which are present in (R)- or (S)-configuration as defined in the respective embodiments defining such compounds of formula (I). In addition, the compounds of formula (I) may contain one or more further stereogenic or asymmetric centers, such as one or more additional asymmetric carbon atoms. The compounds of formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art. The compounds of formula (I) may further encompass compounds with one or more double bonds which are allowed to be present in Z- as well as E-configuration and / or compounds with substituents at a ring system which are allowed to be present, relative to each other, in cis- as well as trans-configuration.

[0035] In case a particular compound (or generic structure) is designated as (R)- or (S)-enantiomer, such designation is to be understood as referring to the respective compound (or generic structure) in enriched enantiomeric form, especially in essentially pure enantiomeric form. Likewise, in case a specific asymmetric center in a compound is designated as being in (R)- or (S)-configuration or as being in a certain relative configuration, such designation is to be understood as referring to the compound that is in enriched, especially essentially pure form with regard to the respective configuration of said asymmetric center. In analogy, cis- or trans-designations are to be understood as referring to the respective stereoisomer of the respective relative configuration in enriched, especially essentially pure form. Likewise, in case a particular compound (or generic structure) is designated as Z- or E-stereoisomer (or in case a specific double bond in a compound is designated as being in Z- or E-configuration), such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure stereoisomeric form (or to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of the double bond).

[0036] The term "enriched", when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least 70:30, especially of at least 90: 10 (i.e., in a purity of at least 70% by weight, especially of at least 90% by weight), with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.

[0037] The term “essentially pure”, when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a purity of at least 95% by weight, especially of at least 99% by weight, with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.

[0038] The present invention also includes isotopically labelled, especially2H (deuterium) labelled compounds of formula (I) according to embodiments 1) to 10), which compounds are identical to the compounds of formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially2H (deuterium) labelled compounds of formula (I) and salts thereof are within the scope of the present invention. In case a certain substituent is specifically indicated as representing hydrogen, it is understood to refer to all isotopes of the atom "H", i.e. the term hydrogen as used for a certain substituent is understood as comprising the isotope2H (deuterium); preferably it refers to the isotope1H (hydrogen). Substitution of hydrogen with the heavier isotope2H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.

[0039] In this patent application, a bond drawn as a dotted line shows the point of attachment of the radical drawn. For example, the radical drawn below is the 4-methyl-pyridin-2-yl group.

[0040] Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like.

[0041] Any reference to compounds of formula (I) according to embodiments 1) to 10) is to be understood as referring to the compound in free base or salt form, thus, referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.

[0042] The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and / or base addition salts depending on the presence of basic and / or acidic groups in the subject compound. For reference see for example “Handbook of Pharmaceutical Salts. Properties, Selection and Use.”, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and “Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.

[0043] Definitions provided herein are intended to apply uniformly to the compounds of formula (I), as defined in any one of embodiments 1) to 10), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein.

[0044] Whenever a substituent is denoted as optional, it is understood that such substituent may be absent (i.e. the respective residue is unsubstituted with regard to such optional substituent), in which case all positions having a free valency (to which such optional substituent could have been attached to; such as for example in an aromatic ring the ring carbon atoms and / or the ring nitrogen atoms having a free valency) are substituted with hydrogen where appropriate. Likewise, in case the term “optionally” is used in the context of (ring) heteroatom(s), the term means that either the respective optional heteroatom(s), or the like, are absent (i.e. a certain moiety does not contain heteroatom(s) / is a carbocycle / or the like), or the respective optional heteroatom(s), or the like, are present as explicitly defined. The term “halogen” means fluorine / fluoro, chlorine / chloro, or bromine / bromo; preferably fluorine / fluoro or chlorine / chloro.

[0045] The term “alkyl”, used alone or in combination, refers to a saturated straight or branched chain hydrocarbon group containing one to six carbon atoms. The term “Cx-y-alkyl” (x and y each being an integer), refers to an alkyl group as defined before, containing x to y carbon atoms. For example, a Ci-e-alkyl group contains 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 avoidance of any doubt, in case a group is referred to as e.g. propyl or butyl, it is meant to be n-propyl, respectively n-butyl. In case R1represents Ci-4-alkyl, the term especially means Ci_3-alkyl, notably methyl. For R2representing Ci-4-alkyl, the term especially means C-i-3-alkyl, notably methyl. In case R3represents Ci-e-alkyl, the term especially means Cs-5-alkyl, notably isobutyl. For R5representing Ci-4-alkyl, the term especially means C-i-3-alkyl, notably methyl. For Ci-4-alkyl as substituent of Ar1, the term especially means C-i-3-alkyl, notably methyl. For Ci-4-alkyl as substituent of Ar2, the term especially means Cis-alkyl, notably methyl.

[0046] The term “Cx-y-alkylene”, used alone or in combination, refers to bivalently bound alkyl group as defined before containing x to y carbon atoms. Preferably, the points of attachment of a Ci-y-alkylene group are in 1,1 -diyl, in 1,2- diyl, or in 1 ,3-diyl arrangement.

[0047] The term “alkoxy”, used alone or in combination, refers to an alkyl-O- group wherein the alkyl group is as defined before. The term “Cx-y-alkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example, a Ci-4-alkoxy group means a group of the formula Ci-4-alkyl-O- in which the term “Ci-4-alkyl” has the previously given significance. Representative examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Preferred is methoxy. For Ci-4-alkoxy as substituent of R4, the term especially means Ci-3-alkoxy, notably methoxy. For R5representing Ci-4-alkoxy, the term especially means Ci-3-alkoxy, notably methoxy. For Ci-4-alkoxy as substituent of Ar1, the term especially means Ci- 3-alkoxy, notably methoxy. For Ci-4-alkoxy as substituent of Ar2, the term especially means Ci-3-alkoxy, notably methoxy.

[0048] The term "fluoroalkyl”, used alone or in combination, refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term “Cx.y-fluoroalky I” (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms. For example, a Ci-3-fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Representative examples of fluoroalkyl groups include especially Ci-fluoroalkyl groups such as trifluoromethyl, and difluoromethyl, as well as 2-fluoroethyl, 2,2- difluoroethyl and 2,2,2-trifluoroethyl. In case R5represents Ci-4-fluoroalkyl, the term especially means Ci- fluoroalkyl, notably trifluoromethyl. The term "cycloalkyl", used alone or in combination, refers to a saturated monocyclic hydrocarbon ring containing three to six carbon atoms. The term "Cx-ycycloalkyl" (x and y each being an integer), refers to a cycloalkyl group as defined before containing x to y carbon atoms. For example, a Cs-e-cycloalkyl group contains from three to six carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, notably cyclopropyl. For Cs-e-cycloalkyl as substituent of R4, the term especially means cyclopropyl.

[0049] The term "aryl", used alone or in combination, means phenyl or naphthyl, especially phenyl. The above-mentioned aryl groups are unsubstituted or substituted as explicitly defined.

[0050] It is understood that a heterocyclic ring, for example "containing one or two heteroatoms independently selected from oxygen and nitrogen" or " containing one oxygen atom", contains exactly the number and type of heteroatoms indicated, the remaining ring atoms being carbon atoms if not explicitly indicated otherwise.

[0051] The term "heteroaryl", used alone or in combination, and if not explicitly defined in a broader or more narrow way, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one to a maximum of four heteroatoms, each independently selected from oxygen, nitrogen and sulfur. Representative examples of such heteroaryl groups are 5-membered heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl; 6-membered heteroaryl groups such as pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl; and 8- to 10-membered bicyclic heteroaryl groups such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyridazinyl, and imidazothiazolyl. The above-mentioned heteroaryl groups are unsubstituted or substituted as explicitly defined.

[0052] For R4representing a "5-membered heteroaryl", the term especially means the above-mentioned 5-membered groups such as especially triazolyl, tetrazolyl, isoxazolyl, and oxadiazolyl. Notably, the term refers to 5-membered groups such as especially isoxazol-5-yl, 1 ,2,4-oxadiazol-5-yl, 2H-tetrazol-2-yl, and 2H-1 ,2,3-triazol-2-yl. The above groups are substituted as explicitly defined.

[0053] The term “x to y-membered heteroarylene”, used alone or in combination, refers to bivalently bound heteroaryl group as defined before containing x to y ring atoms. Preferably, the points of attachment of an x to y-membered heteroarylene group are in 1 ,1 -diyl, in 1 ,2-diyl, or in 1 ,3-diyl arrangement. Particular examples of the fragment: are pyridin-diyl, isoquinolin-diyl, and quinolin-diyl, especially pyridin-3,4-diyl, isoquinolin-5,6-diyl, and quinolin-5,6-diyl. Such Ar1groups are unsubstituted or substituted as explicitly defined.

[0054] For Ar2representing “5- or 6-membered heteroary I” , the term especially means a 6-membered heteroaryl, notably pyridinyl or pyrimidinyl, in particular pyridin-2-yl, pyrimidin-2-yl, or pyrimidin-4-yl, notably pyridin-2-yl or pyrimidineyl.

[0055] The term "cyano" refers to a group -CN.

[0056] Whenever the word “between” is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between 40 °C and 80 °C, this means that the end points 40 °C and 80 °C are included in the range; or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1, 2, 3, or 4.

[0057] Unless used regarding temperatures, the term “about” placed before a numerical value “X” refers in the current application 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 particular case of temperatures, the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10°C to Y plus 10°C, and preferably to an interval extending from Y minus 5°C to Y plus 5°C. Besides, the term “room temperature” as used herein refers to a temperature of about 25°C.

[0058] For avoidance of doubt, the corresponding structures of the above-listed compounds are as shown in Table 3 below, wherein, in case of doubt the depicted structure shall prevail.

[0059] Thus, for example the compound of example 1 : (3S,7S,10R,13R)-13-benzyl-20-fluoro-10-((3- f I uorobicyclo[ 1 .1.1 ]pentan-1 -yl)methyl)-7-isobutyl-N-(2-(3-methoxy-1 ,2, 4-oxadi azol-5-y l)ethyl)-6, 9-di methy I- 1 ,5,8, 11 -tetraoxo-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydro-

[0001] oxa[4,7, 10, 14]tetraazacydoheptadecino [16,17-f]quinoline-3-carboxamide has the structure depicted in Table 3, wherein said compound is in absolute configuration as drawn:

[0060]

[0061] Further embodiments of the invention are presented hereinafter:

[0062] 2) A second aspect relates to compounds of Formula (I) according to embodiment 1), wherein the compounds are compounds of Formula (lE):

[0063] Formula (lE).

[0064] 3) Another embodiment relates to compounds according to embodiments 1) or 2), wherein

[0065] R4represents 5-membered heteroaryl (especially isoxazolyl, oxadiazolyl, tetrazolyl, or triazolyl; in particular isoxazol-5-yl, 1 ,2,4-oxadiazol-5-yl, 2H-tetrazol-2-yl, or 2H-1 ,2,3-triazol-2-yl), wherein said 5-membered heteroaryl is mono- or di-substituted (especially mono-substituted), wherein the substituents are independently selected from

[0066] Ci-4-alkoxy (especially methoxy); halogen (especially fluoro); and Cs-e-cycloalkyl (especially cyclopropyl); [in particular R4represents 3-methoxy-isoxazol-5-yl, 4-fluoro-3-methoxy-isoxazol-5-yl, 3-methoxy-1,2,4-oxadiazol-5- yl, 5-cyclopropyl-2H -tetrazol-2-y I, or 4-methoxy-2H-1 ,2,3-triazol-2-yl];

[0067] W represents -CH2-;

[0068] Z represents -CH2- or -CH2-O-*;

[0069] R5represents halogen (especially fluoro or chloro), Ci-4-alkyl (especially methyl), Ci-4-fluoroalkyl (especially C1- fluoroalkyl; notably trifluoromethyl), or Ci-4-alkoxy (especially methoxy);

[0070] Ar1represents:

[0071] • 6-membered heteroarylene (especially pyridin-3,4-diyl); wherein said 6-membered heteroarylene is disubstituted, wherein the substituents are independently selected from Ci-4-alkyl (especially methyl), and Ci-4-alkoxy (especially methoxy); [in particular such Ar1represents 2-methoxy-6-methyl-pyridin-3,4-diyl]; or

[0072] • 10-membered bicyclic heteroarylene (especially isoquinolin-5,6-diyl or quinolin-5,6-diyl); wherein said 10- membered bicyclic heteroarylene is mono-substituted with Ci-4-alkyl (especially methyl) or halogen (especially fluoro); [in particular such Ar1represents 3-methy l-isoqu i nol i n-5, 6-d iyl or 3-fluoro-quinolin-5,6- diyl];

[0073] [wherein it is understood that in the above groups Ar1the -CO- group and the oxygen (i.e. the groups linking Ar1to the rest of the molecule) are attached in ortho arrangement to aromatic ring carbon atoms of Ar1as depicted in Formula (I)]; and

[0074] Ar2represents phenyl or a 6-membered heteroaryl (especially pyridinyl or pyrimidinyl; in particular pyridin-2-yl, pyrimidin-2-yl, or pyrimidin-4-yl), wherein said phenyl or 6-membered heteroaryl is unsubstituted or monosubstituted with C-i-4-alkyl (especially methyl) or Ci.4-alkoxy (especially methoxy); [in particular Ar2represents phenyl, 4-methyl-pyridin-2-yl, 4-methoxy-pyridin-2-yl, 6-methoxy-pyridin-2-yl, 4-methoxy-pyrimidin-2-yl, or 6- methoxy-pyrimidin-4-yl],

[0075] 4) Another embodiment relates to compounds according to any one of embodiments 1 ) to 3), wherein R4represents a 5-membered heteroaryl (especially isoxazolyl, oxadiazolyl, or tetrazolyl; in particular isoxazol-5-yl, 1,2,4- oxadiazol-5-yl, or 2H-tetrazol-2-yl), wherein said 5-membered heteroaryl is mono-substituted with Ci.4-alkoxy (especially ethoxy) or Cs-e-cycloalkyl (especially cyclopropyl); [in particular R4represents 3-methoxy-isoxazol-5-yl, 3-methoxy-1,2,4-oxadiazol-5-yl, or 5-cyclopropyl-2H-tetrazol-2-yl].

[0076] 5) Another embodiment relates to compounds according to any one of embodiments 1 ) to 4), wherein R5represents halogen (especially fluoro) or Ci-4-fluoroalkyl (especially Ci-fluoroalkyl; notably trifluoromethyl). 6) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein the fragment

[0077] 7) Another embodiment relates to compounds according to any one of embodiments 1) to 6), wherein Ar1represents:

[0078] • 6-membered heteroarylene (especially pyridin-3,4-diyl); wherein said 6-membered heteroarylene is disubstituted, wherein the substituents are independently selected from Ci-4-alkyl (especially methyl), and Ci-4-alkoxy (especially methoxy); [in particular such Ar1represents 2-methoxy-6-methyl-pyridin-3,4-diyl]; or

[0079] • 10-membered bicyclic heteroarylene (especially quinolin-5,6-diyl); wherein said 10-membered bicyclic heteroarylene is mono-substituted with halogen (especially fluoro); [in particular such Ar1represents 3- fluoro-quinolin-5,6-diyl];

[0080] [wherein it is understood that in the above groups Ar1the -CO- group and the oxygen (i.e. the groups linking Ar1to the rest of the molecule) are attached in ortho arrangement to aromatic ring carbon atoms of Ar1as depicted in Formula (I)].

[0081] 8) Another embodiment relates to compounds according to any one of embodiments 1) to 7), wherein Ar2represents:

[0082] • phenyl; or 6-membered heteroaryl (especially pyridinyl or pyrimidinyl; in particular pyridin-2-yl or pyrimidin-2-yl); wherein said 6-membered heteroaryl is mono-substituted with Ci-4-alkoxy (especially methoxy);

[0083] [in particular Ar2represents phenyl, 4-methoxy-pyridin-2-yl, 6-methoxy-pyridin-2-yl, or 4-methoxy-pyrimidin-2-yl].

[0084] 9) The invention, thus, relates to compounds of the formula (I) as defined in embodiment 1 ), or to such compounds further limited by the characteristics of any one of embodiments 2) to 8), under consideration of their respective dependencies; to pharmaceutically acceptable salts thereof; and to the use of such compounds as medicaments especially in the treatment of CFTR-related diseases and disorders including cystic fibrosis as described herein below. For avoidance of any doubt, especially the following embodiments relating to the compounds of formula (I) are thus possible and intended and herewith specifically disclosed in individualized form: 1, 2+1, 3+1 , 3+2+1 , 4+1, 4+2+1 , 4+3+1, 4+3+2+1, 5+1, 5+2+1 , 5+3+1 , 5+3+2+1, 5+4+1 , 5+4+2+1 , 5+4+3+1, 5+4+3+2+1, 6+1 , 6+2+1, 6+3+1 , 6+3+2+1 , 6+4+1 , 6+4+2+1, 6+4+3+1 , 6+4+3+2+1 , 7+1, 7+2+1 , 7+3+1, 7+3+2+1 , 7+4+1 , 7+4+2+1 , 7+4+3+1, 7+4+3+2+1 , 7+5+1, 7+5+2+1, 7+5+3+1 , 7+5+3+2+1 , 7+5+4+1 , 7+5+4+2+1 , 7+5+4+3+1 , 7+5+4+3+2+1 , 7+6+1 , 7+6+2+1 , 7+6+3+1, 7+6+3+2+1, 7+6+4+1, 7+6+4+2+1, 7+6+4+3+1, 7+6+4+3+2+1 , 8+1 , 8+2+1 , 8+3+1, 8+3+2+1, 8+4+1 , 8+4+2+1, 8+4+3+1 , 8+4+3+2+1 , 8+5+1, 8+5+2+1, 8+5+3+1, 8+5+3+2+1 , 8+5+4+1 , 8+5+4+2+1 , 8+5+4+3+1 , 8+5+4+3+2+1, 8+6+1, 8+6+2+1 , 8+6+3+1 , 8+6+3+2+1, 8+6+4+1, 8+6+4+2+1, 8+6+4+3+1 , 8+6+4+3+2+1 , 8+7+1 , 8+7+2+1 , 8+7+3+1, 8+7+3+2+1 , 8+7+4+1, 8+7+4+2+1 , 8+7+4+3+1 , 8+7+4+3+2+1 , 8+7+5+1, 8+7+5+2+1 , 8+7+5+3+1, 8+7+5+3+2+1 , 8+7+5+4+1, 8+7+5+4+2+1, 8+7+5+4+3+1, 8+7+5+4+3+2+1 , 8+7+6+1, 8+7+6+2+1 , 8+7+6+3+1, 8+7+6+3+2+1, 8+7+6+4+1, 8+7+6+4+2+1, 8+7+6+4+3+1, 8+7+6+4+3+2+1 .

[0085] In the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas “+” indicates the dependency from another embodiment. The different individualized embodiments are separated by commas. In other words, “8+7 +3+2+1” for example refers to embodiment 8) depending on embodiment 7), depending on embodiment 3), depending on embodiment 2), depending on embodiment 1), i.e. embodiment “8+7+3+2+1” corresponds to the compounds of formula (I) according to embodiment 8) further limited by all the features of the embodiments 1), 2), 3), and 7).

[0086] 10) Another embodiment relates to compounds of Formula (I) according to embodiment 1), which are selected from the following compounds:

[0087] (3S,7S, 10R, 13R)-13-benzy l-20-f luoro- 10-((3-fl uorobicyclo[1.1.1 ]pentan- 1 -y I) methy l)-7-isobutyl-N -(2-(3-methoxy- 1 , 2, 4-oxad i azol-5-y l)ethy l)-6, 9-d i methy I- 1 ,5,8, 11 -tetraoxo-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10,11 ,12,13,14-tetradecahydro-

[0001] oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;

[0088] (3S,7S,1 OR, 13R)-20-fluoro-10-((3-fluorobicyclo[1 .1 .1]pentan-1 -yl)methyl)-7-isobutyl-N-(2-(3-methoxyisoxazol-5- yl)ethyl)- 13-((6-methoxy py rid in-2-y I) methy l)-6,9-di methy I- 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]tetraazacydoheptadecino[16,17-f]quinoline-3-carboxamide;

[0089] (3S,7S, 10R, 13R)-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-20-fluoro-10-((3-fluorobicyclo[1 .1 .1]pentan-1 - yl)methyl)-7-isobutyl-13-((6-methoxypyridin-2-yl)methyl)-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]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide;

[0090] (3S,7S, 10R, 13 R)-20-f I uoro- 10-((3-f I uorobicyclo[ 1 .1.1 ]pentan- 1 -yl)methyl)-7-isobutyl-N-(2-(3-methoxy-1 ,2,4- oxadiazol-5-yl)ethyl)-13-((6-methoxypyridin-2-yl)methyl)-6,9-dimethyl-1,5,8,11-tetraoxo-

[0091] 1.2.3.4.5.6.7.8.9.10.11.12.13.14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadedno[16,17-f]quinoline-3- carboxamide;

[0092] (3S,7S, 10R, 13R)-13-benzy I- 10-((3-f I uorobicyclo[ 1 .1.1 ]pentan-1 -yl)methyl)-7-isobutyl-N-(2-(3-methoxy-1 ,2,4- oxadi azol-5-yl)ethyl)-6, 9, 20-tri methyl- 1 ,5,8, 11 -tetraoxo-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydro-

[0001] oxa[4,7, 10, 14]tetraazacydoheptadedno[16, 17-f]isoquinoline-3-carboxamide;

[0093] (3S,7S, 10R, 13 R)-13-benzy I- 10-((3-f I uorobicyclo[ 1 .1.1 ]pentan-1 -yl)methyl)-7-isobutyl-N-(2-(3-methoxyisoxazol-5- yl)ethyl)-6,9, 20-trimethy 1-1 ,5,8, 11 -tetraoxo-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahyd roll ]oxa[4, 7, 10, 14]tetraazacycloheptadedno[16, 17-f]isoquinoline-3-carboxamide;

[0094] (3S,7S, 10R, 13R)-13-benzyl-N -(2-(5-cyclopropyl-2 H-tetrazol-2-yl)ethy I)- 10-((3-f I uorobicyclo[ 1.1.1 ]pentan- 1 - yl) methy l)-7-isobu ty I-6, 9, 20-tri methyl- 1 ,5,8, 11 -tetraoxo-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydro-

[0001] oxa[4,7, 10, 14]tetraazacycloheptadedno[16, 17-f]isoquinoline-3-carboxamide;

[0095] (3S,7S, 10R, 13R)-20-fluoro-N-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)-10-((3-fluorobicydo[1.1.1 ]pentan- 1 - yl)methyl)-7-isobutyl-13-((6-methoxypyridin-2-yl)methyl)-6,9-dimethyl-1 ,5,8,11-tetraoxo-

[0096] 1.2.3.4.5.6.7.8.9.10.11.12.13.14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide;

[0097] (3S,7S,10R, 13R)-20-fluoro-10-((3-fluorobicyclo[1.1 ,1]pentan-1-yl)methyl)-7-isobutyl-N-(2-(4-methoxy-2H-1 ,2,3- triazol-2-yl)ethyl)-13-((6-methoxypy rid i n-2-y I) methy l)-6, 9-di methyl- 1 ,5,8, 11 -tetraoxo-

[0098] 1,2,3,4,5,6,7,8,9,10,11 , 12,13, 14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide;

[0099] (3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1 ,2,4-oxadiazol-5-yl)ethyl)-10-((3- methoxybicyclo[1 .1.1 ]pentan-1 -yl)methyl)-13-((6-methoxy pyridi n-2-y I) methy l)-6, 9-d i methy I- 1 ,5,8, 11 -tetraoxo-

[0100] 1,2,3,4,5,6,7,8,9,10,11 , 12,13, 14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide;

[0101] (3S,7S,10R,13R)-20-fluoro-7-isobutyl-10-((3-methoxybicydo[1.1.1]pentan-1-yl)methyl)-N-(2-(3-methoxyisoxazol- 5-yl)ethyl)-13-((6-methoxypy rid i n-2-yl)methyl)-6, 9-di methy I- 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]tetraazacydoheptadecino[16,17-f]quinoline-3-carboxamide;

[0102] (3S,7S, 10R, 13R)-N-(2-(5-cydopropyl-2H-tetrazol-2-yl)ethyl)-20-fluoro-7-isobutyl-10-((3- methoxybicyclo[1 .1.1 ]pentan-1 -yl)methyl)-13-((6-methoxy pyridi n-2-y I) methy l)-6, 9-d i methy I- 1 ,5,8, 11 -tetraoxo-

[0103] 1,2,3,4,5,6,7,8,9,10,11 , 12,13, 14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide; (3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-13-((6-methoxypyridin-2-yl)methyl)-6,9- dimethyl-10-((3-methylbicyclo[1.1.1]pentan-1-yl)methyl)-1,5,8, 11-tetraoxo-1,2,3,4,5,6,7,8,9, 10,11,12,13,14- tetradecahydro-

[0001] oxa[4,7, 10, 14]tetraazacydoheptadecino[16, 17-f]quinoline-3-carboxamide;

[0104] (3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1 ,2,4-oxadiazol-5-yl)ethyl)-13-((6-methoxypyridin-2- yl) methyl)-6, 9-d i methyl- 10-((3-methy I bicyclo[ 1.1.1 ]pentan- 1 -y I) methyl)- 1 ,5,8, 11 -tetraoxo-

[0105] 1.2.3.4.5.6.7.8.9.10.11.12.13.14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide;

[0106] (3S,7S, 10R, 13R)-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-20-fluoro-7-isobutyl-13-((6-methoxypyridin-2- yl) methyl)-6, 9-d i methyl- 10-((3-methy I bicyclo[ 1 .1.1 ]pentan- 1 -y I) methyl)- 1 ,5,8, 11 -tetraoxo-

[0107] 1.2.3.4.5.6.7.8.9.10.11.12.13.14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadedno[16,17-f]quinoline-3- carboxamide;

[0108] (3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(4-methoxy-2H-1 ,2,3-triazol-2-yl)ethyl)-13-((6-methoxypyridin-2- yl) methyl)-6, 9-d i methyl- 10-((3-methy I bicyclo[ 1 .1.1 ]pentan- 1 -y I) methyl)- 1 ,5,8, 11 -tetraoxo-

[0109] 1.2.3.4.5.6.7.8.9.10.11.12.13.14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide;

[0110] (3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-13-((6-methoxypyridin-2-yl)methyl)-6,9- dimethyl-1 ,5,8, 11 -tetraoxo-10-((3-( trifl uoromethy I) bicydo[ 1 .1.1 ]pentan-1 -yl)methyl)-

[0111] 1.2.3.4.5.6.7.8.9.10.11.12.13.14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadedno[16,17-f]quinoline-3- carboxamide;

[0112] (3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1 ,2,4-oxadiazol-5-yl)ethyl)-13-((6-methoxypyridin-2- yl) methyl)-6, 9-d i methyl- 1 ,5,8, 11 -tetraoxo-10-((3-(trifluoromethy I) bicyclo[ 1.1.1 ]pentan-1 -yl)methyl)-

[0113] 1.2.3.4.5.6.7.8.9.10.11.12.13.14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide;

[0114] (3S,7S, 10R, 13R)-N-(2-(5-cydopropyl-2H-tetrazol-2-yl)ethyl)-20-fluoro-7-isobutyl-13-((6-methoxypyridin-2- yl) methyl)-6, 9-d i methyl- 1 ,5,8, 11 -tetraoxo-10-((3-(trifluoromethy I) bicyclo[ 1.1.1 ]pentan-1 -yl)methyl)-

[0115] 1.2.3.4.5.6.7.8.9.10.11.12.13.14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide;

[0116] (3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(4-methoxy-2H-1 ,2,3-triazol-2-yl)ethyl)-13-((6-methoxypyridin-2- yl) methyl)-6, 9-d i methyl- 1 ,5,8, 11 -tetraoxo-10-((3-(trifluoromethy I) bicyclo[ 1.1.1 ]pentan-1 -yl)methyl)-

[0117] 1.2.3.4.5.6.7.8.9.10.11.12.13.14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadedno[16,17-f]quinoline-3- carboxamide;

[0118] (3S,7S, 10R, 13R)-13-benzy l-20-f luoro-7-isobu tyl-N-(2-(3-methoxyisoxazol-5-y l)ethy l)-6, 9-d imethy 1-10-(( 1 -methyl- 2-oxabicyclo[2.1.1 ]hexan-4-yl)methyl)-1 ,5,8, 11 -tetraoxo-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydro-

[0001] oxa[4,7, 10, 14]tetraazacycloheptadedno[16, 17-f]quinoline-3-carboxamide; (3S,7S, 10R, 13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1 ,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-10-((1- methyl-2-oxabicyclo[2.1 .1 ]hexan-4-yl)methyl)-1 ,5,8, 11 -tetraoxo-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydro-

[0001] oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;

[0119] (3S,7S, 10R, 13R)-13-benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-10-((1 - methyl-2-oxabicyclo[2.1 .1 ]hexan-4-yl)methyl)-1 ,5,8, 11 -tetraoxo-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydro-

[0001] oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;

[0120] (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(4-methoxy-2H-1 ,2,3-triazol-2-yl)ethyl)-6,9-dimethyl-10-((1- methyl-2-oxabicyclo[2.1 .1 ]hexan-4-yl)methyl)-1 ,5,8, 11 -tetraoxo-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydro-

[0001] oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;

[0121] (3S,7S, 10R, 13R)-10-((3-fl uorobicyclo[ 1 .1.1 ]pentan- 1 -yl)methyl)-7-isobutyl-N-(2-(3-methoxy-1 ,2,4-oxadiazol-5- yl)ethyl)- 13-((6-methoxy py rid in-2-y I) methy l)-6, 9, 20-tri methy I- 1 ,5,8, 11 -tetraoxo-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14- tetradecahydro-

[0001] oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]isoquinoline-3-carboxamide;

[0122] (3S,7S, 10R, 13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1 , 2, 4-oxadi azol-5-y l)ethyl)- 10-((3- methoxybicyclo[1 .1.1 ]pentan- 1 -y l)methyl)-6, 9-d imethy 1-1 ,5,8, 11 -tetraoxo-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14- tetradecahydro-

[0001] oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;

[0123] (3S,7S, 10R, 13R)-13-benzy l-20-f luoro-7-isobu tyl- 10-((3-methoxybicyclo[1.1.1 ]pentan- 1 -yl)methyl)-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-

[0001] oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;

[0124] (3S,7S, 10R, 13R)-13-benzyl- 10-((3-ch lorobicyclo[ 1.1.1 ]pentan- 1 -yl) methy l)-20-f luoro-7-isobu tyl-N -(2-(3-methoxy- 1 , 2, 4-oxad i azol-5-y l)ethy l)-6, 9-d i methy I- 1 ,5,8, 11 -tetraoxo-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10,11 ,12,13,14-tetradecahydro-

[0001] oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;

[0125] (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-((1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14- tetradecahydro-[1]oxa[4,7,10, 14]tetraazacycloheptadecino[16,17-f]quinoline-3-carboxamide;

[0126] (3R,6R,9S,13S)-9-isobutyl-16-methoxy-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-3-((6-methoxypyridin-2- yl) methy l)-7, 10, 18-trimethyl-5,8, 11,15-tetraoxo-6-((3-(trif I uoromethyl) bicyclof 1.1.1 ]pentan- 1 -yl) methyl)- 2, 3, 4, 5, 6, 7, 8, 9, 10,11 ,12,13, 14, 15-tetradecahydropyrido[3,4-p][1]oxa[4,7, 10, 14]tetraazacycloheptadecine-13- carboxamide;

[0127] (3R,6R,9S,13S)-9-isobutyl-16-methoxy-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-3-((6-methoxypyridin-2-yl)methyl)- 7, 10, 18-trimethyl-5,8, 11 ,15-tetraoxo-6-((3-(trif I uoromethy I) bicyclo[ 1 .1.1 ]pentan- 1 -yl)methyl)-

[0128] 2, 3, 4, 5, 6, 7, 8, 9, 10,11 ,12,13, 14, 15-tetradecahydropyrido[3,4-p][1]oxa[4,7, 10, 14]tetraazacycloheptadecine-13- carboxamide;

[0129] (3R,6R,9S, 13S)-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-9-isobutyl-16-methoxy-3-((6-methoxypyridin-2- yl) methy l)-7, 10, 18-trimethyl-5,8, 11,15-tetraoxo-6-((3-(trif I uoromethyl) bicyclof 1.1.1 ]pentan- 1 -y l)methy I)- 2, 3, 4, 5, 6, 7, 8, 9, 10,11 ,12,13,14, 15-tetradecahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacycloheptadecine-13- carboxamide;

[0130] (3S,7S, 10R, 13R)-N-(2-(5-cydopropyl-2H-tetrazol-2-yl)ethyl)-20-fluoro-7-isobutyl-13-((6-methoxypyridin-2- yl) methyl)-6, 9-d i methyl- 1 ,5,8, 11 -tetraoxo-10-((1 -(trif luoromethy I )-2-oxabicyclo[2.1.1 ]hexan-4-yl)methyl)-

[0131] 1,2,3,4,5,6,7,8,9,10,11 , 12,13, 14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide;

[0132] (3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1 ,2,4-oxadiazol-5-yl)ethyl)-13-((6-methoxypyridin-2- yl) methyl)-6, 9-d i methyl- 1 ,5,8, 11 -tetraoxo-10-((1 -(trifluoromethyl)-2-oxabicydo[2.1.1 ]hexan-4-yl)methyl)-

[0133] 1,2,3,4,5,6,7,8,9,10,11 , 12,13, 14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide;

[0134] (3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-13-((6-methoxypyridin-2-yl)methyl)-6,9- dimethy 1-1 ,5,8, 11 -tetraoxo-10-((1 -(trifl uoromethyl)-2-oxabicyclo[2.1 .1 ]hexan-4-yl)methyl)-

[0135] 1,2,3,4,5,6,7,8,9,10,11 , 12,13, 14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide;

[0136] (3S,7S, 10R, 13R)-13-benzy l-N-(2-(5-cydopropy I-2H -tetrazol-2-yl)ethyl)-20-f I uoro-7-isobuty I-6, 9-d i methyl- 1 ,5,8,11- tetraoxo-10-((1 -(trifluoromethyl)-2-oxabicydo[2.1 .1 ]hexan-4-y I) methyl)- 1 ,2, 3, 4, 5, 6, 7, 8, 9, 10,11,12,13,14- tetradecahydro-[1]oxa[4,7,10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3-carboxamide;

[0137] (3S,7S, 10R, 13R)-13-benzy l-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6, 9-d imethy I- 1 ,5,8,11- tetraoxo-10-((1 -(trifluoromethyl)-2-oxabicydo[2.1 .1 ]hexan-4-y I) methyl)- 1 ,2, 3, 4, 5, 6, 7, 8, 9, 10,11,12,13,14- tetradecahydro-[1]oxa[4,7,10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3-carboxamide;

[0138] (3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1 ,2,4-oxadiazol-5-yl)ethyl)-13-((4-methoxypyridin-2- yl) methyl)-6, 9-d i methyl- 1 ,5,8, 11 -tetraoxo-10-((1 -(trifluoromethyl)-2-oxabicydo[2.1.1 ]hexan-4-yl)methyl)-

[0139] 1,2,3,4,5,6,7,8,9,10,11 , 12,13, 14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide;

[0140] (3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-13-((4-methoxypyridin-2-yl)methyl)-6,9- dimethy 1-1 ,5,8, 11 -tetraoxo-10-((1 -(trifl uoromethyl)-2-oxabicyclo[2.1 .1 ]hexan-4-yl)methyl)-

[0141] 1,2,3,4,5,6,7,8,9,10,11 , 12,13, 14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide;

[0142] (3S,7S, 10R, 13R)-N-(2-(5-cydopropyl-2H-tetrazol-2-yl)ethyl)-20-fluoro-7-isobutyl-13-((4-methoxypyridin-2- yl) methyl)-6, 9-d i methyl- 1 ,5,8, 11 -tetraoxo-10-((1 -(trifluoromethyl)-2-oxabicydo[2.1.1 ]hexan-4-yl)methyl)-

[0143] 1,2,3,4,5,6,7,8,9,10,11 , 12,13, 14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide;

[0144] (3S,7S, 10R, 13 R)-20-f I uoro- 10-((3-f I uorobicyclo[ 1 .1.1 ]pentan- 1 -yl)methyl)-7-isobutyl-N-(2-(3-methoxy-1 ,2,4- oxadiazol-5-yl)ethyl)-13-((4-methoxypyridin-2-yl)methyl)-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]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide;

[0145] (3S,7S,1 OR, 13R)-20-fluoro-10-((3-fluorobicyclo[1 .1 .1]pentan-1 -yl)methyl)-7-isobutyl-N-(2-(3-methoxyisoxazol-5- yl)ethyl)- 13-((4-methoxypy rid i n-2-yl) methy l)-6,9-di methyl- 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]tetraazacycloheptadecino[16,17-f]quinoline-3-carboxamide;

[0146] (3S,7S, 10R, 13R)-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-20-fluoro-10-((3-fluorobicyclo[1 .1 .1]pentan-1 - yl)methyl)-7-isobutyl-13-((4-methoxypyridin-2-yl)methyl)-6,9-dimethyl-1 ,5,8,11-tetraoxo-

[0147] 1.2.3.4.5.6.7.8.9.10.11.12.13.14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide;

[0148] (3S,7S, 10R, 13 R)-20-f I uoro- 10-((3-f I uorobicyclo[ 1 .1.1 ]pentan- 1 -y I) methy l)-7-isobutyl-N-(2-(3-methoxy- 1 ,2,4- oxadiazol-5-yl)ethyl)-6,9-dimethyl-13-((4-methylpyridin-2-yl)methyl)-1,5,8,11-tetraoxo-

[0149] 1.2.3.4.5.6.7.8.9.10.11.12.13.14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadedno[16,17-f]quinoline-3- carboxamide;

[0150] (3S,7S, 10R, 13R)-N-(2-(5-cydopropyl-2H-tetrazol-2-yl)ethyl)-20-fluoro-10-((3-fluorobicyclo[1 .1 .1]pentan-1 - yl)methyl)-7-isobutyl-6,9-dimethyl-13-((4-methylpyridin-2-yl)methyl)-1,5,8, 11-tetraoxo-

[0151] 1.2.3.4.5.6.7.8.9.10.11.12.13.14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadedno[16,17-f]quinoline-3- carboxamide;

[0152] (3S,7S,1 OR, 13R)-20-fluoro-10-((3-fluorobicyclo[1 .1 .1]pentan-1 -yl)methyl)-7-isobutyl-N-(2-(3-methoxyisoxazol-5- yl)ethyl)-6,9-dimethyl-13-((4-methy Ipy rid i n-2-yl) methy l)-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]tetraazacydoheptadecino[16,17-f]quinoline-3-carboxamide;

[0153] (3S,7S, 10R, 13 R)-20-f I uoro- 10-((3-f I uorobicyclo[ 1 .1.1 ]pentan- 1 -y I) methy l)-7-isobutyl-N-(2-(3-methoxy- 1 ,2,4- oxadiazol-5-yl)ethyl)-13-((4-methoxypyrimidin-2-yl)methyl)-6,9-dimethyl-1,5,8,11-tetraoxo-

[0154] 1.2.3.4.5.6.7.8.9.10.11.12.13.14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide; and

[0155] (3S,7S, 10R, 13 R)-20-f I uoro- 10-((3-f I uorobicyclo[ 1 .1.1 ]pentan- 1 -y I) methy l)-7-isobutyl-N-(2-(3-methoxy- 1 ,2,4- oxadiazol-5-yl)ethyl)-13-((6-methoxypyrimidin-4-yl)methyl)-6,9-dimethyl-1,5,8,11-tetraoxo-

[0156] 1,2,3,4,5,6,7,8,9,10,11 , 12,13, 14-tetradecahydro-[1]oxa[4,7, 10, 14]tetraazacydoheptadecino[16,17-f]quinoline-3- carboxamide.

[0157] The compounds of formula (I) according to embodiments 1) to 10) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral e.g. in form of a tablet or a capsule) or parenteral administration (including topical application or inhalation).

[0158] 11 ) Another embodiment relates to a pharmaceutical composition comprising a compound of formula (I) according to any one of embodiments 1) to 10), or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient. The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person 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 bringing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

[0159] The present invention also relates to a method for the prevention / prophylaxis or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) according to embodiments 1) to 10).

[0160] The compounds of formula (I) according to embodiments 1) to 10) are useful for the treatment of CFTR-related diseases and disorders, especially cystic fibrosis.

[0161] CFTR-related diseases and disorders may be defined as including especially cystic fibrosis, as well as further CFTR-related diseases and disorders selected from:

[0162] • chronic bronchitis; rhinosinusitis; constipation; pancreatitis; pancreatic insufficiency; male infertility caused by congenital bilateral absence of the vas deferens (CBAVD); mild pulmonary disease; allergic bronchopulmonary aspergillosis (ABPA); liver disease; coagulation-fibrinolysis deficiencies, such as protein C deficiency; and diabetes mellitus;

[0163] • asthma; COPD; smoke induced COPD; and dry-eye disease; and

[0164] • idiopathic pancreatitis; hereditary emphysema; hereditary hemochromatosis; lysosomal storage diseases such as especially l-cell disease pseudo-Hurler; mucopolysaccharidoses; Sandhoff / Tay-Sachs; osteogenesis imperfecta; Fabry disease; Sjogren's disease; osteoporosis; osteopenia; bone healing and bone growth (including bone repair, bone regeneration, reducing bone resorption and increasing bone deposition); chloride channelopathies, such as myotonia congenita (Thomson and Becker forms); Bartter's syndrome type 3; epilepsy; lysosomal storage disease; Primary Ciliary Dyskinesia (PCD) - a term for inherited disorders of the structure and or function of cilia (including PCD with situs inversus also known as Kartagener syndrome, PCD without situs inversus, and ciliary aplasia); generalized epilepsy with fibrile seizures plus (GEFS+); general epilepsy with febrile and afebrile seizures; myotonia; paramyotonia congenital; potassium-aggravated myotonia; hyperkalemic periodic paralysis; long QT syndrome (LOTS); LQTS / Brugada syndrome; autosomal-dominant LOTS with deafness; autosomal-recessive LOTS; LOTS with dysmorphic features; congenital and acquired LOTS; dilated cardiomyopathy; autosomal-dominant LOTS; osteopetrosis; and Bartter syndrome type 3.

[0165] The term “treatment of cystic fibrosis” refers to any treatment of cystic fibrosis and includes especially treatment that reduces the severity of cystic fibrosis and / or reduces the symptoms of cystic fibrosis. The term “cystic fibrosis” refers to any form of cystic fibrosis, especially to a cystic fibrosis that is associated with one or more gene mutation(s). Preferably, such cystic fibrosis is associated with an CFTR trafficking defect (class II mutations) or reduced CFTR stability (class VI mutations) [in particular, an CFTR trafficking defect / class II mutation], wherein it is understood that such CFTR trafficking defect or reduced CFTR stability may be associated with another disease causing mutation of the same or any other class. Such further disease causing CFTR gene mutation comprises class I mutations (no functional CFTR protein), (a further) class II mutation (CFTR trafficking defect), class III mutations (CFTR regulation defect), class IV mutations (CFTR conductance defect), class V mutations (less CFTR protein due to splicing defects), and / or (a further) class VI mutation (less CFTR protein due to reduced CFTR stability). Said one or more gene mutation(s) may for example comprise at least one mutation selected from F508del, A561 E, and N1303K, as well as l507del, R560T, R1066C and V520F; in particular F508del. In addition to the above-listed, further CFTR gene mutations comprise for example G85E, R347P, L206W, and M1101 K. Said gene mutation(s) may be heterozygous, homozygous or compound hetereozygous. Especially said gene mutation is heterozygous comprising one F508del mutation. Further CFTR gene mutations (which are especially class III and / or IV mutations) comprise G551 D, R117H, D1152H, A455E, S549N, R347H, S945L, and R117C.

[0166] The severity of cystic fibrosis / of a certain gene mutation associated with cystic fibrosis as well as the efficacy of correction thereof may generally be measured by testing the chloride transport effected by the CFTR. In patients, for example average sweat chloride content may be used for such assessment.

[0167] The term “symptoms of cystic fibrosis” refers especially to elevated chloride concentration in the sweat; symptoms of cystic fibrosis further comprise chronic bronchitis; rhinosinusitis; constipation; pancreatitis; pancreatic insufficiency; male infertility caused by congenital bilateral absence of the vas deferens (CBAVD); mild pulmonary disease; allergic bronchopulmonary aspergillosis (ABPA); liver disease; coagulation-fibrinolysis deficiencies such as protein C deficiency; and / or diabetes mellitus.

[0168] For avoidance of any doubt, if compounds are described as useful for the treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the treatment of said diseases. Likewise, such compounds are also suitable in a method for the treatment of such diseases, comprising administering to a subject in need thereof, an effective amount of such compound.

[0169] The term “subject” as used herein refers to a mammal, especially a human.

[0170] 12) Another embodiment relates to a pharmaceutical composition according to embodiment 11), wherein said composition further comprises one or more therapeutically active ingredients acting as CFTR modulator(s); wherein said CFTR modulator(s) is / are one or more CFTR corrector(s) (especially a type-l corrector, and / or a type-ll corrector, and / or a type-l II corrector), and / or a CFTR potentiator, and / or a CFTR stabilizer; or a pharmaceutically acceptable salt thereof. 13) A further embodiment relates to a pharmaceutical composition according to embodiment 12), wherein the one or more therapeutically active ingredients acting as CFTR modulator(s) is / are a type-l corrector selected from lumacaftor, tezacaftor, and galicaftor; and / or a type-l I corrector which is Corrector4a; and / or a type-l 11 corrector selected from elexacaftor, bamocaftor, olacaftor, and vanzacaftor; and / or a CFTR potentiator selected from ivacaftor, navocaftor, icenticaftor, deutivacaftor, GLPG-1837, and GLPG2451 ; or a pharmaceutically acceptable salt thereof.

[0171] 14) A further embodiment relates to a pharmaceutical composition according to embodiment 12), wherein the one or more therapeutically active ingredients acting as CFTR modulator(s) is / are a type-l corrector selected from lumacaftor, tezacaftor, and galicaftor; and / or a type-l I corrector which is Corrector4a; and / or a type-l 11 corrector selected from elexacaftor and vanzacaftor; and / or a CFTR potentiator selected from ivacaftor, navocaftor, icenticaftor, and deutivacaftor; or a pharmaceutically acceptable salt thereof.

[0172] 15) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 12) to 14), wherein said composition comprises the compound of formula (I) and at least one (especially one) therapeutically active ingredient acting as CFTR modulator, wherein said CFTR modulator is a CFTR potentiator; or a pharmaceutically acceptable salt thereof.

[0173] 16) A further embodiment relates to a pharmaceutical composition according to embodiment 12), wherein said composition comprises the compound of formula (I) and at least one (especially one) therapeutically active ingredient acting as CFTR modulator, wherein said CFTR modulator is a CFTR potentiator selected from ivacaftor, icenticaftor, and deutivacaftor; or a pharmaceutically acceptable salt thereof.

[0174] 17) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 12) to 16), wherein said composition comprises the compound of formula (I) and at least two (especially two) therapeutically active ingredients acting as CFTR modulators, wherein one of said CFTR modulators is a CFTR potentiator or a pharmaceutically acceptable salt thereof, and, a second CFTR modulator is a CFTR corrector or a pharmaceutically acceptable salt thereof.

[0175] 18) A further embodiment relates to a pharmaceutical composition according to embodiment 17), wherein said composition comprises the compound of formula (I) and

[0176] • ivacaftor and tezacaftor, or pharmaceutically acceptable salts thereof; or

[0177] • ivacaftor and lumacaftor, or pharmaceutically acceptable salts thereof; or

[0178] • navocaftor and galicaftor, or pharmaceutically acceptable salts thereof.

[0179] 19) A further embodiment relates to a pharmaceutical composition according to any one of embodiments 12) to 18), wherein said composition comprises the compound of formula (I) and three therapeutically active ingredients acting as CFTR modulators, wherein one of said CFTR modulators is a CFTR potentiator or a pharmaceutically acceptable salt thereof, the second CFTR modulator is a type-l corrector or a pharmaceutically acceptable salt thereof, and the third CFTR modulator is a type-l 11 corrector or a pharmaceutically acceptable salt thereof.

[0180] 20) A further embodiment relates to a pharmaceutical composition according to embodiment 19), wherein said composition comprises the compound of formula (I) and

[0181] • ivacaftor, tezacaftor and elexacaftor, or pharmaceutically acceptable salts thereof; or

[0182] • deutivacaftor, tezacaftor and vanzacaftor, or pharmaceutically acceptable salts thereof.

[0183] Such combination pharmaceutical compositions according to embodiments 12) to 20) are especially useful for the prevention or treatment of CFTR-related diseases as defined herein, in particular cystic fibrosis; and in a method for the prevention or treatment of CFTR-related diseases as defined herein, in particular cystic fibrosis, said method comprising administering a pharmaceutically efficacious dose of such combination pharmaceutical composition to a subject (especially a human) in need thereof.

[0184] Accordingly, the compound of formula (I) as defined in any one of embodiments 1) to 10), or a pharmaceutically acceptable salt thereof, according to this invention is for use in combination (or co-therapy) with said further pharmaceutically active ingredients as defined herein which are CFTR modulators (CFTR correctors and / or CFTR potentiators).

[0185] Definitions provided herein are intended to apply uniformly to any one of embodiments 1) to 10), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein.

[0186] The term “therapeutically active ingredients acting as CFTR modulator'1refers to any CFTR corrector (especially type-l-, type-ll-, or type-ill corrector) and / or CFTR potentiator that has shown -alone and / or in combination - potential for therapeutic use (as 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 disease (in particular cystic fibrosis). Examples are especially CFTR potentiators: ivacaftor, navocaftor, icenticaftor, deutivacaftor, GLPG-1837, and GLPG-2451; and CFTR correctors: type-l correctors (lumacaftor, tezacaftor, galicaftor), type-ll correctors (Corrector4a), and type-ill correctors (elexacaftor, bamocaftor, olacaftor, vanzacaftor; and, in addition ABBV-119, ABBV-567).

[0187] In a sub-embodiment, the present invention, thus, relates to the compounds of formula (I) as defined in any one of embodiments 1) to 10), or a pharmaceutically acceptable salt thereof, for use in the prophylaxis / prevention or treatment of CFTR-related diseases as defined herein, in particular cystic fibrosis; wherein said compound of formula (I) is (intended) to be administered / is administered in combination with CFTR potentiator, such as especially ivacaftor, navocaftor, icenticaftor, or deutivacaftor, or a pharmaceutically acceptable salt thereof; optionally additionally in combination with CFTR corrector, such as especially lumacaftor, tezacaftor, galicaftor, elexacaftor, or vanzacaftor, or a pharmaceutically acceptable salt thereof.

[0188] The term “subject” refers to a mammal, especially a human.

[0189] A combined treatment (or co-therapy) may notably be effected simultaneously (in a fixed dose or in a non-fixed dose).

[0190] “Simultaneously”, when referring to an administration type, means in the present application that the administration type concerned consists in the administration of two or more active ingredients and / or treatments at approximately the same time; wherein it is understood that a simultaneous administration will lead to exposure of the subject to the two or more active ingredients and / or treatments at the same time. When administered simultaneously, said two or more active ingredients may be administered in a fixed dose combination, or in a non-fixed dose combination, wherein such 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 to be administered by the same route of administration at approximately the same time), or a non-fixed dose combination using two or more different routes of administration or dosing regimens; wherein in each case said administration leads to essentially simultaneous exposure of the subject to the combined two or more active ingredients and / or treatments. An example of simultaneous administration of a non-fixed dose combination using two different pharmaceutical compositions to be administered by the same route of administration at approximately the same time is a non-fixed dose combination wherein the compound of formula (I) as defined in any one of embodiments 1) to 10) is administered b.i.d., and the respective CFTR modulator(s) is / are administered b.i.d.. Another example of simultaneous administration of a non-fixed dose combination using two different routes of administration is a non-fixed dose combination wherein the compound of formula (I) as defined in any one of embodiments 1) to 10) is administered once a day or b.i.d., and the respective CFTR modulator(s) is / are administered t.i.d.. Another example of simultaneous administration of a non-fixed dose combination using two different routes of administration is a nonfixed dose combination wherein the compound of formula (I) as defined in any one of embodiments 1) to 10) is administered once a day, and the respective CFTR modulator(s) is / are administered b.i.d. Another example of simultaneous administration of a non-fixed dose combination using two different routes of administration is a nonfixed dose combination wherein the compound of formula (I) as defined in any one of embodiments 1) to 10) is administered b.i.d., and the respective CFTR modulator(s) is / are administered once a day.

[0191] “Fixed dose combination”, when referring to an administration type, means in the present application that the administration type concerned consists in the administration of one single pharmaceutical composition comprising the two or more active ingredients, such as especially the pharmaceutical compositions of any one of embodiments 12) to 20).

[0192] 21) Another aspect fo the invention relates to the compound of formula (I) as defined in any one of embodiments 1) to 10), or a pharmaceutically acceptable salt thereof, for use in the treatment of CFTR-related diseases and disorders, especially of cystic fibrosis; wherein said compound is to be used / to be administered / administered in combination with one or more therapeutically active ingredients acting as CFTR modulator(s); wherein said CFTR modulator(s) is / are one or more CFTR corrector(s) (especially a type-l corrector, and / or a type-ll corrector, and / or a type-l II corrector), and / or a CFTR potentiator, and / or a CFTR stabilizer.

[0193] 22) Another embodiment relates to compound of formula (I), or a pharmaceutically acceptable salt thereof for use according to embodiment 21), wherein said CFTR modulator(s) is / are as defined in any one of embodiments 12) to 20).

[0194] 23) Another embodiment relates to compound of formula (I), or a pharmaceutically acceptable salt thereof for use according to embodiment 22), wherein said CFTR modulator(s) is / are as defined in embodiment 18).

[0195] It is understood that any embodiment relating to a compound of formula (I) as defined in any one of embodiments 1) to 10), or a pharmaceutically acceptable salt thereof, for combination use in the treatment of CFTR-related diseases as defined herein (especially of cystic fibrosis), wherein said compound of formula (I) is (intended) to be administered / is administered in combination with one or more CFTR modulator(s), wherein said CFTR modulators(s) is / are CFTR corrector(s) (especially a type-l-, a type-ll-, a type-l I l-corrector) and / or a CFTR potentiator and / or a CFTR stabilizer, or a pharmaceutically acceptable salt thereof, wherein said one or more CFTR modulator(s) are especially as defined in any one of embodiments 12) to 20), also relates

[0196] • to said compound of formula (I) as defined in any one of embodiments 1) to 10), or a pharmaceutically acceptable salt thereof, for combination use in the treatment of CFTR-related diseases as defined herein (especially of cystic fibrosis), wherein said compound of formula (I) is (intended) to be administered / is administered in combination with said one or more CFTR modulator(s);

[0197] • to said CFTR modulator(s) being CFTR corrector(s) and / or a CFTR potentiator, or a pharmaceutically acceptable salt thereof, for use in the treatment of said CFTR-related diseases (especially of cystic fibrosis); wherein said CFTR modulator(s) being CFTR corrector(s) and / or a CFTR potentiator and / or a CFTR stabilizer, is (intended) to be administered in combination with said compound of formula (I);

[0198] • to the use of said compound of formula (I), or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament / a pharmaceutical composition comprising said compound of formula (I), or a pharmaceutically acceptable salt thereof, and said CFTR modulator(s) being CFTR corrector(s) and / or a CFTR potentiator and / or a CFTR stabilizer, or a pharmaceutically acceptable salt thereof, for use in the treatment of said CFTR-related diseases (especially of cystic fibrosis);

[0199] • to the use of said compound of formula (I), or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament / pharmaceutical composition comprising, as active ingredient, said compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of said CFTR-related diseases (especially of cystic fibrosis); wherein said medicament / pharmaceutical composition is (intended) to be used in combination with said CFTR modulator(s) being CFTR corrector(s) and / or a CFTR potentiator and / or a CFTR stabilizer, or a pharmaceutically acceptable salt thereof;

[0200] • to the use of said CFTR modulator(s) being CFTR corrector(s) and / or a CFTR potentiator and / or a CFTR stabilizer, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament / pharmaceutical composition comprising, as active ingredient, said CFTR modulator(s) being CFTR corrector(s) and / or a CFTR potentiator and / or a CFTR stabilizer, or a pharmaceutically acceptable salt thereof, for use in the treatment of said CFTR-related diseases (especially of cystic fibrosis); wherein said medicament / pharmaceutical composition is (intended) to be used in combination with said compound of formula (I), or a pharmaceutically acceptable salt thereof;

[0201] • to the use of a pharmaceutical composition comprising said compound of formula (I), or a pharmaceutically acceptable salt thereof, and said CFTR modulator(s) being CFTR corrector(s) and / or a CFTR potentiator and / or a CFTR stabilizer, or a pharmaceutically acceptable salt thereof, for the treatment of said CFTR- related diseases (especially of cystic fibrosis);

[0202] • to a medicament for use in the prevention or treatment of said CFTR-related diseases (especially of cystic fibrosis), said medicament comprising said compound of formula (I), or a pharmaceutically acceptable salt thereof; wherein said medicament is (intended) to be administered in combination with said CFTR modulator(s) being CFTR corrector(s) and / or a CFTR potentiator and / or a CFTR stabilizer, or a pharmaceutically acceptable salt thereof;

[0203] • to a method of preventing or treating said CFTR-related diseases (especially of cystic fibrosis) comprising administering to a subject (preferably a human) in need thereof an effective amount of said compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is administered in combination with an effective amount of said CFTR modulator(s) being CFTR corrector(s) and / or a CFTR potentiator and / or a CFTR stabilizer, or of a pharmaceutically acceptable salt thereof; wherein it is understood that said combined administration may be in a fixed-dose combination or in a nonfixed dose combination;

[0204] • to a method of preventing or treating said CFTR-related diseases (especially of cystic fibrosis) comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising said compound of formula (I), or a pharmaceutically acceptable salt thereof, and said CFTR modulator(s) being CFTR corrector(s) and / or a CFTR potentiator and / or a CFTR stabilizer, or a pharmaceutically acceptable salt thereof; and

[0205] • to a method of preventing or treating said CFTR-related diseases (especially of cystic fibrosis) comprising administering to a subject (preferably a human) in need thereof an effective amount of said CFTR modulator(s) being CFTR corrector(s) and / or a CFTR potentiator and / or a CFTR stabilizer, or of a pharmaceutically acceptable salt thereof, wherein said anti- CFTR modulator(s) being CFTR corrector(s) and / or a CFTR potentiator and / or a CFTR stabilizer, is administered in combination with an effective amount of said compound of formula (I), or of a pharmaceutically acceptable salt thereof wherein it is understood that said combined administration may be in a fixed-dose combination or in a non-fixed dose combination.

[0206] Preparation of compounds of Formula (I):

[0207] The compounds of formula (I), formula (IE) can be prepared by well-known literature methods, by the methods given below, by the methods given in the experimental part below or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures. In some cases, the order of carrying out the following reaction schemes, and / or reaction steps, may be varied to facilitate the reaction or to avoid unwanted reaction products. In the general sequence of reactions outlined below, the generic groups R1, R2, R3, R4, R5, W, Z, Ar1and Ar2are as defined for formula (I) or formula (IE) unless explicitely otherwise defined. Other abbreviations used herein are explicitly defined, or are as defined in the experimental section. In some instances, the generic groups R1, R2, R3, R4, R5, W, Z, Ar1and Ar2might be incompatible with the assembly illustrated in the schemes below and so will require the use of protecting groups (PG). The use of protecting groups is well known in the art (see for example “Protective Groups in Org. Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-lnterscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place. In some cases, the final product may be further modified, for example, by manipulation of substituents to give a new final product. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, hydrolysis and transition-metal catalysed cross-coupling reactions which are commonly known to those skilled in the art. The compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts, in a manner known per se.

[0208] Compounds of formula (I), formula (lE) of the present invention can be prepared according to the general sequence of reactions outlined below.

[0209] In the following schemes, X represents the group: , wherein R5, W, and Z are as defined for formula (I) or formula (IE) unless explicitely otherwise defined.

[0210] Compounds of formula (I) are prepared following one of the schemes depicted below.

[0211] Reaction Scheme A

[0212] Reaction Scheme A: Syntheses can be performed with racemic or enantiomerically enriched amino acid building blocks. Suitably protected amine building block A and acid B-Ac, prepared following procedures well described in the literature or in Reaction Schemes I and J respectively, are treated with a peptide coupling reagent such as HATU, COMU, T3P, PyBop or EDCI / HOBt in a solvent like THF, DMF or NMP in the presence of a base such as TEA or DI PEA at a temperature between -20°C and +75°C, preferably at RT, to generate the corresponding amide intermediate AB. Deprotection of the amine function of the intermediate AB is achieved according to known methodologies by those skilled in the art, e.g. by treatment with 4M HCI in dioxane or preferably with TFA in the case of a Boc protecting group, or with piperidine or diethylamine in the case of an Fmoc protecting group, or the appropriate treatment in case of other protecting groups such as Cbz or Alloc protecting groups. The deprotected intermediate AB-Am is then reacted with the suitably protected acid C, prepared following procedures described in the literature or in the experimental section, according to the peptide coupling conditions already described above for the formation of the AB intermediate. The obtained linear intermediate ABC is then deprotected before the final peptide coupling macrolactamisation. In some cases, the protecting groups PG1 and PG3 are sequentially removed, but they are preferably removed simultaneously in one single step. For example, afBu ester and Boc protecting groups are removed by treatment with 4M HCI in dioxane or preferably TFA, or alternatively Allyl ester and Alloc protecting groups can be removed by palladium catalyst treatment as extensively reported in the literature. The linear ABC deprotected intermediate is then cylised under standard conditions, i.e. the intermediate can be treated with a coupling reagent such as COMU, T3P, PyBop, EDCI / HOBt, or preferably HATU in diluted conditions such as less than 0.1 M soln, of the ABC starting material in a solvent like DMF or NMP or a mix. of solvents like DMF / DCM (1 :1), in presence of a base such as TEA or DIPEA at a temperature between -20°C and +75°C, preferably at RT to yield the corresponding macrocycle cABC. Depending on the nature of the different residues some remaining deprotection steps may be required to yield the final product. Final purification by preparative HPLC, with standard reverse phase or if required, chiral phase columns gives the target compound as a pure stereoisomer.

[0213] Reaction Scheme B: In a modified version of Reaction Scheme A, the C moiety can be introduced stepwise, one amino acid at a time. The AB intermediate previously described in Reaction Scheme A, and the first amino acid D-1, commercially available or prepared following a procedure described in the literature, or in the experimental section below, are treated according to the peptide coupling conditions already described above to form the corresponding peptide bond. Selective deprotection of the amine function of ABD-1, such as removing an Fmoc group by treatment with piperidine or diethylamine, or removing a Cbz protecting group by hydrogenolysis over a catalyst such as Pd / C or Pd(OH)2 / C in a solvent like EtOAc, TH F or dioxane, or preferably removing a Boc protecting group by treatment with 4M HCI in dioxane or with TFA, affords the free amine or its ammonium salt respectively, ready to be coupled with the second amino acid D-2 in a similar peptide coupling step. The three described coupling / deprotection / coupling steps yield the same linear intermediate ABC as the one previously described in Reaction Scheme A. The remaining steps of the synthesis to furnish the desired macrocycle cABC are the same as described above. cABC

[0214] Reaction Scheme B

[0215] Reaction Scheme C

[0216] Reaction Scheme C: In an alternative approach, the sequence for building the linear intermediate ABC can be modified. Suitably protected building block C and the amine B-Am, prepared following procedures described in the literature or in Reaction Schemes K and J respectively, are treated according to the peptide coupling conditions already described above, with a reagent such as HATU, COMU, T3P, PyBop or EDCI / HOBt in a solvent like THF, DMF or NMP in the presence of a base such as TEA or DIPEA at a temperature between -20°C and +75°C, preferably at RT. Deprotection of the acid function of the intermediate BC, i.e. removal of PG4, is achieved according to known methodologies by those skilled in the art, e.g. by treatment with NaOH or LiOH in aqueous methanol at a temperature ranging from 0°C up to 50°C for methyl or ethyl esters or preferably by hydrogenolysis over a catalyst such as Pd / C or Pd(OH)2 / C in a solvent like EtOAc, THF or dioxane for benzyl esters. The deprotected intermediate BC-Ac is then reacted with the suitably protected amine building block A, prepared following procedures described in the literature or in Reaction Scheme I according to the peptide coupling conditions already described previously. The resulting linear ABC can then be deprotected and cyclised to yield the final product cABC as described in Reaction Scheme A.

[0217] Reaction Scheme D

[0218] Reaction Scheme D: As it is the case when moving from Reaction Scheme A to Reaction Scheme B, the C moiety in Reaction Scheme C can be similarly introduced stepwise, one amino acid at a time. Suitably protected acid D-1 and the amine B-Am, prepared following procedures described in the literature, or in the experimental part, or Reaction Scheme J, are treated according to the peptide coupling conditions already described above. Selective deprotection of the amine function of BD-1, i.e. removal of PG5, such as removing a Cbz protecting group under acidic conditions or more preferable, removing a Boc protecting group by treatment with 4M HOI in dioxane or preferably with TFA, affords the corresponding ammonium salt without removal of the orthogonal protecting group PG4. The resulting intermediate amine can then be coupled with the second amino acid D-2 in a similar peptide coupling step. The three described coupling / deprotection / coupling steps yield the same protected intermediate BC as the one previously described in Reaction Scheme C at which stage the rest of the synthesis can be performed as described above.

[0219] cABC-Ac cABC

[0220] Reaction Scheme E

[0221] Reaction Scheme E: In another variation of Reaction Scheme C, the building block A-Pro is doubly protected with suitable orthogonal protecting groups on the 2 carboxylic acid functions, such as the a-benzyl ester or a- methyl ester in the presence of a p-foutyl ester. Following the sequence described in Reaction Scheme C then yields the corresponding linear intermediate ABC-Pro. Double deprotection of the aspartic acid side chain and the Boc amine using TFA and subsequent cyclisation by a method already described previously yields the cyclised intermediate cABC-Pro, still protected on A. Deprotection of the aspartic acid backbone carboxylic acid, i.e. removal of PG6, can be accomplished by treatment with NaOH or LiOH in methanol / water at a temperature ranging from 0°C to 50°C for methyl or ethyl esters or preferably by hydrogenolysis of the benzyl ester over a catalyst such as Pd / C or Pd(OH)2 / C in a solvent like EtOAc, THF or dioxane. The deprotected intermediate cABC-Ac is then coupled according to peptide coupling conditions already described above with an amine AM, either commercially available or prepared following a procedure described in the literature or in the experimental section to yield the target compound. This strategy is especially efficient for preparation of libraries for the exploration of the AM moiety. cABC-AccABC

[0222] Reaction Scheme F

[0223] Reaction Scheme F: The strategy described in Reaction Scheme E, introducing the A moiety stepwise, can be applied in a different sequence to give the same cABC-Ac intermediate, as illustrated in Reaction Scheme F. The protected A-Pro, doubly protected with suitable orthogonal protecting groups on the 2 carboxylic acid functions, such as the a-benzyl ester or a-methyl ester in the presence of a p-allyl ester can be coupled with the required B- Ac and C building blocks in the same sequence as described in Reaction Scheme A to furnish the corresponding linear intermediate ABC-Pro. Sequential deprotection of the amine protecting group PG3, using TFA in the case of a Boc protecting group followed by removal of the aspartic acid side-chain protecting group PG1, by treatment with 1 , 3-di methyl barbituric acid and Pd(PPh3)4 in a solvent like DOM in the case of an allyl protecting group, leaves only cyclisation as already described above to give the intermediate cABC-Pro, still protected on A as already described in Reaction Scheme E. The remaining steps of the synthesis to furnish the desired macrocycle cABC are the same as already described above.

[0224]

[0225] PG60 H (1 ABC-Pro

[0226] Reaction Scheme G

[0227] Reaction Scheme G: In a variation of Reaction Scheme Faand in close similarity to Reaction Schemes B and D, moiety C can be introduced stepwise, one amino acid at a time. Moreover, the amino acid D-1 can itself be built stepwise, by introducing the desired side-chain R1on an already assembled ABD-1-Pre precursor. The amine deprotected AB intermediate already described in Reaction Scheme F can be coupled with an unsubstituted amino acid precursor of D-1, such as the NH-Boc or preferably the NH-nosyl-amino acid according to already described peptide coupling conditions. The NH-Nosyl function can then either be alkylated by treatment with the desired alkyl halide such as the bromide or preferably iodide in the presence of a base, such as K2CO3 or preferably, via a Mitsunobu reaction with the desired alcohol, performed according to standard conditions well known to those skilled in the art, e.g. by treatment with DEAD or DIAD with a phosphine ligand like triphenylphosphine at a temperature ranging from -80°C up to 60°C in a solvent such as THF or dioxane. The Nosyl activating / protecting group can then be removed by standard treatment with thiophenol in the presence of a base such as K2CO3 in a solvent like DMF to afford the corresponding deprotected intermediate. The amino acid D-2 can be coupled to this intermediate according to the conditions illustrated in Reaction Scheme B. The three described coupling / deprotection / coupling steps yield the same deprotected linear intermediate ABC-Pro as the one previously described in Reaction Scheme F. The remaining steps of the synthesis to furnish the desired macrocycle cABC are the same as already described above.

[0228] Reaction Scheme H Reaction Scheme H: In a further adaptation of Reaction Scheme F, the a-carboxylic acid protecting group of the A-Am building block can be solid phase such as a polymer-linked support, enabling the stepwise solid phase peptide synthesis of the cyclised macrocycle precursor according to established methodologies well known to those skilled in the art of polymer supported peptide synthesis. For instance, the amino acid A-Ac, suitably orthogonally protected on the amine function by for example an Fmoc protecting group and on the p-carboxylic acid function by for example an allylester, can be introduced on Wang resin by treatment with HOBt and DMAP and a coupling reagent such as DOC or DIO in a solvent mix. such as DCM / DMF allowing suitable swelling of the polymer beads. The subsequent sequence of deprotection of the Fmoc protecting group followed by peptide coupling with standard conditions for polymer peptide synthesis allows the stepwise introduction of the different building blocks, B-Ac, D- 1 and finally a suitably protected D-2, like for example alloc-protected D-2 gives the polymer supported linear peptide ABC, analogous to the one described in Reaction Scheme F. Double deprotection of the allyl ester and the N-alloc protecting groups can be achieved by treatment with a palladium catalyst, potentially in the presence of 1,3 -dimethylbarbituric acid to furnish the still supported linear peptide. Cyclisation under standard peptide coupling conditions can be accomplished in these circumstances without risk of oligomer formation. The macrocycle cABC- Ac already described in Reaction Scheme F can then be released from the polymer support by acidic treatment such as with a mix. of TFA / H2O (95 / 5). The liberated cABC-Ac can then be coupled with the appropriate AM amine using coupling conditions as described above to furnish the target compound.

[0229] Reaction Scheme I

[0230] Building blocks A are either commercially available, prepared as described in the literature or may be prepared as illustrated in Reaction Scheme I. A suitably orthogonally protected A-Ac, such as the p-tiutylester of the N-Fmoc or the p-al ly lester of the N-Boc aspartic acid, is coupled with the desired AM amine according to standard peptide coupling conditions, by treatment with COMU or T3P, HATU, PyBop or another peptide coupling reagent, in a solvent like THF, DMF or NMP in the presence of a base such as TEA or DIPEA at a temperature between -20°C and +75°C, preferably at RT. The resulting intermediate can then be selectively deprotected on the amine functionality without removing the p-ester protecting group PG1 , under standard conditions well established in the field of protecting group chemistry. Specific treatment with piperidine or diethylamine to remove the N-Fmoc in the presence of the p-tiutylester or with TFA or 4M HOI in dioxane to remove the N-Boc in the presence of the p- allylester gives access to the target building block A as its free base or its ammonium salt respectively.

[0231] Reaction Scheme J

[0232] The building blocks B, B-Ac or B-Am, are either prepared as described in the literature or may be prepared as illustrated in Reaction Scheme J. An appropriate salicylic acid derivative, protected as an ester on the carboxylic acid function, such as a methyl, ethyl, or benzyl ester, are either commercially available or prepared as described in the literature, or may be prepared as described in the experimental section. Similarly, the amino alcohol protected on the amine function by the Boc or Cbz groups are either commercially available or readily prepared from the corresponding amino acid, as described in the literature, or may also be prepared as described in the experimental section. The alcohol function of the amino alcohol can be activated upon treatment with methanesulfonyl chloride or toluenesulfonyl chloride or a similar activating agent, in the presence of a base such as DIPEA or TEA and reacted with the phenol function of the salicylic acid ester derivative in a solvent such as THF or DMF to furnish the doubly protected B building block. Alternatively, the two building blocks can be reacted together according to Mitsunobu methodology, by treatment with a phosphine ligand like triphenylphosphine and the DEAD or DIAD reagents in a solvent such as THF or dioxane at a temperature ranging from -20°C up to 60°C. The resulting orthogonally protected intermediate can then be selectively deprotected on the acid function or on the amine function to access the corresponding building blocks B-Ac or B-Am respectively. For example saponification of a methyl ester with aq. NaOH or LiOH soln, or hydrogenolysis of a benzyl ester over a palladium catalyst such as charcoal supported Pd or Pd(OH)2 gives access to the corresponding B-Ac. Alternatively, Boc deprotection by treatment with TFA or hydrogenolysis of a Cbz protected amine in the case of a methyl ester leads to the corresponding B-Am.

[0233] Reaction Scheme K

[0234] Building blocks C may be prepared as illustrated in Reaction Scheme K from the key intermediate D-1-Am. The intermediate D-1-Am is either commercially available or prepared as described in the literature or may be prepared as illustrated in this scheme. A suitably PG8 protected bromoacetic acid ester derivative, such as methyl, ethyl or benzyl ester, can be reacted with the appropriate amine RI NH2, in a solvent like MeCN, acetone or DMF in the presence of a base such as K2CO3 or DIPEA at a temperature ranging from RT up to 80°C to yield the amine D-1- Am. Alternatively, a suitably PG8 protected amino acid ester derivative, such as methyl, ethyl or benzyl ester, can be reacted with nitrosulfonylbenzene chloride in the presence of a catalytic amount of DMAP, in a solvent such as DOM or THF to yield the corresponding N-Nosyl protected amine. Alkylation of the sulfonamide nitrogen can then be accomplished by Mitsunobu methodology as already described above, i.e. by reaction in the presence of the desired alcohol R1OH with a phosphine ligand like triphenylphosphine and the DEAD or DIAD reagents, in a solvent such as THF or dioxane at a temperature ranging from 0°C up to 80°C. Subsequent cleavage of the Nosyl group can be achieved by treatment with thiophenol in the presence of a base such as K2CO3 in a solvent like DMF or DOM to give the amine building block D-1-Am. Coupling with the commercially available D-2 amino acid, or prepared as described in the literature, according to standard peptide coupling methodology as described above. Deprotection of the ester can then be accomplished by treatment with aq. NaOH or LiOH soln, in the case of a methyl or ethyl ester, or by hydrogenolysis of the benzyl ester over a palladium catalyst such as charcoal supported Pd or Pd(OH)2 to yield the target C building block.

[0235] The following examples are provided to illustrate the invention. These examples are illustrative only and should not be construed as limiting the invention in any way.

[0236] I. Chemistry

[0237] All temperatures are stated in °C. Commercially available starting materials were used as received without further purification. Unless otherwise specified, all reactions were carried out in oven-dried glassware under an atmosphere of nitrogen. Compounds were purified by flash column chromatography on silica gel or by preparative HPLC. Compounds described in the invention are characterised by LC-MS data (retention time IR is given in min; molecular weight obtained from the mass spectrum is given in g / mol) using the conditions listed below. In cases where compounds of the present invention appear as a mix. of conformational isomers, particularly visible in their LC-MS spectra, the retention time of the most abundant conformer is given.

[0238] HPLC pump: Binary gradient pump, Agilent G4220A or equivalent

[0239] Autosampler: Gilson LH215 (with Gilson 845z injector) or equivalent

[0240] Column compartment: Dionex TCC-3000RS or equivalent

[0241] Degasser: Dionex SRD-3200 or equivalent

[0242] Make-up pump: Dionex HPG-3200SD or equivalent

[0243] DAD detector: Agilent G4212A or equivalent

[0244] MS detector: Single quadrupole mass analyzer, Thermo Finnigan MSQPIus or equivalent

[0245] ELS detector: Sedere SEDEX 90 or equivalent

[0246] LC-MS with acidic conditions

[0247] Method A: Column: Zorbax SB-aq (3.5 pm, 4.6 x 50 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B], Gradient: 95% B —> 5% B over 1.5 min (flow: 4.5 mL / min). Detection: UVA / is + MS.

[0248] Method B: Column: Zorbax RRHD SB-aq (1.8 pm, 2.1 x 50 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B], Gradient: 95% B —> 5% B over 2.0 min (flow: 0.8 mL / min). Detection: UVA / is + MS.

[0249] Method C: Column: Waters XBridge C18 (5 pm, 4.6 x 30 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B], Gradient: 95% B —> 5% B over 1.5 min (flow: 4.5 mL / min). Detection: UVA / is + MS.

[0250] Method D: Column: Waters BEH C18 (2.1 x 50 mm, 2.5 pm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B], Gradient: 95% B —> 5% B over 2.0 min (flow: 0.8 mL / min). Detection: UVA / is + MS.

[0251] Method E: Column: Waters XBridge C18 (2.5 pm, 4.6 x 30 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B], Gradient: 95% B —> 5% B over 1.5 min (flow: 4.5 mL / min). Detection: UVA / is + MS. Method F: Column: Waters XSelect CSH C18 (3.5 pm, 2.1 x 30 mm). Conditions: MeCN + 0.1 % formic acid [eluent A]; water + 0.1 % formic acid [eluent B], Gradient: 95% B —> 2% B over 1 .6 min (flow 1 mL / min), Detection: UVA / is + MS.

[0252] Method G: Column: Waters Atlantis T3 (3.0 pm, 2.1 x 50 mm). Conditions: MeCN + 0.1 % formic acid [eluent A]; water + 0.1% formic acid [eluent B], Gradient: 95% B —> 2% B over 5 min (flow 0.8 mL / min). Detection: UVA / is + MS.

[0253] Method H: Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector or Xevo TQD or SYNAPT G2 MS, DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD. Column ACQUITY UPLC CSH C18 1.7um 2.1 x 50 mm from Waters, thermostated in the Acquity UPLC Column Manager at 60°C. Eluents: A: H2O + 0.05% formic acid; B: MeCN + 0.045% formic acid. Method: Gradient: 2% B —> 98% B over 2.0 min. Flow: 1.0 mL / min. Detection: UV 214 nm and ELSD, and MS, IR is given in min.

[0254] LC-MS with basic conditions

[0255] Method I: Column: Waters BEH C18 (2.5 pm, 2.1 x 50 mm). Conditions: water / NH3[c(NHs) = 13 mmol / l] [eluent A]; MeCN [eluent B], Gradient: 5% B —> 95% B over 2 min (flow 0.8 mL / min). Detection: UVA / is + MS.

[0256] Method J: Column: Waters XSelect CSH C18 (3.5 pm, 2.1 x 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 over 1.6 min (flow 1 mL / min), Detection: UVA / is + MS.

[0257] GC-MS

[0258] Agilent 6890N / Column: RXi-5MS 20m, ID 180 pm, df 0.18 pm; Velocity 50 cm / s, He carrier gas; 100°C —> 250°C over 4.5 min; Detection: MS.

[0259] Preparative HPLC equipment:

[0260] Gilson 333 / 334 HPLC pump equipped with Gilson LH215, Dionex SRD-3200 degasser,

[0261] Dionex ISQ-3100A make-up pump, Dionex DAD-3000 DAD detector, Single quadrupole mass analyzer MS detector, Thermo Finnigan MSQ Plus, MRA100-000 flow splitter, Polymer Laboratories PL-ELS1000 ELS detector

[0262] Preparative HPLC with basic conditions

[0263] Column: Waters XBridge (10 pm, 75 x 30 mm). Conditions: MeCN [eluent A]; water + 0.5% NH4OH (25% aq.) [eluent B]; Gradient see Prep. HPLC Table 1 (flow: 75 mL / min), the starting percentage of Eluent A (x) is determined depending on the polarity of the compound to purify. Detection: UVA / is + MS Prep. HPLC Table 1

[0264] Preparative HPLC with acidic conditions

[0265] Column: Waters Atlantis T3 (10 pm, 75 x 30 mm). Conditions: MeCN [eluent A]; water + 0.5% HCO2H [eluent B]; Gradient see Prep. HPLC Table 2 (flow: 75 mL / min), the starting percentage of Eluent A (x) is determined depending on the polarity of the compound to purify. Detection: UVA / is + MS

[0266] Prep. HPLC Table 2

[0267] Preparative HPLC for chiral separations

[0268] In most cases, desired diastereoisomers can be isolated or purified by standard preparative scale HPLC according to standard methods well-known to those skilled in the art. In some instances, the use of a chiral chromatography column is advisable to separate complex mixtures of diastereoisomers. Best results are obtained using Chiral Stationary Phase columns, such as Chiralpak IA, IB, or IC columns based on an immobilised amylose or cellulose chiral phase, with an isocratic eluent based on a mix. of MeCN with EtOH or MeOH, in a ratio varying from 9:1 to 1 :9. In order to compensate for the presence of ionisable functional groups in the compound being purified, modifiers can be added to the solvent mix. such as 0.1% diethylamine for basic derivatives or 0.1% formic acid for acidic ones. Supercritical Fluid Chromatography was used in some cases, using the same Chiral Stationary Phase columns as described above with isocratic eluents composed of 50% to 90% supercritical carbondioxide together with EtOH, MeOH or a 1 :1 EtOH:MeCN mix.. Detection: UVA / is.

[0269] Abbreviations (as used hereinbefore or hereinafter):

[0270] AcOH acetic acid

[0271] AC2O acetic anhydride

[0272] Alloc allyloxycarbonyl anh. anhydrous aq. aqueous atm atmosphere BnBr benzyl bromide

[0273] Boc tert-butoxycarbonyl

[0274] BOC2O di-tert-butyl dicarbonate

[0275] BOP (benzotriazol-1-yloxy)-tris(dimethylamino)-phosphonium hexafluorophosphate

[0276] BuLi n-butyllithium

[0277] GDI 1 ,1 '-carbonyldiimidazole

[0278] CD3I iodomethane-d3

[0279] CHCI3 chloroform

[0280] COMU (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate

[0281] CU(OAC)2copper (II) acetate d days DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene DCC A / ,A / '-dicyclohexylcarbodiimide DCE 1 ,2-dichloroethane DCM dichloromethane DEAD diethyl azodicarboxylate DIAD diisopropyl azodicarboxylate DIBAL / DIBAL-H diisobutylaluminium hydride DIG N,N -diisopropylcarbodiimide DIPEA diisopropyl-ethylamine, Hunig's base DMAP 4-Dimethylaminopyridine DMF dimethylformamide DMSO dimethylsulfoxide DPPA diphenyl phosphorylazide dppf 1 ,1 '-bis(diphenylphosphino)ferrocene EDO 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et ethyl Et2O diethylether EtOAc ethyl acetate EtOH ethanol evaporated evaporated in vacuo Ex. example FC flash chromatography on silica gel FDPP pentafluorophenyl diphenylphosphinate Fmoc 9-Fluorenylmethoxycarbonyl h hour(s)

[0282] HATU (1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

[0283] Hept heptane(s)

[0284] Hex hexane(s)

[0285] HOBT 1-hydroxybenzotriazol

[0286] HPLC high performance liquid chromatography

[0287] HV high vacuum conditions

[0288] 'Bu isobutyl

[0289] 'Pr isopropyl

[0290] 'PrMgCI isopropylmagnesium chloride

[0291] 'PrOH isopropyl alcohol

[0292] 'PrOAc isopropyl acetate

[0293] KOAc potassium acetate

[0294] KOfBu potassium tert-butoxide

[0295] LAH Lithium aluminium hydride

[0296] LC-MS liquid chromatography - mass spectrometry

[0297] Lit. Literature

[0298] M mol / l mCPBA m-chloroperoxybenzoic acid

[0299] Me methyl

[0300] MeCN acetonitrile

[0301] Mel iodomethane

[0302] Meldrum’s acid 2, 2-Dimethyl-1,3-dioxane-4, 6-dione

[0303] MeOH methanol mL milliliter min minute(s) mix. mixture

[0304] MOM methoxymethyl

[0305] MW microwave

[0306] NaBH(OAc)3sodium triacetoxyborohydride NCS N-chlorosuccinimide NMP N-methyl-2-pyrrolidone nosyl 4-Nitrobenzenesulfonyl "Pr n-propyl

[0307] OAc acetate org. organic

[0308] Pd(fBu3P)2bis(tri-ferf-butylphosphine)palladium(0)

[0309] Pd(OAc)2palladium(ll) acetate

[0310] Pd / C palladium on activated charcoal

[0311] Pd(OH)2 / C palladium hydroxide on activated charcoal (Pearlman’s catalyst)

[0312] Pd2(dba)3tris(dibenzylideneacetone)dipalladium(0)

[0313] PdCI2(PPh3)2bis(triphenylphosphine)palladium(ll) dichloride

[0314] Pd(dppf)CI2[1 ,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)

[0315] Pd(dppf)CI2DCM [1,1 '-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) complex with dichloromethane

[0316] Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0)

[0317] Ph phenyl

[0318] PhMe toluene

[0319] PPh3triphenyl phosphine prep. preparative

[0320] PTFE polytetrafluoroethylene

[0321] PyBOP (benzotriazol-1 -yl-oxy)-tripyrrolidino-phosphonium hexafluorophosphate

[0322] PyClop Chlorotripyrrolidinophosphonium hexafluorophosphate rac racemic

[0323] RM reaction mix.

[0324] Rochelle's salt sodium potassium tartrate

[0325] RT room temperature

[0326] RuPhos 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl s second(s) sat. saturated

[0327] Selectfluor 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)

[0328] SM starting material soln. solution

[0329] SPhos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl

[0330] TBAF tetrabutylammonium fluoride

[0331] TBDMSCI tert-butyldimethylsilyl chloride

[0332] TBME tert-butyl methyl ether tBu tert-butyl = tertiary butyl TEA triethylamine

[0333] Tf trifluoromethanesulfonyl

[0334] TFA trifluoroacetic acid

[0335] THF tetrahydrofuran

[0336] TLC thin layer chromatography

[0337] TM EDA N, N, N’, N’-tetramethylethylenediamine

[0338] TMS trimethylsilyl tosyl p-toluene-sulfonyl

[0339] T3P n-propylphosphonic anhydride tR retention time triflate trifluoromethanesulfonate pTsOH p-toluenesulfonic acid

[0340] Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0341] XPhos 2-dicyclohexylphosphin-2',4',6'-triisopropylbiphenyl

[0342] 2-(4-Methoxy-2H-1,2,3-triazol-2-yl)ethan-1-amine hydrochloride (AM-1)

[0343] Step 1 : K2CO3 (22.1 g, 160 mmol) is added to a RT suspension of 4,5-dibromo-2H-1 , 2 , 3-triazole (30.2 g, 133 mmol) and tert-butyl (2-bromoethyl)carbamate (33.5 g, 146 mmol) in MeCN (300 mL) and the resulting mix. is stirred at 50°C for 65 h. The RM is partitioned between water and EtOAc and the layers are separated. The aq. phase is reextracted with EtOAc (2x) and the combined org. extracts are washed with brine, dried (MgSO^, filtered, and evaporated. The crude product is purified by FC (eluting with 20% EtOAc in hept) to give tert-butyl (2-(4,5-dibromo- 2H-1 ,2,3-triazol-2-yl)ethyl)carbamate as a colourless oil. LC-MS B: tR = 0.95 min; [M+H]+= 370.73.

[0344] Step 2: TFA (51.7 mL, 676 mmol) is added to a RT soln, of tert-butyl (2-(4,5-dibromo-2H-1,2,3-triazol-2- yl)ethyl)carbamate (5.0 g, 13.5 mmol) in DOM (75 mL) and the RM is stirred for 1 h before being concentrated in vacuo. The residue is co-evaporated with DOM (2x) to give 2-(4,5-dibromo-2H-1 ,2,3-triazol-2-yl)ethan-1-amine.TFA as a white solid. LC-MS I: t = 0.66 min; [M+H]+= 270.94.

[0345] Step 3: Sodium acetate (7.0 g, 85.4 mmol), followed by benzaldehyde (3.83 mL, 37.6 mmol) are added to a RT soln, of 2-(4,5-dibromo-2H-1,2,3-triazol-2-yl)ethan-1-amine.TFA (6.56 g, 17.1 mmol) in MeOH (90 mL) and the resulting mix. is stirred for 1 h before NaBHsCN (2.49 g, 37.6 mmol) is added portionwise. The RM is stirred for 48 h before being concentrated. The residue is partitioned between water and DCM and the layers are separated. The aq. phase is re-extracted with DCM (2x) and the combined org. extracts are washed with brine, dried (Na2SO4), filtered, and evaporated to give N, N-dibenzyl-2-(4,5-dibromo-2H-1 ,2,3-triazol-2-yl)ethan-1 -amine as a yellow solid. LC-MS I: tR= 1.38 min; [M+H]+= 450.99.

[0346] Step 4: 'PrMgCI (2.0 M in THF, 13.4 mL, 26.8 mmol) is added dropwise to a -78°C soln, of N,N-dibenzyl-2-(4,5- dibromo-2H-1 ,2,3-triazol-2-yl)ethan-1-amine (6.03 g, 13.4 mmol) in THF (120 mL) and the resulting mix. is stirred for 4 h. The RM is warmed to RT and stirred for 30 min before being quenched by careful addition of sat. aq. NH4CI. The volatiles are evaporated and the remaining aq. phase is extracted with EtOAc (3x). The combined org. extracts are washed with brine, dried (IX^SCU), filtered, and evaporated to give N,N-dibenzyl-2-(4-bromo-2H-1 ,2,3-triazol- 2-yl)ethan-1 -amine as a yellow oil. LC-MS I: tR= 1 .30 min; [M+H]+= 373.07.

[0347] Step 5: A mixture of N, N-dibenzyl-2-(4-bromo-2H-1, 2, 3-triazol-2-yl)ethan-1 -amine (5.27 g, 14.2 mmol), bis(pinacolato)diboron (5.41 g, 21.3 mmol), SPhos (233 mg, 0.57 mmol), tris(dibenzylideneacetone)dipalladium(0) (134 mg, 0.14 mmol) and KOAc (2.40 g, 24.2 mmol) in dioxane (110 mL) is degassed and inertised with Argon. The RM is then heated to 100°C for 3 d. The RM is cooled to RT and filtered over celite rinsing with EtOAC. The volatiles are evaporated and the residue is partitioned between water and EtOAc and the layers are separated. The aq. phase is re-extracted with EtOAc (2x) and the combined org. extracts are washed with brine, dried (Na2SO4), filtered, and evaporated to give (2-(2-(dibenzylamino)ethyl)-2H-1 ,2,3-triazol-4-yl)boronic acid as the major product as a yellow oil. LC-MS I: tR= 0.58 min; [M+H]+= 337.22.

[0348] Step 6: Sodium perborate tetrahydrate (4.72 g, 29.7 mmol) is added to a RT soln, of (2-(2-(dibenzylamino)ethyl)- 2H-1 ,2,3-triazol-4-yl)boronic acid (5.0 g, 14.9 mmol) in THF:H2O 1 :1 (150 mL) and the resulting suspension is stirred for 16 h. The RM is poured into ice water and extracted with EtOAc (3x). The combined org. extracts are washed with brine, dried (MgSO^, filtered, and evaporated. The crude product is purified by FC (eluting with 20% to 80% EtOAc in hept) to give 2-(2-(dibenzylamino)ethyl)-2H-1 ,2,3-triazol-4-ol as a yellow solid. LC-MS I: tR= 0.56 min; [M+H]+= 309.17.1H NMR (DMSO) 6 10.30 (s, 1 H), 7.21-7.31 (m, 10 H), 7.02 (s, 1 H), 4.29 (t, J = 6.3 Hz, 2 H), 3.55 (s, 4 H), 2.80 (t, J = 6.3 Hz, 2 H).

[0349] Step 7: NaH 60% dispersion in mineral oil (540 mg, 11.2 mmol) is added to a RT soln, of 2-(2-(dibenzylamino)ethyl)- 2H-1 ,2,3-triazol-4-ol (3.15 g, 10.2 mmol) in DMF (85 mL). After stirring for 10 min, Mel (0.77 mL, 12.3 mmol) is added and the resulting mix. is stirred for 1 h. The RM is poured into water and extracted with / PrOAc (3x). The combined org. extracts are washed with brine, dried (Na2SO4), filtered, and evaporated to give N,N-dibenzyl-2-(4- methoxy-2H-1 ,2,3-triazol-2-yl)ethan-1-amine as a yellow oil. LC-MS I: tR= 1.23 min; [M+H]+= 323.21.

[0350] Step 8: A RT soln, of N, N-dibenzyl-2-(4-methoxy-2H-1 ,2,3-triazol-2-yl)ethan-1 -amine (3.45 g, 10.7 mmol) in EtOH (85 mL) is inertised with N2 / vacuum (3x) before 10% Pd / C (1.13 g, 1.1 mmol) is added. After inertising another three times a H2 balloon is connected and the resulting mix. is stirred for 24 h. The RM is filtered through a Whatman filter and the filtrate is acidified with 4 M HCI in dioxane (8 mL, 32 mmol) and concentrated to give the title compound AM-1 as a white solid. LC-MS I: tR= 0.39 min; [M+H]+= 143.20.1H NMR (DMSO) 6 8.40 (s, 3 H), 7.41 (s, 1 H), 4.54 (t, J = 6.4 Hz, 2 H), 3.87 (s, 3 H), 3.29-3.23 (m, 2 H).

[0351] 2-(3-Methoxy-1,2,4-oxadiazol-5-yl)ethan-1-amine hydrochloride (AM-2)

[0352] Step 1 : HATU (11.82 g, 31.1 mmol) is added to a RT soln, of boc-beta-Ala-OH (5.0 g, 25.9 mmol), o-methylisourea bisulfate (4.5 g, 25.9 mmol, and DIPEA (18.1 mL, 104 mmol) in DMF (150 mL) and the RM is stirred for 1 .5 h. Water and EtOAc are added to the RM, then the two layers are separated and the aq. layer is extracted with EtOAc (2x). The combined org. extracts are washed with brine, dried (Na2SO4), filtered, and concentrated to give the crude product that is purifird by FC (eluting with 20% to 100% EtOAc in hept) to give tert-butyl (3- ((imino(methoxy)methyl)amino)-3-oxopropyl)carbamate as a white solid. LC-MS I: IR = 0.64 min; [M+H]+= 246.36. Step 2: 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (8.96 mL, 59.3 mmol) is added to a RT soln, 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) and the RM is stirred for 5 h. Additional 1 ,8-diazabicydo[5.4.0]undec-7-ene (1.85 mL, 12.4 mmol) and NBS (2.2 g, 12.4 mmol) are added and stirring is continued for 16 h. The suspension is filtered and the filtrate is washed with water, sat. aq. NaHCO3soln, and brine before being evaporated to dryness. The crude product is purified by FC (eluting with 20% to 100% EtOAc in hept) to give tert-butyl (2-(3-methoxy-1 ,2,4-oxadiazol-5- yl)ethyl)carbamate as a colourless oil. LC-MS I: IR = 0.75 min; [M+H]+= 244.33.

[0353] Step 3: 4 M HCI in dioxane (0.62 mL, 2.47 mmol) is added to a RT soln, of tert-butyl (2-(3-methoxy-1,2,4-oxadiazol- 5-yl)ethyl)carbamate (150 mg, 0.62 mmol) in DCM (2 mL) and the RM is stirred for 4 days at RT, then at 50°C for 6 h. The mixture is evaporated to give the title compound AM-2 as a white solid. LC-MS I: tR=0.35 min; [M+H]+= 144.21.

[0354] 2-(3-Methoxyisoxazol-5-yl)ethan-1-amine hydrochloride (AM-3)

[0355] Step 1 : DPPA (1.32 mL, 6.1 mmol) is added dropwise to a RT soln, 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) and the RM is heated to 100°C for 1.5 h. 2- Methylpropan-2-ol (1.06 mL, 11.1 mmol) is added and the RM is heated to reflux for 16 h. The RM is cooled to RT and partitioned between sat. aq. NaHCO3and EtOAc and the layers are separated. The aq. phase is re-extracted with EtOAc (2x) and the combined org. extracts are washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude product is purified by FC (eluting with 0% to 100% EtOAc in hept) to give tert-butyl (2-(3- methoxyisoxazol-5-yl)ethyl)carbamate as a colourless oil. LC-MS F: tR= 1.80 min; [M+H]+= 243.1.

[0356] Step 2: 4 M HCI in dioxane (13.7 mL, 54.7 mmol) is added to a RT suspension tert-butyl (2-(3-methoxyisoxazol-5- yl)ethyl)carbamate (1 .33 g, 5.47 mmol) in dioxane (30 mL) and the resulting mix. is heated to 50°C for 4 h. The RM is concentrated and co-evaporated with Et20 to give the title compound AM-3 as a white solid. LC-MS I: tR= 0.42 min; [M+H]+= 143.25.

[0357] 2-(4-Fluoro-3-methoxyisoxazol-5-yl)ethan-1-amine hydrochloride (AM-4)

[0358] Step 1 : In a microwave tube, phthalic anhydride (354 mg, 2.36 mmol) is added to a RT suspension of AM-3 (402 mg, 2.25 mmol) and DIPEA (0.47 mL, 2.7 mmol) in dioxane (12 mL). The tube is sealed and heated to 100°C for 48 h. Water is added to the RM, the mixture is acidified with 1 M HCI and the product extracted with EtOAc, dried (MgSO^, filtered, and concentrated to give 2-(2-(3-methoxyisoxazol-5-yl)ethyl)isoindoline-1 , 3-dione (718 mg) as a white solid. LC-MS B: tR=0.85 min; [M+H]+= 273.09.

[0359] Step 2: Selectfluor (1 .07 g, 2.87 mmol) is added to a 40°C soln, 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) and the RM is heated to 120°C for 18 h. The resulting dark brown soln, is cooled to around 50°C, then the RM is poured into pre-stirred H2O (30 mL), followed by EtOAc (10 mL). The two layers are separated and the aq. layer is re-extracted with EtOAc. The combined org. extracts are washed with brine, dried (IX^SCU), filtered, and concentrated. Purification by prep HPLC (acidic) gives 2-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)isoindoline-1 , 3-dione (89 mg, 12%) as a colourless oil. LC-MS B: tR= 0.90 min; [M+H]+= 291 .02.

[0360] Step 3: Hydrazine monohydrate (0.222 mL, 2.93 mmol) is added to a RT soln, of 2-(2-(4-fluoro-3-methoxyisoxazol- 5-yl)ethyl)isoindoline-1 , 3-dione (85 mg, 0.293 mmol) in EtOH (3 mL) and the RM is heated to 80°C for 1 h. The RM is cooled to RT and a white precipitate is formed. Ether is added and the solid (sideproduct) is triturated before being filtered off and discarded. The filtrate is acidified with 4 M HCI in dioxane and concentrated to give the title compound AM-4 as a white solid which was used as such in the next step. LC-MS B: tR= 0.33 min; [M+H]+= 161.08.

[0361] 2-(5-Cyclopropyl-2H-tetrazol-2-yl)ethan-1-amine hydrochloride (AM-5)

[0362] Step 1: tert-butyl (2-bromoethyl)carbamate (53.2 g, 233 mmol) is added to a RT suspension of 5-cyclopropyl-2H- 1,2,3,4-tetrazole (24.0 g, 211 mmol) and K2CO3 (35.1 g, 254 mmol) in MeCN (480 mL) and the RM is heated to 50°C for 18 h. The RM is concentrated and the residue is partitioned between water and EtOAc and the layers are separated. The aq. phase is re-extracted with EtOAc (2x) and the combined org. extracts are washed with brine, dried (MgSO^, filtered, and evaporated. The crude product is purified by FC (eluting with 20% to 80% EtOAc in hept) to give tert-butyl (2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)carbamate as a colourless oil. LC-MS I: tR= 0.80 min; [M+H]+= 254.35.

[0363] Step 2: 4 M HCI in dioxane (290 mL, 1.16 mol) is added to a RT suspension of tert-butyl (2-(5-cyclopropyl-2H- tetrazol-2-yl)ethyl)carbamate (29.45 g, 116 mmol) in dioxane (630 mL) and the resulting mix. is stirred for 4 d. The RM is concentrated and co-evaporated with Et20 to give the title compound AM-5 (1.36 g, 94%) as a white solid. LC-MS I: tR= 0.44 min; [M+H]+= 154.25. tert-Butyl (R)-(1-hydroxy-3-(6-methoxypyridin-2-yl)propan-2-yl)carbamate (AL-1)

[0364] Step 1 : nBuLi (1.6 M in hex, 18.2 mL, 29.1 mmol) is added dropwise to a -78°C soln, of (S)-2-isopropyl-3,6- dimethoxy-2,5-dihydropyrazine (4.70 g, 24.2 mmol) in THF (200 mL) and the RM is stirred for 30 min before a soln, of 2-(bromomethyl)-6-methoxypyridine (5.0 g, 24.2 mmol) in THF (20 mL) is added dropwise. The RM is stirred for 10 min before being quenched with sat. aq. NH4CI. After warming to RT the RM is diluted with water and extracted with EtOAc (3x). The combined org. extracts are washed with brine, dried (MgSO^, filtered, and evaporated. The crude product is purified by FC (eluting with 30% to 100% EtOAc in hept) to give (2S,5R)-2-isopropyl-3,6-dimethoxy- 5-((6-methoxypyridin-2-yl)methyl)-2,5-dihydropyrazine as a yellow oil. LC-MS B: tR= 0.83 min; [M+H]+= 306.03.

[0365] Step 2: 1 M aq. HCI (38.2 mL, 38.2 mmol) is added to a RT soln, of (2S,5R)-2-isopropyl-3,6-dimethoxy-5-((6- methoxypyridin-2-yl)methyl)-2,5-dihydropyrazine (5.8 g, 19.1 mmol) in MeCN (50 mL) and the resulting mix. is stirred for 16 h. The RM is partitioned between sat. aq. NaHCOs and DCM and the layers are separated. The aq. phase is re-extracted with DCM (2x) and the combined org. extracts are washed with brine, dried (Na2SO4), filtered, and evaporated. The crude product is purified by FC (eluting with 80% to 100% EtOAc in hept) to give methyl (R)-

[0366] 2-amino-3-(6-methoxypyridin-2-yl)propanoate as a yellow oil. LC-MS B: IR = 0.46 min; [M+H]+= 211 .26.

[0367] Step 3: BOC2O (2.61 g, 12.0 mmol) is added to a RT suspension of methyl (R)-2-amino-3-(6-methoxypyridin-2- yl)propanoate (2.28 g, 10.8 mmol) and NaHCOs (4.56 g, 54.2 mmol) in a mix. of THF (50 mL) and H2O (50 mL) and the RM is stirred for 1 h. The RM is acidified with 1 M aq. HCI and extracted with EtOAc (3x). The combined org. extracts are dried (MgSO^, filtered, and concentrated to give methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(6- methoxypyridin-2-yl)propanoate as a colourless oil. LC-MS B: IR = 0.89 min; [M+H]+= 311.25.

[0368] Step 4: LAH (906 mg, 22.7 mmol) is added portionwise to a 0°C soln, of methyl (R)-2-((tert-butoxycarbonyl)amino)-

[0369] 3-(6-methoxypyridin-2-yl)propanoate (3.52 g, 11 .3 mmol) in Et20 (150 mL) and the RM is warmed to RT and stirred for 1 h. The RM is cooled back to 0°C and very carefully quenched with H2O followed by addition of EtOAc. The resulting suspension is warmed to RT and filtered. The layers are separated and the aq. layer is re-extracted with EtOAc (2x). The combined org. extracts are washed with brine, dried (Na2SO4), filtered, and evaporated to give the title compound AL-1 as a colourless oil. LC-MS B: IR = 0.62 min; [M+H]+= 283.35. tert-Butyl (R)-(1-(6-bromo-4-methoxypyridin-2-yl)-3-hydroxypropan-2-yl)carbamate (AL-2)

[0370] Step 1 : Zn dust (1.77 g, 26.5 mmol) is heated to 140°C under vacuum for 30 min before being cooled to RT under argon. Iodine (2.02 g, 7.96 mmol) and DMF (10 mL) are added and the resulting mix. is stirred for 20 min before Boc-3-iodo-D-Ala-OMe (3.0 g, 8.84 mmol) is added and stirring is continued for another 20 min. 2,6-Dibromo-4- methoxypyridine (3.07 g, 11.5 mmol) and PdCl2(PPh3)2 (310 mg, 0.44 mmol) are added and the RM is stirred for 16 h at 50°C. The RM is partitioned between water and EtOAc and filtered. The layers are separated, and the aq. layer is re-extracted with EtOAc (2x). The combined org. extracts are washed with brine, dried (Na2SO4), filtered, and evaporated. The crude product is purified by FC (eluting with 40% EtOAc in hept) to give methyl (R)-3-(6- bromo-4-methoxypyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate as a colourless oil. LC-MS B: IR = 0.92 min; [M+H]+= 389.25.

[0371] Step 2: The title compound is prepared from methyl (R)-3-(6-bromo-4-methoxypyridin-2-yl)-2-((tert- butoxycarbonyl)amino)propanoate following the procedure described for AL-1 , step 4. LC-MS B: IR = 0.78 min; [M+H]- = 361.16. tert-Butyl (R)-(1-(6-bromo-4-methylpyridin-2-yl)-3-hydroxypropan-2-yl)carbamate (AL-3)

[0372] The title compound is prepared following the sequence of reactions described for AL-6, substituting 2,6-dibromo-

[0373] 4-methoxypyridine for 2,6-dibromo-4-methylpyridine in step 1. LC-MS I: IR = 0.84 min; [M+H]+= 347.17.

[0374] (R)-2-((tert-butoxycarbonyl)amino)-3-(2-chloro-6-methoxypyrimidin-4-yl)propanoate (IM-1) and methyl (R)- 2-((tert-butoxycarbonyl)amino)-3-(4-chloro-6-methoxypyrimidin-2-yl)propanoate (IM-2)

[0375] Zinc dust (6.6 g, 99 mmol) is put into a flame dried, nitrogen purged flask and heated to 140°C for 30 min, under vacuum. After cooling back to RT, DMF (30 mL) is transferred to the flask which is further purged with nitrogen. Iodine (99.9%, 7.6 g, 30 mmol) is carefully added in one portion. The resulting brown red mixture is stirred and left returning to RT until complete discoloration. Then Boc-beta-iodo-D-Ala-OMe (11.43 g, 33 mmol) is added and stirring is continued for another 10 min at RT under nitrogen. 2,4-Dichloro-6-methoxypyrimidine (5.53 g, 30 mmol) and PdCI2(PPh3)2 (1.05 g, 1.5 mmol) are added and the RM is heated at 40°C for 24h then at 90°C for 1 h then at 110°C for 3h and eventually at 80°C for 16h to push conversion. After cooling back the RM to RT, it is diluted with EtOAc and solid is filtered off. The filtrate is washed with sat. aq. thiosulfate solution then twice with brine, dried over MgSO4, filtered and concentrated to dryness. The crude dark yellow oil (6.23 g) is purified by prep-HPLC (basic conditions) to yield the two expected regioisomers, methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-chloro-6- methoxypyrimidin-2-yl)propanoate (IM-1) (500 mg) as a yellow oil and methyl (R)-2-((tert-butoxycarbonyl)amino)- 3-(2-chloro-6-methoxypyrimidin-4-yl)propanoate (IM-2) (1.14 g) as a yellow oil solidifying at RT. IM-1:1H NMR (500 MHz, DMSO) 5 7.30 (d, J = 8.6 Hz, 1 H), 7.02 (s, 1 H), 4.67 (td, J = 8.6, 6.1 Hz, 1 H), 3.93 (s, 3H), 3.63 (s, 3H), 3.22 (dd, J = 15.4, 5.8 Hz, 1 H), 3.14 (dd, J = 15.4, 7.9 Hz, 1 H), 1.35 (s, 9H); LC-MS B: tR= 0.93 min; [M+H]+= 346.2 ; IM-2:1H NMR (500 MHz, DMSO) 5 7.34 (d, J = 8.4 Hz, 1 H), 6.86 (s, 1 H), 4.42 - 4.37 (m, 1 H), 3.92 (s, 3H), 3.64 (s, 3H), 3.06 (dd, J = 14.0, 5.1 Hz, 1 H), 2.95 (dd, J = 14.0, 9.5 Hz, 1 H), 1.33 (s, 9H); LC-MS B: tR= 0.91 min; [M+H]+= 346.1. tert-Butyl (R)-(1-(4-chloro-6-methoxypyrimidin-2-yl)-3-hydroxypropan-2-yl)carbamate (AL-4)

[0376] The title compound is prepared from methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-chloro-6-methoxypyrimidin-2- yl)propanoate (IM-1) following the procedure described for AL-1 , step 4. LC-MS B: tR= 0.78 min; [M+H]+= 318.2 tert-Butyl (R)-(1-(2-chloro-6-methoxypyrimidin-4-yl)-3-hydroxypropan-2-yl)carbamate (AL-5)

[0377] The title compound is prepared from methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(2-chloro-6-methoxypyrimidin-4- yl)propanoate (IM-2) following the procedure described for AL-1 , step 4. LC-MS B: tR= 0.76 min; [M+H]+= 318.1 tert-Butyl (S)-3-amino-4-((2-(4-methoxy-2H-1,2,3-triazol-2-yl)ethyl)amino)-4-oxobutanoate (A-1)

[0378] Step 1 : HATU (3.20 g, 8.42 mmol) is added to a RT soln, of Fmoc-L-aspartic acid beta-tert-buty I ester (3.54 g, 8.42 mmol), 2-(4-methoxy-2H-1 ,2,3-triazol-2-yl)ethan-1-amine hydrochloride (AM-1 , 1.6 g, 8.42 mmol) and DI PEA (6.34 mL, 33.7 mmol) in DMF (27 mL) and the RM is stirred for 1 h. The RM is partitioned between water and EtOAc and the layers are separated. The aq. phase is re-extracted with EtOAc (2x) and the combined org. extracts are washed with sat. aq. NaHCOs, brine, dried over Na2SO4, filtered and evaporated to give tert-butyl (S)-3-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-4-((2-(4-methoxy-2H-1 ,2,3-triazol-2-yl)ethyl)amino)-4-oxobutanoate as a white solid. LC-MS I: tR= 1.10 min; [M+H]+= 536.28.

[0379] Step 2: Piperidine (4.29 mL, 42.9 mmol) is added to a RT soln, of tert-butyl (S)-3-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-4-((2-(4-methoxy-2H-1 , 2, 3-tri azol-2-yl)ethy I) ami no)-4-oxobutanoate (5.29 g, 8.58 mmol) in DCM (67 mL) and the RM is stirred for 3 h. The RM is concentrated, and the residue directly purified by FC (eluting with 10% MeOH in DCM) to give the title compound A-1 as a yellow oil. LC-MS I: tR= 0.65 min; [M+H]+= 314.27. Listed in Table 1-A below are building blocks A that are prepared in analogy to the 2-step sequence described above for A-1 .

[0380] Table 1-A Benzyl (R)-6-(2-amino-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylate dihydrochloride (B-1)

[0381] Step 1 : A soln, of Br2 (0.17 mL, 3.37 mmol) in AcOH (8.0 mL) is added to a RT soln, of 3-fluoroquinolin-6-ol (0.50 g, 3.06 mmol) and NaOAc (0.30 g, 3.68 mmol) in AcOH (20 mL) and the RM is stirred for 30 min. The RM is concentrated to dryness, the residue is partitioned between sat. aq. NaHCOs and EtOAc and extracted. The layers are separated, and the aq. layer is re-extracted with EtOAc (2x). The combined org. extracts are washed with brine, dried (Na2SO4), filtered, and evaporated to give 5-bromo-3-fluoroquinolin-6-ol as a brown solid. LC-MS J: IR = 1 .38 min; [M+H]+= 239.9.

[0382] Step 2: A soln, of 5-bromo-3-fluoroquinolin-6-ol (0.74 g, 3.06 mmol) in THF (15 mL) is added dropwise to a RT suspension of NaH 60% dispersion in mineral oil (0.17 g, 4.29 mmol) in THF (15 mL) and the resulting mix. is stirred for 15 min before methoxymethyl bromide (0.3 mL, 3.67 mmol) is added dropwise at 0°C. After stirring for 1 .5 h at 0°C the RM is quenched by the addition of H2O and extracted with EtOAc. The org. layer is washed with NaHCOs, brine, dried (Na2SO4), filtered, and evaporated. The crude product is purified by FC (eluting with 2% to 30% EtOAc in hept) to give 5-bromo-3-fluoro-6-(methoxymethoxy)quinoline as a colourless oil. LC-MS J: tR= 2.03 min; No ionisation.

[0383] Step 3: nBuLi (1.6 M in hex, 0.98 mL, 1.57 mmol) is added dropwise to a -78°C soln, of 5-bromo-3-fluoro-6- (methoxymethoxy)quinoline (300 mg, 1.05 mmol) in THF (18 mL) and the RM is stirred for 30 min. The RM is quenched with freshly ground dry ice (1.0 g, 22.7 mmol) and then warmed to RT and stirred for 30 min. The RM is concentrated in vacuo and the intermediate lithium carboxylate is dissolved in DMF (4 mL), then KHCO3 (31.5 mg, 0.315 mmol) and BnBr (0.15 mL, 1.26 mmol) are added, and the RM is stirred at RT for 16 h. The RM is partitioned between sat. aq. NaHCOs and EtOAc and extracted. The layers are separated, and the aq. layer is re-extracted with EtOAc (2x). The combined org. extracts are washed with brine, dried (Na2SO4), filtered, and evaporated. The crude product is purified prep. HPLC (basic) to give benzyl 3-fluoro-6-(methoxymethoxy)quinoline-5-carboxylate as a yellow oil. LC-MS J: tR= 2.08 min; [M+H]+= 342.10.

[0384] Step 4: TFA (0.24 mL, 3.13 mmol) is added to a RT soln, of benzyl 3-fluoro-6-(methoxymethoxy)quinoline-5- carboxylate (107 mg, 0.31 mmol) in DCM (3 mL) and the resulting mix. is stirred for 2 h. The RM is concentrated in vacuo, the residue dissolved in EtOAc, and extracted with aq. sat. NaHCOs soln. The aq. layer is extracted with EtOAc and the combined org. extracts are washed with brine, dried (NaSO^, filtered, and concentrated to give benzyl 3-fluoro-6-hydroxyquinoline-5-carboxylate as a light brown oil. LC-MS J: tR= 2.06 min; [M+H]+= 298.1 .

[0385] Step 5: DIAD (0.064 mL, 0.33 mmol) is added to a 0°C mix. of benzyl 3-fluoro-6-hydroxyquinoline-5-carboxylate (93.8 mg, 0.31 mmol), tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate (82 mg, 0.33 mmol) and PPha (86 mg, 0.33 mmol) in THF (2 mL), and the RM is stirred for 16 h at RT. The mix. is concentrated and the residue directly purified by FC (eluting with 20% to 60% EtOAc in hept) to give benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)- 3-phenylpropoxy)-3-fluoroquinoline-5-carboxylate as a colourless oil. LC-MS J: tR= 2.39 min; [M+H]+= 531.2.

[0386] Step 6: 4M HCI in dioxane (0.44 mL, 1.77 mmol) is added to a soln, benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)- 3-phenylpropoxy)-3-fluoroquinoline-5-carboxylate (94 mg, 0.18 mmol) in dioxane (3 mL) and the RM is stirred for 24 h at RT. The volatiles are removed in vacuo and the residue is triturated with Et20 (3x) to give the title compound B-1 as a white solid. LC-MS J: tR= 2.10 min; [M+H]+= 431.2.

[0387] Benzyl (R)-6-(2-amino-3-(6-methoxypyridin-2-yl)propoxy)-3-fluoroquinoline-5-carboxylate dihydrochloride (B-2)

[0388] The title compound is prepared from benzyl 3-fluoro-6-hydroxyquinoline-5-carboxylate (B-1 , steps 1-4) and tertbutyl (R)-(1-hydroxy-3-(6-methoxypyridin-2-yl)propan-2-yl)carbamate (AL-1) following steps 5&6 described for B-1 . LC-MS B: tR= 0.83 min; [M+H]+= 462.29.

[0389] Benzyl (R)-6-(2-amino-3-(6-bromo-4-methoxypyridin-2-yl)propoxy)-3-fluoroquinoline-5-carboxylate dihydrochloride (B-3)

[0390] The title compound is prepared from benzyl 3-fluoro-6-hydroxyquinoline-5-carboxylate (B-1 , steps 1-4) and tertbutyl (R)-(1-(6-bromo-4-methoxypyridin-2-yl)-3-hydroxypropan-2-yl)carbamate (AL-2) following steps 5&6 described for B-1 . LC-MS I: tR= 1 .05 min; [M+H]+= 540.24. Benzyl (R)-6-(2-amino-3-phenylpropoxy)-3-methylisoquinoline-5-carboxylate dihydrochloride (B-4)

[0391] Step 1 : Trifluoromethanesulfonic anhydride (26.2 mL, 158 mmol) is added dropwise to a -10°C soln, of 2-hydroxy-

[0392] 4-methoxybenzaldehyde (16 g, 105 mmol) and pyridine (42.5 mL, 526 mmol) in DCM (70 mL) and the RM is stirred for 30 min. The RM is quenched with ice water and acidified with 1 M aq. HCI before being extracted with EtOAc (2x). The combined org. extracts are washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give 2-formyl-5-methoxyphenyl trifluoromethanesulfonate as a yellow oil.1H NMR (400 MHz, CDCL) 6 10.13 (s, 1 H), 7.95 (d, J = 8.8 Hz, 1 H), 7.03 (dd, J = 8.7, 2.3 Hz, 1 H), 6.88 (d, J = 2.3 Hz, 1 H), 3.93 (s, 3H).

[0393] Step 2: A RT soln, of 2-formyl-5-methoxyphenyl trifluoromethanesulfonate (19.6 g, 66.4 mmol) and TEA (93 mL, 664 mmol) in DMF (400 mL) is purged with Ar for 30 min. Prop-1 -yne (1 M in DMF, 133 mL, 133 mmol), Cui (1.27 g, 6.64 mmol) and Pd(PPh3)4 (5.0 g, 4.33 mmol) are added successively and the RM is stirred closed for 2 h. The RM is filtered through a pad of celite and the filtrate partially concentrated in vacuo before being diluted with EtOAc and washed successively with 1 M KHSO4soln, and brine and concentrated in vacuo. The crude product is purified by FC (eluting with 0% to 30% EtOAc in hept) to give 4-methoxy-2-(prop-1-yn-1-yl)benzaldehyde as a yellow solid. LC-MS J: tR= 1.80 min; [M+H]+= 175.1.

[0394] Step 3: A RT soln, of 4-methoxy-2-(prop-1-yn-1-yl)benzaldehyde (10.3 g, 58.8 mmol) in MeOH (350 mL) is purged with Ar for 5 min in an autoclave. NH37M in MeOH (150 mL, 1050 mmol) is added and the RM is heated to 65°C for 4 h with a pressure reaching 2 bar. The RM is concentrated in vacuo and the residue is co-evaporated with DCM (2x) to give 6-methoxy-3-methylisoquinoline as a brown solid. LC-MS J: tR= 1.81 min; [M+H]+= 174.1.

[0395] Step 4: BBr3(1 M in DCM, 55.4 mL, 55.4 mmol) is added dropwise to a -78°C soln, of 6-methoxy-3- methylisoquinoline (5.0 g, 27.7 mmol) in DCM (100 mL). The cooling bath is removed and the RM is stirred at RT for 30 h. The RM is carefully quenched into cold MeOH and concentrated in vacuo. The residue is co-evaporated with PhMe, EtOAc and DCM to give 3-methylisoquinolin-6-ol as a brown solid. LC-MS J: tR= 1.10 min; [M+H]+= 160.1.

[0396] Step 5: Br2 (1.3 mL, 25.3 mmol) is added dropwise to a suspension of 3-methylisoquinolin-6-ol (4.67 g, 19.4 mmol) in CHCI3 (75 mL) and the RM is stirred for 2 h. EtOAc is added, and the solids are collected by filtration, washed with EtOAc and hept. The filter residue is neutralised by suspending it in sat. aq. NaHCOs and re-filtered before washing with H2O and hept. The filter residue is suspended in MeCN and evaporated to give 5-bromo-3- methylisoquinolin-6-ol as a brown solid. LC-MS J: tR= 1.02 min; [M+H]+= 238.0.

[0397] Step 6: fert-Butyl (R)-(1-((5-bromo-3-methylisoquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamate is prepared from

[0398] 5-bromo-3-methylisoquinolin-6-ol and tert-butyl (R)-(1-hydroxy-3-phenylpropan-2-yl)carbamate in analogy to the procedure described for B1 Step 5. LC-MS J: tR= 2.21 min; [M+H]+= 471.1.

[0399] Step 7: A RT soln, of tert-butyl (R)-(1-((5-bromo-3-methylisoquinolin-6-yl)oxy)-3-phenylpropan-2-yl)carbamate (2.5 g, 5.30 mmol), benzyl alcohol (2.76 mL, 26.5 mmol) and DIPEA (2.78 mL, 15.9 mmol) in PhMe (20 mL) is purged with Ar for 10 min. The RM is then purged with CO and heated to 88°C under a CO atm before a soln, of Pd^BusP^ (271 mg, 0.53 mmol) in PhMe (5.5 mL) is added via syringe pump (3 mL / h). The temperature is increased to 95°C and the RM is stirred under a CO atm for 24 h. The RM is cooled to RT and concentrated in vacuo and the residue is partitioned between sat. aq. NaHCOs and EtOAc and extracted. The layers are separated and the aq. phase is re-extracted with EtOAc (1x) and the combined org. layers are washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude product is purified by FC (eluting with 5% to 65% EtOAc in hept) to give benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-3-methylisoquinoline-5-carboxylate as a colourless oil. LC- MS J: tR= 2.19 min; [M+H]+= 527.2.

[0400] Step 8: The title compound is prepared from benzyl (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-3- methylisoquinoline-5-carboxylate in analogy to the procedure described for B1, step 6. LC-MS J: tR= 1.95 min;[M+H]+= 427.2.

[0401] Benzyl (R)-6-(2-amino-3-(6-methoxypyridin-2-yl)propoxy)-3-methylisoquinoline-5-carboxylate dihydrochloride (B-5)

[0402] The title compound is prepared in analogy to the procedure described for B-4, switching tert-butyl (R)-(l-hydroxy- 3-phenylpropan-2-yl)carbamate for tert-butyl (R)-(1-hydroxy-3-(6-methoxypyridin-2-yl)propan-2-yl)carbamate (AL- 1) in step 6. LC-MS B: tR= 0.65 min; [M+H]+= 458.3.

[0403] Benzyl (R)-4-(2-amino-3-(6-methoxypyridin-2-yl)propoxy)-2-methoxy-6-methylnicotinate (B-6)

[0404] Step 1 : Ethyl 2,4-dihydroxy-6-methylnicotinate (10 g, 0.0497 mol) is suspended in Benzyl alcohol (26 mL, 0.248 mol) in a flask equipped with a Dean Stark apparatus and a cooler and the reaction mixture is heated at 120°C overnight. The thick suspension becomes a clear solution after 10 min at 120°C. Then precipitation occurs as transesterification further takes place. After 68h, the precipitate is filtered and washed with TBME and dried under HV to give the crude benzyl 2,4-dihydroxy-6-methylnicotinate as a beige solid, m=9.79 g.1H NMR (400 MHz, DMSO) 6 12.45 (s, 1 H), 11.41 (s, 1 H), 7.47 (m, 2 H), 7.31-7.41 (m, 3 H), 5.81 (s, 1 H), 5.31 (s, 2 H), 2.15 (s, 3 H); LC-MS B tR= 0.78 min; [M+H]+= 260.2.

[0405] Step 2: Trimethyloxonium tetrafluoroborate (5353 mg, 35.1 mmol) is added to a suspension of benzyl 2,4- dihydroxy-6-methylnicotinate (4790 mg, 17.6 mmol) in DCM (50 mL). The reaction mixture is heated to 45°C for 4h. The suspension is cooled with an ice bath and the precipitate is collected by filtration. The solid is dissolved back in DCM (100 mL) and treated with NaHCO3 5% aq. (WOmL). The mixture is stirred for 20 min. The layers are separated and the organic layer is washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the benzyl 4-hydroxy-2-methoxy-6-methylnicotinate as a crude off-white solid (3.81 g) which is used without further purification.1H NMR (400 MHz, DMSO) 6 11.14-11.18 (br. s, 1 H), 7.31-7.45 (m, 5 H), 6.43 (s, 1 H), 5.29 (s, 2 H), 3.82 (s, 3 H), 2.30 (s, 3 H); LC-MS I: tR= 0.49 min; [M+H]+= 273.8.

[0406] Step 3: Benzyl (R)-4-(2-((tert-butoxycarbonyl)amino)-3-(6-methoxypyridin-2-yl)propoxy)-2-methoxy-6- methylnicotinate is prepared from benzyl 4-hydroxy-2-methoxy-6-methylnicotinate and tert-butyl (R)-(1 -hydroxy-3- (6-methoxypyridin-2-yl)propan-2-yl)carbamate (AL-1) in analogy to the procedure described for B1 Step 5. LC-MS B: tR= 1.14 min; [M+H]+= 538.35.

[0407] Step 4: TFA (2.98 mL, 38.9 mmol.) is added to a RT solution of benzyl (R)-4-(2-((tert-butoxycarbonyl)amino)-3-(6- methoxypyridin-2-yl)propoxy)-2-methoxy-6-methylnicotinate (697 mg, 1.3 mmol) in DCM (20 mL) and the resulting mixture is stirred at RT for 2h. After completion of the deprotection, the mixture is evaporated to dryness, The crude is redissolved in DCM, re-evaporated (process repeated twice). The residue is partitioned between DCM and 1 M aq. NaOH and the layers are separated. The aq. Layer is further extracted with DCM (2x). The combined organic extracts are dried over MgSO4, filtered and evaporated in vacuo to give the title compound as a light-yellow oil (0.431 g) which is used without further purification. LC-MS B: tR= 0.81 min; [M+H]+= 438.4.

[0408] Benzyl (R)-6-(2-amino-3-(6-bromo-4-methylpyridin-2-yl)propoxy)-3-fluoroquinoline-5-carboxylate dihydrochloride (B-7)

[0409] The title compound is prepared from benzyl 3-fluoro-6-hydroxyquinoline-5-carboxylate (B-1 , steps 1-4) and tertbutyl (R)-(1-(6-bromo-4-methylpyridin-2-yl)-3-hydroxypropan-2-yl)carbamate (AL-3) following steps 5&6 described for B-1 . LC-MS I: tR= 1 .09 min; [M+H]+= 524.22.

[0410] Benzyl (R)-6-(2-amino-3-(4-chloro-6-methoxypyrimidin-2-yl)propoxy)-3-fluoroquinoline-5-carboxylate 2,2,2- trifluoroacetate (B-8)

[0411] The title compound is prepared from benzyl 3-fluoro-6-hydroxyquinoline-5-carboxylate (B-1 , steps 1-4) and tertbutyl (R)-(1-(4-chloro-6-methoxypyrimidin-2-yl)-3-hydroxypropan-2-yl)carbamate (AL-4) following steps 5&6 described for B-1, using TFA instead of HCI (4M in Dioxane) for the Boc-deprotection in the step 6. LC-MS B: tR= 0.85 min; [M+H]+= 497.0.

[0412] Benzyl (R)-6-(2-amino-3-(2-chloro-6-methoxypyrimidin-4-yl)propoxy)-3-fluoroquinoline-5-carboxylate 2,2,2- trifluoroacetate (B-9)

[0413] The title compound is prepared from benzyl 3-fluoro-6-hydroxyquinoline-5-carboxylate (B-1 , steps 1-4) and tertbutyl (R)-(1-(2-chloro-6-methoxypyrimidin-4-yl)-3-hydroxypropan-2-yl)carbamate (AL-5) following steps 5&6 described for B-1, using TFA instead of HCI (4M in Dioxane) for the Boc-deprotection in the step 6. LC-MS B: tR= 0.84 min; [M+H]+= 497.0.

[0414] (RS)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanamido)-3-(3- fluorobicyclo[1.1.1]pentan-1-yl)propanoic acid (C-1)

[0415] Step 1 : HATU (5.04 g, 13.3 mmol) is added to a RT solution of 3-fluorobicyclo[1.1.1]pentane-1 -carboxylic acid (1500 mg, 11.5 mmol), N,O-Dimethylhydroxylamine Hydrochloride (1262 mg, 12.7 mmol) and DIPEA (6.04 mL, 34.6 mmol) in DMF (15 mL) under Argon and the resulting mixture is stirred for 1 h. The mixture is partitioned between water and EtOAc. The layers are separated and the aqueous re-extracted with EtOAc (2x). The combined organic extracts are washed with water and brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude is purified by FC, eluting with a gradient of (Heptane / Ethyl acetate) from (1 :1) to (0:1) to yield.1.6 g of 3-fluoro-N- methoxy-N-methylbicyclo[1.1.1]pentane-1 -carboxamide as a colorless oil.1H NMR (400 MHz, DMSO) 3: 3.65 (s, 3 H), 3.11 (s, 3 H), 2.35 (d, J = 2.6 Hz, 6 H); LC-MS B: tR= 0.65 min; [M+H]+= 174.2.

[0416] Step 2: 3-fluoro-N-methoxy-N-methylbicyclo[1.1.1]pentane-1 -carboxamide (1.6 g, 9.24 mmol) is dissolved in THF (21.4 mL, 21.4 mmol) and the resulting mixture is cooled to -78°C under argon. DIBAH solution 1.0 M in toluene (12 mL, 12 mmol) is added and the resulting mixture is stirred for 1 h30 at -78°C. The mixture is quenched with MeOH (10 mL) and diluted with a large volume of EtOAc. The resulting organic layer is washed with Rochelle's salt (sat. aq.), brine, dried over MgSO4, filtered and concentrated under reduced pressure (down to 50 mbars for 42°C only as the expected compound is assumed volatile) to yield 1.23 g of a crude 3-fluorobicyclo[1 .1.1]pentane-1- carbaldehyde, as a white solid which is used next step without further purification. LC-MS B: tR= 0.86 min; [M +H ]+= 114.0 (poor ionization).

[0417] Step 3: To a solution of 3-fluorobicydo[1.1.1]pentane-1-carbaldehyde (1.23 g, 10.8 mmol) in DCM (30 mL) is added N-Butoxycarbonyl trimethylphosphonoglycine (3.37 g, 11 mmol) and DBU (1.79 mL, 11.9 mmol) and the mixture is stirred at room temperature for 2 h. The mixture is then quenched with aqueous ammonium chloride (saturated) and extracted with DCM (3x). The combined organic layers are washed with brine, dried over MgSO4, filtered and evaporated. The crude is purified by FC, eluting with a gradient of (Heptane / Ethylacetate: from 100 / 0 to 70 / 30) to yield 0.76 g of the putative mixture cis / trans of methyl 2-((tert-butoxycarbonyl)amino)-3-(3- fluorobicyclo[1.1.1]pentan-1-yl)acrylate as a white solid. LC-MS B: tR= 0.92 min; [M+H]+= 286.2

[0418] Step 4: Sodium hydride 60 % in mineral oil (36.9 mg, 0.964 mmol) is added portionwise to a RT solution of the putative cis / trans mixture of methyl 2-((tert-butoxycarbonyl)amino)-3-(3-fluorobicyclo[1.1.1]pentan-1-yl)acrylate (250 mg, 0.876 mmol) and lodomethane (0.0606 mL, 0.964 mmol) in DMF (5 mL) under Argon and the resulting mixture is stirred for 1h. The mixture is then partitioned between water and EtOAc. The layers are separated and the aqueous re-extracted with EtOAc (2x). The combined organic extracts are washed with water and brine, dried over Na2SO4, filtered and evaporated in vacuo. to yield the crude putative cis / trans mixture of methyl 2-((tert- butoxycarbonyl)(methyl)amino)-3-(3-fluorobicyclo[1 .1.1]pentan-1-yl)acrylate as a light yellow oil (270 mg), which is used in the next step without further purification. LC-MS B: tR= 0.99 min; [M+H]+= 300.4.

[0419] Step 5: A soln, of the crude cis / trans mixture of methyl 2-((tert-butoxycarbonyl)(methyl)amino)-3-(3- fluorobicyclo[1 .1.1]pentan-1-yl)acrylate (270 mg, 0.902 mmol, 1 eq) in EtOH (5 mL) is purged with iXL / vacuum (3x) before PtO2 (20.5 mg, 0.0902 mmol) is added. After inertising another three times a H2 balloon is connected and the RM is stirred for 1 h under H2 atmosphere. The heterogeneous reaction mixture is filtered over a glass fiber filter (washing with methanol / THF). The filtrate is then concentrated to dryness under reduced pressure.to give 0.3 g of the crude rac-methyl (R)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(3-fluorobicyclo[1 .1.1]pentan-1- yl)propanoate as a colourless oil. LC-MS B: tR= 1 .00 min; [M+H]+= 302.4.

[0420] Step 6: Trifluoroacetic acid (TFA) (0.778 mL, 9.95 mmol) is added to a RT solution of the crude rac-methyl (R)-2- ((tert-butoxycarbonyl)(methyl)amino)-3-(3-fluorobicyclo[1.1.1]pentan-1-yl)propanoate (300 mg, 0.995 mmol) in DCM (5 mL) and the resulting mixture is stirred at RT for 6h. After completion of the Boc-deprotection, the volatiles are removed in vacuo, and the residue is co-evaporated further with DCM (2x) to give the crude rac-methyl (R)-3- (3-fluorobicyclo[1.1.1]pentan-1-yl)-2-(methylamino)propanoate 2,2,2-trifluoroacetate as a colorless oil (447 mg), which is used in the next step without further purification. LC-MS B: tR= 0.48 min; [M+H]+= 202.6.

[0421] Step 7: HATU (593 mg, 1.56 mmol) is added to a RT solution of rac-methyl (R)-3-(3-fluorobicyclo[1 .1.1]pentan-1- yl)-2-(methylamino)propanoate 2,2,2-trifluoroacetate (447 mg, 1.42 mmol), Boc-N-methyl-L-leucine (366 mg, 1.45 mmol) and DIPEA (0.728 mL, 4.25 mmol) in DMF (10 mL) under Argon and the resulting mixture is stirred for 1 h to reach complete conversion. The mixture is partitioned between water and EtOAc. The layers are separated and the aqueous re-extracted with EtOAc (2x). The combined organic extracts are washed with water and brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude is then purified by FC, using a gradient of (Heptane / Ethyl acetate) from (1 :1) to (0:1) to yield the epimer mixture methyl (RS)-2-((S)-2-((tert- butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanamido)-3-(3-fluorobicyclo[1.1.1]pentan-1-yl)propanoate (317 mg) as a colorless oil. LC-MS B: tR= 1.10 min; [M+H]- = 429.4.

[0422] Step 8: To a solution of the epimer mixture methyl (RS)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-N,4- dimethylpentanamido)-3-(3-fluorobicyclo[1 .1 .1 ]pentan-1-yl)propanoate (317 mg, 0.74 mmol) in Dioxane (5 mL) is added NaOH 2M (0.75 mL, 1.50 mmol). The RM is stirred at 60°C for 1 h to reach complete conversion. The RM is neutralized with a few drops of sat. NH4CI soln. And the mixture is evaporated to dryness. The residue is taken up in DCM and water and the solution is acidified carefully with a 2N aqueous HCI solution (down to pH~3). Then, the DCM layer is collected and the aqueous layer is further extracted with DCM (2x). The combined organic layers are washed with brine, dried over MgSO4 and concentrated under reduced pressure to yield 313 mg of the crude title product (C- 1) as a colorless oil, which is used in next steps without further purification. LC-MS B: tR= 0.99 &1.00 min; [M+H]+= 415,4 (mixture 1 :1 of the epimers)

[0423] Listed in Table 2-C below are building blocks C that are prepared in analogy to the 8-step sequence described above for C-1 .

[0424] Table 2-C

[0425] (R)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-N,4-dimethylpentanamido)-3-(1 -(trifluoromethyl)-2- oxabicyclo[2.1.1]hexan-4-yl)propanoic acid (C-6)

[0426] Step 1 : n-Butyllithi u m solution (1 .6 M in hexanes, 3.05 mL, 4.9 mmol) is added dropwise to a colorless solution of (2S)-(+)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine (0.77 mL, 4.08 mmol) in THF (15 mL) at -78°C. After 30 min stirring a solution of 4-(bromomethyl)-1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hexane (1000 mg, 4.08 mmol) in THF (50 mL) is added dropwise at -78°C. Mixture is allowed to return to RT and stirred at RT for 3 h. The reaction is quenched by addition of saturated aq NH4CI and the reaction is extracted with EtOAc (3x). The combined organic layers are washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to yield 1 .56 g of the crude (2S, 5 R)-2-isopropy I-3, 6-d i methoxy-5-(( 1 -(trifl uoromethyl)-2-oxabicyclo[2.1.1 ]hexan-4-y I) methy l)-2, 5- dihydropyrazine as an orange oil, which is not purified at this stage (almost no UV signal). LC-MS B: IR = 1 .05 min; [M+H]+= 349.3.

[0427] Step 2: 1 M aq HCI (9 mL, 9 mmol) is added to a pale orange solution of crude (2S,5R)-2-isopropyl-3,6- dimethoxy-5-((1 -(trifl uoromethy l)-2-oxabicyclo[2.1.1 ]hexan-4-y I) methy l)-2, 5-d i hyd ropy razi ne (1560 mg, 4.48 mmol, 1 eq) in MeCN (30 mL) at rt and mixture is stirred for 1 h. To the reaction is added sat NaHCOs and DCM.

[0428] The layers are separated and the aqueous layer is extracted further with DCM. The combined organic extracts are washed with water and brine, dried over Na2SO4, filtered and evaporated in vacuo to yield 1.17 g of the crude methyl (R)-2-amino-3-(1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)propanoate as a light yellow oil, which is used without further purification. LC-MS B: IR = 0.52 min; [M+H]+= 254.25. Step 3: Methyl (R)-2-amino-3-(1-(trifluoromethyl)-2-oxabicyclo[2.1.1 ]hexan-4-yl)propanoate (1.17 g, 4.62 mmol) is dissolved in THF (10 mL) and H2O (10 mL). NaHCOs (1.94 g, 23.1 mmol) is added, followed by BOC2O (1.11 g, 5.09 mmol) and the mixture is stirred at RT for 1 h. The reaction is quenched by addition of water and is extracted with EtOAc (3x). The gathered organic phases are dried over MgSCU, filtered and evaporated. The crude is purified by FY (Hept / EtOAc 1 :1) to yield 890 mg of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(1- (trifluoromethyl)-2-oxabicyclo[2.1.1 ]hexan-4-yl)propanoate as a colorless oil.1H NMR (400 MHz, DMSO) 5: 7.40 (d, J = 8.4 Hz, 1 H), 4.12 (ddd, J = 10.5, 8.8, 3.8 Hz, 1 H), 3.71 (d, J = 5.7 Hz, 1 H), 3.69 (d, J = 5.9 Hz, 1 H), 3.64 (s, 3 H), 2.18 (dd, J = 14.6, 3.8 Hz, 1 H), 2.07 (dd, J = 14.6, 10.6 Hz, 1 H), 2.00 (d, J = 5.3 Hz), 1.94 (d, J = 5.5 Hz), 1 .63-1.71 (m, 2 H), 1.39-1 .42 (m, 9 H); LC-MS B: tR= 0.95 min; [M +H ]+= 353.96.

[0429] Step 4: Sodium hydride 60 % in mineral oil (106 mg, 2.77 mmol) is added portion wise to a RT solution of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(1 -(trifluoromethyl)-2-oxabicyclo[2.1 .1 ]hexan-4-yl)propanoate (889 mg, 2.52 mmol) and lodomethane (99%, 0.174 mL, 2.77 mmol) in DMF (10 mL) under Argon and the resulting mixture is stirred for 1h. The mixture is partitioned between water and EtOAc. The layers are separated and the aqueous reextracted with EtOAc (2x). The combined organic extracts are washed with water and brine, dried over Na2SO4, filtered and evaporated in vacuo to yield 945 mg of a crude methyl (R)-2-((tert-butoxycarbonyl)(methyl)amino)-3- (1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)propanoate, which is used without further purification. LC-MS B: tR= 1.02 min; [M+H]+= 368.3.

[0430] Step 5: Trifluoroacetic acid (2.01 mL, 25.7 mmol) is added to a RT solution of methyl (R)-2-((tert- butoxycarbonyl)(methyl)amino)-3-(1 -(trifl uoromethyl)-2-oxabicyclo[2.1.1 ]hexan-4-yl)propanoate (945 mg, 2.57 mmol, 1 eq) in DOM (5 mL) and the resulting mixture is stirred at RT for 6h. The volatiles are removed in vacuo, co-evaporated with DOM (3x) to give 1 .21 g of the crude methyl (R)-2-(methylamino)-3-((1 R,4s)-1 - (trifluoromethyl)-2-oxabicyclo[2.1 .1]hexan-4-yl)propanoate 2,2,2-trifluoroacetate as an orange syrup, which is used without further purification. LC-MS B: tR= 0.52 min; [M+H]+= 268.25.

[0431] Step 6 and 7: The title compound is prepared from Boc-N-methyl-L-leucine and methyl (R)-2-(methylamino)-3- ((1 R,4s)-1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)propanoate 2,2,2-trifluoroacetate following steps 7&8 described for C-1 ; LC-MS B: tR= 1.02 min; [M +H ]+= 481 .2.

[0432] Synthesis of Compounds of Formula (I)

[0433] General Method: GM-A

[0434] Example 1 : (3S,7S,10R,13R)-13-benzyl-20-fluoro-10-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-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]tetraazacycloheptadecino[16,17-f]quinoline-3-carboxamide

[0435] Step 1 : HATU (316 mg, 0.831 mmol) is added to a RT solution of C-1 (313 mg, 0.755 mmol, 1 eq), B-1 (418 mg, 0.831 mmol, 1.1 eq) and DIPEA (0.452 mL, 2.64 mmol) in DMF (5 mL) under Argon and the resulting mixture is stirred for 1h. The RM is partitioned between water and EtOAc and the layers are separated. The aq. phase is reextracted with EtOAc (2x) and the combined org. extracts are washed with brine, dried (Na2SO4), filtered, and evaporated. The crude product is purified by FC, eluting with a gradient of (Heptane / EtOAc) from (1 / 1) to (0 / 1) to give the mixture of epimers benzyl 6-(((6S,9RS,12R)-12-benzyl-9-((3-fluorobicyclo[1 .1 .1]pentan-1-yl)methyl)-6- isobutyl-2,2,5,8-tetramethyl-4,7, 10-trioxo-3-oxa-5,8, 11 -triazatridecan-13-yl)oxy)-3-fluoroquinoline-5-carboxylate as a colorless oil. LC-MS B tR= 1 .31 & 1 .32 min; [M+H]+= 827.5.

[0436] Step 2: A soln, of benzyl 6-(((6S,9RS,12R)-12-benzyl-9-((3-fluorobicydo[1.1 .1]pentan-1-yl)methyl)-6-isobutyl- 2, 2, 5, 8-tetramethyl-4, 7, 10-trioxo-3-oxa-5, 8, 11 -triazatridecan-13-yl)oxy)-3-fluoroquinoline-5-carboxylate (687 mg, 0.83 mmol) in EtOH (10 mL) is evacuated / purged with N2 (3x) before 10% Pd / C (68 mg, 7.5 mol%) is added. The RM is evacuated / purged with H2 (3x) and stirred under a H2 atm for 1 h. The RM is filtered through a glass fiber filter (washing with THF / MeOH 4 / 1) and the filtrate concentrated to dryness under reduced pressure to give the mixture of epimers 6-(((6S,9RS, 12R)-12-benzy l-9-((3-f I uorobicyclo[ 1.1.1 ]pentan-1-yl)methyl)-6-isobutyl-2,2,5,8- tetramethyl-4,7,10-trioxo-3-oxa-5,8, 11 -triazatridecan-13-yl)oxy)-3-fluoroquinoline-5-carboxylic acid as a colorless syrup. LC-MS B tR= 1.16 & 1 .18 min; [M+H]+= 737.5.

[0437] Step 3: HATU (112 mg, 0.30 mmol) is added to a RT soln, of 6-(((6S,9RS,12R)-12-benzyl-9-((3- f I uorobicyclo[ 1 .1.1 ]pentan-1 -yl) methy l)-6-isobu tyl-2, 2, 5, 8-tetramethy I-4, 7, 10-trioxo-3-oxa-5,8, 11 -triazatridecan-13- yl)oxy)-3-fluoroquinoline-5-carboxylic acid (198 mg, 0.34 mmol), A-2 (96 mg, 0.30 mmol) and DIPEA, (0.16 mL, 0.94 mmol) in DMF (5 mL) and the RM is stirred for 1h. The mixture is partitioned between water and EtOAc. The layers are separated and the aqueous re-extracted with EtOAc (2x). The combined organic extracts are washed with water and brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude is purified by FC, using (heptane / ethyl acetate) gradient from (1 :1) to (0:1) to give the mixture of epimers tert-butyl (S)-3-(6- (((6S.9RS, 12R)-12-benzy l-9-((3-f luorobicyclo[ 1 .1.1 ]pentan-1 -yl) methyl)-6-isobu tyl-2, 2, 5, 8-tetramethy I-4, 7, 10- trioxo-3-oxa-5,8,11-triazatridecan-13-yl)oxy)-3-fluoroquinoline-5-carboxamido)-4-((2-(3-methoxy-1 ,2,4-oxadiazol- 5-yl)ethyl)amino)-4-oxobutanoate as a white solid. LC-MS B: tR= 1.23 min; [M+H]+= 1033.5.

[0438] Step 4: TFA (1.04 mL, 13.6 mmol) is added to a RT solution of tert-butyl (S)-3-(6-(((6S,9RS,12R)-12-benzyl-9-((3- f I uorobicyclo[ 1 .1.1 ]pentan- 1 -yl) methy l)-6-isobu tyl-2, 2, 5, 8-tetramethy I-4, 7, 10-trioxo-3-oxa-5,8, 11 -triazatridecan-13- yl)oxy)-3-fluoroquinoline-5-carboxamido)-4-((2-(3-methoxy-1 ,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutanoate (140 mg, 0.136 mmol) in DCM (4 mL) and the resulting mixture is stirred for 1.5h. The RM is concentrated in vacuo and the residue is re-dissolved in DCM and again concentrated in vacuo (2x). The residue is taken up in DMF (4 mL) and DIPEA (0.186 mL, 1.08 mmol) and HATU (61.8 mg, 0.163 mmol) are added and the mixture stirred at RT for 15min. The mixture is partitioned between water and EtOAc. The layers are separated and the aqueous reextracted with EtOAc (2x). The combined organic extracts are washed with water and brine, dried over Na2SO4, filtered and evaporated in vacuo to give the crude product. It is purified by prep. HPLC (basic) to give the title compound, (3S.7S, 10R, 13R)-13-benzy l-20-f I uoro-10-((3-fl uorobicyclo[1.1.1 ]pentan- 1 -yl) methy l)-7-isobuty l-N -(2- (3-methoxy-1 , 2, 4-oxad i azol-5-y l)ethy l)-6, 9-d i methy 1-1 ,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]tetraazacydoheptadecino[16,17-f]quinoline-3-carboxamide, as a white solid. LC- MS I: tR= 1.08 min; [M+H]+= 859.5. Note: The 2ndstereoisomer, (3S,7S, 10S, 13R)-13-benzyl-20-fluoro-10-((3- f I uorobicyclo[ 1.1.1 ]pentan-1 -yl)methyl)-7-isobutyl-N-(2-(3-methoxy-1 ,2, 4-oxad i azol-5-y l)ethyl)-6, 9-di methyl- 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]tetraazacycloheptadecino[16,17-f]quinoline-3-carboxamide is also isolated as a white solid. LC- MS I: tR= 1.03 min; [M+H]+ = 859.5.

[0439] Listed in Table MC-1 below are compounds of general formula (I) that are prepared from the corresponding building blocks A, B, and C in analogy to the description above in General Method A (GM-A). In the following tables * denotes an example compound isolated during the synthesis, most often separated by prep. HPLC purification of the final synthetic step as a minor epimer due to epimerisation of a chiral centre. In certain cases, an enantiomerically or diastereomerically pure building block(s) undergoes epimerisation during the synthesis and the example compound is isolated as a mixture of epimers.

[0440] Table MC-1 (GM-A)

[0441] Listed in the Table of Examples below are example compounds of formula (I) prepared according to the above described methods.

[0442] Table of Examples

[0443] Table 3: Structures of compounds of Example 1 to 48

[0444] IL Biological Assays

[0445] Compounds of the present invention may be further characterized with regard to their general pharmacokinetic and pharmacological properties using conventional assays well known in the art for example relating to their bioavailablility in different species (such as rat or dog); or for their properties with regard to drug safety and / or toxicological properties using conventional assays well known in the art, for example relating to cytochrome P450 enzyme inhibition and time dependent inhibition, pregnane X receptor (PXR) activation, glutathione binding, or phototoxic behavior.

[0446] Biological in vitro Assays

[0447] Evaluation of compound EC50 and Emax values

[0448] The corrector activities of the compounds of formula (I) on CFTR are determined in accordance with the following experimental method. The method measures the effect of over-night compound incubation on F508del-CFTR cell surface expression in a recombinant U2OS cell line (DiscoveRx, #93-0987C3). This cell line is engineered to coexpress (i) human F508del-CFTR tagged with a Prolink (PK =short R-galactosidase fragment) and (ii) the remainder of the R-galactosidase enzyme (Enzyme Acceptor; EA) localized to the plasma membrane. Incubation with compounds that increase PK-tagged F508del-CFTR at the plasma membrane will lead to complementation of the EA fragment to form a functional R-galactosidase enzyme which is quantified by a chemiluminescence reaction.

[0449] Briefly, the cells are seeded at 3500cells / well into 384-well low volume plates (Corning, #3826) in 20pil of full medium (Me Coy's 5a (#36600-021, Gibco) + 10% FBS Gibco + penicillin / streptomycin). The cells are incubated for 5h in the incubator before the addition of 5 pil / well of compound dilution series (5x working stocks in full medium). Final DMSO concentration in the assay is 0.25%. The cells are co-incubated with the compounds for 16h in the incubator at 37°C, 5% CO2. The next day, the cell plates are incubated for 2h at RT in the dark. Then, 10pil / well of Flash detection reagent (Discover , #93-0247) is added, the plate is incubated for another 30min at RT in the dark and chemiluminescence is measured. Concentration-response curves are generated using compound-intrinsic maximal efficacy as upper plateau, and from these CRCs compound-intrinsic EC50 values are determined. Compound-specific Emaxvalues are calculated in relation to the Emaxof the corrector lumacaftor (Emaxlumacaftor = 100%).

[0450] The calculated EC50 values may fluctuate depending on the daily assay performance. Fluctuations of this kind are known to those skilled in the art. EC50 values from several measurements are given as geomean values. The calculated Emaxvalues may fluctuate depending on the daily assay performance. Fluctuations of this kind are known to those skilled in the art. Emaxvalues from several measurements are given as arithmetic mean values.

[0451] References

[0452] Elborn JS. (2016) Cystic fibrosis. Lancet 388:2519-2531. Dalemans W, Barbry P, Champigny G, Jallat S, Dott K, Dreyer D, Crystal RG, Pavirani A, Lecocq JP, Lazdunski M (1991) Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation. Nature 354: 526-8. Table of Biological Data: Evaluation of the inhibition by the compounds of Formula (I) of the midazolam hydroxylation by the enzyme CYP450 3A4.

[0453] CYP3A4 inhibition was studied using midazolam 1 ’-hydroxylation as marker reaction. Midazolam was used at a single concentration of 5 pM around its Km (Michaelis-Menten constant) and the test compounds were incubated at eight different concentrations, up to 50 pM. Nicardipine was used as positive control. Microsomal incubations were initiated by the addition of NADPH-regenerating system and terminated by adding an excess of ice-cold organic solvent. The formation of 1 '-hydroxymidazolam was measured by liquid chromatography-tandem mass spectrometry (LC / MS-MS) and IC50 values were calculated.

[0454] Table of inhibition of the midazolam CYP450 3A4 hydroxylation:

[0455] Evaluation of the inhibition of BSEP transporter channel by compounds of Formula (I).

[0456] The human BSEP inhibition potential was investigated in vesicular uptake assays using 0.2 mM taurocholic acid (TCA, as a mixture of 3H-TCA and cold TCA) as a model substrate. For rat, dog and monkey Bsep inhibition experiments TCA concentration was 2, 0.2, and 0.2 mM (as a mixture of 3H-TCA and cold TCA), respectively. Inverted HEK293 derived membrane vesicles expressing BSEP / Bsep (0.5 mg total protein / mL) were incubated in the presence of 5 mM ATP or AMP. Incubations were carried out at 37 °C in vesicular transport buffer (2 mM Hepes-Tris, pH 7.4, 50 mM sucrose, 100 mM KNO3, 10 mM Mg(NO3)2) containing the model substrate alone or in combination with various concentrations of test article (TA) ranging from 0.03 mM to 100 mM. Incubation time was 5 min for human, rat, and monkey BSEP / Bsep whereas for dog Bsep it was 2 min. The uptake of TCA was stopped by adding ice-cold washing buffer (10 mM Tris-HCI, pH 7.4, 50 mM sucrose and 100 mM KNO3) and filtering the membrane suspension through cellulose nitrate membrane filters (pore size 0.45mm) using a rapid filtration system (Millipore, Zug, Switzerland). Membrane suspensions retained on the filters were washed twice with ice-cold washing buffer and were then transferred into the scintillation vials. After addition of 3.5 mL scintillation cocktail Filter-Count (Perkin Elmer, Zurich, Switzerland), total radioactivity was counted using a Tri-Carb 2300 TR liquid scintillation analyzer (Packard Bioscience, Zurich, Switzerland). Prior to experiments, cellulose nitrate filters were saturated with 1 mM TCA. Cyclosporin A (0.03 mM to 100 mM) was used as a positive control.

[0457] In the screening assay, each concentration was tested once whereas for interesting compounds assay was repeated and each concentration was tested in triplicates.

[0458] BSEP / Bsep-mediated net uptake rates were calculated as the difference between the uptake rates obtained in the presence of ATP or AMP. The net uptake rates are presented as arithmetic mean and standard deviation (SD), when applicable.

[0459] Data from the inhibition experiments were evaluated by plotting the inhibitor concentration (logarithmic scale) against the net uptake rate. IC50 values were then determined from the plot by non-linear regression using the following equation:

[0460] Top y= > + Bottom where y is the net uptake rate [(pmol / (mg protein min)), x is the inhibitor concentration (mM), s is the slope at the point of inversion, and Top and Bottom are the maximum and minimum values for net uptake rate. The minimum value (bottom) was constrained to 0. For all graphical data evaluations, the GraphPad Prism software package (version 8.1.1 , GraphPad Software Inc., La Jolla, USA) was used.

[0461] The calculated IC50 values may fluctuate depending on the daily assay performance. Fluctuations of this kind are known to those skilled in the art. IC50 values from several measurements are given as geomean values.

[0462] Table of inhibition of the BSEP transporter:

[0463] References

[0464] Boyle MP et al (2014). Lancet Respir Med 2(7):527-538.

[0465] Dalemans W et al (1991). Nature 354:526-528.

[0466] 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.

[0467] Fiedorczuk K et al (2022). Cell 185(1):158-168.

[0468] Flores AM et al (2016). FASEB J 30(5):1789-1797.

[0469] Galietta LV et al (2001). Am J Physiol Cell Physiol 281 (5):C 1734-1742.

[0470] Hutt DM et al (2011). ACS Med Chem Lett 2(9):703-707.

[0471] Keating D et al (2018). N Engl J Med 379(17): 1612-1620.

[0472] Le Grand D et al (2021). J Med Chem 64(11 ):7241 -7260.

[0473] 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.

[0474] Patel SD et al (2020). Eur Respir Rev 29(156): 190068.

[0475] Stevers LM et al (2022). Nat Commun 13:3586.

[0476] Van Goor F et al (2011). Proc Natl Acad Sci U S A 108(46): 18843-18848. Veit G et al (2018). Nat Med 24(11):1732-1742.

[0477] Veit G et al (2020). JCI Insight 5(18):e139983.

Claims

Claims1. A compound of Formula (I)whereinR1represents Ci-4-alkyl;R2represents Ci-4-alkyl;R3represents Ci-e-alkyl;R4represents 5-membered heteroaryl, wherein said 5-membered heteroaryl is unsubstituted, or mono-, di- or trisubstituted, wherein the substituents are independently selected from Ci-4-alkyl, Ci.4-alkoxy, C-i-3-fluoroalkyl, C1-3- fluoroalkoxy, halogen, cyano, and Cs-e-cycloalkyl;W represents -CH2- or -CH2-CH2-;Z represents -CH2-, -CH2-CH2-, or -CH2-O-*; wherein the asteriks indicates the bond linked to -C-R5;R5represents halogen, C-i-4-alkyl, Ci-4-fluoroalkyl, or Ci-4-alkoxy;Ar1represents:• 6-membered heteroarylene; wherein said 6-membered heteroarylene is mono-, di- or tri-substituted, wherein the substituents are independently selected from C-i-4-alkyl, Ci-4-alkoxy, Ci-3-fluoroalkyl, C1-3- fluoroalkoxy, cyano, and halogen; or• 8- to 10-membered bicyclic heteroarylene; wherein said 8- to 10-membered bicyclic heteroarylene is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from C1-4- alkyl, C-i-3-fluoroalkyl, Ci-4-alkoxy, Ci-3-fluoroalkoxy, cyano, and halogen; andAr2represents phenyl, or 5- or 6-membered heteroaryl, wherein said phenyl or 5- or 6-membered heteroaryl is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from Ci-4-alkyl, Ci- 3-fluoroalkyl, halogen, cyano, Cs-e-cycloalkyl, Ci-4-alkoxy, and Ci-3-fluoroalkoxy; or a pharmaceutically acceptable salt thereof.

2. A compound of Formula (I) as defined in claim 1 , wherein the compounds are also compounds of Formula (lE):Formula (lE); or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 or 2; whereinR4represents 5-membered heteroaryl, wherein said 5-membered heteroaryl is mono- or di-substituted, wherein the substituents are independently selected from Ci-4-alkoxy, halogen, and Cs-e-cycloalkyl;W represents -CH2-;Z represents -CH2- or -CH2-O-*;R5represents halogen, Ci-4-alkyl, C-i-4-fluoroalkyl, or Ci-4-alkoxy;Ar1represents:• 6-membered heteroarylene; wherein said 6-membered heteroarylene is di-substituted, wherein the substituents are independently selected from C-i-4-alkyl and Ci-4-alkoxy; or• 10-membered bicyclic heteroarylene; wherein said 10-membered bicyclic heteroarylene is monosubstituted with C-i-4-alkyl or halogen; andAr2represents phenyl, or 6-membered heteroaryl, wherein said phenyl or 6-membered heteroaryl is unsubstituted or mono-substituted with Ci-4-alkyl or Ci-4-alkoxy; or a pharmaceutically acceptable salt thereof.

4. A compound according to any of claims 1 to 3; wherein the fragmentor a pharmaceutically acceptable salt thereof.

5. A compound according to any of claims 1 to 4; wherein Ar1represents:• 6-membered heteroarylene; wherein said 6-membered heteroarylene is di-substituted, wherein the substituents are independently selected from Ci-4-alkyl and Ci-4-alkoxy; or• 10-membered bicyclic heteroarylene; wherein said 10-membered bicyclic heteroarylene is monosubstituted with halogen (especially fluoro); or a pharmaceutically acceptable salt thereof.

6. A compound according to any of claims 1 to 5; wherein Ar2represents:• phenyl; or• 6-membered heteroaryl; wherein said 6-membered heteroaryl is mono-substituted with Ci-4-alkoxy; or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 , wherein said compound is:(3S , 7S , 10R, 13R)-13-benzy l-20-f I uoro- 10-((3-fl uorobicyclo[1.1.1 ]pentan- 1 -yl)methyl)-7-isobutyl-N-(2-(3-methoxy- 1 , 2, 4-oxad i azol-5-yl)ethy l)-6, 9-d i methyl- 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]tetraazacydoheptadecino[16, 17-f]quinoline-3-carboxamide;(3S,7S,1 OR, 13R)-20-fluoro-10-((3-fluorobicyclo[1.1 .1]pentan-1 -yl)methyl)-7-isobutyl-N-(2-(3-methoxyisoxazol-5- yl)ethyl)-13-((6-methoxypyridin-2-yl)methyl)-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]tetraazacydoheptadecino[16, 17-f]quinoline-3-carboxamide;(3S , 7S , 10R, 13 R)-N-(2-(5-cydopropy I-2H -tetrazol-2-yl)ethy l)-20-f I uoro- 10-((3-fl uorobicyclo[1.1.1 ]pentan- 1 - yl)methyl)-7-isobutyl-13-((6-methoxypyridin-2-yl)methyl)-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]tetraazacycloheptadecino[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-7-isobutyl-N-(2-(3-methoxy-1,2,4- oxadi azol-5-y l)ethy I)- 13-((6-methoxypy rid i n-2-yl) methyl)-6, 9-d i methyl- 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]tetraazacydoheptadecino[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S, 10R, 13R)-13-benzy I- 10-((3-f I uorobicyclo[ 1.1.1 ]pentan-1 -yl)methyl)-7-isobutyl-N-(2-(3-methoxy-1 ,2,4- oxadi azol-5-yl)ethyl)-6, 9, 20-tri methyl- 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]tetraazacydoheptadedno[16, 17-f]isoquinoline-3-carboxamide;(3S,7S, 10R, 13 R)-13-benzy I- 10-((3-f I uorobicyclo[ 1 .1.1 ]pentan-1 -yl)methyl)-7-isobutyl-N-(2-(3-methoxyisoxazol-5- yl)ethyl)-6,9, 20-trimethy 1-1 ,5,8, 11 -tetraoxo-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahyd roll ]oxa[4, 7, 10, 14]tetraazacydoheptadedno[16, 17-f]isoquinoline-3-carboxamide;(3S,7S, 10R, 13R)-13-benzy l-N -(2-(5-cyclopropy I-2H -tetrazol-2-yl)ethy I)- 10-((3-f I uorobicyclo[1 .1.1 ]pentan- 1 - yl) methy l)-7-isobu ty I-6, 9, 20-tri methyl- 1 ,5,8, 11 -tetraoxo-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-te tradecahyd roll ]oxa[4, 7, 10, 14]tetraazacydoheptadedno[16, 17-f]isoquinoline-3-carboxamide;(3S,7S,1 OR, 13R)-20-fluoro-N-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)-10-((3-fluorobicyclo[1 .1 .1]pentan-1 - yl)methyl)-7-isobutyl-13-((6-methoxypyridin-2-yl)methyl)-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]tetraazacycloheptadecino[16, 17-f]q ui nol i ne-3- carboxamide;(3S,7S,10R, 13R)-20-fluoro-10-((3-fluorobicyclo[1.1 ,1]pentan-1-yl)methyl)-7-isobutyl-N-(2-(4-methoxy-2H-1 ,2,3- triazol-2-yl)ethyl)-13-((6-methoxypy rid i n-2-y I) methy l)-6, 9-di methyl- 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]tetraazacycloheptadecino[16, 17-f]q ui nol i ne-3- carboxamide;(3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1 ,2,4-oxadiazol-5-yl)ethyl)-10-((3- methoxybicyclo[1 .1.1 ]pentan-1 -yl)methyl)-13-((6-methoxy pyridi n-2-y I) methy l)-6, 9-d i methy I- 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]tetraazacycloheptadecino[16, 17-f]q ui nol i ne-3- carboxamide;(3S,7S,10R,13R)-20-fluoro-7-isobutyl-10-((3-methoxybicydo[1.1.1]pentan-1-yl)methyl)-N-(2-(3-methoxyisoxazol- 5-yl)ethyl)-13-((6-methoxypyridin-2-yl)methyl)-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]tetraazacydoheptadecino[16, 17-f]quinoline-3-carboxamide;(3S,7S, 10R, 13R)-N-(2-(5-cydopropyl-2H-tetrazol-2-yl)ethyl)-20-fluoro-7-isobutyl-10-((3- methoxybicyclo[1 .1.1 ]pentan-1 -yl)methyl)-13-((6-methoxy pyridi n-2-y I) methy l)-6, 9-d i methy I- 1 ,5,8, 11 -tetraoxo-1.2.3.4.5.6.7.8.9.10.11.12.13.14-tetradecahyd ro-[ 1 ]oxa[4,7, 10, 14]tetraazacydoheptadecino[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-13-((6-methoxypyridin-2-yl)methyl)-6,9- dimethyl-10-((3-methylbicyclo[1.1 ,1]pentan-1-yl)methyl)-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]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;(3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1 ,2,4-oxadiazol-5-yl)ethyl)-13-((6-methoxypyridin-2- yl) methyl)-6, 9-d i methyl- 10-((3-methy I bicyclo[ 1.1.1 ]pentan- 1 -y I) methy l)-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]tetraazacycloheptadecino[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S, 10R, 13R)-N-(2-(5-cydopropyl-2H-tetrazol-2-yl)ethyl)-20-fluoro-7-isobutyl-13-((6-methoxypyridin-2- yl) methy l)-6, 9-d i methyl- 10-((3-methy I bicyclo[ 1.1.1 ]pentan- 1 -y I) methy l)-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]tetraazacydoheptadedno[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(4-methoxy-2H-1 ,2,3-triazol-2-yl)ethyl)-13-((6-methoxypyridin-2- yl) methy l)-6, 9-d i methyl- 10-((3-methy I bicyclo[ 1.1.1 ]pentan- 1 -y I) methy l)-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]tetraazacydoheptadedno[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-13-((6-methoxypyridin-2-yl)methyl)-6,9- dimethyl-1 ,5,8,11-tetraoxo-10-((3-(trifluoromethyl)bicydo[1 .1 .1]pentan-1-yl)methyl)-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydro-[1 ]oxa[4,7, 10, 14]tetraazacydoheptadedno[16, 17-f]q ui nol i ne-3- carboxamide;(3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1 , 2, 4-oxad i azol-5-y l)ethy l)-13-((6-methoxypyridin-2- yl)methyl)-6,9-dimethyl-1 ,5,8,11-tetraoxo-10-((3-(trifluoromethyl)bicydo[1.1 .1]pentan-1-yl)methyl)-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydro-[1 ]oxa[4,7, 10, 14]tetraazacydoheptadedno[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S, 10R, 13R)-N-(2-(5-cydopropyl-2H-tetrazol-2-yl)ethyl)-20-fluoro-7-isobutyl-13-((6-methoxypyridin-2- yl)methyl)-6,9-dimethyl-1 ,5,8,11-tetraoxo-10-((3-(trifluoromethyl)bicydo[1.1 .1]pentan-1-yl)methyl)-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydro-[1 ]oxa[4,7, 10, 14]tetraazacydoheptadedno[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(4-methoxy-2H-1 ,2,3-triazol-2-yl)ethyl)-13-((6-methoxypyridin-2- yl)methyl)-6,9-dimethyl-1 ,5,8,11-tetraoxo-10-((3-(trifluoromethyl)bicydo[1.1 .1]pentan-1-yl)methyl)-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydro-[1 ]oxa[4,7, 10, 14]tetraazacydoheptadedno[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S, 10R, 13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9-dimethyl-10-((1 -methyl- 2-oxabicyclo[2.1.1 ]hexan-4-yl)methyl)-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]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;(3S,7S, 10R, 13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1 ,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-10-((1- methyl-2-oxabicyclo[2.1 .1 ]hexan-4-yl)methyl)-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]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;(3S,7S, 10R, 13R)-13-benzyl-N -(2-(5-cyclopropy I-2H -tetrazol-2-y l)ethyl)-20-f luoro-7-isobu tyl-6, 9-di methyl- 10-((1 - methyl-2-oxabicyclo[2.1 .1 ]hexan-4-yl)methyl)-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]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;(3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(4-methoxy-2H-1 ,2,3-triazol-2-yl)ethyl)-6,9-dimethyl-10-((1- methyl-2-oxabicyclo[2.1 .1 ]hexan-4-yl)methyl)-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]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;(3S,7S, 10R, 13R)-10-((3-fl uorobicyclo[ 1 .1.1 ]pentan- 1 -yl)methyl)-7-isobutyl-N-(2-(3-methoxy-1 ,2,4-oxadiazol-5- yl)ethyl)-13-((6-methoxypy rid i n-2-yl) methy l)-6, 9, 20-tri methyl- 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]tetraazacycloheptadecino[16, 17-f]isoquinoline-3-carboxamide;(3S,7S, 10R, 13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1 , 2, 4-oxadi azol-5-y l)ethyl)- 10-((3- methoxybicyclo[1 .1.1 ]pentan- 1 -y l)methyl)-6, 9-dimethy 1-1 ,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]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;(3S,7S, 10R, 13R)-13-benzy l-20-f luoro-7-isobu tyl- 10-((3-methoxybicyclo[1.1.1 ]pentan- 1 -yl)methyl)-N-(2-(3- methoxy isoxazol-5-y l)ethyl)-6, 9-d i methy I- 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]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;(3S,7S, 10R, 13R)-13-benzyl-10-((3-chlorobicyclo[1.1 .1 ]pentan-1-yl)methyl)-20-fluoro-7-isobutyl-N-(2-(3-methoxy- 1 , 2, 4-oxad i azol-5-yl)ethy l)-6, 9-d i methy I- 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]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;(3S,7S, 10R, 13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1 ,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl- 1,5,8,11-tetraoxo-10-((1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14- tetradecahydro-[1 ]oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;(3R,6R,9S,13S)-9-isobutyl-16-methoxy-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-3-((6-methoxypyridin-2- yl) methy l)-7, 10, 18-trimethyl-5,8, 11,15-tetraoxo-6-((3-(trif I uoromethyl) bicyclo[ 1.1.1 ]pentan-1 -yl)methyl)- 2, 3, 4, 5, 6, 7, 8, 9, 10,11 ,12,13, 14, 15-tetradecahydropyrido[3,4-p][1]oxa[4,7, 10, 14]tetraazacycloheptadecine-13- carboxamide;(3R,6R,9S,13S)-9-isobutyl-16-methoxy-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-3-((6-methoxypyridin-2-yl)methyl)- 7, 10, 18-trimethyl-5,8, 11 ,15-tetraoxo-6-((3-(trif I uoromethyl) bicyclo[ 1 .1.1 ]pentan- 1 -yl)methyl)-2, 3, 4, 5, 6, 7, 8, 9, 10,11 ,12,13, 14, 15-tetradecahydropyrido[3,4-p][1]oxa[4,7, 10, 14]tetraazacycloheptadecine-13- carboxamide;(3R,6R,9S, 13S)-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-9-isobutyl-16-methoxy-3-((6-methoxypyridin-2- yl) methy l)-7, 10, 18-trimethyl-5,8, 11,15-tetraoxo-6-((3-(trif I uoromethyl) bicyclo[ 1.1.1 ]pentan-1 -yl)methyl)- 2, 3, 4, 5, 6, 7, 8, 9, 10,11 ,12,13,14, 15-tetradecahydropyrido[3,4-p][1]oxa[4,7,10,14]tetraazacycloheptadecine-13- carboxamide;(3S,7S, 10R, 13R)-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-20-fluoro-7-isobutyl-13-((6-methoxypyridin-2- yl) methy l)-6, 9-d i methy I- 1 ,5,8, 11 -tetraoxo-10-((1 -(trif luoromethy I )-2-oxabicyclo[2.1.1 ]hexan-4-yl)methyl)-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydro-[1 ]oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1 , 2, 4-oxad i azol-5-y l)ethy l)-13-((6-methoxypyridin-2- yl) methy l)-6, 9-d i methy I- 1 ,5,8, 11 -tetraoxo-10-((1 -(trif luoromethy I )-2-oxabicyclo[2.1.1 ]hexan-4-yl)methyl)-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydro-[1 ]oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-13-((6-methoxypyridin-2-yl)methyl)-6,9- dimethyl-1 ,5,8, 11 -tetraoxo-10-((1 -(trifl uoromethy l)-2-oxabicyclo[2.1 .1 ]hexan-4-yl)methyl)-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydro-[1 ]oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S, 10R, 13R)-13-benzyl-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1 ,5,8, 11- tetraoxo-10-((1 -(trif I uoromethy l)-2-oxabicyclo[2.1 .1 ]hexan-4-y I) methyl)- 1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14- tetradecahydro-[1 ]oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;(3S,7S, 10R, 13R)-13-benzy l-20-f luoro-7-isobu tyl-N-(2-(3-methoxyisoxazol-5-y l)ethy l)-6, 9-d imethy 1-1 ,5,8,11- tetraoxo-10-((1 -(trif I uoromethy l)-2-oxabicyclo[2.1 .1 ]hexan-4-y I) methyl)- 1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14- tetradecahydro-[1 ]oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]quinoline-3-carboxamide;(3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1 ,2,4-oxadiazol-5-yl)ethyl)-13-((4-methoxypyridin-2- yl) methy l)-6, 9-d i methy I- 1 ,5,8, 11 -tetraoxo-10-((1 -(trif luoromethy l)-2-oxabicyclo[2.1.1 ]hexan-4-yl)methyl)-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydro-[1 ]oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S, 10R, 13R)-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-13-((4-methoxypyridin-2-yl)methyl)-6,9- dimethyl-1 ,5,8, 11 -tetraoxo-10-((1 -(trifl uoromethy l)-2-oxabicyclo[2.1 .1 ]hexan-4-yl)methyl)-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydro-[1 ]oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S, 10R, 13R)-N-(2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)-20-fluoro-7-isobutyl-13-((4-methoxypyridin-2- yl) methy l)-6, 9-d i methy I- 1 ,5,8, 11 -tetraoxo-10-((1 -(trif luoromethy l)-2-oxabicyclo[2.1.1 ]hexan-4-yl)methyl)-1 ,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14-tetradecahydro-[1 ]oxa[4,7, 10, 14]tetraazacycloheptadecino[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1 .1 ,1]pentan-1-yl)methyl)-7-isobutyl-N-(2-(3-methoxy-1,2,4- oxadi azol-5-y l)ethy I)- 13-((4-methoxypy rid i n-2-yl) methyl)-6, 9-d i methyl- 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]tetraazacycloheptadecino[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S,1 OR, 13R)-20-fluoro-10-((3-fluorobicyclo[1.1 .1]pentan-1 -yl)methyl)-7-isobutyl-N-(2-(3-methoxyisoxazol-5- yl)ethyl)-13-((4-methoxypyridin-2-yl)methyl)-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]tetraazacydoheptadecino[16, 17-f]quinoline-3-carboxamide;(3S,7S, 10R, 13 R)-N-(2-(5-cyclopropy I-2H -tetrazol-2-yl)ethy l)-20-f I uoro- 10-((3-fl uorobicyclo[1.1.1 ]pentan- 1 - yl)methyl)-7-isobutyl-13-((4-methoxypyridin-2-yl)methyl)-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]tetraazacycloheptadecino[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-7-isobutyl-N-(2-(3-methoxy-1,2,4- oxadiazol-5-yl)ethyl)-6,9-dimethyl-13-((4-methylpyridin-2-yl)methyl)-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]tetraazacydoheptadecino[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S, 10R, 13 R)-N-(2-(5-cyclopropy I-2H -tetrazol-2-yl)ethy l)-20-f I uoro- 10-((3-fluorobicydo[1.1.1 ]pentan- 1 - yl)methyl)-7-isobutyl-6,9-dimethyl-13-((4-methylpyridin-2-yl)methyl)-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]tetraazacydoheptadecino[16, 17-f]q ui noli ne-3- carboxamide;(3S,7S,1 OR, 13R)-20-fluoro-10-((3-fluorobicyclo[1.1 .1]pentan-1 -yl)methyl)-7-isobutyl-N-(2-(3-methoxyisoxazol-5- yl)ethyl)-6,9-dimethyl-13-((4-methy Ipy rid i n-2-yl) methy l)-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]tetraazacydoheptadecino[16, 17-f]quinoline-3-carboxamide;(3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicydo[1.1.1]pentan-1-yl)methyl)-7-isobutyl-N-(2-(3-methoxy-1,2,4- oxadiazol-5-yl)ethyl)-13-((4-methoxypyrimidin-2-yl)methyl)-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]tetraazacydoheptadecino[16, 17-f]q ui noli ne-3- carboxamide; or(3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-7-isobutyl-N-(2-(3-methoxy-1,2,4- oxadiazol-5-yl)ethyl)-13-((6-methoxypyrimidin-4-yl)methyl)-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]tetraazacydoheptadecino[16, 17-f]q ui noli ne-3- carboxamide; or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

9. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use as a medicament.

10. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in the treatment of CFTR-related diseases and disorders including cystic fibrosis.

11. A method of treatment of CFTR-related diseases and disorders including cystic fibrosis, said method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 7, or of a pharmaceutically acceptable salt thereof.

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