Cyclic benzimidazole 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). JPEG2025537531000121.jpg96150 (in the formula, R 1 , R 2 , R 3 , 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 mislocalization 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 (SIFN-1)." In terferon G enes)" ( 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, II, or III 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] Additionally, compounds of Formula I, II, or III 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.

[0008] 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

[0009] 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 selected from the group consisting of hydrogen, methyl, and halogen; A is selected from the group consisting of -CH2-, -O-, -CF2-, -CHF-, -N(CH3)-, -NH-, and -CHCH3-; D is selected from the group consisting of -CH2-, -O-, -CF2-, -CHF-, and -CHCH3-; E is selected from the group consisting of -CH2-, -O-, -C(CH3)2-, -CHF-, CF2-, and -CHCH3-; G is selected from the group consisting of -NH-, -NCH3-, -CH2-, -O-, -CF2-, -CHF-, -CHCH3-, and -C(CH3)2; J is selected from the group consisting of -CO-, -CH2-, -O-, -CHF-, -CF2-, and -CHCH3-; K is selected from the group consisting of -CH2-, -CF2-, -O-, or is absent; L is selected from the group consisting of -CH2-, -O-, -CHCH3-, -CHF-, -CF2-, or is absent.

[0010] 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. In a preferred embodiment, the present invention provides R 1 is selected from the group consisting of hydrogen, Cl, and F; R 2 is selected from the group consisting of hydrogen and methyl; R 3 is selected from the group consisting of hydrogen, methyl, Cl, and F; A is selected from the group consisting of -CH2-, -O-, -CF2-, and -N(CH3)-; D is selected from the group consisting of -CH2-, -O-, and -CHCH3-; E is selected from the group consisting of —CH—, —O—, and —C(CH)—; G is selected from the group consisting of -NH-, -CH2-, -O-, and -CHCH3-; J is selected from the group consisting of -CO-, -CH2-, -O-, and -CHCH3-; K is selected from the group consisting of -CH2-, -CF2-, -O-, or absent; The present invention relates to the above compounds of formula I, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L is selected from the group consisting of -CH2-, -CF2-, or absent.

[0011] 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. In a further preferred embodiment, the present invention relates to the above compounds of formula I, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L is absent. In a further preferred embodiment, the present invention relates to the above compounds of formula I, and prodrugs, pharmaceutically acceptable salts, or deuterated analogs thereof, wherein L is absent and A is selected from the group consisting of -CH2- and -CF2-. In a further preferred embodiment, the present invention relates to the above compounds of formula I, 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 R 3 is halogen, as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. This allows R 3 is particularly preferably a halogen atom selected from the group consisting of Cl and F.

[0012] In a further preferred embodiment, the present invention provides a compound comprising R 3 is Cl or F and is located at the 5-position of the benzimidazole moiety, as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. In a further preferred embodiment, the present invention provides a compound comprising R 1 is halogen, as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. In another preferred embodiment, the present invention provides R 1 is Cl or F, as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. In a further preferred embodiment, the present invention provides a compound comprising R 1 is hydrogen, as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. In another particularly preferred embodiment, the present invention provides [ka] [ka] and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein the compound of formula I 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 -CH2- and -CF2-; D and E are each -CH2-; 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 -CF2- and -CH2-; The present invention relates to the above compounds of formula I, 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, wherein the compound of formula I is selected from the group consisting of:

[0015] In a further preferred embodiment, the present invention relates to the above compounds of formula I, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein R2 is methyl.

[0016] In another particularly preferred embodiment, the present invention provides a compound of formula II [ka] or a compound of formula III, [ka] and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. (In the formula, R 1 is selected from the group consisting of hydrogen and halogen; R 3 is selected from the group consisting of hydrogen, methyl, and halogen; A is selected from the group consisting of -CH2-, -O-, -CF2-, -CHF-, -N(CH3)-, -NH-, and -CHCH3-; D is selected from the group consisting of -CH2-, -O-, -CF2-, -CHF-, and -CHCH3-; E is selected from the group consisting of -CH2-, -O-, -C(CH3)2-, -CHF-, CF2-, and -CHCH3-; G is selected from the group consisting of -NH-, -NCH3-, -CH2-, -O-, -CF2-, -CHF-, -CHCH3-, and -C(CH3)2; J is selected from the group consisting of -CO-, -CH2-, -O-, -CHF-, -CF2-, and -CHCH3-; K is selected from the group consisting of -CH2-, -CF2-, -O-, or is absent; L is selected from the group consisting of -CH2-, -O-, -CHCH3-, -CHF-, -CF2-, or is absent.

[0017] 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. R 1 is selected from the group consisting of hydrogen, Cl, and F; R 3 is selected from the group consisting of hydrogen, methyl, Cl, and F; A is selected from the group consisting of -CH2-, -O-, -CF2-, and -N(CH3)-; D is selected from the group consisting of -CH2-, -O-, and -CHCH3-; E is selected from the group consisting of —CH—, —O—, and —C(CH)—; G is selected from the group consisting of -NH-, -CH2-, -O-, and -CHCH3-; J is selected from the group consisting of -CO-, -CH2-, -O-, and -CHCH3-; K is selected from the group consisting of -CH2-, -CF2-, -O-, or absent; Further preferred are the above compounds of Formula II or Formula III, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L is selected from the group consisting of -CH2-, -CF2-, or absent.

[0018] 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.

[0019] The above compounds of formula II, as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, are especially preferred. [ka] (In the formula, R 1 is selected from the group consisting of hydrogen, Cl, and F; R 3 is selected from the group consisting of hydrogen, methyl, Cl, and F; A is selected from the group consisting of -CH2-, -O-, -CF2-, and -N(CH3)-; D is selected from the group consisting of -CH2-, -O-, and -CHCH3-; E is selected from the group consisting of -CH2-, -O-, and -C(CH3)2-; G is selected from the group consisting of -NH-, -CH2-, -O-, and -CHCH3-; J is selected from the group consisting of -CO-, -CH2-, -O-, and -CHCH3-; K is selected from the group consisting of -CH2-, -CF2-, -O-, or is absent; L is selected from the group consisting of -CH2-, -CF2-, or absent.

[0020] 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. In another preferred embodiment, the present invention relates to the above compounds of formula II or the above compounds of formula III, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L is absent. In a further preferred embodiment, the present invention relates to the above compounds of formula II or the above compounds of formula III, 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 R 3 is halogen, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0021] In a further preferred embodiment, the present invention provides a compound comprising R 3 is Cl or F, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. In a particularly preferred embodiment, the present invention provides 3 is Cl or F and is located at the 5-position of the benzimidazole moiety, as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. In another preferred embodiment, the present invention provides R 3 is hydrogen, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0022] In a further preferred embodiment, the present invention provides a compound comprising R 1 is halogen, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. In a particularly preferred embodiment, the present invention provides 1is selected from the group consisting of Cl or F, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. In another preferred embodiment, the present invention provides R 1 is hydrogen, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 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 -CH2- and -CF2-; D and E are each -CH2-; 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 -CF2- and -CH2-; The present invention relates to the above compounds of formula II or the above compounds of formula III, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L is absent.

[0023] In another particularly preferred embodiment, the present invention provides [ka] and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0024] In a further particularly preferred embodiment, the present invention provides A is selected from the group consisting of -CH2- and -CF2-; D, E, and G are each -CH2-; J is selected from the group consisting of -CH2- and -O-; K is -CF2-, The present invention relates to the above compounds of formula II or the above compounds of formula III, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L is absent.

[0025] In another particularly preferred embodiment, the present invention provides [ka] and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0026] The prodrug of a compound of formula I is preferably a compound of formula Ia. [ka] (wherein the variable R 1 , R 2 , R 3 , A, D, E, G, J, K, and L are defined as above, R 4 is C 1-4 -Alkyl, aryl, -CH2-aryl, NH-SO2-C 1-3 -alkyl)

[0027] Variable R 1 , R 2 , R 3 , A, D, E, G, J, K, and L are defined as above, and R 4 Particularly preferred are prodrugs of Formula Ia wherein is methyl.

[0028] 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 , A, D, E, G, J, K, and L are defined as above; R 4 is C 1-4 -Alkyl, aryl, -CH2-aryl, NH-SO2-C 1-3 -alkyl)

[0029] Variable R 1 , R 2 , R3 , A, D, E, G, J, K, and L are defined as above, and R 4 Particularly preferred are prodrugs of Formula IIa wherein is methyl.

[0030] The prodrug of the compound of formula III is preferably a compound of formula IIIa. [ka] (wherein the variable R 1 , R 2 , R 3 , A, D, E, G, J, K, and L are defined as above; R 4 is C 1-4 -Alkyl, aryl, -CH2-aryl, NH-SO2-C 1-3 -alkyl)

[0031] Variable R 1 , R 2 , R 3 , A, D, E, G, J, K, and L are defined as above, and R 4 Particularly preferred are prodrugs of Formula IIIa wherein is methyl.

[0032] 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 , A, D, E, G, J, K, and L are defined as above, and R is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl; b) Intermediate compound of formula (A-II) [ka] (In the formula, R 1 , R 2 , R 3, A, D, E, G, J, K, and L are defined as above, and R 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) [ka] (In the formula, R 1 , R 2 , R 3 , A, D, E, G, J, K, and L are defined as above, and R is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl), or d) Intermediate compound of formula (B-II) [ka] (In the formula, R 1 , R 2 , R 3 , A, D, E, G, J, K, and L are defined as above, and R is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl. Regarding.

[0033] In further preferred embodiments, the present invention relates to the above compounds of Formula I, II, or III, or prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof of Formula Ia, IIa, or IIIa, 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), interferonopathies, 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), dermatomyositis, non-ALS. The present invention relates to the compounds of formula I, II, or III, or their prodrugs, deuterated analogues, and pharmaceutically acceptable salts of formula Ia, IIa, or IIIa, for use in the treatment of a disease selected from the group consisting of nonalcoholic steatohepatitis (NASH), interstitial lung disease (ILD), preferably interstitial lung disease with progressive fibrosis (PF-ILD), in particular idiopathic pulmonary fibrosis (IPF), aging, myopathy, sepsis, rheumatoid arthritis, osteoarthritis, and COVID-19.

[0034] In another preferred embodiment, the present invention relates to the above compounds of Formula I, II, or III or prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof of Formula Ia, IIa, or IIIa 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, II or III or their prodrugs, deuterated analogues and pharmaceutically acceptable salts of formula Ia, IIa or IIIa 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).

[0035] In another preferred embodiment, the present invention relates to the above-mentioned compounds of Formula I, II, or III, or prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof of Formula Ia, IIa, or IIIa, 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, II, or III or their prodrugs, deuterated analogs, and pharmaceutically acceptable salts of Formula Ia, IIa, or IIIa, 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, II, or III or their prodrugs, deuterated analogs, and pharmaceutically acceptable salts of Formula Ia, IIa, or IIIa 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.

[0036] In a further preferred embodiment, the present invention relates to a pharmaceutical composition comprising the above-mentioned compound of Formula I, II, or III or its prodrugs, deuterated analogs, and pharmaceutically acceptable salts of Formula Ia, IIa, or IIIa, 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-mentioned compounds of Formula I, II, or III or their prodrugs, deuterated analogs, and pharmaceutically acceptable salts of Formula Ia, IIa, or IIIa, 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, II, or III or their prodrugs, deuterated analogs, and pharmaceutically acceptable salts of Formula Ia, IIa, or IIIa, 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.

[0037] In another preferred embodiment, the present invention relates to a pharmaceutical combination comprising the above-mentioned compound of Formula I, II, or III or prodrugs, deuterated analogues, and pharmaceutically acceptable salts thereof of Formula Ia, IIa, or IIIa, 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

[0038] 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.

[0039] "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]

[0040] "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.

[0041] "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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] "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:

[0046] [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:

[0047] [ka] Examples include:

[0048] 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: [ka] Examples include:

[0049] Unless otherwise specified, the heterocyclic ring (or heterocycle) may be equipped with a keto group. Examples include: [ka] Examples include:

[0050] 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:

[0051] [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.

[0052] 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,

[0053] [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, II, or III 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, II, or III with inorganic or organic acids. On the other hand, compounds of Formula I, II, or III 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 the alkali metal and alkaline earth metal salts of compounds of Formula I, II, or III, 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.

[0054] 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, II, or III according to the present invention may exist as mixtures of diastereoisomers, but may also be obtained as pure diastereoisomers. Compounds with the specific stereochemistry of formula II and III are preferred, especially compounds with the specific stereochemistry of formula II.

[0055] 4.Synthesis method General Procedure The following methods are suitable for preparing compounds of general formula I, II, or III. 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 serve as examples:

[0056] Route A: Compounds of general formulae I, II, and III (particularly where 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, 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) by applying a strong base such as sodium hydride. Methods applicable to the preparation of compound (A-III) will be apparent to those skilled in the art by reference to Routes B and C 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 B. R according to formulas (A-II) and (A-III) can represent hydrogen or a protecting group selected from the group consisting of tert-butyl, methyl, ethyl, and benzyl.

[0057] [ka]

[0058] Route B: Compounds of general formulas I, II, and III can be prepared by reacting a compound of general formula (BI) in the presence of a strong base, such as sodium hydride. R13 can represent hydrogen or a protecting group, such as tert-butyl, which can be removed by standard deprotection methods. Compound (BI) can be prepared by oxidizing a compound of general formula (B-II), for example, by applying 3-chloroperbenzoic acid. Compound (B-II) can be prepared by reacting a compound of general formula (B-III) with a compound of general formula (B-IV) by applying standard amidation conditions. Methods applicable to the preparation of compound (B-III) will be apparent to those skilled in the art by reference to the synthesis of compound (B-VI) and Route C described below, as well as the examples described in the experimental section. Compounds of formula (B-IV) can be prepared through the method described below for the synthesis of intermediate B. Alternatively, compound (B-II) can be prepared by reacting a compound of general formula (BV) with the respective enantiopure hydroxyproline, optionally in the presence of a base. Compound (BV) can be obtained through chlorination of a compound of general formula (B-VI) by applying phosphoryl chloride. Compound (B-VI) can be prepared from a compound of general formula (B-VII) by applying strong alkaline conditions, for example, at elevated temperature. Compound (B-VII) can be reached by reacting a compound of general formula (B-VIII) with a compound of general formula (B-IX) by applying a standard amidation procedure. Compounds of general formula (B-VIII) can be prepared by the methods exemplified below or other standard synthetic methods known to those skilled in the art.

[0059] [ka]

[0060] Route C: Compounds of the general formula can be prepared from compounds of the general formula (CI) by various types of ring-closing reactions, exemplified by, 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 compounds (CI) 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.

[0061] [ka]

[0062] Synthesis of intermediates Intermediate A Intermediate A-01 (racemic tert-butyl trans-4-amino-3-methylpiperidine-1-carboxylate): [ka]

[0063] Step 1: To a solution of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (175 g; 0.82 mol) in THF (1.22 L) cooled to 0 °C, lithium tri-sec-butyl(hydrido)borate (L-Selectride; 1 M in THF; 984 mL; 0.98 mol) was added. The mixture was stirred for 4 h while maintaining the temperature between 0 °C and 10 °C. Aqueous sodium hypochlorite solution (10%; 525 mL) was added, and the mixture was extracted with EtOAc (700 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated. The crude product was purified by FC (silica gel; petroleum ether / EtOAc 2% → 50%). 1 H NMR (400 MHz, CDCl3) δ ppm 3.84 - 3.82 (m, 1H), 3.52 (d, J = 6.40 Hz, 2H), 3.29 (d, J = 5.40 Hz, 2H), 3.06 - 3.02 (m, 1H), 1.76 - 1.74 (m, 3H), 1.65 (s, 9H), 1.24 - 0.89 (m, 3H)

[0064] Step 2: To a solution of the product of Step 1 (330 g; 1.53 mol) in THF (1.65 L) was added triethylamine (341 g; 3.37 mol). Methanesulfonic anhydride (507 g; 2.91 mol) was added at room temperature, and the mixture was stirred at room temperature for 4 hours. Water (550 mL) was added, and the mixture was extracted with EtOAc (1.65 L). The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The product was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ ppm 4.74 - 4.71 (m, 1H), 4.23 - 3.95 (m, 1H), 3.17 - 3.04 (m, 2H), 3.04 (s, 3H), 1.95 - 1.92 (m, 1H), 1.83 (s, 1H), 1.83 - 1.82 (m, 1H), 1.32 (s, 9H), 0.91- 0.79 (m, 3H)

[0065] Step 3: Reaction under nitrogen atmosphere. To a solution of the product of Step 2 (420 g; 1.43 mol) in DMF (2.1 L) was added sodium azide (186 g; 2.86 mol) at room temperature. The mixture was stirred at 100 °C for 4 hours and then cooled to 0 °C. A saturated solution of sodium carbonate (4.0 L) was added while maintaining the temperature below 10 °C. The mixture was extracted with EtOAc, and the organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The product was used in the next step without further purification.

[0066] Step 4: A mixture of the product of Step 3 (200 g; 0.83 mol), palladium on charcoal (60 g), and EtOAc (1.0 L) was stirred under hydrogen pressure (50 psi) at room temperature for 2 h. The catalyst was filtered off with suction and washed with methanol (2 L). The combined filtrates were evaporated under reduced pressure. The crude product was purified by FC (silica gel; petroleum ether / EtOAc 0% to 100%) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 7.85 (s, 1 H) 3.99 - 3.74 (m, 2 H), 2.81 - 2.79 (m, 2H), 2.71 (s, 1 H), 2.72 - 2.70 (m, 1 H), 2.64 - 2.52 (m, 1 H), 2.25 - 2.16 (m, 2 H), 1.66 - 1.57 (m, 1 H), 1.35 - 1.30 (m, 2 H), 1.30 - 1.27 (m, 8 H), 1.17 - 1.06 (m, 2 H), 0.83 - 0.78 (m, 3 H), 0.75 - 0.71 (m, 1H)

[0067] Intermediate B Intermediate B-01: [ka]

[0068] Step 1: A mixture of intermediate A-01 (2 g; 9.97 mmol), 5-chloro-2-fluoronitrobenzene (1.21 mL; 9.97 mmol), DIPEA (3.43 mL; 19.9 mmol), and DMF (17 mL) was stirred at 60 °C until reaction control by RP HPLC showed significant conversion of the starting material (10 h). The mixture was poured into ice water. Further water was added, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with water and then with brine, separated, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by FC (silica gel; cyclohexane / EtOAc 20% to 100%) to give tert-butyl (rac-trans)-4-[(4-chloro-2-nitrophenyl)amino]-3-methylpiperidine-1-carboxylate. ESI-MS: 392 [M+Na] + R t (HPLC): 0.83 min (Method A)

[0069] Step 2: In a Parr apparatus, the product of Step 1 (3.25 g; 7.90 mmol), Raney nickel (410 mg), and THF (60 mL) were shaken under hydrogen pressure (50 psi) at room temperature for 5 h. Further Raney nickel (160 mg) was added in multiple portions, each after another 10–15 h, until reaction control by RP HPLC indicated high conversion of the starting material (in this case: three catalyst additions). The catalyst was filtered off, and the filtrate was evaporated. The crude product was used in the next step. ESI-MS: 340 [M+H] + R t (HPLC): 0.63 min (Method A)

[0070] Step 3: A mixture of the product of Step 2 (2.16 g; 6.37 mmol), 1-(1H-imidazole-1-carbothioyl)-1H-imidazole (1.47 g; 8.25 mmol), and DMF (34 mL) was stirred at room temperature for 2 h. Ice water (200 mL) was slowly added to the reaction mixture with stirring, and stirring was continued for an additional 10 min. The precipitate was filtered off, washed with water, dried at 50 °C overnight, and used in the next step without further purification. ESI-MS: 382 [M+H] + R t (HPLC): 0.71 min (Method A)

[0071] Step 4: Reaction under argon atmosphere. To a solution of the product of Step 3 (2.57 g; 6.26 mmol) in anhydrous DMF, potassium tert-butylate (1.42 g; 12.7 mmol) was added. The mixture was stirred at room temperature for 15 minutes, and then iodomethane (597 μL; 9.49 mmol) was added. The mixture was stirred at room temperature until reaction control by RP HPLC showed almost complete conversion of the starting material (2 hours). Ice water (100 mL) was added, and the mixture was kept at 6 °C overnight. The formed precipitate was filtered off, dissolved in EtOAc, concentrated under reduced pressure, and dried by coevaporation with toluene to give tert-butyl (racemic trans)-4-[5-chloro-2-(methylsulfanyl)-1H-1,3-benzodiazol-1-yl]-3-methylpiperidine-1-carboxylate. ESI-MS: 396 [M+H] + R t (HPLC): 0.73 min (Method A)

[0072] Step 5: The mixture of enantiomers from step 4 was separated by preparative SFC (apparatus: Sepiatec 2 Prep SFC 100; column: Lux Cellulose-2 (21.2 mm × 250 mm, 5 μm); mobile phase: A CO and B IPA; gradient: B% = 20% isocratic elution mode; flow rate: 60 mL / min; wavelength: 220 nm; column temperature: 40 °C; system back pressure: 150 bar). The absolute configurations of the two separated enantiomers were assigned according to the method described by DJ Patel et al, PNAS 2019, 11946-11955 (doi.org / 10.1073 / pnas.1905013116) based on the co-crystal structure of Example 1.01 with human cGAS protein. (of the first eluting isomer) 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.46 - 7.69 (m, 1 H), 7.10 - 7.26 (m, 1 H), 7.17 (br d, J=6.84 Hz, 1 H), 3.87 - 4.22 (m, 3 H), 2.87 - 3.06 (m, 1 H), 2.57 - 2.79 (m, 4 H), 2.31 - 2.45 (m, 1 H), 2.13 - 2.30 (m, 1 H), 1.80 (br d, J=11.79 Hz, 1 H), 1.45 (s, 9 H), 0.58 (d, J=6.46 Hz, 3 H)

[0073] The first eluting isomer was taken on to the next step. Intermediate B-02 was prepared from the second eluting isomer.

[0074] Step 6: To a solution of the first-eluting isomer from Step 5 (811 mg; 2.05 mmol) in DCM (11.8 mL) was added 3-chloroperbenzoic acid (77%; 0.987 g; 4.40 mmol). The mixture was stirred for 2 h, then diluted with more DCM and washed with aqueous potassium carbonate (15%). The aqueous layer was re-extracted with DCM, and the combined organic layers were washed with water, separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound. ESI-MS: 428 [M+H] + R t (HPLC): 0.74 min (Method A)

[0075] The following intermediates were prepared from the indicated starting materials in a manner similar to that described for Intermediate 1.01 above. Accordingly, the reaction temperature in Step 1 was adjusted for the reactivity of the respective nitrobenzene starting material. The absolute configurations of selected intermediates were assigned from the co-crystal structures of example compounds prepared from the respective intermediates with human cGAS protein, according to the method described by DJ Patel et al., PNAS 2019, 11946-11955 (doi.org / 10.1073 / pnas.1905013116). The absolute configurations of other intermediates and examples were assigned based on the assumption that the eutomers share the same absolute stereochemistry in all cases.

[0076] [Table 1-1] [Table 1-2]

[0077] Intermediate B-12 [ka] The product of step 4 of the synthesis of intermediate B-08 was BOC-deprotected according to general procedure D. ESI-MS: 262 [M+H] + Rt (HPLC): 0.47 min (Method E)

[0078] Intermediate B-14 [ka] A mixture of intermediate B-08 (700 mg; 1.78 mmol) and hydrochloric acid in dioxane (4 M; 1.33 mL; 5.45 mmol) was stirred for 2 hours. tert-Butyl methyl ether (20 mL) was added, and the mixture was left without stirring for 1 hour. The precipitate was filtered off and dissolved in methanol. The resulting solution was evaporated under reduced pressure to give the title compound. ESI-MS: 294 [M+H] + R t (HPLC): 0.60 min (Method E)

[0079] Intermediate I Intermediate I.01: [ka] Intermediate NR was reacted with intermediate B-5 according to general procedure A to give the title compound tert-butyl(3S,4S)-4-(2-{[(3S,5S)-1-{4-bromo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(13),2,4,6,9,11-hexaen-6-yl}-5-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]oxy}-1H-1,3-benzodiazol-1-yl)-3-methylpiperidine-1-carboxylate was obtained. ESI-MS: 747 [M+H] + R t (HPLC): 1.27 minutes (Method B)

[0080] Intermediate I.02: [ka]

[0081] Step 1: The reaction was carried out under an argon atmosphere, and the solvent was degassed and dried by adding molecular sieves. To intermediate I.01 (721 mg; 0.916 mmol) in a round-bottom flask was added DMSO (10 mL), methyl bromodifluoroacetate (266 μL; 2.42 mmol), and copper powder (291 mg; 4.58 mmol). The mixture was stirred overnight, and then another equivalent of methyl bromodifluoroacetate and two more equivalents of copper were added. After stirring for an additional 72 hours, the mixture was diluted with EtOAc, potassium dihydrogen phosphate solution (1.27 M; 20 mL) was added, and the mixture was stirred for another 30 minutes before being filtered. The organic layer of the filtrate was washed with water, concentrated and the crude product was purified by FC (silica gel; CH / EtOAc 10%→100%) to give tert-butyl(3S,4S)-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(13),2,4,6,9,11-hexaen-6-yl]pyrrolidin-3-yl]oxy}-1H-1,3-benzodiazol-1-yl)-3-methylpiperidine-1-carboxylate was obtained.

[0082] Step 2: To the product of step 1 (585 mg; 0.647 mmol) in absolute ethanol (dehydrated over molecular sieves 3 Å) was added sodium borohydride (244 mg; 6.40 mmol) in small portions within 1 h. The reaction was quenched by the addition of water, the mixture was extracted three times with EtOAc, and the combined organic layers were washed with water and then with brine, separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by FC (silica gel; CH / EtOAc 20% to 100%) to give tert-butyl(3S,4S)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-[4-(1,1-difluoro-2-hydroxyethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0]. 2,7]trideca-1(13),2,4,6,9,11-hexaen-6-yl]pyrrolidin-3-yl]oxy}-1H-1,3-benzodiazol-1-yl)-3-methylpiperidine-1-carboxylate was obtained.

[0083] Step 3: To a solution of the product of Step 2 (269 mg; 0.359 mmol) and allyl bromide (220 μL; 2.52 mmol) in DMA (1.67 mL) was added sodium hydride (55% in mineral oil; 47 mg; 1.08 mmol). The mixture was stirred for 10 minutes and then quenched by the addition of water. The mixture was extracted three times with EtOAc, and the combined organic layers were washed with water and then brine, separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by FC (silica gel; CH / EtOAc 20%→100%) to give the title compound tert-butyl (3S,4S)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-{4-[1,1-difluoro-2-(prop-2-en-1-yloxy)ethyl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(13),2,4,6,9,11-hexaen-6-yl}pyrrolidin-3-yl]oxy}-1H-1,3-benzodiazol-1-yl)-3-methylpiperidine-1-carboxylate was obtained. ESI-MS: 789 [M+H] + R t (HPLC): 1.29 minutes (Method B)

[0084] Intermediate I.03: [ka] To a solution of 3-allyloxypropionic acid (38 μL; 0.303 mmol) in DMF (500 μL) was added EDC hydrochloride (70 mg; 0.364 mmol) and N,N-diisopropylethylamine (105 μL; 0.606 mmol). The mixture was stirred for 10 min, then intermediate B-14 (100 mg; 0.303 mmol) was added, and the mixture was stirred for 90 min. It was then diluted with methanol (2 mL) and subjected to purification by RP HPLC (Sunfire C18; ACN / water, modifier: TFA). ESI-MS: 406 [M+H] + R t (HPLC): 0.88 min (Method E)

[0085] Intermediate N 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 (Intermediate NA, see Step 4) General Procedure Int-B: Ring closure under basic conditions (Intermediate NA, see Step 5) General Procedure Int-C: Chlorination applying phosphoryl trichloride (Intermediate NA, see Step 7) General Procedure Int-D: S with Hydroxyproline Esters N Ar (Intermediate NA, see Step 8) General Procedure Int-E: Ester Cleavage Applying Lithium Hydroxide (Intermediate NF, see Step 2) General Procedure Int-F: Amidation applying PFTU (Intermediate NF, see step 3) General Procedure Int-G: Heck-Type Coupling (Intermediate NJ, see Step 1)

[0086] Intermediate NA: [ka]

[0087] 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. 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.

[0088] 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 E)

[0089] 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 reaction control by 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 E) 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 E) 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 E)

[0090] Step 7: General Procedure Int-C: A mixture of the product of Step 6 (3.70 g; 11.2 mmol) and phosphoroyl trichloride (70 mL) was stirred at 90 °C for 4 h. Excess phosphoroyl 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 E)

[0091] 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 E)

[0092] 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 E)

[0093] Intermediate NB: [ka] Prepared in analogy to the sequence described for the synthesis of intermediate NA, applying 3-amino-6-chloro-1-benzofuran-2-carboxamide in step 3. ESI-MS: 520 [M+H] + R t (HPLC): 0.50 min (Method A)

[0094] Intermediate NC: [ka] From intermediate NV 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: 504 [M+H] + R t (HPLC): 0.45 min (Method A)

[0095] Intermediate ND: [ka] Prepared analogously to the sequence described for the synthesis of intermediate NA, starting from tert-butyl 2-(3-oxopropoxy)acetate, prepared as described in EP 1939201. ESI-MS: 486 [M+H] + R t (HPLC): 0.71 min (Method E)

[0096] Intermediate NE: [ka] 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-oxa-3,5-diazatricyclo[7.4.0.0]pyrimidine]. 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. 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.

[0097] The product of Step 2 was further reacted in a two-step sequence first according to general procedure Int-C and then Int-D to give the title compound. ESI-MS: 516 [M+H] + R t (HPLC): 0.80 min (Method E)

[0098] Intermediate NF: [ka] 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)

[0099] 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)

[0100] 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)

[0101] 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 TEA (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] - Rt (HPLC): 0.44 min (Method F)

[0102] 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)

[0103] 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 NG: [ka] Preparation similar to the reaction sequence described for the synthesis of intermediate NF, applying 3-amino-6-fluorobenzofuran-2-carboxamide in step 3. Intermediate NH: [ka] Preparation similar to the reaction sequence described for the synthesis of intermediate NF, applying 3-amino-6-chlorobenzofuran-2-carboxamide in step 3. Intermediate NI [ka]

[0104] 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), thereby maintaining the temperature 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 at -75°C. The mixture was stirred at -75°C for an additional 4 hours. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (900 mL) at 0°C, and the pH was then 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)

[0105] 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)

[0106] 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)

[0107] 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). 1 H 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). Step 5: The product of step 4 was chlorinated applying general procedure Int-C.

[0108] 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 NJ: [ka] It was prepared from the intermediate NR applying the following three step sequence:

[0109] Step 1: General Procedure Int-G: Intermediate NR (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.

[0110] 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)

[0111] Step 3: The product of Step 2 was reacted according to general procedure Int-E to give the ester cleaved title compound.

[0112] Intermediate NK: [ka] From the intermediate NR and methyl 3-(but-3-en-2-yloxy)propanoate, the following three step sequence: Step 1: Heck-type coupling according to general procedure Int-G Step 2: Hydrogenation according to General Procedure Int-A Step 3: Ester cleavage according to general procedure Int-E (The starting material methyl 3-(but-3-en-2-yloxy)propanoate was prepared from the respective tert-butyl ester by acidic ester cleavage followed by methyl ester formation (methanol, thionyl chloride) to give the title compound. ESI-MS: 500 [M+H] + R t (HPLC): 1.82 minutes (Method G)

[0113] Intermediate NL: 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]

[0114] 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.

[0115] 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 H)

[0116] 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 H)

[0117] Step 4: The product of Step 2 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 G)

[0118] Intermediate NM: [ka] Prepared analogously to the procedure described for the synthesis of intermediate NL, applying 3-amino-6-chloro-1-benzofuran-2-carboxamide (prepared as described in EP 1 710 233) as starting material in step 2.

[0119] Intermediate NN: [ka] Prepared from intermediate NR and methyl 4,4-dimethylhept-6-enoate following the same reaction sequence as described for the synthesis of intermediate NJ.

[0120] Intermediate No.: [ka] Prepared from intermediate NR and ethyl 6-heptaenoate following the same reaction sequence as described for the synthesis of intermediate NJ.

[0121] Intermediate NP: [ka] Intermediate NU was reacted according to general procedure Int-E to give the title compound. ESI-MS: 414 [M+H] + R t (HPLC): 0.55 min (Method B) Intermediate NQ: [ka] tert-Butyl (2S,4S)-1-[4-(7-ethoxy-7-oxohept-1-en-2-yl)-8-oxa-3,5-diazatricyclo[7.4.0.0]] formed as a by-product in step 1 of the synthesis of intermediate NO 2,7 ]trideca-1(13),2,4,6,9,11-hexaen-6-yl]-4-hydroxypyrrolidine-2-carboxylate was isolated by RP HPLC and further reacted according to the reaction sequence described for the preparation of intermediate NO to give the title compound.

[0122] Intermediate NR: 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]

[0123] 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) and phosphoryl tribromide (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 sodium bicarbonate solution while cooling at 0 °C. The mixture was extracted with EtOAc (3 × 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 based on the weight of the crude product) and EtOAc (3 volumes based on 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] + R t (HPLC): 0.67 min (Method A)

[0124] 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, tert-butyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (4.17 g, 16.6 mmol) and potassium carbonate (7.03 g, 50.8 mmol) were added. 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] + R t (HPLC): 0.64 min (Method A)

[0125] Intermediate NS: [ka]

[0126] 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.

[0127] 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 NT: [ka]

[0128] 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. 1 H 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) 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] +

[0129] 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.

[0130] 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)

[0131] 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)

[0132] Intermediate NU: 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 [ka]

[0133] 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 aqueous hydrochloric acid (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 hours. 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 hours. 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 [M+H] + R t (HPLC): 0.63 min (Method B)

[0134] 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 phosphoryl trichloride (50.0 mL; 547 mmol) 2,7 A mixture of 1,3-dimethyl-2,4-trideca-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 hours. The reaction mixture was cooled to room temperature and added dropwise to an ice bath (500 mL) with stirring over 30 minutes. Ethyl acetate was added and the layers were separated. Saturated bicarbonate solution was slowly added 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 [M+H] + R t (HPLC): 0.43 min (Method A)

[0135] 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 {2,500 g}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) and DIPEA (27.0 mmol; 4.64 mL) were added, and the resulting 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 [M+H] + R t(HPLC): 0.67 min (Method B)

[0136] Intermediate NV: [ka] 11-Fluoro-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ] prepared from trideca-1(13),2(7),9,11-tetraene-4,6-dione following the same reaction sequence as described for the synthesis of intermediate NR. 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 ] was prepared in a manner similar to the synthesis of trideca-1(13),2(7),9,11-tetraene-4,6-dione.

[0137] Preparation of final compounds The absolute configuration of the piperidine moiety of compounds (where R2 is a methyl group) was assigned in some cases (e.g., Example 1.01) 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). In other cases, the absolute configuration was assigned based on the premise that the more potent diastereoisomer always has the (S,S,S,S)-configuration.

[0138] Example 1.01 (General Procedures A, B, C, D) [ka]

[0139] Step 1 (General Procedure A): To intermediate NA (216 mg; 0.418 mmol) and intermediate B-01 (188 mg; 0.439 mmol) dissolved in DMA (4.05 mL) in oven-dried glassware under an argon atmosphere was added sodium hydride (55% in mineral oil; 73.0 mg; 1.67 mmol). After the bubbling subsided, the reaction was warmed to 35 °C and stirred for an additional 25 min. The reaction was then quenched by the addition of ice-water, diluted with EtOAc, and acidified by the addition of aqueous hydrochloric acid (1 M; 1.7 mL). The mixture was extracted three times with EtOAc, and the combined organic layers were washed subsequently with water and brine and evaporated to dryness. The crude reaction mixture was purified by FC (silica gel; cyclohexane / EtOAc 25% to 100%). ESI-MS: 833 [M+H] + R t (HPLC): 0.92 min (Method B)

[0140] Step 2 (General Procedure B): To a mixture of the intermediate from Step 1 (272 mg; 0.326 mmol) and ACN (10 mL), TosOH (124 mg; 0.653 mmol) was added, and the mixture was stirred at room temperature in a closed vial for 3 days. Because HPLC reaction control showed low conversion, additional TosOH (45.0 mg; 0.237 mmol) was added, and the mixture was further heated at 40 °C until HPLC reaction control showed high conversion to the desired product. DMF and a drop of water were added, and the mixture was then filtered and subjected to HPLC purification (Sunfire C18; ACN / water, TFA as modifier). ESI-MS: 733 [M+H] + R t (HPLC): 0.62 min (Method B)

[0141] Step 3 (General Procedure C): In oven-dried glassware under argon, a solution of HATU (81.2 mg; 0.214 mmol) in DMF (4 mL) was slowly added with a syringe pump to a solution of the intermediate from step 2 (145 mg; 0.198 mmol) in DMF (12 mL) under vigorous stirring. The mixture was further stirred until reaction control by HPLC showed high conversion to the desired product. The reaction was then quenched by the addition of water and extracted three times with EtOAc. The combined organic layers were subsequently washed with water and brine and evaporated to dryness. The crude reaction mixture was purified by FC (cyclohexane / EtOAc 50% → 100%, then EtOAc / MeOH 0% → 10%). ESI-MS: 715 [M+H] + R t (HPLC): 0.80 min (Method B)

[0142] Step 4 (General Procedure D): A mixture of the Step 3 intermediate (79.0 mg; 0.110 mmol), DCM (1.06 mL), and TFA (852 μL) was stirred at room temperature for 90 minutes. Because HPLC control of the reaction indicated low conversion, the temperature was increased to 37 °C and stirring was continued for 3 hours. Because HPLC control of the reaction still indicated low conversion, the temperature was increased to 45 °C and stirring was continued until HPLC control indicated high conversion to the desired product. The mixture was evaporated, and the crude product was purified by preparative HPLC (Sunfire C18; ACN / water, TFA as modifier). ESI-MS: 659 [M+H] + R t (HPLC): 0.83 min (Method E)

[0143] In a similar manner to Example 1.01 above, the following compounds were prepared following general procedures A, B, C, and D: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8]

[0144] Example 2.01 [ka]

[0145] Step 1: Intermediate B-09 was reacted according to general procedure D to give the TFA salt of rac-trans-7-chloro-2-methanesulfonyl-1-[3-methylpiperidin-4-yl]-1H-1,3-benzodiazole.

[0146] Step 2: The product of Step 1 was reacted with 1.2 equivalents of 4-{[(tert-butoxy)carbonyl]amino}butanoic acid according to general procedure C.

[0147] Step 3: The product of step 2 is reacted with intermediate NP according to general procedure A to give 2-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-({1-[1-(4-{[(tert-butoxy)carbonyl]amino}butanoyl)-3-methylpiperidin-4-yl]-7-chloro-1H-1,3-benzodiazol-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}acetic acid (with the racemic trans configuration of the piperidine moiety) was obtained.

[0148] Step 4: The product of step 3 was deprotected by reaction with 1.5 equivalents of hydrochloric acid (4 M in dioxane) in dioxane at room temperature overnight. The crude product was purified by RP HPLC (Sunfire C18; ACN / water / modifier: TFA) to give 2-{6-[(2S,4S)-4-({1-[1-(4-aminobutanoyl)-3-methylpiperidin-4-yl]-7-chloro-1H-1,3-benzodiazol-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 TFA salt (with racemic trans configuration of the piperidine moiety) was obtained.

[0149] Step 5: The product of Step 4 is reacted according to General Procedure C to give tert-butyl(12S,14S)-4-chloro-37-methyl-29,34-dioxo-11,18-dioxa-2,9,15,26,30,35,40-heptaazaoctacyclo[33.2.2.1 12,15 .1 16,27 .0 2,10 .0 3,8 .0 17,25 .0 19,24 ] to give hentetraconta-3,5,7,9,16(40),17(25),19(24),20,22,26-decene-14-carboxylate (with the racemic trans configuration of the piperidine moiety).

[0150] Step 6: The product of Step 5 is reacted according to general procedure D to give the title compound (12S,14S)-4-chloro-37-methyl-29,34-dioxo-11,18-dioxa-2,9,15,26,30,35,40-heptaazaoctacyclo[33.2.2.112,15 .1 16,27 .0 2,10 .0 3,8 .0 17,25 .0 19,24 ] to give hentetraconta-3,5,7,9,16(40),17(25),19(24),20,22,26-decene-14-carboxylic acid (with the racemic trans configuration of the piperidine moiety). ESI-MS: 672 [M+H] + R t (HPLC): 0.88 min (Method E)

[0151] Example 3.01 [ka]

[0152] Step 1: Intermediate I.02 was BOC-deprotected according to general procedure B to give tert-butyl(2S,4S)-1-{4-[1,1-difluoro-2-(prop-2-en-1-yloxy)ethyl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-1(13),2,4,6,9,11-hexaen-6-yl}-4-({1-[(3S,4S)-3-methylpiperidin-4-yl]-1H-1,3-benzodiazol-2-yl}oxy)pyrrolidine-2-carboxylate TFA salt was obtained. ESI-MS: 689 [M+H] + R t (HPLC): 0.62 min (Method A)

[0153] Step 2: General Procedure G: To a solution of the product of Step 1 (105 mg; 0.127 mmol), vinylacetic acid (14.5 μL; 0.165 mmol), and DMAP (2.0 mg; 0.016 mmol) in DCM (1.05 mL) at 0 °C, DCC (1 M; 165 μL; 0.165 mmol) was added dropwise. With stirring, the mixture was allowed to warm to room temperature and then stirred for another hour. The mixture was evaporated to dryness, and the residue was subjected to FC (CH / EtOAc 40% → 100%). The resulting impure product was further purified by RP HPLC (Sunfire C18; ACN / water, modifier: TFA) to give tert-butyl(2S,4S)-4-({1-[(3S,4S)-1-(but-3-enoyl)-3-methylpiperidin-4-yl]-1H-1,3-benzodiazol-2-yl}oxy)-1-{4-[1,1-difluoro-2-(prop-2-en-1-yloxy)ethyl]-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: 757 [M+H] + R t (HPLC): 0.77 min (Method A)

[0154] Step 3: General Procedure H: To a solution of the product of Step 2 (dried by azeotropic co-distillation with toluene; 77.0 mg; 0.102 mmol) in 1,2-dichloroethane (degassed; 9.0 ml) in an oven-dried glass vessel, catalyst Grubbs II (5.0 mg) was added. The mixture was stirred at 80 °C for 24 h, then the same amount of catalyst was added again, and the mixture was stirred for another 24 h. The reaction was quenched by the addition of imidazole (10 mg) and then allowed to cool to room temperature. The mixture was concentrated and subjected to FC (silica gel; CH / EtOAc 20% to 100%) to give tert-butyl(1S,12S,14S,32E,38S)-28,28-difluoro-38-methyl-35-oxo-11,18,30-trioxa-2,9,15,26,36,41-hexaazaoctacyclo[34.2.2.1]. 12,15.1 16,27 .0 2,10 .0 3,8 .0 17,25 .0 19,24 ]dotetraconta-3(8),4,6,9,16(41),17(25),19,21,23,26,32-undecene-14-carboxylate was obtained. ESI-MS: 729 [M+H] + R t (HPLC): 0.73 min (Method A)

[0155] Step 4: A mixture of the product of Step 3 (22.0 mg; 0.0302 mmol), ethanol (1.5 mL), and Pd / C 10% was kept under hydrogen (5 psi) in a Parr apparatus overnight. The mixture was filtered, evaporated, and taken on to the next step. ESI-MS: 731 [M+H] + R t (HPLC): 1.09 min (Method E)

[0156] Step 5: The product of step 4 (22.1 mg) was reacted according to general procedure D. The product was further purified by RP HPLC (Sunfire C18, ACN / water, modifier: TFA). ESI-MS: 675 [M+H] + R t (HPLC): 0.60 min (Method A)

[0157] Example 4.01 [ka]

[0158] Step 1: To a degassed solution of intermediate I.02 (150 mg; 0.190 mmol) in ethyl acrylate (1.56 mL; 14.3 mmol) was added Grubbs II catalyst (8.1 mg; 0.0095 mmol). The mixture was stirred for 24 h, then evaporated and subjected to FC (CH / EtOAc 30% to 100%) to give tert-butyl(3S,4S)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-[4-(2-{[4-ethoxy-4-oxobut-2-en-1-yl]oxy}-1,1-difluoroethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0]. 2,7 ]trideca-1(13),2,4,6,9,11-hexaen-6-yl]pyrrolidin-3-yl]oxy}-1H-1,3-benzodiazol-1-yl)-3-methylpiperidine-1-carboxylate was obtained. ESI-MS: 861 [M+H] + R t (HPLC): 1.28 minutes (Method B)

[0159] Step 2: General Procedure E A mixture of the product of Step 1 (140 mg; 0.163 mmol), Pd / C 10% (28 mg), and ethanol (2.0 mL) was reacted in a Parr apparatus at room temperature under hydrogen (50 psi) until HPLC control showed conversion of the starting material (4 h). The mixture was filtered, concentrated under reduced pressure, and subjected to purification by RP HPLC (XBridge C18, ACN / water, modifier: TFA) to give tert-butyl(3S,4S)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-{4-[2-(4-ethoxy-4-oxobutoxy)-1,1-difluoroethyl]-8-oxa-3,5-diazatricyclo[7.4.0.0]. 2,7 ]trideca-1(13),2,4,6,9,11-hexaen-6-yl}pyrrolidin-3-yl]oxy}-1H-1,3-benzodiazol-1-yl)-3-methylpiperidine-1-carboxylate was obtained. ESI-MS: 863 [M+H] + R t (HPLC): 1.28 minutes (Method B)

[0160] Step 3: General Procedure F The product of Step 2 (118 mg; 0.137 mmol) was dissolved in a mixture of aqueous lithium hydroxide (2 M; 153 μL; 0.306 mmol), MeOH (0.80 mL), and THF (4.0 mL). The mixture was stirred at 40 °C until HPLC analysis showed conversion (7 h), concentrated under reduced pressure, diluted with water, and acidified with an equimolar amount of aqueous hydrochloric acid. One drop of methanol was added, and the mixture was extracted with DCM. The organic layer was separated, concentrated under reduced pressure, and used in the next step.

[0161] Step 4: The product of Step 3 is reacted according to General Procedure B to give 4-(2-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-({1-[(3S,4S)-3-methylpiperidin-4-yl]-1H-1,3-benzodiazol-2-yl}oxy)pyrrolidin-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0] 2,7 ]trideca-1(13),2,4,6,9,11-hexaen-4-yl}-2,2-difluoroethoxy)butanoic acid was obtained.

[0162] Step 5: The product of Step 4 is reacted according to General Procedure C to give tert-butyl(1S,12S,14S,37S)-28,28-difluoro-37-methyl-34-oxo-11,18,30-trioxa-2,9,15,26,35,40-hexaazaoctacyclo[33.2.2.1 12,15 .1 16,27 .0 2,10 .0 3,8 .0 17,25 .0 19,24 ]hentetraconta-3,5,7,9,16,19,21,23,25,27(40)-decene-14-carboxylate was obtained. Step 6: The product of Step 5 was reacted according to general procedure D to give the title compound. ESI-MS: 661 [M+H] + R t (HPLC): 0.90 min (Method B)

[0163] Example 5.01 [ka] Starting from intermediates NS and B-11, the synthesis was carried out applying the following reaction sequence:

[0164] Step 1: Aromatic nucleophilic substitution applying general procedure A (reagents: NS and B-11) Step 2: BOC deprotection applying general procedure B Step 3: Reaction with 4-pentenoic acid applying general procedure G Step 4: Metathesis applying general procedure H Step 5: Hydrogenation applying general procedure E Step 6: tert-Butyl ester deprotection applying general procedure D ESI-MS: 643 [M+H] + R t (HPLC): 0.58 min (Method A)

[0165] Example 6.01 [ka] Starting from intermediates NT and B-02, the synthesis was carried out applying the following reaction sequence:

[0166] Step 1: Aromatic nucleophilic substitution applying general procedure A (reagents: NT and B-02) Step 2: Metathesis using methyl 3-butenoate as the second olefin, applying a modification of general procedure H (15 equivalents of methyl 3-butenoate in DCM at room temperature, followed by the addition of another 15 equivalents of methyl 3-butenoate after 24 hours and an additional 0.3 equivalents of catalyst in small portions).

[0167] Step 3: Hydrogenation applying general procedure E (solvent: EtOAc)

[0168] Step 4: Ester saponification applying general procedure F (aqueous lithium hydroxide / THF, 50°C, 5 h) Step 5: BOC deprotection applying general procedure B Step 6: Ring-closing amidation applying general procedure C (solvent: DMA) Step 7: tert-Butyl ester deprotection applying general procedure D ESI-MS: 695 [M+H] + R t (HPLC): 0.72 min (Method A)

[0169] Example 7.01 [ka] Starting from intermediates NR and B-10, the synthesis was carried out applying the following reaction sequence: Step 1: Aromatic nucleophilic substitution applying general procedure A (reagents: NR and B-10) Step 2: BOC deprotection applying general procedure B Step 3: Amidation with (3R)-3-prop-3-en-1-yloxy)butanoic acid applying general procedure C

[0170] Step 4: To a degassed solution (under argon) of the product of Step 3 (162 mg; 0.213 mmol), cesium carbonate (174 mg; 0.533 mmol), and silver iodide (55.1 mg; 0.235 mmol) in dioxane was added the catalyst [1,1'-BIS(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (21.3 mg; 0.0320 mmol). The mixture was stirred at 120 °C for 24 h and then allowed to cool to room temperature. The mixture was diluted with ACN / methanol, filtered and purified by preparative RP HPLC (XBridge C18, ACN / water, modifier: TFA) to give tert-butyl (12S,14S,32R)-32-methyl-34-oxo-11,18,31-trioxa-2,9,15,26,35,40-hexaazaoctacyclo[33.2.2.1 12,15 .1 16,27 .0 2,10 .0 3,8 .0 17,25 .0 19,24 ]hentetraconta-3(8),4,6,9,16(40),17(25),19(24),20,22,26,28-undecene-14-carboxylate was obtained. ESI-MS: 679 [M+H] + R t (HPLC): 0.60 min (Method A)

[0171] Step 5: Hydrogenation applying general procedure E

[0172] Step 6: tert-Butyl ester deprotection applying general procedure D ESI-MS: 625 [M+H] + R t (HPLC): 0.47 min (Method A) Example 8.01 [ka] Starting from intermediates NS and B-10, the synthesis was carried out applying the following reaction sequence:

[0173] Step 1: Aromatic nucleophilic substitution applying general procedure A (reagents: NS and B-10)

[0174] Step 2: Reaction under argon. To a degassed mixture of the product of Step 1 (381 mg; 0.500 mmol), nickel(II) chloride (3.3 mg; 0.025 mmol), sodium carbonate (53 mg; 0.50 mmol), and anhydrous DMF (4.77 ml) was added ethyl bromodifluoroacetate (209 mg; 1.00 mmol) and phenylsilane (223 mg; 2.00 mmol) at room temperature. The mixture was stirred in a sealed vessel at 70 °C for 14 h. The mixture was poured into saturated brine, and the resulting mixture was extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and evaporated. The crude product was purified by preparative RP HPLC (XBridge C18; ACN / water, modifier: TFA) to give tert-butyl 4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-(4-{[(5-ethoxy-4,4-difluoro-5-oxopentyl)oxy]methyl}-8-oxa-3,5-diazatricyclo[7.4.0.0] 2,7 ]trideca-1(13),2,4,6,9,11-hexaen-6-yl)pyrrolidin-3-yl]oxy}-1H-1,3-benzodiazol-1-yl)piperidine-1-carboxylate was obtained. ESI-MS: 649 [M+H] + R t (HPLC): 0.80 min (Method A) Step 3: Ester saponification applying general procedure F (aqueous lithium hydroxide / THF, room temperature, 2.5 h)

[0175] Step 4: BOC deprotection applying general procedure B Step 5: Ring-closing amidation using HATU in DMF applying general procedure C Step 6: tert-Butyl ester deprotection applying general procedure D ESI-MS: 647 [M+H] + Rt (HPLC): 0.53 min (Method A) Example 9.01 [ka] Starting from intermediates NR and B-10, the synthesis was carried out applying the following reaction sequence:

[0176] Step 1: Aromatic nucleophilic substitution applying general procedure A (reagents: NR and B-10) Step 2: General Procedure I: Under argon, palladium(II)-acetate (9.0 mg; 0.040 mmol) and tri-o-tolylphosphine (24.4 mg; 0.080 mmol) were added to a degassed solution of the product of Step 1 (326 mg; 0.400 mmol), allyloxy-acetic acid (133 μL; 1.20 mmol), and triethylamine (112 μL; 0.800 mmol) in DMF (6.52 mL). The vial was sealed, and the reaction mixture was stirred at 115° C. for 2.5 h. The reaction mixture was diluted with ACN / H2O, filtered, and directly purified by preparative RP HPLC (XBridge C18; 30-100% ACN / H2O, modifier: ammonia) to give 2-{[(3-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-[(1-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}-1H-1,3-benzodiazol-2-yl)oxy]pyrrolidin-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0] 2,7 ]trideca-1(13),2,4,6,9,11-hexaen-4-yl}prop-2-en-1-yl]oxy}acetic acid was obtained as a mixture of E / Z isomers. ESI-MS: 769 [M+H] + R t (HPLC): 0.57 / 0.58 min (Method F)

[0177] Step 3: Hydrogenation applying general procedure E (solvent: EtOAc) Step 4: BOC deprotection applying general procedure B Step 5: Ring-closing amidation using HATU in DMF applying general procedure C Step 6: tert-Butyl ester deprotection applying general procedure D ESI-MS: 597 [M+H] + R t (HPLC): 0.42 min (Method A)

[0178] (Examples 10.01 and 10.02) [ka] Starting from intermediates NR and I.03, the synthesis was carried out applying the following reaction sequence:

[0179] Step 1: Aromatic nucleophilic substitution applying general procedure A (reagents: NR and I.03) Step 2: Intramolecular Heck coupling applying general procedure I (reaction time 17 h; 100 °C) Step 3: Hydrogenation applying general procedure E (catalyst: Raney-Ni; solvent: methanol) Step 4: tert-Butyl ester deprotection applying general procedure D Step 5: The resulting diastereomeric mixture was separated by preparative SFC (apparatus: Sepiatec PrepSFC50; column: CHIRAL ART Cellulose-SC (10 mm × 250 mm, 5 μm); mobile phase: A CO and B IPA [+20 mM NH]; gradient: B% = 25% isocratic elution mode; flow rate: 15 mL / min; wavelength: 220 nm; column temperature: 40 °C; system back pressure: 150 bar). Example 10.01 (First eluting) ESI-MS: 625 [M+H] + R t (HPLC): 0.804 min (Method E) Example 10.02 (Second-Eluting) ESI-MS: 625 [M+H] + R t (HPLC): 0.814 min (Method E)

[0180] Example 11.01 [ka] Starting from intermediates NR and B-10, the synthesis was carried out applying the following reaction sequence:

[0181] Step 1: Aromatic nucleophilic substitution applying general procedure A (reagents: NR and B-10) Step 2: A mixture of the product of Step 1 (500 mg; 0.682 mmol), 1,4-butanediol (1.22 mL; 13.6 mmol), potassium tert-butylate (229 mg; 2.04 mmol), and ACN (10 mL; dried over molecular sieves) was stirred overnight at 80 °C in a sealed vial. The mixture was evaporated, and the residue was purified by RP HPLC (Sunfire C18, ACN / water, modifier: TFA) to give tert-butyl 4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-[4-(4-hydroxybutoxy)-8-oxa-3,5-diazatricyclo[7.4.0.0]. 2,7 ]trideca-1(13),2,4,6,9,11-hexaen-6-yl]pyrrolidin-3-yl]oxy}-1H-1,3-benzodiazol-1-yl)piperidine-1-carboxylate was obtained. ESI-MS: 743 [M+H] + R t (HPLC): 0.70 min (Method A)

[0182] Step 3: A mixture of the product of Step 2 (143 mg; 0.193 mmol), 4-nitrophenyl chloroformate (87.1 mg; 0.424 mmol), pyridine (103 μL; 1.27 mmol), and DCM (6.0 mL) was stirred at room temperature for 4 h. The volatiles were evaporated and the crude product was used in the next step without further purification. Step 4: Acidic BOC deprotection was carried out applying the conditions of general procedure D. Step 5: For the carbamate-forming ring closure, the crude product of step 4 was dissolved in excess DIPEA and stirred for 90 min at 70° C. The mixture was evaporated and taken to the next step without purification.

[0183] Step 6: Step 4: tert-Butyl ester deprotection applying general procedure D ESI-MS: 613 [M+H] + R t (HPLC): 0.50 min (Method A)

[0184] Example 12.01 Racemic mixture of trans isomers: [ka]

[0185] Step 1: To a mixture of tert-butyl-3-(2-hydroxyethoxy)propanoate (1.45 g; 7.62 mmol), pyridine (663 mg; 8.38 mmol), and DCM (15 mL) cooled to 0 °C, a solution of 4-nitrophenyl-chloroformate (1.54 g; 7.62 mmol) in DCM (15 mL) was added dropwise. The mixture was stirred at room temperature overnight, then diluted with DCM and extracted with water. The organic layer was evaporated and the crude product was used in the next step.

[0186] Step 2: A mixture of the crude product of Step 1 (686 mg), Intermediate B-12 (500 mg), diisopropyl-ethylamine (742 μL), and THF (8.0 mL) was refluxed for 2 h. The mixture was evaporated, dissolved in EtOAc, extracted twice with aqueous sodium hydroxide (1 M), and then washed with water and brine. The organic layer was evaporated to dryness, and the reaction crude was purified by FC (silica gel; petroleum ether / EtOAc 5% → 35%) to give racemic trans-tert-butyl 2-{3-[3-methyl-4-[2-(methylsulfanyl)-1H-1,3-benzodiazol-1-yl]piperidine-1-carbonyloxy]propoxy}acetate. ESI-MS: 478 [M+H] + R t (HPLC): 0.85 min (Method E)

[0187] Step 3: Acid ester cleavage applying general procedure D without chromatographic purification. Step 4: To a solution of the product of Step 3 (579 mg) in ACN (10 mL) was added 1-chloro-N,N,2-trimethylpropenylamine (259 μL; 3.92 mmol) at room temperature. The mixture was stirred overnight, evaporated, dissolved in DCM, and extracted with water. The organic layer was evaporated and subjected to FC (silica gel; petroleum ether / EtOAc 45% to 95%). ESI-MS: 580 [M+H] + R t (HPLC): 0.81 min (Method E)

[0188] Step 5: The product of Step 4 (650 mg; 1.12 mmol) was suspended in aqueous sodium hydroxide (4 M; 15 mL). The mixture was stirred at 60 °C for 1 h, then allowed to cool to room temperature and then acidified by the addition of aqueous hydrochloric acid (4 M). The supernatant was decanted and the solid was subjected to purification by RP HPLC (Sunfire C18, ACN / water, modifier: TFA). ESI-MS: 562 [M+H] + R t (HPLC): 0.76 min (Method E)

[0189] Step 6: The product of Step 5 (390 mg; 0.694 mmol) was suspended in phosphoryl trichloride (6 mL). The mixture was stirred at 90° C. for 1 h and then evaporated. Water was carefully added to the residue, and the resulting mixture was extracted with EtOAc. The organic layer was separated and evaporated to dryness to give racemic trans-3-({6-chloro-8-oxa-3,5-diazatricyclo[7.4.0.0])-4-(4-chloro ... 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}methoxy)propyl-3-methyl-4-[2-(methylsulfanyl)-1H-1,3-benzodiazol-1-yl]piperidine-1-carboxylate was obtained. ESI-MS: 580, 582 [M+H] + R t (HPLC): 0.89 min (Method E) Step 7: A mixture of the product of Step 6 (300 mg; 0.517 mmol), tert-butyl (2S,4S)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (142 mg; 0.621 mmol), potassium carbonate (173 mg; 1.19 mmol), and DMF (7.0 mL) was stirred at room temperature overnight. Water was added, and the precipitate was collected and purified by RP HPLC (Sunfire C18, ACN / water, modifier: TFA) to give 3-({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}methoxy)propyl-3-methyl-4-[2-(methylsulfanyl)-1H-1,3-benzodiazol-1-yl]piperidine-1-carboxylate (with the racemic trans configuration of the piperidine moiety) was obtained. ESI-MS: 731 [M+H] + R t (HPLC): 0.77 min (Method E)

[0190] Step 8: The product of Step 7 (239 mg; 0.327 mmol) was dissolved in DCM (8.0 mL). m-Chloroperbenzoic acid (77%; 161 mg; 0.719 mmol) was added, and the mixture was stirred for 2 h and then washed with sodium bicarbonate solution. The organic layer was evaporated to give 3-({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}methoxy)propyl-4-(2-methanesulfonyl-1H-1,3-benzodiazol-1-yl)-3-methylpiperidine-1-carboxylate (with the racemic trans configuration of the piperidine moiety) was obtained. ESI-MS: 763 [M+H] + R t (HPLC): 0.85 min (Method E)

[0191] Step 9: Cyclization by aromatic nucreophilic substitution applying general procedure A.

[0192] Step 10: Acidic tert-butyl ester cleavage applying general procedure D affords the title compound. ESI-MS: 627 [M+H] + R t (HPLC): 0.83 min (Method E)

[0193] Example 13.01 [ka]

[0194] Step 1: To an ice-cold solution of N-methyl-(pent-4-en-1-yl)amine (500 mg; 4.79 mmol) in aqueous sodium carbonate (2 M; 4.79 mL; 9.58 mmol) was added dropwise benzyl chloroformate (774 μL; 5.27 mmol). The mixture was stirred at 0 °C for 1 h, then diluted with water and extracted three times with EtOAc. The combined organic layers were washed with water, then with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by FC (silica gel; cyclohexane / EtOAc 25% to 100%). ESI-MS: 234 [M+H] + R t (HPLC): 0.67 min (Method A)

[0195] Step 2: Reaction in oven-dried glassware under argon. To a mixture of the product of Step 1 (191 mg; 0.778 mmol), Intermediate I.01 (200 mg; 0.259 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (20.2 mg; 0.0311 mmol), and pre-degassed DMA (2.4 mL) was added triethylamine (180 μL; 1.30 mmol). The reaction mixture was degassed and then heated to 115 °C in a sealed vial for 10 h. The mixture was evaporated and the residue was subjected to purification by preparative RP HPLC (XBridge C18, ACN / water, modifier: ammonia) to give tert-butyl(3S,4S)-4-(2-{[(3S,5S)-1-{4-[5-{[(benzyloxy)carbonyl](methyl)amino}pent-1-en-1-yl]-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}-1H-1,3-benzodiazol-1-yl)-3-methylpiperidine-1-carboxylate was obtained.

[0196] Step 3: Hydrogenation (including Cbz deprotection) applying general procedure E without chromatographic purification. Step 4: To a solution of the crude product of step 3 (199 mg) in DCM (3 mL) were added triethylamine (125 μL; 1.04 mmol) and 4-nitrophenyl chloroformate (53 mg; 0.26 mmol). The mixture was stirred at room temperature for 1 h. The mixture was evaporated and subjected to purification by FC (cyclohexane / EtOAc 20% → 100%) to give tert-butyl(3S,4S)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-[4-(5-{methyl[(4-nitrophenoxy)carbonyl]amino}pentyl)-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}-1H-1,3-benzodiazol-1-yl)-3-methylpiperidine-1-carboxylate was obtained. Step 5: BOC deprotection applying general procedure B Step 6: The crude product of Step 5 was added dropwise via syringe pump to a solution of N,N-diisopropylethylamine (49 μL) in THF (1.5 mL) over 25 min. The mixture was stirred at 80° C. for 10 h. The mixture was passed through a sodium bicarbonate cartridge and evaporated. N-methylpyrrolidone (3.0 mL) and DIPEA (100 μL) were added, and the mixture was heated to 180° C. in a microwave oven for 30 min. The mixture was subjected to purification by RP HPLC (XBridge C18, ACN / water, modifier: TFA). ESI-MS: 695 [M+H] + R t (HPLC): 0.61 min (Method A)

[0197] Step 7: tert-butyl ester cleavage applying general procedure D gives the title compound. ESI-MS: 638 [M+H]+ R t (HPLC): 0.55 min (Method A)

[0198] 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.

[0199] List of Abbreviations [Table 3]

[0200] Analysis method (HPLC / SFC): [Table 4]

[0201] [Table 5]

[0202] [Table 6]

[0203] [Table 7]

[0204] [Table 8]

[0205] [Table 9]

[0206] [Table 10]

[0207] [Table 11]

[0208] [Table 12] [Example]

[0209] 4. Example 5.1 Example Compounds of Formula I, II, or III of the Invention The following example compounds of Formula I, II, or III, summarized in Table 1, were synthesized and tested for their pharmacological properties with respect to their potency 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.

[0210] The example compounds of formula I, II, or III summarized in Table 1 simultaneously exhibit the following three properties: Satisfactory biochemical (in vitro) IC for cGAS inhibition 50hcGAS 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).

[0211] Additionally, exemplified compounds of Formula I, II, or III exhibit acceptable IC values ​​for inhibition of IFN induction in dsDNA-stimulated human whole blood. 50 Value (hWB IC 50 ) is also shown.

[0212] [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5] [Table 13-6] [Table 13-7]

[0213] 5.2 Comparison of Example Compounds of Formula I, II, or III 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).

[0214] 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 exact 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).

[0215] [Table 14-1] [Table 14-2]

[0216] 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 50 With 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. 50value" (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

[0217] 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 50 Compound 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

[0218] 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.

[0219] [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 50 These values ​​are clearly superior to compound No. 5 of WO 2022 / 174012 (all below 1000 nM for compounds of formula I, II, or III of the invention).

[0220] 5.3 Prodrugs It is known that esters of active agents with carboxylic acid groups can represent viable prodrugs, for example, 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.

[0221] Additionally, experimental indications have been found that the methyl esters of the example compounds of Formula I, II, or III also represent viable prodrugs of the cGAS inhibitors of Formula I, II, or III. 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).

[0222] 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 The IC values ​​of the example compounds are always extremely high, generally higher than 7000 nM. 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).

[0223] 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.

[0224] 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.

[0225] 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, II, or III 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, II, or III will also act as prodrugs.

[0226] [Table 16-1] [Table 16-2] [Table 16-3]

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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

[0233] 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).

[0234] 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).

[0235] 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

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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

[0240] 6. Indications As can be seen, the compounds of formula I, II, or III are characterized by their range of therapeutic applications. Particular mention should be made of the use of the compounds of formula I, II, or III 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.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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).

[0245] 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.

[0246] Additionally, cGAS inhibitors of Formula I, II, or III also 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, II, or III 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). Additionally, cGAS inhibitors of Formula I, II, or III 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."

[0247] Additionally, cGAS inhibitors of Formula I, II, or III 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, II, or III 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."

[0248] Additionally, cGAS inhibitors of Formula I, II, or III 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, II, or III 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, II, or III 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).

[0249] As a result, the compounds of Formula I, II, or III 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, II, or III 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, II, or III 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.

[0250] 7. combination The compounds of Formula I, II, or III can be administered to a patient alone or in combination with one or more other pharmacologically active agents. In preferred embodiments of the invention, the compounds of formula I, II or III 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.

[0251] 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.

[0252] 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.

[0253] 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, II or III according to the above preferred embodiments.

[0254] It is particularly preferred that the compound of formula I, II, or III 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.

[0255] 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.

[0256] 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 selected from the group consisting of hydrogen, methyl, and halogen; A is -CH 2 -, -O-, -CF 2 -, -CHF-, -N(CH 3 )-, -NH-, and -CHCH 3 - selected from the group consisting of D is -CH 2 -, -O-, -CF 2 -, -CHF-, and -CHCH 3 - selected from the group consisting of E is -CH 2 -, -O-, -C(CH 3 ) 2 -, -CHF-, CF 2 - and -CHCH 3 - selected from the group consisting of G is -NH-, -NCH 3 -, -CH 2 -, -O-, -CF 2 -, -CHF-, -CHCH 3 -, and -C(CH 3 ) 2 is selected from the group consisting of J is -CO-, -CH 2 -, -O-, -CHF-, -CF 2 - and -CHCH 3 - selected from the group consisting of K is -CH 2 -, -CF 2 -, -O-, or absent; L is -CH 2 -, -O-, -CHCH 3 -, -CHF-, -CF 2 - or absent)

2. R 1 is selected from the group consisting of hydrogen, Cl, and F; R 2 is selected from the group consisting of hydrogen and methyl; R 3 is selected from the group consisting of hydrogen, methyl, Cl, and F; A is -CH 2 -, -O-, -CF 2 -, and -N(CH 3 )- is selected from the group consisting of D is -CH 2 -, -O-, and -CHCH 3 - selected from the group consisting of E is -CH 2 -, -O-, and -C(CH 3 ) 2 - selected from the group consisting of G is -NH-, -CH 2 -, -O-, -CHCH 3 - selected from the group consisting of J is -CO-, -CH 2 -, -O-, and -CHCH 3 - selected from the group consisting of K is -CH 2 -, -CF 2 -, -O-, or absent; L is -CH 2 -, -CF 2 - or absent, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

3. 3. The compound of formula I according to claim 1 or 2, and prodrugs, deuterated analogues, and pharmaceutically acceptable salts thereof, wherein L is absent.

4. L is absent and A is -CH 2 - and -CF 2 3. A compound of formula I according to claim 1 or 2, selected from the group consisting of: - and a prodrug thereof, a pharmaceutically acceptable salt thereof, or a deuterated analog thereof.

5. L is absent and K is -CF 2 3. The compound of formula I according to claim 1 or 2, wherein -, and prodrugs, deuterated analogues and pharmaceutically acceptable salts thereof.

6. R 3 6. The compound of formula I according to any one of claims 1 to 5, and prodrugs, deuterated analogues and pharmaceutically acceptable salts thereof, wherein is halogen.

7. R 3 7. The compound of formula I according to claim 6, wherein is Cl or F, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

8. R 3 8. The compound of formula I according to claim 7, wherein is Cl or F and is located at the 5-position of the benzimidazole moiety, and prodrugs, deuterated analogues, and pharmaceutically acceptable salts thereof.

9. R 1 9. The compound of formula I according to any one of claims 1 to 8, and prodrugs, deuterated analogues and pharmaceutically acceptable salts thereof, wherein is halogen.

10. R 1 10. The compound of formula I according to claim 9, wherein is Cl or F, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

11. R 1 9. The compound of formula I according to any one of claims 1 to 8, and prodrugs, deuterated analogues and pharmaceutically acceptable salts thereof, wherein is hydrogen. 【Request Item 12】 【Chemistry 2-1】 【Chemistry 2-2】 3. The compound of formula I according to claim 1 or 2, selected from the group consisting of: and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

13. A is -CH 2 - and -CF 2 - selected from the group consisting of D and E are each —CH 2 - and G is -CH 2 - and -O-; J is -CH 2 - and -O-; K is -CF 2 - and -CH 2 - selected from the group consisting of 3. The compound of formula I according to claim 1 or 2, and prodrugs, deuterated analogues, and pharmaceutically acceptable salts thereof, wherein L is absent. 【Request Item 14】 【Chemistry 3】 14. The compound of formula I according to claim 13, selected from the group consisting of: and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

15. R 2 2. The compound of formula I according to claim 1, wherein is methyl, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

16. A compound of formula II according to claim 15 【Chemistry 4】 or a compound of formula III, 【Transformation 5】 and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

17. 17. The compound of formula II according to claim 16, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 【Transformation 6】

18. 18. A compound of formula II according to claim 16 or 17 or a compound of formula III according to claim 16, wherein L is absent, and prodrugs, deuterated analogues, and pharmaceutically acceptable salts thereof.

19. L is absent and K is -CF 2 18. A compound of formula II according to claim 16 or 17 or a compound of formula III according to claim 16, wherein -, and prodrugs, deuterated analogues and pharmaceutically acceptable salts thereof.

20. R 3 18. A compound of formula II according to claim 16 or 17 or a compound of formula III according to claim 16, wherein is a halogen, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

21. R 3 21. The compound of formula II or formula III according to claim 20, wherein is Cl or F, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

22. R 3 22. The compound of formula II or formula III according to claim 21, wherein is Cl or F and is located at the 5-position of the benzimidazole moiety, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

23. R 3 18. A compound of formula II according to claim 16 or 17 or a compound of formula III according to claim 16, wherein is hydrogen, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

24. R 1 18. A compound of formula II according to claim 16 or 17 or a compound of formula III according to claim 16, wherein is a halogen, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

25. R 1 25. The compound of formula II or formula III according to claim 24, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein is selected from the group consisting of Cl or F.

26. R 1 18. A compound of formula II according to claim 16 or 17 or a compound of formula III according to claim 16, wherein is hydrogen, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

27. A is -CH 2 - and -CF 2 - selected from the group consisting of D and E are each —CH 2 - and G is -CH 2 - and -O-; J is -CH 2 - and -O-; K is -CF 2 - and -CH 2 - selected from the group consisting of 18. A compound of formula II according to claim 16 or 17 or a compound of formula III according to claim 16, wherein L is absent, and prodrugs, deuterated analogues, and pharmaceutically acceptable salts thereof. 【Request Item 28】 【Chemistry 7】 28. The compound of formula II of claim 27 selected from the group consisting of: and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

29. A is -CH 2 - and -CF 2 - selected from the group consisting of D, E, and G are each —CH 2 - and J is -CH 2 - and -O-; K is -CF 2 - and 28. The compound of formula II or the compound of formula III according to claim 27, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof, wherein L is absent. 【Request Item 30】 【Transformation 8】 30. The compound of formula II of claim 29 selected from the group consisting of: and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

31. Formula (A-I) 【Chemistry 9】 (In the formula, R 1 , R 2 , R 3 , A, D, E, G, J, K, and L are defined as above, and R13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl). Formula (A-II) 【Chemistry 10】 (In the formula, R 1 , R 2 , R 3 , A, D, E, G, J, K, and L are defined as above, and R13 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; ・Formula (BI) 【Chemistry 11】 (In the formula, R 1 , R 2 , R 3 , A, D, E, G, J, K, and L are defined as above, and R13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl), or ・Formula (B-II) 【Chemistry 12】 (In the formula, R 1 , R 2 , R 3 , A, D, E, G, J, K, and L are defined as above, and R13 is selected from the group consisting of hydrogen, methyl, ethyl, and tert-butyl. An intermediate compound.

32. A compound of formula I as defined in any one of claims 1 to 15 or a compound of formula II or III as defined in any one of claims 16 to 30 for use in the treatment of a disease that can be treated by the inhibition of cGAS.

33. Systemic lupus erythematosus (SLE), interferonism, Aicardi-Goutieres syndrome (AGS), COPA syndrome, familial lupus pernio, 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, muscle disorders, sepsis, rheumatoid arthritis, and glaucoma. A compound of formula I according to any one of claims 1 to 15 or a compound of formula II or III according to any one of claims 16 to 30 for use in the treatment of a disease selected from the group consisting of osteoarthritis, COVID-19, systemic sclerosis (SSc), non-alcoholic steatohepatitis (NASH), interstitial lung disease (ILD), preferably interstitial lung disease with progressive fibrosis (PF-ILD), in particular idiopathic pulmonary fibrosis (IPF).

34. 31. A compound of formula I according to any one of claims 1 to 15 or a compound of formula II or III according to any one of claims 16 to 30 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.

35. A compound of formula I according to any one of claims 1 to 15 or a compound of formula II or III according to any one of claims 16 to 30 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 (ILD), preferably progressive fibrotic interstitial lung diseases (PF-ILD), in particular idiopathic pulmonary fibrosis (IPF).

36. 31. A compound of formula I according to any one of claims 1 to 15 or a compound of formula II or III according to any one of claims 16 to 30 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.

37. A pharmaceutical composition comprising a compound of formula I as defined in any one of claims 1 to 15 or a compound of formula II or III as defined in any one of claims 16 to 30, and optionally comprising one or more pharmaceutically acceptable carriers and / or excipients.

38. 30. A method of 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 15 or a compound of formula II or III according to any one of claims 16 to 30 in combination with one or more active agents selected from the group consisting of anti-inflammatory agents, anti-fibrotic agents, anti-allergic / antihistamines, bronchodilators, beta2 agonists / betamimetics, adrenergic agonists, anticholinergic agents, 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.

39. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 15 or a compound of formula II or III according to any one of claims 16 to 30 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.

40. 31. A pharmaceutical composition comprising a compound of formula I as defined in any one of claims 1 to 15 or a compound of formula II or III as defined in any one of claims 16 to 30 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.

41. A pharmaceutical composition comprising a compound of formula I as defined in any one of claims 1 to 15 or a compound of formula II or III as defined in any one of claims 16 to 30 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.

42. 31. A pharmaceutical combination comprising a compound of formula I according to any one of claims 1 to 15 or a compound of formula II or III according to any one of claims 16 to 30 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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