Macrocyclic cftr modulators

Abstract

The present invention relates to macrocyclic compounds of formula (I) wherein Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , W and Z are as described in the specification, to their manufacture, to their pharmaceutically acceptable salts, and to their use as medicaments, to pharmaceutical compositions containing one or more compounds of formula (I), and to their use as CFTR modulators, alone or in combination with one or more therapeutically active ingredients which act as CFTR potentiators or CFTR correctors or CFTR stabilizers.

Description

Technical Field

[0001] This invention relates to novel macrocyclic compounds of formula (I) and their use as pharmaceuticals in the treatment of CFTR-related diseases and conditions (particularly cystic fibrosis). The invention also relates to related aspects, including processes for preparing said compounds, pharmaceutical compositions containing one or more compounds of formula (I), pharmaceutical compositions containing a combination of a compound of formula (I) and one or more therapeutically active ingredients used as CFTR modulators, wherein the CFTR modulator is one or more CFTR correctors (particularly type I correctors, and / or type II correctors, and / or type III correctors), and / or CFTR enhancers, and / or CFTR stabilizers; and their use in the treatment of CFTR-related diseases and conditions. Background Technology

[0002] Cystic fibrosis (CF; Mucus Plug Disease, sometimes also called pancreatic fibrosis or pancreatic fibrosis) is an autosomal recessive genetic disorder caused by dysfunction of epithelial chloride / bicarbonate channels called cystic fibrosis transmembrane transport regulators (CFTR). CFTR dysfunction leads to dysregulation of chloride, bicarbonate, and water transport on the surface of secretory epithelium, causing the accumulation of viscous mucus in organs including the lungs, pancreas, liver, and intestines, resulting in multi-organ dysfunction. The most debilitating effects observed in CF today occur in the lungs—due to abnormal airway surface fluid hydration, mucus plugging, impaired mucociliary clearance, chronic inflammation, and infection—the lungs lose their function over time, ultimately leading to respiratory failure and death (Elborn, 2016). Human CFTR is a multidomain protein consisting of 1480 amino acids. Many different mutations leading to CFTR dysfunction have been identified in CF patients, such as those causing nonfunctional CFTR protein (Type I mutations), CFTR transport defects (Type II mutations), CFTR regulatory defects (also known as gating defects; Type III mutations), CFTR conduction defects (Type IV mutations), CFTR protein reduction due to splicing defects (Type V mutations), or CFTR protein reduction due to decreased CFTR stability (Type VI mutations), and CFTR protein absence due to mRNA instability (Type VII mutations) (de Boeck, Acta Paediatr. 2020, 109(5):893-895). The CFTR2 database (http: / / cftr2.org; data retrieved on August 22, 2022) currently contains information on 401 pathogenic mutations. The most common pathogenic mutation to date is the deletion of phenylalanine at position 508 (F508del; allele frequency of 0.697 in the CFTR2 database). This mutation causes the channel to misfold during endoplasmic reticulum synthesis, leading to degradation of the misfolded protein and a significant reduction in transport to the cell surface (class II mutation). The residual F508del-CFTR transported to the cell surface is functional, but less functional than wild-type CFTR, meaning that F508del-CFTR also exhibits gating defects (Dalemans, 1991). Approximately 40% of CF patients are homozygous for the F508del mutation, and another approximately 40% are heterozygous for the F508del mutation and carry another pathogenic mutation from classes I, II, III, IV, V, VI, or VII. Such pathogenic mutations are quite rare, followed by type III G551D mutations (allele frequency 0.0210), type I G542X mutations (allele frequency 0.0254), and type II N1303K mutations (allele frequency 0.0158).

[0003] Currently, CF is treated with a range of medications targeting various organs and functional disorders. From the time of diagnosis, intestinal and pancreatic dysfunction is treated by supplementing the diet with pancreatic digestive enzymes. Pulmonary symptoms are primarily treated with hypertonic saline inhalation, mucolytics, anti-inflammatory drugs, bronchodilators, and antibiotics (Elborn, 2016).

[0004] In addition to symptomatic treatment, CFTR modulators have been developed and approved for patients with certain CFTR mutations. These compounds directly improve CFTR folding and transport to the cell surface (CFTR correctors) or improve the function of CFTRs on the cell surface (CFTR enhancers). Other types of modulators are still under investigation, such as compounds that increase the mRNA level of (mutated) CFTRs (CFTR amplifiers) and compounds that increase the plasma membrane stability of mutant CFTRs (CFTR stabilizers), such as the nucleotide-binding domain 1 (NBD1) stabilizer SION-638 (currently in Phase 1) and its follow-up molecule NBD1-A (G. Hurlbut oral presentation at the 2022 North American Cystic Fibrosis Conference) and SION-719 and SION-451 (Pipeline -- SionnaTherapeutics (sionnatx.com); accessed January 12, 2024). CFTR modulators can also enhance the function of non-mutant (i.e., wild-type) CFTR, and therefore their application in diseases where increasing wild-type CFTR function would have beneficial effects (e.g., non-CF diseases) is being investigated, such as the use of CFTR potentiators in the treatment of chronic bronchitis / COPD / bronchial dilatation (LeGrand, 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 OculPharmacol Ther 2020, 36(3):147-153; Felix, Invest Ophthalmol Vis Sci 2017 5(11):4506-4513), and acute respiratory distress syndrome (ARDS) (Erfinanda L, Sci Transl Med. 2022, 14(674):eabg8577). The CFTR potentiator (also known as the activator) VSJ-110 (CFTRact-K267) has been shown to have a pro-secretionary effect in a dry eye disease model. Furthermore, increased surface expression and function of wild-type CFTR by corrective agent treatment has been described (Marchesin 2023), and similar benefits should be expected in the aforementioned diseases. The combination of potentiator and corrective agent can be anticipated to provide further therapeutic benefits in diseases that benefit from increased wild-type CFTR function.

[0005] CFTR modulators and their combinations can be identified and optimized by evaluating their ability to promote the transport and function of mutant CFTR in recombinant and primary cell systems cultured in vitro. Activity in such systems can predict activity in CF patients.

[0006] WO2019 / 161078 discloses macrocyclic compounds as regulators of cystic fibrosis, wherein the macrocyclic compounds are typically 15-membered macrocyclic compounds comprising a (pyridine-carbonyl)-aminosulfonyl moiety attached to another aromatic group. Other macrocyclic compounds are disclosed in WO2022 / 109573 (a macrocyclic compound containing a 1,3,4-oxadiazole ring), WO2022 / 076625, WO2022 / 076626, WO2022 / 076624, WO2022 / 076621, WO2022 / 076620, WO2022 / 076618, WO2021 / 030556, and WO2021 / 030555. A macrocyclic tetrapeptide (12- or 13-membered) containing the compound Apidin (CAS: 183506-66-3) has been proposed as a potential treatment for CF (Hutt DM et al., ACS Med ChemLett. 2011;2(9):703-707. doi:10.1021 / ml200136e). WO2020 / 128925 discloses macrocyclic compounds capable of modulating CFTR activity, wherein the macrocyclic compounds contain an optionally substituted divalent N-(pyridin-2-yl)pyridyl-sulfonamide moiety. Other macrocyclic compounds have been described that can stabilize the chloride channel CFTR (Stevers LM, Nature Communications 2022, 13:3586). Non-macrocyclic CFTR correctors and / or CFTR synergists have been disclosed in, for example, WO2011 / 119984, WO2014 / 015841, WO2007 / 134279, WO2010 / 019239, WO2011 / 019413, WO2012 / 027731, WO2013 / 130669, WO2014 / 078842 and WO2018 / 227049, WO2010 / 037066, WO2011 / 127241, WO2013 / 112804, WO2014 / 071122 and WO2020 / 128768.In addition, specific macrocyclic compounds can be found as screening compounds, wherein the unsubstituted phenylene group is a part of the macrocyclic compound compared to the 8- to 10-membered bicyclic heteroarylene group of the compound of formula (I) of the present invention (CAS Registry Nos.: 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-22131 01-19-8, CAS-2213101-24-5, CAS-2215788-95-5, CAS-2215788-98-8, CAS-2215789-01-6, CAS-2215789-02-7, CAS-2215789-09-4, CA S-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-2 215947-68-3, CAS-2215947-78-5, CAS-2215947-91-2, CAS-2215954-57-5, CAS-2216342-34-4, CAS-2216342-78-6, CAS-2216342-86- 6. CAS-2216343-03-0, CAS-2216343-09-6, CAS-2216343-14-3, CAS-2216343-18-7, CAS-2216343-24-5, CAS-2216343-32-5, CAS-2216 343-38-1, CAS-2216343-45-0, CAS-2216343-53-0, CAS-2216343-59-6, CAS-2216343-64-3, CAS-2216343-74-5, CAS-2216343-76-7).

[0007] CFTR modulators can be further subdivided—among others— into CFTR correctors and CFTR enhancers. CFTR correctors improve the folding of CFTRs and their transport to the cell surface, particularly in CFTRs carrying class II (folding and transport) mutations, thereby increasing CFTR expression on the cell surface. CFTR enhancers increase the probability of CFTRs opening at the cell surface, particularly in CFTRs carrying gating defects (including class II mutants rescued by correctors), and thus can activate CFTRs additively / synergistically with CFTR correctors. Therefore, enhancers and correctors are being / are being used in combination clinically to treat patients with CFTR class II mutations. Numerous CFTR correctors have been described in the literature and patents. Some of these correctors—alone and / or in combination with other CFTR modulators—have been used in clinical trials in patients with CF, such as VX-809 (lumacaftor), VX-661 (tezacaftor), ABBV-2222 (galicaftor), VX-445 (elexacaftor), VX-659 (bamocaftor), VX-440 (olacaftor), VX-121 (vanzacaftor), ABBV-C2 correctors—ABBV-119 and ABBV-567, and PTI-801 (posenacaftor, CAS 2095064-05-2; WO 2019 / 071078, a compound of Example 2). Similarly, numerous potentiators have been described in the literature and patents. Some of these potentiators—alone and / or in combination with other CFTR modulators—have been used in / are being used in clinical trials in patients with CF, such as VX-770 (ivacaftor), VX-561 (deutivacaftor), GLPG-1837, GLPG-2451, ABBV-3067 (navocaftor), and QBW-251 (icenticaftor). The CFTR potentiator / activator VSJ-110 (CFTRact-K267) is being tested in allergic conjunctivitis (Phase 2), a disease characterized by corneal epithelial inflammation, and is believed to benefit from wild-type CFTR activation.

[0008] CFTR correctors have been identified as being further subdivided based on their mechanisms: correctors that act additively or synergistically must have distinct, i.e., complementary, mechanisms of action, likely due to different binding sites on the CFTR protein. Conversely, correctors that act competitively may share the same CFTR binding sites (Okiyoneda 2013, Veit 2018, Veit 2020, Fiedorczuk 2022; Marchesin 2023). Therefore, structure-related correctors VX-809 (lumacaftor), VX-661 (tezacaftor), and ABBV-2222 (galicaftor) have been classified as Type I correctors, Corrector 4a and related compounds have been classified as Type II correctors, and VX-445 (elexacaftor) has been described as a Type III corrector. This also applies to structure-related correctors VX-440 (olacaftor), VX-659 (bamocaftor), and VX-121 (vanzacaftor). ABBV-C2 correctors ABBV-119 and ABBV-567 may also be Type III correctors. PTI-801 may be another Type III corrector. Due to the additive nature of their effects, corrective agents with different mechanisms are being used in combination in clinical practice to achieve greater corrective efficacy together with synergists.

[0009] VX-770 (ivacaftor, KALYDECO, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, CAS 873054-44-5, e.g. WO2006 / 002421, WO2011 / 072241, WO2007 / 079139, WO2007 / 134279, WO2010 / 019239, WO2013 / 130669) is a CFTR enhancer and the first approved CFTR modulator (US and EU: first approved in 2012) for the treatment of CF patients aged 4 months and older with CFTR gene mutations that respond to KALYDEKO based on clinical and / or in vitro assay data. The current VX-770 USPI (December 2020) lists 97 eligible CFTR mutations. VX-770 is also part of ORKAMBI (a combination of VX-809 and VX-770), SYMDEKO / SYMKEVI (a combination of VX-661 and VX-770), and TRIKAFTA / KAFTRIO (a combination of VX-661, VX-445, and VX-770), as described below.

[0010] VX-809 (lumacaftor, 3-[6-({[1-(2,2-difluoro-1,3-benzodioxane-5-yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, CAS) 936727-05-8, such as WO2007 / 056341, WO2009 / 073757, WO2009 / 076141, WO2010 / 037066, WO2011 / 127241), is a type I CFTR corrector and was approved in the United States (2014) and the European Union (2015) as part of ORKAMBI, a combination product of lumacaftor and the CFTR enhancer ivacaftor, for the treatment of cystic fibrosis (CF) patients aged 2 years and older who are homozygous for the F508del mutation in the CFTR gene.

[0011] VX-661 (tezacaftor, 1-(2,2-difluoro-2H-1,3-benzodioxane-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropyl-2-yl)-1H-indol-5-yl}cyclopropane-1-carboxamide, CAS 1152311-62-0, e.g. WO2007 / 117715, WO2011 / 119984, WO2014 / 014841) is a type I CFTR corrector and was approved in the United States (2018) as part of SYMDEKO and in the European Union (2018) as part of SYMKEVI. SYMDEKO / SYMKEVI is a combination product of tezacaftor and the CFTR potentiator ivacaftor, for the treatment of cystic fibrosis (CF) patients aged 6 years and older who are homozygous for the F508del mutation in the CFTR gene or have at least one CFTR gene mutation that responds to tezacaftor / ivacaftor based on in vitro data and / or clinical evidence. The current SYMDEKO USPI (June 2022) lists 154 eligible CFTR mutations.

[0012] VX-445 (elexacaftor, N-(1,3-dimethyl-1H-pyrazole-4-sulfonyl)-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazole-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1-yl]pyridine-3-carboxamide, CAS 2216712-66-0, e.g. WO2016 / 057572, WO2018 / 107100, WO2019 / 152940) is a type III CFTR corrector and was approved in the United States (2019) as part of TRIKAFTA and in the European Union (2020) as part of KAFTRIO. TRIKAFTA / KAFTRIO is a combination product of elexacaftor, the type I CFTR corrector tezacaftor, and the CFTR potentiator ivacaftor, for the treatment of cystic fibrosis (CF) patients aged 6 years and older with at least one F508del mutation in the CFTR gene or a CFTR gene mutation that has responded based on in vitro data. The current TRIKAFTA USPI (October 2021) lists 178 eligible CFTR mutations.

[0013] ABBV-2222 (GLPG-2222, (galicaftor)), 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxane-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromene-2-yl]benzoic acid; CAS 1918143-53-9, e.g. WO2016 / 069757) is a type I CFTR corrector currently in an open-label phase II trial (NCT03969888) in combination with the CFTR enhancer ABBV-3067 (see below). The study enrolled 78 CF patients aged 18 years and older who were homozygous for the F508del-CFTR mutation.

[0014] ABBV-3067 (navocaftor, GLPG-3067, (5-(3-amino-5-((4-(trifluoromethoxy)phenyl)sulfonyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methanol, CAS 2159103-66-7, e.g. WO2017 / 208115) is a CFTR synergist currently undergoing Phase II trials in combination with galicaftor, as described above (NCT03969888).

[0015] 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 enhancer that was tested in a placebo-controlled phase I / II study in a cohort of CF patients aged 18 years and older who carried a CFTR class III or IV mutation (i.e., a mutation on the cell surface that can benefit from the enhancement) in one allele (NCT02190604).

[0016] VX-121 (vanzacaftor, (14S)-8-[3-(2-{dispiro[2.0.2.1]hept-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ6-thia-3,9,11,18,23-pentazatetracyclo[17.3.1.111,14.05,10]tetracoc-1(22),5,7,9,19(23),20-hexaen-2,2,4-trione, CAS) 2374124-49-7, such as WO2019 / 161078 and WO2021 / 030552, is a type III CFTR corrector that is currently being tested in two active-controlled, double-blind, randomized phase III clinical trials in patients with CF as part of a new triple combination containing vanzacaftor, the type I corrector tezacaftor, and the CFTR potentiator VX-561 (deutivacaftor, the deuterated form of ivacaftor).

[0017] VX-561 (deutivacaftor, N-[2-tert-butyl-4-[1,1,1,3,3,3-hexadeutero-2-(trideuteromethyl)propyl-2-yl]-5-hydroxyphenyl]-4-oxo-1H-quinoline-3-carboxamide, CTP-656, name, CAS1413431-07-8, e.g. WO2019 / 109021, WO2019 / 018395) is the deuterated form of ivacaftor for once-daily administration.

[0018] The ability of CFTR correctors such as lumacaftor, tezacaftor, galicaftor, Corr4a, elexacaftor, and bamocaftor to restore the folding of mutant CFTR (especially F508del-CFTR) and its transport to the cell surface has been analyzed in vitro (Van Goor 2011, Okiyoneda 2013, Veit 2018, Keating 2018, Davies 2018). Transport to the cell surface can be analyzed using various assays, including anti-CFTR immunoblotting (CFTR "C-bands" represent mature transported CFTR), anti-CFTR cell surface ELISA, enzyme fragment complementation techniques, or CFTR-HRP fusion proteins expressed in recombinant cell lines or primary cells from CF patients. Importantly, combinations of correctors with different types of corrector mechanisms showed an additive effect in increasing F508del-CFTR cell surface expression. For example, elexacaftor + / - tezacaftor (type III corrector + / - type I corrector; Keating 2018, Veit 2020) or bamocaftor + / - tezacaftor (type III corrector + / - type I corrector; Davies 2018) or type I + type II + type III corrector (Veit, 2018) all demonstrate this.

[0019] Mutated CFTRs transported to the cell surface may still exhibit gating defects, and the function of cell surface F508del-CFTRs has been shown to be significantly enhanced upon the addition of potentiators. Various functional assays are available for analyzing CFTR function. For example, cellular expression of halide-sensitive yellow fluorescent protein can be used to measure iodide influx through functional CFTRs (Galietta 2001). Furthermore, electrophysiological measurements using the using chamber and reconstructed epithelial cells or reconstructed bronchial epithelium from CF patients can be used to characterize the effects of CFTR modulators on CFTR function. For instance, the addition of the potentiator ivacaftor to lumacaftor-corrected F508del-CFTRs has been shown to nearly double CFTR function in reconstructed bronchial epithelium from CF patients (van Goor 2011), consistent with clinical trial data showing improved FEV1 following the addition of ivacaftor in lumacaftor-treated patients (Boyle 2014). Similarly, using the Ussing chamber readings again, the additive effect of type I corrector tezacaftor and type III corrector elexacaftor on F508del-CFTR function correction was demonstrated in the reconstructed CF bronchial epithelium, with a further approximately 2-fold enhancement of function upon the addition of the potentiator ivacaftor. Furthermore, the additive effect of type III corrector elexacaftor on F508del-CFTR function in combination with type I corrector tezacaftor and potentiator ivacaftor was also demonstrated (Keating 2018). The latter comparison is consistent with clinical trial data in F508del-CFTR homozygous patients, where the addition of elexacaftor to tezacaftor + ivacaftor (SYMDEKO) as a base therapy resulted in a 10% increase in ppFEV1 (Keating 2018). The FDA has recognized the predictive power of in vitro studies for the clinical efficacy of CFTR modulators and has approved CFTR modulators for rare CFTR mutations solely based on in vitro evidence (Ussing chamber measurements in Fisher rat thyroid epithelial cells expressing recombinant mutant CFTR; uspi SYMDEKO, uspi KALYDEKO, uspi TRIKAFTA).

[0020] Despite the availability of various CFTR modulators with complementary mechanisms of action for many common mutations, CFTR function in patients is not fully restored (as evidenced by persistently elevated sweat chloride levels), nor is lung function fully restored. These findings highlight the need for additional, novel, and highly effective CFTR corrector mechanisms that can be used alone or on top of existing or future background therapies (i.e., SYMDEKO, ORKAMBI, TRIKAFTA, or [galicaftor + navocaftor], and optional further background therapies), and combinations thereof could enhance the efficacy of such CFTR modulator treatments. Detailed Implementation

[0021] Compounds of formula (I) as defined below have been found to have potential as CFTR correctors with novel mechanisms (i.e., non-type I, non-type II, non-type III correctors) in the prevention and treatment of CFTR-related diseases and conditions, particularly cystic fibrosis, when combined with CFTR correctors with alternative mechanisms (such as type I correctors (lumacaftor, tezacaftor, galicaftor)) and / or type II correctors (Corrector4a) and / or type III correctors (elexacaftor, bamocaftor, olacaftor, vanzacaftor)). When combined with ABBV-119, ABBV-567 and / or CFTR potentiators (ivacaftor, navocaftor, icenticaftor, deutivacaftor, GLPG-1837, GLPG2451), these combinations may have complementary or even synergistic effects in the treatment of CFTR-related diseases and conditions, particularly cystic fibrosis. Therefore, such combinations may be particularly useful in the treatment of cystic fibrosis. When measured in reconstructed tissue from CF patients carrying the F508del-CFTR mutation via the Using Chamber, compounds of formula (I) restored CFTR function in both the absence and presence of potentiators.

[0022] This invention provides macrocyclic compounds that function as CFTR modulators. Therefore, these compounds can be used to treat CFTR-related diseases and conditions, particularly cystic fibrosis.

[0023] 1) The first aspect of the present invention relates to compounds of formula (I). Formula (I) in R 1 Represents C1₋4-alkyl (especially methyl); R 2 Represents C1₋4-alkyl (especially methyl); R 3 Represents C1₋6-alkyl (especially isobutyl); R 4 Representing a 5-membered heteroaryl group (especially isoxazolyl, oxadiazolyl, tetrazolyl, or triazolyl; especially 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 group is unsubstituted, or mono-, di-, or tri-substituted (especially mono- or di-substituted), wherein the substituent is independently selected from C1₋4-alkyl; C1₋4-alkoxy (especially methoxy); C1₋3-fluoroalkyl; C1₋3-fluoroalkoxy; halogen (especially fluorine); cyano; and C3₋6-cycloalkyl (especially cyclopropyl); [especially R 4 Represents 3-methoxy-isoxazol-5-yl, 4-fluoro-3-methoxy-isoxazol-5-yl, 3-methoxy-1,2,4-oxadiazol-5-yl, 5-cyclopropyl-2H-tetrazole-2-yl or 4-methoxy-2H-1,2,3-triazol-2-yl; W represents -CH2- or -CH2-CH2- [especially W represents -CH2-]; Z represents -CH2-, -CH2-CH2-, or -CH2-O- The asterisk (*) indicates a relationship with -CR. 5 Connected bonds; [especially Z represents -CH2- or -CH2-O-] ]; R 5 Represents halogens (especially fluorine or chlorine), C1₋4-alkyl (especially methyl), C1₋4-fluoroalkyl (especially C1-fluoroalkyl; especially trifluoromethyl) or C1₋4-alkoxy (especially methoxy); Ar 1 represent: ● 6-Hyperarylene (especially pyridin-3,4-diyl); wherein the 6-Hyperarylene is mono-, di-, or tri-substituted (especially di-substituted), wherein the substituent is independently selected from C1₋4-alkyl (especially methyl), C1₋4-alkoxy (especially methoxy), C1₋3-fluoroalkyl, C1₋3-fluoroalkoxy, cyano, and halogen; [especially such Ar 1 [Represents 2-methoxy-6-methylpyridine-3,4-diyl]; or ●8- to 10-membered bicyclic heteroarylene (especially 10-membered bicyclic heteroarylene; especially isoquinoline-5,6-diyl or quinoline-5,6-diyl); wherein the 8- to 10-membered bicyclic heteroarylene is unsubstituted, or mono- or di-substituted (especially mono-substituted), wherein the substituent is independently selected from C1₋4-alkyl (especially methyl), C1₋3-fluoroalkyl, C1₋4-alkoxy, C1₋3-fluoroalkoxy, cyano, and halogen (especially fluorine); [especially such Ar 1 [Represents 3-methyl-isoquinoline-5,6-diyl or 3-fluoro-quinoline-5,6-diyl]; [It should be understood that in the above Ar] 1 In the group, the -CO- group and the oxygen atom (i.e., the Ar atom) 1 (The groups of the rest of the molecule) are connected to Ar in an ortho-position arrangement. 1 On the carbon atom of the aromatic ring, as described in formula (I); and Ar 2 Represents a phenyl group, or a 5- or 6-membered heteroaryl group (especially pyridinyl or pyrimidinyl; especially pyridin-2-yl, pyrimidin-2-yl, or pyrimidin-4-yl), wherein the phenyl or 5- or 6-membered heteroaryl group is unsubstituted, or mono- or di-substituted (especially unsubstituted or mono-substituted), wherein the substituent is independently selected from C1₋4-alkyl (especially methyl), C1₋3-fluoroalkyl, halogen, cyano, C3₋6-cycloalkyl, C1₋4-alkoxy (especially methoxy), and C1₋3-fluoroalkoxy; [especially Ar 2 Represents phenyl, 4-methylpyridin-2-yl, 4-methoxypyridin-2-yl, 6-methoxypyridin-2-yl, 4-methoxypyrimidin-2-yl or 6-methoxypyrimidin-4-yl.

[0024] Compounds of formula (I) contain at least four stereocenters or asymmetric centers, which are present in (R)- or (S)-configurations, as defined in the various embodiments defining such compounds of formula (I). Furthermore, compounds of formula (I) may contain one or more other stereocenters or asymmetric centers, such as one or more additional asymmetric carbon atoms. Therefore, compounds of formula (I) can exist as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers can be separated in a manner known to those skilled in the art.

[0025] Compounds of formula (I) may further encompass compounds having one or more double bonds, which may be in Z- and E- configurations, and / or compounds having substituents on the ring system, which may be in cis- and trans- configurations relative to each other.

[0026] If a particular compound (or general structure) is designated as an (R)- or (S)- enantiomer, such designation should be understood as referring to the corresponding compound (or general structure) enriched in enantiomeric form, particularly in substantially pure enantiomeric form. Similarly, if a particular asymmetry center in a compound is designated as an (R)- or (S)- configuration or a particular relative configuration, such designation should be understood as referring to the compound enriched in, particularly in substantially pure form with respect to the corresponding configuration of said asymmetry center. Likewise, cis- or trans- designation should be understood as referring to the enriched in, particularly in substantially pure form of the stereoisomer of the corresponding relative configuration. Likewise, if a particular compound (or general structure) is designated as a Z- or E- stereoisomer (or if a particular double bond in a compound is designated as a Z- or E- configuration), such designation should be understood as referring to the corresponding compound (or general structure) enriched in, particularly in substantially pure stereoisomeric form (or referring to the compound enriched in, particularly in substantially pure form with respect to the corresponding configuration of the double bond).

[0027] In the context of this invention, when used in the context of stereoisomers, the term “enriched” should be understood to mean that, relative to the corresponding other stereoisomers / the whole of the corresponding other stereoisomers, the corresponding stereoisomers are present in a ratio of at least 70:30, and in particular at least 90:10 (i.e., with a purity of at least 70% by weight, and in particular at least 90% by weight).

[0028] In the context of this invention, when used in the context of stereoisomers, the term "substantially pure" should be understood to mean that, relative to the corresponding other stereoisomer / the whole of the corresponding other stereoisomers, the corresponding stereoisomer exists with a purity of at least 95% by weight, particularly at least 99% by weight.

[0029] The present invention also includes isotopic labeling of compounds of formula (I) according to embodiments 1) to 10), particularly 2 H (deuterium) labeled compounds, which are identical to compounds of formula (I), except that one or more atoms are each replaced by atoms having the same atomic number but with a different atomic mass than those commonly found in nature. Isotope labeling, especially 2 Compounds of formula (I) labeled with H (deuterium) and their salts are within the scope of this invention. If a substituent is specifically indicated to represent hydrogen, it should be understood to refer to all isotopes of the atom "H," i.e., the term hydrogen used for a substituent should be understood to include isotopes. 2 H (deuterium); preferably, it refers to isotopes 1 H (hydrogen). Using heavier isotopes. 2Replacing hydrogen with H (deuterium) can lead to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, or can lead to reduced inhibition of cytochrome P450 enzymes, such as resulting in improved safety profiles. In one embodiment of the invention, the compound of formula (I) is unlabeled or labeled only with one or more deuterium atoms. In a sub-implementation, the compound of formula (I) is not labeled at all. Isotopically labeled compounds of formula (I) can be prepared similarly to the methods described below, but using suitable reagents or appropriate isotopic variants of the starting materials.

[0030] In this patent application, the bonds drawn as dashed lines represent the connection sites of the drawn groups. For example, the groups shown in the figure below... It is 4-methyl-pyridin-2-yl.

[0031] When compounds, salts, pharmaceutical compositions, diseases, etc., are used in the plural form, this is intended to also refer to a single compound, salt, etc.

[0032] Any reference to compounds of formula (I) according to embodiments 1) to 10) shall be understood to refer to compounds in the form of free bases or salts, and therefore, where appropriate and convenient, also to salts of such compounds (especially pharmaceutically acceptable salts).

[0033] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the target compound and exhibits minimal undesirable toxicological effects. Depending on the presence of basic and / or acidic groups in the target compound, such salts include inorganic or organic acid and / or base addition salts. 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 Quéré (eds.), RSC Publishing, 2012.

[0034] The definitions provided herein are intended to be uniformly applied to compounds of formula (I) as defined in any of embodiments 1) through 10), and are subject to necessary modifications throughout the specification and claims, unless otherwise expressly stated that a broader or narrower definition is provided. It is well understood that the definitions or preferred definitions of terms are defined independently (in combination with any or all other definitions or preferred definitions of terms herein) and may substitute for the corresponding terms.

[0035] Whenever a substituent is indicated as optional, it should be understood that such a substituent may be absent (i.e., the corresponding residue is unsubstituted with respect to such optional substituent), in which case all positions with free valence (to which such optional substituent may be attached; for example, in an aromatic ring, the cyclic carbon atom and / or cyclic nitrogen atom with free valence) are substituted with hydrogen where appropriate. Similarly, if the term “optionally” is used in the context of (cyclic) heteroatoms, it means that the corresponding optional heteroatom, etc., is absent (i.e., a portion does not contain heteroatoms / is a carbocyclic ring, etc.), or that the corresponding optional heteroatom, etc., is present, as explicitly defined.

[0036] The term "halogen" refers to fluorine / fluorinated, chlorine / chlorinated, or bromine / bromine; preferably fluorine / fluorinated or chlorine / chlorinated.

[0037] The term "alkyl," used alone or in combination, refers to a saturated straight-chain or branched hydrocarbon group containing 1 to 6 carbon atoms. The term "C x-y "-alkyl" (where x and y are integers) refers to an alkyl group containing x to y carbon atoms as defined above. For example, C1₋6-alkyl contains 1 to 6 carbon atoms. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 3-methylbutyl, 2,2-dimethylpropyl, and 3,3-dimethylbutyl. For the avoidance of doubt, if a group is referred to as, for example, propyl or butyl, it means n-propyl or n-butyl. If R 1 If it represents C1₋4-alkyl, then the term specifically refers to C1₋3-alkyl, particularly methyl. For R representing C1₋4-alkyl... 2 The term specifically refers to C1₋3-alkyl, particularly methyl. If R 3 When R represents C1₋6-alkyl, the term specifically refers to C3₋5-alkyl, particularly isobutyl. For R representing C1₋4-alkyl... 5 The term specifically refers to C1₋3-alkyl, particularly methyl. For Ar 1 The term refers to C1₋4-alkyl substituents, particularly C1₋3-alkyl, especially methyl. For Ar... 2 The term refers to C1₋4-alkyl substituents, particularly C1₋3-alkyl, especially methyl.

[0038] Term "C" x "-y-alkylene" is used alone or in combination to refer to a divalently linked alkyl group containing x to y carbon atoms as defined above. Preferably, the linkage sites of the C1-y-alkylene are arranged in a 1,1-diyl, 1,2-diyl, or 1,3-diyl configuration.

[0039] The term "alkoxy," used alone or in combination, refers to an alkyl-O- group, wherein the alkyl group is as defined above. The term "C"x-y -alkoxy (where x and y are integers) refers to an alkoxy group containing x to y carbon atoms as defined above. For example, C1₋4-alkoxy refers to a group of the formula C1₋4-alkyl-O-, where the term "C1₋4-alkyl" has the meaning as described above. Representative examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Methoxy is preferred. For R 4 The term refers to the C1₋4-alkoxy group with substituents, particularly C1₋3-alkoxy, and especially methoxy. For R representing a C1₋4-alkoxy group... 5 The term specifically refers to C1₋3-alkoxy, particularly methoxy. For Ar... 1 The C1₋4-alkoxy group of the substituent, this term particularly refers to the C1₋3-alkoxy group, especially the methoxy group. For Ar... 2 The C1₋4-alkoxy group of the substituent, the term specifically refers to the C1₋3-alkoxy group, especially the methoxy group.

[0040] The term "fluoroalkyl," used alone or in combination, refers to an alkyl group containing 1 to 3 carbon atoms as defined above, wherein one or more (and possibly all) hydrogen atoms have been replaced by fluorine. The term "C x-y "-Fluoroalkyl" (where x and y are integers) refers to a fluoroalkyl group containing x to y carbon atoms as defined above. For example, a C1₋3-fluoroalkyl group contains 1 to 3 carbon atoms, of which 1 to 7 hydrogen atoms have been replaced by fluorine. Representative examples of fluoroalkyl groups include, in particular, C1-fluoroalkyl groups such as trifluoromethyl and difluoromethyl, and 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. If R 5 The term refers specifically to C1-fluoroalkyl, particularly trifluoromethyl.

[0041] The term "cycloalkyl," used alone or in combination, refers to a saturated monocyclic hydrocarbon ring containing 3 to 6 carbon atoms. The term "C"... x-y -Cycloalkyl (where x and y are integers) refers to a cycloalkyl group containing x to y carbon atoms as defined above. For example, C3₋6-cycloalkyl groups contain 3 to 6 carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, especially cyclopropyl. For R 4 The term refers to C3₋6-cycloalkyl substituents, particularly cyclopropyl.

[0042] The term "aryl," used alone or in combination, refers to phenyl or naphthyl, especially phenyl. The aforementioned aryl groups are either unsubstituted or substituted as explicitly defined.

[0043] It should be understood that a heterocycle, such as “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, unless otherwise explicitly stated, with the remaining ring atoms being carbon atoms.

[0044] The term "heteroaryl," used alone or in combination, and unless explicitly defined in a broader or narrower manner, refers to 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, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrroleyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl; 6-membered heteroaryl groups, such as pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl; and 8- to 10-membered bicyclic heteroaryl groups, such as indolyl, isoyindolyl, benzofuranyl, isobenzofuranyl, and benzothiophene. The following are listed: alkyl, indazole, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisoxathiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridyl, quinolinyl, isoquinolinyl, naphridyl, cenolinyl, quinazolinyl, quinoxolinyl, phthalazinyl, pyrrolopyridyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyridyl, imidazopyridazinyl, and imidazothiazolyl. The above heteroaryl groups are either unsubstituted or substituted as explicitly defined.

[0045] For R, which represents "5-membered heteroaryl", 4 The term specifically refers to the aforementioned 5-membered groups, such as, in particular, triazolyl, tetrazolyl, isoxazolyl, and oxadiazolyl. Specifically, the term refers to 5-membered groups, such as, in particular, isoxazol-5-yl, 1,2,4-oxadiazol-5-yl, 2H-tetrazole-2-yl, and 2H-1,2,3-triazol-2-yl. These groups are substituted as explicitly defined.

[0046] The term "x to y-membered heteroarylene," used alone or in combination, refers to a divalently linked heteroarylene containing x to y ring atoms as defined above. Preferably, the linking sites of the x to y-membered heteroarylene are arranged in a 1,1-diyl, 1,2-diyl, or 1,3-diyl configuration.

[0047] Specific examples of segments: These are pyridine-diyl, isoquinoline-diyl, and quinoline-diyl, particularly pyridine-3,4-diyl, isoquinoline-5,6-diyl, and quinoline-5,6-diyl. This class of Ar... 1 The groups are either unsubstituted or substituted as explicitly defined.

[0048] For Ar, which represents "5- or 6-membered heteroaryl", 2The term specifically refers to a 6-membered heteroaryl group, particularly pyridinyl or pyrimidinyl, especially pyridin-2-yl, pyrimidin-2-yl or pyrimidin-4-yl, especially pyridin-2-yl or pyrimidin-2-yl.

[0049] The term "cyano" refers to the -CN group.

[0050] Whenever "between" is used to describe a range of values, it should be understood that the endpoints of the range are explicitly included within that range. For example, if a temperature range is described as being between 40°C and 80°C, it means that the endpoints 40°C and 80°C are included within that range; or if a variable is defined as an integer between 1 and 4, it means that the variable is an integer 1, 2, 3, or 4.

[0051] Unless used for temperature, the term "about" preceding the numerical value "X" in this application refers to the range from X minus 10% of X to X plus 10% of X, preferably from X minus 5% of X to X plus 5% of X. In the specific case of temperature, the term "about" preceding the temperature "Y" in this application refers to the range from temperature Y minus 10°C to Y plus 10°C, preferably from Y minus 5°C to Y plus 5°C. Furthermore, the term "room temperature" as used herein refers to a temperature of approximately 25°C.

[0052] To avoid any doubt, the corresponding structures of the above compounds are shown in Table 3 below. In case of any discrepancy, the structures shown shall prevail.

[0053] Therefore, the compound of Example 1, for example: (3S,7S,10R,13R)-13-benzyl-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide, has the structure shown in Table 3, wherein the compound exhibits the absolute configuration shown in the drawing: Right now .

[0054] Other embodiments of the present invention are given below: 2) The second aspect relates to a compound of formula (I) according to embodiment 1), wherein the compound is of formula (I) E Compounds: Formula (I E ).

[0055] 3) Another embodiment involves a compound according to embodiment 1) or 2), wherein R 4 Representing a 5-membered heteroaryl group (especially isoxazolyl, oxadiazolyl, tetrazolyl, or triazolyl; especially 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 group is mono- or di-substituted (especially mono-substituted), wherein the substituent is independently selected from C1₋4-alkoxy (especially methoxy); halogen (especially fluorine); and C3₋6-cycloalkyl (especially cyclopropyl); [especially R 4 Represents 3-methoxy-isoxazol-5-yl, 4-fluoro-3-methoxy-isoxazol-5-yl, 3-methoxy-1,2,4-oxadiazol-5-yl, 5-cyclopropyl-2H-tetrazole-2-yl or 4-methoxy-2H-1,2,3-triazol-2-yl; W stands for -CH2-; Z represents -CH2- or -CH2-O- ; R 5 Represents halogens (especially fluorine or chlorine), C1₋4-alkyl (especially methyl), C1₋4-fluoroalkyl (especially C1-fluoroalkyl; especially trifluoromethyl) or C1₋4-alkoxy (especially methoxy); Ar 1 represent: ● 6-Hyperarylene (especially pyridine-3,4-diyl); wherein the 6-Hyperarylene is di-substituted, wherein the substituent is independently selected from C1₋4-alkyl (especially methyl) and C1₋4-alkoxy (especially methoxy); [especially such Ar 1 [Represents 2-methoxy-6-methylpyridine-3,4-diyl]; or ● 10-membered bicyclic heteroarylene (especially isoquinoline-5,6-diyl or quinoline-5,6-diyl); wherein the 10-membered bicyclic heteroarylene is mono-substituted by a C1₋4-alkyl (especially methyl) or a halogen (especially fluorine); [especially such Ar 1 [Represents 3-methyl-isoquinoline-5,6-diyl or 3-fluoro-quinoline-5,6-diyl]; [It should be understood that in the above Ar] 1 In the group, the -CO- group and the oxygen atom (i.e., the Ar atom) 1 (The groups of the rest of the molecule) are connected to Ar in an ortho-position arrangement. 1 On the carbon atom of the aromatic ring, as described in formula (I); and Ar 2Represents a phenyl or 6-membered heteroaryl group (especially pyridyl or pyrimidinyl; especially pyridin-2-yl, pyrimidin-2-yl, or pyrimidin-4-yl), wherein the phenyl or 6-membered heteroaryl group is unsubstituted or mono-substituted with a C1₋4-alkyl (especially methyl) or C1₋4-alkoxy (especially methoxy); [especially Ar 2 Represents phenyl, 4-methylpyridin-2-yl, 4-methoxypyridin-2-yl, 6-methoxypyridin-2-yl, 4-methoxypyrimidin-2-yl or 6-methoxypyrimidin-4-yl.

[0056] 4) Another embodiment relates to a compound according to any one of embodiments 1) to 3), wherein R 4 Representing a 5-membered heteroaryl group (especially isoxazolyl, oxadiazolyl, or tetrazolyl; especially isoxazol-5-yl, 1,2,4-oxadiazol-5-yl, or 2H-tetrazol-2-yl), wherein said 5-membered heteroaryl group is mono-substituted by a C1₋4-alkoxy (especially ethoxy) or C3₋6-cycloalkyl (especially cyclopropyl); [especially R 4 Represents 3-methoxy-isoxazol-5-yl, 3-methoxy-1,2,4-oxadiazol-5-yl, or 5-cyclopropyl-2H-tetrazole-2-yl.

[0057] 5) Another embodiment relates to a compound according to any one of embodiments 1) to 4), wherein R 5 Represents halogens (especially fluorine) or C1₋4-fluoroalkyl groups (especially C1-fluoroalkyl groups; especially trifluoromethyl groups).

[0058] 6) Another embodiment relates to a compound according to any one of embodiments 1) to 4), wherein the fragment represent: ; ; ; ; ; ; ; ;or ;in particular ; ; ;or .

[0059] 7) Another embodiment relates to a compound according to any one of embodiments 1) to 6), wherein Ar 1 represent: ● 6-Hyperarylene (especially pyridine-3,4-diyl); wherein the 6-Hyperarylene is di-substituted, wherein the substituent is independently selected from C1₋4-alkyl (especially methyl) and C1₋4-alkoxy (especially methoxy); [especially such Ar 1 [Represents 2-methoxy-6-methylpyridine-3,4-diyl]; or ● 10-membered bicyclic heteroarylene (especially quinoline-5,6-diyl); wherein the 10-membered bicyclic heteroarylene is mono-substituted with a halogen (especially fluorine); [especially such Ar 1 [Represents 3-fluoro-quinoline-5,6-diyl]; [It should be understood that in the above Ar] 1 In the group, the -CO- group and the oxygen atom (i.e., the Ar atom) 1 (The groups of the rest of the molecule) are connected to Ar in an ortho-position arrangement. 1 On the aromatic ring carbon atom, as depicted in formula (I).

[0060] 8) Another embodiment relates to a compound according to any one of embodiments 1) to 7), wherein Ar 2 represent: ●Phenyl; or ● 6-Hyperaryl (especially pyridyl or pyrimidinyl; especially pyridin-2-yl or pyrimidin-2-yl); wherein the 6-Hyperaryl is mono-substituted by a C1₋4-alkoxy (especially methoxy); [Especially Ar] 2 Represents phenyl, 4-methoxy-pyridin-2-yl, 6-methoxy-pyridin-2-yl or 4-methoxy-pyrimidin-2-yl.

[0061] 9) Therefore, the present invention relates to compounds of formula (I) as defined in embodiment 1), or such compounds further defined by the features of any one of embodiments 2) to 8), while taking into account their respective dependencies; to pharmaceutically acceptable salts thereof; and to the use of such compounds as medicines, particularly in the treatment of CFTR-related diseases and conditions (including cystic fibrosis) as described below.For the avoidance of doubt, embodiments relating to compounds of formula (I) are therefore possible and contemplated, and are specifically disclosed herein in individual 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.

[0062] In the list above, numbers refer to implementation schemes according to the numbers provided above, while "+" indicates a dependency on another implementation scheme. Different individualized implementation schemes are separated by commas. In other words, for example, "8+7+3+2+1" refers to implementation scheme 8) which references implementation scheme 7), implementation scheme 7) which references implementation scheme 3), implementation scheme 3) which references implementation scheme 2), and implementation scheme 2) which references implementation scheme 1), that is, implementation scheme "8+7+3+2+1" corresponds to compound of formula (I) according to implementation scheme 8), which is further restricted by all the features of implementation schemes 1), 2), 3) and 7).

[0063] 10) Another embodiment relates to a compound of formula (I) according to embodiment 1), which is selected from the following compounds: (3S,7S,10R,13R)-13-benzyl-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-10-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9,20-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-10-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,20-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-10-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-7-isobutyl-6,9,20-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-N-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-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-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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)-10-((3-methoxybicyclo[1.1.1]pent-1-yl)methyl)-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-7-isobutyl-10-((3-methoxybicyclo[1.1.1]pent-1-yl)methyl)-N-(2-(3-methoxyisoxazo-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-7-isobutyl-10-((3-methoxybicyclo[1.1.1]pent-1-yl)methyl)-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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]pent-1-yl)methyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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-dimethyl-10-((3-methylbicyclo[1.1.1]pent-1-yl)methyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-7-isobutyl-13-((6-methoxypyridin-2-yl)methyl)-6,9-dimethyl-10-((3-methylbicyclo[1.1.1]pent-1-yl)methyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-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-10-((3-methylbicyclo[1.1.1]pent-1-yl)methyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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-dimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-7-isobutyl-13-((6-methoxypyridin-2-yl)methyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-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)bicyclo[1.1.1]pent-1-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-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]hex-4-yl)methyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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]hex-4-yl)methyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-10-((1-methyl-2-oxabicyclo[2.1.1]hex-4-yl)methyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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]hex-4-yl)methyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-10-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-13-((6-methoxypyridin-2-yl)methyl)-6,9,20-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-10-((3-methoxybicyclo[1.1.1]pent-1-yl)methyl)-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-10-((3-methoxybicyclo[1.1.1]pent-1-yl)methyl)-N-(2-(3-methoxyisoxazo-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-10-((3-chlorobicyclo[1.1.1]pent-1-yl)methyl)-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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]hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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)methyl)-7,10,18-trimethyl-5,8,11,15-tetraoxo-6-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecanopyrido[3,4-p][1]oxa[4,7,10,14]tetraazacycloheptadecene-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-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecanopyrido[3,4-p][1]oxa[4,7,10,14]tetraazacycloheptadecene-13-carboxamide; (3R,6R,9S,13S)-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-9-isobutyl-16-methoxy-3-((6-methoxypyridin-2-yl)methyl)-7,10,18-trimethyl-5,8,11,15-tetraoxo-6-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecanopyrido[3,4-p][1]oxa[4,7,10,14]tetraazacycloheptadecene-13-carboxamide; (3S,7S,10R,13R)-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-7-isobutyl-13-((6-methoxypyridin-2-yl)methyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-((1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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-dimethyl-1,5,8,11-tetraoxo-10-((1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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-1,5,8,11-tetraoxo-10-((1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-10-((1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-((1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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)methyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-((1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-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-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-7-isobutyl-13-((4-methoxypyridin-2-yl)methyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-((1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-7-isobutyl-N-(2-(3-methoxyisoxazol-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; and (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide.

[0064] Compounds of formula (I) and their pharmaceutically acceptable salts according to embodiments 1) to 10) may be used as medicines, for example in the form of pharmaceutical compositions for intravenous (particularly oral, e.g., in tablet or capsule form) or parenteral (including topical or inhalation) administration.

[0065] 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.

[0066] The preparation of pharmaceutical compositions can be carried out in any manner familiar to those skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]), by combining the compound of formula (I) or a pharmaceutically acceptable salt thereof, optionally with other therapeutically valuable substances, with a suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier material and (if necessary) conventional pharmaceutical adjuvants to form a pharmaceutical dosage form.

[0067] The present invention also relates to methods for preventing / treating the diseases or conditions described herein, comprising administering to a subject a pharmacologically active amount of a compound of formula (I) according to embodiments 1) to 10).

[0068] According to implementation schemes 1) to 10), the compound of formula (I) can be used to treat CFTR-related diseases and conditions, especially cystic fibrosis.

[0069] CFTR-related diseases and conditions can be defined specifically as including cystic fibrosis, as well as other CFTR-related diseases and conditions selected from the following: ● Chronic bronchitis; sinusitis; constipation; pancreatitis; pancreatic insufficiency; male infertility due to congenital bilateral vas deferens agenesis (CBAVD); mild lung disease; allergic bronchopulmonary aspergillosis (ABPA); liver disease; coagulation-fibrinolysis defects, such as protein C deficiency; and diabetes. ●Asthma; COPD; smoke-induced COPD; and dry eye disease; and ● Idiopathic pancreatitis; hereditary emphysema; hereditary hemochromatosis; lysosomal storage diseases, such as, in particular, I-cell pseudo-Hurler disease; mucopolysaccharidosis; Sandhoff / Tay-Sachs disease; osteogenesis imperfecta; Fabry disease; Sjögren's syndrome; osteoporosis; osteopenia; bone healing and bone growth (including bone repair, bone regeneration, reduced bone resorption, and increased bone deposition); chloride channel diseases, such as congenital myotonia (Thomsen and Becker types); Bart syndrome type 3; epilepsy; lysosomal storage diseases; primary ciliary dyskinesia (PCD) – a term used for hereditary disorders of ciliary structure and / or function (including those associated with...) PCD with visceral inversion (also known as Kartagener syndrome), PCD without visceral inversion and ciliary dysplasia; generalized epilepsy with febrile seizures (GEFS+); generalized epilepsy with febrile and afebrile seizures; myotonia; congenital paramyotonia; potassium-induced myotonia; hyperkalemic periodic paralysis; long QT syndrome (LQTS); LQTS / Brugada syndrome; autosomal dominant LQTS with deafness; autosomal recessive LQTS; LQTS with malformation features; congenital and acquired LQTS; dilated cardiomyopathy; autosomal dominant LQTS; osteosclerosis; and Bart syndrome type 3.

[0070] The term “treatment of cystic fibrosis” refers to any treatment for cystic fibrosis, and in particular includes treatments that reduce the severity of cystic fibrosis and / or reduce the symptoms of cystic fibrosis.

[0071] The term "cystic fibrosis" refers to any form of cystic fibrosis, particularly cystic fibrosis associated with one or more gene mutations. Preferably, such cystic fibrosis is associated with CFTR transport defects (class II mutations) or decreased CFTR stability (class VI mutations) [especially CFTR transport defects / class II mutations], where it should be understood that such CFTR transport defects or decreased CFTR stability may be associated with another pathogenic mutation of the same or any other class. Such other pathogenic CFTR gene mutations include class I mutations (non-functional CFTR protein), (another) class II mutations (CFTR transport defects), class III mutations (CFTR regulatory defects), class IV mutations (CFTR conduction defects), class V mutations (CFTR protein reduction due to splicing defects), and / or (another) class VI mutations (CFTR protein reduction due to decreased CFTR stability). The one or more gene mutations may, for example, include at least one mutation selected from F508del, A561E, and N1303K, and I507del, R560T, R1066C, and V520F; particularly F508del. In addition to the above, other CFTR gene mutations include, for example, G85E, R347P, L206W, and M1101K. These mutations can be heterozygous, homozygous, or compound heterozygous. In particular, the mutations are heterozygous and contain an F508del mutation. Other CFTR gene mutations (especially class III and / or IV mutations) include G551D, R117H, D1152H, A455E, S549N, R347H, S945L, and R117C.

[0072] The severity of cystic fibrosis / specific gene mutations associated with cystic fibrosis and the effectiveness of their correction can often be measured by testing CFTR-mediated chloride ion transport. In patients, for example, average sweat chloride ion content can be used for such assessment.

[0073] The term "symptoms of cystic fibrosis" specifically refers to elevated chloride ion concentrations in sweat; symptoms of cystic fibrosis also include chronic bronchitis; sinusitis; constipation; pancreatitis; pancreatic insufficiency; male infertility due to congenital bilateral absence of vas deferens (CBAVD); mild lung disease; allergic bronchopulmonary aspergillosis (ABPA); liver disease; coagulation-fibrinolysis defects, such as protein C deficiency; and / or diabetes.

[0074] For the avoidance of doubt, if a compound is described as being suitable for treating certain diseases, then such compounds are equally suitable for preparing medicaments for treating said diseases. Similarly, such compounds are also suitable for methods of treating such diseases, including administering an effective amount of such compounds to a subject in need.

[0075] The term “subject” as used in this article refers to mammals, particularly humans.

[0076] 12) Another embodiment relates to a pharmaceutical composition according to embodiment 11), wherein the composition further comprises one or more therapeutically active ingredients used as CFTR modifiers; wherein the CFTR modifier is one or more CFTR correctors (particularly type I correctors, and / or type II correctors, and / or type III correctors), and / or CFTR enhancers, and / or CFTR stabilizers; or pharmaceutically acceptable salts thereof.

[0077] 13) Another embodiment relates to a pharmaceutical composition according to embodiment 12), wherein the one or more therapeutically active ingredients used as CFTR modulators are type I correctors selected from lumacaftor, tezacaftor, and galicaftor; and / or type II correctors of Corrector 4a; and / or type III correctors selected from elexacaftor, bamocaftor, olacaftor, and vanzacaftor; and / or CFTR enhancers selected from ivacaftor, navocaftor, icenticaftor, deutivacaftor, GLPG-1837, and GLPG2451; or pharmaceutically acceptable salts thereof.

[0078] 14) Another embodiment relates to a pharmaceutical composition according to embodiment 12), wherein the one or more therapeutically active ingredients used as CFTR modulators are type I correctors selected from lumacaftor, tezacaftor, and galicaftor; and / or type II correctors of Corrector 4a; and / or type III correctors selected from elexacaftor and vanzacaftor; and / or CFTR enhancers selected from ivacaftor, navocaftor, icenticaftor, and deutivacaftor; or pharmaceutically acceptable salts thereof.

[0079] 15) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 12) to 14), wherein the composition comprises a compound of formula (I) and at least one (particularly one) therapeutically active ingredient used as a CFTR modulator, wherein the CFTR modulator is a CFTR enhancer; or a pharmaceutically acceptable salt thereof.

[0080] 16) Another embodiment relates to a pharmaceutical composition according to embodiment 12), wherein the composition comprises a compound of formula (I) and at least one (particularly one) therapeutically active ingredient used as a CFTR modulator, wherein the CFTR modulator is a CFTR enhancer selected from ivacaftor, icenticaftor and deutivacaftor; or a pharmaceutically acceptable salt thereof.

[0081] 17) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 12) to 16), wherein the composition comprises a compound of formula (I) and at least two (particularly two) therapeutically active ingredients used as CFTR modulators, wherein one of the CFTR modulators is a CFTR enhancer or a pharmaceutically acceptable salt thereof, and the second CFTR modulator is a CFTR corrector or a pharmaceutically acceptable salt thereof.

[0082] 18) Another embodiment relates to a pharmaceutical composition according to embodiment 17), wherein the composition comprises a compound of formula (I) and ● Ivacaftor and tezacaftor, or their pharmaceutically acceptable salts; or ● Ivacaftor and lumacaftor, or their pharmaceutically acceptable salts; or ● Navocaftor and galicaftor, or their pharmaceutically acceptable salts.

[0083] 19) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 12) to 18), wherein the composition comprises a compound of formula (I) and three therapeutically active ingredients used as CFTR modulators, wherein one of the CFTR modulators is a CFTR enhancer or a pharmaceutically acceptable salt thereof, the second CFTR modulator is a type I corrector or a pharmaceutically acceptable salt thereof, and the third CFTR modulator is a type III corrector or a pharmaceutically acceptable salt thereof.

[0084] 20) Another embodiment relates to a pharmaceutical composition according to embodiment 19), wherein the composition comprises a compound of formula (I) and ● Ivacaftor, tezacaftor, and elexacaftor, or pharmaceutically acceptable salts thereof; or ● Deutivacaftor, tezacaftor, and vanzacaftor, or pharmaceutically acceptable salts thereof.

[0085] Such combination pharmaceutical compositions according to embodiments 12) to 20) are particularly useful for the prevention or treatment of CFTR-related diseases as defined herein, especially cystic fibrosis; and in a method for the prevention or treatment of CFTR-related diseases as defined herein, especially cystic fibrosis, said method includes administering a pharmacologically effective dose of such combination pharmaceutical composition to a subject (especially a human) in need.

[0086] Therefore, the compound of formula (I) as defined in any one of embodiments 1) to 10) of the present invention, or a pharmaceutically acceptable salt thereof, may be used in combination (or in combination therapy) with other pharmacologically active ingredients as defined herein as CFTR modulators (CFTR correctors and / or CFTR enhancers).

[0087] The definitions provided herein are intended to be uniformly applicable to any of the embodiments 1) through 10), and, with necessary modifications, throughout the specification and claims, unless otherwise expressly stated, provide for a broader or narrower definition. It is readily understood that the definitions or preferred definitions of terms are defined independently (and in combination with any or all other definitions or preferred definitions of terms herein) and may substitute for the corresponding terms.

[0088] The term “therapeutic active ingredient used as a CFTR modulator” refers to any CFTR corrector (particularly type I, type II, or type III correctors) and / or CFTR enhancer that has shown – alone and / or in combination – the potential for therapeutic use (as tested in in vitro and / or in vivo models, particularly in clinical trials) and / or is indicated for such therapeutic use; wherein such therapeutic use is for CFTR-related diseases (particularly cystic fibrosis). Examples include, in particular: CFTR enhancers (ivacaftor, navocaftor, icenticaftor, deutivacaftor, GLPG-1837 and GLPG-2451); and CFTR correctors (Type I correctors (lumacaftor, tezacaftor, galicaftor), Type II correctors (Corrector4a) and Type III correctors (elexacaftor, bamocaftor, olacaftor, vanzacaftor); and ABBV-119, ABBV-567).

[0089] In one sub-implementation, the invention therefore relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1) to 10) for the prevention or treatment of CFTR-related diseases as defined herein, particularly cystic fibrosis; wherein the compound of formula (I) is (intended) to be administered / is administered in combination with a CFTR potentiator, particularly ivacaftor, navocaftor, icenticaftor, or deutivacaftor or a pharmaceutically acceptable salt thereof; optionally additionally, to be (intended) to be administered / is administered in combination with a CFTR corrector, particularly lumacaftor, tezacaftor, galicaftor, elexacaftor, or vanzacaftor or a pharmaceutically acceptable salt thereof.

[0090] The term "subject" refers to mammals, particularly humans.

[0091] Combination therapy (or combination therapy) can be performed, particularly simultaneously (at a fixed dose or at a non-fixed dose).

[0092] "Simultaneously," when referring to a type of administration, means in this application that the type of administration includes administering two or more active ingredients and / or treatments at approximately the same time; wherein it should be understood that simultaneous administration will result in the subject being simultaneously exposed to two or more active ingredients and / or treatments. When administered simultaneously, the two or more active ingredients may be administered in a fixed-dose combination or in a non-fixed-dose combination, wherein such a non-fixed combination may be a non-fixed-dose combination (e.g., using two or more different pharmaceutical compositions administered via 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 administration regimens; wherein in each case, the administration results in the subject being substantially simultaneously exposed 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 administered via the same route of administration at approximately the same time is a non-fixed-dose combination in which the compound of formula (I) as defined in any one of embodiments 1) to 10) is administered twice daily (bid), and the corresponding CFTR modifier is administered twice daily. Another example of concurrent administration of a non-fixed-dose combination using two different routes of administration is a non-fixed-dose combination in which the compound of formula (I) as defined in any one of embodiments 1) to 10) is administered once or twice daily, and the corresponding CFTR modifier is administered three times daily (tid). Another example of concurrent administration of a non-fixed-dose combination using two different routes of administration is a non-fixed-dose combination in which the compound of formula (I) as defined in any one of embodiments 1) to 10) is administered once daily, and the corresponding CFTR modifier is administered twice daily. Another example of concurrent administration of a non-fixed-dose combination using two different routes of administration is a non-fixed-dose combination in which the compound of formula (I) as defined in any one of embodiments 1) to 10) is administered twice daily, and the corresponding CFTR modifier is administered once daily.

[0093] "Fixed-dose combination" as used in this application, when referring to a type of administration, means that the type of administration includes administering a single pharmaceutical composition containing two or more active ingredients, particularly a pharmaceutical composition as described in any one of embodiments 12) to 20).

[0094] 21) Another aspect of the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1) to 10), for the treatment of CFTR-related diseases and conditions, particularly cystic fibrosis; wherein the compound is used / to be administered / dosed in combination with one or more therapeutically active ingredients used as CFTR modulators; wherein the CFTR modulator is one or more CFTR correctors (particularly type I correctors, and / or type II correctors, and / or type III correctors), and / or CFTR enhancers, and / or CFTR stabilizers.

[0095] 22) Another embodiment involves a compound of formula (I) or a pharmaceutically acceptable salt thereof used according to embodiment 21), wherein the CFTR modifier is defined as in any one of embodiments 12) to 20).

[0096] 23) Another embodiment involves a compound of formula (I) or a pharmaceutically acceptable salt thereof used according to embodiment 22), wherein the CFTR modifier is as defined in embodiment 18.

[0097] It should be understood that any embodiment involving the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any of embodiments 1) to 10) for combination therapy of CFTR-related diseases (particularly cystic fibrosis) as defined herein, wherein the compound of formula (I) is intended to be administered in combination with one or more CFTR modulators, wherein the CFTR modulators are CFTR correctors (particularly type I-, type II-, type III- correctors) and / or CFTR enhancers and / or CFTR stabilizers or pharmaceutically acceptable salts thereof, wherein the one or more CFTR modulators are particularly as defined in any of embodiments 12) to 20), and also involves ●A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any of embodiments 1) to 10) is used in combination for the treatment of CFTR-related diseases (particularly cystic fibrosis) as defined herein, wherein the compound of formula (I) is combined with one or more CFTR modulators (intended for administration / dosage); ●The CFTR modulator, as a CFTR corrector and / or CFTR enhancer or a pharmaceutically acceptable salt thereof, is intended for the treatment of the CFTR-related diseases (particularly cystic fibrosis); wherein the CFTR modulator, as a CFTR corrector and / or CFTR enhancer and / or CFTR stabilizer, is intended to be administered in combination with the compound of formula (I); ● Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical / pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and the CFTR modifier or a pharmaceutically acceptable salt thereof as a CFTR corrector and / or CFTR enhancer and / or CFTR stabilizer for the treatment of the CFTR-related diseases (particularly cystic fibrosis); ● Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical / pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient for the treatment of the CFTR-related diseases (particularly cystic fibrosis); wherein the pharmaceutical / pharmaceutical composition is intended to be used in combination with the CFTR modifier or a pharmaceutically acceptable salt thereof as a CFTR corrector and / or CFTR enhancer and / or CFTR stabilizer; ●The use of the CFTR modifier or its pharmaceutically acceptable salt as a CFTR corrector and / or CFTR enhancer and / or CFTR stabilizer in the preparation of a pharmaceutical / pharmaceutical composition comprising, as an active ingredient, the CFTR modifier or its pharmaceutically acceptable salt as a CFTR corrector and / or CFTR enhancer and / or CFTR stabilizer for the treatment of said CFTR-related diseases (particularly cystic fibrosis); wherein said pharmaceutical / pharmaceutical composition is intended to be used in combination with the compound of formula (I) or its pharmaceutically acceptable salt; ● Use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a CFTR modulator or a pharmaceutically acceptable salt thereof as a CFTR corrector and / or CFTR enhancer and / or CFTR stabilizer in the treatment of the CFTR-related diseases (particularly cystic fibrosis); ●A medicine for the prevention or treatment of the CFTR-related diseases (particularly cystic fibrosis), the medicine comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein the medicine is administered in combination with a CFTR modulator or a pharmaceutically acceptable salt thereof as a CFTR corrector and / or CFTR enhancer and / or CFTR stabilizer (intended); ● A method for preventing or treating the CFTR-related diseases (particularly cystic fibrosis) comprising administering to a subject (preferred) in need an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is administered in combination with an effective amount of the CFTR modifier or a pharmaceutically acceptable salt thereof as a CFTR corrector and / or CFTR enhancer and / or CFTR stabilizer; wherein it should be understood that the combination administration may be a fixed-dose combination or a non-fixed-dose combination; ● Methods for preventing or treating CFTR-related diseases (particularly cystic fibrosis), comprising administering to a subject in need an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a CFTR modulator or a pharmaceutically acceptable salt thereof as a CFTR corrector and / or CFTR enhancer and / or CFTR stabilizer; and ● A method for preventing or treating the CFTR-related diseases (particularly cystic fibrosis) comprising administering to a subject (preferred) in need an effective amount of the CFTR modifier or a pharmaceutically acceptable salt thereof as a CFTR corrector and / or CFTR enhancer and / or CFTR stabilizer, wherein the CFTR modifier as a CFTR corrector and / or CFTR enhancer and / or CFTR stabilizer is administered in combination with an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein it should be understood that the combination administration may be a fixed-dose combination or a non-fixed-dose combination.

[0098] Preparation of compound (I): Formula (I), Formula (I E Compounds of this compound can be prepared by known literature methods, the methods described below, the methods given in the experimental section below, or similar methods. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but these conditions can be determined by those skilled in the art through conventional optimization procedures. In some cases, the reaction scheme and / or the order of reaction steps can be altered to promote the reaction or avoid unwanted reaction products. In the general reaction sequence outlined below, unless otherwise explicitly defined, the general group R... 1 R 2 R 3 R 4 R 5 W, Z, Ar 1 and Ar 2 Such as formula (I) or formula (I) E As defined herein. Other abbreviations used herein are explicitly defined or as defined in the experimental section. In some cases, the general group R... 1 R 2 R 3 R 4 R 5 W, Z, Ar 1 and Ar 2The assembly may be incompatible with the schemes described below, thus requiring the use of protecting groups (PGs). The use of protecting groups is well known in the art (see, for example, "Protective Groups in Org. Synthesis," TW Greene, PGM Wuts, Wiley-Interscience, 1999). For the purposes of this discussion, it will be assumed that such necessary protecting groups are in place. In some cases, the final product can be further modified, for example, by substituent operations, to obtain new final products. These operations may include, but are not limited to, reduction, oxidation, alkylation, acylation, hydrolysis, and transition metal-catalyzed cross-coupling reactions, all of which are well known to those skilled in the art. The resulting compounds can also be converted into salts, particularly pharmaceutically acceptable salts, in a manner known per se.

[0099] Formula (I) and Formula (I) of the present invention E The compounds can be prepared according to the general reaction sequence outlined below.

[0100] In the following scheme, X represents a functional group: , where R 5 W and Z are as shown in equation (I) or equation (I) E As defined thereon, unless otherwise expressly defined.

[0101] The compound of formula (I) is prepared according to one of the schemes described below. Reaction scheme A Reaction Scheme A: Synthesis can be carried out using racemic or enantiomerically enriched amino acid building blocks. Appropriately protected amine building block A and acid B-Ac (prepared according to procedures fully described in the literature or reaction schemes I and J) are treated with a peptide coupling agent (such as HATU, COMU, T3P, PyBop, or EDCI / HOBt) in a solvent (such as 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 room temperature) to generate the corresponding amide intermediate AB. Deprotection of the amine functional group of intermediate AB is achieved according to methods known to those skilled in the art, for example, treatment with a 4M HCl solution of dioxane in the case of a Boc protecting group or preferably with TFA, or treatment with piperidine or diethylamine in the case of an Fmoc protecting group, or appropriate treatment with other protecting groups such as Cbz or Alloc protecting groups. The deprotected intermediate AB-Am is then reacted with a suitable protecting acid C (prepared according to the procedure described in the literature or experimental section) under the peptide coupling conditions for forming the AB intermediate described above. The resulting linear intermediate ABC is deprotected prior to the final macrocyclic lactamation of the peptide coupling. In some cases, protecting groups PG1 and PG3 are removed sequentially, but preferably they are removed simultaneously in one step. For example, t The Boc protecting group and the Bu ester are removed by treatment with a dioxane solution of 4M HCl or preferably with TFA, or the allyl ester and the Alloc protecting group can be removed by treatment with a palladium catalyst, as widely reported in the literature. The deprotected linear ABC intermediate is then cyclized under standard conditions, i.e., the intermediate can be treated with a coupling agent (such as COMU, T3P, PyBop, EDCI / HOBt, or preferably HATU) under dilution conditions (e.g., the concentration of the ABC starting material in a solvent (such as DMF or NMP) or a solvent mixture (such as DMF / DCM (1:1)) less than 0.1M) in the presence of a base (such as TEA or DIPEA) at a temperature between -20°C and +75°C (preferably at room temperature) to give the corresponding macrocyclic compound cABC. Depending on the nature of the various residues, some additional deprotection steps may be required to obtain the final product. Final purification is performed by preparative HPLC using a standard reversed-phase or (if desired) chiral column to give the target compound as a pure stereoisomer.

[0102] Reaction Scheme B: In a modified version of Reaction Scheme A, part C 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 according to the procedure described in the literature or the Experimental Section below) are treated according to the peptide coupling conditions described above to form the corresponding peptide bond. Selective deprotection of the amine functional group of ABD-1, for example by removing the Fmoc group by treatment with piperidine or diethylamine, or by hydrogenolysis in a solvent (such as EtOAc, THF, or dioxane) in the presence of a catalyst (such as Pd / C or Pd(OH)2 / C) to remove the Cbz protecting group, or preferably by treatment with a dioxane solution of 4M HCl or TFA to remove the Boc protecting group, yields a free amine or its ammonium salt, ready to be coupled with the second amino acid D-2 in a similar peptide coupling step. The three coupling / deprotection / coupling steps yield the same linear intermediate ABC as previously described in Reaction Scheme A. The remaining steps for the synthesis of the desired macrocyclic compound cABC are the same as described above. Reaction scheme B Reaction scheme C Reaction Scheme C: In another method, the order of constructing the linear intermediate ABC can be modified. The appropriately protected structural unit C and the amine B-Am (prepared according to the procedures described in the literature or reaction schemes K and J, respectively) are treated with reagents (such as HATU, COMU, T3P, PyBop, or EDCI / HOBt) in a solvent (such as 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 room temperature) according to the peptide coupling conditions described above. Deprotection of the acid functional group of intermediate BC, i.e., removal of PG4, is achieved according to methods known to those skilled in the art, for example, for methyl or ethyl esters, treatment with an aqueous methanolic solution of NaOH or LiOH at a temperature range of 0°C to 50°C, or preferably for benzyl esters, hydrogenolysis in a solvent (such as EtOAc, THF, or dioxane) in the presence of a catalyst such as Pd / C or Pd(OH)2 / C. The deprotected intermediate BC-Ac is then reacted with a suitably protected amine unit A (prepared according to the procedure described in the literature or reaction scheme I) under the peptide coupling conditions described above. The resulting linear ABC can then be deprotected and cyclized to give the final product cABC, as described in reaction scheme A. Reaction scheme D Reaction Scheme D: As with the transition from Reaction Scheme A to Reaction Scheme B, the C portion in Reaction Scheme C can be introduced stepwise, one amino acid at a time. Appropriately protected acid D-1 and amine B-Am (prepared according to the procedure described in the literature or experimental section or Reaction Scheme J) are treated according to the peptide coupling conditions described above. Selective deprotection of the amine functional group of BD-1, i.e., removal of PG5, is performed, for example, by removing the Cbz protecting group under acidic conditions or more preferably by treatment with a dioxane solution of 4M HCl or, more preferably, by TFA, to remove the Boc protecting group, yielding the corresponding ammonium salt without removing the orthogonal protecting group PG4. The resulting intermediate amine can then be coupled with a second amino acid, D-2, in a similar peptide coupling step. These three coupling / deprotection / coupling steps yield the same protected intermediate BC as previously described in Reaction Scheme C, at which point the remainder of the synthesis can be carried out as described above. Reaction scheme E Reaction scheme E: In another variant of reaction scheme C, structural unit A-Pro is doubly protected by suitable orthorhombic protecting groups on both carboxylic acid functional groups, for example, on β- t α-Benzyl ester or α-methyl ester in the presence of butyl ester. Following the order described in reaction scheme C, the corresponding linear intermediate ABC-Pro is then obtained. The aspartic acid side chain and Boc amine are double deprotected using TFA, followed by cyclization via the method described above, to obtain the cyclized intermediate cABC-Pro, which remains protected at A. Deprotection of the aspartic acid backbone carboxylic acid, i.e., removal of PG6, can be achieved by treating the methyl or ethyl ester with a methanol / aqueous solution of NaOH or LiOH at temperatures ranging from 0°C to 50°C, or preferably by hydrogenolysis of the benzyl ester in a solvent (such as EtOAc, THF, or dioxane) in the presence of a catalyst (such as Pd / C or Pd(OH)2 / C). The deprotected intermediate cABC-Ac is then coupled with an amine AM (commercially available or prepared according to the procedures described in the literature or experimental section) under the peptide coupling conditions described above to obtain the target compound. This strategy is particularly effective for preparing libraries for exploring the AM moiety. Reaction scheme F Reaction Scheme F: The strategy described in Reaction Scheme E, introducing part A stepwise, can be applied in different orders to obtain the same cABC-Ac intermediate, as shown in Reaction Scheme F. The protected A-Pro, doubly protected with suitable orthorhombic protecting groups on both carboxylic acid functional groups, such as α-benzyl ester or α-methyl ester in the presence of β-allyl ester, can be coupled with the desired B-Ac and C structural units in the same order described in Reaction Scheme A to obtain the corresponding linear intermediate ABC-Pro. Sequential deprotection of the amine protecting group PG3, using TFA in the case of Boc protecting groups, followed by removal of the aspartic acid side-chain protecting group PG1 (in the case of allyl protecting groups) by treatment with 1,3-dimethylbarbituric acid and Pd(PPh3)4 in a solvent (such as DCM), leaving only cyclization as described above to obtain the intermediate cABC-Pro, which remains protected on A, as described in Reaction Scheme E. The remaining steps of the synthesis of the desired macrocyclic compound cABC are the same as described above. Reaction scheme G Reaction scheme G: A variant of reaction scheme F, and very similar to reaction schemes B and D, where part C can be introduced stepwise, one amino acid at a time. Furthermore, amino acid D-1 itself can be constructed stepwise by introducing the desired side chain R onto the assembled ABD-1-Pre precursor. 1 The amine-deprotected AB intermediate described in reaction scheme F can be coupled with the unsubstituted amino acid precursor of D-1, for example, using NH-Boc or preferably NH-nosyl (4-nitrobenzenesulfonyl)-amino acid according to the peptide coupling conditions described. The NH-nosyl functional group can then be alkylated with the desired alkyl halide (such as bromide or preferably iodide) in the presence of a base (such as K₂CO₃), or preferably by a Mitsunobu reaction with the desired alcohol, the Mitsunobu reaction being carried out according to standard conditions well known to those skilled in the art, for example, in a solvent (such as THF or dioxane) at a temperature range of -80°C to 60°C with DEAD or DIAD and a phosphine ligand such as triphenylphosphine. The nosyl activating / protecting group can then be removed by treatment with a thiophenol standard in a solvent (such as DMF) in the presence of a base (such as K₂CO₃) to obtain the corresponding deprotected intermediate. Amino acid D-2 can then be coupled to this intermediate according to the conditions shown in reaction scheme B. The three coupling / deprotection / coupling steps yield the same deprotected linear intermediate ABC-Pro as previously described in reaction scheme F. The remaining steps for the synthesis of the desired macrocyclic compound cABC are the same as described above. Reaction scheme H Reaction Scheme H: In a further improvement of Reaction Scheme F, the α-carboxylic acid protecting group of the A-Am structural unit can be a solid phase, such as a polymer-linked support, enabling the stepwise solid-phase synthesis of cyclized macrocyclic precursors according to established methods well known to those skilled in the art of polymer-supported peptide synthesis. For example, amino acid A-Ac, appropriately orthogonally protected on the amine functional group by, for example, Fmoc protecting groups, and on the β-carboxylic acid functional group by, for example, allyl ester protecting groups, can be introduced onto Wang resin by treating it with HOBt and DMAP and coupling agents (such as DCC or DIC) in a solvent mixture such as DCM / DMF, allowing the polymer beads to swell appropriately. Subsequently, the Fmoc protecting groups are removed, and then the peptide coupling sequence is performed using standard conditions for polymer peptide synthesis, allowing the stepwise introduction of different structural units B-Ac, D-1, and finally appropriately protected D-2 (e.g., alloc-protected D-2) to obtain the polymer-supported linear peptide ABC, similar to that described in Reaction Scheme F. Dual deprotection of the allyl ester and N-alloc protecting group can be achieved by treatment with a palladium catalyst, possibly in the presence of 1,3-dimethylbarbituric acid, to obtain a still-supported linear peptide. In these cases, cyclization under standard peptide coupling conditions can be achieved without the risk of oligomer formation. The macrocyclic compound cABC-Ac described in reaction scheme F can then be released from the polymer support by acidic treatment such as a mixture of TFA / H2O (95 / 5). The released cABC-Ac can then be coupled with a suitable AM ​​amine under the coupling conditions described above to obtain the target compound. Reaction Scheme I Structural unit A is commercially available and prepared as described in the literature, or as shown in reaction scheme I. Suitable orthogonally protected A-Ac, such as the β- of N-Fmoc aspartic acid... t β-allyl esters of butyl ester or N-Boc aspartic acid are coupled to the desired AM amine according to standard peptide coupling conditions by treatment with COMU or T3P, HATU, PyBop or other peptide coupling agents in a solvent (such as 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 room temperature). The amine functional groups on the resulting intermediate can then be selectively deprotected under standard conditions established in the field of protecting group chemistry without removing the β-ester protecting group PG1. Treatment with piperidine or diethylamine to achieve β- t N-Fmoc was removed in the presence of butyl ester, or N-Boc was removed in the presence of β-allyl ester by treatment with a dioxane solution of TFA or 4M HCl, respectively, to obtain target structural unit A as a free base or its ammonium salt. Reaction scheme J Structural units B, B-Ac, or B-Am are prepared as described in the literature or as shown in reaction scheme J. Suitable salicylic acid derivatives, protected on carboxylic acid functional groups by esters (such as methyl, ethyl, or benzyl esters), are commercially available or prepared as described in the literature or as described in the experimental section. Similarly, amino alcohols protected on amine functional groups by Boc or Cbz groups are commercially available or readily prepared from the corresponding amino acids, as described in the literature or as described in the experimental section. The alcohol functional group of the amino alcohol can be activated by treatment with methanesulfonyl chloride or toluenesulfonyl chloride or similar activators in the presence of a base (such as DIPEA or TEA) and reacted with the phenolic functional group of the salicylic ester derivative in a solvent (such as THF or DMF) to provide a double-protected B structural unit. Alternatively, the two structural units can be reacted together according to the Mitsunobu method by treatment with a phosphine ligand (such as triphenylphosphine) and a DEAD or DIAD reagent in a solvent such as THF or dioxane at a temperature range of -20°C to 60°C. The acid or amine functional groups on the resulting orthogonally protected intermediate can then be selectively deprotected to obtain the corresponding structural units B-Ac or B-Am, respectively. For example, the methyl ester can be saponified with an aqueous solution of NaOH or LiOH, or the benzyl ester can be hydrogenated on a palladium catalyst (such as Pd or Pd(OH)2 supported on activated carbon) to obtain the corresponding B-Ac. Alternatively, Boc can be deprotected by TFA treatment in the presence of the methyl ester, or the Cbz-protected amine can be hydrogenated to obtain the corresponding B-Am. Reaction scheme K Structural unit C can be prepared from the key intermediate D-1-Am as shown in reaction scheme K. Intermediate D-1-Am is commercially available or prepared as described in the literature, or as shown in this scheme. A suitable PG8-protected bromoacetic acid ester derivative (such as methyl, ethyl, or benzyl ester) can be reacted with a suitable amine R1NH2 in a solvent (such as MeCN, acetone, or DMF) in the presence of a base (such as K2CO3 or DIPEA) at a temperature ranging from room temperature to 80°C to give the amine D-1-Am. Alternatively, a suitable PG8-protected amino acid ester derivative (such as methyl, ethyl, or benzyl ester) can be reacted with nitrosulfonylbenzene chloride in a solvent (such as DCM or THF) in the presence of a catalytic amount of DMAP to give the corresponding N-p-nitrobenzenesulfonyl (N-Nosyl)-protected amine. The alkylation of the sulfonamide nitrogen can then be performed using the Mitsunobu method described above, i.e., reacting with a phosphine ligand (such as triphenylphosphine) and a DEAD or DIAD reagent in a solvent (such as THF or dioxane) in the presence of the desired alcohol R1OH, within a temperature range of 0°C to 80°C. Subsequently, the p-nitrobenzenesulfonyl group can be cleaved by treatment with thiophenol in a solvent such as DMF or DCM in the presence of a base such as K2CO3 to obtain the amine structural unit D-1-Am. This is then coupled with a commercially available D-2 amino acid or a D-2 amino acid prepared as described in the literature, according to the standard peptide coupling method described above. The ester can then be deprotected by treating the methyl or ethyl ester with an aqueous solution of NaOH or LiOH, or by hydrogenolysis of the benzyl ester on a palladium catalyst (such as Pd or Pd(OH)2 supported on activated carbon), to obtain the target C structural unit.

[0103] The following examples are provided to illustrate the invention. These examples are merely illustrative and should not be construed as limiting the invention in any way.

[0104] Experimental Section I. Chemical Synthesis All temperatures are expressed in °C. Commercially available starting materials were used as is without further purification. Unless otherwise specified, all reactions were carried out in dried glassware under a nitrogen atmosphere. Compounds were purified by silica gel rapid column chromatography or preparative HPLC. The compounds described in this invention are obtained by LC-MS data (retention time t). R Retention times (in minutes; molecular weights obtained from mass spectrometry are given in g / mol) are characterized under the following conditions. In the case where the compounds of the invention appear as a mixture of conformational isomers, particularly as visible in their LC-MS spectra, the retention times of the most abundant conformational isomers are given.

[0105] Analysis of LC-MS equipment: HPLC pump: binary gradient pump, Agilent G4220A or equivalent. Autosampler: Gilson LH215 (with Gilson 845z injector) or equivalent Column oven: Dionex TCC-3000RS or equivalent Degasser: Dionex SRD-3200 or equivalent Supplemental pump: Dionex HPG-3200SD or equivalent DAD detector: Agilent G4212A or equivalent MS detector: Single quadrupole mass analyzer, Thermo Finnigan MSQPlus or equivalent. ELS detector: Sedere SEDEX 90 or equivalent LC-MS under acidic conditions Method A: Column: Zorbax SB-aq (3.5 µm, 4.6 x 50 mm). Conditions: MeCN [elution buffer A]; water + 0.04% TFA [elution buffer B]. Gradient: 95% B → 5% B within 1.5 min (flow rate: 4.5 mL / min). Detection: UV / Vis+ MS.

[0106] Method B: Column: Zorbax RRHD SB-aq (1.8 µm, 2.1 x 50 mm). Conditions: MeCN [elution buffer A]; water + 0.04% TFA [elution buffer B]. Gradient: 95% B → 5% B over 2.0 min (flow rate: 0.8 mL / min). Detection: UV / Vis + MS.

[0107] Method C: Column: Waters XBridge C18 (5 µm, 4.6 x 30 mm). Conditions: MeCN [elution buffer A]; water + 0.04% TFA [elution buffer B]. Gradient: 95% B → 5% B within 1.5 min (flow rate: 4.5 mL / min). Detection: UV / Vis + MS.

[0108] Method D: Column: Waters BEH C18 (2.1 x 50 mm, 2.5 µm). Conditions: MeCN [elution buffer A]; water + 0.04% TFA [elution buffer B]. Gradient: 95% B → 5% B over 2.0 min (flow rate: 0.8 mL / min). Detection: UV / Vis + MS.

[0109] Method E: Column: Waters XBridge C18 (2.5 µm, 4.6 x 30 mm). Conditions: MeCN [elution buffer A]; water + 0.04% TFA [elution buffer B]. Gradient: 95% B → 5% B within 1.5 min (flow rate: 4.5 mL / min). Detection: UV / Vis + MS.

[0110] Method F: Column: Waters XSelect CSH C18 (3.5 µm, 2.1 x 30 mm). Conditions: MeCN + 0.1% formic acid [elution buffer A]; water + 0.1% formic acid [elution buffer B]. Gradient: 95% B → 2% B within 1.6 min (flow rate 1 mL / min). Detection: UV / Vis + MS.

[0111] Method G: Column: Waters Atlantis T3 (3.0 µm, 2.1 x 50 mm). Conditions: MeCN + 0.1% formic acid [elution buffer A]; water + 0.1% formic acid [elution buffer B]. Gradient: 95% B → 2% B over 5 minutes (flow rate 0.8 mL / min). Detection: UV / Vis + MS.

[0112] 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: Waters ACQUITY UPLC CSH C18 1.7µm 2.1 x 50 mm, isothermal at 60°C in an Acquity UPLC column oven. Eluents: A: H₂O + 0.05% formic acid; B: MeCN + 0.045% formic acid. Method: Gradient: 2% B → 98% B over 2.0 min. Flow rate: 1.0 mL / min. Detection: UV 214 nm and ELSD, as well as MS, t R Given in minutes.

[0113] LC-MS under alkaline conditions Method I: Column: Waters BEH C18 (2.5 µm, 2.1 x 50 mm). Conditions: Water / NH3 [c(NH3) = 13 mmol / L] [elution buffer A]; MeCN [elution buffer B]. Gradient: 5% B → 95% B over 2 minutes (flow rate 0.8 mL / min). Detection: UV / Vis + MS.

[0114] Method J: Column: Waters XSelect CSH C18 (3.5 µm, 2.1 x 30 mm). Conditions: 95% MeCN + 5% water / NH4HCO3 [c(NH4HCO3) = 10 mmol / L] [elution buffer A]; water / NH4HCO3 [c(NH4HCO3) = 10 mmol / L] [elution buffer B]. Gradient: 95% B → 2% B over 1.6 min (flow rate 1 mL / min). Detection: UV / Vis + MS.

[0115] GC-MS Agilent 6890N / column: RXI-5MS 20m, ID 180 µm, df 0.18 µm; velocity 50 cm / s, He carrier gas; 100°C → 250°C in 4.5 minutes; detection: MS.

[0116] Preparative HPLC equipment: Gilson 333 / 334 HPLC pump, equipped with Gilson LH215, Dionex SRD-3200 degasser. Dionex ISO-3100A supplemental pump, Dionex DAD-3000 DAD detector, single quadrupole mass analyzer MS detector, Thermo Finnigan MSQ Plus, MRA100-000 shunt, Polymer Laboratories PL-ELS1000 ELS detector Preparative HPLC under alkaline conditions Column: Waters XBridge (10 µm, 75 x 30 mm). Conditions: MeCN [elution buffer A]; water + 0.5% NH4OH (25% aq.) [elution buffer B]; gradient as shown in Table 1 of preparative HPLC (flow rate: 75 mL / min). The initial percentage (x) of eluent A was determined based on the polarity of the compound to be purified. Detection: UV / Vis + MS Preparative HPLC Table 1 Preparative HPLC under acidic conditions Column: Waters Atlantis T3 (10 µm, 75 x 30 mm). Conditions: MeCN [elution buffer A]; water + 0.5% HCO2H [elution buffer B]; gradient as shown in Table 2 of preparative HPLC (flow rate: 75 mL / min). The initial percentage (x) of eluent A was determined based on the polarity of the compound to be purified. Detection: UV / Vis + MS Preparative HPLC Table 2 Preparative HPLC for chiral separation In most cases, the desired diastereomers can be separated or purified by standard preparative-grade HPLC using methods well known to those skilled in the art. In some cases, the use of chiral columns is preferable for separating complex mixtures of diastereomers. Optimal results are obtained using chiral stationary phase columns, such as Chiralpak IA, IB, or IC columns based on immobilized amylose or cellulose chiral phases, with isocratic elution buffers based on mixtures of MeCN and EtOH or MeOH in ratios ranging from 9:1 to 1:9. To compensate for the presence of ionizable functional groups in the compound to be purified, a modifier can be added to the solvent mixture, such as 0.1% diethylamine for basic derivatives or 0.1% formic acid for acidic derivatives. In some cases, supercritical fluid chromatography is used, employing the same chiral stationary phase column as described above, with isocratic elution buffers consisting of 50% to 90% supercritical carbon dioxide and EtOH, MeOH, or a 1:1 EtOH:MeCN mixture. Detection: UV / Vis.

[0117] Abbreviations (as used above or below): AcOH (acetic acid) Ac2O Acetic anhydride Alloc allyloxycarbonyl anh. waterless aq. aqueous solution Atm atmospheric pressure BnBr benzyl bromide Boc tert-butoxycarbonyl Boc2O ditert-butyl dicarbonate BOP hexafluorophosphate (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium BuLi n-Butyllithium CDI1,1'-carbonyldiimidazole CD3I deuterated iodomethane CHCl3 chloroform COMU (1-cyano-2-ethoxy-2-oxoethyleneaminooxy) dimethylamino-morpholino-carbomony hexafluorophosphate Cu(OAc)₂Copper acetate(II) D day DBU1,8-diazabicyclo[5.4.0]undec-7-ene DCCN, N′-Dicyclohexylcarbodiimide DCE1,2-Dichloroethane DCM dichloromethane DEAD Diethyl azodicarbonate DIAD diisopropyl azodicarbonate DIBAL / DIBAL-H diisobutylaluminum hydride DICN,N′-Diisopropylcarbodiimide DIPEA (diisopropylethylamine), Hünig base DMAP4-Dimethylaminopyridine DMF dimethylformamide DMSO dimethyl sulfoxide DPPA diphenyl phosphate dppf1,1'-bis(diphenylphosphine)ferrocene EDC1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Et ethyl Et2O diethyl ether Ethyl acetate (EtOAc) EtOH (ethanol) Vacuum evaporation Example FC Silica Rapid Chromatography FDPP pentafluorophenyl diphenylphosphine Fmoc9-fluorenylmethoxycarbonyl H hours HATU1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate Heptheptane Hexane HOBT1-hydroxybenzotriazole HPLC (High Performance Liquid Chromatography) HV high vacuum conditions i Bu isobutyl i Pr isopropyl i PrMgCl isopropyl magnesium chloride i PrOH isopropanol iIsopropyl PrOAc acetate KOAc potassium acetate KO t Potassium tert-butoxide LAH Lithium Aluminum Hydrogen LC-MS (Liquid Chromatography-Mass Spectrometry) Lit. Literature M moles / liter mCPBA m-chloroperoxybenzoic acid Memethyl MeCN acetonitrile MeI iodomethane Meldrum acid 2,2-dimethyl-1,3-dioxane-4,6-dione MeOH methanol mL / ml Min minutes mix. MOM methoxymethyl MW microwave NaBH(OAc)3 sodium triacetoxyborohydride NCSN-chlorosuccinimide NMPN-methyl-2-pyrrolidone Nosyl4-nitrobenzenesulfonyl group n Pr n-propyl OAc acetate org. organic Pd( t Bu3P)2bis(tri-tert-butylphosphine)palladium(0) Pd(OAc)₂palladium(II) acetate Pd / C activated carbon supported palladium Pd(OH)₂ / C activated carbon supported palladium hydroxide (Pearlman catalyst) Pd2(dba)3tris(dibenzylacetone)dipalladium(0) PdCl2(PPh3)2bis(triphenylphosphine)palladium(II) dichloride Pd(dppf)Cl2[1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride The complex of Pd(dppf)Cl2·DCM[1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride with dichloromethane Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) Phphenyl PhMe toluene PPh3 triphenylphosphine prep. preparative PTFE (polytetrafluoroethylene) PyBOP (benzotriazol-1-yl-oxy) tripyrrole alkyl phosphonium hexafluorophosphate PyClop tripyrrolyl phosphonium hexafluorophosphate Rac racemic RM reaction mixture Rochelle potassium tartrate sodium salt RT room temperature RuPhos2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl S seconds sat. saturated Selectfluor 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis(tetrafluoroborate) SM starting materials soln. solution SPhos2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl TBAF tetrabutylammonium fluoride TBDMSCl tert-butyldimethylchlorosilane TBME tert-butyl methyl ether t Bu tert-butyl TEA Triethylamine Tf trifluoromethanesulfonyl group TFA (trifluoroacetic acid) THF tetrahydrofuran TLC (Thin-Layer Chromatography) TMEDAN,N,N',N'-Tetramethylethylenediamine TMS Trimethylsilyl Tosyl p-toluenesulfonyl group T3P n-propylphosphonic anhydride t R Retention time Triflate (trifluoromethanesulfonate) p TsOH p-Toluenesulfonic acid Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthanium XPhos2-Dicyclohexylphosphino-2′,4′,6′-Triisopropylbiphenyl 2-(4-Methoxy-2H-1,2,3-triazol-2-yl)ethyl-1-amine hydrochloride (AM-1) Step 1: K₂CO₃ (22.1 g, 160 mmol) was added to a suspension of 4,5-dibromo-2H-1,2,3-triazole (30.2 g, 133 mmol) and (2-bromoethyl)carbamate tert-butyl ester (33.5 g, 146 mmol) in MeCN (300 mL) at room temperature, and the resulting mixture was stirred at 50°C for 65 hours. The reaction mixture was partitioned between water and EtOAc, and the layers were separated. The aqueous phase was re-extracted with EtOAc (twice), and the combined organic extracts were washed with brine, dried (MgSO₄), filtered, and evaporated. The crude product was purified by FC (eluting with 20% EtOAc in heptane) to give (2-(4,5-dibromo-2H-1,2,3-triazol-2-yl)ethyl)carbamate tert-butyl ester, as a colorless oil. LC-MS B: t R = 0.95 min; [M+H] + =370.73.

[0118] Step 2: To a solution of (2-(4,5-dibromo-2H-1,2,3-triazol-2-yl)ethyl)carbamate tert-butyl ester (5.0 g, 13.5 mmol) in DCM (75 mL) at room temperature, TFA (51.7 mL, 676 mmol) was added. The reaction mixture was stirred for 1 hour and then concentrated under vacuum. The residue was co-evaporated with DCM (twice) to give 2-(4,5-dibromo-2H-1,2,3-triazol-2-yl)ethyl-1-amine·TFA, a white solid. LC-MS I:t R = 0.66 min; [M+H] + = 270.94.

[0119] Step 3: Sodium acetate (7.0 g, 85.4 mmol) was added to a solution of 2-(4,5-dibromo-2H-1,2,3-triazol-2-yl)ethyl-1-amine·TFA (6.56 g, 17.1 mmol) in MeOH (90 mL) at room temperature, followed by benzaldehyde (3.83 mL, 37.6 mmol). The mixture was stirred for 1 hour, followed by the addition of NaBH3CN (2.49 g, 37.6 mmol) in portions. The reaction mixture was stirred for 48 hours and then concentrated. The residue was partitioned between water and DCM, and the layers were separated. The aqueous phase was re-extracted with DCM (twice), and the combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated to give N,N-dibenzyl-2-(4,5-dibromo-2H-1,2,3-triazol-2-yl)ethyl-1-amine as a yellow solid. LC-MS I:t R = 1.38 min; [M+H]+ = 450.99.

[0120] Step 4: At -78°C, ^iPrMgCl (2.0 M THF solution, 13.4 mL, 26.8 mmol) was added dropwise to a solution of N,N-dibenzyl-2-(4,5-dibromo-2H-1,2,3-triazol-2-yl)ethyl-1-amine (6.03 g, 13.4 mmol) in THF (120 mL), and the mixture was stirred for 4 hours. The reaction mixture was heated to room temperature and stirred for 30 minutes, then quenched by careful addition of a saturated aqueous solution of NH4Cl. The eluent was evaporated, and the remaining aqueous phase was extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated to give N,N-dibenzyl-2-(4-bromo-2H-1,2,3-triazol-2-yl)ethyl-1-amine as a yellow oil. LC-MS I:t R = 1.30 min; [M+H] + = 373.07.

[0121] Step 5: A mixture of N,N-dibenzyl-2-(4-bromo-2H-1,2,3-triazol-2-yl)ethyl-1-amine (5.27 g, 14.2 mmol), bis(pinacol)diboron (5.41 g, 21.3 mmol), SPhos (233 mg, 0.57 mmol), tris(dibenzylideneacetone)dipalladium(O) (134 mg, 0.14 mmol), and KOAc (2.40 g, 24.2 mmol) in dioxane (110 mL) was degassed and inertized with argon. The reaction mixture was then heated to 100°C for 3 days. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and washed with EtOAC. The evaporation was distilled off, and the residue was partitioned between water and EtOAc to separate the layers. The aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated to give the major product (2-(2-(dibenzylamino)ethyl)-2H-1,2,3-triazol-4-yl)boronic acid, as a yellow oil. LC-MS I:t R = 0.58 min; [M+H] + = 337.22.

[0122] Step 6: Sodium perborate tetrahydrate (4.72 g, 29.7 mmol) was added to a solution of (2-(2-(dibenzylamino)ethyl)-2H-1,2,3-triazol-4-yl)boric acid (5.0 g, 14.9 mmol) in THF:H₂O 1:1 (150 mL) at room temperature. The resulting suspension was stirred for 16 hours. The reaction mixture was poured into ice water and extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried (MgSO₄), filtered, and evaporated. The crude product was purified by FC (eluting with 20% to 80% EtOAc in heptane) to give 2-(2-(dibenzylamino)ethyl)-2H-1,2,3-triazol-4-ol as a yellow solid. LC-MS I:t R = 0.56 min; [M+H] + = 309.17. 1 H NMR (DMSO) δ: 10.30 (s, 1 H), 7.21-7.31 (m, 10H), 7.02 (s, 1 H), 4.29 (t, J = 6.3 Hz, 2 H), 3.55 (s, 4 H), 2.80 (t, J = 6.3Hz, 2 H).

[0123] Step 7: Add NaH (60% mineral oil dispersion, 540 mg, 11.2 mmol) to a solution of 2-(2-(dibenzylamino)ethyl)-2H-1,2,3-triazol-4-ol (3.15 g, 10.2 mmol) in DMF (85 mL) at room temperature. After stirring for 10 minutes, add MeI (0.77 mL, 12.3 mmol), and stir the resulting mixture for 1 hour. Pour the reaction mixture into water and... i PrOAc extraction (3 times). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated to give N,N-dibenzyl-2-(4-methoxy-2H-1,2,3-triazol-2-yl)ethyl-1-amine, as a yellow oil. LC-MS I:t R =1.23 min; [M+H] + = 323.21.

[0124] Step 8: A solution of N,N-dibenzyl-2-(4-methoxy-2H-1,2,3-triazol-2-yl)ethyl-1-amine (3.45 g, 10.7 mmol) in EtOH (85 mL) at room temperature was inertized with N2 / vacuum (3 times), followed by the addition of 10% Pd / C (1.13 g, 1.1 mmol). After three more inertizations, an H2 balloon was attached, and the resulting mixture was stirred for 24 hours. The reaction mixture was filtered through Whatman filter paper, and the filtrate was acidified and concentrated with 4 M HCl in dioxane solution (8 mL, 32 mmol) to give the title compound AM-1 as a white solid. LC-MS I:t R = 0.39 min; [M+H] + = 143.20. 1 H NMR(DMSO)δ: 8.40 (s, 3 H), 7.41 (s, 1 H), 4.54 (t, J = 6.4 Hz, 2 H), 3.87 (s, 3H), 3.29-3.23 (m, 2 H).

[0125] 2-(3-Methoxy-1,2,4-oxadiazol-5-yl)ethyl-1-amine hydrochloride (AM-2) Step 1: HATU (11.82 g, 31.1 mmol) was added to a solution of boc-beta-Ala-OH (5.0 g, 25.9 mmol), O-methylisourea hydrogen sulfate (4.5 g, 25.9 mmol), and DIPEA (18.1 mL, 104 mmol) in DMF (150 mL) at room temperature. The reaction mixture was stirred for 1.5 hours. Water and EtOAc were added to the reaction mixture, and the two layers were separated. The aqueous layer was extracted with EtOAc (twice). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to give a crude product. This crude product was purified by FC (eluting with a heptane solution of 20% to 100% EtOAc) to give tert-butyl (3-((imino(methoxy)methyl)amino)-3-oxopropyl)carbamate, a white solid. LC-MS I:t R = 0.64 min; [M+H] + = 246.36.

[0126] Step 2: To a solution of (3-((imino(methoxy)methyl)amino)-3-oxopropyl)carbamate tert-butyl ester (6.19 g, 24.7 mmol) and NBS (10.56 g, 59.3 mmol) in EtOAc (120 mL) at room temperature, 1,8-diazabicyclo[5.4.0]undec-7-ene (8.96 mL, 59.3 mmol) was added, and the reaction mixture was stirred for 5 hours. Additional 1,8-diazabicyclo[5.4.0]undec-7-ene (1.85 mL, 12.4 mmol) and NBS (2.2 g, 12.4 mmol) were added, and stirring continued for 16 hours. The suspension was filtered, and the filtrate was washed with water, saturated NaHCO3 aqueous solution, and brine, then evaporated to dryness. The crude product was purified by FC (eluting with 20% to 100% EtOAc in heptane) to give tert-butyl (2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)carbamate, as a colorless oil. LC-MS I:t R = 0.75 min; [M+H] + =244.33.

[0127] Step 3: To a solution of tert-butyl 2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)carbamate (150 mg, 0.62 mmol) in DCM (2 mL) at room temperature, a solution of dioxane in 4 M HCl (0.62 mL, 2.47 mmol) was added. The reaction mixture was stirred at room temperature for 4 days, followed by stirring at 50°C for 6 hours. The mixture was evaporated to give the title compound AM-2 as a white solid. LC-MS I:t R = 0.35 min; [M+H] + = 144.21.

[0128] 2-(3-Methoxyisoxazol-5-yl)ethyl-1-amine hydrochloride (AM-3) Step 1: DPPA (1.32 mL, 6.1 mmol) was added dropwise to a solution of 3-(3-methoxyisoxazol-5-yl)propionic acid (1.0 g, 5.55 mmol) and TEA (0.93 mL, 6.66 mmol) in PhMe (25 mL) at room temperature. The reaction mixture was heated to 100°C for 1.5 hours. 2-Methylprop-2-ol (1.06 mL, 11.1 mmol) was added, and the reaction mixture was refluxed for 16 hours. The reaction mixture was cooled to room temperature and partitioned between a saturated aqueous solution of NaHCO3 and EtOAc to separate the layers. The aqueous phase was extracted twice with EtOAc, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum. The crude product was purified by FC (eluting with heptane solution of 0% to 100% EtOAc) to give tert-butyl (2-(3-methoxyisoxazol-5-yl)ethyl)carbamate, as a colorless oil. LC-MS F:t R = 1.80 min; [M+H] + =243.1.

[0129] Step 2: To a suspension of (1.33 g, 5.47 mmol) tert-butyl carbamate in dioxane (30 mL) at room temperature, a solution of dioxane in 4 M HCl (13.7 mL, 54.7 mmol) was added. The resulting mixture was heated to 50°C for 4 hours. The reaction mixture was concentrated and co-evaporated with Et₂O to give the title compound AM-3 as a white solid. LC-MS I:t R = 0.42 min; [M+H] + = 143.25.

[0130] 2-(4-Fluoro-3-methoxyisoxazol-5-yl)ethyl-1-amine hydrochloride (AM-4) Step 1: In a microwave-safe tube, phthalic anhydride (354 mg, 2.36 mmol) was added to a suspension of AM-3 (402 mg, 2.25 mmol) and DIPEA (0.47 mL, 2.7 mmol) in dioxane (12 mL) at room temperature. The tube was sealed and heated to 100°C for 48 hours. Water was added to the reaction mixture, and the mixture was acidified with 1 M HCl. The product was extracted with EtOAc, dried (MgSO4), filtered, and concentrated to give 2-(2-(3-methoxyisoxazol-5-yl)ethyl)isoindoline-1,3-dione (718 mg) as a white solid. LC-MS B:t R = 0.85 min; [M+H]+ = 273.09.

[0131] Step 2: Selectfluor (1.07 g, 2.87 mmol) was added to a solution of 2-(2-(3-methoxyisoxazol-5-yl)ethyl)isoindoline-1,3-dione (710 mg, 2.61 mmol) in sulfolane (21.7 mL, 226 mmol) at 40°C. The reaction mixture was heated to 120°C for 18 hours. The resulting dark brown solution was cooled to approximately 50°C, and the reaction mixture was poured into pre-stirred H₂O (30 mL), followed by the addition of EtOAc (10 mL). The two layers were separated, and the aqueous layer was re-extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na₂SO₄), filtered, and concentrated. 2-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)isoindoline-1,3-dione (89 mg, 12%) was purified by preparative HPLC (acidic) as a colorless oil. LC-MS B:t R = 0.90 min; [M+H] + = 291.02.

[0132] Step 3: To a solution of 2-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)isoindoline-1,3-dione (85 mg, 0.293 mmol) in EtOH (3 mL) at room temperature, hydrazine monohydrate (0.222 mL, 2.93 mmol) was added. The reaction mixture was heated to 80°C for 1 hour. The reaction mixture was cooled to room temperature, and a white precipitate formed. Diethyl ether was added, and the solid (byproduct) was ground and then filtered off. The filtrate was acidified with 4 M HCl in dioxane solution and concentrated to give the title compound AM-4 as a white solid, which was used directly in the next step. LC-MS B:t R = 0.33 min; [M+H] + =161.08.

[0133] 2-(5-Cyclopropyl-2H-Tetraazol-2-yl)Ethyl-1-amine hydrochloride (AM-5) Step 1: To a suspension of 5-cyclopropyl-2H-1,2,3,4-tetrazolium (24.0 g, 211 mmol) and K₂CO₃ (35.1 g, 254 mmol) in MeCN (480 mL) at room temperature, tert-butyl (2-bromoethyl)carbamate (53.2 g, 233 mmol) was added. The reaction mixture was heated to 50°C for 18 hours. The reaction mixture was concentrated, and the residue was partitioned between water and EtOAc, separating the layers. The aqueous phase was re-extracted with EtOAc (twice), and the combined organic extracts were washed with brine, dried (MgSO₄), filtered, and evaporated. The crude product was purified by FC (eluting with a heptane solution of 20% to 80% EtOAc) to give tert-butyl (2-(5-cyclopropyl-2H-tetrazol-2-yl)ethyl)carbamate as a colorless oil. LC-MS I:t R = 0.80 min; [M+H] + = 254.35.

[0134] Step 2: A solution of dioxane in 4 M HCl (290 mL, 1.16 mol) was added to a suspension of (2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)carbamate (29.45 g, 116 mmol) in dioxane (630 mL) at room temperature. The resulting mixture was stirred for 4 days. The reaction mixture was concentrated and co-evaporated with Et₂O to give the title compound AM-5 (1.36 g, 94%) as a white solid. LC-MS I:t R = 0.44 min; [M+H] + = 154.25.

[0135] tert-Butyl(R)-(1-hydroxy-3-(6-methoxypyridin-2-yl)propyl-2-yl)carbamate (AL-1) Step 1: At -78°C, nBuLi (1.6 M hexane solution, 18.2 mL, 29.1 mmol) was added dropwise to a solution of (S)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (4.70 g, 24.2 mmol) in THF (200 mL). The reaction mixture was stirred for 30 minutes, followed by the addition of a solution of 2-(bromomethyl)-6-methoxypyridine (5.0 g, 24.2 mmol) in THF (20 mL). The reaction mixture was stirred for 10 minutes and then quenched with a saturated aqueous NH4Cl solution. After warming to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and evaporated. The crude product was purified by FC (eluting with heptane solution of 30% to 100% EtOAc) 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:t R = 0.83 min; [M+H] + = 306.03.

[0136] Step 2: To a solution 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) at room temperature, 1 M HCl aqueous solution (38.2 mL, 38.2 mmol) was added, and the resulting mixture was stirred for 16 hours. The reaction mixture was partitioned between saturated NaHCO3 aqueous solution and DCM, and the layers were separated. The aqueous phase was re-extracted with DCM (twice), and the combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated. The crude product was purified by FC (eluting with 80% to 100% EtOAc in heptane) to give methyl (R)-2-amino-3-(6-methoxypyridin-2-yl)propionate as a yellow oil. LC-MS B:t R = 0.46 min; [M+H] + = 211.26.

[0137] Step 3: Boc₂O (2.61 g, 12.0 mmol) was added to a suspension of (R)-2-amino-3-(6-methoxypyridin-2-yl)propionate (2.28 g, 10.8 mmol) and NaHCO₃ (4.56 g, 54.2 mmol) in a mixture of THF (50 mL) and H₂O (50 mL) at room temperature. The reaction mixture was stirred for 1 hour. The reaction mixture was acidified with 1 M HCl aqueous solution and extracted with EtOAc (3 times). The combined organic extracts were dried (MgSO₄), filtered, and concentrated to give (R)-2-((tert-butoxycarbonyl)amino)-3-(6-methoxypyridin-2-yl)propionate as a colorless oil. LC-MS B:t R =0.89 min; [M+H] + = 311.25.

[0138] Step 4: At 0°C, LAH (906 mg, 22.7 mmol) was added fractionally to a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-(6-methoxypyridin-2-yl)propionate (3.52 g, 11.3 mmol) in Et2O (150 mL). The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was cooled back to 0°C, quenched very carefully with H2O, and then EtOAc was added. The resulting suspension was heated to room temperature and filtered. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated to give the title compound AL-1 as a colorless oil. LC-MS B:t R = 0.62 min; [M+H] + = 283.35.

[0139] tert-Butyl(R)-(1-(6-bromo-4-methoxypyridin-2-yl)-3-hydroxypropyl-2-yl)carbamate (AL-2) Step 1: Zn powder (1.77 g, 26.5 mmol) was heated to 140°C under vacuum for 30 minutes, then cooled to room temperature under argon. Iodine (2.02 g, 7.96 mmol) and DMF (10 mL) were added, and the mixture was stirred for 20 minutes. Then, Boc-3-iodo-D-Ala-OMe (3.0 g, 8.84 mmol) was added, and stirring was continued for 20 minutes. 2,6-Dibromo-4-methoxypyridine (3.07 g, 11.5 mmol) and PdCl2(PPh3)2 (310 mg, 0.44 mmol) were added, and the reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was partitioned between water and EtOAc and filtered. The layers were separated, and the aqueous layer was extracted again with EtOAc (twice). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated. The crude product was purified by FC (eluting with 40% EtOAc in heptane) to give methyl (R)-3-(6-bromo-4-methoxypyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propionate, as a colorless oil. LC-MS B:t R = 0.92 min; [M+H] + = 389.25.

[0140] Step 2: The title compound was prepared from methyl (R)-3-(6-bromo-4-methoxypyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propionate according to the procedure described in Step 4 of AL-1. LC-MS B: t R = 0.78 min; [M+H] + = 361.16.

[0141] tert-Butyl(R)-(1-(6-bromo-4-methylpyridin-2-yl)-3-hydroxypropyl-2-yl)carbamate (AL-3) The title compound was prepared according to the reaction sequence described for AL-6, in which 2,6-dibromo-4-methylpyridine was substituted for 2,6-dibromo-4-methoxypyridine in step 1. LC-MS I:t R = 0.84 min; [M+H] + = 347.17.

[0142] Methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(2-chloro-6-methoxypyrimidin-4-yl)propionate (IM-1) and methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-chloro-6-methoxypyrimidin-2-yl)propionate (IM-2) Zn powder (6.6 g, 99 mmol) was placed in a flame-dried, nitrogen-purged flask and heated to 140°C under vacuum for 30 minutes. After cooling to room temperature, DMF (30 mL) was transferred to the flask and further purged with nitrogen. Iodine (99.9%, 7.6 g, 30 mmol) was carefully added in one go. The resulting brownish-red mixture was stirred and allowed to return to room temperature until completely decolorized. Then Boc-β-iodo-D-Ala-OMe (11.43 g, 33 mmol) was added, and stirring was continued for 10 minutes at room temperature under nitrogen. 2,4-Dichloro-6-methoxypyrimidine (5.53 g, 30 mmol) and PdCl₂(PPh₃)₂ (1.05 g, 1.5 mmol) were added, and the reaction mixture was heated at 40°C for 24 hours, then at 90°C for 1 hour, then at 110°C for 3 hours, and finally at 80°C for 16 hours to drive the conversion. After cooling the reaction mixture to room temperature, it was diluted with EtOAc, and the solids were removed by filtration. The filtrate was washed with a saturated aqueous thiosulfate solution, then washed twice with brine, dried over MgSO₄, filtered, and concentrated to dryness. The crude, deep yellow oil (6.23 g) was purified by preparative HPLC (under alkaline conditions) to obtain two expected regioisomers: methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-chloro-6-methoxypyrimidin-2-yl)propionate (IM-1) (500 mg), a yellow oil, and methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(2-chloro-6-methoxypyrimidin-4-yl)propionate (IM-2) (1.14 g), a yellow oil that cures at room temperature. IM-1: 1 H NMR (500 MHz, DMSO)δ 7.30 (d, J = 8.6 Hz, 1H), 7.02 (s, 1H), 4.67 (td, J = 8.6, 6.1 Hz,1H), 3.93 (s, 3H), 3.63 (s, 3H), 3.22 (dd, J = 15.4, 5.8 Hz, 1H), 3.14 (dd, J= 15.4, 7.9 Hz, 1H), 1.35 (s, 9H); LC-MS B: t R = 0.93 min; [M+H] + = 346.2; IM-2: 1HNMR (500 MHz, DMSO)δ 7.34 (d, J = 8.4 Hz, 1H), 6.86 (s, 1H), 4.42 - 4.37 (m,1H), 3.92 (s, 3H), 3.64 (s, 3H), 3.06 (dd, J = 14.0, 5.1 Hz, 1H), 2.95 (dd, J= 14.0, 9.5 Hz, 1H), 1.33 (s, 9H); LC-MS B: t R = 0.91 min; [M+H] + = 346.1.

[0143] tert-Butyl(R)-(1-(4-chloro-6-methoxypyrimidin-2-yl)-3-hydroxypropyl-2-yl)carbamate (AL-4) The title compound was prepared from methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(4-chloro-6-methoxypyrimidin-2-yl)propionate (IM-1) according to the procedure described in step 4 of AL-1. LC-MS B:t R = 0.78 min; [M+H] + = 318.2.

[0144] tert-Butyl(R)-(1-(2-chloro-6-methoxypyrimidin-4-yl)-3-hydroxypropyl-2-yl)carbamate (AL-5) The title compound was prepared from methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(2-chloro-6-methoxypyrimidin-4-yl)propionate (IM-2) according to the procedure described in step 4 of AL-1. LC-MS B:t R = 0.76 min; [M+H] + = 318.1.

[0145] tert-Butyl(S)-3-amino-4-((2-(4-methoxy-2H-1,2,3-triazol-2-yl)ethyl)amino)-4-oxobutyrate (A-1) Step 1: Add HATU (3.20 g, 8.42 mmol) to a solution of Fmoc-L-aspartic acid β-tert-butyl ester (3.54 g, 8.42 mmol), 2-(4-methoxy-2H-1,2,3-triazol-2-yl)ethyl-1-amine hydrochloride (AM-1, 1.6 g, 8.42 mmol), and DIPEA (6.34 mL, 33.7 mmol) in DMF (27 mL) at room temperature, and stir the reaction mixture for 1 hour. Partition the reaction mixture between water and EtOAc, separating the layers. The aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered, and evaporated to give (S)-3-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-4-((2-(4-methoxy-2H-1,2,3-triazol-2-yl)ethyl)amino)-4-oxobutyrate tert-butyl ester, a white solid. LC-MS I:t R = 1.10 min; [M+H] + = 536.28.

[0146] Step 2: To a solution of (S)-3-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-4-((2-(4-methoxy-2H-1,2,3-triazol-2-yl)ethyl)amino)-4-oxobutyrate tert-butyl ester (5.29 g, 8.58 mmol) in DCM (67 mL) at room temperature, piperidine (4.29 mL, 42.9 mmol) was added, and the reaction mixture was stirred for 3 hours. The reaction mixture was concentrated, and the residue was directly purified by FC (eluting with 10% MeOH in DCM solution) to give the title compound A-1 as a yellow oil. LC-MS I:t R = 0.65 min; [M+H] + = 314.27.

[0147] Table 1-A below lists structural unit A prepared in a similar manner to the two-step sequence described in A-1 above.

[0148] Table 1-A Benzyl(R)-6-(2-amino-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylate dihydrochloride (B-1) Step 1: To a solution of 3-fluoroquinoline-6-ol (0.50 g, 3.06 mmol) and NaOAc (0.30 g, 3.68 mmol) in AcOH (20 mL) at room temperature, add Br2 (0.17 mL, 3.37 mmol) in AcOH (8.0 mL) and stir the reaction mixture for 30 minutes. Concentrate the reaction mixture to dryness, and partition and extract the residue between a saturated aqueous solution of NaHCO3 and EtOAc. Separate the layers, and extract the aqueous layer again with EtOAc (twice). Wash the combined organic extracts with brine, dry (Na2SO4), filter and evaporate to give 5-bromo-3-fluoroquinoline-6-ol as a brown solid. LC-MS J:t R = 1.38 min; [M+H] + = 239.9.

[0149] Step 2: A solution of 5-bromo-3-fluoroquinoline-6-ol (0.74 g, 3.06 mmol) in THF (15 mL) was added dropwise to a suspension of NaH (60% mineral oil dispersion, 0.17 g, 4.29 mmol) in THF (15 mL) at room temperature. The resulting mixture was stirred for 15 minutes, and then methoxymethyl bromide (0.3 mL, 3.67 mmol) was added dropwise at 0°C. After stirring at 0°C for 1.5 hours, the reaction mixture was quenched by adding H2O and extracted with EtOAc. The organic layer was washed with NaHCO3 and brine, dried (Na2SO4), filtered, and evaporated. The crude product was purified by FC (eluting with a 2% to 30% heptane solution of EtOAc) to give 5-bromo-3-fluoro-6-(methoxymethoxy)quinoline as a colorless oil. LC-MS J:t R = 2.03 min; no ionization.

[0150] Step 3: At -78°C, nBuLi (1.6 M hexane solution, 0.98 mL, 1.57 mmol) was added dropwise to a solution of 5-bromo-3-fluoro-6-(methoxymethoxy)quinoline (300 mg, 1.05 mmol) in THF (18 mL), and the reaction mixture was stirred for 30 min. The reaction mixture was quenched with freshly ground dry ice (1.0 g, 22.7 mmol), then heated to room temperature and stirred for 30 min. The reaction mixture was concentrated under vacuum, and the intermediate lithium carboxylate was dissolved in DMF (4 mL), followed by the addition of KHCO3 (31.5 mg, 0.315 mmol) and BnBr (0.15 mL, 1.26 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned and extracted between saturated NaHCO3 aqueous solution and EtOAc. The layers were separated, and the aqueous layer was extracted again with EtOAc (twice). The combined organic extracts were washed with brine, dried (Na₂SO₄), filtered, and evaporated. The crude product was purified by preparative HPLC (alkaline) to give benzyl 3-fluoro-6-(methoxymethoxy)quinoline-5-carboxylate, a yellow oil. LC-MS J:t R = 2.08 min; [M+H] + = 342.10.

[0151] Step 4: To a solution of 3-fluoro-6-(methoxymethoxy)quinoline-5-carboxylate (107 mg, 0.31 mmol) in DCM (3 mL) at room temperature, TFA (0.24 mL, 3.13 mmol) was added, and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was dissolved in EtOAc and extracted with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with brine, dried (NaSO4), filtered, and concentrated to give 3-fluoro-6-hydroxyquinoline-5-carboxylate as a light brown oil. LC-MS J:t R = 2.06 min; [M+H] + = 298.1.

[0152] Step 5: At 0°C, DIAD (0.064 mL, 0.33 mmol) was added to a mixture of 3-fluoro-6-hydroxyquinoline-5-carboxylate (93.8 mg, 0.31 mmol), tert-butyl(R)-(1-hydroxy-3-phenylprop-2-yl)carbamate (82 mg, 0.33 mmol), and PPh3 (86 mg, 0.33 mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was purified directly by FC (eluting with a heptane solution of 20% to 60% EtOAc) to give (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylate as a colorless oil. LC-MS J:t R = 2.39 min; [M+H] + = 531.2.

[0153] Step 6: To a solution of (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-3-fluoroquinoline-5-carboxylic acid benzyl ester (94 mg, 0.18 mmol) in dioxane (3 mL), a solution of dioxane in 4 M HCl (0.44 mL, 1.77 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. Volatiles were removed under vacuum, and the residue was ground with Et₂O (3 times) to give the title compound B-1 as a white solid. LC-MS J:t R = 2.10 min; [M+H] + = 431.2.

[0154] Benzyl(R)-6-(2-amino-3-(6-methoxypyridin-2-yl)propoxy)-3-fluoroquinoline-5-carboxylate dihydrochloride (B-2) The title compound was prepared according to steps 5 and 6 of B-1 from benzyl 3-fluoro-6-hydroxyquinoline-5-carboxylate (B-1, steps 1-4) and tert-butyl(R)-(1-hydroxy-3-(6-methoxypyridin-2-yl)propyl-2-yl)carbamate (AL-1). LC-MSB: t R = 0.83 min; [M+H] + = 462.29.

[0155] Benzyl(R)-6-(2-amino-3-(6-bromo-4-methoxypyridin-2-yl)propoxy)-3-fluoroquinoline-5-carboxylate dihydrochloride (B-3) The title compound was prepared according to steps 5 and 6 of B-1 from benzyl 3-fluoro-6-hydroxyquinoline-5-carboxylate (B-1, steps 1-4) and tert-butyl(R)-(1-(6-bromo-4-methoxypyridin-2-yl)-3-hydroxypropyl-2-yl)carbamate (AL-2). LC-MS I:t R = 1.05 min; [M+H] + = 540.24.

[0156] Benzyl(R)-6-(2-amino-3-phenylpropoxy)-3-methylisoquinoline-5-carboxylate dihydrochloride (B-4) Step 1: At -10°C, trifluoromethanesulfonic anhydride (26.2 mL, 158 mmol) was added dropwise to a solution of 2-hydroxy-4-methoxybenzaldehyde (16 g, 105 mmol) and pyridine (42.5 mL, 526 mmol) in DCM (70 mL), and the reaction mixture was stirred for 30 minutes. The reaction mixture was quenched with ice water, acidified with 1M HCl aqueous solution, and then extracted (twice) with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum to give 2-formyl-5-methoxyphenyl trifluoromethanesulfonate as a yellow oil. 1 H NMR (400 MHz, CDCl3)δ 10.13 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.03 (dd, J = 8.7, 2.3 Hz, 1H), 6.88 (d, J = 2.3 Hz, 1H), 3.93 (s, 3H).

[0157] Step 2: A solution of 2-formyl-5-methoxyphenyl trifluoromethanesulfonate (19.6 g, 66.4 mmol) and TEA (93 mL, 664 mmol) in DMF (400 mL) at room temperature was purged with Ar for 30 min. Propryl-1-yne (1 M DMF solution, 133 mL, 133 mmol), CuI (1.27 g, 6.64 mmol), and Pd(PPh3)4 (5.0 g, 4.33 mmol) were added sequentially, and the reaction mixture was stirred under a sealed container for 2 h. The reaction mixture was filtered through a diatomaceous earth mat, and the filtrate was partially concentrated under vacuum, diluted with EtOAc, and washed sequentially with 1 M KHSO4 solution and brine, followed by vacuum concentration. The crude product was purified by FC (eluting with 0% to 30% EtOAc in heptane) to give 4-methoxy-2-(propryl-1-yne-1-yl)benzaldehyde as a yellow solid. LC-MSJ:t R = 1.80 min; [M+H]+ = 175.1.

[0158] Step 3: A solution of 10.3 g (58.8 mmol) of 4-methoxy-2-(prop-1-yn-1-yl)benzaldehyde in 350 mL MeOH at room temperature was purged with Ar for 5 min in an autoclave. A 7 M NH3 solution of MeOH (150 mL, 1050 mmol) was added, and the reaction mixture was heated at 65°C for 4 h to a pressure of 2 bar. The reaction mixture was concentrated under vacuum, and the residue was co-evaporated with DCM (twice) to give 6-methoxy-3-methylisoquinoline as a brown solid. LC-MS J:t R = 1.81 min; [M+H] + = 174.1.

[0159] Step 4: At -78°C, BBr3 (1 M DCM solution, 55.4 mL, 55.4 mmol) was added dropwise to a solution of 6-methoxy-3-methylisoquinoline (5.0 g, 27.7 mmol) in DCM (100 mL). The cooling bath was removed, and the reaction mixture was stirred at room temperature for 30 hours. The reaction mixture was carefully quenched in cold MeOH and concentrated under vacuum. The residue was co-evaporated with PhMe, EtOAc, and DCM to give 3-methylisoquinoline-6-ol as a brown solid. LC-MS J:t R = 1.10 min; [M+H] + = 160.1.

[0160] Step 5: Br2 (1.3 mL, 25.3 mmol) was added dropwise to a suspension of 3-methylisoquinoline-6-ol (4.67 g, 19.4 mmol) in CHCl3 (75 mL), and the reaction mixture was stirred for 2 hours. EtOAc was added, and the solid was collected by filtration and washed with EtOAc and heptane. The filter cake was neutralized by resuspending it in a saturated aqueous solution of NaHCO3, filtered again, and then washed with water and heptane. The filter cake was resuspended in MeCN and evaporated to give 5-bromo-3-methylisoquinoline-6-ol as a brown solid. LC-MSJ: t R = 1.02 min; [M+H] + = 238.0.

[0161] Step 6: (R)-(1-((5-bromo-3-methylisoquinoline-6-yl)oxy)-3-phenylprop-2-yl)tert-butyl carbamate was prepared from 5-bromo-3-methylisoquinoline-6-ol and (R)-(1-hydroxy-3-phenylprop-2-yl)tert-butyl carbamate according to the procedure described in Step 5 of B1. LC-MS J:tR = 2.21 min; [M+H] + = 471.1.

[0162] Step 7: A solution of (R)-(1-((5-bromo-3-methylisoquinoline-6-yl)oxy)-3-phenylprop-2-yl)carbamate tert-butyl ester (2.5 g, 5.30 mmol), benzyl alcohol (2.76 mL, 26.5 mmol), and DIPEA (2.78 mL, 15.9 mmol) in PhMe (20 mL) at room temperature was purged with Ar for 10 min. The reaction mixture was then purged with CO and heated to 88°C under a CO atmosphere, followed by the addition of a 5.5 mL solution of Pd(^tBu3P)2 (271 mg, 0.53 mmol) in PhMe (3 mL / h) via a syringe pump. The temperature was raised to 95°C, and the reaction mixture was stirred under a CO atmosphere for 24 h. The reaction mixture was cooled to room temperature and concentrated under vacuum, and the residue was partitioned and extracted between a saturated aqueous solution of NaHCO3 and EtOAc. The layers were separated, and the aqueous phase was extracted again with EtOAc (once). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum. The crude product was purified by FC (eluting with a heptane solution of 5% to 65% EtOAc) to give (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-3-methylisoquinoline-5-carboxylate, as a colorless oil. LC-MS J:t R = 2.19 min; [M+H] + = 527.2.

[0163] Step 8: The title compound was prepared from (R)-6-(2-((tert-butoxycarbonyl)amino)-3-phenylpropoxy)-3-methylisoquinoline-5-carboxylate according to the procedure described in Step 6 of B1. LC-MS J:t R = 1.95 min; [M+H] + =427.2.

[0164] Benzyl(R)-6-(2-amino-3-(6-methoxypyridin-2-yl)propoxy)-3-methylisoquinoline-5-carboxylate dihydrochloride (B-5) The title compound was prepared similarly to the procedure described in B-4, except that in step 6, (R)-(1-hydroxy-3-phenylprop-2-yl)carbamate tert-butyl ester was replaced with tert-butyl(R)-(1-hydroxy-3-(6-methoxypyridin-2-yl)prop-2-yl)carbamate (AL-1). LC-MS B:t R = 0.65 min; [M+H] += 458.3.

[0165] Benzyl(R)-4-(2-amino-3-(6-methoxypyridin-2-yl)propoxy)-2-methoxy-6-methylnicotinate (B-6) Step 1: Ethyl 2,4-dihydroxy-6-methylnicotinate (10 g, 0.0497 mol) was suspended in benzyl alcohol (26 mL, 0.248 mol) in a flask equipped with a Dean-Stark apparatus and a condenser. The reaction mixture was heated at 120°C overnight. The thick suspension became a clear solution after 10 minutes at 120°C. Precipitation occurred as the transesterification reaction proceeded further. After 68 hours, the precipitate was filtered, washed with TBME, and dried under high vacuum to give crude benzyl 2,4-dihydroxy-6-methylnicotinate as a beige solid, weighing 9.79 g. 1 H NMR (400 MHz, DMSO) δ: 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 t R = 0.78 min; [M+H] + = 260.2.

[0166] Step 2: Trimethyloxonium tetrafluoroborate (5353 mg, 35.1 mmol) was added to a suspension of 2,4-dihydroxy-6-methylnicotinic acid benzyl ester (4790 mg, 17.6 mmol) in DCM (50 mL). The reaction mixture was heated to 45°C for 4 hours. The suspension was cooled in an ice bath, and the precipitate was collected by filtration. The solid was redissolved in DCM (100 mL) and treated with 5% NaHCO3 aqueous solution (100 mL). The mixture was stirred for 20 minutes. The layers were separated, the organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum to give crude 4-hydroxy-2-methoxy-6-methylnicotinic acid benzyl ester as an off-white solid (3.81 g), which could be used directly without further purification. 1 H NMR (400 MHz, DMSO) δ: 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: t R = 0.49 min; [M+H]+ = 273.8.

[0167] Step 3: (R)-4-(2-((tert-butoxycarbonyl)amino)-3-(6-methoxypyridin-2-yl)propoxy)-2-methoxy-6-methylnicotinic acid benzyl ester was prepared from 4-hydroxy-2-methoxy-6-methylnicotinic acid benzyl ester and tert-butyl(R)-(1-hydroxy-3-(6-methoxypyridin-2-yl)prop-2-yl)carbamate (AL-1) according to the procedure described in Step 5 of B1. LC-MS B:t R =1.14 min; [M+H] + = 538.35.

[0168] Step 4: To a solution of (R)-4-(2-((tert-butoxycarbonyl)amino)-3-(6-methoxypyridin-2-yl)propoxy)-2-methoxy-6-methylnicotinic acid benzyl ester (697 mg, 1.3 mmol) in DCM (20 mL) at room temperature, TFA (2.98 mL, 38.9 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. After deprotection, the mixture was evaporated to dryness. The crude product was redissolved in DCM and evaporated again (repeated twice). The residue was partitioned between DCM and 1M NaOH aqueous solution, and the layers were separated. The aqueous layer was extracted again with DCM (twice). The combined organic extracts were dried over MgSO4, filtered, and evaporated under vacuum to give the title compound as a pale yellow oil (0.431 g), which could be used directly without further purification. LC-MS B:t R = 0.81 min; [M+H] + = 438.4.

[0169] Benzyl(R)-6-(2-amino-3-(6-bromo-4-methylpyridin-2-yl)propoxy)-3-fluoroquinoline-5-carboxylate dihydrochloride (B-7) The title compound was prepared according to steps 5 and 6 of B-1 from benzyl 3-fluoro-6-hydroxyquinoline-5-carboxylate (B-1, steps 1-4) and tert-butyl(R)-(1-(6-bromo-4-methylpyridin-2-yl)-3-hydroxypropyl-2-yl)carbamate (AL-3). LC-MS I:t R = 1.09 min; [M+H] + = 524.22.

[0170] Benzyl(R)-6-(2-amino-3-(4-chloro-6-methoxypyrimidin-2-yl)propoxy)-3-fluoroquinoline-5-carboxylate 2,2,2-trifluoroacetate (B-8) The title compound was prepared according to steps 5 and 6 of B-1 from benzyl 3-fluoro-6-hydroxyquinoline-5-carboxylate (B-1, steps 1-4) and tert-butyl(R)-(1-(4-chloro-6-methoxypyrimidin-2-yl)-3-hydroxypropyl-2-yl)carbamate (AL-4), wherein in step 6, Boc-deprotection was performed using TFA instead of HCl (4M dioxane solution). LC-MS B:t R = 0.85 min; [M+H] + = 497.0.

[0171] Benzyl(R)-6-(2-amino-3-(2-chloro-6-methoxypyrimidin-4-yl)propoxy)-3-fluoroquinoline-5-carboxylate 2,2,2-trifluoroacetate (B-9) The title compound was prepared according to steps 5 and 6 of B-1 from benzyl 3-fluoro-6-hydroxyquinoline-5-carboxylate (B-1, steps 1-4) and tert-butyl(R)-(1-(2-chloro-6-methoxypyrimidin-4-yl)-3-hydroxypropyl-2-yl)carbamate (AL-5), wherein in step 6, Boc-deprotection was performed using TFA instead of HCl (4M dioxane solution). LC-MS B:t R = 0.84 min; [M+H] + = 497.0.

[0172] (RS)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-N,4-dimethylpentamido)-3-(3-fluorobicyclo[1.1.1]pent-1-yl)propionic acid (C-1) Step 1: Under argon atmosphere, HATU (5.04 g, 13.3 mmol) was added to a 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) at room temperature. The resulting mixture was stirred for 1 hour. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was re-extracted with EtOAc (twice). The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and evaporated under vacuum. The crude product was purified by FC and eluted with a gradient of (heptane / ethyl acetate) from (1:1) to (0:1) to give 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) δ: 3.65 (s, 3 H), 3.11 (s, 3 H), 2.35 (d, J =2.6 Hz, 6 H); LC-MS B: t R = 0.65 min; [M+H] + = 174.2.

[0173] Step 2: 1.6 g (9.24 mmol) of 3-fluoro-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide was dissolved in THF (21.4 mL, 21.4 mmol), and the resulting mixture was cooled to -78°C under argon. A DIBAH solution (1.0 M toluene solution, 12 mL, 12 mmol) was added, and the mixture was stirred at -78°C for 1 hour and 30 minutes. The reaction mixture was quenched with MeOH (10 mL) and diluted with a large amount of EtOAc. The resulting organic layer was washed with Rochelle salt (saturated aqueous solution) and brine, dried over MgSO4, filtered, and concentrated under reduced pressure (only to 50 mbar at 42°C, as the compound was expected to be volatile) to give 1.23 g of crude 3-fluorobicyclo[1.1.1]pentane-1-carboxaldehyde as a white solid, which was used directly for the next step. LC-MSB: t R = 0.86 min; [M+H] + = 114.0 (poor ionization).

[0174] Step 3: N-Butoxycarbonyltrimethylphosphonoglycine (3.37 g, 11 mmol) and DBU (1.79 mL, 11.9 mmol) were added to a solution of 3-fluorobicyclo[1.1.1]pentane-1-carboxaldehyde (1.23 g, 10.8 mmol) in DCM (30 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was then quenched with a saturated aqueous ammonium chloride solution and extracted with DCM (3 times). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. The crude product was purified by FC, eluted with a gradient of (heptane / ethyl acetate: from 100 / 0 to 70 / 30), to give 0.76 g of methyl 2-((tert-butoxycarbonyl)amino)-3-(3-fluorobicyclo[1.1.1]pent-1-yl)acrylate, presumably a cis / trans mixture, as a white solid. LC-MS B: t R = 0.92 min; [M+H] + = 286.2.

[0175] Step 4: At room temperature and under argon atmosphere, sodium hydride (60% mineral oil dispersion, 36.9 mg, 0.964 mmol) was added in portions to a solution of 2-((tert-butoxycarbonyl)amino)-3-(3-fluorobicyclo[1.1.1]pent-1-yl)acrylate (250 mg, 0.876 mmol) and iodomethane (0.0606 mL, 0.964 mmol) in DMF (5 mL), which was presumed to be a cis / trans mixture. The resulting mixture was stirred for 1 hour. The mixture was then partitioned between water and EtOAc. The layers were separated, and the aqueous phase was re-extracted with EtOAc (twice). The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and vacuum evaporated to give crude methyl 2-((tert-butoxycarbonyl)(methyl)amino)-3-(3-fluorobicyclo[1.1.1]pent-1-yl)acrylate, presumably a cis / trans mixture, as a pale yellow oil (270 mg), which was used directly in the next step without further purification. LC-MS B:t R = 0.99 min; [M+H] + = 300.4.

[0176] Step 5: The crude cis / trans mixture of methyl 2-((tert-butoxycarbonyl)(methyl)amino)-3-(3-fluorobicyclo[1.1.1]pent-1-yl)acrylate (270 mg, 0.902 mmol, 1 eq) in EtOH (5 mL) was purged with N2 / vacuum (3 times), and then PtO2 (20.5 mg, 0.0902 mmol) was added. After inertization three more times, an H2 balloon was attached, and the reaction mixture was stirred under H2 atmosphere for 1 hour. The heterogeneous reaction mixture was filtered through glass fiber filter paper (washed with methanol / THF). The filtrate was concentrated to dryness under reduced pressure to give 0.3 g of crude racemic methyl (R)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(3-fluorobicyclo[1.1.1]pent-1-yl)propionate as a colorless oil. LC-MS B:t R = 1.00 min; [M+H] + = 302.4.

[0177] Step 6: Add trifluoroacetic acid (TFA) (0.778 mL, 9.95 mmol) to a solution of crude racemic methyl (R)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(3-fluorobicyclo[1.1.1]pent-1-yl)propionate (300 mg, 0.995 mmol) in DCM (5 mL) at room temperature. Stir the resulting mixture at room temperature for 6 hours. After Boc-deprotection, remove the volatiles under vacuum. Co-evaporate the residue with DCM (twice) to obtain crude racemic methyl (R)-3-(3-fluorobicyclo[1.1.1]pent-1-yl)-2-(methylamino)propionate 2,2,2-trifluoroacetate, a colorless oil (447 mg), which can be used directly in the next step without further purification. LC-MS B:t R = 0.48 min; [M+H] + = 202.6.

[0178] Step 7: Add HATU (593 mg, 1.56 mmol) to a solution of racemic (R)-3-(3-fluorobicyclo[1.1.1]pent-1-yl)-2-(methylamino)propionate 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) at room temperature and under argon atmosphere. Stir the resulting mixture for 1 hour to complete the conversion. Partition the mixture between water and EtOAc. Separate the layers, and extract the aqueous phase twice with EtOAc. Wash the combined organic extracts with water and brine, dry with Na2SO4, filter, and evaporate under vacuum. The crude product was then purified by FC using a gradient of (heptane / ethyl acetate) from (1:1) to (0:1) to give a mixture of epiomers (RS)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-N,4-dimethylpentamido)-3-(3-fluorobicyclo[1.1.1]pent-1-yl)propionate (317 mg), as a colorless oil. LC-MS B:t R = 1.10 min; [M+H] + = 429.4.

[0179] Step 8: A solution of the diastereomer mixture (RS)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-N,4-dimethylpentamido)-3-(3-fluorobicyclo[1.1.1]pent-1-yl)propionate (317 mg, 0.74 mmol) in dioxane (5 mL) was added to a solution of 2M NaOH (0.75 mL, 1.50 mmol). The reaction mixture was stirred at 60°C for 1 hour to complete the conversion. The reaction mixture was neutralized with a few drops of saturated NH4Cl solution and evaporated to dryness. The residue was dissolved in DCM and water and carefully acidified with 2N HCl aqueous solution (to pH ~3). The DCM layer was then collected, and the aqueous layer was extracted with DCM again (twice). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure to give 313 mg of crude title product (C-1) as a colorless oil, which could be used directly for the next step without further purification. LC-MS B:t R = 0.99 and 1.00 min; [M+H] + =415.4 (1:1 epimer mixture).

[0180] Table 2-C below lists the structural unit C prepared in a similar manner to the 8-step sequence described in C-1 above.

[0181] Table 2-C (R)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-N,4-dimethylpentamido)-3-(1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)propionic acid (C-6) Step 1: At -78°C, a solution of n-butyllithium (1.6 M hexane solution, 3.05 mL, 4.9 mmol) was 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). After stirring for 30 minutes, a solution of 4-(bromomethyl)-1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hexane (1000 mg, 4.08 mmol) in THF (50 mL) was added dropwise at -78°C. The mixture was allowed to return to room temperature and stirred at room temperature for 3 hours. The reaction was quenched by adding saturated NH4Cl aqueous solution and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and vacuum evaporated to give 1.56 g of crude (2S,5R)-2-isopropyl-3,6-dimethoxy-5-((1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)methyl)-2,5-dihydropyrazine as an orange oil. Purification was not performed at this stage (almost no UV signal). LC-MS B:t R = 1.05 min; [M+H] + = 349.3.

[0182] Step 2: To a pale orange solution of crude (2S,5R)-2-isopropyl-3,6-dimethoxy-5-((1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)methyl)-2,5-dihydropyrazine (1560 mg, 4.48 mmol, 1 eq) in MeCN (30 mL) at room temperature, 1 M HCl aqueous solution (9 mL, 9 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Saturated NaHCO3 and DCM were added to the reaction mixture. The layers were separated, and the aqueous layer was further extracted with DCM. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and vacuum evaporated to give 1.17 g of crude (R)-2-amino-3-(1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)propionate, a pale yellow oil, which could be used directly without further purification. LC-MS B:t R = 0.52 min; [M+H] + = 254.25.

[0183] Step 3: Methyl (R)-2-amino-3-(1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)propionate (1.17 g, 4.62 mmol) was dissolved in THF (10 mL) and H2O (10 mL). NaHCO3 (1.94 g, 23.1 mmol) was added, followed by Boc2O (1.11 g, 5.09 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with water and extracted (3 times) with EtOAc. The collected organic phase was dried over MgSO4, filtered, and evaporated. The crude product was purified by FC (heptane / EtOAc 1:1) to give 890 mg of (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)propionate, which was a colorless oil. 1 H NMR (400 MHz, DMSO) δ: 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, 1H), 3.69 (d, J = 5.9 Hz, 1 H), 3.64 (s, 3 H), 2.18 (dd, J = 14.6, 3.8 Hz, 1H), 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:t R = 0.95 min; [M+H] + = 353.96.

[0184] Step 4: At room temperature and under argon atmosphere, sodium hydride (60% mineral oil dispersion, 106 mg, 2.77 mmol) was added in portions to a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-(1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl) in DMF (10 mL), 889 mg, 2.52 mmol, and 99% methyl iodide (0.174 mL, 2.77 mmol). The mixture was stirred for 1 hour. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and vacuum evaporated to obtain 945 mg of crude (R)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)propionate, which could be used directly without further purification. LC-MS B:t R = 1.02 min; [M+H] + = 368.3.

[0185] Step 5: Add trifluoroacetic acid (2.01 mL, 25.7 mmol) to a solution of (R)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)propionate (945 mg, 2.57 mmol, 1 eq) in DCM (5 mL) at room temperature. Stir the resulting mixture at room temperature for 6 hours. Remove volatiles under vacuum and co-evaporate with DCM (3 times) to obtain 1.21 g of crude (R)-2-(methylamino)-3-((1R,4s)-1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)propionate 2,2,2-trifluoroacetate, an orange syrup, which can be used directly without further purification. LC-MS B:t R = 0.52 min; [M+H] + = 268.25.

[0186] Steps 6 and 7: The title compound was prepared according to steps 7 and 8 of C-1 from Boc-N-methyl-L-leucine and (R)-2-(methylamino)-3-((1R,4s)-1-(trifluoromethyl)-2-oxabicyclo[2.1.1]hex-4-yl)propionate 2,2,2-trifluoroacetate; LC-MS B: t R = 1.02 min; [M+H] + = 481.2.

[0187] Synthesis of compound (I) General Method: GM-A Example 1: (3S,7S,10R,13R)-13-benzyl-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide Step 1: Add HATU (316 mg, 0.831 mmol) to a 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) at room temperature and under argon atmosphere. Stir the resulting mixture for 1 hour. Partition the reaction mixture between water and EtOAc, separating the layers. Extract the aqueous phase twice with EtOAc, wash the combined organic extracts with brine, dry (Na2SO4), filter, and evaporate. The crude product was purified by FC elution with a (heptane / EtOAc) gradient from (1 / 1) to (0 / 1) to give a mixture of epimers: 6-(((6S,9RS,12R)-12-benzyl-9-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-6-isobutyl-2,2,5,8-tetramethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-13-yl)oxy)-3-fluoroquinoline-5-carboxylic acid benzyl ester, as a colorless oil. LC-MS B t R = 1.31 and 1.32 min; [M+H] + = 827.5.

[0188] Step 2: The solution of 6-(((6S,9RS,12R)-12-benzyl-9-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-6-isobutyl-2,2,5,8-tetramethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-13-yl)oxy)-3-fluoroquinoline-5-carboxylic acid benzyl ester (687 mg, 0.83 mmol) in EtOH (10 mL) was purged / purged (3 times) with N2 / vacuum, and then 10% Pd / C (68 mg, 7.5 mol%) was added. The reaction mixture was purged / purged (3 times) with H2 and stirred for 1 hour under H2 atmosphere. The reaction mixture was filtered through glass fiber filter paper (washed with THF / MeOH 4 / 1), and the filtrate was concentrated to dryness under reduced pressure to give a mixture of epimers: 6-(((6S,9RS,12R)-12-benzyl-9-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-6-isobutyl-2,2,5,8-tetramethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-13-yl)oxy)-3-fluoroquinoline-5-carboxylic acid, as a colorless syrup. LC-MS B t R = 1.16 and 1.18 min; [M+H] + = 737.5.

[0189] Step 3: Add HATU (112 mg, 0.30 mmol) to a solution of 6-(((6S,9RS,12R)-12-benzyl-9-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-6-isobutyl-2,2,5,8-tetramethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-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) at room temperature, and stir the reaction mixture for 1 hour. Partition the mixture between water and EtOAc. Separate the layers, and extract the aqueous phase twice with EtOAc. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and evaporated under vacuum. The crude product was purified by FC using a gradient of (heptane / ethyl acetate) from (1:1) to (0:1) to give a mixture of epimers (S)-3-(6-(((6S,9RS,12R)-12-benzyl-9-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-6-isobutyl-2,2,5,8-tetramethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-13-yl)oxy)-3-fluoroquinoline-5-carboxamido)-4-((2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutyrate tert-butyl ester, as a white solid. LC-MS B:t R = 1.23 min; [M+H] + = 1033.5.

[0190] Step 4: Add TFA (1.04 mL, 13.6 mmol) to a solution of (S)-3-(6-(((6S,9RS,12R)-12-benzyl-9-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-6-isobutyl-2,2,5,8-tetramethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecane-13-yl)oxy)-3-fluoroquinoline-5-carboxamido)-4-((2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)amino)-4-oxobutyrate tert-butyl ester (140 mg, 0.136 mmol) in DCM (4 mL), and stir the resulting mixture for 1.5 hours. Concentrate the reaction mixture under vacuum, redissolve the residue in DCM, and concentrate again under vacuum (twice). The residue was dissolved in DMF (4 mL), and DIPEA (0.186 mL, 1.08 mmol) and HATU (61.8 mg, 0.163 mmol) were added. The mixture was stirred at room temperature for 15 minutes. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and evaporated under vacuum to give the crude product. The title compound (3S,7S,10R,13R)-13-benzyl-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide was purified by preparative HPLC (alkaline) as a white solid. LC-MS I: tR = 1.08 min; [M+H] + = 859.5. Note: The second stereoisomer (3S,7S,10S,13R)-13-benzyl-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide was also isolated as a white solid. LC-MS I:t R = 1.03 min; [M+H] + = 859.5.

[0191] Table MC-1 below lists the compounds of formula (I) prepared from the corresponding structural units A, B, and C according to the general method A (GM-A) described above. In the table below, The example compounds isolated during synthesis are typically minor epimers separated as part of the final synthetic step in preparative HPLC purification due to epimerization of the chiral center. In some cases, enantiomeric or diastereomeric structural units undergo epimerization during synthesis, and the example compounds are separated as a mixture of epimers.

[0192] Table MC-1 (GM-A) The following table lists example compounds of formula (I) prepared according to the method described above.

[0193] Example Table Table 3: Structures of the compounds in Examples 1 to 48 II. Biological assays The compounds of the present invention can be further characterized by conventional assays known in the art, relating to their general pharmacokinetic and pharmacological properties in different species (e.g., rats or dogs); or relating to their drug safety and / or toxicological properties, using conventional assays known in the art, such as those relating to cytochrome P450 enzyme inhibition and time-dependent inhibition, pregnane X receptor (PXR) activation, glutathione binding, or phototoxic behavior.

[0194] Biological in vitro assay Compound EC 50 and E max Value assessment The corrector activity of compound (I) against CFTR was determined using the following experimental method. This method measured the effect of overnight compound incubation on the expression of F508del-CFTR on the cell surface in the recombinant U2OS cell line (DiscoverX, #93-0987C3). This cell line was engineered to co-express (i) human F508del-CFTR labeled with Prolink (PK = short β-galactosidase fragment) and (ii) the remaining portion of β-galactosidase (enzyme receptor; EA) localized to the plasma membrane. Incubation with the compound that increases PK-labeled F508del-CFTR on the plasma membrane resulted in complementary formation of the EA fragment to form a functional β-galactosidase, which was quantified by a chemiluminescent reaction.

[0195] In short, cells were seeded at 3500 cells / well in 384-well low-volume plates (Corning, #3826), with 20 µl of complete culture medium per well (McCoy's 5a (#36600-021, Gibco) + 10% FBS Gibco + penicillin / streptomycin). Cells were incubated for 5 hours, followed by the addition of 5 µl of a compound dilution series (5-fold working stock in complete culture medium) to each well. The final DMSO concentration for the assay was 0.25%. Cells and compounds were co-incubated at 37°C, 5% CO2 for 16 hours. The next day, the cell plates were incubated at room temperature in the dark for 2 hours. Then, 10 µl of Flash assay reagent (DiscoverX, #93-0247) was added to each well, and the plates were incubated at room temperature in the dark for another 30 minutes, and chemiluminescence was measured. Concentration-response curves were generated using the compound's intrinsic maximum power as the platform limit, and the intrinsic EC of the compound was determined from these CRCs. 50 Value. Compound specificity E max The value relative to the corrector lumacaftor E max Calculation (E) max Lumacaftor (100%)

[0196] Calculated EC 50 Values ​​may fluctuate due to daily performance measurements. Such fluctuations are known to those skilled in the art. EC values ​​from multiple measurements 50 The values ​​are given as geometric mean. The calculated E... max Values ​​may fluctuate due to daily performance measurements. Such fluctuations are known to those skilled in the art. E values ​​from multiple measurements max The values ​​are given as the arithmetic mean.

[0197] References 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. Biological data table: Evaluation of the inhibitory effect of compound (I) on CYP450 3A4 enzyme-mediated midazolam hydroxylation.

[0198] CYP3A4 inhibition was investigated using midazolam 1'-hydroxylation as a marker reaction. Midazolam was used at a single concentration of 5 µM near its Km (Michaelis constant), and the test compound was incubated at eight different concentrations up to 50 µM. Nicardipine was used as a positive control. Microsomal incubation was initiated by adding an NADPH regeneration 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.

[0199] Table of inhibitory effects of midazolam CYP450 3A4 hydroxylation: Evaluation of the inhibitory effect of compound (I) on BSEP transporter channels.

[0200] The inhibitory potential of human BSEP was investigated in vesicle uptake assays using 0.2 mM taurocholic acid (TCA, as a mixture of 3H-TCA and cold TCA) as a model substrate. For BSEP inhibition assays in rats, dogs, and monkeys, the TCA concentrations were 2, 0.2, and 0.2 mM (as a mixture of 3H-TCA and cold TCA), respectively.

[0201] 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. Incubation was performed at 37°C in vesicle transport buffer (2 mM Hepes-Tris, pH 7.4, 50 mM sucrose, 100 mM KNO3, 10 mM Mg(NO3)2) containing the model substrate itself or in combination with various concentrations of test substance (TA), ranging from 0.03 mM to 100 mM. The incubation time for BSEP / Bsep in humans, rats, and monkeys was 5 min, while that for Bsep in dogs was 2 min. TCA uptake was terminated by adding ice-cold wash buffer (10 mM Tris-HCl, pH 7.4, 50 mM sucrose, and 100 mM KNO3) and filtering the membrane suspension through a nitrocellulose membrane filter (0.45 mm pore size) using a rapid filtration system (Millipore, Zug, Switzerland). The membrane suspension retained on the filter was washed twice with ice-cold wash buffer and then transferred to a scintillation vial. After adding 3.5 mL of scintillation fluid (Filter-Count, Perkin Elmer, Zürich, Switzerland), total radioactivity was counted using a Tri-Carb 2300 TR liquid scintillation analyzer (Packard Bioscience, Zürich, Switzerland). The nitrocellulose filter was saturated with 1 mM TCA before the experiment. Cyclosporine A (0.03 mM to 100 mM) was used as a positive control.

[0202] In the screening assay, each concentration was tested once, while for the compound of interest, the assay was repeated three times for each concentration.

[0203] BSEP / Bsep-mediated net uptake is calculated as the difference in uptake rates obtained in the presence of ATP or AMP. Net uptake is expressed as arithmetic mean and standard deviation (SD) (if applicable).

[0204] Data from the inhibition experiments were assessed by plotting inhibitor concentration (logarithmic scale) against net uptake. The IC50 value was then determined from the plot using a nonlinear regression with the following equation: Where y is the net uptake rate [(pmol / (mg protein∙min))], x is the inhibitor concentration (mM), s is the slope at the inflection point, and Top and Bottom are the maximum and minimum net uptake rates. The minimum (Bottom) is constrained to 0. All graphical data were evaluated using the GraphPad Prism software package (version 8.1.1, GraphPad Software Inc., La Jolla, USA).

[0205] The calculated IC50 value may fluctuate due to daily performance measurements. Such fluctuations are known to those skilled in the art. IC50 values ​​from multiple measurements are given as a geometric mean.

[0206] Table of BSEP transporter inhibitory effects: References Boyle MP et al (2014). Lancet Respir Med 2(7):527-538. Dalemans W et al (1991). Nature 354:526-528. Davies JC et al (2018). N Engl J Med 379(17):1599-1611 de Boeck K (2020). Acta Paediatr 109(5):893-895 Elborn JS (2016). Lancet 388:2519-2531. Fiedorczuk K et al (2022). Cell 185(1):158-168. Flores AM et al (2016). FASEB J 30(5):1789-1797. Galietta LV et al (2001). Am J Physiol Cell Physiol 281(5):C1734-1742. Hutt DM et al (2011). ACS Med Chem Lett 2(9):703-707. Keating D et al (2018). N Engl J Med 379(17):1612-1620. Le Grand D et al (2021). J Med Chem 64(11):7241-7260. Marchesin V et al (2023). / / doi.org / 10.1101 / 2023.08.15.552928 Okiyoneda T et al (2013). Nat Chem Biol 9(7):444-454. Patel SD et al (2020). Eur Respir Rev 29(156):190068. Stevers LM et al (2022). Nat Commun 13:3586. Van Goor F et al (2011). Proc Natl Acad Sci USA 108(46):18843-18848. Veit G et al (2018). Nat Med 24(11):1732-1742. Veit G et al (2020). JCI Insight 5(18):e139983.

Claims

1. A compound of formula (I) Formula (I) in R 1 Represents C1₋4-alkyl; R 2 Represents C1₋4-alkyl; R 3 Represents C1₋6-alkyl; R 4 Represents a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from C1₋4-alkyl, C1₋4-alkoxy, C1₋3-fluoroalkyl, C1₋3-fluoroalkoxy, halogen, cyano, and C3₋6-cycloalkyl; W represents -CH2- or -CH2-CH2-; Z represents -CH2-, -CH2-CH2-, or -CH2-O- The asterisk (*) indicates the relationship with -CR. 5 Connected keys; R 5 Represents halogen, C1₋4-alkyl, C1₋4-fluoroalkyl, or C1₋4-alkoxy; Ar 1 represent: ●6-Hyperarylene; wherein the 6-heterarylene is mono-, di-, or tri-substituted, wherein the substituent is independently selected from C1₋4-alkyl, C1₋4-alkoxy, C1₋3-fluoroalkyl, C1₋3-fluoroalkoxy, cyano, and halogen; or ●8- to 10-membered bicyclic heteroarylene; wherein the 8- to 10-membered bicyclic heteroarylene is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from C1₋4-alkyl, C1₋3-fluoroalkyl, C1₋4-alkoxy, C1₋3-fluoroalkoxy, cyano, and halogen; and Ar 2 Represents a phenyl, or a 5- or 6-membered heteroaryl, wherein the phenyl or 5- or 6-membered heteroaryl is unsubstituted, or mono- or di-substituted, wherein the substituent is independently selected from C1₋4-alkyl, C1₋3-fluoroalkyl, halogen, cyano, C3₋6-cycloalkyl, C1₋4-alkoxy, and C1₋3-fluoroalkoxy; Or its pharmaceutically acceptable salt.

2. The compound of formula (I) as defined in claim 1, wherein the compound is also of formula (I) E Compounds of: Equation (I E ) ; Or its pharmaceutically acceptable salt.

3. The compound according to claim 1 or 2; wherein R 4 Represents a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is mono- or di-substituted, wherein the substituents are independently selected from C1₋4-alkoxy, halogen, and C3₋6-cycloalkyl; W stands for -CH2-; Z represents -CH2- or -CH2-O- ; R 5 Represents halogen, C1₋4-alkyl, C1₋4-fluoroalkyl, or C1₋4-alkoxy; Ar 1 represent: ●6-Hyperarylene; wherein the 6-heteroarylene is di-substituted, wherein the substituents are independently selected from C1₋4-alkyl and C1₋4-alkoxy; or ●10-membered bicyclic heteroarylene; wherein the 10-membered bicyclic heteroarylene is mono-substituted with a C1₋4-alkyl group or a halogen; and Ar 2 Represents a phenyl or 6-membered heteroaryl group, wherein the phenyl or 6-membered heteroaryl group is unsubstituted or mono-substituted by a C1₋4-alkyl or C1₋4-alkoxy group; Or its pharmaceutically acceptable salt.

4. The compound according to any one of claims 1 to 3; wherein the fragment represent: ; ; ; ; ; ; ; ;or ; Or its pharmaceutically acceptable salt.

5. The compound according to any one of claims 1 to 4; wherein Ar 1 represent: ●6-Hyperarylene; wherein the 6-heteroarylene is di-substituted, wherein the substituents are independently selected from C1₋4-alkyl and C1₋4-alkoxy; or ●10-membered bicyclic heteroarylene; wherein the 10-membered bicyclic heteroarylene is mono-substituted by a halogen (especially fluorine); Or its pharmaceutically acceptable salt.

6. The compound according to any one of claims 1 to 5; wherein Ar 2 represent: ●Phenyl; or ●6-Hyperaryl; wherein the 6-heteraryl group is mono-substituted by a C1₋4-alkoxy group; Or its pharmaceutically acceptable salt.

7. The compound according to claim 1, wherein the compound is: (3S,7S,10R,13R)-13-benzyl-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-10-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9,20-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-10-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9,20-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-10-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-7-isobutyl-6,9,20-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-N-(2-(4-fluoro-3-methoxyisoxazol-5-yl)ethyl)-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-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-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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)-10-((3-methoxybicyclo[ 1.1.1]pent-1-yl)methyl)-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-7-isobutyl-10-((3-methoxybicyclo[ 1.1.1] pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-7-isobutyl-10-((3-methoxybicyclo[ 1.1.1]pent-1-yl)methyl)-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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]pent-1-yl)methyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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-dimethyl-10-((3-methylbicyclo[1.1.1]pent-1-yl)methyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-7-isobutyl-13-((6-methoxypyridin-2-yl)methyl)-6,9-dimethyl-10-((3-methylbicyclo[1.1.1]pent-1-yl)methyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-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-10-((3-methylbicyclo[1.1.1]pent-1-yl)methyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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-dimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-7-isobutyl-13-((6-methoxypyridin-2-yl)methyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-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)bicyclo[1.1.1]pent-1-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazo-5-yl)ethyl)-6,9-dimethyl-10-((1-methyl-2-oxabicyclo[ 2.1.1] Hex-4-yl)methyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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] Hex-4-yl)methyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (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] Hex-4-yl)methyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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] Hex-4-yl)methyl)-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-10-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-13-((6-methoxypyridin-2-yl)methyl)-6,9,20-trimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]isoquinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-10-((3-methoxybicyclo[ 1.1.1]pent-1-yl)methyl)-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-10-((3-methoxybicyclo[ 1.1.1]pent-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-tetradecano-[1]oxaza[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-10-((3-chlorobicyclo[1.1.1]pent-1-yl)methyl)-20-fluoro-7-isobutyl-N-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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] Hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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)methyl)-7,10,18-trimethyl-5,8,11,15-tetraoxo-6-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecanopyrido[3,4-p][1]oxa[4,7,10,14]tetraazacycloheptadecene-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-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecanopyrido[3,4-p][1]oxa[4,7,10,14]tetraazacycloheptadecene-13-carboxamide; (3R,6R,9S,13S)-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-9-isobutyl-16-methoxy-3-((6-methoxypyridin-2-yl)methyl)-7,10,18-trimethyl-5,8,11,15-tetraoxo-6-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl)-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecanopyrido[3,4-p][1]oxa[4,7,10,14]tetraazacycloheptadecene-13-carboxamide; (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-dimethyl-1,5,8,11-tetraoxo-10-((1-(trifluoromethyl)-2-oxabicyclo[ 2.1.1] Hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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-dimethyl-1,5,8,11-tetraoxo-10-((1-(trifluoromethyl)-2-oxabicyclo[ 2.1.1] Hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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-1,5,8,11-tetraoxo-10-((1-(trifluoromethyl)-2-oxabicyclo[ 2.1.1] Hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-7-isobutyl-6,9-dimethyl-1,5,8,11-tetraoxo-10-((1-(trifluoromethyl)-2-oxabicyclo[ 2.1.1] Hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-13-benzyl-20-fluoro-7-isobutyl-N-(2-(3-methoxyisoxazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-((1-(trifluoromethyl)-2-oxabicyclo[ 2.1.1] Hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[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)methyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-((1-(trifluoromethyl)-2-oxabicyclo[ 2.1.1] Hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-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-(trifluoromethyl)-2-oxabicyclo[ 2.1.1] Hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-7-isobutyl-13-((4-methoxypyridin-2-yl)methyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-((1-(trifluoromethyl)-2-oxabicyclo[ 2.1.1] Hex-4-yl)methyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-N-(2-(5-cyclopropyl-2H-tetrazole-2-yl)ethyl)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-7-isobutyl-N-(2-(3-methoxyisoxazol-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; or (3S,7S,10R,13R)-20-fluoro-10-((3-fluorobicyclo[1.1.1]pent-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-tetradecano-[1]oxa[4,7,10,14]tetraazacycloheptadecano[16,17-f]quinoline-3-carboxamide; Or its pharmaceutically acceptable salt.

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. The use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 as a medicine.

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

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

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