Benzimidazole derivatives as cgas inhibitors

Abstract

The invention relates to compounds of formula (I), wherein R1 is selected from the group consisting of H, C1-3-alkyl, C1-3-haloalkyl, -CH2-CO-NH2, -CH2-CO-NHCH3 and -CH2-CO-N(CH3)2 R2 is selected from the group consisting of H, halogen, (C1-3)-alkyl and halo-(C1-3)-alkyl, R3 is selected from the group consisting of C1-3-alkyl, five- or six-membered heterocyclic ring with 1 to 3 heteroatoms selected from N, O, S or SO2 and a five- or six-membered carbocyclic ring, wherein R3 is substituted by one or two substituents R8 which are each independently selected from the group consisting of H, C1-3-alkyl, -CO-O-(C1-4-alkyl), halogen, CN, OH, O-C1-3-methyl and -CO-(C1-3-alkyl), wherein each V, U, Q and T are independently from each other selected from C or N, wherein R4 is selected from the group consisting of H, halogen, -methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl, wherein R5 is selected from H, halogen, methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl, wherein R6 is selected from H, halogen, methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl, wherein R7 is selected from H, halogen, methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl, and pharmaceutical acceptable salts thereof, for the treatment of diseases such as systemic lupus erythematosus, systemic sclerosis (SSc), interferonopathies, metabolic dysfunction associated Steatohepatitis (MASH), interstitial lung disease (ILD), decompensated liver cirrhosis and idiopathic pulmonary fibrosis (IPF).

Description

[0001]01-3591-ff-text BENZIMIDAZOLE DERIVATIVES AS cGAS INHIBITORS 1. BACKGROUND OF THE INVENTION1.1 cGAS inhibitorsInnate immunity is considered a first line cellular stress response defending the host cell againstinvading pathogens and initiating signaling to the adaptive immune system. These processes are triggered by conserved pathogen-associated molecular patterns (PAMPs) through sensing by diverse pattern recognition receptors (PRRs) and subsequent activation of cytokine and type I interferon gene expression. The major antigen-presenting cells, such as monocytes, macrophages, anddendritic cells produce type I interferons and are critical for eliciting adaptive T- and B-cell immunesystem responses. The major PRRs detect aberrant, i.e. mislocalized, immature or unmodified nucleic acids on either the cell surface, the inside of lysosomal membranes or within other cellular compartments (Barbalat et al., Annu. Rev. Immunol.29, 185-214 (2011)).“Cyclic GMP-AMP Synthase” (cGAS, UniProtKB – Q8N884)) is the predominant sensor for aberrantdouble-stranded DNA (dsDNA) originating from pathogens or mislocalization or misprocessing of nuclear or mitochondrial cellular dsDNA (Sun et al., Science 339, 786-791 (2013); Wu et al., Science339, 826-830 (2013); Ablasser et al., Nature 498, 380-384 (2013)). Binding of dsDNA to cGASactivates the reaction of GTP and ATP to form the cyclic dinucleotide GMP-AMP (referred to as cGAMP). cGAMP then travels to and activates the endoplasmatic reticulum membrane-anchored adaptor protein, “Stimulator of Interferon Genes” (STING). Activated STING recruits and activatesTANK-binding kinase 1 (TBK1) which in turn phosporylates the transcription factor family ofinterferon regulatory factors (IRFs) inducing cytokine and type I interferon mRNA expression. The critical role of cGAS in dsDNA sensing has been established in different pathogenic bacteria(Hansen et al., EMBOJ.33, 1654 (2014)), viruses (Ma et al., PNAS 112, E4306 (2015)) and retroviruses(Gao et al., Science 341, 903-906 (2013)). Additionally, cGAS is essential in various other biologicalprocesses such as cellular senescence (Yang et al., PNAS 114, E4612 (2017), Glück et al., Nat. Cell Biol.19, 1061-1070 (2017)) and recognition of ruptured micronuclei in the surveillance of potential cancer cells (Mackenzie et al., Nature 548, 461-465 (2017); Harding et al., Nature 548, 466-470 (2017)). 1 01-3591-ff-textWhile the cGAS pathway is important for host defense against invading pathogens, cellular stressand genetic factors may also cause production of aberrant cellular dsDNA, e.g. by nuclear or mitochondrial leakage, and thereby trigger autoinflammatory responses. Aicardi-Goutieressyndrome (AGS; Crow et al., Nat. Genet.38, 917-920 (2006)) – a lupus-like severe autoinflammatoryimmune-mediated disorder – arises from loss-of-function mutations in TREX1, a primary DNAexonuclease responsible for degrading aberrant DNA in cytosol. Knock-out of cGAS in TREX1- deficient mice prevented otherwise lethal autoimmune responses, supporting cGAS as 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 of DNAse2, an endonuclease responsible for degradation of excessive DNA in lysosomes during endocytosis, was completelyrescued by additional knock-out of cGAS (Gao et. al, PNAS 112, E5699-E5705 (2015)) or STING (Ahnet al., PNAS 109, 19386-19391 (2012)). These observations support cGAS as a drug target and inhibition of cGAS may provide a therapeutic strategy for preventing autoinflammation and treating diseases such as systemic lupus erythematosus (SLE) with involvement of anti-dsDNA antibodies (Pisetsky et al., Nat. Rev. Rheumatol.12, 102-110 (2016)).1.2 Prior ArtDue to the observation that inhibition of the cGAS-pathway may provide a therapeutic strategy for preventing autoinflammation and for treating e.g. autoimmune diseases many efforts to develop cGAS inhibitors have been undertaken. In WO 2019 / 241787 for example, methyl 4-amino-6-(phenylamino)-1,3,5-triazine-2-carboxylates such as CU-32 and CU-76 have been disclosed as cGAS-inhibitors with „in vitro hcGAS IC50-values“slightly below 1 µM (IC50(CU-32) = 0.66 µM and IC50(CU-76 = 0.27 µM).In Hall et al., PLoS ONE 12(9); e0184843 (2017), compound PF-06928215 has been published as aninhibitor of cGAS with an „in vitro hcGAS IC50-value“ of 0.049 µM as measured by a fluorescencepolarization assay. However, compound PF-06928215 showed no acceptable cellular activity as a cGAS inhibitor.In WO 2020 / 142729 and in WO2022 / 174012, (benzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acid derivatives have been disclosed as cGAS inhibitors for the therapy of autoimmune 2 01-3591-ff-text disorders such as Aicardi-Goutieres Syndrome (AGS), lupus erythematosus, scleroderma, inflammatory bowel disease and non-alcoholic steatohepatitis (NASH). However, the compounds ofthis invention differ from the (benzofuro[3,2-d]pyrimidin-4-yl)pyrrolidine-2-carboxylic acidderivatives of WO 2020 / 142729 and of WO2022 / 174012 in their completely different substitutionpattern in the 4-position of the pyrrolidine ring. Recently provided cGAS inhibitors, such as the ones in WO 2020 / 142729 or in WO 2022 / 174012, usually show an insufficient cellular cGAS inhibitory potency (with IC50-values regarding inhibition of the cGAS / STING pathway as measured in cellular assays of usually larger than 1 µM, often of larger than 5 µM). However, it is crucial to provide therapeutic cGAS inhibitors that do not only show a satisfying biochemical (in vitro) inhibitory potency (“hcGAS IC50”), but also a satisfying cellular inhibitory potency (for example by showing inhibition of IFN induction in virus-stimulated THP-1 cells(THP1(vir) IC50)) in order to ensure that the compound is able to show a therapeutic effect in a patient.Other important properties that may be predictive for successful development of a cGAS inhibitor as a therapeutic agent are satisfying cGAS-selectivity (versus off-target activity) and acceptable inhibitory potency in human whole blood. Further structurally similar cGAS-inhibitors have been disclosed in WO 2022 / 238327 and in WO 2022 / 238335. However, the main structural difference of the compounds of the invention compared to WO 2022 / 238327 and WO 2022 / 238335 is that the 4-hydroxy-proline structural unit is here attached to a benzimidazolyl residue and not to a pyridinyl residue. Despite of this structuraldifference it has been surprisingly found that the compounds of formula I show at the same time thefollowing three advantageous properties: • a satisfying “biochemical (in vitro) IC50-value regarding cGAS inhibition” (with a hcGAS IC50 of ≤ 100 nM, preferably of ≤ 50 nM, in particular of ≤ 10 nM), •a satisfying “inhibition of IFN induction in virus-stimulated THP-1 cells (with a THP1 IC50(vir) of≤ 5 µM, ≤ 2 µM ≤ 1 µM, preferably of ≤ 500 nM, more preferably of ≤ 100 nM, in particularof ≤ 50 nM)and •a satisfying selectivity for cGAS-inhibition(with a ratio THP1 IC50(cGAMP) / THP1 IC50(vir) of preferably ≥10, more preferably ≥50, morepreferably ≥500, in particular ≥1000). 3 01-3591-ff-textAdditionally the compounds of formula I also show acceptable IC50-values with regard to inhibitionof IFN induction in dsDNA-stimulated human whole blood assays, preferably with human wholeblood IC50-values with regard to cGAS inhibition (hWB IC50) of ≤ 5000 nM, more preferably of ≤ 1000 nM, in particular of ≤ 100 nM. The cGAS inhibitors of the invention with this particular pharmacological profile which combines an excellent in vitro inhibitory potency and an excellent cellular inhibitory potency with a high selectivity for cGAS inhibition have a high probability to also exhibit a good therapeutic effect in the patient. Due to their high cellular inhibitory potency compounds with this particular pharmacological profile should be able to pass the cell membrane barrier and therefore reach their intracellular target location and due to their selectivity to exclusively inhibit cGAS activity, these compounds should not show unwanted off target effects, for example side effects somewhere within the signaling pathway downstream of cGAS or cytotoxic effects. 4 01-3591-ff-text 2. DESCRIPTION OF THE INVENTIONThe invention relates to a compound of formula I , wherein R1is selected from the group consisting of H, C1-3-alkyl, C1-3-haloalkyl, -CH2-CO-NH2, -CH2-CO-NHCH3and -CH2-CO-N(CH3)2R2 is selected from the group consisting of H, halogen, C1-3-alkyl and C1-3-haloalkyl,R3 is selected from the group consisting of C1-3-alkyl, five- or six-membered heterocyclic ring with 1to 3 heteroatoms selected from N, O, S or SO2 and a five- or six-membered carbocyclic ring,wherein R3is substituted by one or two substituents R8which are each independently selected from the group consisting of H, C1-3-alkyl, -CO-O-(C1-4-alkyl), halogen, OH, O-(C1-3-methyl) and -CO-(C1-3-alkyl), 5 01-3591-ff-text -CNwherein V is either C or N,wherein U is either C or N,wherein Q is either C or N,wherein T is either C or N, wherein R4is selected from the group consisting of H, halogen, -methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl,wherein R5 is selected from H, halogen, methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl,wherein R6is selected from H, halogen, methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl, wherein R7is selected from H, halogen, methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl, and deuterated analogues and pharmaceutical acceptable salts thereof.In a preferred embodiment the invention concerns the above-mentioned compounds of formula I,which are selected from the group consisting of 6 01-3591-ff-text 7 01-3591-ff-text 8 01-3591-ff-text 9 01-3591-ff-text 10 01-3591-ff-text 11 01-3591-ff-text 12 01-3591-ff-text and deuterated analogues and pharmaceutical acceptable salts thereof.In a further preferred embodiment the invention relates to the above-mentioned compounds offormula I, 13 01-3591-ff-textwherein V is C,wherein U is C,wherein Q is C,wherein T is C,and wherein R1 is selected from the group consisting of H, C1-3-alkyl and C1-3-haloalkyl,and deuterated analogues and pharmaceutical acceptable salts thereof. In another preferred embodiment the invention concerns the above-mentioned compounds offormula I,wherein R2is H, and deuterated analogues and pharmaceutical acceptable salts thereof. In a further preferred embodiment the invention relates to the above-mentioned compounds of formula I, wherein R1is selected from the group consisting of H, C1-3-alkyl, C1-3-haloalkyl, R3is selected from the group consisting of C1-3-alkyl, a six-membered heterocyclic ring with 1 to 3 heteroatoms selected from N, O or S and a six-membered carbocyclic ring, wherein R3is substituted by one or two substituents R8which are each independently selected fromthe group consisting of H, C1-3-alkyl, -CO-O-(C1-4-alkyl), halogen, -CN and -CO-(C1-3-alkyl),and deuterated analogues and pharmaceutical acceptable salts thereof. In another preferred embodiment the invention concerns the above-mentioned compounds of formula I, wherein R1is selected from the group consisting of H, methyl, ethyl, isopropyl, -CF3, -CHF2, -CH2F, R3is selected from the group consisting of a six-membered heterocyclic ring with 1 or 2 heteroatoms selected from N, O or S, and a six-membered carbocyclic ring, wherein R3is substituted by one or two substituents R8which are independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl, -CO-O-tert-butyl, F, Cl, Br,-CN and -CO-methyl,and deuterated analogues and pharmaceutical acceptable salts thereof. 14 01-3591-ff-text In a further preferred embodiment the invention relates to the above-identified compounds offormula I, whereinR1is selected from the group consisting of H, methyl, ethyl, isopropyl, -CF3, -CHF2, -CH2F, •and wherein R3 is selected from the group consisting of a six-membered heterocyclic ringwith 1 or 2 heteroatoms selected from N, O or S selected from the group consisting of piperidinyl, piperazinyl, pyrimidinyl, tetrahydropyranyl and tetrahydrothiopyranyl,wherein R3 is substituted by one or two substituents R8 which are each independentlyselected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl, - CO-O-tert-butyl, F, Cl, Br, -CN and -CO-methyl, •or wherein R3 is a methyl-substituted cyclohexyl ringand deuterated analogues and pharmaceutical acceptable salts thereof. In another preferred embodiment the invention relates to the above-mentioned compounds of formula I, wherein R1is selected from the group consisting of H, methyl, ethyl, isopropyl, -CF3, -CHF2, -CH2F, R2is H, and wherein •R3 is selected from the group consisting of a six-membered heterocyclic ring with 1 or 2heteroatoms selected from N, O or S selected from the group consisting of piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl, wherein R3 is substituted by one or two substituents R8 which are each independentlyselected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl, - CO-O-tert-butyl, F, Cl, Br, -CN and -CO-methyl, •or wherein R3 is a methyl-substituted cyclohexyl ring,and wherein V, U, T and Q are each C,15 01-3591-ff-textand wherein R4 is selected from the group consisting of H, Cl, F, -O-CF3, -O-CHF2, -O-CH2F, methyl and-CF3, -CHF2, -CH2F,and wherein R5 is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F,and wherein R6 is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F,and wherein R7 is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F,and deuterated analogues and pharmaceutical acceptable salts thereof. In a further particularly preferred embodiment the invention concerns the above-mentionedcompounds of formula I, which is selected from the group consisting of 16 01-3591-ff-text 17 01-3591-ff-text 18 01-3591-ff-text 19 01-3591-ff-text 20 01-3591-ff-text and deuterated analogues and pharmaceutical acceptable salts thereof.In another particularly preferred embodiment the invention concerns the above-mentionedcompounds of formula I, wherein R1is selected from the group consisting of H, methyl, ethyl, isopropyl, -CF3, -CHF2, -CH2F, R2is H,and wherein R3• is selected from the group consisting of a six-membered heterocyclic ring with 1 or 2 heteroatoms selected from N, O or S selected from the group consisting ofpiperidinyl and tetrahydropyranyl, tetrahydrothiopyranyl, wherein this R3 is substituted by one or two substituents R8 which are each independentlyselected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl and -CN, 21 01-3591-ff-text or wherein R3• is selected from a methyl-substituted cyclohexyl ring from the group consisting of , wherein this methyl-substituted cyclohexyl ring is further substituted by one substituent R9selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl,-CO-O-tert-butyl, F, Cl, Br, -CN and -CO-methyl,or wherein R3• is selected from the group consisting of , wherein this methyl- and acetyl-substituted piperidinyl ring is further substituted by onesubstituent R9selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl, -CO-O-tert-butyl and -CN,and wherein V, U, T and Q are each C,and wherein R4is selected from the group consisting of H, Cl, -O-CF3, -O-CHF2, -O-CH2F, methyl and-CF3, -CHF2, -CH2F,and wherein R5is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F, and wherein R6is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F,and wherein R7 is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F,and deuterated analogues and pharmaceutical acceptable salts thereof. In another particularly preferred embodiment the invention relates to the above-mentionedcompounds of formula I,which are selected from the group consisting of 22 01-3591-ff-text 23 01-3591-ff-text 24 01-3591-ff-text 25 01-3591-ff-text 26 01-3591-ff-text and deuterated analogues and pharmaceutical acceptable salts thereof. In another preferred embodiment the invention relates to the compounds of formula A , wherein 27 01-3591-ff-text R1is selected from the group consisting of H, methyl, ethyl, isopropyl, -CF3, -CHF2, -CH2F, R2is H,wherein R3• is selected from the group consisting of a six-membered heterocyclic ring with 1 or 2 heteroatoms selected from N, O or S selected from the group consisting ofpiperidinyl and tetrahydropyranyl, tetrahydrothiopyranyl, wherein this R3 is substituted by one or two substituents R8 which are each independentlyselected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl, F, Cl, Br and -CN or wherein R3• is selected from a methyl-substituted cyclohexyl ring from the group consisting of , wherein this methyl-substituted cyclohexyl ring is further substituted by one substituent R9selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl,-CO-O-tert-butyl, F, Cl, Br, -CN and -CO-methyl,or wherein R3• is selected from the group consisting of , wherein this methyl- and acetyl-substituted piperidinyl ring is further substituted by onesubstituent R9selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl, -CO-O-tert-butyl, F, Cl, Br, -CN and -CO-methyl,and wherein V, U, T and Q are each C,and wherein R4is selected from the group consisting of H, Cl, -O-CF3, -O-CHF2, -O-CH2F, methyl and - CF3, -CHF2, -CH2F, and wherein R5is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F, and wherein R6is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F, 28 01-3591-ff-textand wherein R7 is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F,and deuterated analogues and pharmaceutical acceptable salts thereof. In a further preferred embodiment the invention relates to the intermediate compounds of formula II , whereinR3 is selected from the group consisting of C1-3-alkyl, five- or six-membered heterocyclic ring with 1to 3 heteroatoms selected from N, O, S or SO2 and a five- or six-membered carbocyclic ring,wherein R3is substituted by one or two substituents R8which are each independently selected fromthe group consisting of H, C1-3-alkyl, -CO-O-(C1-4-alkyl), halogen, -CN, OH, -O-C1-3-methyl and-CO-(C1-3-alkyl),and wherein V is either C or N,and wherein U is either C or N,and wherein Q is either C or N,and wherein T is either C or N, and wherein R4is selected from the group consisting of H, halogen, -methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl,and wherein R5 is selected from H, halogen, methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl,and wherein R6is selected from H, halogen, methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl, and wherein R7is selected from H, halogen, methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl,and wherein LG is a leaving group selected from the group consisting of Cl, Br or -SO2-CH3,and pharmaceutical acceptable salts thereof. In a particularly preferred embodiment the invention refers to the above-identified intermediatecompounds of formula II,29 01-3591-ff-textwherein R3• is selected from the group consisting of a six-membered heterocyclic ring with 1 or 2 heteroatoms selected from N, O or S selected from the group consisting ofpiperidinyl and tetrahydropyranyl, tetrahydrothiopyranyl, wherein this R3 is substituted by one or two substituents R8 which are each independentlyselected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl, F, Cl, Br and -CN, or wherein R3• is selected from a methyl-substituted cyclohexyl ring from the group consisting of , wherein this methyl-substituted cyclohexyl ring is further substituted by one substituent R9selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl,-CO-O-tert-butyl, F, Cl, Br, -CN and -CO-methyl,or wherein R3• is selected from the group consisting of , wherein this methyl- and acetyl-substituted piperidinyl ring is further substituted by onesubstituent R9selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl, -CO-O-tert-butyl, F, Cl, Br, -CN and -CO-methyl,and wherein V, U, T and Q are each C,30 01-3591-ff-text and wherein R4is selected from the group consisting of H, Cl, -O-CF3, -O-CHF2, -O-CH2F, methyl and -CF3, -CHF2, -CH2F, and wherein R5is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F, and wherein R6is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F,and wherein R7 is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F,and wherein LG is a leaving group selected from the group consisting of Cl, Br or -SO2-CH3,and pharmaceutical acceptable salts thereof.In another preferred embodiment the invention concerns the above-mentioned compounds offormula I or to the above-mentioned compounds of formula A for use in the treatment of a diseasethat can be treated by the inhibition of cGAS.In a further preferred embodiment the invention relates to the above-mentioned compounds offormula I or to the above-mentioned compounds of formula A for use in the treatment of a diseaseselected from the group consisting of systemic lupus erythematosus (SLE), cutaneous lupus,interferonopathies, Aicardi- Goutières syndrome (AGS), COPA syndrome, familial chilblain lupus,age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), retinopathy, glaucoma, diabetes, obesity, Huntington’s disease, Alzheimer’s disease, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom’s syndrome, ischaemic stroke, myotonic dystrophy type 2, dermatomyositis, Sjogren’s syndrome, Parkinsons disease, heart failure, cancer,aging, muscle disorders, sepsis, rheumatoid arthritis, osteoarthritis, COVID-19, Long COVID, systemicsclerosis (SSc), metabolic dysfunction associated Steatohepatitis (MASH), liver cirrhosis, in particular decompensated liver cirrhosis, interstitial lung disease (ILD), preferably progressive fibrosing interstitial lung disease (PF-ILD), in particular idiopathic pulmonary fibrosis (IPF).In another preferred embodiment the invention refers to the above-mentioned compounds offormula I or to the above-mentioned compounds of formula A for use in the treatment of a diseaseselected from the group consisting of systemic lupus erythematosus (SLE), interferonopathies,Aicardi- Goutières syndrome (AGS), COPA syndrome, familial chilblain lupus, dermatomyositis, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory boweldisease (IBD), chronic obstructive pulmonary disease (COPD), Long COVID, Bloom’s syndrome,Sjogren’s syndrome, rheumatoid arthritis and Parkinsons disease.31 01-3591-ff-textIn a further preferred embodiment the invention concerns the above-mentioned compounds offormula I or the above-mentioned compounds of formula A for use in the treatment of a diseaseselected from the group consisting of systemic sclerosis (SSc), metabolic dysfunction associated Steatohepatitis (MASH), liver cirrhosis, in particular decompensated liver cirrhosis, interferonopathies, interstitial lung disease (ILD), preferably progressive fibrosing interstitial lung disease (PF-ILD), in particular idiopathic pulmonary fibrosis (IPF).In another preferred embodiment the invention relates to the above-mentioned compounds offormula I or to the above-mentioned compounds of formula A for use in the treatment of a diseaseselected from the group consisting of age-related macular degeneration (AMD), retinopathy, glaucoma, diabetes, obesity, aging, muscle disorders, sepsis, osteoarthritis, heart failure, anti- neutrophil cytoplasm antibody (ANCA) associated vasculitis, alopecia, chronic kidney disease,COVID-19 / SARS-CoV-2 infection, Long COVID, renal inflammation, renal fibrosis, dysmetabolism,vascular diseases, cardiovascular diseases and cancer. In a further preferred embodiment the invention refers to a pharmaceutical composition comprisingan above-mentioned compound of formula I and optionally one or more pharmaceuticallyacceptable carriers and / or excipients. In another preferred embodiment the invention relates to a pharmaceutical composition comprisingan above-mentioned compound of formula A and optionally one or more pharmaceuticallyacceptable carriers and / or excipients. In a further preferred embodiment the invention concerns a pharmaceutical composition comprising an above-mentioned compound of formula I 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, beta 2 agonists / betamimetics, adrenergic agonists, anticholinergic agents, methotrexate, mycophenolate mofetil, leukotriene modulators, JAK inhibitors, anti- interleukin antibodies, non-specific immunotherapeutics such as interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators, toll-like receptor agonists, immune checkpoint regulators, an anti-TNF antibody such as Humira™, an anti-BAFF antibody such as Belimumab and Etanercept, and optionally one or more pharmaceutically acceptable carriers and / or excipients. In another preferred embodiment the invention relates to a pharmaceutical composition comprisingan above-mentioned compound of formula A in combination with one or more active agentsselected from the group consisting of anti-inflammatory agents, anti-fibrotic agents, anti-allergic agents / anti-histamines, bronchodilators, beta 2 agonists / betamimetics, adrenergic agonists, anticholinergic agents, methotrexate, mycophenolate mofetil, leukotriene modulators, JAK inhibitors, anti-interleukin antibodies, non-specific immunotherapeutics such as interferons or other 32 01-3591-ff-text cytokines / chemokines, cytokine / chemokine receptor modulators, toll-like receptor agonists, immune checkpoint regulators, an anti-TNF antibody such as Humira™, an anti-BAFF antibody such as Belimumab and Etanercept, and optionally one or more pharmaceutically acceptable carriers and / or excipients. In a further preferred embodiment the invention refers to a pharmaceutical composition comprisingan above-mentioned compound of formula I in combination with one or more anti-fibrotic agentsselected from the group consisting of Pirfenidon and Nintedanib, and optionally one or more pharmaceutically acceptable carriers and / or excipients. In another preferred embodiment the invention relates to a pharmaceutical composition comprisingan above-mentioned compound of formula I in combination with one or more anti-inflammatoryagents selected from the group consisting of NSAIDs and corticosteroids, and optionally one or more pharmaceutically acceptable carriers and / or excipients. In another preferred embodiment the invention refers to a pharmaceutical composition comprising •an above-mentioned compound of formula I or an above-mentioned compound of formulaA •in combination with one or more anti-fibrotic agents selected from the group consisting ofPirfenidon and Nintedanib or 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.33 01-3591-ff-text 3. TERMS AND DEFINITIONS USEDUnless stated otherwise, all the substituents are independent of one another. If for example a number of C1-6-alkyl groups are possible substituents at a group, in the case of three substituents, for example, C1-6-alkyl could represent, independently of one another, a methyl, a n-propyl and a tert-butyl. A crossed bond like the middle bond in following butyl-molecule represents a double bond of unknown configuration (either cis, trans or a mixture thereof). By the term "C1-6-alkyl" (including those which are part of other groups) are meant branched and unbranched alkyl groups with 1 to 6 carbon atoms and by the term "C1-3-alkyl" are meant branched and unbranched alkyl groups with 1 to 3 carbon atoms. "C1-4-alkyl" accordingly denotes branched and unbranched alkyl groups with 1 to 4 carbon atoms. Alkyl groups with 1 to 4 carbon atoms are preferred. Examples of these include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, n-pentyl, iso-pentyl, neo-pentyl and hexyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu,t-Bu, etc., may also optionally be used for the above-mentioned groups. Unless stated otherwise, thedefinitions propyl, butyl, pentyl and hexyl include all the possible isomeric forms of the groups inquestion. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc. By the term "C1-6-alkylene" (including those which are part of other groups) are meant branched and unbranched alkylene groups with 1 to 6 carbon atoms and by the term "C1-4-alkylene" are meant branched and unbranched alkylene groups with 1 to 4 carbon atoms. Alkylene groups with 1 to 4 carbon atoms are preferred. Examples of these 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 stated otherwise, the definitions propylene, butylene,pentylene and hexylene include all the possible isomeric forms of the groups in question with the same number of carbons. Thus, for example, propyl includes also 1-methylethylene and butyleneincludes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene etc.If the carbon chain is substituted by a group which together with one or two carbon atoms of the alkylene chain forms a carbocyclic ring with 3, 5 or 6 carbon atoms, this includes, inter alia, the following examples of the rings: 34 01-3591-ff-text By the term "C2-6-alkenyl" (including those which are part of other groups) are meant branched and unbranched alkenyl groups with 2 to 6 carbon atoms and by the term "C2-4-alkenyl" are meant branched and unbranched alkenyl groups with 2 to 4 carbon atoms, provided that they have at least one double bond. Alkenyl groups with 2 to 4 carbon atoms are preferred. Examples include: ethenylor vinyl, propenyl, butenyl, pentenyl or hexenyl. Unless stated otherwise, the definitions propenyl,butenyl, pentenyl and hexenyl include all the possible isomeric forms of the groups in question. Thus,for example, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl etc. By the term "C2-5-alkynyl" (including those which are part of other groups) are meant branched and unbranched alkynyl groups with 2 to 5 carbon atoms and by the term "C2-4-alkynyl" are meant branched and unbranched alkynyl groups with 2 to 4 carbon atoms, provided that they have at least one triple bond. Alkynyl groups with 2 to 4 carbon atoms are preferred. By the term "C2-6-alkenylene" (including those which are part of other groups) are meant branched and unbranched alkenylene groups with 2 to 6 carbon atoms and by the term "C2-4-alkenylene" are meant branched and unbranched alkylene groups with 2 to 4 carbon atoms. Alkenylene groups with 2 to 4 carbon atoms are preferred. Examples of these 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 stated otherwise, thedefinitions propenylene, butenylene, pentenylene and hexenylene include all the possible isomeric forms of the groups in question with the same number of carbons. Thus, for example, propenyl also includes 1-methylethenylene and butenylene includes 1-methylpropenylene, 1,1- dimethylethenylene, 1, 2-dimethylethenylene. By the term "aryl" (including those which are part of other groups) are meant aromatic ring systems with 6 or 10 carbon atoms. Examples include phenyl or naphthyl, the preferred aryl group being phenyl. Unless otherwise stated, the aromatic groups may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine. 35 01-3591-ff-text By the term "aryl-C1-6-alkylene" (including those which are part of other groups) are meant branched and unbranched alkylene groups with 1 to 6 carbon atoms, which are substituted by an aromatic ringsystem with 6 or 10 carbon atoms. Examples include benzyl, 1- or 2-phenylethyl and 1- or 2-naphthylethyl. Unless otherwise stated, the aromatic groups may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine. By the term "heteroaryl-C1-6-alkylene" (including those which are part of other groups) are meant -even though they are already included under "aryl-C1-6-alkylene" - branched and unbranched alkylenegroups with 1 to 6 carbon atoms, which are substituted by a heteroaryl.If not specifically defined otherwise, a heteroaryl of this kind includes five- or six-memberedheterocyclic aromatic groups or 5-10-membered, bicyclic heteroaryl rings which may contain one, two, three or four heteroatoms selected from among oxygen, sulfur and nitrogen, and contain so many conjugated double bonds that an aromatic system is formed. The following are examples of five-or six-membered heterocyclic aromatic groups and bicyclic heteroaryl rings:, , , , , , , .Unless otherwise stated, these heteroaryls may be substituted by one or more groups selected fromamong methyl, ethyl, iso-propyl, tert-butyl, hydroxy, amino, nitro, alkoxy, fluorine, chlorine, bromine and iodine. The following are examples of heteroaryl-C1-6-alkylenes: 36 01-3591-ff-text By the term "C1-6-haloalkyl" (including those which are part of other groups) are meant branched and unbranched alkyl groups with 1 to 6 carbon atoms, which are substituted by one or more halogen atoms. By the term "C1-4-haloalkyl" are meant branched and unbranched alkyl groups with 1 to 4 carbon atoms, which are substituted by one or more halogen atoms. Alkyl groups with 1 to 4 carbon atoms are preferred. Examples include: CF3, CHF2, CH2F, CH2CF3. By the term "C3-7-cycloalkyl" (including those which are part of other groups) are meant cyclic alkyl groups with 3 to 7 carbon atoms, if not specifically defined otherwise. Examples include: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Unless otherwise stated, the cyclic alkyl groupsmay be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine. If not specifically defined otherwise, by the term "C3-10-cycloalkyl" are also meant monocyclic alkyl groups with 3 to 7 carbon atoms and also bicyclic alkyl groups with 7 to 10 carbon atoms, or monocyclic alkyl groups which are bridged by at least one C1-3-carbon bridge.By the term "heterocyclic rings" or "heterocycle" are meant, unless stated otherwise, five-, six- orseven-membered, saturated, partially saturated or unsaturated heterocyclic rings which may contain one, two or three heteroatoms selected from among oxygen, sulfur and nitrogen, while the ring may be linked to the molecule through a carbon atom or through a nitrogen atom, if there is one. Although included by the term "heterocyclic rings" or "heterocycles", the term "saturated heterocyclic ring"refers to five-, six- or seven-membered saturated rings. Examples include:, , . Although included by the term "heterocyclic rings" or "heterocyclic group", the term "partiallysaturated heterocyclic group" refers to five-, six- or seven-membered partially saturated rings whichcontain one or two double bonds, without so many double bonds being produced that an aromatic system is formed, unless specifically defined otherwise. Examples include: 37 01-3591-ff-text Although included by the term "heterocyclic rings" or "heterocycles", the term "heterocyclic aromaticrings", "unsaturated heterocyclic group" or "heteroaryl" refers to five- or six-membered heterocyclicaromatic groups or 5-10-membered, bicyclic heteroaryl rings which may contain one, two, three or four heteroatoms selected from among oxygen, sulfur and nitrogen, and contain so many conjugated double bonds that an aromatic system is formed, unless not specifically defined otherwise. Examplesof five- or six-membered heterocyclic aromatic groups include:, , , ,, .Unless otherwise mentioned, a heterocyclic ring (or heterocycle) may be provided with a keto group. Examples include: , , , , , , , , . Although covered by the term "cycloalkyl", the term "bicyclic cycloalkyls" generally denotes eight-,nine- or ten-membered bicyclic carbon rings. Examples include: , , , , , , , . Although already included by the term "heterocycle", the term "bicyclic heterocycles" generallydenotes eight-, nine- or ten-membered bicyclic rings which may contain one or more heteroatoms,38 01-3591-ff-text preferably 1-4, more preferably 1-3, even more preferably 1-2, particularly one heteroatom, selected from among oxygen, sulfur and nitrogen, unless not specifically defined otherwise. The ring may belinked to the molecule through a carbon atom of the ring or through a nitrogen atom of the ring, ifthere is one. Examples include: , , , , , . Although already included by the term "aryl", the term "bicyclic aryl" denotes a 5-10 membered, bicyclic aryl ring which contains sufficient conjugated double bonds to form an aromatic system. One example of a bicyclic aryl is naphthyl. Although already included under "heteroaryl", the term "bicyclic heteroaryl" denotes a 5-10 membered, bicyclic heteroaryl ring which may contain one, two, three or four heteroatoms, selected from among oxygen, sulfur and nitrogen, and contains sufficient conjugated double bonds to form an aromatic system, unless specifically defined otherwise. Although included by the term "bicyclic cycloalkyls" or "bicyclic aryl", the term "fused cycloalkyl" or "fused aryl" denotes bicyclic rings wherein the bridge separating the rings denotes a direct single bond. The following are examples of a fused, bicyclic cycloalkyl: , , , , , . Although included by the term "bicyclic heterocycles" or "bicyclic heteroaryls", the term "fused bicyclicheterocycles" or "fused bicyclic heteroaryls" denotes bicyclic 5-10 membered heterorings whichcontain one, two, three or four heteroatoms, selected from among oxygen, sulfur and nitrogen andwherein the bridge separating the rings denotes a direct single bond. The "fused bicyclic heteroaryls"moreover contain sufficient conjugated double bonds to form an aromatic system. Examples include pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine, 39 01-3591-ff-text "Halogen" within the scope of the present invention denotes fluorine, chlorine, bromine or iodine. Unless stated to the contrary, fluorine, chlorine and bromine are regarded as preferred halogens.As mentioned previously, the compounds of formula I may be converted into the salts thereof,particularly for pharmaceutical use into the physiologically and pharmacologically acceptable salts thereof. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissue of human beings and animals without excessivetoxicity, irritation, allergic response, or other problem or complication, and commensurate with areasonable benefit / risk ratio. These salts may be present on the one hand as physiologically andpharmacologically acceptable acid addition salts of the compounds of formula I with inorganic ororganic acids. On the other hand, the compound of formula I may be converted by reaction with inorganic bases into physiologically and pharmacologically acceptable salts with alkali or alkaline earth metal cations as counter-ion. The acid addition salts may be prepared for example using hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, p-toluenesulfonic acid,acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. It is alsopossible to use mixtures of the above-mentioned acids. To prepare the alkali and alkaline earth metal salts of the compounds of formula I it is preferable to use the alkali and alkaline earth metal hydroxides and hydrides, of which the hydroxides and hydrides of the alkali metals, particularly sodium, potassium, magnesium, calcium, zinc and diethanolamine, are preferred, while sodium and potassium hydroxide are particularly preferred. The invention relates to the compounds in question, optionally in the form of the individual optical isomers, diastereomers, mixtures of diastereomers, mixtures of the individual enantiomers orracemates, in the form of the tautomers as well as in the form of the free bases or thecorresponding acid addition salts with pharmacologically acceptable acids - such as for example acid40 01-3591-ff-textaddition salts with hydrohalic acids - for example hydrochloric or hydrobromic acid - or organic acids– such as for example oxalic, fumaric, diglycolic or methanesulfonic acid.The compounds of formula I according to the invention may optionally be present as mixtures ofdiastereomeric isomers but may also be obtained as pure diastereoisomers (with respect to all chiralcenters which are not specifically defined in the compounds of formula I).The compounds of formula I according to the invention may optionally be present as an isotopicvariation of a compound of the invention. An isotopic variation of a compound of the invention, is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 18F and 36CI,respectively. Certain isotopic variations of a compound of formula I or a salt or solvate thereof, forexample, those in which a radioactive isotope such as 3H or 14O is incorporated, are useful in drugand / or substrate tissue distribution studies. Tritiated, i.e., 3H, and carbon-14, i.e., 14O, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution withisotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Thus, in one embodiment, the present invention includes a compound of the invention, wherein one or more hydrogen atoms attached to carbon atoms are replaced by deuterium. Isotopic variations of a compound of the invention, can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents. 41 01-3591-ff-text 4METHODS OF SYNTHESISThe compounds according to the invention and their intermediates may be obtained using the methods described in the examples that follow, which may also be combined for this purpose with methods known to those skilled in the art and known from literature. In particular, the invention provides processes for making compounds of Formula (I). Optimal reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperature, pressures and other reaction conditions, may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Typically, reaction progress may be monitored by thin layer chromatography (TLC) or liquid chromatography mass spectrometry (LC-MS), if desired, and intermediates and products maybe purified by chromatography on silica gel, HPLC and / or by recrystallization. The examples whichfollow are illustrative and, as one skilled in the art will recognize, particular reagents or conditions could be modified as needed for individual compounds without undue experimentation. Starting materials and intermediates used in the methods below are either commercially available or easily prepared from commercially available materials by those skilled in the art.A compound of Formula (I) may be prepared by the methods outlined in Schemes 1- 3, wherein R1,R2, R3, R4, R5, R6, R7,R8, R9 and Q, U, T and V are defined as in claim 1:Scheme 1: As illustrated in Scheme 1, the reaction of chloro-pyrimidine (IV) with (2S,4S)-4-hydroxy-pyrrolidine-2-carboxylic acid in the presence of a suitable base such as DIPEA, K2CO3, or NaH in a suitable solvent 42 01-3591-ff-text such as DMSO or DMF provides a hydroxyproline derivative of formula (III). Reaction of hydroxyprolinederivative (III) with a benzimidazole derivative of formula (II) (where LG is a leaving group, e.g. Cl, Bror -SO2-Me) in the presence of a suitable base such as NaH in a suitable solvent such as DMA, DMF or NMP provides a compound of formula (I). Scheme 2: The synthesis of intermediates with general formula (II) where LG represents a leaving group is illustrated in scheme 2 for LG = -SO2-Me (intermediate (II-a) and for LG = Cl (intermediate (II-b): The aryl halide (V) reacts with a primary amine (R3-NH2) in presence of a base such as DIPEA in a suitable solvent such as DMF to form compound (VI). In the next reaction step, (VI) is reduced to the aniline(VII) applying a suitable method, e.g. using a catalyst such as Raney-nickel in a suitable solvent such asTHF under hydrogen pressure or Tin(II) chloride dihydrate in conc. HCl. Alternatively, anilineintermediate (VII) can be obtained by reductive amination reaction between an aldehyde or ketone and the dianiline compound (VIII) using a reducing agent such as triacetoxyborohydride in a solvent such as dichloromethane. The diamine (VII) can be converted in two steps into intermediate (IIb). In the first step it is treated either with CDI to form intermediate (IX), or alternatively it is treated with 1-(1H-imidazole-1-carbothioyl)-1H-imidazole in a suitable solvent such as DMF to form intermediate (X); from bothintermediates (IX) or (X), the final intermediate (II-b) can be obtained by chlorination with a suitable agent such as POCl3 or thionyl chloride. In an alternative synthesis route, intermediate (VII) is reacted with 1-(1H-imidazole-1-carbothioyl)-1H-imidazole in a suitable solvent such as DMF to give intermediate (X). This compound is then treatedwith a suitable base such as potassium tert-butylate followed by iodomethane in a suitable solvent43 01-3591-ff-text such as DMF to give intermediate (XI) which is finally oxidized with a suitable oxidizing agent such as 3-chloroperoxybenzoic acid in a suitable solvent such as DCM to yield intermediate (II-a). A compound of formula (IV) can be prepared as illustrated in Scheme 3. Scheme 3: The reaction of a carbonitrile of formula (XII) with an anhydride of formula (XIII) (or the correspondingacid under activation with an activation reagent as i.e. HATU in the presence of a base such as i.e.DIPEA in a suitable solvent such as i.e. DMF) provides amide (XIV). Upon reaction with a suitable chlorination reagent such as phosphorus pentachloride in a suitable solvent such as sulfolane, amide (XIV) cyclizes to form a compound of formula (IV).In an alternative synthetic sequence, a compound of formula (XV) reacts with 2-bromoacetamide (XVI)in the presence of a suitable base such as K2CO3or KOH in a suitable solvent such as ethanol to providea 3-amino-1-benzofuran-2-carboxamide (XVII). Compound (XVII) reacts with a dimethylamide offormula (XVIII) in the presence of a suitable chlorination reagent such as phosphorus oxychloride and forms a compound of formula (IV). In another alternative synthetic sequence, a compound of formula (XV) reacts with bromoacetonitrile in the presence of a suitable base such as K2CO3in a suitable solvent such as DMF to yield a compoundof formula (XIX). This compound cyclizes in the presence of a suitable base such as potassium tert-butoxide in a suitable solvent such as THF to form a carbonitrile of formula (XII), and can be converted into a compound of formula (XIV) and subsequently into a compound of formula (III) as described above. 44 01-3591-ff-text SYNTHESIS OF INTERMEDIATES INTERMEDIATE 1INTERMEDIATE 1.1 (general procedure)N-(2-cyano-1-benzofuran-3-yl)-2,2,2-trifluoroacetamide Int.1.1TFAA (5.31 g, 25.3 mmol) was added to a mixture of 3-amino-1-benzofuran-2-carbonitrile (4.00 g, 25.3mmol) in pyridine (40.0 mL) at RT. The mixture was stirred at 25°C for 12 h, then concentrated underreduced pressure, diluted with 20 mL water and extracted with EtOAc. The combined organic layerswere washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography (silica gel; PE / EtOAc = 20 / 1 to 5 / 1).ESI-MS: 255 [M+H]+Rt (HPLC): 0.56 min (method A)The following intermediate was prepared according to the general procedure (INTERMEDIATE 1.1) described above: INTERMEDIATE 2 45 01-3591-ff-textINTERMEDIATE 2.1 (general procedure)6-Chloro-4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaene Int.1.1 Int.2.1To a solution of N-(2-cyano-1-benzofuran-3-yl)-2,2,2-trifluoroacetamide (INTERMEDIATE 1.1., 4.00 g,15.7 mmol) in sulfolane (10.0 mL) was added phosphorus pentachloride (13.1 g, 63.0 mmol). Themixture was stirred at 110°C for 16h. After cooling to RT, the reaction mixture was poured onto icewater and extracted with EtOAc. The combined org. layers were washed with brine, dried over Na2SO4,filtered and concentrated under reduced pressure. The residue was purified by FC (silica gel; PE / EtOAc= 20 / 1 to 10 / 1). ESI-MS: 273 [M+H]+Rt (HPLC): 0.71 min (method A)The following intermediate was prepared according to the general procedure (INTERMEDIATE 2.1) described above: INTERMEDIATE 3INTERMEDIATE 3.1 (general procedure)(2S,4S)-4-Hydroxy-1-[4-(trifluoromethyl)-8-oxa-3,5-diazatricyclo[7.4.0.02,7]-trideca- 1(9),2(7),3,5,10,12-hexaen-6-yl]pyrrolidine-2-carboxylic acid 46 01-3591-ff-text FFFFF F H O N N N N O N OH OH O N O Cl HO OH Int. 2.1 Int. 3.1To a preheated mixture of (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid (1.44 g, 11.0 mmol) in DMSO(25.0 mL) at 110 °C was added DIPEA (3.90 g, 30.0 mmol) and 6-chloro-4-(trifluoromethyl)-8-oxa- 3,5diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaene (INTERMEDIATE 2.1, 2.73 g, 10.0 mmol). Stirring was continued at 110°C for 10 min. The heating was removed, the reaction mixtureadded dropwise into water and acidified with 4M HCl. The precipitate was filtered and dried.ESI-MS: 368 [M+H]+Rt (HPLC): 0.50 min (method A)The following intermediates were prepared according to the general procedure (INTERMEDIATE 3.1)described above: 47 01-3591-ff-text INTERMEDIATE 3.4 tert-Butyl (2S,4S)-1-[4-(2-ethoxy-2-oxoethyl)-8-oxa-3,5-diazatricyclo[7.4.0.02,7]trideca- 1(9),2(7),3,5,10,12-hexaen-6-yl]-4-hydroxypyrrolidine-2-carboxylate . .Step 1: Ethyl 2-{6-oxo-8-oxa-3,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,10,12-pentaen-4-yl}-acetateTo a mixture of ethyl-3-aminobenzofuran-2-carboxylate (5.00 g, 24.4 mmol) (synthesis described inWO2017 / 62581) in 4 M aq. HCl (50.00 mL, 200 mmol) was added ethyl cyanoacetate (5.19 mL,48.7 mmol) at RT. The mixture was heated at 100°C for 4h. After cooling to RT, another 2.6 mL(24. mmol) of ethyl cyanoacetate were added and heating was continued for 48h at 100°C. The solventwas evaporated and the crude residue was diluted with 100mL MeOH, filtered and dried. The crudeproduct was taken directly to the next step.ESI-MS: 273 [M+H]+Rt(HPLC): 0.63 min (method B)Step 2: Ethyl 2-{6-chloro-8-oxa-3,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}-acetate A mixture of Ethyl 2-{6-oxo-8-oxa-3,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,10,12-pentaen-4-yl}-acetate (3.35 g; 12.3 mmol) in phosphoryl trichloride (50.0 mL, 547 mmol) was heated at 110°C for 1.5h. The reaction mixture was cooled to RT and added dropwise to an ice bath (500 mL) under stirringover 30^min. EtOAc was added and the layers were separated. To the org. layer, sat. bicarbonate48 01-3591-ff-textsolution was added slowly, and the phases were separated. The org. layer was washed with H2O andbrine, dried over Na2SO4, filtered, and concentrated in vacuo.ESI-MS: 291 [M+H]+Rt (HPLC): 0.43 min (method A)Step 3: tert-Butyl (2S,4S)-1-[4-(2-ethoxy-2-oxoethyl)-8-oxa-3,5-diazatricyclo[7.4.0.02,7]-trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]-4-hydroxypyrrolidine-2-carboxylate To Ethyl 2-{6-chloro-8-oxa-3,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}acetate(8.17 mmol, 1.00 eq, 2.50 g) in 30 mL N-Methyl-2-pyrrolidone was added tert-butyl (2S,4S)-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 cooled to RT andadded slowly to 300 mL of ice water. The precipitate was filtered, washed several times with H2O anddried.ESI-MS: 442 [M+H]+Rt (HPLC): 0.67 min (method B) Step 4: 2-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidin-1-yl]-8-oxa-3,5-diazatricyclo- [7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}acetic acid Lithium hydroxide (49.5 mg, 2.10 mmol) was added to a mixture of tert-butyl (2S,4S)-1-[4-(2-ethoxy- 2-oxoethyl)-8-oxa-3,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl]-4-hydroxypyrrolidine-2-carboxylate obtained in the previous step (640 mg, 1.40 mmol) in 6.0 mL of a 2:1(v / v) THF / H2O and the reaction mixture was stirred at RT until reaction control by RP-HPLC indicatedconsumption of the starting material. Volatiles were removed in vacuo, the residue was taken up in DMF acidified with TFA and purified via RP-HPLC (Sunfire C18, ACN, H2O + TFA) to yield the title compound.ESI-MS: 414 [M+H]+Rt (HPLC): 0.55 min (method F) Step 5: tert-butyl(2S,4S)-4-hydroxy-1-{4-[(methylcarbamoyl)methyl]-8-oxa-3,5- diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl}pyrrolidine-2-carboxylate 49 01-3591-ff-textTEA (0.18 mL; 1.3 mmol) and HATU (166 mg; 0.44mmol) was added to a mixture of 2-{6-[(2S,4S)-2-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidin-1-yl]-8-oxa-3,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl}acetic acid obtained in the previous step (150 mg; 0.36 mmol) andDMF (3 mL) and stirred for 10 minutes before methylamine (1.1 mL, 2.2 mmol) was added in small portions under stirring. After reaction control by RP-HPLC indicated formation of product, H2O was added to the mixture and the mixture purified via RP-HPLC (X-bridge C18, ACN, H2O +ammonia) to yield the title compound.ESI-MS: 427 [M+H]+Rt (HPLC): 0.73 min (method F) INTERMEDIATE AINTERMEDIATE A-01 : Racemic trans tert-butyl trans-4-amino-3-methylpiperidine-1-carboxylate Intermediate A-01Step 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(hydrido)borate (L-selectride, 1M in THF, 984 mL, 0.98mol). The mixture was stirred for 4 h while keeping the temperature between 0 °C and 10 °C. Aq.sodium hypochlorite solution (10%, 525 mL) was added and the mixture was extracted with EtOAc(700 mL). The org. layer was separated, washed with brine, dried over Na2SO4 and evaporated. Thecrude product was purified by FC (silica gel; PE / EtOAc 2% -> 50%). ppm 3.84 - 3.82 (m, 1H), 3.52 (d, J = 6.40 Hz, 2H), 3.29 (d, J = 5.40 Hz, 2H),3.06 - 3.02 (m, 1H), 1.76 - 1.74 (m, 3H), 1.65 (s, 9H), 1.24 - 0.89 (m, 3H).50 01-3591-ff-text Step 2:To a solution of the product from step 1 (330 g, 1.53 mol) in THF (1.65 L) was added TEA (341 g, 3.37mol). Methanesulfonic anhydride (507 g, 2.91 mol) was added at RT and the mixture was stirred at Rtfor 4 h. Water (550 mL) was added and the mixture was extracted with EtOAc (1.65 L). The org. layerwas separated, washed with brine, dried over Na2SO4and concentrated under reduced pressure. The product was taken to the next step without further purification. NMR (400 MHz, CDCl3) δ ppm 4.74 - 4.71 (m, 1H), 4.23 - 3.95 (m, 1H), 3.17 - 3.04 (m, 2H), 3.04 (s,3H), 1.95 - 1.92 (m, 1H), 1.83 (s, 1H), 1.83 - 1.82 (m, 1H), 1.32 (s, 9H), 0.91- 0.79 (m, 3H)Step 3:Reaction under nitrogen atmosphere. To a solution of the product from step 2 (420 g, 1.43 mol) inDMF (2.1 L) was added at RT sodium azide (186 g, 2.86 mol). The mixture was stirred at 100 °C for 4 h,then cooled to 0°C. A sat. solution of sodium carbonate (4.0 L) was added while keeping thetemperature 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 productwas taken to the next step without further purification. Step 4:A mixture of the product from step 3 (200 g, 0.83 mol), palladium on charcoal (60 g) and EtOAc (1.0 L)was stirred under hydrogen pressure (50 psi) at RT for 2 h. The catalyst was filtered off with suctionand washed with MeOH (2 L). The combined filtrates were evaporated under reduced pressure. Thecrude product was purified by FC (silica gel; PE / EtOAc 0% -> 100%) to yield the title compound. Intermediate A-02Step 1: racemic trans-4-Azido-3-methyl-tetrahydropyran51 01-3591-ff-text To a mixture of methanesulfonic acid (racemic-trans)-3-methyl-tetrahydro-pyran-4-yl ester (describedin EP2680844; page 49) (27.1 g; 0.140 mol; 1.00 eq) in DMF (271 mL) was added sodium azide (13.6 g,0.209 mol; 1.50 eq) at RT: The resulting mixture was heated under stirring at 85 °C for 4 h, allowed tocool to RT and stirred overnight. The reaction was quenched by addition of sat. sodium bicarbonatesolution followed by extraction with diethyl ether. The organic layer was washed with H2O and brineand then dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure to givethe crude product which was used in the next step without further purification.Step 2: racemic trans-4-amino-3-methyl-tetrahydropyran hydrochlorideA mixture of (racemic trans)-4-Azido-3-methyl-tetrahydro-pyran (16.5 g, 117 mmol, 1.0 eq) and 10%palladium on charcoal (3.42 g, 32.0 mmol) in MeOH (165 mL) was stirred at atmosphere hydrogenpressure overnight. The reaction mixture was filtered over a Celite pad and washed with MeOH. 2Maqueous HCl solution (120 mL) was added to the filtrate while cooling at 0 °C and stirring for 1 h. Thevolatiles were evaporated to dryness under reduced pressure. To the remainder, 50 mL diethyl etherwas added, followed by 120 mL 2M HCl solution in diethyl ether, and the mixture was stirred at RT for1 h. The solid was filtered and dried under reduced pressure to give the desired product as a white solid.ESI-MS: 116 [M+H]+Rt (HPLC): 0.34 min (method D)1H NMR (400 MHz, DMSO-d6) δ ppm 8.30 (bs, 3 H), 3.87 (br dd, J=11.5 Hz, 4.3Hz, 1H), 3.74(dd, J=11.5 Hz, 4.3 Hz, 1H), 3.26 – 3.77 (m, 3 H), 2.95 (t, J=11.2 Hz, 1H), 2.80 – 2.93 (m, 1H),1.87 – 1.96 (m, 1H), 1.66 – 1.80 (m, 1H), 1.50 – 1.62 (m, 1H), 0.88 (d, J=6.5 Hz, 3H).INTERMEDIATE A-03 Step 1: 5-chloro-N1-(3-methyloxan-4-yl)benzene-1,2-diamine1.69 mL acetic acid (28.9 mmol; 1.10 eq) was added to a mixture of 3-methyl-tetrahydropyran-4-one(3.00 g, 26.3 mmol, 1.00 eq) and 1,2-diamino-4-chlorobenzene (3.75 g, 26.3 mmol, 1.00 eq) in 100 mLDCM. The mixture was stirred at RT for 15 min, then cooled to 0°C, and 11.70 g sodiumtriacetoxyborohydride (55.2 mmol, 2.10 eq) was added. The reaction was allowed to come to RT under52 01-3591-ff-text stirring overnight. DCM and sat. sodium bicarbonate solution was added to the reaction mixture andit was stirred for 30 min. The org. layer was separated, washed with H2O, separated, dried overmagnesium sulfate, filtered and concentrated. The crude product was purified by FC (silica gel;cyclohexane / EtOAc 5% -> 100%).ESI-MS: 239 [M+H]+Rt (HPLC): 0.69 min (method D)INTERMEDIATE B Intermediate B-01: Step 1:A mixture of intermediate A-01 (2.00 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 controlby RP-HPLC indicated predominant conversion of the starting materials (10 h). The mixture waspoured on ice water. Further H2O was added and the mixture was extracted three times with EtOAc.The combined org. layers were washed with H2O and then with brine, separated, dried overmagnesium sulfate, filtered and concentrated. The crude product was purified by FC (silica gel; cyclohexane / EtOAc 20% -> 100%) to yield tert-butyl (rac-trans)-4-[(4-chloro-2-nitrophenyl)-amino]-3- methylpiperidine-1-carboxylate.ESI-MS: 392 [M+Na]+Rt(HPLC): 0.83 min (method A) 53 01-3591-ff-text Step 2:The product from step 1 (3.25 g, 7.90 mmol), Raney nickel (410 mg) and THF (60 mL) were shaken ina Parr apparatus under hydrogen pressure (50 psi) at RT for 5 h. Further Raney nickel (160 mg) wasadded multiple times after further 10-15 h each, until reaction control by RP-HPLC indicated high conversion of the starting material (here: catalyst addition 3 times). The catalyst was filtered off and the filtrate was evaporated. The crude product was taken to the next step.ESI-MS: 340 [M+H]+Rt (HPLC): 0.63 min (method A) Step 3:A mixture of the product from step 2 (2.16 g, 6.37 mmol), 1-(1H-imidazole-1-carbothioyl)-1H-imidazole (1.47 g, 8.25 mmol) and DMF (34 mL) was stirred at RT for 2 h. Ice water (200 mL) was addedslowly to the reaction mixture while stirring and stirring was continued for further 10 min. The precipitate was filtered off, washed with H2O, dried overnight at 50 °C and taken to the next step without further purification.ESI-MS: 382 [M+H]+Rt (HPLC): 0.71 min (method A) Step 4: tert-butyl (racemic trans) -4-[5-chloro-2-(methylsulfanyl)-1H-1,3-benzodiazol-1-yl]-3- methylpiperidine-1-carboxylateTo a mixture of the product from step 3 (2.57 g, 6.26 mmol) in anhydrous DMF in an inert atmospherewas added potassium tert-butylate (1.42 g, 12.7 mmol) and the mixture was stirred at RT for 15 min.Then iodomethane (597 µL, 9.49 mmol) was added and the mixture was stirred at RT until reactioncontrol by RP-HPLC indicated near-complete conversion of the starting material (~2 h). Ice water (100 mL) was added and the mixture was kept at 6°C overnight. The precipitate formed was filtered off, taken up in EtOAc, concentrated under reduced pressure and dried by co-evaporation with toluene.ESI-MS: 396 [M+H]+Rt(HPLC): 0.73 min (method A) Step 5: 54 01-3591-ff-text The mixture of enantiomers from step 4 was separated by means of preparative SFC (Instrument: Sepiatec 2 Prep SFC 100; Column: Lux Cellulose-2 (21.2 mm * 250mm, 5um); Mobile phase: A for CO2and B for isopropyl alcohol Gradient: B% = 20% isocratic elution mode; Flow rate: 60 mL / min;Wavelength: 220nm; Column temperature: 40 °C; System back pressure: 150 bar). The absolute configuration of the two separated enantiomers was assigned based on a co-crystalstructure of EXAMPLE 1.01 with human cGAS protein according to methods described by D. J. Patel etal, PNAS 2019, 11946-11955 (doi.org / 10.1073 / pnas.1905013116).1H NMR (of the isomer eluting first) (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)The isomer eluting second was taken to the next step.Step 6:To a solution of the isomer eluting second from step 5 (864 mg; 2.18 mmol) in DCM (12.59 mL) wasadded 3-chloroperoxybenzoic acid (77%; 1.05 g; 4.64 mmol). The mixture was stirred at roomtemperature for 2 h, then diluted with further DCM and washed with aq. potassium carbonate (15%).The aq. layer was reextracted with DCM and the combined org. layers were washed with H2O,separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound.ESI-MS: 428 / 430 [Cl] [M+H]+Rt (HPLC): 0.75 min (method A)The following intermediates were prepared analogously to Intermediate B-01 described above fromthe starting materials indicated. Thereby, the reaction temperature in step 1 was adjusted to the reactivity of the respective nitrobenzene starting material. The absolute configuration of selectedintermediates was assigned from a co-crystal structure of an example compound prepared from therespective intermediate with human cGAS protein according to methods described by D. J. Patel et al, PNAS 2019, 11946-11955 (doi.org / 10.1073 / pnas.1905013116). The absolute configuration of otherintermediates and examples was assigned based on the assumption that eutomers share the sameabsolute stereochemistry in all cases. 55 01-3591-ff-text 56 01-3591-ff-text 57 01-3591-ff-text INTERMEDIATE C INTERMEDIATE C-01 procedure A: 58 01-3591-ff-text Step 1:Racemic trans-3-methyl-4-aminotetrahydropyran hydrochloride (380 mg; 2.51 mmol) was dissolvedin 10mL DMF, 1.08 mL; 10.00 mmol DIPEA was added and stirred for 3 min. Then 2-chloro-6-fluoronitrobenzene (440 mg; 2.51 mmol) was added and stirring continued for 10min. The reactionmixture is allowed stirring at 80°C for 24h. After cooling the reaction to RT, the reaction was pouredinto 100 mL of H2O. This mixture was washed 3 times with 30 mL EtOAc. The combined org. layerswere dried over Na2SO4 and concentrated. The residue was purified using HPLC (Agilent ZorbaxStableBond; ACN; H2O; FA) Product fractions were then pooled and concentrated under reducedpressure to yield the title compound.ESI-MS: 271 [M+H]+ +Rt(HPLC): 0.98 min (method F) Step 2:To a mixture of (racemic trans)-N-(3-chloro-2-nitrophenyl)-3-methyloxan-4-amine (290 mg, 1.07mmol) and conc. HCl (5.00mL), was added Tin(II) chloride dihydrate (966.89 mg; 4.28 mmol) inportions. Stirring continued for 10 min. The reaction was poured into 200 g ice and adjusted to pH 9using 4M aq. sodium hydroxide. This mixture was washed 3 times with 30 mL DCM. The combined org.layers were dried using Na2SO4 and concentrated under reduced pressure.ESI-MS: 241 [M+H]+Rt (HPLC): 0.83 min (method F) Step 3: To a mixture of 3-chloro-N1-[(racemic trans)-3-methyloxan-4-yl]benzene-1,2-diamine (210 mg;0.870 mmol) in 10 mL THF was added 1,1'-carbonyldiimidazol (212 mg; 1.31 mmol). The reaction59 01-3591-ff-text mixture was stirred at RT for 3h, then 50mL H2O was added while stirring. The formed precipitate was collected by filtration, washed with H2O and dried at 50°C for 3h.ESI-MS: 267 [M+H]+Rt (HPLC): 0.76 min (method F) Step 4: 4-chloro-1-[(racemic trans)-3-methyloxan-4-yl]-2,3-dihydro-1H-1,3-benzodiazol-2-one (120 mg, 0.450 mmol) was dissolved in 5 mL phosphorus oxychloride and allowed stirring at 80°C for 5h. The reaction was concentrated in vacuum, taken up in 10 mL ACN and concentrated in vacuum again. This process was repeated twice.ESI-MS: 285 [M+H]+Rt (HPLC): 0.86 min (method E) Intermediate C-02 procedure B: Intermediate C-02Step 1:To a mixture of (3R,4S)-3-methyloxan-4-amine hydrochloride (580 mg, 3.30 mmol, 1.00 eq) and DIPEA(1.71 mL, 10 mmol, 3.00 eq) in 15.0 mL DMF was added 2-fluoro-3-chloronitrobenzene (501 mg, 3.30mmol, 1.00 eq) at RT. The reaction was allowed stirring at 80°C for 4 h. After cooling to RT the reactionmixture was poured in 100 mL H2O and washed twice with 50 mL EtOAc. The combined org. layerswere washed with 50 mL 20% citric acid in H2O and sat. sodium bicarbonate in H2O. The org. layer wasdried and evaporated.60 01-3591-ff-textESI-MS: 271 [M+H]+Rt (HPLC): 0.97 min (method F) Step 2:To a mixture of (3R,4S)-N-(2-chloro-6-nitrophenyl)-3-methyloxan-4-amine (860 mg, 3.18 mmol)) inconc. HCl (20.0 mL) was added Tin(II) chloride dihydrate (0.287 g, 12.7 mmol) in portions. Stirring wascontinued for 10 min, before the mixture was poured onto ice and adjusted to pH 9 using 4M aq.sodium hydroxide solution. The precipitated solid was collected by filtration, washed with 20 mL ofH2O and dried at 50°C for 3h.ESI-MS: 241 [M+H]+Rt (HPLC): 0.77 min (method E) Step 3:To a mixture of 6-chloro-N1-[(3R,4S)-3-methyloxan-4-yl]benzene-1,2-diamine (750 mg, 3.12 mmol,) in20 mL THF was added1-(1H-imidazole-1-carbothioyl)-1H-imidazole (1.11 g, 6.23 mmol) at RT. Thereaction mixture was stirred at RT for 24 h. The THF was removed under reduced pressure, the residuewas taken up in 100 mL EtOAc, and the organic phase was washed successively with 50 mL 1 M HCland 50 mL sat. sodium bicarbonate. The org. layer was dried over Na2SO4 and concentrated underreduced pressure. ESI-MS: 283 [M+H]+Rt(HPLC): 0.82 min (method E) Step 4: A mixture of 7-chloro-1-[(3R,4S)-3-methyloxan-4-yl]-2,3-dihydro-1H-1,3-benzodiazole-2-thione(920 mg, 3.24 mmol; 1.00 eq) and thionyl dichloride (10.0 mL, 138 mmol) was heated to 90°C understirring for 45 min. The reaction was concentrated under reduced pressure, dissolved in 20 mL tolueneand concentrated again under reduced pressure to yield the title compound. ESI-MS: 285 [M+H]+Rt(HPLC): 0.92 min (method E) The following intermediates were prepared analogously: 61 01-3591-ff-text 62 01-3591-ff-text 63 01-3591-ff-text Preparation of Final Compounds The absolute configuration of the cyclic side chain attached to the benzimidazole nitrogen (piperidine,tetrahydropyrane or thianedione) has in part (e.g. EXAMPLE 1.03, 1.04, 1.06, 1.07, 1.08, 2.04, 3.01)been assigned from a co-crystal structure with human cGAS protein according to methods described by D. J. Patel et al, PNAS 2019, 11946-11955 (doi.org / 10.1073 / pnas.1905013116). In other cases, absolute configuration has been assigned based on the assumption, that the more potent diastereoisomer always has (S,S,S,S)-configuration.EXAMPLE 1.01(Starting materials: 3.1, B-01)To a mixture of 15 mg (0.040 mmol)) INTERMEDIATE 3.1 ((2S,4S)-4-HYDROXY-1-[2-(trifluormethyl)benzofuro[3,2-D]pyrimidin-4-yl]pyrrolidine-2-carboxylic acid) in 1.0 mL DMF wasadded NaH 55% oil dispersion (8.9 mg, 0.20 mmol) at RT and the mixture was stirred at RT for 10 min.Then (19.3 mg, 0.0440 mmol) INTERMEDIATE B-01 (tert-butyl (3S,4S)-4-(5-chloro-2-methanesulfonyl-1H-1,3-benzodiazol-1-yl)-3-methylpiperidine-1-carboxylate) was added, and the reaction mixture wasstirred at RT for a further 5 min, then heated to 55°C for 2 h. After cooling to RT, the mixture wastreated with 10 mL H2O and acidified with acetic acid. The precipitate was filtered, washed with anadditional 2 mL H2O and dried. This crude solid product was purified by preparative columnchromatography (Waters X-Bridge C18, ACN, H2O, TFA). Product fractions were then pooled and lyophilized.ESI-MS: 715 / 717 [Cl] [M+H]+Rt (HPLC): 0.85 min (method A) 64 01-3591-ff-text The following compounds were prepared analogously to EXAMPLE 1.01 described above: 65 01-3591-ff-text 66 01-3591-ff-text 67 01-3591-ff-text 68 01-3591-ff-text 69 01-3591-ff-text 70 01-3591-ff-text EXAMPLE 2.01 Step1 :To as solution of INTERMEDIATE 3.2 (300 mg, 0.86 mmol) in DMF (15.0 mL) was added NaH (60% oildispersion, 137 mg, 3.44 mmol). After stirring for 10 min, INTERMEDIATE B-15 (407 mg, 0.86 mmol)was added, and the mixture was stirred 2h at 50°C. Following complete conversion, the reaction mixture was cooled to RT and poured into a solution of 150 mL H2O containing 4.5 mL of a 1M KHSO4 71 01-3591-ff-text solution. The precipitate was recovered by filtration, washed with several small portion of H2O, and dried under vacuum at 50°C to afford the title compound. ESI-MS: 649 [M+H]+Rt (HPLC): 1.03 min (method E)Step2The product obtained in step 1 (480 mg, 0.74 mmol) was added a hydrogen chloride solution (4M indioxane, 15 mL, 60 mmol) and stirred one day. Following complete conversion, the mixture was diluted with cold dioxane, the precipitate was collected by filtration, and dried under vacuum to afford the title compound. ESI-MS: 549 [M+H]+Rt (HPLC): 0.77 min (method E) Step3 To a mixture of the above intermediate (41 mg, 0.070 mmol) in ACN (3.0 mL) and H2O (1.0 mL) wasadded K2CO3 (30 mg, 0.22 mmol). The mixture was stirred 10 min before adding acetic anhydride (14^L, 0.14 mmol). The mixture was stirred at RT during 4h. Following complete conversion, the reaction mixture was diluted with cold H2O, then acidified by adding an aq. solution of HCl (1M, 3 mL) and stirred for 30 min. The precipitate was collected by filtration, dissolved in minimal amount of DMF, filtered through a syringe filter and purified by preparative RP-HPLC (C18, ACN, H2O +TFA) to afford the title compound. ESI-MS: 591 [M+H]+Rt (HPLC): 0.95 min (method E)The following compounds were prepared analogously to EXAMPLE 2.01 described above:72 01-3591-ff-text 73 01-3591-ff-text EXAMPLE 3.01 Step1: INTERMEDIATE 3.4 (tert-butyl (2S,4S)-4-hydroxy-1-{4-[(methylcarbamoyl)methyl]-8-oxa-3,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-6-yl}pyrrolidine-2-carboxylate, 10 mg,0.021 mmol) and INTERMEDIATE B-03 (7.5 mg, 0.021 mmol) were added to DMA (2.0 mL) andstirred, before NaH (3.4 mg of a 60% oil dispersion, 0.084 mmol) was added and the mixture stirred until reaction control by RP-HPLC indicated completion of the reaction. The reaction was quenched by the addition of H2O acidified with TFA, the resulting mixture filtered and submitted to RP-HPLC (Sunfire, C18, ACN, H2O +TFA) to yield the depicted intermediate that was directly taken to the next step.ESI-MS: 702 [M]+Rt(HPLC): 0.88 min (method F) Step2: 74 01-3591-ff-textThe product of step1 (10.0 mg, 0.014 mmol) and TFA (6.0 µL, 0.078 mmol) were added to 1.0 mL DCMand stirred at 40°C overnight. Volatiles were removed in vacuo and the remaining mixture purified via RP-HPLC (Sunfire, C18, ACN, H2O+TFA) to yield EXAMPLE 3.01.ESI-MS: 648 [M+H]+Rt (HPLC): 0.78 min (method F) List of Abbreviations ACN acetonitrileaq. aqueousconc. concentratedDCM dichloromethaneDIPEA diisopropylethylamineDMA dimethylacetamideDMF N,N-dimethylformamideDMSO dimethyl sulfoxideds diastereoisomerESI-MS electrospray ionisation mass spectrometryEtOAc ethyl acetateeq equivalentFA formic acidFC flash-chromatography, SiO2 is used if no further details are givenh hour(s)H2O waterHCl hydrogen chlorideHATU [dimethylamino-(1,2,3-triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate HPLC high performance liquid chromatographyL literMeOH methanol75 01-3591-ff-textmin minutemL milliliterM molarMS mass spectrumNaH sodium hydrideNa2SO4sodium sulfaten.d. not determinedorg. organicPE petrol etherRP reverse phaseRT room temperature (about 20°C)sat. saturatedSFC Supercritical fluid chromatographyTEA triethyl amineTFA trifluoroacetic acidTFAA trifluoroacetic acid anhydrideTHF tetrahydrofuraneRP-HPLC reverse phase HPLCRf retardation factor (TLC) Rtretention time in minutesVol% volume percentv / v volume per volume76 01-3591-ff-text Analytical Methods (HPLC / SFC): HPLC method A HPLC method B HPLC method C HPLC method D HPLC method E 77 01-3591-ff-text HPLC method F HPLC method G HPLC method H HPLC method I 78 01-3591-ff-text HPLC method J HPLC method K HPLC method L 79 01-3591-ff-text 5. EXAMPLES5.1 Example Compounds of formula I of the inventionThe following Example compounds of formula I as summarized in Table 1 have been synthesized and tested with respect to their pharmacological properties regarding their potency to inhibit cGAS activity.In particular the „biochemical (in vitro) IC50-values“ with regard to cGAS-inhibition (hcGAS IC50), the„IC50-value with regard to the inhibition of IFN induction in virus-stimulated THP1 cells “(THP(vir) IC50),the „IC50-value with regard to the inhibition of IFN induction in cGAMP-stimulated THP1 cells“(THP(cGAMP) IC50) and the „IC50-value with regard to inhibition of IFN induction in dsDNA-stimulatedhuman whole blood“ (hWB IC50) has been experimentally determined according to the assaymethods as described in section 6 below. The results are summarized in Table 1.The Example compounds of formula I as summarized in Table 1 show at the same time the followingthree properties: •a satisfying “biochemical (in vitro) IC50-value with regard to cGAS inhibition” (with a hcGASIC50of ≤ 100 nM, preferably of ≤ 50 nM, in particular of ≤ 10 nM), •a satisfying “cellular IC50-value regarding cGAS inhibition” (with a THP1(vir) IC50 of ≤ 5 µM, ≤ 2µM, ≤ 1 µM, preferably of ≤ 500 nM, more preferably of ≤ 100 nM, in particular of ≤ 50 nM)and •a satisfying selectivity for cGAS-inhibition(with a ratio THP1(cGAMP)IC50 / THP1(vir)IC50 of ≥10, more preferably ≥50, more preferably ≥500, in particular ≥1000).Additionally, the Example compounds of formula I also show acceptable IC50-values with regard toinhibition of IFN induction in dsDNA-stimulated human whole blood (hWB IC50).80 01-3591-ff-textTable 1: Pharmacological properties of the Example compounds of formula I of the invention 81 01-3591-ff-text 82 01-3591-ff-text 83 01-3591-ff-text 84 01-3591-ff-text 85 01-3591-ff-text 86 01-3591-ff-text 87 01-3591-ff-text 88 01-3591-ff-text 5.2 Comparison of the Example Compounds of formula I with Prior Art Compounds5.2.1 Compounds of WO 2020 / 142729In WO 2020 / 142729 cGAS-inhibitiors with partially similar structures have been disclosed.On page 44 and 45 of WO 2020 / 142729 the „biochemical (in vitro) IC50-values“ with regard to cGAS-inhibition (corresponding to “hcGAS IC50”) have been disclosed. Hereby compounds with a„biochemical (in vitro) IC50-value“ of less than 100 nM had been designated into „group A“,compounds with a „biochemical (in vitro) IC50-value“ of greater than 100 nM and less than 500nMhad been designated into „group B“, compounds with a „biochemical (in vitro) IC50-value“ of greaterthan 500 nM and less than 1 µM had been designated into „group C“, compounds with a„biochemical (in vitro) IC50-value“ of greater than 1 µM and less than 10 µM had been designatedinto „group D“ and compounds with a „biochemical (in vitro) IC50-value“ of greater than 10 µM hadbeen designated into „group E“ (see page 44 of WO 2020 / 142729). On page 45 of WO 2020 / 142729 it is disclosed that only compound No.25 could be designated to„group A“ having a „biochemical (in vitro) IC50-value“ of less than 100 nM. All other examplecompounds of WO 2020 / 142729 show „biochemical (in vitro) IC50-values“ of greater than 100 nM.Selected prior art compounds of WO 2020 / 142729 including compound No.25 have been synthesized and then have been tested with respect to their pharmacological properties regarding their potency to inhibit the cGAS / STING pathway using exactly the same assays as used for testing the compoundsof the invention. In particular the „biochemical (in vitro) IC50-values“ with regard to cGAS-inhibition(hcGAS IC50), the „cellular IC50-values with regard to inhibition of IFN induction in virus-stimulatedTHP1 cells” (THP1(vir) IC50), the „cellular IC50-value with regard to inhibition of IFN induction in cGAMP-89 01-3591-ff-text stimulated THP1 cells“ (THP1(cGAMP) IC50) and the „IC50-value with regard to inhibition of IFN induction in human whole blood“ (hWB) have been experimentally determined for the structurally closestexamples of WO 2020 / 142729 according to the assay methods as described in section 6 below (seeTable 2). Table 2: Pharmacological properties of a selection of Example compounds from WO 2020 / 142729 90 01-3591-ff-text The pharmacological properties for the Example compounds of the invention as summarized in Table 1 and the respective pharmacological properties for the compounds of WO 2020 / 142729 assummarized in Table 2 can be compared to each other, since they were experimentally determinedaccording to the identical assay procedures as described in section 6 below.From data as shown in Table 2 it is clear that all example compounds of WO 2020 / 142729 show„biochemical (in vitro) IC50-values“ (= hcGAS IC50) that are significantly larger than 100 nM – with theonly exception of Example No.25 of WO 2020 / 142729 (in WO 2020 / 142729 designated in „Group A“having a „biochemical (in vitro) IC50-value“ (= hcGAS IC50) of less than 100 nM). In contrast to that theExample compounds of the invention all have „biochemical (in vitro) IC50-values“ (hcGAS IC50) of ≤ 100nM. However, Example No. 25 of WO 2020 / 142729 which has a „biochemical (in vitro) IC50-value“(hcGAS IC50) of 55 nM, does not at all comply with the selection criterium of a „satisfying cellularinhibitory potency“ shown by a THP1(vir) IC50 of lower than 5 µM, because THP1(vir) IC50 for Example No.25 of WO 2020 / 142729 is >17 µM.5.2.2 Compounds of WO 2022 / 174012In WO 2022 / 174012 cGAS-inhibitiors with partially similar structures have been disclosed.On page 65 of WO 2022 / 174012 the „biochemical (in vitro) IC50-values“ with regard to cGAS-inhibition and on page 67 of WO 2022 / 174012 the “cellular IC50-values” (IFNβ ELISA stimulated withTHP-1) have been disclosed. Compound 5 (BBL0100455) of WO 2022 / 174012 seems to be the only 91 01-3591-ff-text compound of WO 2022 / 174012 that may have the potential to satisfy the selection criteria of the instant invention that means to have a) an “biochemical (or enzymatic) (in vitro) IC50-value“ of ≤ 100 nM (in the “enzymatic assay ofWO 2022 / 174012” compound 5 has been measured to fall into “group B” which represents an “enzymatic IC50-value” of 50 nM to 100 nM” ,see page 65, Table 2 of WO 2022 / 174012) b) and to have a “cellular IC50-value” (IFNβ ELISA stimulated with THP-1) of smaller than 5 µM(in the “cellular assay“ of WO 2022 / 174012 compound 5 has been measured to fall into “group A” representing an “cellular IC50-value” of < 1 µM”, see page 67 and 68, Table 3 ofWO 2022 / 174012). However both, the biochemical / enzymatic assay and the cellular assays of WO 2022 / 174012, are not identical to the respective “biochemical / enzymatic assays and cellular assays” of the instant invention and therefore the measured biochemical / enzymatic IC50-values and cellular IC50-values of WO 2022 / 174012 are not comparable to the respective IC50-values as measured for the compounds of the instant invention. Therefore compound 5 of WO 2022 / 174012 has been synthesized and thenhas been tested with respect to its pharmacological properties regarding its potency to inhibit thecGAS / STING pathway using exactly the same assays as used for testing the compounds of the instant invention and as described in Section 6 below. Table 3: Pharmacological properties of Compound No.5 of WO 2022 / 174012 92 01-3591-ff-text As the data from Table 3 shows compound No.5 (BBL0100455) of WO 2022 / 174012 has an acceptable biochemical / enzymatic IC50-value of 55 nM (hcGAS IC50 = 55 nM), but a cellular IC50-value of largerthan 10000 nM (THP1(vir) IC50 = 10000 nM). Consequently the compounds of the instant invention allare comparable to the compound No. 5 of WO 2022 / 174012 with respect to their biochemical / enzymatic IC50-values, but are clearly superior over compound No.5 of WO 2022 / 174012 with respect to their cellular IC50-values (which are all smaller than 5 µM for the compounds of formulaI of the invention.5.3 ProdrugsIt is known that esters of active agents with a carboxylic acid group may represent viable prodrugs which may e. g. show an improved oral absorption / bioavailability compared to the respective active agent. Frequently used prodrugs of active agents with a carboxylic acid group are for example methyl esters, ethyl esters, iso-propyl esters etc. (see Beaumont et al., Current Drug Metabolism,2003, Vol.4, Issue 6, 461 - 485).Further, Nakamura et al., Bioorganic & Medicinal Chem., Vol.15, Issue 24, p.7720-7725 (2007), describes that also N-acylsulfonamide derivatives and N-acylsulfonylurea derivatives of a specific active agent with a free carboxylic acid group have the potential of being a viable prodrug. Additionally, experimental hints have been found that also the methyl esters of the examplecompounds of formula I represent viable prodrugs of the cGAS inhibitors of formula I.WO2022 / 238327 and WO2022 / 238335 both disclose structurally similar cGAS-inhibitors as thecGAS-inhibitors of the instant invention which all comprise also carboxylic acid group attached to a pyrrolidine moiety. In both, WO2022 / 238327 and WO2022 / 238335 it has been experimentally shown that methyl esters derivatives of these cGAS-inhibitors carrying a carboxylic acid group attached to the pyrrolidine moiety act as viable prodrugs of the cGAS-inhibitors with the free carboxylic acid group.Compounds P01, P02, P03 and P04 of WO2022 / 238327 were methyl ester derivatives and putativeprodrugs of the respective Example compounds 4.04, 1.10, 1.12 and 3.14 of WO2022 / 238327 (which all had a free carboxylic group and were active cGAS-inhibitors with low biochemical IC50-values and low cellular IC50-values with regard to cGAS-inhibition). 93 01-3591-ff-textCompounds P01, P02 and P03 of WO2022 / 238335 were methyl ester derivatives and putativeprodrugs of the respective Example compounds 2.12, 1.13 and 1.05 of WO2022 / 238335 (which all had a free carboxylic group and were active cGAS-inhibitors with low biochemical IC50-values and low cellular IC50-values with regard to cGAS-inhibition). In both, WO2022 / 238327 and WO2022 / 238335, the “active cGAS-inhibitors / Example compounds with their free carboxylic acid” and their “respective methyl ester derivatives / putative prodrugs” have been synthesized and have been tested for their pharmacological properties with respect totheir potency to inhibit the cGAS / STING pathway.This comparison of the properties of the Example compounds of WO2022 / 238327 and of WO2022 / 238335 with their free carboxylic acid on the one hand and the properties of their corresponding methyl ester derivatives / putative prodrugs shows that the “biochemical IC50-values (hcGAS IC50-values)” for the Example compounds are always around or even smaller than 10 nM, whereas the ”biochemical IC50-values” (hcGAS IC50-values) for the corresponding methyl ester derivatives / prodrugs are always extremely large, that means generally larger than 7000 nM. That large difference between the IC50-values of the Example compounds on the one hand and the IC50-values of their corresponding methyl ester derivatives / prodrugs on the other hand has never been observed for the respective cellular IC50-values (THP1(vir)IC50-values) which always stay more or less in the same range between example compounds and their corresponding prodrugs (see Table 4 below). One possible explanation for that observation is that the Example compounds all have a free carboxylic group which seems to be crucial for inhibition of cGAS activity, whereas in all “methyl ester derivatives / prodrugs” the carboxyl group is masked by a carboxy-methyl ester group. Consequently, the methyl ester derivatives / prodrugs lose their inhibitory potency in the “in vitro human cGAS enzyme assay” (see section 6.1 below), because in this assay intracellular enzymes that cleave the carboxy-methyl ester group are absent and therefore the crucial free carboxylic acid group can not berestored in the biochemical assay. Therefore, the prodrugs show extremely large “biochemical (invitro) IC50-values” (=hcGAS IC50) in this “in vitro human cGAS enzyme assay”, whereas thecorresponding Example compounds (which have a free carboxylic acid group from the beginning on) show small “biochemical (in vitro) IC50-values” (=hcGAS IC50). In the cellular assay (=“human cGAS cell and the counter cell assay”, see section 6.2 below) endogenous cellular enzymes that cleave the carboxy-methyl ester group are present. Consequently not only the Example compounds of WO2022 / 238327 and of WO2022 / 238335 themselves (that already carry a free carboxylic acid group) show small THP1(vir)IC50-values, but also the correspondingmethyl ester derivatives / prodrugs show relatively small “THP1(vir)IC50-values”, because in this “human94 01-3591-ff-textcGAS cell assay” the carboxy-methyl ester group of the prodrugs can be cleaved by the endogenousintracellular enzymes and thereby will release the “active Example Compounds with the free carboxylic acid group” that shows cGAS-inhibitory potency again. This explanation together with the measurements as shown in Table 4 imply that carboxy-methyl ester derivatives of the structurally similar Example compounds of WO2022 / 238327 and of WO2022 / 238335 really seem to represent viable prodrugs of the respective Example compound with the free carboxylic acid group (which themselves have no inhibitory potency regarding the in vitro human biochemical cGAS inhibition). However, upon cleavage of the carboxy-methyl ester by endogenous intracellular enzymes present in the cellular assays the “active Example Compounds” are restored, that exhibit again an inhibitory potency regarding the cGAS / STING pathway.Since the Example Compounds of formula I of the present invention have the very same freecarboxylic acid attached to the pyrrolidinyl moiety as the Example Compounds of WO2022 / 238327 or of WO2022 / 238335, it can be expected that carboxy-methyl ester derivatives of these compoundsof formula I, that means the compounds of formula A ,wherein R1, R2, R3, R4, R5, R6, R7, V, U, T and Q are defined as mentioned in described in Chapter 2,will also act as prodrugs of the cGAS-inhibitors of formula I.95 01-3591-ff-textTable 4: Comparison between selected cGAS-inhibitor compounds as disclosed in WO2022 / 238327and WO2022 / 238335 and their respective methyl ester prodrugs: 96 01-3591-ff-text 97 01-3591-ff-text 98 01-3591-ff-text 4. BIOLOGICAL EXPERIMENTSThe activity of the compounds of the invention may be demonstrated using the following in vitro cGASenzyme and cell assays:6.1 Method: human cGAS enzyme assay (hcGAS IC50 (in vitro))Human cGAS enzyme was incubated in the presence of a 45 base pair double stranded DNA to activatethe enzyme and GTP and ATP as substrates. Compound activity was determined by measuring theeffect of compounds on the formation of the product of the enzyme reaction, cGAMP, which ismeasured by a mass spectrometry method. Enzyme preparation:HumancGAS (amino acid 1-522) with an N-terminal 6x-His-tag and SUMO-tag was expressed in E. coliBL21(DE3) pLysS (Novagen) cells for 16h at 18°C. Cells were lysed in buffer containing 25 mM Tris (pH8), 300 mM NaCl, 10 mM imidazole, 10 % glycerol, protease inhibitor cocktail (cOmplete™, EDTA-free,Roche) and DNase (5 µg / mL). The cGAS protein was isolated by affinity chromatography on Ni-NTAagarose resin and further purified by size exclusion chromatography using a Superdex 200 column (GEHealthcare) equilibrated in 20 mM Tris (pH 7.5), 500 mM KCl, and 1 mM TCEP. Purified protein wasconcentrated to 1,7 mg / mL and stored at -80 °C. Assay methodCompounds were delivered in 10mM DMSO solution, serially diluted and transferred to the 384 wellassay plate (Greiner #781201) using an Echo acoustic dispenser. Typically, 8 concentrations were usedwith the highest concentration at 10 µM in the final assay volume followed by ~1:5 dilution steps.DMSO concentration was set to 1% in the final assay volume. The 384 well assay plate contained 22test compounds (column 1-22), and DMSO in column 23 and 24.After the compound transfer, 15 µL of the enzyme-DNA-working solution (12 nM cGAS, 0.32 µM45base pair DNA in assay buffer, 10 mM Tris pH 7.5 / 10 mM KCl / 5 mM MgCl2 / 1 mM DTT) wereadded to each well from column 1-23 via a MultiDrop Combi dispenser. In column 24, 15 µl of assaybuffer without enzyme / DNA were added as a low control.The plates were then pre-incubated for 60 min at room temperature.Following that, 10 µL of GTP (ThermoFisher #R0461)-ATP (Promega #V915B) mix in assay buffer wereadded to the assay plate (columns 1-24, 30 µM final concentration each) using a Multidrop Combi.99 01-3591-ff-textThe plates were incubated again for 90 min at room temperature.Following the incubation, the reaction was stopped by 80 µL of 0,1% formic acid in assay buffercontaining 5 nM cyclic-di-GMP (Sigma #SML1228) used as internal standard for the massspectrometry. The total volume / well was 105 µL.Rapidfire MS detectionThe plates were centrifuged at 4000 rpm, 4°C, for 5 min.The RapidFire autosampler was coupled to a binary pump (Agilent 1290) and a Triple Quad 6500(ABSciex, Toronto,Canada). This system was equipped with a 10 μL loop, C18 [12 µL bed volume]cartridge (Agilent, Part No. G9210A) containing 10 mM NH4Ac (aq) water (pH7.4) as eluent A (pump1 at 1.5mL / min, pump 2 at 1.25 mL / min) and 10 mM NH4Ac in v / v / v 47.5 / 47.5 / 5 ACN / MeOH / H2O(pH7.4) as eluent B (pump 3 at 1.25 mL / min). Aspiration time: 250 ms; Load time: 3000 ms; Elute time:3000 ms; Wash volume: 500 µL.The MS was operated in positive ion mode with HESI ion source, with a source temperature of 550 C,curtain gas = 35, gas 1 = 65, and gas 2 = 80. Unit mass resolution in SRM mode. The following transitionsand MS parameters (DP: declustering potential and CE: collision energy) for cGAMP and DicGMP weredetermined:Analyte: cGAMP at 675.1 / 524, DP = 130, CE = 30 andInternal standard: cyclic-di-GMP at 690.1 / 540, DP = 130, CE = 30.The formation of cGAMP was monitored and evaluated as ratio to cyclic-di-GMP.Data evaluation and calculation:For data evaluation and calculation, the measurement of the low control was set as 0 % control andthe measurement of the high control was set as 100% control. The IC50 values were calculated using the standard 4 parameter logistic regression formula. Calculation: [y=(a-d) / (1+(x / c)^b)+d], a = lowvalue, d = high value; x = conc M; c=IC50 M; b = slope6.2 Method: human cGAS cell assay and cGAMP stimulated counter cell assay (THP1(vir) IC50 andTHP1(cGAMP) IC50)THP1-Dual™ cells (InvivoGen #thpd-nfis) expressing IRF dependent Lucia luciferase reporter were usedas basis for both assays. For the detection of cellular cGAS activity cells were stimulated by a100 01-3591-ff-textbaculovirus (pFastbac-1, Invitrogen, no coding insert) infection that delivers the cGAS enzymestimulating double-stranded DNA (measurement of THP1(vir) IC50).For the counter assay, cells were stimulated by cGAMP (SigmaAldrich #SML1232) to activate theidentical pathway independent and directly downstream of cGAS (measurement of THP1(cGAMP) IC50).Pathway activity was monitored by measuring the Lucia luciferase activity induced by either DNAstimulated cGAS enzyme activity (measurement of THP1(vir) IC50) or by cGAMP directly (measurementof THP1(cGAMP) IC50, counter assay). Assay MethodCompounds were delivered in 10mM DMSO solution, serially diluted and transferred to the 384 wellassay plate (Greiner #781201) using an Echo acoustic dispenser. Typically, 8 concentrations were usedwith the highest concentration at 10 µM in the final assay volume followed by ~1:5 dilution steps.DMSO concentration was set to 1% in the final assay volume. The 384 well assay plate contained 21test compounds (column 1-22), and DMSO in column 23 and 24.Cells, cultivated according to manufacturer conditions, were harvested by centrifugation at300g / 10min and were then resuspended and diluted to 1.66E5 cells / ml in fresh cell culture medium(RPMI 1640 (Gibco #A10491-01), 10% FCS (Gibco #10500), 1x GlutaMax (Gibco #35050-061) ,1xPen / Strep solution (Gibco #15140-122), 100µg / ml Normocin (InvivoGen #ant-nr), 100 µg / ml Zeocin(InvivoGen #ant-zn), 10µg / ml Blasticidin S (Life Technologies #A11139-03)). The baculovirus solutionwas then added 1:200 (have varied according to virus batch) to the cells (measurement of THP1(vir)IC50). Alternatively, for the counter assay cGAMP was added to the cells at a final concentration of 10µM (measurement of THP1(cGAMP) IC50).30 µL of the cell / virus-mix were added to each well of the compound plate from column 1-23 viaMultiDrop Combi dispenser (5000 cells / well). In column 24, 30 µl / 5000 cells / well without virus wereadded as a low control.The plates were then incubated for 18 h at 37 °C in a humidified incubator.Following that, 15 µL of QuantiLuc detection reagent (InvivoGen #rep-qlcg5) were added to each wellusing a MultiDrop Combi. Measurement was done immediately after the addition using an EnVisionreader (US-luminescence read-mode). Data evaluation and calculation: For data evaluation and calculation, the measurement of the low control was set as 0 % control and the measurement of the high control was set as 100% control. The IC50values were calculated using 101 01-3591-ff-text the standard 4 parameter logistic regression formula. Calculation: [y=(a-d) / (1+(x / c)^b)+d], a = lowvalue, d = high value; x = conc M; c=IC50 M; b = slope6.3 Method: human whole blood assay (human WB IC50)For the detection of cellular cGAS activity human whole blood was stimulated by transfection withdouble stranded DNA. Pathway activity was monitored by measuring the IFNα2α production. Assay methodCompounds were delivered as 10 mM DMSO solution and serially diluted and transferred to the 96-well cell culture plate (Corning #3595), prefilled with 20 µl OptiMEM (Gibco, #11058-021) in each well,using an Echo acoustic dispenser. Typically, 8 concentrations were used with the highest concentrationat 10 µM in the final assay volume followed by ~1:5 dilution steps. DMSO concentration was set to0.1% in the final assay volume. The 96-well assay plate contained 10 test compounds, and DMSO incontrol wells. Collection of human whole blood from 3 or more healthy donors (male or female, no medication for7 days except contraceptive and thyroxine) as Na-Citrate blood (e.g. 3.8% in Monovettes fromSarstedt) was conducted in parallel. Whole blood was kept at room temperature for a maximum of 3hours after collection until use in the assay.160 µl of the whole blood samples was transferred to each well of the 96-well assay plates filled withcompound / OptiMEM. All assay plates were prepared as duplicates with blood from different donors.Blood plates were kept at room temperature for 60 minutes and continuous shaking with 450 rpm,covered with the lid, but not sealed.DNA-Fugene mix (Herring DNA, Sigma Aldrich #D6898-1G, Fugene (5x 1 mL), Promega # E2312) wasprepared in OptiMEM and incubated for 10min at RT (125 ng DNA / 20 µl and Fugene ratio 9.6:1).20µl of the DNA Fugene mix was added to each well, resulting in 125 ng DNA / well / 200 µl, and FugeneRatio 9.6:1.20 µl OptiMEM and 9.6:1 Fugene was added to all low control wells.After covering assay plates with aera seals and the lid, blood plates were kept at room temperaturefor 30 minutes and continuous shaking with 450 rpm, followed by an overnight incubation of 22 h at37°C in the incubator, without shaking. 102 01-3591-ff-text For the detection of IFNα-2α in human plasma, the biotinylated 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 directions. U-PlexMSD GOLD 96-well Small Spot Streptavidin SECTOR Plates (Meso Scale Diagnostics # L45SA-5) werecoated with 25 µl diluted capture antibody. Coated plates were incubated for 60 min at roomtemperature under continuous shaking at 700 rpm. MSD IFNα-2α plates were washed three timeswith 150 µl wash buffer (1x HBSS, 0.05% Tween).After blocking the plates with 100 µl block solution / well (1x HBSS with 0.2% Tween, 2% BSA) for 60min at room temperature and continuous shaking at 700 rpm, plates were emptied as dry as possibleby dumping just before continuing with the human plasma.Whole Blood assay plates were centrifuged at 1600 rpm for 10 minutes. 25 µl of supernatant wastransferred with a pipetting robot from each whole blood plate to the corresponding IFNα-2α plate. Plates were sealed with microplate seals and kept at room temperature again under continuousshaking at 700 rpm for two hours.Next MSD IFNα-2α plates were washed three times with 150 µl wash buffer (1x HBSS, 0.05% Tween),before adding 25µl MSD SULFO-TAG IFNα-2α Antibody solution (1:100 diluted in Diluent 3 (Meso Scale Diagnostics # R50AP-2) to each well of the plates. Afterwards plates were sealed with microplate seals and kept at room temperature again undercontinuous shaking at 700 rpm for two hours. Finally, MSD IFNα-2α plates were washed three timeswith 150 µl wash buffer (1x HBSS, 0.05% Tween). 150 µl 2x Read buffer was added to each well andplates were immediately measured with the MSD Sector S600 Reader using the vendor barcode. Data evaluation and calculation:For data evaluation and calculation, % control calculation of each well was based on the mean of high(DNA stimulated control) and mean of low (unstimulated control) controls by using the following formula:[counts(sample) - counts(low)) / (counts(high) - counts(low))]*100The IC50-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 = conc M; c=IC50 M; b = slope103 01-3591-ff-text 5. INDICATIONSAs has been found, the compounds of formula I (or the compounds of formula A) are characterized bytheir range of applications in the therapeutic field. Particular mention should be made of thoseapplications for which the compounds of formula I (or the compounds of formula A) according to theinvention are preferably used on the basis of their pharmaceutical activity as cGAS inhibitors. While the cGAS pathway is important for host defense against invading pathogens, such as viral infection and invasion by some intracellular bacteria, cellular stress and genetic factors may also causeproduction of aberrant cellular dsDNA, e.g. by nuclear or mitochondrial leakage, and thereby triggerautoinflammatory responses. Consequently, cGAS inhibitors have a strong therapeutic potential to be used in the treatment of diverse autoinflammatory and autoimmune diseases.An et al., Arthritis Rheumatol.2017 Apr;69(4):800-807, disclosed that cGAS expression in peripheralblood mononuclear cells (PBMCs) was significantly higher in patients with the autoimmune disease systemic lupus erythematosus (SLE) than in normal controls. Targeted measurement of cGAMP by tandem mass spectrometry detected cGAMP in 15% of the tested SLE patients, but none of the normal or rheumatoid arthritis controls. Disease activity was higher in SLE patients with cGAMP versus those without cGAMP. Whereas higher cGAS expression may be a consequence of exposure to type I interferon (IFN), detection of cGAMP in SLE patients with increased disease activity indicates potential involvement of the cGAS pathway in disease expression.Park et al., Ann Rheum Dis.2018 Oct;77(10):1507-1515, also discloses the involvement of the cGASpathway in the development of SLE.Thim-Uam et al.,Science 2020 Sep 4;23(9), 101530 (doi: 10.1016 / j.isci.2020.101530), discloses thatthe STING pathway mediates lupus via the activation of conventional dendritic cell maturationand plasmacytoid dendritic cell differentiation. Skopelja-Gardner et al reported that ultraviolet Blight triggers cGAS / STING-dependent skin and systemic IFN-I signature and could contribute tocutaneous lupus and flares of disease in patients with SLE (Sci Rep 202010:7908).Gao et al., Proc. Natl. Acad. Sci. U S A.2015 Oct 20;112(42):E5699-705, describes that the activationof cGAS by self-DNA leads to certain autoimmune diseases such as interferonopathies.Tonduti et al., Expert Rev. Clin. Immunol.2020 Feb;16(2):189-198 discloses that cGAS inhibitors haveparticular therapeutic potential in Aicardi- Goutières syndrome and familial chilblain lupus, whichare lupus-like severe autoinflammatory immune-mediated disorders.104 01-3591-ff-textSteiner et al., Nat Commun.2022 Apr 28;13(1):232; doi: 10.1038, shows that deficiency in coatomercomplex I causes aberrant activation of STING signalling and COPA syndrome, and that cGAS isrequired to drive type I IFN signalling in a COPA syndrome cell model.Li et al show that plasma-derived DNA containing-extracellular vesicles induce STING-mediatedproinflammatory responses in dermatomyositis (Theranostics.2021; 11(15): 7144–7158). Zhou et al(J Clin Lab Anal.2022 Oct; 36(10): e24631) describes a correlation between activation of cGAS-STING pathway and myofiber atrophy / necrosis in dermatomyositis.In Yu et al., Cell 2020 Oct 29;183(3):636-649, the link between TDP-43 triggered mitochondrial DNAand the activation of the cGAS / STING pathway in amyotrophic lateral sclerosis (ALS) is described.Ryu et al., Arthritis Rheumatol.2020 Nov;72(11):1905-1915, also shows that bioactive plasmamitochondrial DNA is associated with disease progression in specific fibrosing diseases such as systemic sclerosis (SSc) or interstitial lung deseases (ILDs), progressive fibrosing interstitial lungdiseases (PF-ILDs), and idiopathic pulmonary fibrosis (IPF).In Schuliga et al., Clin. Sci. (Lond).2020 Apr 17;134(7):889-905, it is described that self-DNAperpetuates IPF lung fibroblast senescence in a^cGAS-dependent manner. Additional scientific hints linking the cause for other fibrosing diseases such as metabolic dysfunctionassociated steatohepatitis (MASH) (formerly named “non-alcoholic steatohepatitis (NASH)”) with thecGAS / STING pathway have been described in Yu et al., J. Clin. Invest.2019 Feb 1;129(2):546-555, andin Cho et al., Hepatology.2018 Oct;68(4): 1331-1346.Nascimento et al., Sci. Rep.2019 Oct 16;9(1):14848, discloses that self-DNA release and STING-dependent sensing drives inflammation due to cigarette smoke in mice hinting at a link between thecGAS-STING pathway and chronic obstructive pulmonary disease (COPD).Ma et al., Sci. Adv.2020 May 20;6(21):eaaz6717, discloses that ulcerative colitis and inflammatorybowel disease (IBD) may be restrained by controlling cGAS-mediated inflammation.Gratia et al., J. Exp. Med.2019 May 6;216(5):1199-1213, shows that Bloom syndrome proteinrestrains innate immune sensing of micronuclei by cGAS. Consequently cGAS-inhibitors have a therapeutic potential in treating Bloom’s syndrome. 105 01-3591-ff-textKerur et al., Nat. Med.2018 Jan;24(1):50-61, describes that cGAS plays a significant role innoncanonical-inflammasome activation in age-related macular degeneration (AMD).Visitchanakun et al., Int J Mol Sci.2021 Oct 23;22(21):11450, shows that GAS deficient mice wereless severe than the wildtype mice in the cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) injection sepsis models.Wang et al., Mediators Inflamm.2015;2015:192329, describes that cGAS Is required for cellproliferation and Inflammatory cytokine production in rheumatoid arthritis synoviocytes. It has alsobeen reported that in an inflammatory arthritis mouse model, cGAS deficiency suppressedinterferon responses, inflammatory cell infiltration and joint swelling (Willemsen et al., Cell Rep.2021 Nov 9;37(6):109977).Guo et al., Osteoarthritis Cartilage.2021 Aug;29(8):1213-1224, described that damaged DNA is a keypathologic factor for osteoarthritis (OA) and this is likely mediated by the cGAS / STING pathway,since STING knockdown alleviated destabilization of the medial meniscus-induced OA development in mice. Mao et al., Arterioscler Thromb Vasc Biol (2017) 37(5):920–929, shows that the cGAS / STING pathway mediates endothelial inflammation in response to free fatty acid-Induced Mitochondrialdamage in diet-Induced obesity, indicating that cGAS inhibitors have also the potential in thetreatment of obesity and diabetes. Kerur et al, Nat Med.2018 Jan;24(1):50-61, describes that cGAS levels were elevated in the retinalpigmented epithelium in human eyes with geographic atrophy, and cGAS drives activation ofnoncanonical-inflammasome activation in age-related macular degeneration.cGAS promotes cellular senescence and senescence-associated secretory phenotype (Yang et al,Proc Natl Acad Sci USA 2017 Jun 6;114:E4612-E4620). Cytoplasmic chromatin triggers inflammationin senescence through cGAS / STING, and STING null- mice have reduced tissue inflammation andaging (Dou et al, Nature.2017550: 402–406). Furthermore, in humans a variation within the STING gene is associated with healthy aging, most likely due to a decreased inflammaging (Hamann et al, Gerontology 2019;65:145–154). Taken together, a STING inhibitor will reduce senescence associated inflammation and senescent cell accumulation and will leads improvement in senescence associated diseases such as aging, muscle disorders and fibrosis. 106 01-3591-ff-textFurther, the cGAS inhibitors of formula I (or the compounds of formula A) also have a therapeuticpotential in the treatment of cancer (see Hoong et al., Oncotarget.2020 Jul 28;11(30):2930-2955,and Chen et al., Sci. Adv.2020 Oct 14;6(42):eabb8941).Additionally, the cGAS inhibitors of formula I (or the compounds of formula A) have also atherapeutic potential in the treatment of heart failure (Hu et al., Am. J. Physiol. Heart Circ. Physiol.2020 Jun 1;318(6):H1525-H1537). Further scientific hints at 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 thecGAS / STING pathway (Papinska et al., J. Dent. Res.2018 Jul;97(8):893-900) exist.Furthermore, cGAS inhibitors of formula I (or the compounds of formula A) have also a therapeuticpotential in the treatment of COVID-19 / SARS-CoV-2 infections as shown in Di Domizio et al., Nature.2022 Jan 19. doi: 10.1038 / s41586-022-04421-w: “The cGAS-STING pathway drives type I IFNimmunopathology in COVID-19“, and in 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 responsethrough cGAS-STING and NF-kappaB”. It has also been shown that severe COVID-19 and Long COVIDare associated with high expression of STING, cGAS and IFN-α (Sci Rep 202414:4974).Additionally, cGAS inhibitors of formula I (or the compounds of formula A) have a therapeuticpotential in the treatment of renal inflammation and renal fibrosis as shown in Chung et al., CellMetab.201930:784-799: “Mitochondrial Damage and Activation of the STING Pathway Lead toRenal Inflammation and Fibrosis”, and in Maekawa et al., Cell Rep.201929:1261-1273:“Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury”. Ithas also been shown that genetic deletion or pharmacological inhibition of STING ameliorates kidneyinflammation fibrosis in a mouse models of chronic kidney disease (Cell Metab 201930:784-799).Furthermore, cGAS inhibitors of formula I (or the compounds of formula A) have a therapeuticpotential in the treatment of cancer as shown in Bakhoum et el., Nature.2018 Jan25;553(7689):467-472: “Chromosomal instability drives metastasis through a cytosolic DNAresponse”, and in Liu et al., Nature.2018 Nov;563(7729):131-136: “Nuclear cGAS suppresses DNArepair and promotes tumorigenesis“. 107 01-3591-ff-textFurthermore, cGAS inhibitors of formula I (or the compounds of formula A) have a therapeuticpotential in the treatment of liver cirrhosis, in particular in decompensated liver cirrhosis: Irvine etal, Front Immunol.10: 293: “Causes and Consequences of Innate Immune Dysfunction in Cirrhosis”. Further, two cases of STING GOV mutants have been reported with alopecia symptom (Front Immunol 201910:2770. doi: 10.3389; Pediatr Rheumatol Online J.202422:9 doi: 10.1186). One caseof a pathogenic mutation of SAMHD1, developed alopecia areata (Pediatric Neurology 201996:37-39). SAMHD1 hydrolyses deoxynucleoside triphosphates and regulates cGAS / STING activation(Nature 2018557:57-61). Blood mitochondrial DNA copy number has been reported as a diagnosticmarker and indicator of degree of severity in alopecia areata (J Immunoassay Immunochem 202344:256-268). Serum levels of IFNa and TNFa (both are targets downstream of cGAS / STING pathway),are induced in alopecia areata and associated with disease severity (International Journal of Dermatology 2021, 60, 1397–1404).In addition, ANCA vasculitis patients show increased levels of cGAMP and enhanced IFN-I signature.STING deficiency or a STING inhibitor protects a mouse model for ANCA associated pulmonary vasculitis (J Exp Med.2022219:e20220759). ANCA pulmonary vasculitis has also been reported in a SAVI patient (STING GOV mutation) (Front Immunol.202011:575219). Additionally, it has been shown that in myotonic dystrophy type 2 (DM2) disease, patient PBMCs and fibroblasts show elevated type I interferon (IFN) signature which is mediated by the cGAS / STING pathway (Nat Commun.202415:1534). In Huntington’s disease (HD), the mutated huntingtin gene induces DNA damage and cytosolic DNA accumulation and activates the cGAS–STING pathway to mediate inflammation and apoptosis (ProcNatl Acad Sci U S A.2024121:e2313652121). Depletion of cGAS in HD neuron cells decreases theexpression of inflammatory genes while suppressing the up-regulation of autophagy (Proc Natl Acad Sci 117:15989-15999). In addition, Xie et al detected binding of cGAS with dsDNA in cytoplasm and the activation of themicroglial cGAS-STING pathway in brains of human Alzheimer’s disease (AD) and aged mice. A STINGinhibitor suppressed the activation of the cGAS-STING pathway and ameliorated AD pathogenesis in a mouse model of Alzheimer’s disease (Nat Aging 20233:202-212). 108 01-3591-ff-text Additionally, during ischemic stroke, tissue damage results in misplaced DNA within the cellular environment activates the cGAS / STING pathway, leading to cytokine production, neuroinflammation, and cell death (Expert Opin Drug Discov 202318:1133-1149; Drug Discov Today. 202328:103792). STING knockout decreased infarct progression, oedema volume and neuronal damage in mouse stroke model (Stroke Vasc Neurol 2023 Jul 3:svn-2023-002320. doi: 10.1136).Additionally, cGAS inhibitors of formula I (or the compounds of formula A) have a therapeuticpotential in the treatment of dysmetabolism, because STINGgtanimals show reduced macrophage infiltration in adipose tissue upon subchronic high caloric intake (HFD) and STINGgtand IRF3- deficiency leads to a decrease in blood glucose and insulin and reduced body weight (Mao et al, Arterioscler Thromb Vasc Biol, 2017;37 (5): 920-929).Furthermore, cGAS inhibitors of formula I (or the compounds of formula A) have a therapeuticpotential in the treatment of vascular diseases and leads to vascular repair / regeneration, because the release of mitochondrial DNA into the cytosol of endothelial cells results in cGAS / STING pathway activation and suppression of endothelial proliferation. Further, knockout of the cGAS gene restores endothelial repair / regeneration in a mouse model of inflammatory lung injury (Huang et al, Immunity, 2020, Mar 2017; 52 (3): 475-486.e5. doi: 10.1016 / j.immuni.2020,02.002).Additionally, cGAS inhibitors of formula I (or the compounds of formula A) have a therapeuticpotential in the treatment of age-related and obesity-related cardiovascular diseases (Hamann et al, Immun Ageing, 2020, Mar 14; 17: 7; doi: 10.1186 / s12979-020-00176-y.eCollection 2020).Consequently the compounds of formula I (or the compounds of formula A) as cGAS inhibitors canbe used in the therapy of autoinflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE), cutaneous lupus, interferonopathies, Aicardi-Goutières syndrome(AGS), COPAsyndrome, familial chilblain lupus, age-related macular degeneration (AMD), amyotrophic lateralsclerosis (ALS), Huntington’s disease, Alzheimer's disease, inflammatory bowel disease (IBD), chronicobstructive pulmonary disease (COPD), Bloom’s syndrome, ischaemic stroke, myotonic dystrophytype 2, Sjogren’s syndrome, rheumatoid arthritis and Parkinson disease.Additionally the compounds of formula I (or the compounds of formula A) as cGAS inhibitors can beused in the therapy of fibrosing disease such as systemic sclerosis (SSc), interferonopathies,metabolic dysfunction associated hepatosteatitis (MASH) (formerly named “non-alcoholic109 01-3591-ff-textsteatohepatitis (NASH)”), liver cirrhosis, in particular decompensated liver cirrhosis, interstitial lungdisease (ILD), preferably progressive fibrosing interstitial lung disease (PF-ILD), in particularidiopathic pulmonary fibrosis (IPF).Further, the compounds of formula I (or the compounds of formula A) as cGAS inhibitors can beused in the therapy of age-related macular degeneration (AMD), retinopathy, glaucoma, diabetes,obesity, aging, muscle disorders, sepsis, osteoarthritis, heart failure, anti-neutrophil cytoplasmantibody (ANCA) associated vasculitis, alopecia, chronic kidney disease, COVID-19 / SARS-CoV-2 infection, Long COVID, renal inflammation, renal fibrosis, dysmetabolism, vascular diseases,cardiovascular diseases and cancer.6. COMBINATIONSThe compounds of formula I may be administered to the patient alone or in combination with one ormore other pharmacologically active agents.The compounds of formula A may be administered to the patient alone or in combination with oneor more other pharmacologically active agents.In a preferred embodiment of the invention the compounds of formula I or of formula A may becombined 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 / betamimetics, adrenergic agonists, anticholinergic agents, methotrexate, mycophenolatemofetil, leukotriene modulators, JAK inhibitiors, anti-interleukin antibodies, non-specificimmunotherapeutics such as interferones or other cytokines / chemokines, cytokine / chemokine receptor modulators (i.e. cytokine receptor agonists or antagonists), Toll-like receptor agonists (=TLR agonists), immune checkpoint regulators, anti-TNF antibodies (Humira™), and anti-BAFF agents (Belimumab and Etanercept). Anti-fibrotic agents are preferably selected from Pirfenidone and tyrosine kinase inhibitors such as Nintedanib, wherein Nintedanib is preferred in particular.Preferred examples of anti-inflammatory agents are NSAIDs and corticosteroids.NSAIDs are preferably selected from ibuprofen, naproxen, diclofenac, meloxicam, celecoxib, acetylsalicylic acid (Aspirin™), indomethacin, mefenamic acid and etoricoxib. 110 01-3591-ff-text Corticosteroids are preferably selected from Flunisolide, Beclomethasone, Triamcinolone, Budesonide, Fluticasone, Mometasone, Ciclesonide, Rofleponide and Dexametasone.Antiallergic agents / anti-histamines are preferably selected from Epinastine, Cetirizine, Azelastine,Fexofenadine, Levocabastine, Loratadine, Ebastine, Desloratidine and Mizolastine.Beta 2 agonists / betamimetics may be either long acting beta 2 Agonists (LABAs) or short acting betaagonists (SABAs). Particularly preferred beta 2 agonists / betamimetics are selected fromBambuterol, Bitolterol, Carbuterol, Clenbuterol, Fenoterol, Formoterol, Hexoprenalin, Ibuterol,Pirbuterol, Procaterol, Reproterol, Salmeterol, Sulfonterol, Terbutalin, Tolubuterol, Olodaterol, andSalbutamol, in particular Olodaterol.Anticholinergic agents are preferably selected from ipratropium salts, tiotropium salts,glycopyrronium salts, and theophylline, wherein tiotropium bromide is preferred in particular.Leukotriene modulators are preferably selected from Montelukast, Pranlukast, Zafirlukast, Ibudilastand Zileuton.JAK inhibitors are preferably selected from Baricitinib, Cerdulatinib, Fedratinib, Filgotinib,Gandotinib, Lestaurtinib, Momelotinib, Pacritinib, Peficitinib, Ruxolitinib, Tofacitinib, and Upadacitinib.Anti-interleukin antibodies are preferably selected from anti-IL23 antibodies such as Risankizumab,anti-IL17 antibodies, anti-IL1 antibodies, anti-IL4 antibodies, anti-IL13 antibodies, anti-lL-5antibodies, anti-IL-6 antibodies such as Actemra™, anti-IL-12 antibodies, anti-IL-15 antibodies.7. FORMULATIONSThe compounds of the invention may 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 by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, intrasternal, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin. The compounds of the invention may be administered via eye drops to treat Sjogren's syndrome. 111 01-3591-ff-text Suitable forms for administration are for example tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. The content of the pharmaceutically effective compound(s) in each case should be in the range from 0.1 to 90 wt.%, preferably 0.5 to 50 wt.% of the total composition, i.e. in amounts which are sufficient to achieve the dosage range specified hereinafter. The preparations may be administered orally in the form of a tablet, as a powder, as a powder in a capsule (e.g. a hard gelatin capsule), as a solution or suspension. When administered by inhalation the active substance combination may be given as a powder, as an aqueous or aqueous-ethanolic solution or using a propellant gas formulation. Preferably, therefore, pharmaceutical formulations are characterized by the content of one or morecompounds of formula I or by one or more compounds of formula A according to the preferredembodiments above.It is particularly preferable if the compounds of formula I or of formula A are administered orally, andit is also particularly preferable if they are administered once or twice a day. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inertdiluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch oralginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and / or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers. Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example kollidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may alsoconsist of a number of layers. Similarly, the tablet coating may consist of a number of layers to achievedelayed release, possibly using the excipients mentioned above for the tablets. Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavor enhancer, e.g. a flavoring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates. 112 01-3591-ff-text Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatin capsules. Suitable suppositories may be made for example by mixingwith carriers provided for this purpose, such as neutral fats or polyethylene glycol or the derivativesthereof. Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineralpowders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate). For oral administration the tablets may, of course, contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletingprocess. In the case of aqueous suspensions, the active substances may be combined with variousflavor enhancers or colorings in addition to the excipients mentioned above. 113

Claims

01-3591-ff-text PATENT CLAIMS, wherein R1is selected from the group consisting of H, C1-3-alkyl, C1-3-haloalkyl, -CH2-CO-NH2, -CH2-CO-NHCH3 and -CH2-CO-N(CH3)2R2 is selected from the group consisting of H, halogen, C1-3-alkyl and C1-3-haloalkyl,R3 is selected from the group consisting of C1-3-alkyl, five- or six-membered heterocyclic ring with 1to 3 heteroatoms selected from N, O, S or SO2 and a five- or six-membered carbocyclic ring,wherein R3 is substituted by one or two substituents R8 which are each independently selected fromthe group consisting of H, C1-3-alkyl, -CO-O-(C1-4-alkyl), 11401-3591-ff-text halogen, OH,O-(C1-3-methyl) and -CO-(C1-3-alkyl),-CNwherein V is either C or N,wherein U is either C or N,wherein Q is either C or N,wherein T is either C or N,wherein R4 is selected from the group consisting of H, halogen, -methyl, -O-C1-3-haloalkyl and-C1-3-haloalkyl,wherein R5 is selected from H, halogen, methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl,wherein R6is selected from H, halogen, methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl, wherein R7is selected from H, halogen, methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl, and pharmaceutical acceptable salts thereof.

2. The compounds of formula I according to claim 1, which are selected from the groupconsisting of11501-3591-ff-text11601-3591-ff-text11701-3591-ff-text11801-3591-ff-text11901-3591-ff-text12001-3591-ff-text12101-3591-ff-text12201-3591-ff-text and pharmaceutical acceptable salts thereof.

3. The compounds of formula I according to claim 1,wherein V is C,wherein U is C,wherein Q is C,wherein T is C,and wherein R1 is selected from the group consisting of H, C1-3-alkyl and C1-3-haloalkyl,and pharmaceutical acceptable salts thereof.

4. The compounds of formula I according to claims 1 or 3,wherein R2is H, and pharmaceutical acceptable salts thereof.

5. The compounds of formula I according to claims 1, 3 or 4,wherein R1is selected from the group consisting of H, C1-3-alkyl, C1-3-haloalkyl,R3 is selected from the group consisting of C1-3-alkyl, a six-membered heterocyclic ring with 1 to 3heteroatoms selected from N, O or S and a six-membered carbocyclic ring,wherein R3 is substituted by one or two substituents R8 which are each independently selected fromthe group consisting of H, C1-3-alkyl, 12301-3591-ff-text -CO-O-(C1-4-alkyl), halogen, and -CO-(C1-3-alkyl), -CN, and pharmaceutical acceptable salts thereof.

6. The compounds of formula I according to claims 1, 3, 4 and 5,wherein R1is selected from the group consisting of H, methyl, ethyl, isopropyl, -CF3, -CHF2, -CH2F,R3 is selected from the group consisting of a six-membered heterocyclic ring with 1 or 2 heteroatomsselected from N, O or S, and a six-membered carbocyclic ring,wherein R3 is substituted by one or two substituents R8 which are independently selected from thegroup consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl, -CO-O-tert-butyl, F, Cl, Br, -CN and -CO-methyl, and pharmaceutical acceptable salts thereof.

7. The compounds of formula I according to claims 1, 3, 4, 5 and 6,wherein R1is selected from the group consisting of H, methyl, ethyl, isopropyl, -CF3, -CHF2, -CH2F, •and wherein R3 is selected from the group consisting of a six-membered heterocyclic ringwith 1 or 2 heteroatoms selected from N, O or S selected from the group consisting ofpiperidinyl, piperazinyl, pyrimidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,12401-3591-ff-text wherein this R3 is substituted by one or two substituents R8 which are each independentlyselected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl, -CO-O-tert-butyl, F, Cl, Br, -CN and -CO-methyl,or •wherein R3 is a methyl-substituted cyclohexyl ringand pharmaceutical acceptable salts thereof.

8. The compounds of formula I according to claims 1 or 3 to 7,wherein R1is selected from the group consisting of H, methyl, ethyl, isopropyl, -CF3, -CHF2, -CH2F, R2is H, •and wherein R3 is selected from the group consisting of a six-membered heterocyclic ringwith 1 or 2 heteroatoms selected from N, O or S selected from the group consisting of piperidinyl, tetrahydropyranyl and tetrahydrothiopyranyl,wherein this R3 is substituted by one or two substituents R8 which are each independentlyselected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl, - CO-O-tert-butyl, F, Cl, Br, -CN and -CO-methyl,or •wherein R3 is a methyl-substituted cyclohexyl ring,wherein V, U, T and Q are each C,wherein R4 is selected from the group consisting of H, Cl, F, -O-CF3, -O-CHF2, -O-CH2F, methyl and-CF3, -CHF2, -CH2F,wherein R5 is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F,wherein R6 is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F,wherein R7 is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F,and pharmaceutical acceptable salts thereof. 12501-3591-ff-text9. The compounds of formula I according to claims 1 or 2 to 8, which is selected from the groupconsisting of12601-3591-ff-text12701-3591-ff-text12801-3591-ff-text12901-3591-ff-text13001-3591-ff-textand pharmaceutical acceptable salts thereof.

10. The compounds of formula I according to claim 8,wherein R1is selected from the group consisting of H, methyl, ethyl, isopropyl, -CF3, -CHF2, -CH2F, R2is H,wherein R3• is selected from the group consisting of a six-membered heterocyclic ring with 1 or 2 heteroatoms selected from N, O or S selected from the group consisting ofpiperidinyl and tetrahydropyranyl, tetrahydrothiopyranyl,wherein this R3 is substituted by one or two substituents R8 which are each independentlyselected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl and -CN, or wherein R3• is selected from a methyl-substituted cyclohexyl ring from the group consisting of13101-3591-ff-text, wherein this methyl-substituted cyclohexyl ring is further substituted by one substituent R9selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl,-CO-O-tert-butyl, F, Cl, Br, -CN and -CO-methyl,or wherein R3• is selected from the group consisting of, wherein this methyl- and acetyl-substituted piperidinyl ring is further substituted by onesubstituent R9selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl, -CO-O-tert-butyl and -CNwherein V, U, T and Q are each C,wherein R4is selected from the group consisting of H, Cl, -O-CF3, -O-CHF2, -O-CH2F, methyl and -CF3, -CHF2, -CH2F, wherein R5is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F, wherein R6is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F,wherein R7 is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F,and pharmaceutical acceptable salts thereof. 13201-3591-ff-text11. The compounds of formula I according to claim 10,13301-3591-ff-text13401-3591-ff-text13501-3591-ff-text13601-3591-ff-text13701-3591-ff-text and pharmaceutical acceptable salts thereof.A, wherein R1is selected from the group consisting of H, methyl, ethyl, isopropyl, -CF3, -CHF2, -CH2F, R2is H,wherein R3• is selected from the group consisting of a six-membered heterocyclic ring with 1 or 2 heteroatoms selected from N, O or S selected from the group consisting ofpiperidinyl and tetrahydropyranyl, tetrahydrothiopyranyl, wherein R3 is substituted by one or two substituents R8 which are each independentlyselected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl, F, Cl, Br and -CN13801-3591-ff-text or wherein R3• is selected from a methyl-substituted cyclohexyl ring from the group consisting of, wherein this methyl-substituted cyclohexyl ring is further substituted by one substituent R9selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl,-CO-O-tert-butyl, F, Cl, Br, -CN and -CO-methyl,or wherein R3• is selected from the group consisting of, wherein this methyl- and acetyl-substituted piperidinyl ring is further substituted by onesubstituent R9selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl, -CO-O-tert-butyl, F, Cl, Br, -CN and -CO-methyl,wherein V, U, T and Q are each C,wherein R4is selected from the group consisting of H, Cl, -O-CF3, -O-CHF2, -O-CH2F, methyl and -CF3, - CHF2, -CH2F, wherein R5is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F, wherein R6is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F,wherein R7 is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F,and pharmaceutical acceptable salts thereof. 13901-3591-ff-text 13. Intermediate compounds of formula IIII, whereinR3 is selected from the group consisting of C1-3-alkyl, five- or six-membered heterocyclic ring with 1to 3 heteroatoms selected from N, O, S or SO2 and a five- or six-membered carbocyclic ring,wherein R3is substituted by one or two substituents R8which are each independently selected from the group consisting of H, C1-3-alkyl, -CO-O-(C1-4-alkyl), halogen, -CN, OH, O-C1-3-methyl and -CO-(C1-3-alkyl),wherein V is either C or N,wherein U is either C or N,wherein Q is either C or N,wherein T is either C or N, wherein R4is selected from the group consisting of H, halogen, -methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl,wherein R5 is selected from H, halogen, methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl,wherein R6is selected from H, halogen, methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl, 14001-3591-ff-text wherein R7is selected from H, halogen, methyl, -O-C1-3-haloalkyl and -C1-3-haloalkyl,wherein LG is a leaving group selected from the group consisting of Cl, Br or -SO2-CH3,and pharmaceutical acceptable salts thereof.

14. The intermediate compound of formula II according to claim 13,wherein R3• is selected from the group consisting of a six-membered heterocyclic ring with 1 or 2 heteroatoms selected from N, O or S selected from the group consisting ofpiperidinyl and tetrahydropyranyl, tetrahydrothiopyranyl, wherein R3 is substituted by one or two substituents R8 which are each independentlyselected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl, F, Cl, Br and -CN,or wherein R3• is selected from a methyl-substituted cyclohexyl ring from the group consisting ofwherein this methyl-substituted cyclohexyl ring is further substituted by one substituent R9selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl,-CO-O-tert-butyl, F, Cl, Br, -CN and -CO-methyl,or wherein R3• is selected from the group consisting of,14101-3591-ff-text wherein this methyl- and acetyl-substituted piperidinyl ring is further substituted by onesubstituent R9selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, -CO-O-isopropyl, -CO-O-tert-butyl, F, Cl, Br, -CN and -CO-methyl,wherein V, U, T and Q are each C,wherein R4is selected from the group consisting of H, Cl, -O-CF3, -O-CHF2, -O-CH2F, methyl and -CF3, - CHF2, -CH2F, wherein R5is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F, wherein R6is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F,wherein R7 is selected from H, F, Cl, methyl, -O-CF3, -O-CF2H, -O-CH2F and -CF3, -CHF2, -CH2F,wherein LG is a leaving group selected from the group consisting of Cl, Br or -SO2-CH3,and pharmaceutical acceptable salts thereof.

15. The compound of formula I according to claims 1 to 11 or the compound of formula Aaccording to claim 12 for use in the treatment of a disease that can be treated by the inhibition of cGAS.

16. The compound of formula I according to claims 1 to 11 or the compound of formula Aaccording to claim 12 for use in the treatment of a disease selected from the group consistingof systemic lupus erythematosus (SLE), cutaneous lupus, interferonopathies, Aicardi-Goutières syndrome (AGS), COPA syndrome, familial chilblain lupus, age-related maculardegeneration (AMD), amyotrophic lateral sclerosis (ALS), retinopathy, glaucoma, diabetes,obesity, Huntington’s disease, Alzheimer’s disease, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom’s syndrome, ischaemic stroke, myotonic dystrophy type 2, dermatomyositis, Sjogren’s syndrome, Parkinsons disease, heart failure, cancer, aging, muscle disorders, sepsis, rheumatoid arthritis, osteoarthritis, COVID-19, Long COVID, systemic sclerosis (SSc), metabolic dysfunction associated Steatohepatitis (MASH),liver cirrhosis, in particular decompensated liver cirrhosis, interstitial lung disease (ILD), preferably progressive fibrosing interstitial lung disease (PF-ILD), in particular idiopathic pulmonary fibrosis (IPF). 14201-3591-ff-text17. The compound of formula I according to claims 1 to 11 or the compound of formula Aaccording to claim 12 for use in the treatment of a disease selected from the group consistingof systemic lupus erythematosus (SLE), interferonopathies, Aicardi- Goutières 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), Long COVID, Bloom’s syndrome, Sjogren’s syndrome, rheumatoid arthritis and Parkinsons disease.

18. The compound of formula I according to claims 1 to 11 or the compound of formula Aaccording to claim 12 for use in the treatment of a disease selected from the group consistingof systemic sclerosis (SSc), metabolic dysfunction associated Steatohepatitis (MASH), livercirrhosis, in particular decompensated liver cirrhosis, interferonopathies, interstitial lung disease (ILD), preferably progressive fibrosing interstitial lung disease (PF-ILD), in particular idiopathic pulmonary fibrosis (IPF).

19. The compound of formula I according to claims 1 to 11 or the compound of formula Aaccording to claim 12 for use in the treatment of a disease selected from the group consistingof age-related macular degeneration (AMD), retinopathy, glaucoma, diabetes, obesity, aging,muscle disorders, sepsis, osteoarthritis, heart failure, anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis, alopecia, chronic kidney disease, COVID-19 / SARS-CoV-2 infection, Long COVID, renal inflammation, renal fibrosis, dysmetabolism, vascular diseases,cardiovascular diseases and cancer.

20. Pharmaceutical composition comprising a compound of formula I according to at least one ofclaims 1 to 11 and optionally one or more pharmaceutically acceptable carriers and / or excipients.

21. Pharmaceutical composition comprising a compound of formula A according to claim 12 andoptionally one or more pharmaceutically acceptable carriers and / or excipients.

22. Pharmaceutical composition comprising the compound of formula I according to at least oneof claims 1 to 11 in combination with one or more active agents selected from the groupconsisting of anti-inflammatory agents, anti-fibrotic agents, anti-allergic agents / anti- histamines, bronchodilators, beta 2 agonists / betamimetics, adrenergic agonists, 14301-3591-ff-text anticholinergic agents, methotrexate, mycophenolate mofetil, leukotriene modulators, JAK inhibitors, anti-interleukin antibodies, non-specific immunotherapeutics such as interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators, toll-like receptor agonists, immune checkpoint regulators, an anti-TNF antibody such as Humira™, an anti-BAFF antibody such as Belimumab and Etanercept, and optionally one or more pharmaceutically acceptable carriers and / or excipients.

23. Pharmaceutical composition comprising the compound of formula A according to claim 12 incombination with one or more active agents selected from the group consisting of anti- inflammatory agents, anti-fibrotic agents, anti-allergic agents / anti-histamines, bronchodilators, beta 2 agonists / betamimetics, adrenergic agonists, anticholinergic agents,methotrexate, mycophenolate mofetil, leukotriene modulators, JAK inhibitors, anti- interleukin antibodies, non-specific immunotherapeutics such as interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators, toll-like receptor agonists, immune checkpoint regulators, an anti-TNF antibody such as Humira™, an anti-BAFF antibody such as Belimumab and Etanercept, and optionally one or more pharmaceutically acceptable carriers and / or excipients.

24. Pharmaceutical composition comprising the compound of formula I according to at least oneof claims 1 to 11 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.

25. Pharmaceutical composition comprising the compound of formula I according to at least oneof claims 1 to 11 in combination with one or more anti-inflammatory agents selected fromthe group consisting of NSAIDs and corticosteroids, and optionally one or more pharmaceutically acceptable carriers and / or excipients. 14401-3591-ff-text26. Pharmaceutical composition comprising• the compound of formula I according to at least one of claims 1 to 11 or a compound offormula A according to claim 12• in combination with one or more anti-fibrotic agents selected from the group consisting ofPirfenidon and Nintedanib or 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.145

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