Further heterocyclic compounds as sting antagonists and the use thereof as medicament

Abstract

This invention relates to compounds of formula (I) and their use in the prevention, delaying and / or treatment of diseases or conditions which can be influenced by STING inhibition.

Description

[0001] 01-3596-WO-1 1 Further Heterocyclic Compounds as STING Antagonists and the Use Thereof asMedicament This application claims priority to the US provisional application 63 / 640359, filed on April 30, 2024. 5 Field of the invention This invention relates to compounds of formula (I) and their use as STING antagonists e.g. for thetreatment of a disease selected from the group consisting of systemic lupus erythematosus (SLE), cutaneous lupus, (monogenic and digenic) interferonopathies (including STING-associated 10 vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome, and familial chilblain lupus), type 1 interferonopathies with mutations in DNASE2 or ATAD3A genes, age-related macular degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), Huntington disease, Alzheimer's disease, diabetes, obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom’s syndrome, Niemann-Pick Disease, Type C, ischaemic15 stroke, myotonic dystrophy type 2, Sjogren’s syndrome, Parkinson’s disease, heart failure, cancer, systemic sclerosis (SSc), vitiligo, prurigo nodularis, idiopathic inflammatory myopathy, myositisincluding dermatomyositis, metabolic dysfunction–associated steatotic liver disease (MASLD) (previously referred to as non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction associatedsteatohepatitis (MASH, previously non-alcoholic steatotic hepatitis (NASH)), compensated and 20 decompensated liver cirrhosis, acute on chronic liver failure (ACLF), alcoholic liver disease (ALD), interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), long COVID, aging / muscle disorders, sepsis, heart failure, anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis, alopecia, chronic kidney disease, rheumatoid arthritis and osteoarthritis. 25 Background of the invention Innate immunity is considered a first line cellular stress response defending the host cell against invading pathogens and initiating signaling to the adaptive immune system. These processes are triggered by conserved pathogen-associated molecular patterns (PAMPs) through sensing by diversepattern recognition receptors (PRRs) and subsequent activation of cytokine and type I interferon gene 30 expression. The major antigen-presenting cells, such as monocytes, macrophages, and dendritic cells produce type I interferons and are critical for eliciting adaptive T- and B-cell immune systemresponses. 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)). 35 01-3596-WO-1 2 “Cyclic GMP-AMP Synthase” (cGAS) is the predominant sensor for aberrant double-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., Science 339, 826-830 (2013); Ablasser et al., Nature 498, 380-384 (2013)). Binding of dsDNA to cGAS activates the reaction of GTP 5 and ATP to form the cyclic dinucleotide GMP-AMP (referred to as cGAMP). cGAMP then binds to and activates the endoplasmatic reticulum membrane-anchored adaptor protein, “Stimulator of Interferon Genes” (STING, UniProtKB – Q86WV6). Activated STING recruits and activates TANK-binding kinase 1(TBK1) which in turn phosporylates the transcription factor family of interferon regulatory factors (IRFs) inducing cytokine and type I interferon mRNA expression. STING activation by cGAMP also leads 10 to activation of NF-kB signaling pathway and downstream production of proinflammatory cytokines (Sun et al., Science 339, 786-791 (2013). Human GoF STING mutants lead to an autoinflammatory syndrome, cutaneous vasculopathy and lung fibrosis (STING-associated vasculopathy with onset in infancy, SAVI). SAVI patients have a highly activated PBMCs and dermal fibroblasts, exhibiting an upregulated type-1 IFN signature and expression of NF^B-mediated profibrotic and proinflammatory15 genes (e.g. TNF^, IL-6) (Liu et al., 2014). The critical role of STING in dsDNA sensing has been established in different pathogenic bacteria and viruses. Additionally, STING is essential in various other biological processes such as cellular senescence (Yang et al., PNAS 114, E4612 (2017), Glueck et al., Nat. Cell Biol.19, 1061-1070 (2017)), 20 autophagy 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)). While the cGAS / STING pathway is important for host defense against invading pathogens, cellular stress and genetic factors may also cause production of aberrant cellular dsDNA, e.g. by nuclear or 25 mitochondrial leakage, and thereby trigger autoinflammatory responses. Aicardi-Goutieres syndrome (AGS; Crow et al., Nat. Genet.38, 917-920 (2006)) – a lupus-like severe autoinflammatory immune-mediated disorder – arises from genetic mutations such as loss-of-function mutations in TREX1, aprimary DNA exonuclease responsible for degrading aberrant DNA in cytosol. Knock-out of STING inTREX1-deficient mice prevented otherwise lethal autoimmune responses, supporting STING as driver 30 of interferonopathies (Gall et al., Immunity 36(1), 120-131 (2012); 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 completely rescued by additional knock-out of STING (Ahn et al., PNAS 109, 19386-19391 (2012)). A STING inhibitor may provide a therapeutic strategy for preventing (monogenic and digenic) 35 interferonopathy diseases such as SAVI, AGS, familial chilblain lupus and COPA. A STING inhibitor will 01-3596-WO-1 3 block inflammation and aberrant tissue remodeling in a cluster of autoimmune and inflammatory diseases including systemic lupus erythematosus (SLE), systemic sclerosis, vitiligo, prurigo nodularis, idiopathic inflammatory myopathy, myositis including dermatomyositis, inflammatory bowel disease,sepsis, Sjogren’s syndrome, atopic dermatitis, as well as a cluster fibrosis diseases including NASH, IPF, 5 chronic kidney fibrosis. A STING inhibitor also has applications to additional diseases such as cancer, heart failure, AMD, retinopathy, glaucoma, aging, decompensated liver cirrhosis, anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis, alopecia, chronic kidney disease; Niemann-Pick Disease, Type C, ischaemic stroke, myotonic dystrophy type 2, Huntington disease, Bloom syndrome,Huntington disease, muscle disorders, rheumatoid arthritis, osteoarthritis, ALS, Parkinson’s disease,10 Alzheimer’s disease, COVID-19 (Decout et al, Nat Rev Immunol.202121:548-569). Due to the observation that inhibition of the STING pathway may provide a therapeutic strategy for preventing autoinflammation and for treating e.g. autoimmune diseases efforts to develop STING inhibitors or inhibition of the STING signaling pathway have been undertaken. 15 •In WO2019122202 for example, compounds C-178 or C-176 are described interfering with STINGsignaling pathway in HEK293T cells or bone marrow derived macrophages (BMDMs) stimulated with a cyclic dinucleotide such as e.g. cGAMP which are irreversible inhibitors blocking the palmitoylation of STING at an allosteric site of STING.20 • In ACS Med Chem Lett. (2019, 10, 1, pp 92-97), Siu et all described novel cGAMP competitiveligands. It is believed that inhibiting the orthosteric site of cGAMP mediated STING activation leads to a suppression of all STING mediated activation in contrast to palmitoylation inhibitors. Compound 13 or 15 in this publication inhibits the HAQ STING variant (displacement assay) with a moderate IC50 of 84 or 41 nM and shows low cellular inhibitory activity of about 11 uM based on25 a cGAMP stimulated INFb production in THP1 cells. •In International patent application WO2019069270, claims modulators of STING which eitheractivate or inhibit STING accordingly. •In the international patent applications WO23148129 and WO23237457 modulators of STING aredisclosed that are relatively large macrocycles with demanding synthesis and handling of the30 molecules. However, inhibitors of the STING receptor for therapeutic use face challenges. For example, it is expected that most inhibitors of the STING receptor binding its ligand binding site similar to the natural ligand, i.e. two molecules in the binding pocket. Yet, for the design of inhibitors of STING 35 receptors this provides the additional challenge that the inhibitor molecules not only need to interact 01-3596-WO-1 4 with the correct portion the STING receptor, but also will interact with the second molecule of the inhibitor in the ligand binding pocket of STING. Hence the potential interface between inhibitor and inhibitor is also important to consider for good inhibition results of STING. Also, the polarity of the inhibitor molecules needs to be optimized on the one hand to allow sufficient 5 crossing of the cell membranes to reach the target, while not enhancing the degradation of the inhibitor. Another challenge for a therapeutic inhibitor of STING receptors is that in many STING mediated disease patients are likely to be co-administered with more than one medications to treat the symptoms of said diseases or the diseases itself. The inhibitors of STING should in such a situation not 10 add additional workload to the detoxifying processes or catabolism of the other medication administered, which could lead to undesired changes in the half-life of any of the therapeutic compounds or have negative effects on the patient’s metabolism. Aim of the invention15 It has now been found that compounds of the present invention according to general formula (I), or pharmaceutically acceptable salt thereof, are effective STING inhibitors.In addition to the antagonistic property toward STING, the compounds of the present invention provide further advantageous properties as to be viable for human therapy, such as but not limited to:20 Being optimised for binding of two molecules of the inhibitor to the target’s ligand binding pocket,sufficiently easy to synthesize and handle, good bioavailability, good mobility across the cell membrane and good access to the target receptor in the cells, acceptable cytotoxicity and / or genotoxicity, good ligand efficiency, good metabolic stability, low interaction with catabolic processes e.g. by cytochrome p450s or other CYP that are important with respect to possibly co-administered25 drugs, good degradation ex-situ of the inhibitor or its break-down product e.g. in sewage plants. The inhibitors of the invention perform better in one or several of these properties than the inhibitors of the STING receptor available so far. Accordingly, one aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of STING. Another aspect of the invention refers to compounds according to formula (I), or salts thereof as 30 inhibitors of STING optimised for binding of two molecules of the inhibitor to the target’s ligand binding pocket and / or good ligand efficiency. Another aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of STING having good metabolic stability and potency. 01-3596-WO-1 5 Another aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of STING optimised in polarity for good mobility across the cell membrane and good access to the target receptor in the cells while having good metabolic stability and potency. Another aspect of the invention refers to compounds according to formula (I), or salts thereof as 5 inhibitors of STING having good metabolic stability with acceptable cytotoxicity and / or genotoxicity. Another aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of STING having good metabolic stability and low interaction with catabolic processes e.g. by cytochrome p450s or other CYP that are important with respect to possibly co-administered drugs. Another aspect of the invention refers to compounds according to formula (I), or salts thereof as 10 inhibitors of STING having good metabolic stability and low interaction with catabolic processes of other pharmaceutical compound administered overlappingly or simultaneously, including but not limited to further inhibitors of STING, and with acceptable cytotoxicity and / or genotoxicity. Another aspect of the invention refers to compounds according to formula (I), or salts thereof as 15 inhibitors of STING having good metabolic stability and low interaction with catabolic processes of other pharmaceutical compounds administered overlappingly or simultaneously, including but not limited to further inhibitors of STING, and with acceptable cytotoxicity and / or genotoxicity and optimised in polarity for good mobility across the cell membrane and good access to the target receptor in the cells and good potency. 20 Another aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of having good metabolic stability and low interaction with catabolic processes of other pharmaceutical compounds administered overlappingly or simultaneously, including but not limited to further inhibitors of STING, and with acceptable cytotoxicity and / or genotoxicity and optimised in polarity for good mobility across the cell membrane and good access to the target receptor in the cells 25 and good potency and optimised for binding of two molecules of the inhibitor to the target’s ligand binding pocket and good ligand efficiency. In a further aspect this invention relates to pharmaceutical compositions containing at least one compound according to general formula (I), or pharmaceutically acceptable salts thereof, optionally30 together with one or more inert adjuvant, diluent and / or carrier. Afurther aspect of the present invention relates to compounds according to general formula (I) orpharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compoundsaccording to formula (I) or pharmaceutically acceptable salts thereof, for the use in the prevention of35 and / or treatment of and / or delaying the occurrence of and / or delaying the progression of disorders 01-3596-WO-1 6 related to elevated and / or deregulated STING activity. In one aspect of the invention the use is to prevent one or more disorders related to elevated STING activity. Another aspect of the invention the use is to treat one or more disorders related to elevated STING activity. A further aspect the inventive use is to delay the occurrence of one or more disorders related to elevated STING activity. In yet 5 another aspect the inventive compounds and use is to delay the progression one or more disorders related to elevated STING activity, for example but not limited to progression of scleroderma renal crisis (SRC) to end stage renal disease / kidney failure; progression of MAFLD or MASH for example from MAFLD to MASH, or from MASH to Mash with cirrhosis as assessed with the NAFLD Activity Score (NAS) with or without steatosis, activity, and fibrosis (SAF) score and / or progression of10 Rheumatoid arthritis as assessed via the 2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria for example but not limited to from a point value from 3 to 5 or from a point value 4 to point value 7. Another aspect of the invention relates to processes of manufacture of the compounds of the present invention according to general formula (I) or salts thereof, particularly pharmaceutically acceptablesalts. 15 Other aims of the present invention will become apparent to the skilled man directly from the foregoing and following remarks. Detailed description 20 In a first aspect the present invention relates to compounds of general formula (I) wherein 25 X-Y-Z is selected from the group X-Y-Za consisting of =CH-N-N= and -N=C-NH- and -CH2-NH-C(O)-; 01-3596-WO-1 7 Wis selected from the group Wa consisting of =C- and -NH-;V-B-A is selected from the group V-B-Aa consisting of -C=C-N- and -N-C=C-;R1is selected from the group R1aconsisting of C1-5-alkyl-, C1-3-alkyl-O-, C3-6-cycloalkyl- and C3-6-cycloalkyl-C1-3-alkyl-;wherein the C1-3-alkyl-O-group and / or the C1-5-alkyl-group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-3- alkyl-O-, Halogen and HO-; R2is selected from the group R2aconsisting of C1-3-alkyl-; 5 R3is selected from the group R3aconsisting of C3-6-cycloalkyl- and C3-6-cycloalkyl- C1-3-alkyl;R4is selected from the group R4aconsisting of H and Halogen; R5is selected from the group R5aconsisting of R9-C(R8)(R7)-CH(R12)- and R9-S(O)-CH(R12)- and ,wherein R5 denotes the attachment point of this R5 group to Y;R6is selected from the group R6aconsisting of C2-6-alkenyl, and 01-3596-WO-1 8 C1-6-alkyl optionally substituted independently of one another by one or two substituents selected from the group consisting of C3-6-cycloalkyl-, halogen, HO-, C1-6- alkyl-O-, C1-6-alkyl-HN-, (C1-6-alkyl)2N-, NC-, (C1-6-alkyl)2(O)P-, (4- methoxyphenyl)methyl-, oxetane and , wherein * denotes the attachmentpoint of this R6group to Ax; and C3-5-heterocycloalkyl , preferably a heterocycle selected from tetrahydrofuran-, 1, 4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, triazole- oroxetane, each optionally substituted independently of one another by one or two substituents selected from the group consisting of C1-6-alkyl-, halogen, O=; R7is selected from the group R7aconsisting of H-, Halogen, HO- and C1-3-alkyl-O-;R8is selected from the group R8aconsisting of H- and Halogen;R9is selected from the group R9aconsisting of phenyl-, piperidyl-, morpholinyl- and C5-6-cycloalkyl-,wherein the piperidyl-group is optionally substituted with 1 substituent independently selected from the group consisting of C1-3-alkyl-S(O)2-, C1-3-alkyl-C(O)-, C1-5-alkyl-C(O)-O-; R10is selected from the group R10aconsisting of H-, HO-, H2N-C(O)-, C1-3-alkyl-, C1-3-alkyl-O-, C3-4-cycloalkyl- and phenyl-,wherein the phenyl-group and / or the C1-3-alkyl-group are optionally substituted with 1 substituent independently selected from the group consisting of Halogen and HO-; 5 R11is selected from the group R11aconsisting of 01-3596-WO-1 9 H-, HO-, H2N-C(O)-, C1-3-alkyl-, C1-3-alkyl-O-, C3-4-cycloalkyl- and phenyl-,wherein the phenyl-group and the C1-3-alkyl-group is optionally substituted with 1 substituent independently selected from the group consisting of Halogen and HO-, wherein preferably R10 and R11 are not both H- at the same time;R12is selected from the group R12aconsisting of H-, HO- and Halogen;or a salt thereof, preferably a pharmaceutically acceptable salt. 5 Unless otherwise stated, the groups, residues, and substituents, particularly V-B-A, W, X-Y-Z, R1, R2, R3,R4, R5, R6, R7, R8, R9, R10, R11and R12 are defined as above and hereinafter. If residues, substituents, orgroups occur several times in a compound they may have the same or different meanings. Some preferred meanings of groups and substituents of the compounds according to the invention will be 10 given hereinafter. In a further embodiment of the present invention X-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N=.In a further embodiment of the present invention X-Y-Z is selected from the group X-Y-Zc consisting of -N=C-NH-.15 In a further embodiment of the present invention X-Y-Z is selected from the group X-Y-Zd consisting of -CH2-NH-C(O)-.In a further embodiment of the present invention X-Y-Z is selected from the group X-Y-Ze consisting of -N=C-NH- and -CH2-NH-C(O)-.20 In a further embodiment of the present invention Wis selected from the group Wb consisting of =CH-.In a further embodiment of the present invention Wis selected from the group Wc consisting of =N-.25 In a further embodiment of the present invention 01-3596-WO-1 10 V-B-A is selected from the group V-B-Ab consisting of -C=C-N-;V-B-A is selected from the group V-B-Ac consisting of -N-C=C-;In a further embodiment of the present invention, V-B-A is V-B-Aband W is Wc. In a preferred embodiment, the compound is a compound of formula (Ia) 5 In another preferred embodiment, the compound is a compound of formula (Ib) 10 In yet another preferred embodiment, the compound is a compound of formula (Ic) In a further embodiment of the present invention R1is selected from the group R1bconsisting of 01-3596-WO-1 11 H3C-, (H3C)2C-, H3C-CH2-, cyclopropyl-, cyclopropylmethyl-, cyclopropylhydroxymethyl-, F3C-O-, F3C-O-, H3C-CH(OH)-, H3C-CH2-CH(OH)-, H3C-CH2-O-, and H3C-O-CH2-CH2-. In a further embodiment of the present invention R1 is selected from the group R1c consisting of cyclopropylhydroxymethyl- (H5C3-CH(OH)-).In a further embodiment of the present invention R1is selected from the group R1dconsisting of H3C-CH2-CH(OH)-. 5 In a further embodiment of the present invention R1is selected from the group R1econsisting of (H3C)2C-. In a further embodiment of the present invention R2is selected from the group R2bconsisting of H3C-. 10 In a further embodiment of the present invention R3is selected from the group R3bconsisting of cyclopropyl- and cyclopropylmethyl-.In a further embodiment of the present invention R3is selected from the group R3cconsisting of cyclopropyl-. 15 In a further embodiment of the present invention R4is selected from the group R4bconsisting of H- and F-.In a further embodiment of the present invention 01-3596-WO-1 12 R4is selected from the group R4cconsisting of . In a further embodiment of the present invention R5is selected from the group R5bconsisting of R9-C(R8)(R7)-CH(R12)-, and , wherein R5 denotes the attachment point of this R5 group to5 Y. In a further embodiment of the present invention R5is selected from the group R5cconsisting of , wherein R5 denotes the attachment point of this R5 group to Y.. In a further embodiment of the present invention R5is selected from the group R5dconsisting of ,wherein R5 denotes the attachment point of this R5 group to Y.10 In a further embodiment of the present invention, R5is selected from the group R5econsisting of R9- C(R8)(R7)-CH(R12)-. In a further embodiment of the present invention, R5is selected from the group R5fconsisting of 01-3596-WO-1 13 ,wherein R5 denotes the attachment point of this R5 group to Y.In a further embodiment of the present invention, R5is selected from the group R5gconsisting of , wherein R5 denotes the attachment point of this R5group to Y. 5 In a further embodiment of the present invention, R5is selected from the group R5hconsisting of ,wherein R5 denotes the attachment point of this R5 group to Y.In a further embodiment of the present invention, R5is selected from the group R5iconsisting of 10 , wherein R5 denotes the attachment point of this R5 group to Y. 01-3596-WO-1 14 In a further embodiment of the present invention, R5is selected from the group R5jconsisting of R9-S(O)-CH(R12)-. In a further embodiment of the present invention R6is selected from the group R6bconsisting of C1-5-alkyl- and oxetane- and oxetane- and tetrahydrofuran-,wherein the C1-5-alkyl- group is optionally substituted with 1 to 2 substituentsindependently selected from the group consisting of oxetane. 5 In a further embodiment of the present invention R6is selected from the group R6cconsisting of C1-3-alkyl- and oxetane- and oxetane-,wherein the C1-3-alkyl- group is optionally substituted with 1 to 2 substituentsindependently selected from the group consisting of oxetane. In a further embodiment of the present invention R6is selected from the group R6dconsisting of H3C-. In a further embodiment of the present invention R6is selected from the group R6econsisting of oxetane- and oxetane-methyl-.10 In a further embodiment of the present invention R6is selected from the group R6fconsisting of oxetane-. In a further embodiment of the present invention R6is selected from the group R6gconsisting of 01-3596-WO-1 15 ,wherein the attachment to the core is via the bond shown on the left.In a further embodiment of the present invention R6is selected from the group R6hconsisting of Oxetane-methyl-. In a further embodiment of the present invention R6is selected from the group R6iconsisting of , wherein the attachment to the core is via the bond on the left. 5 In a further embodiment of the present invention R7is selected from the group R7bconsisting of H-, F-, H3C-O- and HO-.In a further embodiment of the present invention R7is selected from the group R7cconsisting of H-. 10 In a further embodiment of the present invention R7is selected from the group R7dconsisting of F-. In a further embodiment of the present invention R7is selected from the group R7econsisting of HO-. 01-3596-WO-1 16 In a further embodiment of the present invention R7is selected from the group R7fconsisting of H3C-O-. In a further embodiment of the present invention R8is selected from the group R8bconsisting of H- and F-..5 In a further embodiment of the present invention R8is selected from the group R8cconsisting of H-. In a further embodiment of the present invention R8is selected from the group R8dconsisting of F-. In a further embodiment of the present invention R9is selected from the group R9bconsisting of phenyl-, 3-piperidyl-, 2-morpholinyl-, 3-morpholinyl-, 4-morpholinyl- and cyclohexyl-,wherein the piperidyl-group is optionally substituted at the N-atom with 1 substituent independently selected from the group consisting of C1-3-alkyl-S(O)2-, C1-3-alkyl-C(O)-, C1-5-alkyl-C(O)-O-. 10 R9is selected from the group R9cconsisting of phenyl- and cyclohexyl-.In a further embodiment of the present invention R9is selected from the group R9dconsisting of phenyl-. 01-3596-WO-1 17 In a further embodiment of the present invention R9is selected from the group R9econsisting of cyclohexyl-. In a further embodiment of the present invention R10is selected from the group R10bconsisting of H2N-C(O)-, H3C-, cyclopropyl- and phenyl-,wherein the phenyl-group and / or the H3C-group is optionally substituted with 1 substituent independently selected from the group consisting of F- and HO-.5 In a further embodiment of the present invention R10is selected from the group R10cconsisting of phenyl-. In a further embodiment of the present invention R10is selected from the group R10dconsisting of cyclopropyl-. In a further embodiment of the present invention R11is selected from the group R11bconsisting of H-, HO-, H2N-C(O)-, HO-CH2-, H3C-O- and phenyl-.10 In a further embodiment of the present invention R11is selected from the group R11cconsisting of HO-. In a further embodiment of the present invention 01-3596-WO-1 18 R11is selected from the group R11dconsisting of H3C-O-. In a further embodiment of the present invention R12is selected from the group R12bconsisting of H-, HO-, F- and Cl-.In a further embodiment of the present invention R12is selected from the group R12cconsisting of H- and HO-.5 In a further embodiment of the present invention R12is selected from the group R12dconsisting of H-. In a further embodiment of the present invention R12is selected from the group R12econsisting of HO-. 10 V-B-A, W, X-Y-Z, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11and R12represent a characterized, individual embodiment for the corresponding substituent as described above. Thus, given the above definitions, individual embodiments of the first aspect of the invention are fully characterized by the term ( V-B-Ax,WX, X-Y-ZX, R1X, R2x, R3X, R4X, R5X, R6X, R7X, R8X, R9X, R10X, R11xand R12x), wherein for each index ‘x’ an individual figure is given that ranges from ‘a’ to the highest letter given above. All individual 15 embodiments described by the term in parentheses with full permutation of the indices ‘x’, referring to the definitions above, shall be comprised by the present invention. The following table 1 shows such embodiments E-1 to E-27of the compound of general formula (I) or a salt thereof, preferably a pharmaceutically acceptable salt, that are considered preferred.20 Table 1: Embodiments E-1 to E-27 of the invention 01-3596-WO-1 19 01-3596-WO-1 20 Accordingly, for example E-7 covers compounds of general formula (I), wherein V-B-A is selected from the group V-B-Ac consisting of -N-C=C-;W is selected from the group Wc consisting of =N-;X-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N=;R1is selected from the group R1econsisting of (H3C)2C-; R2is selected from the group R2bconsisting of H3C-; R3is selected from the group R3cconsisting of cyclopropyl-; R4is selected from the group R4cconsisting of H-; R5is selected from the group R5gconsisting of , wherein R5 denotes the attachment point of this R5group to Y; with R7is selected from the group R7econsisting of HO-; R8is selected from the group R8cconsisting of H-; R9is selected from the group R9dconsisting of phenyl-; R12is selected from the group R12dconsisting of H-; R6is selected from the group R6dconsisting of H3C-. 5 or a salt thereof, preferably a pharmaceutically acceptable salt. Accordingly, for example E-12 covers compounds of general formula (I),wherein V-B-A Is selected from the group V-B-Ab consisting of -C=C-N-; 01-3596-WO-1 21 Wis selected from the group Wc consisting of =N-;X-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N=;R1is selected from the group R1econsisting of (H3C)2C-; R2is selected from the group R2bconsisting of H3C-; R3is selected from the group R3cconsisting of cyclopropyl-; R4is selected from the group R4cconsisting of H-; R5is selected from the group R5gconsisting of , wherein R5 denotes the attachment point of this R5group to Y; with R7is selected from the group R7econsisting of HO-; R8is selected from the group R8cconsisting of H-; R9is selected from the group R9dconsisting of phenyl-; R12is selected from the group R12dconsisting of H-; R6 is selected from the group R6i consisting of ; or a salt thereof, preferably a pharmaceutically acceptable salt.Accordingly, for example E-22 covers compounds of general formula (I),wherein V-B-A Is selected from the group V-B-Ac consisting of -N-C=C-W is selected from the group Wc consisting of =N-;X-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N=;R1is selected from the group R1econsisting of (H3C)2C-; R2is selected from the group R2bconsisting of H3C-; 01-3596-WO-1 22 R3is selected from the group R3cconsisting of cyclopropyl-; R4is selected from the group R4cconsisting of H-; R5is selected from the group R5hconsisting of , wherein R5 denotes the attachment point of this R5group to Y; with R7is selected from the group R7cconsisting of H-; R8is selected from the group R8cconsisting of H-; R9is selected from the group R9dconsisting of phenyl-; R12is selected from the group R12econsisting of HO-; R6is selected from the group R6dconsisting of H3C-; or a salt thereof, preferably a pharmaceutically acceptable salt. Further preferred are the following compounds listed in table 2 or salt thereof or stereoisomers5 thereof (the No. refers to the No. assigned to the compound in the experimental section). Eachcompound of table 2 is represented without indicating the stereochemistry thereof, if any. Specificinformation concerning stereochemical properties of compounds of table 2 can be taken from theexperimental section. In case the final compounds according of said experimental section are saltforms, they can be converted into the neutral compound by conventional methods.10

[0002] 01-3596-WO-1 23 Table 2: 01-3596-WO-1 24 or a salt thereof. A further embodiment of the present invention covers the compounds of general formula (I), preferably compounds of formula (Ia), (Ib) or (Ic), more preferably the compounds listed in table 2, in5 form of their pharmaceutically acceptable salts. Afurther embodiment of the present invention refers to pharmaceutical compositions comprising atleast one compound according to formula (I), preferably according to formula (Ia), (Ib) or (Ic), or pharmaceutically acceptable salts thereof, optionally together with at least one inert adjuvant, diluent10 and / or carrier. In a further embodiment, the present invention relates to a compound of the present invention or apharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least onecompound according to general formula (I), preferably according to formula (Ia), (Ib) or (Ic), or15 pharmaceutically acceptable salts thereof, for use as a medicament.In a further embodiment, the present invention relates to compounds according to general formula (I), preferably according to formula (Ia), (Ib) or (Ic), or pharmaceutically acceptable salts thereof, orpharmaceutical compositions comprising compounds according to general formula (I), preferably 20 according to formula (Ia), (Ib) or (Ic), or pharmaceutically acceptable salts thereof, for use in the prevention , the delaying of the occurrence, the delaying of the progression and / or treatment of diseases or conditions which can be influenced by STING inhibition. Inhibition of the STING proteinmay not require to be a complete inhibition of the STING proteins within a cell, tissue, organ or the body of a patient to cause the desired positive effects in a patient. A partial inhibition maybe sufficient25 and possibly desirable in some patients. Used terms and definitions 01-3596-WO-1 25 Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following 5 conventions are adhered to. In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C1-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, in groups like HO-, H2N-, (O)S-, (O)2S-, NC- (cyano), HOOC-, F3C- or the like, the10 skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself. For combined groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent "aryl-C1-3-alkyl-" means an aryl group which is bound to a C1-3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached. 15 In case a compound of the present invention is depicted in the form of a chemical name and as a formula, in case of any discrepancy the formula shall prevail. The numeration of the atoms of a substituent starts with the atom which is closest to the core or to 20 the group to which the substituent is attached. For example, the term "3-carboxypropyl-group" represents the following substituent: wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms "1-25 methylpropyl-", "2, 2-dimethylpropyl-" or "cyclopropylmethyl-" group represent the following groups: The asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. 30 01-3596-WO-1 26 The term "substituted" as used herein, means that one or more hydrogens on the designated atom are replaced by a group selected from a defined group of substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound. Likewise, the term “substituted” may be used in connection with a chemical moiety instead of a single 5 atom, e.g. “substituted alkyl”, “substituted aryl” or the like. Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomer’s and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E / Z isomers etc…) and racemates thereof as well as mixtures in different 10 proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as solvates thereof such as for instance hydrates. Unless specifically indicated, also “pharmaceutically acceptable salts” as defined in more detail below shall encompass solvates thereof such as for instance hydrates. 15 In general, substantially pure stereoisomers can be obtained according to synthetic principles known to a person skilled in the field, e.g. by separation of corresponding mixtures, by using stereochemically pure starting materials and / or by stereoselective synthesis. It is known in the art how to prepareoptically active forms, such as by resolution of racemic forms or by synthesis, e.g. starting from20 optically active starting materials and / or by using chiral reagents. Enantiomerically pure compounds of this invention or intermediates may be prepared via asymmetric synthesis, for example by preparation and subsequent separation of appropriate diastereomeric compounds or intermediates which can be separated by known methods (e.g. by chromatographic 25 separation or crystallization) and / or by using chiral reagents, such as chiral starting materials, chiral catalysts, or chiral auxiliaries. Further, it is known to the person skilled in the art how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, such as by chromatographic separation of the 30 corresponding racemic mixtures on chiral stationary phases; or by resolution of a racemic mixture using an appropriate resolving agent, e.g. by means of diastereomeric salt formation of the racemic compound with optically active acids or bases, subsequent resolution of the salts and release of the desired compound from the salt; or by derivatization of the corresponding racemic compounds withoptically active chiral auxiliary reagents, subsequent diastereomer separation and removal of the 35 chiral auxiliary group; or by kinetic resolution of a racemate (e.g. by enzymatic resolution); by 01-3596-WO-1 27 enantioselective crystallization from a conglomerate of enantiomorphous crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary. 5 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 judgment, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. 10 As used herein, "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. 15 For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malicacid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid. Further pharmaceutically acceptablesalts can be formed with cations from ammonia, L-arginine, calcium, 2, 2’-iminobisethanol, L-lysine,20 magnesium, N-methyl-D-glucamine, potassium, sodium and tris(hydroxymethyl)-aminomethane. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient 25 amount of the appropriate base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts, ) also comprise a part of the30 invention. The term halogen denotes fluorine, chlorine, bromine and iodine. The term "C1-n-alkyl-", wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4, 5, or 6, either 35 alone or in combination with another radical, denotes an acyclic, saturated, branched or linear 01-3596-WO-1 28 hydrocarbon radical with 1 to n C atoms. For example the term C1-5-alkyl embraces the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C- C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.5 The term "C2-m-alkenyl" is used for a group "C2-m-alkyl" wherein m is an integer selected from 3, 4, 5 or 6, preferably 4, 5 or 6, if at least two carbon atoms of said group are bonded to each other by a double bond. 10 The term "C3-k-cycloalkyl", wherein k is an integer selected from 3, 4, 5, 7 or 8, preferably 4, 5 or 6, either alone or in combination with another radical, denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to k C atoms. For example the term C3-7-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.15 The term "carbocyclyl", either alone or in combination with another radical, means a mono , bi ortricyclic ring structure consisting of 3 to 14 carbon atoms. The term "carbocyclyl" refers to fully saturated, partially saturated and aromatic ring systems. The term "carbocyclyl" encompasses fused, bridged and spirocyclic systems. Examples without limitation are: 20 The term "aryl" as used herein, either alone or in combination with another radical, denotes a 25 carbocyclic aromatic monocyclic group containing 6 carbon atoms which is optionally further fused to a second five or six membered, carbocyclic group which is aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl. 01-3596-WO-1 29 The term "heterocyclyl" means a saturated or unsaturated mono- or polycyclic ring system optionallycomprising aromatic rings, containing one or more heteroatoms selected from N, O, S, SO or SO2 consisting of 3 to 14 ring atoms wherein none of the heteroatoms is part of the aromatic ring. The 5 term "heterocyclyl" is intended to include all the possible isomeric forms. Thus, the term "heterocyclyl" includes the following exemplary structures (not depicted as radicals as each form is optionally attached through a covalent bond to any atom so long as appropriate valences are maintained): 10 15 01-3596-WO-1 30 H H N N N N H N N N N O O S S S S O S O S O S S O O O O OO OS O O H N H H H N N N NN O O OS S O 5 01-3596-WO-1 31 . The term "heteroaryl" means a mono- or polycyclic ring system, comprising at least one aromatic ring,5 containing one or more heteroatoms selected from N, O, S, SO or SO2, consisting of 5 to 14 ring atoms wherein at least one of the heteroatoms is part of an aromatic ring. The term "heteroaryl" is intended to include all the possible isomeric forms. Thus, the term "heteroaryl" includes the following exemplary structures (not depicted as radicals as 10 each form is optionally attached through a covalent bond to any atom so long as appropriate valences are maintained): 15 01-3596-WO-1 32 . The term "aryl" as used herein, either alone or in combination with another radical, denotes a 5 carbocyclic aromatic monocyclic group containing 6 carbon atoms which is optionally further fused to asecond five- or six-membered, carbocyclic group which is aromatic, saturated or unsaturated. Arylincludes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl. 10 Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another. The term „bicyclic ring systems” means groups consisting of 2 joined cyclic substructures including spirocyclic, fused, and bridged ring systems. 15 Synthesis The compounds according to the invention may be obtained using methods of synthesis known in principle, known to the one skilled in the art and described in the literature of organic synthesis. 20 Preferably, the compounds are obtained in analogous fashion to the methods of preparation explained more fully hereinafter, in particular as described in the experimental section. In some cases, the order in carrying out the reaction steps may be varied. Variants of the reaction methods that are known to the one skilled in the art but not described in detail here may also be used. Preferably, the compounds are obtained by the following methods according to the invention which are described in 25 more detail hereinafter. The following Schemes illustrate generally how to manufacture the compounds of the present invention by way of example. Starting materials may be prepared by methods that are described inthe literature or herein or may be prepared in an analogous or similar manner. Any functional groups 30 in the starting materials or intermediates may be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage within the reaction sequence using 01-3596-WO-1 33 methods familiar to the one skilled in the art. The abbreviated substituents may be as defined above ifnot defined otherwise within the context of the schemes. Optimum reaction conditions and reaction times may vary depending on reactants used. Unless 5 otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Experimental section. Typically, reaction progress may be monitored by thin layer chromatography (TLC), liquid chromatography – mass spectrometry (LC-MS) if desired, and intermediates and products may bepurified by chromatography and / or by recrystallization. 10 The examples which follow are illustrative and, as recognized by one skilled in the art, 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 eithercommercially available or easily prepared from commercially available materials by those skilled in the15 art. Examples and experimental data The following examples are for the purpose of illustration of the invention only and are not intended in20 any way to limit the scope of the present invention. The term "room temperature" designate a temperature of about 20 °C, e.g., 15 to 25 °C. As a rule,1H-NMR and / or mass spectra have been obtained for the compounds prepared. 25 Flash chromatography or MPLC is performed with commercial silica gel and is equivalent to silica gel chromatography. Unless otherwise specified, compounds containing chiral centers have the stereochemistry depicted. 30 The assignment of stereochemistry has been made either by use of a chiral starting material of known stereochemistry, by stereoselective synthesis of known stereochemistry, or by biological activity. In addition, absolute configuration of representative examples is either defined via single crystal x-ray structure determination of intermediates or examples or protein-ligand X-ray determinations. 35 01-3596-WO-1 34 Scheme 1a: General synthesis scheme for patent examples 5Scheme 1b: Synthesis scheme for benzimidazole examples 10 All starting materials not described are either commercially available or described in literature. Synthesis of intermediates A1 – A3Synthesis of intermediate A115 Step 1: Synthesis of (1R)-2-{[(2-bromo-6-nitrophenyl) methyl] amino}-1-phenylethan-1-ol 01-3596-WO-1 35 (1R)-2-Amino-1-phenylethan-1-ol (5.00 g, 17.0 mmol) is dissolved in ACN (20 mL) and DIPEA (8.75 mL, 50.9 mmol).1-Bromo-2-(bromomethyl)-3-nitrobenzene (6.98 g, 50.9 mmol) is slowly added. The reaction mixture is stirred at RT for 2 h. The reaction mixture is concentrated and purified by flash 5chromatography (CycH / EtOAc 100 / 0 à CycH / EtOAc 10 / 90) to afford the desired compound.Analysis (method A): Rt: 0.36 min, [M+H] +: 351 / 353 (Br)Step 2: Synthesis of (1R)-2-(4-bromo-2H-indazol-2-yl)-1-phenylethan-1-ol (intermediate A1) 10 (1R)-2-{[(2-Bromo-6-nitrophenyl) methyl] amino}-1-phenylethan-1-ol (5.44 g, 15.5 mmol) is suspended in MeOH (25 mL). Zinc (5.06 g, 77.45 mmol) is added, and then ammonium formate (977mg, 15.5 mmol) in MeOH (5 mL) is added dropwise over 5 min. The reaction mixture is stirred at RT overnight. The reaction mixture is filtered, washed with MeOH and the filtrate is concentrated. The residue is triturated with water. The precipitate is filtered and re-crystallized from ACN to afford intermediate15 A1. Analysis (method A): Rt: 0.58 min, [M+H] +: 317 / 319 (Br)Synthesis of intermediate A2 Step 1: Synthesis of (2S)-N-(2-amino-3-bromophenyl)-2-hydroxy-3-phenylpropanamide 20 01-3596-WO-1 36 3-Bromobenzene-1,2-diamine (600 mg, 3.11 mmol) and (2S)-2-hydroxy-3-phenylpropanoic acid (633 mg, 3.73 mmol) are dissolved in DMF (4 mL) and DIPEA (2.10 mL, 12.2 mmol). HATU (1.80 g, 4.73 mmol) is added. The reaction mixture is stirred at RT overnight. The reaction mixture is given to DCM,ammonium hydroxide and water and the mixture is stirred at RT for 15 min. The organic phase is 5 separated and concentrated. The residue is purified by HPLC (ACN / water / NH3) to afford the title compound. Analysis (method L): Rt: 0.53 min, [M+H] +: 335Step 2: Synthesis of (1S)-1-(4-bromo-1H-1,3-benzodiazol-2-yl)-2-phenylethan-1-ol (intermediate A2)10 (2S)-N-(2-Amino-3-bromophenyl)-2-hydroxy-3-phenylpropanamide (200 mg, 0.597 mmol) is diluted in acetic acid (2 mL). The reaction mixture is stirred at 80°C for 1h. The reaction mixture is purified by HPLC (ACN / water / TFA) to obtain intermediate A2.Analysis (method A): Rt: 0.41 min, [M+H] +: 31715 Synthesis of intermediate A3 Synthesis of 4-bromo-2-[(2R)-2-hydroxy-2-phenylethyl]-2,3-dihydro-1H-isoindol-1-one 20 Methyl 3-bromo-2-(bromomethyl)benzoate (150 mg, 0.487 mmol) is dissolved in DMF (8 mL). (1R)-2-amino-1-phenylethan-1-ol (151 mg, 1.07 mmol) and TEA (176 µL, 1.21 mmol) is added and the reaction mixture is stirred at RT overnight. The reaction mixture is concentrated. The residue is diluted with EtOAc and extracted with 1 M HCl, sat. NaHCO3solution and brine. The organic phase is separated, dried over Na2SO4 and concentrated to afford the intermediate A3. 01-3596-WO-1 37 Analysis (method B): Rt: 0.89 min, [M+H] +: 332Synthesis of intermediates B1 – B55 Synthesis of (1R)-1-phenyl-2-[4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-2H-indazol-2-yl] ethan-1-ol (B1) 1R)-2-(4-Bromo-2H-indazol-2-yl)-1-phenylethan-1-ol (A1) (10 g, 31.5 mmol) is dissolved in dioxane (200 mL). Bis(pinacolato)diboron (9.61 g, 37.8 mmol), potassium acetate (8.03 g, 82 mmol) and10Pd(dppf)Cl2 x DCM (2.00 g, 2.45 mmol) are added at RT, and the reaction mixture is stirred at 80 °C overnight. After the reaction mixture is cooled to RT the formed precipitate is filtered and washed with 3 x 20 mL dioxane. The filtrate is concentrated, and the residue is suspended and triturated in CycH overnight. The precipitate is filtered, washed with 2 x 20 mL CycH and dried in an oven at 50 °C overnight to afford the desired intermediate B1.15 Analysis (method B): Rt: 1.12 min, [M+H] +: 365The intermediates compiled in the following table are obtained by following a reaction sequence analogous to that described for intermediate B1. 01-3596-WO-1 38 Synthesis of (1R)-2-[4-(5, 5-dimethyl-1, 3, 2-dioxaborinan-2-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol (B2) and {2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl} boronic acid (B2) 5 (1R)-2-(4-Bromo-2H-indazol-2-yl)-1-phenylethan-1-ol (A1) (7.50 g, 23.7 mmol) is dissolved in dioxane (60 mL). Bis (neopentyl glycolato) diboron (8.01 g, 35.5 mmol) and potassium acetate (7.00 g, 71.3 mmol) are added, and the mixture is purged with nitrogen. Pd(dppf)Cl2x DCM (0.71 g, 0.87 mmol) is added, and the reaction mixture is stirred at 85 °C for 4.5 h. After the reaction mixture is cooled to RT, it is filtered through Celite and Thiol-Resin, and the filtrate is concentrated. The residue is diluted with 10 DCM, and the organic phase is washed 2 x with water and with brine. The organic layer is dried (Na2SO4), filtered and evaporated. The residue is triturated with diethyl ether and the formed precipitate is filtered and dried in an oven at 50 °C overnight to afford intermediate B6.Analysis (method B): Rt: 0.77 min, [M+H] +: 351The filtrate is concentrated, and the residue is purified by reversed phase chromatography (HPLC;15 Sunfire, ACN / water including TFA) to afford intermediate B2.Analysis (method B): Rt: 0.66 min, [M+H] +: 283Synthesis of intermediate B5: 01-3596-WO-1 39 Step 1: Synthesis of [2-(3-oxocyclobutyl)-2H-indazol-4-yl]boronic acid (1H-Indazol-4-yl)boronic acid (3.4 g, 20.9 mmol), 3-bromocyclobutan-1-one (4.69 g, 31.4 mmol) andaluminum powder (1.13 g, 41.9 mmol; -100+325 mesh) is dissolved in DMF / water 3 / 1 (120 mL). The 5 reaction mixture is stirred at 70 °C for 6 h. The aluminum is filtered off and washed with DMF. The filtrate is concentrated. The residue is purified by preparative HPLC (ACN / water / TFA) to afford the intermediate B5. Analysis (method D): Rt: 0.44 min, [M+H] +: 231 10 Synthesis of intermediates C1-C5 Synthesis of intermediate C1 Step 1: Synthesis of 5-cyclopropyl-1-methyl-1H-imidazole 15 Under an argon atmosphere, 5-bromo-1-methyl-1H-imidazole (7.50 g, 46.6 mmol), cyclopropylzinc bromide (132 mL, 65.90 mmol, 0.5 M in THF) and Pd(dppf)Cl2 (2.20 g, 3.01 mmol) are mixed, and the reaction mixture is stirred at 70 °C for 20 h. The reaction mixture is concentrated, and the residue is purified by flash chromatography (DCM / MeOH 100 / 0 à DCM / MeOH 90 / 10) to afford the desiredproduct.20 Analysis (method E): Rt: 0.31 min, [M+H] +: 123o-5-cyclopropyl-1-methyl-1H-imidazole (intermediate C1) 5-Cyclopropyl-1-methyl-1H-imidazole (9.20 g, 52.7 mmol) is dissolved in ACN (200 mL). At -5 °C NBS 25 (18.8 g, 105 mmol) is added in portions and the reaction mixture is stirred at -5 °C for 30 min and at RT for 4 h. The reaction mixture is quenched at 0 °C with an aq. saturated solution of Na2S2O3. The 01-3596-WO-1 40 formed precipitate is filtered and washed with ACN. The filtrate is extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is purified by flash chromatography (CycH / EtOAc 95 / 5 à CycH / EtOAc 65 / 35) to afford intermediate C1. Analysis (method D): Rt: 0.77 min, [M+H] +: 2795 Synthesis of intermediate C2 Synthesis of 3-amino-1-methyl-1H-pyrazole-4-carbaldehyde 10 DIBALH in hexane 1M (515 mL, 0.52 mol) is added slowly to a suspension of 3-amino-1-methyl-1H- pyrazole-4-carbonitrile (21.6 g, 0.18 mol) in toluene (432 mL) at -78 °C under argon. After addition the solution is stirred for 20 min and then warmed to RT. The reaction mixture is slowly poured at 0 °C into 4 M HCl aq. (177 mL, 0.71 mol) and stirred for 1 h. The pH is adjusted with potassium carbonate to pH ~9, and the mixture is extracted with IPA / DCM15 25 / 75 (1750 mL) and concentrated to yield intermediate C2. 1H-NMR (DMSO-d6, 300 MHz): d = 9.61 (1H, s), 8.03 (1H, s), 5.66 (2H, s, br), 3.64 (3H, s) Synthesis of intermediate C3: Step 1: Synthesis of 5-cyclopropyl-1-methyl-1H-imidazole 20 Under an argon atmosphere, 5-bromo-1-methyl-1H-imidazole (7.50 g, 46.6 mmol), cyclopropylzinc bromide (132 mL, 65.90 mmol, 0.5 M in THF) and Pd(dppf)Cl2(2.20 g, 3.01 mmol) are mixed together, and the reaction mixture is stirred at 70 °C for 20 h. The reaction mixture is concentrated, and the residue is purified by flash chromatography (DCM / MeOH 100 / 0 à DCM / MeOH25 90 / 10) to afford the desired product. Analysis (method E): Rt: 0.31 min, [M+H] +: 123Step 2: Synthesis of 5-cyclopropyl-1, 2-dimethyl-1H-imidazole 01-3596-WO-1 41 Under an argon atmosphere, 5-cyclopropyl-1-methyl-1H-imidazole (1.00 g, 8.12 mmol) is dissolved in THF (15.00 mL) and cooled to -78°C. n-BuLi (6.14 mL, 9.81 mmol, 1.6 M) is added dropwise and the reaction mixture is stirred at -78°C for 30 min. Then MeI (663 µL, 10.6 mmol) is added dropwise and 5 the reaction mixture is stirred at -78°C for 1 h. The reaction mixture is quenched with a half saturated NH4Cl solution and stirred for 10 min.2 mL of aqueous NH4OH (25 %) is added and the mixture is stirred for 30 min. The layers are separated, and the aqueous layer is extracted 3x with EtOAc. The combined organic layers are dried (Na2SO4), filtered and evaporated to afford the desired compound. Analysis (method G): Rt: 0.72 min, [M+H] +: 13710 Step 3: Synthesis of methyl 2-[(tert-butyldimethylsilyl)oxy]acetate Methyl 2-hydroxyacetate (3.00 mL, 39.3 mmol) is dissolved in THF (30 mL). At 0 °C 2,6-lutidine (13.0 mL, 112 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (23.2 mL, 100 mmol) are added15 dropwise, and the reaction mixture is stirred at 0 °C for 1h and at RT for 1 h. The reaction mixture isdiluted with DCM and washed 2x with 1 M HCl and 1x with an aqueous saturated solution of NaHCO3. The organic layer is dried, filtered, and concentrated. The residue is purified by flash chromatography (CycH / EtOAc 95 / 5 à CycH / EtOAc 80 / 20) to afford the desired compound.Analysis (TLC silica CycH / EtOAc 9 / 1): Rf: 0.54 20 Step 4: Synthesis of 1-[(tert-butyldimethylsilyl)oxy]-3-(5-cyclopropyl-1-methyl-1H-imidazol-2- yl)propan-2-one (intermediate C3) 5-Cyclopropyl-1, 2-dimethyl-1H-imidazole (3.18 g, 23.3 mmol) is dissolved in THF (45 mL). At - 75 °C n-25 BuLi (17.5 mL, 28.0 mmol, 1.6 M) is added dropwise and the reaction mixture is stirred at - 75 °C for 15min. Then methyl 2-[(tert-butyldimethylsilyl)oxy]acetate (6.19 g, 30.3 mmol) dissolved in THF (30 mL) is added dropwise, and the reaction mixture is stirred at - 75 °C for 1 h. The reaction mixture is 01-3596-WO-1 42 quenched with a half saturated NH4Cl solution and extracted 2x EtOAc. The combined organic layers are dried (Na2SO4), filtered and concentrated to afford the desired intermediate C3. Analysis (method B): Rt: 0.78 min, [M+H] +: 3095 Synthesis of intermediate C4: Synthesis of 1-(5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-3-methylbutan-2-one (intermediate C4) 5-Cyclopropyl-1,2-dimethyl-1H-imidazole (730 mg, 5.36 mmol) is dissolved in THF (30 mL). At - 75 °C n-BuLi (5.03 mL, 8.04 mmol, 1.6 M) is added dropwise and the reaction mixture is stirred at - 75 °C for 5010 min. Then methyl 2-methylpropanoate (1.01 mL, 8.04 mmol) is added dropwise, and the reaction mixture is stirred at - 75 °C for 15 min. The reaction mixture is quenched with 10% NH4Cl solution andextracted with EtOAc. The combined organic layers are concentrated to afford the desired intermediate C4. Analysis (method A): Rt: 0.31 min, [M+H] +: 20715 Synthesis of intermediate C5: Step 1: Synthesis of ethyl 3-amino-1-[(4-methoxyphenyl) methyl]-1H-pyrazole-4-carboxylate Asolution of NaOEt is prepared (using 4.08 g Na (177 mmol) and 100 mL of EtOH) to which [(4-20 methoxyphenyl) methyl] hydrazine hydrochloride (11.2 g, 59 mmol) is added. Then a solution of ethyl (2Z)-2-cyano-3-ethoxyprop-2-enoate (10 g, 59 mmol) in THF (50 mL) is added dropwise over 45 min at 0 °C under Argon. The reaction mixture is stirred at 0 °C for 90 min. The reaction mixture is quenched with 4 M HCl in dioxane (29.6 mL, 118 mmol) and concentrated to dryness. Then the residue is dissolved in EtOAc and washed with a sat. NaHCO3 solution. The aqueous layer is extracted with EtOAc. The25 combined organic layers are dried (Na2SO4), filtered and concentrated to afford the title product. Analysis (method S): Rt: 1.55 min, [M-H] --: 274 Step 2: Synthesis of {3-amino-1-[(4-methoxyphenyl) methyl]-1H-pyrazol-4-yl} methanol 01-3596-WO-1 43 Ethyl 3-amino-1-[(4-methoxyphenyl) methyl]-1H-pyrazole-4-carboxylate (16.3 g, 56.3 mmol, 95 % purity) is dissolved in THF (81.5 mL), and at -7 °C LiAlH4 (2 M in THF, 28.1 mL, 56.3 mmol) is added dropwise over 30 min. The reaction mixture is stirred at RT for 3 h. The reaction mixture is quenched 5 with 2 V of THF / H2O 8 / 2 and 1 V of aq. sat. Na2SO4solution and stirred 30 min at RT. The reaction mixture is filtered through Celite and washed with MeOH and DCM / MeOH. The filtrate is dried (Na2SO4), filtered, concentrated and co-evaporated with toluene to afford the title product. Analysis (method S): Rt: 1.34 min, [M+H] +: 23410 Step 3: Synthesis of 3-amino-1-[(4-methoxyphenyl) methyl]-1H-pyrazole-4-carbaldehyde {3-Amino-1-[(4-methoxyphenyl) methyl]-1H-pyrazol-4-yl} methanol (13.1 g, 50.5 mmol, 90 % purity) is dissolved in ACN (131 mL) and water (26.2 mL), then MnO2 (34.2 g, 354 mmol) is added, and the reaction mixture is stirred at RT for 2h. The reaction mixture is filtered through Celite and washed with 15 DCM / acetone. The filtrate is concentrated to dryness and the residue is triturated with MTBE to afford the intermediate C5. TLC: silica gel, DCM / MeOH 95 / 5: Rf: 0.55 Analysis (method S): Rt: 1.55 min 20 Synthesis of intermediates D1-D8 Synthesis of intermediate D1 Step 1: Synthesis of 6-bromo-2-methyl-7-(propan-2-yl)imidazo[1,2-a]pyrimidine25 01-3596-WO-1 44 5-Bromo-4-(propan-2-yl)pyrimidin-2-amine (1.00 g, 4.39 mmol) is dissolved in ethanol (10 mL) and 1- bromo-2,2-dimethoxypropane (2.45 mL, 17.5 mmol) is added and the reaction mixture is stirred at 80 °C 7.5 h. The reaction mixture is concentrated, with water diluted and with sat. NaHCO3 solution neutralized. After 30 min of stirring the precipitation is filtered to obtain the title compound. 5Analysis (method Q): Rt: 0.61 min, [M+H] +: 254Synthesis of 2-methyl-7-(propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyrimidine 10 6-Bromo-2-methyl-7-(propan-2-yl)imidazo[1,2-a]pyrimidine (400 mg, 1.57 mmol) and 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (611 mg, 2.36 mmol) are dissolved in ACN (6 mL). Potassium pivalate (275 mg, 1.96 mmol) is added and the mixture is purged with argon. PdCl2(PPh3)2 (56.4 mg, 0.0787 mmol) is added, and the reaction mixture is stirred at 80 °C for 4 h. After the reaction mixture is cooled to RT, it is extracted with EtOAc. The organic 15 phase is dried with MgSO4, filtered and concentrated. The residue is purified by preparative HPLC (ACN / water / NH3) to afford the desired product. Analysis (method Q): Rt: 0.53 min, [M+H] +: 302Step 3: 20 4-Bromo-5-cyclopropyl-1-methyl-2-[2-methyl-7-(propan-2-yl)imidazo[1,2-a]pyrimidin-6-yl]-1H- imidazole 2,4-Dibromo-5-cyclopropyl-1-methyl-1H-imidazole (C1) (83.6 mg, 0.299 mmol) and 2-methyl-7- (propan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyrimidine (75.0 mg, 0.24925 mmol) are dissolved in dioxane (4 mL). Addition of an aq. solution of Na2CO3 (2 M, 418 µL, 0.836mmol) and Pd(dppf)Cl2x DCM (20.3 mg, 0.0249 mmol) to the reaction mixture. The reaction mixture is 01-3596-WO-1 45 stirred at 80 °C for 2 h. After the reaction mixture is cooled to RT, diluted with water and extracted with EtOAc. The organic phase is dried over MgSO4, filtered, and concentrated to afford intermediate D1. Analysis (method Q): Rt: 0.76 min 5 Synthesis of intermediate D2 and D3: Synthesis of 2-(6-{[(tert-butyldimethylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5-cyclopropyl-1-methyl-1H-imidazole 10 1-[(Tert-butyldimethylsilyl)oxy]-3-(5-cyclopropyl-1-methyl-1H-imidazol-2-yl)propan-2-one (C3) (7.85 g, 20.4 mmol), 3-amino-1-methyl-1h-pyrazole-4-carbaldehyde (C2) (2.55 g, 20.4 mmol), piperidine (5.04 mL, 50.9 mmol) are dissolved in EtOH (50 mL) and stirred at 100 °C overnight. The reaction mixture is concentrated and purified by flash chromatography (DCM / MeOH 100 / 0 à DCM / MeOH 85 / 15) to15 afford the desired compound. Analysis (method G): Rt: 1.07 min, [M+H] +: 398Step 2: Synthesis of 4-bromo-2-(6-{[(tert-butyldimethylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5-cyclopropyl-1-methyl-1H-imidazole 20 2-(6-{[(Tert-butyldimethylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5-cyclopropyl-1- methyl-1H-imidazole (6.35 g, 12.8 mmol, 80 % purity) is dissolved in DCM (100 mL). NBS (2.40 g, 13.5mmol) is added at 0 °C, and the reaction mixture is stirred at 0 °C for 15 min and at RT for 10 min. The 01-3596-WO-1 46 reaction mixture is quenched with a 10 % Na2S2O3 and a saturated NaHCO3 solution, the layers are separated, and the water phase is extracted three times with DCM. The combined organic layers are dried (Na2SO4), filtered, and concentrated to afford the desired compound. Analysis (method G): Rt: 1.14 min, [M+H] +: 476 / 478 (Br)5 Step 3: Synthesis of [5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl]methanol 4-Bromo-2-(6-{[(tert-butyldimethylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5- 10 cyclopropyl-1-methyl-1H-imidazole (7.90 g, 13.3 mmol, 80 % purity) is dissolved in THF (60 mL). TBAF (15.9 mL, 15.9 mmol) is added, and the reaction mixture is stirred at RT for 2 h. The reaction is quenched with water and the THF is concentrated. The aqueous residue is extracted two time with EtOAc. The combined organic layers are washed with brine, dried, filtered, and concentrated. The crude residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the15 desired compound. Analysis (method B): Rt: 0.59 min, [M+H] +: 362 / 364 (Br)Step 4: Synthesis of 5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridine-6-carbaldehyde D2 20 [5-(4-Bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-6- yl]methanol (100.0 mg, 0.276 mmol) is dissolved in DCM (3 mL). DIPEA (334 µl, 1.93 mmol) and DMSO (100 µl, 1.40 mmol) are added to the mixture. Then pyridine sulfonylideneoxidane is added to the 01-3596-WO-1 47 reaction mixture and stirred at RT for 1h. Water is added, and the precipitation is filtered to afford intermediate D2. Analysis (method A): Rt: 0.32 min, [M+H] +: 360 / 3625 Step 5: [5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-6- 5-(4-Bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridine-6- 10 carbaldehyde (500 mg, 1.38 mmol) in dissolved in THF (20 mL) under inert atmosphere. While cooling with an ice bath bromo(cyclopropyl)magnesium (5.5 mL, 2.77 mmol) is added and stirred until complete conversion. The reaction mixture is diluted with half conc. NH4Cl solution and is extracted with EtOAc. The organic phase is dried with MgSO4, filtered and concentrated. The residue is purified by HPLC (ACN / water / TFA) to afford intermediate D3.15 Analysis (method Q): Rt: 0.70 min, [M+H] +: 402Synthesis of intermediate D4: Synthesis of 5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-20 yl]-1H-imidazole 1-(5-Cyclopropyl-1-methyl-1H-imidazol-2-yl)-3-methylbutan-2-one (C4) (1.28 g, 4.97 mmol, 80 % purity), 3-amino-1-methyl-1h-pyrazole-4-carbaldehyde (C2) (684 mg, 5.47 mmol), piperidine (984 µL, 9.94 mmol) are dissolved in EtOH (11 mL) and stirred at 95 °C overnight. The reaction mixture is 01-3596-WO-1 48 concentrated and purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford thedesired compound. Analysis (method A): Rt: 0.32 min, [M+H] +: 2965 Step 2: Synthesis of 4-bromo-5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4- b]pyridin-5-yl]-1H-imidazole (intermediate D4) 5-Cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazole (2.04 g, 6.91 mmol) is dissolved in DCM (60 mL). NBS (1.23 g, 6.91 mmol) is added at 0 °C, and the 10 reaction mixture is stirred at 0 °C for 15 min and at RT for 1 h. The reaction mixture is quenched with a saturated NaHCO3 solution, the layers are separated, and the water phase is extracted three times with DCM. The combined organic layers are dried (Na2SO4), filtered, and concentrated. The residue is purified by flash chromatography (EtOAc / MeOH 100 / 0 à EtOAc / MeOH 95 / 5) to afford theintermediate D4.15 Analysis (method A): Rt: 0.44 min, [M+H] +: 374 / 376 (Br)Synthesis of intermediate D5: Step 1: Synthesis of 1-[5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H-20 pyrazolo[3,4-b]pyridin-6-yl]propan-1-ol D2 Under an atmosphere of argon, 5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H- pyrazolo[3,4-b]pyridine-6-carbaldehyde (337 mg, 0.89 mmol) is dissolved in THF (8 mL). At – 78 °C, 01-3596-WO-1 49 bromo(ethyl)magnesium (1.07 mL, 1.07 mmol) is added dropwise, and the reaction mixture is stirred at – 78 °C for 2 h and at RT. The reaction is quenched by the addition of 1 M HCl and extracted 3x withEtOAc. The combined organic layers are dried, filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the title compound.5 Analysis (method A): Rt: 0.40 min, [M+H] +: 390 / 392 (Br)Step 2: Synthesis of (1R)-1-[5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl]propan-1-ol (intermediate D5) 10 1-[5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-6- yl]propan-1-ol (1.06 g, 2.71 mmol) is separated by chiral purification method O to afford the compound (1R)-1-[5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4- b]pyridin-6-yl]propan-1-ol (intermediate D5) (Analysis (method N): Rt: 0.86 min) 15 Synthesis of intermediate D6: Synthese of 4-bromo-5-cyclopropyl-1-methyl-2-{2-[(oxetan-2-yl)methyl]-6-(propan-2-yl)-2H- pyrazolo[3,4-b]pyridin-5-yl}-1H-imidazole 20 4-Bromo-5-cyclopropyl-1-methyl-2-[6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazole (D8) (150 mg, 0.416 mmol) and 2-(bromomethyl)oxetane (86 mg, 0.541 mmol) are dissolved in ACN (2 mL). Potassium carbonate (172 mg, 1.25 mmol) is added to the reaction mixture and then stirred at 40°C 01-3596-WO-1 50 overnight an 1.5 h at 60°C. The reaction mixture is diluted with ACN and purified by reversed phase chromatography (ACN / water / TFA) to obtain intermediate D6. Analysis (method B): Rt: 0.78 min, [M+H] +: 4305 The intermediates compiled in the following table are obtained by following a reaction sequence analogous to that described for intermediate D6. 10 Synthesis of intermediate D8: Step 1 is synthesized by following a procedure analogous to that described for Intermediate D4 (step1) using intermediate C4 and C5.Analysis (method B): Rt: 0.75 min, [M+H] +: 40215 Step 2 is synthesized by following a procedure analogous to that described for Intermediate D4 (step2) to obtain 4-bromo-5-cyclopropyl-2-{2-[(4-methoxyphenyl)methyl]-6-(propan-2-yl)-2H-pyrazolo[3,4- b]pyridin-5-yl}-1-methyl-1H-imidazole. Analysis (method B): Rt: 0.90 min, [M+H] +: 480 01-3596-WO-1 51 Synthese of 4-bromo-5-cyclopropyl-1-methyl-2-[6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-5 yl]-1H-imidazole 4-Bromo-5-cyclopropyl-2-{2-[(4-methoxyphenyl)methyl]-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5- yl}-1-methyl-1H-imidazole (4.14 g, 8.61 mmol) and anisole (1.8 mL, 17.2 mmol) are dissolved in DCE (30 mL) and TFA (15 mL). The reaction mixture is stirred at 60 °C overnight. The reaction mixture is 10 concentrated and purified by reversed phase chromatography (ACN / water / TFA) to afford intermediate D8. Analysis (method B): Rt: 0.79 min, [M+H] +: 36015 Synthesis of patent examples Synthesis of example 1 Synthesis of (1R)-2-(4-{5-cyclopropyl-1-methyl-2-[2-methyl-7-(propan-2-yl)imidazo[1,2-a]pyrimidin-6- yl]-1H-imidazol-4-yl}-2H-indazol-2-yl)-1-phenylethan-1-ol 20 01-3596-WO-1 52 4-Bromo-5-cyclopropyl-1-methyl-2-[2-methyl-7-(propan-2-yl)imidazo[1,2-a]pyrimidin-6-yl]-1H- imidazole (D1) (100 mg, 0.187 mmol), (1R)-1-phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-2H-indazol-2-yl]ethan-1-ol (B1) (78.9 mg, 0.206 mmol), potassium phosphate (2 M, 280 µL, 0.561 5mmol) and Xphos PD G3 (15.8 mg, 0.0187 mmol) are dissolved in 2-methyltetrahydrofuran (3 mL). Thereaction mixture is purged with argon and stirred at 80 °C for 2 h. After the reaction mixture is cooled to RT, it is extracted with methylTHF twice. The organic phase is dried with MgSO4, filtered and concentrated. The residue is purified by preparative HPLC (ACN / water / NH3) to afford the title compound.10 Analysis (method Q): Rt: 0.76 min, [M+H] +: 532The examples compiled in the following table are obtained by following a reaction sequence analogous to that described for example 1. 01-3596-WO-1 53 01-3596-WO-1 54 Synthesis of example 2 Synthesis of (1R)-2-[4-(5-cyclopropyl-2-{6-[(R)-cyclopropyl(hydroxy)methyl]-2-methyl-2H-pyrazolo[3,4-5 b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol 01-3596-WO-1 55 example 4(1R)-2-[4-(5-Cyclopropyl-2-{6-[cyclopropyl(hydroxy)methyl]-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}- 1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol (Example 13) (30.0 mg, 0.0536 mmol) is separated by chiral purification method P to afford the compound (1R)-2-[4-(5-cyclopropyl-2-{6-[(R)- 5 cyclopropyl(hydroxy)methyl]-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H- indazol-2-yl]-1-phenylethan-1-ol (example 2) (Analysis (method P): Rt: 4.29 min)Synthesis of example 3 10 Synthesis of (1s,3s)-3-(4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4- b]pyridin-5-yl]-1H-imidazol-4-yl}-2H-indazol-2-yl)-1-phenylcyclobutan-1-ol Step1: Synthesis of 3-(4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-15 1H-imidazol-4-yl}-2H-indazol-2-yl)cyclobutan-1-one 4-Bromo-5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H- imidazole (D4) (200 mg, 0.534 mmol), [2-(3-oxocyclobutyl)-2H-indazol-4-yl]boronic acid (B5) (147 mg, 0.641 mmol), potassium phosphate (2 M, 801 µL, 1.60 mmol) and Xphos PD G3 (81.4 mg, 0.096120 mmol) are dissolved in dioxane (6 mL). The reaction mixture is purged with argon and stirred at 90 °Covernight. After the reaction mixture is cooled to RT, it is extracted with DCM twice. The organic phase is dried, filtered, and concentrated. The residue is purified by preparative HPLC (ACN / water / TFA) to afford the desired product. 01-3596-WO-1 56 Analysis (method D): Rt: 0.57 min, [M+H] +: 480Step 2: 5 3-(4-{5-Cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazol- 4-yl}-2H-indazol-2-yl)cyclobutan-1-one (90 mg, 0.187 mmol) in dissolved in THF (5 mL) under inert atmosphere. While cooling with an ice bath bromo(phenyl)magnesium (281 µL, 0.281 mmol) is added. The reaction mixture is stirred for 2 h while warming to RT. The reaction mixture is diluted with half conc. NH4Cl solution and is extracted with DCM. The organic phase is dried, filtered, and concentrated.10 The residue is purified by HPLC (ACN / water / NH3) to afford example 3.Analysis (method D): Rt: 0.67 min, [M+H] +: 558Synthesis of intermediate E1 and example 8 and 9 15 Synthesis of 4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]- 1H-imidazol-4-yl}-2-(3,4-dihydro-1H-2-benzopyran-3-yl)-1H-1,3-benzodiazole Step 1: Synthesis of 3-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazol-4-yl}-2-nitroaniline 20 01-3596-WO-1 57 Under an argon atmosphere, 4-bromo-5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H- pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazole (D4) (374 mg, 1.00 mmol) and 2-nitro-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (630 mg, 2.29 mmol) are dissolved in dioxane (20 mL). K3PO42 M (2.5 mL, 5.00 mmol) and XPhos Pd G3 (42.3 mg, 0.05 mmol) are added, and the reaction 5 mixture is stirred at 100 °C overnight. The reaction mixture is filtered and washed with dioxane (10 mL). The filtrate is concentrated and purified by reversed phase chromatography (HPLC; ACN / water including NH3) to afford the desired compound. Analysis (method B): Rt: 0.79 min, [M+H] +: 43210 Step 2: Synthesis of 3-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazol-4-yl}benzene-1,2-diamine (intermediate E1) 3-{5-Cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazol-4- yl}-2-nitroaniline (341 mg, 0.79 mmol) is dissolved in MeOH (20 mL). Pd / C 10 % (100 mg) is added, and 15 the reaction mixture is hydrogenated at RT and 50 psi (344.738 kPa) for 2 h. The reaction mixture is filtered, and the filtrate is concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water including NH3) to afford the intermediate E1. Analysis (method G): Rt: 0.89 min, [M+H] +: 40220 3-{5-Cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazol-4- yl}benzene-1,2-diamine (E1) (35.0 mg, 0.0871 mmol) and 3,4-dihydro-1H-2-benzopyran-3-carboxylic 01-3596-WO-1 58 acid (16.0 mg, 0.0871 mmol) are dissolved in DMF (2 mL). HATU (33.1 mg, 0.0871 mmol) and DIPEA (45 µl, 0.261 mmol) are added to the reaction mixture. The reaction mixture is stirred at RT for 2 h. The mixture is concentrated. The residue is diluted in acetic acid (1 mL) and is stirred at 85°C for 2 h. The reaction mixture is concentrated, and the residue 5 is purified by HPLC to afford example 8. Analysis (method T): Rt: 0.62 min, [M+H] +: 544The examples compiled in the following table are obtained by following a reaction sequence analogous to that described for example 8. 10 HPLC Methods: Where indicated, a back pressure of 14996.097 kPa (2175.0 psi) is applied.Method A (X012_S01) 01-3596-WO-1 59 Method B (Z018_S04) 5 Method D (X018_S03) Method E (X011_S05) 01-3596-WO-1 60 Method G (Z011_S03) 5 Method K (007_CA11) Method L (X015_S04) 01-3596-WO-1 61 Method N (I_AC_30_Meoh_NH3_002) 5 Method P (I_SB_25_MEOH_NH3_003) Method Q (Z017_S04) 10 Method S (SLV-Method-36) 01-3596-WO-1 62 column: Acquity UPLC BEH C181.7 µm (2.1 x 100 mm); column temperature: 40 °CMethod T (007_CA02) 5 Method V (008_CA11) Method W (007_CA10) 10 01-3596-WO-1 63 List of Abbreviations: Ac acetylACN acetonitrile5 AIBN 2,2´-azobis(isobutyronitrile)Burgess (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanideBoc tert-butyloxycarbonylCbz benzyloxycarbonylCycH cyclohexane10 d day(s)DAST diethylamino sulfur trifluorideDCE 1,2-dichloroethaneDCM dichloromethaneDEAD diethyl azodicarboxylate15 DIAD diisopropyl azodicarboxylateDIPEA N,N-diisopropylethylamineDMF N,N-dimethylformamideDMP Dess–Martin PeriodinaneDMSO dimethyl sulfoxide20 EtOAc ethyl acetateEtOH ethanolh hour(s)HATU O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium-hexafluorophosphate 25 HPLC high performance liquid chromatography HPLC-MS coupled high performance liquid chromatography-mass spectrometryIPA isopropyl alcoholLC liquid chromatographyLC-MS coupled liquid chromatography – mass spectrometry30 LiHMDS Lithium-bis(trimethylsilyl)amideM molar (mol / L)MeI methyl iodideMeTHF 2-methyltetrahydrofuranMeOH methanol35 min minute(s) 01-3596-WO-1 64 MS mass spectrometryMTBE methyl-tertbutyl-ether n-BuLi n-ButhyllithiumNBS N-Bromosuccinimide5 NIS N-IodosuccinimideNMP N-methyl-2-pyrrolidoneNMR nuclear magnetic resonancePEPPSI(TM)-IPR (1,3-Bis(2,6-diisopropylphenyl)imidazolidene) (3-chloropyridyl)palladium(II) dichloride10 PdCl2(dtbpf) 1,1ʹ-Bis-(di-tert-butylphosphino-)ferrocene-palladiumdichloridePd(dppf)Cl21,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) Pd(PPh3)4 palladium (0) tetrakis(triphenylphosphine)XPhos Pd G3 2-Dicyclohexylphosphino-2ʹ,4ʹ,6ʹ-triisopropyl-1,1ʹ-biphenyl)[2-(2ʹ- amino-1,1ʹ- biphenyl)]palladium(II) methanesulfonat15 pet. petroleumRf retention factor RP reverse phasert room temperaturetRretention time (in HPLC / LC)20 SFC supercritical fluid chromatographyTBAF tetrabutylammonium fluorideTBTU O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborateTEA triethylamineTFA trifluoroacetic acid25 THF tetrahydrofuranTHP tetrahydro-2h-pyranTLC thin-layer chromatographyTMAD N,N,NʹNʹ-TetramethylazodicarboxamideUV ultraviolet30 V volumeBIOLOGICAL ASSAYS and DATA 01-3596-WO-1 65 The activity of the compounds of the invention may be demonstrated using the following in vitro STING biochemical and cell assays. Human STING HTRF binding assay 5 Binders to human STING WT (R232) were identified using a competitive HTRF assay format (Cisbio 64BDSTGPEG), which uses d2-labeled STING ligand, a 6His tagged human STING protein, and an anti 6His Cryptate-labeled antibody. Compounds compete with the STING ligand-d2 and thereby prevents FRET from occurring, which can be measured by an EnVision™ reader (PerkinElmer).10 Assay method: Compounds were delivered as 10mM DMSO solution, serially diluted by an Agilent Bravo Workstation and transferred to the 384well assay plate (Perkin Elmer # 6005359) using a Cybiwell dispenser. Typically, 8 concentrations were used with the highest concentration at 10µM or 1µM in the final assay volume followed by ~1:5 dilution steps. DMSO concentration was set to 1% in 15 the final assay volume. The 384well assay plate contained 20 test compounds and DMSO in column 23 and 24. A cGAMP standard dilution row was prepared according to the manufacturer and transferred to each assay plate. After transfer of compound solution or dilution buffer for negative (high) and positive (low) controls, 5µl of the human STING protein (cyclic binding domain (residues 138-379) of the WT R232 human version, fused to a 6 His tag at the Nter part; 1:50 dilution in detection buffer) 20 were dispensed to all wells except of the positive control, which received detection buffer only. Plates were the centrifuged for 20 sec at 1000rpm. After that, 10µl of Anti-6His-Cryptate antibody / Sting ligand-d2 mix was added to all wells using a Multidrop combi dispenser, followed by another 20sec / 1000rpm centrifugation step. After an incubation of the plates for 180 min at room temperature, excitation at 665 / 620 nM (HTRF ratio) was measured using an Envison Reader 25 (PerkinElmer) Data evaluation and calculation: For data evaluation and calculation, HTRF ratios were calibrated using the cGAMP standard curve. After that, the measurement of the low control was set as 0 % control and the measurement of the high control was set as 100% control. The IC50 values were30 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 = slope; The results of this assay are shown in the characterising data table below. 01-3596-WO-1 66 Determination of the increase of stability of STING protein against thermal denaturation, Differential Scanning Fluorimetry (DSF) 5 The binding affinity of the compounds of the invention may be demonstrated using a thermal shift assay that measures the stability of a suitable protein material of human STING against thermal denaturation in the presence of compounds. In this assay, the unfolding temperature of a protein is monitored in the presence of a fluorescent dye which exhibits affinity for the hydrophobic amino acids of the protein that are buried in its folded state and are gradually exposed during unfolding. Dye 10 fluorescence is quenched in aqueous environment and increases upon association of the dye with the hydrophobic parts of the unfolding protein. A plot of the fluorescence intensity as a function of temperature typically displays a sigmoidal curve that is interpreted by a two-state model of protein unfolding (Differential Scanning Fluorimetry). The inflection point of the curve represents the “melting” temperature of the protein (Tm) which is calculated numerically using the Boltzmann15 equation. Method: The thermal stability of the STING protein was measured using a specific expression construct of the cGAMP binding domain of wild-type (GRR) human STING comprising residues 155-341 and a N-terminal 8x His-tag in assay buffer containing 20mM Tris, 150mM NaCl at pH7.5. 20 The assay uses Hard-Shell®PCR Plates 384-Well CLR / WHT (Catalog# HSP3805, BIO-RAD), Microseal®’B’ Adhesive Seals for PCR Plates (Catalog# MSB-1001, BIO-RAD) and was run on a CFX384 Real-Time System (Bio-Rad). 25 A DMSO stock solution of SYPRO orange (SIGMA S5692-500UL) was prepared. Compound stock solutions (10mM in DMSO) were diluted 1:2 in DMSO to an intermediate compound concentration of 5mM and then further diluted 1:40 in assay buffer resulting in a compound concentration of 125µM and 2.5% DMSO. 30 Fluorescent dye stock solution (5000x SYPRO Orange) was then mixed with target protein and buffer to a concentration of 15uM Protein and 25x SYPRO Orange.2ul of this protein-dye-mixture was added to 8ul compound solution. Final volume was 10uL.3-6 well positions were used as negative control (protein with 2% DMSO). The plates were prepared for duplicate measurement and centrifuged for 2 01-3596-WO-1 67 min at 1000g. In the measurement, 160 cycles of 0.5 °C were used (temperature ramp 15s / cycle, 15 °C to 95 °C). Final Assay concentrations for compound characterization were as follows: 5 100uM compound, 3uM target protein, 5x SYPRO Orange, 2% DMSO in 10ul. All dispensing steps were performed using a HamiltonStar pipetting robot (Hamilton). Dissociation curves were processed in Bio-Rad CFX Manager. Peak type was set to "negative". Compound codes for screen were assigned in the plate layout. 10 Two replicates of TM measurements were averaged, and the standard deviation was calculated. In cases of SD>1.5 °C the measurement was repeated. The melting point (Tm) obtained for STING protein alone was subtracted from T obtained for proteinincubated with ligand to generate ∆Tm values. 15 Protein production and purification: The protein used for the biophysical experiments was a recombinant human STING protein comprising its cytosolic ectodomain. A codon optimized DNA sequence (for expression in Escherichia coli) encoding amino acid residues 155 to 341 (Swiss Prot Q86WV6) of human STING (WT) was synthesized by GeneArt (Regensburg, Germany) and inserted intoa pET17b E. coli expression vector. The protein construct encodes an N-terminal 8x His-tag followed by 20 tobacco etch virus protease (TEV) cleavage site and the above STING gene sequence. The resulting protein sequence for the used STING variant is listed below: His-TEV—hSTING (WT) (SEQ ID NO: 1)25 MHHHHHHHHENLYFQSGVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSM ADPNIRFLDKLPQQTGDRAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFC RTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEV For expression of recombinant human STING above construct was transformed into E. coli BL21 DE3 30 strain and grown in shake flasks in LB-medium at 37°C. Expression was induced by addition of isopropyl β-D-1-thiogalactopyranoside to a final concentration of 1mM and cultures shaken overnight. Cell pellets were centrifuged and stored at -70°C until further use. Protein was purified by cell thawing in lysis buffer (20mM TRIS-HCl, pH 8, 300mM NaCl, 2mM mercaptoethanol, 20mM imidazole, Complete Protease Inhibitor (Roche) and DNase (Roche)),35 followed by metal affinity purification using Ni-NTA resins and elution buffer consisting of 20mM TRIS- 01-3596-WO-1 68 HCl, pH 8, 300mM NaCl, 2mM mercaptoethanol, 300mM imidazole and size exclusion chromatography in running buffer (20mM TRIS-HCl, pH 8, 100mM NaCl, 2mM DTT). The peak fraction was collected and concentrated to 2.5mg / mL. 5 The results of this assay are shown in the characterising data table below. Human whole blood assay (HWBA) 10 For the detection of STING inhibition in physiological environment human whole blood was stimulated by the cyclic dinucleotide cGAMP. Pathway activity was monitored by measuring the IFNα2α production. Assay method: Compounds were delivered as 10mM DMSO solution and serial diluted and transferred15 to the 96-well Cell culture Plate (Corning #3595), prefilled with 20µl OptiMEM (Gibco #11058-021) in each well, using an Echo acoustic dispenser. Typically, 8 concentrations were used with the highest concentration at 10µM in the final assay volume followed by ~1:5 dilution steps. DMSO concentration was set to 0.1% in the final assay volume. The 96well assay plate contained 9 test compounds, a reference compound and DMSO in control wells. 20 Collection of human whole blood from 3 or more healthy donors (male or female, no medication for 7 days, exception contraceptive and thyroxine) as Na-citrate blood (e.g.3.8% in Monovettes from Sarstedt) is conducted in parallel. Whole blood was kept at room temperature for a maximum of 3 hours after collection until use in the assay. 25 160µl of the whole blood samples were transferred to each well of the 96-well assay plates filled with compound / OptiMEM. All assay plates are prepared as duplicates with blood from different donors. Blood plates were kept at room temperature for 60minutes and continuous shaking with 450rpm, covered with the lid, but not sealed. 30 A 10x cGAMP assay solution was diluted from a 2mM stock solution in 1xHBSS immediately before use at room temperature.20µl of the 10x cGAMP / HBSS were added to all compound and all high control wells, whereas HBSS only was added to all low control wells. After covering assay plates with aera seals and the lid, blood plates were kept at room temperature for 30minutes and continuous shaking with 450rpm, followed by an overnight incubation of 22h at35 37°C in the incubator, without shaking. 01-3596-WO-1 69 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. U-Plex MSD GOLD 96- 5 well Small Spot Streptavidin SECTOR Plates (Meso Scale Diagnostics # L45SA-5) were coated with 25µl diluted capture antibody. Coated plates were incubated for 60min at room temperature under continuous shaking at 700rpm. MSD IFNα-2α plates were washed three times with 150µl wash buffer (1x HBSS, 0.05% Tween). 10 After blocking the plates with 100µl block solution / well (1x HBSS with 0.2% Tween, 2% BSA) for 60min at room temperature and continuous shaking at 700rpm, plates were emptied as dry as possible by dumping just before continuing with the human plasma. Whole Blood assay plates were centrifuged at1600rpm for 10 minutes.25µl of supernatant was transferred with a pipetting robotics from each whole blood plate to the corresponding IFNα-2α plate. Plates were sealed with microplate seals and15 kept at room temperature again under continuous shaking at 700rpm for two hours. Next MSD IFNα- 2α plates were washed three times with 150µl 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 under continuous shaking at 700rpm for two hours. Finally MSD IFNα-2α 20 plates were washed three times with 150µl wash buffer (1x HBSS, 0.05% Tween).150µl 2x Read buffer was added to each well and plates 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 25 well was based on the mean of high (cGAMP 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 = slope; 30 The results of this assay are shown in the characterising data table below. Human STING reportergene assay 35 01-3596-WO-1 70 A THP1-BlueISG reporter cell line expressing wildtype STING and IRF dependent alkaline phosphatase reporter was used for the potency measurement of activators of human wildtype STING. Assay Method: Compounds were delivered 10mM DMSO solution and serially diluted in assay 5 medium (RPMI 1640 (Life Technologies #A10491-01), 10% FCS (Life Technologies #10500-064), 1x Pen / Strep solution (Life Technologies #15140-122). Typically, 8 concentrations were used with the highest concentration at 10 or 100 µM in the final assay volume followed by ~1:5 dilution steps. DMSO concentration was set to 1% in the final assay volume. The 384well assay plate contained 21 test compounds (column 1-21), a reference compound (column 22) and DMSO in column 23 and 24; 10 Cells, cultivated according to manufacturer’s conditions (culture medium: RPMI 1640 (Life Technologies #A10491-01), 10% FCS (Life Technologies #10500-064), 1x Pen / Strep solution (Life Technologies #15140-122), 100µg / mL Normocin (Life Technologies # ant-nr-1), 100µg / mL Zeocin (Life Technologies # R25001) were harvested, resuspended and diluted in fresh assay medium. The cells 15 were then seeded in 15µl assay media to the assay plates (10000 cells / well), followed by addition of 5µl prediluted compound solution to wells of the assay plates. Afterwards 5ul per well of assay medium was added to the wells containing compounds, followed by a 30 min incubation at RT and a 24h incubation at 37°C. Then 5ul per well of assay medium with DMSO (1% f.c.) was added to the wells for the controls, plus 5 µl of assay medium alone for negative controls (low values) or 5µl of prediluted 20 2`3`-cGAMP (20µM f.c.; BIOLOG Life Science Institute # C 161 or Invivogen # tlrl-nacga23) for positive controls (high values). Finally 75µl of Quanti Blue reagent was added to the plates using a MultiDrop Combi, followed by 30min incubation at 37°C. The absorbance was measured on the EnVision™ reader (PerkinElmer).25 Data evaluation and calculation: For data evaluation and calculation, the measurement of the low control was set as 100 % control and the measurement of the high control was set as 200% control. The EC50 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 = slope; 30 The results of this assay are negative for agonism, wherein the threshold was set larger than 30 µM. Characterising Data Table 01-3596-WO-1 71 As shown by the characterizing data, the inventive compounds can inhibit STING and by doing so are advantageous in the prevention, delaying and / or treatment of diseases or conditions which can be influenced by STING inhibition, for example but not limited to those disclosed herein above. 5 In a preferred embodiment, the inventive compounds have in a competitive HTRF assay format (Cisbio 64BDSTGPEG) an IC50 value of at least and including 0.3nM and not more than 250nM, preferably notmore than 150nM, more preferably not more than 125nM and even more preferably not more than70nM. In another preferred embodiment, said IC 50 value is at least and including 0.8nM or at least and including 2nM. In another preferred embodiment said IC50 value is not more than 45nM, more10 preferably not more than 40nM. Further characterization Efflux ratio from MDCK-PGP The efflux ratio from MDCK-PGP cells is measured using standard methods according to the 15 international patent application published as WO24089006 or as in the publication by Dong et al. Pharm Res (2020) 37: 194, https: / / doi.org / 10.1007 / s11095-020-02895-9. In one embodiment the efflux ratio in MDCK-PgP cell is equal to or below 25, preferably equal to or below 15, 12, 10, more preferably equal to or below 8, 7, 6, 5 or 4.5. In a more preferred embodiment, the efflux ratio is less than 5 but higher than 0.5. 20 Efflux ratio from CACO2 cells 01-3596-WO-1 72 The efflux ratio from CACO2 cells is determined using standard methods for example as disclosed in the international patent applications published as WO15048318, WO22254371 and WO24110851, or as in the publication by Dong et al. Pharm Res (2020) 37: 194, https: / / doi.org / 10.1007 / s11095-020- 02895-9. 5 In one embodiment the CACO2 cell efflux ratio of the inventive compounds is equal to or below 12, 10, 8, 7, 6, 5, 4.5, 4,3.5, 3,2.5, 2, 1.5, 1.3. In one embodiment the efflux ratio is above 0.7. Inhibition of cytochrome P450 enzymes CYP2D6 and CYP3A4Standard assays for testing the inhibition of cytochrome P450 enzymes using typical substrates are 10 known in the art. For example, the susbtrate dextromethorphan is known to be primarily metabolized by CYP2D6 (Schadel M, Wu D, Otton SV, Kalow W, Sellers EM. Pharmacokinetics of dextromethorphan and metabolites in humans: influence of the CYP2D6 phenotype and quinidine inhibition. J Clin Psychopharmacol.1995 Aug;15(4):263-9. doi: 10.1097 / 00004714-199508000-00005. PMID: 7593709.) and inhibiting effects of new compounds on the metabolization of dextromethorphan in human liver 15 microsomes by drug-drug-interaction are commonly used (see for example experimental sections of the patent applications published as WO15073310& WO14197345 and the patent US8138188 BB). For testing the possible inhibition of the compounds of the invention, demethylation of Dextromethorphan (5 µM) by the test compound at five different concentrations or no compound (high control) is assayed at 37°C with human liver microsomes and measured with LC-MS / MS. The 20 IC50 values of the compounds are determined. The IC50 of a positive control inhibitor (quinidine) is also determined as a control. Similar assay systems using human liver microsomes for the possible inhibition of other cytochrome P450 enzymes for example CYP3A4 are known (see for example experimental sections of the patent25 applications published as WO15073310& WO14197345 and the patent US8138188 BB). For testing the possible inhibition of the compounds of the invention, hydroxylation of Midazolam (5 µM) by the test compound at five different concentrations or no compound (high control) is assayed at 37°C with human liver microsomes and measured with LC-MS / MS. The IC50 values of the compounds are determined. The IC50 of a positive control inhibitor (ketoconazole) is also determined30 as a control. CYP3A4 and / or CYP2D6 inhibition is observed for the inventive compounds with IC50 values of equal to or greater 1 µmol, preferably equal to or greater 10 µmol and more preferred equal to or greater 20 µmol and even more preferred equal to or greater 25 µmol and most preferred over 30 µmol. 35 01-3596-WO-1 73 Measuring clearance from human hepatocytes The metabolic degradation of a test compound is assayed in a human hepatocyte suspension using known methods as in the patent application. US2024327429. In one embodiment the hepatocyte clearance is lower than 25% Qh [%], preferably equal to or lower 5than 20 %, 15 %, 10 %, or more preferably at most 8 %.Plasma protein binding Plasma protein binding of a test compound is assessed with known methods, for example as known from the international patent application WO17004537 or the more recent WO25036713. The 10 equilibrium dialysis technique is used to determine the approximate in vitro fractional binding of test compounds to plasma proteins applying Dianorm Teflon dialysis cells (micro 0.2). Each dialysis cell consists of a donor and an acceptor chamber, separated by an ultrathin semipermeable membrane with a 5 kDa molecular weight cutoff. Stock solutions for each test compound are prepared in DMSOat 1 mM and serially diluted to obtain a final test concentration of 1 µM. The subsequent dialysis 15 solutions are prepared in plasma (supplemented with NaEDTA as anticoagulant), and aliquots of 200 µl test compound dialysis solution in plasma are dispensed into the donor (plasma) chambers. Aliquots of 200 µl dialysis buffer (100 mM potassium phosphate, pH 7.4, supplemented with up to 4.7 % Dextran) are dispensed into the buffer (acceptor) chamber. Incubation is carried out for 2 hours under rotation at 37°C for establishing equilibrium. 20 At the end of the dialysis period, aliquots obtained from donor and acceptor chambers, respectively, are transferred into reaction tubes and processed for HPLC-MS / MS analysis. Analyte concentrations are quantified in aliquots of samples by HPLC-MS / MS against calibration curves. Percent bound compound is calculated using the formula:25 %bound = (plasma concentration - buffer concentration / plasma concentration) x 100In one embodiment the plasma protein binding of the compounds of the invention is equal to or less than 3 %, preferably less than 2 percent and more preferably less than 1.5 %. 30 IP10 production in human dermal MicroVascular Endothelial Cells (MVEC) after double-stranded DNAstimulation Interferon gamma-induced protein 10 (IP-10) also known as C-X-C motif chemokine ligand 10 (CXCL10) is produced as one of the responses of the presence of double-stranded DNA in the cytoplasm and35 resulting STING activity. In some diseases, imbalanced STING activation can result to damage in the 01-3596-WO-1 74 endothelium, for example in SAVI patients (Liu Yet al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med.2014 Aug 7;371(6):507-518. doi: 10.1056 / NEJMoa1312625). To test the efficacy of the inventive STING inhibitors, experiments in human microvascular endothelial cells (HMVEC) are performed with one inventive compound. Dermal HMVEC are available from Lonza, US.5 They are cultured in 96 well plates according to the manufacturer’s instructions. Using typical protocols, the cells are serum starved and then treated with the compound for 1 hour. The cells are then treated with 400 ng / mL of dsDNA as a complex with Lipofectamine 3000 (from Thermo Fisher Scientific Inc., Waltham, MA, USA) and incubated for 6 hours. The supernatants are collected and assayed for IP10 production. 10 Detection of IP10 is done using the U-PLEX HUMAN IP-10 ASSAY from Meso Scale Diagnostics (1601 Research Boulevard, Rockville, Maryland 20850-3173, USA) according to manufacturer’s protocols. Results: The inventive compound shows good inhibition of IP10 production after stimulation ofHMVEC with dsDNA. This demonstrates that the inventive compounds show direct target engagement15 in MVEC cells which is not the case for some known STING inhibitors. Table Exemplary Inhibition of Human microvascular endothelial cells by the inventive compounds The rounded average of multiple experiments is shown. In a preferred embodiment, the compounds of the invention for the prevention of progression or the 20 treatment of a disease that involves undesirable STING activation in endothelial cells are those compounds, that show IC50 values of at least 0.001 nM and less than 150 nM, preferably less than 100 nM, more preferably less than 50 nM, even more preferably less than 20 nM when tested for inhibition of human dermal MVEC as described above. In another embodiment said IC 50 value of the inventive compound is in the range of and including 5nM to and including 35 nM. 25 Inhibition of STING mutants associated with SAVI by the inventive compounds Several gain of function mutants of STING have been reported to be associated with SAVI and in vitro cell tests with these mutant proteins of STING have been described (Liu Yet al. Activated STING in a 30 vascular and pulmonary syndrome. N Engl J Med.2014 Aug 7;371(6):507-518. doi: 10.1056 / NEJMoa1312625) Methods for testing STING activity in THP1 cells with the reporter gene encoding luciferase are known (see the patent publication US2020181153 and references therein). These known methods are 01-3596-WO-1 75 modified slightly: As for these gain of function mutants of STING that are associated with SAVI, no stimulation by cGAMP is needed, the assay can be performed without cGAMP or similar as astimulant. The assay relies on THP1 cells that contain an engineered “knock in” of the mutated STING gene that expresses a constitutively activated protein. The pathway activation is measured using ISG- 5 luciferase reporter gene luminescence. Compound potency is evident by its ability to inhibit the SAVI associated mutant STING proteins and consequently shut down the ISG linked luciferase reporter expression. A subset of the inventive compounds as well as two known STING inhibitors for comparison are tested using THP1 cells with the two known mutants of the STING protein N154S and V155M associated with10 SAVI. SEQ ID NO: 2 shows the wildtype and these variant positions of the STING protein. The knownSTING inhibitor SN-011 has previously been reported to inhibit these mutant versions of STING in cell assays (Z. Hong et al, STING inhibitors target the cyclic dinucleotide binding pocket, Proc. Natl. Acad. Sci. U.S.A.118 (24) e2105465118, https: / / doi.org / 10.1073 / pnas.2105465118 (2021). Used as comparative compounds are SN-011 and another known STING inhibitor H-151 (Haag, S.M., 15 Gulen , M.F., Reymond, L. et al. Targeting STING with covalent small-molecule inhibitors. Nature 559, 269–273 (2018). https: / / doi.org / 10.1038 / s41586-018-0287-8). Using materials and instruments commercially available and methods similar to the known methods, the luciferase activity in these modified THP1 cells is measured with and without the test compounds. After correction for background and controls, the IC50 values are calculated using the 4-parameter 20 logistic model for the compounds of the invention, as well as for the known STING inhibitors SN-011 and H-151 (see above for details) for comparison. As the known inhibitor of STING SN-011 had been reported to inhibit the two mutants of STING tested, the potency of the compounds of the invention in comparison to that of SN-011 is determined. The results are expressed as the ratio of the IC50 value of the compound tested, i.e. the compound of the 25 invention or the second known inhibitor H-151 to the IC 50 value determined for SN-011 in the particular assay. These are normalized to the SN-011 being set to 100% and the others expressed as apercentage number in relation thereto. Table S shows the results, based on multiple repetitions. Table S 01-3596-WO-1 76 As can be seen from the results in table S, the other known inhibitor of STING, H-151, requires only a concentration of 10.7 % of the concentration of SN-011 to achieve the same inhibition of the N154S mutant of STING, and only 6.2 % of the concentration of SN-011 for the same inhibition of the second mutant V155M of STING. However, the compound 1 of the invention required even less, only 5 between 0.3 % and 0.5 % of the concentration of SN-011 to inhibit these STING mutants, which is also superior to the known inhibitor H-151. The compound 1 of the invention are more potent in inhibiting these two SAVI associated mutants of the human STING protein. In one embodiment, the IC 50 values of the compounds of the invention to inhibit either or both of the 10 N154S and V155M mutants of the human STING protein are at least 0.01 nM, but less than 150 nM, preferably less than 120 nM and more preferably less than 50 nM and even more preferably less than 20 nM. In another embodiment, the IC50 values for the compounds of the invention and either or both of these mutants of STING are between at least and including 0.2 nM and no more than 10 nM.15 Inhibition of STING in fibroblasts As many of the above-mentioned diseases like IPF or SAVI involve fibrosis, it is interesting to check theefficacy of the compounds in fibroblast cells. In an initial test, fibroblasts from human patients suffering from SSc are stimulated with dsDNA and the response with or without the test compounds is assessed. Interestingly, the known STING inhibitors SN-011 and H-151 (for details see above), which20 had been reported to be effective in other fibroblasts, show very little inhibition in these fibroblasts. In one embodiment, the compounds of the invention have an IC 50 value in human SSc fibroblasts of at least 0.1 nM to no more than 300 nM, preferably no more than 150 nM and even more preferably no more than 100 nM and most preferably no more than 80 nM. 25 Inhibition of IP10 production in human monocyte derived dendritic cells after cGAMP stimulation Monocyte derived dendritic cells derived from a specimen of a human donor are cultivated using standard techniques. With the exception of the respective negative controls, the cells are stimulated with cGAMP (Invivogen) in the presence or absence of different concentration of the compounds of the invention. Supernatants are collected and analysed by ELISA for IP10 presence (IP10 MSD kit, 30 MesoScale Diagnostics). IC50 values of STING protein inhibition are calculated using standard methods. The IC50 values for the compounds of the invention are preferably in the range and including 0.03 nM to 6.00 nM, preferably equal to or less than 4.00 nM, and more preferably equal to or less than 3.00 nM, and even more preferably equal to or less than 2.5 nM. In yet another preferred embodiment the average IC 50 value is between and including 0.07 nM and 2.10 nM. 35 01-3596-WO-1 77 Use in treatment / method of use As has been found, the compounds of formula (I) are characterized by their range of applications inthe therapeutic field. Preferably, the compounds of the invention are used in diseases that can be5 treated by the inhibition of STING and / or whose progression can be prevented by the inhibition of STING. Particular mention should be made of those applications for which the compounds of the inventionare used on the basis of their pharmaceutical activity as STING inhibitors. While the cGAS / STING 10 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 cause production of aberrant cellular dsDNA, e.g. by nuclear or mitochondrial leakage, and thereby trigger autoinflammatory responses. Consequently, STING inhibitors have a strong therapeutic potential to beused in the treatment of diverse autoinflammatory and autoimmune diseases. 15 A STING inhibitor of the invention will block in full or in part inflammation and aberrant tissue remodeling in a cluster of autoimmune and inflammatory diseases including systemic lupus erythematosus (SLE), cutaneous lupus, systemic sclerosis, inflammatory bowel disease, sepsis, Sjogren’s syndrome, vitiligo, prurigo nodularis, idiopathic inflammatory myopathy, myositis including20 dermatomyositis, rheumatoid arthritis, as well as a cluster fibrosis diseases including NASH (nowreferred to as MASH), IPF, chronic kidney fibrosis. In one embodiment the inventive use of the novel STING inhibitors is to prevent or delay the progression of any of these diseases involving elevated STING activation from a milder to a more sever 25 stage of said disease. Non-limiting examples are the progression from compensated to decompensated liver cirrhosis or the progression of chronic kidney disease from stage 2 to 3A, or 3A to 3B or from 3B to 4. In one aspect of the invention the progression of said disease is the progression of a renal disease for example but not limited to SSC renal crisis (SRC) to end stage renal disease / kidney failure, or renal death in the patient, with the use of the STING inhibitors of the30 invention preventing or delaying said progression. A STING inhibitor also has applications to additional diseases such as cancer, decompensated liver cirrhosis, heart failure, AMD, retinopathy, glaucoma, diabetes, obesity, aging, muscle disorders, anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis, alopecia, chronic kidney disease; 01-3596-WO-1 78 Niemann-Pick Disease, Type C, myotonic dystrophy type 2, Huntington disease, Bloom syndrome, osteoarthritis, ALS, Parkinson’s disease, COVID-19. ^An et al., Arthritis Rheumatol.2017 Apr;69(4):800-807, disclosed that cGAS expression in5 peripheral blood mononuclear cells (PBMCs) was significantly higher in patients with the autoimmune disease systemic lupus erythematosus (SLE) than in normal controls. Targeted measurement of cGAMP by tandem mass spectrometry detected cGAMP in 15% of 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.10 ^ Thim-Uam et al (iScience.2020 Sep 4;23(9):101530) demonstrated that STING deficiencyameliorated lupus development in Fcgr2b-deficient mice. Prabakaran et al (EBioMedicine.2021 Apr;66:103314) shows that a STING pathway inhibitor ISD017 blocks STING activity in vivo and ameliorates disease development in a mouse model for lupus. ISD017 treatment also blocks pathological cytokine responses in PBMCs from lupus patients with elevated IFN-I levels.15 ^ Skopelja-Gardner et al reported that ultraviolet B light triggers cGAS / STING-dependent skin andsystemic IFN-I signature and could contribute to cutaneous lupus Alzeand fares of disease in patients with SLE (Sci Rep 202010:7908 ) ^Ryu et al (Arthritis Rheumatol.2020 Nov;72(11):1905-1915) showed that plasma mtDNAconcentrations were increased in the 2 Systemic sclerosis–associated interstitial lung disease (SSc-20 ILD) cohorts, reflective of ventilatory decline, and were positively associated with both TLR-9 and cGAS / STING activation as well as type I IFN and IL-6 expression. Liu et al (Rheumatology (Oxford) 2022 Jun 10;keac324.) showed increased DNA leakage, STING expression and vascular inflammation in skins of SSc patients, and STING deficiency or H151 administration ameliorated fibrosis and vasculopathy both in vitro and in BLM-induced SSc mice.25 ^ 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. Feng et al. suggested STINGcould be a potential therapeutic target in idiopathic inflammatory myositis-associated interstitial30 lung disease (IIM–ILD) (Feng et al., International Immunopharmacology, March 2025, 149,doi:10.1016). It was also reported that the GAS-STING pathway is activated in the muscle biopsiesof idiopathic inflammatory myopathy (IIM) patients and its activation may lead to myofiber atrophy and necrosis in IIM and dermatomyositis patients (Zhou et al., J Clin Lab Anal. 2022;36:e24631.). 01-3596-WO-1 79 ^Haag et al (Nature.2018 Jul;559(7713):269-273) demonstrated that a covalent STING inhibitorattenuated pathological features of autoinflammatory disease in TREX1_KO mice. Loss of function mutation of TREX1 leads rare monogenic interferonopathies such as Aicardi-Goutières syndrome (AGS). 5^ Hu et al (EBioMedicine.2019 Mar;41:497-508) showed that in human abdominal sepsis, STINGexpression was elevated in peripheral blood mononuclear cells and intestinal biopsies compared with healthy controls. In human abdominal sepsis, STING expression was elevated in peripheral blood mononuclear cells and intestinal biopsies compared with healthy controls. STING knockout mice attenuated alleviated inflammatory response, gut permeability, and decreased bacterial 10 translocation in a sepsis model. Zeng et al (ci Transl Med.2017 Oct 18;9(412):eaan5689) also showed that STING deficiency in mice protected two sepsos modeled (LPS model and cecal ligation and puncture model) and the degree of STING expression in the human intestinal lamina propria correlated with the intestinal inflammation in septic patients. Inhibition of the ALK-STING pathway protects mice against CLP-induced polymicrobial sepsis.15 ^ 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. Benmerzoug et al (Nat.Commun.9, 1–19 (2018)) shows that STING- dependent sensing of self- DNA drives silica-inducedlung inflammation, which can lead to lung fibrosis. ^Additional scientific hints linking the cause for metabolic diseases such as non-alcoholic fatty liver20 disease (NAFLD), now referred to as metabolic dysfunction–associated steatotic liver disease(MASLD), see https: / / easl.eu / news / new_fatty_liver_disease_nomenclature-2, https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC10653297 / ), other fibrosing diseases such as non-alcoholic steatohepatitis (NASH) , now referred to as metabolic dysfunction associated steatohepatitis (MASH ), and alcoholic liver disease (ALD) with the cGAS / STING pathway have25 been described in Yu et al., J. Clin. Invest.2019 Feb 1;129(2):546-555, and in Cho et al.,Hepatology.2018 Oct;68(4): 1331-1346, and in Qiao et al., Metabolism 2018 Apr;81:13-24 doi: 10.1016 / j.metabol.2017.09.010. Epub 2017 Oct 26, Petrasek et al., PNAS 2013 Oct8;110(41):16544-9. doi: 10.1073 / pnas.1308331110. Epub 2013 Sep 19 ^Nascimento et al., Sci. Rep.2019 Oct 16;9(1):14848, discloses that self-DNA release and STING-30 dependent sensing drives inflammation due to cigarette smoke in mice hinting at a link between the cGAS-STING pathway and chronic obstructive pulmonary disease (COPD). ^Ahn et al (Cell Rep 201721:3873-3884) describes that STING-deficient mice protects in anInflammatory Colitis model. Martin et al (Sci Rep 2019 Oct 3; 9:14281) describes that STING deletion protects while or STING stimulation, exacerbates intestinal inflammation in the dextran 01-3596-WO-1 80 sodium sulphate (DSS) model of colitis. These publications support STING as a potential therapeutic target for prevention of inflammatory bowel disease (IBD). ^Kerur 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). 5^ Further, the STING inhibitors also have a therapeutic potential in the treatment of cancer (seeHoong et al., Oncotarget.2020 Jul 28;11(30):2930-2955, and Chen et al., Sci. Adv.2020 Oct14;6(42):eabb8941). Furthermore shown in Bakhoum et el., Nature.2018 Jan 25;553(7689):467- 472: “Chromosomal instability drives metastasis through a cytosolic DNA response”, and in Liu et al., Nature.2018 Nov;563(7729):131-136: “Nuclear cGAS suppresses DNA repair and promotes10 tumorigenesis“. ^STING inhibitors have also the potential in the treatment of obesity and diabetes as shown in Maoet al., Arterioscler Thromb Vasc Biol (2017) 37(5):920–9. doi: 10.1161 / ATVBAHA.117.309017 ^Additionally, the STING inhibitors have also a therapeutic potential in the treatment of heartfailure (King et al, Nat Med 2017 Dec;23(12):1481-1487; Hu et al.,15 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), between amyotrophic lateral sclerosis (ALS)and STING (Yu et al, Cell 2020;183:636-649) and between Sjogren’s syndrome and the cGAS / STING pathway (Papinska et al., J. Dent. Res.2018 Jul;97(8):893-900) exist.20 ^ Furthermore, STING inhibitors have also a therapeutic potential 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 IFN immunopathology 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 response through cGAS-STING and NF-kappaB”. It 25 has also been shown that severe COVID-19 and long COVID are associated with high expression of STING, cGAS and IFN-α (Sci Rep 202414:4974). ^Additionally, STING inhibitors have a therapeutic potential in the treatment of renal inflammationand renal fibrosis as shown in Chung et al., Cell Metab.201930:784-799: “Mitochondrial Damage and Activation of the STING Pathway Lead to Renal Inflammation and Fibrosis”, and in Maekawa 30 et al., Cell Rep.201929:1261-1273: “Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury”. It has also been shown that genetic deletion or pharmacological inhibition of STING ameliorates kidney inflammation fibrosis in a mouse models of chronic kidney disease (Cell Metab 201930:784-799). 01-3596-WO-1 81 ^Further, two cases of STING GOF mutants have been reported with alopecia symptom indicatingSTING activation can lead to alopecia (Front Immunol 201910:2770. doi: 10.3389; Pediatr Rheumatol Online J.202422:9 doi: 10.1186). Blood mitochondrial DNA copy number has been reported as a diagnostic marker and indicator of degree of severity in alopecia areata (J 5 Immunoassay Immunochem 202344:256-268). ^In addition, ANCA vasculitis patients show increased levels of cGAMP and enhanced IFN-Isignature. 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).10 ^ Furthermore, the lysosomal membrane protein Niemann-Pick type C1 (NPC1) has been identifiedas a cofactor in the trafficking of STING. Genetic deletion of STING significantly reduced the activation of microglia and relieved the loss of Purkinje neurons in the cerebellum of Npc1- / - mice,leading to improved motor function. This study indicates STING inhibitors as potential therapy for Niemann–Pick disease type C (Nature 2021596(7873):570-575).15 ^ Additionally, it has been shown that in myotonic dystrophy type 2 (DM2) disease, patient PBMCsand 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 cytosolicDNA accumulation and activates the cGAS–STING pathway to mediate inflammation and apoptosis20 (Proc Natl Acad Sci U S A.2024121:e2313652121). Depletion of cGAS in HD neuron cells decreasesthe expression 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 AD and aged mice. A STING inhibitor 25 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). ^Additionally, during ischemic stroke, tissue damage results in misplaced DNA within the cellularenvironment activates the cGAS / STING pathway, leading to cytokine production, neuroinflammation, and cell death (Expert Opin Drug Discov 202318:1133-1149; Drug Discov 30 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) ^Further, it has been shown that STING promotes senescence, apoptosis, and extracellular matrixdegradation in osteoarthritis (Guo et al, Cell Death Dis.2021 Jan 4;12(1):13. doi: 10.1038). 01-3596-WO-1 82 cGAS / STING null- mice have reduced tissue inflammation, improved heart / muscle function andhave an extended lifespan (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 5 will reduce senescence associated inflammation and senescent cell accumulation and will leads improvement in senescence associated diseases such as aging / muscle disorders and osteoarthritis. ^Also, it was reported that the STING protein is involved in vitiligo, as the cytosolic mtDNA-cGAS-STING axis of melanocytes plays an important role in oxidative stress-triggered CD8+ T-cell10 response via melanocyte pyroptosis (Xu et al., Journal of Dermatological Science, 2025, 117(3),March 2025 doi:10.1016). Oxidative stress-induced mitochondrial damage in epidermal cells led to cytosolic mtDNA accumulation, which served as a trigger in activating the cGAS-STING axis in melanocytes resulting in production of IL-1β and IL-18.^ Prurigo nodularis is a chronic inflammatory skin condition characterized by intensely itchy pruritic15 nodules on the extremities and trunk that are often a result of persistent scratching. It was reported that both systemic and cutaneous immune responses in patients with PN are skewed toward a Th22 / IL-22 profile (Belzberg et al., Journal of Investigative Dermatology (2021) 141, 2208e2218). Aden et al. reported that IL-22 aggravates epithelial cell death–mediated inflammation through STING activation in intestinal epithelial cells (Aden et al., J. Exp. Med.2018 20 Vol.215: 2868–2886). STING may also play a role in IL22 mediated pathogenic responses in the skin epithelium in Prurigo nodularis. The compounds of formula (I) or (Ia) or (Ib) or (Ic), or the salts thereof for use in patients with adisease whose progression can be prevented by the inhibition of STING is an embodiment of the25 invention. In one embodiment, the STING inhibitors of the invention are useful in the prevention of progression, and / or for the treatment of a condition or disease caused by immune dysregulation and involving the STING protein(s). 30 The use of the compounds of the invention for the prevention of progression or for the treatment of a disease or condition that involves undesirable STING activation in a manner independent of cGAS activity is one embodiment of the intervention, for examples but not limited to subjects with deregulated STING mutants, e.g. but not limited to SAVI, or Niemann–Pick disease type C. In a preferred embodiment, the compounds of the invention for the prevention of progression and / or 35 for the treatment of a disease or condition that involves undesirable STING activation by mutations of 01-3596-WO-1 83 the STING protein are those compounds, that show IC50 values of at least 0.001 nM and less than 150 nM, preferably less than 100 nM, more preferably less than 50 nM, even more preferably less than 20nM when tested for inhibition of any of the mutant N154S or V155M of the STING protein associatedwith SAVI, preferably both, as described in section BIOLOGICAL ASSAYS AND DATA. 5 In another embodiment the compounds of the inventions are used as anti-fibrotic agents. An embodiment of the invention is the use of the compounds of the invention in the therapy ofinterferon-driven inflammatory and / or fibrotic diseases or symptoms, preferably those that are a sideeffect of an underlying disease that leads to cell damage and cytosolic DNA presence that is not10 derived from pathogens.Combinations The compounds of formula 1 may be administered to the patient alone or in combination with one or more other pharmacologically active agents. 15 In a preferred embodiment of the invention the compounds may be combined with one or morepharmacologically active agents selected from the group of PDE 4 inhibitors (preferably 1-[[(5R)-2-[4-(5-chloropyrimidin-2-yl)-1-piperidyl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4- yl]amino]cyclobutyl]methanol and [1-[[(5R)-2-[4-(5-chlorophenyl-2-yl)-1-piperidyl]-5-oxo-6,7- 20 dihydrothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol as disclosed in WO 2013 / 026797), 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-limiting examples are anti-IL-23 such as Risankizumab, anti-IL-17 antibodies, anti-IL-1 antibodies, anti-25 IL-4 antibodies, anti-IL-13 antibodies, anti-lL-5 antibodies, anti-IL-6 antibodies such as Actemra™, anti- IL-12 antibodies and anti-IL-15 antibodies, non-specific immunotherapeutics such as interferons orother 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 for example but not limited to Humira™ and anti- B-cell activating factor (BAFF) agents e.g.30 without limitation Belimumab and Etanercept. Such a combination with anti-inflammatory agentsand / or anti-fibrotic agents in one embodiment is a combination of one or more compounds of theinvention with a) one or more known STING inhibitors and / or b) known cGAS inhibitors and / or c) anti-inflammatory agents that are not STING inhibitors and / or anti-fibrotic agents that are not STINGinhibitors, for example but not limited to Pirfenidon, Nintedanib or Nerandomilast. Another aspect of35 the invention is to the combined use of the STING inhibitors of the invention in combination with 01-3596-WO-1 84 known cGAS and / or STING inhibitors, for example those disclosed in the international patent applications PCT / EP2023 / 080705, PCT / EP2023 / 080711, PCT / EP2022 / 062496, PCT / EP2022 / 062480, PCT / EP2023 / 079890 or published as WO2021 / 138419, WO2023 / 148129, WO2023 / 237457,WO2024 / 263860, WO2025 / 012195 or WO2025 / 017045.5 In a further aspect of the present invention, the one or more other pharmacologically active agents include immunosuppressive drugs, Nonsteroidal anti-inflammatory drug (NSAID), corticosteroids e.g. glucocorticoids, hydroxychloroquine or methotrexate, antibodies for example anti- B-cell activatingfactor (BAFF) antibody or CAR (chimeric antigen receptors) T cells. 10 In another aspect of the present invention, the one or more other pharmacologically active agents are RAAS inhibitors (Renin–Angiotensin–Aldosterone System). In one aspect of the present invention, the one or more other therapeutic substances is a direct renin inhibitor, an Angiotensin-Converting Enzyme (ACE) inhibitor and / or an angiotensin II receptor blocker (ARB). 15 In one embodiment , the invention comprise pharmaceutical compositions comprising one or more compounds of the invention and one or more other pharmacologically active agents for use in the treatment or prevention of progression of a disease selected from the group consisting of disease selected from the group consisting of systemic lupus erythematosus (SLE), cutaneous lupus, (monogenic and digenic) interferonopathies (including STING-associated vasculopathy with onset in20 infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome, and familial chilblain lupus), type 1interferonopathies with mutations in DNASE2 or ATAD3A genes, age-related macular degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), Huntington disease, Alzheimer's disease, diabetes, obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom’s syndrome, Niemann-Pick Disease, Type C, ischaemic stroke, myotonic dystrophy type25 2, Sjogren’s syndrome, Parkinson’s disease, heart failure, cancer, systemic sclerosis (SSc), vitiligo,prurigo nodularis, idiopathic inflammatory myopathy, myositis including dermatomyositis, metabolicdysfunction–associated steatotic liver disease (MASLD) (previously referred to as non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction associated steatohepatitis (MASH, previously non-alcoholic steatotic hepatitis (NASH)), compensated and decompensated liver cirrhosis, acute on 30 chronic liver failure (ACLF), alcoholic liver disease (ALD), interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), long COVID, aging / muscle disorders, sepsis, heart failure, anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis, alopecia, chronic kidney disease, rheumatoid arthritis and osteoarthritis. 35 Formulations 01-3596-WO-1 85 The 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 5 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. 10 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. 15 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 more20 compounds of formula (I), preferably according to formula (Ia), (Ib) or (Ic), according to the preferredembodiments above. It is particularly preferable if the compounds of formula (I), preferably according to formula (Ia), (Ib) or(Ic), are administered orally, and it is also particularly preferable if they are administered once or twicea day. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known25 excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose,disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and / or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.30 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 also consist of a number of layers. Similarly, the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets. 35 01-3596-WO-1 86 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, 5 condensation products of fatty alcohols with ethylene oxide, or preservatives such as p- hydroxybenzoates. Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and 10 packing them into gelatin capsules. Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethylene glycol or the derivatives thereof. Excipients which may be used include, for example, water, pharmaceutically acceptable organic 15 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,20 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 25 magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tableting process. In the case of aqueous suspensions, the active substances may be combined with various flavor enhancers or colorings in addition to the excipients mentioned above. The inventive use in the prevention of and / or treatment of and / or delaying the occurrence of and / or 30 delaying the progression of disorders is to be understood to refer to a prevention that reduces the risk for disorders related to elevated and / or deregulated STING activity, wherein prevention can be a reduction of the risk of such disorders whereby some risk may remain. Despite the use of the compounds of the invention, individual patients may still suffer from such disorders at least to some extent, although for the overall group of patients the use of the compounds of the invention typically35 is suitable to delay the occurrence and / or prevent such disorders. 01-3596-WO-1 87 Prevention or delay is typically identified by comparison with a control patient group or a patient not receiving any compound of the invention, preferably a patient group / patient receiving placebo and standard of care. The treatment group / patient receives standard of care for any other disorder not related to elevated and / or deregulated STING activity, and if applicable the standard of care for 5 disorders related to elevated and / or deregulated STING activity, plus in addition one or more compound(s) of the invention. Identification of a prevention or delay will typically require studies in a large group of patients and control group under controlled conditions, typically in a clinical trial, but the identified prevention or delay normally applies to any individual patient receiving the compound(s) of the invention, whereas 10 the quantity of prevention or delay for the individual patient can be expected by the average value observed in the large group but modified due to individual factors. Therefore, the prevention or delay may be present but smaller than the observed average in large trials, or higher for the individual patient. Throughout this description the term disorders is used interchangeably with diseases or conditions. 15 A further aspect of the present invention is to a method of preparation of a pharmaceutical composition comprising the compound of the invention for the use in the prevention of and / or treatment of and / or delaying the occurrence of and / or delaying the progression of disorders related to elevated and / or deregulated STING activity, wherein the method comprises the steps of a) producing the inventive compound or a salt thereof, preferably a pharmaceutically acceptable salt 20 thereof, b) optionally adding with one or more inert adjuvant, diluent and / or carrier, c) optionally adding one or more pharmacologically active agents selected from the group of PDE 4 inhibitors(preferably 1-[[(5R)-2-[4-(5-chloropyrimidin-2-yl)-1-piperidyl]-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-4-yl]amino]cyclobutyl]methanol and [1-[[(5R)-2-[4-(5-chlorophenyl-2-yl)-1-piperidyl]-5- oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol as disclosed in WO 25 2013 / 026797), 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, preferably anti-IL-23 such as Risankizumab, anti-IL-17 antibodies, anti-IL-1 antibodies, anti-IL-4 antibodies, anti-IL-13 antibodies, anti-lL-5 antibodies, anti-IL-6 antibodies such as Actemra™, anti-30 IL-12 antibodies and / or anti-IL-15 antibodies, non-specific immunotherapeutics such as interferons orother 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, preferably Humira™, and anti-BAFF agents, preferably Belimumab and / orEtanercept.Another aspect of the invention is to the combined use of one or more of the STING 01-3596-WO-1 88 inhibitors of the invention in combination with known cGAS and / or STING inhibitors, and d) optionallyformulating into a form for the preferred administration. 5

Claims

01-3596-WO-1 89 Claims 1. A compound of formula (I),5 wherein X-Y-Z isa. selected from the group X-Y-Ze consisting of -N=C-NH- and -CH2-NH-C(O)- andwherein V-B-A is selected from the group V-B-Aa consisting of -C=C-N- and -N-C=C-; andR1is selected from the group R1aconsisting of C1-5-alkyl-, C1-3-alkyl-O-, C3-6-cycloalkyl- and C3-6-cycloalkyl-C1-3-alkyl-;wherein the C1-3-alkyl-O-group and / or the C1-5-alkyl-group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-3-alkyl-O-, Halogen and HO-; and R5is selected from the group R5aconsisting of R9-C(R8)(R7)-CH(R12)- and R9-S(O)-CH(R12)- and, wherein R5 denotes the attachment point of this R5 group to Y;and R6is selected from the group R6aconsisting of C2-6-alkenyl,01-3596-WO-1 90 b. and C1-6-alkyl optionally substituted independently of one another by one or two substituents selected from the group consisting of C3-6-cycloalkyl-, halogen, HO-, C1-6-alkyl-O-, C1-6-alkyl-HN-, (C1-6-alkyl)2N-, NC-, (C1-6-alkyl)2(O)P-, (4-methoxyphenyl)methyl-, oxetane and,wherein * denotes the attachment point of this R6group to Ax; and C3-5-heterocycloalkyl, preferably a heterocycle selected from tetrahydrofuran-, 1, 4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, triazole- or oxetane, each optionally substitutedindependently of one another by one or two substituents selected from the group consisting of C1-6-alkyl-, halogen, O=; or is =CH-N-N= and i. R1 is selected from the group R1c consisting of cyclopropylhydroxymethyl-; orii. V-B-A is selected from the group V-B-Ac consisting of -N-C=C-; or5 iii. R5 is selected from the group consisting of,and, wherein R5 denotes the attachment point of this R5 group to Y,10 or01-3596-WO-1 91 iv. R6 is selected from the group R6e consisting of Oxetane-methyl- and Oxetane-;or v. a combination of any of i. to iv;and wherein Wis selected from the group Wa consisting of =C- and -NH-;R2is selected from the group R2aconsisting of C1-3-alkyl-; R3is selected from the group R3aconsisting of C3-6-cycloalkyl- and C3-6-cycloalkyl- C1-3-alkyl;R4is selected from the group R4aconsisting of H and Halogen; R7is selected from the group R7aconsisting of H-, Halogen, HO- and C1-3-alkyl-O-;R8is selected from the group R8aconsisting of H- and Halogen;R9is selected from the group R9aconsisting of phenyl-, piperidyl-, morpholinyl- and C5-6-cycloalkyl-,wherein the piperidyl-group is optionally substituted with 1 substituent independently selected from the group consisting of C1-3-alkyl-S(O)2-, C1-3-alkyl-C(O)-, C1-5-alkyl-C(O)-O-; R10is selected from the group R10aconsisting of H-, HO-, H2N-C(O)-, C1-3-alkyl-, C1-3-alkyl-O-, C3-4-cycloalkyl- and phenyl-,wherein the phenyl-group and / or the C1-3-alkyl-group are optionally substituted with 1 substituent independently selected from the group consisting of Halogen and HO-; R11is selected from the group R11aconsisting of H-, HO-, H2N-C(O)-, C1-3-alkyl-, C1-3-alkyl-O-, C3-4-cycloalkyl- and phenyl-,wherein the phenyl-group and the C1-3-alkyl-group is optionally substituted with 1 substituent independently selected from the group consisting of Halogen and HO-,5 wherein preferably R10 and R11 are not both H- at the same time;R12is selected from the group R12aconsisting of H-, HO- and Halogen;or a salt thereof.01-3596-WO-1 92 2. A compound according to claim 1, whereinW is selected from the group Wc consisting of =N-;or a salt thereof.

3. A compound according to one of the claims 1 to 2, whereinR2is selected from the group R2bconsisting of H3C-; 5 or a salt thereof.

4. A compound according to one of the claims 1 to 3, whereinR3is selected from the group R3bconsisting of cyclopropyl- and cyclopropylmethyl-.or a salt thereof.10 5. A compound according to one of the claims 1 to 4, whereinR4is selected from the group R4bconsisting of H- and F-.or a salt thereof.

6. A compound according to one of the claims 1 to 5, whereinR6is selected from the group R6fconsisting of oxetane-. or a salt thereof. 15 7. A compound according to one of the claims 1 to 6, whereinX-Y-Z is selected from the group X-Y-Ze consisting of -N=C-NH- and -CH2-NH-C(O)-and R1is selected from the group R1dconsisting of H3C-CH2-CH(OH)-; 20 or a salt thereof.

8. A compound according to one of the claims 1 to 7, wherein the compound of formula (I) is acompound of formula (Ia)01-3596-WO-1 93.

9. A compound according to one of the claims 1 to 7, wherein the compound of formula (I) is a5 compound of formula (Ib)or a salt thereof.

10. A compound according to one of the claims 1 to 7, wherein the compound of formula (I) is a10 compound of formula (Ic)or a salt thereof. 1501-3596-WO-1 94 11. A compound according to one of the claims 1 to 7, selected from the following examples:01-3596-WO-1 95.

12. A compound according to one of the claims 1 to 7, selected from any of the examples 1 to 10.

13. A salt, preferably a pharmaceutically acceptable salt, of any of the compounds of claims 11 or5 12.

14. The compound of formula (I), (Ia), (Ib) or (Ic), according to any of claims 1 to 12 or the saltthereof according to claim 13 for use in the treatment of a disease that can be treated by the10 inhibition of STING.

15. The compound of formula (I), (Ia), (Ib) or (Ic), according to any of claims 1 to 12 or the saltthereof according to claim 13 for use in the treatment of a disease selected from the groupconsisting of disease selected from the group consisting of systemic lupus erythematosus15 (SLE), cutaneous lupus, (monogenic and digenic) interferonopathies (including STING- associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome, and familial chilblain lupus), type 1 interferonopathies with mutations in DNASE2or ATAD3A genes, age-related macular degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), Huntington disease, Alzheimer's disease, diabetes, obesity, 20 inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom’s syndrome, Niemann-Pick Disease, Type C, ischaemic stroke, myotonic dystrophy type 2,Sjogren’s syndrome, Parkinson’s disease, heart failure, cancer, systemic sclerosis (SSc), vitiligo, prurigo nodularis, idiopathic inflammatory myopathy, myositis includingdermatomyositis, metabolic dysfunction–associated steatotic liver disease (MASLD)25 (previously referred to as non-alcoholic fatty liver disease (NAFLD), metabolic dysfunctionassociated steatohepatitis (MASH, previously non-alcoholic steatotic hepatitis (NASH)), compensated and decompensated liver cirrhosis, acute on chronic liver failure (ACLF), alcoholic liver disease (ALD), interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), long COVID, aging / muscle disorders, sepsis, heart failure, anti-neutrophil cytoplasm antibody 30 (ANCA) associated vasculitis, alopecia, chronic kidney disease, rheumatoid arthritis and osteoarthritis.

16. Pharmaceutical composition comprising a compound of any of claims 1 to 12 and / or the saltthereof according to claim 13, and optionally one or more pharmaceutically acceptable35 carriers and / or excipients.

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