Cyclic pyridine derivatives as cGAS inhibitors

Abstract

The present invention provides compounds of formula I for the treatment of diseases such as systemic lupus erythematosus, systemic sclerosis (SSc), interferonosis, nonalcoholic steatohepatitis (NASH), interstitial lung disease (ILD), and idiopathic pulmonary fibrosis (IPF). JPEG2026504613000125.jpg8493 (in the formula, R 1 , R 2 , R 3 , R 4 , A, D, E, G, J, K, and L are as defined in claim 1), and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

Description

[Background technology]

[0001] 1. Background of the Invention 1.1 cGAS inhibitors Innate immunity is considered a frontline cellular stress response that protects host cells from invading pathogens and initiates signaling to the adaptive immune system. These processes are triggered by conserved pathogen-associated molecular patterns (PAMPs) through sensing by diverse pattern recognition receptors (PRRs) and subsequent activation of cytokine and type I interferon gene expression. Primary antigen-presenting cells, such as monocytes, macrophages, and dendritic cells, produce type I interferons and are crucial for triggering adaptive immune responses in T and B cells. Primary PRRs detect aberrant nucleic acids—i.e., mislocalized, immature, or unmodified nucleic acids—on the cell surface, within lysosomal membranes, or within other cellular compartments (Barbalat et al., Annu. Rev. Immunol. 29, 185-214 (2011)).

[0002] "Cyclic GMP-AMP synthetase ( C yclic G MP- A MP S synthesis)" ( cGAS, UniProtKB-Q8N884) is a major sensor of aberrant double-stranded DNA (dsDNA) derived from pathogens or from aberrant localization or processing of cellular dsDNA in the nucleus or mitochondria (Sun et al., Science 339, 786-791 (2013); Wu et al., Science 339, 826-830 (2013); Ablasser et al., Nature 498, 380-384 (2013)). Binding of dsDNA to cGAS activates a reaction of GTP and ATP to form the cyclic dinucleotide GMP-AMP (termed cGAMP). cGAMP then binds to the endoplasmic reticulum membrane-bound adaptor protein "Stimulator of Interferon Genes" ( STING ) and activates the protein. Activated STING binds to TANK-binding kinase ( T ANK- b inding k inase) 1 ( TBK1 ), which recruits and activates interferon regulatory factor (IFN)-1 (IFN-1), which induces the mRNA expression of cytokines and type I interferons. i Interferon r egulatory f actor)( IRF ) family of transcription factors.

[0003] The crucial role of cGAS in sensing dsDNA has been demonstrated in various pathogenic bacteria (Hansen et al., EMBOJ. 33, 1654 (2014)), viruses (Ma et al., PNAS 112, E4306 (2015)), and retroviruses (Gao et al., Science 341, 903-906 (2013)). Additionally, cGAS is essential in various other biological processes, such as cellular senescence (Yang et al., PNAS 114, E4612 (2017), Gluck et al., Nat. Cell Biol. 19, 1061-1070 (2017)) and the recognition of ruptured micronuclei in the surveillance of potential cancer cells (Mackenzie et al., Nature 548, 461-465 (2017); Harding et al., Nature 548, 466-470 (2017)). While the cGAS pathway is important for host defense against invading pathogens, cellular stress and genetic factors can also lead to the production of abnormal cellular dsDNA, for example, through nuclear or mitochondrial leakage, which can trigger an autoinflammatory response. Aicardi-Goutières syndrome (AGS; Crow et al., Nat. Genet. 38, 917-920 (2006)), a severe lupus-like autoinflammatory immune-mediated disorder, results from loss-of-function mutations in the major DNA exonuclease TREX1, which is responsible for the degradation of abnormal DNA in the cytosol. Knocking out cGAS in TREX1-deficient mice prevents otherwise lethal autoimmune responses, supporting cGAS as a driver of interferonopathy (Gray et al., J. Immunol. 195, 1939-1943 (2015); Gao et al., PNAS 112, E5699-E5705 (2015)). Similarly, embryonic lethality caused by deficiency of DNAse2, an endonuclease responsible for degrading excess DNA in lysosomes during endocytosis, was fully rescued by additional knockout of cGAS (Gao et al., PNAS 112, E5699-E5705 (2015)) or STING (Ahn et al., PNAS 109, 19386-19391 (2012)). These observations support cGAS as a drug target, and inhibition of cGAS could provide a therapeutic strategy for preventing autoinflammation and treating diseases such as systemic lupus erythematosus (SLE), which are associated with anti-dsDNA antibodies (Pisetsky et al., Nat. Rev. Rheumatol. 12, 102-110 (2016)).

[0004] 1.2 Prior art Due to the observation that inhibition of the cGAS pathway can prevent autoinflammation and provide a therapeutic strategy for treating, for example, autoimmune diseases, many attempts have been made to develop cGAS inhibitors. For example, WO 2019 / 241787 reports that methyl 4-amino-6-(phenylamino)-1,3,5-triazine-2-carboxylates such as CU-32 and CU-76 have an "in vitro hcGAS IC" of slightly below 1 μM. 50 value" (IC 50 (CU-32) = 0.66 μM and IC 50 (CU-76=0.27 μM) Hall et al., PLoS ONE 12(9); e0184843 (2017) reported that the compound PF-06928215 had an in vitro hcGAS IC of 0.049 μM as measured by a fluorescence polarization assay. 50 However, compound PF-06928215 did not exhibit acceptable cellular activity as a cGAS inhibitor.

[0005] In WO 2020 / 142729 and WO 2022 / 174012, (benzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid derivatives were disclosed as cGAS inhibitors for treating autoimmune disorders such as Aicardi-Goutieres syndrome (AGS), lupus erythematosus, scleroderma, inflammatory bowel disease, and nonalcoholic steatohepatitis (NASH). However, the compounds of the present invention differ from the (benzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid derivatives of WO 2020 / 142729 in that the substitution pattern at the 4-position of the pyrrolidine ring is completely different. Recently provided cGAS inhibitors, such as those in WO 2020 / 142729 or WO 2022 / 174012, typically exhibit insufficient cellular cGAS inhibitory potency (IC for inhibition of the cGAS / STING pathway). 50 However, to ensure that a compound can demonstrate therapeutic efficacy in patients, it is necessary to have a satisfactory biochemical (in vitro) inhibitory potency ("hcGAS IC 50") as well as satisfactory cytostatic potency (e.g., inhibition of IFN induction in virus-stimulated THP-1 cells (THP1 (vir) I C 50 It is critically important to provide therapeutic cGAS inhibitors that demonstrate (by demonstrating) satisfactory cGAS selectivity (versus off-target activity) and acceptable inhibitory potency in human whole blood.

[0006] Surprisingly, it has now been found that compounds of formula I or II simultaneously exhibit the following three properties: Satisfactory biochemical (in vitro) IC for cGAS inhibition 50 hcGAS IC value (≦100 nM, preferably ≦50 nM, in particular ≦10 nM) 50 ), Satisfactory "inhibition of IFN induction in virus-stimulated THP-1 cells (THP1 IC of ≦1 μM, preferably ≦500 nM, more preferably ≦100 nM, especially ≦50 nM) 50(vir) ), and Satisfactory selectivity for cGAS inhibition (THP1 IC of ≥ 10, more preferably ≥ 50, more preferably ≥ 500, especially ≥ 1000) 50(cGAMP) / THP1 IC 50(vir) ratio).

[0007] In addition, compounds of Formula I or II exhibit acceptable IC values ​​for inhibition of IFN induction in a dsDNA-stimulated human whole blood assay. 50 human whole blood IC50 for cGAS inhibition of ≤ 5000 nM, more preferably ≤ 1000 nM, especially ≤ 100 nM 50 Value (hWB IC 50 ) is also shown. The cGAS inhibitors of the present invention, particularly those with this pharmacological profile that combines excellent in vitro inhibitory potency and excellent cellular inhibitory potency with high selectivity for cGAS inhibition, are also likely to exhibit good therapeutic efficacy in patients. Due to their high cellular inhibitory potency, particularly those with this pharmacological profile, compounds should be able to cross cell membrane barriers and thus reach their intracellular target locations, and due to their selectivity to exclusively inhibit cGAS activity, these compounds should not exhibit undesirable off-target effects, such as side effects or cytotoxic effects elsewhere in the signaling pathway downstream of cGAS. Summary of the Invention

[0008] 2. Description of the invention The present invention relates to compounds of Formula I, as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. [ka] (In the formula, R 1 is selected from the group consisting of hydrogen, halogen, methyl, ethyl, —CF3, —CHF2, —CFH2, and methoxy; R 2 is selected from the group consisting of hydrogen and methyl; R 3 is hydrogen, methyl, halogen, ethynyl, propynyl, -CO-(C 1-3 -CO-N(CH3)2, and a 5- or 6-membered heteroaryl ring having 1 or 2 heteroatoms each independently selected from N, S, or O, which heteroaryl ring may be further substituted by 1 or 2 additional substituents each independently selected from the group consisting of F, Cl, Br, -O-CH3, methyl, -CF3, -CHF2, and CH2F; R 4 is selected from the group consisting of hydrogen, —OH, and F; A is selected from the group consisting of -CH2-, -O-, -CF2-, and -CHCH3-; D is selected from the group consisting of -CH2-, -O-, -CF2-, and -CHCH3-; E is selected from the group consisting of -CH2-, -CO-, -O-, -CF2-, and -CHCH3-; G is selected from the group consisting of -NH-, -NCH3-, -CH2-, -O-, -CF2-, and -CHCH3-; J is selected from the group consisting of -CO-, -CH2-, -O-, -CF2-, and -CHCH3-; K is selected from the group consisting of -CH2-, -CF2-, and -O-, or is absent; L is selected from the group consisting of -CH2-, -CHCH3-, and -CF2-, or is absent. Thereby, the variables A, D, E, G, J, K, and L are preferably selected such that no two or more heteroatoms can directly follow each other.

[0009] In a preferred embodiment, the present invention relates to compounds of formula II, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof: [ka] (In the formula, R 1 is hydrogen or a halogen, preferably selected from the group consisting of F and Cl; R 2 is selected from the group consisting of hydrogen and methyl; R 3 is selected from the group consisting of hydrogen, Cl, Br, ethynyl, propynyl, -CO-(CH), and a 5- or 6-membered heteroaryl ring having 1 or 2 heteroatoms each independently selected from N, S, or O, which heteroaryl ring may be further substituted by 1 or 2 additional substituents each independently selected from the group consisting of F, -O-CH, and methyl; R 4 is F, A is selected from the group consisting of -CH2-, -O-, -CF2-, and -CHCH3-; D is selected from the group consisting of —CH— and —O—; E is selected from the group consisting of -CH2-, -CO-, and -O-; G is selected from the group consisting of -NH-, -NCH3-, -CH2-, and -O-; J is selected from the group consisting of -CO-, -CH2-, and -O-; K is selected from the group consisting of -CH2-, -CF2-, and -O-, or is absent; L is -CH2- or absent. Thereby, the variables A, D, E, G, J, K, and L are preferably selected such that no two or more heteroatoms can directly follow each other.

[0010] In a further preferred embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: The present invention relates to the above compounds of formula I or the above compounds of formula II, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L is absent. In a further preferred embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: The present invention relates to the above compounds of formula I or the above compounds of formula II, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L and K are absent. In a further preferred embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: The present invention relates to the above compounds of formula I or the above compounds of formula II, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L is absent and K is -CF2-. In another preferred embodiment, the present invention provides The present invention relates to the above compounds of formula I or the above compounds of formula II, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L is absent and A is selected from the group consisting of -CH2- and -CF2-.

[0011] In a further preferred embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: The present invention relates to the above compounds of formula I or the above compounds of formula II, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L is absent and A is -O-. In another preferred embodiment, the present invention provides The present invention relates to the above compounds of formula I or the above compounds of formula II, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L is absent and D is -O-. In a further preferred embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: L is non-existent, R 3 is selected from the group consisting of Cl, Br, ethynyl, propynyl, and a 5- or 6-membered heteroaryl ring selected from the group consisting of pyridinyl and pyrazolyl, which heteroaryl ring may be further substituted with one or two additional substituents each independently selected from the group consisting of F, —O—CH, and methyl, as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. In another preferred embodiment, the present invention provides R 1 is selected from the group consisting of F and Cl, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0012] In a further preferred embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: R 1 is hydrogen, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. In another particularly preferred embodiment, the present invention provides [ka] [ka] [ka] and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein the compound of formula I or the compound of formula II is selected from the group consisting of:

[0013] In a further preferred embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: A is selected from the group consisting of —CH— and —O—; D is selected from the group consisting of —CH— and —O—; E is selected from the group consisting of -CH2- and -O-; G is selected from the group consisting of -CH2- and -O-; J is selected from the group consisting of -CH2- and -O-; K is selected from the group consisting of -CH2- and -CF2-; The present invention relates to the above compounds of formula I or the above compounds of formula II, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L is absent.

[0014] In another particularly preferred embodiment, the present invention provides [ka] and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0015] In another particularly preferred embodiment, the present invention provides A is selected from the group consisting of —CH— and —O—; D is selected from the group consisting of —CH— and —O—; E is -CH2-, G is selected from the group consisting of -CH2- and -O-; J is -CH2-, K is selected from the group consisting of -CH2- and -CF2-; The present invention relates to the above compounds of Formula I or the above compounds of Formula II, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L is absent.

[0016] In another particularly preferred embodiment, the present invention provides [ka] and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0017] Prodrugs of compounds of formula I are preferably compounds of formula Ia. [ka] (wherein the variable R 1 , R 2 , R 3 , R 4 , A, D, E, G, J, K, and L are defined as above; R 5 is C 1-4 -Alkyl, aryl, -CH2-aryl, NH-SO2-C 1-3 -alkyl) Variable R 1 , R 2 , R 3 , R 4 , A, D, E, G, J, K, and L are defined as above, and R 5 Particularly preferred are prodrugs of Formula Ia wherein is methyl.

[0018] The prodrug of the compound of formula II is preferably a compound of formula IIa. [ka] (wherein the variable R 1 , R 2 , R 3 , R 4 , A, D, E, G, J, K, and L are defined as above; R 5 is C 1-4 -Alkyl, aryl, -CH2-aryl, NH-SO2-C 1-3 -alkyl) Variable R 1 , R 2 , R3 , R 4 , A, D, E, G, J, K, and L are defined as above, and R 5 Particularly preferred are prodrugs of Formula Ia wherein is methyl.

[0019] In another preferred embodiment, the present invention provides a) an intermediate compound of formula (AI) [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , A, D, E, G, J, K, and L are defined as above, and R 13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl; b) an intermediate compound of formula (A-II)

[0020] [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , A, D, E, G, J, K, and L are defined as above; R 13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl; R is hydrogen or a protecting group selected from the group consisting of tert-butyl, methyl, ethyl, and benzyl; c) an intermediate compound of formula (BI)

[0021] [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , A, D, E, G, J, K, and L are defined as above, and R 13is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl; d) an intermediate compound of formula (CI)

[0022] [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , A, D, E, G, J, K, and L are defined as above, and R 13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl), or e) Formula (C-II)

[0023] [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , A, D, E, G, J, K, and L are defined as above, and R 13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl; PG is selected from the group consisting of tert-butoxycarbonyl (Boc), allyloxycarbonyl (Alloc), benzyloxycarbonyl (Cbz), and fluorenylmethoxycarbonyl (Fmoc). Regarding.

[0024] In a further preferred embodiment, the present invention relates to the above-mentioned compounds of formula I or the above-mentioned compounds of formula II, or prodrugs, deuterated analogues, and pharmaceutically acceptable salts thereof of formula Ia or IIa, for use in the treatment of diseases that can be treated by inhibition of cGAS. In further preferred embodiments, the present invention relates to a method for treating systemic lupus erythematosus (SLE), interferonopathy, Aicardi-Goutieres syndrome (AGS), COPA syndrome, familial lupus chilblains, age-related macular degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), diabetes, obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Sjogren's syndrome, Parkinson's disease, heart failure and cancer, systemic sclerosis (SSc), skin diseases. The present invention relates to the above compounds of formula I or II or their prodrugs, deuterated analogues, and pharmaceutically acceptable salts of formula Ia or IIa for use in the treatment of a disease selected from the group consisting of myositis, non-alcoholic steatohepatitis (NASH), interstitial lung disease (ILD), preferably interstitial lung disease with progressive fibrosis (PF-ILD), in particular idiopathic pulmonary fibrosis (IPF), aging, muscle disorders, sepsis, rheumatoid arthritis, osteoarthritis, and COVID-19.

[0025] In another preferred embodiment, the present invention relates to the above compounds of Formula I or II or their prodrugs, deuterated analogues, and pharmaceutically acceptable salts of Formula Ia or IIa for use in the treatment of a disease selected from the group consisting of systemic lupus erythematosus (SLE), interferonopathy, Aicardi-Goutieres syndrome (AGS), COPA syndrome, familial lupus chilblains, dermatomyositis, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Sjogren's syndrome, rheumatoid arthritis, and Parkinson's disease. In a further preferred embodiment, the present invention relates to the above-mentioned compounds of formula I or II or their prodrugs, deuterated analogues and pharmaceutically acceptable salts of formula Ia or IIa for use in the treatment of a disease selected from the group consisting of systemic sclerosis (SSc), non-alcoholic steatohepatitis (NASH), interferonopathies, interstitial lung diseases (ILDs), preferably interstitial lung diseases with progressive fibrosis (PF-ILDs), in particular idiopathic pulmonary fibrosis (IPF).

[0026] In another preferred embodiment, the present invention relates to the above compounds of Formula I or II or their prodrugs, deuterated analogues, and pharmaceutically acceptable salts of Formula Ia or IIa for use in the treatment of a disease selected from the group consisting of age-related macular degeneration (AMD), retinopathy, glaucoma, diabetes, obesity, aging, myopathy, sepsis, osteoarthritis, heart failure, COVID-19 / SARS-CoV-2 infection, renal inflammation, renal fibrosis, metabolic disorders, vascular diseases, cardiovascular diseases, and cancer. In another preferred embodiment, the present invention relates to pharmaceutical compositions comprising the above compounds of formula I or II or their prodrugs, deuterated analogues, and pharmaceutically acceptable salts of formula Ia or IIa, and optionally one or more pharmaceutically acceptable carriers and / or excipients. In another preferred embodiment, the present invention relates to pharmaceutical compositions comprising the above compounds of Formula I or II or their prodrugs, deuterated analogues, and pharmaceutically acceptable salts of Formula Ia or IIa in combination with one or more active agents selected from the group consisting of anti-inflammatory agents, antifibrotic agents, antiallergic / antihistamines, bronchodilators, beta-2 agonists / betamimetics, adrenergic agonists, anticholinergic agents, methotrexate, mycophenolate mofetil, leukotriene modifiers, JAK inhibitors, anti-interleukin antibodies, nonspecific immunotherapeutics such as interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators, Toll-like receptor agonists, immune checkpoint regulators, anti-TNF antibodies such as Humira™, anti-BAFF antibodies such as belimumab and etanercept, and optionally one or more pharmaceutically acceptable carriers and / or excipients.

[0027] In a further preferred embodiment, the present invention relates to a pharmaceutical composition comprising the above-mentioned compound of formula I or II or its prodrugs, deuterated analogues, and pharmaceutically acceptable salts of formula Ia or IIa, and one or more antifibrotic agents selected from the group consisting of pirfenidone and nintedanib, and optionally one or more pharmaceutically acceptable carriers and / or excipients. In another preferred embodiment, the present invention relates to a pharmaceutical composition comprising the above compounds of formula I or II or their prodrugs, deuterated analogues, and pharmaceutically acceptable salts of formula Ia or IIa, and one or more anti-inflammatory agents selected from the group consisting of NSAIDs and corticosteroids, and optionally one or more pharmaceutically acceptable carriers and / or excipients. In a further preferred embodiment, the present invention relates to a pharmaceutical composition comprising the above compounds of formula I or II or their prodrugs, deuterated analogues and pharmaceutically acceptable salts of formula Ia or IIa, and one or more active agents selected from the group consisting of bronchodilators, beta-agonists / betamimetics, adrenergic agonists and anticholinergic agents, and optionally one or more pharmaceutically acceptable carriers and / or excipients.

[0028] In another preferred embodiment, the present invention relates to a pharmaceutical combination comprising the above-mentioned compound of formula I or II or its prodrugs, deuterated analogues, and pharmaceutically acceptable salts of formula Ia or IIa and one or more anti-interleukin antibodies selected from the group consisting of anti-IL-23 such as risankizumab, anti-IL-17 antibodies, anti-IL-1 antibodies, anti-IL-4 antibodies, anti-IL-13 antibodies, anti-IL-5 antibodies, anti-IL-6 antibodies such as Actemra™, anti-IL-12 antibodies, and anti-IL-15 antibodies. DETAILED DESCRIPTION OF THE INVENTION

[0029] 3. Terms and definitions used Unless otherwise stated, all substituents are independent of one another. For example, some C 1-6 - When alkyl groups are possible substituents of a group, for example in the case of three substituents, C 1-6 -Alkyl can independently represent methyl, n-propyl and tert-butyl. Crossed bonds, such as the central bond in the butyl molecule below, [ka] Represents a double bond of unknown configuration (cis, trans, or a mixture thereof). "C 1-6 The term "C -alkyl" (including those that are part of other groups) means branched and unbranched alkyl groups having 1 to 6 carbon atoms, and "C 1-3 The term "C -alkyl" refers to branched and unbranched alkyl groups having 1 to 3 carbon atoms. 1-4 "-Alkyl" denotes branched and unbranched alkyl groups having 1 to 4 carbon atoms. Alkyl groups having 1 to 4 carbon atoms are preferred. Examples of these include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and hexyl. Abbreviations such as Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may also be used for the above groups. Unless otherwise stated, the definitions propyl, butyl, pentyl and hexyl include all the possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and isopropyl, butyl includes isobutyl, sec-butyl and tert-butyl, etc.

[0030] "C 1-6 The term "-alkylene" (including those that are part of other groups) means branched and unbranched alkylene groups having 1 to 6 carbon atoms, and "C 1-4The term "-alkylene" denotes branched and unbranched alkylene groups having 1 to 4 carbon atoms. Alkylene groups having 1 to 4 carbon atoms are preferred. Examples thereof include methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, and hexylene. Unless otherwise specified, the definitions propylene, butylene, pentylene, and hexylene include all the possible isomeric forms of the groups in question having the same number of carbon atoms. Thus, for example, propyl also includes 1-methylethylene, butylene includes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, etc. When the carbon chain is substituted with a group which, together with one or two carbon atoms of the alkylene chain, forms a carbocyclic ring having 3, 5 or 6 carbon atoms, this includes, among others, the following ring examples: [ka]

[0031] "C 2-6 The term "-alkenyl" (including those that are part of other groups) refers to branched and unbranched alkenyl groups having 2 to 6 carbon atoms, and "C 2-4 The term "-alkenyl" denotes branched and unbranched alkenyl groups having 2 to 4 carbon atoms, provided that they have at least one double bond. Alkenyl groups having 2 to 4 carbon atoms are preferred. Examples include ethenyl or vinyl, propenyl, butenyl, pentenyl, or hexenyl. Unless otherwise stated, the definitions propenyl, butenyl, pentenyl, and hexenyl include all the possible isomeric forms of the groups in question. Thus, for example, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2-, and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, etc. "C 2-5 The term "alkynyl" (including those that are part of other groups) refers to branched and unbranched alkynyl groups having 2 to 5 carbon atoms, and "C 2-4 The term "alkynyl" refers to branched and unbranched alkynyl groups having 2 to 4 carbon atoms, provided that they contain at least one triple bond. Alkynyl groups having 2 to 4 carbon atoms are preferred.

[0032] "C 2-6 The term "-alkenylene" (including those that are part of other groups) means branched and unbranched alkenylene groups having 2 to 6 carbon atoms, and "C 2-4 The term "-alkenylene" denotes branched and unbranched alkenylene groups having 2 to 4 carbon atoms. Alkenylene groups having 2 to 4 carbon atoms are preferred. Examples thereof include ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, and hexenylene. Unless otherwise stated, the definitions propenylene, butenylene, pentenylene, and hexenylene include all the possible isomeric forms of the groups in question with the same number of carbon atoms. Thus, for example, propenyl includes 1-methylethenylene, butenylene includes 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene.

[0033] The term "aryl" (including those that are part of other groups) refers to an aromatic ring system having 6 or 10 carbon atoms. Examples include phenyl or naphthyl, with phenyl being the preferred aryl group. Unless otherwise specified, aromatic groups may be substituted with one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine. "Aryl-C 1-6 The term "-alkylene" (including those that are part of other groups) refers to branched and unbranched alkylene groups having 1 to 6 carbon atoms substituted by an aromatic ring system having 6 or 10 carbon atoms. Examples include benzyl, 1- or 2-phenylethyl, and 1- or 2-naphthylethyl. Unless otherwise specified, the aromatic group may be substituted by one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine. "Heteroaryl-C 1-6 The term "aryl-C -alkylene" (including those that are part of other groups) is already used in the context of "aryl-C 1-6 Although encompassed by "-alkylene", this refers to branched and unbranched alkylene groups having 1 to 6 carbon atoms, which are substituted by heteroaryl.

[0034] Unless specifically defined otherwise, this type of heteroaryl includes a 5- or 6-membered heteroaromatic group or a 5- to 10-membered bicyclic heteroaryl ring that can contain 1, 2, 3, or 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and that can contain so many conjugated double bonds that an aromatic system is formed. The following are examples of 5- or 6-membered heteroaromatic groups and bicyclic heteroaryl rings: [ka] Unless otherwise specified, these heteroaryls may be substituted with one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, amino, nitro, alkoxy, fluorine, chlorine, bromine, and iodine.

[0035] The following are heteroaryl-C 1-6 - is an example of alkylene. [ka] "C 1-6 The term "haloalkyl" (including those that are part of other groups) refers to branched and unbranched alkyl groups having 1 to 6 carbon atoms, substituted with one or more halogen atoms. 1-4 The term "haloalkyl" refers to branched and unbranched alkyl groups having 1 to 4 carbon atoms, substituted by one or more halogen atoms. Alkyl groups having 1 to 4 carbon atoms are preferred. Examples include CF3, CHF2, CH2F, and CH2CF3.

[0036] "C 3-7 The term "cycloalkyl" (including those that are part of other groups) means, unless specifically defined otherwise, a cyclic alkyl group having 3 to 7 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise specified, cyclic alkyl groups may be optionally substituted with one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine. Unless specifically defined otherwise, "C 3-10 The term "cycloalkyl" refers to a monocyclic alkyl group having 3 to 7 carbon atoms, and also to a bicyclic alkyl group having 7 to 10 carbon atoms or at least one C 1-3 Also meant are monocyclic alkyl groups bridged by a -carbon bridge. The term "heterocyclic ring" or "heterocycle", unless otherwise specified, refers to a 5-, 6-, or 7-membered saturated, partially saturated, or unsaturated heterocyclic ring which may contain 1, 2, or 3 heteroatoms selected from oxygen, sulfur, and nitrogen, and which ring may be connected to the molecule via a carbon or nitrogen atom, if present. Although encompassed by the term "heterocyclic ring" or "heterocycle", the term "saturated heterocyclic ring" refers to a 5-, 6-, or 7-membered saturated ring. Examples include:

[0037] [ka] Examples include: Although encompassed by the term "heterocyclic ring" or "heterocyclic group," the term "partially saturated heterocyclic group," unless specifically defined otherwise, refers to a 5-, 6-, or 7-membered partially saturated ring that contains one or two double bonds, but not so many double bonds that an aromatic system is formed. Examples include:

[0038] [ka] Examples include: Although encompassed by the term "heterocyclic ring" or "heterocycle," the terms "heteroaromatic ring," "unsaturated heterocyclic group," or "heteroaryl" refer to a 5- or 6-membered heteroaromatic group or a 5- to 10-membered bicyclic heteroaryl ring, which may contain 1, 2, 3, or 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and which may contain so many conjugated double bonds that an aromatic system is formed. Examples of 5- or 6-membered heteroaromatic groups include:

[0039] [ka] Examples include: Unless otherwise specified, the heterocyclic ring (or heterocycle) may be equipped with a keto group. Examples include: [ka] Examples include:

[0040] Although encompassed by the term "cycloalkyl," the term "bicyclic cycloalkyl" generally refers to an 8-, 9-, or 10-membered bicyclic carbocyclic ring. Examples include: [ka] Examples include: Although already encompassed by the term "heterocycle," the term "bicyclic heterocycle," unless specifically defined otherwise, generally refers to an 8-, 9-, or 10-membered bicyclic ring that can contain one or more heteroatoms, preferably 1 to 4, more preferably 1 to 3, even more preferably 1 to 2, and especially 1, selected from oxygen, sulfur, and nitrogen. The ring may be linked to the molecule via a ring carbon atom or a ring nitrogen atom, if present. Examples include:

[0041] [ka] Examples include: Although already encompassed by the term "aryl," the term "bicyclic aryl" refers to a 5- to 10-membered bicyclic aryl ring containing sufficient conjugated double bonds to form an aromatic system. An example of a bicyclic aryl is naphthyl. Although already encompassed by "heteroaryl," the term "bicyclic heteroaryl" refers to a 5- to 10-membered bicyclic heteroaryl ring that may contain 1, 2, 3, or 4 heteroatoms selected from oxygen, sulfur, and nitrogen, unless specifically defined otherwise, and that contains sufficient conjugated double bonds to form an aromatic system.

[0042] Although encompassed by the terms "bicyclic cycloalkyl" or "bicyclic aryl," the terms "fused cycloalkyl" or "fused aryl" refer to bicyclic rings in which the bridge separating the rings represents a direct single bond. The following are examples of fused bicyclic cycloalkyls: [ka] Although encompassed by the terms "bicyclic heterocycle" or "bicyclic heteroaryl," the terms "fused bicyclic heterocycle" or "fused bicyclic heteroaryl" refer to a 5- to 10-membered bicyclic heterocycle containing one, two, three, or four heteroatoms selected from oxygen, sulfur, and nitrogen, and wherein the bridge separating the rings represents a direct single bond. A "fused bicyclic heteroaryl" further contains sufficient conjugated double bonds to form an aromatic system. Examples include pyrrolidine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzothiazole, benzisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine,

[0043] [ka] Examples include: Within the scope of the present invention, "halogen" denotes fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine, chlorine and bromine are considered to be the preferred halogens. As mentioned above, compounds of Formula I or II can be converted into their salts, particularly physiologically and pharmacologically acceptable salts, for use as pharmaceuticals. The term "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio. These salts may exist, on the one hand, as physiologically and pharmacologically acceptable acid addition salts of compounds of Formula I or II with inorganic or organic acids. On the other hand, compounds of Formula I or II can be converted into physiologically and pharmacologically acceptable salts with alkali metal cations or alkaline earth metal cations as counterions by reaction with inorganic bases. Acid addition salts can be prepared using, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, or maleic acid. Mixtures of the above acids can also be used. To prepare alkali metal and alkaline earth metal salts of compounds of formula I or II, it is preferred to use hydroxides and hydrides of alkali metals and alkaline earth metals, among which hydroxides and hydrides of alkali metals, particularly sodium, potassium, magnesium, calcium, zinc, and diethanolamine, are preferred, with sodium and potassium hydroxide being particularly preferred.

[0044] The present invention relates to such compounds which may be in the form of individual optical isomers, diastereomers, mixtures of diastereomers, mixtures of individual enantiomers, or in the form of racemates, tautomers, and the free base or the corresponding acid addition salt with a pharmacologically acceptable acid, such as a hydrohalic acid, e.g., hydrochloric acid or hydrobromic acid, or an organic acid, such as, e.g., oxalic acid, fumaric acid, diglycolic acid, or methanesulfonic acid. The compounds of formula I or II according to the invention can exist as mixtures of diastereoisomers, but can also be obtained as pure diastereoisomers. Compounds with the specific stereochemistry of formula II or III, especially compounds of formula II, are preferred.

[0045] Synthesis method General Procedure The following methods are suitable for preparing compounds of general formula I or II. The compounds according to the invention can be obtained using synthetic methods known to those skilled in the art and described in the literature of organic synthesis. General methods for functional group protection and deprotection steps are described, for example, in Greene, TW and Wuts, PGM (eds.): Protective Groups in Organic Synthesis, third edition 1999; John Wiley and Sons, Inc. Preferably, the compounds are obtained analogously to the preparation methods described in more detail hereinafter, in particular in the experimental section. The compounds of general formula (I) can be prepared using several alternative synthetic routes, of which the following routes shall serve as examples:

[0046] Route A: Compounds of general formula I and II (particularly, A represents -CH2- or substituted -CH2-) can be reached from compounds of formula (AI) through standard amidation procedures. R13 can thereby represent hydrogen or a protecting group, such as tert-butyl or methyl, which can be removed by standard deprotection methods. R can represent hydrogen or a protecting group, such as tert-butyl, benzyl, methyl, or ethyl, which can be removed by standard deprotection methods. Compounds of formula (AI) can be prepared from compounds of formula (A-II) by applying standard deprotection methods. Compounds of formula (A-II) can be prepared by reacting compounds of formula (A-III) with compounds of formula (A-IV), applying a strong base, such as sodium hydride. Methods applicable to the preparation of compounds (A-III) will be apparent to those skilled in the art by reference to routes C and D described below and the examples described in the experimental section. Compounds of formula (A-IV) can be prepared through the method described hereinafter for the synthesis of intermediate P.

[0047] [ka]

[0048] Route B: Compounds of general formulas I and II can be prepared by reacting compounds of general formula (BI) in the presence of a strong base, such as sodium hydride. R can represent hydrogen or a protecting group, such as tert-butyl, which can be removed by standard deprotection methods. Compounds (BI) can be prepared by reacting compounds of general formula (B-II) with compounds of general formula (B-III) using standard amidation conditions. Methods applicable to the preparation of compounds (B-III) will be apparent to those skilled in the art by reference to the synthesis of intermediate P described in the experimental section. Alternatively, compounds of general formula (BI) can be prepared by reacting compounds of general formula (B-IV) with compounds of general formula (BV) using standard reaction conditions for a transition metal-catalyzed coupling reaction (e.g., Heck reaction), followed by hydrogenation of the resulting alkene under standard hydrogenation conditions. Compounds of formula (BV) can be prepared through the method described hereinafter for the synthesis of intermediate P.

[0049] [ka]

[0050] Route C: The compounds of general formulas I and II can be prepared by reacting a compound of general formula (CI) with an activating agent such as BOP (((1H-benzo[d][1,2,3]triazol-1yl)oxy)tris(dimethylamino)-phosphonium hexafluorophosphate (V)) in the presence of a base, i.e., DBU. (CI) is generated by removing the protecting group PG from (C-II) under standard deprotection conditions known to those skilled in the art. PG in formula (C-II) can represent, for example, tert-butoxycarbonyl (Boc), allyloxycarbonyl (Alloc), or benzyloxycarbonyl (Cbz). The compounds of general formula (C-II) can be prepared from compounds of general formula (C-III) using the respective enantiopure hydroxyprolines (which may have a protecting group R13), optionally in the presence of a base. Compounds of general formula (C-III) are accessible from compounds of general formula (C-IV) by applying alkaline conditions, e.g., triethylamine / TMSCl at elevated temperature. Compounds of general formula (C-IV) can be synthesized from carboxylic acids of general formula (C-VI) by reaction with amino-benzofurans of general formula (CV) under standard amidation conditions.

[0051] [ka]

[0052] Route D: Compounds of general formula I and II can be prepared from compounds of general formula (DI) by various types of ring-closing reactions, exemplified but not limited to Heck-type coupling reactions (R11 represents a bromine or iodine atom and R12 contains a terminal alkene), ring-closing metathesis reactions (both R11 and R12 contain a terminal alkene), followed by hydrogenation of the resulting alkene, amidation (R11 carries a carboxylic acid and R12 carries a primary or secondary amino group, or vice versa). R13 can thereby represent hydrogen or a protecting group, such as tert-butyl, which can be removed by standard deprotection methods. Methods for the synthesis of compound (DI) will be apparent to those skilled in the art by reference to Routes A and B above and the examples described in the experimental section.

[0053] [ka]

[0054] Synthesis of intermediates The syntheses described hereinafter were carried out in part according to the following general procedures where indicated. General Procedure Int-A: Pd / C Catalyzed Hydrogenation (See Intermediate N-09, Step 4) General Procedure Int-B: Ring closure under basic conditions (see Intermediate N-09, Step 5) General Procedure Int-C: Chlorination Applying Phosphoryl Trichloride (See Intermediate N-09, Step 7) General Procedure Int-D: S with Hydroxyproline Esters N Ar (see Intermediate N-09, Step 8) General Procedure Int-E: Ester Cleavage Applying Lithium Hydroxide (See Intermediate N-04, Step 2) General Procedure Int-F: Amidation applying PFTU (see Intermediate N-04, Step 3) General Procedure Int-G: Heck-Type Coupling (See Intermediate N-17, Step 1) General Procedure A: Amidation (TBTU / NMP) (See EX-01 Step 1) General Procedure B:S N Ar(NaH / DMA) (See EX-01-Step 2) General Procedure C: Ester Hydrolysis (LiOH / THF) (See EX-01 Step 4) General Procedure D: Amidation (HATU / DMF) (See EX-01 Step 5) General Procedure E: Amidation (HATU / DMA) (See EX-02 Step 5) General Procedure F: BOC Deprotection Applying PTSA (See EX-03, Step 2) General Procedure G: Macrocyclization (HATU / DMA) (See EX-03 Step 3) General Procedure H: tBu Deprotection (TFA / DCM) (See EX-04 Step 6) General Procedure I: Cyclization to Pyridine (NaH / NMP) (See EX-05 Step 2) General Procedure J: Amidation using DCC (see EX-08 step 3) General Procedure K: Olefin Metathesis (See EX-08 Step 4) General Procedure L: Hydrogenation using Raney-Ni (see EX-08 Step 5) General Procedure M: Heck Coupling (See EX-22 Step 1) General Procedure N: Hydrogenation using Pd / C (see EX15 Step 3) General Procedure O: Suzuki Coupling (See EX-20.01 Step 1)

[0055] Intermediate N-01 tert-Butyl(2S,4S)-1-[4-(2-ethoxy-2-oxoethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]-4-hydroxypyrrolidine-2-carboxylate

[0056] [ka]

[0057] Step 1: Ethyl 2-{6-oxo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,10,12-pentaen-4-yl}acetate To a mixture of ethyl 3-aminobenzofuran-2-carboxylate (5.00 g; 24.4 mmol) in 4 M HCl (50.00 mL; 200 mmol) was added ethyl cyanoacetate (5.19 mL; 48.7 mmol) at room temperature. The mixture was heated at 100° C. for 4 h. After cooling to room temperature, an additional 2.6 mL (24.4 mmol) of ethyl cyanoacetate was added and heating was continued at 100° C. for 48 h. The solvent was evaporated and the crude residue was diluted with 100 mL of MeOH, filtered, and dried. The crude product was used directly in the next step. ESI-MS: 273.0 [M+H] + ; R t (HPLC): 0.63 min (Method B)

[0058] Step 2: Ethyl 2-{6-chloro-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}acetate Ethyl 2-{6-oxo-8-oxa-3,5-diazatricyclo[7.4.0.0 in POCl3 (50.0 mL; 547 mmol) 2,7 A mixture of 1,3-dimethyl-2,4-tridec-1(9),2(7),3,10,12-pentaen-4-yl}acetate (3.35 g; 12.3 mmol) was heated at 110° C. for 1.5 h. The reaction mixture was cooled to room temperature and added dropwise to an ice bath (500 mL) with stirring over 30 min. Ethyl acetate was added and the layers were separated. Saturated NaHCO3 solution was added slowly to the organic layer, and the phases were separated. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. ESI-MS: 291.0 [M+H] + ; R t (HPLC): 0.43 min (Method A)

[0059] Step 3: tert-Butyl (2S,4S)-1-[4-(2-ethoxy-2-oxoethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]-4-hydroxypyrrolidine-2-carboxylate Ethyl 2-{6-chloro-8-oxa-3,5-diazatricyclo[7.4.0.0] in 30 mL of NMP 2,7 To {2,50 g}(2,5-trideca-1(9),2(7),3,5,10,12-hexaen-4-yl)acetate (8.17 mmol; 1.00 equivalents), tert-butyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (8.99 mmol; 2.01 g, preparation described in WO 2005 / 35525) and DIPEA (27.0 mmol; 4.64 mL) were added, and the mixture was stirred at 70° C. for 1.5 hours. The reaction mixture was cooled to room temperature and slowly added to 300 mL of ice water. The precipitate was filtered, washed several times with water, and dried. ESI-MS: 442.0 [M+H] + ; R t (HPLC): 0.67 min (Method B)

[0060] Intermediate N-02 tert-Butyl(2S,4S)-1-{4-bromo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(13),2(7),3,5,9,11-hexaen-6-yl}-4-hydroxypyrrolidine-2-carboxylate [ka]

[0061] Step 1: 4,6-Dibromo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7]Trideca-1(13),2(7),3,5,9,11-hexaene A mixture of 1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione (11.6 g; 0.0573 mol, preparation described in Korean Patent Application Publication No. 2015 / 84657) and POBr (40.8 mL, 0.402 mol) was heated at 150 °C for 3 h. The mixture was cooled to room temperature, and the pH was adjusted to pH = 7 using saturated aqueous NaHCO solution while cooling at 0 °C. The mixture was extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over sodium sulfate, and evaporated under reduced pressure. The remaining residue was purified by dissolving in a mixture of DCM (3 volumes relative to the weight of the crude product) and EtOAc (3 volumes relative to the weight of the crude product) with stirring. After stirring at room temperature for 30 min, the mixture was filtered, and the supernatant was evaporated under reduced pressure. ESI-MS: 327 / 329 / 331 [M+H] + (2Br); R t (HPLC): 0.67 min (Method A)

[0062] Step 2: tert-Butyl(2S,4S)-1-{4-bromo-8-oxa-3,5-diazatricyclo[7.4.0.0] 2,7 ]trideca-1(13),2(7),3,5,9,11-hexaen-6-yl}-4-hydroxypyrrolidine-2-carboxylate To a mixture of 4,6-dibromo-8-oxa-3,5-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene (5.56 g, 16.9 mmol) in 93 mL of DMF was added tert-butyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (4.17 g, 16.6 mmol, as described in WO 2005 / 35525) and K2CO3 (7.03 g, 50.8 mmol). After stirring overnight at room temperature, the reaction mixture was poured into water and neutralized with 4 M aqueous HCl. The precipitate was collected by filtration and dried under vacuum. ESI-MS: 434 / 436 [M+H] + (2Br); R t(HPLC): 0.64 min (Method A)

[0063] Intermediate N-03: [ka]

[0064] N-03 Step 1: tert-Butyl (2S,4S)-1-[4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-8-oxa-3,5-diazatricyclo-[7.4.0.0 2,7 ]trideca-1(13),2(7),3,5,9,11-hexaen-6-yl]-4-hydroxypyrrolidine-2-carboxylate Copper bronze powder (508 mg, 8.00 mmol) was added to a mixture of ethyl bromodifluoroacetate (533 μL, 4.00 mmol) and intermediate N-02 (914 mg, 2.00 mmol) in 19.4 mL of DMSO. The mixture was heated to 70 °C and stirred for 3 h. An additional amount of ethyl bromodifluoroacetate (533 μL, 2.00 equiv.) and copper bronze powder (508 mg, 4.00 equiv.) was then added, and stirring was continued at 70 °C for 1 h. The reaction mixture was diluted with ACN / HO, acidified with TFA, filtered through a pad of Celite, and purified by preparative HPLC (P09; XBridge C18; ACN / HO / TFA). ESI-MS: 478 [M+H] + ; R t (HPLC): 0.67 min (Method A)

[0065] N-03 Step 2: 2-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidin-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}-2,2-difluoroacetic acid The product (ethyl ester) obtained in the previous step (217 mg, 0.432 mmol) in 4.34 mL of THF was treated with 2 M aqueous LiOH solution (432 μL; 2.00 equiv., 0.864 mmol) at room temperature until the starting material was completely consumed (1 h). The reaction mixture was diluted with 10 mL of water, acidified with 1 mL of 1 N HCl, and extracted with DCM. The combined organic phases were dried over sodium sulfate, filtered, and evaporated. The residue was dissolved in ACN / HO and lyophilized. ESI-MS: 450 [M+H] + ; R t (HPLC): 0.53 min (Method A)

[0066] N-03 Step 3: tert-Butyl(2S,4S)-1-(4-{difluoro[(4-methoxy-4-oxobutyl)(methyl)carbamoyl]methyl}-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl)-4-hydroxypyrrolidine-2-carboxylate HATU (250 mg, 0.624 mmol) was dissolved in 3.17 mL of DMF in 2-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidin-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 To a mixture of 422 mg (0.939 mmol) of methyl trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}-2,2-difluoroacetic acid, methyl 4-(methylamino)butanoate hydrochloride (110 mg; 0.624 mmol, 1.0 equiv., preparation described in Chinese Patent Application Publication No. 114173824) and DIPEA (231 μL, 1.34 mmol) was added. The reaction mixture was stirred at room temperature until the starting material was completely consumed (2.5 h), then diluted with ACN / HO, acidified with TFA, and purified by preparative HPLC (XBridge C18; ACN / HO / TFA). ESI-MS: 563 [M+H] + ; R t (HPLC): 0.61 min (Method A)

[0067] N-03 Step 4: 4-(2-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidin-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}-2,2-difluoro-N-methylacetamido)-butanoic acid The product obtained in the previous step was reacted according to general procedure Int-E to give intermediate N-03 as the final product. ESI-MS: 450 [M+H] + ; R t (HPLC): 0.53 min (Method A)

[0068] Intermediate N-04: [ka]

[0069] N-04 Step 1: The zinc dust used was washed with 2% aqueous hydrochloric acid, water, and acetone before use. The purified powder was dried under high vacuum and stored under argon. A flask was charged with zinc dust (2.44 g; 36.9 mmol), nickel(II) chloride hexahydrate (0.754 g; 3.14 mmol), THF (35.0 mL), and 3 drops of water, and the mixture was stirred at room temperature for 10 minutes. Then, tert-butyl hex-5-enoate (4.63 g; 18.5 mmol; prepared as described in WO 2010 / 15447) was added in one portion, followed by dropwise addition of ethyl iodofluoroacetate (2.80 mL; 18.5 mmol), maintaining the temperature below 30°C (exothermic reaction during the addition). After the addition was complete, the reaction mixture was stirred at 60°C for 4 hours. The reaction mixture was poured into a mixture of saturated ammonium chloride solution (100 mL) and diethyl ether (100 mL) and stirred for 10 min. The mixture was then filtered through a Celite pad and, after phase separation, the aqueous phase was extracted with diethyl ether. The combined organic layers were washed with water, dried over sodium sulfate, filtered and evaporated. The crude product was purified by FC (silica gel; CH / DCM 10% to 100%). ESI-MS: 312 [M+NH4] + R t (HPLC): 0.78 min (Method A)

[0070] N-04 Step 2: General Procedure Int-E: Lithium hydroxide (276 mg; 11.0 mmol) was added to a solution of the product of step 1 in THF / HO (2:1), and the reaction mixture was stirred at room temperature until reaction control by RP HPLC indicated consumption of the starting material (in this case: 2.5 h). Volatiles were removed in vacuo. The residue was acidified to pH = 1 by adding 5.50 mL of 1 N aqueous hydrochloric acid, and the mixture was extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, and evaporated. ESI-MS: 211 [M-isobutene + H] + R t (HPLC): 0.59 min (Method A)

[0071] N-04 Step 3: General Procedure Int-F: At room temperature, PFTU (2.40 g; 5.60 mmol) was added to a stirred solution of the product of Step 2 (1.40 g; 5.09 mmol) and DIPEA (970 μL; 5.60 mmol) in DMF (21.0 mL), and the mixture was stirred for 30 min. 3-Aminobenzofuran-2-carboxamide (1.01 g; 5.60 mmol) and additional DIPEA (970 μL; 5.60 mmol) were then added, and the mixture was stirred at room temperature for 10 min. The reaction mixture was then heated to 50° C. and stirred at this temperature for 16 h. When reaction control by RP HPLC indicated incomplete consumption of the starting material, additional DIPEA (441 μL; 2.80 mmol) and PFTU (0.86 g; 2.04 mmol) were added, and stirring was continued at 50° C. for an additional 2.5 h. The reaction mixture was diluted with water, acidified with TFA, filtered and purified by RP HPLC (XBridge C18; ACN / water; modifier: TFA). ESI-MS: 425 [M+H] + R t (HPLC): 0.72 min (Method A)

[0072] N-04 Step 4: At room temperature, chlorotrimethylsilane (4.05 mL; 30.3 mmol) was slowly added to a solution of the product of Step 3 (950 mg; 2.13 mmol) and triethylamine (13.0 mL; 92.4 mmol) in 1,2-dichloroethane (28.5 mL). After the addition was complete, the reaction mixture was heated to 85 °C and stirred at this temperature for 24 h. The reaction mixture was poured into 30 mL of 4 M hydrochloric acid (pH = 1) and extracted twice with DCM. The combined organic phases were washed with water, dried over sodium sulfate, filtered, and evaporated to give tert-butyl 7,7-difluoro-7-{6-oxo-8-oxa-3,5-diazatricyclo[7.4.0.0]. 2,7 ]trideca-1(13),2(7),3,9,11-pentaen-4-yl}heptanoate was obtained. ESI-MS:405 [MH] - R t(HPLC): 0.44 min (Method D)

[0073] N-04 Step 5: General procedure Int-C was applied to convert the product of step 4 to the chlorinated product, followed by purification by RP-HPLC (XBridge C18; ACN / water; modifier: TFA). ESI-MS:367 [MH] - R t (HPLC): 0.64 min (Method A)

[0074] N-04 Step 6: The product of Step 6 was reacted according to general procedure Int-D to give the title compound. ESI-MS: 520 [M+H] + R t (HPLC): 0.61 min (Method A) Intermediate N-05 [ka]

[0075] N-05 Step 1: To a solution of magnesium powder (45.0 g; 1.85 mol) in THF (285 mL) was added iodine (1.00 g; 3.94 mmol), followed by the dropwise addition of a solution of 1-bromo-3-butene (111 g; 821 mmol) in THF (850 mL). The temperature was maintained below 50 °C. The resulting mixture was cooled to -75 °C, and a solution of diethyl oxalate (100 g; 684 mmol; 93.5 mL) in THF (1.89 L) was added dropwise. The mixture was stirred at -75 °C for an additional 4 h and then quenched by the addition of saturated aqueous ammonium chloride solution (900 mL) at 0 °C. The pH was adjusted to pH 3 by the addition of aqueous hydrochloric acid (1 M). The mixture was extracted three times with EtOAc (500 mL). The combined organic layers were washed with brine (900 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by FC (silica gel; petroleum ether / ethyl acetate 0%→100%). 1 H NMR: (400 MHz, CDCl3) δ = 5.85 - 5.72 (m, 1H), 5.11 - 4.92 (m, 2H), 4.37 - 4.24 (m, 2H), 2.92 (t, J = 7.3 Hz, 2H), 2.36 (q, J = 7.1 Hz, 2H), 1.24 - 1.21 (m, 3H)

[0076] N-05 Step 2: To a solution of the product of Step 1 (50.0 g, 320 mmol) in DCM (1000 mL) was added bis-(2-methoxyethyl)aminosulfur trifluoride (deoxofluor) (120 g, 544 mmol, 119 mL) and ethanol (2.95 g, 64.0 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by adding 500 mL of saturated aqueous sodium bicarbonate and then extracted three times with DCM (500 mL). The combined organic layers were washed with aqueous hydrochloric acid (1 M; 200 mL) and brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product was distilled in vacuo (30 °C, 0.09 MPa / oil pump). 1 H NMR: (400 MHz, CDCl3): δ = 5.80 (br dd, J = 10.3, 16.9 Hz, 1H), 5.13 - 5.00 (m, 2H), 4.39 - 4.28 (m, 2H), 2.30 - 2.12 (m, 4H), 1.43 - 1.34 (m, 3H)

[0077] N-05 Step 3: To a mixture of zinc dust (8.79 g, 134 mmol) and THF (30.0 mL) was added nickel(II) chloride hexahydrate (804 mg, 3.38 mmol). The mixture was stirred at −65° C. for 5 minutes. Then, ethyl difluoroiodoacetate (12.0 g, 48.0 mmol) and the product of Step 2 (6.00 g, 33.7 mmol) were added dropwise at −65° C. The mixture was stirred at 25° C. for 12 hours. The reaction mixture was quenched by adding saturated aqueous ammonium chloride (60.0 mL) at 0° C. and then extracted three times with DCM (60.0 mL). The combined organic layers were washed with brine (60.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. 1 H NMR: (400 MHz, chloroform-d): δ = 4.33 (q, J = 7.2 Hz, 4H), 2.18 - 1.98 (m, 4H), 1.56 (td, J = 3.8, 8.0 Hz, 4H), 1.36 (t, J = 7.2 Hz, 6H)

[0078] N-05 Step 4: To a solution of the product of Step 3 (11.0 g, 36.4 mmol) in dioxane (30.0 mL) were added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (14.2 g, 102 mmol) and 3-amino-1-benzofuran-2-carboxamide (4.50 g, 25.5 mmol). The mixture was stirred at 110 °C for 2 h, then diluted with water (30.0 mL) and extracted three times with EtOAc (30.0 mL). The combined organic layers were washed with brine (30.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by RP HPLC (ACN / water, modifier: TFA). 1H NMR: (400 MHz,DMSO-d): δ = 8.09 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 2.40 - 2.37 (m, 2H), 2.12 - 2.07 (m, 2H), 1.54 - 1.48 (m, 4H). N-05 Step 5: The product of step 4 was chlorinated applying general procedure Int-C.

[0079] N-05 Step 6: The product of Step 5 was reacted applying general procedure Int-D to give the title compound. ESI-MS: 556 [M+H] + R t (HPLC): 0.64 min (Method A) Intermediate N-06 [ka]

[0080] N-06 Step 1: 2-Allyloxyacetic acid (9.02 g; 73.8 mmol) was dissolved in DCM containing one drop of DMF and cooled to 0°C. Oxalyl chloride (23.4 g; 184 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 2 hours. The solvent was then evaporated under reduced pressure. The residue was dissolved in DMF and added to a stirred solution of 3-aminobenzofuran-2-carboxamide (13.0 g; 73.8 mmol) in DMF. After 2 hours, the mixture was poured into 100 mL of water and stirred for 5 minutes. The solid that formed was collected, dissolved in DCM, and dried over magnesium sulfate. The volatiles were evaporated, and the solid was triturated with tert-butyl methyl ether to give 3-[2-(prop-2-en-1-yloxy)acetamido]-1-benzofuran-2-carboxamide.

[0081] N-06 Step 2: A suspension of the product of Step 1 in 4 M aqueous sodium hydroxide was stirred at 70° C. for 2 hours. The mixture was acidified by adding aqueous hydrochloric acid, and the precipitate that formed was collected and dried to give 4-[(prop-2-en-1-yloxy)methyl]-8-oxa-3,5-diazatricyclo[7.4.0.0]. 2,7 ]trideca-1(9),2(7),3,10,12-pentaen-6-one was obtained. The product of Step 2 was further reacted in a two-step sequence according to general procedure Int-C followed by Int-D to give the title compound. ESI-MS: 426 [M+H] + R t (HPLC): 0.49 min (Method A) Intermediate N-07: [ka]

[0082] N-07 Step 1: A mixture of 3-aminobenzofuran-2-carboxamide (2.00 g; 11.4 mmol), ethyl 2-[2-(2-ethoxy-2-oxoethoxy)ethoxy]acetate (5.32 g; 22.7 mmol), and 1H,2H,3H,4H,6H,7H,8H-[1,3]diazino[1,2-a]pyrimidine (6.45 g; 45.4 mmol) was heated to 120°C for 150 min. After cooling to room temperature, aqueous hydrochloric acid (1 M; 70 mL) was added. The precipitate was filtered off with suction, washed with water, dried in vacuo at 60°C, and purified to give ethyl 2-[2-({6-oxo-8-oxo-3,5-diazatricyclo[4-(4-methyl-2-propanol]-4-yl)-2-methyl-2-propanol]-4-methyl-2-propanol]-4-methyl-2-propanol. 2,7 A mixture of ]trideca-1(9),2(7),3,10,12-pentaen-4-yl}methoxy)ethoxy]acetate and the respective free acids was obtained, which was used in the next step.

[0083] N-07 Step 2: For the re-esterification of the acid, the mixture from step 1 (2.8 g) was dissolved in DCM (200 mL). Two drops of DMF were added, followed by oxalyl chloride (392 μL, 4.57 mmol). The mixture was stirred overnight, then ethanol (10 mL) was added, and the mixture was stirred for an additional 2 h. The mixture was concentrated under reduced pressure. Methyl tert-butyl ether was added, and the precipitate that formed was washed with methyl tert-butyl ether and dried at 50 °C to give ethyl 2-[2-({6-oxo-8-oxa-3,5-diazatricyclo[7.4.0.0]. 2,7 ]trideca-1(9),2(7),3,10,12-pentaen-4-yl}methoxy)ethoxy]acetate was obtained. The product of Step 2 was further reacted in a two-step sequence according to general procedure Int-C followed by Int-D to give the title compound. ESI-MS: 516 [M+H] + R t (HPLC): 0.80 min (Method E)

[0084] Intermediate N-08 [ka]

[0085] N-08 Step 1: Sodium hydride (60% in mineral oil; 1.73 g, 44.2 mmol) was added in portions over 2 min to sodium 2-chloro-2,2-difluoroacetate (4.5 g, 29.5 mmol) and prop-2-en-1-ol (2.14 g, 36.8 mmol) in THF (30 mL) at 0 °C under nitrogen. The resulting suspension was stirred at 65 °C for 16 h. The reaction mixture was cooled and diluted with aqueous hydrochloric acid (2 M) to reach pH = 5-6, and the aqueous layer was then extracted twice with DCM (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated to give the crude product. The crude product was purified by FC (silica gel; petroleum ether / EtOAc 0% to 30%) to give 2-(allyloxy)-2,2-difluoroacetic acid. 1H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 6.01 - 5.91 (m, 1H), 5.45 - 5.36 (m, 1H), 5.33 - 5.26 (m, 1H), 4.50 (dt, J = 5.8, 1.2 Hz, 2H) N-08 Step 2: To a solution of the product of Step 1 (5 g, 33 mmol) in pyridine (100 mL) was added 3-amino-1-benzofuran-2-carboxamide (4.63 g, 26 mmol), followed by dropwise addition of phosphoryl trichloride (15.3 g, 0.1 mol) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with water (200 mL) and extracted three times with EtOAc (200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by FC (silica gel; petroleum ether / EtOAc 15%) to give 3-(2-(allyloxy)-2,2-difluoroacetamido)benzofuran-2-carboxamide. ESI-MS: 311 [M+H] +

[0086] N-08 Step 3: The product of Step 2 (3 g, 9.7 mmol) was added to aqueous sodium hydroxide (14.5 mL, 4 M, 58.2 mmol), followed by THF (1.5 mL). The reaction mixture was stirred at 70 °C for 4 h. The cooled (room temperature) reaction mixture was acidified with aqueous hydrochloric acid (2 M) to pH = 5-6, and the formed precipitate was collected and dried to give crude 2-((allyloxy)difluoromethyl)benzofuro[3,2-d]pyrimidin-4(3H)-one, which was used in the next step without further purification.

[0087] N-08 Step 4: A 0.5 L three-neck flask equipped with a thermometer and a nitrogen balloon was charged with DMF (1.36 g, 18.6 mmol) and DCM (250 mL). The flask was cooled to 0 °C, and a solution of oxalyl chloride (3.54 g, 27.9 mmol) in DCM (5 mL) was added dropwise over 5 min, maintaining the temperature between 0 and 5 °C. The mixture was stirred at ambient temperature for 0.5 h. The reaction was cooled to 0 °C in an ice-water bath, and the product of Step 3 (1.8 g, 6.2 mmol) was added in small portions. The reaction was stirred at room temperature for 15 min and then at 40 °C for 2 h. After cooling to room temperature, the reaction was poured onto ice, neutralized with aqueous sodium bicarbonate, and extracted twice with DCM (100 mL). The combined organic phase was washed with water, dried over sodium sulfate, and concentrated. The crude product was purified by FC (silica gel; petroleum ether / EtOAc 2%→10%) to yield the title compound 2-((allyloxy)difluoromethyl)-4-chlorobenzofuro[3,2-d]pyrimidine. 1 H NMR (400 MHz, DMSO-d6) δ 8.41 - 8.31 (m, 1H), 7.79 (m, 2H), 7.60 - 7.54 (m, 1H), 7.26 (s, 1H), 6.06 (dq, J = 10.8, 6.0 Hz, 1H), 5.45 (dd, J = 17.2, 1.2 Hz, 1H), 5.30 (dd, J = 10.4, 1.0 Hz, 1H), 4.70 (d, J = 6.0 Hz, 2H)

[0088] N-08 Step 5: The product of Step 4 was reacted according to general procedure Int-D to give the title compound. ESI-MS: 462 [M+H] + R t (HPLC): 0.68 min (Method A) Intermediate N-09: [ka]

[0089] N-09 Step 1: A mixture of tert-butyl 3-(2-oxoethoxy)propanoate (7.25 g; 38.5 mmol) prepared as described in EP 2409977 and methyl (triphenylphosphoranylidene)acetate (13.1 g; 38.5 mmol) in DCM (200 mL) was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and dissolved in CH / EtOAc (3:1). Insoluble material was removed by filtration, and the filtrate was evaporated. The crude product was purified by FC (silica gel; CH / EtOAc 10% to 45%) to give the product as a mixture of cis- and trans-isomers. N-09 Step 2: The product of Step 1 (1.50 g; 6.14 mmol) was stirred overnight in a mixture of DCM (15 mL) and TFA (10 mL). The mixture was evaporated and dissolved in methanol (10 mL). Polymer-bound tetraalkylammonium carbonate (2 weight equivalents) was added and the mixture was stirred for 90 minutes. The insoluble material was filtered off and the filtrate was evaporated.

[0090] N-09 Step 3: To a solution of the product of Step 2 (5.00 g; 21.3 mmol) in ACN (140 mL) was added 1-chloro-N,N,2-trimethylpropenylamine (4.45 mL; 33.6 mmol). The mixture was stirred at room temperature for 10 min, then pyridine (5.10 mL; 63.0 mmol) and 3-aminobenzofuran-2-carboxamide (3.70 g; 21.0 mmol) were added. The mixture was stirred at room temperature overnight, then water was added. The mixture was extracted with DCM, and the organic layer was separated and evaporated. The crude product was purified first by FC (silica gel; petroleum ether / EtOAc 40% to 80%) and then by RP HPLC (Sunfire C18, ACN / water, modifier: TFA). ESI-MS: 347 [M+H] + R t (HPLC): 0.80 min (Method C) N-09 Step 4: General Procedure Int-A: A mixture of the product of Step 3 (3.40 g; 9.73 mmol), palladium on charcoal (10%; 350 mg), and ethanol (500 mL) was shaken under hydrogen pressure (50 psi) until RP HPLC showed conversion of the starting material (in this case: 90 min). The catalyst was filtered off, and the filtrate was evaporated to dryness. ESI-MS: 349 [M+H] + R t (HPLC): 0.81 min (Method C)

[0091] N-09 Step 5: General Procedure Int-B: A mixture of the product of Step 4 (4.55 g; 13.1 mmol) and aqueous sodium hydroxide (4 M; 100 mL; 400 mmol) was stirred at 60 °C until reaction control by RP HPLC showed conversion of the starting material (in this case: 60 min). The mixture was allowed to cool to room temperature and then acidified by adding aqueous hydrochloric acid (4 M). The precipitate was collected and dried at 60 °C. ESI-MS: 317 [M+H] + R t (HPLC): 0.73 min (Method C) N-09 Step 6: To a mixture of the product of Step 5 (3.53 g; 11.2 mmol), DCM (60 mL), and a few drops of DMF was added oxalyl chloride (1.24 mL; 14.5 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours, then methanol was added and stirring was continued for another 60 minutes. The mixture was extracted with water, and the organic layer was separated and evaporated to dryness. ESI-MS: 331 [M+H] + R t (HPLC): 0.82 min (Method C)

[0092] N-09 Step 7: General Procedure Int-C: A mixture of the product of Step 6 (3.70 g; 11.2 mmol) and phosphoryl trichloride (70 mL) was stirred at 90 °C for 4 h. Excess phosphoryl trichloride was removed by distillation, and water was carefully added. The resulting mixture was extracted with EtOAc, and the organic layer was separated and evaporated. The crude product was used in the next step. ESI-MS: 349 [M+H] + R t (HPLC): 1.02 min (Method C) N-09 Step 8: General Procedure Int-D: A mixture of the product of Step 7 (300 mg; 0.896 mmol), tert-butyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (253 mg; 1.08 mmol), potassium carbonate (300 mg; 2.06 mmol), and DMF (7.0 mL) was stirred at room temperature overnight. Water was added, and the mixture was acidified by adding aqueous hydrochloric acid (1 M). The mixture was extracted with EtOAc, the organic layer was evaporated, and the crude product was purified by FC (silica gel; petroleum ether / EtOAc 40% to 75%). ESI-MS: 500 [M+H] + R t (HPLC): 0.75 min (Method C)

[0093] N-09 Step 9: The product of Step 8 was reacted according to general procedure Int-E to give the ester cleaved title compound. ESI-MS: 486 [M+H] + R t (HPLC): 0.70 min (Method C) Intermediate N-10 [ka] Prepared from intermediate N-02 and methyl (2S)-3-allyloxy-2-methyl-propanoate in a similar three-step sequence to that described for the synthesis of N-17. ESI-MS: 500.3 [M+H] + R t(HPLC): 2.44 minutes (Method H)

[0094] Intermediate N-11 [ka] Prepared from intermediate N-02 and methyl (2R)-3-allyloxy-2-methyl-propanoate in a similar three-step sequence to that described for the synthesis of N-17. ESI-MS: 500.6 [M+H] + R t (HPLC): 2.44 minutes (Method H)

[0095] Intermediate N-12 [ka] From intermediate N-02 and 2-(but-3-en-1-yloxy)acetic acid, a two-step sequence: Step 1: Follow General Procedure Int-G Step 2: Follow General Procedure Int-A was applied to give the title compound. ESI-MS: 486 [M+H] + R t (HPLC): 0.54 min (Method B)

[0096] Intermediate N-13 [ka] From intermediate N-18 and 2-(but-3-en-1-yloxy)acetic acid, a two-step sequence: N-13 Step 1: Comply with General Procedure Int-G N-13 Step 2: Follow General Procedure Int-A was applied to give the title compound. ESI-MS: 504 [M+H] + R t (HPLC): 0.45 min (Method A)

[0097] Intermediate N-14: 2-(4-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidin-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(13),2,4,6,9,11-hexaen-4-yl}-4,4-difluorobutoxy)acetic acid [ka]

[0098] N-14 Step 1: A dry reaction vessel equipped with a magnetic stir bar was charged with tert-butyl 2-allyloxyacetate (1.00 g; 5.81 mmol), anhydrous nickel(II) chloride (0.038 g; 0.290 mmol), and sodium carbonate (0.61 g; 5.81 mmol). The reaction vessel was then briefly evacuated and backfilled with argon (this sequence was repeated a total of three times). Anhydrous DMF (40 mL), ethyl bromodifluoroacetate (1.5 mL, 11.6 mmol), and phenylsilane (2.9 mL; 23.2 mmol) were added sequentially to the reaction vessel via syringe. The vessel was heated in an oil bath at 70 °C and stirred until TLC monitoring indicated consumption of the starting material (in this case: overnight). The reaction mixture was diluted with 30 mL of EtOAc, and the organic layer was washed with 80 mL of saturated aqueous sodium chloride solution. The organic layer was then dried over sulfate, concentrated under reduced pressure and further purified by FC (silica gel; hexane / EtOAc) to give ethyl 5-(2-tert-butoxy-2-oxo-ethoxy)-2,2-difluoro-pentanoate.

[0099] N-14 Step 2: At room temperature, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.79 g; 5.68 mmol) was added to a solution of 3-aminobenzofuran-2-carboxamide (0.25 g; 1.42 mmol) in 1,4-dioxane (1 mL). The product of Step 1 (0.84 g; 2.84 mmol) was then added, the temperature was raised to 120 °C, and stirring was continued until TLC showed nearly complete conversion (in this case: 18 h). The reaction mixture was diluted with water (15 mL) and extracted with DCM (3 x 7 mL). The pH of the resulting aqueous layer was adjusted to 4-5, and the precipitated solid was filtered off. ESI-MS: 353 [M+H] + R t (HPLC): 1.61 min (Method F) N-14 Step 3: The product of Step 2 was reacted according to general procedure Int-C. ESI-MS: 371 [M+H] + R t (HPLC): 1.82 minutes (Method F) N-14 Step 4: The product of Step 3 was reacted according to general procedure Int-D to give the title compound. ESI-MS: 522.6 [M+H] + R t (HPLC): 2.96 minutes (Method E)

[0100] Intermediate N-15 [ka] Prepared analogously to the procedure described for the synthesis of intermediate N-14, applying 3-amino-6-fluoro-1-benzofuran-2-carboxamide as starting material for step 2. The starting material 3-amino-6-fluoro-1-benzofuran-2-carboxamide was prepared as follows: 4-Fluoro-2-hydroxybenzonitrile (2.06 g; 14.3 mmol) was dissolved in ethanol (80 mL). Potassium carbonate (3.02 g; 21.8 mmol) and 2-bromoacetamide (2.40 g; 17.4 mmol) were added, and the mixture was heated to 78 °C for 1 hour. Potassium hydroxide (powdered; 1.91 g; 28.97 mmol) was added, and stirring and heating were continued overnight. The mixture was allowed to cool to room temperature, water was added, the ethanol was evaporated, and the precipitate was filtered, washed with water, and air-dried.

[0101] Intermediate N-16 [ka] Prepared analogously to the procedure described for the synthesis of intermediate N-14, applying 3-amino-6-chloro-1-benzofuran-2-carboxamide (prepared as described in EP 1 710 233) as starting material for step 2. Intermediate N-17 [ka] It was prepared from intermediate N-02 applying the following three step sequence:

[0102] N-17 Step 1: General Procedure Int-G: Intermediate N-02 (300 mg; 0.69 mmol) and 5-hexenoic acid methyl ester (298 μL; 2.07 mmol) were dissolved in DMF (10 mL; 123 mmol). Triethylamine (0.39 mL, 2.76 mmol) was added, and the mixture was degassed with argon. Palladium(II)-acetate (31 mg; 0.14 mmol) and tri-o-tolylphosphine (84 mg; 0.28 mmol) were added under argon. The sealed vial was stirred at 95 °C overnight. The mixture was diluted with ACN / water, acidified with TFA, and filtered through a syringe filter. Purification by preparative RP HPLC (Sunfire C18, ACN / water; modifier: TFA) gave tert-butyl(2S,4S)-4-hydroxy-1-{4-[6-methoxy-6-oxohex-1-en-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(13),2,4,6,9,11-hexaen-6-yl}pyrrolidine-2-carboxylate was obtained.

[0103] N-17 Step 2: The product of Step 1 is hydrogenated according to General Procedure Int-A to give tert-butyl(2S,4S)-4-hydroxy-1-[4-(6-methoxy-6-oxohexyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(13),2,4,6,9,11-hexaen-6-yl]pyrrolidine-2-carboxylate was obtained. ESI-MS: 484 [M+H] + R t (HPLC): 0.65 min (Method B) N-17 Step 3: The product of Step 2 was reacted according to general procedure Int-E to give the ester cleaved title compound. Intermediate N-18: tert-Butyl(2S,4S)-1-{4-bromo-11-fluoro-8-oxa-3,5-diazatricyclo-[7.4.0.0 2,7 ]trideca-1(13),2,4,6,9,11-hexaen-6-yl}-4-hydroxypyrrolidine-2-carboxylate

[0104] [ka] 11-Fluoro-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(13),2(7),9,11-tetraene-4,6-dione, prepared in the same manner as the reaction sequence described for the synthesis of intermediate N-02. Starting material 11-fluoro-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(13),2(7),9,11-tetraene-4,6-dione was reacted with 11-chloro-8-oxa-3,5-diazatricyclo[7.4.0.0] as described in WO 2019059577 2,7 ]-trideca-1(13),2(7),9,11-tetraene-4,6-dione was prepared in a similar manner to the synthesis of

[0105] Intermediate P-01 tert-Butyl (3S,4R)-4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carboxylate [ka]

[0106] P-01 Step 1: tert-butyl 4-(5-chloro-2-fluoropyridin-3-yl)-4-hydroxy-3-methylpiperidine-1-carboxylate Under an argon atmosphere, a solution of 3-bromo-5-chloro-2-fluoropyridine (10.0 g, 48.0 mmol, commercially available as Activate, MFCD04972409) in THF (150 mL; 15.0 V) was cooled to −78° C. Isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 38.4 mL, 50.0 mmol) was then added dropwise, maintaining the temperature below −65° C. The reaction mixture was then stirred at −78° C. for an additional 50 minutes. A premixed solution of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (11.6 g; 55.0 mmol, preparation as described in WO 2011 / 159852) and lanthanum trichloride lithium chloride complex (0.6 M in THF, 7.92 mL, 5.00 mmol) in THF (20.0 mL; 2.00 V) was then added dropwise, maintaining the temperature below −65° C., and after the addition was complete, the reaction mixture was allowed to reach room temperature overnight. The reaction mixture was quenched with 20 mL of saturated NH4Cl solution, and the THF was removed in vacuo. The mixture was acidified with 6 mL of 1N HCl and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was coevaporated three times with 15 mL of toluene. The crude product was used in the next step without further purification. ESI-MS: 289.0 / 291.0 [M+H] + ; R t (HPLC): 0.64 / 0.68 min (Method A) 1H NMR: (400 MHz, CDCl3): δ ppm 8.02 - 8.11 (m, 2H) 3.80 - 4.20 (m, 2H) 3.01 - 3.20 (m, 1H) 2.68 - 2.91 (m, 1H) 2.25 - 2.49 (m, 2H) 1.99 (s, 1H) 1.48 (s, 9H) 0.65 (d, J = 6.80 Hz, 3H).

[0107] P-01 Step 2: tert-butyl 4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carboxylate To a solution of tert-butyl 4-(5-chloro-2-fluoropyridin-3-yl)-4-hydroxy-3-methylpiperidine-1-carboxylate (5.00 g, 15.0 mmol) in anhydrous DCM (70 mL, 14.0 V), DAST (3.83 mL, 29.0 mmol) was added dropwise while the reaction mixture was cooled in an ice-MeOH bath. The reaction was stirred in the ice-MeOH bath for 3.5 hours, quenched by adding saturated NaHCO3 solution, and extracted three times with DCM. The combined organic layers were dried over sodium sulfate, filtered, evaporated, and the crude product was further purified by flash column chromatography (n-heptane / EA = 50 / 1 to 5 / 1). ESI-MS: 291.0 / 291.0 [M-isobutene]+, chlorine isotope pattern, R t (HPLC): 0.75 min (rac-trans) and 0.80 min (rac-cis) (Method A)

[0108] P-01 Step 3: tert-butyl (3S,4R)-4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carboxylate The cis-racemate obtained in Step 2 was purified by preparative HPLC (neutral conditions) and then further separated by chiral SFC (column: REGIS (s,s) WHELK-O1 (250 mm × 50 mm, 10 μm); mobile phase: [0.1% NH3HO IPA]; B%: 11%-11%, 2.3 min).

[0109] Intermediate P-01 (3S,4R) was the first eluting peak under these conditions. 1H NMR (400 MHz, CDCl3): δ ppm 8.10 - 8.14 (m, 1H) 7.93 (dd, J = 8.19, 2.56 Hz, 1H) 4.08 (br s, 2H) 3.11 (br s, 1H) 2.82 (br s, 1H) 2.18 - - 19F NMR (400 MHz, CDCl3): δ ppm -69.5, -179.4. The absolute configuration of this intermediate was confirmed by single-crystal X-ray diffraction.

[0110] Intermediate P-02 5-chloro-2-fluoro-3-[(3S,4R)-4-fluoro-3-methylpiperidin-4-yl]pyridine hydrochloride [ka] Tert-butyl (3S,4R)-4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carboxylate (8.27 mmol, 3.02 g) was dissolved in 4N HCl (10.3 mL, 41.4 mmol) in 1,4-dioxane, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with diethyl ether, and the formed precipitate was collected by filtration, washed with diethyl ether, and dried. ESI-MS: 247 / 249 (1Cl) [M+H] + ; R t (HPLC): 0.33 min (Method A)

[0111] Intermediate P-03: tert-Butyl 4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoropiperidine-1-carboxylate [ka] This intermediate was prepared following the synthesis of intermediate P-01 (Step 1-Step 2), starting from tert-butyl 4-oxopiperidine-1-carboxylate.

[0112] P-03 Step 1: tert-butyl 4-(5-chloro-2-fluoropyridin-3-yl)-4-hydroxypiperidine-1-carboxylate ESI-MS: 275 / 277 (1Cl) [M+H] + ; R t (HPLC): 0.61 min (Method A) P-03 Step 2: tert-butyl 4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoropiperidine-1-carboxylate ESI-MS: 333 / 335 (1Cl) [M+H] + ; R t (HPLC): 0.74 min (Method A)

[0113] Intermediate P-04: tert-Butyl (3S,4R)-4-(5-bromo-2-fluoropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carboxylate [ka] This intermediate was prepared following the synthesis of intermediate P-01 (steps 1-3), starting from 3,5-dibromo-2-fluoro-pyridine. Analytical data for step 2: ESI-MS: 335 / 337 [M-isobutene], chlorine isotope pattern, Rt (HPLC): 0.75 min (rac-cis) and 0.80 min (rac-trans) (Method A). Chiral separation conditions for cis-enantiomers: Separation by chiral SFC (column: DAICEL CHIRALPAK IG (250 mm × 50 mm, 10 μm); mobile phase: MeOH [0.1% NH] / CO; 15 / 85).

[0114] Intermediate P-04 (3S,4R) was the second eluting peak under these conditions. Final assignment of the absolute stereochemistry of these products was made retrospectively based on the X-ray of Example EX-17. Intermediates P-05 and P-06: [ka] P-05: tert-butyl(3S,4R)-4-(2-{[(3S,5S)-1-{4-bromo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl}-5-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]oxy}-5-chloropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carboxylate This intermediate was prepared from intermediates P-01 and N-02 according to general procedure Int-D. ESI-MS:760 / 762 / 764 (Cl, Br) [M+H] + ; R t (HPLC): 0.99 min (Method A)

[0115] P-06: tert-Butyl(3S,4R)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-[4-(1,1-difluoro-2-methoxy-2-oxoethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidin-3-yl]oxy}-5-chloropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carboxylate Molecular sieves (3 Å) were added to a degassed solution of intermediate P-05 (240 mg, 0.300 mmol) in DMSO (4.26 mL) under argon at room temperature, followed by the addition of methyl bromodifluoroacetate (89.7 μL, 0.792 mmol) and copper bronze powder (101 mg, 1.52 mmol). After stirring at room temperature for 4 days, the reaction mixture was diluted with 10 mL of EA and quenched with an aqueous KH2PO4 solution (1.27 M, 5.00 mL). The mixture was filtered through a Celite pad, and the solid was washed with EA. The aqueous phase was extracted with EA. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and evaporated to give the crude product. The residue was dissolved in DMF / ACN, acidified with 10% TFA, and purified by preparative HPLC (XBridge C18; 60-100% ACN / H2O / TFA). ESI-MS: 790 / 792 (1Cl) [M+H] + ; R t (HPLC): 1.00 min (Method A)

[0116] Intermediate P-07: Pent-4-en-1-yl (3S,4R)-4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carboxylate [ka] A mixture of intermediate P-02 (100 mg, 0.279 mmol), DIPEA (144 μL, 0.892 mmol), and 4-nitrophenylpent-4-en-1-yl carbonate (94 mg, 0.200 mmol, prepared as described in WO 2014 / 11769) in THF (1.00 mL) was stirred for 2 h at 80° C. Volatiles were removed in vacuo, and the crude mixture was purified by preparative HPLC (ACN, Sunfire, TFA, Narrow). ESI-MS: 359 [M+H] + ; R t (HPLC): 1.11 min (Method B)

[0117] Intermediate P-08: 3-{2-[(3S,4R)-4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carbonyloxy]ethoxy}propanoic acid [ka]

[0118] P-08 Step 1: tert-Butyl 3-(2-{[(4-nitrophenoxy)carbonyl]oxy}ethoxy)propanoate tert-Butyl 3-(2-hydroxyethoxy)propanoate (5.10 g, 26.8 mmol, preparation described in WO 2019 / 195609) was dissolved in 40.0 mL of DCM, pyridine (2.16 mL, 26.9 mmol) was added, and the mixture was cooled to 0 °C. At this temperature, a solution of 4-nitrophenyl chloroformate (5.57 g, 26.8 mmol) in DCM (20.0 mL) was slowly added. Once the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. Water (150 mL) was added, and the layers were separated. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (CH / EtOAc = 95 / 5 → 80 / 20). ESI-MS: 378 [M+Na] + , R t (HPLC): 0.93 min (Method B)

[0119] P-08 Step 2: tert-butyl 3-{2-[(3S,4R)-4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carbonyloxy]ethoxy}propanoate To a mixture of the product obtained in Step 1 of P-08 (3.24 g, 7.31 mmol) and intermediate P-02 (2.30 g, 8.12 mmol) in THF (46 mL) was added DIPEA (4.36 mL) and the mixture was heated to 65 °C for 2 h. The reaction mixture was cooled to room temperature and diluted with EtOAc. The phases were separated and the organic phase was washed with dilute sodium hydroxide solution. The organic phase was dried over sodium sulfate and evaporated to dryness. ESI-MS: 463 [M+H] + , R t (HPLC): 1.05 min (Method B) P-08 Step 3: 3-{2-[(3S,4R)-4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carbonyloxy]ethoxy}propanoic acid This step was carried out according to general procedure H. ESI-MS: 407 [M+H] + , R t (HPLC): 0.79 min (Method B)

[0120] Intermediate P-09 5-Bromo-2-fluoro-3-[(3S,4R)-4-fluoro-3-methylpiperidin-4-yl]pyridine hydrochloride [ka] This intermediate was prepared following the synthesis of intermediate P-02, starting from P-04. ESI-MS: 291 / 293 (1Br) [M+H] + ; R t (HPLC): 0.35 min (Method A)

[0121] Synthesis of Examples The syntheses described hereinafter were carried out in part according to the following general procedures where indicated. General Procedure A: Amidation (TBTU / NMP) (See EX-01 Step 1) General Procedure B:S N Ar(NaH / DMA) (See EX-01-Step 2) General Procedure C: Ester Hydrolysis (LiOH / THF) (See EX-01 Step 4) General Procedure D: Amidation (HATU / DMF) (See EX-01 Step 5) General Procedure E: Amidation (HATU / DMA) (See EX-02 Step 5) General Procedure F: BOC Deprotection Applying PTSA (See EX-03 Step 2) General Procedure G: Macrocyclization (HATU / DMA) (See EX-03 Step 3) General Procedure H: tBu Deprotection (TFA / DCM) (See EX-04 Step 6) General Procedure I: Cyclization to Pyridine (NaH / NMP) (See EX-05 Step 2) General Procedure J: Amidation using DCC (see EX-08 step 3) General Procedure K: Olefin Metathesis (See EX-08 Step 4) General Procedure L: Hydrogenation using Raney-Ni (see EX-08 Step 5) General Procedure M: Heck Coupling (See EX-22 Step 1) General Procedure N: Hydrogenation using Pd / C (see EX15 Step 3) General Procedure O: Suzuki Coupling (See EX-20.01 Step 1)

[0122] (Example EX-01) (1R,9S,11S,34S)-4-chloro-1-fluoro-34-methyl-26,31-dioxo-8,15-dioxa-6,12,23,27,32,37-hexaaza-heptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13(37),14(22),16(21),17,19,23-nonane-11-carboxylic acid

[0123] [ka]

[0124] EX-01 Step 1: tert-butyl N-{4-[(3S,4R)-4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3-methylpiperidin-1-yl]-4-oxobutyl}carbamate General Procedure A: Amidation (TBTU / NMP) To a solution of 4-{[(tert-butoxy)carbonyl]amino}butanoic acid (BOC-GABA-OH) (59.8 mg, 0.29 mmol) in 1-methyl-2-pyrrolidinone (1.5 mL), DIPEA (270 μL, 1.20 mmol) was added, followed by TBTU (94.5 mg, 0.290 mmol), and the mixture was stirred at room temperature for 5 minutes. Intermediate P-02 was then added, and the reaction mixture was stirred at room temperature overnight. Water and ethyl acetate were added, the phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed successively with water, 5% LiCl solution, saturated NaHCO3 solution, and brine, dried over sodium sulfate, and evaporated to dryness. ESI-MS: 432 / 434 [M+H] + (1Cl); R t (HPLC): 0.70 min (Method A)

[0125] EX-01 Step 2: General Procedure B:S N Ar(NaH / DMA) tert-Butyl(2S,4S)-4-({3-[(3S,4R)-1-(4-{[(tert-butoxy)carbonyl]amino}butanoyl)-4-fluoro-3-methylpiperidin-4-yl]-5-chloropyridin-2-yl}oxy)-1-[4-(2-ethoxy-2-oxoethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylate The reaction was carried out under an argon atmosphere. To a stirred solution of hydroxyproline ester N-01 (100 mg, 0.220 mmol) and the product obtained in Step 1 (120 mg, 0.270 mmol) in DMA (2.00 mL) cooled in an ice / water bath, sodium hydride (60% dispersion in mineral oil, 25.8 mg, 0.65 mmol) was added. Stirring was continued at 0 °C until the hydroxyproline was consumed (15 min). Under ice cooling, water was added dropwise, followed by EtOAc and water. The mixture was acidified and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. ESI-MS: 853 [M+H] + ; R t (HPLC): 1.18 min (Method B)

[0126] EX-01 Step 3: tert-Butyl(2S,4S)-4-({3-[(3S,4R)-1-(4-aminobutanoyl)-4-fluoro-3-methylpiperidin-4-yl]-5-chloropyridin-2-yl}oxy)-1-[4-(2-ethoxy-2-oxoethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylate A mixture of the product obtained in step 2 (158 mg, 0.185 mmol) in dioxane (10 mL) was reacted with 4 N HCl in dioxane (0.14 mL, 0.555 mmol) at room temperature overnight. An additional 0.05 mL (0.18 mmol) of 4 N HCl in dioxane was added, and after 4 h, another 0.05 mL (0.18 mmol) was added. Water was added to the reaction mixture, and the volatiles were removed under reduced pressure. The residue was coevaporated with toluene, and the crude product was further purified by preparative HPLC (Sunfire, ACN / TFA, Narrow). ESI-MS: 753 / 755 [M+H] + (1Cl); R t (HPLC): 0.83 min (Method B)

[0127] EX-01 Step 4: 2-{6-[(2S,4S)-4-({3-[(3S,4R)-1-(4-aminobutanoyl)-4-fluoro-3-methylpiperidin-4-yl]-5-chloropyridin-2-yl}oxy)-2-[(tert-butoxy)carbonyl]pyrrolidin-1-yl]-8-oxa-3,5-diazatricyclo-[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}acetic acid General Procedure C: Ester Hydrolysis (LiOH / THF) To a mixture of the product obtained in Step 3 (59 mg, 70.0 mmol) in THF (0.59 mL) at room temperature, 2 M aqueous LiOH solution (0.223 mL, 0.440 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was diluted with EA and water and acidified with acetic acid. The phases were separated, and the organic phase was washed with water and brine, dried over sodium sulfate, filtered, and evaporated to dryness. ESI-MS: 725 / 727 [M+H] + (1Cl); R t (HPLC): 0.75 min (Method B)

[0128] EX-01 Step 5: tert-Butyl (1R,9S,11S,34S)-4-chloro-1-fluoro-34-methyl-26,31-dioxo-8,15-dioxa-6,12,23,27,32,37-hexaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13(37),14(22),16(21),17,19,23-nonane-11-carboxylate General Procedure D: Amidation (HATU / DMF) To a mixture of HATU (25 mg, 0.065 mmol) in DMF (2.50 mL) at room temperature, a solution of the product obtained in Step 4 (39 mg, 0.050 mmol) and DIPEA (19 μL, 0.11 mmol) in DMF (2.50 mL) was slowly added under stirring. The mixture was stirred at room temperature for 1 h, then acidified with acetic acid and diluted with ACN. The crude product was purified using HPLC (Sunfire, ACN, TFA, Narrow). R t (HPLC): 0.75 min (Method B)

[0129] EX-01 Step 6: (1R,9S,11S,34S)-4-chloro-1-fluoro-34-methyl-26,31-dioxo-8,15-dioxa-6,12,23,27,32,37-hexaaza-heptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13(37),14(22),16(21),17,19,23-nonane-11-carboxylic acid The product obtained in Step 5 (15 mg, 0.021 mmol) in DCM (2.00 mL) was reacted with TFA (16 μL, 0.21 mmol) at room temperature, and the mixture was stirred overnight. TFA (32 μL, 0.42 mmol) was added again, and the mixture was stirred for 4 hours. TFA (16 μL, 0.21 mmol) was added again, and the mixture was stirred for 3 days. The mixture was diluted with ACN and water, filtered, and directly purified by preparative HPLC (Sunfire, ACN, TFA, Narrow). ESI-MS: 649 / 651 [M+H] + (1Cl); R t (HPLC): 0.85 min (Method B)

[0130] (Example 02) (1R,9S,11S,34S)-4-chloro-1-fluoro-34-methyl-26,31-dioxo-8,15,30-trioxa-6,12,23,27,32,37-hexaazaheptacyclo[30.2.2.19,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13(37),14(22),16(21),17,19,23-nonane-11-carboxylic acid

[0131] [ka]

[0132] EX-02 Step 1: 2-{[(tert-butoxy)carbonyl]amino}ethyl (3S,4R)-4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carboxylate 2.70 mL of THF, P-02 (270 mg, 0.906 mmol), 1-{[(2-{[(tert-butoxy)carbonyl]amino}ethoxy)carbonyl]oxy}-4-nitrobenzene (373 mg, 0.915 mmol, preparation described in U.S. Patent Application Publication No. 2019 / 192668), and DIPEA (439 μL, 2.72 mmol) were mixed and heated to 80 °C for 2 h under stirring. After cooling to room temperature, the reaction mixture was diluted with EA and water. NaHCO solution was added and the phases were separated. The organic layer was washed twice with water and brine, dried over NaSO, filtered, and evaporated. The crude product was purified by preparative HPLC (Sunfire, ACN, TFA, Narrow). ESI-MS: 434 [M+H] + ; R t (HPLC): 0.99 min (Method B)

[0133] EX-02 Step 2: 2-{[(tert-butoxy)carbonyl]amino}ethyl(3S,4R)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-[4-(2-ethoxy-2-oxoethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidin-3-yl]oxy}-5-chloropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carboxylate To a mixture of intermediate N-01 (150 mg, 0.340 mmol) and tert-butyl N-{4-[(3S,4R)-4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3-methylpiperidin-1-yl]-4-oxobutyl}-carbamate (145 mg, 0.334 mmol) in DMA (3.00 mL), sodium hydride (60% dispersion in mineral oil, 25.8 mg, 0.65 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by the dropwise addition of slightly acidified water (TFA) and directly purified by preparative HPLC (Sunfire, ACN / TFA, Narrow). ESI-MS: 855 [M+H] + ; R t (HPLC): 1.17 minutes (Method B)

[0134] EX-02 Step 3: 2-Aminoethyl(3S,4R)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-[4-(2-ethoxy-2-oxoethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidin-3-yl]oxy}-5-chloropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carboxylate Under an argon atmosphere, the product obtained in Step 2 in DCM (2.0 mL) was cooled to -15 °C (acetone / ice bath), and TMSI (17 μL, 0.12 mmol) was slowly added. The reaction mixture was maintained at -15 °C for 45 min and then at 0 °C for 30 min. TMSI (9 μL, 0.060 mmol) was added again, and stirring was continued at 0 °C for 45 min. The reaction was quenched by adding 2.0 mL of methanol. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (Sunfire, ACN / TFA, Narrow). ESI-MS: 755 [M+H] + ; R t (HPLC): 0.82 min (Method B)

[0135] EX-02 Step 4: 2-{6-[(2S,4S)-4-({3-[(3S,4R)-1-[(2-aminoethoxy)carbonyl]-4-fluoro-3-methylpiperidin-4-yl]-5-chloropyridin-2-yl}oxy)-2-[(tert-butoxy)carbonyl]pyrrolidin-1-yl]-8-oxa-3,5-diazatricyclo-[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}acetic acid To a solution of the product obtained in Step 3 (53 mg, 0.070 mmol) in THF (0.53 mL) was added 2N aqueous LiOH solution (100 μL, 0.200 mmol) and water (60 μL, 3.33 mmol). The reaction mixture was stirred at room temperature for 4 hours, then acidified with acetic acid (13 μL, 0.23 mmol) and diluted with ACN and methanol. The formed precipitate was removed by filtration, and the filtrate was evaporated under reduced pressure to give the title compound. ESI-MS: 727 [M+H] + ; R t (HPLC): 0.75 min (Method B)

[0136] EX-02 Step 5: tert-Butyl (1R,9S,11S,34S)-4-chloro-1-fluoro-34-methyl-26,31-dioxo-8,15,30-trioxa-6,12,23,27,32,37-hexaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13(37),14(22),16(21),17,19,23-nonane-11-carboxylate General Procedure E A solution of the product obtained in Step 4 (46 mg, 0.063 mmol) and DIPEA (0.030 mL, 0.18 mmol) in DMA (1.00 mL) was slowly added to a solution of HATU (25 mg, 0.065 mmol) in DMA (3.0 mL) over 30 min via syringe pump, and stirring was continued for 30 min at room temperature. The reaction mixture was acidified with TFA and directly purified by preparative RP-HPLC (Sunfire, ACN / HO / TFA, Narrow). ESI-MS: 769 [M+H] + ; R t (HPLC): 1.01 min (Method B)

[0137] EX-02 Step 6: (1R,9S,11S,34S)-4-chloro-1-fluoro-34-methyl-26,31-dioxo-8,15,30-trioxa-6,12,23,27,32,37-hexaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13(37),14(22),16(21),17,19,23-nonane-11-carboxylic acid To a solution of the product obtained in Step 5 (5.0 mg, 0.0071 mmol) in DCM (0.25 mL) was added TFA (100 μL, 1.30 mmol) at room temperature, and the reaction mixture was stirred overnight. TFA (100 μL, 1.30 mmol) was added again, and stirring was continued for 6 h. The volatiles were removed under a stream of nitrogen, and the residue was dissolved in ACN / water and lyophilized. ESI-MS: 653 [M+H] + ; R t (HPLC): 0.91 min (Method B)

[0138] (Example 03) (1R,9S,11S,34S)-4-chloro-1,25,25-trifluoro-27,34-dimethyl-26,31-dioxo-8,15-dioxa-6,12,23,27,32,37-hexaazaheptacyclo[30.2.2.1 9,12 .113,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13,16,18,20,22,24(37)-nonane-11-carboxylic acid [ka]

[0139] EX-03 Step 1: 4-(2-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-({3-[(3S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoro-3-methylpiperidin-4-yl]-5-chloropyridin-2-yl}oxy)pyrrolidin-1-yl]-8-oxa-3,5-diazatricyclo-[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}-2,2-difluoro-N-methylacetamido)butanoic acid Following the general procedure, intermediate N-03 was reacted with intermediate P-01 to give the title compound. ESI-MS: 875 / 877 (1Cl) [M+H] + ; R t (HPLC): 0.92 min (Method A)

[0140] EX-03 Step 2: 4-(2-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-({5-chloro-3-[(3S,4R)-4-fluoro-3-methylpiperidin-4-yl]pyridin-2-yl}oxy)pyrrolidin-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}-2,2-difluoro-N-methylacetamido)butanoic acid General Procedure F: BOC Deprotection Applying PTSA A mixture of the BOC-protected amine (72 mg, 0.078 mmol) obtained in the previous step in ACN (2.50 mL) was reacted with PTSA (31.3 mg, 0.156 mmol, 2.00 equiv.) at 0 °C. The cooling bath was removed, and the mixture was stirred until complete conversion of the starting material to the free amine was observed (2-24 h). The reaction mixture was quenched by adding water, diluted with ACN, filtered, and purified by semi-preparative HPLC (XBridge C18; ACN / HO / TFA) to give the title compound. ESI-MS: 775 / 777 (1Cl) [M+H] + ; R t (HPLC): 0.65 min (Method A)

[0141] EX-03 Step 3: tert-Butyl (1R,9S,11S,34S)-4-chloro-1,25,25-trifluoro-27,34-dimethyl-26,31-dioxo-8,15-dioxa-6,12,23,27,32,37-hexaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13,16,18,20,22,24(37)-nonane-11-carboxylate General Procedure G: Macrocyclization (HATU / DMA) A mixture of the product obtained in step 3 (44 mg, 0.054 mmol) and DIPEA (0.030 mL, 0.162 mmol) in DMA (1.10 mL) was slowly added via syringe to a solution of HATU (23 mg, 0.060 mmol) in DMA (2.42 mL) over 30 min and stirring was continued at room temperature until complete consumption of the starting material was observed. The reaction mixture was acidified with TFA and directly purified by preparative RP-HPLC (Sunfire, ACN / HO / TFA, Narrow). ESI-MS: 757 / 759 (1Cl) [M+H] + ; R t (HPLC): 0.86 min (Method A)

[0142] EX-03 Step 4: (1R,9S,11S,34S)-4-chloro-1,25,25-trifluoro-27,34-dimethyl-26,31-dioxo-8,15-dioxa-6,12,23,27,32,37-hexaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13,16,18,20,22,24(37)-nonane-11-carboxylic acid The product obtained in the previous step was dissolved in 0.50 mL of DCM at room temperature and treated with TFA (38.7 μL, 0.502 mmol, 20 equiv) for 21 h at 36 °C. An additional amount of TFA (19.4 μL; 10 equiv) was added, and stirring was continued for an additional 6 h at 36 °C. Again, TFA (38.7 μL; 20 equiv) was added, and stirring was continued for an additional 20 h at 36 °C. The volatiles were removed in vacuo, and the residue was dissolved in ACN / HO and purified by semi-preparative HPLC (XBridge C18; ACN / HO / TFA). ESI-MS: 701 / 703 (1Cl) [M+H] + ; R t (HPLC): 0.71 min (Method A) The absolute configuration of the final compound was confirmed by co-crystallization of the compound with human cGAS protein.

[0143] (Example 04) (1R,9S,11S,34S)-4-chloro-1,25,25-trifluoro-34-methyl-26,31-dioxo-8,15-dioxa-6,12,23,27,32,37-hexaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13,16,18,20,22,24(37)-nonane-11-carboxylic acid

[0144] [ka]

[0145] EX-04 Step 1: 2-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-({3-[(3S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoro-3-methylpiperidin-4-yl]-5-chloropyridin-2-yl}oxy)pyrrolidin-1-yl]-8-oxa-3,5-diazatricyclo-[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}-2,2-difluoroacetic acid This compound was prepared from P-06 according to general procedure C. ESI-MS: 776 / 778 (1Cl) [M+H] + ; R t (HPLC): 0.94 min (Method A)

[0146] EX-04 Step 2: tert-Butyl(3S,4R)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-(4-{difluoro[(4-methoxy-4-oxobutyl)carbamoyl]methyl}-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl)pyrrolidin-3-yl]oxy}-5-chloropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carboxylate This compound was prepared according to general procedure D from the product obtained in the previous step and methyl-4-aminobutanoate hydrochloride. ESI-MS: 875 / 877 (1Cl) [M+H] + ; R t (HPLC): 0.96 min (Method A)

[0147] EX-04 Step 3: 4-(2-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-({3-[(3S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoro-3-methylpiperidin-4-yl]-5-chloropyridin-2-yl}oxy)pyrrolidin-1-yl]-8-oxa-3,5-diazatricyclo-[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}-2,2-difluoroacetamido)butanoic acid This compound was prepared according to general procedure C from the product obtained in the previous step. ESI-MS: 861 / 863 (1Cl) [M+H] + ; R t (HPLC): 0.91 min (Method A) EX-04 Step 4: 4-(2-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-({5-chloro-3-[(3S,4R)-4-fluoro-3-methylpiperidin-4-yl]pyridin-2-yl}oxy)pyrrolidin-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}-2,2-difluoroacetamido)butanoic acid This compound was prepared according to general procedure D from the product obtained in the previous step. ESI-MS: 761 / 763 (1Cl) [M+H] + ; R t (HPLC): 0.64 min (Method A)

[0148] EX-04 Step 5: tert-Butyl (1R,9S,11S,34S)-4-chloro-1,25,25-trifluoro-34-methyl-26,31-dioxo-8,15-dioxa-6,12,23,27,32,37-hexaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21]Octatriaconta-2,4,6,13,16,18,20,22,24(37)-nonane-11-carboxylate This compound was prepared according to general procedure G from the product obtained in the previous step. ESI-MS: 743 / 745 (1Cl) [M+H] + ; R t (HPLC): 0.93 min (Method A)

[0149] EX-04 Step 6: 2-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-({3-[(3S,4R)-1-[(tert-butoxy)carbonyl]-4-fluoro-3-methylpiperidin-4-yl]-5-chloropyridin-2-yl}oxy)pyrrolidin-1-yl]-8-oxa-3,5-diazatricyclo-[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}-2,2-difluoroacetic acid General Procedure H: tBu Deprotection (TFA / DCM) The product obtained in the previous step (33 mg, 0.042 mmol) was dissolved in 0.33 mL of DCM at room temperature and treated with TFA (130 μL, 1.67 mmol, 40 equiv.). The mixture was stirred at room temperature until complete consumption of the starting material was observed (24 h). The volatiles were removed in vacuo, and the residue was dissolved in ACN / HO and purified by semi-preparative HPLC (XBridge C18; ACN / HO / TFA). ESI-MS: 687 / 689 (1Cl) [M+H] + ; R t (HPLC): 0.73 min (Method A)

[0150] (Example 05) (1R,9S,11S,34S)-4-chloro-1,25,25-trifluoro-34-methyl-31-oxo-8,15-dioxa-6,12,23,32,37-pentaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21]Octatriaconta-2,4,6,13,16,18,20,22,24(37)-nonane-11-carboxylic acid [ka]

[0151] EX-05 Step 1: This compound was prepared according to general procedure A from intermediate N-04 and intermediate P-02. ESI-MS: 748 / 750 [M+H] + ; R t (HPLC): 0.79 min (Method A) EX-05 Step 2: General Procedure I: Cyclization via Pyridine (NaH / NMP) A mixture of the product (fluoropyridine) obtained in EX-05 Step 1 (75.0 mg; 0.0095 mmol) in NMP (2.00 mL) was added dropwise within 2 min to a suspension of NaH (16.6 mg; 0.381 mmol) in NMP (1.00 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. Additional NaH (16.6 mg, 0.381 mmol) was added, and stirring was continued at room temperature for 20 min. To avoid the formation of further by-products, the reaction mixture was quenched with water, acidified with TFA, diluted with ACN / HO, filtered, and purified by semi-preparative HPLC (XBridge C18; ACN / HO / TFA) to give the macrocyclized product. ESI-MS: 728 [M+H] + ; R t (HPLC): 0.91 min (Method A)

[0152] EX-05 Step 3: EX-05 The product obtained in step 2 was reacted according to general procedure H to give the final product. ESI-MS: 672 / 674 (1Cl) [M+H] + ; R t (HPLC): 0.87 min (Method A)

[0153] The following compounds were prepared in a similar manner to Example EX-05 above, following general procedures A, I, H: [Table 1]

[0154] (Example EX-06) (1R,9S,11S,34S)-4-chloro-1,25,25,30,30-pentafluoro-34-methyl-31-oxo-8,15-dioxa-6,12,23,32,37-pentaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]-Octatriaconta-2,4,6,13(37),14(22),16(21),17,19,23-nonane-11-carboxylic acid

[0155] [ka]

[0156] EX-06 Step 1: Following general procedure B, intermediate N-05 was reacted with intermediate P-01 using NMP as a solvent to give the title compound. ESI-MS: 883 / 885 (1Cl) [M+H] + ; R t (HPLC): 0.95 min (Method A) EX-06 Step 2: This compound was prepared from the product obtained in EX-06 Step 1 according to general procedure F. ESI-MS: 782 / 784 (1Cl) [M+H] + ; R t (HPLC): 0.69 min (Method A)

[0157] EX-06 Step 3: This compound was prepared from the product obtained in EX-06 Step 2 according to general procedure G. ESI-MS: 765 / 767 (1Cl) [M+H] + ; R t (HPLC): 0.96 min (Method A) EX-06 Step 4: EX-06 The product obtained in step 3 was reacted according to general procedure H to give the final compound. ESI-MS: 708 / 710 (1Cl) [M+H] + ; R t (HPLC): 0.86 min (Method A)

[0158] The following compounds can be prepared in a similar manner to Example 06 above, applying general procedures B, F, G, and H. [Table 2-1] [Table 2-2] [Table 2-3]

[0159] (Example EX-08) (1R,9S,11S,34S)-4-chloro-1-fluoro-34-methyl-31-oxo-8,15,26-trioxa-6,12,23,32,37-pentaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13(37),14(22),16(21),17,19,23-nonane-11-carboxylic acid

[0160] [ka]

[0161] EX-08 Step 1: Following general procedure B, intermediate N-06 was reacted with intermediate P-01 using NMP as a solvent to give the title compound. ESI-MS: 752 / 754 (1Cl) [M+H] + ; R t (HPLC): 0.89 min (Method A) EX-08 Step 2: EX-08 The product obtained in Step 1 was reacted according to general procedure F. ESI-MS: 652 / 654 (1Cl) [M+H] + ; R t (HPLC): 1.03 min (Method B)

[0162] EX-08 Step 3: General Procedure J: Amidation using DCC At 0 °C, a 1 M solution of DCC in DCM (387 μL, 0.387 mmol, 1.30 equiv.) was added dropwise to a stirred mixture of piperidine (200 mg, 0.297 mmol), DMAP (4.7 mg, 0.039 mmol), and vinylacetic acid (34.0 μL, 0.387 mmol) obtained from EX-08 Step 2 in DCM (2.00 mL). The reaction mixture was allowed to reach room temperature and stirred at room temperature until complete conversion of the starting material was observed (30 h). The reaction mixture was then cooled to 0 °C, diluted with DCM, filtered, and the filtrate was concentrated to give the crude product. The crude product was further purified by preparative HPLC (XBridge C18; 30-100% ACN / HO / TFA). ESI-MS: 720 / 722 (1Cl) [M+H] + ; R t (HPLC): 0.80 min (Method A)

[0163] EX-08 Step 4: General Procedure K: Olefin Metathesis Under argon, Grubbs Catalyst® Second Generation (25.0 mg, 0.028 mmol, 10 mol%) was added to a degassed solution of the product obtained in EX-08 Step 3 (212 mg, 0.280 mmol) in 1,2-dichloroethane (8.48 mL). The vial was sealed, and the reaction mixture was heated to 60 °C and stirred at this temperature until the starting material was consumed (in this case: approximately 45 min). If necessary, an additional amount of catalyst (25.0 mg, 0.028 mmol, 10 mol%) was added, and stirring was continued at 60 °C. Once the conversion of the starting material was complete (in this case: approximately 2 h), the volatiles were removed in vacuo, and the residue was dissolved in ACN / HO, filtered, and purified by semi-preparative HPLC (XBridge C18; ACN / HO / TFA). ESI-MS: 692 / 694 (1Cl) [M+H] + ; R t (HPLC): 0.73 min (Method A)

[0164] EX-08 Step 5: General Procedure L: Hydrogenation using Raney-Ni To a mixture of the product obtained in EX-08 Step 5 in MeOH (0.10 mL) and EtOAc (1.00 mL) in a Parr apparatus, Raney-Ni (2 mg) was added. The reaction mixture was placed under 2 bar of hydrogen pressure at room temperature for 2 hours. The solids were removed by filtration, and the filtrate was concentrated to dryness in vacuo. The residue was dissolved in ACN / HO and lyophilized. ESI-MS: 694 / 696 (1Cl) [M+H] + ; R t (HPLC): 0.76 min (Method A) EX-08 Step 6: EX-08 The product obtained in step 5 was reacted according to general procedure H to give the final compound. ESI-MS: 638 / 640 (1Cl) [M+H] + ; R t (HPLC): 0.63 min (Method A)

[0165] (Example EX-09) (1R,9S,11S,30S,34S)-4-chloro-1-fluoro-30,34-dimethyl-31-oxo-8,15,26-trioxa-6,12,23,32,37-pentaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13,16,18,20,22,24(37)-nonane-11-carboxylic acid [ka]

[0166] EX-09 Step 1: EX-08 tert-Butyl (2S,4S)-4-({5-chloro-3-[(3S,4R)-4-fluoro-3-methylpiperidin-4-yl]pyridin-2-yl}oxy)-1-{4-[(prop-2-en-1-yloxy)methyl]-8-oxa-3,5-diazatricyclo[7.4.0.0] obtained as the product from Step 2 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl}pyrrolidine-2-carboxylate was reacted with 2-methyl-3-butenoic acid according to general procedure J. ESI-MS: 734 / 736 ​​(1Cl) [M+H] + ; R t (HPLC): 0.83 min (Method A)

[0167] EX-09 Step 2: The product obtained in the previous step was reacted according to general procedure K and carried to the next step as a mixture of diastereomers. ESI-MS: 706 / 708 (1Cl) [M+H] + ; R t (HPLC): 0.74 / 0.76 min (Method A) EX-09 Step 3: The product obtained in the previous step was reacted according to general procedure L and carried to the next step as a mixture of diastereomers. ESI-MS: 708 / 710 (1Cl) [M+H] + ; R t (HPLC): 0.77 min (Method A)

[0168] EX-09 Step 4: The product obtained in the previous step was reacted according to general procedure H to give two diastereomers, which were separated by HPLC (XBridge C18, CAN / HO / TFA). EX-09 was the first eluting peak under the applied conditions. The absolute configuration of the α-methyl substituent was arbitrarily assigned. ESI-MS: 652 / 654 (1Cl) [M+H] + ; R t (HPLC): 0.61 min (Method A) ds of EX-08 ESI-MS: 652 / 654 (1Cl) [M+H] + ; R t (HPLC): 0.69 min (Method A) EX-08 (Example EX-10) (1R,9S,11S,34S)-4-chloro-1,30,30-trifluoro-34-methyl-31-oxo-8,15,26-trioxa-6,12,23,32,37-pentaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13,16,18,20,22,24(37)-nonane-11-carboxylic acid

[0169] [ka]

[0170] EX-10 Step 1: Ethyl bromodifluoroacetate (41.8 mg, 26.7 μL, 0.200 mmol) and phenylsilane (44.6 mg, 50.9 μL, 0.400 mmol) were added to tert-butyl(3S,4R)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-{4-[(prop-2-en-1-yloxy)methyl]-8-oxa-3,5-diazatricyclo[7.4.0.0] methyl]-4-methyl-2-propan-2-yloxymethyl]-2-methyl ... 2,7 To a degassed suspension of ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl}pyrrolidin-3-yl]oxy}-5-chloropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carboxylate (EX-08, obtained as product from Step 1) (80.0 mg, 0.100 mmol), nickel(II) chloride (0.66 mg, 0.0050 mmol), and sodium carbonate (10.6 mg, 0.100 mmol) in anhydrous DMF (1.00 mL) was added. The vial was sealed, and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was quenched with 10% aqueous TFA, diluted with ACN / HO, and purified by semi-preparative HPLC (XBridge C18; ACN / HO / TFA). ESI-MS: 876 / 878 (1Cl) [M+H] + ; R t (HPLC): 0.93 min (Method A)

[0171] The product obtained in EX-10 step 1 was further reacted applying the following reaction sequence: EX-10 Step 2: Ester Hydrolysis Applying General Procedure C ESI-MS: 848 / 850 (1Cl) [M+H] + ; R t (HPLC): 0.85 min (Method A) EX-10 Step 3: BOC deprotection using general procedure F ESI-MS: 748 / 750 (1Cl) [M+H] + ; R t (HPLC): 0.64 min (Method A) EX-10 Step 4: Amidation using General Procedure D ESI-MS: 730 / 732 (1Cl) [M+H] + ; R t (HPLC): 0.86 min (Method A) EX-10 Step 5: tert-Butyl ester deprotection applying general procedure H ESI-MS: 674 / 676 (1Cl) [M+H] + ; R t (HPLC): 0.68 min (Method A)

[0172] (Example EX-11) (1R,9S,11S,33S)-4-chloro-1-fluoro-33-methyl-27,30-dioxo-8,15,26-trioxa-6,12,23,31,36-pentaazaheptacyclo[29.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Heptatriaconta-2,4,6,13(36),14(22),16(21),17,19,23-nonane-11-carboxylic acid

[0173] [ka]

[0174] EX-11 Step 1: tert-Butyl (3S,4R)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-{4-[(prop-2-en-1-yloxy)methyl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7A mixture of ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl}pyrrolidin-3-yl]oxy}-5-chloropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carboxylate (EX-08, see Step 1) (31.6 mg, 0.040 mmol), 1,3-dimethylbarbituric acid (12.6 mg, 0.080 mmol), and Pd(PPh) (2.31 mg, 0.0020 mmol) was stirred at room temperature for 5.5 hours. The reaction mixture was then heated to 65 °C for 15 hours. After cooling to room temperature, the mixture was diluted with ACN / HO, filtered, and purified by semi-preparative HPLC (XBridge C18; ACN / HO / TFA). ESI-MS: 712 / 714 (1Cl) [M+H] + ; R t (HPLC): 0.81 min (Method A)

[0175] EX-11 Step 2: To a mixture of the product obtained in the previous step (60.0 mg, 0.0800 mmol) in pyridine (0.60 mL) at room temperature, succinic anhydride (25.0 mg, 0.250 mmol) was added, and the mixture was stirred at 50 °C for 5 h. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 days. Further succinic anhydride (25.0 mg; 0.25 mmol) was added, and the mixture was stirred at 50 °C for 6 h. The reaction mixture was acidified by adding TFA, diluted with ACN / water, and purified by preparative HPLC (ACN / HO / TFA). ESI-MS: 812 [M+H] + ; R t (HPLC): 1.20 minutes (Method B) EX-11 The product obtained in step 2 was further reacted applying the following reaction sequence: EX-11 Step 3: BOC deprotection using general procedure F ESI-MS: 712 [M+H] + ; R t (HPLC): 0.77 min (Method B) EX-11 Step 4: Amidation using general procedure D ESI-MS: 694 [M+H] + ; R t (HPLC): 0.92 min (Method D) EX-11 Step 5: tert-Butyl ester deprotection applying general procedure H ESI-MS: 638 [M+H] + ; R t (HPLC): 0.82 min (Method B)

[0176] (Example EX-12) tert-Butyl(2S,4S)-4-({5-chloro-3-[(3S,4R)-4-fluoro-3-methylpiperidin-4-yl]pyridin-2-yl}oxy)-1-{4-[(prop-2-en-1-yloxy)methyl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl}pyrrolidine-2-carboxylate [ka]

[0177] EX-12 Step 1: To a mixture of pent-4-enoic acid (30.0 mg, 0.303 mmol) in DCM (2.00 mL) at room temperature, triethylamine (0.084 mL, 0.606 mmol) was added, followed by EDC hydrochloride (70.0 mg, 0.363 mmol). After stirring at room temperature for 10 min, the product obtained in EX-08 Step 2 (290 mg, 0.303 mmol) was added, and the mixture was stirred at room temperature for 4 h. The reaction mixture was poured into ice water and extracted with EtOAc. The organic phases were combined, washed with water, dried over sodium sulfate, and evaporated to dryness. ESI-MS: 734 [M+H] + ; R t (HPLC): 1.059 min (Method C)

[0178] EX-11 The product obtained in step 2 was further reacted applying the following reaction sequence: EX-12 Step 2: Olefin Metathesis by General Procedure K ESI-MS: 706 [M+H] + ; R t (HPLC): 0.998 min (Method C) EX-12 Step 3: Hydrogenation using General Procedure L ESI-MS: 708 [M+H] + ; R t (HPLC): 1.063 min (Method C) EX-12 Step 4: tert-Butyl ester deprotection applying general procedure H ESI-MS: 652 [M+H] + ; R t (HPLC): 0.951 min (Method C)

[0179] (Example EX-13) (1R,9S,11S,34S)-4-chloro-1-fluoro-34-methyl-31-oxo-8,15,26,30-tetraoxa-6,12,23,32,37-pentaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2(7),3,5,13(37),14(22),16(21),17,19,23-nonane-11-carboxylic acid

[0180] [ka]

[0181] EX-13 Step 1: tert-Butyl 2-(3-{[(4-nitrophenoxy)carbonyl]oxy}propoxy)acetate To a solution of tert-butyl-2-(3-hydroxypropoxy)acetate (1.000 g, 5.10 mmol, preparation described in WO 2019 / 195609) and pyridine (0.441 mL, 5.48 mmol) in DCM (10 mL) was added dropwise over 30 minutes at 0°C. The reaction mixture was allowed to warm to room temperature overnight. Water was added and the phases were separated. The organic phase was dried and evaporated to dryness. ESI-MS: 300 [M-tBu+H] + ; R t (HPLC): 1.00 min (Method C)

[0182] EX-13 Step 2: tert-Butyl 2-{3-[(3S,4R)-4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carbonyloxy]propoxy}acetate A mixture of intermediate P-02 (250 mg, 0.883 mmol), tert-butyl 2-(3-{[(4-nitrophenoxy)carbonyl]-oxy}propoxy)acetate (396 mg, 0.891 mmol), and DIPEA (0.426 mL, 2.65 mmol) in THF (4.60 mL) was heated to reflux for 2 h. After cooling to room temperature, the reaction mixture was diluted with diethyl ether and extracted twice with 1 M aqueous NaOH solution. The organic phase was washed with water and saturated aqueous NaCl solution, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was used in the next step without further purification. ESI-MS: 463 [M+H] + ; R t (HPLC): 0.76 min (Method A) EX-13 Step 3: 2-{3-[(3S,4R)-4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carbonyloxy]propoxy}acetic acid The product obtained from the previous step was reacted according to general procedure H to give the expected product. ESI-MS: 407 / 409 (1Cl) [M+H] + ; Rt (HPLC): 0.58 min (Method A)

[0183] EX-13 Step 4: 3-{[(2-amino-1-benzofuran-3-yl)carbamoyl]methoxy}propyl (3S,4R)-4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carboxylate At room temperature, DIPEA (360 μL, 2.08 mmol) was added to a stirred solution of 2-{3-[(3S,4R)-4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carbonyloxy]propoxy}acetic acid (380 mg, 0.934 mmol) and PFTU (440 mg, 1.03 mmol) in DMF (5.50 mL), and the mixture was stirred at this temperature for 5 minutes. 3-Amino-1-benzofuran-2-carboxamide (190 mg, 1.035 mmol) was then added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was heated to 50° C. and stirred at this temperature for 36 hours. It was diluted with diethyl ether, and the organic phase was washed with dilute NaOH and brine. The organic phase was dried over sodium sulfate and evaporated to dryness. The residue was dissolved in MeOH acidified with TFA, filtered and purified by preparative HPLC (XBridge C18; ACN / H2O / TFA). ESI-MS: 565 / 567 (1Cl) [M+H] + ; R t (HPLC): 0.68 min (Method A)

[0184] EX-13 Step 5: A mixture of 3-{[(2-amino-1-benzofuran-3-yl)carbamoyl]methoxy}propyl (3S,4R)-4-(5-chloro-2-fluoropyridin-3-yl)-4-fluoro-3-methylpiperidine-1-carboxylate (110 mg, 0.195 mmol), chlorotrimethylsilane (0.352 mL, 2.77 mmol), and triethylamine (1.185 mL, 8.44 mmol) in dichloroethane (4.75 mL) was heated to reflux for 40 h. After cooling to room temperature, the reaction mixture was diluted with DCM. The phases were separated, and the organic phase was washed with dilute hydrochloric acid, dried over sodium sulfate, and concentrated in vacuo to give the crude product. The crude product was used in the next step without purification. ESI-MS: 447 / 449 (1Cl) [M+H] + ; R t (HPLC): 0.68 min (Method A)

[0185] EX-13 Step 6: The product obtained from EX-13 Step 5 was reacted with (2S,4S)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid according to general procedure B. ESI-MS: 758 / 760 (1Cl) [M+H] + ; R t (HPLC): 0.81 min (Method A) EX-13 Step 7: The product from EX-13 Step 5 (140 mg, 0.185 mmol) was dissolved in methanol and thionyl chloride (89 μL, 1.21 mmol) was added. After stirring for 2 h, another portion of thionyl chloride (55 μL, 0.754 mmol) was added and stirring was continued overnight. The reaction mixture was concentrated in vacuo, and the crude product was purified by HPLC (XBridge C18; ACN / HO / TFA). ESI-MS: 672 / 674 (1Cl) [M+H] + ; R t (HPLC): 0.58 min (Method A)

[0186] EX-13 Step 8: The product from EX-13 Step 7 (21 mg, 0.030 mmol) was dissolved in DMF (2.00 mL) at room temperature. DBU (22.4 μL, 0.148 mmol) and BOP (35 mg, 0.077 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After adding water, the mixture was extracted with diethyl ether (twice). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in vacuo. ESI-MS: 654 / 656 (1Cl) [M+H] + ; R t (HPLC): 0.74 min (Method A) EX-13 Step 9: To a mixture of the product from EX-13 Step 8 (25 mg, 0.038 mmol) in dioxane (2.00 mL), 1 M aqueous NaOH solution (450 μL, 0.450 mmol) was added. The reaction mixture was heated at 60° C. for 30 min. At room temperature, the reaction mixture was acidified, diluted with methanol, and purified by HPLC (XBridge C18; ACN / HO / TFA). ESI-MS: 640 / 642 (1Cl) [M+H] + ; R t (HPLC): 0.68 min (Method A)

[0187] (Example EX-15) (1R,9S,11S,34S)-4-chloro-1,25,25-trifluoro-34-methyl-31-oxo-8,15,26-trioxa-6,12,23,32,37-pentaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2(7),3,5,13(37),14(22),16(21),17,19,23-nonane-11-carboxylic acid

[0188] [ka]

[0189] EX-15 Step 1: NaH (130 mg, 3.25 mmol, 60% in mineral oil) was added to a mixture of N-08 (370 mg, 0.802 mmol) and P-01 (285 mg, 0.812 mmol) in DMF (10.0 mL), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added dropwise to cold water and acidified using 1 M HCl aqueous solution. The precipitate was dissolved in diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was further purified by silica gel chromatography using cyclohexane / EA as the eluent. ESI-MS: 788 / 790 (1Cl) [M+H] + ; R t (HPLC): 1.01 min (Method A)

[0190] EX-15 Step 2: Under argon, Grubbs Catalyst® Second Generation (4.07 mg, 0.005 mmol, 6 mol%) was added to a degassed solution of the product obtained in EX-15 Step 1 (63.0 mg, 0.076 mmol) and methyl 3-butenoate (128 μL, 1.139 mmol) in DCM (0.50 mL). The vial was sealed, and the reaction mixture was stirred at room temperature for 2 h. Additional methyl 3-butenoate (42.7 μL, 5.0 equiv.) was added, and stirring was continued for 2 h. An additional aliquot of Grubbs Catalyst® Second Generation (4.07 mg, 0.005 mmol, 6 mol%) was then added, and stirring was continued for 1.5 h. Another addition of catalyst (4.07 mg; 6 mol%) and methyl 3-butenoate (42.7 μL; 3.00 equiv.) was made, and stirring was continued at room temperature for an additional 18 h. The volatiles were removed in vacuo and the residue was dissolved in EtOAc / cyclohexane and directly purified by silica gel chromatography. ESI-MS: 860 / 862 (1Cl) [M+H] + ; R t (HPLC): 0.75 min (Method G)

[0191] EX-15 Step 3: General Procedure N: Hydrogenation using Pd / C In a Parr apparatus, 10% Pd / C (90.0 mg) was added to a solution of the product obtained in EX-15 Step 3 (250 mg, 0.276 mmol) in 40 mL of EtOAc, and the reaction mixture was placed under 3 bar of hydrogen pressure at room temperature for 18 hours. The solids were removed by filtration, and the filtrate was concentrated to dryness in vacuo to give the crude product. The crude product was purified by semi-preparative HPLC (Sunfire C18; ACN / HO / TFA). ESI-MS: 862 / 864 (1Cl) [M+H] + ; R t (HPLC): 1.12 minutes (Method B)

[0192] The product obtained in EX-15 Step 3 was further reacted applying the following reaction sequence: EX-15 Step 4: Ester Hydrolysis Applying General Procedure C ESI-MS: 848 / 850 (1Cl) [M+H] + ; R t (HPLC): 0.94 min (Method A) EX-15 Step 5: BOC deprotection using general procedure F ESI-MS: 748 / 750 (1Cl) [M+H] + ; R t (HPLC): 0.82 min (Method B) EX-15 Step 6: Amidation using general procedure E ESI-MS: 730 / 732 (1Cl) [M+H] + ; R t (HPLC): 0.98 min (Method D) EX-15 Step 7: tert-Butyl ester deprotection applying general procedure H ESI-MS: 674 / 676 (1Cl) [M+H] + ; R t (HPLC): 0.68 min (Method A)

[0193] (Example EX-18) (1R,9S,11S,34S)-4-ethynyl-1-fluoro-34-methyl-31-oxo-8,15,27-trioxa-6,12,23,32,37-pentaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13,16,18,20,22,24(37)-nonane-11-carboxylic acid

[0194] [ka] Under an argon atmosphere, Pd(dppf)Cl (9.0 mg, 0.012 mmol) and CuI (3.0 mg, 0.016 mmol) were added to a mixture of Example EX-17 (30 mg, 0.044 mmol), (triisopropylsilyl)acetylene (24 μL, 0.11 mmol), and triethylamine (30 μL, 4.8 equiv.) in 2-methyltetrahydrofuran (0.75 mL), and the reaction mixture was stirred at 80 °C for 2 h. After cooling to room temperature, it was filtered, and the filtrate was concentrated in vacuo. To the residue of 2.00 mL, TBAF (1 M solution in THF, 100 μL, 0.100 mmol) was added, and the mixture was stirred at room temperature for 30 min. It was then added dropwise to cold water, acidified using 1 M aqueous HCl solution, and extracted twice with diethyl ether. The combined organic layers were washed with water and brine and concentrated in vacuo. The product was purified by HPLC (XBridge C18; ACN / H2O / TFA). ESI-MS 628 [M+H] + ; R t (HPLC): 0.59 min (Method A)

[0195] (Example EX-19) [ka] EX-17 The product obtained from the synthesis of Step 3 was subjected to Sonogashira reaction conditions according to EX-18, followed by deprotection of the t-butyl group by applying general procedure EX-D to give the title compound. ESI-MS 646 [M+H] + ; R t (HPLC): 0.64 min (Method A) (Example EX-20.01) (1R,9S,11S,34S)-1-Fluoro-4-(2-methoxypyridin-3-yl)-34-methyl-31-oxo-8,15,27-trioxa-6,12,23,32,37-pentaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13(37),14(22),16(21),17,19,23-nonane-11-carboxylic acid

[0196] [ka]

[0197] EX-20.01 Step 1: General Procedure O: Suzuki Coupling Under an argon atmosphere at room temperature, (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(ii) methanesulfonate (XPhos Pd G3) was added to a degassed mixture of aryl bromide (EX-17 Step 3, 35 mg, 0.047 mmol), (2-methoxypyridin-3-yl)boronic acid (11 mg, 0.071 mmol), and potassium carbonate (2 N aqueous solution, 95 μL, 0.19 mmol). The vial was sealed and heated at 90 °C until complete conversion of the starting material was observed (1 h). The heat was removed, and the mixture was allowed to warm to room temperature. Water was added, and the mixture was extracted twice with DCM. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to dryness. ESI-MS: 767 [M+H] + ; R t (HPLC): 0.70 min (Method A)

[0198] EX-20.01 Step 2: The products of the Suzuki coupling reaction were deprotected applying general procedure H to give the final compounds. ESI-MS 711 [M+H] + ; R t (HPLC): 0.61 min (Method A) Following the reaction sequence above (general procedures O and H (t-Bu not applicable when the free acid is subjected to Suzuki coupling)), the following examples were prepared: [Table 3]

[0199] (Example EX-21) (1R,9S,11S,34S)-4-chloro-1,25,25-trifluoro-34-methyl-31-oxo-8,15,27-trioxa-6,12,23,32,37-penta-azaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13(37),14(22),16(21),17,19,23-nonane-11-carboxylic acid

[0200] [ka]

[0201] EX-21 Step 1: Under an argon atmosphere at 0 °C, sodium borohydrate (90 mg, 2.38 mmol) was added to a solution of intermediate P-06 (730 mg, 794 mmol) in absolute ethanol (8.34 mL). The reaction mixture was stirred at 0 °C for 1 h and at room temperature for 2 h. Water was added to the mixture, and the product was extracted three times with EtOAc. The organic phase was subsequently washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica column chromatography (10% to 100% EtOAc / CH). ESI-MS 762 / 764 (1Cl) [M+H] + ; R t (HPLC): 0.94 min (Method A) EX-21 Step 2: The material obtained in the previous step was dissolved in DMA (2.44 mL), sodium hydride (50 mg, 1.15 mmol) was added, followed immediately by allyl bromide (250 μL, 2.86 mmol), and the mixture was stirred at room temperature for 10 min. Ice was added to the reaction mixture, and the product was extracted three times with EtOAc. The organic phase was subsequently washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by semi-preparative HPLC (ACN, Xbridge, TFA) using a narrow gradient (80-100% ACN / water). ESI-MS 803 / 805 (1Cl) [M+H] + ; R t (HPLC): 1.03 min (Method A)

[0202] EX-21 Step 3: The product from the previous step (232 mg, 0.289 mmol) was dissolved in ethyl acrylate (2.00 mL). The mixture was degassed by bubbling argon through it for 5 minutes, after which Grubbs Catalyst® Second Generation (24.5 mg, 0.029 mmol) was added to the reaction. The mixture was stirred under argon at room temperature for 1 hour, then concentrated under reduced pressure while adsorbed directly onto extrelute and purified by flash chromatography. 20% to 100% EtOAc / CH. ESI-MS 875 / 877 (1Cl) [M+H] + ; R t (HPLC): 1.00 min (Method A)

[0203] EX-21 The product obtained in step 3 was further reacted applying the following reaction sequence: EX-21 Step 4: Hydrogenation applying General Procedure L EX-21 Step 5: Ester Hydrolysis Applying General Procedure C ESI-MS 848 / 850 (1Cl) [M+H] + ; R t (HPLC): 0.68 min (Method G) EX-21 Step 6: BOC deprotection using general procedure F ESI-MS: 748 / 751 (1Cl) [M+H] + ; R t (HPLC): 0.69 min (Method A) EX-21 Step 7: Amidation using general procedure D ESI-MS: 731 / 733 (1Cl) [M+H] + ; R t (HPLC): 0.88 min (Method A) EX-21 Step 8: tert-Butyl ester deprotection applying general procedure H ESI-MS: 675 / 677 (1Cl) [M+H] + ; R t (HPLC): 0.79 min (Method A)

[0204] (Example EX-22) (1R,9S,11S,34S)-4-chloro-1-fluoro-34-methyl-31-oxo-8,15,30-trioxa-6,12,23,32,37-pentaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13(37),14(22),16(21),17,19,23-nonane-11-carboxylic acid

[0205] [ka]

[0206] EX-22 Step 1: General Procedure M: Heck Coupling A mixture of intermediate P-07 (85 mg, 0.213 mmol), intermediate N-02 (70 mg, 0.176 mmol), palladium(II)-acetate (7.9 mg, 0.035 mmol), tri(o-tolyl)phosphine (22 mg, 0.070 mmol), and triethylamine (71 mg, 0.70 mmol) in DMF (2.85 mL) was heated to 95 °C in a sealed tube under an argon atmosphere for 6 h. The reaction mixture was allowed to cool to room temperature and stirred at room temperature overnight. The volatiles were removed in vacuo, and the crude mixture was purified by silica column chromatography (20-50% EE / CH). The product was isolated as a mixture of isomers and used as such in the next reaction step. ESI-MS 656 [M+H] + ; R t (HPLC): 0.70 / 0.71 / 0.73 min (Method B)

[0207] The product obtained in EX-22 Step 1 was further reacted applying the following reaction sequence: EX-22 Step 2: Hydrogenation applying General Procedure L ESI-MS 658 [M+H] + ; R t (HPLC): 0.76 min (Method B) EX-22 Step 3: Apply General Procedure I N Macrocyclization via Ar ESI-MS 638 [M+H] + ; R t (HPLC): 0.85 min (Method B) (Example EX-23) (1R,9S,11S,34S)-4-chloro-1-fluoro-34-methyl-31-oxo-8,15,28-trioxa-6,12,23,32,37-pentaazaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2,4,6,13(37),14(22),16(21),17,19,23-nonane-11-carboxylic acid

[0208] [ka]

[0209] The following reaction sequence was applied to prepare the title compound starting from intermediate P-05: EX-23 Step 1: Heck coupling with 3-(prop-2-en-1-yloxy)propanoic acid applying general procedure M ESI-MS: 810 / 812 (1Cl); R t (HPLC): 0.81 / 0.82 min (Method A) EX-23 Step 2: Hydrogenation (Pd / C) by General Procedure N ESI-MS: 812 / 814 (1Cl) [M+H] + ; R t (HPLC): 0.98 min (Method B) EX-23 Step 3: BOC deprotection using general procedure F ESI-MS 712 / 714 (1Cl) [M+H] + ; R t (HPLC): 0.67 min (Method B) EX-23 Step 4: Amidation applying general procedure E ESI-MS 694 / 696 (1Cl) [M+H] + ; R t (HPLC): 0.97 min (Method D) EX-23 Step 5: tert-Butyl ester deprotection using general procedure H ESI-MS 638 / 640 (1Cl) [M+H] + ; R t (HPLC): 0.74 min (Method A)

[0210] (Example EX-24) (1R,9S,11S,34S)-1-fluoro-34-methyl-31-oxo-8,15,28-trioxa-6,12,23,32,37-pentaazaheptacyclo-[30.2.2.1 9,12 .1 13,24 .0 2,7 .014,22 .0 16,21 ]Octatriaconta-2,4,6,13(37),14(22),16(21),17,19,23-nonane-11-carboxylic acid

[0211] [ka] This compound was prepared from EX-24 via hydrogenation applying general procedure N. ESI-MS 604 [M+H] + ; R t (HPLC): 0.65 min (Method B)

[0212] (Example EX-29) (1R,9S,11S,34S)-1-fluoro-34-methyl-31-oxo-4-(prop-1-yn-1-yl)-8,15,29-trioxa-6,12,23,32,37-penta-azaheptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Octatriaconta-2(7),3,5,13,16(21),17,19,22,24(37)-nonane-11-carboxylic acid [ka] This compound was prepared from EX-28 via Sonogashira coupling as described for EX-28. ESI-MS: 642 [M+H] + ; R t (HPLC): 0.61 min (Method A)

[0213] (Example EX-34) (1R,9S,11S,34S)-4-chloro-1-fluoro-34-methyl-31-oxo-8,15,27,30-tetraoxa-6,12,23,32,37-pentaaza-heptacyclo[30.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .016,21 ]Octatriaconta-2,4,6,13(37),14(22),16(21),17,19,23-nonane-11-carboxylic acid

[0214] [ka]

[0215] EX-34 Step 1: To a solution of intermediate P-08 (115 mg, 0.284 mmol) in acetonitrile (2.00 mL) at room temperature, 1-chloro-N,N,2-trimethylpropenylamine (50 μL, 0.378 mmol) was added, and the resulting mixture was stirred for 10 minutes. Pyridine (70 μL, 0.856 mmol) was then added to the mixture, followed by 3-aminobenzofuran-2-carboxamide (230 mg, 1.31 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness, and water and DCM were added. The phases were separated, and the organic phase was dried and concentrated to dryness. ESI-MS: 565 / 567 (1Cl) [M+H] + ; R t (HPLC): 0.64 min (Method A) EX-34 Step 2: To a solution of the product of Step 1 (160 mg, 0.283 mmol) in 1,2-dichloroethane (7.00 mL) at room temperature, chlorotrimethylsilane (0.512 mL, 4.03 mmol) was added, followed by triethylamine (1.724 mL, 12.3 mmol), and the resulting mixture was stirred under reflux for 40 h. The reaction was cooled to room temperature and diluted with DCM. The organic phase was washed with dilute aqueous HCl, dried over sodium sulfate, and concentrated to dryness. ESI-MS: 547 / 549 (1Cl) [M+H] + ; R t (HPLC): 0.64 min (Method A)

[0216] EX-34 Step 3: To a solution of tert-butyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (151 mg, 0.635 mmol) in DMF (2.17 mL) was added NaH (60% in mineral oil, 50.8 mg, 1.27 mmol) at room temperature. After stirring for 5 min, a solution of the product obtained in EX-34 Step 2 (217 mg, 0.32 mmol) in DMF (2.17 mL) was slowly added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was added dropwise to water, acidified with acetic acid, and extracted twice with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, and evaporated to dryness. The crude product was purified by HPLC (Sunfire, ACN / H2O / TFA, Narrow). ESI-MS: 758 / 760 (1Cl) [M+H] + ; R t (HPLC): 1.06 min (Method B) EX-34 Step 4: EX-34 The product from Step 3 (100 mg, 0.130 mmol) was dissolved in methanol (2.00 mL), and thionyl chloride (0.060 mL, 0.79 mmol) was added slowly at room temperature. The reaction mixture was stirred at room temperature for 48 hours, then concentrated under reduced pressure and purified by HPLC (Sunfire, ACN / HO / TFA, Narrow). ESI-MS: 672 / 674 (1Cl) [M+H] + ; R t (HPLC): 0.70 min (Method B)

[0217] EX-34 Step 5: DBU (54 μL, 0.353 mmol) was added to a mixture of the product obtained in EX-34 Step 4 (50 mg, 0.071 mmol) and BOP (84 mg, 0.184 mmol) in acetonitrile (5.00 mL) and DMF (5.00 mL). The reaction mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure, and the crude product was purified by HPLC (Sunfire, ACN / HO / TFA). ESI-MS: 654 / 656 (1Cl) [M+H] + ; R t(HPLC): 0.84 min (Method B) EX-34 Step 6: EX-34 The product from step 6 was deprotected according to general procedure C to give the title compound. ESI-MS: 640 / 642 (1Cl) [M+H] + ; R t (HPLC): 0.78 min (Method B)

[0218] (Example EX-35) (1R,9S,11S,33S)-4-chloro-1-fluoro-33-methyl-30-oxo-8,15,29-trioxa-6,12,23,31,36-pentaazaheptacyclo[29.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Heptatriaconta-2,4,6,13(36),14(22),16(21),17,19,23-nonane-11-carboxylic acid

[0219] [ka]

[0220] EX-35 Step 1: Intermediate P-05 (200 mg, 0.250 mmol) and 3-buten-1-ol (86 μL, 1.00 mmol) were added to a microwave vial, and the system was flushed with argon. DMA (2.31 mL) was added, followed by triethylamine (696 μL, 4.99 mmol), and the tube was degassed under a stream of argon for 5 minutes. 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (24.4 mg, 0.037 mmol) was then added, the vial was sealed, and the reaction mixture was heated at 115°C for 4 hours. After cooling to room temperature, the reaction mixture was filtered through a catalyst scavenging cartridge, diluted with additional ACN, and acidified with 2.5 M acetic acid. The crude product was directly purified by HPLC (Sunfire, ACN / HO / TFA). ESI-MS: 753 / 755 (1Cl) [M+H] + ; R t (HPLC): 0.79 min (Method A) EX-35 Step 2: EX-35 The product obtained in Step 2 was hydrogenated according to general procedure N. ESI-MS: 755 / 757 (1Cl) [M+H] + ; R t (HPLC): 0.77 min (Method A)

[0221] EX-35 Step 3: EX-35 The product from Step 2 (21 mg, 0.028 mmol) was dissolved in DCM (0.36 mL) and pyridine (2 μL, 0.03 mmol) was added. The mixture was cooled to 0 °C and 4-nitrophenyl chloroformate (6.3 mg, 0.030 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 3 h. The volatiles were removed under reduced pressure, and the remaining crude material was carried on to the next step without further purification. ESI-MS: 920 / 922 (1Cl) [M+H] + ; R t (HPLC): 0.85 min (Method A) EX-35 Step 4: EX-35 The product obtained in step 3 was deprotected according to general procedure F. ESI-MS: 820 / 822 (1Cl) [M+H] + ; R t (HPLC): 0.66 min (Method A) EX-35 Step 5: Triethylamine (39 mg, 0.053 mL, 0.384 mmol) was added to a solution of the product (21 mg, 0.026 mmol) obtained in EX-35 Step 4 in THF (3.00 mL). The reaction mixture was heated to 70° C. for 3 h, then concentrated under reduced pressure and carried to the next step without further purification. ESI-MS: 681 / 683 (1Cl) [M+H] + ; R t (HPLC): 0.73 min (Method A)

[0222] EX-35 Step 6: EX-35 The product obtained in step 5 was deprotected according to general procedure H. ESI-MS: 625 [M+H] + ; R t (HPLC): 0.60 min (Method A) (Example EX-37) (1R,9S,11S,33S)-4-chloro-1-fluoro-33-methyl-30-oxo-8,15,28-trioxa-6,12,23,31,36-pentaaza-heptacyclo[29.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Heptatriaconta-2,4,6,13(36),14(22),16(21),17,19,23-nonane-11-carboxylic acid

[0223] [ka]

[0224] The following reaction sequence was applied to prepare the title compound starting from intermediate P-05: EX-37 Step 1: Heck coupling with 2-(prop-2-en-1-yloxy)acetic acid applying general procedure M ESI-MS: 796 / 798 (1Cl) [M+H] + ; R t (HPLC): 0.65 / 0.66 min (Method D) EX-37 Step 2: Hydrogenation (Pd / C) by General Procedure N ESI-MS: 798 / 800 (1Cl) [M+H] + ; R t (HPLC): 0.97 min (Method B) EX-37 Step 3: BOC deprotection using general procedure F ESI-MS 698 / 700 (1Cl) [M+H] + ; R t(HPLC): 0.63 min (Method B) EX-37 Step 4: Amidation applying general procedure E ESI-MS 680 / 682 (1Cl) [M+H] + ; R t (HPLC): 0.93 min (Method D) EX-37 Step 5: tert-Butyl ester deprotection applying general procedure H ESI-MS 624 / 626 (1Cl) [M+H] + ; R t (HPLC): 0.48 min (Method D)

[0225] (Example EX-38) (1R,9S,11S,33S)-4-chloro-1-fluoro-33-methyl-30-oxo-8,15,27-trioxa-6,12,23,31,36-pentaaza-heptacyclo[29.2.2.1 9,12 .1 13,24 .0 2,7 .0 14,22 .0 16,21 ]Heptatriaconta-2,4,6,13(36),14(22),16(21),17,19,23-nonane-11-carboxylic acid

[0226] [ka]

[0227] The following reaction sequence was applied to prepare the title compound starting from intermediate P-05: EX-38 Step 1: Heck coupling with ethyl 3-(ethenyloxy)propanoate applying general procedure M ESI-MS:768 / 770 (1Cl) [M-tBu+H] + ; R t (HPLC): 0.83 min (Method A) EX-38 Step 2: Hydrogenation (Pd / C) by General Procedure N ESI-MS: 826 / 828 (1Cl) [M+H] + ; R t(HPLC): 1.10 minutes (Method B) EX-38 Step 3: Ester hydrolysis by general procedure C ESI-MS: 798 / 800 (1Cl) [M+H] + ; R t (HPLC): 0.99 min (Method B) EX-38 Step 4: BOC deprotection using general procedure F ESI-MS 698 / 700 (1Cl) [M+H] + ; R t (HPLC): 0.65 min (Method B) EX-38 Step 5: Amidation applying general procedure E ESI-MS 680 / 682 (1Cl) [M+H] + ; R t (HPLC): 0.93 min (Method D) EX-37 Step 6: tert-Butyl ester deprotection applying general procedure H ESI-MS 624 / 626 (1Cl) [M+H] + ; R t (HPLC): 0.53 min (Method A)

[0228] General technical matters The terms "ambient temperature" and "room temperature" are used interchangeably and refer to a temperature of about 20°C, for example, 15-25°C. In general, the compounds prepared 1 H NMR and / or mass spectra were obtained. Unless otherwise stated, all chromatographic operations were carried out at room temperature.

[0229] General method NMR spectra were recorded on a Bruker Avance 400 MHz 1H NMR spectrometer. LCMS was performed on a Shimadzu LCMS 2010 (column: Sepax ODS 50 × 2.0 mm, 5 μm) or an Agilent 1200 HPLC, 1956 MSD (column: Shim-pack XR-ODS 30 × 3.0 mm, 2.2 μm) quadrupole mass spectrometer operating in ES(+) ionization mode. Chromatographic purification was performed by flash chromatography using 100-200 mesh silica gel. Anhydrous solvents were pre-conditioned on a 3 Å MS column prior to use. All commercially available reagents were used as received unless otherwise noted. The absolute configurations of selected examples (EX-01, EX-03, EX-11, EX-17, EX-37) were assigned from the co-crystal structure with human cGAS protein according to the method described by DJ Patel et al., PNAS 2019, 11946-11955 (doi.org / 10.1073 / pnas.1905013116).

[0230] List of Abbreviations [Table 4-1] [Table 4-2]

[0231] Analysis method (HPLC / SFC): [Table 5]

[0232] [Table 6]

[0233] [Table 7]

[0234] [Table 8]

[0235] [Table 9]

[0236] [Table 10]

[0237] [Table 11]

[0238] [Table 12] [Example]

[0239] 4. Example 5.1 Example Compounds of Formula I or II of the Invention The following example compounds of Formula I or II, summarized in Table 1, were synthesized and tested for their pharmacological properties with respect to their efficacy in inhibiting cGAS activity. In particular, cGAS inhibition (hcGAS IC 50 ) regarding "Biochemical (in vitro) IC 50 IC value for inhibition of IFN induction in virus-stimulated THP1 cells 50 Value" (THP (vir) I C 50 ), "IC for inhibition of IFN induction in cGAMP-stimulated THP1 cells" 50 Value" (THP (cGAMP) I C 50 ), and "IC for inhibition of IFN induction in dsDNA-stimulated human whole blood 50 value" (hWB IC 50) was determined experimentally according to the assay described in Section 6 below. The results are summarized in Table 1.

[0240] The example compounds of formula I or II summarized in Table 1 simultaneously exhibit the following three properties: Satisfactory biochemical (in vitro) IC for cGAS inhibition 50 hcGAS IC value (≦100 nM, preferably ≦50 nM, in particular ≦10 nM) 50 ), Satisfactory cellular IC50 for cGAS inhibition 50 value (≦1 μM, preferably ≦500 nM, more preferably ≦100 nM, especially ≦50 nM THP1 (vir) I C 50 ), and Satisfactory selectivity for cGAS inhibition (≥10, more preferably ≥50, more preferably ≥500, especially ≥1000 THP1 (cGAMP) I C 50 / THP1 (vir) I C 50 ratio).

[0241] In addition, Example compounds of Formula I or II exhibit acceptable IC50 values ​​for inhibition of IFN induction in dsDNA-stimulated human whole blood. 50 Value (hWB IC 50 ) is also shown. [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5] [Table 13-6] [Table 13-7] [Table 13-8] [Table 13-9]

[0242] 5.2 Comparison of Example Compounds of Formula I or II with Prior Art Compounds 5.2.1 Compounds of WO 2020 / 142729 WO 2020 / 142729 disclosed cGAS inhibitors with a partially similar structure. On pages 44 and 45 of International Publication No. 2020 / 142729, regarding cGAS inhibition, there is a description of "biochemical (in vitro IC 50 value ("hcGAS IC 50 This resulted in a biochemical (in vitro) IC50 value of less than 100 nM. 50 Compounds with a "biochemical (in vitro) IC value" greater than 100 nM and less than 500 nM were designated "Group A." 50 Compounds with a "biochemical (in vitro) IC value" greater than 500 nM and less than 1 μM were designated "Group B." 50 Compounds with a "biochemical (in vitro) IC value" greater than 1 μM and less than 10 μM were designated "Group C." 50 Compounds with a biochemical (in vitro) IC value greater than 10 μM are designated as "Group D." 50 Compounds having "values" were designated "Group E" (see WO 2020 / 142729, page 44).

[0243] On page 45 of International Publication No. 2020 / 142729, only Compound No. 25 had a "biochemical (in vitro) IC40 of less than 100 nM." 50 It is disclosed that the compounds can be designated as "Group A" having "biochemical (in vitro) IC values" higher than 100 nM. All of the other example compounds in WO 2020 / 142729 have "biochemical (in vitro) IC values" higher than 100 nM. 50 Indicates "value". Selected prior art compounds of WO 2020 / 142729, including Compound No. 25, were synthesized and then tested for their pharmacological properties with respect to their potency in inhibiting the cGAS / STING pathway using the same assays used to test the compounds of the present invention. In particular, the structurally closest examples of WO 2020 / 142729 were tested for cGAS inhibition using "biochemical (in vitro) IC 50 value" (hcGAS IC 50 ), "Cellular IC for inhibition of IFN induction in virus-stimulated THP1 cells" 50 value" (THP1 (vir) I C 50 ), "Cell IC on the inhibition of IFN induction in cGAMP-stimulated THP1 cells" 50 value" (THP1 (cGAMP) I C 50 ), and "IC for inhibition of IFN induction in human whole blood" 50 The "hWB" (human weight basis) values ​​were experimentally determined according to the assay methods described in Section 6 below (see Table 2).

[0244] [Table 14-1] [Table 14-2]

[0245] The pharmacological properties of the example compounds of the present invention summarized in Table 1 and the respective pharmacological properties of the compounds of WO 2020 / 142729 summarized in Table 2 were experimentally determined according to the same assay procedures described in Section 6 below and can therefore be compared to each other. From the data shown in Table 2 (WO 2020 / 142729), it is clear that the “biochemical (in vitro) IC 50 value" (= hcGAS IC 50With the sole exception of Example No. 25 of WO 2020 / 142729 (designated as "Group A" having a "biochemical (in vitro IC50"), all of the example compounds of WO 2020 / 142729 have "biochemical (in vitro IC50") significantly higher than 100 nM. 50 value" (= hcGAS IC 50 In contrast, all of the example compounds of the present invention exhibit a "biochemical (in vitro) IC" of less than 100 nM. 50 value" (hcGAS IC 50 However, it has a biochemical (in vitro) IC50 of 55 nM. 50 value" (hcGAS IC 50 Example No. 25 of WO 2020 / 142729 having the formula THP1 (vir) I C 50 is 17 μM, so THP1 is lower than 1 μM (vir) I C 50 These compounds do not at all meet the selection criteria of "satisfactory cell inhibitory potency" as indicated by

[0246] 5.2.2 Compounds of WO 2022 / 174012 In WO 2022 / 174012, cGAS inhibitors with partially similar structures were disclosed. On page 65 of International Publication No. 2022 / 174012, regarding cGAS inhibition, "biochemical (in vitro) IC 50 value,” and on page 67 of International Publication No. WO 2022 / 174012, “Cell IC 50 Compound 5 (BBL0100455) of WO 2022 / 174012 was a) Biochemical (or enzymatic) (in vitro) IC50 of less than 100 nM 50 Compound 5 was measured to have an "enzyme IC value" of 50 nM to 100 nM in the "enzyme assay of WO 2022 / 174012." 50 "These compounds are included in "Group B" which represents "values ​​of 100-150% of the total ... b) Cellular IC lower than 1 μM 50Compound 5 was measured to have a "cellular IC value" of <1 μM in a "THP-1 stimulated IFNβ ELISA" (the "cellular assay" of WO 2022 / 174012). 50 (See Table 3 on pages 67 and 68 of WO 2022 / 174012) It appears that these compounds are the only compounds of WO 2022 / 174012 that may have the potential to satisfy the selection criteria of the present invention, which means

[0247] However, both the biochemical / enzyme assays and the cellular assays of WO 2022 / 174012 are not identical to the respective "biochemical / enzyme assays and cellular assays" of the present invention, and therefore the measured biochemical / enzyme ICs of WO 2022 / 174012 are not identical to the respective "biochemical / enzyme assays and cellular assays" of the present invention. 50 Value and cell IC 50 The values ​​are the respective IC values ​​measured for the compounds of the present invention. 50 Therefore, compound 5 of WO 2022 / 174012 was synthesized and then tested for its pharmacological properties with respect to its efficacy in inhibiting the cGAS / STING pathway using the exact same assay used to test compounds of the present invention and described in Section 6 below.

[0248] [Table 15] As the data in Table 3 show, Compound No. 5 of WO 2022 / 174012 (BBL0100455) exhibited an acceptable biochemical / enzymatic IC of 55 nM. 50 Value (hcGAS IC 50 = 55 nM), but has a cellular IC higher than 10,000 nM 50 Value(THP1 (vir) I C 50 = 10000 nM). As a result, all of the compounds of the present invention have their biochemical / enzymatic IC 50 Although the compound is comparable to compound No. 5 of WO 2022 / 174012 in terms of cellular IC 50These are clearly superior to compound No. 5 of WO 2022 / 174012 in terms of their potency values ​​(all below 1000 nM for compounds of formula I or II according to the invention).

[0249] 5.3 Prodrugs It is known that esters of active agents with carboxylic acid groups can represent viable prodrugs, i.e., can exhibit improved oral absorption / bioavailability compared to the respective active agents. Commonly used prodrugs of active agents with carboxylic acid groups include, for example, methyl esters, ethyl esters, isopropyl esters, etc. (see Beaumont et al., Current Drug Metabolism, 2003, Vol. 4, Issue 6, 461-485). Furthermore, Nakamura et al., Bioorganic & Medicinal Chem., Vol. 15, Issue 24, pp. 7720-7725 (2007) describe that N-acylsulfonamide derivatives and N-acylsulfonylurea derivatives of specific active agents with free carboxylic acid groups may also be useful prodrugs.

[0250] Additionally, experimental indications have been found that the methyl esters of the example compounds of Formula I or II also represent viable prodrugs of the cGAS inhibitors of Formula I or II. International Application Nos. PCT / EP2022 / 062480 and PCT / EP2022 / 062496 (both previously unpublished applications) both disclose cGAS inhibitors structurally similar to the cGAS inhibitors of the present invention, all of which also contain a carboxylic acid group attached to the pyrrolidine moiety. In both International Application Nos. PCT / EP2022 / 062480 and PCT / EP2022 / 062496, experiments have shown that methyl ester derivatives of these cGAS inhibitors having a carboxylic acid group attached to the pyrrolidine moiety act as viable prodrugs of the cGAS inhibitors having a free carboxylic acid group. Compounds P01, P02, P03, and P04 of International Application No. PCT / EP2022 / 062480 were methyl ester derivatives and putative prodrugs of Example compounds 4.04, 1.10, 1.12, and 3.14, respectively, of International Application No. PCT / EP2022 / 062480 (all possessing a free carboxylic acid group and exhibiting low biochemical IC values ​​for cGAS inhibition). 50 Value and low cell IC 50 (It was an active cGAS inhibitor with significant efficacy).

[0251] Compounds P01, P02, and P03 of International Application PCT / EP2022 / 062496 were methyl ester derivatives and putative prodrugs of Example compounds 2.12, 1.13, and 1.05, respectively, of International Application PCT / EP2022 / 062496 (all possessing a free carboxylic acid group and exhibiting low biochemical IC values ​​for cGAS inhibition). 50 Value and low cell IC 50 (It was an active cGAS inhibitor with significant efficacy). In both International Application No. PCT / EP2022 / 062480 and International Application No. PCT / EP2022 / 062496, "active cGAS inhibitors / example compounds with their free carboxylic acids" and their "respective methyl ester derivatives / putative prodrugs" were synthesized and tested for their pharmacological properties with respect to their potency in inhibiting the cGAS / STING pathway. On the other hand, this comparison of the properties of the example compounds of International Application Nos. PCT / EP2022 / 062480 and PCT / EP2022 / 062496 with their free carboxylic acids and their corresponding methyl ester derivatives / putative prodrugs allows the "biochemical IC" of the example compounds to be compared. 50 Value (hcGAS IC 50 While the "biochemical IC value" of the corresponding methyl ester derivatives / prodrugs is always around 10 nM or much lower than 10 nM, 50 Value (hcGAS IC 50 It is shown that the "IC value" is always extremely high, generally higher than 7000 nM. On the other hand, the IC 50values ​​and on the other hand the IC of their corresponding methyl ester derivatives / prodrugs 50 Such large differences between the values ​​are consistent with the respective cellular IC values, which always remain in almost the same range between the example compounds and their corresponding prodrugs. 50 Value(THP1 (vir) I C 50 values) was not observed (see Table 4 below).

[0252] One possible explanation for this observation is that all of the example compounds have a free carboxylic acid group, which appears to be crucial for inhibiting cGAS activity, but in all of the "methyl ester derivatives / prodrugs," the carboxyl group is masked by a carboxy-methyl ester group. As a result, the methyl ester derivatives / prodrugs lose their inhibitory potency in the "in vitro human cGAS enzyme assay" (see Section 6.1 below), because in this assay there is no intracellular enzyme to cleave the carboxy-methyl ester group, and therefore the crucial free carboxylic acid group cannot be restored in the biochemical assay. Therefore, the prodrugs have very high "biochemical (in vitro) IC" in this "in vitro human cGAS enzyme assay." 50 value" (=hcGAS IC 50 ), whereas the corresponding example compounds (which originally had a free carboxylic acid group) showed low "biochemical (in vitro) IC 50 value" (=hcGAS IC 50 ) is shown.

[0253] In cellular assays (= "Human cGAS Cellular and Counter-Cellular Assays", see section 6.2 below), there are endogenous cellular enzymes that cleave the carboxy-methyl ester group. As a result, the example compounds of International Application Nos. PCT / EP2022 / 062480 and PCT / EP2022 / 062496 themselves (which already have a free carboxylic acid group) exhibit low THP1 activity. (vir) I C 50Not only do they show relatively low THP1 values, but the corresponding methyl ester derivatives / prodrugs also show relatively low THP1 values. (vir) I C 50 "Values" are shown because in this "Human cGAS Cellular Assay," the carboxy-methyl ester group of the prodrug can be cleaved by endogenous intracellular enzymes, thereby liberating "active Example Compounds with a free carboxylic acid group," which again exhibit cGAS inhibitory potency.

[0254] This explanation, together with the measurements shown in Table 4, suggests that the carboxy-methyl ester derivatives of the structurally similar Example Compounds of International Applications PCT / EP2022 / 062480 and PCT / EP2022 / 062496 do indeed appear to represent viable prodrugs of the respective Example Compounds bearing a free carboxylic acid group, which themselves have no inhibitory potency with respect to in vitro human biochemical cGAS inhibition. However, following cleavage of the carboxy-methyl ester by endogenous intracellular enzymes present in cellular assays, the "active Example Compounds" are reinstated, again demonstrating inhibitory potency with respect to the cGAS / STING pathway. Since the example compounds of formula I or II of the present invention have exactly the same free carboxylic acid attached to the pyrrolidinyl moiety as the example compounds of International Application No. PCT / EP2022 / 062480 or International Application No. PCT / EP2022 / 062496, it can be expected that carboxy-methyl ester derivatives of these compounds of formula I or II also act as prodrugs.

[0255] [Table 16-1] [Table 16-2] [Table 16-3]

[0256] 5. Biological experiments The activity of the compounds of the present invention can be demonstrated using the following in vitro cGAS enzyme and cellular assays: 6.1 Methods: Human cGAS Enzyme Assay (hcGAS IC 50 (in vitro) The human cGAS enzyme was incubated in the presence of 45 base pairs of double-stranded DNA to activate the enzyme and GTP and ATP as substrates. Compound activity was determined by measuring the effect of the compound on the formation of the enzymatic reaction product, cGAMP, as measured by mass spectrometry.

[0257] Enzyme preparation: Human cGAS (amino acids 1-522) with an N-terminal 6xHis tag and SUMO tag was expressed in Escherichia coli (E. coli) BL21(DE3) pLysS (Novagen) cells at 18°C ​​for 16 hours. Cells were lysed in a buffer containing 25 mM Tris (pH 8), 300 mM NaCl, 10 mM imidazole, 10% glycerol, a protease inhibitor cocktail (cOmplete™, EDTA-free, Roche), and DNase (5 μg / mL). cGAS protein was isolated by affinity chromatography on Ni-NTA agarose resin and further purified by size-exclusion chromatography using a Superdex 200 column (GE Healthcare) equilibrated in 20 mM Tris (pH 7.5), 500 mM KCl, and 1 mM TCEP. The purified protein was concentrated to 1.7 mg / mL and stored at -80°C.

[0258] Assay Method Compounds were provided as 10 mM DMSO solutions, serially diluted, and transferred to a 384-well assay plate (Greiner #781201) using an Echo acoustic dispenser. Typically, eight concentrations were used, with the highest concentration being 10 μM in the final assay volume, followed by approximately 1:5 dilution steps. DMSO concentration was set to 1% in the final assay volume. The 384-well assay plate contained 22 test compounds (columns 1-22), with columns 23 and 24 containing DMSO. After compound transfer, 15 μL of enzyme-DNA working solution (12 nM cGAS, 0.32 μM 45 base pair DNA / assay buffer, 10 mM Tris pH 7.5 / 10 mM KCl / 5 mM MgCl2 / 1 mM DTT) was added via a MultiDrop Combi dispenser to each well in columns 1 through 23. In column 24, 15 μL of assay buffer without enzyme / DNA was added as a low control. The plates were then pre-incubated at room temperature for 60 minutes.

[0259] Then, 10 μL of GTP (ThermoFisher #R0461)-ATP (Promega #V915B) mix in assay buffer was added to the assay plate (columns 1-24, final concentration 30 μM each) using a Multidrop Combi. The plates were again incubated at room temperature for 90 minutes. After incubation, the reaction was stopped with 80 μL of 0.1% formic acid in assay buffer containing 5 nM cyclic-di-GMP (Sigma #SML1228), used as an internal standard for mass spectrometry analysis. The total volume per well was 105 μL.

[0260] Rapidfire MS detection The plate was centrifuged at 4000 rpm at 4°C for 5 minutes. The RapidFire autosampler was connected to a binary pump (Agilent 1290) and a Triple Quad 6500 (ABSciex, Toronto, Canada). The system was equipped with a 10 μL loop of a C18 [12 μL bed volume] cartridge (Agilent, part number G9210A) containing 10 mM NH4Ac (aqueous) water (pH 7.4) as eluent A (pump 1 1.5 mL / min, pump 2 1.25 mL / min) and 10 mM NH4Ac (pH 7.4) in 47.5 / 47.5 / 5 (v / v / v) ACN / MeOH / HO (pump 3 1.25 mL / min) as eluent B. Aspiration time: 250 ms; load time: 3000 ms; elution time: 3000 ms; wash volume: 500 μL.

[0261] The MS was operated in positive ion mode with a HESI ion source, source temperature 550°C, curtain gas = 35, gas 1 = 65, and gas 2 = 80. Unit mass resolution in SRM mode. The following transition and MS parameters (DP: declustering voltage and CE: collision energy) were determined for cGAMP and DicGMP: Analyte: cGAMP, 675.1 / 524, DP=130, CE=30 Internal standard: cyclic-di-GMP, 690.1 / 540, DP=130, CE=30. The formation of cGAMP was monitored and assessed as a ratio to cyclic-di-GMP. Data evaluation and calculations: For data evaluation and calculation, the measurement of the low control was set as the 0% control and the measurement of the high control was set as the 100% control. 50 Values ​​were calculated using the standard 4-parameter logistic regression equation: [y = (ad) / (1 + (x / c)^b) + d], where a = low value, d = high value; x = conc M; c = IC. 50 M;b=slope

[0262] 6.2 Methods: Human cGAS cell assay and cGAMP-stimulated counter cell assay (THP1 (vir) I C 50 and THP1(cGAMP) I C 50 ) THP1-Dual™ cells (InvivoGen #thpd-nfis) expressing an IRF-dependent Lucia luciferase reporter were used as the basis for both assays. For detection of cellular cGAS activity, cells were stimulated by infection with a baculovirus (pFastbac-1, Invitrogen, no coding insert) delivering cGAS enzyme-stimulating double-stranded DNA (THP1 (vir) I C 50 measurement). In a counter assay, cells were stimulated with cGAMP (SigmaAldrich #SML1232) to activate the same pathway directly downstream of cGAS (THP1 (cGAMP) I C 50 measurement). Pathway activity was measured by DNA-stimulated cGAS enzyme activity (THP1 (vir) I C 50 Measurement of cGAMP (THP1 (cGAMP) I C 50 The activity was monitored by measuring the Lucia luciferase activity induced by the IL-1 receptor (measurement of IL-1, counter assay).

[0263] Assay Method Compounds were provided as 10 mM DMSO solutions, serially diluted, and transferred to a 384-well assay plate (Greiner #781201) using an Echo acoustic dispenser. Typically, eight concentrations were used, with the highest concentration being 10 μM in the final assay volume, followed by approximately 1:5 dilution steps. DMSO concentration was set to 1% in the final assay volume. The 384-well assay plate contained 21 test compounds (columns 1-22), with columns 23 and 24 containing DMSO. Cells cultured according to the manufacturer's conditions were harvested by centrifugation at 300g / 10 min and resuspended in fresh cell culture medium (RPMI 1640 (Gibco #A10491-01), 10% FCS (Gibco #10500), 1x GlutaMax (Gibco #35050-061), 1x Pen / Strep solution (Gibco #15140-122), 100µg / ml Normocin (InvivoGen #ant-nr), 100µg / ml Zeocin (InvivoGen #ant-zn), 10µg / ml Blasticidin S (Life Technologies #A11139-03)) and diluted to 1.66E5 cells / ml. The baculovirus solution was then added to the cells (THP1) at a 1:200 ratio (varied depending on the virus batch). (vir) I C 50 Alternatively, in the counter assay, cGAMP was added to the cells at a final concentration of 10 μM (THP1 (cGAMP) I C 50 measurement).

[0264] 30 μL of cell / virus mix was added via a Multidrop Combi dispenser to each well (5000 cells / well) of the compound plate in columns 1 to 23. In column 24, 30 μL / 5000 cells / well without virus was added as a low control. The plates were then incubated in a humidified incubator at 37°C for 18 hours. Then, 15 μL of QuantiLuc detection reagent (InvivoGen #rep-qlcg5) was added to each well using a Multidrop Combi. Immediately after addition, measurements were taken using an EnVision reader (US-luminescence reading mode). Data evaluation and calculations: For data evaluation and calculation, the measurement of the low control was set as the 0% control and the measurement of the high control was set as the 100% control. 50Values ​​were calculated using the standard 4-parameter logistic regression equation: [y = (ad) / (1 + (x / c)^b) + d], where a = low value, d = high value; x = conc M; c = IC. 50 M;b=slope

[0265] 6.3 Method: Human Whole Blood Assay (Human WB IC 50 ) To detect cellular cGAS activity, human whole blood was stimulated by transfection with double-stranded DNA, and pathway activity was monitored by measuring IFNα2α production. Assay Method Compounds were provided as 10 mM DMSO solutions, serially diluted, and transferred to a 96-well cell culture plate (Corning #3595), with each well pre-filled with 20 μl OptiMEM (Gibco, #11058-021) using an Echo acoustic dispenser. Typically, eight concentrations were used, with the highest concentration being 10 μM in the final assay volume, followed by approximately 1:5 dilution steps. The DMSO concentration was set to 0.1% in the final assay volume. The 96-well assay plate contained 10 test compounds, with control wells containing DMSO. Human whole blood was collected in parallel from three or more healthy donors (male or female, free of contraceptives and medications other than thyroxine for 7 days) as sodium citrated blood (e.g., 3.8% in Mononovettes from Sarstedt). Whole blood was kept at room temperature for a maximum of 3 hours after collection until use in the assay.

[0266] 160 μl of whole blood sample was transferred to each well of a 96-well assay plate filled with compound / OptiMEM. All assay plates were prepared in duplicate using blood from different donors. The blood plate was kept at room temperature for 60 minutes, continuously shaken at 450 rpm, and covered but not sealed. A DNA-Fugene mix (Herring DNA, Sigma Aldrich #D6898-1G, Fugene (5 x 1 mL), Promega #E2312) was prepared in OptiMEM and incubated at room temperature for 10 minutes (125 ng DNA / 20 μl and a Fugene ratio of 9.6:1). 20 μl of DNA Fugene mix was added to each well, resulting in 125 ng DNA / well / 200 μl and a Fugene ratio of 9.6:1. 20 μl of OptiMEM and 9.6:1 Fugene were added to all low control wells. After covering the assay plate with an aera seal and lid, the blood plate was kept at room temperature for 30 minutes, continuously shaken at 450 rpm, and then incubated overnight in an incubator at 37° C. without shaking for 22 hours.

[0267] For detection of IFNα-2α in human plasma, biotinylated capture antibody (antibody set IFNA2, Meso Scale Diagnostics #B21VH-3, including coating and capture antibodies) was diluted 1:17.5 in Diluent 100 (Meso Scale Diagnostics #R50AA-4) according to the manufacturer's instructions. U-Plex MSD GOLD 96-well small spot streptavidin SECTOR plates (Meso Scale Diagnostics #L45SA-5) were coated with 25 μl of diluted capture antibody. The coated plates were incubated at room temperature for 60 minutes with continuous shaking at 700 rpm. The MSD IFNα-2α plates were washed three times with 150 μl of wash buffer (1x HBSS, 0.05% Tween). Plates were blocked with 100 μl of blocking solution / well (1× HBSS containing 0.2% Tween, 2% BSA) for 60 min at room temperature and shaken continuously at 700 rpm, followed immediately by human plasma after the plates were emptied as dry as possible by dumping.

[0268] The whole blood assay plates were centrifuged at 1600 rpm for 10 minutes. 25 μl of supernatant was transferred from each whole blood plate to the corresponding IFNα-2α plate using a pipetting robot. The plates were sealed with microplate seals and again maintained at room temperature with continuous shaking at 700 rpm for 2 hours. The MSD IFNα-2α plate was then washed three times with 150 μl of wash buffer (1× HBSS, 0.05% Tween), after which 25 μl of MSD SULFO-TAG IFNα-2α antibody solution (diluted 1:100 in Diluent 3 (Meso Scale Diagnostics # R50AP-2)) was added to each well of the plate. The plate was then sealed with a microplate seal and again maintained at room temperature under continuous shaking at 700 rpm for 2 hours. Finally, the MSD IFNα-2α plate was washed three times with 150 μl of wash buffer (1×HBSS, 0.05% Tween). 150 μl of 2×Read buffer was added to each well, and the plate was immediately read on an MSD Sector S600 reader using the supplier's barcode. Data evaluation and calculations: For data evaluation and calculation, the calculation of % control for each well was based on the mean of the high control (DNA stimulated control) and the mean of the low control (unstimulated control) by using the following formula: [Count(sample) - Count(low)) / (Count(high) - Count(low))] x 100 I C 50 Values ​​were calculated using the standard 4-parameter logistic regression equation: [y = (ad) / (1 + (x / c)^b) + d], where a = low value, d = high value; x = conc M; c = IC. 50 M;b=slope

[0269] 6. Indications As can be seen, the compounds of formula I or II are characterized by their range of therapeutic applications. Particular mention should be made of the use of the compounds of formula I or II according to the present invention, preferably as cGAS inhibitors based on their pharmaceutical activity. While the cGAS pathway is important for host defense against invading pathogens, such as viral infections and invasion by some intracellular bacteria, cellular stress and genetic factors can also lead to the production of abnormal cellular dsDNA, for example, due to nuclear or mitochondrial leakage, which can trigger autoinflammatory responses. Consequently, cGAS inhibitors have strong therapeutic potential for use in the treatment of a variety of autoinflammatory and autoimmune diseases. An et al., Arthritis Rheumatol. 2017 Apr;69(4):800-807, reported that cGAS expression in peripheral blood mononuclear cells (PBMCs) was significantly higher in patients with the autoimmune disease systemic lupus erythematosus (SLE) than in normal controls. Targeted measurement of cGAMP by tandem mass spectrometry detected cGAMP in 15% of SLE patients tested but not in healthy or rheumatoid arthritis controls. SLE patients with cGAMP had higher disease activity than patients without cGAMP. Because elevated cGAS expression may be the result of exposure to type I interferon (IFN), the detection of cGAMP in SLE patients with increased disease activity indicates the potential involvement of the cGAS pathway in disease development.

[0270] Park et al., Ann Rheum Dis. 2018 Oct;77(10):1507-1515 also discloses the involvement of the cGAS pathway in the development of SLE. Thim-Uam et al., iScience 2020 Sep 4;23(9), 101530 (doi: 10.1016 / j.isci.2020.101530) discloses that the STING pathway mediates lupus through activation of normal dendritic cell maturation and plasmacytoid dendritic cell differentiation. Gao et al., Proc. Natl. Acad. Sci. USA 2015 Oct 20;112(42):E5699-705, describes that activation of cGAS by self-DNA leads to several autoimmune diseases, such as interferonopathies. Tonduti et al., Expert Rev. Clin. Immunol. 2020 Feb;16(2):189-198, discloses that cGAS inhibitors have particular therapeutic potential in Aicardi-Goutieres syndrome and familial lupus chilblains, which are severe lupus-like autoinflammatory immune-mediated disorders. Steiner et al., Nat Commun. 2022 Apr 28;13(1):232; doi: 10.1038 show that deficiency of coatomer complex I leads to aberrant activation of STING signaling and COPA syndrome, and that cGAS is required to drive type I IFN signaling in a COPA syndrome cell model.

[0271] Li et al. show that plasma-derived DNA-containing extracellular vesicles induce a STING-mediated proinflammatory response in dermatomyositis (Theranostics. 2021; 11(15): 7144-7158). Zhou et al. (J Clin Lab Anal. 2022 Oct; 36(10): e24631) describe a correlation between activation of the cGAS-STING pathway and muscle fiber atrophy / necrosis in dermatomyositis. Yu et al., Cell 2020 Oct 29;183(3):636-649, describes the association between mitochondrial DNA and cGAS / STING pathway activation caused by TDP-43 in amyotrophic lateral sclerosis (ALS). Ryu et al., Arthritis Rheumatol. 2020 Nov;72(11):1905-1915, also show that bioactive plasma mitochondrial DNA is associated with disease progression in certain fibrotic diseases, such as systemic sclerosis (SSc) or interstitial lung disease (ILD), progressive fibrotic interstitial lung disease (PF-ILD), and idiopathic pulmonary fibrosis (IPF). Schuliga et al., Clin. Sci. (Lond). 2020 Apr 17;134(7):889-905, describes how autologous DNA perpetuates IPF lung fibroblast senescence in a cGAS-dependent manner.

[0272] Additional scientific indications implicating other causes of fibrosis, such as nonalcoholic steatohepatitis (NASH), with the cGAS / STING pathway are described in Yu et al., J. Clin. Invest. 2019 Feb 1;129(2):546-555 and Cho et al., Hepatology. 2018 Oct;68(4): 1331-1346. Nascimento et al., Sci. Rep. 2019 Oct 16;9(1):14848, discloses that release of self-DNA and STING-dependent sensing mediate cigarette smoke-induced inflammation in mice, suggesting a link between the cGAS-STING pathway and chronic obstructive pulmonary disease (COPD). Ma et al., Sci. Adv. 2020 May 20;6(21):eaaz6717, discloses that ulcerative colitis and inflammatory bowel disease (IBD) can be suppressed by controlling cGAS-mediated inflammation. Gratia et al., J. Exp. Med. 2019 May 6;216(5):1199-1213, show that Bloom syndrome proteins suppress innate immune sensing of micronuclei by cGAS. Consequently, cGAS inhibitors have therapeutic potential in treating Bloom syndrome.

[0273] Kerur et al., Nat. Med. 2018 Jan;24(1):50-61, describes that cGAS plays an important role in non-canonical inflammasome activation in age-related macular degeneration (AMD). Visitchanakun et al., Int J Mol Sci. 2021 Oct 23;22(21):11450, show that GAS-deficient mice were less severely affected than wild-type mice in cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) injection sepsis models. Wang et al., Mediators Inflamm. 2015;2015:192329, reported that cGAS is required for cell proliferation and inflammatory cytokine production in rheumatoid arthritis synovial cells. It was also reported that cGAS deficiency suppressed interferon responses, inflammatory cell infiltration, and joint swelling in a mouse model of inflammatory arthritis (Willemsen et al., Cell Rep. 2021 Nov 9;37(6):109977).

[0274] Guo et al., Osteoarthritis Cartilage. 2021 Aug;29(8):1213-1224, described that damaged DNA is an important pathological factor in osteoarthritis (OA), which may be mediated by the cGAS / STING pathway, as STING knockdown attenuates the destabilization of medial meniscus-induced OA development in mice. Mao et al., Arterioscler Thromb Vasc Biol (2017) 37(5):920-929, showed that the cGAS / STING pathway mediates endothelial inflammation in response to free fatty acid-induced mitochondrial damage in diet-induced obesity, indicating that cGAS inhibitors may also have potential in the treatment of obesity and diabetes. Kerur et al, Nat Med. 2018 Jan;24(1):50-61, describes that cGAS levels are elevated in the retinal pigment epithelium in human eyes with geographic atrophy and that cGAS drives activation of non-canonical inflammasome activation in age-related macular degeneration. cGAS promotes cellular senescence and senescence-associated secretory events (Yang et al., Proc Natl Acad Sci USA 2017 Jun 6;114:E4612-E4620). Cytoplasmic chromatin mediates inflammation in aging through cGAS / STING, and STING-null mice exhibit reduced tissue inflammation and aging (Dou et al., Nature. 2017 550:402-406). Furthermore, mutations in the STING gene are associated with healthy aging in humans, most likely through reduced inflammation-induced aging (Hamann et al., Gerontology 2019;65:145-154). Collectively, STING inhibitors reduce senescence-associated inflammation and senescent cell accumulation, leading to improvements in aging-related diseases such as aging, myopathy, and fibrosis.

[0275] Additionally, cGAS inhibitors of Formula I or II have therapeutic potential in the treatment of cancer (see Hoong et al., Oncotarget. 2020 Jul 28;11(30):2930-2955, and Chen et al., Sci. Adv. 2020 Oct 14;6(42):eabb8941). Additionally, cGAS inhibitors of Formula I or II have therapeutic potential in the treatment of heart failure (Hu et al., Am. J. Physiol. Heart Circ. Physiol. 2020 Jun 1;318(6):H1525-H1537). Further scientific evidence exists regarding the correlation between Parkinson's disease and the cGAS / STING pathway (Sliter et al., Nature. 2018 Sep;561(7722):258-262) and Sjögren's syndrome and the cGAS / STING pathway (Papinska et al., J. Dent. Res. 2018 Jul;97(8):893-900). Furthermore, cGAS inhibitors of Formula I or II have therapeutic potential in the treatment of COVID-19 / SARS-CoV-2 infection, as shown in Di Domizio et al., Nature. 2022 Jan 19. doi: 10.1038 / s41586-022-04421-w: "The cGAS-STING pathway drives type I IFN immunopathology in COVID-19," and Neufeldt et al., Commun Biol. 2022 Jan 12;5(1):45. doi: 10.1038 / s42003-021-02983-5: "SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS-STING and NF-kappaB."

[0276] Additionally, cGAS inhibitors of Formula I or II have therapeutic potential in treating renal inflammation and fibrosis, as shown in Chung et al., Cell Metab. 2019 30:784-799: "Mitochondrial Damage and Activation of the STING Pathway Lead to Renal Inflammation and Fibrosis," and Maekawa et al., Cell Rep. 2019 29:1261-1273: "Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury." Additionally, cGAS inhibitors of Formula I or II have therapeutic potential in the treatment of cancer, as shown in Bakhoum et al., Nature. 2018 Jan 25;553(7689):467-472: "Chromosomal instability drives metastasis through a cytosolic DNA response" and Liu et al., Nature. 2018 Nov;563(7729):131-136: "Nuclear cGAS suppresses DNA repair and promotes tumorigenesis."

[0277] Additionally, cGAS inhibitors of Formula I or II have therapeutic potential in the treatment of metabolic disorders because STING gt Animals showed reduced macrophage infiltration in adipose tissue after subchronic high-calorie diet (HFD), and STING gt and IRF3 deficiency leads to decreased blood glucose and insulin levels and weight loss (Mao et al, Arterioscler Thromb Vasc Biol, 2017;37 (5): 920-929). Furthermore, cGAS inhibitors of Formula I or II have therapeutic potential in the treatment of vascular diseases, leading to vascular repair / regeneration, since release of mitochondrial DNA into the cytosol of endothelial cells activates the cGAS / STING pathway and suppresses endothelial proliferation. Furthermore, knockout of the cGAS gene restores endothelial repair / regeneration in a mouse model of inflammatory lung injury (Huang et al., Immunity, 2020, Mar 2017; 52 (3): 475-486.e5. doi: 10.1016 / j.immuni.2020,02.002). Additionally, cGAS inhibitors of Formula I or II have therapeutic potential in the treatment of age-related and obesity-related cardiovascular disease (Hamann et al, Immun Ageing, 2020, Mar 14; 17: 7; doi: 10.1186 / s12979-020-00176-y.eCollection 2020).

[0278] As a result, the compounds of formula I or II as cGAS inhibitors can be used in the treatment of autoinflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE), interferonopathy, Aicardi-Goutieres syndrome (AGS), COPA syndrome, familial lupus chilblains, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Sjogren's syndrome, rheumatoid arthritis, and Parkinson's disease. In addition, the compounds of formula I or II as cGAS inhibitors can be used in the treatment of fibrosis such as systemic sclerosis (SSc), interferonosis, non-alcoholic steatohepatitis (NASH), interstitial lung disease (ILD), preferably interstitial lung disease with progressive fibrosis (PF-ILD), in particular idiopathic pulmonary fibrosis (IPF). Furthermore, the compounds of formula I or II as cGAS inhibitors can be used in the treatment of age-related macular degeneration (AMD), retinopathy, glaucoma, diabetes, obesity, aging, myopathies, sepsis, osteoarthritis, heart failure, COVID-19 / SARS-CoV-2 infection, renal inflammation, renal fibrosis, metabolic disorders, vascular diseases, cardiovascular diseases, and cancer.

[0279] 7. combination The compounds of Formula I or II may be administered to a patient alone or in combination with one or more other pharmacologically active agents. In a preferred embodiment of the invention, the compounds of formula I or II may be combined with one or more pharmacologically active agents selected from the group of anti-inflammatory agents, antifibrotic agents, antiallergics / antihistamines, bronchodilators, beta2 agonists / betamimetics, adrenergic agonists, anticholinergics, methotrexate, mycophenolate mofetil, leukotriene modifiers, JAK inhibitors, anti-interleukin antibodies, non-specific immunotherapeutics such as interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators (i.e. cytokine receptor agonists or antagonists), Toll-like receptor agonists (=TLR agonists), immune checkpoint regulators, anti-TNF antibodies (Humira™), and anti-BAFF agents (belimumab and etanercept). The anti-fibrotic agent is preferably selected from tyrosine kinase inhibitors such as pirfenidone and nintedanib, with nintedanib being particularly preferred.

[0280] Preferred examples of anti-inflammatory agents are NSAIDs and corticosteroids. The NSAID is preferably selected from ibuprofen, naproxen, diclofenac, meloxicam, celecoxib, acetylsalicylic acid (Aspirin™), indomethacin, mefenamic acid, and etoricoxib. The corticosteroid is preferably selected from flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, and dexamethasone. The antiallergic / antihistamine is preferably selected from epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, ebastine, desloratidine, and mizolastine. The beta2 agonists / betamimetics may be long-acting beta2 agonists (LABAs) or short-acting beta agonists (SABAs). Particularly preferred beta2 agonists / betamimetics are selected from bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulfonterol, terbutaline, tolubuterol, olodaterol, and salbutamol, especially olodaterol.

[0281] The anticholinergic agent is preferably selected from ipratropium salts, tiotropium salts, glycopyrronium salts, and theophylline, with tiotropium bromide being particularly preferred. The leukotriene modifier is preferably selected from montelukast, pranlukast, zafirlukast, ibudilast, and zileuton. The JAK inhibitor is preferably selected from baricitinib, selzulatinib, fedratinib, filgotinib, gandotinib, lestaurtinib, momelotinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib. The anti-interleukin antibody is preferably selected from an anti-IL23 antibody such as risankizumab, an anti-IL17 antibody, an anti-IL1 antibody, an anti-IL4 antibody, an anti-IL13 antibody, an anti-IL-5 antibody, an anti-IL-6 antibody such as Actemra™, an anti-IL-12 antibody, an anti-IL-15 antibody.

[0282] 8. formulation The compounds of the present invention can be administered by any suitable route, including both systemic and local administration. Systemic administration includes oral, parenteral, transdermal, rectal, and inhalation administration. Parenteral administration refers to any route of administration other than enteral, transdermal, or inhalation, and is typically administered by injection or infusion. Parenteral administration includes intravenous, intramuscular, intrasternal, and subcutaneous injection or infusion. Inhalation refers to administration to the patient's lungs, whether inhaled through the mouth or nasal passages. Local administration includes application to the skin. The compounds of the present invention can be administered via eye drops to treat Sjögren's syndrome. Suitable forms for administration are, for example, tablets, capsules, solutions, syrups, emulsions, or inhalable powders or aerosols. In each case, the content of the pharmaceutically active compound should be in the range of 0.1 to 90% by weight of the total composition, preferably 0.5 to 50% by weight, i.e., an amount sufficient to achieve the dosage ranges specified hereinafter. The preparations can be administered orally in the form of tablets, powders, powders in capsules (e.g., hard gelatin capsules), solutions or suspensions. When administered by inhalation, the active substance combinations can be administered as powders, as aqueous or aqueous-ethanolic solutions, or using propellant gas formulations. Preferably, therefore, the pharmaceutical formulation is characterized by the content of one or more compounds of formula I or II according to the above preferred embodiments.

[0283] It is particularly preferred that the compound of formula I or II is administered orally, and particularly preferred that it is administered once or twice a day.Suitable tablets can be obtained, for example, by mixing the active substance with known excipients, such as inert diluents such as calcium carbonate, calcium phosphate, or lactose, disintegrating agents such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or release retardants such as carboxymethylcellulose, cellulose acetate phthalate, or polyvinyl acetate.Tablets can also include several layers. Coated tablets can be prepared accordingly by coating cores produced in the same way as tablets with substances commonly used for tablet coatings, such as Kollidon or shellac, gum arabic, talc, titanium dioxide, or sugar. The core can also consist of several layers to achieve delayed release or to prevent incompatibility. Similarly, tablet coatings can consist of several layers to achieve delayed release, possibly using the excipients described above for tablets.

[0284] Syrups containing the active substances or combinations thereof according to the invention can additionally contain sweeteners such as saccharin, cyclamate, glycerol or sugar, and flavor enhancers, for example flavorings such as vanillin or orange extract. They can also contain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates. Capsules containing one or more active substances or combinations of active substances can be prepared, for example, by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatin capsules. Suitable suppositories can be prepared by mixing with carriers provided for this purpose, such as neutral fats or polyethylene glycol or their derivatives.

[0285] Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffin (e.g., petroleum fractions), vegetable oils (e.g., peanut or sesame oil), monofunctional or polyfunctional alcohols (e.g., ethanol or glycerol), carriers such as natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates), sugars (e.g., sucrose, lactose, and glucose), emulsifiers (e.g., lignin, sulfite waste liquor, methylcellulose, starch, and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium lauryl sulfate). For oral administration, tablets may contain, in addition to the above-mentioned carriers, additives such as sodium citrate, calcium carbonate, and dicalcium phosphate, together with various additives such as starch, preferably potato starch, gelatin, etc. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc may be used at the same time in the tableting process. In the case of aqueous suspensions, the active substance may be combined with various flavor enhancers or colorants in addition to the above-mentioned excipients.

Claims

1. Compounds of Formula I, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 【Chemistry 1】 (In the formula, R 1 is hydrogen, halogen, methyl, ethyl, -CF 3 , -CHF 2 , -CFH 2 and methoxy; R 2 is selected from the group consisting of hydrogen and methyl; R 3 is hydrogen, methyl, halogen, ethynyl, propynyl, -CO-(C 1-3 -alkyl), -CO-NH 2 , —CO—NHCH 3 , —CO—N(CH 3 ) 2 and a 5- or 6-membered heteroaryl ring having 1 or 2 heteroatoms each independently selected from N, S, or O, wherein the heteroaryl ring is selected from the group consisting of F, Cl, Br, —O—CH 3 , methyl, -CF 3 , -CHF 2 , C.H. 2 and optionally further substituted by one or two additional substituents each independently selected from the group consisting of F; R 4 is selected from the group consisting of hydrogen, —OH, and F; A is -CH 2 -, -O-, -CF 2 - and -CHCH 3 - selected from the group consisting of D is -CH 2 -, -O-, -CF 2 - and -CHCH 3 - selected from the group consisting of E is -CH 2 -, -CO-, -O-, -CF 2 - and -CHCH 3 - selected from the group consisting of G is -NH-, -NCH 3 -, -CH 2 -, -O-, -CF 2 - and -CHCH 3 - selected from the group consisting of J is -CO-, -CH 2 -, -O-, -CF 2 - and -CHCH 3 - selected from the group consisting of K is -CH 2 -, -CF 2 - and -O-, or is absent; L is -CH 2 --, --CHCH 3 - and -CF 2 - or absent)

2. 10. The compound of formula II according to claim 1, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 【Chemistry 2】 (In the formula, R 1 is selected from the group consisting of hydrogen and halogen, wherein the halogen is selected from the group consisting of F and Cl; R 2 is selected from the group consisting of hydrogen and methyl; R 3 is hydrogen, Cl, Br, ethynyl, propynyl, -CO-(CH 3 ), and a 5- or 6-membered heteroaryl ring having 1 or 2 heteroatoms each independently selected from N, S, or O, wherein the heteroaryl ring is selected from the group consisting of F, —O—CH 3 and methyl; R 4 is F, A is -CH 2 -, -O-, -CF 2 - and -CHCH 3 - selected from the group consisting of D is -CH 2 - and -O-; E is -CH 2 is selected from the group consisting of —, —CO—, and —O—; G is -NH-, -NCH 3 -, -CH 2 -, and -O-; J is -CO-, -CH 2 -, and -O-; K is -CH 2 -, -CF 2 -, -O-, or absent; L is -CH 2 - or non-existent)

3. 10. A compound of formula I according to claim 1 or a compound of formula II according to claim 2, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L is absent.

4. 10. A compound of formula I according to claim 1 or a compound of formula II according to claim 2, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L and K are absent.

5. L is absent and K is -CF 2 10. The compound of formula I according to claim 1 or the compound of formula II according to claim 2, wherein: -, and prodrugs, deuterated analogues and pharmaceutically acceptable salts thereof.

6. L is absent and A is -CH 2 - and -CF 2 - A compound of formula I according to claim 1 or a compound of formula II according to claim 2, selected from the group consisting of: - and prodrugs, deuterated analogues, and pharmaceutically acceptable salts thereof.

7. 10. The compound of formula I of claim 1 or the compound of formula II of claim 2, wherein L is absent and A is -O-, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

8. 10. The compound of formula I of claim 1 or the compound of formula II of claim 2, wherein L is absent and D is -O-, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

9. L is absent and R 3 is selected from the group consisting of Cl, Br, ethynyl, propynyl, and a 5- or 6-membered heteroaryl ring selected from the group consisting of pyridinyl and pyrazolyl, wherein the heteroaryl ring is selected from the group consisting of F, —O—CH 3 and methyl, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

10. R 1 is selected from the group consisting of F and Cl, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

11. R 1 10. The compound of formula I of claim 1 or the compound of formula II of claim 2, wherein is hydrogen, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 【Request Item 12】 【Chemistry 3-1】 【Chemistry 3-2】 【Chemistry 3-3】 10. A compound of formula I according to claim 1 or a compound of formula II according to claim 2, selected from the group consisting of: and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

13. A is -CH 2 - and -O-; D is -CH 2 - and -O-; E is -CH 2 - and -O-; G is -CH 2 - and -O-; J is -CH 2 - and -O-; K is -CH 2 - and -CF 2 - selected from the group consisting of 10. A compound of formula I according to claim 1 or a compound of formula II according to claim 2, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L is absent. 【Request Item 14】 【Chemistry 4】 14. The compound of formula II of claim 13 selected from the group consisting of: and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

15. A is -CH 2 - and -O-; D is -CH 2 - and -O-; E is -CH 2 - and G is -CH 2 - and -O-; J is -CH 2 - and K is -CH 2 - and -CF 2 - selected from the group consisting of 10. A compound of formula I according to claim 1 or a compound of formula II according to claim 2, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L is absent. 【Request Item 16】 【Chemistry 5】 16. The compound of formula II of claim 15 selected from the group consisting of: and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

17. a) Formula (AI) 【Transformation 6】 (In the formula, R 1 , R 2 , R 3 , R 4 , A, D, E, G, J, K, and L are defined as above, and R 13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl), b) Formula (A-II) 【Transformation 7】 (In the formula, R 1 , R 2 , R 3 , R 4 , A, D, E, G, J, K, and L are defined as above; R 13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl; R is hydrogen or a protecting group selected from the group consisting of tert-butyl, methyl, ethyl, and benzyl. c) Formula (BI) 【Transformation 8】 (In the formula, R 1 , R 2 , R 3 , R 4 , A, D, E, G, J, K, and L are defined as above, and R 13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl), d) Formula (CI) 【Chemistry 9】 (In the formula, R 1 , R 2 , R 3 , R 4 , A, D, E, G, J, K, and L are defined as above, and R 13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl), or e) Formula (C-II) 【Chemistry 10】 (In the formula, R 1 , R 2 , R 3 , R 4 , A, D, E, G, J, K, and L are defined as above, and R 13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl; PG is selected from the group consisting of tert-butoxycarbonyl (Boc), allyloxycarbonyl (Alloc), benzyloxycarbonyl (Cbz), and fluorenylmethoxycarbonyl (Fmoc). An intermediate compound.

18. A compound of formula I as defined in any one of claims 1 to 16 or a compound of formula II as defined in any one of claims 2 to 16 for use in the treatment of a disease that can be treated by the inhibition of cGAS.

19. 17. A compound of formula I according to any one of claims 1 to 16 or a compound of formula II according to any one of claims 2 to 16 for use in the treatment of a disease selected from the group consisting of systemic lupus erythematosus (SLE), interferonopathies, Aicardi-Goutieres syndrome (AGS), COPA syndrome, familial lupus chilblains, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), retinopathy, glaucoma, diabetes, obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, dermatomyositis, Sjogren's syndrome, Parkinson's disease, heart failure, cancer, aging, myopathies, sepsis, rheumatoid arthritis, osteoarthritis, COVID-19, systemic sclerosis (SSc), non-alcoholic steatohepatitis (NASH), interstitial lung diseases (ILDs), preferably interstitial lung diseases with progressive fibrosis (PF-ILDs), in particular idiopathic pulmonary fibrosis (IPF).

20. 17. A compound of formula I according to any one of claims 1 to 16 or a compound of formula II according to any one of claims 2 to 16 for use in the treatment of a disease selected from the group consisting of systemic lupus erythematosus (SLE), interferonopathy, Aicardi-Goutieres syndrome (AGS), COPA syndrome, familial lupus chilblains, dermatomyositis, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Sjogren's syndrome, rheumatoid arthritis, and Parkinson's disease.

21. A compound of formula I according to any one of claims 1 to 16 or a compound of formula II according to any one of claims 2 to 16 for use in the treatment of a disease selected from the group consisting of systemic sclerosis (SSc), non-alcoholic steatohepatitis (NASH), interferonopathies, interstitial lung diseases (ILDs), preferably interstitial lung diseases with progressive fibrosis (PF-ILDs), in particular idiopathic pulmonary fibrosis (IPF).

22. 17. A compound of formula I according to any one of claims 1 to 16 or a compound of formula II according to any one of claims 2 to 16 for use in the treatment of a disease selected from the group consisting of age-related macular degeneration (AMD), retinopathy, glaucoma, diabetes, obesity, aging, myopathy, sepsis, osteoarthritis, heart failure, COVID-19 / SARS-CoV-2 infection, renal inflammation, renal fibrosis, metabolic disorders, vascular diseases, cardiovascular diseases, and cancer.

23. 17. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 16 or a compound of formula II according to any one of claims 2 to 16, and optionally one or more pharmaceutically acceptable carriers and / or excipients.

24. 16. A method for treating or preventing rheumatoid arthritis comprising administering to a subject a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 16 or a compound of formula II according to any one of claims 2 to 16 in combination with one or more active agents selected from the group consisting of anti-inflammatory agents, anti-fibrotic agents, anti-allergics / antihistamines, bronchodilators, beta2 agonists / betamimetics, adrenergic agonists, anticholinergics, methotrexate, mycophenolate mofetil, leukotriene modifiers, JAK inhibitors, anti-interleukin antibodies, non-specific immunotherapeutics such as interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators, Toll-like receptor agonists, immune checkpoint regulators, anti-TNF antibodies such as Humira™, anti-BAFF antibodies such as belimumab or etanercept, A pharmaceutical composition which may include one or more pharmaceutically acceptable carriers and / or excipients.

25. 17. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 16 or a compound of formula II according to any one of claims 2 to 16 in combination with one or more antifibrotic agents selected from the group consisting of pirfenidone and nintedanib, and optionally one or more pharmaceutically acceptable carriers and / or excipients.

26. 17. A pharmaceutical composition comprising a compound of formula I as defined in any one of claims 1 to 16 or a compound of formula II as defined in any one of claims 2 to 16 in combination with one or more anti-inflammatory agents selected from the group consisting of NSAIDs and corticosteroids, and optionally one or more pharmaceutically acceptable carriers and / or excipients.

27. 17. A pharmaceutical composition comprising a compound of formula I as defined in any one of claims 1 to 16 or a compound of formula II as defined in any one of claims 2 to 16 in combination with one or more active agents selected from the group of bronchodilators, beta2 agonists / betamimetics, adrenergic agonists and anticholinergics, and optionally one or more pharmaceutically acceptable carriers and / or excipients.

28. 19. A pharmaceutical combination comprising a compound of formula I according to any one of claims 1 to 16 or a compound of formula II according to any one of claims 2 to 16 and one or more anti-interleukin antibodies selected from the group consisting of anti-IL-23 such as risankizumab, anti-IL-17 antibodies, anti-IL-1 antibodies, anti-IL-4 antibodies, anti-IL-13 antibodies, anti-IL-5 antibodies, anti-IL-6 antibodies such as Actemra™, anti-IL-12 antibodies, and anti-IL-15 antibodies.

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