WO2025228902A1

WO2025228902A1 - Heterocyclic acids as sting antagonists and the use thereof as medicament

Info

Publication number: WO2025228902A1
Application number: PCT/EP2025/061552
Authority: WO
Inventors: Matthias Hoffmann; Georg Dahmann; Sandra Ruth Handschuh; Jun Li; Camilla MAYER; Herbert Nar; Thorsten Oost; Viktor VINTONYAK
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 2024-04-30
Filing date: 2025-04-28
Publication date: 2025-11-06
Anticipated expiration: 2026-10-30

Abstract

This invention relates to compounds of formula (I), wherein these compounds comprise heterocyclic acids at the R4 position in formula (I) and their use in the prevention, delaying and/or treatment of diseases or conditions which can be influenced by STING inhibition.

Description

01-3598-WO-1 1 H_{eterocyclic Acids as STING Antagonists and the Use Thereof as Medicament} This application claims priority to the US provisional application 63/640365, filed on April 30, 2024. 5 Field of the invention T_{his invention relates to compounds of formula (I) and their use as STING antagonists e.g. for the} treatment of a disease selected from the group consisting of systemic lupus erythematosus (SLE), cutaneous lupus, (monogenic and digenic) interferonopathies (including STING-associated 10 vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome, and f_{amilial chilblain lupus), type 1 interferonopathies with mutations in DNASE2 or ATAD3A genes, age-} related macular degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), Huntington disease, Alzheimer's disease, diabetes, obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom’s syndrome, Niemann-Pick Disease, Type C, 15 ischaemic stroke, myotonic dystrophy type 2, Sjogren’s syndrome, Parkinson’s disease, heart failure, c_{ancer, 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 dysfunction} associated steatohepatitis (MASH, previously non-alcoholic steatotic hepatitis (NASH)), compensated 20 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 t_{riggered by conserved pathogen-associated molecular patterns (PAMPs) through sensing by diverse} pattern recognition receptors (PRRs) and subsequent activation of cytokine and type I interferon 30 gene expression. The major antigen-presenting cells, such as monocytes, macrophages, and dendritic c_{ells produce type I interferons and are critical for eliciting adaptive T- and B-cell immune system} responses. The major PRRs detect aberrant, i.e. mislocalized, immature or unmodified nucleic acids on either the cell surface, the inside of lysosomal membranes or within other cellular compartments (Barbalat et al., Annu. Rev. Immunol.29, 185-214 (2011)). 35 01-3598-WO-1 2 “Cyclic GMP-AMP Synthase” (cGAS) is the predominant sensor for aberrant double-stranded DNA (dsDNA) originating from pathogens or mislocalization or misprocessing of nuclear or mitochondrial cellular dsDNA (Sun et al., Science 339, 786-791 (2013); Wu et al., Science 339, 826-830 (2013); Ablasser et al., Nature 498, 380-384 (2013)). Binding of dsDNA to cGAS activates the reaction of GTP 5 and ATP to form the cyclic dinucleotide GMP-AMP (referred to as cGAMP). cGAMP then binds to and activates the endoplasmatic reticulum membrane-anchored adaptor protein, “Stimulator of I_{nterferon Genes” (STING, UniProtKB – Q86WV6). Activated STING recruits and activates TANK-} _{binding kinase 1 (TBK1) which in turn phosporylates the transcription factor family of interferon} regulatory factors (IRFs) inducing cytokine and type I interferon mRNA expression. STING activation 10 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 fibroblasts, exhibiting an upregulated type-1 IFN signature and expression of NF^B-mediated_{15 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 senescence (Yang et al., PNAS 114, E4612 (2017), Glueck et al., Nat. Cell Biol.19, 1061-1070 (2017)), 20 autophagy and recognition of ruptured micronuclei in the surveillance of potential cancer cells (Mackenzie et al., Nature 548, 461-465 (2017); Harding et al., Nature 548, 466-470 (2017)). While the cGAS/STING pathway is important for host defense against invading pathogens, cellular stress and genetic factors may also cause production of aberrant cellular dsDNA, e.g. by nuclear or 25 mitochondrial leakage, and thereby trigger autoinflammatory responses. Aicardi-Goutieres syndrome (_{AGS; Crow et al., Nat. Genet.38, 917-920 (2006)) – a lupus-like severe autoinflammatory immune-} _{mediated disorder – arises from genetic mutations such as loss-of-function mutations in TREX1, a} _{primary DNA exonuclease responsible for degrading aberrant DNA in cytosol. Knock-out of STING in} TREX1-deficient mice prevented otherwise lethal autoimmune responses, supporting STING as driver 30 of interferonopathies (Gall et al., Immunity 36(1), 120-131 (2012); Gao et al., PNAS 112, E5699-E5705 (2015)). Likewise, embryonic lethality caused by deficiency of DNAse2, an endonuclease responsible for degradation of excessive DNA in lysosomes during endocytosis, was completely rescued by additional knock-out of STING (Ahn et al., PNAS 109, 19386-19391 (2012)). A STING inhibitor may provide a therapeutic strategy for preventing (monogenic and digenic) 35 interferonopathy diseases such as SAVI, AGS, familial chilblain lupus and COPA. A STING inhibitor will 01-3598-WO-1 3 block inflammation and aberrant tissue remodeling in a cluster of autoimmune and inflammatory d_{iseases including systemic lupus erythematosus (SLE), systemic sclerosis, vitiligo, prurigo nodularis,} _{idiopathic inflammatory myopathy, myositis including dermatomyositis, inflammatory bowel disease,} sepsis, Sjogren’s syndrome, atopic dermatitis, as well as a cluster fibrosis diseases including NASH, 5 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; N_{iemann-Pick Disease, Type C, ischaemic stroke, myotonic dystrophy type 2, Huntington disease,} _{Bloom syndrome, Huntington disease, muscle disorders, rheumatoid arthritis, osteoarthritis, ALS,}10 Parkinson’s disease, Alzheimer’s disease, COVID-19 (Decout et al, Nat Rev Immunol.202121:548- 569). Due to the observation that inhibition of the STING pathway may provide a therapeutic strategy for preventing autoinflammation and for treating e.g. autoimmune diseases efforts to develop STING15 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 STING} 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 the20 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 competitive} ligands. It is believed that inhibiting the orthosteric site of cGAMP mediated STING activation leads to a suppression of all STING mediated activation in contrast to palmitoylation inhibitors. Compound 13 or 15 in this publication inhibits the HAQ STING variant (displacement assay) with 25 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 either} activate or inhibit STING accordingly. •_{In the international patent applications WO23148129 and WO23237457 modulators of STING are} _{30 disclosed that are relatively large macrocycles with demanding synthesis and handling of the} molecules. However, inhibitors of the STING receptor for therapeutic use face challenges. For example, it is expected that most inhibitors of the STING receptor binding its ligand binding site similar to the 35 natural ligand, i.e. two molecules in the binding pocket. Yet, for the design of inhibitors of STING 01-3598-WO-1 4 receptors this provides the additional challenge that the inhibitor molecules not only need to interact w_{ith the correct portion the STING receptor, but also will interact with the second molecule of the} inhibitor in the ligand binding pocket of STING. Hence the potential interface between inhibitor and inhibitor is also important to consider for good inhibition results of STING. 5 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 of the inhibitor. A_{nother challenge for a therapeutic inhibitor of STING receptors is that in many STING mediated} _{disease patients are likely to be co-administered with more than one medications to treat the} 10 symptoms of said diseases or the diseases itself. The inhibitors of STING should in such a situation n_{ot add additional workload to the detoxifying processes or catabolism of the other medication} administered, which could lead to undesired changes in the half-life of any of the therapeutic compounds or have negative effects on the patient’s metabolism. _{15 Aim of the invention} _{It has now been found that compounds of the present invention according to general formula (I), or} _{pharmaceutically acceptable salt thereof, are effective STING inhibitors.} In addition to the antagonistic property toward STING, the compounds of the present invention _{20 provide further advantageous properties as to be viable for human therapy, such as the following} without limitation: B_{eing optimised for binding of two molecules of the inhibitor to the target’s ligand binding pocket,} _{sufficiently easy to synthesize and handle, good bioavailability, good mobility across the cell} _{membrane and good access to the target receptor in the cells, acceptable cytotoxicity and/ or} _{25 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 the inhibitor or its break-down product e.g. in sewage plants. T_{he inhibitors of the invention perform better in one or several of these properties than the} _{30 inhibitors of the STING receptor available so far. Accordingly, one aspect of the invention refers to} compounds according to formula (I), or salts thereof as inhibitors of STING. Another aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of STING optimised for binding of two molecules of the inhibitor to the target’s ligand binding pocket and / or good ligand efficiency. 01-3598-WO-1 5 Another aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of STING having good metabolic stability and potency. 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 5 to the target receptor in the cells while having good metabolic stability and potency. Another aspect of the invention refers to compounds according to formula (I), or salts thereof as 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. 10 by cytochrome p450s or other CYP that are important with respect to possibly co-administered drugs. Another aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of STING having good metabolic stability and low interaction with catabolic processes of other pharmaceutical compound administered overlappingly or simultaneously, including but not15 limited to further inhibitors of STING, and with acceptable cytotoxicity and/ or genotoxicity. Another aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of STING having good metabolic stability and low interaction with catabolic processes of other pharmaceutical compounds administered overlappingly or simultaneously, including but not 20 limited to further inhibitors of STING, and with acceptable cytotoxicity and/ or genotoxicity and optimised in polarity for good mobility across the cell membrane and good access to the target receptor in the cells and good potency. 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 25 pharmaceutical compounds administered overlappingly or simultaneously, including but not limited to further inhibitors of STING, and with acceptable cytotoxicity and/ or genotoxicity and optimised in polarity for good mobility across the cell membrane and good access to the target receptor in the c_{ells and good potency and optimised for binding of two molecules of the inhibitor to the target’s} ligand binding pocket and good ligand efficiency. 30 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, optionally together with one or more inert adjuvant, diluent and/or carrier. 01-3598-WO-1 6 A_{further aspect of the present invention relates to compounds according to general formula (I) or} _{pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds} _{according to formula (I) or pharmaceutically acceptable salts thereof, for the use in the prevention of} _{and/or treatment of and / or delaying the occurrence of and/or delaying the progression of disorders} _{5 related to elevated and / or deregulated STING activity. In one aspect of the invention the use is to} prevent one or more disorders related to elevated STING activity. Another aspect of the invention the use is to treat one or more disorders related to elevated STING activity. A further aspect the inventive use is to delay the occurrence of one or more disorders related to elevated STING activity. In yet another aspect the inventive compounds and use is to delay the progression one or more 10 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 M_{ASH for example from MAFLD to MASH, or from MASH to Mash with cirrhosis as assessed with the} _{NAFLD Activity Score (NAS) with or without steatosis, activity, and fibrosis (SAF) score and / or} progression of Rheumatoid arthritis as assessed via the 2010 ACR / EULAR Rheumatoid Arthritis 15 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 p_{resent invention according to general formula (I) or salts thereof, particularly pharmaceutically} acceptable salts. 20 Other aims of the present invention will become apparent to the skilled man directly from the foregoing and following remarks. Detailed description 25 In a first aspect the present invention relates to compounds of general formula (I) 01-3598-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 is} C 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-;} 5 V_{is selected from the group Va consisting of =CH- and =N-;} _{Wherein preferably W and V are not =N- at the same time;} R¹ is selected from the group R1^a consisting of C_{1-5-alkyl- and C3-6-cycloalkyl-;} R² is selected from the group R^2a consisting of R_{9-C(R8)(R7)-CH(R6)- and R9-S(O)-CH(R6)- and} ∗ _{, wherein * denotes the attachment point to the core structure;} ; 10 R³ is selected from the group R^3a consisting of h_{alogen, HO-, C1-3-alkyl-, C1-5-alkyl-O-, C3-5-alkenyl-O-, C3-6-cycloalkyl- and heterocyclyl-} ; wherein the C_1-3-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 C_1-5-alkyl-group of the C_1-5-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; R⁴ is selected from the group R^4a consisting of 01-3598-WO-1 8 a_{t least one heterocyclyl or carbocyclyl group substituted with a tetrazole,} carboxylate or methylcarboxylate group and optionally substituted independently w_{ith one to three groups consisting of H, methyl, ethyl or H3C-O-;} R⁵ is selected from the group R^5a consisting of C_1-4-alkyl-; R⁶ is selected from the group R^6a consisting of H_{-, HO- and Halogen;} R⁷ is selected from the group R^7a consisting of H_{-, Halogen, HO- and C1-3-alkyl-O-;} R⁸ is selected from the group R^8a consisting of H_{- and Halogen;} 5 R⁹ is selected from the group R^9a consisting of p_{henyl-, piperidyl-, morpholinyl- and C5-6-cycloalkyl-,} wherein the piperidyl-group is optionally substituted with 1 substituent independently selected from the group consisting of C_1-3-alkyl-S(O)₂-, C_1-3-alkyl- C(O)-, C1-5-alkyl-C(O)-O-; R¹⁰ is selected from the group R^10a consisting of H_{-, HO-, H2N-C(O)-, C1-3-alkyl-, C1-3-alkyl-O-, C3-4-cycloalkyl- and phenyl-,} _{wherein the phenyl-group and/or the C1-3-alkyl-group are optionally substituted} _{with 1 substituent independently selected from the group consisting of Halogen} and HO-; R¹¹ is selected from the group R^11a consisting of H_{-, HO-, H2N-C(O)-, C1-3-alkyl-, C1-3-alkyl-O-, C3-4-cycloalkyl- and phenyl-,} wherein the phenyl-group and the C1-3-alkyl-group is optionally substituted with 1 substituent independently selected from the group consisting of Halogen and HO-; w_{herein preferably R10 and R11 are not both H- at the same time,} or a salt thereof, preferably a pharmaceutically acceptable salt, or an ester thereof, preferably an C_1-310 esters. 01-3598-WO-1 9 U_{nless 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, or} groups occur several times in a compound they may have the same or different meanings. Some 5 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.} 10 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-.} In a further embodiment of the present invention X_{-Y-Z is selected from the group X-Y-Zc consisting of =CH-N-N=.} 15 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 W_{is selected from the group Wb consisting of =CH-.} 20 In a further embodiment of the present invention V_{is selected from the group Vb consisting of =N-.} In a preferred embodiment, the compound is a compound of formula (Ia). 01-3598-WO-1 10 In another preferred embodiment, the compound is a compound of formula (Ib). 5 In a further embodiment of the present invention R¹ is selected from the group R1^b consisting of i_{sopropyl- and cyclopropyl-;} 10 In a further embodiment of the present invention R¹ is selected from the group R1^c consisting of isopropyl-; In a further embodiment of the present invention R¹ is selected from the group R1^d consisting of cyclopropyl-; In a further embodiment of the present invention 01-3598-WO-1 11 R² is selected from the group R^2b consisting of R_{9-C(R8)(R7)-CH(R6)- and R9-S(O)-CH2-.} R² is selected from the group R^2c consisting of R⁹-C(R⁸)(R⁷)-CH(R⁶)-. In a further embodiment of the present invention R² is selected from the group R^2d consisting of , , , , wherein * denotes the attachment point to the core structure. 5 In a further embodiment of the present invention R³ is selected from the group R^3b consisting of C_1-3-alkyl-, C_1-5-alkyl-O-; wherein the C_1-5-alkyl-group of the C_1-5-alkyl-O-group is optionally substituted with 1_{to 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 R³ is selected from the group R^3c consisting of H_{3C-, and H3C-O-.} 10 In a further embodiment of the present invention R³ is selected from the group R^3d consisting of H3C-. In a further embodiment of the present invention R³ is selected from the group R^3e consisting of 01-3598-WO-1 12 H_{3C-O -.} In a further embodiment of the present invention R⁴ is selected from the group R^4b consisting of C_3-8-cycloalkyl, C_3-8-heterocycloalkyl, C₅-C₁₁-spiro cycloalkyl, C₅-C₁₁ hetero-spiro c_{ycloalkyl, C6-C9 bicycloalkyl, C6-C9 heterobicycloalkyl and heteroaryl group} _{substituted with a tetrazole, carboxylate or methylcarboxylate group and optionally} _{substituted independently with one to three groups consisting of H, methyl, ethyl or} H3C-O-. In a further embodiment of the present invention R⁴ is selected from the group R^4c consisting of o_{rganic acids comprising at least one C6-8-carbocyclyl.} 5 In a further embodiment of the present invention R⁴ is selected from the group R^4d consisting of , 01-3598-WO-1 13 , , , ,_{5 wherein the attachment of the R4d is via the bond at the bottom left corner of each formula shown} above. In a further embodiment of the present invention R⁴ is selected from the group R^4e consisting of

01-3598-WO-1 15 wherein the attachment of the R^4e is via the bond at the bottom left corner of each formula shown. 5 Non-limiting examples are compounds XI 01-3598-WO-1 16 and XV . 5 In a further embodiment of the present invention R⁵ is selected from the group R^5b consisting of H_{3C-, H3C-CH2-, H3C-CH2-CH2- and (H3C)2C-.} In a further embodiment of the present invention R⁵ is selected from the group R^5c consisting of H₃C-. In a further embodiment of the present invention R⁶ is selected from the group R^6b consisting of H_{-, HO-, F- and Cl-.} 10 01-3598-WO-1 17 In a further embodiment of the present invention R⁶ is selected from the group R^6c consisting of H_{- and HO-.} In a further embodiment of the present invention R⁶ is selected from the group R^6d consisting of H-. 5 In a further embodiment of the present invention R⁶ is selected from the group R^6e consisting of HO-. In a further embodiment of the present invention R⁷ is selected from the group R^7b consisting of H_{-, F-, H3C-O- and HO-.} 10 In a further embodiment of the present invention R⁷ is selected from the group R^7c consisting of H-. In a further embodiment of the present invention R⁷ is selected from the group R^7d consisting of F-. In a further embodiment of the present invention R⁷ is selected from the group R^7e consisting of HO-. 15 In a further embodiment of the present invention R⁷ is selected from the group R^7f consisting of 01-3598-WO-1 18 H3C-O-. In a further embodiment of the present invention R⁸ is selected from the group R^8b consisting of H_{- and F-.} In a further embodiment of the present invention R⁸ is selected from the group R^8c consisting of H-. 5 In a further embodiment of the present invention R⁸ is selected from the group R^8d consisting of F-. In a further embodiment of the present invention R⁹ is selected from the group R^9b consisting of p_{henyl-, 3-piperidyl-, 2-morpholinyl-, 3-morpholinyl-, 4-morpholinyl- and cyclohexyl-,} _{wherein the piperidyl-group is optionally substituted at the N-atom with 1} substituent independently selected from the group consisting of C_1-3-alkyl-S(O)₂-, C_1-3-alkyl-C(O)-, C_1-5-alkyl-C(O)-O-. R⁹ is selected from the group R^9c consisting of p_{henyl- and cyclohexyl-.} 10 In a further embodiment of the present invention R⁹ is selected from the group R^9d consisting of phenyl-. In a further embodiment of the present invention 01-3598-WO-1 19 R⁹ is selected from the group R^9e consisting of cyclohexyl-. In a further embodiment of the present invention R¹⁰ is selected from the group R^10b consisting of H_{2N-C(O)-, H3C-, cyclopropyl- and phenyl-,} wherein the phenyl-group and/or the H3C-group is optionally substituted with 1 s_{ubstituent independently selected from the group consisting of F- and HO-.} 5 In a further embodiment of the present invention R¹¹ is selected from the group R^11b consisting of H_{O-, H2N-C(O)-, HO-CH2-, H3C-O- and phenyl-.} In a further embodiment of the present invention R¹¹ is selected from the group R^11c consisting of HO-. In a further embodiment of the present invention R¹¹ is selected from the group R^11d consisting of H₃C-O-. 10 B-A, W, X-Y-Z, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ represents a characterized, individual embodiment for the corresponding substituent as described above. Thus, given the above definitions, individual embodiments of the first aspect of the invention are fully characterized by the term (B-A^X, W^X, X-Y-Z^X, R^1X, R^2x, R^3X, R^4X, R^5X, R^6X, R^7X, R^8X, R^9X, R^10Xand R^11X), 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. 01-3598-WO-1 20 T_{he following table 1 shows such embodiments E-1 to E-18 of the compound of general formula (I) or} a salt thereof, preferably a pharmaceutically acceptable salt, or an ester thereof, preferably an C1-3 esters, that are considered preferred. _{5 Table 1: Embodiments E-1 to E-18 of the invention} 01-3598-WO-1 21 Accordingly, for example E-7 covers compounds of general formula (I), wherein B_{-A is selected from the group B-Ab consisting of =C-N-; this means A is N; B is C;} _{W is selected from the group Wb consisting of =CH-;} _{V is selected from the group Vb consisting of =N-;} _{X-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N= and -N=C-NH-.} R¹ is selected from the group R1^a consisting of C_{1-5-alkyl- and C3-6-cycloalkyl-;} R² is selected from the group R^2a consisting of R_{9-C(R8)(R7)-CH(R6)- and R9-S(O)-CH(R6)- and} ; R³ is selected from the group R^3c consisting of H_{3C- and H3C-O-;} R⁴ is selected from the group R^4a consisting of a_{t least one heterocyclyl or carbocyclyl group substituted with a tetrazole, carboxylate} or methylcarboxylate group and optionally substituted independently with one to three groups consisting of H, methyl, ethyl or H3C-O-; R⁵ is selected from the group R^5a consisting of C1-4-alkyl-; R⁶ is selected from the group R^6a consisting of H_{-, HO- and Halogen;} R⁷ is selected from the group R^7a consisting of H_{-, Halogen, HO- and C1-3-alkyl-O-;} R⁸ is selected from the group R^8a consisting of H_{- and Halogen;} R⁹ is selected from the group R^9a consisting of 01-3598-WO-1 22 p_{henyl-, piperidyl-, morpholinyl- and C5-6-cycloalkyl-,} wherein the piperidyl-group is optionally substituted with 1 substituent independently selected from the group consisting of C1-3-alkyl-S(O)2-, C1-3-alkyl- C(O)-, C_1-5-alkyl-C(O)-O-; R¹⁰ is selected from the group R^10a consisting of H_{-, HO-, H2N-C(O)-, C1-3-alkyl-, C1-3-alkyl-O-, C3-4-cycloalkyl- and phenyl-,} wherein the phenyl-group and/or the C1-3-alkyl-group are optionally substituted with 1 substituent independently selected from the group consisting of Halogen and HO-; R¹¹ is selected from the group R^11a consisting of H_{-, HO-, H2N-C(O)-, C1-3-alkyl-, C1-3-alkyl-O-, C3-4-cycloalkyl- and phenyl-,} wherein the phenyl-group and the C_1-3-alkyl-group is optionally substituted with 1 substituent independently selected from the group consisting of Halogen and HO- ; or a salt thereof, preferably a pharmaceutically acceptable salt, or an ester thereof, preferably an C1-3 esters. 5 Accordingly, for example E-10 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-;} _{V is selected from the group Vb consisting of =N-;} _{X-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N= and -N=C-NH-;} R¹ is selected from the group R1^a consisting of C_{1-5-alkyl- and C3-6-cycloalkyl-;} R² is selected from the group R^2a consisting of R_{9-C(R8)(R7)-CH(R6)- and R9-S(O)-CH(R6)- and} ; R³ is selected from the group R^3c consisting of H_{3C- and H3C-O-;} R⁴ is selected from the group R^4a consisting of 01-3598-WO-1 23 a_{t least one heterocyclyl or carbocyclyl group substituted with a tetrazole, carboxylate} or methylcarboxylate group and optionally substituted independently with one to three groups consisting of H, methyl, ethyl or H3C-O-; R⁵ is selected from the group R^5a consisting of C_1-4-alkyl-; R⁶ is selected from the group R^6a consisting of H_{-, HO- and Halogen;} R⁷ is selected from the group R^7a consisting of H_{-, Halogen, HO- and C1-3-alkyl-O-;} R⁸ is selected from the group R^8a consisting of H_{- and Halogen;} R⁹ is selected from the group R^9a consisting of p_{henyl-, piperidyl-, morpholinyl- and C5-6-cycloalkyl-,} wherein the piperidyl-group is optionally substituted with 1 substituent independently selected from the group consisting of C1-3-alkyl-S(O)2-, C1-3-alkyl- C(O)-, C1-5-alkyl-C(O)-O-; R¹⁰ is selected from the group R^10b consisting of H_{2N-C(O)-, H3C-, cyclopropyl- and phenyl-,} wherein the phenyl-group and/or the H₃C-group is optionally substituted with 1 s_{ubstituent independently selected from the group consisting of F- and HO-;} R¹¹ is selected from the group R^11b consisting of H_{O-, H2N-C(O)-, HO-CH2-, H3C-O- and phenyl-;} or a salt thereof, preferably a pharmaceutically acceptable salt, or an ester thereof, preferably an C1-3 esters. Accordingly, for example E-13 covers compounds of general formula (I), 5 wherein B_{-A is selected from the group B-Ab consisting of =C-N-; this means A is N; B is C;} _{W is selected from the group Wb consisting of =CH-;} _{V is selected from the group Vb consisting of =N-;} _{X-Y-Z is selected from the group X-Y-Zc consisting of =CH-N-N=;} R¹ is selected from the group R^1b consisting of i_{sopropyl- and cyclopropyl-;} R² is selected from the group R^2b consisting of 01-3598-WO-1 24 R_{9-C(R8)(R7)-CH(R6)- and R9-S(O)-CH2-;} R³ is selected from the group R³c consisting of H_{3C- and H3C-O-;} R⁴ is selected from the group R^4b consisting of C_3-8-cycloalkyl, C_3-8-heterocycloalkyl, C₅-C₁₁-spiro cycloalkyl, C₅-C₁₁ hetero-spiro c_{ycloalkyl, C6-C9 bicycloalkyl, C6-C9 heterobicycloalkyl and heteroaryl group} substituted with a tetrazole, carboxylate or methylcarboxylate group and optionally substituted independently with one to three groups consisting of H, methyl, ethyl or H3C-O-; R⁵ is selected from the group R^5b consisting of H_{3C-, H3C-CH2-, H3C-CH2-CH2- and (H3C)2C-;} R⁶ is selected from the group R^6b consisting of H_{-, HO-, F- and Cl-;} R⁷ is selected from the group R^7a consisting of H_{-, Halogen, HO- and C1-3-alkyl-O-;} R⁸ is selected from the group R^8a consisting of H_{- and Halogen;} R⁹ is selected from the group R^9c consisting of p_{henyl- and cyclohexyl-;} or a salt thereof, preferably a pharmaceutically acceptable salt, or an ester thereof, preferably an C_1-3 esters. F_{urther preferred are the following compounds listed in table 2 or salt thereof or stereoisomers} _{5 thereof (the No. refers to the No. assigned to the compound in the experimental section). Each} _{compound of table 2 is represented without indicating the stereochemistry thereof, if any. Specific} _{information concerning stereochemical properties of compounds of table 2 can be taken from the} _{experimental section. In case the final compounds according of said experimental section are salt} _{forms, they can be converted into the neutral compound by conventional methods.} 10 Table 2: 01-3598-WO-1 25 Example ^Structure Example ^Structure

93 01-3598-WO-1 30 or a salt thereof, or an ester thereof, preferably an C_1-3 esters. A further embodiment of the present invention covers the compounds of general formula (I), p_{articularly the compounds listed in table 2, in form of their pharmaceutically acceptable salts.} 5 01-3598-WO-1 31 A_{further embodiment of the present invention refers to pharmaceutical compositions comprising at} least one compound according to formula (I), or pharmaceutically acceptable salts thereof, optionally t_{ogether with at least one inert adjuvant, diluent and/or carrier.} _{5 In a further embodiment, the present invention relates to a compound of the present invention or a} _{pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one} _{compound according to general formula (I) or pharmaceutically acceptable salts thereof, for use as a} medicament. 10 In a further embodiment, the present invention relates to compounds according to general formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds according to general formula (I) or pharmaceutically acceptable salts thereof, for use in the prevention, the delaying of the occurrence, the delaying of the progression and/or treatment of diseases or conditions which can be influenced by STING inhibition. Inhibition of the STING protein 15 may not require to be a complete inhibition of the STING proteins within a cell, tissue, organ or the body of a patient to cause the desired positive effects in a patient. A partial inhibition maybe sufficient and possibly desirable in some patients. Used terms and definitions 20 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. 25 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 a_{toms. In general, in groups like HO-, H2N-, (O)S-, (O)2S-, NC- (cyano), HOOC-, F3C- or the like, the} skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the 30 group itself. For combined groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent "aryl-C_1-3-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. 01-3598-WO-1 32 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 5 the group to which the substituent is attached. For example, the term "3-carboxypropyl-group" represents the following substituent: wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms "1- 10 methylpropyl-", "2, 2-dimethylpropyl-" or "cyclopropylmethyl-" group represent the following groups: The asterisk may be used in sub-formulas to indicate the bond which is connected to the core15 molecule as defined. 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. 20 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. 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. 25 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 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 below30 shall encompass solvates thereof such as for instance hydrates. 01-3598-WO-1 33 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 s_{tereochemically pure starting materials and/or by stereoselective synthesis. It is known in the art} 5 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. Enantiomerically pure compounds of this invention or intermediates may be prepared via asymmetric synthesis, for example by preparation and subsequent separation of appropriate 10 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 starting materials, chiral catalysts, or chiral auxiliaries. Further, it is known to the person skilled in the art how to prepare enantiomerically pure compounds 15 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 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 20 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 c_{onditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically} active chiral auxiliary. 25 The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable30 benefit/risk ratio. As used herein, "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of p_{harmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic}35 residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. 01-3598-WO-1 34 For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, 5 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 tris(hydroxymethyl)-aminomethane. 10 The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient 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. 15 Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts) also comprise a part of the invention. _{20 The term “C1-6 esters” refers to an alcohol group with 1 to 4 carbon atoms (e.g. MeOH, EtOH,} _{propanol, butanol, hexanol group) linked to an acid group of the compound of the invention via an} ester linkage. The term halogen denotes fluorine, chlorine, bromine and iodine. 25 The term "C_1-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 C_1-5-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- 30 C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H_{3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.} The term "C_2-m-alkenyl" is used for a group "C_2-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 a35 double bond. 01-3598-WO-1 35 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 C_3-7-cycloalkyl includes cyclopropyl, 5 cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. T_{he term "heterocyclyl" means a saturated or unsaturated mono- or polycyclic or spirocyclic ring} system optionally comprising aromatic rings, containing one or more heteroatoms selected from N, O, S, SO or SO2 consisting of 3 to 14 ring atoms wherein none of the heteroatoms is part of the10 aromatic ring. The term "heterocyclyl" is intended to include all the possible isomeric forms. 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 15 includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl. T_{he term "carbocyclyl", either alone or in combination with another radical, means a mono-, bi- or} tricyclic or spirocyclic ring structure consisting of 3 to 14 carbon atoms. The term "carbocyclyl" refers 20 to fully saturated, partially saturated and aromatic ring systems. The term "carbocyclyl" encompasses f_{used, bridged and spirocyclic systems. These are non-limiting examples} 25 01-3598-WO-1 36 A_{carbocyclyl group, in which one, two or three or more of the carbon atoms of the ring structure} _{have been independently replaced by other elements, e.g. without limitation nitrogen, oxygen,} _{sulphur, is typically considered a heterocyclyl.} 5 Thus, the term "heterocyclyl" includes the following non-limiting exemplary structures (not depicted as radicals as each form is optionally attached through a covalent bond to any atom so long as appropriate valences are maintained): 10 15 01-3598-WO-1 37 H H N N N H N N N N N O O S S S S O S O S O S S O O O O O _{O O} S O O H N H H H N N N N _{N O O O} S S O 5 S S O _S O N O O H O S 01-3598-WO-1 38 5_{The term "heteroaryl" means a mono- or polycyclic ring system, comprising at least one aromatic} 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. 10 Thus, the term "heteroaryl" 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): 15 01-3598-WO-1 39 . 5 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 including10 spirocyclic, fused, and bridged ring systems. 15 Synthesis The compounds according to the invention may be obtained using methods of synthesis known in principle, known to the one skilled in the art and described in the literature of organic synthesis. Preferably, the compounds are obtained in analogous fashion to the methods of preparation 20 explained more fully hereinafter, in particular as described in the experimental section. In some cases, the order in carrying out the reaction steps may be varied. Variants of the reaction methods that are known to the one skilled in the art but not described in detail here may also be used. Preferably, the compounds are obtained by the following methods according to the invention which are described in more detail hereinafter. 25 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 01-3598-WO-1 40 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 s_{equence using methods familiar to the one skilled in the art. The abbreviated substituents may be} as defined above if not defined otherwise within the context of the schemes. 5 Optimum reaction conditions and reaction times may vary depending on reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Experimental section. Typically, reaction progress may be monitored by thin layer chromatography (TLC), liquid _{10 chromatography – mass spectrometry (LC-MS) if desired, and intermediates and products may be} purified by chromatography and/or by recrystallization. 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 _{15 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. 20 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. The term "room temperature" designate a temperature of about 20 °C, e.g., 15 to 25 °C. 25 As a rule, ¹H-NMR and/or mass spectra have been obtained for the compounds prepared. Flash chromatography or MPLC is performed with commercial silica gel and is equivalent to silica gel chromatography. 30 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. In addition, absolute configuration of representative examples is either35 defined via single crystal x-ray structure determination of intermediates or examples or protein- ligand X-ray determinations. 01-3598-WO-1 41 S_{cheme 1a: General synthesis scheme for indazole patent examples} 5 Scheme 1b: General synthesis scheme for benzimidazole patent examples _{10 Scheme 2a: General synthesis of intermediates A} Scheme 2b: Alternative synthesis of intermediates A 01-3598-WO-1 42 Scheme 2c: Alternative synthesis of intermediates A Scheme 3: Synthesis of intermediates E X R2 5 C_G 01-3598-WO-1 43 S_{cheme 4b: Synthesis of intermediates F and G} 5_{Scheme 5: Synthesis of intermediates H} All starting materials not described are either commercially available or described in literature. _{10 Synthesis of Intermediates A1 – A4:} Synthesis of Intermediate A1: S_{tep 1: Synthesis of (1R)-2-{[(2-bromo-6-nitrophenyl) methyl] amino}-1-phenylethan-1-ol} 15 01-3598-WO-1 44 (1R)-2-Amino-1-phenylethan-1-ol (5.00 g, 17.0 mmol) is dissolved in ACN (20 mL) and DIPEA (8.75 mL, 50.9 mmol).1-Bromo-2-(bromomethyl)-3-nitrobenzene (6.98 g, 50.9 mmol) is slowly added. The reaction mixture is stirred at RT for 2 h. The reaction mixture is concentrated and p_{urified by flash chromatography (CycH/EtOAc 100/0} _{CycH/EtOAc 10/90) to afford the} 5 desired compound. A_{nalysis (method A): Rt: 0.36 min, [M+H] +: 351/353 (Br)} _{Step 2: Synthesis of (1R)-2-(4-bromo-2H-indazol-2-yl)-1-phenylethan-1-ol} 10 (1R)-2-{[(2-Bromo-6-nitrophenyl) methyl] amino}-1-phenylethan-1-ol (5.44 g, 15.5 mmol) is suspended in MeOH (25 mL). Zinc (5.06 g, 77.45 mmol) is added, and then ammonium formate (977mg, 15.5 mmol) in MeOH (5 mL) is added dropwise over 5 min. The reaction mixture is s_{tirred at RT overnight. The reaction mixture is filtered, washed with MeOH and the filtrate is} concentrated. The residue is triturated with water. The precipitate is filtered and re-crystallized15 from ACN to afford the title compound. A_{nalysis (method A): Rt: 0.58 min, [M+H] +: 317/319 (Br)} Synthesis of intermediate A2: _{20 Step 1: Synthesis of 2-[(benzenesulfinyl)methyl]-4-bromo-2H-indazole} 4-Bromo-1H-indazole (400 mg, 1.99 mmol) is dissolved in DMF (5 mL). K2CO3 (1.10 g, 7.96 mmol) and chloromethyl phenyl sulfoxide (716 mg, 3.98 mmol) are added and the reaction mixture is stirred at 50 °C overnight. K2CO3 (1.10 g, 7.96 mmol) is added, and the reaction 25 mixture is stirred at 70 °C overnight. The reaction mixture is filtered, and the filtrate is purified by reversed phase chromatography (HPLC; ACN/water including TFA) to afford compound A3. A_{nalysis (method D): Rt: 0.90 min, [M+H] +: 335/337 (Br)} 01-3598-WO-1 45 Synthesis of intermediate A3: S_{tep 1: Synthesis of 2-(4-bromo-2H-indazol-2-yl)-1-phenylethan-1-one} 5 4-Bromo-2H-indazole (2 g, 10.2 mmol), 2-bromo-1-phenylethan-1-one (4.04 g, 20.3 mmol) and aluminum powder (548 mg, 20.3 mmol; -100+325 mesh) are dissolved in DMF/water 3/1 (20 mL). The reaction mixture is stirred at 80 °C overnight. The aluminum is filtered off and washed with DMF. The filtrate is diluted with water and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered, and concentrated. The residue is first triturated with water and then with 10 MeOH. The precipitate is filtered to afford the desired compound. A_{nalysis (method A): Rt: 0.60 min, [M+H] +: 315/317 (Br)} _{Step 2: Synthesis of 4-bromo-2-(2,2-difluoro-2-phenylethyl)-2H-indazole} 15 2-(4-Bromo-2H-indazol-2-yl)-1-phenylethan-1-one (1.08 g, 3.41 mmol) is dissolved in toluene (6 mL) and DCM (6 mL). At 0 °C DAST (3.93 mL, 30 mmol) is added dropwise, and the reaction mixture is stirred at RT for 4 d. The reaction mixture is quenched with a saturated NaHCO3 solution and extracted with DCM. The organic layer is dried (Na2SO4), filtered, and concentrated. The residue is purified by flash chromatography (CycH/EtOAc 70/30) to afford 20 the desired intermediate A3. A_{nalysis (method A): Rt: 0.68 min, [M+H] +: 337/339 (Br)} Synthesis of intermediate A4: _{25 Step 1: Synthesis of 2-(4-bromo-2H-indazol-2-yl)-1-cyclohexylethan-1-one} 01-3598-WO-1 46 4-Bromo-1H-indazole (500 mg, 2.54 mmol) is dissolved in ACN (8 mL). K2CO3 (877 mg, 6.34 mmol) and 2-bromo-1-cyclohexyletan-1-one (521 mg, 2.54 mmol) are added, and the reaction mixture is stirred at 50 °C overnight. The reaction mixture is purified by reversed phase 5 chromatography (HPLC; ACN/water including NH3) to afford the desired product. A_{nalysis (method D): Rt: 1.13 min, [M+H] +: 321/323 (Br)} _{Step 2: Synthesis of 2-(4-bromo-2H-indazol-2-yl)-1-cyclohexylethan-1-ol} 10 2-(4-Bromo-2H-indazol-2-yl)-1-cyclohexylethan-1-one (200 mg, 0.62 mmol) is dissolved in THF (3 mL) and MeOH (3 mL). At 0 °C sodium borohydride (23.6 mg, 0.62 mmol) is added, and the reaction mixture is stirred at 0 °C for 2 h. The reaction mixture is quenched with 1 M HCl and stirred at RT for 15 min. Then the reaction mixture is basified with a saturated NaHCO3 solution and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and 15 concentrated to afford the desired product A4. A_{nalysis (method D): Rt: 1.13 min, [M+H] +: 323/325 (Br)} _{Synthesis of Intermediates B1 – B20:} 20 Synthesis of (1R)-1-phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H- indazol-2-yl] ethan-1-ol (B1) 01-3598-WO-1 47 (1R)-2-(4-Bromo-2H-indazol-2-yl)-1-phenylethan-1-ol (A1,10 g, 31.5 mmol) is dissolved in dioxane (200 mL). Bis(pinacolato)diboron (9.61 g, 37.8 mmol), potassium acetate (8.03 g, 82 mmol) and Pd(dppf)Cl₂ x DCM (2.00 g, 2.45 mmol) are added at RT, and the reaction mixture is stirred at 80 °C overnight. After the reaction mixture is cooled to RT the formed precipitate 5 is filtered and washed with 3 x 20 mL dioxane. The filtrate is concentrated, and the residue is suspended and triturated in CycH overnight. The precipitate is filtered, washed with 2 x 20 mL CycH and dried in an oven at 50 °C overnight to afford the desired product B1. A_{nalysis (method D): Rt: 1.12 min, [M+H] +: 365} 10 Synthesis of (1R)-2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-2-yl]-1- phenylethan-1-ol (B2) and {2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl} boronic acid (B3) 15 (1R)-2-(4-Bromo-2H-indazol-2-yl)-1-phenylethan-1-ol (7.50 g, 23.7 mmol) is dissolved in dioxane (60 mL). Bis (neopentyl glycolato) diboron (8.01 g, 35.5 mmol), potassium acetate (7.00 g, 71.3 mmol) are added, and the mixture is purged with nitrogen. Pd(dppf)Cl₂ x DCM (0.71 g, 0.87 mmol) is added, and the reaction mixture is stirred at 85 °C for 4.5 h. After the 20 reaction mixture is cooled to RT, it is filtered through Celite and Thiol-Resin, and the filtrate is concentrated. The residue is diluted with DCM, and the organic phase is washed 2 x with water and with brine. The organic layer is dried (Na₂SO₄), filtered and evaporated. The residue is triturated with diethyl ether and the formed precipitate is filtered and dried in an oven at 50 °C overnight to afford compound B2. _{25 Analysis (method D): Rt: 0.77 min, [M+H] +: 351} The filtrate is concentrated, and the residue is purified by reversed phase chromatography (HPLC; Sunfire, ACN/water including TFA) to afford compound B3. A_{nalysis (method D): Rt: 0.66 min, [M+H] +: 283} 01-3598-WO-1 48 Synthesis of 2-[(benzenesulfinyl)methyl]-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2H- indazole (B4) U_{nder an argon atmosphere, 2-[(benzenesulfinyl)methyl]-4-bromo-2H-indazole (150 mg, 0.45} 5 mmol) is dissolved in dioxane (2.5 mL). Bis (neopentyl glycolato)diboron (152 mg, 0.67 mmol), potassium acetate (131.8 mg, 1.34 mmol) and Pd(dppf)Cl₂ x DCM (97 mg, 0.12 mmol) are added and the reaction mixture is stirred at 100 °C for 2 h. The reaction mixture is filtered, and the filtrate is concentrated to yield the desired product B8 which is used in the next step without purification. _{10 Analysis (method D): Rt: 0.68 min, [M+H] +: 301 (mass of corresponding boronic acid)} Synthesis of [2-(2,2-difluoro-2-phenylethyl)-2H-indazol-4-yl] boronic acid (B5) 15 Under an argon atmosphere, 4-bromo-2-(2,2-difluoro-2-phenylethyl)-2H-indazole (A3, 677 mg, 2.01 mmol), bis (neopentyl glycolato)diboron (1.36 g, 6.02 mmol), potassium acetate (985 mg, 10 mmol) and Pd(dppf)Cl₂ x DCM (82 mg, 0.10 mmol) are dissolved in dioxane (9 mL) and the reaction mixture is stirred at 80 °C for 3h. The reaction mixture is filtered with ACN through a thiol scavenger resin and the filtrate is evaporated. The residue is purified by reversed phase20 chromatography (HPLC; ACN/water including TFA) to afford the desired product B5. A_{nalysis (method A): Rt: 0.46 min, [M+H] +: 303} Synthesis of 1-cyclohexyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol- 2-yl] ethan-1-ol (B6) 01-3598-WO-1 49 Under an argon atmosphere, 2-(4-bromo-2H-indazol-2-yl)-1-cyclohexylethan-1-ol (A4, 1000 mg, 3 mmol) and 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (1.735 g, 4.5 mmol) are dissolved in 2-Me-THF (20 mL). Potassium pivalate 5 (1.29 g, 9 mmol) and bis(triphenylphosphine)palladium(ii) dichloride (222 mg, 0.3 mmol) are added, and the reaction mixture is stirred at 80 °C for 16 h and 2 days at RT. The reaction mixture is diluted with 2-MeTHF (80 mL) and water (25 mL). The organic phase is concentrated, and the product purified via reversed phase chromatography to afford B6. A_{nalysis (method B): Rt: 1.00 min, [M+H] +: 427} 10 Synthesis of Intermediates C Synthesis of Intermediate C1: 15 S_{tep 1: Synthesis of 2-acetyl-3-methylbutanenitrile} A_{solution of diisopropylamine (177 mL, 1.25 mol) in THF (1.17 L) is cooled to -78°C. N-} 20 butyllithium 2.5M in hexane (469 mL, 1.17 mol) is added and the reaction mixture is allowed to warm to 0°C and stirred 1 h at 0°C. The reaction mixture is cooled to -78°C and 3-methyl- butyronitrile (81.8 mL, 0.782 mol) in 80 mL THF is added dropwise, while maintaining the temperature below -65°C. The reaction mixture is stirred at -78^oC for 1h. After that, a solution of acetic anhydride (88.7 mL, 0.938 mol) in 80 mL THF is added dropwise over 30 min. The 25 reaction mixture is allowed to warm to 0^oC for 1h, then 15°C for 0.5h. The reaction mixture is quenched with citric acid (10 %, 200 mL) and extracted with EtOAc. The organic layer is dried (Na₂SO₄), filtered and concentrated to afford the desired product, which is used without further purification in the next step. 01-3598-WO-1 50 Analysis (TLC): R_f : 0.3 (20% EtOAc/ petrol ether) S_{tep 2: Synthesis of 5-methyl-4-(propan-2-yl)-1H-pyrazol-3-amine} 5 2-Acetyl-3-methylbutanenitrile (80 g, 0.64 mol) is dissolved in EtOH (352 mL). Glacial acetic acid (47.6 mL, 0.83 mol) and hydrazine monohydrate (49.6 mL, 1.02 mol) are added, and the reaction mixture is stirred at 80 °C overnight. After cooling to 0 °C the pH is carefully adjusted to 9 with a saturated NaHCO3 solution. The reaction mixture is then diluted with water and ¹⁰ extracted 3 x with EtOAc. The organic layer is washed with brine, dried (Na2SO4), filtered and concentrated to afford the desired product. A_{nalysis (method B): Rt: 0.36 min, [M+H] +: 140} _{Step 3: Synthesis of 3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole} 15 5-Methyl-4-(propan-2-yl)-1H-pyrazol-3-amine (1 g, 7.2 mmol) is dissolved in ACN (8 mL). Under cooling with ice/acetone, sodium nitrite (0.59 g, 8.6 mmol) is added, and the reaction mixture is stirred at -5 °C for 30 min. Then KI (1.55 g, 9.34 mmol) is added, and the reaction mixture is stirred at 0 °C for 1.5 h. The reaction mixture is quenched with Na2S2O3 and is diluted 20 with Me-THF (10 mL) and water (10 mL). After stirring for 1h the layers are separated. The organic layer is washed with brine, dried (Na2SO4), and concentrated to afford 1.6 g of the desired product C1. A_{nalysis (method A): Rt: 0.52 min, [M+H] +: 251} 25 Alternative synthesis of intermediate C1 S_{tep 1: Synthesis of 5-iodo-3-methyl-4-(propan-2-yl)-1H-pyrazole} 01-3598-WO-1 51 3-Methyl-4-(propan-2-yl)-1H-pyrazole (10 g, 80.5 mmol) is dissolved in ACN (150 mL). NIS (25 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 5 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 _{afford intermediate C1.} _{Analysis (method D): Rt: 0.93 min, [M+H] +: 251} 10 S_{tep 3: Synthesis of 3-iodo-5-methyl-4-(cyclopropanyl)-1H-pyrazole} 5-Methyl-4-(cyclopropanyl)-1H-pyrazol-3-amine (5.17 g, 37.6 mmol) is dissolved in ACN (108 mL) and cooled to 0°C. Then acetic acid (6.5 mL, 112 mmol) is carefully added, followed by 15 dropwise addition of potassium iodide (11.2 mL, 93.9 mmol dissolved in 54 mL of water) is added. The mixture is stirred for 10 min at 0°C, then tert-butyl nitrite (11.2 mL, 94 mmol, dissolved in ACN) is added dropwise. The mixture is stirred for 10 min at °C followed by 1h at RT. The reaction mixture is adjusted to pH 8 by addition of aqueous saturated sodium bicarbonate and extracted with EtOAc. The organic phase is washed with 0.5 M, 200 mL 20 Na₂S₂O₃ and brine and then dried over Na₂SO₄. The concentrated organic phase is then purified by flash column chromatography using EtOAC /CycH mixtures as eluent to yield the desired product C2. A_{nalysis (method B): Rt: 0.57 min, [M+H] +: 249} 25 Synthesis of intermediate C3 S_{tep 1: Synthesis of 5-cyclopropyl-1-methyl-1H-imidazole} 01-3598-WO-1 52 Under an argon atmosphere, 5-bromo-1-methyl-1H-imidazole (7.50 g, 46.6 mmol), cyclopropylzinc bromide (132 mL, 65.90 mmol, 0.5 M in THF) and Pd(dppf)Cl₂ (2.20 g, 3.01 mmol) are mixed, and the reaction mixture is stirred at 70 °C for 20 h. The reaction mixture is 5 concentrated, and the residue is purified by flash chromatography (DCM/MeOH 100/0 ^ DCM/MeOH 90/10) to afford the desired product. A_{nalysis (method B): Rt: 0.31 min, [M+H] +: 123} _{Step 2: Synthesis of 5-cyclopropyl-1,2-dimethyl-1H-imidazole} 10 Under an argon atmosphere, 5-cyclopropyl-1-methyl-1H-imidazole (1 g, 8.12 mmol) is dissolved in THF (15.00 mL) and cooled to -78°C. n-BuLi (6.1 mL, 9.8 mmol, 1.6 M) is added dropwise and the reaction mixture is stirred at -78°C for 30 min. Then MeI (663 µL, 10.6 mmol) is added dropwise and the reaction mixture is stirred at -78°C for 1 h. The reaction mixture is 15 quenched with a half saturated NH₄Cl solution and stirred for 10 min.2 mL of aqueous NH₄OH (25 %) is added and the mixture is stirred for 30 min. The layers are separated, and the aqueous layer is extracted 3x with EtOAc. The combined organic layers are dried (Na₂SO₄), filtered and evaporated to afford intermediate C3. A_{nalysis (method E): Rt: 0.72 min, [M+H] +: 137} 20 Synthesis of intermediates D Synthesis of intermediates D1 25 Synthesis of (1R)-2-{4-[5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl]-2H-indazol-2-yl}-1- phenylethan-1-ol (D1) 01-3598-WO-1 53 (1R)-1-Phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethan-1-ol (_{B1) (109 mg, 0.3mmol) and 5-iodo-3-methyl-4-(propan-2-yl)-1H-pyrazole (C1) (82 mg, 0.33} mmol) are dissolved in dioxane (2 mL). K3PO4 (2N, 300 µL) and Pd-XPhos-G3 (25 mg) are 5 added, and the reaction mixture is stirred at 100 °C overnight. The mixture is then filtered, diluted with ACN and purified by reversed phase HPLC to yield the desired intermediate D1. A_{nalysis (method E): Rt: 0.99 min, [M+H] +: 361} 10 Synthesis of 2-[(benzenesulfinyl)methyl]-4-[5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl]- 2H-indazole (D2) {_{2-[(Benzenesulfinyl)methyl]-2H-indazol-4-yl}boronic acid (B4) (160 mg, 0.53 mmol) and 5-} _{iodo-3-methyl-4-(propan-2-yl)-1H-pyrazole (C1) (115 mg, 0.46 mmol) are dissolved in dioxane} 15 (2.5 mL). Cs2CO3 (2N, 440 µL) and [1,1'-bis(diphenylphosphino) ferrocene] dichloropalladium(II), (18 mg) are added, and the reaction mixture is stirred at 80 °C for 6 h. The mixture is then diluted with water and extracted several times with ethyl acetate, the organic phase washed with brine, filtered, and purified by reversed phase HPLC to yield the desired intermediate D2. _{20 Analysis (method D): Rt: 0.82 min, [M+H] +: 379} Synthesis of intermediates E and F Synthesis of (1R)-2-{4-[1-(6-chloro-2-methylpyridin-3-yl)-5-methyl-4-(propan-2-yl)-1H- pyrazol-3-yl]-2H-indazol-2-yl}-1-phenylethan-1-ol (E1) 01-3598-WO-1 54 (1R)-2-{4-[5-Methyl-4-(propan-2-yl)-1H-pyrazol-3-yl]-2H-indazol-2-yl}-1-phenylethan-1-ol (D1) (500 mg, 1.39 mmol), 6-chloro-3-iodo-2-methylpyridine (435 mg,1.67 mmol), 8-hydroxy-2- methylquinoline (68 mg, 0.42 mmol), Cs2CO3 (452 mg) are suspended in DMSO (5 mL) under 5 Argon and heated at 100°C overnight. The reaction mixture is added on water and extracted with ethyl acetate (150 mL). The organic phase is dried and concentrated, and the residual purified by reversed phase HPLC to yield the desired intermediate E1. A_{nalysis (method D): Rt: 1.08 min, [M+H] +: 486} 10 Synthesis of 4-[1-(6-chloro-2-methylpyridin-3-yl)-5-methyl-4-(propan-2-yl)-1H-pyrazol-3- yl]-2-(2,2-difluoro-2-phenylethyl)-2H-indazole (E2) Step 1: 15 3-Iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (C1) (2g, 8 mmol), 6-chloro-2-methylpyridine-3- boronic acid (1.54 g,8.8 mmol), Cu(II) acetate (3.63 g) and pyridine (3.2 mL) is suspended in acetonitrile (40 mL) at 65°C in an open flask. After 2 h additional boronic acid (500 mg) is added and after 1h further boronic acid (500 mg). The reaction is filtered, and the filtrate 20 concentrated, and the residual purified by reversed phase HPLC to yield the desired intermediate F1. A_{nalysis (method D): Rt: 1.19 min, [M+H] +: 376/378} 01-3598-WO-1 55 [2-(2,2-Difluoro-2-phenyl ethyl)-2H-indazol-4-yl]boronic acid (B6) (400 mg, 1.23 mmol, 6- c_{hloro-3-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2-methylpyridine (F1) (473 mg,} 5 1.23 mmol), Na₂CO₃ (1M, 3.8 mL) are suspended in dioxane (14 mL) under Argon. Tetrakis(triphenylphosphine) palladium(0), (145 mg) is added, and the reaction mixture is stirred at 90 °C for 2 h. The mixture is filtered and purified by reversed phase HPLC to yield the desired intermediate E2. A_{nalysis (method C): Rt: 1.2 min, [M+H] +: 506/508} 10 Synthesis of (1R)-2-{4-[1-(6-chloro-2-methoxypyridin-3-yl)-5-methyl-4-(propan-2-yl)-1H- pyrazol-3-yl]-2H-indazol-2-yl}-1-phenylethan-1-ol (E3) Step 1: 15 3-Iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (C1) (1g, 4 mmol), 6-chloro-2-methoxypyridine- 3-boronic acid (0.87 g, 4.4 mmol), Cu(II) acetate (1.8 g) and pyridine (1.59 mL) is suspended in acetonitrile (10 mL) at 65°C in an open flask. The reaction is filtered, and the filtrate concentrated, and the residual purified by reversed phase HPLC to yield the desired intermediate F2. _{20 Analysis (method D): Rt: 1.24 min, [M+H] +: 392/394} Step 2: 01-3598-WO-1 56 {2-[(2R)-2-Hydroxy-2-phenylethyl]-2H-indazol-4-yl}boronic acid (B3) (265 mg, 0.94 mmol), (6- c_{hloro-2-methoxypyridin-3-yl)boronic acid (F2) (370 mg, 0.94 mmol) and Na2CO3 (1M, 2.8 mL)} _{are suspended in dioxane (8 mL) under Argon. Tetrakis(triphenylphosphine) palladium(0) (108} 5 mg) is added, and the reaction mixture is stirred at 110 °C for 2 h. The mixture is filtered and purified by reversed phase HPLC to yield the desired intermediate E3. A_{nalysis (method D): Rt: 1.21 min, [M+H] +: 502/504} Synthesis of (1R)-2-{4-[1-(6-fluoro-2-methylpyridin-3-yl)-5-methyl-4-(propan-2-yl)-1H-10 pyrazol-3-yl]-2H-indazol-2-yl}-1-phenylethan-1-ol (E4) Step 1: 3-Iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (C1) (500 mg, 2 mmol), 2-fluoro-6-picoline-5- 15 boronic acid (341 g, 2.2 mmol), Cu(II) acetate (0.9 g) and pyridine (1 mL) are suspended in acetonitrile (4 mL) at 50°C in an open flask overnight. The reaction is filtered, and the filtrate concentrated, diluted with DCM and washed with aq. NH₃ (2 mL), then saturated NH₄Cl solution. The organic phase is concentrated, and the residual purified by reversed phase HPLC to yield the desired intermediate F3. _{20 Analysis (method E): Rt: 1.1 min, [M+H] +: 360} Step 2: 01-3598-WO-1 57 (1R)-1-Phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethan-1-ol (B1) (703 mg, 1.93 mmol), 6-fluoro-3-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2- m_{ethylpyridine (F3) (500 mg, 1.76 mmol), K3PO4 (2M, 2.6 mL) are suspended in 2-MeTHF (8} _{5 mL) under Argon. Pd-XPhos-G3 (74 mg) is added, and the reaction mixture is stirred at 80 °C} for 4 h. The mixture is diluted with water and extracted with ethyl acetate, filtered and the concentrate purified by reversed phase HPLC to yield the desired intermediate E4. A_{nalysis (method D): Rt: 1.07 min, [M+H] +: 470} 10 Synthesis of 2-[(benzenesulfinyl)methyl]-4-[1-(6-chloro-2-methylpyridin-3-yl)-5-methyl- 4-(propan-2-yl)-1H-pyrazol-3-yl]-2H-indazole (E5) 2-[(Benzenesulfinyl)methyl]-4-[5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl]-2H-indazole (D2) (245 mg; 0.676 mmol), copper (I) iodid (25 mg), 8-hydroxy-2-methylquinoline (32 mg; 0.19 15 mmol), Cs2CO3 (211 mg; 0.65 mmol) and 6-chloro-3-iodo-2-methylpyridine (203 mg; 0.77 mmol) in DMSO (2 ml) were combined and stirred under argon at 100 °C for 24h. The mixture is diluted with water and extracted with ethyl acetate. The organic phase is concentrated, and the product purified via reversed phase chromatography to afford E5. A_{nalysis (method D): Rt: 1.05 min, [M+H] +: 504} 20 Synthesis of intermediates G 01-3598-WO-1 58 Synthesis of ethyl (1r,4r)-4-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-6- methylpyridin-2-yl}cyclohexane-1-carboxylate (G1) Step 1: 5 (Ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (1000 mg, 3.43 mmol), 3-amino-6-chloro-2-picoline (480 mg, 3.37 mmol), K3PO4 (2M, 5.05 mL) are s_{uspended in 2-MeTHF (15 mL). Pd-XPhos-G3, (200 mg) is added, and the reaction mixture} is stirred under reflux 3 h. The organic phase is separated, mixture is diluted with water and extracted with ethyl acetate, filtered over MgSO₄ and concentrated. The residue is purified by10 reversed phase HPLC to yield ethyl 4-(5-amino-6-methylpyridin-2-yl)cyclohex-3-ene-1- carboxylate. A_{nalysis (method A): Rt: 0.365 min, [M+H] +: 261} Step 2: 15 Ethyl 4-(5-amino-6-methylpyridin-2-yl) cyclohex-3-ene-1-carboxylate (380 mg; 1.02 mmol) is dissolved in methanol (10 ml; 247 mmol) and Pd/C 10% (80 mg) and hydrogen (3 bar) is added at RT. When the required amount of hydrogen is consumed the solids are filtered off and the filtrate concentrated to give ethyl 4-(5-amino-6-methylpyridin-2-yl) cyclohexane-1-carboxylate. A_{nalysis (method A): Rt: 0.376 min, [M+H] +: 263} 20 Step 3: Under stirring sodium (3 g; 130 mmol) is added to ethanol dry (60 ml; 1028 mmol). The mixture is stirred at 20-50 °C until the sodium is dissolved. The solution of ethyl 4-(5-amino-6- 25 methylpyridin-2-yl) cyclohexane-1-carboxylate (3.48 g; 13.3 mmol) in dry ethanol (20 ml; 343 mmol) is added and the mixture was refluxed for 48 h. The mixture is cooled down to 5 °C and acidified with 4 M HCl in dioxane (38 ml; 152 mmol) and refluxed for 16 h. The solids are filtered off, washed with ethanol and the filtrate is concentrated in vacuum. The residue is solved in DCM (50 mL) and saturated aqueous sodium hydrogen carbonate (20 mL) and stirred at room 01-3598-WO-1 59 temperature for 15 min. The organic layer is separated and concentrated in vacuum to give ethyl (1r,4r)-4-(5-amino-6-methylpyridin-2-yl)cyclohexane-1-carboxylate. A_{nalysis (method A): Rt: 0.376 min, [M+H] +: 263} Analysis (method F): Rt: 0.87 min (trans 96%) and Rt: 1.08 min (cis 4%) 5 Step 4: To the solution of ethyl (1r,4r)-4-(5-amino-6-methylpyridin-2-yl)cyclohexane-1-carboxylate (3.5 g; 12 mmol) and diiodomethane (40 ml; 496 mmol) is added isoamyl nitrite (2.52 ml; 18 mmol) 10 (over a period of 5 min). At RT the reaction mixture is stirred 30 min and at 70 °C for 3 h. The mixture is concentrated, and the residue is purified by reversed phase HPLC. A_{nalysis (method B): Rt: 0.86 min, [M+H] +: 374} Step 5: _{15 5-Iodo-4-isopropyl-3-methyl-1h-pyrazole (C1) (2.3 g; 8.8 mmol), copper (I)iodid (1.36 g; 7.1} mmol), 8-hydroxy-2-methylquinoline (0.347 g; 2.2 mmol), Cs₂CO₃ (4.6 g; 14 mmol) and the solution of ethyl (1r,4r)-4-(5-iodo-6-methylpyridin-2-yl)cyclohexane-1-carboxylate (2.0 g; 5.4 mmol) in DMSO (25 ml) were combined and stirred at 100 °C for 22 h. The reaction mixture is cooled down to room temperature and SiliaMetS® Imidazole Resin (1,12 mmol/g; 2 g) is 20 added. The mixture is stirred for 2 h at room temperature, the solids are filtered off and the filtrate is concentrated in vacuum. The residue is purified via reverse phase HPLC to yield the intermediate G1. A_{nalysis (method B): Rt: 0.86 min, [M+H] +: 374} 25 Synthesis of (1S,6R)-3-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-6- methylpyridin-2-yl}-3-azabicyclo[4.1.0]heptane-6-carboxylate (G2) 01-3598-WO-1 60 6-Fluoro-3-(3-iodo-4-isopropyl-5-methylpyrazol-1-yl)-2-methylpyridine (F3) (550 mg, 1.52 mmol), methyl (1S,6R)-3-azabicyclo[4.1.0]heptane-6-carboxylate hydrochloride (436 mg, 2.27 mmol, for synthesis see WO2013025425), K₂CO₃ (0.838 g) and NMP (3 mL) is mixed together 5 and heated at 100°C for 14h. The mixture is diluted with water (30 mL) and the desired product collected and washed with water, dissolved in methanol, and dried. A_{nalysis (method D): Rt:.0.96 min, [M+H] +: 495} Synthesis of (1R,6S)-3-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-6-10 methylpyridin-2-yl}-3-azabicyclo[4.1.0]heptane-6-carboxylate (G3) 6-Fluoro-3-(3-iodo-4-isopropyl-5-methylpyrazol-1-yl)-2-methylpyridine (F3) (550 mg, 1.52 mmol), methyl (1R,6S)-3-azabicyclo[4.1.0]heptane-6-carboxylate hydrochloride (436 mg, 2.27 ¹⁵ mmol, for synthesis see WO2013025425), K2CO3 (0.838 g) and NMP (3 mL) is mixed together and heated at 100°C for 14h. The mixture is diluted with water (30 mL) and the desired product G_{3 collected and washed with water, dissolved in methanol, and dried.} _{Analysis (method D): Rt:.0.96 min, [M+H] +: 495} 20 Synthesis of methyl (1S,4R,5R)-2-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-6- methylpyridin-2-yl}-2-azabicyclo[2.2.1]heptane-5-carboxylate (G4) 01-3598-WO-1 61 6-Fluoro-3-(3-iodo-4-isopropyl-5-methylpyrazol-1-yl)-2-methylpyridine (F3) (300 mg, 0.83 mmol), methyl (1S,4R,5R)-2-azabicyclo[2.2.1]heptane-5-carboxylate hydrochloride (237 mg, 1.24 mmol), K2CO3 (0.457 g) and NMP (3 mL) is mixed together and heated at 100°C for 14h. 5_{The mixture is diluted with water (30 mL) and the desired product G3 collected and washed} with water, dissolved in methanol, and dried. A_{nalysis (method G): Rt: 0.85 min, [M+H] +: 495} Synthesis of methyl (1S,5S)-3-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-6-10 methylpyridin-2-yl}-3-azabicyclo[3.1.0]hexane-1-carboxylate (G5) 6-Fluoro-3-(3-iodo-4-isopropyl-5-methylpyrazol-1-yl)-2-methylpyridine (F3) (200 mg, 0.55 mmol), methyl (1S,5S)-3-azabicyclo[3.1.0]hexane-1-carboxylate (147 mg, 0.83 mmol⁾, K2CO3 (0.304 g) and NMP (3 mL) is mixed together and heated at 100°C for 14h. The mixture is 15 diluted with water (30 mL) and extracted with ethyl acetate and the organic phase concentrated. A_{nalysis (method G): Rt: 0.96 min, [M+H] +: 481} 20 Synthesis of methyl 2-[(3S)-1-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-6- methylpyridin-2-yl}pyrrolidin-3-yl]acetate (G6) 01-3598-WO-1 62 6-Fluoro-3-(3-iodo-4-isopropyl-5-methylpyrazol-1-yl)-2-methylpyridine (F3) (1000 mg, 2.76 mmol), methyl 2-[(3S)-pyrrolidin-3-yl] acetate hydrochloride (990 mg, 5.5 mmol), K₂CO₃ (1.52 g) and NMP (15 mL) is mixed and heated at 100°C for 14h. The mixture is diluted with water 5_{(30 mL) and the desired product G6 collected and dried.} _{Analysis (method C): Rt: 0.70 min, [M+H] +: 483} Synthesis of methyl 1-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-6- methylpyridin-2-yl}piperidine-4-carboxylate (G7) 10 6-Fluoro-3-(3-iodo-4-isopropyl-5-methylpyrazol-1-yl)-2-methylpyridine (F3) (1000 mg, 2.76 mmol), methyl piperidine-4-carboxylate hydrochloride (990 mg, 5.5 mmol), K₂CO₃ (1.52 g) and NMP (15 mL) is mixed and heated at 100°C overnight. The mixture is diluted with water and extracted with ethyl acetate. The organic phase is dried and concentrated to provide 15 intermediate G7. A_{nalysis (method C): Rt: 0.85 min, [M+H] +: 483} Synthesis of ethyl 1-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-6-20 methylpyridin-2-yl}-4-methylpiperidine-4-carboxylate (G8) 6-Fluoro-3-(3-iodo-4-isopropyl-5-methylpyrazol-1-yl)-2-methylpyridine (F3) (200 mg, 0.55 mmol), ethyl 4-methylpiperidine-4-carboxylate hydrochloride (241 mg, 1.1 mmol), K₂CO₃ (381 01-3598-WO-1 63 mg) and NMP (5 mL) is mixed and heated at 110°C for 4 h. The mixture is purified via reversed phase HPLC to provide to provide intermediate G8. A_{nalysis (method D): Rt: 1.1 min, [M+H] +: 511} 5 Synthesis of methyl 4-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-6- methylpyridin-2-yl}bicyclo[2.2.2]octane-1-carboxylate (G9) Step 1: 10 4-(Methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (6.92 g, 33 mmol) and 2-methyl-3- nitropyridine (3 g, 21.7 mmol) are suspended in ACN (90 mL) and water (90 mL). Sulfo oxidanesulfonoperoxoate diamine (5 g, 21.7 mmol) and Ag(I) NO3 (738 mg) is added, and the mixture is stirred at 80°C for 2h. The organic phase is extracted and the concentrated residual purified via silica gel chromatography (CyH/ EE gradient 0-100%) to provide methyl 4-(6-15 methyl-5-nitropyridin-2-yl)bicyclo[2.2.2]octane-1-carboxylate. A_{nalysis (method C): Rt: 1.14 min, [M+H] +: 304} Step 2: 20 Methyl 4-(6-methyl-5-nitropyridin-2-yl)bicyclo[2.2.2]octane-1-carboxylate (570 mg, 1.87 mmol) is dissolved in MeOH (10 mL) and Pd/C 10% (60 mg) is added and the mixture hydrogenated to yield methyl 4-(5-amino-6-methylpyridin-2-yl)bicyclo[2.2.2]octane-1-carboxylate. A_{nalysis (method C): Rt: 0.48 min, [M+H] +: 275} 25 Step 3: Methyl 4-(5-amino-6-methylpyridin-2-yl)bicyclo[2.2.2]octane-1-carboxylate (450 mg, 1.64 mmol) dissolved in aq. HCl (4M, 2 mL) and cooled to -5°C. NaNO2 (170 mg in 0.5 mL water) 01-3598-WO-1 64 is added and the mixture stirred for 1 h at 0°C. KI (600 mg, 3.6 mmol) is added and the mixture stirred for 2 h. The reaction mixture is neutralized with NaOH and extracted with DCM and separated to give methyl 4-(5-iodo-6-methylpyridin-2-yl)bicyclo[2.2.2]octane-1-carboxylate. A_{nalysis (method C): Rt: 0.96 min, [M+H] +: 386} 5 Step 4: (_{3-Iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (C1) (400 mg; 1.6 mmol), copper (I) iodid (61} mg), 8-hydroxy-2-methylquinoline (78 mg; 0.48 mmol), Cs₂CO₃ (199 mg; 0.61 mmol) and 10 methyl 4-(5-iodo-6-methylpyridin-2-yl)bicyclo[2.2.2]octane-1-carboxylate (521 mg; 1.6 mmol) in DMSO (15 ml) were combined and stirred under Argon at 100 °C overnight. The mixture is diluted with water and extracted with ethyl acetate. The organic phase is concentrated, and the product purified via silica gel chromatography (CyH/EE gradient 0-100). A_{nalysis (method C): Rt: 1.19 min, [M+H] +: 508} 15 Synthesis of methyl 4-[5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-6- methylpyridin-2-yl]cyclohex-3-ene-1-carboxylate (G10) S_{tep 1: Synthesis of 5-cyclopropyl-1-methyl-1H-imidazole} 20 Under an argon atmosphere, 5-bromo-1-methyl-1H-imidazole (7.50 g, 46.6 mmol), cyclopropyl zinc bromide (132 mL, 66 mmol, 0.5 M in THF) and Pd(dppf)Cl2 (2.20 g, 3 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 product. _{25 Analysis (method B): Rt: 0.31 min, [M+H] +: 123} _{Step 2: Synthesis of 2,4-dibromo-5-cyclopropyl-1-methyl-1H-imidazole} 01-3598-WO-1 65 5-Cyclopropyl-1-methyl-1H-imidazole (9.20 g, 52.7 mmol,) is dissolved in ACN (200 mL). At – 5_{°C NBS (18.8 g, 105 mmol) is added in portions and the reaction mixture is stirred at – 5 °C} for 30 min and at RT for 4 h. The reaction mixture is quenched by the addition of a saturated 5 Na₂S₂O₃ solution (40 mL, 4.4 M). The formed precipitate is filtered and washed with ACN. 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 product. A_{nalysis (method C): Rt: 0.77 min, [M+H] +: 279/281/283 (2x Br)} 10 Step 3: 2,4-Dibromo-5-cyclopropyl-1-methyl-imidazole (1 g, 3.55 mmol), (6-chloro-2-methylpyridin-3- yl)boronic acid (641 mg; 3.55 mmol), Cs2CO3 (3.47 g), palladium (0) 15 tetrakis(triphenylphosphine) (0.41 g) is suspended in dioxane (20 mL) and water( 3 mL) and stirred at 95°C for 2 h under Argon. The product is purified via reversed phase chromatography. A_{nalysis (method C): Rt: 0.98 min, [M+H] +: 326/328/330} Step 4: 20 3-(4-Bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-6-chloro-2-methylpyridine (300 mg; 0.92 mmol), Na₂CO₃ (1M, 2.7 mL)), palladium (0) tetrakis(triphenylphosphine) (106 mg) is 01-3598-WO-1 66 suspended in dioxane (13 mL) and stirred at 95°C for 2 h under Argon. The product is purified via reversed phase chromatography to afford G10. A_{nalysis (method D): Rt: 0.87 min, [M+H] +: 430/432} 5 Synthesis of intermediates H Synthesis of and methyl (1S,6R)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)bicyclo[4.1.0]hept-4-ene-1-carboxylate (H1) and (1R,6S)-4-(4,4,5,5-tetramethyl-1,3,2-10 dioxaborolan-2-yl)bicyclo[4.1.0]hept-4-ene-1-carboxylate (H2) Step 1: Methyl 4-oxobicyclo[4.1.0]heptane-1-carboxylate (1 g, 5.6 mmol) and N,N- diisopropylethylamine (3.9 mL)dissolved in toluene (20 mL). Trifluoromethanesulfonyl 15 trifluoromethanesulfonate (3.8 mL) is added slowly at 37°C and the reaction temperature is kept 50°C and stirred further for 2 h at 40°C. The mixture is poured on ethyl acetate (150 mL). The organic phase is extracted with sat. NaHCO3 solution and the water phase with ethyl acetate. To the organic phase is added activated carbon, filtered, and concentrated. The r_{esidue is purified via silica gel chromatography (CyH/EE 1/0 ^} _8/2) _{20 Analysis (method D): Rt: 1,04 min, [M+H] +: 300} Step 2: Methyl 4-(trifluoromethanesulfonyloxy)bicyclo[4.1.0]hept-4-ene-1-carboxylate (1.7 g; 5.6 mmol), bis(pinacolato)diboron (2.2g, 8.5 mmol), potassium acetate (1.7 g; 17 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (139 mg), 25 1,1'-bis(diphenylphosphino)ferrocene (96 mg) is suspended in dioxane (15 ml) and stirred at 90°C under Argon for 14 h. The mixture is then concentrated, ethyl acetate (100 mL) is added, and the organic phase washed with sat NaHCO3. The organic phase is concentrated, and the p_{roduct purified via silica gel chromatography (CyH/EE} _85/15). _{Analysis (method D): Rt: 1.08 min, [M+H] +: 278} 30 Step 3: 01-3598-WO-1 67 Chiral separation of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[4.1.0]hept- 4-ene-1-carboxylate with method L is affording the intermediates methyl (1S,6R or 1R,6S))-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[4.1.0]hept-4-ene-1-carboxylate (H1) and 5 methyl (1R,6S or 1S,6R)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[4.1.0]hept-4- ene-1-carboxylate (H2). Analysis (method L): Rt: 1.42 min (H2) Analysis (method L): Rt: 2.42 min (H1) T_{he absolute stereochemistry of H1 and H2 is not determined.} 10 Synthesis of ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[3.1.0]hex-2- ene-6-carboxylate (H3) Step 1: 15 Ethyl 3-oxobicyclo[3.1.0]hexane-6-carboxylate (1 g, 5.6 mmol) and N,N-diisopropylethylamine (3.9 mL) dissolved in toluene (20 mL). Trifluoromethanesulfonyl trifluoromethanesulfonate (3.8 mL) is added slowly at 37°C and the reaction temperature is kept 50°C and stirred further for 2 h at 45°C. The mixture is poured on ethyl acetate (150 mL). The organic phase is extracted with sat. NaHCO3 solution and the water phase with ethyl acetate. To the organic phase is 20 added activated carbon, filtered, and concentrated. The residue is purified via silica gel c_{hromatography (CyH/EE 1/0 ^ 8/2)} _{Analysis (method D): Rt: 1.03 min, [M+H] +: 300} Step 2: Ethyl 3-(trifluoromethanesulfonyloxy)bicyclo[3.1.0]hex-2-ene-6-carboxylate (750 mg; 2.5 25 mmol), bis(pinacolato)diboron (961 mg, 3.7 mmol), potassium acetate (735 mg; 7.5 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (61 mg), 1,1'-bis(diphenylphosphino)ferrocene (42 mg) is suspended in dioxane (10 ml) and stirred at 90°C under Argon for 14 h. The mixture is then diluted with ethyl acetate (100 mL), and the 01-3598-WO-1 68 organic phase washed with sat NaHCO₃. The organic phase is concentrated, and the product p_{urified via silica gel chromatography (CyH/EE 1/0 ^ 85/15) to afford intermediate H3.} _{Analysis (method D): Rt: 1.04 min, [M+H] +: 278} 5 Synthesis of ethyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3- ene-1-carboxylate (H4) Step 1: To pyridine (244 mg) dissolved in toluene (10 mL), trifluoromethanesulfonyl 10 trifluoromethanesulfonate (0.56 mL) is added slowly at 15°C and the reaction stirred further for 30 min. Ethyl 1-methyl-4-oxocyclohexanecarboxylate (500 mg in 1 ml toluene) is added slowly and the mixture stirred at 40°C for 24 h. The mixture is added to water and extracted with ethyl acetate. The organic phase is washed with sat. NaHCO3 solution, concentrated and purified via silica gel chromatography. To the organic phase is added activated carbon, filtered, and_{15 concentrated. The residue is purified via silica gel chromatography (CyH/EE} _8/2) Step 2: Ethyl 1-methyl-4-(trifluoromethanesulfonyloxy)cyclohex-3-ene-1-carboxylate (300 mg; 0.948 mmol), bis(pinacolato)diboron (365 mg, 1.4 mmol), potassium acetate (279mg; 2.85 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (23 _{20 mg), 1,1'-bis(diphenylphosphino)ferrocene (16 mg) is suspended in dioxane (5.5 ml) and} stirred at 90°C under Argon for 14 h. The mixture is then concentrated and diluted with ethyl acetate (100 mL), and the organic phase washed with sat NaHCO3. The organic phase is c_{oncentrated, and the product purified via silica gel chromatography (CyH/EE 1/0} _{85/15) to} afford intermediate H4. _{25 Analysis (method D): Rt: 1.17 min, [M+H] +: 295} Synthesis of patent examples 01-3598-WO-1 69 Synthesis of 4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4- (propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl] bicyclo[2.2.1]heptane-1- carboxylate (example 1) 5 Step 1: 4-(Methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid (3.23 g, 16.3 mmol) and 2-methyl- 3-nitropyridine (1.5 g, 10.9 mmol) are suspended in DCM (60 mL) and water (60 mL). Sulfo 10 oxidanesulfonoperoxoate diamine (2.48 g, 10.8 mmol) and Ag(I) NO₃ (369 mg) is added and the mixture is stirred at 50°C overnight. The organic phase is separated and the concentrated residual purified via silica gel chromatography (CyH/ EE gradient 0-100%) to provide methyl 4-(6-methyl-5-nitropyridin-2-yl)bicyclo[2.2.1]heptane-1-carboxylate. A_{nalysis (method D): Rt:.1.04 min, [M+H] +: 290} 15 Step 2: Methyl 4-(6-methyl-5-nitropyridin-2-yl)bicyclo[2.2.1]heptane-1-carboxylate (800 mg, 2.76 mmol) is dissolved in MeOH (30 mL) and Pd/C 10% (150 mg) is added and the mixture20 hydrogenated to yield methyl 4-(5-amino-6-methylpyridin-2-yl)bicyclo[2.2.1]heptane-1- carboxylate. A_{nalysis (method D): Rt:.0.46 min, [M+H] +: 261} Step 3: 25 Methyl 4-(5-amino-6-methylpyridin-2-yl)bicyclo[2.2.1]heptane-1-carboxylate (560 mg, 2.15 mmol) dissolved in aq. HCl (4M, 2.7 mL) and cooled to -5°C. NaNO₂ (223 mg in 5 mL) is added and the mixture stirred for 1 h at 0°C. KI (786 mg, 4.7 mmol) is added and the mixture stirred 01-3598-WO-1 70 for 2 h. The reaction mixture is neutralized with NaOH and extracted with DCM and separated to give methyl 4-(5-iodo-6-methylpyridin-2-yl)bicyclo[2.2.1]heptane-1-carboxylate. A_{nalysis (method D): Rt:.0.85 min, [M+H] +: 372} 5 Step 4: (1R)-2-{4-[5-Methyl-4-(propan-2-yl)-1H-pyrazol-3-yl]-2H-indazol-2-yl}-1-phenylethan-1-ol (D1) (220 mg; 0.61 mmol), copper (I)iodid (23 mg), 8-hydroxy-2-methylquinoline (30 mg; 0.18 mmol), Cs₂CO₃ (199 mg; 0.61 mmol) and methyl 4-(5-iodo-6-methylpyridin-2- 10 yl)bicyclo[2.2.1]heptane-1-carboxylate (234 mg; 0.61 mmol) in DMSO (15 ml) were combined and stirred under Argon at 100 °C overnight. The mixture is diluted with water and extracted with ethyl acetate. The organic phase is concentrated, and the product purified via silica gel chromatography (CyH/EE gradient 0-100). A_{nalysis (method C): Rt: 1.03 min, [M+H] +: 604} 15 Step 5: Methyl 4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4-(propan-2-yl)- 1H-pyrazol-1-yl)-6-methylpyridin-2-yl]bicyclo[2.2.1]heptane-1-carboxylate (220 mg, 0.36 20 mmol) is dissolved in methanol (10 mL)and aq NaOH (4N, 364 µL) is added and the mixture stirred at RT overnight. The mixture is concentrated, dissolved in MeOH and TFA and purified via reversed phase HPLC to provide example 1. Analysis (method C): Rt: 0.9 min, [M+H] +: 590 01-3598-WO-1 71 Synthesis of 4-[5-(3-{2-[(1S)-1-hydroxy-2-phenylethyl]-1H-1,3-benzodiazol-4-yl}-5- methyl-4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]bicyclo[2.2.2]octane-1- carboxylic acid (example 2) 5 Step 1: Methyl 4-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-6-methylpyridin-2-yl}bicyclo [2.2.2]octane-1-carboxylate (320 mg; 0.63 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzene-1,2-diamine (148 mg; 0.63 mmol), K3PO4 (2N, 0.95 mL), XPhos Pd G3 (54 mg) 10 is suspended in dioxane (10 mL) and stirred for 4 h at 80°C. The mixture is diluted with water and extracted with DCM. The organic phase is concentrated and purified via silica gel chromatography (CyH/EE gradient 0-100%). Analysis (method C): Rt: 0.75 min, [M+H] +: 488 15 Step 2: Methyl 4-{5-[3-(2,3-diaminophenyl)-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-6-methylpyridin- 2-yl}bicyclo[2.2.2]octane-1-carboxylate (260 mg, 0.553 mmol), (2S)-2-hydroxy-3- phenylpropanoic acid (136 mg, 0.8 mmol), HATU (243 mg; 0.64 mmol), DIPEA (0.277 mL) is 20 suspended in DMF (6 mL) and stirred at RT for 2 h. The mixture is then diluted with water and extracted with ethyl acetate. The organic phase is dried, concentrated and HOAc (4 mL) is added, and the mixture stirred for 6 h at 85°C. Then the mixture is concentrated and purified 01-3598-WO-1 72 by reversed phase HPLC to provide methyl 4-[5-(3-{2-[(1S)-1-hydroxy-2-phenylethyl]-1H-1,3- benzodiazol-4-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2- yl]bicyclo[2.2.2]octane-1-carboxylate Analysis (method C): Rt: 0.76 min, [M+H] +: 604 5 Step 3: e_{xample 2} Methyl 4-[5-(3-{2-[(1S)-1-hydroxy-2-phenylethyl]-1H-1,3-benzodiazol-4-yl}-5-methyl-4- 10 (propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]bicyclo[2.2.2]octane-1-carboxylate (105 mg, 0.17 mmol) is dissolved in methanol (5 mL) and aq NaOH (4N, 1.2mL) is added and the mixture stirred at RT for 3 h. The mixture is concentrated, dissolved in MeOH and TFA and purified via reversed phase HPLC to provide example 2. Analysis (method C): Rt: 0.76 min, [M+H] +: 604 15 Synthesis of (1r,4r)-4-[5-(3-{2-[(1S)-1-hydroxy-2-phenylethyl]-1H-1,3-benzodiazol-4-yl}- 5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]cyclohexane-1- carboxylic acid (example 4) E_{xample 4 was synthesized in 3 steps according to example 2 using intermediate G1 instead} _{20 of G9 in step 1.} 01-3598-WO-1 73 Analysis step 1 (method D): Rt: 1.1 min, [M+H] +: 476 Analysis step 2(method D): Rt: 0.87 min, [M+H] +: 606 Analysis step 3 (method D): Rt: 0.76 min, [M+H] +: 578 5 Synthesis of (1r,4r)-4-(5-{3-[2-(2-cyclohexyl-2-hydroxyethyl)-2H-indazol-4-yl]-5- methyl-4-(propan-2-yl)-1H-pyrazol-1-yl}-6-methylpyridin-2-yl)cyclohexane-1- carboxylic acid (example 3) 10 Step 1: Ethyl (1r,4r)-4-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-6-methylpyridin-2- y_{l}cyclohexane-1-carboxylate (G1) (50 mg; 0.1 mmol), 1-cyclohexyl-2-[4-(4,4,5,5-tetraethyl-} _{1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethan-1-ol (B6) (56 mg, 0.13 mmol), Xphos Pd G3 (15} 15 mg), aq. K3PO4 (2N, 0.2 mL) are suspended in 2-MeTHF (2 mL) and stirred under Argon at 80 °C for 2 h. The mixture is diluted with DCM (10 mL) and the organic layer separated and concentrated. A_{nalysis (method A): Rt: 0.96 min, [M+H] +: 613} 01-3598-WO-1 74 Step 2: Ethyl (1r,4r)-4-(5-{3-[2-(2-cyclohexyl-2-hydroxyethyl)-2H-indazol-4-yl]-5-methyl-4-(propan-2- yl)-1H-pyrazol-1-yl}-6-methylpyridin-2-yl)cyclohexane-1-carboxylate (100 mg, 0.1 mmol) is 5 dissolved in ethanol (1 mL) and aq NaOH (1N, 0.5 mL) is added and the mixture stirred at RT for 16 h. The mixture is concentrated, dissolved in ACN and TFA and purified via reversed phase HPLC to provide example 3. Analysis (method H): Rt: 0.82 min, [M+H] +: 584 ¹⁰ Synthesis of (1S,6R)-3-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}- 5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]-3- azabicyclo[4.1.0]heptane-6-carboxylic acid example 5 Step 1: 15 Methyl (1S,6R)-3-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-6-methylpyridin-2-yl}-3- azabicyclo[4.1.0]heptane-6-carboxylate (G2) (250 mg; 0.51 mmol), (1R)-1-phenyl-2-[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethan-1-ol (B1) (184 mg, 0.51 mmol), Xphos Pd G3 (21 mg), aq. K₃PO₄ (2M, 1 mL) are suspended in dioxane (6 mL) and stirred under Argon at 80 °C for 3 h. The mixture is concentrated, and the residue suspended 20 in water and ethyl acetate, the organic phase separated, and the concentrated residue purified v_{ia silica gel chromatography gradient: CyH} _1:1). _{Analysis (method D): Rt: 0.97 min, [M+H] +: 605} Step 2: 25 Methyl (1S,6R)-3-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4- (propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]-3-azabicyclo[4.1.0]heptane-6-carboxylate (140 mg, 0.23 mmol) is dissolved in methanol (6 mL)and aq NaOH (1N, 2 mL) is added and the mixture stirred at RT for 48 h. The mixture is diluted with water and (10 mL) and HCl (1M, 01-3598-WO-1 75 2.1 mL) is added, and the precipitate collected and dried. The precipitate is dissolved in ACN and water and the product purified via reversed phase HPLC to afford example 5. Analysis (method G): Rt: 0.86 min, [M+H] +: 591 _{5 The following examples are synthesized according to example 3 or 5:} 01-3598-WO-1 76 01-3598-WO-1 77 Synthesis of (1R,5R)-3-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5- methyl-4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]-3- azabicyclo[3.1.0]hexane-1-carboxylic acid (example 7) 5 Methyl (1R,5R)-3-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-6-methylpyridin-2-yl}- 3-azabicyclo[3.1.0]hexane-1-carboxylate (G5) (100 mg), 0.146 mmol), (1R)-1-phenyl-2-[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethan-1-ol (B1) (61 mg, 0.16 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'- 10 biphenyl)]palladium(ii) methanesulfonate (12 mg, 0.015 mmol), K3PO4 (2M, 0.36 mL) are suspended in 2-MeTHF (3 mL)and are stirred at 80°C for 3 h under Argon). The mixture is diluted with water and extracted with 2-MeTHF, concentrated, and purified via reversed phase HPLC. Analysis (method J): Rt: 0.54 min, [M+H] +: 577 15 Synthesis of (1r,4r)-4-[5-(3-{2-[(benzenesulfinyl)methyl]-2H-indazol-4-yl}-5-methyl-4- (propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]cyclohexane-1-carboxylic acid (example 8) Step 1: 20 01-3598-WO-1 78 2-[(Benzenesulfinyl)methyl]-4-[1-(6-chloro-2-methylpyridin-3-yl)-5-methyl-4-(propan-2-yl)-1H- pyrazol-3-yl]-2H-indazole (E5) (90 mg; 0.18 mmol), ethyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)cyclohex-3-enecarboxylate (63 mg, 0.21 mmol), Xphos Pd G3 (8 mg), aq. K₃PO₄ (2M, 268 µL) are suspended in dioxane (2.5 mL) and stirred under Argon at 90 °C for 5 5 h. The mixture is concentrated, and the residue suspended in MeOH, filtered purified and the product purified via reversed phase HPLC. A_{nalysis (method D): Rt: 1.07 min, [M+H] +: 622} 10 Ethyl 4-[5-(3-{2-[(benzenesulfinyl)methyl]-2H-indazol-4-yl}-5-methyl-4-(propan-2-yl)-1H- pyrazol-1-yl)-6-methylpyridin-2-yl]cyclohex-3-ene-1-carboxylate (100 mg, 0.16 mmol) is dissolved in methanol (10 mL) and Pd/C 10% (15 mg) is added. The mixture is then hydrogenated at 50°C and 50 psi (344.738 kPa) H2 for 3 h. The mixture is filtrated and15 concentrated. A_{nalysis (method D): Rt: 0.97 min, [M+H] +: 624} Ethyl 4-[5-(3-{2-[(benzenesulfinyl)methyl]-2H-indazol-4-yl}-5-methyl-4-(propan-2-yl)-1H- pyrazol-1-yl)-6-methylpyridin-2-yl]cyclohexane-1-carboxylate (35 mg) is separted via chiral20 HPLC to afford (1s,4s)-4-[5-(3-{2-[(benzenesulfinyl)methyl]-2H-indazol-4-yl}-5-methyl-4- (propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]cyclohexane-1-carboxylate and (1r,4r)-4- [5-(3-{2-[(benzenesulfinyl)methyl]-2H-indazol-4-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl)- 6-methylpyridin-2-yl]cyclohexane-1-carboxylate using chiral method K. Analysis (method K): Rt: 4.33 min (cis isomer) 25 Analysis (method K): R_t: 5.56 min, (trans isomer) Step 4: 01-3598-WO-1 79 e_{xample 8} (1r,4r)-4-[5-(3-{2-[(Benzenesulfinyl)methyl]-2H-indazol-4-yl}-5-methyl-4-(propan-2-yl)-1H- pyrazol-1-yl)-6-methylpyridin-2-yl]cyclohexane-1-carboxylate (25 mg, 0.04 mmol) is dissolved i_{n ethanol (1 mL)and aq NaOH (1M, 0.05 mL) is added and the mixture stirred at RT overnight.} 5 To the mixture is added HCl (4M), concentrated and a small amount of acetone added, filtered and the filtrate concentrated to provide example 8. Analysis (method D): Rt: 0.87 min, [M+H] +: 596 Synthesis of (1S,4R,6S)-4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-10 methyl-4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]bicyclo[4.1.0]heptane-1- carboxylate (example 9) and (1S,4S,6S)-4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H- indazol-4-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2- yl]bicyclo[4.1.0]heptane-1-carboxylate (example 12) Step 1: 15 (1R)-2-{4-[1-(6-Chloro-2-methylpyridin-3-yl)-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl]-2H- indazol-2-yl}-1-phenylethan-1-ol (E1) (400 mg; 0.82 mmol), methyl (1S,6R or 1R, 6S)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[4.1.0]hept-4-ene-1-carboxylate (H1) (354 mg, 1.24 mmol), Xphos Pd G3 (40 mg), aq. K3PO4 (2M, 1235 µL) are suspended in dioxane 20 (8 mL) and stirred under Argon at 90 °C for 3 h. The mixture is concentrated, and the residue 01-3598-WO-1 80 suspended in ethyl acetate and concentrated, and the product purified via silica gel c_{hromatography (CyH/EE 9/1 ^ 0/1).} _{Analysis (method D): Rt: 1.07 min, [M+H] +: 602} 5 Step 2: Methyl (1S,6R or 1R,6S)-4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl- 4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]bicyclo[4.1.0]hept-4-ene-1-carboxylate (470 mg, 0.78 mmol) is dissolved in methanol(30 mL) and Pd/C 10% (100 mg) is added. The _{10 mixture is hydrogenated at 50°C under 50 psi (344.738 kPa) hydrogen for 13 h. The mixture} was filtrated and concentrated, and the product purified via silica gel chromatography (CyH/EE g_radient _{Analysis (method D): Rt: 0.99 min, [M+H] +: 604} 15 Step 3: methyl (1S,6S or 1R,6R)-4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl- 4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]bicyclo[4.1.0]heptane-1-carboxylate is separted via chiral HPLC (method N) to afford (1S,4S,6S)-4-[5-(3-{2-[(2R)-2-hydroxy-2- phenylethyl]-2H-indazol-4-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-20 yl]bicyclo[4.1.0]heptane-1-carboxylate (A) and (1S,4R,6S)-4-[5-(3-{2-[(2R)-2-hydroxy-2- phenylethyl]-2H-indazol-4-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2- yl]bicyclo[4.1.0]heptane-1-carboxylate (B) Analysis (method O): Rt: 4.85 min, A Analysis (method O): Rt: 6.62 min, B _{25 Absolute and relative stereochemistry is not determined for A and B.} Synthesis of example 9 01-3598-WO-1 81 Methyl (1S,4R,6S)-4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4- (propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]bicyclo[4.1.0]heptane-1-carboxylate (B) (110 mg) is dissolved in methanol (6 mL) and NaOH (1M, 2 mL) is added and the mixture 5 stirred at RT for 48h. Water is added (10 mL) and aq HCl (1M, 2.1 mL). The precipitate is collected and washed with water (4 mL) to afford example 9. A_{nalysis (method G): Rt: 0.92 min, [M+H] +: 590} Synthesis of example 12 10 Methyl (1S,4S,6S)-4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4- (propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]bicyclo[4.1.0]heptane-1-carboxylate (A) (110 mg) is dissolved in methanol (6 mL) and NaOH (1M, 2 mL) is added and the mixture stirred at RT for 48h. Water is added (10 mL) and aq HCl (1M, 2.1 mL). The precipitate is15 collected and washed with water (4 mL) to afford example 12. A_{nalysis (method G): Rt: 0.92 min, [M+H] +: 590} Synthesis of example 10 and example 11 T_{he synthesis of example 10 and 11 is synthesized in analogy to example 9 and 12 using} _{20 intermediate H2 instead of intermediate H1 in step 1 of the synthesis.} 01-3598-WO-1 82 The enantiomers are separated using chiral method P. Analysis (method O): R_t: 6.33 min, C Analysis (method O): R_t: 7.64 min, D 5_{Absolute and relative stereochemistry is not determined for C and D.} _{Synthesis of example 10 using intermediate C and synthesis of example 11 using intermediate} _{10 Analysis example 10 (method G): Rt: 0.93 min, [M+H] +: 590} _{Analysis example 11 (method G): Rt: 0.92 min, [M+H] +: 590} Synthesis of 4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4- (propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]bicyclo[2.2.2]octane-1-carboxylic15 acid (example 13) 01-3598-WO-1 83 Step 1: (1R)-2-{4-[5-Methyl-4-(propan-2-yl)-1H-pyrazol-3-yl]-2H-indazol-2-yl}-1-phenylethan-1-ol (D1) (200 mg; 0.56 mmol), copper (I)iodid (21 mg), 8-hydroxy-2-methylquinoline (27 mg; 0.17 5 mmol), Cs₂CO₃ (181 mg; 0.56 mmol) and methyl 4-(5-iodo-6-methylpyridin-2- yl)bicyclo[2.2.2]octtane-1-carboxylate (220 mg; 0.56 mmol) in DMSO (15 ml) were combined and stirred under Argon at 100 °C for 6 h. The mixture is diluted with water and extracted with ethyl acetate. The organic phase is concentrated, and the product purified via silica gel chromatography (CyH/EE gradient 0-100%). _{10 Analysis (method C): Rt: 1.09 min, [M+H] +: 618} Step 2: Methyl 4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4-(propan-2-yl)- 1H-pyrazol-1-yl)-6-methylpyridin-2-yl]bicyclo[2.2.2]octane-1-carboxylate (140 mg, 0.23 mmol) _{15 is dissolved in methanol (10 mL) and aq NaOH (4M, 0.45 mL) is added and the mixture stirred} at RT for 4 days. The mixture is concentrated and purified via reversed phase HPLC (acidic conditions) to afford example 13. Analysis (method C): Rt: 0.92 min, [M+H] +: 604 20 (1R,3r,5S,6S)-3-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4- (propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]bicyclo[3.1.0]hexane-6-carboxylic acid (example 16) and 1R,3r,5S,6R)-3-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H- indazol-4-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2- yl]bicyclo[3.1.0]hexane-6-carboxylic acid (example 25) 25 Step 1: 01-3598-WO-1 84 (1R)-2-{4-[1-(6-Chloro-2-methylpyridin-3-yl)-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl]-2H- indazol-2-yl}-1-phenylethan-1-ol (E1) (270 mg; 0.56 mmol), ethyl 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)bicyclo[3.1.0]hex-2-ene-6-carboxylate (H3) (239 mg, 0.83 mmol), Xphos Pd 5 G3 (50 mg), aq. K₃PO₄ (2M, 833 µL) are suspended in dioxane (8 mL) and stirred under Argon at 90 °C for 1 h. The mixture is concentrated, and the residue suspended in ethyl acetate and extracted with water, the organic phase concentrated, and the product purified via silica gel c_{hromatography (CyH/EE 9/1 ^ 1/1).} _{Analysis (method G): Rt: 1.09 min, [M+H] +: 602} 10 Step 2: Ethyl 3-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4-(propan-2-yl)-1H- pyrazol-1-yl)-6-methylpyridin-2-yl]bicyclo[3.1.0]hex-2-ene-6-carboxylate (150 mg, 0.25 mmol) 15 is dissolved in ethanol (30 mL) and Pd/C 10% (25 mg) is added. The mixture is hydrogenated a_{t 50°C under 50 psi (344.738 kPa) hydrogen for 3 h. The mixture was filtrated and} concentrated. Analysis (method G): R_t: 1.05 min 20 Step 3: 01-3598-WO-1 85 Ethyl 3-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4-(propan-2-yl)-1H- pyrazol-1-yl)-6-methylpyridin-2-yl]bicyclo[3.1.0]hexane-6-carboxylate (100 mg) dissolved in DMF (2 mL) and NaH (15 mg) is added and the mixture stirred for 2 h at RT. Formic acid (20 5_{µL) is added and the products separated with chiral HPLC method Q to afford example 16 and} example 25. A_{nalysis for example 16 (method R): Rt: 0.98 min; (method H): Rt: 0.78 min, [M+H] +: 576} _{Analysis for example 25 (method R): Rt: 1.32 min; (method H): Rt: 0.77 min, [M+H] +: 576} _{10 Absolute stereochemistry of example 16 and 25 is unknown, relative stereochemistry is} resolved. Synthesis of (1r,4r)-4-(5-{3-[2-(2,2-difluoro-2-phenylethyl)-2H-indazol-4-yl]-5-methyl-4- (propan-2-yl)-1H-pyrazol-1-yl}-6-methylpyridin-2-yl)cyclohexane-1-carboxylic acid15 (example 18) Step 1: 01-3598-WO-1 86 4-[1-(6-Chloro-2-methylpyridin-3-yl)-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl]-2-(2,2-difluoro- 2-phenylethyl)-2H-indazole (E2) (200 mg; 0.395 mmol), ethyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)cyclohex-3-enecarboxylate (148 mg, 0.51 mmol), Xphos Pd G3 (33 mg), aq. K₃PO₄ (2M, 593 µL) are suspended in dioxane (5 mL) and stirred under Argon at 100 °C for 2 5 h. The mixture is concentrated, the product via reversed phase chromatography. A_{nalysis (method E): Rt: 1.28 min, [M+H] +: 624} Step 2: 10 Ethyl 4-(5-{3-[2-(2,2-difluoro-2-phenylethyl)-2H-indazol-4-yl]-5-methyl-4-(propan-2-yl)-1H- pyrazol-1-yl}-6-methylpyridin-2-yl)cyclohex-3-ene-1-carboxylate (100 mg, 0.16 mmol) is dissolved in ethanol (10 mL) and Pd/C 10% (20 mg) is added. The mixture is hydrogenated at 5_{0°C under 50 psi (344.738 kPa) hydrogen for 2 h. The mixture was filtrated and concentrated,} and the product purified via reversed phase chromatography. _{15 Analysis (method D): Rt: 1.15 min; [M+H] +: 626} e_{xample 18} 01-3598-WO-1 87 Ethyl 4-(5-{3-[2-(2,2-difluoro-2-phenylethyl)-2H-indazol-4-yl]-5-methyl-4-(propan-2-yl)-1H- pyrazol-1-yl}-6-methylpyridin-2-yl)cyclohexane-1-carboxylate (30 mg, 0.048 mmol) is dissolved in ethanol (1 mL) and sodium ethoxide (90 µL) is added and the mixture stirred for 2 days at 40°C. To the mixture is added TFA and the product is purified via reversed phase 5 chromatography. A_{nalysis (method D): Rt: 1.14 min; [M+H] +: 598} Synthesis of (1R)-2-[4-(5-methyl-1-{2-methyl-6-[(1r,4r)-4-(2H-1,2,3,4-tetrazol-5-10 yl)cyclohexyl]pyridin-3-yl}-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1- phenylethan-1-ol (example 19) Step 1: 15 (1R)-2-{4-[1-(6-chloro-2-methylpyridin-3-yl)-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl]-2H- indazol-2-yl}-1-phenylethan-1-ol (E1) (200 mg; 0.56 mmol), 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)cyclohex-3-ene-1-carbonitrile (96 mg, 0.41 mmol), Xphos Pd G3 (35 mg), aq. K3PO4 (2M, 617 µL) are suspended in dioxane (10 mL) and stirred under Argon at 80 °C for 4 h. The mixture is suspended in DCM and extracted with water, the organic phase20 concentrated, and the product purified via reversed phase chromatography. A_{nalysis (method C): Rt: 1.01 min, [M+H] +: 557} Step 2: 01-3598-WO-1 88 4-[5-(3-{2-[(2R)-2-Hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4-(propan-2-yl)-1H- pyrazol-1-yl)-6-methylpyridin-2-yl]cyclohex-3-ene-1-carbonitrile (190 mg, 0.34 mmol), sodium azide (110 mg), NH4Cl (91 mg) are suspended in DMF (dry, 12 mL) and the mixture stirred at 5 100°C for 2 h. and for 3 days at 120°C. The mixture is filtered, and the product purified by reversed phase chromatography. A_{nalysis (method C): Rt: 0.85 min, [M+H] +: 600} Step 3: 10 (1R)-2-[4-(5-Methyl-1-{2-methyl-6-[4-(2H-1,2,3,4-tetrazol-5-yl)cyclohex-1-en-1-yl]pyridin-3-yl}- 4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol (100 mg) is dissolved in MeOH (15 mL) and Pd/C 10% (20 mg) is added. The mixture is hydrogenated at 50 psi (_{344.738 kPa) at 50°C overnight.} _{Analysis (method C): Rt: 0.76 min, [M+H] +: 602} 15 Step 4: (1R)-2-[4-(5-Methyl-1-{2-methyl-6-[4-(2H-1,2,3,4-tetrazol-5-yl)cyclohexyl]pyridin-3-yl}-4- (propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol (80 mg) is separated via20 chiral separation method S to afford example 19. 01-3598-WO-1 89 Analysis (method T): R_t: 2.22 min Synthesis of (1r,4r)-4-[5-(5-cyclopropyl-4-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol- 4-yl}-1-methyl-1H-imidazol-2-yl)-6-methylpyridin-2-yl]cyclohexane-1-carboxylic acid 5 (example 20) Step 1: (1R)-1-phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethan-1-ol (B1) (290 mg; 0.97 mmol), methyl 4-[5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-6- 10 methylpyridin-2-yl]cyclohex-3-ene-1-carboxylate (491 mg, 0.88 mmol), Xphos Pd G3 (80 mg), aq. K3PO4 (2M, 1200 µL) are suspended in dioxane (12 mL) and stirred under Argon at 100 °C for 2 h. The product is purified via reversed phase chromatography. A_{nalysis (method E): Rt: 1.12 min, [M+H] +: 588} 15 Step 2: Methyl 4-[5-(5-cyclopropyl-4-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-1-methyl-1H- imidazol-2-yl)-6-methylpyridin-2-yl]cyclohex-3-ene-1-carboxylate (378 mg, 0.64 mmol) is dissolved in methanol (30 mL) and Pd/C 10% (100 mg) is added. The mixture is hydrogenated 01-3598-WO-1 90 a_{t 50°C under 50 psi (344.738 kPa) hydrogen for 2 h. The mixture was filtrated and} concentrated. A_{nalysis (method D): Rt: 0.87 min; [M+H] +: 590} 5 Step 3: Methyl 4-[5-(5-cyclopropyl-4-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-1-methyl-1H- imidazol-2-yl)-6-methylpyridin-2-yl]cyclohexane-1-carboxylate (312 mg) is separated with chiral preparative method U to afford methyl (1s,4s)-4-[5-(5-cyclopropyl-4-{2-[(2R)-2-10 hydroxy-2-phenylethyl]-2H-indazol-4-yl}-1-methyl-1H-imidazol-2-yl)-6-methylpyridin-2- yl]cyclohexane-1-carboxylatemethyl and methyl (1r,4r)-4-[5-(5-cyclopropyl-4-{2-[(2R)-2- hydroxy-2-phenylethyl]-2H-indazol-4-yl}-1-methyl-1H-imidazol-2-yl)-6-methylpyridin-2- yl]cyclohexane-1-carboxylate. A_{nalysis (method V): Rt: 6.51 min; [M+H] +: 590 (cis product)} _{15 Analysis (method V): Rt: 7.51 min; [M+H] +: 590 (trans product)} Step 4: Methyl (1r,4r)-4-[5-(5-cyclopropyl-4-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-1- 20 methyl-1H-imidazol-2-yl)-6-methylpyridin-2-yl]cyclohexane-1-carboxylate (40 mg) is dissolved in THF (10 mL) and methanol (2 mL) and LiOH (14.5 mg) and the mixture stirred at RT for 2 01-3598-WO-1 91 h. Aq. HCl (4N) is added and the mixture concentrated and the product purified via reversed phase chromatography to afford example 20. A_{nalysis (method D): Rt: 0.81 min; [M+H] +: 576)} 5 Synthesis of (1r,4r)-4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl- 4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]cyclohexane-1-carboxylic acid (example 21) Step 1: 10 (1R)-2-{4-[1-(6-Chloro-2-methylpyridin-3-yl)-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl]-2H- indazol-2-yl}-1-phenylethan-1-ol (E1) (551 mg; 1.1 mmol), ethyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)cyclohex-3-enecarboxylate (342 mg, 1.27 mmol), Xphos Pd G3 (96 mg), aq. K3PO4 (2M, 1700 µL) are suspended in dioxane (15 mL) and stirred under Argon at 100 °C for15 2 h. The mixture is concentrated, and the product purified via reversed phase HPLC. A_{nalysis (method D): Rt: 1.16 min, [M+H] +: 590} Step 2: 20 Methyl 4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4-(propan-2-yl)- 1H-pyrazol-1-yl)-6-methylpyridin-2-yl]cyclohex-3-ene-1-carboxylate (671 mg, 1.138 mmol) is 01-3598-WO-1 92 dissolved in methanol (60 mL) and Pd/C 10% (150 mg) is added. The mixture is hydrogenated a_{t 50°C under 50 psi (344.738 kPa) hydrogen for 2 h. The mixture was filtrated, and the product} purified via reversed phase chromatography. A_{nalysis (method D): Rt: 1.05 min; [M+H] +: 592} 5 Step 3: Methyl 4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4-(propan-2-yl)- 1H-pyrazol-1-yl)-6-methylpyridin-2-yl]cyclohexane-1-carboxylate is separated via chiral10 separation method X to afford methyl (1s,4s)-4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H- indazol-4-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]cyclohexane-1- carboxylate and methyl (1r,4r)-4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5- methyl-4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]cyclohexane-1-carboxylate. A_{nalysis (method V): Rt: 1.72 min; [M+H] +: 590 (cis product)} _{15 Analysis (method V): Rt: 2.45 min; [M+H] +: 590 (trans product)} Step 4: e_{xample 21} Methyl (1r,4r)-4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4-(propan- 20 2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]cyclohexane-1-carboxylate (41 mg, 0.07 mmol) is 01-3598-WO-1 93 dissolved in methanol (10 mL) and NaOH (1M, 4 mL) is added and the mixture stirred at 65°C for 2 h. The mixture is concentrated, HCL (1N) is added, and the precipitate collected to afford example 21. A_{nalysis (method D): Rt: 0.96 min; [M+H] +: 578} 5 I_{n analogy to example 21 are the following examples synthesized in 4 steps} 01-3598-WO-1 94 Synthesis of (1r,4r)-4-[5-(3-{2-[(2R)-2-methoxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl- 4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]cyclohexane-1-carboxylic acid (example 22) 5 Methyl (1s,4s)-4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4-(propan- 2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]cyclohexane-1-carboxylate (100 mg, 0.17 mmol) is suspended in DMF (3 mL) and NaH (15 mg) is added and the mixture stirred at RT for 10 min. Then iodomethane (12 µL) is added and the mixture stirred at RT for 3 h. 10 The product is purified via reversed phase chromatography (method including TFA) to afford example 22. A_{nalysis (method D): Rt: 1.03 min; [M+H] +: 592} Synthesis of (1r,3r or 1s, 3s))-3-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-15 5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]cyclobutane-1- carboxylic acid (example 24) Step 1: 01-3598-WO-1 95 (1R)-2-{4-[1-(6-Chloro-2-methylpyridin-3-yl)-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl]-2H- indazol-2-yl}-1-phenylethan-1-ol (145 mg, 0.298 mmol), ethyl 3-bromocyclobutane-1- carboxylate (195 mg, 0.895 mmol) is suspended in 1,2-dimethoxyethan (8 mL). Then 5 tris(trimethylsilyl)silane (95 µL), 2-tert-butyl-1,1,3,3-tetramethylguanidine (117 µL), complex of 4,4'-di-tert-butyl-2,2'-bipyridine dichloronickel (24 mg) and 4CZIPN (23.5 mg) is stirred under N₂ and light (395 nm LED) for 2.5 h. The mixture is diluted with water and extracted with ethyl acetate and the organic phase is concentrated and the product purified with reversed phase HPLC. _{10 Analysis (method D): Rt: 0.99 min; [M+H] +: 578, M} _{Analysis (method D): Rt: 1.01 min; [M+H] +: 578, N} Step 2: Ethyl (1r,3r or 1s,3s)-3-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4- 15 (propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]cyclobutane-1-carboxylate is dissolved in ethanol (1.5 mL) and NaOH (4M, 36 µL) and the mixture stirred at RT for 5.5 h. HCl (4M) is added and concentrated. The residue is suspended in a small amount of aceton, and the precipitate collected to afford example 24. A_{nalysis (method D): Rt: 0.89 min; [M+H] +: 550} 20 01-3598-WO-1 96 Synthesis of 4-ethyl-1-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5- methyl-4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]piperidine-4-carboxylic acid (example 27) 5 (1R)-2-{4-[1-(6-Fluoro-2-methylpyridin-3-yl)-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl]-2H- indazol-2-yl}-1-phenylethan-1-ol (E4) (25 mg, 0.053 mmol), methyl 4-ethylpiperidine-4- carboxylate hydrochloride (35 mg, 0.16 mmol), K2CO3 (59 mg) is suspended in NMP (0.5 mL) and the mixture stirred at 150°C for 5 h. Then the mixture is cooled to 70°C, NaOH (1N, 400 µL) is added and stirred for 1 h. TFA is added, and the product purified via reversed phase10 HPLC to afford example 27. A_{nalysis (method D): Rt: 0.97 min; [M+H] +: 607} The following examples are synthesized in analogy to example 27 01-3598-WO-1 97 01-3598-WO-1 98 01-3598-WO-1 99 Synthesis of (1R,5S,8S)-3-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5- methyl-4-(propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]-3-5 azabicyclo[3.2.1]octane-8-carboxylic acid (example 33) e_{xample 33} (1R)-2-{4-[1-(6-Fluoro-2-methylpyridin-3-yl)-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl]-2H- indazol-2-yl}-1-phenylethan-1-ol (E4) (20 mg, 0.043 mmol), (1R,5S,8S)-3- azabicyclo[3.2.1]octane-8-carboxylic hydrochloride (24.5 mg, 0.128 mmol), NMP (0.5 mL) and 01-3598-WO-1 100 K₂CO₃ (47 mg) is stirred at 150°C for 5 h. The product is purified via reversed phase chromatography to afford example 33. acid A_{nalysis (method I): Rt: 0.76 min; [M+H] +: 605} 5 01-3598-WO-1 101 Synthesis of 5-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-ndazol-4-yl}-5-methyl-4- (propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]-5-azaspiro[2.4]heptane-1- 5 carboxylic acid (example 34) e_{xample 34} Step 1: 5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-1-carboxylic acid (38 mg; 0.16 mmol) is dissolved in DCM/TFA (5 mL 1:1) and stirred for 2 h at RT, then concentrated and used in step10 2 without further purification. Step 2: (1R)-2-{4-[1-(6-Fluoro-2-methylpyridin-3-yl)-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl]-2H- indazol-2-yl}-1-phenylethan-1-ol (E4) (25 mg, 0.053 mmol), 5-azaspiro[2.4]heptane-1- carboxylic acid (from step 1), K2CO3 (59 mg) is suspended in NMP (0.5 mL) and the mixture15 stirred at 150°C for 5 h. The product purified via reversed phase HPLC to afford example 34. A_{nalysis (method D): Rt: 0.91 min; [M+H] +: 591} Synthesis of (example 40) Step 1: 01-3598-WO-1 102 P_{roduct from step 1 of example 37 is separated via preparative chiral HPLC (method AD) to} give ethyl (1s,4s)-4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4- (propan-2-yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]-1-methylcyclohexane-1-carboxylate and 5 ethyl (1r,4r)-4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4-(propan-2- yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]-1-methylcyclohexane-1-carboxylate Analysis (method AE): Rt: 0.95 min, E Analysis (method AE): Rt: 1.54 min, F 10 Step 2: F_{example 40} Ethyl (1r,4r)-4-[5-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4-(propan-2- yl)-1H-pyrazol-1-yl)-6-methylpyridin-2-yl]-1-methylcyclohexane-1-carboxylate (F) (41 mg, 0.066 mmol) is dissolved in EtOH (4 mL) and NaOH (4M, 132 µL) is added and the mixture 15 stirred for 4 days at RT. The mixture is concentrated, triturated with acetone, precipitate was filtered and mother liquor was concentrated in vacuo to provide example 40. A_{nalysis (method D): Rt: 0.92 min; [M+H] +: 592} 01-3598-WO-1 104 List of abbreviations: 4_{CZIPN 1,2,3,5-Tetrakis(carbazol-9-yl)-4,6-dicyanobenzene,2,4,5,6-} Tetrakis(9H-carbazol-9-yl) isophthalonitrile 5_{Ac acetyl} _{ACN acetonitrile} _{AIBN 2,2´-azobis(isobutyronitrile)} _{Boc tert-butyloxycarbonyl} _{Cbz benzyloxycarbonyl} _{10 CycH cyclohexane} _{d day(s)} _{DAST diethylamino sulfur trifluoride} _{DCE 1,2-dichloroethane} _{DCM dichloromethane} _{15 DEAD diethyl azodicarboxylate} _{DIAD diisopropyl azodicarboxylate} _{DIPEA N,N-diisopropylethylamine} _{DMF N,N-dimethylformamide} _{DMP Dess–Martin Periodinane} _{20 DMSO dimethyl sulfoxide} _{EtOAc ethyl acetate} _{EtOH ethanol} _{h hour(s)} _{HATU O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium-}25 hexafluorophosphate HPLC high performance liquid chromatography H_{PLC-MS coupled high performance liquid chromatography-mass spectrometry} _{IPA isopropyl alcohol} _{LC liquid chromatography} _{30 LC-MS coupled liquid chromatography – mass spectrometry} _{LiHMDS Lithium-bis(trimethylsilyl)amide} _{M molar (mol/L)} _{MeI methyl iodide} _{MeTHF 2-methyltetrahydrofuran} _{35 MeOH methanol} _{min minute(s)} _{MS mass spectrometry} 01-3598-WO-1 105 MTBE methyl-tertbutyl-ether n_{-BuLi n-Buthyllithium} _{NBS N-Bromosuccinimide} _{NIS N-Iodosuccinimide} _{5 NMP N-methyl-2-pyrrolidone} _{NMR nuclear magnetic resonance} _{PEPPSI(TM)-IPR (1,3-Bis(2,6-diisopropylphenyl)imidazolidene) (3-chloropyridyl)} palladium(II) dichloride P_{dCl2(dtbpf) 1,1′-Bis-(di-tert-butylphosphino-)ferrocene-palladiumdichloride}10 Pd(dppf)Cl2 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) P_{d(PPh3)4 palladium (0) tetrakis(triphenylphosphine)} XPhos Pd G3 2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′- a_{mino-1,1′- biphenyl)]palladium(II) methanesulfonat} _{pet. petroleum} 15 Rf retention factor R_{P reverse phase} _{rt room temperature} tR retention time (in HPLC / LC) S_{FC supercritical fluid chromatography} _{20 TBAF tetrabutylammonium fluoride} _{TBTU O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate} _{TEA triethylamine} _{TFA trifluoroacetic acid} _{THF tetrahydrofuran} _{25 THP tetrahydro-2h-pyran} _{TLC thin-layer chromatography} _{TMAD N,N,N′N′-Tetramethylazodicarboxamide} _{UV ultraviolet} _{V volume} 30 01-3598-WO-1 106 HPLC Methods: W_{here indicated, a back pressure of 14996.097 kPa (2175.0 psi) is applied.} Method A (X012_S01) 5 column: XBridge BEH C18_2.1 x 30 mm, 1.7 μm; column temperature: 60°C Method B (X011_S05) 10 column: Sunfire C18 (Waters) 2.5 µm; 3.0 x 30 mm; column temperature: 60 °C Method D (Z018_S04) 01-3598-WO-1 107 column: Sunfire (Waters) 2.5 µm; 3.0 x 30 mm; column temperature: 60°C Method E (Z011_S03) column: Xbridge (Waters); C18_3.0 x 30 mm_2.5 µm; column temperature: 60°C Method F (I_SZ_15_IPA_NH3_004) 5 Method G (Z017_S04) A_{gilent 1200 with DA- and MS-Detector; column: Zorbax StableBond C18_3.0 x 30 mm_1.8 µm} Method H (007_CA10) 01-3598-WO-1 108 _{Column: Sunfire C18_3.0 x 30 mm_2.5 µm: device: Waters Acquity, QDa Detector} Method I (007_CA02) _{Column: Sunfire C18_3.0 x 30 mm_2.5 µm: device: Waters Acquity, QDa Detector} Method J (008_CA11) Method K Method L 01-3598-WO-1 109 Method M (I_IG_05_MEOH_NH3_003) Method N Method O: (I_IG_40_IPA_NH3_003) 01-3598-WO-1 110 Method P: Method Q Method R (I_IH_30_IPA_NH3_004) Method S 01-3598-WO-1 111 Method T (I_IH_35_IPA_NH3_004) Method U Method V (I_SZ_35_ETOH_NH3_003) 01-3598-WO-1 112 Method X Method Y (I_IG_40_IPA_NH3_004) Method Z: Method AB: (I_IG_35_IPA_NH3_004) 01-3598-WO-1 113 Method AC: 007_CA11 Waters Acquity; Sunfire C18_3.0 x 30 mm_2.5 µm; column temperature: 60°C Method AD: Method AE: (I_SZ_35_MEOH_NH3_004) 5 01-3598-WO-1 114 BIOLOGICAL ASSAYS and DATA The activity of the compounds of the invention may be demonstrated using the following in vitro STING biochemical and cell assays. 5 Human STING HTRF binding assay 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_{10 FRET from occurring, which can be measured by an EnVision™ reader (PerkinElmer).} 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 15 1µM 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 20 test compounds and DMSO in column 23 and 24. A cGAMP standard dilution row was prepared according to the manufacturer and transferred to each assay plate. After transfer of compound solution or dilution buffer for negative (high) and positive (low) controls, 5µl of the human STING protein (cyclic binding domain (residues 20 138-379) of the WT R232 human version, fused to a 6 His tag at the Nter part; 1:50 dilution in detection buffer) were dispensed to all wells except of the positive control, which received detection buffer only. Plates were the centrifuged for 20 sec at 1000rpm. After that, 10µl of Anti-6His-Cryptate antibody / Sting ligand-d2 mix was added to all wells using a Multidrop combi dispenser, followed by another 20sec/1000rpm centrifugation step. After an incubation of the plates for 180 min at room 25 temperature, excitation at 665/620 nM (HTRF ratio) was measured using an Envison Reader (PerkinElmer) Data evaluation and calculation: For data evaluation and calculation, HTRF ratios were calibrated using the cGAMP standard curve. After that, the measurement of the low control was set as 0 % 30 control and the measurement of the high control was set as 100% control. The IC50 values were calculated using the standard 4 parameter logistic regression formula. Calculation: [y=(a- d)/(1+(x/c)^b)+d], a = low value, d = high value; x = conc M; c=IC50 M; b = slope; The results of this assay are shown in the characterising data table below. 01-3598-WO-1 115 Determination of the increase of stability of STING protein against thermal denaturation, Differential Scanning Fluorimetry (DSF) 5 The binding affinity of the compounds of the invention may be demonstrated using a thermal shift assay that measures the stability of a suitable protein material of human STING against thermal denaturation in the presence of compounds. In this assay, the unfolding temperature of a protein is monitored in the presence of a fluorescent dye which exhibits affinity for the hydrophobic amino 10 acids of the protein that are buried in its folded state and are gradually exposed during unfolding. 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 15 “melting” temperature of the protein (Tm) which is calculated numerically using the Boltzmann 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 155-20 341 and a N-terminal 8x His-tag in assay buffer containing 20mM Tris, 150mM NaCl at pH7.5. The assay uses Hard-Shell®PCR Plates 384-Well CLR/WHT (Catalog# HSP3805, BIO-RAD), Microseal®’B’ Adhesive Seals for PCR Plates (Catalog# MSB-1001, BIO-RAD) and was run on a CFX384 Real-Time System (Bio-Rad). 25 A DMSO stock solution of SYPRO orange (SIGMA S5692-500UL) was prepared. Compound stock solutions (10mM in DMSO) were diluted 1:2 in DMSO to an intermediate compound concentration of 5mM and then further diluted 1:40 in assay buffer resulting in a compound 30 concentration of 125µM and 2.5% DMSO. 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 35 control (protein with 2% DMSO). The plates were prepared for duplicate measurement and 01-3598-WO-1 116 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: 5 100uM compound, 3uM target protein, 5x SYPRO Orange, 2% DMSO in 10ul. All dispensing steps were performed using a HamiltonStar pipetting robot (Hamilton). Dissociation curves were processed in Bio-Rad CFX Manager. Peak type was set to "negative". Compound codes for screen were assigned in the plate layout. 10 Two replicates of TM measurements were averaged, and the standard deviation was calculated. In cases of SD>1.5 °C the measurement was repeated. T_{he melting point (Tm) obtained for STING protein alone was subtracted from T obtained for protein} incubated with ligand to generate ∆Tm values. 15 Protein production and purification: The protein used for the biophysical experiments was a recombinant human STING protein comprising its cytosolic ectodomain. A codon optimized DNA sequence (for expression in Escherichia coli) encoding amino acid residues 155 to 341 (Swiss Prot Q_{86WV6) 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 20 followed by tobacco etch virus protease (TEV) cleavage site and the above STING gene sequence. The resulting protein sequence for the used STING variant is listed below: H_{is-TEV—hSTING (WT) (SEQ ID NO: 1)} 25 MHHHHHHHHENLYFQSGVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLS MADPNIRFLDKLPQQTGDRAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKL FCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEV For expression of recombinant human STING above construct was transformed into E. coli BL21 DE3 30 strain and grown in shake flasks in LB-medium at 37°C. Expression was induced by addition of isopropyl β-D-1-thiogalactopyranoside to a final concentration of 1mM and cultures shaken overnight. Cell pellets were centrifuged and stored at -70°C until further use. Protein was purified by cell thawing in lysis buffer (20mM TRIS-HCl, pH 8, 300mM NaCl, 2mM mercaptoethanol, 20mM imidazole, Complete Protease Inhibitor (Roche) and DNase (Roche)), 35 followed by metal affinity purification using Ni-NTA resins and elution buffer consisting of 20mM 01-3598-WO-1 117 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. 5 The results of this assay are shown in the characterising data table below. Human whole blood assay (HWBA) 10 For the detection of STING inhibition in physiological environment human whole blood was stimulated by the cyclic dinucleotide cGAMP. Pathway activity was monitored by measuring the IFNα2α production. Assay method: Compounds were delivered as 10mM DMSO solution and serial diluted and 15 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. 20 Collection of human whole blood from 3 or more healthy donors (male or female, no medication for 7 days, exception contraceptive and thyroxine) as Na-citrate blood (e.g.3.8% in Monovettes from Sarstedt) is conducted in parallel. Whole blood was kept at room temperature for a maximum of 3 hours after collection until use in the assay. 25 160µl of the whole blood samples were transferred to each well of the 96-well assay plates filled with compound/OptiMEM. All assay plates are prepared as duplicates with blood from different donors. Blood plates were kept at room temperature for 60minutes and continuous shaking with 450rpm, covered with the lid, but not sealed. 30 A 10x cGAMP assay solution was diluted from a 2mM stock solution in 1xHBSS immediately before use at room temperature.20µl of the 10x cGAMP/HBSS were added to all compound and all high control wells, whereas HBSS only was added to all low control wells. After covering assay plates with aera seals and the lid, blood plates were kept at room temperature for 30minutes and continuous shaking with 450rpm, followed by an overnight incubation of 22h at35 37°C in the incubator, without shaking. 01-3598-WO-1 118 For the detection of IFNα-2α in human plasma, the biotinylated capture antibody (Antibody set IFNA2, Meso Scale Diagnostics #B21VH-3, including coating and capture antibody) was diluted 1:17.5 in Diluent 100 (Meso Scale Diagnostics #R50AA-4, according to the manufacturer. U-Plex MSD GOLD 5 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). 10 After blocking the plates with 100µl block solution/well (1x HBSS with 0.2% Tween, 2% BSA) for 60min at room temperature and continuous shaking at 700rpm, plates were emptied as dry as p_{ossible by dumping just before continuing with the human plasma. Whole Blood assay plates were} centrifuged at 1600rpm for 10 minutes.25µl of supernatant was transferred with a pipetting robotics from each whole blood plate to the corresponding IFNα-2α plate. Plates were sealed with microplate 15 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 microplate seals and kept at room temperature again under continuous shaking at 700rpm for two 20 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. Data evaluation and calculation: For data evaluation and calculation, % control calculation of each 25 well was based on the mean of high (cGAMP stimulated control) and mean of low (unstimulated control) controls by using the following formula: [_{counts(sample) - counts(low))/(counts(high) - counts(low))]*100} The IC50 values were calculated using the standard 4 parameter logistic regression formula. Calculation: [y=(a-d)/(1+(x/c)^b)+d], a = low value, d = high value; x = conc M; c=IC50 M; b = slope; 30 The results of this assay are shown in the characterising data table below. Human STING reportergene assay 35 01-3598-WO-1 119 A THP1-BlueISG reporter cell line expressing wildtype STING and IRF dependent alkaline phosphatase reporter was used for the potency measurement of activators of human wildtype STING. Assay Method: Compounds were delivered 10mM DMSO solution and serially diluted in assay 5 medium (RPMI 1640 (Life Technologies #A10491-01), 10% FCS (Life Technologies #10500-064), 1x Pen/Strep solution (Life Technologies #15140-122). Typically, 8 concentrations were used with the highest concentration at 10 or 100 µM in the final assay volume followed by ~1:5 dilution steps. DMSO concentration was set to 1% in the final assay volume. The 384well assay plate contained 21 test compounds (column 1-21), a reference compound (column 22) and DMSO in column 23 and 24; 10 Cells, cultivated according to manufacturer’s conditions (culture medium: RPMI 1640 (Life Technologies #A10491-01), 10% FCS (Life Technologies #10500-064), 1x Pen/Strep solution (Life Technologies #15140-122), 100µg/mL Normocin (Life Technologies # ant-nr-1), 100µg/mL Zeocin (Life Technologies # R25001) were harvested, resuspended and diluted in fresh assay medium. The cells 15 were then seeded in 15µl assay media to the assay plates (10000 cells/well), followed by addition of 5µl prediluted compound solution to wells of the assay plates. Afterwards 5ul per well of assay medium was added to the wells containing compounds, followed by a 30 min incubation at RT and a 24h incubation at 37°C. Then 5ul per well of assay medium with DMSO (1% f.c.) was added to the wells for the controls, plus 5 µl of assay medium alone for negative controls (low values) or 5µl of 20 prediluted 2`3`-cGAMP (20µM f.c.; BIOLOG Life Science Institute # C 161 or Invivogen # tlrl-nacga23) for positive controls (high values). F_{inally 75µl of Quanti Blue reagent was added to the plates using a MultiDrop Combi, followed by 30} _{min incubation at 37°C. The absorbance was measured on the EnVision™ reader (PerkinElmer).} 25 Data evaluation and calculation: For data evaluation and calculation, the measurement of the low control was set as 100 % control and the measurement of the high control was set as 200% control. The EC50 values were calculated using the standard 4 parameter logistic regression formula. Calculation: [y=(a-d)/(1+(x/c)^b)+d], a = low value, d = high value; x = conc M; c=IC50 M; b = slope; 30 The results of this assay are negative for agonism, wherein the threshold was set larger than 30 µM. Characterising Data Table 01-3598-WO-1 120 01-3598-WO-1 121 As shown by the characterizing data, the inventive compounds can inhibit STING and by doing so are advantageous in the prevention, delaying and/or treatment of diseases or conditions which can be influenced by STING inhibition, for example but not limited to those disclosed herein above. 5 In a preferred embodiment, the inventive compounds have in a competitive HTRF assay format (_{Cisbio 64BDSTGPEG) an IC50 value of at least and including 0.3nM and not more than 250nM,} preferably not more than 150nM, more preferably not more than 125nM and even more preferably n_{ot more than 70 nM. In another preferred embodiment, said IC 50 value is at least and including} 0.8nM or at least and including 2nM. In another preferred embodiment said IC50 value is not more10 than 45nM, more preferably not more than 40nM. Further characterization Efflux ratio from MDCK-PGP The efflux ratio from MDCK-PGP cells is measured using standard methods according to the 15 international patent application published as WO24089006 or as in the publication by Dong et al. Pharm Res (2020) 37: 194, https://doi.org/10.1007/s11095-020-02895-9. In one embodiment the efflux ratio in MDCK-PgP cell is equal to or below 25, preferably equal to or below 15, 12, 10, more preferably equal to or below 8, 7, 6, 5 or 4.5. In a more preferred embodiment, the efflux ratio is less than 5 but higher than 0.5. 20 Efflux ratio from CACO2 cells The efflux ratio from CACO2 cells is determined using standard methods for example as disclosed in the international patent applications published as WO15048318, WO22254371 and WO24110851, or 01-3598-WO-1 122 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. 5 I_{nhibition of cytochrome P450 enzymes CYP2D6 and CYP3A4} Standard 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 m_{etabolized by CYP2D6 (Schadel M, Wu D, Otton SV, Kalow W, Sellers EM. Pharmacokinetics of} 10 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& WO1419734515 and the patent US8138188 BB). For testing the possible inhibition of the compounds of the invention, demethylation of Dextromethorphan (5 µM) by the test compound at five different concentrations or no compound (high control) is assayed at 37°C with human liver microsomes and measured with LC-MS/MS. The IC50 values of the compounds are determined. The IC50 of a positive control inhibitor (quinidine) is 20 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). 25 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. 30 CYP3A4 and/ or CYP2D6 inhibition is observed for the inventive compounds with IC50 values of equal to or greater 1 µmol, preferably equal to or greater 10 µmol and more preferred equal to or greater 20 µmol and even more preferred equal to or greater 25 µmol and most preferred over 30 µmol. 35 Measuring clearance from human hepatocytes 01-3598-WO-1 123 The metabolic degradation of a test compound is assayed in a human hepatocyte suspension using known methods as in the patent application. US2024327429. In one embodiment the hepatocyte clearance is lower than 25% Qh [%], preferably equal to or lower t_{han 20 %, 15 %, 10 %, or more preferably at most 8 %.} 5 Plasma protein binding Plasma protein binding of a test compound is assessed with known methods, for example as known from the international patent application WO17004537 or the more recent WO25036713. The equilibrium dialysis technique is used to determine the approximate in vitro fractional binding of test 10 compounds to plasma proteins applying Dianorm Teflon dialysis cells (micro 0.2). Each dialysis cell consists of a donor and an acceptor chamber, separated by an ultrathin semipermeable membrane with a 5 kDa molecular weight cutoff. Stock solutions for each test compound are prepared in DMSO at 1 mM and serially diluted to obtain a final test concentration of 1 µM. The subsequent dialysis solutions are prepared in plasma (supplemented with NaEDTA as anticoagulant), and aliquots of 200 15 µl test compound dialysis solution in plasma are dispensed into the donor (plasma) chambers. Aliquots of 200 µl dialysis buffer (100 mM potassium phosphate, pH 7.4, supplemented with up to 4.7 % Dextran) are dispensed into the buffer (acceptor) chamber. Incubation is carried out for 2 hours under rotation at 37°C for establishing equilibrium. At the end of the dialysis period, aliquots obtained from donor and acceptor chambers, respectively, 20 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: %_{bound = (plasma concentration - buffer concentration/ plasma concentration) x 100} 25 In 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 %. I_{P10 production in human dermal MicroVascular Endothelial Cells (MVEC) after double-stranded DNA}30 stimulation Interferon gamma-induced protein 10 (IP-10) also known as C-X-C motif chemokine ligand 10 (CXCL10) is produced as one of the responses of the presence of double-stranded DNA in the c_{ytoplasm 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 35 and pulmonary syndrome. N Engl J Med.2014 Aug 7;371(6):507-518. doi: 10.1056/NEJMoa1312625). 01-3598-WO-1 124 To test the efficacy of the inventive STING inhibitors, experiments in human microvascular 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 5 compound for 1 hour. The cells are then treated with 400 ng/mL of dsDNA as a complex with Lipofectamine 3000 (from Thermo Fisher Scientific Inc., Waltham, MA, USA) and incubated for 6 hours. The supernatants are collected and assayed for IP10 production. 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. 10 R_{esults: The inventive compounds show good inhibition of IP10 production after stimulation of} _{HMVEC with dsDNA. This demonstrates that the inventive compounds show direct target} engagement in MVEC cells which is not the case for some known STING inhibitors. 15 Table Exemplary Inhibition of Human microvascular endothelial cells by the inventive compounds The rounded average of multiple experiments is shown. nd = not determined yet 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 20 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 75 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 5 nM to and including 35 nM. 25 Inhibition of STING mutants associated with SAVI by the inventive compounds Several gain of function mutants of STING have been reported to be associated with SAVI and in vitro cell tests with these mutant proteins of STING have been described (Liu Yet al. Activated STING in a 01-3598-WO-1 125 vascular and pulmonary syndrome. N Engl J Med.2014 Aug 7;371(6):507-518. doi: 10.1056/NEJMoa1312625) Methods for testing STING activity in THP1 cells with the reporter gene encoding luciferase are known (see the patent publication US2020181153 and references therein). These known methods 5 are modified slightly: As for these gain of function mutants of STING that are associated with SAVI, no s_{timulation by cGAMP is needed, the assay can be performed without cGAMP or similar as a} stimulant. The assay relies on THP1 cells that contain an engineered “knock in” of the mutated STING gene that expresses a constitutively activated protein. The pathway activation is measured using ISG- luciferase reporter gene luminescence. Compound potency is evident by its ability to inhibit the SAVI 10 associated mutant STING proteins and consequently shut down the ISG linked luciferase reporter expression. A subset of the inventive compounds as well as two known STING inhibitors for comparison are tested using THP1 cells with the two known mutants of the STING protein N154S and V155M associated with SAVI. SEQ ID NO: 2 shows the wildtype and these variant positions of the STING protein. 15 The known STING inhibitor SN-011 has previously been reported to inhibit these mutant versions of STING in cell assays (Z. Hong et al, STING inhibitors target the cyclic dinucleotide binding pocket, Proc. Natl. Acad. Sci. U.S.A.118 (24) e2105465118, https://doi.org/10.1073/pnas.2105465118 (_{2021). Used as comparative compounds are SN-011 and another known STING inhibitor H-151} (Haag, S.M., Gulen , M.F., Reymond, L. et al. Targeting STING with covalent small-molecule inhibitors. 20 Nature 559, 269–273 (2018). https://doi.org/10.1038/s41586-018-0287-8). Using materials and instruments commercially available and methods similar to the known methods, the luciferase activity in these modified THP1 cells is measured with and without the test compounds. After correction for background and controls, the IC50 values are calculated using the 4- parameter logistic model for the compounds of the invention, as well as for the known STING inhibitors SN-01125 and H-151 (see above for details) for comparison. As the known inhibitor of STING SN-011 had been reported to inhibit the two mutants of STING tested, the potency of the compounds of the invention in comparison to that of SN-011 is determined. The results are expressed as the ratio of the IC50 value of the compound tested, i.e. the compound of the invention or the second known inhibitor H-151 to the IC 50 value determined for _{30 SN-011 in the particular assay. These are normalized to the SN-011 being set to 100% and the others} _{expressed as a percentage number in relation thereto. Table S shows the results, based on multiple} repetitions. Table S 01-3598-WO-1 126 As can be seen from the results in table S, the other known inhibitor of STING, H-151, requires only a concentration of 10.7 % of the concentration of SN-011 to achieve the same inhibition of the N154S mutant of STING, and only 6.2 % of the concentration of SN-011 for the same inhibition of the second 5 mutant V155M of STING. However, the compounds of the invention with the exception of example 2 require even less, only between 0.1 % and 0.5 % of the concentration of SN-011 to inhibit these STING mutants, which is also superior to the known inhibitor H-151. The preferred compounds of the invention are more potent in inhibiting these two SAVI associated mutants of the human STING protein 10 F_{rom the data above example 2 with a benzimidazol as the attachment point for R5 (i.e. X-Y-Z of} formula (I) is selected from the group X-Y-Z^d) shows generally good inhibition of wildtype STING protein, but not of the two SAVI associated mutants of STING tested. In contrast to this, the other compounds tested showing good inhibition of these mutants as well as inhibition of the wildtype 15 STING protein are all having an indazol structure as the attachment point for R5 (i.e.. X-Y-Z of formula (I) is selected from the group X-Y-Z^c). In one embodiment, the IC 50 values of the compounds of the invention to inhibit either or both of the N154S and V155M mutants of the human STING protein are at least 0.01 nM, but less than 150 20 nM, preferably less than 120 nM and more preferably less than 50 nM and even more preferably less t_{han 20 nM and most preferably less than 10 nM. In another embodiment, the IC50 values for the} _{compounds of the invention and either or both of these mutants of STING are between at least and} including 0.2 nM and no more than 10 nM, and the compound is a compound of formula (I) wherein X-Y-Z is selected from the group consisting of X-Y-Z^c. 01-3598-WO-1 127 Preferably the compounds of the invention used to inhibit the SAVI associated mutants of the STING p_{rotein, preferably either or both of the N154S and V155M mutants of STING, are compounds of} formula (Ia) as shown above. 5 Inhibition of STING in fibroblasts As many of the above-mentioned diseases like IPF or SAVI involve fibrosis, it is important to d_{emonstrate 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 without} the test compound is assessed. Interestingly, the known STING inhibitors SN-011 and H-151(details 10 see above), which had been reported to be effective in other fibroblasts,show very little 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 preferably15 no more than 120 nM and most preferably no more than 100 nM. I_{nhibition of IP10 production in human monocyte derived dendritic cells after cGAMP stimulation} _{Monocyte derived dendritic cells derived from a specimen of a human donor are cultivated using} _{standard techniques. With the exception of the respective negative controls, the cells are stimulated} 20 with cGAMP (Invivogen) in the presence or absence of different concentration of the compounds of the invention. Supernatants are collected and analysed by ELISA for IP10 presence (IP10 MSD kit, 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 t_{o 6.00 nM, preferably equal to or less than 4.00 nM, and more preferably equal to or less than 3.00} 25 nM, and even more preferably equal to or less than 2.5 nM. In yet another preferred embodiment the average IC 50 value is between and including 0.07 nM and 2.10 nM. Exemplary values are 0.08 nM, 0.53 nM and 1.44 nM. Use in treatment/method of use 30 A_{s has been found, the compounds of formula (I) are characterized by their range of applications in} _{the therapeutic field. Preferably, the compounds of the invention are used in diseases that can be} treated by the inhibition of STING and/or whose progression can be prevented by the inhibition of STING. 35 01-3598-WO-1 128 Particular mention should be made of those applications for which the compounds of the invention are 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 5 of aberrant cellular dsDNA, e.g. by nuclear or mitochondrial leakage, and thereby trigger autoinflammatory responses. Consequently, STING inhibitors have a strong therapeutic potential to 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} 10 remodeling in a cluster of autoimmune and inflammatory diseases including systemic lupus erythematosus (SLE), cutaneous lupus, systemic sclerosis, inflammatory bowel disease, sepsis, S_{jogren’s syndrome, vitiligo, prurigo nodularis, idiopathic inflammatory myopathy, myositis including} _{dermatomyositis, rheumatoid arthritis, as well as a cluster fibrosis diseases including NASH (now} referred to as MASH), IPF, chronic kidney fibrosis. 15 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 20 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. 25 A STING inhibitor also has applications to additional diseases such as cancer, decompensated liver c_{irrhosis, 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. 30 ^_{An et al., Arthritis Rheumatol.2017 Apr;69(4):800-807, disclosed that cGAS expression in} peripheral blood mononuclear cells (PBMCs) was significantly higher in patients with the autoimmune disease systemic lupus erythematosus (SLE) than in normal controls. Targeted measurement of cGAMP by tandem mass spectrometry detected cGAMP in 15% of the tested 01-3598-WO-1 129 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 deficiency} ameliorated lupus development in Fcgr2b-deficient mice. Prabakaran et al (EBioMedicine.2021 5 Apr;66:103314) shows that a STING pathway inhibitor ISD017 blocks STING activity in vivo and ameliorates disease development in a mouse model for lupus. ISD017 treatment also blocks pathological cytokine responses in PBMCs from lupus patients with elevated IFN-I levels. ^_{Skopelja-Gardner et al reported that ultraviolet B light triggers cGAS/STING-dependent skin and} systemic IFN-I signature and could contribute to cutaneous lupus Alzeand fares of disease in10 patients with SLE (Sci Rep 202010:7908 ) ^_{Ryu et al (Arthritis Rheumatol.2020 Nov;72(11):1905-1915) showed that plasma mtDNA} concentrations 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 _{15 (Oxford) 2022 Jun 10;keac324.) showed increased DNA leakage, STING expression and vascular} inflammation in skins of SSc patients, and STING deficiency or H151 administration ameliorated fibrosis and vasculopathy both in vitro and in BLM-induced SSc mice. ^_{Li et al show that plasma-derived DNA containing-extracellular vesicles induce STING-mediated} proinflammatory responses in dermatomyositis (Theranostics.2021; 11(15): 7144–7158). Zhou et20 al (J Clin Lab Anal.2022 Oct; 36(10): e24631) describes a correlation between activation of cGAS- S_{TING pathway and myofiber atrophy/necrosis in dermatomyositis. Feng et al. suggested STING} could be a potential therapeutic target in idiopathic inflammatory myositis-associated interstitial lung disease (IIM–ILD) (Feng et al., International Immunopharmacology, March 2025, 149, d_{oi:10.1016). It was also reported that the GAS-STING pathway is activated in the muscle} 25 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 inhibitor} attenuated pathological features of autoinflammatory disease in TREX1_KO mice. Loss of 30 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, STING} expression was elevated in peripheral blood mononuclear cells and intestinal biopsies compared with healthy controls. In human abdominal sepsis, STING expression was elevated in peripheral 01-3598-WO-1 130 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 cecal 5 ligation and puncture model) and the degree of STING expression in the human intestinal lamina propria correlated with the intestinal inflammation in septic patients. Inhibition of the ALK-STING pathway protects mice against CLP-induced polymicrobial sepsis. ^_{In Schuliga et al., Clin. Sci. (Lond).2020 Apr 17;134(7):889-905, it is described that self-DNA} _{perpetuates IPF lung fibroblast senescence in a^cGAS-dependent manner. Benmerzoug et al (Nat.} _{10 Commun.9, 1–19 (2018)) shows that STING- dependent sensing of self- DNA drives silica-induced} lung inflammation, which can lead to lung fibrosis. ^_{Additional scientific hints linking the cause for metabolic diseases such as non-alcoholic fatty liver} _{disease (NAFLD), now referred to as metabolic dysfunction–associated steatotic liver disease} (MASLD), see https://easl.eu/news/new_fatty_liver_disease_nomenclature-2, 15 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653297/), other fibrosing diseases such as non-alcoholic steatohepatitis (NASH) , now referred to as metabolic dysfunction associated s_{teatohepatitis (MASH ), and alcoholic liver disease (ALD) with the cGAS/STING pathway have} _{been described in Yu et al., J. Clin. Invest.2019 Feb 1;129(2):546-555, and in Cho et al.,} Hepatology.2018 Oct;68(4): 1331-1346, and in Qiao et al., Metabolism 2018 Apr;81:13-24 doi: _{20 10.1016/j.metabol.2017.09.010. Epub 2017 Oct 26, Petrasek et al., PNAS 2013 Oct} 8;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). _{25 ^ Ahn et al (Cell Rep 201721:3873-3884) describes that STING-deficient mice protects in an} Inflammatory Colitis model. Martin et al (Sci Rep 2019 Oct 3; 9:14281) describes that STING d_{eletion protects while or STING stimulation, exacerbates intestinal inflammation in the dextran} sodium sulphate (DSS) model of colitis. These publications support STING as a potential therapeutic target for prevention of inflammatory bowel disease (IBD). _{30 ^ Kerur et al., Nat. Med.2018 Jan;24(1):50-61, describes that cGAS plays a significant role in} noncanonical-inflammasome activation in age-related macular degeneration (AMD). ^_{Further, the STING inhibitors also have a therapeutic potential in the treatment of cancer (see} _{Hoong et al., Oncotarget.2020 Jul 28;11(30):2930-2955, and Chen et al., Sci. Adv.2020 Oct} 14;6(42):eabb8941). Furthermore shown in Bakhoum et el., Nature.2018 Jan 25;553(7689):467- 01-3598-WO-1 131 472: “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 in} 5 Mao et al., Arterioscler Thromb Vasc Biol (2017) 37(5):920–9. doi: 10.1161/ATVBAHA.117.309017 ^_{Additionally, the STING inhibitors have also a therapeutic potential in the treatment of heart} failure (King et al, Nat Med 2017 Dec;23(12):1481-1487; Hu et al., A_{m. J. Physiol. Heart Circ. Physiol.2020 Jun 1;318(6):H1525-H1537).} _{^ Further scientific hints at a correlation between Parkinson’s disease and the cGAS/STING} _{10 pathway (Sliter et al., Nature.2018 Sep;561(7722):258-262), between amyotrophic lateral} sclerosis (ALS) and STING (Yu et al, Cell 2020;183:636-649) and between Sjogren’s syndrome and t_{he 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: 15 10.1038/s41586-022-04421-w: “The cGAS-STING pathway drives type I IFN immunopathology in COVID-19“, and in Neufeldt et al., Commun Biol.2022 Jan 12;5(1):45. doi: 10.1038/s42003-021- 02983-5: “SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS- STING and NF-kappaB”. It 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). _{20 ^ Additionally, STING inhibitors have a therapeutic potential in the treatment of renal} inflammation 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 25 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 indicating} STING activation can lead to alopecia (Front Immunol 201910:2770. doi: 10.3389; Pediatr R_{heumatol Online J.202422:9 doi: 10.1186). Blood mitochondrial DNA copy number has been} 30 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-I} signature. STING deficiency or a STING inhibitor protects a mouse model for ANCA associated 01-3598-WO-1 132 pulmonary vasculitis (J Exp Med.2022219:e20220759). ANCA pulmonary vasculitis has also been reported in a SAVI patient (STING GOV mutation) (Front Immunol.202011:575219). ^_{Furthermore, the lysosomal membrane protein Niemann-Pick type C1 (NPC1) has been identified} as a cofactor in the trafficking of STING. Genetic deletion of STING significantly reduced the 5 activation of microglia and relieved the loss of Purkinje neurons in the cerebellum of Npc1-/- mice, leading to improved motor function. This study indicates STING inhibitors as potential therapy for Niemann–Pick disease type C (Nature 2021596(7873):570-575). ^_{Additionally, it has been shown that in myotonic dystrophy type 2 (DM2) disease, patient PBMCs} and fibroblasts show elevated type I interferon (IFN) signature which is mediated by the10 cGAS/STING pathway (Nat Commun.202415:1534). ^_{In Huntington’s disease (HD), the mutated huntingtin gene induces DNA damage and cytosolic} DNA accumulation and activates the cGAS–STING pathway to mediate inflammation and a_{poptosis (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 of15 autophagy (Proc Natl Acad Sci 117:15989-15999). ^_{In addition, Xie et al detected binding of cGAS with dsDNA in cytoplasm and the activation of the} microglial 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). _{20 ^ Additionally, during ischemic stroke, tissue damage results in misplaced DNA within the cellular} environment activates the cGAS/STING pathway, leading to cytokine production, neuroinflammation, and cell death (Expert Opin Drug Discov 202318:1133-1149; Drug Discov Today.202328:103792). STING knockout decreased infarct progression, oedema volume and neuronal damage in mouse stroke model (Stroke Vasc Neurol 2023 Jul 3:svn-2023-002320. doi:25 10.1136) ^_{Further, it has been shown that STING promotes senescence, apoptosis, and extracellular matrix} degradation in osteoarthritis (Guo et al, Cell Death Dis.2021 Jan 4;12(1):13. doi: 10.1038). c_{GAS/STING null- mice have reduced tissue inflammation, improved heart/muscle function and} have an extended lifespan (Dou et al, Nature.2017550: 402–406). Furthermore, in humans a 30 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. 01-3598-WO-1 133 ^_{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 5 to cytosolic mtDNA accumulation, which served as a trigger in activating the cGAS-STING axis in melanocytes resulting in production of IL-1β and IL-18. ^_{Prurigo nodularis is a chronic inflammatory skin condition characterized by intensely itchy} pruritic nodules on the extremities and trunk that are often a result of persistent scratching. It w_{as reported that both systemic and cutaneous immune responses in patients with PN are} 10 skewed toward a Th22/IL-22 profile (Belzberg et al., Journal of Investigative Dermatology (2021) 141, 2208e2218). Aden et al. reported that IL-22 aggravates epithelial cell death–mediated inflammation through STING activation in intestinal epithelial cells (Aden et al., J. Exp. Med.2018 Vol.215: 2868–2886). STING may also play a role in IL22 mediated pathogenic responses in the skin epithelium in Prurigo nodularis. 15 T_{he compounds of formula (I) or (Ia) or (Ib), or the salts thereof for use in patients with a disease} _{whose progression 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, 20 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 a disease or condition that involves undesirable STING activation in a manner independent of cGAS activity is one embodiment of the intervention, for examples but not limited to subjects with25 deregulated STING mutants, e.g. but not limited to SAVI, or Niemann–Pick disease type C. I_{n a preferred embodiment, the compounds of the invention useful in the prevention of progression} _{and/or for the treatment of a disease or condition that involves undesirable STING activation by} mutations of the STING protein are those compounds, of formula (I) wherein X_{-Y-Z is =CH-N-N= ;} 30 In a preferred embodiment, the compounds of the invention for the prevention of progression and/or for the treatment of a disease or condition that involves undesirable STING activation by mutations of the STING protein are those compounds, that show IC50 values of at least 0.001 nM a_{nd 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 any of the mutant N154S or V155M of the} 01-3598-WO-1 134 STING protein associated with SAVI, preferably both, as described in section BIOLOGICAL ASSAYS AND DATA, and preferably for these compounds X_{-Y-Z is =CH-N-N= .} 5 In another embodiment the compounds of the inventions are used as anti-fibrotic agents. An e_{mbodiment of the invention is the use of the compounds of the invention in the therapy of} _{interferon-driven inflammatory and/or fibrotic diseases or symptoms, preferably those that are a} _{side effect of an underlying disease that leads to cell damage and cytosolic DNA presence that is not} _{derived from pathogens.} 10 Combinations The compounds of formula (I) may be administered to the patient alone or in combination with one or more other pharmacologically active agents. _{15 In a preferred embodiment of the invention the compounds may be combined with one or more} _{pharmacologically active agents selected from the group of PDE 4 inhibitors (preferably 1-[[(5R)-2-[4-} (5-chloropyrimidin-2-yl)-1-piperidyl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4- yl]amino]cyclobutyl]methanol and [1-[[(5R)-2-[4-(5-chlorophenyl-2-yl)-1-piperidyl]-5-oxo-6,7- dihydrothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol as disclosed in WO 2013/026797), 20 anti-inflammatory agents, anti-fibrotic agents, anti-allergic agents/ anti-histamines, bronchodilators, beta 2 agonists /betamimetics, adrenergic agonists, anticholinergic agents, methotrexate, mycophenolate mofetil, leukotriene modulators, JAK inhibitors, anti-interleukin antibodies, non- limiting examples are anti-IL-23 such as Risankizumab, anti-IL-17 antibodies, anti-IL-1 antibodies, anti-IL-4 antibodies, anti-IL-13 antibodies, anti-lL-5 antibodies, anti-IL-6 antibodies such as Actemra™, 25 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 agonists or antagonists), Toll-like receptor agonists (=TLR agonists), immune checkpoint regulators, a_{nti-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-} _{30 inflammatory agents and/or anti-fibrotic agents in one embodiment is a combination of one or more} compounds of the invention with a) one or more known STING inhibitors and/or b) known cGAS i_{nhibitors and/or c) anti-inflammatory agents that are not STING inhibitors and/or anti-fibrotic agents} _{that are not STING inhibitors, for example but not limited to Pirfenidon, Nintedanib or} _{Nerandomilast. Another aspect of the invention is to the combined use of the STING inhibitors of the} 01-3598-WO-1 135 invention in combination with known cGAS and/or STING inhibitors, for example those disclosed in the international patent applications PCT/EP2023/080705, PCT/EP2023/080711, P_{CT/EP2022/062496, PCT/EP2022/062480, PCT/EP2023/079890 or published as WO2021/138419,} _{WO2023/148129, WO2023/237457, WO2024/263860, WO2025/012195 or WO2025/017045.} 5 I_{n a further aspect of the present invention, the one or more other pharmacologically active agents} include immunosuppressive drugs, Nonsteroidal anti-inflammatory drug (NSAID), corticosteroids e.g. g_{lucocorticoids, hydroxychloroquine or methotrexate, antibodies for example anti- B-cell activating} factor (BAFF) antibody or CAR (chimeric antigen receptors) T cells. _{10 In another aspect of the present invention, the one or more other pharmacologically active agents} are RAAS inhibitors (Renin–Angiotensin–Aldosterone System). In one aspect of the present invention, the one or more other therapeutic substances is a direct renin inhibitor, an Angiotensin- Converting Enzyme (ACE) inhibitor and/or an angiotensin II receptor blocker (ARB). 15 In one embodiment , the invention comprise pharmaceutical compositions comprising one or more compounds of the invention and one or more other pharmacologically active agents for use in the treatment or prevention of progression of a disease selected from the group consisting of disease selected from the group consisting of systemic lupus erythematosus (SLE), cutaneous lupus, (monogenic and digenic) interferonopathies (including STING-associated vasculopathy with onset in 20 infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome, and familial chilblain lupus), t_{ype 1 interferonopathies with mutations in DNASE2 or ATAD3A genes, age-related macular} degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), Huntington disease, Alzheimer's disease, diabetes, obesity, inflammatory bowel disease (IBD), chronic obstructive p_{ulmonary disease (COPD), Bloom’s syndrome, Niemann-Pick Disease, Type C, ischaemic stroke,} 25 myotonic dystrophy type 2, Sjogren’s syndrome, Parkinson’s disease, heart failure, cancer, systemic s_{clerosis (SSc), vitiligo, prurigo nodularis, idiopathic inflammatory myopathy, myositis including} dermatomyositis, metabolic dysfunction–associated steatotic liver disease (MASLD) (previously r_{eferred to as non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction associated} steatohepatitis (MASH, previously non-alcoholic steatotic hepatitis (NASH)), compensated and 30 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. 35 Formulations 01-3598-WO-1 136 The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other 5 than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, intrasternal, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin. The compounds of the invention may be administered via eye drops to treat Sjogren's syndrome. 10 Suitable forms for administration are for example tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. The content of the pharmaceutically effective compound(s) in each case should be in the range from 0.1 to 90 wt.%, preferably 0.5 to 50 wt.% of the total composition, i.e. in amounts which are sufficient to achieve the dosage range specified hereinafter. 15 The preparations may be administered orally in the form of a tablet, as a powder, as a powder in a capsule (e.g. a hard gelatin capsule), as a solution or suspension. When administered by inhalation the active substance combination may be given as a powder, as an aqueous or aqueous-ethanolic solution or using a propellant gas formulation. Preferably, therefore, pharmaceutical formulations are characterized by the content of one or more20 compounds of formula (I) according to the preferred embodiments above. I_{t is particularly preferable if the compounds of formula (I)) are administered orally, and it is also} particularly preferable if they are administered once or twice a day. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch 25 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. Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets 30 with substances normally used for tablet coatings, for example kollidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly, the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets. 01-3598-WO-1 137 Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavor enhancer, e.g. a flavoring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for 5 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 example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol 10 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. Excipients which may be used include, for example, water, pharmaceutically acceptable organic 15 solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), m_{ono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral} powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate,20 talc, stearic acid and sodium lauryl sulphate). For oral administration the tablets may, of course, contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like. Moreover, lubricants such as 25 magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tableting process. In the case of aqueous suspensions, the active substances may be combined with various flavor enhancers or colorings in addition to the excipients mentioned above. The inventive use in the prevention of and/or treatment of and / or delaying the occurrence of 30 and/or delaying the progression of disorders is to be understood to refer to a prevention that reduces the risk for disorders related to elevated and / or deregulated STING activity, wherein prevention can be a reduction of the risk of such disorders whereby some risk may remain. Despite t_{he use of the compounds of the invention, individual patients may still suffer from such disorders at} least to some extent, although for the overall group of patients the use of the compounds of the35 invention typically is suitable to delay the occurrence and/or prevent such disorders. 01-3598-WO-1 138 Prevention or delay is typically identified by comparison with a control patient group or a patient not receiving any compound of the invention, preferably a patient group / patient receiving placebo and standard of care. The treatment group/patient receives standard of care for any other disorder not related to elevated and / or deregulated STING activity, and if applicable the standard of care for 5 disorders related to elevated and / or deregulated STING activity, plus in addition one or more compound(s) of the invention. Identification of a prevention or delay will typically require studies in a large group of patients and control group under controlled conditions, typically in a clinical trial, but the identified prevention or delay normally applies to any individual patient receiving the compound(s) of the invention, whereas 10 the quantity of prevention or delay for the individual patient can be expected by the average value observed in the large group but modified due to individual factors. Therefore, the prevention or delay may be present but smaller than the observed average in large trials, or higher for the individual patient. T_{hroughout this description the term disorders is used interchangeably with diseases or conditions.} 15 A further aspect of the present invention is to a method of preparation of a pharmaceutical composition comprising the compound of the invention for the use in the prevention of and/or treatment of and / or delaying the occurrence of and/or delaying the progression of disorders related to elevated and / or deregulated STING activity, wherein the method comprises the steps of a) 20 producing the inventive compound or a salt thereof, preferably a pharmaceutically acceptable salt t_{hereof, or an ester thereof, preferably an C1-3 esters, 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)-2-25 [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, mycophenolate mofetil, leukotriene m_{odulators, JAK inhibitors, anti-interleukin antibodies, preferably anti-IL-23 such as Risankizumab,} 30 anti-IL-17 antibodies, anti-IL-1 antibodies, anti-IL-4 antibodies, anti-IL-13 antibodies, anti-lL-5 a_{ntibodies, anti-IL-6 antibodies such as Actemra™, anti-IL-12 antibodies and/or anti-IL-15 antibodies,} non-specific immunotherapeutics such as interferons or other cytokines/chemokines, cytokine/chemokine receptor modulators (i.e. cytokine receptor agonists or antagonists), Toll-like r_{eceptor agonists (=TLR agonists), immune checkpoint regulators, anti-TNF antibodies , preferably} _{35 Humira™, and anti-BAFF agents, preferably Belimumab and/or Etanercept. Another aspect of the} 01-3598-WO-1 139 i_{nvention is to the combined use of one or more of the STING inhibitors of the invention in} combination with known cGAS and/or STING inhibitors, and d) optionally formulating into a form for the preferred administration. 5

Claims

01-3598-WO-1 140 Claims 1_{. 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 is C 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-;} _{V is selected from the group Va consisting of =CH- and =N-;} 5 w_{herein W and V are preferably not =N-; at the same time;} R¹ is selected from the group R1^a consisting of C_{1-5-alkyl- and C3-6-cycloalkyl-;} R² is selected from the group R^2a consisting of R_{9-C(R8)(R7)-CH(R6)- and R9-S(O)-CH(R6)- and} ∗ , wherein * denotes the attachment point to the core structure; ; R³ is selected from the group R^3a consisting of h_{alogen, HO-, C1-3-alkyl-, C1-5-alkyl-O-, C3-5-alkenyl-O-, C3-6-cycloalkyl- and} heterocyclyl-; wherein the 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 01-3598-WO-1 141 consisting of fluorine, HO-, H2N-C(O)-, C3-4-cycloalkyl-, C1-3-alkyl-O-, heterocyclyl and heteroaryl; R⁴ is selected from the group R^4a consisting of a_{t least one heterocyclyl or carbocyclyl group substituted with a tetrazole,} carboxylate or methylcarboxylate group and optionally substituted i_{ndependently with one to three groups consisting of H, methyl, ethyl or H3C-O-;} ; R⁵ is selected from the group R^5a consisting of C1-4-alkyl-; R⁶ is selected from the group R^6a consisting of H_{-, HO- and Halogen;} R⁷ is selected from the group R^7a consisting of H_{-, Halogen, HO- and C1-3-alkyl-O-;} R⁸ is selected from the group R^8a consisting of H_{- and Halogen;} R⁹ is selected from the group R^9a consisting of p_{henyl-, piperidyl-, morpholinyl- and C5-6-cycloalkyl-,} wherein the piperidyl-group is optionally substituted with 1 substituent independently selected from the group consisting of C_1-3-alkyl-S(O)₂-, C_1-3-alkyl- C(O)-, C_1-5-alkyl-C(O)-O-; R¹⁰ is selected from the group R^10a consisting of H_{-, HO-, H2N-C(O)-, C1-3-alkyl-, C1-3-alkyl-O-, C3-4-cycloalkyl- and phenyl-,} wherein the phenyl-group and/or the C1-3-alkyl-group are optionally substituted with 1 substituent independently selected from the group consisting of Halogen and HO-, R¹¹ is selected from the group R^11a consisting of H_{-, HO-, H2N-C(O)-, C1-3-alkyl-, C1-3-alkyl-O-, C3-4-cycloalkyl- and phenyl-,} wherein the phenyl-group and the C_1-3-alkyl-group is optionally substituted with 1 substituent independently selected from the group consisting of Halogen and HO-, w_{herein preferably R10 and R11 are not both H- at the same time,} or a salt thereof, or an ester thereof, preferably an C_1-3 esters. _{2. A compound according to claim 1, wherein} 01-3598-WO-1 142 B_{-A is selected from the group B-Ab consisting of =C-N-; this means A is N; B is C,} _{or a salt thereof or an ester thereof, preferably an C1-3 esters.} _{3. A compound according to claim 1 or 2, wherein} _{V is selected from the group Vb consisting of =N-,} _{or a salt thereof or an ester thereof, preferably an C1-3 esters.} 5 4_{. A compound according to one of the claims 1 to 3, wherein} _{W is selected from the group Wb consisting of =CH-,} _{or a salt thereof or an ester thereof, preferably an C1-3 esters.} _{5. A compound according to one of the claims 1 to 4, wherein} _{X-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N= and -N=C-NH-,}10 or a salt thereof. 6_{. A compound according to one of the claims 1 to 5, wherein} R² is selected from the group R^2b consisting of R_{9-C(R8)(R7)-CH(R6)- and R9-S(O)-CH2-,} _{or a salt thereof or an ester thereof, preferably an C1-3 esters.} _{7. A compound according to one of the claims 1 to 6, wherein} R³ is selected from the group R^3b consisting of C_1-3-alkyl-, C_1-5-alkyl-O-, wherein the C_1-5-alkyl-group of the C_1-5-alkyl-O-group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluorine, HO-, H2N-C(O)-, C3-4-cycloalkyl-, C1-3-alkyl-O-, heterocyclyl and heteroaryl; _{15 or a salt thereof or an ester thereof, preferably an C1-3 esters.} _{8. A compound according to one of the claims 1 to 7, wherein} R⁴ is selected from the group R^4b consisting of C3-8-cycloalkyl, C3-8-heterocycloalkyl, C5-C11-spiro cycloalkyl, C5-C11 hetero-spiro cycloalkyl, C6-C9 bicycloalkyl, C6-C9 heterobicycloalkyl and heteroaryl group substituted with a tetrazole, carboxylate or methylcarboxylate group and 01-3598-WO-1 143 optionally substituted independently with one to three groups consisting of H, methyl, ethyl or H3C-O-; o_{r a salt thereof or an ester thereof, preferably an C1-3 esters.} _{9. A compound according to one of the claims 1 to 8, wherein the compound of formula (I) is a} compound of formula (Ia) 5 o_{r a salt thereof or an ester thereof, preferably an C1-3 esters.} _{10. A compound according to one of the claims 1 to 8, wherein the compound of formula (I) is a} compound of formula (Ib) 10 o_{r a salt thereof or an ester thereof, preferably an C1-3 esters.} _{11. A compound according to one of the claims 1 to 8, selected from the following examples:} 15 01-3598-WO-1 144



ZH 01-3598-WO-1 149 o_{r an ester thereof, preferably an C1-3 ester thereof,.} _{12. A compound according to one of the claims 1 to 8, selected from any of the examples 1 to 40} or an ester thereof, preferably an C_1-3 esters. 5_{13. A salt, preferably a pharmaceutically acceptable salt, of any of the compounds of claims 11 or} 12. 01-3598-WO-1 150 1_{4. The compound of formula (I), (Ia) or (Ib), according to any of claims 1 to 12 or an ester} _{thereof, preferably an C1-3 ester thereof, or the salt of the compound according to claim 13} for use in the treatment of a disease that can be treated by the inhibition of STING. 5 1_{5. The compound of formula (I), (Ia) or (Ib), according to any of claims 1 to 12 or an ester} _{thereof, preferably an C1-3 ester thereof, or the salt of the compound according to claim 13} for use in the treatment of a disease selected from the group consisting of disease selected from the group consisting of systemic lupus erythematosus (SLE), cutaneous lupus, 10 (monogenic and digenic) interferonopathies (including STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome, and familial c_{hilblain 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 bowel15 disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom’s syndrome, Niemann- P_{ick 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- _{20 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-neutrophil cytoplasm antibody (ANCA) 25 associated vasculitis, alopecia, chronic kidney disease, rheumatoid arthritis and osteoarthritis. 1_{6. Pharmaceutical composition comprising a compound of any of claims 1 to 12 or an ester} _{thereof, preferably an C1-3 ester thereof, and / or the salt of the compound according to} _{30 claim 13, and optionally one or more pharmaceutically acceptable carriers and/or excipients.}