Monoaryl and hetaryl substituted indazoles and benzimidazoles 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] 01-3594-WO-1 1 Monoaryl and Hetaryl Substituted Indazoles and Benzimidazoles as STING Antagonists and the UseThereof as Medicament This application claims priority to the US provisional application 63 / 640354, 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), 10 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 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),15 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 including dermatomyositis, metabolic dysfunction–associated steatotic liver disease(MASLD) (previously referred to as non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction20 associated 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 (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 diverse30 pattern recognition receptors (PRRs) and subsequent activation of cytokine and type I interferon gene 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 compartments35 (Barbalat et al., Annu. Rev. Immunol.29, 185-214 (2011)). 01-3594-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); 5 Ablasser et al., Nature 498, 380-384 (2013)). Binding of dsDNA to cGAS activates the reaction of GTP 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 interferon10 regulatory factors (IRFs) inducing cytokine and type I interferon mRNA expression. STING activation by cGAMP also leads 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 15 fibroblasts, exhibiting an upregulated type-1 IFN signature and expression of NF^B-mediated profibrotic and proinflammatory 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 20 senescence (Yang et al., PNAS 114, E4612 (2017), Glueck et al., Nat. Cell Biol.19, 1061-1070 (2017)), 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 25 stress and genetic factors may also cause production of aberrant cellular dsDNA, e.g. by nuclear or 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 in 30 TREX1-deficient mice prevented otherwise lethal autoimmune responses, supporting STING as driver 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)). 01-3594-WO-1 3 A STING inhibitor may provide a therapeutic strategy for preventing (monogenic and digenic) interferonopathy diseases such as SAVI, AGS, familial chilblain lupus and COPA. A STING inhibitor will block inflammation and aberrant tissue remodeling in a cluster of autoimmune and inflammatory diseases including systemic lupus erythematosus (SLE), systemic sclerosis, vitiligo, prurigo nodularis, 5idiopathic inflammatory myopathy, myositis including dermatomyositis, inflammatory bowel disease,sepsis, Sjogren’s syndrome, atopic dermatitis, as well as a cluster fibrosis diseases including NASH, IPF, 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;10 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, Alzheimer’s disease, COVID-19 (Decout et al, Nat Rev Immunol.202121:548- 569). 15 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. •In WO2019122202 for example, compounds C-178 or C-176 are described interfering with STING20 signaling 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. •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 25 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 on a cGAMP stimulated INFb production in THP1 cells. •In International patent application WO2019069270, claims modulators of STING which either30 activate 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 themolecules. 01-3594-WO-1 4 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 receptors this provides the additional challenge that the inhibitor molecules not only need to interact 5with the correct portion the STING receptor, but also will interact with the second molecule of theinhibitor 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 crossing of the cell membranes to reach the target, while not enhancing the degradation of10 the inhibitor. Another challenge for a therapeutic inhibitor of STING receptors is that in many STING mediateddisease patients are likely to be co-administered with more than one medications to treat thesymptoms of said diseases or the diseases itself. The inhibitors of STING should in such a situation not add additional workload to the detoxifying processes or catabolism of the other medication15 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 inventionIt has now been found that compounds of the present invention according to general formula (I), or20 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 limitedto: Being optimised for binding of two molecules of the inhibitor to the target’s ligand binding25 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- administered drugs, low degradation by light, e.g. sun light, yet good degradation ex-situ of the30 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. 01-3594-WO-1 5 Another aspect of the invention refers to compounds according to formula (I), or salts thereof as 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 5 inhibitors of STING having good metabolic stability and potency. 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 as10 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. 15 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 of other pharmaceutical compound administered overlappingly or simultaneously, including but not limited to further inhibitors of STING, and with acceptable cytotoxicity and / or genotoxicity. 20 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 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 target25 receptor in the cells and good potency. 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 30 polarity for good mobility across the cell membrane and good access to the target receptor in the cells 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, optionally35 together with one or more inert adjuvant, diluent and / or carrier. 01-3594-WO-1 6 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 of5 and / or treatment of and / or delaying the occurrence of and / or delaying the progression of disordersrelated 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. 10 In yet 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 theNAFLD Activity Score (NAS) with or without steatosis, activity, and fibrosis (SAF) score and / or15 progression of 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 pharmaceutically20 acceptable salts. Other aims of the present invention will become apparent to the skilled man directly from the foregoing and following remarks. 25 Detailed description In a first aspect the present invention relates to compounds of general formula (I) 01-3594-WO-1 7 (I) wherein B-A is selected from the group B-Aa consisting of =C-N- or -N-C=; this means A is C or N; B isC or N; but A and B are not N at the same time; X-Y-Z is selected from the group X-Y-Za consisting of =CH-N-N=, -N=C-NH- and -CH2-N-C(O)-;5 Wis selected from the group Wa consisting of =CH- and =N-;R1is selected from the group R1aconsisting of R6-C1-5-alkyl- and C3-6-cycloalkyl-;R2is selected from the group R2aconsisting of ; , and10 wherein * denotes the attachment point R2 in formula (I)R3is selected from the group R3aconsisting of halogen, HO-, C1-3-alkyl-, C1-5-alkyl-O-,C1-3-alkyl-O- C1-3-alkyl-, C3-5-alkenyl-O-, C2-3-alkenyl-O- C1-3-alkyl-C3-6-cycloalkyl- and heterocyclyl-;wherein a C1-3-alkyl-group is optionally substituted with 1 to 3 selected from the group consisting of fluorine, HO-, H3C-O-, F3C-O-, and F2HC-O-; wherein the C1-5-alkyl-group of the C1-5-alkyl-O-group is optionally substituted with 1 to 5 (e.g.2, 3 or 4) substituents independently selected from the group consisting of fluorine, HO-, H2N-C(O)-, C3-4-cycloalkyl-, C1-3-alkyl-O-, heterocyclyl and heteroaryl; R4is selected from the group R4aconsisting of 01-3594-WO-1 8 C1-3-alkyl-S(O)2-, C1-3-alkyl-S(O)-, (C1-3-alkyl)2P(O)-, (C1-3-alkyl)(C3-6-cycloalkyl)P(O)-, - C(O)-, H2N-C(O)-, C1-3-alkyl-NH-C(O)-, (C1-3-alkyl)2N-C(O)- and ; wherein * denotes the attachment point of R4aR5is selected from the group R5aconsisting of C1-4-alkyl-; R6is selected from the group R6aconsisting of H-, HO- and Halogen;R7is selected from the group R7aconsisting of H-, Halogen, HO-, HO(C1-6-alkyl)2C-CH2-, C1-3-alkyl-O-, C1-6-alkyl-, C3-5-alkenyl-, C3-6-cycloalkyl-, aryl, heteroaryl and heterocyclyl; wherein the C1-6-alkyl-group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Halogen, HO-, and C1-3-alkyl- O-, wherein the heteroaryl group is optionally substituted with 1 substituent selected from the group consisting of C1-3-alkyl-, wherein the C3-6-cycloalkyl- and / or aryl group is optionally substituted with 1 to 3substituents independently selected from the group consisting of (H3C)2N-C(O)-; 5 R8is selected from the group R8aconsisting of H-, C1-6-alkyl-O- and heterocyclyl-O-;wherein the C1-6-alkyl-O-group is optionally substituted with 1 substituent selected from the group consisting of C1-3-alkyl-O- and (H3C)2N-C(O)-;C1-5-alkyl-O- and Halogen;R9is selected from the group R9aconsisting of H-, C1-3-alkyl- and H2N-C(O)-CH2-; 01-3594-WO-1 9 R10is selected from the group R10aconsisting of C1-3-alkyl-, C2-3-alkenyl-, C1-3-alkyl-O-, C1-3-alkyl-S- and C3-4-cycloalkyl-,wherein the C1-3-alkyl-group is optionally substituted with 1 to 3 substituents selected from the group consisting of F-; R11is selected from the group R11aconsisting of C1-5-alkyl-, or -C1-5-alkyl-C(O)-, wherein the C1-5-alkyl-, group is optionally substituted independently of one another with 1 to 3 substituents selected from the group consisting of C1-3-alkyl-, halogen and HO-.5 or a salt thereof, preferably a pharmaceutically acceptable salt. Unless otherwise stated, the groups, residues, and substituents, particularly B-A, W, X-Y-Z, R1, R2, R3,R4, R5, R6, R7, R8, R9, R10 and R11 are defined as above and hereinafter. If residues, substituents, or10 groups 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 given hereinafter. In a further embodiment of the present invention B-A is selected from the group B-Ab consisting of =C-N-; this means A is N; B is C.15 In a further embodiment of the present invention B-A is selected from the group B-Ac consisting of -N-C=; this means A is C; B is N.In a further embodiment of the present invention X-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N= and -N=C-NH-.20 In a further embodiment of the present invention X-Y-Z is selected from the group X-Y-Zc consisting of =CH-N-N=.In a further embodiment of the present invention X-Y-Z is selected from the group X-Y-Zd consisting of -N=C-NH-.In a further embodiment of the present invention 01-3594-WO-1 10 Wis selected from the group Wb consisting of =CH-.In a preferred embodiment, the compound is a compound of formula (Ia) 5 In a further embodiment of the present invention R1is selected from the group R1bconsisting of isopropyl- and cyclopropyl-;In a further embodiment of the present invention R1is selected from the group R1cconsisting of cyclopropyl-; In a further embodiment of the present invention R2is selected from the group R2bconsisting of10 and ,wherein * denotes the attachment points. In a further embodiment of the present invention R2is selected from the group R2cconsisting of 01-3594-WO-1 11 , wherein * denotes the attachment point. In a further embodiment of the present invention R2is selected from the group R2dconsisting of , wherein * denotes the attachment point. In a further embodiment of the present invention 5 R3is selected from the group R3bconsisting of halogen, HO-, C1-3-alkyl-, C1-5-alkyl-O-, C1-3-alkyl-O- C1-3-alkyl-, C3-5-alkenyl-O-,cyclopropyl- and heterocyclyl-;wherein the C1-5-alkyl-group of the C1-5-alkyl-O-group is optionally substituted with 1to 3 substituents independently selected from the group consisting of fluorine,HO-, H2N-C(O)-, C3-4-cycloalkyl-, C1-3-alkyl-O-, heterocyclyl and heteroaryl. In a further embodiment of the present invention R3is selected from the group R3cconsisting of F-, Cl-, HO-, H3C-, F3C-, (H3C)2C-, H3C-CH2-, cyclopropyl-, H3C-O-, FH2C-O-, F2HC-O-,F3C-O-, (H3C)2CH-O-, (H3C)3C-O-, H3C-CH2-O-, F2HC-CH2-O-, F2C(CH3)-CH2-O-, H3C-CH2-CH2-O-, F-CH2-CH2-O-, HO-CH2-CH2-O-, H2N-CH2-C(O)-, H2C=CH-CH2-O-, H3C-O-CH2-CH2-O-, H3C-O-CH2-CH2-CH2-O-, (H3C)2C(OH)-CH2-CH2-O-, (H3C)2CH-CH2-O-,cyclopropyl-O-, cyclopropyl-CH2-O-, H3C-O-CH2-CH2-, H3C-O-CH2-, 01-3594-WO-1 12 , wherein * denotes the attachment point. In a further embodiment of the present invention R3is selected from the group R3dconsisting of F-, Cl-, HO-, H3C-, F3C-, (H3C)2C-, H3C-CH2-, cyclopropyl-, H3C-O-, FH2C-O-, F2HC-O-, F3C-O-, (H3C)2CH-O-, (H3C)3C-O-, H3C-CH2-O-, F2HC-CH2-O-, F2C(CH3)-CH2-O-, H3C- CH2-CH2-O-, F-CH2-CH2-O-, HO-CH2-CH2-O-, H2N-CH2-C(O)-, H2C=CH-CH2-O-, H3C-O- CH2-CH2-O-,H3C-O-CH2-CH2-CH2-O-, (H3C)2C(OH)-CH2-CH2-O-, (H3C)2CH-CH2-O-, H3C- O-CH2-,cyclopropyl-O-, cyclopropyl-CH2-O-. In a further embodiment of the present invention R3is selected from the group R3econsisting of H3C-, F2HC-CH2-O-, F3C-O-, and H3C-O-CH2-. 5 In a further embodiment of the present invention R3is selected from the group R3fconsisting of H3C-. In a further embodiment of the present invention R3is selected from the group R3gconsisting of F2HC-CH2-O-. 10 In a further embodiment of the present invention R3is selected from the group R3hconsisting of F3C-O-. In a further embodiment of the present invention R3is selected from the group R3iconsisting of H3C-O-CH2-. 01-3594-WO-1 13 In a further embodiment of the present invention R4is selected from the group R4bconsisting of (C1-3-alkyl)2P(O)-, C1-3-alkylNH-C(O)-, (C1-3-alkyl)2N-C(O)- and H2N-C(O)-.In a further embodiment of the present invention R4is selected from the group R4cconsisting of (CH3CH2)2P(O)-, (CH3)(CH3CH2)P(O)-, (CH3)2P(O)-, (CH3)NH-C(O)-, (CH3)2N-C(O)- andH2N-C(O)-. 5 In a further embodiment of the present invention R4is selected from the group R4dconsisting of (CH3CH2)2P(O)-, (CH3)(CH3CH2)P(O)- and (CH3)2P(O)-.In a further embodiment of the present invention R4is selected from the group R4econsisting of (CH3CH2)2P(O)-. In a further embodiment of the present invention R4is selected from the group R4fconsisting of (CH3)(CH3CH2)P(O)-. 10 In a further embodiment of the present invention R4is selected from the group R4gconsisting of (CH3)2P(O)-. In a further embodiment of the present invention R4is selected from the group R4hconsisting of H2N-C(O)-. 15 In a further embodiment of the present invention R5is selected from the group R5bconsisting of H3C-, H3C-CH2-, H3C-CH2-CH2- and (H3C)2C-. 01-3594-WO-1 14 In a further embodiment of the present invention R5is selected from the group R5cconsisting of H3C-. In a further embodiment of the present invention R5is selected from the group R5dconsisting of H3C-CH2-. 5 In a further embodiment of the present invention R6is selected from the group R6bconsisting of H-, HO-, F- and Cl-.In a further embodiment of the present invention R6is selected from the group R6cconsisting of H- and HO-.In a further embodiment of the present invention R6is selected from the group R6dconsisting of H-. 10 In a further embodiment of the present invention R7is selected from the group R7bconsisting of C1-3-alkyl-, C3-4-cycloalkyl- and HO(C1-3-alkyl)2C-CH2-.In a further embodiment of the present invention R7is selected from the group R7cconsisting of H3C-, cyclopropyl-, HO(CH3)2C-CH2- -.15 In a further embodiment of the present invention R7is selected from the group R7dconsisting of H3C-. 01-3594-WO-1 15 In a further embodiment of the present invention R7is selected from the group R7econsisting of cyclopropyl-. In a further embodiment of the present invention R7is selected from the group R7fconsisting of HO(CH3)2C-CH2-. 5 In a further embodiment of the present invention R8is selected from the group R8bconsisting of C1-5-alkyl-O . In a further embodiment of the present invention R8is selected from the group R8cconsisting of C1-3-alkyl-O- 10 In a further embodiment of the present invention R8is selected from the group R8dconsisting of H3C-O-. In a further embodiment of the present invention R8is selected from the group R8econsisting of H3C-CH2-O-. In a further embodiment of the present invention R9is selected from the group R9bconsisting of H- and H3C- and H3C-CH2-.15 In a further embodiment of the present invention 01-3594-WO-1 16 R9is selected from the group R9cconsisting of H-. In a further embodiment of the present invention R9is selected from the group R9dconsisting of H3C-. In a further embodiment of the present invention R9is selected from the group R9econsisting of H3C-CH2-. 5 In a further embodiment of the present invention R10is selected from the group R10bconsisting of C1-3-alkyl-, and C3-4-cycloalkyl-, wherein the C1-3-alkyl-group is optionally substituted with 1 to 3 substituents selected from the group consisting of F. In a further embodiment of the present invention R10is selected from the group R10cconsisting of cyclopropyl-, F2H C - and F3C-.10 In a further embodiment of the present invention R10is selected from the group R10dconsisting of cyclopropyl-. In a further embodiment of the present invention R10is selected from the group R10econsisting of 01-3594-WO-1 17 F3C-. R10is selected from the group R10fconsisting of F2HC-. R11is selected from the group R11bconsisting of C1-5-alkyl-, wherein the C1-5-alkyl-, group is optionally substituted with a substituent selected 5from the group consisting of C1-3-alkyl-, fluorine or HO- .R11is selected from the group R11cconsisting of F2HC- , F3C- , H3C , H3C-CH2- and H3C-CH2-CH2- .10 B-A, W, X-Y-Z, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11represents a characterized, individualembodiment 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 (B-AX, WX, X-Y-ZX, R1X, R2x, R3X, R4X, R5X, R6X, R7X, R8X, R9X, R10X and R11X), 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-20 of the compound of general formula (I) or a salt thereof, preferably a pharmaceutically acceptable salt, that are considered preferred. Table 1: Embodiments E-1 to E-20 of the invention 01-3594-WO-1 18 01-3594-WO-1 19 Accordingly, for example E-14 covers compounds of general formula (I), wherein B-A is selected from the group B-Ac consisting of -N-C=; this means A is C; B is N;W is selected from the group Wb consisting of =CH-;X-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N= and -N=C-NH-;R1is selected from the group R1bconsisting of isopropyl- and cyclopropyl-;R2is selected from the group R2aconsisting of R2is selected from the group R2aconsisting of ; , and , wherein * denotes the attachment point to the core; R3is selected from the group R3cconsisting of F-, Cl-, HO-, H3C-, F3C-, (H3C)2C-, H3C-CH2-, cyclopropyl-, H3C-O-, FH2C-O-, F2HC-O-, F3C-O-, (H3C)2CH-O-, (H3C)3C-O-, H3C-CH2-O-, F2HC-CH2-O-, F2C(CH3)-CH2-O-, H3C- CH2-CH2-O-, F-CH2-CH2-O-, HO-CH2-CH2-O-, H2N-CH2-C(O)-, H2C=CH-CH2-O-, H3C-O- CH2-CH2-O-, H3C-O-CH2-CH2-CH2-O-, (H3C)2C(OH)-CH2-CH2-O-, (H3C)2CH-CH2-O-, cyclopropyl-O-, cyclopropyl-CH2-O-, H3C-O-CH2-CH2-, H3C-O-CH2-, 01-3594-WO-1 20 , wherein * denotes the attachment point; R4is selected from the group R4bconsisting of (C1-3-alkyl)2P(O)-, C1-3-alkylNH-C(O)-, (C1-3-alkyl)2N-C(O)- and H2N-C(O)-;R5is selected from the group R5bconsisting of H3C-, H3C-CH2-, H3C-CH2-CH2- and (H3C)2C-;R7is selected from the group R7aconsisting of H-, Halogen, HO-, HO(C1-6-alkyl)2C-CH2-, C1-3-alkyl-O-, C1-6-alkyl-, C3-5-alkenyl-, C3-6- cycloalkyl-, aryl, heteroaryl and heterocyclyl; wherein the C1-6-alkyl-group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Halogen, HO-, and C1-3-alkyl- O-, wherein the heteroaryl group is optionally substituted with 1 substituent selected from the group consisting of C1-3-alkyl-, wherein the C3-6-cycloalkyl- and / or aryl group is optionally substituted with 1 to 3substituents independently selected from the group consisting of (H3C)2N-C(O)-; R8is selected from the group R8aconsisting of H-, C1-6-alkyl-O- and heterocyclyl-O-;wherein the C1-6-alkyl-O-group is optionally substituted with 1 substituent selected from the group consisting of C1-3-alkyl-O- and (H3C)2N-C(O)-;C1-5-alkyl-O- and Halogen;R9is selected from the group R9aconsisting of H-, C1-3-alkyl- and H2N-C(O)-CH2-;R10is selected from the group R10aconsisting of C1-3-alkyl-, C2-3-alkenyl-, C1-3-alkyl-O-, C1-3-alkyl-S- and C3-4-cycloalkyl-,wherein the C1-3-alkyl-group is optionally substituted with 1 to 3 substituents selected from the group consisting of F-; R11is selected from the group R11aconsisting of C1-5-alkyl-, or -C1-5-alkyl-C(O)-, wherein the C1-5-alkyl-, group is optionally substituted independently of one another with 1 to 3 substituents selected from the group consisting of C1-3-alkyl-, halogen and HO-; 01-3594-WO-1 21 or a salt thereof, preferably a pharmaceutically acceptable salt. Accordingly, for example E-18 covers compounds of general formula (I), wherein is selected from the group B-Ac consisting of -N-C=; this means A is C; B is N;is selected from the group Wb consisting of =CH-;X-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N= and -N=C-NH-;is selected from the group R1bconsisting of isopropyl- and cyclopropyl-;group R2cconsisting of , wherein * denotes the attachment point; is selected from the group R3dconsisting of F-, Cl-, HO-, H3C-, F3C-, (H3C)2C-, H3C-CH2-, cyclopropyl-, H3C-O-, FH2C-O-, F2HC-O-, F3C-O-, (H3C)2CH-O-, (H3C)3C-O-, H3C-CH2-O-, F2HC-CH2-O-, F2C(CH3)-CH2-O-, H3C- CH2-CH2-O-, F-CH2-CH2-O-, HO-CH2-CH2-O-, H2N-CH2-C(O)-, H2C=CH-CH2-O-, H3C-O- CH2-CH2-O-,H3C-O-CH2-CH2-CH2-O-, (H3C)2C(OH)-CH2-CH2-O-, (H3C)2CH-CH2-O-, H3C- O-CH2-,cyclopropyl-O-, cyclopropyl-CH2-O-; is selected from the group R4cconsisting of (CH3CH2)2P(O)-, (CH3)(CH3CH2)P(O)-, (CH3)2P(O)-, (CH3)NH-C(O)-, (CH3)2N-C(O)- andH2N-C(O)-; is selected from the group R5bconsisting of H3C-, H3C-CH2-, H3C-CH2-CH2- and (H3C)2C-;is selected from the group R7cconsisting of H3C-, cyclopropyl-, HO(CH3)2C-CH2-; is selected from the group R8cconsisting of C1-3-alkyl-O-; 5 or a salt thereof, preferably a pharmaceutically acceptable salt. Accordingly, for example E-20 covers compounds of general formula (I), wherein 01-3594-WO-1 22 B-A is selected from the group B-Ac consisting of -N-C=; this means A is C; B is N,W is selected from the group Wb consisting of =CH-;X-Y-Z is selected from the group X-Y-Zc consisting of =CH-N-N=;R1is selected from the group R1cconsisting of cyclopropyl-; R2is selected from the group R2dconsisting of , wherein * denotes the attachment point; R3is selected from the group R3econsisting of H3C-, F2HC-CH2-O-, F3C-O-, and H3C-O-CH2-; R4is selected from the group R4dconsisting of (CH3CH2)2P(O)-, (CH3)(CH3CH2)P(O)- and (CH3)2P(O)-;R5is selected from the group R5bconsisting of H3C-, H3C-CH2-, H3C-CH2-CH2- and (H3C)2C-;R9is selected from the group R9dconsisting of H3C-; R10is selected from the group R10cconsisting of cyclopropyl- CF2H- and CF3-;or a salt thereof, preferably a pharmaceutically acceptable salt. Further preferred are the following compounds listed in table 2 or table 2A or salt thereof or5 stereoisomers thereof (the No. refers to the No. assigned to the compound in the experimentalsection). Each compound of table 2 or table 2A is represented without indicating thestereochemistry thereof, if any. Specific information concerning stereochemical properties ofcompounds of table 2 or table 2A can be taken from the experimental section. In case the finalcompounds according of said experimental section are salt forms, they can be converted into the10 neutral compound by conventional methods.Table 2: Examples I to XX 01-3594-WO-1 23 01-3594-WO-1 25In a preferred embodiment, the compounds of the invention are selected from one or more examplesI to XX in Table 2, or salts thereof or stereoisomers thereof.Table 2A: Examples XXI to XXX

[0002] 01-3594-WO-1 26 01-3594-WO-1 27 F or a salt of any thereof. A further embodiment of the present invention covers the compounds of general formula (I), 5preferably of formula (Ia), particularly the compounds listed in table 2 or table 2A, more preferablythose listed in table 2, in form of their pharmaceutically acceptable salts.A further embodiment of the present invention refers to pharmaceutical compositions comprising atleast one compound according to formula (I), preferably according to formula (Ia), or10 pharmaceutically acceptable salts thereof, optionally together with at least one inert adjuvant,diluent 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 one15 compound according to general formula (I), preferably according to formula (Ia), or pharmaceuticallyacceptable 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), or pharmaceutically acceptable salts thereof, or 20 pharmaceutical compositions comprising compounds according to general formula (I), preferably according to formula (Ia), 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 nhibition. Inhibition of the STING protein may notrequire to be a complete inhibition of the STING proteins within a cell, tissue, organ or the body of a 01-3594-WO-1 28 patient to cause the desired positive effects in a patient. A partial inhibition maybe sufficient and possibly desirable in some patients. Used terms and definitions 5 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 conventions are adhered to. 10 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, theskilled artisan can see the radical attachment point(s) to the molecule from the free valences of the 15 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. 20 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 the group to which the substituent is attached. For example, the term "3-carboxypropyl-group"25 represents the following substituent: wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms "1- methylpropyl-", "2, 2-dimethylpropyl-" or "cyclopropylmethyl-" group represent the following30 groups: 01-3594-WO-1 29 The asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. 5 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 atom, e.g. “substituted alkyl”, “substituted aryl” or the like. 10 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 proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of 15 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. 20 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 prepare optically active forms, such as by resolution of racemic forms or by synthesis, e.g. starting from optically active starting materials and / or by using chiral reagents. 25 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 separation or crystallization) and / or by using chiral reagents, such as chiral starting30 materials, chiral catalysts, or chiral auxiliaries. 01-3594-WO-1 30 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 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 5 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 with optically active chiral auxiliary reagents, subsequent diastereomer separation and removal of the chiral auxiliary group; or by kinetic resolution of a racemate (e.g. by enzymatic resolution); by enantioselective crystallization from a conglomerate of enantiomorphous crystals under suitable 10 conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary. 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 15 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. As used herein, "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds 20 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. For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, 25 ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid. Further pharmaceutically acceptable salts can be formed with cations from ammonia, L-arginine, calcium, 2, 2’- iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium and 30 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 01-3594-WO-1 31 sufficient 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 5 isolating the compounds of the present invention (e.g. trifluoro acetate salts, ) also comprise a part of the invention. The term halogen denotes fluorine, chlorine, bromine and iodine. 10 The term "C1-n-alkyl-", wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4, 5, or 6, either alone or in combination with another radical, denotes an acyclic, saturated, branched or linear 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-15C(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)-.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 a20 double bond. 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,25 cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "carbocyclyl", either alone or in combination with another radical, means a mono , bi or tricyclic 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,30 bridged and spirocyclic systems. Examples without limitation are: 01-3594-WO-1 32 5 The term "aryl" as used herein, either alone or in combination with another radical, denotes a 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,10 tetrahydronaphthyl and dihydronaphthyl. 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 SO2consisting of 3 to 14 ring atoms wherein none of the heteroatoms is part of the aromatic ring. The15 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): 20 01-3594-WO-1 33 O O 5 N O 10 01-3594-WO-1 34 5 . The term "heteroaryl" means a mono- or polycyclic ring system, comprising at least one aromatic10 ring, 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 15 each form is optionally attached through a covalent bond to any atom so long as appropriate valences are maintained): 01-3594-WO-1 35 5 . 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 20 01-3594-WO-1 36 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. 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 5 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 more detail hereinafter. 10 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 in the literature or herein or may be prepared in an analogous or similar manner. Any functional groups 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 using15 methods familiar to the one skilled in the art. The abbreviated substituents may be as defined aboveif not defined otherwise within the context of the schemes. Optimum reaction conditions and reaction times may vary depending on reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily20 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. 25 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 either commercially available or easily prepared from commercially available materials by those skilled in the art. 30 Examples and experimental data The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention. 01-3594-WO-1 37 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. 5 Flash chromatography or MPLC is performed with commercial silica gel and is equivalent to silica gel chromatography. Absolute configuration of representative examples is either defined via the chemical starting material, single crystal x-ray structure determination or protein-ligand X-ray determinations. 10 Unless otherwise specified, compounds containing chiral centers have the stereochemistry depicted. 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. 15 Scheme 1: General synthesis scheme for patent examples 20 Scheme 2a: General synthesis of intermediates A: 01-3594-WO-1 38 G1 = Boronic acids / boronate esters intermediate AScheme 2a: General synthesis of intermediates A: 5 Scheme 3a: General synthesis of intermediates B: 10 Scheme 3b: Alternative synthesis of intermediate B nterme ateScheme 3c: Alternative synthesis of intermediate B15 01-3594-WO-1 39 Scheme 4: Synthesis of pyrazole intermediates G Intermediate D Intermediate F Intermediates GStep 15 Scheme 5: Synthesis of imidazole intermediates G:

[0003] 01-3594-WO-1 40 G1 = Boronic acids / boronate esters Intermediate D Intermediates F Intermediates G2 All starting materials not described are either commercially available or described in literature. Absolute stereochemistry was either determined by single Xray analysis or by Xray 5 of protein ligand complexes of examples. Synthesis of intermediates A1 – A4:Synthesis of intermediate A1 10 Step 1: Synthesis of 1-cyclopropyl-3-methoxy-4-nitro-1H-pyrazole 3-Methoxy-4-nitro-1H-pyrazole (4.00 g, 28.0 mmol) and cyclopropylboronic acid (4.32 g, 50.3 mmol) are dissolved in ACN (80 mL) and DCM (20 mL). Copper (II) acetate (12.7 g, 69.9 mmol) and pyridine (12.0 mL) are added, and the reaction mixture is stirred under air at 65 01-3594-WO-1 41 °C for 5 d. The reaction mixture is filtered through a pad of Celite and the filtrate is evaporated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the desired compound. Analysis (method A): Rt: 0.38 min, [M+H] +: 1845 Step 2: Synthesis of 1-cyclopropyl-3-methoxy-1H-pyrazol-4-amine (intermediate A1) 1-Cyclopropyl-3-methoxy-4-nitro-1H-pyrazole (2.00 g, 10.9 mmol) is dissolved in MeOH (60 10 mL). Pd / C 10 % (200 mg) is added, and the reaction mixture is hydrogenated at RT and 3 bar for 1 h. The reaction mixture is filtered, 4 M HCl in dioxane (15 mL) is added and the filtrate is evaporated to afford the intermediate A1. Analysis (method A): Rt: 0.20 min, [M+H] +: 15415 Synthesis of intermediate A2 Step 1: Synthesis of 4-(3-methoxy-4-nitro-1H-pyrazol-1-yl)-2-methylbutan-2-ol 3-Methoxy-4-nitro-1H-pyrazole (600 mg, 4.19 mmol) is dissolved in DMF (10 mL). K2CO3(2.89 g, 21.0 mmol) and 4-bromo-2-methylbutan-2-ol (1.40 g, 8.39 mmol) are added, and the 20 reaction mixture is stirred at RT for 2 h. The reaction is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the desired compound. Analysis (method B): Rt: 0.76 min, [M+H] +: 230Step 2: Synthesis of 4-(4-amino-3-methoxy-1H-pyrazol-1-yl)-2-methylbutan-2-ol 25 (intermediate A2) 01-3594-WO-1 42 4-(3-Methoxy-4-nitro-1H-pyrazol-1-yl)-2-methylbutan-2-ol (900 mg, 3.93 mmol) is dissolved in MeOH (30 mL). Pd / C 10 % (100 mg) is added, and the reaction mixture is hydrogenated at RT and 50 psi (344.738 kPa) for 2 h. The reaction mixture is filtered, and the filtrate is5 evaporated to afford the intermediate A2. Analysis (method B): Rt: 0.59 min, [M+H] +: 200Synthesis of intermediate A3 Step 1: Synthesis of tert-butyl N-[5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl]carbamate 10 5-(Difluoromethyl)-1-methyl-1H-pyrazole-3-carboxylic acid (1.00 g, 5.39 mmol) is dissolved in t-BuOH (15 mL) and TEA (2.30 mL, 16.4 mmol). Diphenylphosphoryl azide (1.40 mL, 6.49 mmol) is slowly added dropwise over a period of 10 min, and the reaction mixture is stirred at RT for 15 min and at 80 °C for 3 h and again at RT overnight. The reaction mixture is 15 concentrated, and the crude residue is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the desired compound. Analysis (method C): Rt: 0.56 min, [M+H-isobuten] +: 192Step 2: Synthesis of 5-(difluoromethyl)-1-methyl-1H-pyrazol-3-amine (intermediate A3) 20 Tert-butyl N-[5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl]carbamate (485 mg, 1.96 mmol) isdissolved in dioxane (4 mL). HCl in dioxane (4 M, 6.00 mL, 24.0 mmol) is added, and the 01-3594-WO-1 43 reaction mixture is stirred at RT for 18 h. The reaction mixture is concentrated, triturated with DCM (10 mL) and evaporated to dryness to afford the intermediate A3. Analysis (method D): Rt: 0.21 min, [M+H] +: 1485 Synthesis of intermediate A4 Step 1: Synthesis of 1-(3-methoxy-4-nitro-1H-pyrazol-1-yl)-2-methylpropan-2-ol In a microwave vial 3-methoxy-4-nitro-1H-pyrazole (1.00 g, 6.64 mmol) is dissolved in DMF (20 mL). Cs2CO3 (4.33 g, 13.3 mmol) and 2,2-dimethyloxirane (1.78 mL, 19.9 mmol) are10added, and the reaction mixture is stirred in the closed vial at 100 °C for 2 h. The reaction is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the desired compound. Analysis (method B): Rt: 0.71 min, [M+H] +: 21615Step 2: Synthesis of 1-(4-amino-3-methoxy-1H-pyrazol-1-yl)-2-methylpropan-2-ol (intermediate A4) 1-(3-Methoxy-4-nitro-1H-pyrazol-1-yl)-2-methylpropan-2-ol (350 mg, 1.63 mmol) is dissolved in MeOH (20 mL). Pd / C 10 % (50 mg) is added, and the reaction mixture is hydrogenated at 20 RT and 3 bar for 2 h. The reaction mixture is filtered, and the filtrate is evaporated to afford the intermediate A4. Analysis (method B): Rt: 0.44 min, [M+H] +: 186Synthesis of intermediates B1 – B9:25 01-3594-WO-1 44 Synthesis of intermediates B1 Step 1: Synthesis of 1-bromo-2-(bromomethyl)-3-nitrobenzene 2-Bromo-6-nitrotoluene (50 g, 231 mmol) is dissolved in DCE (300 mL). A suspension of NBS 5 (61.8 g, 347 mmol) in DCE (400 mL) is added at RT and the reaction mixture is stirred at reflux. Then AIBN (2.66 g, 16.2 mmol) in DCM (35 mL) is slowly added (syringe pump, pump rate approximately 1 drop per 6 seconds), and the reaction mixture is stirred at reflux overnight. The reaction mixture is concentrated, the residue is dissolved in DCM (500 mL) and washed 3 x with water. The organic layer is dried over MgSO4 and filtered through a 10 short plug of silica, and the silica is washed with DCM (50 ml). The filtrate is concentrated and dried in high vacuum to afford the desired product. TLC: silica gel, CycH / EtOAc 5 / 1: Rf: 0.4 Step 2: Synthesis of N-[(2-bromo-6-nitrophenyl)methyl]-1-cyclopropyl-3-methoxy-1H-15 pyrazol-4-amine 1-Cyclopropyl-3-methoxy-1H-pyrazol-4-amine hydrochloride (A1) (418 mg, 1.41 mmol) is dissolved in ACN (50 mL) and DIPEA (0.61 mL, 3.52 mmol) is added.1-Bromo-2- (bromomethyl)-3-nitrobenzene (3.19 g, 10.8 mmol) is added in portions and the reaction 20 mixture is stirred at RT overnight. The reaction is filtered and purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the desired compound. Analysis (method A): Rt: 0.50 min, [M+H] +: 367Step 3: Synthesis of 4-bromo-2-(1-cyclopropyl-3-methoxy-1H-pyrazol-4-yl)-2H-indazole25 (intermediate B1) 01-3594-WO-1 45 N-[(2-bromo-6-nitrophenyl)methyl]-1-cyclopropyl-3-methoxy-1H-pyrazol-4-amine (2.61 g, 7.12 mmol) is suspended in MeOH (40 mL). Zinc (2.33 g, 35.6 mmol) is added, a solution of ammonium formate (449 mg, 7.12 mmol) in MeOH (20 mL) is added dropwise, and the 5 reaction mixture is stirred at RT overnight. The reaction mixture is diluted with DCM, filtered through a pad of Celite, washed with DCM, and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the intermediate B1. Analysis (method A): Rt: 0.68 min, [M+H] +: 33310 The intermediates compiled in the following table are obtained by following a reaction sequence analogous to that described for intermediate B1 using 1-bromo-2-(bromomethyl)- 3-nitrobenzene and the corresponding hetaryl amines as starting material. 01-3594-WO-1 46 Synthesis of intermediate B5: Step 1: Synthesis of 1-bromo-2-(bromomethyl)-3-nitrobenzene 5 2-Bromo-6-nitrotoluene (50 g, 231 mmol) is dissolved in DCE (300 mL). A suspension of NBS (61.8 g, 347 mmol) in DCE (400 mL) is added at RT and the reaction mixture is stirred at reflux. Then AIBN (2.66 g, 16.2 mmol) in DCM (35 mL) is slowly added (syringe pump, pump rate approximately 1 drop per 6 seconds), and the reaction mixture is stirred at reflux overnight. The reaction mixture is concentrated, the residue is dissolved in DCM (500 mL) 10 and washed 3 x with water. The organic layer is dried over MgSO4 and filtered through a 01-3594-WO-1 47 short plug of silica, and the silica is washed with DCM (50 ml). The filtrate is concentrated and dried in high vacuum to afford the desired product. TLC: silica gel, CycH / EtOAc 5 / 1: Rf: 0.4 5 Step 2: Synthesis of N-[(2-bromo-6-nitrophenyl)methyl]-5-(difluoromethyl)-1-methyl-1H- pyrazol-3-amine Under an atmosphere of argon, 5-(difluoromethyl)-1-methyl-1H-pyrazol-3-amine hydrochloride (A3) (0.36 g, 1.96 mmol) and DIPEA (1.70 mL, 9.83 mmol) are dissolved in10NMP (7 mL).1-Bromo-2-(bromomethyl)-3-nitrobenzene (0.75 g, 2.55 mmol) is added, and the reaction mixture is stirred at 80 °C for 3 h. The reaction mixture is diluted with MeTHF (90 mL) and water (70 mL) and is extracted. The organic layer is washed with water, dried, filtered, and concentrated. The residue is purified by flash chromatography (CycH / EtOAc 100 / 0 ^ CycH / EtOAc 30 / 70) to afford the desired compound.15 Analysis (method C): Rt: 0.85 min, [M+H] +: 361Step 3: Synthesis of 4-bromo-2-[5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl]-2H-indazole (intermediate B5) 20 N-[(2-bromo-6-nitrophenyl)methyl]-5-(difluoromethyl)-1-methyl-1H-pyrazol-3-amine (440mg, 0.91 mmol, 75 % purity) is dissolved in MeOH (10 mL). Zinc (400 mg, 6.12 mmol) is added, a solution of ammonium formate (70 mg, 1.11 mmol) in MeOH (5 mL) is added dropwise over a period of 10 min, and the reaction mixture is stirred at RT for 20 h. More ammonium formate (70 mg, 1.11 mmol) is added, and the reaction mixture is stirred at RT 25 for 3 h. The reaction mixture is diluted with DCM (15 mL) and an aqueous saturated solution 01-3594-WO-1 48 of NaHCO3 (0.2 mL) and stirred a few minutes. Then it is filtered, and the filtrate is concentrated. The residue is crystallized with ACN / water (2 mL each) and the precipitate is filtered to afford the intermediate B5. Analysis (method C): Rt: 0.98 min, [M+H] +: 3275 Synthesis of intermediate B6: Step 1: Synthesis of 1-bromo-2-(bromomethyl)-3-nitrobenzene 2-Bromo-6-nitrotoluene (50 g, 231 mmol) is dissolved in DCE (300 mL). A suspension of NBS 10 (61.8 g, 347 mmol) in DCE (400 mL) is added at RT and the reaction mixture is stirred at reflux. Then AIBN (2.66 g, 16.2 mmol) in DCM (35 mL) is slowly added (syringe pump, pump rate approximately 1 drop per 6 seconds), and the reaction mixture is stirred at reflux overnight. The reaction mixture is concentrated, the residue is dissolved in DCM (500 mL) and washed 3 x with water. The organic layer is dried over MgSO4 and filtered through a 15 short plug of silica, and the silica is washed with DCM (50 ml). The filtrate is concentrated and dried in high vacuum to afford the desired product. TLC: silica gel, CycH / EtOAc 5 / 1: Rf: 0.4 Step 2: Synthesis of N-[(2-bromo-6-nitrophenyl)methyl]-1-methyl-5-(trifluoromethyl)-1H-20pyrazol-3-amine 1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine hydrochloride (2.03 g, 10.1 mmol) and K2CO3(1.39 g, 10.1 mmol) are dissolved in NMP (40 mL). DIPEA (3.48 mL, 20.1 mmol) and 1- bromo-2-(bromomethyl)-3-nitrobenzene (2.00 g, 6.71 mmol) are added, and the reaction 25 mixture is stirred at 80 °C for 6 h. The reaction mixture is quenched by the addition of water 01-3594-WO-1 49 (600 mL) and saturated NH4Cl. The formed precipitate is filtered washed with water, dissolved in EtOAc, dried over MgSO4, filtered, and concentrated to afford the desired compound. Analysis (method E): Rt: 1.07 min, [M+H] +: 3795 Step 3: Synthesis of 4-bromo-2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazole (intermediate B6) N-[(2-bromo-6-nitrophenyl)methyl]-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (29010 mg, 0.76 mmol) is dissolved in MeOH (15 mL). Zinc (152 mg, 2.27 mmol) is added, a solution of ammonium formate (66.9 mg, 1.06 mmol) in MeOH (5 mL) is added dropwise, and the reaction mixture is stirred at RT overnight. More zinc (75 mg, 1.12 mmol) ammonium formate (30 mg, 0.48 mmol) are added, and the reaction mixture is stirred at RT for 3 h. The reaction mixture is diluted with DCM (20 mL), filtered through a pad of Celite, washed with 15 DCM / MeOH 1 / 1, and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the intermediate B6. Analysis (method E): Rt: 1.15 min, [M+H] +: 345Synthesis of intermediate B8: 20 Step 1: Synthesis of N-(2-amino-3-bromophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole- 3-carboxamide 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (800 mg, 3.92 mmol), 3- 25 bromobenzene-1,2-diamine (830 mg, 4.31 mmol), DIPEA (1.69 mL, 9.79 mmol) and HATU 01-3594-WO-1 50 (1.94 g, 5.09 mmol) is dissolved in DMF (15 mL). The reaction mixture is stirred at RT overnight. The reaction mixture is quenched with 150 mL water, stirred for 20 min and the precipitation is filtered, washed with water and dried to afford the desired product. Analysis (method N): Rt: 0.9 min, [M+H] +: 3635 Step 2: Synthesis of 4-bromo-2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-1H-1,3- benzodiazole (intermediate B8) 10 N-(2-Amino-3-bromophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide (1.42 g, 3.72 mmol) is dissolved in Acetic acid (15 mL). The reaction mixture is stirred at 105°C for 2h. The reaction mixture is diluted with water, stirred for 5 min and the precipitation is filtered, washed with water, and dried to afford the intermediate B8. Analysis (method N): Rt: 0.80 min, [M+H] +: 34515 Synthesis of intermediate B9: Step 1: Synthesis of (E)-1-(2-bromo-6-nitrophenyl)-N-(5-cyclopropyl-1-methyl-1H-pyrazol-3- yl)methanimine 20 2-Bromo-6-nitrobenzaldehyde (1.60 g, 6.74 mmol), 5-cyclopropyl-1-methyl-1H-pyrazol-3- amine (1.03 g, 7.13 mmol) and mole sieve 3A (2.00 g) is dissolved in methanol (20 mL). The reaction mixture is stirred at RT for 16 h. Acetic acid (0.773 ml, 13.4 mmol) is added to thereaction mixture and is stirred at RT for 2h. The reaction mixture is filtered and the filtrate is25 concentrated to afford the desired product. 01-3594-WO-1 51 Analysis (method D): Rt: 0.66 min, [M+H] +: 349Step 2: Synthesis of 4-bromo-2-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-2H-indazole (intermediate B9) 5 (E)-1-(2-Bromo-6-nitrophenyl)-N-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)methanimine (2.70 g, 6.72 mmol) is dissolved in triethyl phosphite (15 mL). The reaction mixture is stirred at 150°C for 45 min. The reaction mixture is concentrated, and the residue is purified by10reversed phase chromatography (HPLC; ACN / water / NH3) to afford the intermediate B9. Analysis (method A): Rt: 0.72 min, [M+H] +: 317Synthesis of intermediate B10 (mixture of regioisomers): 15 Step 1: 1-Bromo-2-(bromomethyl)-3-nitrobenzene (2.5 g; 8.05 mmol) is dissolved in acetonitrile (50 mL) and 5-(trifluoromethyl)-1H-pyrazol-3-amine (2.56 g, 16 mmol) is added and the mixturestirred for 10 h at 80°C. The mixture is concentrated and extracted with water and20 ethylacetate and the organic phase concentrated and purified via reversed phasechromatography. Analysis (method N): Rt: 0.81 min, [M+H] +: 365Step 2: 01-3594-WO-1 52 N-[(2-Bromo-6-nitrophenyl)methyl]-5-(trifluoromethyl)-1H-pyrazol-3-amine (1.7 g; 3 mmol),Zn nanopowder (1.38 g, 21 mmol) and MeOH ( 5 mL) are combined and ammonium formate (0.23 g dissolved in MeOH (5 mL) is added dropwise over 60 min and stirred for 17 h. Themixture is filtered and the filtrate concentrated. 5Analysis (method N): Rt: 0.97 min, [M-H] -: 329Step 3: 4-Bromo-2-[5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazole (430 mg, 1.23 mmol) isdissolved in DMF (5 mL) and NaH (113 mg, 2.6 mmol) is added at RT and stirred for 15 min.10 Then 4-methoxybenzyl chloride (0.234 mL, 1.67 mmol) is added and the mixture stirred for 6h at RT. The mixture is diluted with water and extracted with ethylacetate. The organic phase is concentrated and the product purified via silica gel chromatography (CycH / EE gradient 95 / 5 ^ 8 / 2) to afford intermediate B10Analysis (method N): Rt: 1.18 min and 1.29, [M-H] -: 451 (mixture of regioisomers)15 Synthesis of intermediates C1 – C12:Synthesis of intermediate C1: 20 Synthesis of [2-(1-cyclopropyl-3-methoxy-1H-pyrazol-4-yl)-2H-indazol-4-yl]boronic acid (intermediate C1) 4-Bromo-2-(1-cyclopropyl-3-methoxy-1H-pyrazol-4-yl)-2H-indazole (B1) (700 mg, 2.10 mmol)is dissolved in dioxane (10 mL). Bis(neopentyl glycolato)diboron (1.47 g, 6.30 mmol) and25potassium acetate (1.03 g, 10.5 mmol) are added, and the mixture is purged with argon. Pd(dppf)Cl2 x DCM (85.8 mg, 0.11 mmol) is added, and the reaction mixture is stirred at 80 °C for 3 h. After the reaction mixture is cooled to RT the reaction mixture is diluted with ACN, filtered, and purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate C1. 01-3594-WO-1 53 Analysis (method A): Rt: 0.41 min, [M+H] +: 299Synthesis of intermediate C2: Synthesis of 4-{3-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2- 5yl]-1H-pyrazol-1-yl}-2-methylbutan-2-ol (intermediate C2) 4-[4-(4-Bromo-2H-indazol-2-yl)-3-methoxy-1H-pyrazol-1-yl]-2-methylbutan-2-ol (B2) (300mg, 0.79 mmol) is dissolved in dioxane (5 mL). Bis(pinacolato)diboron (261 mg, 1.03 mmol) and potassium acetate (233 mg, 2.37 mmol) are added, and the mixture is purged with 10 argon. Pd(dppf)Cl2x DCM (64.6 mg, 0.08 mmol) is added, and the reaction mixture is stirred at 100 °C for 2 h. After the reaction mixture is cooled to RT the precipitate is filtered, washed with dioxane (5 mL), and the filtrate is concentrated afford the intermediate C2. Analysis (method E): Rt: 1.15 min, [M+H] +: 42715 Synthesis of intermediate C3: Synthesis of 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-(3-methoxy-1-methyl-1H-pyrazol-4- yl)-2H-indazole (intermediate C3) 4-Bromo-2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-2H-indazole (B3) (0.63 g, 1.83 mmol, 90 %20purity) is dissolved in dioxane (10 mL). Bis(neopentyl glycolato)diboron (0.62 g, 2.75 mmol) and potassium acetate (0.54 g, 5.49 mmol) are added, and the mixture is purged with argon. Pd(dppf)Cl2x DCM (0.22 g, 0.28 mmol) is added, and the reaction mixture is stirred at 90 °C for 1.5 h. After the reaction mixture is cooled to RT, it is diluted with iPrOAc (15 mL) and is 01-3594-WO-1 54 purified by flash chromatography (DCM / MeOH 100 / 0 ^ DCM / MeOH 90 / 10) to afford theintermediate C3. Analysis (method C): Rt: 0.51 min, [M+H] +: 273 (boronic acid)5 The intermediates compiled in the following table are obtained by following a reaction sequence analogous to that described for intermediate C2 or C3. 01-3594-WO-1 55 Synthesis of intermediate C5: Synthesis of {2-[5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl]-2H-indazol-4-yl}boronic acid (intermediate C5) 5 4-Bromo-2-[5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl]-2H-indazole (B5) (240 mg, 0.73mmol) is dissolved in dioxane (6 mL). Bis(neopentyl glycolato)diboron (249 mg, 1.10 mmol) and potassium acetate (216 mg, 2.20 mmol) are added, and the mixture is purged with argon. Pd(dppf)Cl2x DCM (159 mg, 0.19 mmol) is added, and the reaction mixture is stirred 10 at 100 °C for 2 h. After the reaction mixture is cooled to RT the reaction mixture is concentrated, diluted with DMF, filtered, and purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate C5. Analysis (method E): Rt: 0.78 min, [M+H] +: 29315 Synthesis of intermediate C7: Synthesis of 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-[1-methyl-5-(trifluoromethyl)-1H- pyrazol-3-yl]-2H-indazole (intermediate C7) 01-3594-WO-1 56 4-Bromo-2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazole (B6) (1.00 g, 2.90mmol) is dissolved in dioxane (15 mL). Bis(neopentyl glycolato)diboron (0.98 g, 4.35 mmol) and potassium acetate (0.85 g, 8.69 mmol) are added, and the mixture is purged with argon. 5 Pd(dppf)Cl2x DCM (0.71 g, 0.87 mmol) is added, and the reaction mixture is stirred at 100 °C for 3 h. After the reaction mixture is cooled to RT, it is filtered through a pad of Celite and is purified by flash chromatography (hexane / acetone 100 / 0 ^ hexane / acetone 0 / 100). Theresidue is triturated with pentane / diethyl ether to afford the intermediate C7.Analysis (method F): Rt: 2.65 min, [M+H] +: 311 (boronic acid)10 Synthesis of intermediate C9: Synthesis of 2-[5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl]-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2H-indazole (intermediate C9) 15 4-Bromo-2-[5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl]-2H-indazole (B5) (15.0 g, 44.6mmol), Bis(pinacolato)diboron (12.5 g, 49.0 mmol), potassium acetate (14.0 g, 142 mmol), Pd(dppf)Cl2 x DCM (2.00 g, 2.45 mmol) are dissolved in dioxane (200 mL). The mixture is purged with argon and is stirred at 90 °C for 3 h. After the reaction mixture is cooled to RT, it20 is diluted with DCM (200 mL), filtered, and concentrated to afford the intermediate C9. Analysis (method C): Rt: 1.16 min, [M+H] +: 375Synthesis of intermediate C10: 01-3594-WO-1 57 Synthesis of 2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-1,3-benzodiazole (intermediate C10) 4-Bromo-2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-1H-1,3-benzodiazole (B8) (1.30 g,5 3.77 mmol) is dissolved in dioxane (50 mL). Bis(pinacolato)diboron (1.45 g, 5.65 mmol) and potassium acetate (1.12 g, 11.3 mmol) are added, and the mixture is purged with argon. Pd(dppf)Cl2x DCM (153 mg, 0.19 mmol) is added, and the reaction mixture is stirred at 80 °C for 3 h. After the reaction mixture is cooled to RT the reaction mixture is filtered over celite and concentrated. The residue is extracted with EtOAc and sat. NaCI solution. The organic10 layer is dried over MgSO4, filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / formic acid) to afford the intermediate C10. Analysis (method N): Rt: 0.67 min, [M+H] +: 311Synthesis of intermediate C11: 15 Synthesis of 2-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-4-(5,5-dimethyl-1,3,2-dioxaborinan- 2-yl)-2H-indazole (intermediate C11) 4-Bromo-2-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-2H-indazole 4 (B9) (950 mg, 2.99mmol), bis(neopentylglycolato)diboron (1.39 g, 5.99 mmol), potassium acetate (0.88 g, 8.9820 mmol) and Pd(dppf)Cl2x DCM (244 mg, 0.300 mmol) are dissolved in dioxane (15 mL). The mixture is purged with argon and is stirred at 80 °C for 3 h. After the reaction mixture is cooled to RT the reaction mixture is absorbed on diatomaceous earth and is purified by flash 01-3594-WO-1 58 chromatography (CH / EtOAc 100 / 0 ^ 0 / 100). The residue is diluted in n-heptane, sonicatedfor 5 min and the precipitation is filtered to afford the intermediate C11. Analysis (method A): Rt: 0.45 min, [M+H] +: 3515 Synthesis of intermediate C12: Synthesis of {2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazol-4-yl}boronic acid (intermediate C12) 4-Bromo-2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazole (B6) (475 mg, 1.3710 mmol), Bis(neopentylglycolato)diboron (466 mg, 2.06 mmol), potassium acetate (405 mg, 2.06 mmol) and Pd(dppf)Cl2 x DCM (279 mg, 0.365 mmol) are dissolved in dioxane (15 mL). The mixture is purged with argon and is stirred at 100 °C for 2.5 h. After the reaction mixture is cooled to RT, filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate C12.15 Analysis (method E): Rt: 0.87 min, [M+H] +: 311Synthesis of intermediate C13: Synthesis of 2-{1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)pyrazol-3-yl}-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)indazole and 2-{2-[(4-methoxyphenyl)methyl]-5-20 (trifluoromethyl)pyrazol-3-yl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (intermediate C13) 01-3594-WO-1 59 4-Bromo-2-{1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)pyrazol-3-yl}indazole (B10) (550 mg, 1.29 mmol) is dissolved in acetonitril (10 mL). Bis(pinacolato)diboron (625 mg, 2.44mmol) and potassium pivalate (540 mg, 3.7 mmol) are added, and the mixture is purged withargon. Pd(dppf)Cl2 x DCM (100 mg, 0.12 mmol) is added, and the reaction mixture is stirred5 at 80 °C for 3 h. After the reaction mixture is cooled to RT the reaction mixture is. extracted with EtOAc and water. The organic layer is dried over to afford the intermediate C13. Analysis (method E): Rt: 1.00 and 1.25 min 10 Synthesis of intermediates D1 and D2: Synthesis of intermediate D1: 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), cyclopropyl zinc bromide (132 mL, 65.9 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 ^ DCM / MeOH 90 / 10) to afford the desired compound.20 Analysis (method D): Rt: 0.31 min, [M+H] +: 123Step 2: Synthesis of 2, 4-dibromo-5-cyclopropyl-1-methyl-1H-imidazole (intermediate D1) 5-Cyclopropyl-1-methyl-1H-imidazole (9.20 g, 52.7 mmol) is dissolved in ACN (200 mL). At – 525 °C NBS (18.8 g, 105 mmol) is added in portions and the reaction mixture is stirred at – 5 °Cfor 30 min and at RT for 4 h. The reaction mixture is quenched by the addition of a saturated Na2S2O3 solution (40.7 mL, 4.4 M). The formed precipitate is filtered and washed with ACN. 01-3594-WO-1 60 The filtrate is extracted with EtOAc and the organic layer is dried (Na2SO4), filtered and concentrated. The residue is purified by flash chromatography (CycH / EtOAc 95 / 5 CycH / EtOAc 65 / 35) to afford the intermediate D1. Analysis (method C): Rt: 0.77 min, [M+H] +: 2795 Synthesis of intermediate D2: Synthesis of 5-iodo-3-methyl-4-(propan-2-yl)-1H-pyrazole (intermediate D2) 3-Methyl-4-(propan-2-yl)-1H-pyrazole (10 g, 80.5 mmol) is dissolved in ACN (150 mL). NIS (25 10 g, 111 mmol) is added, and the reaction mixture is stirred at 80 °C overnight. The reaction mixture is filtered, and the filtrate is evaporated. The residue is quenched with a half saturated Na2S2O3 solution and extracted three times with DCM. The combined organic layers are dried (Na2SO4), filtered and concentrated. The crude product is purified by flash chromatography (CycH / EtOAc 95 / 5 ^ CycH / EtOAc 76 / 24) to afford the intermediate D2.15 Analysis (method E): Rt: 0.93 min, [M+H] +: 251Synthesis of intermediates E1 – E7:Synthesis of intermediate E1:20Synthesis of 4-chloro-N-methyl-3-(trifluoromethoxy)benzamide (intermediate E1) 4-Chloro-3-(trifluoromethoxy)benzoic acid (1.00 g, 4.16 mmol) is dissolved in DMF (8 mL).DIPEA (2.20 mL, 12.7 mmol) and HATU (1.90 g, 5.00 mmol) are added, and the reaction mixture is stirred at rt for 10 min. Then methylamine (2 M in THF) (4.20 mL, 8.40 mmol) is25 added, and it is stirred at rt for 18 h. The reaction mixture is diluted with DCM (20 mL) and 01-3594-WO-1 61 washed with an aqueous NaHCO3 solution (1.1 M) (10 mL). The organic layer is dried and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the intermediate E1. Analysis (method D): Rt: 0.56 min, [M+H] +: 2545 Synthesis of intermediate E2 and E3: Step 1: Synthesis of ethyl [4-chloro-3-(trifluoromethoxy)phenyl](methyl)phosphinate Under an argon atmosphere 4-bromo-1-chloro-2-(trifluoromethoxy)benzene (700 mg, 2.41 10 mmol) and ethyl methylphosphinate (604 mg, 5.31 mmol) are dissolved in ACN (5 mL) and DIPEA (1.67 mL, 9.66 mmol). Pd(PPh3)4 (279 mg, 0.24 mmol) is added and the reaction mixture is stirred at 85 °C overnight. The reaction mixture is filtered, and the filtrate is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to obtain the title compound.15 Analysis (method B): Rt: 0.93 min, [M+H] +: 303Step 2: Synthesis of 1-chloro-4-[ethyl(methyl)phosphoryl]-2-(trifluoromethoxy)benzene (intermediate E2) 20Under a nitrogen atmosphere ethyl [4-chloro-3- (trifluoromethoxy)phenyl](methyl)phosphinate (748 mg, 2.47 mmol) is dissolved in THF (10mL). Ethyl magnesium bromide (2.91 mL, 3.4 M, 9.89 mmol) is added at – 10 °C dropwiseand the reaction mixture is stirred at RT overnight. Ethyl magnesium bromide (3.0 mL) is 01-3594-WO-1 62 added at 0 °C dropwise and the reaction mixture is stirred at RT for 4 h. The reaction mixture is quenched with water and is extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated to afford the intermediate E2. Analysis (method E): Rt: 0.87 min, [M+H] +: 2875 Step 3: Synthesis of 1-chloro-4-[(S)-ethyl(methyl)phosphoryl]-2-(trifluoromethoxy)benzene (intermediate E3) 1-Chloro-4-[ethyl(methyl)phosphoryl]-2-(trifluoromethoxy)benzene (2.94 g, 9.96 mmol) is10 separated by chiral purification method O to afford the compounds 1-chloro-4-[(S)- ethyl(methyl)phosphoryl]-2-(trifluoromethoxy)benzene E3 (analysis (method G): Rt: 2.49min) and 1-chloro-4-[(R)-ethyl(methyl)phosphoryl]-2-(trifluoromethoxy)benzene (Analysis (method G): Rt: 2.71 min).15Synthesis of intermediate E4: Synthesis of 1-chloro-4-(dimethylphosphoryl)-2-methylbenzene (intermediate E4) Under an argon atmosphere, 4-bromo-1-chloro-2-methylbenzene (2.00 g, 9.74 mmol) and (methylphosphonoyl)methane (840 mg, 10.8 mmol) are dissolved in ACN (40 mL) and DIPEA 20 (6.74 mL, 39.0 mmol). Pd(PPh3)4(1.12 g, 0.97 mmol) is added and the reaction mixture is stirred at 80 °C overnight. The reaction mixture is filtered, and the filtrate is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to obtain the intermediate E4. Analysis (method C): Rt: 0.57 min, [M+H] +: 203 01-3594-WO-1 63 Synthesis of intermediate E5: Step 1: Synthesis of methyl 4-bromo-3-(hydroxymethyl)benzoate 5 4-Bromo-3-(hydroxymethyl)benzoic acid (200 mg, 0.85 mmol) is dissolved in MeOH (5 mL). HCl (4 M in dioxane) (5 mL, 20.0 mmol) is added, and the reaction mixture is stirred at 70 °C for 3 h. The reaction mixture is concentrated to dryness to afford the desired compound. Analysis (method E): Rt: 0.82 min, [M+H] +: 24510Step 2: Synthesis of 4-bromo-3-(methoxymethyl)benzoic acid Methyl 4-bromo-3-(hydroxymethyl)benzoate (210 mg, 0.86 mmol) is dissolved in THF (5 mL).NaH (55 %, 86.0 mg, 1.97 mmol) is added, and the reaction mixture is stirred at rt for 0.5 h. Then MeI (64.0 µL, 1.03 mmol) is added, and the reaction mixture is stirred at rt for 1 h. 15 More NaH (55 %, 86.0 mg, 1.97 mmol) and MeI (64.0 µL, 1.03 mmol) are added, and the reaction mixture is stirred at rt overnight. The reaction is diluted with EtOAc and washed with 1 M HCl and water. The organic layer is dried (MgSO4), filtered, and evaporated to afford the titled compound. Analysis (method H): Rt: 0.92 min, [M+H] +: 24320 Step 3: Synthesis of methyl 4-bromo-3-(methoxymethyl)benzoate (intermediate E5) 01-3594-WO-1 64 4-Bromo-3-(methoxymethyl)benzoic acid (210 mg, 0.86 mmol) is dissolved in MeOH (5 mL). HCl (4 M in dioxane) (5 mL, 20.0 mmol) is added, and the reaction mixture is stirred at 70 °C for 2 h. The reaction mixture is concentrated to dryness to afford the intermediate E5. Analysis (method E): Rt: 0.99 min, [M+H] +: 2595 Synthesis of intermediate E6: Synthesis of 1-chloro-4-(diethylphosphoryl)-2-(trifluoromethoxy)benzene (intermediate E6) Under an argon atmosphere, 4-bromo-1-chloro-2-(trifluoromethoxy)benzene (1.00 g, 3.4510mmol) and (ethylphosphonoyl)ethane (700 mg, 6.27 mmol) are dissolved in ACN (5 mL) and DIPEA (2.50 mL, 14.5 mmol). Pd(PPh3)4 (1.40 g, 1.21 mmol) is added and the reaction mixture is stirred at 80 °C for 19.5 h. The reaction mixture is filtered, concentrated, and the residue is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to obtain the intermediate E6.15 Analysis (method A): Rt: 0.55 min, [M+H] +: 301Synthesis of intermediate E7: Synthesis of 1-chloro-4-(dimethylphosphoryl)-2-(trifluoromethoxy)benzene (intermediate E7) 20 Under an argon atmosphere, 4-bromo-1-chloro-2-(trifluoromethoxy)benzene (1.00 g, 3.44 mmol) and (methylphosphonoyl)methane (425 mg, 5.17 mmol) are dissolved in ACN (5 mL) and DIPEA (2.40 mL, 13.8 mmol). Pd(PPh3)4(400 mg, 0.34 mmol) is added and the reaction 01-3594-WO-1 65 mixture is stirred at 80 °C for 24 h. The reaction mixture is filtered, and the filtrate is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to obtain the intermediate E7. Analysis (method D): Rt: 0.56 min, [M+H] +: 2735 Synthesis of intermediates F1 – F9:Synthesis of intermediate F1: Synthesis of 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N-methyl-3-(trifluoromethoxy)10 benzamide (intermediate F1) 4-Chloro-N-methyl-3-(trifluoromethoxy)benzamide (E1) (750 mg, 2.96 mmol) is dissolved indioxane (15 mL). Bis(neopentyl glycolato)diboron (1.20 g, 5.31 mmol) and potassium acetate (900 mg, 9.17 mmol) are added, and the mixture is purged with argon. XPhos Pd G3 (300 mg, 15 0.35 mmol) is added, and the reaction mixture is stirred at 100 °C for 1.5 h. After the reaction mixture is cooled to RT, it is diluted with ACN (20 mL), and the precipitate is filtered. The filtrate is concentrated, and the residue is triturated with MTBE. The formed precipitate is filtered and dried to afford the intermediate F1. Analysis (method C): Rt: 0.42 min, [M+H] +: 264 (boronic acid)20 Synthesis of intermediate F2: Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethoxy)benzonitrile (intermediate F2) 01-3594-WO-1 66 4-Bromo-3-(trifluoromethoxy)benzonitrile (7.50 g, 28.2 mmol) is dissolved in dioxane (120 mL). Bis(pinacolato)diboron (10.7 g, 42.3 mmol) and potassium acetate (6.91 g, 70.5 mmol) are added, and the mixture is purged with argon. Pd(dppf)Cl2 x DCM (2.30 g, 2.82 mmol) is 5 added, and the reaction mixture is stirred at 80 °C for 2 h. After the reaction mixture is cooled to RT it is diluted with ACN / MeOH 5 / 1 and is filtered through a pad of celite and SiO2. The filtrated is concentrated and the residue is purified by flash chromatography(CycH / EtOAc 100 / 0 ^ CycH / EtOAc 75 / 25 ^ CycH / EtOAc 0 / 100) to afford the intermediateF2. 10 Analysis (method C): Rt: 0.61 min and 1.14 min (boronic ester) TLC: silica gel, CycH / EtOAc 4 / 1: Rf: 0.4 – 0.5Synthesis of intermediate F3: Synthesis of [2-(2,2-difluoroethoxy)-4-(methoxycarbonyl)phenyl]boronic acid (intermediate15F3) Methyl 4-bromo-3-(2,2-difluoroethoxy)benzoate (300 mg, 0.97 mmol, 95 % purity) isdissolved in dioxane (5 mL). Bis(neopentyl glycolato)diboron (240 mg, 1.06 mmol) and potassium acetate (303 mg, 3.09 mmol) are added, and the mixture is purged with argon. 20 Pd(dppf)Cl2x DCM (78.9 mg, 0.10 mmol) is added, and the reaction mixture is stirred at 100 °C for 2 h. After the reaction mixture is cooled to RT, it is diluted with ACN, filtered, and purified by reversed phase chromatography (HPLC; ACN / water / TFA) to obtain the intermediate F3. Analysis (method E): Rt: 0.78 min, [M+H] +: 261 01-3594-WO-1 67 Synthesis of intermediate F4: Synthesis of 2-{4-[(S)-ethyl(methyl)phosphoryl]-2-(trifluoromethoxy)phenyl}-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (intermediate F4) 5 1-Chloro-4-[ethyl(methyl)phosphoryl]-2-(trifluoromethoxy)benzene (E3) (100 mg, 0.35 mmol) is dissolved in dioxane (3 mL). Bis(pinacolato)diboron (177 mg, 0.70 mmol) and potassium acetate (105 mg, 1.07 mmol) are added, and the mixture is purged with argon. Xphos Pd G3 (20.0 mg, 0.02 mmol) is added, and the reaction mixture is stirred at 80 °C for 10 40 min and at 100 °C for 1 h. After the reaction mixture is cooled to RT it is filtered and the filtrate is concentrated to afford the intermediate F4.Analysis (method C): Rt: 0.90 min, [M+H] +: 379The intermediates compiled in the following table are obtained by following a reaction15 sequence analogous to that described for intermediate F3. 01-3594-WO-1 68 Synthesis of intermediate F9: Synthesis of [4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]boronic acid (intermediate F9) 01-3594-WO-1 69 1-Chloro-4-(dimethylphosphoryl)-2-(trifluoromethoxy)benzene (E7) (613 mg, 2.24 mmol), Bis(neopentyl glycolato)diboron (1.27 g, 5.62 mmol), Pd(dppf)Cl2 x DCM (300 mg, 0.367 5 mmol) and potassium acetate (662 mg, 6.74 mmol) are dissolved in dioxane (10 mL). The mixture is purged with argon and is stirred at 100 °C for 3 h. After the reaction mixture is cooled to RT, filtered and the filtrate is concentrated. To the residue is added ACN (10 ml), water (2 ml) and TFA (0.5 ml) and the precipitation is filtered. The filtrate is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to obtain the intermediate F9.10 Analysis (method C): Rt: 0.37 min, [M+H] +: 283Synthesis of intermediates G1 – G10:Synthesis of intermediate G1: 15 Synthesis of 4-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-N-methyl-3- (trifluoromethoxy)benzamide (intermediate G1) 2,4-Dibromo-5-cyclopropyl-1-methyl-1H-imidazole (D1) (0.80 g, 2.86 mmol) is dissolved in dioxane (12 mL) and water (3 mL).4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N-methyl-3-20(trifluoromethoxy) benzamide (F1) (2.00 g, 2.96 mmol, 49 % purity) and an aq. solution of Cs2CO3 (1 M, 9.00 mL, 9.00 mmol) are added, and the mixture is purged with argon. Pd(PPh3)4 (0.33 g, 0.29 mmol) is added, and the reaction mixture is stirred at 80 °C for 3 h. After the reaction mixture is cooled to RT, it is diluted with isopropyl acetate (20 mL). The 01-3594-WO-1 70 organic layer is separated and concentrated. The residue is purified by preparative HPLC (HPLC; ACN / water / NH3) to afford intermediate G1.Analysis (method C): Rt: 0.76 min, [M+H] +: 4185 The intermediates compiled in the following table are obtained by following a reaction sequence analogous to that described for intermediate G1. 01-3594-WO-1 71 Synthesis of intermediate G10: Synthesis of 4-bromo-5-cyclopropyl-2-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]- 1-methyl-1H-imidazole (intermediate G10) 5 01-3594-WO-1 72 2,4-Dibromo-5-cyclopropyl-1-methyl-1H-imidazole (D1) (360 mg, 1.28 mmol), [4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]boronic acid (400 mg, 0.851 mmol), Xphos Pd G3 (75.0 mg, 0.0868 mmol) and an aq. solution of Cs2CO3 (1 M, 2.55 mL, 2.55 mmol) are dissolved in dioxane (5 mL). The reaction mixture is stirred at 80 °C for 3 h and after at RT for 5 14 h. The reaction mixture is extracted with DCM and water. The organic layer is separated and concentrated. The residue is purified by preparative HPLC (HPLC; ACN / water / TFA) to afford intermediate G10.Analysis (method C): Rt: 0.70 min, [M+H] +: 43710 Synthesis of intermediate G4: Synthesis of 4-bromo-5-cyclopropyl-2-{4-[(S)-ethyl(methyl)phosphoryl]-2-(trifluoromethoxy) phenyl}-1-methyl-1H-imidazole (intermediate G4) 2,4-Dibromo-5-cyclopropyl-1-methyl-1H-imidazole (D1) (98.0 mg, 0.35 mmol) is dissolved in15 dioxane (3 mL).2-{4-[Ethyl(methyl)phosphoryl]-2-(trifluoromethoxy)phenyl}-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (F4) (0.30 g, 0.35 mmol, 44 % purity) and an aq. solution of Cs2CO3 (1 M, 1.40 mL, 1.40 mmol) are added, and the mixture is purged with argon. Xphos Pd G3 (30.0 mg, 0.04 mmol) is added, and the reaction mixture is stirred at 80 °C for 2 h. After the reaction mixture is cooled to RT, it is diluted with DCM (20 mL) and water (10 mL). 20 The organic layer is separated and concentrated. The residue is purified by preparative HPLC (HPLC; ACN / water / TFA) to afford intermediate G4.Analysis (method C): Rt: 0.75 min, [M+H] +: 451Synthesis of intermediate G5: 25 Synthesis of 1-[4-(dimethylphosphoryl)-2-methylphenyl]-3-iodo-5-methyl-4-(propan-2-yl)- 1H-pyrazole (intermediate G5) 01-3594-WO-1 73 3-Iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (D2) (280 mg, 1.12 mmol), [4- (dimethylphosphoryl)-2-methylphenyl]boronic acid (F5) (261 mg, 1.23 mmol) and copper (II) acetate (61.0 mg, 0.34 mmol) are dissolved in ACN (10 mL), DCM (10 mL) and pyridine (159 5 mg, 2.02 mmol). The reaction mixture is stirred at 60 °C for 14 h under an atmosphere of air. The reaction mixture is filtered, and the filtrate is purified by preparative HPLC (HPLC; ACN / water / TFA) to afford intermediate G5. Analysis (method E): Rt: 1.02 min, [M+H] +: 41710Synthesis of intermediate G8: Step 1: Synthesis of 4-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-3- (trifluoromethoxy)benzoic acid 4-(4-Bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-3-(trifluoromethoxy)benzonitrile (G2)15(0.20 g, 0.52 mmol) is dissolve in EtOH (5 mL). NaOH (4 M, 1.50 mL, 6.00 mmol) is added, and the reaction mixture is stirred at 80 °C for 1.5 h. After the reaction mixture is cooled to RT, it is acidified with TFA (1 mL) and purified by preparative HPLC (HPLC; ACN / water / TFA) to afford the desired compound. Analysis (method C): Rt: 0.75 min, [M+H] +: 40520 Step 2: Synthesis of 4-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-N,N-dimethyl-3- (trifluoromethoxy)benzamide (intermediate G8) 01-3594-WO-1 74 4-(4-Bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-3-(trifluoromethoxy)benzoic acid x TFA (0.17 g, 0.32 mmol) is dissolved in DMF (3 mL). DIPEA (0.28 mL, 1.65 mmol) and HATU (0.19 g, 0.49 mmol) are added and stirred at rt for 5 min. Then dimethyl amine (2 M in THF, 0.415 mL, 0.81 mmol) is added and the reaction mixture is stirred at rt for 20 min. The reaction mixture is purified by preparative HPLC (HPLC; ACN / water / NH3) to afford the intermediate G8. Analysis (method C): Rt: 0.78 min, [M+H] +: 43210 Synthesis of Examples: Synthesis of Examples 1, 2, 9, 15, 17, 18 and 19: Synthesis of 4-{5-cyclopropyl-4-[2-(1-cyclopropyl-3-methoxy-1H-pyrazol-4-yl)-2H-indazol-4- yl]-1-methyl-1H-imidazol-2-yl}-N-methyl-3-(trifluoromethoxy)benzamide (example 1) 15 4-(4-Bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-N-methyl-3-(trifluoromethoxy) benzamide (G1) (63.1 mg, 0.15 mmol) is dissolved in dioxane (2 mL). [2-(1-Cyclopropyl-3- methoxy-1H-pyrazol-4-yl)-2H-indazol-4-yl]boronic acid (C1) (45.0 mg, 0.15 mmol) and an aqueous solution of K3PO4 (2 M, 604 µL, 1.21 mmol) are added, and the mixture is purged 20 with argon. XPhos Pd G3 (6.39 mg, 0.01 mmol) is added, and the reaction mixture is stirred at 80 °C for 3 h. After the reaction mixture is cooled to RT, it is filtered, and the residue is purified by preparative HPLC (HPLC; ACN / water / TFA) to afford example 1. 01-3594-WO-1 75Analysis (method C): Rt: 0.67 min, [M+H] +: 592The examples compiled in the following table are obtained by following a reaction sequence analogous to that described for example 1. 01-3594-WO-1 76 01-3594-WO-1 77 Synthesis of examples 4, 8, 11 and 16: Synthesis of example 4: Step 1: Synthesis of 4-{5-cyclopropyl-4-[2-(3-ethoxy-1-methyl-1H-pyrazol-4-yl)-2H-indazol-4- 5 yl]-1-methyl-1H-imidazol-2-yl}-3-(trifluoromethoxy)benzonitrile 4-(4-Bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-3-(trifluoromethoxy)benzonitrile (G2) (59.1 mg, 0.153 mmol) is dissolved in dioxane (1 mL).4-(5,5-dimethyl-1,3,2-dioxaborinan-2- 10 yl)-2-(3-ethoxy-1-methyl-1H-pyrazol-4-yl)-2H-indazole (C4) (86.0 mg, 0.153 mmol) and an aqueous solution of K3PO4(2 M, 382 µL, 0.765 mmol) are added, and the mixture is purged with argon. XPhos Pd G3 (20.0 mg, 0.0236 mmol) is added, and the reaction mixture is 01-3594-WO-1 78 stirred at 80 °C for 2 h. After the reaction mixture is cooled to RT, diluted with DCM and water. The organic phase is separated and concentrated to afford the desired compound. Analysis (method C): Rt: 0.73 min, [M+H] +: 5485 Step 2: Synthesis 4-{5-cyclopropyl-4-[2-(3-ethoxy-1-methyl-1H-pyrazol-4-yl)-2H-indazol-4-yl]- 1-methyl-1H-imidazol-2-yl}-3-(trifluoromethoxy)benzamide (example 4) 4-{5-cyclopropyl-4-[2-(3-ethoxy-1-methyl-1H-pyrazol-4-yl)-2H-indazol-4-yl]-1-methyl-1H- 10 imidazol-2-yl}-3-(trifluoromethoxy)benzonitrile (135 mg, 0.153 mmol) is dissolved in DMSO (1.5 mL). H2O2(30 %, 394 µL, 3.82 mmol) and K2CO3(71.0 mg, 0.514 mmol) are added, and the reaction mixture is stirred at rt for 30 min. The reaction mixture is filtered, and the residue is purified by preparative HPLC (HPLC; ACN / water / TFA) to afford example 4.Analysis (method C): Rt: 0.63 min, [M+H] +: 56615 The examples compiled in the following table are obtained by following a reaction sequence analogous to that described for example 4. 01-3594-WO-1 79 01-3594-WO-1 80 Synthesis of examples 3 and 5: Synthesis of example 3: Step 1: Synthesis of 4-{5-cyclopropyl-4-[2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-2H-indazol- 5 4-yl]-1-methyl-1H-imidazol-2-yl}-3-(trifluoromethoxy)benzonitrile 4-(4-Bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-3-(trifluoromethoxy)benzonitrile (G2) (0.27 g, 0.70 mmol) is dissolved in dioxane (5 mL).4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)- 2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-2H-indazole (C3) (0.30 g, 0.75 mmol, 85 % purity)10and an aqueous solution of K3PO4 (2 M, 1.05 mL, 2.10 mmol) are added, and the mixture is purged with argon. XPhos Pd G3 (59.2 mg, 0.07 mmol) is added, and the reaction mixture is stirred at 80 °C for 2 h. After the reaction mixture is cooled to RT, it is diluted with ACN (4 mL), filtered, and concentrated. The residue is purified by preparative HPLC (HPLC; ACN / water / TFA) to afford the desired compound.15 Analysis (method C): Rt: 0.68 min, [M+H] +: 534Step 2: Synthesis of 4-{5-cyclopropyl-4-[2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-2H-indazol- 4-yl]-1-methyl-1H-imidazol-2-yl}-3-(trifluoromethoxy)benzoic acid 01-3594-WO-1 81 4-{5-Cyclopropyl-4-[2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-2H-indazol-4-yl]-1-methyl-1H- imidazol-2-yl}-3-(trifluoromethoxy)benzonitrile x TFA (0.14 g, 0.22 mmol) is dissolved in EtOH (2 mL). NaOH (4 M, 0.55 mL, 2.20 mmol) is added, and the reaction mixture is stirred at 80 °C for 1 h and at rt overnight. The reaction mixture is diluted with water (10 mL) and acidified 5 with 4 M HCl (0.55 mL) till pH 4. The formed precipitate is filtered, washed with water, and dried in vacuum at 40 °C to afford the desired compound. Analysis (method C): Rt: 0.64 min, [M+H] +: 553Step 3: Synthesis of 4-{5-cyclopropyl-4-[2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-2H-indazol-10 4-yl]-1-methyl-1H-imidazol-2-yl}-N,N-dimethyl-3-(trifluoromethoxy)benzamide (example 3) 4-{5-Cyclopropyl-4-[2-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-2H-indazol-4-yl]-1-methyl-1H- imidazol-2-yl}-3-(trifluoromethoxy)benzoic acid x HCl (60.0 mg, 0.09 mmol, 91 % purity) is dissolved in DMF (1 mL). DIPEA (48.1 µL, 0.28 mmol) and HATU (38.8 mg, 0.10 mmol) are15added and stirred at rt for 10 min. Then dimethyl amine (2 M in THF, 92.7 µL, 0.19 mmol) is added and the reaction mixture is stirred at rt overnight. The reaction mixture is filtered and purified by SFC (preparative SFC; BEH_2-EP; MeOH / CO2; 40 °C; BPR: 120 bar) to afford example 3. Analysis (method I): Rt: 0.85 min, [M+H] +: 58020 The examples compiled in the following table are obtained by following a reaction sequence analogous to that described for example 3. 01-3594-WO-1 82 Synthesis of example 6 and 12: Synthesis of example 6: Step 1: Synthesis of methyl 4-{5-cyclopropyl-4-[2-(1-cyclopropyl-3-methoxy-1H-pyrazol-4-yl)- 5 2H-indazol-4-yl]-1-methyl-1H-imidazol-2-yl}-3-(2,2-difluoroethoxy)benzoate Methyl 4-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-3-(2,2- difluoroethoxy)benzoate (G3) (93.8 mg, 0.23 mmol) is dissolved in dioxane (5 mL). [2-(1- Cyclopropyl-3-methoxy-1H-pyrazol-4-yl)-2H-indazol-4-yl]boronic acid (C1) (80.8 mg, 0.2710mmol) and an aqueous solution of Cs2CO3 (2 M, 1.00 mL, 2.00 mmol) are added, and the mixture is purged with argon. Pd(dtbpf)Cl2 (14.7 mg, 0.02 mmol) is added, and the reaction mixture is stirred at 80 °C for 5 h. After the reaction mixture is cooled to RT, it is filtered, and the residue is purified by preparative HPLC (HPLC; ACN / water / TFA) to afford the desired compound.15 Analysis (method E): Rt: 0.83 min, [M+H] +: 589 01-3594-WO-1 83 Step 2: Synthesis of 4-{5-cyclopropyl-4-[2-(1-cyclopropyl-3-methoxy-1H-pyrazol-4-yl)-2H- indazol-4-yl]-1-methyl-1H-imidazol-2-yl}-3-(2,2-difluoroethoxy)benzoic acid 5 4-{5-Cyclopropyl-4-[2-(1-cyclopropyl-3-methoxy-1H-pyrazol-4-yl)-2H-indazol-4-yl]-1-methyl- 1H-imidazol-2-yl}-3-(2,2-difluoroethoxy)benzoate (117 mg, 0.20 mmol) is dissolved in MeOH (4 mL). NaOH (1 M, 500 µL, 0.50 mmol) is added, and the reaction mixture is stirred at rt overnight. The reaction mixture is neutralized with 1 M HCl and concentrated. The residue is 10 triturated with acetone, the precipitate is filtered, and the filtrate is concentrated to afford the desired compound. Analysis (method E): Rt: 0.80 min, [M+H] +: 575Step 3: Synthesis of 4-{5-cyclopropyl-4-[2-(1-cyclopropyl-3-methoxy-1H-pyrazol-4-yl)-2H-15 indazol-4-yl]-1-methyl-1H-imidazol-2-yl}-3-(2,2-difluoroethoxy)benzamide (example 6) 4-{5-Cyclopropyl-4-[2-(1-cyclopropyl-3-methoxy-1H-pyrazol-4-yl)-2H-indazol-4-yl]-1-methyl- 1H-imidazol-2-yl}-3-(2,2-difluoroethoxy)benzoic acid (40.0 mg, 0.07 mmol) is dissolved in DMF (2 mL). DIPEA (60.2 µL, 0.35 mmol), HATU (29.1 mg, 0.08 mmol) and ammonium 20 chloride (11.2 mg, 0.21 mmol) are added, and the reaction mixture is stirred at rt overnight. 01-3594-WO-1 84 The reaction mixture is filtered and purified by preparative HPLC (HPLC; ACN / water / NH3) to afford example 6.Analysis (method E): Rt: 0.78 min, [M+H] +: 5745 The examples compiled in the following table are obtained by following a reaction sequence analogous to that described for example 6. Synthesis of example 7: Synthesis of 4-(5-cyclopropyl-2-{4-[(S)-ethyl(methyl)phosphoryl]-2-10(trifluoromethoxy)phenyl}-1-methyl-1H-imidazol-4-yl)-2-[5-(difluoromethyl)-1-methyl-1H- pyrazol-3-yl]-2H-indazole (example 7) 01-3594-WO-1 85 4-Bromo-5-cyclopropyl-2-{4-[(S)-ethyl(methyl)phosphoryl]-2-(trifluoromethoxy)phenyl}-1- methyl-1H-imidazole (G4) (29.0 mg, 0.06 mmol) is dissolved in dioxane (2 mL). {2-[5- (Difluoromethyl)-1-methyl-1H-pyrazol-3-yl]-2H-indazol-4-yl}boronic acid (C5) (24.0 mg, 0.08 5 mmol, 95 % purity) and an aqueous solution of Cs2CO3 (1 M, 0.20 mL, 0.20 mmol) are added, and the mixture is purged with argon. Pd(dtbpf)Cl2 (8.00 mg, 0.01 mmol) is added, and the reaction mixture is stirred at 80 °C for 3 h and at rt for 14 h. After the reaction mixture is cooled to RT, it is diluted with DCM (10 mL) and water (5 mL). The organic layer is separated and concentrated. The residue is purified by preparative HPLC (HPLC; ACN / water / TFA) to10 afford example 7. Analysis (method C): Rt: 0.67 min, [M+H] +: 619Synthesis of example 10: Synthesis of 4-(5-cyclopropyl-2-{4-[(S)-ethyl(methyl)phosphoryl]-2-15 (trifluoromethoxy)phenyl}-1-methyl-1H-imidazol-4-yl)-2-[1-methyl-5-(trifluoromethyl)-1H- pyrazol-3-yl]-2H-indazole (example 10) 4-Bromo-5-cyclopropyl-2-{4-[(S)-ethyl(methyl)phosphoryl]-2-(trifluoromethoxy)phenyl}-1- methyl-1H-imidazole (G4) (33.0 mg, 0.06 mmol, 84 % purity) is dissolved in dioxane (3 mL).204-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]- 01-3594-WO-1 86 2H-indazole (C7) (38.3 mg, 0.09 mmol, 91 % purity) and an aqueous solution of Cs2CO3 (1 M, 0.20 mL, 0.20 mmol) are added, and the mixture is purged with argon. Pd(dtbpf)Cl2 (4.00 mg, 0.006 mmol) is added, and the reaction mixture is stirred at 80 °C for 3 h and at rt for 16 h. After the reaction mixture is cooled to RT, it is diluted with ACN (5 mL), filtered, and 5 concentrated. The residue is purified by preparative HPLC (HPLC; ACN / water / TFA) to afford example 10. Analysis (method L): Rt: 0.73 min, [M+H] +: 637Synthesis of examples 13 and 14: 10 Step 1: Synthesis of 4-(5-cyclopropyl-2-{4-[ethyl(methyl)phosphoryl]-2- (trifluoromethoxy)phenyl}-1-methyl-1H-imidazol-4-yl)-2-(1-cyclopropyl-3-methoxy-1H- pyrazol-4-yl)-2H-indazole 4-Bromo-5-cyclopropyl-2-{4-[ethyl(methyl)phosphoryl]-2-(trifluoromethoxy)phenyl}-1-15 methyl-1H-imidazole (G7) (50.0 mg, 0.11 mmol) is dissolved in dioxane (2.5 mL). [2-(1- Cyclopropyl-3-methoxy-1H-pyrazol-4-yl)-2H-indazol-4-yl]boronic acid (C1) (50.0 mg, 0.17 mmol) and an aqueous solution of Cs2CO3 (2 M, 177 µL, 0.36 mmol) are added, and the mixture is purged with argon. Pd(dtbpf)Cl2 (7.22 mg, 0.01 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 filtered,20concentrated and the residue is purified by preparative HPLC (HPLC; ACN / water / TFA) to afford the desired compound. Analysis (method E): Rt: 0.80 min, [M+H] +: 625Step 2: Synthesis of 4-(5-cyclopropyl-2-{4-[(R)-ethyl(methyl)phosphoryl]-2-25(trifluoromethoxy)phenyl}-1-methyl-1H-imidazol-4-yl)-2-(1-cyclopropyl-3-methoxy-1H- 01-3594-WO-1 87 pyrazol-4-yl)-2H-indazole (example 13) and 4-(5-cyclopropyl-2-{4-[(S)- ethyl(methyl)phosphoryl]-2-(trifluoromethoxy)phenyl}-1-methyl-1H-imidazol-4-yl)-2-(1- cyclopropyl-3-methoxy-1H-pyrazol-4-yl)-2H-indazole (example 14) 5 4-(5-Cyclopropyl-2-{4-[ethyl(methyl)phosphoryl]-2-(trifluoromethoxy)phenyl}-1-methyl-1H- imidazol-4-yl)-2-(1-cyclopropyl-3-methoxy-1H-pyrazol-4-yl)-2H-indazole (67.0 mg, 0.11mmol) is separated by chiral purification method P to afford the compounds 4-(5- cyclopropyl-2-{4-[(R)-ethyl(methyl)phosphoryl]-2-(trifluoromethoxy)phenyl}-1-methyl-1H- imidazol-4-yl)-2-(1-cyclopropyl-3-methoxy-1H-pyrazol-4-yl)-2H-indazole (example 13)10 (Analysis (method M): Rt: 0.76 min, [M+H] +: 625) and 4-(5-cyclopropyl-2-{4-[(S)-ethyl(methyl)phosphoryl]-2-(trifluoromethoxy)phenyl}-1-methyl-1H-imidazol-4-yl)-2-(1- cyclopropyl-3-methoxy-1H-pyrazol-4-yl)-2H-indazole (example 14) (Analysis (method M): Rt: 1.10 min, [M+H] +: 625).15Synthesis of example 20: Synthesis of 4-{5-cyclopropyl-2-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-1- methyl-1H-imidazol-4-yl}-2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazole (example 20) 204-Bromo-5-cyclopropyl-2-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-1-methyl-1H- imidazole (G10) (65.0 mg, 0.118 mmol), {2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]- 01-3594-WO-1 88 2H-indazol-4-yl}boronic acid (C12) (55.0 mg, 0.177 mmol), K3PO4 (2 M, 176 µL, 0.35 mmol) and XPhos Pd G3 (20.0 mg, 0.0232 mmol) are dissolved in dioxane (2 mL).The mixture ispurged with argon and is stirred at 80 °C for 14 h. After the reaction mixture is cooled to RT, it is filtered, concentrated and the residue is purified by preparative HPLC (HPLC; 5 ACN / water / TFA) to afford example 20. Analysis (method C): Rt: 0.70 min, [M+H] +: 623Synthesis of example 21: Synthesis of 4-{5-cyclopropyl-2-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-1-10 methylimidazol-4-yl}-2-[5-(trifluoromethyl)-1H-pyrazol-3-yl]indazole (example 21) Step 1: 4-Bromo-5-cyclopropyl-2-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-1-methyl-1H- imidazole (G10) (100 mg, 0.226 mmol), C13 (mixture of regioisomers, 135 mg, 0.272 mmol),15 K3PO4 (2 M, 340 µL, 0.68 mmol) and XPhos Pd G3 (14 mg, 0.016 mmol) are dissolved in 2-methyltetrahydrofuran (2 mL).The mixture is purged with argon and is stirred at 80 °C for 3h. After the reaction mixture is cooled to RT, it is filtered, concentrated and the residue is purified by preparative HPLC to afford an intermediate used for step 2. Analysis (method A): Rt: 0.63 min, [M+H] +: 72920 Step 2: 4-{5-Cyclopropyl-2-[4-(dimethylphosphoryl)-2-(trifluoromethoxy)phenyl]-1-methyl-1H- imidazol-4-yl}-2-{1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1H-pyrazol-3-yl}-2H- indazole (60 mg, 0.082 mmol) is dissolved in TFA (1 mL) and anisol (9 µL) and stirred at 120°C25 for 20 min under microwave. The mixture is diluted with acetonitrile and concentrated. The residue is dissolved in acetonitrile and purified via reversed phase chromatography to affordexample 21. 01-3594-WO-1 89 Analysis (method A): Rt: 0.51 min, [M+H] +: 609The example 22 5 22 is obtained by following a reaction sequence analogous to that described for example 21,using the intermediate G4 (see above) instead of G10.By analogous methods to the methods disclosed herein above the other compounds shown10 in Table 2A can be synthesized using the corresponding intermediates.Analytical HPLC methods 15 Method A (X012_S01) Device description: Waters Acquity; Analytical column: Xbridge (Waters) BEH C18_2.1 x 30 mm_1.7 µm; column temperature: 60°C Method B (Z011_S03) 01-3594-WO-1 90 Device description: Agilent 1200; Analytical column: Xbridge (Waters) C18_3.0 x 30 mm_2.5µm; column temperature: 60°C Method C (X018_S03) Device description: Waters Acquity; Analytical column: Sunfire (Waters) C18_3.0 x 30 mm_2.5 µm; column temperature: 60°C Method D (X011_S05) Device description: Waters Acquity; Analytical column: Xbridge (Waters) BEH C18_2.1 x 30 mm_2.5 µm; column temperature: 60°C Method E (Z018_S04) 01-3594-WO-1 91 Device description: Agilent 1200; Analytical column: Sunfire (Waters) C18_3.0 x 30 mm_2.5 µm; column temperature: 60°C Method F (SLV-Method-111) Device description: Dionex UHPLC Ultimate 3000; Analytical column: Kinetex XB-C18_4.6 x 50mm_2.6 µm; column temperature: 25°C Method G (I_IH_15_IPA_NH3_003) Device description: Agilent 1260 Infinity II SFC; Analytical column: Chiralpak® (Daicel) IH_4.6 x 250 mm_5 µm; column temperature: 40°C; back pressure: 2175 psi (14996.097 kPa) 01-3594-WO-1 92 Method H (Z020_S01) Device description: Agilent 1200; Analytical column: Sunfire (Waters) C18_3.0 x 30 mm_2.5 µm; column temperature: 60°C Method I (008_CA02) Device description: Waters Acquity; Analytical column: Xbridge (Waters) C18_3.0 x 30 mm_2.5µm; column temperature: 60°C5Method J (008_CA11) Device description: Waters Acquity; Analytical column: Xbridge (Waters) C18_3.0 x 30 mm_2.5 µm; column temperature: 60°C 01-3594-WO-1 93 Method K (008_CA10) Device description: Waters Acquity; Analytical column: Xbridge (Waters) C18_3.0 x 30 mm_2.5 µm; column temperature: 60°C Method L (007_CA11) Device description: Waters Acquity; Analytical column: Sunfire (Waters) C18_3.0 x 30 mm_2.5 µm; column temperature: 60°C 5 Method M (I_AC_20_MEOH_NH3_002) Device description: Agilent 1260 Infinity II SFC; Analytical column: Chiralpak® (Daicel) IH_4.6 x 250 mm_5 µm; column temperature: 40°C; back pressure: 2175 psi (14996.097 kPa)Method N (Z017_S04) 01-3594-WO-1 94 Device description: Agilent 1200; Analytical column: StableBond (Zorbax) C18_ . _1.8 µm; column temperature: 60°C Method O 5 Method P 01-3594-WO-1 95 List of Abbreviations: Ac acetylACN acetonitrile5 AIBN 2,2´-azobis(isobutyronitrile)Boc tert-butyloxycarbonylCbz benzyloxycarbonylCycH cyclohexaned day(s)10 DAST diethylamino sulfur trifluorideDCE 1,2-dichloroethaneDCM dichloromethaneDEAD diethyl azodicarboxylateDIAD diisopropyl azodicarboxylate15 DIPEA N,N-diisopropylethylamineDMF N,N-dimethylformamideDMP Dess–Martin PeriodinaneDMSO dimethyl sulfoxideEtOAc ethyl acetate20 EtOH ethanolh hour(s)HATU O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium-hexafluorophosphate HPLC high performance liquid chromatography25 HPLC-MS coupled high performance liquid chromatography-mass spectrometryIPA isopropyl alcoholLC liquid chromatographyLC-MS coupled liquid chromatography – mass spectrometryLiHMDS Lithium-bis(trimethylsilyl)amide30 M molar (mol / L)MeI methyl iodideMeTHF 2-methyltetrahydrofuran 01-3594-WO-1 96 MeOH methanolmin minute(s)MS mass spectrometryMTBE methyl-tertbutyl-ether 5n-BuLi n-ButhyllithiumNBS N-BromosuccinimideNIS N-IodosuccinimideNMP N-methyl-2-pyrrolidoneNMR nuclear magnetic resonance10 PEPPSI(TM)-IPR (1,3-Bis(2,6-diisopropylphenyl)imidazolidene) (3-chloropyridyl)palladium(II) dichloride PdCl2(dtbpf) 1,1ʹ-Bis-(di-tert-butylphosphino-)ferrocene-palladiumdichloridePd(dppf)Cl21,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) Pd(PPh3)4 palladium (0) tetrakis(triphenylphosphine)15 XPhos Pd G3 2-Dicyclohexylphosphino-2ʹ,4ʹ,6ʹ-triisopropyl-1,1ʹ-biphenyl)[2-(2ʹ- amino-1,1ʹ- biphenyl)]palladium(II) methanesulfonatpet. petroleumRfretention factor RP reverse phase20 rt room temperaturetRretention time (in HPLC / LC) SFC supercritical fluid chromatographyTBAF tetrabutylammonium fluorideTBTU O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate25 TEA triethylamineTFA trifluoroacetic acidTHF tetrahydrofuranTHP tetrahydro-2h-pyranTLC thin-layer chromatography30 TMAD N,N,NʹNʹ-TetramethylazodicarboxamideUV ultravioletV volume 01-3594-WO-1 97 BIOLOGICAL ASSAYS and DATA 5 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 10 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).15 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% inthe final assay volume. The 384well assay plate contained 20 test compounds and DMSO in column 20 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 indetection buffer) were dispensed to all wells except of the positive control, which received detection 25 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 (PerkinElmer) 30 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 were 01-3594-WO-1 98 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. 5 Determination of the increase of stability of STING protein against thermal denaturation, Differential Scanning Fluorimetry (DSF) 10 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. 15 Dye 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 Boltzmann20 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. 25 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). 30 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. 35 01-3594-WO-1 99 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 5 centrifuged for 2 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: 100uM compound, 3uM target protein, 5x SYPRO Orange, 2% DMSO in 10ul. All dispensing steps10 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. Two replicates of TM measurements were averaged, and the standard deviation was calculated. In15 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. Protein production and purification: The protein used for the biophysical experiments was a 20 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 into a pET17b E. coli expression vector. The protein construct encodes an N-terminal 8x His-tag followed by tobacco etch virus protease (TEV) cleavage site and the above STING gene sequence. The25 resulting protein sequence for the used STING variant is listed below: His-TEV—hSTING (WT) (SEQ ID NO: 1)MHHHHHHHHENLYFQSGVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLS 30 MADPNIRFLDKLPQQTGDRAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKL FCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEV For expression of recombinant human STING above construct was transformed into E. coli BL21 DE3 strain and grown in shake flasks in LB-medium at 37°C. Expression was induced by addition of 01-3594-WO-1 100 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)), 5 followed by metal affinity purification using Ni-NTA resins and elution buffer consisting of 20mM TRIS-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.10 The results of this assay are shown in the characterising data table below.Human whole blood assay (HWBA) 15 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 20 transferred 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. 25 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. 30 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. 01-3594-WO-1 101 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 5 for 30minutes and continuous shaking with 450rpm, followed by an overnight incubation of 22h at 37°C in the incubator, without shaking. 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 10 in Diluent 100 (Meso Scale Diagnostics #R50AA-4, according to the manufacturer. U-Plex MSD GOLD 96-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). 15 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 werecentrifuged at 1600rpm for 10 minutes.25µl of supernatant was transferred with a pipetting robotics 20 from each whole blood plate to the corresponding IFNα-2α plate. Plates were sealed with microplate seals and 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 25 microplate seals and kept at room temperature again under continuous shaking at 700rpm for two hours. Finally, MSD IFNα-2α 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. 30 Data evaluation and calculation: For data evaluation and calculation, % control calculation of each 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. 35 Calculation: [y=(a-d) / (1+(x / c)^b)+d], a = low value, d = high value; x = conc M; c=IC50 M; b = slope; 01-3594-WO-1 102 The results of this assay are shown in the characterising data table below. 5 Human STING reportergene assay 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. 10 Assay Method: Compounds were delivered 10mM DMSO solution and serially diluted in assay 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 2115 test compounds (column 1-21), a reference compound (column 22) and DMSO in column 23 and 24; 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 (Life20 Technologies # R25001) were harvested, resuspended, and diluted in fresh assay medium. The cellswere 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 25 wells for the controls, plus 5 µl of assay medium alone for negative controls (low values) or 5µl of prediluted 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).30 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; 35 01-3594-WO-1 103 The results of this assay are negative for agonism, wherein the threshold was set larger than 30 µM. Characterising Data Table 5 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. 01-3594-WO-1 104 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 not more than 150nM, more preferably not more than 125nM and even more preferably not more than 70 nM. In another preferred embodiment, said IC 50 value is at least and including5 0.8nM or at least and including 2nM. In another preferred embodiment said IC50 value is not more than 45nM, more preferably not more than 40nM. Further characterization Efflux ratio from MDCK-PGP 10 The efflux ratio from MDCK-PGP cells is measured using standard methods according to the 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 30, preferably equal to or below 25 more preferably equal to or below 15. In a more preferred embodiment, the efflux ratio is15 less than 15 but higher than 0.5. Exemplary values are ratios of 22 or 13.Efflux ratio from CACO2 cells The efflux ratio from CACO2 cells is determined using standard methods for example as disclosed inthe international patent applications published as WO15048318, WO22254371 and WO24110851, or20 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 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. Anexemplary efflux value is around 1. 25 Inhibition of cytochrome P450 enzymes CYP2D6 and CYP3A4Standard assays for testing the inhibition of cytochrome P450 enzymes using typical substrates are 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 of30 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 microsomes by drug-drug-interaction are commonly used (see for example experimental sections of the patent applications published as WO15073310& WO1419734535 and the patent US8138188 BB). 01-3594-WO-1 105 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 IC50 values of the compounds are determined. The IC50 of a positive control inhibitor (quinidine) is 5 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 patent applications published as WO15073310& WO14197345 and the patent US8138188 BB). 10 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 determined as a control. 15 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. 20 Measuring clearance from human hepatocytes The metabolic degradation of a test compound is assayed in a human hepatocyte suspension usingknown methods as in the patent application. US2024327429. In one embodiment the hepatocyte clearance is lower than 25% Qh [%], preferably equal to or lowerthan 20 %, 15 %, 10 %, 8 %, 7 %, 6 %, 5 %, 4 %, 3 % or 2 %. Exemplary values of inventive compounds25 are 6.5 % and about 2 %.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. The30 equilibrium dialysis technique is used to determine the approximate in vitro fractional binding of testcompounds 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 membranewith 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 dialysis35 solutions are prepared in plasma (supplemented with NaEDTA as anticoagulant), and aliquots of 200 01-3594-WO-1 106 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 2hours under rotation at 37°C for establishing equilibrium. 5 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:10 %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 %. Exemplary values are 1.0 % and 0.85 %.15 IP10 production in human dermal MicroVascular Endothelial Cells (MVEC) after double-stranded DNA stimulation Interferon gamma-induced protein 10 (IP-10) also known as C-X-C motif chemokine ligand 10 20 (CXCL10) is produced as one of the responses of the presence of double-stranded DNA in the cytoplasm and resulting STING activity. In some diseases, imbalanced STING activation can result to damage in the 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 25 endothelial cells (HMVEC) are performed with the inventive compounds. Dermal HMVEC are available from Lonza, US. 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 630 hours. The supernatants are collected and assayed for IP10 production. 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. 01-3594-WO-1 107 Results: The inventive compounds show good inhibition of IP10 production after stimulation ofHMVEC with dsDNA. This demonstrates that the inventive compounds show direct targetengagement in MVEC cells which is not the case for some known STING inhibitors. 5 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 treatment of a disease that involves undesirable STING activation in endothelial cells are those 10 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. 15 Inhibition of STING in fibroblasts As many of the above-mentioned diseases like IPF or SAVI involve fibrosis, it is important to demonstrate the efficacy of the inventive compounds in fibroblast cells. In an initial test, fibroblasts from human patients suffering from SSc are stimulated with dsDNA and the response with or withoutthe test compound is assessed, and in addition the known STING inhibitors SN-011 and H-151 (20 (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); Haag, S.M., 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). These known inhibitors had been reported to be effective in other fibroblasts, but show very little25 inhibition in SSC fibroblast, while the compounds of the invention show IC50 values in the range from 3 nM to 300 nM. 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. 30 01-3594-WO-1 108 Inhibition of IP10 production in human monocyte derived dendritic cells after cGAMP stimulationMonocyte derived dendritic cells derived from a specimen of a human donor are cultivated usingstandard 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 5 the invention. Supernatants are collected and analysed by ELISA for IP10 presence (IP10 MSD kit, MesoScale Diagnostics). IC50 values of STING protein inhibition are calculated using standard methods. The IC50 values for the compounds of the invention are 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 3.00nM, and even more preferably equal to or less than 2.5 nM. In yet another preferred embodiment10 the average IC 50 value is between and including 0.07 nM and 2.10 nM. Exemplary values are 0.26nM and 2.03 nM.Use in treatment / method of use15 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 betreated by the inhibition of STING and / or whose progression can be prevented by the inhibition of STING.20 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 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 25 autoinflammatory responses. Consequently, STING inhibitors have a strong therapeutic potential to be used in the treatment of diverse autoinflammatory and autoimmune diseases. 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 30 erythematosus (SLE), cutaneous lupus, systemic sclerosis, inflammatory bowel disease, sepsis, Sjogren’s syndrome, vitiligo, prurigo nodularis, idiopathic inflammatory myopathy, myositis includingdermatomyositis, rheumatoid arthritis, as well as a cluster fibrosis diseases including NASH (nowreferred to as MASH), IPF, chronic kidney fibrosis. 01-3594-WO-1 109 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 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 5 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 the invention preventing or delaying said progression. 10 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; Niemann-Pick Disease, Type C, myotonic dystrophy type 2, Huntington disease, Bloom syndrome, osteoarthritis, ALS, Parkinson’s disease, COVID-19. 15 ^An et al., Arthritis Rheumatol.2017 Apr;69(4):800-807, disclosed that cGAS expression inperipheral 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 20 SLE patients, but none of the normal or rheumatoid arthritis controls. Disease activity was higher in SLE patients with cGAMP versus those without cGAMP. ^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 25 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. ^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 )30 ^ 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-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 01-3594-WO-1 110 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. ^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 5 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 interstitial 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 muscle10 biopsies of 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.). ^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 15 function mutation of TREX1 leads rare monogenic interferonopathies such as Aicardi-Goutières syndrome (AGS). ^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 20 blood mononuclear cells and intestinal biopsies compared with healthy controls. STING knockout mice attenuated alleviated inflammatory response, gut permeability, and decreased bacterial 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 cecalligation and puncture model) and the degree of STING expression in the human intestinal lamina 25 propria correlated with the intestinal inflammation in septic patients. Inhibition of the ALK-STING pathway protects mice against CLP-induced polymicrobial sepsis. ^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-induced30 lung inflammation, which can lead to lung fibrosis. ^Additional scientific hints linking the cause for metabolic diseases such as non-alcoholic fatty liverdisease (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 01-3594-WO-1 111 non-alcoholic steatohepatitis (NASH) , now referred to as metabolic dysfunction associated steatohepatitis (MASH ), and alcoholic liver disease (ALD) with the cGAS / STING pathway havebeen 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: 510.1016 / 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-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).10 ^ 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 dextransodium sulphate (DSS) model of colitis. These publications support STING as a potential therapeutic target for prevention of inflammatory bowel disease (IBD).15 ^ 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). ^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- 20 472: “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 promotes tumorigenesis“. ^STING inhibitors have also the potential in the treatment of obesity and diabetes as shown inMao et al., Arterioscler Thromb Vasc Biol (2017) 37(5):920–9. doi: 10.1161 / ATVBAHA.117.30901725 ^ 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., 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 / STINGpathway (Sliter et al., Nature.2018 Sep;561(7722):258-262), between amyotrophic lateral30 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.^ 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 01-3594-WO-1 112 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 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). 5^ Additionally, STING inhibitors have a therapeutic potential in the treatment of renalinflammation and 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 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 10 genetic deletion or pharmacological inhibition of STING ameliorates kidney inflammation fibrosis in a mouse models of chronic kidney disease (Cell Metab 201930:784-799). ^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 15 reported as a diagnostic marker and indicator of degree of severity in alopecia areata (J 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 also20 been reported in a SAVI patient (STING GOV mutation) (Front Immunol.202011:575219). ^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 potential25 therapy for Niemann–Pick disease type C (Nature 2021596(7873):570-575). ^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 cytosolic30 DNA accumulation and activates the cGAS–STING pathway to mediate inflammation and apoptosis (Proc Natl Acad Sci U S A.2024121:e2313652121). Depletion of cGAS in HD neuron cells decreases the expression of inflammatory genes while suppressing the up-regulation of autophagy (Proc Natl Acad Sci 117:15989-15999). 01-3594-WO-1 113 ^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 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). 5^ 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 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 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). 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 15 variation within the STING gene is associated with healthy aging, most likely due to a decreased inflammaging (Hamann et al, Gerontology 2019;65:145–154). Taken together, a STING inhibitor will reduce senescence associated inflammation and senescent cell accumulation and will leads improvement in senescence associated diseases such as aging / muscle disorders and osteoarthritis.20 ^ 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-cell 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 in25 melanocytes resulting in production of IL-1β and IL-18. ^Prurigo nodularis is a chronic inflammatory skin condition characterized by intensely itchypruritic 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 areskewed toward a Th22 / IL-22 profile (Belzberg et al., Journal of Investigative Dermatology (2021) 30 141, 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 Vol.215: 2868–2886). STING may also play a role in IL22 mediated pathogenic responses in the skin epithelium in Prurigo nodularis. 01-3594-WO-1 114 The compounds of formula (I) or (Ia), or the salts thereof for use in patients with a disease whoseprogression can be prevented by the inhibition of STING is an embodiment of the invention.In one embodiment, the STING inhibitors of the invention are useful in the prevention of progression, 5 and / or for the treatment of a condition or disease caused by immune dysregulation and involving the STING protein(s). The use of the compounds of the invention for the prevention of progression or for the treatment of adisease or condition that involves undesirable STING activation in a manner independent of cGASactivity is one embodiment of the intervention, for examples but not limited to subjects with10 Niemann–Pick disease type C. 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 a15 side effect of an underlying disease that leads to cell damage and cytosolic DNA presence that is notderived from pathogens.Combinations 20 The compounds of formula (I) may be administered to the patient alone or in combination with one or more other pharmacologically active agents. 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-[4-25 (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 2013 / 026797), anti-inflammatory agents, anti-fibrotic agents, anti-allergic agents / anti-histamines, bronchodilators, beta 2 agonists / betamimetics, adrenergic agonists, anticholinergic agents, methotrexate, 30 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-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 or other cytokines / chemokines, cytokine / chemokine receptor modulators (i.e. cytokine receptor 35 agonists or antagonists), Toll-like receptor agonists (=TLR agonists), immune checkpoint regulators, 01-3594-WO-1 115 anti-TNF antibodies for example but not limited to Humira™ and anti- B-cell activating factor (BAFF)agents e.g. without limitation Belimumab and Etanercept. Such a combination with anti-inflammatory agents and / or anti-fibrotic agents in one embodiment is a combination of one or morecompounds of the invention with a) one or more known STING inhibitors and / or b) known cGAS 5inhibitors and / or c) anti-inflammatory agents that are not STING inhibitors and / or anti-fibrotic agentsthat are not STING inhibitors, for example but not limited to Pirfenidon, Nintedanib orNerandomilast. Another aspect of the invention is to the combined use of the STIGN inhibitors of theinvention in combination with known cGAS and / or STING inhibitors, for example those disclosed inthe international patent applications PCT / EP2023 / 080705, PCT / EP2023 / 080711,10 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.In a furhter aspect of the present invention, the one or more other pharmacologically active agentsinclude immunosuppressive drugs, Nonsteroidal anti-inflammatory drug (NSAID), corticosteroids e.g.15 glucocorticoids, hydroxychloroquine or methotrexate, antibodies for example anti- B-cell activatingfactor (BAFF) antibody or CAR (chimeric antigen receptors) T cells. In one 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-Converting20 Enzyme (ACE) inhibitor and / or an angiotensin II receptor blocker (ARB). 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 25 selected from the group consisting of systemic lupus erythematosus (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 DNASE2 or ATAD3A genes, age-related maculardegeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), Huntington disease, 30 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 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) (previously35 referred to as non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction associated 01-3594-WO-1 116 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 (ANCA) associated vasculitis, alopecia, 5 chronic kidney disease, rheumatoid arthritis and osteoarthritis. Formulations The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes 10 oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, intrasternal, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the 15 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. 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 20 case should be in the range from 0.1 to 90 wt.%, preferably 0.5 to 50 wt.% of the total composition, i.e. in amounts which are sufficient to achieve the dosage range specified hereinafter. The preparations may be administered orally in the form of a tablet, as a powder, as a powder in a capsule (e.g. a hard gelatin capsule), as a solution or suspension. When administered by inhalation the active substance combination may be given as a powder, as an aqueous or aqueous-ethanolic25 solution or using a propellant gas formulation. Preferably, therefore, pharmaceutical formulations are characterized by the content of one or more compounds of formula (I) according to the preferred embodiments above. It is particularly preferable if the compounds of formula (I), preferably of formula (Ia), areadministered orally, and it is also particularly preferable if they are administered once or twice a day. 30 Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and / or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers. 35 01-3594-WO-1 117 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 5 achieve delayed release, possibly using the excipients mentioned above for the tablets. Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavor enhancer, e.g. a flavoring such as vanillin or orange extract. They may also contain suspension 10 adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p- hydroxybenzoates. Capsules containing one or more active substances or combinations of active substances may for 15 example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatin capsules. Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethylene glycol or the derivatives thereof. 20 Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineralpowders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite 25 liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate). For oral administration the tablets may, of course, contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various 30 additives such as starch, preferably potato starch, gelatin and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the 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 35 and / or delaying the progression of disorders is to be understood to refer to a prevention that 01-3594-WO-1 118 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 atleast to some extent, although for the overall group of patients the use of the compounds of the 5 invention typically is suitable to delay the occurrence and / or prevent such disorders. 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 10 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 15 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. 20 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) 25 producing the inventive compound or a salt thereof, preferably a pharmaceutically acceptable salt 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- 30 oxo-6,7-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, preferably anti-IL-23 such as Risankizumab, anti-IL-17 antibodies, anti-IL-1 antibodies,35 anti-IL-4 antibodies, anti-IL-13 antibodies, anti-lL-5 antibodies, anti-IL-6 antibodies such as Actemra™, 01-3594-WO-1 119 anti-IL-12 antibodies and / or anti-IL-15 antibodies, non-specific immunotherapeutics such asinterferons or other cytokines / chemokines, cytokine / chemokine receptor modulators (i.e. cytokine receptor agonists or antagonists), Toll-like receptor agonists (=TLR agonists), immune checkpoint regulators, anti-TNF antibodies, preferably Humira™, and anti-BAFF agents, preferably Belimumab5 and / or Etanercept. Another aspect of the invention is to the combined use of one or more of theSTING inhibitors of the invention in combination with known cGAS and / or STING inhibitors, and d)optionally formulating into a form for the preferred administration. 10

Claims

01-3594-WO-1 120 Claims1. A compound of formula (I),wherein B-A is selected from the group B-Aa consisting of =C-N- or -N-C=; this means A is C or N; B isC or N; but A and B are not N at the same time; X-Y-Z is selected from the group X-Y-Za consisting of =CH-N-N=, -N=C-NH- and -CH2-N-C(O)-;W is selected from the group Wa consisting of =CH- and =N-;R1is selected from the group R1aconsisting of R6-C1-5-alkyl- and C3-6-cycloalkyl-;R2is selected from the group R2aconsisting of ; 5wherein * denotes the attachment point R2 in formula (I); R3is selected from the group R3aconsisting of halogen, HO-, C1-3-alkyl-, C1-5-alkyl-O-,C1-3-alkyl-O- C1-3-alkyl-, C3-5-alkenyl-O-, C2-3-alkenyl-O- C1-3-alkyl-C3-6-cycloalkyl- and heterocyclyl-;wherein a C1-3-alkyl-group is optionally substituted with 1 to 3 selected from the group consisting of fluorine, HO-, H3C-O-, F3C-O-, and F2HC-O-;, wherein the C1-5-alkyl-group of the C1-5-alkyl-O-group is optionally substituted with 1 to 5 (e.g.2, 3 or 4) substituents independently selected from the group01-3594-WO-1 121 consisting of fluorine, HO-, H2N-C(O)-, C3-4-cycloalkyl-, C1-3-alkyl-O-, heterocyclyl and heteroaryl; R4is selected from the group R4aconsisting of C1-3-alkyl-S(O)2-, C1-3-alkyl-S(O)-, (C1-3-alkyl)2P(O)-, (C1-3-alkyl)(C3-6-cycloalkyl)P(O)-, - C(O)-, H2N-C(O)-, C1-3-alkyl-NH-C(O)-, (C1-3-alkyl)2N-C(O)- and; wherein * denotes the attachment point of R4a; R5is selected from the group R5aconsisting of C1-4-alkyl-; R6is selected from the group R6aconsisting of H-, HO- and Halogen;R7is selected from the group R7aconsisting of H-, Halogen, HO-, HO(C1-6-alkyl)2C-CH2-, C1-3-alkyl-O-, C1-6-alkyl-, C3-5-alkenyl-, C3-6- cycloalkyl-, aryl, heteroaryl and heterocyclyl; wherein the C1-6-alkyl-group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Halogen, HO-, and C1-3-alkyl- O-, wherein the heteroaryl group is optionally substituted with 1 substituent selected from the group consisting of C1-3-alkyl-, wherein the C3-6-cycloalkyl- and / or aryl group is optionally substituted with 1 to 3substituents independently selected from the group consisting of (H3C)2N-C(O)-; R8is selected from the group R8aconsisting of H-, C1-6-alkyl-O- and heterocyclyl-O-;wherein the C1-6-alkyl-O-group is optionally substituted with 1 substituent selected from the group consisting of C1-3-alkyl-O- and (H3C)2N-C(O)-;C1-5-alkyl-O- and Halogen;R9is selected from the group R9aconsisting of H-, C1-3-alkyl- and H2N-C(O)-CH2-;R10is selected from the group R10aconsisting of C1-3-alkyl-, C2-3-alkenyl-, C1-3-alkyl-O-, C1-3-alkyl-S- and C3-4-cycloalkyl-,wherein the C1-3-alkyl-group is optionally substituted with 1 to 3 substituents selected from the group consisting of F-;01-3594-WO-1 122 R11is selected from the group R11aconsisting of C1-5-alkyl-, or -C1-5-alkyl-C(O)-, wherein the C1-5-alkyl-, group is optionally substituted independently of one another with 1 to 3 substituents selected from the group consisting of C1-3-alkyl-, halogen and HO-; 5 or a salt thereof.

2. A compound according to claim 1, whereinB-A is selected from the group B-Ac consisting of -N-C=; this means A is C; B is N,or a salt thereof.10 3. A compound according to one of the claims 1 or 2, whereinW is selected from the group Wb consisting of =CH-,or a salt thereof.

4. A compound according to claim 1 to 3, whereinX-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N= and -N=C-NH-,or a salt thereof. 15 5. A compound according to claim 1 to 4, whereinR2is selected from the group R2bconsisting of,and ,wherein * denotes the attachment points to the core structure, 20 or a salt thereof.

6. A compound according to one of the claims 1 to 5, whereinR3is selected from the group R3cconsisting of F-, Cl-, HO-, H3C-, F3C-, (H3C)2C-, H3C-CH2-, cyclopropyl-, H3C-O-, FH2C-O-, F2HC-O-, F3C-O-, (H3C)2CH-O-, (H3C)3C-O-, H3C-CH2-O-, F2HC-CH2-O-, F2C(CH3)-CH2-O-, H3C-01-3594-WO-1 123 CH2-CH2-O-, F-CH2-CH2-O-, HO-CH2-CH2-O-, H2N-CH2-C(O)-, H2C=CH-CH2-O-, H3C-O- CH2-CH2-O-, H3C-O-CH2-CH2-CH2-O-, (H3C)2C(OH)-CH2-CH2-O-, (H3C)2CH-CH2-O-, cyclopropyl-O-, cyclopropyl-CH2-O-, H3C-O-CH2-CH2-, H3C-O-CH2-,, wherein * denotes the attachment point to the core structure,or a salt thereof.

7. A compound according to one of the claims 1 to 6, whereinR4is selected from the group R4bconsisting of (C1-3-alkyl)2P(O)-, C1-3-alkylNH-C(O)-, (C1-3-alkyl)2N-C(O)- and H2N-C(O)-,or a salt thereof. 5 8. A compound according to one of the claims 1 to 7, wherein the compound of formula (I) is acompound of formula (Ia)or a salt thereof. 10 9. A compound according to one of the claims 1 to 8, whereinB-A is selected from the group B-Ac consisting of -N-C=; this means A is C; B is N;W is selected from the group Wb consisting of =CH-;X-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N= and -N=C-NH-;R1is selected from the group R1bconsisting of isopropyl- and cyclopropyl-;R2is selected from the group R2aconsisting of01-3594-WO-1 124 R2is selected from the group R2aconsisting of; , and , wherein * denotes the attachment point to the core; R3is selected from the group R3cconsisting of F-, Cl-, HO-, H3C-, F3C-, (H3C)2C-, H3C-CH2-, cyclopropyl-, H3C-O-, FH2C-O-, F2HC-O-, F3C-O-, (H3C)2CH-O-, (H3C)3C-O-, H3C-CH2-O-, F2HC-CH2-O-, F2C(CH3)-CH2-O-, H3C- CH2-CH2-O-, F-CH2-CH2-O-, HO-CH2-CH2-O-, H2N-CH2-C(O)-, H2C=CH-CH2-O-, H3C-O- CH2-CH2-O-, H3C-O-CH2-CH2-CH2-O-, (H3C)2C(OH)-CH2-CH2-O-, (H3C)2CH-CH2-O-, cyclopropyl-O-, cyclopropyl-CH2-O-, H3C-O-CH2-CH2-, H3C-O-CH2-, ∗, wherein * denotes the attachment point, R4is selected from the group R4bconsisting of (C1-3-alkyl)2P(O)-, C1-3-alkylNH-C(O)-, (C1-3-alkyl)2N-C(O)- and H2N-C(O)-;R5is selected from the group R5bconsisting of H3C-, H3C-CH2-, H3C-CH2-CH2- and (H3C)2C-;R7is selected from the group R7aconsisting of H-, Halogen, HO-, HO(C1-6-alkyl)2C-CH2-, C1-3-alkyl-O-, C1-6-alkyl-, C3-5-alkenyl-, C3-6- cycloalkyl-, aryl, heteroaryl and heterocyclyl; wherein the C1-6-alkyl-group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Halogen, HO-, and C1-3-alkyl- O-, wherein the heteroaryl group is optionally substituted with 1 substituent selected from the group consisting of C1-3-alkyl-, wherein the C3-6-cycloalkyl- and / or aryl group is optionally substituted with 1 to 3substituents independently selected from the group consisting of (H3C)2N-C(O)-;01-3594-WO-1 125 R8is selected from the group R8aconsisting of H-, C1-6-alkyl-O- and heterocyclyl-O-;wherein the C1-6-alkyl-O-group is optionally substituted with 1 substituent selected from the group consisting of C1-3-alkyl-O- and (H3C)2N-C(O)-;C1-5-alkyl-O- and Halogen;R9is selected from the group R9aconsisting of H-, C1-3-alkyl- and H2N-C(O)-CH2-;R10is selected from the group R10aconsisting of C1-3-alkyl-, C2-3-alkenyl-, C1-3-alkyl-O-, C1-3-alkyl-S- and C3-4-cycloalkyl-,wherein the C1-3-alkyl-group is optionally substituted with 1 to 3 substituents selected from the group consisting of F-; R11is selected from the group R11aconsisting of C1-5-alkyl-, or -C1-5-alkyl-C(O)-, wherein the C1-5-alkyl-, group is optionally substituted independently of one another with 1 to 3 substituents selected from the group consisting of C1-3-alkyl-, halogen and HO-; 5 or a salt thereof, preferably a pharmaceutically acceptable salt.

10. A compound according to one of the claims 1 to 9, whereinB-A is selected from the group B-Ac consisting of -N-C=; this means A is C; B is N;W is selected from the group Wb consisting of =CH-;X-Y-Z is selected from the group X-Y-Zc consisting of =CH-N-N=;R1is selected from the group R1cconsisting of cyclopropyl-; R2is selected from the group R2dconsisting of, wherein * denotes the attachment point; R3is selected from the group R3econsisting of H3C-, F2HC-CH2-O-, F3C-O-, and H3C-O-CH2-, R4is selected from the group R4dconsisting of (CH3CH2)2P(O)-, (CH3)(CH3CH2)P(O)- and (CH3)2P(O)-;R5is selected from the group R5bconsisting of01-3594-WO-1 126 H3C-, H3C-CH2-, H3C-CH2-CH2- and (H3C)2C-;R9is selected from the group R9dconsisting of H3C-, or from group R9c consisting of H-;R10is selected from the group R10cconsisting of cyclopropyl- CF2H- and CF3-;or a salt thereof, preferably a pharmaceutically acceptable salt.

11. A compound according to one of the claims 1 to 7, selected from the following examples:01-3594-WO-1 12701-3594-WO-1 12901-3594-WO-1 130.

12. A compound according to one of the claims 1 to 7, selected from any of the examples 1 to22. 5 13. A salt, preferably a pharmaceutically acceptable salt, of any of the compounds of claims 11 or12.

14. The compound of formula (I) or (Ia), according to any of claims 1 to 12 or the salt thereof10 according to claim 13 for use in the treatment of a disease that can be treated by theinhibition of STING.

15. The compound of formula (I) or (Ia) according to any of claims 1 to 12 or the salt thereofaccording to claim 13 for use in the treatment of a disease selected from the group15 consisting of systemic lupus erythematosus (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 1interferonopathies with mutations in DNASE2 or ATAD3A genes, age-related macular degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), Huntington 20 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 type 2, Sjogren’s syndrome, Parkinson’s disease, heart failure, cancer, systemic sclerosis (SSc), vitiligo, prurigo nodularis, idiopathic inflammatorymyopathy, myositis including dermatomyositis, metabolic dysfunction–associated steatotic25 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 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- 30 neutrophil cytoplasm antibody (ANCA) associated vasculitis, alopecia, chronic kidney disease, rheumatoid arthritis and osteoarthritis.

16. Pharmaceutical composition comprising at least one compound of formula (I) or (Ia)according to any of claims 1 to 12 and / or the salt thereof according to claim 13, and35 optionally one or more pharmaceutically acceptable carriers and / or excipients.