Cyclic benzimidazole derivatives as cGAS inhibitors

Abstract

The invention relates to compounds of formula I wherein R1, R2, R3, A, D, E, G, J, K and L are as defined in claim 1; as well as prodrugs, deuterated analogs and pharmaceutically acceptable salts thereof; the compounds are useful in the treatment of diseases such as systemic lupus erythematosus, systemic sclerosis (SSc), interferon lesions, non-alcoholic steatohepatitis (NASH), interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF).

Description

This application is a divisional application of Chinese patent application No. 202380077865.5 (filed on November 3, 2023, entitled "Cyclic Benzimidazole Derivatives as cGAS Inhibitors"). 1. Background Technology

[0001] 1.1 cGAS inhibitors Innate immunity is considered a first-line cellular stress response, protecting host cells from pathogen invasion and initiating signaling for the adaptive immune system. These processes are triggered by conserved pathogen-associated molecular patterns (PAMPs) sensing different pattern recognition receptors (PRRs) and subsequently activating the expression of cytokines and type I interferon genes. Major antigen-presenting cells, such as monocytes, macrophages, and dendritic cells, produce type I interferons and are crucial for evoking adaptive T-cell and B-cell immune system responses. Major PRRs detect abnormal nucleic acids on the cell surface, inside lysosomal membranes, or in other cellular compartments—namely, mislocated, immature, or unmodified nucleic acids (Barbalat et al., Annu. Rev. Immunol. 29, 185-214 (2011)).

[0002] “Circular GMP-AMP synthase” C yclic G MP- A MP S ynthase, cGAS UniProtKB-Q8N884 is a primary sensor for the mislocalization or misprocessing of abnormal double-stranded DNA (dsDNA) or nuclear or mitochondrial dsDNA originating from pathogens (Sun et al., Science 339, 786-791 (2013); Wu et al., Science 339, 826-830 (2013); Ablasser et al., Nature 498, 380-384 (2013)). The binding of dsDNA to cGAS activates the GTP-ATP reaction to form a cyclic dinucleotide GMP-AMP (called cGAMP). cGAMP then travels to and activates endoplasmic reticulum membrane anchoring adaptor proteins, “interferon gene stimulators” (ILS). St imulator of In terferon G ene, STING Activated STING recruits and activates TANK-binding kinase 1 (TANK-binding kinase 1). T ANK- b inding k inase 1 , TBK1 This further affects interferon regulators (i nterferon r egulatory f actor, IRF ) of the transcription factor family phosphorylate, inducing the expression of cytokine and type I interferon mRNAs.

[0003] The key role of cGAS in dsDNA sensing has been identified in different pathogenic bacteria (Hansen et al., EMBO J. 33, 1654 (2014)), viruses (Ma et al., PNAS 112, E4306 (2015)) and retroviruses (Gao et al., Science 341, 903-906 (2013)). In addition, 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 broken micronuclei when monitoring potential cancer cells (Mackenzie et al., Nature 548, 461-465 (2017); Harding et al., Nature 548, 466-470 (2017)).

[0004] While the cGAS pathway is essential for host defense against pathogen invasion, cellular stress and genetic factors can also cause aberrant cellular dsDNA production, for example through nuclear or mitochondrial leakage, and thereby trigger autoinflammatory responses. Aicardi-Goutieres syndrome (AGS; Crow et al., Nat. Genet. 38, 917-920 (2006)), a severe autoinflammatory immune-mediated disorder resembling lupus, is caused by loss-of-function mutations in TREX1, a major DNA exonuclease responsible for degrading aberrant DNA in the cytosol. Knocking out cGAS in TREX1-deficient mice prevents the development of otherwise fatal autoimmune responses, supporting cGAS as a driver of interferonopathies (Gray et al., J. Immunol. 195, 1939-1943 (2015); Gao et al., PNAS 112, E5699-E5705 (2015)). Likewise, embryonic lethality caused by deficiency in DNAse2, an endonuclease responsible for degrading excess DNA in lysosomes during endocytosis, is completely rescued by additional genetic 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 can provide a therapeutic strategy for preventing autoinflammation and treating diseases involving anti-dsDNA antibodies, such as systemic lupus erythematosus (SLE) (Pisetsky et al., Nat. Rev. Rheumatol. 12, 102-110 (2016)).

[0005] 1.2 Prior art As inhibition of the cGAS pathway was observed to provide a therapeutic strategy for preventing autoinflammation and treating, for example, autoimmune diseases, many efforts have been made to develop cGAS inhibitors.

[0006] For example, in WO 2019 / 241787, 4-amino-6-(phenylamino)-1,3,5-triazine-2-carboxylic acid methyl esters, such as CU-32 and CU-76, have been disclosed as cGAS inhibitors, wherein the “in vitro hcGAS IC 50 values” are slightly below 1 mM (IC 50 (CU-32) = 0.66 mM and IC 50 (CU-76 = 0.27 mM).

[0007] In Hall et al., PLoS ONE 12(9); e0184843 (2017), the compound PF-06928215 has been disclosed as a cGAS inhibitor, wherein the “in vitro hcGAS IC 50 value” measured by a fluorescence polarization assay was 0.049 µM. However, the compound PF-06928215 does not exhibit an acceptable cellular activity as a cGAS inhibitor.

[0008] In WO 2020 / 142729 and WO 2022 / 174012, (benzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid derivatives have been disclosed as cGAS inhibitors for the therapy of autoimmune disorders, such as Aicardi-Goutieres Syndrome (AGS), lupus erythematosus, scleroderma, inflammatory bowel disease and non-alcoholic 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 the substitution pattern at the 4-position of the pyrrolidine ring.

[0009] Recently provided cGAS inhibitors, such as the ones in WO 2020 / 142729 or WO 2022 / 174012, typically exhibit insufficient cellular cGAS inhibition potency (wherein the IC 50 values measured in cellular assays with respect to inhibition of the cGAS / STING pathway are typically greater than 1 µM, often greater than 5 µM). However, it is essential to provide therapeutic cGAS inhibitors that not only exhibit a satisfactory biochemical (in vitro) inhibition potency (“hcGAS IC 50 ”), but also a satisfactory cellular inhibition potency (e.g. by exhibiting inhibition of IFN induction in virus-stimulated THP-1 cells (THP1 (vir) IC 50 ), to ensure that the compounds are capable of exhibiting a therapeutic effect in patients. Other important properties for the successful development of a cGAS inhibitor as a therapeutic agent are a satisfactory cGAS selectivity (versus off-target activities) and an acceptable inhibition potency in human whole blood.

[0010] Surprisingly, it has now been found that the compounds of formula I, II or III exhibit simultaneously the following three properties: • a satisfactory “biochemical (in vitro) IC 50 value with respect to cGAS inhibition” (wherein the hcGAS IC 50 ≤ 100 nM, preferably ≤ 50 nM, in particular ≤ 10 nM), • a satisfactory "inhibition of IFN induction in virus-stimulated THP-1 cells" (where THP1 IC 50(vir) ≤ 1 μΜ, preferably ≤ 500 nM, more preferably ≤ 100 nM, especially ≤ 50 nM) and • a satisfactory selectivity for cGAS inhibition (where THP1 IC 50(cGAMP) / THP1 IC 50(vir) ratio ≥ 10, more preferably ≥ 50, more preferably ≥ 500, especially ≥ 1000).

[0011] In addition, the compounds of the formula I, II or III also exhibit acceptable IC 50 values with respect to the inhibition of IFN induction in the dsNAb-stimulated human whole blood assay, preferably wherein the human whole blood IC 50 values (hWB IC 50 ) with respect to cGAS inhibition are ≤ 5000 nM, more preferably ≤ 1000 nM, especially ≤ 100 nM.

[0012] The cGAS inhibitors of the present application having this particular pharmacological profile, combined with the excellent in vitro inhibitory potency and the excellent cellular inhibitory potency as well as the high selectivity for cGAS inhibition, are very likely to also exhibit a good therapeutic action in patients. Due to their high cellular inhibitory potency, the compounds having this particular pharmacological profile should be able to pass the cellular membrane barrier and thereby reach their intracellular target site, and due to their selectivity to specifically inhibit the activity of cGAS, these compounds should not exhibit undesirable off-target effects, such as side effects or cytotoxic effects somewhere downstream of the signaling pathway of cGAS. 2. SUMMARY

[0013] The present application relates to compounds of the formula I wherein R 1 is selected from the group consisting of hydrogen, halogen, methyl, ethyl, -CF3, -CHF2, CFH2and 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, and wherein A is selected from the group consisting of -CH2-, -0-, -CF2-, -CHF-, -N(CH3)-, -NH- and -CHCH3-; D is selected from the group consisting of -CH2-, -0-, -CF2-, -CHF- and -CHCH3-. E is selected from the group consisting of -CH2-, -0-, -C(CH3)2-, -CHF-, CF2-, and -CHCH3-; G is selected from the group consisting of -NH-, -NCH3-, -CH2-, -0-, -CF2-, -CHF-, -CHCH3-, and -C(CH3)2; J is selected from the group consisting of -CO-, -CH2-, -0-, -CHF-, -CF2-, and -CHCH3-; K is selected from the group consisting of -CH2-, -CF2-, -0-, or is absent; L is selected from the group consisting of -CH2-, -0-, -CHCH3-, -CHF-, -CF2-, or is absent; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0014] Herein, the variables A, D, E, G, J, K, and L are preferably selected in such a way that two or more heteroatoms can not directly follow each other.

[0015] In a preferred embodiment, the present application relates to compounds of the formula I mentioned above, wherein 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, and wherein A is selected from the group consisting of -CH2-, -0-, -CF2-, -N(CH3)-, D is selected from the group consisting of -CH2-, -0-, and -CHCH3-, E is selected from the group consisting of -CH2-, -0-, and -C(CH3)2-, G is selected from the group consisting of -NH-, -CH2-, -0-, -CHCH3-, J is selected from the group consisting of -CO-, -CH2-, -0-, and -CHCH3-; K is selected from the group consisting of -CH2-, -CF2-, -0-, or is absent; L is selected from the group consisting of -CH2-, -CF2-, or is absent; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0016] Herein, the variables A, D, E, G, J, K and L are preferably selected in such a way that two or more heteroatoms can not directly follow each other.

[0017] In another preferred embodiment, the present application relates to a compound of formula I as mentioned above, wherein L is absent; as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0018] In another preferred embodiment, the present application relates to a compound of formula I as mentioned above, wherein L is absent, and wherein A is selected from the group consisting of -CH2- and -CF2-; as well as prodrugs, pharmaceutically acceptable salts, or deuterated analogs thereof.

[0019] In another preferred embodiment, the present application relates to a compound of formula I as mentioned above, wherein L is absent, and wherein K is CF2; as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0020] In another preferred embodiment, the present application relates to a compound of formula I as mentioned above, wherein R 3 is halogen; as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0021] Herein, especially preferably, R 3 is a halogen atom selected from the group consisting of Cl and F.

[0022] In another preferred embodiment, the present application relates to a compound of formula I as mentioned above, wherein 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.

[0023] In another preferred embodiment, the present application relates to a compound of formula I as mentioned above, wherein R 1 is halogen; as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0024] In another preferred embodiment, the present application relates to a compound of formula I as mentioned above, wherein R 1 is Cl or F; as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0025] In another preferred embodiment, the present application relates to a compound of formula I as mentioned above, wherein R 1 is hydrogen; as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0026] In another especially preferred embodiment, the present application relates to a compound of formula I as mentioned above, selected from the group consisting of: and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0027] In another preferred embodiment, the present application relates to compounds of formula I as mentioned above, wherein 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-, and L is absent, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0028] In another especially preferred embodiment, the present application relates to compounds of formula I as mentioned above, selected from the group consisting of: and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0029] In another preferred embodiment, the present application relates to compounds of formula I as mentioned above, wherein R 2 is methyl; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0030] In another especially preferred embodiment, the present application relates to compounds of formula II or of formula III wherein 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, and wherein 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-, -0-, -CF2-, -CHF-, -CHCH3-, and -C(CH3)2; J is selected from the group consisting of -CO-, -CH2-, -0-, -CHF-, -CF2-, and -CHCH3-; K is selected from the group consisting of -CH2-, -CF2-, -0-, or is absent; L is selected from the group consisting of -CH2-, -0-, -CHCH3-, -CHF-, -CF2-, or is absent; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0031] Herein, the variables A, D, E, G, J, K, and L are preferably selected in such a way that two or more heteroatoms can not directly follow each other.

[0032] More preferred are the compounds of the above-mentioned formula II or formula III, wherein 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, and wherein A is selected from the group consisting of -CH2-, -0-, -CF2-, and -N(CH3)-, D is selected from the group consisting of -CH2-, -0-, and -CHCH3-, E is selected from the group consisting of -CH2-, -0-, and -C(CH3)2-, G is selected from the group consisting of -NH-, -CH2-, -0-, -CHCH3-, J is selected from the group consisting of -CO-, -CH2-, -0-, and -CHCH3-; K is selected from the group consisting of -CH2-, -CF2-, -0-, or is absent; L is selected from the group consisting of -CH2-, -CF2-, or is absent; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0033] Herein, the variables A, D, E, G, J, K, and L are preferably selected in such a way that two or more heteroatoms can not directly follow each other.

[0034] More preferred are the compounds of the above-mentioned formula II or formula III, wherein 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, and wherein A is selected from the group consisting of -CH2-, -0-, -CF2- and -N(CH3)-, D is selected from the group consisting of -CH2-, -0- and -CHCH3-, E is selected from the group consisting of -CH2-, -0- and -C(CH3)2-, G is selected from the group consisting of -NH-, -CH2-, -0-, -CHCH3-, J is selected from the group consisting of -CO-, -CH2-, -0- and -CHCH3-; K is selected from the group consisting of -CH2-, -CF2-, -0- or is absent; L is selected from the group consisting of -CH2-, -CF2- or is absent; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0035] Herein, the variables A, D, E, G, J, K and L are preferably selected in such a way that two or more heteroatoms can not directly follow each other.

[0036] In another preferred embodiment, the present application relates to the above-mentioned compound of formula II or the above-mentioned compound of formula III, wherein L is absent; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0037] In another preferred embodiment, the present application relates to the above-mentioned compound of formula II or the above-mentioned compound of formula III, wherein L is absent and wherein K is CF2; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0038] In another preferred embodiment, the present application relates to the above-mentioned compound of formula II or the above-mentioned compound of formula III, wherein R 3 is halogen; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0039] In another preferred embodiment, the present application relates to the above-mentioned compound of formula II or the above-mentioned compound of formula III, wherein R 3 is Cl or F; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0040] In a particularly preferred embodiment, the present application relates to the above- mentioned compound of formula II or the above-mentioned compound of formula III, wherein 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.

[0041] In another preferred embodiment, the present application relates to the above- mentioned compound of formula II or the above-mentioned compound of formula III, wherein R 3 is hydrogen; as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0042] In another preferred embodiment, the present application relates to the above- mentioned compound of formula II or the above-mentioned compound of formula III, wherein R 1 is halogen; as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0043] In a particularly preferred embodiment, the present application relates to the above- mentioned compound of formula II or the above-mentioned compound of formula III, wherein R 1 is selected from the group consisting of Cl or F; as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0044] In another preferred embodiment, the present application relates to the above- mentioned compound of formula II or the above-mentioned compound of formula III, wherein R 1 is hydrogen; as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0045] In another preferred embodiment, the present application relates to the above- mentioned compound of formula II or the above-mentioned compound of formula III, wherein 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-, and L is absent, as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0046] In another particularly preferred embodiment, the present application relates to the above- mentioned compound of formula II, which is selected from the group consisting of: as well as prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0047] In another especially preferred embodiment, the present application relates to the above-mentioned compound of formula II or the above-mentioned compound of formula III, wherein 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-, and L is absent, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0048] In another especially preferred embodiment, the present application relates to the above-mentioned compound of formula II, which is selected from the group consisting of: and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0049] The prodrugs of the compound of formula I are preferably compounds of formula la wherein the variables R 1 , R 2 , R 3 , A, D, E, G, J, K and L are as defined before, and wherein R 4 is C 1-4 -alkyl, aryl, -CH2-aryl, NH-SO2-C 1-3 -alkyl.

[0050] Especially preferred are prodrugs of formula la, wherein the variables R 1 , R 2 , R 3 , A, D, E, G, J, K and L are as defined before, and wherein R 4 is methyl.

[0051] The prodrugs of the compound of formula II are preferably compounds of formula Ila wherein the variables R 1 , R 2 , R 3 , A, D, E, G, J, K and L are as defined before, and wherein R 4 is C 1-4 -alkyl, aryl, -CH2-aryl, NH-SO2-C 1-3 -alkyl.

[0052] Especially preferred are prodrugs of formula Ila, wherein the variables R1 R 2 R 3 A, D, E, G, J, K and L are as defined above, and wherein R 4 is methyl.

[0053] The prodrug of the compound of formula III is preferably a compound of formula Ilia wherein the variables R 1 R 2 R 3 A, D, E, G, J, K and L are as defined above, and wherein R 4 is C 1-4 -alkyl, aryl, -CH2-aryl, NH-SO2-C 1-3 -alkyl.

[0054] Especially preferred are prodrugs of formula Ilia, wherein the variables R 1 R 2 R 3 A, D, E, G, J, K and L are as defined above, and wherein R 4 is methyl.

[0055] In another preferred embodiment, the present application relates to a) an intermediate compound of formula (A-I) wherein R 1 R 2 R 3 A, D, E, G, J, K and L are as defined above, and wherein R13is selected from the group consisting of hydrogen, methyl, ethyl and tert-butyl, b) an intermediate compound of formula (A-II), wherein R 1 R 2 R 3 A, D, E, G, J, K and L are as defined above, and wherein R13is selected from the group consisting of hydrogen, methyl, ethyl and tert-butyl, and wherein 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 (B-I) wherein R 1 R 2 R 3A, D, E, G, J, K and L are defined as above, and wherein R13is selected from the group consisting of hydrogen, methyl, ethyl and tert-butyl, or d) the intermediate compound of formula (B-II) wherein R 1 , R 2 , R 3 , A, D, E, G, J, K and L are defined as above, and wherein R13is selected from the group consisting of hydrogen, methyl, ethyl and tert-butyl.

[0056] In another preferred embodiment, the present application relates to a compound of formula I, II or III or a prodrug of formula la, Ila or Ilia, deuterated analogues and pharmaceutically acceptable salts thereof mentioned above for use in the treatment of a disease which can be treated by inhibition of cGAS.

[0057] In another preferred embodiment, the present application relates to a compound of formula I, II or III or a prodrug of formula la, Ila or Ilia, deuterated analogues and pharmaceutically acceptable salts thereof mentioned above for use in the treatment of a disease selected from the group consisting of systemic lupus erythematosus (SLE); interferonopathies; Aicardi-Goutieres syndrome (AGS); COPA syndrome; familial chilblain lupus; 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; cancer; systemic sclerosis (SSc); dermatomyositis; nonalcoholic steatohepatitis (NASH); interstitial lung disease (ILD), preferably progressive fibrosing interstitial lung disease (PF-ILD), especially idiopathic pulmonary fibrosis (IPF); aging; muscle disorders; sepsis; rheumatoid arthritis; osteoarthritis; and COVID-19.

[0058] In another preferred embodiment, the present application relates to a compound of formula I, II or III or a prodrug of formula la, Ila or Ilia, deuterated analogues thereof, and pharmaceutically acceptable salts thereof mentioned hereinbefore for use in the treatment of a disease selected from the group consisting of systemic lupus erythematosus (SLE), interferonopathies, Aicardi-Goutieres syndrome (AGS), COPA syndrome, familial chilblain lupus, dermatomyositis, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom syndrome, Sjogren syndrome, rheumatoid arthritis and Parkinson’s disease.

[0059] In another preferred embodiment, the present application relates to a compound of formula I, II or III or a prodrug of formula la, Ila or Ilia, deuterated analogues thereof, and pharmaceutically acceptable salts thereof mentioned hereinbefore for use in the treatment of a disease selected from the group consisting of systemic sclerosis (SSc); non-alcoholic steatohepatitis (NASH); interferonopathies; interstitial lung disease (ILD), preferably progressive fibrosing interstitial lung disease (PF-ILD), in particular idiopathic pulmonary fibrosis (IPF).

[0060] In another preferred embodiment, the present application relates to a compound of formula I, II or III or a prodrug of formula la, Ila or Ilia, deuterated analogues thereof, and pharmaceutically acceptable salts thereof mentioned hereinbefore for use in the treatment of a disease selected from the group consisting of age-related macular degeneration (AMD), retinopathy, glaucoma, diabetes, obesity, aging, muscle disorders, sepsis, osteoarthritis, heart failure, COVID19 / SARS-CoV-2 infection, kidney inflammation, kidney fibrosis, metabolic disorders, vascular diseases, cardiovascular diseases and cancer.

[0061] In another preferred embodiment, the present application relates to a pharmaceutical composition comprising a compound of formula I, II or III or a prodrug of formula la, Ila or Ilia, deuterated analogues thereof, and pharmaceutically acceptable salts thereof mentioned hereinbefore and one or more optional pharmaceutically acceptable carriers and / or excipients.

[0062] In another preferred embodiment, the present application relates to a pharmaceutical composition comprising the above-mentioned compounds of the formula I, II or III or the prodrugs of the formula la, Ila or Ilia, their deuterated analogs and pharmaceutically acceptable salts, and one or more active agents selected from the group consisting of anti-inflammatory agents; anti-fibrotic agents; anti-allergic agents / antihistamines; bronchodilators; beta2 agonists / beta mimetics; adrenergic agonists; anticholinergic agents; methotrexate; mycophenolate mofetil; leukotriene modulators; JAK inhibitors; anti- interleukin antibodies; non-specific immunotherapeutic agents, such as interferons or other cytokines / chemokines; cytokine / chemokine receptor modulators; TLR agonists; immune checkpoint modulators; anti-TNF antibodies, such as Humira TM ; anti-BAFF antibodies, such as Belimumab and Etanercept; and one or more optional pharmaceutically acceptable carriers and / or excipients.

[0063] In another preferred embodiment, the present application relates to a pharmaceutical composition comprising the above-mentioned compounds of the formula I, II or III or the prodrugs of the formula la, Ila or Ilia, their deuterated analogs and pharmaceutically acceptable salts, and one or more anti-fibrotic agents selected from the group consisting of Pirfenidon and Nintedanib and one or more optional pharmaceutically acceptable carriers and / or excipients.

[0064] In another preferred embodiment, the present application relates to a pharmaceutical composition comprising the above-mentioned compounds of the formula I, II or III or the prodrugs of the formula la, Ila or Ilia, their deuterated analogs and pharmaceutically acceptable salts, and one or more anti-inflammatory agents selected from the group consisting of NSAIDs and corticosteroids and one or more optional pharmaceutically acceptable carriers and / or excipients.

[0065] In another preferred embodiment, the present application relates to a pharmaceutical composition comprising the above-mentioned compounds of the formula I, II or III or the prodrugs of the formula la, Ila or Ilia, their deuterated analogs and pharmaceutically acceptable salts, and one or more active agents selected from the group consisting of bronchodilators, beta2 agonists / beta mimetics, adrenergic agonists and anticholinergic agents and one or more optional pharmaceutically acceptable carriers and / or excipients.

[0066] In another preferred embodiment, the present application relates to a pharmaceutical combination comprising a compound of formula I, II or III or a prodrug of formula la, Ila or Ilia, deuterium analogs and pharmaceutically acceptable salts thereof mentioned herein above, and one or more anti-interleukin antibodies selected from the group consisting of: anti-IL-23 antibodies, e.g. Risankizumab; anti-IL-17 antibodies; anti-IL-1 antibodies; anti-IL-4 antibodies; anti-IL-13 antibodies; anti-lL-5 antibodies; anti-IL-6 antibodies, e.g. Actemra TM ; anti-IL-12 antibodies; and anti-IL-15 antibodies.

[0067] 3. Terms and definitions used Unless stated otherwise, all substituents are independent of each other. For example, if a plurality of C 1-6 alkyl groups are possible substituents on a group, then in the case of, for example, three substituents, the C 1-6 alkyl groups can each independently represent a methyl group, a n-propyl group and a t-butyl group.

[0068] a cross bond, like the intermediate bond in the following butyl molecule, represents a double bond of unknown configuration (cis, trans or a mixture thereof).

[0069] The term "C 1-6 alkyl" (including those alkyl groups which are part of other groups) means branched and unbranched alkyl groups having 1 to 6 carbon atoms, and the term "C 1-3 alkyl" means branched and unbranched alkyl groups having 1 to 3 carbon atoms. "C 1-4 alkyl" thus denotes branched and unbranched alkyl groups having 1 to 4 carbon atoms. Preferred are alkyl groups having 1 to 4 carbon atoms. Examples of these alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl and hexyl. The above mentioned groups can optionally also be used with the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu and the like. Unless stated otherwise, the definition of propyl, butyl, pentyl and hexyl includes all possible isomeric forms of the said groups. Thus, for example, propyl includes n-propyl and i-propyl, butyl includes i-butyl, s-butyl and t-butyl and the like.

[0070] The term "C 1-6 alkylene" (including those alkylene groups which are part of other groups) means branched and unbranched alkylene groups having 1 to 6 carbon atoms, and the term "C 1-4"Alkylene" means branched and unbranched alkylene groups having 1 to 4 carbon atoms. Preferred are alkylene groups having 1 to 4 carbon atoms. Examples of these alkylene groups 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 indicated, the definition of propylene, butylene, pentylene, and hexylene includes all possible isomeric forms of the group having the same number of carbons. Thus, for example, propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, and the like.

[0071] If the carbon chain is substituted with a group that forms a carbocyclic ring having 3, 5, or 6 carbon atoms together with one or two carbon atoms of the alkylene chain, it includes, inter alia, the following ring examples:

[0072] The term "C 2-6 "Aryl" (including aryl groups as part of other groups) means a monocyclic or bicyclic aromatic ring radical, having 6 to 12 carbon atoms, preferably 6 to 10 carbon atoms. Examples include phenyl, naphthyl, indanyl, indenyl, and the like. Unless otherwise indicated, the definition of aryl includes all possible isomeric forms of the group. Thus, for example, phenyl includes 1-phenyl and 2-phenyl. 2-4 "Aryl" (including aryl groups as part of other groups) means a monocyclic or bicyclic aromatic ring radical, having 6 to 12 carbon atoms, preferably 6 to 10 carbon atoms. Examples include phenyl, naphthyl, indanyl, indenyl, and the like. Unless otherwise indicated, the definition of aryl includes all possible isomeric forms of the group. Thus, for example, phenyl includes 1-phenyl and 2-phenyl.

[0073] The term "C 2-5 "Aryl" (including aryl groups as part of other groups) means a monocyclic or bicyclic aromatic ring radical, having 6 to 12 carbon atoms, preferably 6 to 10 carbon atoms. Examples include phenyl, naphthyl, indanyl, indenyl, and the like. Unless otherwise indicated, the definition of aryl includes all possible isomeric forms of the group. Thus, for example, phenyl includes 1-phenyl and 2-phenyl. 2-4 "Aryl" (including aryl groups as part of other groups) means a monocyclic or bicyclic aromatic ring radical, having 6 to 12 carbon atoms, preferably 6 to 10 carbon atoms. Examples include phenyl, naphthyl, indanyl, indenyl, and the like. Unless otherwise indicated, the definition of aryl includes all possible isomeric forms of the group. Thus, for example, phenyl includes 1-phenyl and 2-phenyl.

[0074] The term "C 2-6 "Aryl" (including aryl groups as part of other groups) means a monocyclic or bicyclic aromatic ring radical, having 6 to 12 carbon atoms, preferably 6 to 10 carbon atoms. Examples include phenyl, naphthyl, indanyl, indenyl, and the like. Unless otherwise indicated, the definition of aryl includes all possible isomeric forms of the group. Thus, for example, phenyl includes 1-phenyl and 2-phenyl. 2-4Alkenylene" means branched and unbranched alkylene groups having 2 to 4 carbon atoms. Preferred are alkenylenes having 2 to 4 carbon atoms. Examples of these alkenylenes 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 definition of propenylene, butenylene, pentenylene and hexenylene includes all possible isomeric forms of the group in question having the same number of carbons. Thus, for example, propenylene also includes 1-methylethenylene and butenylene includes 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene.

[0075] The term "aryl" (including aryl groups as part of other groups) means an aromatic ring system having 6 or 10 carbon atoms. Examples include phenyl or naphthyl, preferably the aryl group is phenyl. Unless otherwise stated, the aromatic group can be substituted by one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

[0076] The term "aryl-C 1-6 Alkylene" (including those groups as part of other groups) means branched and unbranched alkylene groups having 1 to 6 carbon atoms, which are substituted by an aromatic ring system having 6 or 10 carbon atoms. Examples include benzyl, 1-phenylethyl or 2-phenylethyl and 1-naphthylethyl or 2-naphthylethyl. Unless otherwise stated, the aromatic group can be substituted by one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

[0077] The term "heteroaryl-C 1-6 Alkylene" (including those groups as part of other groups) means branched and unbranched alkylene groups having 1 to 6 carbon atoms, which are substituted by an aromatic ring system having 6 or 10 carbon atoms. Examples include benzyl, 1-phenylethyl or 2-phenylethyl and 1-naphthylethyl or 2-naphthylethyl. Unless otherwise stated, the aromatic group can be substituted by one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine. 1-6 Alkylene" (including those groups as part of other groups) means branched and unbranched alkylene groups having 1 to 6 carbon atoms, which are substituted by an aromatic ring system having 6 or 10 carbon atoms. Examples include benzyl, 1-phenylethyl or 2-phenylethyl and 1-naphthylethyl or 2-naphthylethyl. Unless otherwise stated, the aromatic group can be substituted by one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

[0078] Unless otherwise specifically defined, such heteroaryl groups include five- or six-membered heterocyclic aromatic groups or 5- to 10-membered bicyclic heteroaryl rings, which can contain one, two, three or four heteroatoms selected from oxygen, sulfur and nitrogen and contain a number of conjugated double bonds which form an aromatic system. The following are examples of five- or six-membered heterocyclic aromatic groups and bicyclic heteroaryl rings:

[0079] Unless otherwise indicated, these heteroaryl groups can be substituted by one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, amino, nitro, alkoxy, fluorine, chlorine, bromine, and iodine.

[0080] The following are heteroaryl-C 1-6 Examples of alkylene groups:

[0081] The term "C 1-6 "Haloalkyl" (including those haloalkyl groups that are part of other groups) means a branched and unbranched alkyl group having 1 to 6 carbon atoms that is substituted by one or more halogen atoms. The term "C 1-4 "Haloalkyl" means a branched and unbranched alkyl group having 1 to 4 carbon atoms that is substituted by one or more halogen atoms. Preferred is an alkyl group having 1 to 4 carbon atoms. Examples include: CF3, CHF2, CH2F, CH2CF3.

[0082] The term "C 3-7 "Cycloalkyl" (including those cycloalkyl groups that are part of other groups) means a cycloalkyl group having 3 to 7 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise indicated, cycloalkyl groups can be substituted by one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine.

[0083] The term "C 3-10 "Cycloalkyl" also means a monocycloalkyl group having 3 to 7 carbon atoms and also means a bicycloalkyl group having 7 to 10 carbon atoms, or a monocycloalkyl group bridged by at least one C 1-3 monocycloalkyl group bridged by a carbon bridge.

[0084] Unless otherwise indicated, the term "heterocyclic ring" or "heterocycle" means a five-, six-, or seven-membered saturated, partially saturated, or unsaturated heterocyclic ring that can contain one, two, or three heteroatoms selected from oxygen, sulfur, and nitrogen, and if present, the ring can be attached to the molecule through a carbon atom or through a nitrogen atom. The term "saturated heterocyclic ring" refers to a five-, six-, or seven-membered saturated ring, although included within the term "heterocyclic ring" or "heterocycle". Examples include:

[0085] While encompassed by the term "heterocyclic ring" or "heterocycle", the term "partially saturated heterocyclyl" refers to a five-, six-, or seven-membered partially saturated ring which contains one or two double bonds, but not so many as to create an aromatic system, unless otherwise specifically defined. Examples include:

[0086] While encompassed by the term "heterocyclic ring" or "heterocycle", the term "partially saturated heterocyclyl" refers to a five-, six-, or seven-membered partially saturated ring which contains one or two double bonds, but not so many as to create an aromatic system, unless otherwise specifically defined. Examples include:

[0087] Unless otherwise mentioned, a heterocyclic ring / heterocycle can have a keto group. Examples include:

[0088] While encompassed by the term "cycloalkyl", the term "bicyclic cycloalkyl" generally denotes an eight-, nine-, or ten-membered bicyclic carbocyclic ring. Examples include:

[0089] While encompassed by the term "heterocyclic ring", the term "bicyclic heterocycle" generally denotes an eight-, nine-, or ten-membered bicyclic ring which can contain one or more heteroatoms, preferably 1 to 4, more preferably 1 to 3, even more preferably 1 to 2, in particular one heteroatom selected from oxygen, sulfur and nitrogen. The ring can be attached to the molecule through a carbon atom in the ring or through a nitrogen atom in the ring, if one is present. Examples include:

[0090] While encompassed by the term "aryl", the term "bicyclic aryl" denotes a 5- to 10-membered bicyclic aryl ring containing sufficient conjugated double bonds to form an aromatic system. One example of a bicyclic aryl is naphthyl.

[0091] While encompassed by the term "heteroaryl", the term "bicyclic heteroaryl" denotes a 5- to 10-membered bicyclic heteroaryl ring which can contain one, two, three or four heteroatoms selected from oxygen, sulfur and nitrogen, and contains sufficient conjugated double bonds to form an aromatic system, unless otherwise specifically defined.

[0092] While included within the term "bicyclic cycloalkyl" or "bicyclic aryl", the term "fused cycloalkyl" or "fused aryl" denotes bicyclic rings wherein the bridge separating the rings represents a direct single bond. The following are examples of fused bicyclic cycloalkyl groups:

[0093] While included within the term "bicyclic heterocycle" or "bicyclic heteroaryl", the term "fused bicyclic heterocycle" or "fused bicyclic heteroaryl" denotes 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. "Fused bicyclic heteroaryl" furthermore contains a sufficient number of conjugated double bonds to form an aromatic system. Examples include pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzothiazole, benzoisothiazole, pyrido-pyrimidine, pteridine, pyrimido-pyrimidine,

[0094] "Halogen" within the scope of the present application means fluorine, chlorine, bromine or iodine. Fluorine, chlorine and bromine are considered as preferred halogens, unless stated to the contrary.

[0095] As mentioned previously, the compounds of formula I, II or III can be converted into their salts, especially into their physiologically and pharmacologically acceptable salts, especially for pharmaceutical use. The expression "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. In one aspect, these salts can exist in the form of physiologically and pharmacologically acceptable acid addition salts of the compounds of formula I, II or III with inorganic or organic acids. In another aspect, the compounds of formula I, II or III can be converted into physiologically and pharmacologically acceptable salts by reaction with inorganic bases, wherein an alkali metal or alkaline earth metal cation serves as a counterion. Acid addition salts can be prepared, for example, using 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-mentioned acids can also be used. For the preparation of alkali metal and alkaline earth metal salts of the compounds of formula I, II or III, alkali metal and alkaline earth metal hydroxides and hydrides are preferably used, wherein the hydroxides and hydrides of the alkali metals, especially sodium, potassium, magnesium, calcium, zinc and diethanolamine, are preferred, and sodium hydroxide and potassium hydroxide are especially preferred.

[0096] The present application relates to said compounds, optionally in the form of individual optical isomers, diastereoisomers, mixtures of diastereoisomers, individual enantiomers or mixtures of racemates; in the form of tautomers; and in the form of the free base or the corresponding acid addition salt with a pharmacologically acceptable acid, for example an acid addition salt with a hydrohalic acid, such as hydrochloric acid or hydrobromic acid, or an organic acid, such as oxalic acid, fumaric acid, digluconic acid or methanesulfonic acid.

[0097] The compounds of the formula I, II or III according to the application can optionally be present in the form of mixtures of diastereoisomers, but can also be obtained in the form of pure diastereoisomers. Preference is given to compounds having the specific stereochemistry of the formula II and III, in particular the specific stereochemistry of the formula II.

[0098] 4. Synthesis methods General procedures The following methods are suitable for preparing the compounds of the general formula I, II or III. The compounds according to the application can be obtained using synthetic methods known to the person skilled in the art and described in the literature on organic synthesis. General methods for the protection and deprotection of functional groups are described, for example, in: Greene, T. W. and Wuts, P. G. M. (Eds.): Protective Groups in Organic Synthesis, 3rdedition 1999; John Wiley and Sons, Inc. Preferably, the compounds are obtained analogously to the methods explained more fully hereinafter, in particular the preparation methods described in the experimental section. The compounds of the general formula (I) can be prepared using several alternative synthesis routes, of which the following routes should serve as examples.

[0099] Route A: Compounds of general formula I, II and III, in particular compounds of general formula I, II and III wherein A represents -CH2- or substituted -CH2-, can be accessed from compounds of formula (A-I) by standard amidation procedures. R13may thus represent hydrogen or a protecting group, for example tert-butyl, which can be removed by standard deprotection methods. Compounds of formula (A-I) can be prepared from compounds of formula (A-II) applying standard deprotection methods. Compounds of formula (A-I) can be prepared from compounds of formula (A-II) applying standard deprotection methods. Compounds of formula (II) can be prepared by reacting compounds of formula (A-III) with compounds of formula (A-IV) in the presence of a strong base, for example sodium hydride. Methods suitable for the preparation of compounds (A-III) become apparent to the skilled person by consulting routes B and C described hereinafter and the examples described in the experimental section. Compounds of formula (A-IV) can be prepared by the methods described hereinafter for the synthesis of Intermediate B. R according to formula (A-II) and (A-III) can represent hydrogen or a protecting group selected from the group consisting of tert-butyl, methyl, ethyl and benzyl. Route A

[0100] Route B: Compounds of general formula I, II and III can be prepared by reacting compounds of general formula (B-I) in the presence of a strong base, for example sodium hydride. R13may thus represent hydrogen or a protecting group, for example tert-butyl, which can be removed by standard deprotection methods. Compounds (B-I) can be prepared by oxidation of compounds of general formula (B-II) applying for example 3-chloro-perbenzoic acid. Compounds (B-II) can be prepared by reacting compounds of general formula (B-III) with compounds of general formula (B-IV) applying standard amidation conditions. Methods suitable for the preparation of compounds (B-III) become apparent to the skilled person by consulting the synthesis of compounds (B-VI) and routes C described hereinafter and the examples described in the experimental section. Compounds of formula (B-IV) can be prepared by the methods described hereinafter for the synthesis of Intermediate B. Alternatively, compounds (B-II) can be prepared by reacting compounds of general formula (B-V) with the respective enantiopure hydroxyproline, optionally in the presence of a base. Compounds (B-V) can be obtained by chlorination of compounds of general formula (B-VI) applying phosphorus oxychloride. Compounds (B-VI) can be prepared from compounds of general formula (B-VII) applying strong basic conditions, for example at elevated temperature. Compounds (B-VII) can be obtained by reacting compounds of general formula (B-VIII) with compounds of general formula (B-IX) applying standard amidation procedures. Compounds of general formula (B-VIII) can be prepared by the methods exemplified hereinafter or other standard synthetic methods known to the skilled person. Route B

[0101] Route C: The compounds of general formula can be prepared from compounds of general formula (C-I) by various types of ring closure reactions, such as (but not limited to): Heck type coupling reactions (where R11represents a bromine or iodine atom and R12contains a terminal olefin), ring closing metathesis reactions (where both R11and R12contain a terminal olefin); followed by hydrogenation of the resulting olefin; amidation (where R11carries a carboxylic acid and R12carries a primary or secondary amino group, or vice versa). R13may thus represent hydrogen or a protecting group, such as a tert-butyl group, which can be removed by standard deprotection methods. Methods for the synthesis of compounds (C-I) become apparent to the skilled person by consulting the above routes A and B and the examples described in the experimental section. Route C

[0102] Synthesis of intermediates Intermediate A Intermediate A-01 (rac-trans-4-amino-3-methylpiperidine-1 -carboxylic acid tert-butyl ester): 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 was added lithium-tri-sec-butyl(borohydride) (1 M in THF; 984 mL; 0.98 mol). The mixture was stirred for 4 h while the temperature was kept between 0 °C and 10 °C. Aqueous sodium hypochlorite (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, CDC13) δ ppm 3.84-3.82 (m, 1 H), 3.52 (d, J = 6.40 Hz, 2 H), 3.29 (d, J = 5.40 Hz, 2 H), 3.06-3.02 (m, 1 H), 1.76-1.74 (m, 3 H), 1.65 (s, 9 H), 1.24-0.89 (m, 3 H)

[0103] 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 h. 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, CDC13 ) δ ppm 4.74-4.71 (m, 1 H), 4.23-3.95 (m, 1 H), 3.17-3.04 (m, 2 H), 3.04 (s, 3 H), 1.95-1.92 (m, 1 H), 1.83 (s, 1 H), 1.83-1.82 (m, 1 H), 1.32 (s, 9 H), 0.91-0.79 (m, 3 H)

[0104] Step 3: The reaction was carried out under an atmosphere of nitrogen. 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 h, then cooled to 0 °C. A saturated solution of sodium carbonate (4.0 L) was added while keeping the temperature below 10 °C. The mixture was extracted with EtOAc, 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.

[0105] Step 4: A mixture of the product of Step 3 (200 g; 0.83 mol), palladium on carbon (60 g) and EtOAc (1.0 L) was stirred under a hydrogen pressure (50 psi) at room temperature for 2 h. The catalyst was filtered off by 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% -> 100%) to give the title compound. 1 H NMR (400 MHz, CDC13 ) δ ppm 7.85 (s, 1 H) 3.99-3.74 (m, 2 H), 2.81-2.79 (m, 2 H), 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, 1 H)

[0106] Intermediate B Intermediate B-01 : 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 indicated that the starting material had been clearly converted (10 h). The mixture was poured onto ice water. Water was then 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% -> 100%) to give (rac-trans)-tert-butyl 4-[(4-chloro-2-nitrophenyl)amino]-3-methylpiperidine-1-carboxylate. ESI-MS: 392 [M+Na] + R t (HPLC): 0.83 min (Method A)

[0107] Step 2 : A mixture of the product of Step 1 (3.25 g; 7.90 mmol), Raney nickel (410 mg) and THF (60 mL) was shaken in a Parr apparatus at room temperature under hydrogen pressure (50 psi) for 5 h. Raney nickel (160 mg) was then added more times after every 10-15 h until reaction control by RP HPLC indicated that the starting material had been highly converted (here: 3 times of catalyst addition). 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)

[0108] Step 3 : A mixture of the product of Step 2 (2.16 g; 6.37 mmol), 1-(1H-imidazole-1- thio carbonyl)-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 while stirring and stirring was continued for another 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)

[0109] Step 4: The reaction was carried out under an argon atmosphere. To a solution of the product of Step 3 (2.57 g; 6.26 mmol) in dry DMF was added potassium tert-butoxide (1.42 g; 12.7 mmol). The mixture was stirred at room temperature for 15 min, then iodomethane (597 μL; 9.49 mmol) was added. The mixture was stirred at room temperature until reaction control by RP HPLC indicated that the starting material had been nearly completely converted (2 h). 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 co-evaporation with toluene to yield (racemic trans)-tert-butyl 4-[5-chloro-2-(methylthio)-1 H-1,3-benzoxazol-1 -yl]-3- methylpiperidine-1 -carboxylate. ESI-MS: 396 [M+H] + R t (HPLC): 0.73 min (Method A)

[0110] Step 5: The mixture of enantiomers of Step 4 was separated by preparative SFC (Instrument: Sepiatec 2Prep SFC 100; Column: Lux Cellulose-2 (21.2 mm*250 mm, 5 pm); Mobile phase: A for CO2 and B for IPA; Gradient: B% = 20% isocratic elution mode; Flow rate: 60 mL / min; Wavelength: 220 nm; Column temperature: 40 °C; System back pressure: 150 bar).

[0111] The absolute configuration of the two separated enantiomers was assigned based on the co-crystal structure of Example 1.01 with the human cGAS protein according to the method described by D.J. Patel et al., PNAS 2019, 11946-11955 (doi.org / 10.1073 / pnas.1905013116). 1H NMR (first eluting isomer) (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)

[0112] This first eluting isomer was used for the next step. The second eluting isomer was used to prepare intermediate B-02.

[0113] Step 6: To a solution of the first eluting isomer of 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 additional DCM and washed with aqueous potassium carbonate solution (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 give the title compound. ESI-MS: 428 [M+H] + R t (HPLC): 0.74 min (Method A)

[0114] The following intermediates were prepared in an analogous manner to intermediate 1.01 as described above. From this, the reaction temperature in step 1 was adjusted according to the reactivity of the respective nitrobenzene starting material. The absolute configuration of the selected intermediates was assigned according to the co-crystal structure of exemplary compounds prepared from each intermediate with the human cGAS protein according to the method described by D.J. Patel et al., PNAS 2019, 11946-11955 (doi.org / 10.1073 / pnas.1905013116). The absolute configuration of the other intermediates and examples was assigned based on the assumption that the eutomer shares the same absolute stereochemistry in all cases.

[0115] Intermediate B-12 The product of step 4 of synthetic intermediate B-08 was deprotected from the BOC protecting group according to general procedure D. ESI-MS: 262 [M+H] + R t (HPLC): 0.47 min (Method E)

[0116] Intermediate B-14 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 h. Tert-Butyl methyl ether (20 mL) was added and the mixture was left to stand without stirring for 1 h. 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)

[0117] Intermediate I Intermediate I.01: Intermediate N-R was reacted with intermediate B-5 according to the general procedure A to give the title compound (3S,4S)-4-(2-{[(3S,5S)-1-{4-bromo-8-oxa-3,5- diazabicyclo[7.4.0]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-carboxylic acid tert-butyl ester. 2,7 ESI-MS: 747 [M+H] + R t (HPLC): 1.27 min (Method B)

[0118] Intermediate I.02: Step 1: ​The reaction was carried out under an argon atmosphere, the solvent was degassed and dried by addition of molecular sieves. To intermediate 1.01 (721 mg; 0.916 mmol) in a round bottom flask were added DMSO (10 ml), methyl bromodifluoroacetate (266 μL; 2.42 mmol) and copper powder (291 mg; 4.58 mmol). The mixture was stirred overnight, then an additional equivalent of methyl bromodifluoroacetate and two additional equivalents of copper were added. After further stirring for 72 h, the mixture was diluted with EtOAc, a solution of potassium dihydrogen phosphate (1.27 M; 20 mL) was added and the mixture was stirred for another 30 min 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 (3S,4S)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-[4-(1,1-difluoro-2-methoxy-2-oxoethyl)-8-oxa-3,5-diazabicyclo[7.4.0.0 2,7 ]thirteen-1(13),2,4,6,9,11-hexaen-6-yl]pyrrolidin-3-yl]oxy}-1H-1,3-benzodiazol-1-yl)-3-methylpiperidine-1-carboxylic acid tert-butyl ester.

[0119] Step 2: To a solution of the product of step 1 (585 mg; 0.647 mmol) in dry ethanol (dried over molecular sieves) was added sodium borohydride (244 mg; 6.40 mmol) portionwise over 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 sequentially with water and brine, separated and 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 (3S,4S)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-[4-(1,1-difluoro-2-hydroxyethyl)-8-oxa-3,5-diazabicyclo[7.4.0.0 2,7 ]thirteen-1(13),2,4,6,9,11-hexaen-6-yl]pyrrolidin-3-yl]oxy}-1H-1,3-benzodiazol-1-yl)-3-methylpiperidine-1-carboxylic acid tert-butyl ester.

[0120] 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 min, then quenched by the addition of water. The mixture was extracted three times with EtOAc, and the combined organic layers were washed sequentially with water and brine, separated, and 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 (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-diazabicyclo[7.4.0.02,7]trideca-1(13),2,4,6,9,11-hexaen-6-yl}pyrrolidin-3-yl]oxy}-1H-1,3-benzodiazol-1-yl)-3-methylpiperidine-1-carboxylic acid tert-butyl ester. 2,7 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-diazabicyclo[7.4.0.02,7]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. ESI-MS: 789 [M+H] + R t (HPLC): 1.29 min (Method B)

[0121] Intermediate I.03: To a solution of 3-allyloxypropanoic 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, then diluted with methanol (2 mL) and purified by RP HPLC (Sunfire C18; ACN / water, modifier: TFA). ESI-MS: 406 [M+H] + R t (HPLC): 0.88 min (Method E)

[0122] Intermediate N The synthetic section described below was performed in part according to the general procedures indicated below. General procedure Int-A: hydrogenation with Pd / C catalyst (see Intermediate N-A, step 4) General procedure Int-B: ring closure under basic conditions (see: Intermediate N-A, step 5) General procedure Int-C: Chlorination with phosphorous oxychloride (see: Intermediate N-A, step 7) General procedure Int-D: S-acylation with hydroxyproline ester N Ar (see: Intermediate N-A, step 8) General procedure Int-E: Ester cleavage with lithium hydroxide (see: Intermediate N-F, step 2) General procedure Int-F: Amide formation with PFTU (see: Intermediate N-F, step 3) General procedure Int-G: Heck-type coupling (see: Intermediate N-J, step 1)

[0123] Intermediate N-A: Step 1: A mixture of tert-butyl 3-(2-oxoethoxy)propanoate (7.25 g; 38.5 mmol) and (triphenylphosphoranyl)acetate (13.1 g; 38.5 mmol) in DCM (200 mL) was stirred at room temperature overnight. The mixture was evaporated under reduced pressure and dissolved in CH / EtOAc (3:1). Insolubles were removed by filtration and the filtrate was evaporated. The crude product was purified by FC (silica gel; CH / EtOAc 10% -> 45%) to give the product as a mixture of cis and trans isomers.

[0124] Step 2: The product of step 1 (1.50 g; 6.14 mmol) was stirred into a mixture of DCM (15 mL) and TFA (10 mL) overnight. The mixture was evaporated and dissolved in methanol (10 mL). Polymeric tetraalkylammonium carbonate (2 eq by weight) was added and the mixture was stirred for 90 min. Insolubles were filtered off and the filtrate was evaporated.

[0125] 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% -> 80%) and second by RP HPLC (Sunfire C18, ACN / water, modifier: TFA). ESI-MS: 347 [M+H] + R t (HPLC): 0.80 min (Method E)

[0126] Step 4: General Procedure Int-A: A mixture of the product of Step 3 (3.40 g; 9.73 mmol), palladium on carbon (10%; 350 mg) and ethanol (500 mL) was shaken under hydrogen pressure (50 psi) until the reaction control by RP HPLC indicated that the starting material had been converted (here: 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)

[0127] Step 5: General Procedure Int-B: A mixture of the product of Step 4 (4.55 g; 13.1 mmol) and aqueous sodium hydroxide solution (4 M; 100 mL; 400 mmol) was stirred at 60 °C until the reaction control by RP HPLC indicated that the starting material had been converted (here: 60 min). The mixture was allowed to cool to room temperature and was then acidified by the addition of aqueous hydrochloric acid solution (4 M). The precipitate was collected and dried at 60 °C. ESI-MS: 317 [M+H] + R t (HPLC): 0.73 min (Method E)

[0128] 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 h, then methanol was added and stirring was continued for 60 min. 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)

[0129] Step 7: General Procedure Int-C: A mixture of the product of Step 6 (3.70 g; 11.2 mmol) and phosphorous oxychloride (70 mL) was stirred at 90 °C for 4 h. Excess phosphorous oxychloride was removed by distillation and water was carefully added. The resulting mixture was extracted with EtOAc, the organic layer was separated and evaporated. The crude product was used in the next step without further purification. ESI-MS: 349 [M+H] + R t (HPLC): 1.02 min (Method E)

[0130] Step 8: General procedure Int-D: A mixture of the product of Step 7 (300 mg; 0.896 mmol), (2S,4S)-4- hydroxypyrrolidine-2-carboxylic acid tert-butyl ester 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 the addition of 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% -> 75%). ESI-MS: 500 [M+H] + R t (HPLC): 0.75 min (Method E)

[0131] Step 9: The product of Step 8 was reacted according to general procedure Int-E to give the title compound which was cleaved from the ester. ESI-MS: 486 [M+H] + R t (HPLC): 0.70 min (Method E)

[0132] Intermediate N-B: Prepared in Step 3 applying 3-amino-6-chloro-1-benzofuran-2-carboxamide in analogy to the sequence described for the synthesis of Intermediate N-A. ESI-MS: 520 [M+H] + R t (HPLC): 0.50 min (Method A)

[0133] Intermediate N-C: was prepared from intermediate N-V and 2-(but-3-en-1-yloxy)acetic acid using a two-step sequence: Step 1 : According to general procedure Int-G Step 2: According to general procedure Int-A to give the title compound. ESI-MS: 504 [M+H] + R t (HPLC): 0.45 min (Method A)

[0134] Intermediate N-D: Analogous to the sequence described for the synthesis of intermediate N-A, using tert-butyl 2-(3-oxopropoxy)acetate prepared as described in EP1939201 as starting material. ESI-MS: 486 [M+H] + R t (HPLC): 0.71 min (Method E)

[0135] Intermediate N-E: 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]diazepino[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 suction filtered off, washed with water and dried under vacuum at 60 °C to give a mixture of ethyl 2-[2-({6-oxo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]thirteen-1 (9),2(7),3,10,12-penten-4-yl}methoxy)ethoxy]acetate and the respective free acids which was used as such in the next step.

[0136] Step 2: For re-esterification with acid, the mixture of Step 1 (2.8 g) was dissolved in DCM (200 mL). 2 drops of DMF were added followed by oxalyl chloride (392 μί, 4.57 mmol). The mixture was stirred overnight, then ethanol (10 mL) was added and the mixture was stirred for another 2 h. The mixture was concentrated under reduced pressure. Methyl-tert-butyl ether was added, the formed precipitate was washed with methyl-tert-butyl ether and dried at 50 °C to give 2-[2-({6-oxo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]thirteen-1 (9), 2(7), 3, 10, 12-penten-4-yl}methoxy)ethoxy]acetic acid ethyl ester.

[0137] The product of Step 2 was further reacted in a 2-step sequence according to the first 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)

[0138] Intermediate N-F: Step 1: The zinc powder 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 powder (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 min. Then, tert-butyl hex-5-enoate (4.63 g; 18.5 mmol; prepared as described in WO 2010 / 15447) was added in one portion and ethyl iodo-fluoroacetate (2.80 mL; 18.5 mmol) was added dropwise (an exothermic reaction occurred during the addition) while keeping the temperature below 30 °C. After the addition was complete, the reaction mixture was stirred at 60 °C for 4 h. 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. Then, the mixture was filtered through a pad of celite, the aqueous phase was extracted with diethyl ether after phase separation. 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% -> 100%). ESI-MS: 312 [M+NH4] + R t (HPLC): 0.78 min (Method A)

[0139] 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 2:1 THF / H2O and the reaction mixture was stirred at room temperature until reaction control by RP HPLC indicated depletion of starting material (here: 2.5 h). The volatiles were removed in vacuo, the residue was acidified to pH = 1 by addition of 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-isobuten + H] + R t (HPLC): 0.59 min (Method A)

[0140] Step 3: General procedure Int-F: 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) at room temperature and the mixture was stirred for 30 min. Subsequently, 3-aminobenzofuran-2-carboxamide (1.01 g; 5.60 mmol) and additional DIPEA (970 μL; 5.60 mmol) were added and the mixture was stirred at room temperature for 10 min. Subsequently, the reaction mixture was heated to 50 °C and stirred at this temperature for 16 h. Since reaction control by RP HPLC indicated that the starting material was not completely depleted, 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 another 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)

[0141] Step 4: Chlorotrimethylsilane (4.05 mL; 30.3 mmol) was added slowly 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) at room temperature. 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 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 yield 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. ESI-MS: 405 [M-H] - R t (HPLC): 0.44 min (Method F)

[0142] Step 5: The product of Step 4 was converted to the chlorinated product using the general procedure Int-C, followed by purification by RP-HPLC (XBridge C18; ACN / water; modifier: TFA). ESI-MS: 367 [M-H] - R t (HPLC): 0.64 min (Method A)

[0143] Step 6: The product of Step 6 was reacted according to the general procedure Int-D to give the title compound. ESI-MS: 520 [M+H] + R t (HPLC): 0.61 min (Method A)

[0144] Intermediate N-G: The reaction sequence described for the synthesis of Intermediate N-F was followed, applying 3-amino-6-fluorobenzofuran-2-carboxamide in Step 3.

[0145] Intermediate N-H: The reaction sequence described for the synthesis of Intermediate N-F was followed, applying 3-amino-6-chlorobenzofuran-2-carboxamide in Step 3.

[0146] Intermediate N-I: 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 dropwise addition of a solution of 1-bromo-3-butene (111 g; 821 mmol) in THF (850 mL). The temperature was maintained below 50 °C. The resulting mixture was cooled to -75 °C and a solution of diethyl oxalate (100 g; 684 mmol; 93.5 mL) in THF (1.89 L) was added dropwise at -75 °C. The mixture was further stirred at -75 °C for 4 h. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution (900 mL) at 0 °C followed by adjusting the pH to pH 3 by addition of aqueous hydrochloric acid (1 M). The mixture was extracted with EtOAc (500 mL) three times. The combined organic layers were washed with brine (900 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by FC (silica gel; petroleum ether / ethyl acetate 0% -> 100%). 1 H NMR: (400 MHz, CDC13): 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)

[0147] Step 2: To a solution of the product of Step 1 (50.0 g, 320 mmol) in DCM (1000 mL) was added 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 addition of 500 mL of saturated aqueous sodium bicarbonate solution and then extracted with DCM (500 mL) three times. 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 under vacuum (30 °C, 0.09 MPa / oil pump). 1 H NMR: (400 MHz, CDC13): 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)

[0148] 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 min. 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 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (60.0 mL) at 0 °C, and then extracted with DCM (60.0 mL) three times. 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)

[0149] Step 4: To a solution of the product of Step 3 (11.0 g, 36.4 mmol) in dioxane (30.0 mL) was 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 hours, then diluted with water (30.0 mL) and extracted with EtOAc (30.0 mL) three times. 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).

[0150] Step 5: The product of Step 4 was chlorinated using General Procedure Int-C.

[0151] Step 6: The product of Step 5 was reacted using General Procedure Int-D to give the title compound. ESI-MS: 556 [M+H] + R t (HPLC): 0.64 min (Method A)

[0152] Intermediate N-J: The following 3-step sequence was applied to prepare from Intermediate N-R: Step 1: General Procedure Int-G: Intermediate N-R (300 mg; 0.69 mmol) and methyl 5-hexenoate (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) afforded tert-butyl (2S,4S)-4-hydroxy-l-{4-[6-methoxy-6-oxohex-l-en- 1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]trideca-l(13),2,4,6,9,11-hexen-6-yl}pyrrolidine-2-carboxylate.

[0153] Step 2: The product of Step 1 was hydrogenated according to General Procedure Int-A to give tert-butyl (2S,4S)-4-hydroxy-l-[4-(6-methoxy-6-oxohexyl)-8-oxa-3,5- diazatricyclo[7.4.0.0 2,7 ]trideca-l(13),2,4,6,9,11-hexen-6-yl]pyrrolidine-2-carboxylate. ESI-MS: 484 [M+H] + R t (HPLC): 0.65 min (Method B)

[0154] Step 3: The product of Step 2 was reacted according to General Procedure Int-E to give the title compound with ester cleavage.

[0155] Intermediate N-K: Prepared from intermediate N-R and 3-(but-3-en-2-yloxy)propionic acid methyl ester (starting material 3-(but-3-en-2-yloxy)propionic acid methyl ester was prepared from the respective tert-butyl ester by acidic ester cleavage followed by methyl ester formation (methanol, thionyl chloride)) applying 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 to yield the title compound. ESI-MS: 500 [M+H] + R t (HPLC): 1.82 min (Method G)

[0156] Intermediate N-L: 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 Step 1 : A dry reaction vessel was equipped with a magnetic stir bar and 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). The reaction vessel was charged with anhydrous DMF (40 mL), bromo-difluoro-acetic acid ethyl ester (1.5 mL, 11.6 mmol) and phenylsilane (2.9 mL; 23.2 mmol) in this order via syringe. The vessel was heated in an oil bath at 70 °C and stirred until TLC monitoring indicated consumption of starting material (here: overnight). The reaction mixture was diluted with 30 mL EtOAc and the organic layer was washed with 80 mL saturated aqueous sodium chloride solution. Thereafter, the organic layer was dried over sulfate and concentrated under reduced pressure and further purified by FC (silica gel; hexanes / EtOAc) to yield 5-(2-tert-butoxy-2-oxo-ethoxy)-2,2-difluoro-pentanoic acid ethyl ester.

[0157] Step 2: To a solution of 3-amino-6-chloro-1-benzofuran-2-carboxylic acid (0.50 g; 2.28 mmol) in 1,4-dioxane (1 mL) was added 1,5,7-triazabicyclodec-5-ene (0.79 g; 5.68 mmol) at room temperature. Subsequently, the product of Step 1 (0.84 g; 2.84 mmol) was added, the temperature was raised to 120 °C and stirring was continued until TLC indicated almost complete conversion (here: 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 between 4 and 5 and the precipitated solid was filtered off. ESI-MS: 353 [M+H] + R t (HPLC): 1.61 min (Method H)

[0158] 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 min (Method H)

[0159] 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 min (Method G)

[0160] Intermediate N-M: Prepared in analogy to the procedure described for the synthesis of Intermediate N-L applying 3-amino-6-chloro-1-benzofuran-2-carboxylic acid (prepared as described in EP1710233) as starting material in Step 2.

[0161] Intermediate N-N: Prepared in analogy to the reaction sequence described for the synthesis of Intermediate N-J from Intermediate N-R and methyl 4,4-dimethylhept-6-enoate.

[0162] Intermediate N-O: Prepared in analogy to the reaction sequence described for the synthesis of Intermediate N-J from Intermediate N-R and ethyl 6-heptenoate.

[0163] Intermediate N-P: Intermediate N-U was reacted according to the general procedure Int-E to give the title compound. ESI-MS: 414 [M+H] + R t (HPLC): 0.55 min (Method B)

[0164] Intermediate N-Q: (2S,4S)-1-[4-(7-ethoxy-7-oxohept-1-en-2-yl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]thirteen-1(13),2,4,6,9,11-hexaen-6-yl]-4-hydroxypyrrolidine-2-carboxylic acid tert-butyl ester formed as a by-product in step 1 of the synthesis of Intermediate N-O was isolated by RP HPLC and further reacted according to the reaction sequence described for the preparation of Intermediate N-O to give the title compound.

[0165] Intermediate N-R: (2S,4S)-1-{4-bromo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]thirteen-1(13),2(7),3,5,9,11-hexaen-6-yl}-4-hydroxypyrrolidine-2-carboxylic acid tert-butyl ester Step 1 : 4,6-dibromo-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]thirteen-1(13),2(7),3,5,9,11-hexaene A mixture of 1 H-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, the pH was adjusted to pH = 7 using saturated aqueous sodium bicarbonate solution while cooling at 0 °C and the mixture was extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over sodium sulfate and evaporated under reduced pressure. The remaining residue was purified by dissolution in a mixture of DCM (3 V compared to the weight of the crude material) and EtOAc (3 V compared to the weight of the crude material) under 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)

[0166] Step 2: (2S,4S)-1-{4-bromo-8-oxa-3,5-diazatricyclo[7.4.0.0]} 2,7 [13-1(13),2(7),3,5,9,11-hexane-6-yl}-4-hydroxypyrrolidine-2-carboxylic acid tert-butyl ester] Add (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid tert-butyl hydrochloride (4.17 g, 16.6 mmol) and potassium carbonate (7.03 g, 50.8 mmol) to a mixture of 4,6-dibromo-8-oxa-3,5-diazatricyclo[7.4.0.02,7]decadecyl-1(13),2(7),3,5,9,11-hexane (5.56 g, 16.9 mmol) in 93 mL of DMF. After stirring overnight at room temperature, pour the reaction mixture into water and neutralize with 4 M HCl aqueous solution. Collect the precipitate by filtration and dry under vacuum. ESI-MS: 434 / 436 [M+H] + R t (HPLC): 0.64 min (Method A)

[0167] Intermediate NS: 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. Oxygenyl chloride (23.4 g; 184 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 2 h. 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 h, the mixture was poured into 100 mL of water and stirred for 5 min. The resulting solid was collected, dissolved in DCM, and dried over magnesium sulfate. The evaporation was evaporated, and the solid was wet-milled with tert-butyl methyl ether to give 3-[2-(prop-2-en-1-yloxy)acetamito]-1-benzofuran-2-carboxamide.

[0168] Step 2: The product of step 1 was stirred in a suspension in a 4M sodium hydroxide aqueous solution at 70°C for 2 h. The mixture was acidified by adding hydrochloric acid aqueous solution, and the resulting precipitate was collected and dried to give 4-[(prop-2-en-1-yloxy)methyl]-8-oxa-3,5-diazatricyclo[7.4.0.0] 2,7Tridecane-1(9),2(7),3,10,12-penten-6-one.

[0169] The product of Step 2 is further reacted in a 2-step sequence according to General Procedures Int-C and then Int-D to yield the title compound. ESI-MS: 426 [M+H] + R t (HPLC): 0.49 min (Method A)

[0170] Intermediate N-T: Step 1: Sodium hydride (60% in mineral oil; 1.73 g, 44.2 mmol) was added portionwise to a solution of 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 over a period of 2 minutes 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) until pH = 5-6 was reached, then the aqueous layer was 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% -> 30%) to give 2-(allyloxy)-2,2-difluoroacetic acid. 1 H NMR (400 MHz, CDC13) 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)

[0171] 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 phosphorus oxychloride (15.3 g, 0.1 mol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL) three times. 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] +

[0172] Step 3: The product of Step 2 (3 g, 9.7 mmol) was added to an aqueous sodium hydroxide solution (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 (RT) reaction mixture was acidified with aqueous hydrochloric acid (2 M) to pH = 5 to 6, the formed precipitate was collected and dried to yield crude 2-((allyloxy)difluoromethyl)benzofuro[3,2-d]pyrimidin-4(3H)-one which was used in the next step without further purification.

[0173] Step 4: A 3-necked 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 followed by the dropwise addition of oxalyl chloride (3.54 g, 27.9 mmol) in DCM (5 mL) over 5 min while maintaining the temperature at 0 °C to 5 °C. The mixture was stirred at ambient temperature for 0.5 h. The reaction was cooled to 0 °C in an ice bath and the product of Step 3 (1.8 g, 6.2 mmol) was added in portions. The reaction was stirred at room temperature for 15 min followed by stirring at 40 °C for 2 h. After cooling to room temperature, the reaction was poured into ice, neutralized with aqueous sodium bicarbonate, extracted twice with DCM (100 mL). The combined organic phases were 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) d 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)

[0174] Step 5: The product of Step 4 was reacted according to the general procedure Int-D to yield the title compound. ESI-MS: 462 [M+H] + R t (HPLC): 0.68 min (Method A)

[0175] Intermediate N-U: (2S,4S)-1-[4-(2-ethoxy-2-oxoethyl)-8-oxa-3,5-diazabicyclo[7.4.0.0 2,7 ]tridec-1(9),2(7),3,5,10,12-hexaen-6-yl]-4-hydroxypyrrolidine-2-carboxylic acid tert-butyl ester Step 1 : Ethyl 2-{6-oxo-8-oxa-3,5-diazabicyclo[7.4.0.0 2,7 ]tridec-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 h. After cooling to room temperature, an additional 2.6 mL (24.4 mmol) of ethyl cyanoacetate was added and heating at 100 °C was continued for 48 h. The solvent was evaporated and the crude residue was diluted with 100 mL of MeOH, filtered and dried. The crude product was used directly in the next step. ESI-MS: 273 [M+H] + R t (HPLC): 0.63 min (Method B)

[0176] Step 2: Ethyl 2-{6-chloro-8-oxa-3,5-diazabicyclo[7.4.0.0 2,7 ]tridec-1(9),2(7),3,5,10,12-hexaen-4-yl}acetate A mixture of ethyl 2-{6-oxo-8-oxa-3,5-diazabicyclo[7.4.0.0 2,7 ]tridec-1(9),2(7),3,10,12-pentaen-4-yl}acetate (3.35 g; 12.3 mmol) in phosphorus oxychloride (50.0 mL; 547 mmol) was heated at 110 °C for 1.5 h. The reaction mixture was allowed to cool to room temperature and added dropwise to an ice bath (500 mL) under stirring over 30 min. Ethyl acetate was added and the layers were separated. To the organic layer was added slowly a saturated bicarbonate solution 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)

[0177] Step 3: (2S,4S)-1-[4-(2-ethoxy-2-oxoethyl)-8-oxa-3,5-diazabicyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]-4-hydroxypyrrolidine-2-carboxylic acid tert-butyl ester To a solution of ethyl 2-{6-chloro-8-oxa-3,5-diazabicyclo[7.4.0.0 2,7 ]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}acetate (8.17 mmol; 2.50 g) in 30 mL of NMP was added (2S,4S)-tert-butyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (8.99 mmol; 2.01 g) and DIPEA (27.0 mmol; 4.64 mL) and the resulting mixture was stirred at 70 °C for 1.5 h. The reaction mixture was allowed to cool to room temperature and was 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)

[0178] Intermediate N-V: Prepared in analogy to the reaction sequence described for the synthesis of Intermediate N-R from 11-fluoro-8-oxa-3,5-diazabicyclo[7.4.0.0 2,7 ]trideca-1(13),2(7),9,11-tetraene-4,6-dione. The starting material 11-fluoro-8-oxa-3,5- diazabicyclo[7.4.0.0 2,7 ]trideca-1(13),2(7),9,11-tetraene-4,6-dione was prepared in analogy to the synthesis of 11-chloro-8-oxa-3,5-diazabicyclo[7.4.0.0 2,7 ]trideca-1(13),2(7),9,11-tetraene-4,6-dione as described in WO2019059577.

[0179] Preparation of final compounds The absolute configuration of the piperidine moiety of the compounds for which R2is methyl has been assigned based on the co-crystal structure with the human cGAS protein according to the method described by D.J. Patel et al., PNAS 2019, 11946-11955 (doi.org / 10.1073 / pnas.1905013116) in part (e.g. for Example 1.01). In other cases, the absolute configuration has been assigned based on the assumption that the stronger diastereomer always has the (S, S, S, S)-configuration.

[0180] Example 1.01 (General procedure A, B, C, D) Step 1 (General procedure A): To intermediate N-A (216 mg; 0.418 mmol) and intermediate B-01 (188 mg; 0.439 mmol) dissolved in DMA (4.05 ml) was added sodium hydride (55% in mineral oil; 73.0 mg; 1.67 mmol) in an oven-dried glassware under an argon atmosphere. After the bubbling had subsided, the reaction was warmed to 35 °C and stirred for 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, the combined organic layers were then washed with water and brine and evaporated to dryness. The crude reaction mixture was purified by FC (silica gel; cyclohexane / EtOAc 25% -> 100%). ESI-MS: 833 [M+H] + R t (HPLC): 0.92 min (Method B)

[0181] Step 2 (General procedure B): To a mixture of the intermediate of step 1 (272 mg; 0.326 mmol) and ACN (10 mL) was added TosOH (124 mg; 0.653 mmol) and the mixture was stirred in a closed vial at room temperature for 3 days. Reaction control by HPLC indicated a low conversion, additional TosOH (45.0 mg; 0.237 mmol) was added and the mixture was further heated at 40 °C until reaction control by HPLC indicated a high conversion of the desired product. DMF and one drop of water were added, the mixture was then filtered and purified by HPLC (Sunfire C18; ACN / water with TFA as modifier). ESI-MS: 733 [M+H] + R t (HPLC): 0.62 min (Method B)

[0182] Step 3 (General procedure C): In an oven-dried glassware, under argon, a solution of the intermediate of step 2 (145 mg; 0.198 mmol) in DMF (12 mL) was slowly added by syringe pump to a solution of HATU (81.2 mg; 0.214 mmol) in DMF (4 mL) under vigorous stirring. The mixture was further stirred until reaction control by HPLC indicated a high conversion of the desired product. The reaction was then quenched by the addition of water, extracted three times with EtOAc, the combined organic layers were then 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)

[0183] Step 4 (General procedure D): A mixture of the intermediate of step 3 (79.0 mg; 0.110 mmol), DCM (1.06 ml) and TFA (852 μί) was stirred at room temperature for 90 min. Since reaction control by HPLC indicated a low conversion, the temperature was increased to 37 °C and stirring was continued for 3 h. Since reaction control by HPLC indicated a still low conversion, the temperature was increased to 45 °C and stirring was continued until reaction control by HPLC indicated a high conversion of the desired product. The mixture was evaporated and the crude product was purified by preparative HPLC (Sunfire C18; ACN / water with TFA as modifier). ESI-MS: 659 [M+H] + R t (HPLC): 0.83 min (Method E)

[0184] The following compounds were prepared in analogy to example 1.01 following general procedures A, B, C and D:

[0185] Example 2.01: Step 1: Intermediate B-09 was reacted according to general procedure D to give the TFA salt of rac-trans-7-chloro-2-methanesulfonyl-l-[3-methylpiperidin-4-yl]-lH- 1,3-benzodiazole

[0186] Step 2: The product of Step 1 was reacted according to general procedure C with 1.2 equivalents of 4-{[(tert-butoxy)carbonyl]amino}butyric acid.

[0187] Step 3: The product of Step 2 was reacted according to general procedure A with Intermediate N-P to give 2-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-({l-[l-(4-{[(tert- butoxy)carbonyl]amino}butanoyl)-3-methylpiperidin-4-yl]-7-chloro-lH-l,3- benzodiazol-2-yl}oxy)pyrrolidin-l-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]thirteen-l(9),2(7),3,5,10,12-hexaen-4-yl}acetic acid (with rac trans configuration at the piperidine moiety).

[0188] Step 4: The product of Step 3 was deprotected from the BOC group by reaction with 1.5 equivalents of hydrochloric acid (4 M in dioxane) in dioxane overnight at room temperature. The crude product was purified by RP HPLC (Sunfire C18; ACN / water / modifier: TFA) to give the TFA salt of 2-{6-[(2S,4S)-4-({l-[l-(4- aminobutanoyl)-3-methylpiperidin-4-yl]-7-chloro-lH-l,3-benzodiazol-2-yl}oxy)-2- [(tert-butoxy)carbonyl]pyrrolidin-l-yl]-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]thirteen-l(9),2(7),3,5,10,12-hexaen-4-yl}acetic acid (with rac trans configuration at the piperidine moiety).

[0189] Step 5: The product of Step 4 was reacted according to general procedure C to give (12S,14S)-4-chloro-37-methyl-29,34-dioxo-l l,18-dioxa-2,9,15,26,30,35,40- heptazatetracyclo[33.2.2.1 12,15 .1 16,27 .0 2,10 .0 3,8 .0 17 ,25 .0 19,24Tert-butyl (2S,4S)-1-{4-[1,1 -difluoro-2-(prop-2-en-1 -yloxy)ethyl]-8-oxa-3,5- diazatricyclo[7.4.0.0

[0190] Step 6: The product from Step 5 was 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- heptazatetracyclo[33.2.2.1 12,15 .1 16,27 .0 2 ,10 .0 3,8 .0 17,25 .0 19,24 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 ESI-MS: 672 [M+H] + R t (HPLC): 0.88 min (Method E)

[0191] Example 3.01 : Step 1 : 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 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 ESI-MS: 689 [M+H] + R t (HPLC): 0.62 min (Method A)

[0192] 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) was added dropwise DCC (1 M; 165 μL; 0.165 mmol) at 0 °C. The mixture was allowed to warm to room temperature while stirring and then stirred for a further 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 (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-diazabicyclo[7.4.0.0 2,7 ]trideca-1(13),2,4,6,9,11-hexaen-6-yl}pyrrolidine-2-carboxylic acid tert-butyl ester. ESI-MS: 757 [M+H] + R t (HPLC): 0.77 min (Method A)

[0193] Step 3: General procedure H: To a solution of the product of Step 2 (purified by co-distillation with toluene; 77.0 mg; 0.102 mmol) in 1,2-dichloroethane (degassed; 9.0 ml) was added Grubbs II catalyst (5.0 mg) in an oven-dried glass vessel. The mixture was stirred at 80 °C for 24 h, whereupon the same amount of catalyst was added again and the mixture was stirred for a further 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% -> 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 trideca-1(13),2,4,6,9,11-hexaen-6-yl}pyrrolidine-2-carboxylic acid tert-butyl ester. ESI-MS: 729 [M+H] + R t (HPLC): 0.73 min (Method A)

[0194] 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) overnight in a Parr apparatus. The mixture was filtered, evaporated and used in the next step. ESI-MS: 731 [M+H] + R t (HPLC): 1.09 min (Method E)

[0195] 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)

[0196] Example 4.01: 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% -> 100%) to give (3S,4S)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-[4-(2-{[4-ethoxy-4-oxobutan-2- en-1 -yl]oxy}-1,1 -difluoroethyl)-8-oxa-3,5-diazatricyclo[7.4.0.0 2,7 ]thirteen-1 (13),2,4,6,9,11-hexaen-6-yl]pyrrolidin-3-yl]oxy}-1 H-1,3-benzodiazol-1 -yl)-3- methylpiperidine-1 -carboxylic acid tert-butyl ester. ESI-MS: 861 [M+H] + R t (HPLC): 1.28 min (Method B)

[0197] 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 stirred in a Parr apparatus under hydrogen (50 psi) at room temperature until HPLC control indicated that the starting material had been converted (4 h). The mixture was filtered, concentrated under reduced pressure and purified by RP HPLC (XBridge C18, ACN / water, modifier: TFA) to give (3S,4S)-4-(2-{[(3S,5S)-5-[(tert-butoxy)carbonyl]-1-{4-[2-(4-ethoxy-4-oxobutoxy)-1,1-difluoroethyl]-8-oxa-3,5-diazabicyclo[7.4.0.0 2,7 ]thirteen-1(13),2,4,6,9,11-hexaen-6-yl}pyrrolidin-3-yl]oxy}-1H-1,3-benzodiazol-1-yl)-3-methylpiperidine-1-carboxylic acid tert-butyl ester. ESI-MS: 863 [M+H] + R t (HPLC): 1.28 min (Method B)

[0198] 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 μί; 0.306 mmol), MeOH (0.80 mL) and THF (4.0 mL). The mixture was stirred at 40 °C until HPLC analysis indicated conversion (7 h), concentrated under reduced pressure, diluted with water and acidified with an equimolar amount of aqueous hydrochloric acid. A 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.

[0199] Step 4: The product of Step 3 was 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-diazabicyclo[7.4.0.0 2,7 ]thirteen-1(13),2,4,6,9,11-hexaen-4-yl}-2,2-difluoroethoxy)butanoic acid.

[0200] Step 5: The product of Step 4 was reacted according to General Procedure C to give (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 tert-Butyl 41 -3, 5, 7, 9, 16, 19, 21, 23, 25, 27(40)-decatriene-14-carboxylate.

[0201] 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)

[0202] Example 5.01: The following reaction sequence was applied using intermediates N-S and B-11 as starting materials: Step 1 : Nucleophilic aromatic substitution using General Procedure A (reagents: N-S and B-11) Step 2: Removal of the BOC protecting group using General Procedure B Step 3: Reaction with 4-pentenoic acid using General Procedure G Step 4: Metathesis using General Procedure H Step 5: Hydrogenation using General Procedure E Step 6: Removal of the tert-butyl ester protecting group using General Procedure D ESI-MS: 643 [M+H] + R t (HPLC): 0.58 min (Method A)

[0203] Example 6.01: The following reaction sequence was applied using intermediates N-T and B-02 as starting materials: Step 1 : Nucleophilic aromatic substitution using General Procedure A (reagents: N-T and B-02) Step 2: Cross-metathesis applying a modified version of general procedure H using methyl 3-butenoate as the second olefin (reaction in DCM at room temperature, applying 15 eq of methyl 3-butenoate and adding additional 15 eq of methyl 3-butenoate and additional 0.3 eq of catalyst in portions after 24 h). Step 3: Hydrogenation applying general procedure E (solvent: EtOAc) Step 4: Ester saponification applying general procedure F (aqueous lithium hydroxide solution / THF, 50 °C, 5 h) Step 5: Removal of the BOC protecting group applying general procedure B Step 6: Ring closing amidation applying general procedure C (solvent: DMA) Step 7: Removal of the tert-butyl ester protecting group applying general procedure D ESI-MS: 695 [M+H] + R t (HPLC): 0.72 min (method A)

[0204] Example 7.01: The synthesis was performed applying the following reaction sequence starting with intermediate N-R and intermediate B-10: Step 1: Nucleophilic aromatic substitution applying general procedure A (reagents: N-R and B-10) Step 2: Removal of the BOC protecting group applying general procedure B Step 3: Amidation applying general procedure C using (3R)-3-prop-3-en-1- yloxy)butanoic acid 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 catalyst [1,1 '-bis(di-tert-butylphosphino)ferrocene] palladium(II) dichloride (21.3 mg; 0.0320 mmol). The mixture was stirred at 120 °C for 24 h, 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 (12S,14S,32R)-32-methyl-34-oxo-11,18,31 -trioxa-2,9,15,26,35,40- hexaazaoctacyclo[33.2.2.12,5.17'0]nona-3(8),4,6,9,11,13,15,17,19,21,23,25-undecaen- 12-yl 2,2-dimethylpropionate (12 mg; 0.017 mmol, 8% yield) as a white solid. 12,15 .1 16,27 .0 2,10 .0 3,8 .017,25 .0 19,24 ]Fourty-one-3(8),4,6,9,16(40),17(25),19(24),20,22,26,28-undecene-14-carboxylic acid tert-butyl ester. ESI-MS: 679 [M+H] + R t (HPLC): 0.60 min (Method A) Step 5: Hydrogenation applying general procedure E. Step 6: Removal of the tert-butyl ester protecting group applying general procedure D ESI-MS: 625 [M+H] + R t (HPLC): 0.47 min (Method A)

[0205] Example 8.01 : The synthesis was performed applying the following reaction sequence starting with intermediates N-S and B-10: Step 1: Nucleophilic aromatic substitution applying general procedure A (reagents: N-S and B-10) 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 dry 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 yield 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-diazabicyclo[7.4.0.0 2,7 ]thirteen-1(13),2,4,6,9,11-hexaen-6-yl)pyrrolidin-3-yl]oxy}-1H-1,3-benzodiazol-1- yl)piperidine-1-carboxylate. ESI-MS: 649 [M+H] + R t(HPLC): 0.80 min (Method A) Step 3: Saponification of the ester applying general procedure F (aqueous lithium hydroxide solution / THF, rt, 2.5 h) Step 4: Removal of the BOC protecting group applying general procedure B Step 5: Ring closing amidation applying general procedure C, applying DMF containing HATU Step 6: Removal of the tert-butyl ester protecting group applying general procedure D ESI-MS: 647 [M+H] + R t (HPLC): 0.53 min (Method A)

[0206] Example 9.01: The synthesis was performed applying the following reaction sequence starting with intermediate N-R and intermediate B-10: Step 1: Nucleophilic aromatic substitution applying general procedure A (reagents: N-R and B-10) Step 2: General procedure I: Palladium (II) acetate (9.0 mg; 0.040 mmol) and tri-o-tolylphosphine (24.4 mg; 0.080 mmol) were added under argon to a degassed solution of the product of step 1 (326 mg; 0.400 mmol), allyloxyacetic acid (133 μί; 1.20 mmol) and triethylamine (112 μί; 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 yield 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 as a mixture of E / Z isomers. ESI-MS: 769 [M+H] + R t (HPLC): 0.57 / 0.58 min (Method F) Step 3: Hydrogenation applying general procedure E (solvent: EtOAc) Step 4: Removal of the BOC protecting group applying general procedure B Step 5: Ring closing amidation applying general procedure C applying DMF containing HATU Step 6: Removal of the tert-butyl ester protecting group applying general procedure D ESI-MS: 597 [M+H] + R t (HPLC): 0.42 min (Method A)

[0207] Example 10.01 and Example 10.02: The synthesis was performed applying the following reaction sequence starting with intermediate N-R and intermediate I.03: Step 1: Nucleophilic aromatic substitution applying general procedure A (reagents: N-R 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: Removal of the tert-butyl ester protecting group applying general procedure D Step 5: The resulting diastereomeric mixture was separated by preparative SFC (Instrument: Sepiatec PrepSFC 50; Column: CHIRALART Cellulose-SC (10 mm x 250 mm, 5 pm); Mobile phase: A for CO2 and B for IPA [+ 20 mM NH3]; 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 eluate) ESI-MS: 625 [M+H] + R t (HPLC): 0.804 min (Method E) and Example 10.02 (second eluate). ESI-MS: 625 [M+H] + R t (HPLC): 0.814 min (Method E)

[0208] Example 11.01: The synthesis was performed using the following reaction sequence starting with intermediate N-R and intermediate B-10: Step 1 : Nucleophilic aromatic substitution applying general procedure A (reagents: N-R 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-butoxide (229 mg; 2.04 mmol) and ACN (10 mL; dried over molecular sieves) was stirred in a sealed vial at 80 °C overnight. 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-diazabicyclo[7.4.0.0 2,7 ]tridec-1 (13),2,4,6,9,1 1 -hexaen-6-yl]pyrrolidin-3-yl]oxy}-1 H-1,3-benzodiazol-1 - yl)piperidine-1 -carboxylate. ESI-MS: 743 [M+H] + R t (HPLC): 0.70 min (Method A) 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 μί; 1.27 mmol) and DCM (6.0 mL) was stirred at rt for 4 h. The volatiles were evaporated and the crude product was used in the next step without further purification. Step 4: Acidic removal of the BOC protecting group applying the conditions of general procedure D. Step 5: For the ring closure of the carbamate formation the crude product of step 4 was dissolved in excess DIPEA and stirred at 70 °C for 90 min. The mixture was evaporated and used in the next step without purification. Step 6: Step 4: Removal of the tert-butyl ester protecting group applying general procedure D ESI-MS: 613 [M+H] + R t (HPLC): 0.50 min (Method A)

[0209] Example 12.01 (racemic mixture of the trans isomers): Example 12.01 (racemic mixture of the trans isomers): 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 was added dropwise a solution of 4-nitrophenyl- chloroformate (1.54 g; 7.62 mmol) in DCM (15 mL). 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.

[0210] Step 2: A mixture of the crude product of Step 1 (686 mg), Intermediate B-12 (500 mg), diisopropyl-ethylamine (742 μί) and THF (8.0 mL) was refluxed for 2 h. The mixture was evaporated, dissolved in EtOAc and extracted twice with aqueous sodium hydroxide solution (1 M), followed by water and brine. The organic layer was evaporated to dryness and the crude reaction product was purified by FC (silica gel; petroleum ether / EtOAc 5% -> 35%) to give racemic trans tert-butyl 2-{3-[3-methyl-4-[2-(methylsulfanyl)-1 H-1,3-benzodiazol-1 - yl]piperidine-1 -carbonyloxy]propoxy}acetate. ESI-MS: 478 [M+H] + R t (HPLC): 0.85 min (Method E)

[0211] Step 3: Acidic ester cleavage was performed applying the general procedure D without chromatographic purification.

[0212] 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 μί; 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% -> 95%). ESI-MS: 580 [M+H] + R t (HPLC): 0.81 min (Method E)

[0213] 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, acidified by the addition of aqueous hydrochloric acid (4 M). The supernatant was decanted and the solid purified by RP HPLC (Sunfire C18, ACN / water, modifier: TFA). ESI-MS: 562 [M+H] + R t (HPLC): 0.76 min (Method E)

[0214] Step 6: The product of Step 5 (390 mg; 0.694 mmol) was suspended in phosphorus oxychloride (6 mL). The mixture was stirred at 90 °C for 1 h, 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 2,7 ]thirteen-1(9),2(7),3,5,10,12-hexaen-4-yl}methoxy)propyl-3-methyl-4-[2-(methylthio)-1H-1,3-benzodiazol-1-yl]piperidine-1-carboxylate. ESI-MS: 580, 582 [M+H] + R t (HPLC): 0.89 min (Method E)

[0215] Step 7: A mixture of the product of Step 6 (300 mg; 0.517 mmol), (2S,4S)-tert-butyl 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, 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 ]thirteen-1(9),2(7),3,5,10,12-hexaen-4-yl}methoxy)propyl-3-methyl-4-[2-(methylthio)-1H-1,3-benzodiazol-1-yl]piperidine-1-carboxylate (the piperidine moiety having the racemic trans configuration). ESI-MS: 731 [M+H]+ R t (HPLC): 0.77 min (Method E)

[0216] 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, 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 ]thirteen-1(9),2(7),3,5,10,12-hexaen-4-yl}methoxy)propyl-4-(2-methylsulfonyl-1H-1,3-benzoxazol-1-yl)-3-methylpiperidine-1-carboxylate (racemic trans configuration with piperidine moiety). ESI-MS: 763 [M+H] + R t (HPLC): 0.85 min (Method E)

[0217] Step 9: Cyclization by aromatic nucleophilic substitution applying General Procedure A.

[0218] Step 10: Acidic tert-butyl ester cleavage applying General Procedure D to give the title compound. ESI-MS: 627 [M+H] + R t (HPLC): 0.83 min (Method E)

[0219] Example 13.01: 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 solution (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 with EtOAc three times. The combined organic layers were washed with water then brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by FC (silica gel; cyclohexane / EtOAc 25% -> 100%). ESI-MS: 234 [M+H] + R t(HPLC): 0.67 min (Method A)

[0220] Step 2: The reaction was performed under argon in oven-dried glassware. 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)ferrocene palladium dichloride (20.2 mg; 0.0311 mmol) and previously 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 purified 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-diazabicyclo[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. Step 3: Hydrogenation (including removal of the Cbz protecting group) was performed applying the general procedure E without chromatographic purification.

[0221] Step 4: To a solution of the crude product of Step 3 (199 mg) in DCM (3 mL) was 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 purified 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-diazabicyclo[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.

[0222] Step 5: Removal of the BOC protecting group applying the general procedure B

[0223] Step 6: The crude product from step 5 was added dropwise via a syringe pump to a solution of N,N-diisopropylethylamine (49 μL) in 1.5 mL of THF over 25 minutes. The mixture was stirred at 80 °C for 10 h. The mixture was then passed through a sodium bicarbonate filter 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 purified by RP HPLC (XBridge C18, ACN / water, conditioner: TFA). ESI-MS: 695 [M+H] + R t (HPLC): 0.61 min (Method A)

[0224] Step 7: Apply general procedure D to cleave tert-butyl ester to obtain the title compound. ESI-MS: 638 [M+H] + R t (HPLC): 0.55 min (Method A)

[0225] General Technology Review The terms “ambient temperature” and “room temperature” are used interchangeably and refer to a temperature of approximately 20°C, such as 15°C to 25°C.

[0226] Generally speaking, the prepared compound has been obtained. 1 1H NMR spectroscopy and / or mass spectrometry. Unless otherwise specified, all chromatographic operations are performed at room temperature.

[0227] List of abbreviations ACN Acetonitrile aq. Aqueous solution BOC tert-butyloxycarbonyl ℃ Celsius CH cyclohexane DCM dichloromethane DIPEA (diisopropylethylamine) DMA dimethylacetamide DMAP 4-Dimethylaminopyridine DMF N,N-dimethylformamide DMSO (dimethyl sulfoxide) EDC ({[3-(dimethylamino)propyl]imino}methylene)(ethyl)amine ESI-MS electrospray ionization mass spectrometry (m / z) EtOAc (ethyl acetate) FC rapid chromatography; SiO2 is used unless otherwise specified. Grubbs II dichloro[l,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]- (phenylmethylene)-(tricyclohexylphosphine)ruthenium(II) h hours HCl hydrochloric acid HATU [dimethylamino-(l,2,3-triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl- ammonium hexafluorophosphate HPLC high performance liquid chromatography IPA isopropyl alcohol MeOH methanol min minutes mL milliliters M molar n.d. not determined Pd / C(x%) palladium (x weight %) on carbon PFTU pentafluorophenol-tetramethyluronium hexafluorophosphate rac racemic RP reversed phase RT room temperature (about 20 °C) SFC supercritical fluid chromatography TFA trifluoroacetic acid THF tetrahydrofuran TosOH p-toluenesulfonic acid monohydrate R t Retention time in minutes Vol% volume percent

[0228] Analytical methods (HPLC / SFC): HPLC Method A: Column: XBridge BEH C18_2.1 x 30 mm_1.7 pm (Waters); CT: 60 °C HPLC Method B: Column: Sunfire C18_3.0 x 30 mm_2.5 pm (Waters); CT: 60 °C HPLC Method C: Column: XSelect HSS PFP_2.1 x 30 mm_1.8 pm (Waters); CT: 60 °C HPLC Method D: Column: Zorbax StableBond C18_3.0×30mm_1.8μm (Agilent); CT: 60℃ HPLC Method E: Column: Sunfire C18_3.0×30mm_2.5μm (Waters); CT: 60℃ HPLC Method F: Column: XBridge BEH C18_2.1×30mm_2.5μm (Waters); CT: 60℃ HPLC Method G: Column: Kinetex XB-C18 2.6μm (4.6×50mm), CT: 25℃ HPLC method H: Column: Acquity UPLC BEH C18 1.7μm (2.1×100mm); CT: 40℃; HPLC Method I: Column: Kinetex XB-C18 2.6μm (4.6×50mm), CT: 25℃ 4. Example 5.1 Example compounds of formula I, II or III of the present invention The example compounds of formulas I, II, or III as outlined in Table 1 have been synthesized and their pharmacological properties regarding their efficacy in inhibiting cGAS activity have been tested.

[0230] Specifically, the biochemical (in vitro) IC50 for cGAS inhibition was experimentally determined according to the assay methods described in Chapter 6 below. 50 Value (hcGAS IC) 50 ); "Regarding IFN-induced IC50 in THP1 cells inhibited by viral stimulation" 50 Value (THP) (vir) IC 50 ); "Regarding IFN-induced IC50 in THP1 cells inhibited by cGAMP stimulation" 50 Value (THP) (cGAMP) IC 50); and "Regarding IFN-induced IC50 in human whole blood with inhibition of dsDNA stimulation" 50 Value (hWB IC) 50 The results are summarized in Table 1.

[0231] The compounds of formulas I, II, or III summarized in Table 1 exhibit the following three properties simultaneously: Satisfactory results on the biochemical (in vitro) IC50 analysis of cGAS inhibition. 50 Value (where hcGAS IC) 50 ≤100nM, preferably ≤50nM, especially ≤10nM), • Satisfactory results regarding cellular IC50 for cGAS inhibition 50 Value (of which THP1) (vir) IC 50 ≤1μM, preferably ≤500nM, more preferably ≤100nM, especially ≤50nM) as well as Satisfactory selectivity for cGAS inhibition (of which THP1) (cGAMP) IC 50 / THP1 (vir) IC 50 (≥10, more preferably ≥50, more preferably ≥500, especially ≥1000).

[0232] In addition, the compounds of Formula I, II, or III also showed acceptable IC50 values ​​for inhibiting IFN-induced inhibition in human whole blood stimulated by dsDNA. 50 Value (hWB IC) 50 ). Table 1: Pharmacological properties of the compounds of Formula I, II or III of the present invention

[0233] 5.2 Comparison of example compounds of formula I, II or III with prior art compounds 5.2.1 Compounds of WO 2020 / 142729 In WO 2020 / 142729, cGAS inhibitors with partially similar structures have been disclosed.

[0234] On page 44 and 45 of WO 2020 / 142729, “biochemical (in vitro) IC 50 values” (corresponding to “hcGAS IC 50 ”) have been disclosed for cGAS inhibition. Here, compounds with “biochemical (in vitro) IC 50 values” less than 100 nM have been assigned to “Group A”, compounds with “biochemical (in vitro) IC 50 values” greater than 100 nM and less than 500 nM have been assigned to “Group B”, compounds with “biochemical (in vitro) IC 50 values” greater than 500 nM and less than 1 µM have been assigned to “Group C”, compounds with “biochemical (in vitro) IC 50 values” greater than 1 µM and less than 10 µM have been assigned to “Group D”, and compounds with “biochemical (in vitro) IC 50 values” greater than 10 µM have been assigned to “Group E” (see page 44 of WO 2020 / 142729).

[0235] On page 45 of WO 2020 / 142729, only compound no. 25 can be assigned to “Group A” with “biochemical (in vitro) IC 50 values” less than 100 nM. All other example compounds of WO 2020 / 142729 exhibit “biochemical (in vitro) IC 50 values” exceeding 100 nM.

[0236] Selected prior art compounds of WO 2020 / 142729, including compound no. 25, have been synthesized and subsequently tested for pharmacological properties with respect to their potency to inhibit the cGAS / STING pathway using exactly the same assays as used for testing the compounds of the present invention. In particular, the “biochemical (in vitro) IC 50 values” (hcGAS IC 50 ) for cGAS inhibition; the “cellular IC 50 values” (THP1 (vir) IC 50 ) for inhibition of IFN induction in virus-stimulated THP1 cells; the “cellular IC 50 values” (THP1 (cGAMP) IC 50 ) for inhibition of IFN induction in cGAMP-stimulated THP1 cells; and the “IC 50 values” (hWB) for inhibition of IFN induction in human whole blood (see Table 2) have been determined experimentally according to the assay methods described in Chapter 6 below for the structurally closest examples of WO 2020 / 142729. Table 2: Pharmacological properties of a series of example compounds of WO 2020 / 142729

[0237] The pharmacological properties of the example compounds of the present application outlined in Table 1 and the respective pharmacological properties of the compounds of WO 2020 / 142729 outlined in Table 2 can be compared with each other, since these compounds were determined experimentally according to the same assay procedures described in Chapter 6 below.

[0238] From the data shown in Table 2 it is evident that all example compounds of WO 2020 / 142729 exhibit a “biochemical (in vitro) IC 50 value” (= hcGAS IC 50 ) significantly greater than 100 nM, with the only exception being example No. 25 of WO 2020 / 142729 (in WO 2020 / 142729 designated in “Group A” with a “biochemical (in vitro) IC 50 value” (= hcGAS IC 50 ) less than 100 nM). In contrast, the “biochemical (in vitro) IC 50 value” (hcGAS IC 50 ) of the example compounds of the present application are all less than 100 nM. However, example No. 25 of WO 2020 / 142729 with a “biochemical (in vitro) IC 50 value” (hcGAS IC 50 ) of 55 nM does not fully comply with the selection criterion of exhibiting a “satisfactory cellular inhibitory potency” with a THP1 (vir) IC 50 lower than 1 µM, since the THP1 (vir) IC 50 of example No. 25 of WO 2020 / 142729 is 17 µM.

[0239] 5.2.2 Compounds of WO 2022 / 174012 In WO 2022 / 174012 cGAS inhibitors with a similar structure have been disclosed.

[0240] The “biochemical (in vitro) IC 50 value” for cGAS inhibition has been disclosed in WO 2022 / 174012 on page 65 and the “cellular IC 50“IFNbeta ELISA with THP-1 stimulation”. Compound 5 (BBL0100455) of WO 2022 / 174012 seems to be the only compound of WO 2022 / 174012 that can meet the selection criteria of the present application, which indicates that it has a) a “biochemical (or enzymatic) (in vitro) IC 50 value” less than 100 nM (in the “enzyme assay of WO 2022 / 174012, compound 5 was measured to belong to “Group B” which indicates an “enzyme IC 50 value” between 50 nM and 100 nM, see Table 2 of WO 2022 / 174012, page 65) b) and a “cellular IC 50 value” less than 1 pM (IFNbeta ELISA with THP-1 stimulation) (in the “cellular assay” of WO 2022 / 174012, compound 5 was measured to belong to “Group A” which indicates a “cellular IC 50 value” < 1 pM, see Table 3 of WO 2022 / 174012, pages 67 and 68).

[0241] However, the biochemical / enzymatic assay and the cellular assay of WO 2022 / 174012 are different from the respective “biochemical / enzymatic assay and cellular assay” of the present application, and therefore the biochemical / enzymatic IC 50 value and the cellular IC 50 value measured in WO 2022 / 174012 cannot be compared to the respective IC 50 value measured for the compounds of the present application. Therefore, compound 5 of WO 2022 / 174012 has been synthesized and subsequently tested for its pharmacological properties regarding its potency to inhibit the cGAS / STING pathway, using exactly the same assays as used for testing the compounds of the present application and described in chapter 6 below. Table 3: Pharmacological properties of compound 5 of WO 2022 / 174012

[0242] As shown by the data of Table 3, compound number 5 of WO 2022 / 174012 (BBL0100455) has an acceptable biochemical / enzymatic IC 50 value (hcGAS IC 50 = 55 nM), but a cellular IC 50 value greater than 10000 nM (THP1 (vir) IC 50 = 10000 nM). Therefore, the compounds of the present application have a biochemical / enzymatic IC 50comparable to compound no. 5 of WO 2022 / 174012 in terms of its cellular IC 50 significantly better than compound no. 5 of WO 2022 / 174012 (all of which are less than 1000 nM of the compounds of the present application of formula I, II or III).

[0243] 5.3 Prodrugs It is known that esters of active agents having a carboxylic acid group can represent viable prodrugs, which can exhibit improved oral absorption / bioavailability compared to the respective active agent. Commonly used prodrugs of active agents having a carboxylic acid group are, for example, methyl esters, ethyl esters, isopropyl esters and the like. (See Beaumont et al., Current Drug Metabolism, 2003, Vol. 4, Issue 6, 461-485).

[0244] Furthermore, Nakamura et al., Bioorganic & Medicinal Chem., Vol. 15, Issue 24, pages 7720-7725 (2007) describe that N-acylsulfonamide derivatives and N-acylsulfourea derivatives of specific active agents having a free carboxylic acid group can also be viable prodrugs.

[0245] In addition, experiments suggest that methyl esters of the example compounds of formula I, II or III have also been found to represent viable prodrugs of cGAS inhibitors of formula I, II or III.

[0246] PCT / EP2022 / 062480 and PCT / EP2022 / 062496 (both not published to date) both disclose structurally similar cGAS inhibitors as cGAS inhibitors of the present application, all of which also comprise a carboxylic acid group attached to the pyrrolidine moiety. In both PCT / EP2022 / 062480 and PCT / EP2022 / 062496, methyl ester derivatives of these cGAS inhibitors carrying a carboxylic acid group attached to the pyrrolidine moiety have been experimentally shown to be viable prodrugs of the cGAS inhibitors having a free carboxylic acid group.

[0247] Compounds P01, P02, P03 and P04 of PCT / EP2022 / 062480 are methyl ester derivatives and putative prodrugs of respective example compounds 4.04, 1.10, 1.12 and 3.14 of PCT / EP2022 / 062480 (all of which have a free carboxylic group and are active cGAS inhibitors with lower biochemical IC 50 values and lower cellular IC 50 values than compound no. 5 of WO 2022 / 174012).

[0248] The compounds P01, P02 and P03 of PCT / EP2022 / 062496 are the methyl ester derivatives and putative prodrugs of the respective example compounds 2.12, 1.13 and 1.05 of PCT / EP2022 / 062496 (all of which have a free carboxyl group and are active cGAS inhibitors with lower biochemical IC 50 values and lower cellular IC 50 values regarding cGAS inhibition).

[0249] In both PCT / EP2022 / 062480 and PCT / EP2022 / 062496, the “active cGAS inhibitors / example compounds with their free carboxylic acids” and their “respective methyl ester derivatives / putative prodrugs” have been synthesized and tested for their pharmacological properties regarding their potency to inhibit the cGAS / STING pathway.

[0250] This comparison between the properties of the example compounds of PCT / EP2022 / 062480 and PCT / EP2022 / 062496 with their free carboxylic acids on the one hand and the properties of their corresponding methyl ester derivatives / putative prodrugs on the other hand shows that the “biochemical IC 50 values (hcGAS IC 50 values) of the example compounds are always about or even less than 10 nM, whereas the “biochemical IC 50 values (hcGAS IC 50 values) of the corresponding methyl ester derivatives / prodrugs are always much larger, i.e. typically more than 7000 nM. The large difference between the IC 50 values of the example compounds on the one hand and the IC 50 values of their corresponding methyl ester derivatives / prodrugs on the other hand is never observed on the respective cellular IC 50 values (THP1 (vir) IC 50 values), the cellular IC 50 values of the example compounds and their corresponding prodrugs more or less always remain in the same range (see Table 4 below).

[0251] One possible explanation for this observation is that the example compounds all have a free carboxyl group, which seems to be essential for inhibiting cGAS activity, whereas in all “methyl ester derivatives / prodrugs” the carboxyl group is masked by a carboxyl-methyl ester group. Therefore, the methyl ester derivatives / prodrugs lose their inhibitory potency in the “in vitro human cGAS enzyme assay” (see chapter 6.1 below), because in this assay no intracellular enzymes are present that cleave the carboxyl-methyl ester group, so that the key free carboxylic acid group cannot be restored in the biochemical assay. Therefore, the prodrugs exhibit a much larger “biochemical (in vitro) IC 50 value” (= hcGAS IC50 ), whereas the corresponding example compounds, which from the outset already have a free carboxylic acid group, exhibit a smaller “biochemical (in vitro) IC 50 value” (= hcGAS IC 50 ).

[0252] In the cellular assay (= “human cGAS cell and counter cell assay”, see chapter 6.2 below), there are endogenous cellular enzymes which cleave the carboxy-methyl ester group. Thus, not only the example compounds of PCT / EP2022 / 062480 and PCT / EP2022 / 062496 themselves (which already carry a free carboxylic acid group) exhibit a smaller THP1 (vir) IC 50 value, but also the corresponding methyl ester derivatives / prodrugs exhibit a relatively small “THP1 (vir) IC 50 value”, since in this “human cGAS cell assay” the carboxy-methyl ester group of the prodrug can be cleaved by endogenous intracellular enzymes, whereby the “active example compound with free carboxylic acid group” would be released, which in turn exhibits cGAS inhibition potency.

[0253] This explanation together with the measured results shown in Table 4 indicates that the carboxy-methyl ester derivatives of the structurally similar example compounds of PCT / EP2022 / 062480 and PCT / EP2022 / 062496 actually seem to represent viable prodrugs of the respective example compounds with free carboxylic acid groups, which themselves do not have an inhibitory potency with regard to in vitro human biochemical cGAS inhibition. However, after cleavage of the carboxy-methyl ester by the endogenous intracellular enzymes present in the cellular assay, the “active example compound” is restored, which again exhibits an inhibitory potency with regard to the cGAS / STING pathway.

[0254] Since the example compounds of the application of formula I, II or III have a free carboxylic acid which is attached to the pyrrolidine moiety exactly as in the example compounds of PCT / EP2022 / 062480 or PCT / EP2022 / 062496, it can be expected that the carboxy-methyl ester derivatives of these compounds of formula I, II or III will also serve as prodrugs. Table 4: Comparison between selected cGAS inhibitor compounds disclosed in PCT / EP2022 / 062480 and PCT / EP2022 / 062496 and their respective methyl ester prodrugs:

[0255] 5. Biological experiments The activity of the compounds of the application can be demonstrated using the following in vitro cGAS enzyme and cell assays:

[0256] 6.1 Method: Human cGAS enzyme assay (hcGAS IC 50 (in vitro)) Human cGAS enzyme was incubated in the presence of 45 base pair double stranded DNA to activate the enzyme, GTP and ATP as substrates. Compound activity was determined by measuring the effect of the compound on the formation of the enzyme reaction product cGAMP, which was measured by mass spectrometry.

[0257] Enzyme preparation: Human cGAS (amino acids 1-522) with an N-terminal 6x-His tag and SUMO tag was expressed in E. coli BL21(DE3)pLysS (Novagen) cells at 18°C for 16h. Cells were lysed in a buffer containing 25mM Tris (pH8), 300mM NaCl, 10mM imidazole, 10% glycerol, cOmplete TM , EDTA-free, Roche) and DNAse (5pg / 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 20mM Tris (pH 7.5), 500mM KCl and 1mM TCEP. Purified protein was concentrated to 1,7mg / mL and stored at -80°C.

[0258] Assay methods Compounds were delivered into 10mM DMSO solution, serially diluted and transferred into 384 well assay plates (Greiner #781201) using an Echo acoustic dispenser. Typically 8 concentrations were used with the highest concentration in the final assay volume being 10mM, followed by approximately 1 :5 dilution steps. The DMSO concentration was set to 1% in the final assay volume. The 384 well assay plates contained 22 test compounds (rows 1-22) and DMSO in rows 23 and 24.

[0259] Following compound transfer, 15mL of enzyme-DNA working solution (12nM cGAS, 0.32mM 45 base pair DNA in assay buffer, 10mM Tris pH 7.5 / 10mM KCl / 5mM MgCl2 / 1mM DTT) was added to each well in rows 1-23 by a MultiDrop Combi dispenser. In row 24, 15mL of assay buffer without enzyme / DNA was added as a low control.

[0260] The plates were then pre-incubated at room temperature for 60 min.

[0261] Afterwards, 10 pL of GTP (ThermoFisher #R0461)-ATP (Promega #V915B) mix in assay buffer was added to the assay plates (rows 1-24, 30 pM final concentration each) using a Multidrop Combi.

[0262] The plates were again incubated at room temperature for 90 min.

[0263] After incubation, the reaction was stopped by 80 pL of 0,1 % formic acid containing 5 nM cyclic-di-GMP (Sigma #SML1228) assay buffer used as internal standard for mass spectrometry. Total volume / well was 105 pL.

[0264] Rapidfire MS detection Each plate was centrifuged at 4000 rpm, 4°C for 5 min.

[0265] The RapidFire automated sampler was connected to a binary pump (Agilent 1290) and Triple Quad 6500 (ABSciex, Toronto, Canada). The system was equipped with a 10 pL loop, C18 [12 pL bed volume] cartridge (Agilent, part number G9210A) containing 10 mM NH4Ac (aq) water (pH 7.4) as eluent A (pump 1 at 1.5 mL / min, pump 2 at 1.25 mL / min) and 10 mM NH4Ac v / v / v 47.5 / 47.5 / 5 ACN / MeOH / H2O (pH 7.4) as eluent B (pump 3 at 1.25 mL / min). Aspiration time: 250 ms; loading time: 3000 ms; elution time: 3000 ms; wash volume: 500 pL.

[0266] MS was run in positive ion mode with a HESI ion source with source temperature 550 °C, Gas curtain = 35, Gas 1 = 65, Gas 2 = 80. Unit mass resolution was obtained in SRM mode. The following transitions and MS parameters (DP: de-clustering potential and CE: collision energy) were determined for cGAMP and DicGMP: Analyte: cGAMP at 675.1 / 524, DP = 130, CE = 30, and Internal standard: cyclic-di-GMP at 690.1 / 540, DP = 130, CE = 30.

[0267] The formation of cGAMP was monitored and evaluated as a ratio to cyclic-di-GMP.

[0268] Data evaluation and calculation: For data evaluation and calculation, the measurement of the low control was set to 0% control and the measurement of the high control was set to 100% control. IC50 values were calculated using the standard 4 parameter logistic regression formula 50 . Calculation: [y = (a - d) / (1+(x / c)^b) + d], a = low value, d = high value; x = concentration M; c = IC50 M; b = slope.

[0269] 6.2 Methods: Human cGAS cell assay and reverse cell assay with cGAMP stimulation (THP1 (vir) IC 50 and THP1 (cGAMP) IC 50 ) THP1 -Dual™ cells expressing the IRF-dependent Lucia luciferase reporter gene (InvivoGen #thpd-nfis) were used as basis for both assays. For the detection of cellular cGAS activity, cells were stimulated by baculovirus (pFastbac-1, Invitrogen, no coding insert) infection delivering cGAS enzyme stimulating baculovirus (pFastbac-1, Invitrogen, no coding insert) to stimulate cells (measuring THP1 (vir) IC 50 ).

[0270] For the reverse assay, cells were stimulated by cGAMP (SigmaAldrich #SML1232) to activate the same pathway independent of cGAS and directly downstream of cGAS (measuring THP1 (cGAMP) IC 50 ).

[0271] Pathway activity was monitored by measuring Lucia luciferase activity induced by DNA-stimulated cGAS enzyme activity (measuring THP1 (vir) IC 50 ) or directly by cGAMP (measuring THP1 (cGAMP) IC 50 , reverse assay).

[0272] Assay methods Compounds were delivered in 10 mM DMSO solution, serially diluted and transferred into 384 well assay plates (Greiner #781201) using an Echo acoustic dispenser. Typically 8 concentrations were used with the highest concentration in the final assay volume being 10 mM, followed by about 1 :5 dilution steps. The DMSO concentration was set to 1% in the final assay volume. The 384 well assay plates contained 21 test compounds (rows 1-22) and DMSO in rows 23 and 24.

[0273] Cells cultured according to manufacturer conditions were collected by centrifugation at 300g / 10min, followed by resuspension 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), 100 pg / ml Normocin (InvivoGen #ant-nr), 100 pg / ml Zeocin (InvivoGen #ant-zn), 10 pg / ml Blasticidin S (Life Technologies #A11139-03)) and diluted to 1.66E5 cells / ml. Then the baculovirus solution was added to the cells at 1:200 (different depending on the virus batch) (measuring THP1 (vir) IC 50 ). Alternatively, for the reverse assay, cGAMP was added to the cells at a final concentration of 10 mM (measuring THP1 (cGAMP) IC 50 ). 30 pL of the cell / virus mixture was added to each well of the compound plate, rows 1-23 (5000 cells / well) by the MultiDrop Combi dispenser. In row 24, 30 pL / 5000 cells / well (without virus) was added as a low control.

[0274] The plates were then incubated at 37°C for 18h in a humidified incubator.

[0275] Afterwards, 15 pL of the QuantiLuc detection reagent (InvivoGen #rep-qlcg5) was added to each well using the MultiDrop Combi. Measurements were taken immediately after addition using the EnVision reader (US- luminescence readout mode).

[0276] Data evaluation and calculation: For data evaluation and calculation, the measurement of the low control was set to 0% control and the measurement of the high control was set to 100% control. The IC 50 values were calculated using the standard 4-parameter logistic regression formula. Calculation: [y = (a-d) / (1+(x / c)^b)+d], a = low value, d = high value; x = concentration M; c = IC50 M; b = slope.

[0277] 6.3 Method: Human Whole Blood Assay (Human WB IC 50 ) For detection of cellular cGAS activity, human whole blood was stimulated by transfection with double stranded DNA. Pathway activity was monitored by measuring production of IFNa2a.

[0278] Assay methods Compounds were delivered as 10 mM DMSO solutions and serially diluted using an Echo acoustic dispenser into 96-well cell culture plates (Corning #3595) pre-filled with 20 μΐ OptiMEM (Gibco, #11058-021) per well. Typically 8 concentrations were used with the highest concentration in the final assay volume being 10 μΜ followed by approximately 1 :5 dilution steps. The DMSO concentration was set to 0.1% in the final assay volume. The 96-well assay plates contained 10 test compounds and DMSO in control wells.

[0279] Human whole blood was collected from 3 or more healthy donors (male or female, non- medicated for 7 days, except for contraceptives and thyroid medication) in the form of sodium citrate blood (e.g. 3.8% in Monovettes from Sarstedt) at the same time. After collection, the whole blood was kept at room temperature for up to 3 hours until used in the assay.

[0280] 160 μΐ whole blood samples were transferred to each well of the 96-well assay plates filled with compound / OptiMEM. All assay plates were prepared in duplicate with blood from different donors. The blood plates were kept at room temperature for 60 minutes and continuously shaken at 450 rpm, covered with a lid, but not sealed.

[0281] DNA-Fugene mixtures were prepared in OptiMEM (Herring DNA, Sigma Aldrich #D6898-1G; Fugene (5x 1 mL), Promega #E2312) and incubated for 10 min at room temperature (125 ng DNA / 20 μΐ, Fugene ratio 9.6:1). 20 μΐ of the DNA Fugene mixture was added to each well resulting in 125 ng DNA / well / 200 μΐ, Fugene ratio 9.6:1. 20 μΐ OptiMEM and 9.6:1 Fugene were added to all low control wells.

[0282] After the assay plates were covered with aera seals and lids, the blood plates were kept at room temperature for 30 minutes and continuously shaken at 450 rpm, followed by overnight incubation at 37°C in an incubator for 22 h without shaking.

[0283] To detect IFN alpha-2a in human plasma, biotin labeled capture antibody (antibody set IFNA2, Meso Scale Diagnostics #B21VH-3, including coating and capture antibody) 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 μΐ of diluted capture antibody. Coated plates were incubated for 60 min at room temperature under continuous shaking at 700 rpm. MSD IFN alpha-2a plates were washed three times with 150 μΐ wash buffer (1 x HBSS, 0.05% Tween).

[0284] After blocking of the plates with 100 μΐ blocking solution per well (1 x HBSS containing 0.2% Tween, 2% BSA) for 60 min at room temperature under continuous shaking at 700 rpm, the plates were emptied as much as possible by pouring and were then ready for use with human plasma.

[0285] Whole blood assay plates were centrifuged for 10 min at 1600 rpm. 25 μΐ of supernatant was transferred from each whole blood plate to the corresponding IFN alpha-2a plate using a pipetting robot. Plates were sealed with a microplate sealer and were kept for another two hours at room temperature under continuous shaking at 700 rpm.

[0286] Subsequently, MSD IFN alpha-2a plates were washed three times with 150 μΐ wash buffer (1 x HBSS, 0.05% Tween) and 25 μΐ MSD SULFO-TAG IFN alpha-2a antibody solution (1 : 100 diluted in diluent 3 (Meso Scale Diagnostics #R50AP-2)) was added to each well of the plates.

[0287] Subsequently, plates were sealed with a microplate sealer and were kept for another two hours at room temperature under continuous shaking at 700 rpm. Finally, MSD IFN alpha-2a plates were washed three times with 150 μΐ wash buffer (1 x HBSS, 0.05% Tween). 150 μΐ 2x read buffer was added to each well and plates were immediately measured using a MSD Sector S600 reader using the supplier's bar code.

[0288] Data evaluation and calculation: For data evaluation and calculation, the % control of each well was calculated based on the mean of the high (DNA stimulated control) and the mean of the low (unstimulated control) control by using the following formula: [Count (sample) - Count (low)) / (Count (high) - Count (low)] * 100 IC was calculated using the standard 4-parameter logistic regression formula 50 Values. Calculation: [y = (a - d) / (1 + (x / c)^b) + d], a = low value, d = high value; x = concentration M; c = IC 50 M; b = slope.

[0289] 6. Indications As has been found, the compounds of the formula I, II or III are characterized by their range of use in the therapeutic area. In particular, those applications of the compounds of the formula I, II or III according to the application should be mentioned which are preferably used on the basis of their pharmaceutical activity as cGAS inhibitors. While the cGAS pathway is essential for the host defense against pathogenic invasions, such as viral infections and the invasion of some intracellular bacteria, cellular stress and genetic factors can also lead to the production of aberrant cellular dsDNA and thus trigger an autoinflammatory response, for example through nuclear or mitochondrial leakage. cGAS inhibitors thus have a strong therapeutic potential for the treatment of various autoinflammatory and autoimmune diseases.

[0290] An et al., Arthritis Rheumatol. 2017 Apr; 69(4): 800-807, discloses that cGAS expression in peripheral blood mononuclear cells (PBMCs) of patients with the autoimmune disease systemic lupus erythematosus (SLE) was significantly higher than in normal controls. cGAMP was measured by targeted mass spectrometry and was detected in 15% of the SLE patients tested, but not in normal or rheumatoid arthritis controls. SLE patients with cGAMP had higher disease activity than SLE patients without cGAMP. Although higher cGAS expression can be a result of exposure to type I interferons (IFNs), the detection of cGAMP in SLE patients with increased disease activity indicates that the cGAS pathway can be involved in disease expression.

[0291] Park et al., Ann Rheum Dis. 2018 Oct; 77(10): 1507-1515, also discloses that the cGAS pathway is involved in the development of SLE.

[0292] 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 conventional dendritic cell maturation and plasmacytoid dendritic cell differentiation.

[0293] Gao et al., Proc. Natl. Acad. Sci. U S A. 2015 Oct 20; 112(42): E5699-705 describe that activation of cGAS by self-DNA causes certain autoimmune diseases, e.g. interferonopathies.

[0294] Tonduti et al., Expert Rev. Clin. Immunol. 2020 Feb; 16(2): 189-198 disclose that cGAS inhibitors have specific therapeutic potential in Aicardi-Goutieres syndrome and familial chilblain lupus, which are severe autoinflammatory immune-mediated conditions resembling lupus.

[0295] Steiner et al., Nat Commun. 2022 Apr 28; 13(1): 232; doi: 10.1038 show that deficiency in the coatomer complex I causes 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.

[0296] Li et al. show that extracellular vesicles containing plasma-derived DNA induce STING-mediated proinflammatory responses in dermatomyositis (Theranostics. 2021; 11(15): 7144-7158). Zhou et al. (J Clin Lab Anal. 2022 Oct; 36(10): e24631) describe a correlation between cGAS-STING pathway activation and muscle fiber atrophy / necrosis in dermatomyositis.

[0297] In Yu et al., Cell 2020 Oct 29; 183(3): 636-649, a link between TDP-43-triggered mitochondrial DNA and activation of the cGAS / STING pathway in amyotrophic lateral sclerosis (ALS) is described.

[0298] Ryu et al., Arthritis Rheumatol. 2020 Nov; 72(11): 1905-1915 also show that bioactive plasma mitochondrial DNA is associated with disease progression in specific fibrotic diseases, such as systemic sclerosis (SSc) or interstitial lung disease (ILD), progressive fibrotic interstitial lung disease (PF-ILD), and idiopathic pulmonary fibrosis (IPF).

[0299] In Schuliga et al., Clin. Sci. (Lond). 2020 Apr 17; 134(7): 889-905, it is described that self-DNA keeps IPF lung fibroblasts senescent in a cGAS-dependent manner.

[0300] Other scientific hints linking the etiology of other fibrotic diseases, such as nonalcoholic steatohepatitis (NASH), to the cGAS / STING pathway have been 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.

[0301] Nascimento et al., Sci. Rep. 2019 Oct 16;9(1):14848 disclosed that self-DNA release and STING-dependent sensing drive inflammation in mice due to cigarette smoke, implicating a link between the cGAS-STING pathway and chronic obstructive pulmonary disease (COPD).

[0302] Ma et al., Sci. Adv. 2020 May 20;6(21):eaaz6717 disclosed that ulcerative colitis and inflammatory bowel disease (IBD) can be limited by controlling cGAS-mediated inflammation.

[0303] Gratia et al., J. Exp. Med. 2019 May 6;216(5):1199-1213 showed that the Bloom syndrome protein restricts innate immune sensing of micronuclei through cGAS. Thus, cGAS inhibitors have therapeutic potential for treating Bloom syndrome.

[0304] Kerur et al., Nat. Med. 2018 Jan;24(1):50-61 described that cGAS plays an important role in atypical inflammasome activation in age-related macular degeneration (AMD).

[0305] Visitchanakun et al., Int J Mol Sci. 2021 Oct 23;22(21):11450 showed that GAS-deficient mice were less severe than wild-type mice in a cecal ligation puncture (CLP) and lipopolysaccharide (LPS) injection sepsis model.

[0306] Wang et al., Mediators Inflamm. 2015;2015:192329 described that cGAS is required for cell proliferation and inflammatory cytokine production in rheumatoid arthritis synoviocytes. It has also been reported that cGAS deficiency suppresses the interferon response, inflammatory cell infiltration, and joint swelling in a mouse model of inflammatory arthritis (Willemsen et al., Cell Rep. 2021 Nov 9;37(6):109977).

[0307] Guo et al., Osteoarthritis Cartilage. 2021 Aug;29(8): 1213-1224 describe that damaged DNA is a key pathogenic factor in osteoarthritis (OA), which can be mediated by the cGAS / STING pathway, as STING knockdown alleviates instability of the medial meniscus-induced OA development in mice.

[0308] Mao et al., Arterioscler Thromb Vasc Biol (2017) 37(5):920-929 show that in diet-induced obesity, the cGAS / STING pathway mediates endothelial inflammation in response to free fatty acid-induced mitochondrial damage, indicating that cGAS inhibitors also have potential to treat obesity and diabetes.

[0309] Kerur et al., Nat Med. 2018 Jan;24(l):50-61 describe elevated cGAS content in retinal pigment epithelium in human eyes with geographic atrophy, and cGAS drives activation of non-canonical inflammasomes in age-related macular degeneration.

[0310] cGAS promotes cellular senescence and the senescence-associated secretory phenotype (Yang et al., Proc Natl Acad Sci USA 2017 Jun 6;114:E4612-E4620). Cytoplasmic chromatin triggers inflammation in the process of senescence through cGAS / STING, and STING null mice have reduced tissue inflammation and senescence (Dou et al., Nature. 2017 550:402-406). Furthermore, variants within the human STING gene are associated with healthy aging, most likely due to reduced inflammation (Hamann et al., Gerontology 2019;65:145-154). Overall, STING inhibitors will reduce senescence-associated inflammation and accumulation of senescent cells, and will improve senescence-associated diseases, such as sarcopenia and fibrosis.

[0311] Furthermore, cGAS inhibitors of Formula I, II or III 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).

[0312] In addition, cGAS inhibitors of Formula I, II, or III also 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).

[0313] There are other scientific hints of a correlation between Parkinson’s disease and the cGAS / STING pathway (Sliter et al., Nature. 2018 Sep; 561(7722): 258-262) and between Sjogren’s syndrome and the cGAS / STING pathway (Papinska et al., J. Dent. Res. 2018 Jul; 97(8): 893-900).

[0314] Furthermore, cGAS inhibitors of Formula I, II, or III also have therapeutic potential in the treatment of COVID-19 / SARS-CoV-2 infection, as shown in the following documents: 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”.

[0315] In addition, cGAS inhibitors of Formula I, II, or III have therapeutic potential in the treatment of kidney inflammation and kidney 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”.

[0316] Furthermore, 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”.

[0317] In addition, because STING gt Animals exhibit reduced macrophage infiltration in adipose tissue after subchronic high caloric intake (HFD), and STING gt And deficiency in IRF3 causes blood glucose and insulin reduction and weight loss, so cGAS inhibitors of Formula I, II, or III have therapeutic potential in the treatment of metabolic disorders (Mao et al., Arterioscler Thromb Vasc Biol, 2017; 37(5):920-929).

[0318] Furthermore, cGAS inhibitors of Formula I, II or III have therapeutic potential in the treatment of vascular diseases and cause vascular repair / regeneration, because mitochondrial DNA release in the cytosol of endothelial cells causes activation of the cGAS / STING pathway and suppresses endothelial cell proliferation. In addition, genetic knockout of the cGAS gene restores endothelial repair / regeneration in a mouse model of inflammatory lung injury (Huang et al., Immunity, March 2020, 2017; 52(3):475-486.e5. doi: 10.1016 / j.immuni.2020,02.002).

[0319] In addition, cGAS inhibitors of Formula I, II or III have therapeutic potential in the treatment of aging-related and obesity-related cardiovascular diseases (Hamann et al., Immun Ageing, March 14, 2020; 17:7; doi: 10.1186 / s12979-020-00176-y. eCollection 2020).

[0320] Thus, compounds of Formula I, II or III as cGAS inhibitors can be used for the treatment of autoinflammatory and autoimmune diseases, such as systemic lupus erythematosus (SLE), interferonopathies, Aicardi-Goutieres syndrome (AGS), COPA syndrome, familial chilblain lupus, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom syndrome, Sjogren syndrome, rheumatoid arthritis and Parkinson’s disease.

[0321] In addition, compounds of Formula I, II or III as cGAS inhibitors can be used for the treatment of fibrotic diseases, such as systemic sclerosis (SSc), interferonopathies, nonalcoholic steatohepatitis (NASH), interstitial lung disease (ILD), preferably progressive fibrosing interstitial lung disease (PF-ILD), in particular idiopathic pulmonary fibrosis (IPF).

[0322] Furthermore, compounds of Formula I, II or III as cGAS inhibitors can be used for the treatment of age-related macular degeneration (AMD), retinopathies, glaucoma, diabetes, obesity, aging, muscle disorders, sepsis, osteoarthritis, heart failure, COVID-19 / SARS-CoV-2 infection, kidney inflammation, kidney fibrosis, metabolic disorders, vascular diseases, cardiovascular diseases and cancer.

[0323] 7. Combinations 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.

[0324] In a preferred embodiment of the application, the compound of formula I, II or III can be combined with one or more pharmacologically active agents selected from the group of anti-inflammatory agents; anti-fibrotic agents; anti-allergic agents / anti-histamines; bronchodilators; beta2 agonists / beta mimetics; adrenergic agonists; anticholinergic agents; methotrexate; mycophenolate mofetil; leukotriene modulators; JAK inhibitors; anti- interleukin antibodies; non-specific immunotherapeutic agents, 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 modulators; anti-TNF antibodies (Humira TM ); and anti-BAFF antibodies (Belimumab and Etanercept).

[0325] The anti-fibrotic agent is preferably selected from pirfenidone or a tyrosine kinase inhibitor, such as nintedanib, with nintedanib being particularly preferred.

[0326] Preferred examples of anti-inflammatory agents are NSAIDs and corticosteroids.

[0327] The NSAID is preferably selected from the group consisting of ibuprofen, naproxen, diclofenac, meloxicam, celecoxib, acetylsalicylic acid (Aspirin TM ), indomethacin, mefenamic acid and etoricoxib.

[0328] The corticosteroid is preferably selected from the group consisting of Flunisolide, Beclomethasone, Triamcinolone, Budesonide, Fluticasone, Mometasone, Ciclesonide, Rofleponide and Dexametasone.

[0329] The anti-allergic agent / anti-histamine is preferably selected from the group consisting of Epinastine, Cetirizine, Azelastine, Fexofenadine, Levocabastine, Loratadine, Ebastine, Desloratidine and Mizolastine.

[0330] The beta2 agonist / beta mimetic can be a long-acting beta2 agonist (LABA) or a short-acting beta agonist (SABA). Especially preferred beta2 agonists / beta mimetics are selected from the group consisting of Bambuterol, Bitolterol, Carbuterol, Clenbuterol, Fenoterol, Formoterol, Hexoprenalin, Ibuterol, Pirbuterol, Procaterol, Reproterol, Salmeterol, Sulfonterol, Terbutalin, Tolubuterol, Olodaterol and Salbutamol, especially Olodaterol.

[0331] The anticholinergic agent is preferably selected from the group consisting of ipratropium salts, tiotropium salts, glycopyrronium salts and theophylline, with tiotropium bromide being especially preferred.

[0332] The leukotriene modulator is preferably selected from the group consisting of Montelukast, Pranlukast, Zafirlukast, Ibudilast and Zileuton.

[0333] The JAK inhibitor is preferably selected from the group consisting of Baricitinib, Cerdulatinib, Fedratinib, Filgotinib, Gandotinib, Lestaurtinib, Momelotinib, Pacritinib, Peficitinib, Ruxolitinib, Tofacitinib and Upadacitinib.

[0334] The anti-interleukin antibody is preferably selected from the group consisting of an anti-IL23 antibody (e.g. 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 (e.g. Actemra TM), anti-IL-12 antibodies, anti-IL-15 antibodies.

[0335] 8. Formulations The compounds of the present application can be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration through an inhaler. Parenteral administration refers to administration by injection or infusion into a patient, and generally is by injection or infusion into a vein, muscle, or under the skin. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration to the lungs of a patient, whether by mouth or by nasal passage. Topical administration includes application to the skin. The compounds of the present application can be administered by eye drops for the treatment of Sjogren's syndrome.

[0336] Suitable 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 from 0.1 to 90% by weight, preferably 0.5 to 50% by weight, of the total composition, i.e. in amounts which are sufficient to achieve the dosage range specified below.

[0337] The formulations can be administered orally in the form of tablets, powders, capsules (for example gelatin capsules), solutions or suspensions. For administration by inhalation, the active substance combination can be administered in the form of a powder, an aqueous or ethanolic solution or using a propellant gas formulation.

[0338] It is therefore preferred that the pharmaceutical preparation is characterized by the content of one or more compounds of the formula I, II or III according to the above preferred embodiments.

[0339] Oral administration of the compounds of the formula I, II or III is particularly preferred, as is administration once or twice a day. Suitable tablets can be obtained, for example, by mixing the active substance with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc, and / or agents for delaying release, for example carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate). The tablets can also comprise several layers.

[0340] Coated tablets can therefore be prepared by coating cores produced similarly to the tablets with substances used for tablet coating, such as kollidone or shellac, gum arabic, talc, titanium dioxide or sugar. In order to achieve delayed release or to prevent incompatibilities, the cores can also consist of several layers. Similarly, the tablet coatings can consist of several layers to achieve delayed release, using the excipients mentioned above for the tablets.

[0341] According to the application, the syrup containing the active substance or combinations thereof can additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, and a flavor enhancer (e.g. a flavoring agent such as vanilla or orange extract). It can also contain a suspending adjuvant or a thickening agent, such as sodium carboxymethylcellulose; a wetting agent, such as a condensation product of fatty alcohols with ethylene oxide; or a preservative, such as a p-hydroxybenzoic acid ester.

[0342] Capsules containing one or more active substances or combinations of active substances can be prepared, for example, by mixing the active substance with an inert carrier such as lactose or sorbitol and filling it into gelatin capsules. Suitable suppositories can be manufactured, for example, by mixing the carrier, which is provided for this purpose, such as a neutral fat or polyethylene glycol or a derivative thereof, with the active substance.

[0343] Excipients that can be used include, for example, water; pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut oil or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol); carriers such as natural mineral powders (e.g. high- silica 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 liquids, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium Of course, for oral administration, tablets can also contain, in addition to the above carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate, as well as various additives such as starch (preferably potato starch), gelatin and the like. Furthermore, lubricants such as magnesium stearate, sodium dodecyl sulfate and talc can be used simultaneously in the tabletting process. In the case of aqueous suspensions, the active substance can be combined with various flavor enhancers or colorants in addition to the excipients mentioned above. The present disclosure relates to the following embodiments 1. A compound of formula I wherein R 1 is selected from the group consisting of hydrogen, halogen, methyl, ethyl, -CF3, -CHF2, -CFH2and 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, and wherein A is selected from the group consisting of -CH2-, -0-, -CF2-, -CHF-, -N(CH3)-, -NH- and -CHCH3-; D is selected from the group consisting of -CH2-, -0-, -CF2-, -CHF-, and -CHCH3-; E is selected from the group consisting of -CH2-, -0-, -C(CH3)2-, -CHF-, CF2-, and -CHCH3-; G is selected from the group consisting of -NH-, -NCH3-, -CH2-, -0-, -CF2-, -CHF-, -CHCH3-, and -C(CH3)2; J is selected from the group consisting of -CO-, -CH2-, -0-, -CHF-, -CF2-, and -CHCH3-; K is selected from the group consisting of -CH2-, -CF2-, -0-, or is absent; L is selected from the group consisting of -CH2-, -0-, -CHCH3-, -CHF-, -CF2-, or is absent; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 2. The compound of formula I according to item 1, wherein 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, and wherein A is selected from the group consisting of -CH2-, -0-, -CF2-, and -N(CH3)-, D is selected from the group consisting of -CH2-, -0-, and -CHCH3-, E is selected from the group consisting of -CH2-, -0-, and -C(CH3)2-, G is selected from the group consisting of -NH-, -CH2-, -0-, -CHCH3-, J is selected from the group consisting of -CO-, -CH2-, -0-, and -CHCH3-; K is selected from the group consisting of -CH2-, -CF2-, -0-, or is absent; L is selected from the group consisting of -CH2-, -CF2-, or is absent; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 3. The compound of formula I according to at least one of items 1 or 2, wherein L is absent; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 4. The compound of Formula I according to at least one of the items 1 or 2, wherein L is absent, and wherein A is selected from the group consisting of -CH2- and -CF2-, and prodrugs, pharmaceutically acceptable salts, or deuterated analogs thereof. 5. The compound of Formula I according to item 1 or 2, wherein L is absent, and wherein K is CF2; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 6. The compound of Formula I according to at least one of the items 1 to 5, wherein R 3 is halogen; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 7. The compound of Formula I according to item 6, wherein R 3 is Cl or F; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 8. The compound of Formula I according to item 7, wherein R 3 is Cl or F and is located at the 5-position of the benzimidazole moiety; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 9. The compound of Formula I according to at least one of the items 1 to 8, wherein R 1 is halogen; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 10. The compound of Formula I according to item 9, wherein R 1 is Cl or F; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 11. The compound of Formula I according to at least one of the items 1 to 8, wherein R 1 is hydrogen; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 12. The compound of Formula I according to at least one of the items 1 or 2, selected from the group consisting of: and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 13. The compound of Formula I according to at least one of the items 1 or 2, wherein 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-, and L is absent, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 14. The compound of formula I according to item 13, selected from the group consisting of: and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 15. The compound of formula I according to item 1, wherein R 2 is methyl; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 16. The compound of formula II according to item 15 or a compound of formula III and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 17. The compound of formula II according to item 16 and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 18. The compound of formula II according to at least one of items 16 or 17 or the compound of formula III according to item 16, wherein L is absent; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 19. The compound of formula II according to at least one of items 16 or 17 or the compound of formula III according to item 16, wherein L is absent and wherein K is CF2; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 20. The compound of formula II according to at least one of items 16 or 17 or the compound of formula III according to item 16, wherein R 3 is halogen; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 21. The compound of formula II or formula III according to item 20, wherein R 3 is CI or F; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 22. The compound of formula II or formula III according to item 21, wherein R 3 is CI or F and is located at the 5-position of the benzimidazole moiety; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 23. The compound of formula II according to at least one of items 16 or 17 or the compound of formula III according to item 16, wherein R 3 is hydrogen; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 24. The compound of formula II according to at least one of items 16 or 17 or the compound of formula III according to item 16, wherein R 1halogen; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 25. The compound of Formula II or Formula III according to item 24, wherein R 1 is selected from the group consisting of Cl or F; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 26. The compound of Formula II according to at least one of items 16 or 17 or the compound of Formula III according to item 16, wherein R 1 is hydrogen; and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 27. The compound of Formula II according to at least one of items 16 or 17 or the compound of Formula III according to item 16, wherein 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-, and L is absent, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 28. The compound of Formula II according to item 27, selected from the group consisting of: and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 29. The compound of Formula II or Formula III according to item 27, wherein 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-, and L is absent, and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 30. The compound of Formula II according to item 29, selected from the group consisting of: and prodrugs, deuterated analogs, and pharmaceutically acceptable salts thereof. 31. An intermediate compound having Formula (A-I) wherein R 1 , R 2 , R 3A, D, E, G, J, K and L are as defined above, and wherein R13is selected from the group consisting of hydrogen, methyl, ethyl and tert-butyl, formula (A-II), wherein R 1 , R 2 , R 3 A, D, E, G, J, K and L are as defined above, and wherein R13is selected from the group consisting of hydrogen, methyl, ethyl and tert-butyl, and wherein R is hydrogen or a protecting group selected from the group consisting of tert-butyl, methyl, ethyl and benzyl, formula (B-I) wherein R 1 , R 2 , R 3 A, D, E, G, J, K and L are as defined above, and wherein R13is selected from the group consisting of hydrogen, methyl, ethyl and tert-butyl, or formula (B-II) wherein R 1 , R 2 , R 3 A, D, E, G, J, K and L are as defined above, and wherein R13is selected from the group consisting of hydrogen, methyl, ethyl and tert-butyl. 32. The compound of formula I according to one or more of the items 1 to 15 or the compound of formula II or III according to one or more of the items 16 to 30 for use in the treatment of a disease which can be treated by inhibition of cGAS. 33. The compound of formula I according to one or more of the items 1 to 15 or the compound of formula II or III according to one or more of the items 16 to 30 for use in the treatment of a disease selected from the group consisting of systemic lupus erythematosus (SLE); interferonopathies; Aicardi-Goutieres syndrome (AGS); COPA syndrome; familial lupus erythematosus profundus; age-related macular degeneration (AMD); amyotrophic lateral sclerosis (ALS); retinopathy; glaucoma; diabetes; obesity; inflammatory bowel disease (IBD); chronic obstructive pulmonary disease (COPD); Bloom syndrome; dermatomyositis; Sjogren syndrome; Parkinson’s disease; heart failure; cancer; aging; muscle disorders; sepsis; rheumatoid arthritis; osteoarthritis; COVID-19; systemic sclerosis (SSc); non-alcoholic steatohepatitis (NASH); interstitial lung disease (ILD), preferably progressive fibrosing interstitial lung disease (PF-ILD), in particular idiopathic pulmonary fibrosis (IPF). 34. The compound of formula I according to one or more of the items 1 to 15 or the compound of formula II or III according to one or more of the items 16 to 30 for use in the treatment of a disease selected from the group consisting of systemic lupus erythematosus (SLE), interferonopathies, Aicardi-Goutieres syndrome (AGS), COPA syndrome, familial lupus erythematosus profundus, dermatomyositis, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom syndrome, Sjogren syndrome, rheumatoid arthritis and Parkinson’s disease. 35. The compound of formula I according to one or more of the items 1 to 15 or the compound of formula II or III according to one or more of the items 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 disease (ILD), preferably progressive fibrosing interstitial lung disease (PF-ILD), in particular idiopathic pulmonary fibrosis (IPF). 36. The compound of formula I according to one or more of the items 1 to 15 or the compound of formula II or III according to one or more of the items 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, muscle disorders, sepsis, osteoarthritis, heart failure, COVID19 / SARS-CoV-2 infection, kidney inflammation, kidney fibrosis, metabolic disorders, vascular diseases, cardiovascular diseases and cancer. 37. A pharmaceutical composition comprising a compound of formula I according to one or more of items 1 to 15 or a compound of formula II or III according to one or more of items 16 to 30 and optionally one or more pharmaceutically acceptable carriers and / or excipients. 38. A pharmaceutical composition comprising a compound of formula I according to one or more of items 1 to 15 or a compound of formula II or III according to one or more of items 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 agents / anti-histamines; bronchodilators; beta2 agonists / beta mimetics; adrenergic agonists; anticholinergic agents; methotrexate; mycophenolate mofetil; leukotriene modulators; JAK inhibitors; anti- interleukin antibodies; non-specific immunotherapeutic agents, such as interferons or other cytokines / chemokines; cytokine / chemokine receptor modulators; Toll-like receptor agonists; immune checkpoint modulators; anti-TNF antibodies, such as Humira TM ; anti-BAFF antibodies, such as Belimumab and Etanercept; and optionally one or more pharmaceutically acceptable carriers and / or excipients. 39. A pharmaceutical composition comprising a compound of formula I according to one or more of items 1 to 15 or a compound of formula II or III according to one or more of items 16 to 30 in combination with one or more anti-fibrotic agents selected from the group consisting of Pirfenidon and Nintedanib and optionally one or more pharmaceutically acceptable carriers and / or excipients. 40. A pharmaceutical composition comprising a compound of formula I according to one or more of items 1 to 15 or a compound of formula II or III according to one or more of items 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 according to one or more of items 1 to 15 or a compound of formula II or III according to one or more of items 16 to 30 in combination with one or more active agents selected from the group of bronchodilators, beta2 agonists / beta mimetics, adrenergic agonists and anticholinergic agents; and optionally one or more pharmaceutically acceptable carriers and / or excipients. 42. A pharmaceutical combination comprising a compound of Formula I according to one or more of items 1 to 15 or a compound of Formula II or Formula III according to one or more of items 16 to 30 and one or more anti-interleukin antibodies selected from the group consisting of: anti-IL-23 antibodies, such as Risankizumab; anti-IL-17 antibodies; anti-IL-1 antibodies; anti-IL-4 antibodies; anti-IL-13 antibodies; anti-lL-5 antibodies; anti-IL-6 antibodies, such as Actemra TM ; anti-IL-12 antibodies; and anti-IL-15 antibodies.

Claims

1. A compound of formula I and a pharmaceutically acceptable salt thereof. in R 1 Choose from the following groups: halogen, -CF3, -CHF2, and -CFH2. R 2 Choose from the group consisting of hydrogen and methyl groups. R 3 Choose from the group consisting of hydrogen, methyl, and halogen. And among them A is selected from the following groups: -CH2-, -O-, -CF2-, -CHF-, -N(CH3)-, -NH-, and -CHCH3-; D. Choose from the following groups: -CH2-, -O-, -CF2-, -CHF-, and -CHCH3-; E can be selected from the following groups: -CH2-, -O-, -C(CH3)2-, -CHF-, CF2-, and -CHCH3-; G is selected from the following groups: -NH-, -NCH3-, -CH2-, -O-, -CF2-, -CHF-, -CHCH3- and -C(CH3)2; J can be selected from the following groups: -CO-, -CH2-, -O-, -CHF-, -CF2-, and -CHCH3-; K can be selected from the group consisting of -CH2-, -CF2-, and -O- or it may not exist; L can be selected from the group consisting of -CH2-, -O-, -CHCH3-, -CHF-, -CF2- or it may not exist.

2. The compound of formula I according to claim 1 and its pharmaceutically acceptable salt, wherein... R 1 Choose the group composed of hydrogen, Cl, and F. R 2 Choose from the group consisting of hydrogen and methyl groups. R 3 Choose from the following groups: hydrogen, methyl, Cl, and F. And among them A is selected from the following groups: -CH2-, -O-, -CF2-, and -N(CH3)-. Option D is the group consisting of -CH2-, -O-, and -CHCH3-. E is a group consisting of -CH2-, -O-, and -C(CH3)2-. G is selected from the following groups: -NH-, -CH2-, -O-, -CHCH3-. J can be selected from the following groups: -CO-, -CH2-, -O-, and -CHCH3-; K can be selected from the group consisting of -CH2-, -CF2-, and -O- or it may not exist; L can be selected from groups consisting of -CH2- and -CF2- or it may not exist.

3. The compound of formula I according to at least one of claims 1 or 2, and its pharmaceutically acceptable salt, wherein L is absent.

4. The compound of formula I according to at least one of claims 1 or 2 and its pharmaceutically acceptable salt, wherein L is absent, and wherein A is selected from the group consisting of -CH2- and -CF2-.

5. The compound of formula I according to claim 1 or 2 and its pharmaceutically acceptable salt, wherein L is absent and wherein K is CF2.

6. The compound of formula I according to at least one of claims 1 to 5 and its pharmaceutically acceptable salt, wherein R 3 It is a halogen.

7. The compound of formula I according to claim 6 and its pharmaceutically acceptable salt, wherein R 3 It is Cl or F.

8. The compound of formula I according to claim 7 and its pharmaceutically acceptable salt, wherein R 3 It is Cl or F and is located at the 5th position of the benzimidazole moiety.

9. The compound of formula I according to at least one of claims 1 to 8 and its pharmaceutically acceptable salt, wherein R 1 It is a halogen.

10. The compound of formula I according to claim 9 and its pharmaceutically acceptable salt, wherein R 1 It is Cl or F.

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