Hetaryl substituted indazoles and benzimidazoles as sting antagonists and the use thereof as medicament

Abstract

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

Description

[0001] 01-3595-WO-1 1 Hetaryl Substituted Indazoles and Benzimidazoles as STING Antagonists and the Use Thereof asMedicament This application claims priority to the US provisional application 63 / 640357, filed on April 30, 2024 5and to the priority filing EP 24209201.3, filed on October 28, 2024.Field of the invention This invention relates to compounds of formula (I) and their use as STING antagonists e.g. for the10 treatment of a disease selected from the group consisting of systemic lupus erythematosus (SLE), cutaneous lupus, (monogenic and digenic) interferonopathies (including STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome, and familial chilblain lupus), type 1 interferonopathies with mutations in DNASE2 or ATAD3A genes, age-related macular degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), 15 Huntington disease, Alzheimer's disease, diabetes, obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom’s syndrome, Niemann-Pick Disease, Type C, ischaemic stroke, myotonic dystrophy 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 disease20 (MASLD) (previously referred to as non-alcoholic fatty liver disease (NAFLD), metabolic dysfunctionassociated steatohepatitis (MASH, previously non-alcoholic steatotic hepatitis (NASH)), compensated and decompensated liver cirrhosis, acute on chronic liver failure (ACLF), alcoholic liver disease (ALD), interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), long COVID, aging / muscle disorders, sepsis, heart failure, anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis, alopecia,25 chronic kidney disease, rheumatoid arthritis and osteoarthritis. 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 are30 triggered by conserved pathogen-associated molecular patterns (PAMPs) through sensing by diversepattern recognition receptors (PRRs) and subsequent activation of cytokine and type I interferon gene expression. The major antigen-presenting cells, such as monocytes, macrophages, and dendritic cells produce type I interferons and are critical for eliciting adaptive T- and B-cell immune systemresponses. The major PRRs detect aberrant, i.e. mislocalized, immature or unmodified nucleic acids 01-3595-WO-1 2 on either the cell surface, the inside of lysosomal membranes or within other cellular compartments (Barbalat et al., Annu. Rev. Immunol.29, 185-214 (2011)). “Cyclic GMP-AMP Synthase” (cGAS) is the predominant sensor for aberrant double-stranded DNA 5 (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 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 of10 Interferon Genes” (STING, UniProtKB – Q86WV6). Activated STING recruits and activates TANK-binding kinase 1 (TBK1) which in turn phosporylates the transcription factor family of interferonregulatory factors (IRFs) inducing cytokine and type I interferon mRNA expression. STING activation by cGAMP also leads to activation of NF-kB signaling pathway and downstream production of proinflammatory cytokines (Sun et al., Science 339, 786-791 (2013). Human GoF STING mutants lead 15 to an autoinflammatory syndrome, cutaneous vasculopathy and lung fibrosis (STING-associated vasculopathy with onset in infancy, SAVI). SAVI patients have a highly activated PBMCs and dermal fibroblasts, exhibiting an upregulated type-1 IFN signature and expression of NF^B-mediated profibrotic and proinflammatory genes (e.g. TNF^, IL-6) (Liu et al., 2014).20 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)), 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)). 25 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 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-30 mediated disorder – arises from genetic mutations such as loss-of-function mutations in TREX1, aprimary DNA exonuclease responsible for degrading aberrant DNA in cytosol. Knock-out of STING in TREX1-deficient mice prevented otherwise lethal autoimmune responses, supporting STING as driver of interferonopathies (Gall et al., Immunity 36(1), 120-131 (2012); Gao et al., PNAS 112, E5699-E5705 (2015)). Likewise, embryonic lethality caused by deficiency of DNAse2, an endonuclease responsible 01-3595-WO-1 3 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) interferonopathy diseases such as SAVI, AGS, familial chilblain lupus and COPA. A STING inhibitor will 5 block inflammation and aberrant tissue remodeling in a cluster of autoimmune and inflammatory diseases including systemic lupus erythematosus (SLE), systemic sclerosis, vitiligo, prurigo nodularis,idiopathic inflammatory myopathy, myositis including dermatomyositis, inflammatory bowel disease,sepsis, Sjogren’s syndrome, atopic dermatitis, as well as a cluster fibrosis diseases including NASH, IPF, chronic kidney fibrosis. A STING inhibitor also has applications to additional diseases such as10 cancer, heart failure, AMD, retinopathy, glaucoma, aging, decompensated liver cirrhosis, anti- neutrophil cytoplasm antibody (ANCA) associated vasculitis, alopecia, chronic kidney disease; Niemann-Pick Disease, Type C, ischaemic stroke, myotonic dystrophy type 2, Huntington disease,Bloom syndrome, Huntington disease, muscle disorders, rheumatoid arthritis, osteoarthritis, ALS,Parkinson’s disease, Alzheimer’s disease, COVID-19 (Decout et al, Nat Rev Immunol.202121:548-15 569). Due to the observation that inhibition of the STING pathway may provide a therapeutic strategy for preventing autoinflammation and for treating e.g. autoimmune diseases efforts to develop STING inhibitors or inhibition of the STING signaling pathway have been undertaken. 20 •In WO2019122202 for example, compounds C-178 or C-176 are described interfering with STINGsignaling pathway in HEK293T cells or bone marrow derived macrophages (BMDMs) stimulated with a cyclic dinucleotide such as e.g. cGAMP which are irreversible inhibitors blocking the palmitoylation of STING at an allosteric site of STING.25 • In ACS Med Chem Lett. (2019, 10, 1, pp 92-97), Siu et all described novel cGAMP competitiveligands. It is believed that inhibiting the orthosteric site of cGAMP mediated STING activation leads to a suppression of all STING mediated activation in contrast to palmitoylation inhibitors. Compound 13 or 15 in this publication inhibits the HAQ STING variant (displacement assay) with a moderate IC50 of 84 or 41 nM and shows low cellular inhibitory activity of about 11 uM based30 on a cGAMP stimulated INFb production in THP1 cells. •In International patent application WO2019069270, claims modulators of STING which eitheractivate or inhibit STING accordingly. •In the international patent applications WO23148129 and WO23237457 modulators of STING aredisclosed that are relatively large macrocycles with demanding synthesis and handling of the35 molecules. 01-3595-WO-1 4 However, inhibitors of the STING receptor for therapeutic use face challenges. For example, it is expected that most inhibitors of the STING receptor binding its ligand binding site similar to the natural ligand, i.e. two molecules in the binding pocket. Yet, for the design of inhibitors of STING 5 receptors this provides the additional challenge that the inhibitor molecules not only need to interact with the correct portion the STING receptor, but also will interact with the second molecule of the inhibitor in the ligand binding pocket of STING. Hence the potential interface between inhibitor and inhibitor is also important to consider for good inhibition results of STING. Also, the polarity of the inhibitor molecules needs to be optimized on the one hand to allow 10 sufficient crossing of the cell membranes to reach the target, while not enhancing the degradation of the inhibitor. Another challenge for a therapeutic inhibitor of STING receptors is that in many STING mediated disease patients are likely to be co-administered with more than one medications to treat the symptoms of said diseases or the diseases itself. The inhibitors of STING should in such a situation 15 not 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.20 Aim of the inventionIt 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 invention25 provide further advantageous properties as to be viable for human therapy, such as but not limitedto: .Being optimised for binding of two molecules of the inhibitor to the target’s ligand binding pocket, sufficiently easy to synthesize and handle, good bioavailability, good mobility across the cell membrane and good access to the target receptor in the cells, acceptable cytotoxicity and / or genotoxicity, good ligand efficiency, good metabolic stability, low interaction with catabolic30 processes e.g. by cytochrome p450s or other CYP that are important with respect to possibly co-administered drugs, sufficient passage across the blood–brain barrier into the brain, gooddegradation ex-situ of the inhibitor or its break-down product e.g. in sewage plants. The inhibitors of the invention perform better in one or several of these properties than the inhibitors of the STING receptor available so far. Accordingly, one aspect of the invention refers to35 compounds according to formula (I), or salts thereof as inhibitors of STING. 01-3595-WO-1 5 Another aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of STING optimised for binding of two molecules of the inhibitor to the target’s ligand binding pocket and / or good ligand efficiency. Another aspect of the invention refers to compounds according to formula (I), or salts thereof as 5 inhibitors of STING having good metabolic stability and potency. Another aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of STING optimised in polarity for good mobility across the cell membrane and good access to the target receptor in the cells while having good metabolic stability and potency. Another aspect of the invention refers to compounds according to formula (I), or salts thereof as10 inhibitors of STING having good metabolic stability with acceptable cytotoxicity and / or genotoxicity. Another aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of STING having good metabolic stability and low interaction with catabolic processes e.g. by cytochrome p450s or other CYP that are important with respect to possibly co-administered drugs. 15 Another aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of STING having good metabolic stability and low interaction with catabolic processes of other pharmaceutical compound administered overlappingly or simultaneously, including but not limited to further inhibitors of STING, and with acceptable cytotoxicity and / or genotoxicity. 20 Another aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of STING having good metabolic stability and low interaction with catabolic processes of other pharmaceutical compounds administered overlappingly or simultaneously, including but not limited to further inhibitors of STING, and with acceptable cytotoxicity and / or genotoxicity and optimised in polarity for good mobility across the cell membrane and good access to the target25 receptor in the cells and good potency. Another aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of having good metabolic stability and low interaction with catabolic processes of other pharmaceutical compounds administered overlappingly or simultaneously, including but not limited to further inhibitors of STING, and with acceptable cytotoxicity and / or genotoxicity and optimised in 30 polarity for good mobility across the cell membrane and good access to the target receptor in the cells and good potency and optimised for binding of two molecules of the inhibitor to the target’s ligand binding pocket and good ligand efficiency. 01-3595-WO-1 6 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. 5A further aspect of the present invention relates to compounds according to general formula (I) orpharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compoundsaccording to formula (I) or pharmaceutically acceptable salts thereof, for the use in the prevention ofand / or treatment of and / or delaying the occurrence of and / or delaying the progression of disorders related to elevated and / or deregulated STING activity. In one aspect of the invention the use is to 10 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 disorders related to elevated STING activity, for example but not limited to progression of 15 scleroderma renal crisis (SRC) to end stage renal disease / kidney failure; progression of MAFLD or MASH for example from MAFLD to MASH, or from MASH to Mash with cirrhosis as assessed with the NAFLD Activity Score (NAS) with or without steatosis, activity, and fibrosis (SAF) score and / orprogression of Rheumatoid arthritis as assessed via the 2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria for example but not limited to from a point value from 3 to 5 or from a point20 value 4 to point value 7. Another aspect of the invention relates to processes of manufacture of the compounds of the present invention according to general formula (I) or salts thereof, particularly pharmaceuticallyacceptable salts. 25 Other aims of the present invention will become apparent to the skilled man directly from the foregoing and following remarks. Detailed description In a first aspect the present invention relates to compounds of general formula (I) 30 01-3595-WO-1 7 wherein X-Y-Z is selected from the group X-Y-Za consisting of =CH-N-N= and -N=C-NH-;5 Wis selected from the group Wa consisting of =CH- and =N-;R1is selected from the group R1aconsisting of C1-5-alkyl-, C1-3-alkyl-O-, and C3-6-cycloalkyl-;wherein the C1-3-alkyl-O-group and / or the C1-5-alkyl-group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-3- alkyl-O-, Halogen and HO-; R2is selected from the group R2aconsisting of C1-3-alkyl-; R3is selected from the group R3aconsisting of C3-6-cycloalkyl- and C1-3-alkyl-, either optionally substituted independently with 1 to 3substituents selected from the group consisting of fluorine, HO-, H3C-O-, F3C-O-, and F2HC-O-; R4is selected from the group R4aconsisting of H and Halogen; 10 R5is selected from the group R5aconsisting of , 01-3595-WO-1 8 wherein * denotes the attachment point to the core; R6is selected from the group R6aconsisting of C1-5-alkyl and heterocyclyl-wherein the C1-5-alkyl- group is optionally substituted with 1 to 5 substituentsindependently of one another selected from the group consisting of C3-6-cycloalkyl-,halogen, HO-, C1-6-alkyl-O-, C1-6-alkyl-HN-, (C1-6-alkyl)2N-, NC-, (C1-6-alkyl)2(O)P-, (4- methoxyphenyl)methyl-, C1-6-alkyl-, branched C3-6-alkyl-, tetrahydrofuranyl, piperidinyl,piperazinyl, tetrahydropyranyl, and morpholinyl,wherein the heterocyclyl-group is optionally substituted independently of oneanother by one or two substituents selected from the group consisting of C1-6-alkyl-, halogen, O=; R7is selected from the group R7aconsisting of C1-6-alkyl-, C3-5-alkenyl-, C3-6-cycloalkyl-, aryl, heteroaryl and heterocyclyl;wherein the C1-6-alkyl-group is optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of Halogen, HO-, and C1-3-alkyl- O-, wherein the heteroaryl group is optionally substituted with 1 substituent selected from the group consisting of C1-3-alkyl-, wherein the C3-6-cycloalkyl- and / or aryl group is optionally substituted with 1 to 3substituents independently selected from the group consisting of (H3C)2N-C(O)-; R8is selected from the group R8aconsisting of H-, C1-6-alkyl-O- and heterocyclyl-O-;wherein the C1-6-alkyl-O-group is optionally substituted with 1 substituent selected from the group consisting of C1-3-alkyl-O- and (H3C)2N-C(O)-;5 R9is selected from the group R9aconsisting of H-, C1-3-alkyl- and H2N-C(O)-CH2-;R10is selected from the group R10aconsisting of 01-3595-WO-1 9 C1-3-alkyl-, C2-3-alkenyl-, C1-3-alkyl-O-, C1-3-alkyl-S- and C3-6-cycloalkyl-,wherein the C1-3-alkyl-group or the C2-3-alkenyl-group is optionally substituted with1 to 3 substituents selected from the group consisting of Halogen- and C1-3-alkyl-;R11is selected from the group R11aconsisting of C1-3-alkyl-, C2-3-alkenyl-, C1-3-alkyl-O-, C1-3-alkyl-S- and C3-6-cycloalkyl-,wherein the C1-3-alkyl-group or the C2-3-alkenyl-group is optionally substituted with 1to 3 substituents selected from the group consisting of Halogen-, O= and C1-3-alkyl-; or a salt thereof, preferably a pharmaceutically acceptable salt. 5Unless otherwise stated, the groups, residues, and substituents, particularly 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 groupsoccur several times in a compound they may have the same or different meanings. Some preferred meanings of groups and substituents of the compounds according to the invention will be given hereinafter. 10 In a further embodiment of the present invention X-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N=.In a further embodiment of the present invention X-Y-Z is selected from the group X-Y-Zc consisting of -N=C-NH-.15 In a further embodiment of the present invention Wis selected from the group Wb consisting of =CH-.In a further embodiment of the present invention Wis selected from the group Wc consisting of =N-;In a preferred embodiment, the compound is a compound of formula (Ia) 01-3595-WO-1 10 In a further embodiment of the present invention R1is selected from the group R1bconsisting of H3C-, (H3C)2C-, H3C-CH2-, cyclopropyl-, F3C-O-, F3C-O-, H3C-CH(OH)-, H3C-CH2-CH(OH)- , H3C-CH2-O-, and H3C-O-CH2-CH2-. 5 In a further embodiment of the present invention R1is selected from the group R1cconsisting of H3C-, (H3C)2C-, H3C-CH2-, cyclopropyl-, F2C-O-, F3C-O-, H3C-CH(OH)-, H3C-CH2-CH(OH)- , H3C-CH2-O-, and H3C-O-CH2-CH2-. R1is selected from the group R1dconsisting of (H3C)2C-, cyclopropyl-, F2C-O-, F3C-O-, H3C-CH(OH)-, H3C-CH2-CH(OH)- and H3C-CH2-O-. R1is selected from the group R1econsisting of H3C-CH(OH)-. R1 is selected from the group R1f consisting ofF2C-O- and F3C-O-.R1 is selected from the group R1g consisting of(H3C)2C-. 10 In a further embodiment of the present invention R2is selected from the group R2bconsisting of H3C-. 01-3595-WO-1 11 In a further embodiment of the present invention R3is selected from the group R3bconsisting of cyclopropyl-. In a further embodiment of the present invention R4is selected from the group R4bconsisting of H- and F-.5 In a further embodiment of the present invention R4is selected from the group R4cconsisting of H-. In a further embodiment of the present invention R5is selected from the group R5bconsisting of , wherein * denotes the attachment point. 10 In a further embodiment of the present invention R5is selected from the group R5cconsisting of R8 , wherein * denotes the attachment point. In a further embodiment of the present invention R5is selected from the group R5dconsisting of , wherein * denotes the attachment point. In a further embodiment of the present invention R6is selected from the group R6bconsisting of 01-3595-WO-1 12 C1-3-alkyl-. In a further embodiment of the present invention R6is selected from the group R6cconsisting of H3C-. In a further embodiment of the present invention R7is selected from the group R7bconsisting of C1-6-alkyl-, C3-5-alkenyl-, C3-6-cycloalkyl-, phenyl, the C1-6-alkyl-group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of F-, HO- and H3C-O-.5 In a further embodiment of the present invention R7is selected from the group R7cconsisting of C1-3-alkyl-, C3-4-alkenyl-, C3-4-cycloalkyl-, phenyl, , the C1-6-alkyl-group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of F-, HO- and H3C-O-.In a further embodiment of the present invention R7is selected from the group R7dconsisting of10 H3C-, Cyclopropyl-, H2C=C(CH3)-, F2C- and 01-3595-WO-1 13 , wherein * denotes the attachment point.In a further embodiment of the present invention R8is selected from the group R8bconsisting of H-, C1-6-alkyl-O- and ; wherein * denotes the attachment pointandwherein the C1-6-alkyl-O-group is optionally substituted with 1 substituent selected from the group consisting of C1-3-alkyl-O- and (H3C)2N-C(O)-.5 In a further embodiment of the present invention R8is selected from the group R8cconsisting of H-, H3C-O-, H3C-O-CH2-CH2-O-, H3C-CH2-O-, (H3C) 2CH-O-, (H3C) 2N-C(O)-CH2-O-, and , wherein * denotes the attachment point. In a further embodiment of the present invention R8is selected from the group R8dconsisting of H-. In a further embodiment of the present invention R9is selected from the group R9bconsisting of C1-3-alkyl-. 10 In a further embodiment of the present invention R9is selected from the group R9cconsisting of H- and H3C-.R9is selected from the group R9dconsisting of 01-3595-WO-1 14 H3C-. R9is selected from the group R9econsisting of H-. In a further embodiment of the present invention R10is selected from the group R10bconsisting of C1-3-alkyl-, C2-3-alkenyl-, C1-3-alkyl-O-, C1-3-alkyl-S- and C3-4-cycloalkyl-,wherein the C1-3-alkyl-group or the C2-3-alkenyl-group is optionally substituted with1 to 3 substituents selected from the group consisting of F- and H3C-;5 In a further embodiment of the present invention R10is selected from the group R10cconsisting of F3C-, F2HC-, F2HC-O- , (CH2) (CH3)C-, H3C-O-, H3C-H2C- , H3C-S- and cyclopropyl.In a further embodiment of the present invention R10is selected from the group R10dconsisting of F3C-. 10 In a further embodiment of the present invention R10is selected from the group R10econsisting of F2HC-. R10 is selected from the group R10f consisting ofcylcopropyl. In a further embodiment 01-3595-WO-1 15 of the present invention R11is selected from the group R11bconsisting of C1-3-alkyl-, C1-3-alkyl-O-, and C3-6-cycloalkyl-, wherein the C1-3-alkyl-group is optionally substituted with 1 to 2 substituentsselected from the group consisting of Fluorine-, O= and C1-2-alkyl-; W, X-Y-Z, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 represents a characterized, individual embodimentfor the corresponding substituent as described above. Thus, given the above definitions, individual 5 embodiments of the first aspect of the invention are fully characterized by the term (WX, X-Y-ZX, R1X, R2x, R3X, R4X, R5X, R6X, R7X, R8X, R9X, R10Xand R11x), wherein for each index ‘x’ an individual figure is given that ranges from ‘a’ to the highest letter given above. All individual 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.10 The following table 1 shows such embodiments E-1 to E-23 of the compound of general formula (I) ora salt thereof, preferably a pharmaceutically acceptable salt, that are considered preferred. Table 1: Embodiments E-1 to E-29 of the invention 01-3595-WO-1 16 Accordingly, for example E-7 covers compounds of general formula (I), wherein Wis selected from the group Wc consisting of =N-;X-Y-Z is selected from the group X-Y-Za consisting of =CH-N-N= and -N=C-NH-;R1is selected from the group R1aconsisting of C1-5-alkyl-, C1-3-alkyl-O-, and C3-6-cycloalkyl-; wherein the C1-3-alkyl-O-group and / or the C1-5-alkyl-group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-3- alkyl-O-, Halogen and HO-; 01-3595-WO-1 17 R2is selected from the group R2aconsisting of C1-3-alkyl-; R3is selected from the group R3aconsisting of C3-6-cycloalkyl- and C1-3 alkyl, either optionally substituted independently with 1 to 3substituents selected from the group consisting of fluorine, HO-, H3C-O-, F3C-O-, and F2HC-O-; R4is selected from the group R4cconsisting of H-; R5is selected from the group R5bconsisting of R6is selected from the group R6bconsisting of C1-3-alkyl-; R7is selected from the group R7aconsisting of C1-6-alkyl-, C3-5-alkenyl-, C3-6-cycloalkyl-, aryl, heteroaryl and heterocyclyl; wherein the C1-6-alkyl-group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Halogen, HO-, and C1-3-alkyl- O-, wherein the heteroaryl group is optionally substituted with 1 substituent selected from the group consisting of C1-3-alkyl-, wherein the C3-6-cycloalkyl- and / or aryl group is optionally substituted with 1 to 3substituents independently selected from the group consisting of (H3C)2N-C(O)-; R8is selected from the group R8aconsisting of H-, C1-6-alkyl-O- and heterocyclyl-O-;wherein the C1-6-alkyl-O-group is optionally substituted with 1 substituent selected from the group consisting of C1-3-alkyl-O- and (H3C)2N-C(O)-;R9is selected from the group R9aconsisting of H-, C1-3-alkyl- and H2N-C(O)-CH2-;R10is selected from the group R10aconsisting of C1-3-alkyl-, C2-3-alkenyl-, C1-3-alkyl-O-, C1-3-alkyl-S- and C3-6-cycloalkyl-,wherein the C1-3-alkyl-group or the C2-3-alkenyl-group is optionally substituted with 1 to 3 substituents selected from the group consisting of Halogen- and C1-3-alkyl-; 01-3595-WO-1 18 or a salt thereof, preferably a pharmaceutically acceptable salt. Accordingly, for example E-17 covers compounds of general formula (I), wherein Wis selected from the group Wc consisting of =N-;X-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N=.R1is selected from the group R1cconsisting of H3C-, (H3C)2C-, H3C-CH2-, cyclopropyl-, F2C-O-, F3C-O-, H3C-CH(OH)-, H3C-CH2- CH(OH)-, H3C-CH2-O-, and H3C-O-CH2-CH2-; R2is selected from the group R2bconsisting of H3C-; R3is selected from the group R3bconsisting of cyclopropyl-; R4is selected from the group R4cconsisting of H-; R5is selected from the group R5dconsisting of ; R6is selected from the group R6bconsisting of C1-3-alkyl-; R9is selected from the group R9bconsisting of C1-3-alkyl-; R10is selected from the group R10cconsisting of F3C-, F2HC-, F2HC-O-, (CH2)(CH3)C-, H3C-O-, H3C-H2C- , H3C-S- and cylcopropyl;5 or a salt thereof, preferably a pharmaceutically acceptable salt. Accordingly, for example E-19 covers compounds of general formula (I), wherein Wis selected from the group Wc consisting of =N-;X-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N=;R1is selected from the group R1bconsisting of 01-3595-WO-1 19 H3C-, (H3C)2C-, H3C-CH2-, cyclopropyl-, F3C-O-, F3C-O-, H3C-CH(OH)-, H3C-CH2- CH(OH)-, H3C-CH2-O-, and H3C-O-CH2-CH2-; R2is selected from the group R2bconsisting of H3C-; R3is selected from the group R3bconsisting of cyclopropyl-; R4is selected from the group R4cconsisting of H-; R5is selected from the group R5cconsisting of ; R7is selected from the group R7bconsisting of C1-6-alkyl-, C3-5-alkenyl-, C3-6-cycloalkyl-, phenyl, , , , , , , an .wherein the C1-6-alkyl-group is optionally substitutedwith 1 to 3 substituents independently selected from the group consisting of F-, HO- and H3C-O-;R8is selected from the group R8cconsisting of H-, H3C-O-, H3C-O-CH2-CH2-O-, H3C-CH2-O-, (H3C) 2CH-O-, (H3C) 2N-C(O)-CH2-O-, and or a salt thereof, preferably a pharmaceutically acceptable salt. Further preferred are the following compounds listed in table 2 or salt thereof or stereoisomersthereof (the No. refers to the No. assigned to the compound in the experimental section). Each5 compound of table 2 is represented without indicating the stereochemistry thereof, if any. Specificinformation concerning stereochemical properties of compounds of table 2 can be taken from theexperimental section. In case the final compounds according of said experimental section are saltforms, they can be converted into the neutral compound by conventional methods. 01-3595-WO-1 20 Table 2: 01-3595-WO-1 30 or a salt thereof. A further embodiment of the present invention covers the compounds of general formula (I), preferably of formula (Ia), particularly the compounds listed in table 2, in form of their5 pharmaceutically acceptable salts. Afurther embodiment of the present invention refers to pharmaceutical compositions comprising atleast one compound according to formula (I), preferably according to formula (Ia), orpharmaceutically acceptable salts thereof, optionally together with at least one inert adjuvant,10 diluent and / or carrier. In a further embodiment, the present invention relates to a compound of the present invention or apharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least onecompound according to general formula (I), preferably according to formula (Ia), or pharmaceutically 01-3595-WO-1 31 acceptable salts thereof, for use as a medicament.In a further embodiment, the present invention relates to compounds according to general formula (I), preferably according to formula (Ia), or pharmaceutically acceptable salts thereof, or 5 pharmaceutical compositions comprising compounds according to general formula (I), preferably according to formula (Ia), or pharmaceutically acceptable salts thereof, for use in the prevention thedelaying 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 may not require to be a complete inhibition of the STING proteins within a cell, tissue, organ or the body of a 10 patient to cause the desired positive effects in a patient. A partial inhibition maybe sufficient and possibly desirable in some patients. . 15 Used terms and definitions 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 following20 conventions are adhered to. In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C1-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, in groups like HO-, H2N-, (O)S-, (O)2S-, NC- (cyano), HOOC-, F3C- or the like, the25 skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself. For combined groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent "aryl-C1-3-alkyl-" means an aryl group which is bound to a C1-3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached. 30 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. 01-3595-WO-1 32 The numeration of the atoms of a substituent starts with the atom which is closest to the core or to the group to which the substituent is attached. For example, the term "3-carboxypropyl-group" represents the following substituent: 5 wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms "1- methylpropyl-", "2, 2-dimethylpropyl-" or "cyclopropylmethyl-" group represent the following groups: 10 The asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. The term "substituted" as used herein, means that one or more hydrogens on the designated atom 15 are replaced by a group selected from a defined group of substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound. Likewise, the term “substituted” may be used in connection with a chemical moiety instead of a single atom, e.g. “substituted alkyl”, “substituted aryl” or the like. 20 Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomer’s and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E / Z isomers etc…) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as solvates thereof such as25 for instance hydrates. Unless specifically indicated, also “pharmaceutically acceptable salts” as defined in more detail below shall encompass solvates thereof such as for instance hydrates. In general, substantially pure stereoisomers can be obtained according to synthetic principles known 30 to a person skilled in the field, e.g. by separation of corresponding mixtures, by using 01-3595-WO-1 33 stereochemically pure starting materials and / or by stereoselective synthesis. It is known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, e.g. starting from optically active starting materials and / or by using chiral reagents. 5 Enantiomerically pure compounds of this invention or intermediates may be prepared via asymmetric synthesis, for example by preparation and subsequent separation of appropriate diastereomeric compounds or intermediates which can be separated by known methods (e.g. by chromatographic separation or crystallization) and / or by using chiral reagents, such as chiral starting materials, chiral catalysts, or chiral auxiliaries. 10 Further, it is known to the person skilled in the art how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, such as by chromatographic separation of the corresponding racemic mixtures on chiral stationary phases; or by resolution of a racemic mixture using an appropriate resolving agent, e.g. by means of diastereomeric salt formation of the racemic 15 compound with optically active acids or bases, subsequent resolution of the salts and release of the desired compound from the salt; or by derivatization of the corresponding racemic compounds with optically active chiral auxiliary reagents, subsequent diastereomer separation and removal of the chiral auxiliary group; or by kinetic resolution of a racemate (e.g. by enzymatic resolution); by enantioselective crystallization from a conglomerate of enantiomorphous crystals under suitable 20 conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical 25 judgment, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds 30 wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, 35 ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, 01-3595-WO-1 34 malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid. Further pharmaceutically acceptable salts can be formed with cations from ammonia, L-arginine, calcium, 2, 2’- iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium and 5 tris(hydroxymethyl)-aminomethane. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a 10 sufficient amount of the appropriate base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts, ) also comprise a part15 of the invention. The term halogen denotes fluorine, chlorine, bromine and iodine. The term "C1-n-alkyl-", wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4, 5, or 6, either 20 alone or in combination with another radical, denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term C1-5-alkyl embraces the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C- C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.25 The term "C2-m-alkenyl" is used for a group "C2-m-alkyl" wherein m is an integer selected from 3, 4, 5 or 6, preferably 4, 5 or 6, if at least two carbon atoms of said group are bonded to each other by a double bond. 30 The term "C3-k-cycloalkyl", wherein k is an integer selected from 3, 4, 5, 7 or 8, preferably 4, 5 or 6, either alone or in combination with another radical, denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to k C atoms. For example the term C3-7-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. 01-3595-WO-1 35 The term "carbocyclyl", either alone or in combination with another radical, means a mono, bi or tricyclic ring structure consisting of 3 to 14 carbon atoms. The term "carbocyclyl" refers to fully saturated, partially saturated and aromatic ring systems. The term "carbocyclyl" encompasses fused, bridged and spirocyclic systems. Examples without limitation are: 5 10 The term "aryl" as used herein, either alone or in combination with another radical, denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which is optionally further fused to a second five or six membered, carbocyclic group which is aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl. 15 The term "heterocyclyl" means a saturated or unsaturated mono- or polycyclic ring system optionallycomprising aromatic rings, containing one or more heteroatoms selected from N, O, S, SO or SO2 consisting of 3 to 14 ring atoms wherein none of the heteroatoms is part of the aromatic ring. The term "heterocyclyl" is intended to include all the possible isomeric forms. 20 Thus, the term "heterocyclyl" includes the following exemplary structures (not depicted as radicals as each form is optionally attached through a covalent bond to any atom so long as appropriate valences are maintained): 01-3595-WO-1 36 5 10 01-3595-WO-1 37 5 .10 The term "heteroaryl" means a mono- or polycyclic ring system, comprising at least one aromaticring, 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. 01-3595-WO-1 38 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): 5 10 . The term "aryl" as used herein, either alone or in combination with another radical, denotes a 15 carbocyclic aromatic monocyclic group containing 6 carbon atoms which is optionally further fused to asecond five- or six-membered, carbocyclic group which is aromatic, saturated or unsaturated. Arylincludes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl. 01-3595-WO-1 39 Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another. The term „bicyclic ring systems” means groups consisting of 2 joined cyclic substructures including 5 spirocyclic, fused, and bridged ring systems. 10 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. 15 Preferably, the compounds are obtained in analogous fashion to the methods of preparation explained more fully hereinafter, in particular as described in the experimental section. In some cases, the order in carrying out the reaction steps may be varied. Variants of the reaction methods that are known to the one skilled in the art but not described in detail here may also be used. Preferably, the compounds are obtained by the following methods according to the invention which 20 are described in more detail hereinafter. The following Schemes illustrate generally how to manufacture the compounds of the present invention by way of example. Starting materials may be prepared by methods that are described in the literature or herein or may be prepared in an analogous or similar manner. Any functional groups25 in the starting materials or intermediates may be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage within the reaction sequence using 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. 30 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 01-3595-WO-1 40 chromatography – mass spectrometry (LC-MS) if desired, and intermediates and products may bepurified by chromatography and / or by recrystallization. The examples which follow are illustrative and, as recognized by one skilled in the art, particular 5 reagents or conditions could be modified as needed for individual compounds without undue experimentation. Starting materials and intermediates used, in the methods below, are either commercially available or easily prepared from commercially available materials by those skilled in the art. 10 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. 15 The term "room temperature" designate a temperature of about 20 °C, e.g., 15 to 25 °C. As a rule,1H-NMR and / or mass spectra have been obtained for the compounds prepared. Flash chromatography or MPLC is performed with commercial silica gel and is equivalent to silica gel20 chromatography. Absolute configuration of representative examples is either defined via the chemical starting material, single crystal x-ray structure determination or protein-ligand X-ray determinations. 25 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. Scheme 1a: General synthesis scheme for patent examples30 01-3595-WO-1 41 Scheme 1b: Alternative synthesis scheme for patent examples 5 Scheme 3a: General synthesis of intermediates B Scheme 3b: Alternative synthesis of intermediates B 10 01-3595-WO-1 42 Scheme 3c: Alternative synthesis of intermediates B Intermediate B5 Scheme 4a: General synthesis of intermediates G Scheme 4b: Alternative synthesis of intermediates G 01-3595-WO-1 43 All starting materials not described are either commercially available or described in literature. 5Synthesis of intermediates A1 – A26:Synthesis of intermediates A1, A2, A3 and A9: Step 1: Synthesis of 3-methoxy-1'-methyl-4-nitro-1'H-1,4'-bipyrazole 10 3-Methoxy-4-nitro-1H-pyrazole (350 mg, 2.32 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (322mg, 2.56 mmol) are dissolved in ACN (30 mL) and DCM (30 mL). Copper (II) acetate (127 mg, 0.70 mmol) and pyridine (331 mg, 4.18 mmol) are added, and the reaction mixture is stirred under air at 55 °C for 2h. The reaction mixture is filtered, washed with DCM (10 mL) and the filtrate is evaporated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to15 afford the desired compound. Analysis (method A): Rt: 0.81 min, [M+H] +: 224Step 2: Synthesis of 3-methoxy-1'-methyl-1'H-[1,4'-bipyrazol]-4-amine (intermediate A1) 01-3595-WO-1 44 3-Methoxy-1'-methyl-4-nitro-1'H-1,4'-bipyrazole (73 mg, 0.33 mmol) is dissolved in MeOH (10 mL). Pd / C 10 % (50 mg) is added, and the reaction mixture is hydrogenated at RT and 50 psi (344.738 kPa) for 4 h. The reaction mixture is filtered, 4 M HCl in dioxane (1 mL) is added and the filtrate is 5 evaporated to afford the intermediate A1. Analysis (method B): Rt: 0.57 min, [M+H] +: 194The intermediates compiled in the following table are obtained by following a reaction sequence analogous to that described for intermediate A1 using 3-Methoxy-4-nitro-1H-pyrazole and the10 corresponding boronic acids or boronate esters as starting material. 01-3595-WO-1 45 Synthesis of intermediate A4: Step 1: Synthesis of tert-butyl 3-methoxy-4-nitro-1H-pyrazole-1-carboxylate 5 3-Methoxy-4-nitro-1H-pyrazole (5.00 g, 33.2 mmol) is dissolved in DCM (100 mL). TEA (9.25 mL, 66.4 mmol) and DMAP (203 mg, 1.66 mmol) are added. Then di-tert-butyl dicarbonate (11.0 g, 49.8 mmol)dissolved in DCM (100 mL) is added dropwise and the reaction mixture is stirred at RT overnight. The reaction is washed 3x with 0.1 M and 1x with 1 M HCl. The organic layer is dried and concentrated. The crude residue is purified by flash chromatography (CycH / EtOAc 100 / 0 --> CycH / EtOAc 70 / 30) to10 afford the desired compound. Analysis (method C): Rt: 0.56 min, [M+H] +: 244Step 2: Synthesis of tert-butyl 4-amino-3-methoxy-1H-pyrazole-1-carboxylate (intermediate A4) 15 Tert-butyl 3-methoxy-4-nitro-1H-pyrazole-1-carboxylate (6.88 g, 28.3 mmol) is dissolved in MeOH (50 mL). Pd / C 10 % (700 mg) is added, and the reaction mixture is hydrogenated at RT and 3 bar for 3 h. The reaction mixture is filtered, washed with DCM, and the filtrate is evaporated. The crude residue 01-3595-WO-1 46 is purified by flash chromatography (DCM / MeOH 100 / 0 --> DCM / MeOH 98 / 2) to afford theintermediate A4. Analysis (method D): Rt: 0.41 min, [M+H] +: 2145 Synthesis of intermediate A5: Step 1: Synthesis of 3-methoxy-4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole 3-Methoxy-4-nitro-1H-pyrazole (2.00 g, 14.0 mmol) is dissolved in DCM (20 mL). DIPEA (3.61 mL, 21.0 mmol) is added. After that [2-(chloromethoxy)ethyl]trimethylsilane (2.97 mL, 16.8 mmol) is added 10 dropwise and the reaction mixture is stirred at RT overnight. The reaction is washed with 1 M NaOH (10 mL). The organic layer is dried and concentrated to afford the desired compound. Analysis (method B): Rt: 1.10 min Step 2: Synthesis of 3-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-amine15 (intermediate A5) 3-Methoxy-4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole (3.80 g, 13.9 mmol) is dissolved in MeOH (100 mL). Pd / C 10 % (100 mg) is added, and the reaction mixture is hydrogenated at RT and 50 psi (344.738 kPa) for 2 h. The reaction mixture is filtered, and20 the filtrate is evaporated to afford the intermediate A5. Analysis (method B): Rt: 0.95 min, [M+H] +: 244Synthesis of intermediates A6, A10, A11, A17, A23 and A24: Step 1: Synthesis of 4-(3-methoxy-4-nitro-1H-pyrazol-1-yl)-2-methylbutan-2-ol 01-3595-WO-1 47 3-Methoxy-4-nitro-1H-pyrazole (600 mg, 4.19 mmol) is dissolved in DMF (10 mL). K2CO3(2.89 g, 21.0 mmol) and 4-bromo-2-methylbutan-2-ol (1.40 g, 8.39 mmol) are added, and the reaction mixture is stirred at RT for 2 h. The reaction is purified by reversed phase chromatography (HPLC; 5 ACN / water / NH3) to afford the desired compound. Analysis (method B): Rt: 0.76 min, [M+H] +: 230Step 2: Synthesis of 4-(4-amino-3-methoxy-1H-pyrazol-1-yl)-2-methylbutan-2-ol (intermediate A6) 10 4-(3-Methoxy-4-nitro-1H-pyrazol-1-yl)-2-methylbutan-2-ol (900 mg, 3.93 mmol) is dissolved in MeOH (30 mL). Pd / C 10 % (100 mg) is added, and the reaction mixture is hydrogenated at RT and 50 psi (344.738 kPa) for 2 h. The reaction mixture is filtered, and the filtrate is evaporated to afford the intermediate A6. Analysis (method B): Rt: 0.59 min, [M+H] +: 20015 The intermediates compiled in the following table are obtained by following a reaction sequence analogous to that described for intermediate A6 using 3-Methoxy-4-nitro-1H-pyrazole and thecorresponding alkyl halogenides as starting material. 01-3595-WO-1 48 Synthesis of intermediate A7: Step 1: Synthesis of 1-methyl-4-nitro-2,3-dihydro-1H-pyrazol-3-one 01-3595-WO-1 49 1-Methyl-1H-pyrazol-3-ol (3 g, 30.0 mmol) is added in portions to a concentrated sulfuric acid (40 mL) at – 5 °C. At 0 °C nitric acid (43 mL) is added very slowly dropwise to the reaction, and the reactionmixture is stirred at 0 °C for 2 h. The reaction is poured slowly on ice and water (150 mL) and is 5 stirred at RT. The formed precipitate is filtered, washed with water, and dried in the air to afford the desired compound. Analysis (method B): Rt: injection peak, [M+H] +: 144Step 2: Synthesis of 1-methyl-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole 10 1-Methyl-4-nitro-2,3-dihydro-1H-pyrazol-3-one (300 mg, 2.10 mmol) is dissolved in DMF (3 mL). K2CO3(869 mg, 6.29 mmol) and 3-bromooxetane (359 µL, 4.19 mmol) are added, and the reaction mixture is stirred at 70 °C overnight. Still starting material left. More 3-bromooxetane (1.00 mL, 11.7 mmol) is added, and the reaction mixture is stirred at 85 °C for 4 days. The reaction is purified by15 reversed phase chromatography (HPLC; ACN / water / NH3) to afford the desired compound. Analysis (method B): Rt: 0.62 min, [M+H] +: 200Step 3: Synthesis of 1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-amine (intermediate A7) 01-3595-WO-1 50 1-Methyl-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole (141 mg, 0.71 mmol) is dissolved in MeOH (10 mL). Pd / C 10 % (30 mg) is added, and the reaction mixture is hydrogenated at RT and 3 bar for 3 h. The reaction mixture is filtered, and the filtrate is evaporated to afford the intermediate A7. Analysis (method B): Rt: 0.18 min, [M+H] +: 1705 Synthesis of intermediate A8: Step 1: Synthesis of tert-butyl N-(5-bromo-1-methyl-1H-pyrazol-3-yl)carbamate 5-Bromo-1-methyl-1H-pyrazol-3-amine hydrobromide (2 g, 7.40 mmol), di-tert-butyl dicarbonate 10 (3.55 g, 16.3 mmol), TEA (2.59 mL, 18.5 mmol) and DMAP (5 mg, 0.04 mmol) are dissolved in DCM (30 mL), and the reaction mixture is stirred at RT overnight. The reaction is quenched with water (20 mL) and is concentrated. The crude residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the desired compound. Analysis (method E): Rt: 0.79 min, [M+H-isoButen] +: 220 / 222 (Br)15 Step 2: Synthesis of tert-butyl N-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)carbamate Tert-butyl N-(5-bromo-1-methyl-1H-pyrazol-3-yl)carbamate (0.64 g, 2.32 mmol) is dissolved in dioxane (13 mL). Cyclopropylboronic acid (1.20 g, 13.9 mmol) and K2CO3 (2.40 g, 17.4 mmol) are 20 added, and the mixture is purged with argon. Pd(dppf)Cl2x DCM (0.28 g, 0.35 mmol) is added, and the reaction mixture is stirred at 80 °C for 20 h. After the reaction mixture is cooled to RT, it is filtered, and the filtrate is concentrated. The crude residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the desired compound. Analysis (method E): Rt: 0.77 min, [M+H] +: 23825 Step 3: Synthesis of 5-cyclopropyl-1-methyl-1H-pyrazol-3-amine (intermediate A8) 01-3595-WO-1 51 Tert-butyl N-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)carbamate (0.35 g, 1.48 mmol) is dissolved in dioxane (0.5 mL). HCl in dioxane (4 M, 3.50 mL, 14.0 mmol) is added, and the reaction mixture is stirred at RT for 3 days. The reaction mixture is concentrated to dryness to afford the intermediate 5 A8. Analysis (method E): Rt: 0.28 min, [M+H] +: 138Synthesis of intermediate A12: Step 1: Synthesis of tert-butyl N-(5-bromo-1-methyl-1H-pyrazol-3-yl)carbamate 10 5-Bromo-1-methyl-1H-pyrazol-3-amine hydrobromide (2 g, 7.40 mmol), di-tert-butyl dicarbonate (3.23 g, 14.8 mmol), pyridine (1.79 mL, 22.2 mmol) and DMAP (4 mg, 0.03 mmol) are dissolved in DCM (40 mL), and the reaction mixture is stirred at RT overnight. The reaction is quenched with MeOH (5 mL) and it is stirred at RT for 5 h. Then the reaction mixture is washed with water (20 mL). 15 The organic layer is dried and concentrated. The residue is triturated with n-heptane (10 mL) and is concentrated to dryness to afford the desired compound. Analysis (method E): Rt: 0.81 min, [M+H-isoButen] +: 276 / 278 (Br)Step 2: Synthesis of tert-butyl N-[1-methyl-5-(prop-1-en-2-yl)-1H-pyrazol-3-yl]carbamate 20 Tert-butyl N-(5-bromo-1-methyl-1H-pyrazol-3-yl)carbamate (2.07 g, 7.50 mmol) is dissolved in isopropanol (50 mL). Potassium isopropenyltrifluoroborate (2.26 g, 15.0 mmol) and TEA (5.23 mL, 37.5 mmol) are added, and the mixture is purged with argon. Pd(dppf)Cl2 x DCM (0.92 g, 1.12 mmol) is added, and the reaction mixture is stirred at 80 °C for 18 h. After the reaction mixture is cooled to 01-3595-WO-1 52 RT, it is filtered, and the filtrate is concentrated. The crude residue is purified by flash chromatography (CycH / EtOAc 100 / 0 -->CycH / EtOAc 0 / 100) to afford the desired compound. Analysis (method D): Rt: 0.62 min, [M+H] +: 2385 Step 3: Synthesis of 1-methyl-5-(prop-1-en-2-yl)-1H-pyrazol-3-amine (intermediate A12) Tert-butyl N-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)carbamate (1.49 g, 6.28 mmol) is dissolved in dioxane (7.5 mL). HCl in dioxane (4 M, 7.50 mL, 30.0 mmol) is added, and the reaction mixture is10 stirred at RT for 20 h. The reaction mixture is concentrated to dryness to afford the intermediateA12. Analysis (method D): Rt: 0.32 min, [M+H] +: 138Synthesis of intermediate A13: 15 Step 1: Synthesis of tert-butyl N-[5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl]carbamate 5-(Difluoromethyl)-1-methyl-1H-pyrazole-3-carboxylic acid (1.00 g, 5.39 mmol) is dissolved in t-BuOH (15 mL) and TEA (2.30 mL, 16.4 mmol). Diphenylphosphoryl azide (1.40 mL, 6.49 mmol) is slowly added dropwise over a period of 10 min, and the reaction mixture is stirred at RT for 15 min and at20 80 °C for 3 h and again at RT overnight. The reaction mixture is concentrated, and the crude residue is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the desired compound. Analysis (method E): Rt: 0.56 min, [M+H-isobuten] +: 19225 Step 2: Synthesis of 5-(difluoromethyl)-1-methyl-1H-pyrazol-3-amine (intermediate A13) 01-3595-WO-1 53 Tert-butyl N-[5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl]carbamate (485 mg, 1.96 mmol) isdissolved in dioxane (4 mL). HCl in dioxane (4 M, 6 mL, 24.0 mmol) is added, and the reaction mixture is stirred at RT for 18 h. The reaction mixture is concentrated, triturated with DCM (10 mL) and 5 evaporated to dryness to afford the intermediate A13. Analysis (method D): Rt: 0.21 min, [M+H] +: 148Synthesis of intermediate A14: Step 1: Synthesis of ethyl (1R,2R)-2-(3-methoxy-4-nitro-1H-pyrazol-1-yl)cyclopropane-1-carboxylate 10 3-Methoxy-4-nitro-1H-pyrazole (1 g, 6.64 mmol) and ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)cyclopropane-1-carboxylate (2.48 g, 9.29 mmol) are dissolved in ACN (80 mL). Copper (II) acetate x H2O (1.69 g, 8.03 mmol), potassium phosphate (1 M, 19.9 mL, 19.9 mmol), and 1.10-phenanthroline (1.45 g, 7.97 mmol) are added, and the reaction mixture is stirred under air at 80 °C overnight. The15 reaction mixture is filtered, washed with ACN (10 mL) and the filtrate is evaporated. The residue ispurified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the desired compound. Analysis (method A): Rt: 0.93 min, [M+H] +: 256Step 2: Synthesis of trans-2-(3-methoxy-4-nitro-1H-pyrazol-1-yl)cyclopropane-1-carboxylic acid 20 Ethyl (trans)-2-(3-methoxy-4-nitro-1H-pyrazol-1-yl)cyclopropane-1-carboxylate (850 mg, 3.33 mmol) is dissolved in EtOH (40 mL). NaOH (1 M, 20.0 mL, 20.0 mmol) is added, and the reaction mixture is stirred at 70 °C for 2 h. The reaction mixture is concentrated, and the aqueous residue is slightly 01-3595-WO-1 54 acidified with 1 M HCl. The formed precipitate is filtered, washed with water, and dried in vacuum to afford the desired compound. Analysis (method A): Rt: 0.74 min, [M+H] +: 2285 Step 3: Synthesis of (trans)-2-(3-methoxy-4-nitro-1H-pyrazol-1-yl)-N,N-dimethylcyclopropane-1- carboxamide (trans)-2-(3-methoxy-4-nitro-1H-pyrazol-1-yl)cyclopropane-1-carboxylic acid (540 mg, 2.38 mmol) is dissolved in DMF (10 mL) and DIPEA (822 µL, 4.75 mmol). Dimethylamine 2 M in dioxane (3.57 mL, 10 7.13 mmol) and HATU (904 mg, 2.38 mmol) are added, and the reaction mixture is stirred at RT for 2 h. The reaction is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the desired compound. Analysis (method A): Rt: 0.79 min, [M+H] +: 25515 Step 4: Synthesis of (trans)-2-(4-amino-3-methoxy-1H-pyrazol-1-yl)-N,N-dimethylcyclopropane-1- carboxamide (intermediate A14) (trans)-2-(3-methoxy-4-nitro-1H-pyrazol-1-yl)-N,N-dimethylcyclopropane-1-carboxamide (500 mg, 1.97 mmol) is dissolved in MeOH. Pd / C 10 % (100 mg) is added, and the reaction mixture is 20 hydrogenated at RT and 50 psi (344.738 kPa) for 2 h. The reaction mixture is filtered, and the filtrate is evaporated to afford the intermediate A14. Analysis (method B): Rt: 0.61 min, [M+H] +: 225Synthesis of intermediate A15: 25 Step 1: Synthesis of 2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol 01-3595-WO-1 55 4-Nitro-1H-pyrazole (2.00 g, 17.7 mmol) is dissolved in DMF (20 mL). Cs2CO3 (11.5 g, 35.4 mmol) and 2,2-dimethyloxirane (4.74 mL, 53.1 mmol) are added, and the reaction mixture is stirred at 100 °C for 1.5 h. The reaction mixture is cooled to RT, quenched with water, and extracted three times with 5EtOAc. The combined organic layers are washed two times with brine, dried (Na2SO4), filtered andconcentrated to afford the desired compound. Analysis (method A): Rt: 0.68 min, [M+H] +: 186Step 2: Synthesis of 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol (intermediate A15) 10 2-Methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol (500 mg, 2.70 mmol) is dissolved in MeOH (30 mL). Raney nickel is added, and the reaction mixture is hydrogenated at RT and 3 bar overnight. The reaction mixture is filtered, and the filtrate is evaporated to afford the intermediate A15. Analysis (method B): Rt: 0.18 min, [M+H] +: 15615 Synthesis of intermediate A16: Step 1: Synthesis of 3,5-dibromo-1-[(4-methoxyphenyl)methyl]-1H-pyrazole 3,5-Dibromo-1H-pyrazole (5.00 g, 22.1 mmol) is dissolved in DMF. NaH (60 %, 2.21 g, 55.3 mmol) is20 added, and the reaction mixture is stirred at 0 °C for 20 min. Then 1-(chloromethyl)-4- methoxybenzene (5.20 g, 33.2 mmol) is added at 0 °C and the reaction mixture is stirred at RT overnight. The reaction is quenched at 0 °C with an aqueous saturated solution of NH4Cl and 01-3595-WO-1 56 extracted with EtOAc (3 x 50 mL). The combined organic layers are washed with water (2 x 40 mL) and brine (50 mL), dried (Na2SO4), filtered, and concentrated. The crude residue is purified by flash chromatography (CycH / EtOAc 90 / 10) to afford the desired compound. Analysis (method F): Rt: 1.57 min 5 Step 2: Synthesis of 3-bromo-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-5-carbaldehyde 3,5-Dibromo-1-[(4-methoxyphenyl)methyl]-1H-pyrazole (7.44 g, 21.5 mmol) is dissolved in THF (86 mL). At – 75 °C n-BuLi 2.5 M in hexane (9.50 mL, 23.7 mmol) is added dropwise, and the reaction10 mixture is stirred at – 75 °C for 30 min. DMF (2.10 mL, 26.9 mmol) is added, and the reaction mixtureis stirred at – 75 °C for 30 min, and then allowed to warm to RT. The reaction is quenched with anaqueous saturated solution of NH4Cl and extracted with EtOAc. The organic layer is dried, filtered, and concentrated. The crude residue is purified by flash chromatography (CycH / EtOAc 90 / 10) to afford the desired compound. 15 Analysis (method F): Rt: 1.44 min Step 3: Synthesis of 3-bromo-5-(difluoromethyl)-1-[(4-methoxyphenyl)methyl]-1H-pyrazole 3-Bromo-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-5-carbaldehyde (4.40 g, 14.9 mmol) is dissolved 20 in DCM (60 mL). At 0 °C DAST (5.90 mL, 44.7 mmol) is added dropwise, and the reaction mixture is stirred at 0 °C for 1 h and at RT for 3 h. At 0 °C the reaction is quenched with an aqueous saturated solution of NaHCO3 and extracted with DCM: The organic layer is dried, filtered, and concentrated. The crude residue is purified by flash chromatography (CycH / EtOAc 90 / 10) to afford the desired compound. 25 Analysis (method F): Rt: 1.49 min 01-3595-WO-1 57 Step 4: Synthesis of 5-(difluoromethyl)-1-[(4-methoxyphenyl)methyl]-1H-pyrazol-3-amine (intermediate A16) Under an atmosphere of argon, 3-bromo-5-(difluoromethyl)-1-[(4-methoxyphenyl)methyl]-1H- 5 pyrazole (4.32 g, 13.5 mmol), copper(II) acetylacetonate (0.88 g, 3.37 mmol), and Cs2CO3 (8.79 g, 27.0 mmol) are dissolved in DMF (67 mL). Acetylacetone (0.83 mL, 8.09 mmol) and an aqueous ammonia solution (28 – 30 %) (3.50 mL, 53.9 mmol) are added and the reaction mixture is stirred at 90 °C for24 h. Additional copper(II) acetylacetonate (0.88 g, 3.37 mmol), Cs2CO3(8.79 g, 27.0 mmol), acetylacetone (0.83 mL, 8.09 mmol) and an aqueous ammonia solution (28 – 30 %) (3.50 mL, 53.910 mmol) are added and the reaction mixture is stirred at 90 °C for 24 h. EtOAc is added and the reaction mixture is filtered through a pad of celite. The filtrate is extracted with EtOAc. The organic layer is dried, filtered, and concentrated. The crude residue is purified by flash chromatography (CycH / EtOAc 50 / 50) to afford the intermediate A16. Analysis (method F): Rt: 1.18 min 15 Synthesis of intermediate A18: 3-methoxy-1H-pyrazol-4-amine 3-Methoxy-4-nitro-1H-pyrazole (1.00 g, 6.99 mmol) is dissolved in MeOH (10 mL). Pd / C 10 % (300 mg) is added, and the reaction mixture is hydrogenated at RT and 3 bar for 3 h. The reaction mixture20 is filtered, and the filtrate is evaporated to afford the intermediate A18. Analysis (method B): Rt: 0.13 min, [M+H] +: 114Synthesis of intermediate A19: Step 1: Synthesis of 1-cyclopropyl-2,3-dihydro-1H-pyrazol-3-one 25 01-3595-WO-1 58 Methyl 2-chloroprop-2-enoate (1.00 mL, 9.67 mmol) is dissolved in THF (20 mL) and TEA (2.02 mL, 14.5 mmol) is added. Cyclopropylhydrazine hydrochloride (1.44 g, 12.6 mmol) is added in portions and the reaction mixture is stirred at RT overnight. The reaction is quenched with an aqueous solution of Na2CO32 M (pH 9 – 10) and the THF is concentrated. The reaction mixture is extracted5 with EtOAc (3 x 40 mL), the combined organic layers are dried, filtered, and concentrated. The residue is triturated with diethyl ether, the precipitate is filtered to afford the desired compound. Analysis (method A): Rt: 0.27 min, [M+H] +: 125Step 2: Synthesis of 1-cyclopropyl-4-nitro-2,3-dihydro-1H-pyrazol-3-one 10 1-Cyclopropyl-2,3-dihydro-1H-pyrazol-3-one (440 mg, 3.54 mmol) is dissolved in concentrated sulfuric acid (4 mL). At around – 5 – 0 °C nitric acid (2 mL) is slowly added dropwise, and the reactionmixture is stirred at 0 °C for 30 min. The reaction is quenched with a mixture of ice and water. The formed precipitate is filtered, washed with water, and dried in the air to afford the desired 15 compound. Analysis (method A): Rt: 0.54 min, [M+H] +: 170Step 3: Synthesis of methyl 2-[(1-cyclopropyl-4-nitro-1H-pyrazol-3-yl)oxy]acetate 20 1-Cyclopropyl-4-nitro-2,3-dihydro-1H-pyrazol-3-one (150 mg, 0.89 mmol) is dissolved in DMF (1 mL). K2CO3 (368 mg, 2.66 mmol) and methyl 2-bromoacetate (163 mg, 1.06 mmol) are added and the reaction mixture is stirred at 60 °C for 2 h. The reaction is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the desired compound. Analysis (method A): Rt: 0.84 min, [M+H] +: 24225 Step 4: Synthesis of methyl 2-[(4-amino-1-cyclopropyl-1H-pyrazol-3-yl)oxy]acetate (intermediate A19) 01-3595-WO-1 59 Methyl 2-[(1-cyclopropyl-4-nitro-1H-pyrazol-3-yl)oxy]acetate (136 mg, 0.56 mmol) is dissolved in MeOH (10 mL). Pd / C 10 % (50 mg) is added, and the reaction mixture is hydrogenated at RT and 50 psi (344.738 kPa) for 2 h. The reaction mixture is filtered, and the filtrate is evaporated to afford the 5 intermediate A19. Analysis (method A): Rt: 0.53 min, [M+H] +: 212Synthesis of intermediates A20 and A22: Step 1: Synthesis of 1-methyl-4-nitro-2,3-dihydro-1H-pyrazol-3-one 10 At – 5 °C, 1-methyl-1H-pyrazol-3-ol (3.00 g, 30.0 mmol) is dissolved in concentrated sulfuric acid (40mL) and nitric acid (43 mL) is slowly added dropwise, and the reaction mixture is stirred at 0 °C for 2 h. The reaction is quenched with a mixture of ice and water. The formed precipitate is filtered,washed with water, and dried in the air to afford the desired compound.15 Analysis (method B): Rt: injection peak, [M+H] +: 144Step 2: Synthesis of 2-[(1-methyl-4-nitro-1H-pyrazol-3-yl)oxy]ethan-1-ol 1-Methyl-4-nitro-2,3-dihydro-1H-pyrazol-3-one (250 mg, 1.75 mmol) is dissolved in DMF (3 mL). 20 K2CO3(724 mg, 5.24 mmol) and 2-bromoethan-1-ol (466 µL, 5.24 mmol) are added and the reaction mixture is stirred at 70 °C overnight. The reaction is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the desired compound. Analysis (method B): Rt: 0.45 min, [M+H] +: 18825 Step 3: Synthesis of 2-[(4-amino-1-methyl-1H-pyrazol-3-yl)oxy]ethan-1-ol (intermediate A20) 01-3595-WO-1 60 2-[(1-Methyl-4-nitro-1H-pyrazol-3-yl)oxy]ethan-1-ol (210 mg, 1.12 mmol) is dissolved in MeOH (10mL). Pd / C 10 % (30 mg) is added, and the reaction mixture is hydrogenated at RT and 3 bar for 3 h. The reaction mixture is filtered, and the filtrate is evaporated to afford the intermediate A20. 5Analysis (method B): Rt: injection peak, [M+H] +: 158The intermediates compiled in the following table are obtained by following a reaction sequence analogous to that described for intermediate A20. 10 Synthesis of intermediate A21: Step 1: Synthesis of ethyl (1R,2R)-2-(3-methoxy-4-nitro-1H-pyrazol-1-yl)cyclopropane-1-carboxylate 3-Methoxy-4-nitro-1H-pyrazole (146 mg, 1.00 mmol) and potassium [(trans)-2- (ethoxycarbonyl)cyclopropyl]trifluoroboranuide (324 mg, 1.40 mmol) are dissolved in ACN (10 mL).15Copper (II) acetate x H2O (254 mg, 1.21 mmol), potassium phosphate (1 M, 3.00 mL, 3.00 mmol), and 1.10-phenanthroline (218 mg, 1.20 mmol) are added, and the reaction mixture is stirred under air at 80 °C overnight. The reaction mixture is filtered, washed with ACN (10 mL) and the filtrate is 01-3595-WO-1 61 evaporated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the desired compound. Analysis (method A): Rt: 0.94 min, [M+H] +: 2565 Step 2: Synthesis of ethyl (trans)-2-(4-amino-3-methoxy-1H-pyrazol-1-yl)cyclopropane-1-carboxylate (intermediate A21) Ethyl (trans)-2-(3-methoxy-4-nitro-1H-pyrazol-1-yl)cyclopropane-1-carboxylate (81 mg, 0.32 mmol) is 10 dissolved in MeOH (10 mL). Pd / C 10 % (30 mg) is added, and the reaction mixture is hydrogenated at RT and 50 psi (344.738 kPa) for 2 h. The reaction mixture is filtered, and the filtrate is evaporated to afford the intermediate A21. Analysis (method A): Rt: 0.64, [M+H] +: 22615 Synthesis of intermediate A25: Step 1: Synthesis of 1-(difluoromethyl)-3-methoxy-4-nitro-1H-pyrazole Under an atmosphere of argon, 3-methoxy-4-nitro-1H-pyrazole (1.50 g, 9.96 mmol) is dissolved in ACN (30 mL). KF (1.16 g, 19.9 mmol) and diethyl (bromodifluoromethyl) phosphonate (2.71 g, 9.96 20 mmol) are added, and the reaction mixture is stirred at RT overnight. The reaction mixture is filtered and the filtrate is concentrated. The crude residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the desired compound. Analysis (method E): Rt: 0.61 min, [M+H] +: 19425 Step 2: Synthesis of 1-(difluoromethyl)-3-methoxy-1H-pyrazol-4-amine (intermediate A25) 01-3595-WO-1 62 1-(Difluoromethyl)-3-methoxy-4-nitro-1H-pyrazole (0.76 g, 3.96 mmol) is dissolved in MeOH (15 mL). Raney nickel is added, and the reaction mixture is hydrogenated at RT and 3 bar for 7 h. The reaction mixture is filtered, and the filtrate is evaporated to afford the intermediate A25. 5Analysis (method E): Rt: 0.15, [M+H] +: 164Synthesis of intermediate A26: Step 1: Synthesis of ethyl (trans)-2-(3-methoxy-4-nitro-1H-pyrazol-1-yl)cyclopropane-1-carboxylate 10 3-Methoxy-4-nitro-1H-pyrazole (1.00 g, 6.64 mmol) and ethyl 2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)cyclopropane-1-carboxylate (2.48 g, 9.29 mmol) are dissolved in ACN (80 mL). Copper (II) acetate x H2O (1.69 g, 8.03 mmol), potassium phosphate (1 M, 19.9 mL, 19.9 mmol), and 1.10-phenanthroline (1.45 g, 7.97 mmol) are added, and the reaction mixture is stirred under air at 80 °C overnight. The reaction mixture is filtered, washed with ACN (10 mL) and the filtrate is15 evaporated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the desired compound. Analysis (method A): Rt: 0.93 min, [M+H] +: 256Step 2: Synthesis of (trans)-2-(3-methoxy-4-nitro-1H-pyrazol-1-yl)cyclopropane-1-carboxylic acid 20 Ethyl (trans)-2-(3-methoxy-4-nitro-1H-pyrazol-1-yl)cyclopropane-1-carboxylate (850 mg, 3.33 mmol) is dissolved in EtOH (40 mL). NaOH (1 M, 20.0 mL, 20.0 mmol) is added, and the reaction mixture is stirred at 70 °C for 2 h. The reaction mixture is concentrated, and the aqueous residue is slightly 01-3595-WO-1 63 acidified with 1 M HCl. The formed precipitate is filtered, washed with water, and dried in vacuum to afford the desired compound. Analysis (method A): Rt: 0.74 min, [M+H] +: 2285 Step 3: Synthesis of (trans)-2-(3-methoxy-4-nitro-1H-pyrazol-1-yl)-N- methylcyclopropane-1-carboxamide (trans)-2-(3-methoxy-4-nitro-1H-pyrazol-1-yl)cyclopropane-1-carboxylic acid (500 mg, 2.20 mmol) is dissolved in DMF (10 mL) and DIPEA (761 µL, 4.40 mmol). Methanamine 10 2 M in THF (3.30 mL, 6.60 mmol) and HATU (836 mg, 2.20 mmol) are added, and the reaction mixture is stirred at RT for 2 h. The reaction is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the desired compound. Analysis (method B): Rt: 0.66 min, [M+H] +:15 Step 4: Synthesis of (trans)-2-(4-amino-3-methoxy-1H-pyrazol-1-yl)-N-methylcyclopropane-1- carboxamide (intermediate A26) (trans)-2-(3-methoxy-4-nitro-1H-pyrazol-1-yl)-N-methylcyclopropane-1-carboxamide (370 mg, 1.54 mmol) is dissolved in MeOH. Pd / C 10 % (100 mg) is added, and the reaction mixture is hydrogenated 20 at RT and 50 psi (344.738 kPa) for 2 h. The reaction mixture is filtered, and the filtrate is evaporated to afford the intermediate A26. Analysis (method B): Rt: 0.31 min, [M+H] +: 21125 Synthesis of intermediates B1 – B23:Synthesis of intermediates B1, B3, B5, B6, B7, B8, B9, B10, B11, B15, B16 and B18: 01-3595-WO-1 64 Step 1: Synthesis of 1-bromo-2-(bromomethyl)-3-nitrobenzene 2-Bromo-6-nitrotoluene (50 g, 231 mmol) is dissolved in DCE (300 mL). A suspension of NBS (61.8 g, 347 mmol) in DCE (400 mL) is added at RT and the reaction mixture is stirred at reflux. Then AIBN 5(2.66 g, 16.2 mmol) in DCM (35 mL) is slowly added (syringe pump, pump rate approximately 1 dropper 6 seconds), and the reaction mixture is stirred at reflux overnight. The reaction mixture is concentrated, the residue is dissolved in DCM (500 mL) and washed 3 x with water. The organic layer is dried over MgSO4 and filtered through a short plug of silica, and the silica is washed with DCM (50 ml). The filtrate is concentrated and dried in high vacuum to afford the desired product. 10 TLC: silica gel, CycH / EtOAc 5 / 1: Rf: 0.4 Step 2: Synthesis of 4-(4-{[(2-bromo-6-nitrophenyl)methyl]amino}-3-methoxy-1H-pyrazol-1-yl)-N,N- dimethylbenzamide 15 1-Bromo-2-(bromomethyl)-3-nitrobenzene (350 mg, 1.17 mmol) is dissolved in NMP (10 mL).4-(4- amino-3-methoxy-1H-pyrazol-1-yl)-N,N-dimethylbenzamide hydrochloride (A2) (418 mg, 1.41 mmol) and DIPEA (0.61 mL, 3.52 mmol) are added, and the reaction mixture is stirred at 80 °C for 2 h. The reaction is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the desired compound.20 Analysis (method B): Rt: 1.04 min, [M+H] +: 474Step 3: Synthesis of 4-[4-(4-bromo-2H-indazol-2-yl)-3-methoxy-1H-pyrazol-1-yl]-N,N- dimethylbenzamide (intermediate B1) 01-3595-WO-1 65 4-(4-{[(2-Bromo-6-nitrophenyl)methyl]amino}-3-methoxy-1H-pyrazol-1-yl)-N,N-dimethylbenzamide (290 mg, 0.61 mmol) is dissolved in MeOH (10 mL). Zinc (80.0 mg, 1.22 mmol) is added, a solution of ammonium formate (231 mg, 3.67 mmol) in MeOH (20 mL) is added dropwise, and the reaction 5 mixture is stirred at RT for 2 h. The reaction mixture is concentrated, and the residue is dissolved in DCM (20 mL) and washed with 1 M NaOH. The aqueous layer is extracted again with DCM (2 x 20 mL), and the combined organic layers are dried, filtered, and evaporated to afford the intermediate B1. Analysis (method A): Rt: 1.17 min, [M+H] +: 44010 The intermediates compiled in the following table are obtained by following a reaction sequence analogous to that described for intermediate B1 using 1-bromo-2-(bromomethyl)-3-nitrobenzeneand the corresponding hetaryl amines as starting material. 01-3595-WO-1 66 01-3595-WO-1 67 01-3595-WO-1 68 Synthesis of intermediate B2: Step 1: Synthesis of 1-bromo-2-(bromomethyl)-3-nitrobenzene 5 2-Bromo-6-nitrotoluene (50 g, 231 mmol) is dissolved in DCE (300 mL). A suspension of NBS (61.8 g, 347 mmol) in DCE (400 mL) is added at RT and the reaction mixture is stirred at reflux. Then AIBN (2.66 g, 16.2 mmol) in DCM (35 mL) is slowly added (syringe pump, pump rate approximately 1 drop per 6 seconds), and the reaction mixture is stirred at reflux overnight. The reaction mixture isconcentrated, the residue is dissolved in DCM (500 mL) and washed 3 x with water. The organic layer 10 is dried over MgSO4 and filtered through a short plug of silica, and the silica is washed with DCM (50 ml). The filtrate is concentrated and dried in high vacuum to afford the desired product. TLC: silica gel, CycH / EtOAc 5 / 1: Rf: 0.4 Step 2: Synthesis of N-[(2-bromo-6-nitrophenyl)methyl]-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-15 amine 01-3595-WO-1 69 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine hydrochlorid (2.03 g, 10.1 mmol) and K2CO3 (1.39 g, 10.1 mmol) are dissolved in NMP (40 mL). DIPEA (3.48 mL, 0.020 mmol) and 1-Bromo-2- (bromomethyl)-3-nitrobenzene (2.00 g, 6.71 mmol) are added, and the reaction mixture is stirred at 5 80 °C for 6 h. The reaction is quenched with water and NH4Cl solution. The precipitation is filtered and washed with water. The filtrate is diluted in EtOAc, dried over MgSO4, filtered, and concentrated to afford the desired compound. Analysis (method A): Rt: 1.07 min, [M+H] +: 37910 Step 3: Synthesis of 4-bromo-2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazole (intermediate B2) N-[(2-bromo-6-nitrophenyl)methyl]-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (290 mg, 0.757 mmol) is dissolved in MeOH (15 mL). Zinc (151 mg, 2.27 mmol) is added, a solution of ammonium15 formate (66.8 mg, 1.06 mmol) in MeOH (5 mL) is added dropwise, and the reaction mixture is stirredat RT overnight. Addition of Zinc (75 mg, 1.12 mmol) and a solution of ammonium formate (30 mg, 0.475 mmol) in MeOH is added dropwise and the reaction mixture is stirred at RT for 3h. The reaction mixture is diluted with 20 mL DCM and is filtered through celite, washed with DCM / MeOH 1 / 1 and concentrated. The residue is purified by reversed phase chromatography (HPLC;20ACN / water / NH3) to afford the intermediate B2. Analysis (method A): Rt: 1.15 min, [M+H] +: 345Synthesis of intermediate B4: Step 1: is synthesized by following a procedure analogous to that described for intermediate B1. 25 Step 2: Synthesis of tert-butyl 4-{[(2-bromo-6-nitrophenyl)methyl]amino}-3-methoxy-1H-pyrazole-1- carboxylate 01-3595-WO-1 70 1-Bromo-2-(bromomethyl)-3-nitrobenzene (6.07 g, 20.6 mmol) is dissolved in ACN (50 mL). Tert-butyl 4-amino-3-methoxy-1H-pyrazole-1-carboxylate (A4) (4.39 g, 20.6 mmol) and DIPEA (10.7 mL, 61.8 mmol) are added, and the reaction mixture is stirred at RT overnight. Still starting material left. More 5tert-butyl 4-amino-3-methoxy-1H-pyrazole-1-carboxylate (A4) (0.50 g, 7.04 mmol) is added, and thereaction mixture is stirred at RT for 7 h. The reaction is filtered and purified by flash chromatography (CycH / EtOAc 100 / 0 --> CycH / EtOAc 85 / 15) to afford the desired compound.Analysis (method D): Rt: 0.74 min, [M+H] +: 42710 Step 3: Synthesis of 4-bromo-2-(3-methoxy-1H-pyrazol-4-yl)-2H-indazole Tert-butyl 4-{[(2-bromo-6-nitrophenyl)methyl]amino}-3-methoxy-1H-pyrazole-1-carboxylate (3.25 g, 7.61 mmol) is dissolved in MeOH (25 mL). Zinc (2.49 g, 38.0 mmol) is added, a solution of ammonium formate (480 mg, 7.61 mmol) in MeOH (25 mL) is added dropwise, and the reaction mixture is stirred15 at RT for 5 h. The reaction mixture is quenched at 0 °C with glacial acetic acid until all zinc isdissolved. The residue is dissolved in DCM and washed two times with water. The organic layer is dried, filtered, and evaporated. The crude residue is purified by flash chromatography (DCM / MeOH100 / 0 --> DCM / MeOH 98 / 2) and the concentrated fractions are crystallized with ACN / water to affordthe desired compound.20 Analysis (method D): Rt: 0.62 min, [M+H] +: 293Step 4: Synthesis of 4-bromo-2-[3-methoxy-1-(prop-1-en-2-yl)-1H-pyrazol-4-yl]-2H-indazole (intermediate B4) 01-3595-WO-1 71 4-Bromo-2-(3-methoxy-1H-pyrazol-4-yl)-2H-indazole (209 mg, 0.70 mmol) and potassium isopropenyltrifluoroborate (150 mg, 0.98 mmol) are dissolved in ACN (10 mL). Copper (II) acetate xH2O (178 mg, 0.85 mmol), potassium phosphate (1 M, 2.10 mL, 2.10 mmol), and 1.10-phenanthroline 5 (153 mg, 0.84 mmol) are added, and the reaction mixture is stirred under air at 80 °C overnight. The reaction mixture is filtered, washed with ACN (10 mL) and the filtrate is evaporated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the intermediate B4. Analysis (method B): Rt: 1.19 min, [M+H] +: 33310 Synthesis of intermediate B2DM (mixture of regioisomers): Step 1: 1-Bromo-2-(bromomethyl)-3-nitrobenzene (2.5 g; 8.05 mmol) is dissolved in acetonitrile (50 mL) and 5-(trifluoromethyl)-1H-pyrazol-3-amine (2.56 g, 16 mmol) is added and the mixture stirred for 10 h at 15 80°C. The mixture is concentrated and extracted with water and ethylacetate and the organic phase concentrated and purified via reversed phase chromatography. Analysis (method N): Rt: 0.81 min, [M+H] +: 365Step 2: 20 N-[(2-Bromo-6-nitrophenyl)methyl]-5-(trifluoromethyl)-1H-pyrazol-3-amine (1.7 g; 3 mmol), Zn nanopowder (1.38 g, 21 mmol) and MeOH ( 5 mL) are combined and ammonium formate (0.23 g dissolved in MeOH (5 mL) is added dropwise over 60 min and stirred for 17 h. The mixture is filtered, and the filtrate concentrated. Analysis (method N): Rt: 0.97 min, [M-H] -: 32925 Step 3: 01-3595-WO-1 72 4-Bromo-2-[5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazole (430 mg, 1.23 mmol) is dissolved in DMF (5 mL) and NaH (113 mg, 2.6 mmol) is added at RT and stirred for 15 min. Then 4- methoxybenzyl chloride (0.234 mL, 1.67 mmol) is added and the mixture stirred for 6 h at RT. The mixture is diluted with water and extracted with ethylacetate. The organic phase is concentrated and 5the product purified via silica gel chromatography (CycH / EE gradient 95 / 5 --> 8 / 2) to affordintermediate B2DM Analysis (method N): Rt: 1.18 min and 1.29, [M-H] -: 451 (mixture of regioisomers)10 Synthesis of intermediate B12: Step 1: Synthesis of (E)-1-(2-bromo-6-nitrophenyl)-N-[1-methyl-5-(prop-1-en-2-yl)-1H-pyrazol-3- yl]methanimine 2-Bromo-6-nitrobenzaldehyde (1.25 g, 5.43 mmol), 1-methyl-5-(prop-1-en-2-yl)-1H-pyrazol-3-amine 15 hydrochloride (A12) (1.03 g, 5.69 mmol) and molsieve 3 A are dissolved in MeOH (30 mL), and the reaction mixture is stirred at RT for 21 h. The reaction mixture is filtered, and the filtrate is concentrated to dryness to afford the desired compound. Analysis (method E): Rt: 0.72 min, [M+H] +: 34920 Step 2: Synthesis of 4-bromo-2-[1-methyl-5-(prop-1-en-2-yl)-1H-pyrazol-3-yl]-2H-indazole (intermediate B12) (E)-1-(2-bromo-6-nitrophenyl)-N-[1-methyl-5-(prop-1-en-2-yl)-1H-pyrazol-3-yl] methanimine (2.40 g, 5.43 mmol, 79 % purity) and triethyl phosphite (10 mL) are combined, and the reaction mixture is 25 stirred at 150 °C for 40 min. The reaction mixture is concentrated, and the residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate B12. Analysis (method E): Rt: 1.16 min, [M+H] +: 317 01-3595-WO-1 73 Synthesis of intermediate B13: Step 1: Synthesis of 1-bromo-2-(bromomethyl)-3-nitrobenzene 2-Bromo-6-nitrotoluene (50 g, 231 mmol) is dissolved in DCE (300 mL). A suspension of NBS (61.8 g, 5 347 mmol) in DCE (400 mL) is added at RT and the reaction mixture is stirred at reflux. Then AIBN (2.66 g, 16.2 mmol) in DCM (35 mL) is slowly added (syringe pump, pump rate approximately 1 drop per 6 seconds), and the reaction mixture is stirred at reflux overnight. The reaction mixture is concentrated, the residue is dissolved in DCM (500 mL) and washed 3 x with water. The organic layer is dried over MgSO4 and filtered through a short plug of silica, and the silica is washed with DCM (5010 ml). The filtrate is concentrated and dried in high vacuum to afford the desired product. TLC: silica gel, CycH / EtOAc 5 / 1: Rf: 0.4 Step 2: Synthesis of N-[(2-bromo-6-nitrophenyl)methyl]-5-(difluoromethyl)-1-methyl-1H-pyrazol-3- amine 15 Under an atmosphere of argon, 5-(difluoromethyl)-1-methyl-1H-pyrazol-3-amine hydrochloride (A13) (0.36 g, 1.96 mmol) and DIPEA (1.70 mL, 9.83 mmol) are dissolved in NMP (7 mL).1-Bromo-2- (bromomethyl)-3-nitrobenzene (0.75 g, 2.55 mmol) is added, and the reaction mixture is stirred at 80 °C for 3 h. The reaction mixture is diluted with MeTHF (90 mL) and water (70 mL) and is extracted. 20 The organic layer is washed with water, dried, filtered, and concentrated. The residue is purified by flash chromatography (CycH / EtOAc 100 / 0 --> CycH / EtOAc 30 / 70) to afford the desired compound.Analysis (method E): Rt: 0.85 min, [M+H] +: 361Step 3: Synthesis of 4-bromo-2-[5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl]-2H-indazole25 (intermediate B13) 01-3595-WO-1 74 N-[(2-bromo-6-nitrophenyl)methyl]-5-(difluoromethyl)-1-methyl-1H-pyrazol-3-amine (440 mg, 0.91mmol, 75 % purity) is dissolved in MeOH (10 mL). Zinc (400 mg, 6.12 mmol) is added, a solution of ammonium formate (70 mg, 1.11 mmol) in MeOH (5 mL) is added dropwise over a period of 10 min, 5 and the reaction mixture is stirred at RT for 20 h. More ammonium formate (70 mg, 1.11 mmol) is added, and the reaction mixture is stirred at RT for 3 h. The reaction mixture is diluted with DCM (15 mL) and an aqueous saturated solution of NaHCO3 (0.2 mL) and stirred a few minutes. Then it is filtered, and the filtrate is concentrated. The residue is crystallized with ACN / water (2 mL each) and the precipitate is filtered to afford the intermediate B13.10 Analysis (method E): Rt: 0.98 min, [M+H] +: 327Synthesis of intermediate B14: Step 1: Synthesis of (E)-1-(2-bromo-6-nitrophenyl)-N-[5-(difluoromethyl)-1-[(4- methoxyphenyl)methyl]-1H-pyrazol-3-yl]methanimine 15 2-Bromo-6-nitrobenzaldehyde (1.54 g, 6.71 mmol) and 5-(difluoromethyl)-1-[(4- methoxyphenyl)methyl]-1H-pyrazol-3-amine (A16) (1.70 g, 6.71 mmol) are dissolved in MeOH (34 mL), and the reaction mixture is stirred at 45 °C for 72 h. The reaction mixture is concentrated, and the residue is purified by flash chromatography (CycH / EtOAc 75 / 25) to afford the desired compound.20 Analysis (method F): Rt: 1.54 min, [M+H] +: 465Step 2: Synthesis of 4-bromo-2-[5-(difluoromethyl)-1-[(4-methoxyphenyl)methyl]-1H-pyrazol-3-yl]- 2H-indazole (intermediate B14) 01-3595-WO-1 75 (E)-1-(2-bromo-6-nitrophenyl)-N-[5-(difluoromethyl)-1-[(4-methoxyphenyl)methyl]-1H-pyrazol-3- yl]methanimine (2.50 g, 4.03 mmol, 75 % purity) and triethyl phosphite (17 mL) are combined, and the reaction mixture is stirred at 150 °C for 40 min in the microwave. The reaction mixture is 5concentrated, and the residue by flash chromatography (CycH / EtOAc 85 / 15) to afford theintermediate B14. Analysis (method F): Rt: 1.72 min Synthesis of intermediate B17:10 Step 1 - 3: is synthesized by following a procedure analogous to that described for intermediate B4.Step 4: Synthesis of 4-bromo-2-[1-(2,5-dihydrofuran-3-yl)-3-methoxy-1H-pyrazol-4-yl]-2H-indazole (intermediate B17) 15 4-Bromo-2-(3-methoxy-1H-pyrazol-4-yl)-2H-indazole (209 mg, 0.70 mmol) and 2-(2,5-dihydrofuran-3- yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (202 mg, 0.98 mmol) are dissolved in ACN (10 mL). Copper (II) acetate x H2O (178 mg, 0.85 mmol), potassium phosphate (1 M, 2.10 mL, 2.10 mmol), and 1.10-phenanthroline (153 mg, 0.84 mmol) are added, and the reaction mixture is stirred under air at 80 °C overnight. The reaction mixture is filtered, washed with ACN (10 mL) and the filtrate is20 evaporated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate B17. Analysis (method A): Rt: 1.16 min, [M+H] +: 361Synthesis of intermediate B19: 25 Step 1: Synthesis of (E)-1-(2-bromo-3-fluoro-6-nitrophenyl)-N-(3-methoxy-1H-pyrazol-4- yl)methanimine 01-3595-WO-1 76 2-Bromo-3-fluoro-6-nitrobenzaldehyde (600 mg, 2.30 mmol), 3-methoxy-1H-pyrazol-4-amine hydrochloride (A18) (344 mg, 2.30 mmol) and molecular sieve 4 A are dissolved in MeOH (18 mL) and the reaction mixture is stirred at RT for 72 h. The formed precipitate is filtered, washed with DMF, 5 and the filtrate is concentrated to afford the desired compound. Analysis (method B): Rt: 0.85 min, [M+H] +: 343Step 2: Synthesis of 4-bromo-5-fluoro-2-(3-methoxy-1H-pyrazol-4-yl)-2H-indazole 10 (E)-1-(2-bromo-3-fluoro-6-nitrophenyl)-N-(3-methoxy-1H-pyrazol-4-yl)methanimine (594 mg, 1.73 mmol) and triethyl phosphite (4 mL) are combined, and the reaction mixture is stirred at 150 °C for 60 min in the microwave. The reaction mixture is concentrated, and the residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA). To get the free base, it is dissolved in DCM and washed with a mixture of an aqueous solution of NaHCO3 and Na2CO3. The organic layer is dried,15 filtered and evaporated to afford the desired compound. Analysis (method A): Rt: 0.93 min, [M+H] +: 311Step 3: Synthesis of 4-bromo-2-(1-cyclopropyl-3-methoxy-1H-pyrazol-4-yl)-5-fluoro-2H-indazole (intermediate B19) 20 4-Bromo-5-fluoro-2-(3-methoxy-1H-pyrazol-4-yl)-2H-indazole (256 mg, 0.79 mmol) and cyclopropylboronic acid (136 mg, 1.58 mmol) are dissolved in ACN (4 mL) and DCE (4 mL). Copper (II) acetate (146 mg, 0.79 mmol) and Cs2CO3 (1.03 g, 3.16 mmol) are added, and the reaction mixture is stirred under air at 70 °C overnight. The reaction mixture is filtered, washed with DMF and the 01-3595-WO-1 77 filtrate is evaporated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the intermediate B19. Analysis (method B): Rt: 1.04 min, [M+H] +: 3515 Synthesis of intermediate B20: Step 1: Synthesis of N-(2-amino-3-bromophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3- carboxamide 1-Methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (400 mg, 1.96 mmol) is dissolved in DMF10 (15 mL) and DIPEA (0.85 mL, 4.89 mmol). HATU (968 mg, 2.55 mmol) and 3-bromobenzene-1,2- diamine (415 mg, 2.15 mmol) are added, and the reaction mixture is stirred at RT overnight. The reaction is quenched with water and the formed precipitate is filtered and dried to afford the desired compound. Analysis (method A): Rt: 0.92 min, [M+H] +: 36315 Step 2: Synthesis of 4-bromo-2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-1H-1,3-benzodiazole (intermediate B20) N-(2-amino-3-bromophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide (620 mg, 1.62 20 mmol) is dissolved in glacial acetic acid (10 mL) and it is stirred at 105 °C for 2 h. The reaction mixture is quenched with water and extracted three times with EtOAc. The combined organic layers are washed with water, an aqueous saturated solution of NaHCO3 and brine, dried, filtered, and concentrated to afford the intermediate B20. 25 Synthesis of intermediate B22: 01-3595-WO-1 78 Step 1: Synthesis of (E)-1-(2-bromo-6-nitrophenyl)-N-[5-(difluoromethyl)-1H-pyrazol-3- yl]methanimine 2-Bromo-6-nitrobenzaldehyde (1.22 g, 5.32 mmol) and 5-(difluoromethyl)-1H-pyrazol-3-amine (7455 mg, 5.32 mmol) are dissolved in MeOH (20 mL), and the reaction mixture is stirred at RT for 72 h. The reaction mixture is concentrated. Analysis (method D): Rt: 0.54 min, [M+H] +: 345Step 2: Synthesis of 4-bromo-2-[5-(difluoromethyl)-1H-pyrazol-3-yl]-2H-indazole 10 (E)-1-(2-bromo-6-nitrophenyl)-N-[5-(difluoromethyl)-1H-pyrazol-3-yl]methanimine (1.80 g, 4.69mmol) and triethyl phosphite (17 mL) are combined, and the reaction mixture is stirred at 150 °C for 40 min in the microwave. The reaction mixture is concentrated, and the residue is quenched with ACN / water and the formed precipitate is filtered and dried to afford the desired compound. 15 The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA). Analysis (method C): Rt: 0.58 min, [M+H] +: 313Step 3: Synthesis of 2-[3-(4-bromo-2H-indazol-2-yl)-5-(difluoromethyl)-1H-pyrazol-1-yl]acetamide (intermediate B22) 20 01-3595-WO-1 79 4-bromo-2-[5-(difluoromethyl)-1H-pyrazol-3-yl]-2H-indazole (200 mg, 0.638 mmol) is dissolved in DMF (4 mL). Cesium carbonate (208 mg, 0.638 mmol) and 2-bromoacetamide (88 mg, 0.638 mmol) are added and the reaction mixture is stirred at RT for 2 h. The reaction mixture is diluted with water and DCM and is extracted. The product ist unsoluble in 5 both layers. The product is separated and diluted in methanol and concentrated. the residue is purified by flash chromatography (CycH / EtOAc 100 / 0 to 0 / 100 then EtOAc / MeOH 100 / 0 to 95 / 5) toafford the intermediate B22. Analysis (method C): Rt: 0.54 min, [M+H] +: 37010 Synthesis of intermediate B23: Step 1: Synthesis of ethyl (trans)-2-{4-[(E)-[(2-bromo-6-nitrophenyl)methylidene]amino]-3-methoxy- 1H-pyrazol-1-yl}cyclopropane-1-carboxylate 2-Bromo-6-nitrobenzaldehyde (0.52 g, 2.18 mmol), ethyl (1R,2R)-2-(4-amino-3-methoxy-1H-pyrazol- 15 1-yl)cyclopropane-1-carboxylate (A21) (504 mg, 1.46 mmol) and molecular sieve 3A are dissolved in MeOH (10 mL), and the reaction mixture is stirred at RT for 16 h. Addition of acetic acid and the reaction mixture is concentrated to dryness to afford the desired compound. Analysis (method D): Rt: 0.78 min, [M+H] +: 43720 Step 2: Synthesis of ethyl (trans)-2-[4-(4-bromo-2H-indazol-2-yl)-3-methoxy-1H-pyrazol-1- yl]cyclopropane-1-carboxylate (intermediate B23) Ethyl (trans)-2-{4-[(E)-[(2-bromo-6-nitrophenyl)methylidene]amino]-3-methoxy-1H-pyrazol-1- yl}cyclopropane-1-carboxylate (1.40 g, 1.46 mmol) and triethyl phosphite (5 mL) are combined, and 25 the reaction mixture is stirred at 150 °C for 1h. The reaction mixture is concentrated, and the residue 01-3595-WO-1 80 is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the intermediate B23. Analysis (method D): Rt: 0.84 min, [M+H] +: 4055 Synthesis of intermediates C1 – C27:Synthesis of 4-{3-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]-1H- pyrazol-1-yl}-N,N-dimethylbenzamide (C1) 10 4-[4-(4-Bromo-2H-indazol-2-yl)-3-methoxy-1H-pyrazol-1-yl]-N,N-dimethylbenzamide (B1) (113 mg, 0.26 mmol) is dissolved in dioxane (10 mL). Bis(pinacolato)diboron (84.7 mg, 0.33 mmol) and potassium acetate (75.6 mg, 0.77 mmol) are added, and the mixture is purged with argon. Pd(dppf)Cl2x DCM (20.9 mg, 0.03 mmol) is added, and the reaction mixture is stirred at 100 °C for 2 15 h. After the reaction mixture is cooled to RT the formed precipitate is filtered and washed with dioxane (5 mL). The filtrate is concentrated to afford the desired intermediate C1.Analysis (method A): Rt: 1.20 min, [M+H] +: 488Synthesis of {2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazol-4-yl}boronic acid (C2) 20 4-Bromo-2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazole (B2) (308 mg, 0.89 mmol) is dissolved in dioxane (10 mL). Bis(neopentyl glycolato)diboron (302 mg, 1.34 mmol) and potassium acetate (263 mg, 2.68 mmol) are added, and the mixture is purged with argon. Pd(dppf)Cl2 x DCM (193 mg, 0.24 mmol) is added, and the reaction mixture is stirred at 100 °C for 2.5 h. After the 25 reaction mixture is cooled to RT the formed precipitate is filtered and washed with dioxane. The filtrate is concentrated, and the residue is purified by reversed phase chromatography (HPLC;ACN / water / TFA) to afford the intermediate C2. 01-3595-WO-1 81 Analysis (method A): Rt: 0.88 min, [M+H] +: 311Synthesis of 2-[5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl]-4-(5,5-dimethyl-1,3,2-dioxaborinan-2- yl)-2H-indazole (C15) 5 4-bromo-2-[5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl]-2H-indazole (B13) (80 mg, 0.23 mmol) is dissolved in dioxane (2 mL). Bis(neopentyl glycolato)diboron (75 mg, 0.32 mmol) and potassium acetate (75 mg, 0.76 mmol) are added, and the mixture is purged with argon. Pd(dppf)Cl2 x DCM (23.0 mg, 0.03 mmol) is added, and the reaction mixture is stirred at 90 °C for 4 h. After the reaction 10 mixture is cooled to RT, it is diluted with DCM (20 mL) and is washed with water (10 mL). The organic layer is dried, filtered and concentrated to afford the intermediate C15. Analysis (method E): Rt: 0.63 min, [M+H] +: 293 (boronic acid)The intermediates compiled in the following table are obtained by following a reaction sequence15 analogous to that described for intermediate C1 or C2 or C15. 01-3595-WO-1 82 01-3595-WO-1 83 01-3595-WO-1 84 01-3595-WO-1 85 01-3595-WO-1 86 01-3595-WO-1 87 Synthesis of intermediate C6: Synthesis of 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3- yl]-2H-indazole (C6) 01-3595-WO-1 88 4-Bromo-2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazole (B2) (3.22 g, 9.09 mmol) isdissolved in dioxane (40 mL). Bis(neopentyl glycolato)diboron (3.08 g, 13.6 mmol) and potassium acetate (2.67 g, 27.3 mmol) and Pd(dppf)Cl2 x DCM (1.00 g, 1.22 mmol) are added, and the mixture is 5 purged with argon. The reaction mixture is stirred at 95 °C for 1.25 h. After the reaction mixture is cooled to RT, ACN is added, and the precipitation is filtered. The residue is dissolved in DCM / MeOH, filtered, and concentrated. The residue is dissolved in ACN / water / TFA and the precipitation is filtered to afford the intermediate C6. Analysis (method A): Rt: 0.74 min, [M+H] +: 311 (boronic acid)10 Synthesis of intermediate C6DM: Synthesis of 2-{1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)pyrazol-3-yl}-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)indazole and 2-{2-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)pyrazol-3-yl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (intermediate C13) B2DM 15 4-Bromo-2-{1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)pyrazol-3-yl}indazole (B2DM) (550 mg, 1.29 mmol) is dissolved in acetonitril (10 mL). Bis(pinacolato)diboron (625 mg, 2.44 mmol) andpotassium pivalate (540 mg, 3.7 mmol) are added, and the mixture is purged with argon. Pd(dppf)Cl2 x DCM (100 mg, 0.12 mmol) is added, and the reaction mixture is stirred at 80 °C for 3 h. After the 20 reaction mixture is cooled to RT the reaction mixture is. extracted with EtOAc and water. The organic layer is dried over to afford the intermediate C6DM. Analysis (method E): Rt: 1.00 and 1.25 min 01-3595-WO-1 89 Synthesis of intermediates D1 – D6:5 Synthesis of intermediate D1: Step 1: Synthesis of 5-cyclopropyl-1-methyl-1H-imidazole 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 10 mmol) are mixed together, and the reaction mixture is stirred at 70 °C for 20 h. The reaction mixture is concentrated, and the residue is purified by flash chromatography (DCM / MeOH 100 / 0 --> DCM / MeOH 90 / 10) to afford the desired product. Analysis (method D): Rt: 0.31 min, [M+H] +: 12315 Step 2: Synthesis of 5-cyclopropyl-1, 2-dimethyl-1H-imidazole Under an argon atmosphere, 5-cyclopropyl-1-methyl-1H-imidazole (1.00 g, 8.12 mmol) is dissolved in THF (15.00 mL) and cooled to -78°C. n-BuLi (6.14 mL, 9.81 mmol, 1.6 M) is added dropwise and thereaction mixture is stirred at -78°C for 30 min. Then MeI (663 µL, 10.6 mmol) is added dropwise and 20 the reaction mixture is stirred at -78°C for 1 h. The reaction mixture is quenched with a half saturated NH4Cl solution and stirred for 10 min.2 mL of aqueous NH4OH (25 %) is added and the mixture is stirred for 30 min. The layers are separated, and the aqueous layer is extracted 3x with EtOAc. The combined organic layers are dried (Na2SO4), filtered and evaporated to afford the desired compound. Analysis (method B): Rt: 0.72 min, [M+H] +: 13725 Step 3: Synthesis of 1-cyclopropyl-2-(5-cyclopropyl-1-methyl-1H-imidazol-2-yl) ethan-1-one (intermediate D1) 01-3595-WO-1 90 5-Cyclopropyl-1, 2-dimethyl-1H-imidazole (700 mg, 5.14 mmol) is dissolved in THF (7 mL). At -78 °C n- BuLi (6.42 mL, 10.3 mmol, 1.6 M) is added dropwise and the reaction mixture is stirred 30 min at -78 °C. Then ethyl cyclopropane carboxylate (1.10 mL, 9.25 mmol) is added dropwise, and the reaction5 mixture is stirred at -78 °C for 30 min and then allowed to reach RT. The reaction mixture is quenched with a saturated NH4Cl solution and extracted 3 x with DCM / IPA 8 / 2. The combined organic layers are dried (Na2SO4), filtered, and concentrated to afford the intermediate D1. Analysis (method D): Rt: 0.45 min, [M+H] +: 20510 Synthesis of intermediate D2: Step 1: Synthesis of 5-cyclopropyl-1-methyl-1H-imidazole 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 15 mmol) are mixed together, and the reaction mixture is stirred at 70 °C for 20 h. The reaction mixture is concentrated, and the residue is purified by flash chromatography (DCM / MeOH 100 / 0 --> DCM / MeOH 90 / 10) to afford the desired product. Analysis (method D): Rt: 0.31 min, [M+H] +: 12320 Step 2: Synthesis of 5-cyclopropyl-1, 2-dimethyl-1H-imidazole Under an argon atmosphere, 5-cyclopropyl-1-methyl-1H-imidazole (1.00 g, 8.12 mmol) is dissolved in THF (15.00 mL) and cooled to -78°C. n-BuLi (6.14 mL, 9.81 mmol, 1.6 M) is added dropwise and the reaction mixture is stirred at -78°C for 30 min. Then MeI (663 µL, 10.6 mmol) is added dropwise and 25 the reaction mixture is stirred at -78°C for 1 h. The reaction mixture is quenched with a half saturated NH4Cl solution and stirred for 10 min.2 mL of aqueous NH4OH (25 %) is added and the mixture is 01-3595-WO-1 91 stirred for 30 min. The layers are separated, and the aqueous layer is extracted 3x with EtOAc. The combined organic layers are dried (Na2SO4), filtered and evaporated to afford the desired compound. Analysis (method B): Rt: 0.72 min, [M+H] +: 1375 Step 3: Synthesis of 1-(5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-3-methylbutan-2-one (intermediate D2) 5-Cyclopropyl-1, 2-dimethyl-1H-imidazole (2.55 g, 18.7 mmol) is dissolved in THF (120 mL). At -78 °C n-BuLi (17.5 mL, 28.1 mmol, 1.6 M) is added dropwise and the reaction mixture is stirred 1 h at -78 10 °C. Then methylisobutyrate (3.54 mL, 28.1 mmol) is added dropwise, and the reaction mixture is stirred at -78 °C for 1 h. The reaction mixture is quenched with a saturated NH4Cl solution and extracted 3x EtOAc. The combined organic layers are dried (Na2SO4), filtered and concentrated and purified by silica gel chromatography (DCM / MeOH 100 / 0 --> DCM / MeOH 94 / 4) to afford the desiredintermediate D2.15 Analysis (method D): Rt: 0.45 min, [M+H] +: 207Synthesis of intermediate D3: Step 1: Synthesis of 5-cyclopropyl-1-methyl-1H-imidazole 20 Under an argon atmosphere, 5-bromo-1-methyl-1H-imidazole (7.50 g, 46.6 mmol), cyclopropylzinc bromide (132 mL, 65.90 mmol, 0.5 M in THF) and Pd(dppf)Cl2 (2.20 g, 3.01 mmol) are mixed together, and the reaction mixture is stirred at 70 °C for 20 h. The reaction mixture is concentrated, and the residue is purified by flash chromatography (DCM / MeOH 100 / 0 à DCM / MeOH 90 / 10) to afford the desired product.25 Analysis (method D): Rt: 0.31 min, [M+H] +: 123Step 2: Synthesis of 5-cyclopropyl-1, 2-dimethyl-1H-imidazole 01-3595-WO-1 92 Under an argon atmosphere, 5-cyclopropyl-1-methyl-1H-imidazole (1.00 g, 8.12 mmol) is dissolved in THF (15.00 mL) and cooled to -78°C. n-BuLi (6.14 mL, 9.81 mmol, 1.6 M) is added dropwise and the reaction mixture is stirred at -78°C for 30 min. Then MeI (663 µL, 10.6 mmol) is added dropwise and 5 the reaction mixture is stirred at -78°C for 1 h. The reaction mixture is quenched with a half saturated NH4Cl solution and stirred for 10 min.2 mL of aqueous NH4OH (25 %) is added and the mixture is stirred for 30 min. The layers are separated, and the aqueous layer is extracted 3x with EtOAc. The combined organic layers are dried (Na2SO4), filtered and evaporated to afford the desired compound. Analysis (method B): Rt: 0.72 min, [M+H] +: 13710 Step 3: Synthesis of methyl 2-[(tert-butyldimethylsilyl)oxy]acetate Methyl 2-hydroxyacetate (3.00 mL, 39.3 mmol) is dissolved in THF (30 mL). At 0 °C 2,6-lutidine (13.0 mL, 112 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (23.2 mL, 100 mmol) are added15 dropwise, and the reaction mixture is stirred at 0 °C for 1h and at RT for 1 h. The reaction mixture isdiluted with DCM and washed 2x with 1 M HCl and 1x with an aqueous saturated solution of NaHCO3. The organic layer is dried, filtered, and concentrated. The residue is purified by flash chromatography (CycH / EtOAc 95 / 5 --> CycH / EtOAc 80 / 20) to afford the desired compound.Analysis (TLC silica CycH / EtOAc 9 / 1): Rf: 0.54 20 Step 4: Synthesis of 1-[(tert-butyldimethylsilyl)oxy]-3-(5-cyclopropyl-1-methyl-1H-imidazol-2- yl)propan-2-one (intermediate D3) 5-Cyclopropyl-1, 2-dimethyl-1H-imidazole (3.18 g, 23.3 mmol) is dissolved in THF (45 mL). At - 75 °C25 n-BuLi (17.5 mL, 28.0 mmol, 1.6 M) is added dropwise and the reaction mixture is stirred at - 75 °Cfor 15 min. Then methyl 2-[(tert-butyldimethylsilyl)oxy]acetate (6.19 g, 30.3 mmol) dissolved in THF (30 mL) is added dropwise, and the reaction mixture is stirred at - 75 °C for 1 h. The reaction mixture 01-3595-WO-1 93 is quenched with a half saturated NH4Cl solution and extracted 2x EtOAc. The combined organic layers are dried (Na2SO4), filtered and concentrated to afford the desired intermediate D3. Analysis (method A): Rt: 0.78 min, [M+H] +: 3095 Synthesis of intermediate D4: Step 1: Synthesis of 5-cyclopropyl-1-methyl-1H-imidazole Under an argon atmosphere, 5-bromo-1-methyl-1H-imidazole (7.50 g, 46.6 mmol), cyclopropyl zinc bromide (132 mL, 65.9 mmol, 0.5 M in THF) and Pd(dppf)Cl2(2.20 g, 3.01 mmol) are mixed together, 10 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 thedesired compound. Analysis (method D): Rt: 0.31 min, [M+H] +: 12315 Step 2: Synthesis of 2, 4-dibromo-5-cyclopropyl-1-methyl-1H-imidazole (intermediate D4) 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 at20 RT for 4 h. The reaction mixture is quenched by the addition of a saturated Na2S2O3solution (40.7 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 intermediate D4.Analysis (method E): Rt: 0.77 min, [M+H] +: 27925 Synthesis of intermediate D5: Step 1: Synthesis of 5-cyclopropyl-1-methyl-1H-imidazole-2-carbaldehyde 01-3595-WO-1 94 Under an argon atmosphere, 5-cyclopropyl-1-methyl-1H-imidazole (6.30 g, 51.6 mmol) is dissolved in THF (63 mL). At – 78 °C n-BuLi (38.7 mL, 61.9 mmol, 1.6 M) is added dropwise and the reactionmixture is stirred at – 78 °C for 1 h. Then DMF (5.03 mL, 61.9 mmol) is added dropwise, and thereaction mixture is stirred at –78 °C for 30 min. The reaction mixture is quenched with a saturated 5 NH4Cl solution and water. Then it is extracted 3x with diethyl ether. The combined organic layers are dried (Na2SO4), filtered and concentrated to afford the product which is used in the next step without further purification. Analysis (method D): Rt: 0.35 min, [M+H] +: 15110 Step 2: Synthesis of 4-bromo-5-cyclopropyl-1-methyl-1H-imidazole-2-carbaldehyde 5-Cyclopropyl-1-methyl-1H-imidazole-2-carbaldehyde (17.8 g, 94.8 mmol) is dissolved in DCM (300 mL). At 0 °C NBS (16.9 g, 94.8 mmol) is added, and the reaction mixture is stirred at 0 °C for 1 h. The reaction mixture is washed with a 0.5 M solution of Na2S2O3, water and brine. The organic layer is 15 dried (Na2SO4), filtered, and concentrated. The residue is purified by flash chromatography (CycH / EtOAc 100 / 0 --> CycH / EtOAc 50 / 50) to afford the desired compound.Analysis (method D): Rt: 0.49 min, [M+H] +: 229 / 231 (Br)Step 3: Synthesis of 4-bromo-5-cyclopropyl-1-methyl-2-[(1E)-2-nitrobut-1-en-1-yl]-1H-imidazole 20 4-Bromo-5-cyclopropyl-1-methyl-1H-imidazole-2-carbaldehyde (10.1 g, 40.7 mmol) is dissolved in nitropropane (18.1 mL, 203 mmol). Ammonium acetate (6.27 g, 81.4 mmol) is added, and the reaction mixture is stirred at 60 °C for 4 d. The reaction mixture is quenched with a half saturated NaCl solution and is extracted 3 x with EtOAc. The combined organic layers are dried (Na2SO4), 25 filtered and concentrated to afford the product which is used without further purification in the next step. Analysis (method D): Rt: 0.76 min, [M+H] +: 300 / 302 (Br) 01-3595-WO-1 95 Step 4: Synthesis of 1-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl) butan-2-one (intermediate D5) Iron powder (11.2 g, 0.20 mol) is suspended in acetic acid (150 mL) and the mixture is heated to 60 5 °C.4-Bromo-5-cyclopropyl-1-methyl-2-[(1E)-2-nitrobut-1-en-1-yl]-1H-imidazole (12.0 g, 0.04 mol) in acetic acid (50 mL) is added slowly dropwise and the reaction mixture is stirred at 60 °C for 1.5 h and at 70 °C for 2 h. The hot reaction mixture is filtered, and the solids are washed with acetic acid. The filtrate is diluted with EtOAc and basified with a 2 M solution of Na2CO3. Charcoal is added and thereaction mixture is filtered through celite. The layers are separated, and the organic layer is dried 10 (Na2SO4), filtered, and concentrated. The residue is purified by flash chromatography (CycH / EtOAc 20 / 80 --> CycH / EtOAc 0 / 100) to afford the intermediate D5.Analysis (method E): Rt: 0.46 min, [M+H] +: 271 / 273 (Br)Synthesis of intermediate D6:15 Step 1 - 2: are synthesized by following a procedure analogous to that described for intermediate D1.Step 3: Synthesis of 1-(5-cyclopropyl-1-methyl-1H-imidazol-2-yl)propan-2-one (intermediate D6) 5-Cyclopropyl-1, 2-dimethyl-1H-imidazole (4.00 g, 29.4 mmol) is dissolved in THF (80 mL). At -78 °C n- 20 BuLi (15.0 mL, 37.5 mmol, 2.5 M) is added dropwise and the reaction mixture is stirred 20 min at -78 °C. Then ethyl acetate (10.0 mL, 102 mmol) is added dropwise, and the reaction mixture is stirred at RT for 10 min. The reaction mixture is quenched with a 10 % NH4Cl solution (100 mL), the THF is concentrated, and the aqueous residue is extracted 3 x with EtOAc. The combined organic layers are washed with brine, dried (Na2SO4), filtered, and concentrated to afford the intermediate D6.25 Analysis (method B): Rt: 0.70 min, [M+H] +: 179Synthesis of intermediates E1 and E2: 01-3595-WO-1 96 Synthesis of 3-amino-1-methyl-1H-pyrazole-4-carbaldehyde (intermediate E1): DIBALH in hexane 1M (515 mL, 0.52 mol) is added slowly to a suspension of 3-amino-1-methyl-1H- 5 pyrazole-4-carbonitrile (21.6 g, 0.18 mol) in toluene (432 mL) at -78 °C under argon. After addition the solution is stirred for 20 min and then warmed to RT. The reaction mixture is slowly poured at 0 °C into 4 M HCl aq. (177 mL, 0.71 mol) and stirred for 1 h. The pH is adjusted with potassium carbonate to pH ~9, and the mixture is extracted with IPA / DCM 25 / 75 (1750 mL) and concentrated to yield intermediate E1. 101H-NMR (DMSO-d6, 300 MHz): d = 9.61 (1H, s), 8.03 (1H, s), 5.66 (2H, s, br), 3.64 (3H, s) Synthesis of intermediate E2: Step 1: Synthesis of ethyl 3-amino-1-[(4-methoxyphenyl) methyl]-1H-pyrazole-4-carboxylate 15 A solution of NaOEt is prepared (using 4.08 g Na (177 mmol) and 100 mL of EtOH) to which [(4-methoxyphenyl) methyl] hydrazine hydrochloride (11.2 g, 59.1 mmol) is added. Then a solution of ethyl (2Z)-2-cyano-3-ethoxyprop-2-enoate (10.0 g, 59.1 mmol) in THF (50 mL) is added dropwise over 45 min at 0 °C under Argon. The reaction mixture is stirred at 0 °C for 90 min. The reaction mixture is quenched with 4 M HCl in dioxane (29.6 mL, 118 mmol) and concentrated to dryness. Then the 20 residue is dissolved in EtOAc and washed with an aqueous saturated solution of NaHCO3. The aqueous layer is extracted with EtOAc. The combined organic layers are dried (Na2SO4), filtered and concentrated to afford the product. Analysis (method I): Rt: 1.55 min, [M-H] -: 27425 Step 2: Synthesis of {3-amino-1-[(4-methoxyphenyl) methyl]-1H-pyrazol-4-yl} methanol 01-3595-WO-1 97 Ethyl 3-amino-1-[(4-methoxyphenyl) methyl]-1H-pyrazole-4-carboxylate (16.3 g, 56.3 mmol, 95 % purity) is dissolved in THF (81.5 mL), and at -7 °C LiAlH4(2 M in THF, 28.1 mL, 56.3 mmol) is added dropwise over 30 min. The reaction mixture is stirred at RT for 3 h. The reaction mixture is quenched 5 with 2 V of THF / H2O 8 / 2 and 1 V of aq. sat. Na2SO4 solution and stirred 30 min at RT. The reaction mixture is filtered through Celite and washed with MeOH and DCM / MeOH. The filtrate is dried (Na2SO4), filtered, concentrated and co-evaporated with toluene to afford the product. Analysis (method I): Rt: 1.34 min, [M+H] +: 23410 Step 3: Synthesis of 3-amino-1-[(4-methoxyphenyl) methyl]-1H-pyrazole-4-carbaldehyde (intermediate E2) {3-Amino-1-[(4-methoxyphenyl) methyl]-1H-pyrazol-4-yl} methanol (13.1 g, 50.5 mmol, 90 % purity) is dissolved in ACN (131 mL) and water (26.2 mL), then MnO2 (34.2 g, 354 mmol) is added, and the 15 reaction mixture is stirred at RT for 2 h. The reaction mixture is filtered through Celite and washed with DCM / acetone. The filtrate is concentrated to dryness and the residue is triturated with MTBE to afford the intermediate E2. TLC: silica gel, DCM / MeOH 95 / 5: Rf: 0.55Analysis (method I): Rt: 1.55 min 20 Synthesis of intermediates F1 – F6:Synthesis of intermediate F1: Step 1: Synthesis of [(2-bromo-6-nitrophenyl)methoxy](tert-butyl)dimethylsilane 01-3595-WO-1 98 (2-Bromo-6-nitrophenyl)methanol (25.0 g, 108 mmol) is dissolved in DCM (250 mL). Imidazole (14.7g, 215 mmol) and TBDMS-Cl (24.4 g, 162 mmol) are added, and the reaction mixture is stirred at RT for 1 h. The solids are filtered off, washed with DCM (100 mL) and the filtrate is concentrated. The 5 residue is diluted with water (250 mL) and extracted with EtOAc (2 x 250 mL). The combined organic layers are washed with 1 M HCl aq. (250 mL) and brine (250 mL), dried, filtered, and concentrated. The crude residue is filtered with CycH through a pad of silica and washed with CycH / EtOAc 5 / 1 to afford the desired compound. Analysis (method B): Rt: 1.29 min, [M+H] +: 346 / 348 (Br)10 Step 2: Synthesis of tert-butyldimethyl{[2-nitro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methoxy}silane (intermediate F1) [(2-Bromo-6-nitrophenyl)methoxy](tert-butyl)dimethylsilane (14.5 g, 41.9 mmol) is dissolved in 15 dioxane (240 mL). Bis(pinacolato)diboron (11.7 g, 46.1 mmol) and potassium acetate (12.3 g, 126 mmol) are added, and the mixture is purged with argon. Pd(dppf)Cl2 x DCM (3.42 g, 4.19 mmol) is added, and the reaction mixture is stirred at 95 °C for 4 h. After the reaction mixture is cooled to RT the formed precipitate is filtered, washed with dioxane (20 mL) and the filtrate is concentrated. The crude residue is filtered with CycH through a pad of silica and washed with CycH / EtOAc 5 / 1 to afford20 the intermediate F1.Analysis (method A): Rt: 1.37 min, [M+H] +: 394Synthesis of intermediate F2: Step 1: Synthesis of 2-methyl-5-(trifluoromethoxy)aniline 01-3595-WO-1 99 1-Methyl-2-nitro-4-(trifluoromethoxy)benzene (1.00 g, 4.52 mmol) is dissolved in EtOH (25 mL).Ammonium formate (1.31 g, 9.50 mmol) and Pd / C 10 % (0.50 g) are added, and the reaction mixture is stirred at 85 °C for 2 h. The reaction mixture is filtered, and the filtrate is concentrated. The crude 5residue is purified by flash chromatography (DCM / MeOH 100 / 0 --> DCM / MeOH 90 / 10) to afford thedesired compound. Analysis (method E): Rt: 0.77 min, [M+H] +: 192Step 2: Synthesis of 4-bromo-2-methyl-5-(trifluoromethoxy)aniline 10 2-Methyl-5-(trifluoromethoxy)aniline (656 mg, 3.43 mmol) is dissolved in chloroform (25 mL). At 0 °C NBS (611 mg, 3.43 mmol) is added in portions and the reaction mixture is stirred at 0 °C for 1 h. The reaction is quenched by the addition of a 0.5 M solution of Na2S2O3 and diluted and extracted with DCM. The organic layer is dried, filtered, and concentrated. The residue is purified by flash15 chromatography (DCM / MeOH 100 / 0 --> DCM / MeOH 90 / 10) to afford the desired compound.Analysis (method E): Rt: 0.96 min, [M+H] +: 270 / 272 (Br)Step 3: Synthesis of 5-bromo-6-(trifluoromethoxy)-2H-indazole 20 Boron trifluoride diethyl etherate (0.53 mL, 4.27 mmol) is dissolved in DCM (5 mL). At – 78 °C 4-bromo-2-methyl-5-(trifluoromethoxy) aniline (855 mg, 2.85 mmol, 90 % purity) in DCM (3 mL) is added dropwise, followed by dropwise addition of tert-butyl nitrite (0.41 mL, 3.42 mmol). The reaction mixture is allowed to warm to RT and is stirred at RT overnight. To the reaction mixture is added potassium acetate (531 mg, 5.41 mmol) and 18-crown-6 (37.7 mg, 0.14 mmol) and it is stirred 01-3595-WO-1 100 at RT for 2 h. The reaction mixture is filtered and washed with DCM. The filtrate is washed with water, brine, dried, filtered, and concentrated. The crude residue is purified by flash chromatography (DCM / MeOH 100 / 0 --> DCM / MeOH 90 / 10) to afford the desired compound.Analysis (method E): Rt: 0.88 min, [M+H] +: 281 / 283 (Br)5 Step 4: Synthesis of 5-bromo-2-methyl-6-(trifluoromethoxy)-2H-indazole 5-Bromo-6-(trifluoromethoxy)-2H-indazole (500 mg, 1.60 mmol, 90 % purity) is dissolved in EtOAc (10 mL). Trimethyloxonium tetrafluoroborate (308 mg, 2.08 mmol) is added and the reaction mixture is 10 stirred at RT for 1 h. The reaction is quenched by the dropwise addition of an 10 % NaHCO3solution until a basic pH is reached. It is diluted with DCM and extracted. The organic layer is dried, filtered, and concentrated. The crude residue is purified by flash chromatography (DCM / MeOH 100 / 0 --> DCM / MeOH 90 / 10) to afford the desired compound. Analysis (method E): Rt: 0.93 min, [M+H] +: 295 / 297 (Br)15 Step 5: Synthesis of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethoxy)- 2H-indazole (intermediate F2) 5-Bromo-2-methyl-6-(trifluoromethoxy)-2H-indazole (260 mg, 0.88 mmol) is dissolved in dioxane 20 (7.77 mL). Bis(pinacolato)diboron (0.34 g, 1.32 mmol) and potassium acetate (259 mg, 2.64 mmol) are added, and the mixture is purged with argon. Pd(dppf)Cl2x DCM (72.0 mg, 0.09 mmol) is added, and the reaction mixture is stirred at 90 °C for 2 h. After the reaction mixture is cooled to RT the formed precipitate is filtered, washed with MeOH and the filtrate is concentrated. The crude residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate F2.25 Analysis (method C): Rt: 0.69 min, [M+H] +: 343 01-3595-WO-1 101 Synthesis of intermediate F3: Step 1: Synthesis of 5-bromo-2-methyl-2H-pyrazolo[3,4-b]pyridin-7-ium-7-olate 5-Bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine (8.00 g, 37.7 mmol) is dissolved in DCM (250 mL). 5 MCPBA (15.8 g, 68.7 mmol) is added in portions, and the reaction mixture is stirred at RT overnight. The reaction is filtered, and the filtrate is concentrated. The residue is dissolved in DCM (+ a small amount of MeOH) and is washed with an aqueous saturated solution of NaHCO3. The organic layer is dried, filtered, and concentrated. The residue is triturated with MTBE and the precipitate is filtered and dried at 50 °C to afford the desired compound.10 Analysis (method B): Rt: 0.39 min, [M+H] +: 228 / 230 (Br)Step 2: Synthesis of 5-bromo-6-chloro-2-methyl-2H-pyrazolo[3,4-b]pyridine Under an atmosphere of nitrogen, DMF (20 mL) and Toluene (10 mL) are mixed together, and at 0 °C 15 POCl3(261 µL, 2.80 mmol) is added dropwise, and the reaction mixture is stirred at 0 °C for 10 min. Then 5-bromo-2-methyl-2H-pyrazolo[3,4-b]pyridin-7-ium-7-olate (650 mg, 2.85 mmol) is added and the reaction mixture is stirred at 0 °C for 45 min. The reaction is quenched with an aqueous saturated solution of NaHCO3 and extracted three times with DCM. The combined organic layers are dried, filtered, and concentrated. The residue is triturated with ACN, and the precipitate is filtered and 20 dried in the air to afford the desired compound. Analysis (method J): Rt: 0.80 min, [M+H] +: 246Step 3: Synthesis of 5-bromo-6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine 01-3595-WO-1 102 5-Bromo-6-chloro-2-methyl-2H-pyrazolo[3,4-b]pyridine (238 mg, 0.97 mmol) is dissolved in dioxane(15 ml) and EtOH (7.5 mL). Sodium ethoxide (21 % in EtOH, 1.80 mL, 4.83 mmol) is added and the reaction mixture is stirred at 50 °C for 3 h. The reaction is neutralized with TFA, concentrated, and 5purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the desired compound.Analysis (method J): Rt: 0.88 min, [M+H] +: 256Step 4: Synthesis of {6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}boronic acid (intermediate F3) 10 5-Bromo-6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine (224 mg, 0.88 mmol) is dissolved in dioxane (12 mL). Bis(pinacolato)diboron (444 mg, 1.75 mmol) and potassium acetate (258 mg, 2.62 mmol) are added, and the mixture is purged with argon. Pd(dppf)Cl2 x DCM (45.0 mg, 0.06 mmol) is added, and the reaction mixture is stirred at 100 °C for 6 h. After the reaction mixture is cooled to RT the formed precipitate is filtered, washed with ACN and the filtrate is concentrated. The crude residue is purified15 by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate F3.Analysis (method J): Rt: 0.64 min, [M+H] +: 222Synthesis of intermediate F4: Step 1: Synthesis of 4-ethoxy-1-methyl-2-nitrobenzene 20 4-Methyl-3-nitrophenol (800 mg, 5.22 mmol) is dissolved in DMF (9 mL). Cs2CO3(2.04 g, 6.25 mmol) and iodoethane (836 µL, 10.4 mmol) are added, and the reaction mixture is stirred at RT overnight. The reaction is diluted with EtOAc and washed with an aqueous saturated solution of NH4Cl. The 01-3595-WO-1 103 aqueous layer is extracted two times with EtOAc and the combined organic layers are dried, filtered and concentrated. The residue is purified by flash chromatography (CycH / EtOAc 100 / 0 --> CycH / EtOAc 80 / 20) to afford the desired compound. Analysis (method C): Rt: 0.61 min, [M+H] +: 1825 Step 2: Synthesis of 5-ethoxy-2-methylaniline 4-Ethoxy-1-methyl-2-nitrobenzene (925 mg, 5.11 mmol) is dissolved in EtOH (5 mL). Pd / C 10 % (10 mg) is added, and the reaction mixture is hydrogenated at RT and 3 bar overnight. The reaction 10 mixture is filtered, and the filtrate is concentrated. The crude residue is purified by flash chromatography (CycH / EtOAc 100 / 0 --> CycH / EtOAc 80 / 20) to afford the desired compound.Analysis (method D): Rt: 0.48 min, [M+H] +: 152Step 3: Synthesis of 4-bromo-5-ethoxy-2-methylaniline 15 5-Ethoxy-2-methylaniline (640 mg, 4.23 mmol) is dissolved in DCM (20 mL). At 0 °C NBS (753 mg, 4.23 mmol) is added in portions and the reaction mixture is stirred at 0 °C for 1.5 h. The reaction is quenched by the addition of an aqueous solution of Na2S2O3 and extracted with DCM. The organic layer is dried, filtered, and concentrated. The residue is purified by flash chromatography20 (CycH / EtOAc 100 / 0 --> CycH / EtOAc 70 / 30) to afford the desired compound.Analysis (method D): Rt: 0.65 min, [M+H] +: 230 / 232 (Br)Step 4: Synthesis of 5-bromo-6-ethoxy-2H-indazole 01-3595-WO-1 104 Under an atmosphere of argon, boron trifluoride diethyl etherate (575 µL, 4.66 mmol) is dissolved in DCM (7.5 mL). At – 78 °C 4-bromo-5-ethoxy-2-methylaniline (715 mg, 3.11 mmol) in DCM (7.5 mL) isadded dropwise, followed by dropwise addition of tert-butyl nitrite (445 µL, 3.73 mmol). The reaction 5 mixture is allowed to warm to RT and is stirred at RT for 3 h. To the reaction mixture is added potassium acetate (579 mg, 5.90 mmol) and 18-crown-6 (41.1 mg, 0.16 mmol) and it is stirred at RT for 2 h. The reaction mixture is filtered, and the filtrate is washed with water, dried, filtered, and concentrated. The crude residue is purified by flash chromatography (CycH / EtOAc 100 / 0 --> CycH / EtOAc 60 / 40) to afford the desired compound.10 Analysis (method D): Rt: 0.62 min, [M+H] +: 241 / 243 (Br)Step 5: Synthesis of 5-bromo-6-ethoxy-2-methyl-2H-indazole 5-Bromo-6-ethoxy-2H-indazole (340 mg, 1.40 mmol) is dissolved in EtOAc (9 mL). Trimethyloxonium 15 tetrafluoroborate (271 mg, 1.83 mmol) is added and the reaction mixture is stirred at RT for 1 h. The reaction is quenched by the dropwise addition of an 10 % NaHCO3solution until a basic pH is reached. It is diluted with DCM and extracted. The organic layer is dried, filtered, and concentrated. The crude residue is purified by flash chromatography (CycH / EtOAc 100 / 0 --> CycH / EtOAc 40 / 60) toafford the desired compound.20 Analysis (method C): Rt: 0.52 min, [M+H] +: 255 / 257 (Br)Step 6: Synthesis of (6-ethoxy-2-methyl-2H-indazol-5-yl)boronic acid (intermediate F4) 01-3595-WO-1 105 5-Bromo-6-ethoxy-2-methyl-2H-indazole (190 mg, 0.75 mmol) is dissolved in dioxane (4 mL). Bis(neopentylglycolato)diboron (336 mg, 1.49 mmol) and potassium acetate (219 mg, 2.23 mmol) are added, and the mixture is purged with argon. Pd(dppf)Cl2x DCM (60.8 mg, 0.07 mmol) is added, and 5 the reaction mixture is stirred at 90 °C for 5 h. After the reaction mixture is cooled to RT, it is filtered, and purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediateF4. Analysis (method C): Rt: 0.29 min, [M+H] +: 22110 Synthesis of intermediate F5: Step 1: Synthesis of 4-bromo-2-methyl-5-(propan-2-yl)aniline 2-Methyl-5-(propan-2-yl)aniline (640 mg, 4.23 mmol) is dissolved in DCM (20 mL). At 0 °C NBS (753mg, 4.23 mmol) is added in portions and the reaction mixture is stirred at 0 °C for 1.5 h. The reaction 15 is quenched by the addition of an aqueous solution of Na2S2O3and extracted with DCM. The organic layer is dried, filtered, and concentrated. The residue is purified by flash chromatography (CycH / EtOAc 100 / 0 --> CycH / EtOAc 70 / 30) to afford the desired compound.Analysis (method D): Rt: 0.65 min, [M+H] +: 230 / 232 (Br)20 Step 2: Synthesis of 5-bromo-6-(propan-2-yl)-2H-indazole Under an atmosphere of argon, boron trifluoride diethyl etherate (755 µL, 6.12 mmol) is dissolved in DCM (7.5 mL). At – 78 °C 4-bromo-2-methyl-5-(propan-2-yl)aniline (930 mg, 4.08 mmol) in DCM (7.5 01-3595-WO-1 106 mL) is added dropwise, followed by dropwise addition of tert-butyl nitrite (584 µL, 4.89 mmol). The reaction mixture is allowed to warm to RT and is stirred at RT for 3 h. To the reaction mixture is added potassium acetate (760 mg, 7.75 mmol) and 18-crown-6 (53.9 mg, 0.20 mmol) and it is stirred at RT for 2 h. The reaction mixture is filtered, and the filtrate is washed with water, dried, filtered, 5 and concentrated. The crude residue is purified by flash chromatography (CycH / EtOAc 100 / 0 --> CycH / EtOAc 70 / 30) to afford the desired compound.Analysis (method D): Rt: 0.74 min, [M+H] +: 239 / 241 (Br)Step 3: Synthesis of 5-bromo-2-methyl-6-(propan-2-yl)-2H-indazole 10 5-Bromo-6-(propan-2-yl)-2H-indazole (506 mg, 2.12 mmol) is dissolved in EtOAc (13 mL). Trimethyloxonium tetrafluoroborate (407 mg, 2.75 mmol) is added and the reaction mixture is stirred at RT for 1 h. The reaction is quenched by the dropwise addition of an 10 % NaHCO3solution until a basic pH is reached. It is diluted with DCM and extracted. The organic layer is dried, filtered,15 and concentrated. The crude residue is purified by flash chromatography (CycH / EtOAc 100 / 0 --> CycH / EtOAc 50 / 50) to afford the desired compound. Analysis (method C): Rt: 0.52 min, [M+H] +: 255 / 257 (Br)Step 4: Synthesis of 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-6-(propan-2-yl)-2H-indazole20 (intermediate F5) 5-Bromo-2-methyl-6-(propan-2-yl)-2H-indazole (425 mg, 1.68 mmol) is dissolved in dioxane (10 mL). Bis(neopentylglycolato)diboron (758 mg, 3.36 mmol) and potassium acetate (494 mg, 5.04 mmol) are 25 added, and the mixture is purged with argon. Pd(dppf)Cl2 x DCM (137 mg, 0.17 mmol) is added, and the reaction mixture is stirred at 90 °C for 5 h. After the reaction mixture is cooled to RT, it is filtered, 01-3595-WO-1 107 and purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediateF5. Analysis (method C): Rt: 0.28 min, [M+H] +: 219 (boronic acid)5 Synthesis of intermediate F6: Step 1: Synthesis of methyl 5-bromo-2-methyl-2H-indazole-6-carboxylate Methyl 5-bromo-1h-indazole-6-carboxylate (1 g, 3.72 mmol) is dissolved in ethyl acetate (20mL) and trimethyloxonium tetrafluoroborate (480 mg, 3.25 mmol) is added and the mixture stirred10 at room temperature for 18 h. Saturated aqueous sodium hydrogencarbonate solution (7 mL) isadded slowly, the mixture was diluted with ethyl acetate (50 mL); diatomaceous earth (10 g) isadded, the solids were filtered off and the filtrate was concentrated in vacuum to give the desired product. Analysis (method C): Rt: 0.47 min, [M+H] +: 269 / 27115 Step 2: Synthesis of [6-(methoxycarbonyl)-2-methyl-2H-indazol-5-yl]boronic acid Methyl 5-bromo-2-methyl-indazole-6-carboxylate (1.560 g, 5.39 mmol), bis(neopentyl 20 glycolato)diboron (1.461 g, 6.47 mmol), potassium pivalate (2.4 g, 16.3 mmol), bis(triphenylphosphine)palladium(ii) chloride (0.5 g, 0.712 mmol) and acetonitril (40 mL) arecombined and degassed under a stream of argon for 1 min. The reaction mixture is allowed to stirunder reflux for 2 h. To the reaction mixture is added acetonitril (50 mL) and thiol resin (1.2 mmol / g;Biotage). After 1 h at room temperature the solids are filtered off, the filtrate is concentrated in25 vacuum and the residue is purified by HPLC to give the desired compound.Analysis (method D): Rt: 0.237 min, [M+H] +: 235 01-3595-WO-1 108 Synthesis of intermediates G1 – G15:Synthesis of intermediate G1: 5 Step 1: Synthesis of 5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1- methyl-1H-imidazole 1-Cyclopropyl-2-(5-cyclopropyl-1-methyl-1H-imidazol-2-yl)ethan-1-one (D1) (7.60 g, 29.8 mmol), 3- amino-1-methyl-1h-pyrazole-4-carbaldehyde (E1) (4.10 g, 32.7 mmol), piperidine (5.89 mL, 59.5 10 mmol) are dissolved in EtOH (120 mL) and stirred at 100 °C overnight. The reaction mixture is concentrated and purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford thedesired compound. Analysis (method D): Rt: 0.47 min, [M+H] +: 29415 Step 2: Synthesis of 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl}-1-methyl-1H-imidazole (intermediate G1) 5-Cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole (3.80 g, 12.3 mmol, 95 % purity) is dissolved in DCM (100 mL). NBS (2.20 g, 12.4 mmol) is added at 0 20 °C, and the reaction mixture is stirred at RT for 1 h. The reaction mixture is quenched with a 10 % Na2S2O3and a saturated NaHCO3solution, the layers are separated, and the water phase is extracted two times with DCM. The combined organic layers are dried (Na2SO4), filtered, and concentrated to afford the intermediate G1. Analysis (method C): Rt: 0.44 min, [M+H] +: 372 / 374 (Br)25 01-3595-WO-1 109 Synthesis of intermediate G2: Step 1: Synthesis of 5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5- yl]-1H-imidazole 5 1-(5-Cyclopropyl-1-methyl-1H-imidazol-2-yl)-3-methylbutan-2-one (D2) (1.28 g, 4.97 mmol, 80 % purity), 3-amino-1-methyl-1h-pyrazole-4-carbaldehyde (E1) (684 mg, 5.47 mmol), piperidine (984 µL, 9.94 mmol) are dissolved in EtOH (11 mL) and stirred at 95 °C overnight. The reaction mixture is concentrated and purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford thedesired compound.10 Analysis (method C): Rt: 0.32 min, [M+H] +: 296Step 2: Synthesis of 4-bromo-5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4- b]pyridin-5-yl]-1H-imidazole (intermediate G2) 15 5-Cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazole (2.04 g, 6.91 mmol) is dissolved in DCM (60 mL). NBS (1.23 g, 6.91 mmol) is added at 0 °C, and the reaction mixture is stirred at 0 °C for 15 min and at RT for 1 h. The reaction mixture is quenched with a saturated NaHCO3solution, the layers are separated, and the water phase is extracted three times with DCM. The combined organic layers are dried (Na2SO4), filtered, and concentrated. The residue is20 purified by flash chromatography (EtOAc / MeOH 100 / 0 --> EtOAc / MeOH 95 / 5) to afford theintermediate G2. Analysis (method C): Rt: 0.44 min, [M+H] +: 374 / 376 (Br)Synthesis of intermediate G3: 01-3595-WO-1 110 Step 1: Synthesis of 2-(6-{[(tert-butyldimethylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)-5-cyclopropyl-1-methyl-1H-imidazole 1-[(Tert-butyldimethylsilyl)oxy]-3-(5-cyclopropyl-1-methyl-1H-imidazol-2-yl)propan-2-one (D3) (7.85 5 g, 20.4 mmol), 3-amino-1-methyl-1h-pyrazole-4-carbaldehyde (E1) (2.55 g, 20.4 mmol), piperidine (5.04 mL, 50.9 mmol) are dissolved in EtOH (50 mL) and stirred at 100 °C overnight. The reaction mixture is concentrated and purified by flash chromatography (DCM / MeOH 100 / 0 --> DCM / MeOH85 / 15) to afford the desired compound. Analysis (method B): Rt: 1.07 min, [M+H] +: 39810 Step 2: Synthesis of 4-bromo-2-(6-{[(tert-butyldimethylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)-5-cyclopropyl-1-methyl-1H-imidazole 2-(6-{[(Tert-butyldimethylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5-cyclopropyl-1-15 methyl-1H-imidazole (6.35 g, 12.8 mmol, 80 % purity) is dissolved in DCM (100 mL). NBS (2.40 g, 13.5mmol) is added at 0 °C, and the reaction mixture is stirred at 0 °C for 15 min and at RT for 10 min. The reaction mixture is quenched with a 10 % Na2S2O3and a saturated NaHCO3solution, the layers are separated, and the water phase is extracted three times with DCM. The combined organic layers are dried (Na2SO4), filtered, and concentrated to afford the desired compound.20 Analysis (method B): Rt: 1.14 min, [M+H] +: 476 / 478 (Br)Step 3: Synthesis of [5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4- b]pyridin-6-yl]methanol 01-3595-WO-1 111 4-Bromo-2-(6-{[(tert-butyldimethylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5- cyclopropyl-1-methyl-1H-imidazole (7.90 g, 13.3 mmol, 80 % purity) is dissolved in THF (60 mL). TBAF (15.9 mL, 15.9 mmol) is added, and the reaction mixture is stirred at RT for 2 h. The reaction is 5 quenched with water and the THF is concentrated. The aqueous residue is extracted two time with EtOAc. The combined organic layers are washed with brine, dried, filtered, and concentrated. The crude residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford thedesired compound. Analysis (method A): Rt: 0.59 min, [M+H] +: 362 / 364 (Br)10 Step 4: Synthesis of 4-bromo-5-cyclopropyl-2-[6-(methoxymethyl)-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl]-1-methyl-1H-imidazole (intermediate G3) [5-(4-Bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-6- 15 yl]methanol (50.0 mg, 0.14 mmol) is dissolved in DMF (1 mL). At 0 °C, NaH (60 %, 6.63 mg, 0.17 mmol) is added, and the reaction mixture is stirred at 0 °C for 39 min. MeI (21.3 µL, 0.35 mmol) is added, and the reaction mixture is stirred at RT. The reaction is quenched with water, acidified with TFA, and purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford theintermediate G3.20 Analysis (method A): Rt: 0.67 min, [M+H] +: 376 / 378 (Br)Synthesis of intermediate G4: 5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-6- (trifluoromethoxy)-2H-indazole 01-3595-WO-1 112 Under an argon atmosphere, 2,4-dibromo-5-cyclopropyl-1-methyl-1H-imidazole (D4) (279 mg, 1.00 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethoxy)-2H- indazole (F2) (409 mg, 1.19 mmol) are dissolved in dioxane (6.6 mL). Cs2CO3 (973 mg, 2.99 mmol) and 5 Pd(PPh3)4(115 mg, 0.10 mmol) are added, and the reaction mixture is stirred at 80 °C overnight. The reaction mixture is poured into ice water, the formed precipitate is filtered and purified by flash chromatography (DCM / MeOH 100 / 0 --> DCM / MeOH 85 / 15) to afford the intermediate G4.Analysis (method C): Rt: 0.51 min, [M+H] +: 415 / 417 (Br)10 Synthesis of intermediate G5: Step 1: Synthesis of 5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4- b]pyridin-5-yl}-1-methyl-1H-imidazole 15 1-Cyclopropyl-2-(5-cyclopropyl-1, 2-dimethyl-1H-imidazol-4-yl) ethan-1-one (D1) (1.40 g, 5.48 mmol, 80 % purity) and 3-amino-1-[(4-methoxyphenyl) methyl]-1H-pyrazole-4-carbaldehyde (E2) (1.65 g, 7.13 mmol) are dissolved in EtOH (35 mL). Piperidine (1.63 mL, 16.5 mmol) is added, and the reaction mixture is stirred at 80 °C overnight. The reaction mixture is concentrated and co-evaporated 3x with toluene. The residue is purified by flash chromatography (DCM / acetone 100 / 0 --> DCM / Acetone20 30 / 70) to afford the desired compound. Analysis (method I): Rt: 1.40 min, [M+H] +: 400Step 2: Synthesis of 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl) methyl]-2H- pyrazolo[3, 4-b] pyridin-5-yl}-1-methyl-1H-imidazole 01-3595-WO-1 113 5-Cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl) methyl]-2H-pyrazolo[3, 4-b] pyridin-5-yl}-1- methyl-1H-imidazole (0.60 g, 1.50 mmol) is dissolved in DCM (21 mL). NBS (0.29 g, 1.65 mmol) is added at 0 °C and the reaction mixture is stirred at RT for 30 min. The reaction mixture is quenched 5 with a saturated Na2S2O3 solution and extracted with DCM. The organic layer is washed with a saturated K2CO3solution, dried (Na2SO4), filtered, and concentrated. The residue is purified by flash chromatography (DCM / Acetone 100 / 0 --> DCM / Acetone 90 / 10) to afford the desired compound.Analysis (method K): Rt: 3.82 min, [M+H] +: 478 / 480 (Br)10 Step 3: Synthesis of 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1- methyl-1H-imidazole 4-Bromo-5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl) methyl]-2H-pyrazolo[3, 4-b] pyridin-5- yl}-1-methyl-1H-imidazole (500 mg, 1.05 mmol) is dissolved in DCE (10 mL). TFA (5 mL) and anisole 15 (229 µL, 2.09 mmol) are added, and the reaction mixture is stirred at 60 °C for 3 days. The reaction is concentrated and purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford thedesired compound. Analysis (method A): Rt: 0.84 min, [M+H] +: 358 / 360 (Br)20 Step 4: Synthesis of 4-bromo-2-{2-tert-butyl-6-cyclopropyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5- cyclopropyl-1-methyl-1H-imidazole (intermediate G5) 01-3595-WO-1 114 4-Bromo-5-cyclopropyl-2-{6-cyclopropyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole x trifluoroacetic acid (70.0 mg, 0.14 mmol), 2-methylpropan-2-ol (52.2 mg, 0.70 mmol) and concentrated sulfuric acid (7.51 µL, 0.14 mmol) are mixed together, and stirred at 100 °C for 40 min 5 and at RT for 3 days. The reaction mixture is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate G5.Analysis (method A): Rt: 0.93 min, [M+H] +: 414 / 416 (Br)Synthesis of intermediate G6: 10 Step 1: Synthesis of 2-(6-{[(tert-butyldimethylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl)-5-cyclopropyl-1-methyl-1H-imidazole 1-[(Tert-butyldimethylsilyl)oxy]-3-(5-cyclopropyl-1-methyl-1H-imidazol-2-yl)propan-2-one (D3) (7.85 g, 20.4 mmol), 3-amino-1-methyl-1h-pyrazole-4-carbaldehyde (E1) (2.55 g, 20.4 mmol), piperidine 15 (5.04 mL, 50.9 mmol) are dissolved in EtOH (50 mL) and stirred at 100 °C overnight. The reaction mixture is concentrated and purified by flash chromatography (DCM / MeOH 100 / 0 --> DCM / MeOH85 / 15) to afford the desired compound. Analysis (method B): Rt: 1.07 min, [M+H] +: 39820 Step 2: Synthesis of 4-bromo-2-(6-{[(tert-butyldimethylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)-5-cyclopropyl-1-methyl-1H-imidazole 01-3595-WO-1 115 2-(6-{[(Tert-butyldimethylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5-cyclopropyl-1- methyl-1H-imidazole (6.35 g, 12.8 mmol, 80 % purity) is dissolved in DCM (100 mL). NBS (2.40 g, 13.5mmol) is added at 0 °C, and the reaction mixture is stirred at 0 °C for 15 min and at RT for 10 min. 5 The reaction mixture is quenched with a 10 % Na2S2O3 and a saturated NaHCO3 solution, the layers are separated, and the water phase is extracted three times with DCM. The combined organic layers are dried (Na2SO4), filtered, and concentrated to afford the desired compound. Analysis (method B): Rt: 1.14 min, [M+H] +: 476 / 478 (Br)10 Step 3: Synthesis of [5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4- b]pyridin-6-yl]methanol 4-Bromo-2-(6-{[(tert-butyldimethylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5- cyclopropyl-1-methyl-1H-imidazole (7.90 g, 13.3 mmol, 80 % purity) is dissolved in THF (60 mL). TBAF 15 (15.9 mL, 15.9 mmol) is added, and the reaction mixture is stirred at RT for 2 h. The reaction is quenched with water and the THF is concentrated. The aqueous residue is extracted two time with EtOAc. The combined organic layers are washed with brine, dried, filtered, and concentrated. The crude residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford thedesired compound.20 Analysis (method A): Rt: 0.59 min, [M+H] +: 362 / 364 (Br)Step 4: Synthesis of 5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4- b]pyridine-6-carbaldehyde 01-3595-WO-1 116 [5-(4-Bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-6- yl]methanol (500 mg, 1.38 mmol) is dissolved in DCM (15 mL). DIPEA (1.67 mL, 9.66 mmol), DMSO (491 µL, 6.90 mmol) and sulfur trioxide pyridine complex (659 mg, 4.14 mmol) are added, and the 5 reaction mixture is stirred at RT for 2 h. The reaction mixture is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the desired compound.Analysis (method L): Rt: 0.98 min, [M+H] +: 360 / 362 (Br)Step 5: Synthesis of 1-[5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H-10 pyrazolo[3,4-b]pyridin-6-yl]propan-1-ol (intermediate G6) Under an atmosphere of argon, 5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H- pyrazolo[3,4-b]pyridine-6-carbaldehyde (337 mg, 0.89 mmol) is dissolved in THF (8 mL). At – 78 °C,bromo(ethyl)magnesium (1.07 mL, 1.07 mmol) is added dropwise, and the reaction mixture is stirred15 at – 78 °C for 2 h and at RT. The reaction is quenched by the addition of 1 M HCl and extracted 3 xwith EtOAc. The combined organic layers are dried, filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / NH3) to afford the intermediate G6.Analysis (method C): Rt: 0.40 min, [M+H] +: 390 / 392 (Br)20 Synthesis of intermediate G7: 4-bromo-5-cyclopropyl-2-{6-ethyl-2-methyl-2H-pyrazolo[3,4-b]pyridin- 5-yl}-1-methyl-1H-imidazole 01-3595-WO-1 117 1-(4-Bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)butan-2-one (5.51 g, 20.3 mmol) is dissolved in EtOH (60 mL).3-Amino-1-methyl-1-H-pyrazole-4-carbaldehyde (2.80 g, 22.4 mmol) and piperidine (4.02 mL, 40.6 mmol) are added and the reaction mixture is stirred at 90 °C overnight. The reaction 5 mixture is filtered and purified by reversed phase chromatography (HPLC; Xbridge-C18, ACN / water including NH3) to afford the intermediate G7. Analysis (method E): Rt: 0.55 min, [M+H] +: 360 / 362 (Br)Synthesis of intermediate G8:10 Step 1 - 4: are synthesized by following a procedure analogous to that described for intermediate G6.Step 5: Synthesis of 1-[5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H- pyrazolo[3,4-b]pyridin-6-yl]ethan-1-ol (intermediate G8) 15 Under an atmosphere of nitrogen, 5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl- 2H-pyrazolo[3,4-b]pyridine-6-carbaldehyde (17.0 mg, 0.05 mmol) is dissolved in THF (0.5 mL). At – 17°C, bromo(methyl)magnesium (3 M, 17.9 µL, 0.05 mmol) is added dropwise, and the reaction mixtureis stirred at – 15 °C for 15 min. The reaction is quenched by the addition of water and extracted with20 DCM. The organic layer is dried, filtered, and concentrated. The residue is filtered through a pad of silica and washed with DCM / MeOH 80 / 20. The filtrate is evaporated to afford the intermediate G8. Analysis (method B): Rt: 0.76 min, [M+H] +: 376 / 378 (Br)Synthesis of intermediate G9: 4-bromo-5-cyclopropyl-2-{6-ethoxy-2-methyl-2H-pyrazolo[3,4-25 b]pyridin-5-yl}-1-methyl-1H-imidazole 01-3595-WO-1 118 Under an argon atmosphere, 2,4-dibromo-5-cyclopropyl-1-methyl-1H-imidazole (D4) (193 mg, 0.69 mmol) and {6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}boronic acid (F3) (117 mg, 0.53 mmol) are dissolved in dioxane (3 mL). Cs2CO3(690 mg, 2.12 mmol) and Pd(dppf)Cl2x DCM (43.2 mg, 0.05 5 mmol) are added, and the reaction mixture is stirred at 65 °C for 5 h. The reaction mixture is acidified with TFA, filtered, and purified by reversed phase chromatography (HPLC; ACN / water including TFA) to afford the intermediate G9. Analysis (method J): Rt: 0.87 min, [M+H] +: 376 / 378 (Br)10 Synthesis of intermediate G10: Step 1 - 3: are synthesized by following a procedure analogous to that described for intermediate G5.Step 4: Synthesis of 4-{2-[5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-6-cyclopropyl-2H- pyrazolo[3,4-b]pyridin-2-yl]ethyl}morpholine (intermediate G10) 15 4-Bromo-5-cyclopropyl-2-{6-cyclopropyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole (382 mg, 1.07 mmol), 4-(2-bromoethyl)morpholine hydrobromide (449 mg, 1.60 mmol) and K2CO3(442 mg, 3.20 mmol) are dissolved in ACN (20 mL) and DMF (10 mL), and the reaction mixture is stirred at 20 70 °C overnight. The reaction mixture is purified by reversed phase chromatography (HPLC; ACN / water including TFA) to afford the intermediate G10. Analysis (method A): Rt: 0.76 min, [M+H] +: 471Synthesis of intermediate G11: 5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-6-ethoxy-2-25 methyl-2H-indazole 01-3595-WO-1 119 Under an argon atmosphere, 2,4-dibromo-5-cyclopropyl-1-methyl-1H-imidazole (D4) (146 mg, 0.52 mmol) and (6-ethoxy-2-methyl-2H-indazol-5-yl)boronic acid (F4) (104 mg, 0.47 mmol) are dissolved in dioxane (3 mL). Cs2CO3(462 mg, 1.42 mmol) and Pd(PPh3)4(54.6 mg, 0.05 mmol) are added, and 5 the reaction mixture is stirred at 80 °C for 3 h. The reaction mixture is filtered and purified by reversed phase chromatography (HPLC; ACN / water including NH3) to afford the intermediate G11. Analysis (method M): Rt: 0.60 min, [M+H] +: 375 / 377 (Br)Synthesis of intermediate G12: 5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-6-10 (propan-2-yl)-2H-indazole Under an argon atmosphere, 2,4-dibromo-5-cyclopropyl-1-methyl-1H-imidazole (D4) (382 mg, 1.37 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-6-(propan-2-yl)-2H-indazole (F5) (355 mg, 1.24 mmol) are dissolved in dioxane (9 mL). Cs2CO3 (1.21 g, 3.72 mmol) and Pd(PPh3)4 (143 mg, 15 0.12 mmol) are added, and the reaction mixture is stirred at 80 °C for 3 h. The reaction mixture is filtered and purified by reversed phase chromatography (HPLC; ACN / water including NH3) to afford the intermediate G12. Analysis (method M): Rt: 0.64 min, [M+H] +: 373 / 375 (Br)20 Synthesis of intermediate G13: Step 1: Synthesis of 5-cyclopropyl-2-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H- imidazole 01-3595-WO-1 120 1-(5-Cyclopropyl-1-methyl-1H-imidazol-2-yl)propan-2-one (D6) (5.00 g, 28.1 mmol), 3-amino-1- methyl-1h-pyrazole-4-carbaldehyde (E1) (3.86 g, 30.9 mmol), piperidine (5.56 mL, 56.1 mmol) are dissolved in EtOH (15 mL) and stirred at 95 °C overnight. The reaction mixture is concentrated and purified by flash chromatography (DCM / MeOH + NH4OH (1 %) 99 / 1 --> DCM / MeOH + NH4OH (1 %)5 80 / 20) to afford the desired compound. Analysis (method A): Rt: 0.58 min, [M+H] +: 268Step 2: Synthesis of 4-bromo-5-cyclopropyl-2-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl- 1H-imidazole (intermediate G13) 10 5-Cyclopropyl-2-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole (5.40 g, 20.2mmol) is dissolved in DCM (100 mL). NBS (3.60 g, 20.2 mmol) is added in portions at 0 °C, and the reaction mixture is stirred at 0 °C for 15 min and at RT. The reaction mixture is quenched with a saturated NaHCO3 and a 10 % Na2S2O3 solution, the layers are separated, and the water phase is 15 extracted two times with DCM. The combined organic layers are dried (Na2SO4), filtered, and concentrated. The residue is triturated with EtOAc, the precipitate is filtered, washed with EtOAc, and dried at 50 °C overnight to afford the intermediate G13. Analysis (method A): Rt: 0.74 min, [M+H] +: 346 / 348 (Br)20 Synthesis of intermediate G14: Intermediate G6 (1.06 g) was separated by chiral HPLC (method A1) to give intermediate G14 (1R)-1-[5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-6- yl]propan-1-ol. Analysis (method Z): Rt: 0.86 min (>98%ee) and (1S)-1-[5-(4-bromo-5-cyclopropyl-1- 01-3595-WO-1 121 methyl-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl]propan-1-ol Analysis (method Z): Rt: 1.27 min (>98%ee). Synthesis of intermediate G15 5 Step 1: Synthesis of methyl 5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H- indazole-6-carboxylate 2,4-Dibromo-5-cyclopropyl-1-methyl-imidazole (1415 mg, 5.05 mmol), (6-methoxycarbonyl-2-methyl-indazol-5-yl)boronic acid (835 mg, 3.57 mmol),1,1'-Bis(diphenylphosphino)ferrocene10 palladium(II)dichloride (Pd(dppf)Cl2) (350 mg, 0.478 mmol),1,4-Dioxan (50 mL) and 1.0 M cesiumcarbonate (13.80 mL, 13.8 mmol) are combined and degassed under a stream of argon for 2 min.Then the mixture is allowed to stir at 80 °C for 2.5 h. The reaction mixture is extracted from DCM (30mL) and Water (10 mL). The organic phase was separated and concentrated in vacuum. The residuewas purified by HPLC. The product fractions were concentrated in vacuum to give the desired15 compound. Analysis (method C): Rt: 0.51 min, [M+H] +: 389 / 391Step 2: Synthesis of methyl 5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H- indazole-6-carboxylate -> 1-[5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl-2H-20 indazol-6-yl]propan-1-one Methyl 5-(4-bromo-5-cyclopropyl-1-methyl-imidazol-2-yl)-2-methyl-indazole-6-carboxylate (69 mg, 0.177 mmol) is dissolved in tetrahydrofuran (2 mL) and triethylamine (TEA) (0.1 mL, 0.721 mmol), 01-3595-WO-1 122 cooled down with an ethanol / ice bath and 1.1 M ethylmagnesium bromide in THF (0.8 mL, 0.880mmol) is added over a period of 40 min. The mixture is allowed to stir under cooling for 1 h.Saturated aqueous ammonium chloride (1 mL) is added, and the mixture is extracted fromDCM / water. The organic phase is separated and concentrated in vacuum to give the desired product 5Analysis (method C): Rt: 0.422 min, [M+H] +: 387 / 389.Synthesis of intermediate H1: Step 1: Synthesis of [2-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-10 methyl-1H-imidazol-4-yl)-6-nitrophenyl]methanol Under an argon atmosphere, 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl}-1-methyl-1H-imidazole (G1) (9.00 g, 24.2 mmol) and tert-butyldimethyl{[2-nitro-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}silane (F1) (14.5 g, 26.6 mmol, 72 % 15 purity) are dissolved in dioxane (400 mL). K3PO42 M (36.3 mL, 72.5 mmol) and XPhos Pd G3 (1.02 g, 1.21 mmol) are added, and the reaction mixture is stirred at 95 °C for 2 h. The reaction mixture is filtered and washed with dioxane (20 mL). The filtrate is concentrated, filtered through a pad of silica, and washed with CycH / EtOAc 1 / 1 (500 mL) and DCM / MeOH 10 / 1 (600 mL). The desired fractions are concentrated to afford the intermediate still with the TBDMS protecting group. The 20 residue is dissolved in ACN / water 1 / 1 (50 mL) and TFA (2 mL) is added. The reaction mixture is stirred at RT for 2 h. The reaction is concentrated, and the residue is dissolved in DCM (150 mL) and washed with NaOH 1 M (40 ml). The aqueous layer is extracted with DCM (2 x 150 mL) and the combined organic layers are dried, filtered, and concentrated. The residue is triturated with diethyl ether (30 mL), the precipitate is filtered, washed with diethyl ether (10 mL) to afford the desired compound.25 Analysis (method A): Rt: 0.79 min, [M+H] +: 445Step 2: Synthesis of 4-[2-(chloromethyl)-3-nitrophenyl]-5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole (intermediate H1) 01-3595-WO-1 123 [2-(5-Cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazol-4- yl)-6-nitrophenyl]methanol (2.40 g, 5.29 mmol) is dissolved in thionyl chloride (20 mL). TEA (100 µL, 0.72 mmol) is added and the reaction mixture is stirred at RT for 1 h. The reaction is concentrated,5 the residue is triturated with DCM (10 mL) and diethyl ether (10 mL) and concentrated to dryness to afford the intermediate H1. Analysis (method B): Rt: 1.03 min, [M+H] +: 463 / 465 (Cl)Synthesis of intermediate I1: 10 Step 1: Synthesis of ethyl 1-cyclopropyl-3-methoxy-1H-pyrazole-4-carboxylate Ethyl 3-methoxy-1H-pyrazole-4-carboxylate (100 mg, 0.59 mmol) is dissolved in ACN (8 mL) and DCM (2 mL). Cyclopropylboronic acid (60.6 mg, 0.71 mmol), copper (II) acetate (267 mg, 1.47 mmol) and pyridine (232 µL, 2.94 mmol) are added, and the reaction mixture is stirred in the air at 65 °C 15 overnight. The reaction is filtered through a pad of Celite and the filtrate is concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water including TFA) to afford the desired compound. Analysis (method C): Rt: 0.45 min, [M+H] +: 21120 Step 2: Synthesis of 1-cyclopropyl-3-methoxy-1H-pyrazole-4-carboxylic acid (intermediate I1) Ethyl 1-cyclopropyl-3-methoxy-1H-pyrazole-4-carboxylate (30.0 mg, 0.14 mmol) is dissolved in THF (3 mL). NaOH 4 M (107 µL, 0.43 mmol) is added and the reaction mixture is stirred at 50 °C overnight. 01-3595-WO-1 124 The reaction mixture is concentrated, and the residue is dissolved in water and acidified with HCl 4 M (111 µL, 0.44 mmol). The formed precipitate is filtered to afford the intermediate I1. Analysis (method C): Rt: 0.30 min, [M+H] +: 1835 Synthesis of intermediate J1: Step 1: Synthesis of 3-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4- b]pyridin-5-yl]-1H-imidazol-4-yl}-2-nitroaniline 10 Under an argon atmosphere, 4-bromo-5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H- pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazole (G2) (374 mg, 1.00 mmol) and 2-nitro-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (630 mg, 2.29 mmol) are dissolved in dioxane (20 mL). K3PO42 M (2.5 mL, 5.00 mmol) and XPhos Pd G3 (42.3 mg, 0.05 mmol) are added, and the reaction mixture is stirred at 100 °C overnight. The reaction mixture is filtered and washed with dioxane (10 15 mL). The filtrate is concentrated and purified by reversed phase chromatography (HPLC; ACN / water including NH3) to afford the desired compound. Analysis (method A): Rt: 0.79 min, [M+H] +: 432Step 2: Synthesis of 3-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-20 b]pyridin-5-yl]-1H-imidazol-4-yl}benzene-1,2-diamine (intermediate J1) 3-{5-Cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazol- 4-yl}-2-nitroaniline (341 mg, 0.79 mmol) is dissolved in MeOH (20 mL). Pd / C 10 % (100 mg) is added, and the reaction mixture is hydrogenated at RT and 50 psi (344.738 kPa) for 2 h. The reaction mixture 25 is filtered, and the filtrate is concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water including NH3) to afford the intermediate J1. 01-3595-WO-1 125 Analysis (method B): Rt: 0.89 min, [M+H] +: 402Synthesis of intermediate K1 and K2: 5 Synthesis of intermediate K1: Step 1: Synthesis of N-{[2-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1- methyl-1H-imidazol-4-yl)-6-nitrophenyl]methyl}-3-methoxy-1H-pyrazol-4-amine 10 4-[2-(Chloromethyl)-3-nitrophenyl]-5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl}-1-methyl-1H-imidazole trihydrochloride (H1) (300 mg, 0.50 mmol, 95 % purity) is dissolved in NMP (11 mL). DIEPA (861 µL, 4.98 mmol) and 3-methoxy-1H-pyrazol-4-amine hydrochloride (A18) (186 mg, 1.25 mmol) are added, and the reaction mixture is stirred at RT for 3 days. The reaction mixture is acidified with TFA, filtered, and purified by reversed phase 15 chromatography (HPLC; ACN / water including TFA) to afford the desired compound. Analysis (method A): Rt: 0.71 min, [M+H] +: 540Step 2: Synthesis of 4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1- methyl-1H-imidazol-4-yl)-2-(3-methoxy-1H-pyrazol-4-yl)-2H-indazole (intermediate K1) 20 N-{[2-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b] pyridin-5-yl}-1-methyl-1H- imidazol-4-yl)-6-nitrophenyl]methyl}-3-methoxy-1H-pyrazol-4-amine (322 mg, 0.40 mmol) is dissolved in MeOH (10 mL). Zinc (91.2 mg, 1.40 mmol) is added, and ammonium formate (50.3 mg,0.80 mmol), dissolved in MeOH (5 mL), is added dropwise, and the reaction mixture is stirred at RT 25 overnight. The reaction is diluted with DCM, filtered through a pad of silica, and washed with 01-3595-WO-1 126 DCM / MeOH 90 / 10. The filtrate is concentrated, and the residue is purified by reversed phase chromatography (HPLC; ACN / water including NH3) to afford the intermediate K1. Analysis (method B): Rt: 0.84 min, [M+H] +: 5065 Synthesis of intermediate K2: 4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b] pyridin-5-yl]-1H-imidazol-4-yl}-2-(3-methoxy-1H-pyrazol-4-yl)-2H-indazole 4-Bromo-5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H- imidazole (G2) (216 mg, 0.57 mmol) and 2-(3-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- 10 pyrazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (C7) (222 mg, 0.47 mmol) are dissolved in dioxane (15 mL). K3PO42 M (708 µL, 1.42 mmol) and XPhos Pd G3 (39.9 mg, 0.05 mmol) are added, and the reaction mixture is stirred at 100 °C for 3 h. The reaction mixture is filtered and purified by reversed phase chromatography (HPLC; ACN / water including TFA) to afford the intermediate with SEM protecting group. The intermediate is dissolved in MeOH (10 mL), 4 M HCl in 15 dioxane (5 mL) is added, and the reaction mixture is stirred at 50 °C for 2 h. The reaction is concentrated and purified by reversed phase chromatography (HPLC; ACN / water including TFA). The desired fractions are evaporated, and the residue is dissolved in DCM (30 mL) and washed with 1 M NaOH (5mL). The organic layer is dried, filtered and concentrated to afford the intermediate K2. Analysis (method A): Rt: 0.80 min, [M+H] +: 50820 Synthesis of Examples 1 – 79:Synthesis of Example 1, 2, 11, 12, 16, 17, 32, 35, 36, 44, 45, 47, 55, 57, 61, 63, 70, 72 – 74:4-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b] pyridin-5-yl}-1-methyl-1H-imidazol-25 4-yl)-2H-indazol-2-yl]-3-methoxy-1'-methyl-1'H-1,4'-bipyrazole (example 1) 01-3595-WO-1 127 4-[2-(Chloromethyl)-3-nitrophenyl]-5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b] pyridin-5-yl}-1-methyl-1H-imidazole dihydrochloride (H1) (60.0 mg, 0.10 mmol, 90 % purity) is dissolved in NMP (1 mL).3-Methoxy-1'-methyl-1'H-[1,4'-bipyrazol]-4-amine hydrochloride (A1) (56.0 5 mg, 0.24 mmol) and DIPEA (52.3 µL, 0.30 mmol) are added, and the reaction mixture is stirred at 80 °C for 1 h. The reaction mixture is purified by reversed phase chromatography (HPLC; ACN / water including NH3) to afford the ring opened intermediate. The intermediate is dissolved in MeOH (2 mL), zinc (13 mg, 0.20 mmol) and ammonium formate (6 mg, 0.10 mmol), dissolved in MeOH (0.5 mL), are added, and the reaction mixture is stirred at RT for 2 h. The reaction mixture is purified by reversed10 phase chromatography (HPLC; ACN / water including NH3) to afford example 1.Analysis (method N): Rt: 0.79 min, [M+H] +: 586The examples compiled in the following table are obtained by following a reaction sequence analogous to that described for example 1. 01-3595-WO-1 128 01-3595-WO-1 129 01-3595-WO-1 130 01-3595-WO-1 131 01-3595-WO-1 132 01-3595-WO-1 133 01-3595-WO-1 134 Synthesis of Example 3 – 8, 10, 13 – 15, 18, 20 – 23, 25 – 28, 30, 34, 42, 43, 46, 49, 50, 56, 59, 60, 62,66 – 69, 77:4-[4-(4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b] pyridin-5-yl]-1H- imidazol-4-yl}-2H-indazol-2-yl)-3-methoxy-1H-pyrazol-1-yl]-N,N-dimethylbenzamide (example 3)5 Under an atmosphere of argon, 4-bromo-5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H- pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazole (G2) (45.8 mg, 0.12 mmol) and 4-{3-methoxy-4-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]-1H-pyrazol-1-yl}-N,N-dimethylbenzamide (C1) 10 (48.7 mg, 0.10 mmol) are dissolved in dioxane (4 mL). K3PO42 M (150 µL, 0.30 mmol) and XPhos Pd G3 (8.46 mg, 0.01 mmol) are added, and the reaction mixture is stirred at 100 °C for 30 min. The reaction mixture is purified by reversed phase chromatography (HPLC; ACN / water including TFA) to afford example 3.Analysis (method A): Rt: 0.89 min, [M+H] +: 65515 The examples compiled in the following table are obtained by following a reaction sequence analogous to that described for example 3. 01-3595-WO-1 135 01-3595-WO-1 136 01-3595-WO-1 137 01-3595-WO-1 138 01-3595-WO-1 139 01-3595-WO-1 140 01-3595-WO-1 141 01-3595-WO-1 142 01-3595-WO-1 143 01-3595-WO-1 144 01-3595-WO-1 145 Synthesis of example 9 and 48: 01-3595-WO-1 146 4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazol- 4-yl}-2-[3-methoxy-1-(methoxymethyl)-1H-pyrazol-4-yl]-2H-indazole (example 9) Under an atmosphere of argon, 4-bromo-5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H- 5 pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazole (G2) (280 mg, 0.60 mmol) and 2-(3-methoxy-1-{[2- (trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H- indazole (C7) (273 mg, 0.71 mmol) are dissolved in dioxane (15 mL). K3PO42 M (893 µL, 1.79 mmol) and XPhos Pd G3 (50.4 mg, 0.06 mmol) are added, and the reaction mixture is stirred at 100 °C for 3 h. The reaction mixture is purified by reversed phase chromatography (HPLC; ACN / water including 10 TFA) to afford the intermediate with SEM protecting group. The intermediate is dissolved in MeOH (10 mL), 4 M HCl in dioxane (5 mL) is added, and the reaction mixture is stirred at 50 °C for 2 h. The reaction is concentrated and purified by reversed phase chromatography (HPLC; ACN / water including TFA) to afford example 9.Analysis (method A): Rt: 0.85 min, [M+H] +: 55215 The examples compiled in the following table are obtained by following a reaction sequence analogous to that described for example 9. 01-3595-WO-1 147 Synthesis of example 19, 31, 33, 75: Synthesis of example 19: 5 Step 1: Synthesis of 1-[5-(5-cyclopropyl-1-methyl-4-{2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]- 2H-indazol-4-yl}-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b] pyridin-6-yl] ethan-1-ol Under an atmosphere of argon, 1-[5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl- 2H-pyrazolo[3,4-b]pyridin-6-yl]ethan-1-ol (G8) (16.0 mg, 0.04 mmol) and {2-[1-methyl-5- 10 (trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazol-4-yl}boronic acid (C2) (14.5 mg, 0.05 mmol) are dissolved in dioxane (1 mL). K3PO42 M (63.8 µL, 0.13 mmol) and XPhos Pd G3 (7.20 mg, 0.01 mmol) are added, and the reaction mixture is stirred at 95 °C for 3.5 h. The reaction mixture is purified by reversed phase chromatography (HPLC; ACN / water including TFA) to afford the desired compound. Analysis (method B): Rt: 0.96 min, [M+H] +: 56215 Step 2: Synthesis of (1S)-1-[5-(5-cyclopropyl-1-methyl-4-{2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol- 3-yl]-2H-indazol-4-yl}-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl]ethan-1-ol (example 19) and (1R)-1-[5-(5-cyclopropyl-1-methyl-4-{2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H- indazol-4-yl}-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl]ethan-1-ol (example 31) 20 01-3595-WO-1 148 1-[5-(5-Cyclopropyl-1-methyl-4-{2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazol-4-yl}- 1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl]ethan-1-ol (12.0 mg, 0.02 mmol) is separated by chiral purification method A2 to afford the compounds (1S)-1-[5-(5-cyclopropyl-1- methyl-4-{2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazol-4-yl}-1H-imidazol-2-yl)-2- 5methyl-2H-pyrazolo[3,4-b]pyridin-6-yl]ethan-1-ol (example 19) (Analysis (method S): Rt: 2.52 min)and (1R)-1-[5-(5-cyclopropyl-1-methyl-4-{2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H- indazol-4-yl}-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl]ethan-1-ol (example 31)(Analysis (method S): Rt: 1.88 min). 10 The examples compiled in the following table are obtained by following a reaction sequence analogous to that described for example 19 / 31. 01-3595-WO-1 149 Synthesis of Example 24 and 65: Step 1: Synthesis of 1-[5-(5-cyclopropyl-1-methyl-4-{2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]- 2H-indazol-4-yl}-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl]propan-1-ol 5 Under an atmosphere of argon 1-[5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-2-methyl- 2H-pyrazolo[3,4-b]pyridin-6-yl]propan-1-ol (G6) (90.0 mg, 0.231 mmol) and 4-(5,5-dimethyl-1,3,2- dioxaborinan-2-yl)-2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazole (C6) (87.2 mg, 0.231 mmol) are dissolved in dioxane (1.5 mL). K3PO42 M (461 µL, 0.922 mmol) and XPhos Pd G3 (11.7 mg, 10 0.0138 mmol) are added, and the reaction mixture is stirred at 80 °C for 3 h. The reaction mixture is purified by reversed phase chromatography (HPLC; ACN / water including TFA) to afford the desired compound. Analysis (method C): Rt: 0.52 min, [M+H] +: 57615 Step 2: Synthesis of (1R)-1-[5-(5-cyclopropyl-1-methyl-4-{2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazol-4-yl}-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl]propan-1-ol (example 24) and (1S)-1-[5-(5-cyclopropyl-1-methyl-4-{2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazol-4-yl}-1H-imidazol-2-yl)-2H-pyrazolo[3,4-b]pyridin-6-yl]propan-1-ol (example 65) 01-3595-WO-1 150 1-[5-(5-cyclopropyl-1-methyl-4-{2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazol-4-yl}-1H- imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl]propan-1-ol (73.0 mg, 0.106 mmol) isseparated by chiral purification method A3 to afford the compounds (1R)-1-[5-(5-cyclopropyl-1- 5 methyl-4-{2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazol-4-yl}-1H-imidazol-2-yl)-2- methyl-2H-pyrazolo[3,4-b]pyridin-6-yl]propan-1-ol (example 24) (Analysis (method U): Rt: 3.37 min)and (1S)-1-[5-(5-cyclopropyl-1-methyl-4-{2-[1-methyl-5- (trifluoromethyl)-1H-pyrazol-3-yl]-2H-indazol-4-yl}-1H-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4- b]pyridin-6-yl]propan-1-ol (example 65) (Analysis (method U): Rt: 4.47 min).10 Alternatively, example 24 was synthesized from intermediate G14 and C6 using described synthesismethod for step 1 to yield example 24. Analysis (method C): Rt: 0.53 min, [M+H] +: 576.Example 78 and 78A can be synthesized by an analogous method using intermediate C6DM instead15 of intermediate C6. In a first step, intermediates G6 and C6DM are joined, and in a second step the 4-methoxyphenylgroup is removed.

[0002] 01-3595-WO-1 151 5 Synthesis of example 29, 32, 40, 64: Synthesis of example 32: Synthesis of trans-2-{4-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-10 methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-3-methoxy-1H-pyrazol-1-yl}-N,N-dimethylcyclopropane-1- carboxamide 01-3595-WO-1 152 4-[2-(Chloromethyl)-3-nitrophenyl]-5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b] pyridin-5-yl}-1-methyl-1H-imidazole dihydrochloride (H1) (580 mg, 1.43 mmol, 90 % purity) is dissolved in ACN (30 mL). Trans-2-(4-amino-3-methoxy-1H-pyrazol-1-yl)-N,N-dimethylcyclopropane- 5 1-carboxamide (A14) (400 mg, 1.69 mmol) and DIPEA (988 µL, 5.71 mmol) are added, and the reaction mixture is stirred at 60 °C for 2 h. The reaction mixture is concentrated to dryness to afford the ring opened intermediate. The intermediate is dissolved in MeOH (4 mL), zinc (150 mg, 2.30 mmol) and ammonium formate (360 mg, 5.71 mmol), dissolved in MeOH (30 mL), are added, and the reaction mixture is stirred at RT overnight. The reaction mixture is purified by reversed phase10 chromatography (HPLC; MeOH / water including TFA) to afford the desired example 32. Analysis (method A): Rt: 0.86 min, [M+H] +: 617Synthesis of example 29 and 64: Synthesis of (1S,2S or 1R,2R)-2-{4-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-15 b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-3-methoxy-1H-pyrazol-1-yl}-N,N- dimethylcyclopropane-1-carboxamide (example 64) and (1R,2R or 1S, 2S)-2-{4-[4-(5-cyclopropyl-2-{6- cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-3- methoxy-1H-pyrazol-1-yl}-N,N-dimethylcyclopropane-1-carboxamide (example 29) 20 Trans-2-{4-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H- imidazol-4-yl)-2H-indazol-2-yl]-3-methoxy-1H-pyrazol-1-yl}-N,N-dimethylcyclopropane-1- carboxamide (example 32) (590 mg, 0.81 mmol) is separated by chiral purification method V toafford the compounds (1S,2S or 1R,2R)-2-{4-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H- 01-3595-WO-1 153 pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-3-methoxy-1H-pyrazol-1-yl}- N,N-dimethylcyclopropane-1-carboxamide (example 64) (Analysis (method V): Rt: 1.28 min) and(1R,2R or 1S, 2S)-2-{4-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1- methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-3-methoxy-1H-pyrazol-1-yl}-N,N-dimethylcyclopropane-1- 5carboxamide (example 29) (Analysis (method V): Rt: 1.67 min).The examples in the following table are obtained by following a reaction sequence analogous to that described for example 29. 10 Synthesis of example 37 – 39 and 71:Synthesis of Example 37: 2-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-4-{5-cyclopropyl-1-methyl-2-[2- methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b] pyridin-5-yl]-1H-imidazol-4-yl}-1H-1,3-benzodiazole 01-3595-WO-1 154 3-{5-Cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazol- 4-yl}benzene-1,2-diamine (J1) (4.42 mg, 11.0 µmol), 5-cyclopropyl-1-methyl-1H-pyrazole-3-carboxylic acid (1.92 mg, 11.6 µmol), HATU (4.18 mg, 11.0 µmol) and DIPEA (5.71 µL, 33.0 µmol) are dissolved in 5 DMF (0.5 mL) and stirred at RT overnight. The reaction is concentrated. Glacial acetic acid (0.5 mL) is added, and the reaction mixture is stirred at 70 °C for 4 h. It is concentrated and purified by reversed phase chromatography (HPLC; ACN / water including TFA) to afford example 37. Analysis (method T: Rt: 0.82 min, [M+H] +: 55810 The examples compiled in the following table are obtained by following a reaction sequence analogous to that described for example 37. 01-3595-WO-1 155 Synthesis of example 41: Step 1: Synthesis of 4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b] pyridin-5-yl]-1H-imidazol-4-yl}-2-[5-(difluoromethyl)-1-[(4-methoxyphenyl)methyl]-1H-pyrazol-3-yl]-5 2H-indazole 01-3595-WO-1 156 Under an atmosphere of argon, 4-bromo-5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H- pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazole (G2) (87.1 mg, 0.23 mmol) and {2-[5-(difluoromethyl)-1-[(4- methoxyphenyl)methyl]-1H-pyrazol-3-yl]-2H-indazol-4-yl}boronic acid (C18) (103 mg, 0.23 mmol) are dissolved in dioxane (2 mL). K3PO42 M (466 µL, 0.93 mmol) and XPhos Pd G3 (11.8 mg, 0.01 mmol) 5 are added, and the reaction mixture is stirred at 80 °C for 1 h. The reaction mixture is purified by reversed phase chromatography (HPLC; ACN / water including TFA) to afford the desired compound. Analysis (method C): Rt: 0.61 min, [M+H] +: 648Step 2: Synthesis of 4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-10 b]pyridin-5-yl]-1H-imidazol-4-yl}-2-[5-(difluoromethyl)-1H-pyrazol-3-yl]-2H-indazole (example 41) In a MW vial, 4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]- 1H-imidazol-4-yl}-2-[5-(difluoromethyl)-1-[(4-methoxyphenyl)methyl]-1H-pyrazol-3-yl]-2H-indazole (154 mg, 0.20 mmol) is dissolved in TFA (2 mL) and anisole (22.1 µL, 0.20 mmol), and the reaction 15 mixture is stirred in the MW at 120 °C for 20 min. The reaction is concentrated and purified by reversed phase chromatography (HPLC; ACN / water including TFA) to afford example 41.Analysis (method C): Rt: 0.48 min, [M+H] +: 528Synthesis of example 51: 4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-20 b]pyridin-5-yl]-1H-imidazol-4-yl}-2-[5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl]-2H-indazole Under an atmosphere of argon, 4-bromo-5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H- pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazole (G2) (40.1 mg, 0.11 mmol) and 2-[5-(difluoromethyl)-1- methyl-1H-pyrazol-3-yl]-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2H-indazole (C15) (66.7 mg, 0.11 01-3595-WO-1 157 mmol, 61 % purity) are dissolved in dioxane (1 mL). K3PO42 M (200 µL, 0.40 mmol) and XPhos Pd G3 (20.3 mg, 0.02 mmol) are added, and the reaction mixture is stirred at 80 °C for 2 h. The reaction mixture is purified by reversed phase chromatography (HPLC; ACN / water including NH3) to afford example 51.5 Analysis (method E): Rt: 0.66 min, [M+H] +: 542Synthesis of example 52, 58 and 76: Synthesis of example 52: 4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2-[3-methoxy-1-(1,2-thiazol-4-yl)-1H-pyrazol-4-yl]-2H-indazole 10 Under an atmosphere of argon, in a vial, 4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4- b] pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2-(3-methoxy-1H-pyrazol-4-yl)-2H-indazole (K1) (23.0 mg, 0.05 mmol) and 4-bromo-1,2-thiazole (11.8 mg, 0.07 mmol, 95 % purity) are dissolved in dioxane (2 mL). CuI (0.43 mg, 0.002 mmol), trans-(1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (6.60 µL, 15 0.04 mmol) and tri-potassium orthophosphate (19.3 mg, 0.09 mmol) are added, and the reaction mixture is stirred in the closed vial at 110 °C for 12 h. The reaction mixture is concentrated, filtered, and purified by reversed phase chromatography (HPLC; ACN / water including TFA) to afford example 52. Analysis (method A): Rt: 0.81 min, [M+H] +: 58920 The examples compiled in the following table are obtained by following a reaction sequence analogous to that described for example 52. 01-3595-WO-1 158 Synthesis of example 53: Step 1: Synthesis of trans-ethyl-2-[4-(4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-5 pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazol-4-yl}-2H-indazol-2-yl)-3-methoxy-1H-pyrazol-1- yl]cyclopropane-1-carboxylate 01-3595-WO-1 159 Under an atmosphere of nitrogen, 4-bromo-5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H- pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazole (G2) (300 mg, 0.78 mmol) and ethyl (1R,2R)-2-{4-[4-(5,5- dimethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-2-yl]-3-methoxy-1H-pyrazol-1-yl}cyclopropane-1- 5 carboxylate (C27) (640 mg, 0.93 mmol) are dissolved in dioxane (5 mL). K3PO42 M (1.2 mL, 2.40 mmol) and XPhos Pd G3 (100 mg, 0.118 mmol) are added, and the reaction mixture is stirred at 90 °C for 1.75h. The reaction mixture is purified by flash chromatography (EtOAc / MeOH 100 / 0 --> 50 / 50)to afford the desired compound. Analysis (method C): Rt: 0.56 min, [M+H] +: 62010 Step 2: Synthesis of trans-2-[4-(4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazol-4-yl}-2H-indazol-2-yl)-3-methoxy-1H-pyrazol-1- yl]cyclopropane-1-carboxylic acid 15 Ethyl-2-[4-(4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]- 1H-imidazol-4-yl}-2H-indazol-2-yl)-3-methoxy-1H-pyrazol-1-yl]cyclopropane-1-carboxylate (437 mg, 0.648 mmol) is dissolved in MeOH (10 mL). NaOH 2 M (5.00 mL, 10.0 mmol) is added, and the reaction mixture is stirred at 60 °C for 2 h. The reaction mixture is acidified with trifluoroacetic acid,filtered and the methanol was removed in vacuum. 01-3595-WO-1 160 The residue is purified by reversed phase chromatography (HPLC; ACN / water including TFA) to afford the desired compound. Analysis (method C): Rt: 0.46 min, [M+H] +: 5925 Step 3: Synthesis of (1R,2R)-2-[4-(4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H- pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazol-4-yl}-2H-indazol-2-yl)-3-methoxy-1H-pyrazol-1-yl]-N,N- dimethylcyclopropane-1-carboxamide (example 53) 10 Trans-2-[4-(4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]- 1H-imidazol-4-yl}-2H-indazol-2-yl)-3-methoxy-1H-pyrazol-1-yl]cyclopropane-1-carboxylic acid (105 mg, 0.148 mmol) is dissolved in NMP (2 mL). DIPEA (80 µL, 0.463 mmol), HATU (113 mg, 0.297 mmol) and dimethylamine 2 M in THF (372 µL, 0.744 mmol) are added, and the reaction mixture is stirred at 15 RT for 1.5 h. The reaction mixture is purified by reversed phase chromatography (HPLC; ACN / water including NH3). The residue is purified by chiral purification method V to afford example 53. Analysis (method V): Rt: 1.21 min, [M+H] +: 61920 Synthesis of example 54: Step 1: Synthesis of methyl 2-({1-cyclopropyl-4-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b] pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1H-pyrazol-3-yl}oxy)acetate 01-3595-WO-1 161 4-[2-(Chloromethyl)-3-nitrophenyl]-5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b] pyridin-5-yl}-1-methyl-1H-imidazole dihydrochloride (H1) (220 mg, 0.37 mmol, 90 % purity) is dissolved in ACN (4 mL). Methyl 2-[(4-amino-1-cyclopropyl-1H-pyrazol-3-yl)oxy]acetate (A19) (103 mg, 0.46 mmol, 95 % purity) and DIPEA (256 µL, 1.48 mmol) are added, and the reaction mixture is 5 stirred at 60 °C for 2 h. The reaction mixture is concentrated to dryness to afford the ring opened intermediate. The intermediate is dissolved in MeOH (4 mL), zinc (15.0 mg, 0.23 mmol) and ammonium formate (36.0 mg, 0.57 mmol), dissolved in MeOH (3 mL), are added, and the reaction mixture is stirred at RT overnight. The reaction mixture is purified by reversed phase chromatography (HPLC; ACN / water including TFA) to afford the desired compound.10 Analysis (method A): Rt: 0.89 min, [M+H] +: 604Step 2: Synthesis of 2-({1-cyclopropyl-4-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1H-pyrazol-3-yl}oxy)acetic acid 15 Methyl 2-({1-cyclopropyl-4-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b] pyridin-5- yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1H-pyrazol-3-yl}oxy)acetate (60.0 mg, 0.10 mmol) is dissolved in MeOH (10 mL). NaOH 1 M (4.00 mL, 4.00 mmol) is added, and the reaction mixture is stirred at 60 °C for 2 h. The MeOH is evaporated, and the aqueous residue is acidified with 4 M HCl. The reaction mixture is purified by reversed phase chromatography (HPLC; ACN / water including TFA)20 to afford the desired compound. Analysis (method A): Rt: 0.85 min, [M+H] +: 590Step 3: Synthesis of 2-({1-cyclopropyl-4-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4- b] pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1H-pyrazol-3-yl}oxy)-N,N-25 dimethylacetamide (example 54) 01-3595-WO-1 162 2-({1-Cyclopropyl-4-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b] pyridin-5-yl}-1- methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1H-pyrazol-3-yl}oxy)acetic acid (13.4 mg, 0.02 mmol) is dissolved in DMF (1 mL). DIPEA (9.88 µL, 0.06 mmol), HATU (7.96 mg, 0.02 mmol) and dimethylamine 5 2 M in THF (28.6 µL, 0.06 mmol) are added, and the reaction mixture is stirred at RT for 2 h. The reaction mixture is purified by reversed phase chromatography (HPLC; ACN / water including TFA) to afford example 54.Analysis (method R): Rt: 0.62 min, [M+H] +: 61710 Synthesis of example 79: Step1: Synthesis of 1-[5-(5-cyclopropyl-1-methyl-4-{2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]- 2H-indazol-4-yl}-1H-imidazol-2-yl)-2-methyl-2H-indazol-6-yl]propan-1-one 1-[5-(4-Bromo-5-cyclopropyl-1-methyl-imidazol-2-yl)-2-methyl-indazol-6-yl]propan-1-ol (52 mg,15 0.0254 mmol), 1-[5-(4-bromo-5-cyclopropyl-1-methyl-imidazol-2-yl)-2-methyl-indazol-6-yl]propan-1-one (52 mg, 0.0349 mmol) and 3-[5-(4-bromo-5-cyclopropyl-1-methyl-imidazol-2-yl)-2-methyl-indazol-6-yl]pentan-3-ol (52.00 mg, 0.0660 mmol) in 2-methyltetrahydrofuran (2 mL) is combinedwith 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]indazole(150.0 mg, 0.397 mmol), methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-20 biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(ii) (15 mg, 0.0174 mmol) and 2.0 M potassiumphosphate tribasic (0.4 mL, 0.8 mmol). The mixture is degassed under a stream of argon for 1 min and stirred under reflux for 2 h and at room temperature for 14 h.2-Methyltetrahydrofuran (40mL) is added and the solution is dried over diatomaceous earth and magnesium sulfate. The solids 01-3595-WO-1 163 are filtered off, the filtrate is concentrated in vacuum and the residue is purified by HPLC to give the desired product. Analysis (method A4): Rt: 0.50 min, [M+H] +: 5735 Step 2: Synthesis of 1-[5-(5-cyclopropyl-1-methyl-4-{2-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]- 2H-indazol-4-yl}-1H-imidazol-2-yl)-2-methyl-2H-indazol-6-yl]propan-1-ol (Example 79) Example 791-[5-[5-Cyclopropyl-1-methyl-4-[2-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]indazol-4-yl]imidazol-2- yl]-2-methyl-indazol-6-yl]propan-1-one (8 mg, 0.0140 mmol) was dissolved in ethanol (110 mL) and sodium borohydride (1 mg, 0.0264 mmol) was added. The mixture was allowed to stir atroom temperature for 2.5 h. The reaction solution is diluted with acetonitrile (2 mL), basified withammonium hydroxide, filtered and purified by HPLC to give example 80.Analysis (method D): Rt: 0.921 min, [M+H] +: 57515 HPLC Methods: Method A (Z018_S04) 20 01-3595-WO-1 164 Method B (Z011_S03) Method C (X012_S01) 5 Method D (X011_S05) 10 Method E (X018_S03) 01-3595-WO-1 165 Method F (SLV-Method-45) column: Acquity UPLC BEH C181.7 µm (2.1 x 100 mm); column temperature: 40 °C5 Method G (SLV-Method-111) column: Kinetex XB-C182.6µm (4.6 x 50 mm); column temperature: 25 °CMethod H (Z017_S04) 01-3595-WO-1 166 Method I (SLV-Method-36) column: Acquity UPLC BEH C181.7 µm (2.1 x 100 mm); column temperature: 40 °C5 Method J (Z021_S01) Method L (Z003_003) 01-3595-WO-1 167 Method M (X015_S04) 5 Method N (008_CA02) Method O (007_CA02) 01-3595-WO-1 168 Method P (008_CA11) 5 Method Q (007_CA10) Method R (007_CA11) 01-3595-WO-1 169 Method S (I_SB_30_IPA_NH3_002) 5 Method T (008_CA10) Method U (I_SB_25_ETOH_NH3_003) 10 01-3595-WO-1 170 Method V (I_AC_35_IPA_NH3_002) 5 Method W (I_SB_30_MEOH_NH3_003) Method X (I_SZ_40_MEOH_NH3_003) 10 Method Y (I_SB_25_MEOH_NH3_003) 01-3595-WO-1 171 Method Z (I_AC_30_MEOH_NH3_002) Method A1: 5 Method A2: Method A3: 01-3595-WO-1 172 Method A4: (X011_U04) 5 10 List of Abbreviations: Ac acetylACN acetonitrileAIBN 2,2´-azobis(isobutyronitrile)Boc tert-butyloxycarbonyl15 Cbz benzyloxycarbonylCycH cyclohexaned day(s)DAST diethylamino sulfur trifluorideDCE 1,2-dichloroethane20 DCM dichloromethane 01-3595-WO-1 173 DEAD diethyl azodicarboxylateDIAD diisopropyl azodicarboxylateDIPEA N,N-diisopropylethylamineDMF N,N-dimethylformamide5 DMP Dess–Martin PeriodinaneDMSO dimethyl sulfoxideEtOAc ethyl acetateEtOH ethanolh hour(s)10 HATU O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium-hexafluorophosphate HPLC high performance liquid chromatography HPLC-MS coupled high performance liquid chromatography-mass spectrometryIPA isopropyl alcohol15 liquid chromatographyLC-MS coupled liquid chromatography – mass spectrometryLiHMDS Lithium-bis(trimethylsilyl)amidemolar (mol / L)MeI methyl iodide20 MeTHF 2-methyltetrahydrofuranMeOH methanolmin minute(s)MS mass spectrometryMTBE methyl-tertbutyl-ether25 n-BuLi n-ButhyllithiumNBS N-BromosuccinimideNIS N-IodosuccinimideNMP N-methyl-2-pyrrolidoneNMR nuclear magnetic resonance30 PEPPSI(TM)-IPR (1,3-Bis(2,6-diisopropylphenyl)imidazolidene) (3-chloropyridyl)palladium(II) dichloride PdCl2(dtbpf) 1,1ʹ-Bis-(di-tert-butylphosphino-)ferrocene-palladiumdichloridePd(dppf)Cl21,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) Pd(PPh3)4 palladium (0) tetrakis(triphenylphosphine)35 XPhos Pd G3 2-Dicyclohexylphosphino-2ʹ,4ʹ,6ʹ-triisopropyl-1,1ʹ-biphenyl)[2-(2ʹ- 01-3595-WO-1 174 amino-1,1ʹ- biphenyl)]palladium(II) methanesulfonatpet. petroleumRf retention factor RP reverse phase5 rt room temperaturetRretention time (in HPLC / LC) SFC supercritical fluid chromatographyTBAF tetrabutylammonium fluorideTBTU O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate10 TEA triethylamineTFA trifluoroacetic acidTHF tetrahydrofuranTHP tetrahydro-2h-pyranTLC thin-layer chromatography15 TMAD N,N,NʹNʹ-TetramethylazodicarboxamideUV ultravioletV volume20 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. Human STING HTRF binding assay 25 Binders to human STING WT (R232) were identified using a competitive HTRF assay format (Cisbio 64BDSTGPEG), which uses d2-labeled STING ligand, a 6His tagged human STING protein, and an anti 6His Cryptate-labeled antibody. Compounds compete with the STING ligand-d2 and thereby prevents FRET from occurring, which can be measured by an EnVision™ reader (PerkinElmer).30 Assay method: Compounds were delivered as 10mM DMSO solution, serially diluted by an Agilent Bravo Workstation and transferred to the 384well assay plate (Perkin Elmer # 6005359) using a Cybiwell dispenser. Typically, 8 concentrations were used with the highest concentration at 10µM or 1µM in the final assay volume followed by ~1:5 dilution steps. DMSO concentration was set to 1% in 01-3595-WO-1 175 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 5 138-379) 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 10 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 % 15 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. 20 Determination of the increase of stability of STING protein against thermal denaturation, Differential Scanning Fluorimetry (DSF) 25 The binding affinity of the compounds of the invention may be demonstrated using a thermal shift assay that measures the stability of a suitable protein material of human STING against thermal denaturation in the presence of compounds. In this assay, the unfolding temperature of a protein is monitored in the presence of a fluorescent dye which exhibits affinity for the hydrophobic amino acids of the protein that are buried in its folded state and are gradually exposed during unfolding. 30 Dye fluorescence is quenched in aqueous environment and increases upon association of the dye with the hydrophobic parts of the unfolding protein. A plot of the fluorescence intensity as a function of temperature typically displays a sigmoidal curve that is interpreted by a two-state model of protein unfolding (Differential Scanning Fluorimetry). The inflection point of the curve represents the “melting” temperature of the protein (Tm) which is calculated numerically using the Boltzmann35 equation. 01-3595-WO-1 176 Method: The thermal stability of the STING protein was measured using a specific expression construct of the cGAMP binding domain of wild-type (GRR) human STING comprising residues 155- 341 and a N-terminal 8x His-tag in assay buffer containing 20mM Tris, 150mM NaCl at pH7.5. 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). 10 A DMSO stock solution of SYPRO orange (SIGMA S5692-500UL) was prepared. Compound stock solutions (10mM in DMSO) were diluted 1:2 in DMSO to an intermediate compound concentration of 5mM and then further diluted 1:40 in assay buffer resulting in a compound concentration of 125µM and 2.5% DMSO. 15 Fluorescent dye stock solution (5000x SYPRO Orange) was then mixed with target protein and buffer to a concentration of 15uM Protein and 25x SYPRO Orange.2ul of this protein-dye-mixture was added to 8ul compound solution. Final volume was 10uL.3-6 well positions were used as negative control (protein with 2% DMSO). The plates were prepared for duplicate measurement and 20 centrifuged for 2 min at 1000g. In the measurement, 160 cycles of 0.5 °C were used (temperature ramp 15s / cycle, 15 °C to 95 °C). Final Assay concentrations for compound characterization were as follows: 100uM compound, 3uM target protein, 5x SYPRO Orange, 2% DMSO in 10ul. All dispensing steps25 were performed using a HamiltonStar pipetting robot (Hamilton). Dissociation curves were processed in Bio-Rad CFX Manager. Peak type was set to "negative". Compound codes for screen were assigned in the plate layout. Two replicates of TM measurements were averaged, and the standard deviation was calculated. In30 cases of SD>1.5 °C the measurement was repeated. The melting point (Tm) obtained for STING protein alone was subtracted from T obtained for proteinincubated with ligand to generate ∆Tm values. Protein production and purification: The protein used for the biophysical experiments was a 35 recombinant human STING protein comprising its cytosolic ectodomain. A codon optimized DNA 01-3595-WO-1 177 sequence (for expression in Escherichia coli) encoding amino acid residues 155 to 341 (Swiss Prot Q86WV6) of human STING (WT) was synthesized by GeneArt (Regensburg, Germany) and inserted into a pET17b E. coli expression vector. The protein construct encodes an N-terminal 8x His-tag followed by tobacco etch virus protease (TEV) cleavage site and the above STING gene sequence. The 5resulting protein sequence for the used STING variant is listed below:His-TEV—hSTING (WT) (SEQ ID NO: 1)MHHHHHHHHENLYFQSGVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLS MADPNIRFLDKLPQQTGDRAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKL 10 FCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEV For expression of recombinant human STING above construct was transformed into E. coli BL21 DE3 strain and grown in shake flasks in LB-medium at 37°C. Expression was induced by addition of isopropyl β-D-1-thiogalactopyranoside to a final concentration of 1mM and cultures shaken 15 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)), followed by metal affinity purification using Ni-NTA resins and elution buffer consisting of 20mM TRIS-HCl, pH 8, 300mM NaCl, 2mM mercaptoethanol, 300mM imidazole and size exclusion 20 chromatography in running buffer (20mM TRIS-HCl, pH 8, 100mM NaCl, 2mM DTT). The peak fraction was collected and concentrated to 2.5mg / mL. The results of this assay are shown in the characterising data table below. 25 Human whole blood assay (HWBA) 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 the30 IFNα2α production. Assay method: Compounds were delivered as 10mM DMSO solution and serial diluted and 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 35 with the highest concentration at 10µM in the final assay volume followed by ~1:5 dilution steps. 01-3595-WO-1 178 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. Collection of human whole blood from 3 or more healthy donors (male or female, no medication for 5 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. 160µl of the whole blood samples were transferred to each well of the 96-well assay plates filled 10 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. 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 high15 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 at 37°C in the incubator, without shaking. 20 For the detection of IFNα-2α in human plasma, the biotinylated capture antibody (Antibody set IFNA2, Meso Scale Diagnostics #B21VH-3, including coating and capture antibody) was diluted 1:17.5 in Diluent 100 (Meso Scale Diagnostics #R50AA-4, according to the manufacturer. U-Plex MSD GOLD 96-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 25 continuous shaking at 700rpm. MSD IFNα-2α plates were washed three times with 150µl wash buffer (1x HBSS, 0.05% Tween). 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 as30 possible by dumping just before continuing with the human plasma. Whole Blood assay plates werecentrifuged at 1600rpm for 10 minutes.25µl of supernatant was transferred with a pipetting robotics from each whole blood plate to the corresponding IFNα-2α plate. Plates were sealed with microplate seals and kept at room temperature again under continuous shaking at 700rpm for two hours. Next MSD IFNα-2α plates were washed three times with 150µl wash buffer (1x HBSS, 0.05% Tween), 35 before adding 25µl MSD SULFO-TAG IFNα-2α Antibody solution (1:100 diluted in Diluent 3 (Meso 01-3595-WO-1 179 Scale Diagnostics # R50AP-2) to each well of the plates. Afterwards plates were sealed with microplate seals and kept at room temperature again under continuous shaking at 700rpm for two hours. Finally MSD IFNα-2α 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 5 the MSD Sector S600 Reader using the vendor barcode. Data evaluation and calculation: For data evaluation and calculation, % control calculation of each well was based on the mean of high (cGAMP stimulated control) and mean of low (unstimulatedcontrol) controls by using the following formula:10 [counts(sample) - counts(low)) / (counts(high) - counts(low))]*100The IC50 values were calculated using the standard 4 parameter logistic regression formula. Calculation: [y=(a-d) / (1+(x / c)^b)+d], a = low value, d = high value; x = conc M; c=IC50 M; b = slope; The results of this assay are shown in the characterising data table below. 15 Human STING reportergene assay A THP1-BlueISG reporter cell line expressing wildtype STING and IRF dependent alkaline phosphatase20 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 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 25 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; Cells, cultivated according to manufacturer’s conditions (culture medium: RPMI 1640 (Life 30 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 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 35 medium was added to the wells containing compounds, followed by a 30 min incubation at RT and a 01-3595-WO-1 180 24h incubation at 37°C. Then 5ul per well of assay medium with DMSO (1% f.c.) was added to the wells for the controls, plus 5 µl of assay medium alone for negative controls (low values) or 5µl of prediluted 2`3`-cGAMP (20µM f.c.; BIOLOG Life Science Institute # C 161 or Invivogen # tlrl-nacga23) for positive controls (high values). 5 Finally 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).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. 10 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; The results of this assay are negative for agonism, wherein the threshold was set larger than 30 µM. 15 Characterising Data Table 01-3595-WO-1 181 01-3595-WO-1 182 01-3595-WO-1 183 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 not more than 70 nM. In another preferred embodiment, said IC 50 value is at least and including0.8nM 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. An exemplary value is a ratio of20 around 4. 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, or25 as in the publication by Dong et al. Pharm Res (2020) 37: 194, https: / / doi.org / 10.1007 / s11095-020- 02895-9. In one embodiment the CACO2 cell efflux ratio of the inventive compounds is equal to or below 12, 10, 8, 7, 6, 5, 4.5, 4,3.5, 3,2.5, 2, 1.5, 1.3. In one embodiment the efflux ratio is above 0.7. Anexemplary efflux value is around 1. 01-3595-WO-1 184 In a preferred embodiment the compound of the invention is subject to active efflux from the CACO2 cells. Inhibition of cytochrome P450 enzymes CYP2D6 and CYP3A45 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 metabolized by CYP2D6 (Schadel M, Wu D, Otton SV, Kalow W, Sellers EM. Pharmacokinetics of dextromethorphan and metabolites in humans: influence of the CYP2D6 phenotype and quinidine inhibition. J Clin Psychopharmacol.1995 Aug;15(4):263-9. doi: 10.1097 / 00004714-199508000-00005. 10 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& WO14197345 and the patent US8138188 BB). For testing the possible inhibition of the compounds of the invention, demethylation of 15 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 also determined as a control. 20 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).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 25 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. CYP3A4 and / or CYP2D6 inhibition is observed for the inventive compounds with IC50 values of equal30 to or greater 10 µmol, preferably equal to or greater 15 µmol and more preferred equal to or greater20 µmol and even more preferred equal to or greater 25 µmol and most preferred over 30 µmol. Measuring clearance from human hepatocytes The metabolic degradation of a test compound is assayed in a human hepatocyte suspension using35 known methods as in the patent application US2024327429. 01-3595-WO-1 185 In one embodiment the hepatocyte clearance is lower than 25 % Qh [%], preferably equal to or lowerthan 20 %, 15 %, 10 %, or more preferably at most 8%. An exemplary value of inventive compoundsis 7.5 %. 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 compounds to plasma proteins applying Dianorm Teflon dialysis cells (micro 0.2). Each dialysis cell 10 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 µl test compound dialysis solution in plasma are dispensed into the donor (plasma) chambers. 15 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, are transferred into reaction tubes and processed for HPLC-MS / MS analysis. Analyte concentrations 20 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 10025 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 %. An exemplary value is 0.8 %. IP10 production in human dermal MicroVascular Endothelial Cells (MVEC) after double-stranded DNA30 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 cytoplasm and resulting STING activity. In some diseases, imbalanced STING activation can result todamage 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). 01-3595-WO-1 186 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 the5 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 Results: The inventive compounds show good inhibition of IP10 production after stimulation of HMVEC with dsDNA. This demonstrates that the inventive compounds show direct targetengagement 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 yetIn 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 those20 compounds, that show IC50 values of at least 0.001 nM and less than 150 nM, preferably less than100 nM, more preferably less than 50 nM, even more preferably less than 20 nM when tested for inhibition of human dermal MVEC as described above. In another embodiment said IC 50 value of theinventive compound is in the range of and including 5nM to and including 35 nM. 25 Inhibition of STING mutants associated with SAVI by the inventive compounds 01-3595-WO-1 187 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 vascular and pulmonary syndrome. N Engl J Med.2014 Aug 7;371(6):507-518. doi: 10.1056 / NEJMoa1312625) 5Methods for testing STING activity in THP1 cells with the reporter gene encoding luciferase areknown (see the patent publication US2020181153 and references therein). These known methods are modified slightly: As for these gain of function mutants of STING that are associated with SAVI, no stimulation by cGAMP is needed, the assay can be performed without cGAMP or similar as a stimulant. The assay relies on THP1 cells that contain an engineered “knock in” of the mutated STING10 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 associated mutant STING proteins and consequently shut down the ISG linked luciferase reporter expression. 15 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. The known STING inhibitor SN-011 has previously been reported to inhibit these mutantversions of STING in cell assays (Z. Hong et al, STING inhibitors target the cyclic dinucleotide binding 20 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. Nature 559, 269–273 (2018). https: / / doi.org / 10.1038 / s41586-018-0287-8). 25 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 STING30 inhibitors SN-011 and H-151 (see above for details) for comparison. As the known inhibitor of STING SN-011 had been reported to inhibit the two mutants of STING tested, the potency of the compounds of the invention in comparison to that of SN-011 is determined. The results are expressed as the ratio of the IC50 value of the compound tested, i.e. the compound of the invention or the second known inhibitor H-151 to the IC 50 values determined for35 SN-011 in the particular assay. These are normalized so that the value for SN-011 is set to 100% and 01-3595-WO-1 188 the others expressed as a percentage number in relation thereto Table S shows the results, roundedto one digit, based on multiple repetitions unless otherwise stated. Table S 5 * single experiment 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 10 mutant V155M of STING. However, the compounds of the invention with the exception of example 71 require even less, only between 0.1 % and 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. 15 From the data above example 71 with a benzimidazol as the attachment point for R5 (i.e. X-Y-Z of formula (I) is selected from the group X-Y-Zc) 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 showing good inhibition of these mutants as well as inhibition of the wildtype STING protein are all having an indazol structure as the attachment point for R5 (i.e.. X-Y-Z of formula (I) is20 selected from the group X-Y-Zb). 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 STING are at least 0.01 nM, but less than 150 nM, preferably less than 120 nM and more preferably less than 50 nM and even more preferably less than 20 nM. In 01-3595-WO-1 189 another embodiment, the IC50 values for the compounds of the invention and either or both of these mutants of STING are between and including 0.2 nM and no more than 10nM, and the compound is a compound of formula (I) wherein X-Y-Z is selected from the group consisting of X-Y- Zb. 5 Preferably the compounds of the invention used to inhibit the SAVI associated mutants of the STING protein, preferably either or both of the N154S and V155M mutants of STING, are compounds of formula (Ia) as shown above. Inhibition of STING in fibroblasts10 As many of the above-mentioned diseases like IPF or SAVI involve fibrosis, it is important todemonstrate the efficacy of the inventive compounds in fibroblast cells. In an initial test, fibroblastsfrom human patients suffering from SSc are stimulated with dsDNA and the response with or without the test compounds is assessed. Interestingly, the known STING inhibitors SN-011 and H-151 (fordetails see above), which had been reported to be effective in other fibroblasts, show very little15 inhibition in these fibroblasts, while the compounds of the invention show IC50 values in the rangefrom 3 nM to 300 nM. In one embodiment, the compounds of the invention have an IC 50 value in human SSc fibroblasts of at least 0.1 nM to no more than 300 nM, preferably no more than 150 nM and even more preferably no more than 100 nM and most preferably no more than 80 nM. 20 Inhibition of IP10 production in human monocyte derived dendritic cells after cGAMP stimulationMonocyte derived dendritic cells derived from a specimen of a human donor are cultivated usingstandard techniques. With the exception of the respective negative controls, the cells are stimulated with cGAMP (Invivogen) in the presence or absence of different concentration of the compounds of 25 the invention. Supernatants are collected and analysed by ELISA for IP10 presence (IP10 MSD kit, MesoScale Diagnostics). IC50 values of STING protein inhibition are calculated using standard methods. The IC50 values for the compounds of the invention are in the range and including 0.03 nM to 6.00 nM, preferably equal to or less than 4.00 nM, and more preferably equal to or less than 3.00nM, and even more preferably equal to or less than 2.5 nM. In yet another preferred embodiment30 the average IC 50 value is between and including 0.07 nM and 2.10 nM. An exemplary value is 0.8nM. Muscle to brain ratio The muscle:brain ratio of the compound of the invention is determined in rats and / or mouse using35 standard methods (see for example the publication of Cui and co-workers in Pharmaceutics in 2019; 01-3595-WO-1 190 Cui Y, Lotz R, Rapp H, Klinder K, Himstedt A, Sauer A. Muscle to Brain Partitioning as Measure of Transporter-Mediated Efflux at the Rat Blood-Brain Barrier and Its Implementation into Compound Optimization in Drug Discovery. Pharmaceutics.2019 Nov 11;11(11):595. doi: 10.3390 / pharmaceutics11110595. PMID: 31718023; PMCID: PMC6920949). 5An inventive compound shows for example such a ratio of 3.5. Inventive compounds with such amuscle:brain ratio are useful when STING inhibition in brain and / or CNS tissue is desirable andsufficient passage across the blood–brain barrier into the brain is needed for administration not directly into the brain or CNS, e.g. oral administration. Such potency in the brain and / or CNS of the inventive compounds can be assessed by known methods for determining the inhibitory result on10 mRNA levels of inflammatory proteins in brain cells or the inflammatory proteins themselves. For example, with the preferred inventive compounds a dose-dependent down-regulation of ISG mRNA in brain and spleen is observed. In a preferred embodiment the inventive compounds have a ratio of exposure in muscle tissue versus presence in brain tissue (muscle:brain ratio) of at least 50, more preferably at least 45, 40, 35, 25, 20,15 16, 12, 8, 4 but not lower than 0.3. Preferably, compounds with sufficient passage across the blood– brain barrier into the brain are compounds according to formula (I) with R5selected from the group consisting of R5dand with R9selected from the group consisting of R9b; preferably R9is R9d. Use in treatment / method of use 20 As has been found, the compounds of formula (I), preferably of formula (Ia), are characterized by their range of applications in the therapeutic field. Preferably, the compounds of the invention areused in diseases that can be treated by the inhibition of STING and / or whose progression can beprevented by the inhibition of STING. 25 Particular mention should be made of those applications for which the compounds of the inventionare used on the basis of their pharmaceutical activity as STING inhibitors. While the cGAS / STING pathway is important for host defense against invading pathogens, such as viral infection and invasion by some intracellular bacteria, cellular stress and genetic factors may also cause production 30 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 35 remodeling in a cluster of autoimmune and inflammatory diseases including systemic lupus 01-3595-WO-1 191 erythematosus (SLE), cutaneous lupus, systemic sclerosis, inflammatory bowel disease, sepsis, Sjogren’s syndrome, prurigo nodularis, idiopathic inflammatory myopathy, myositis including dermatomyositis, rheumatoid arthritis and vitiligo, as well as a cluster fibrosis diseases includingNASH (now referred to as MASH), IPF, chronic kidney fibrosis.5 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 10 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. 15 A STING inhibitor also has applications to additional diseases such as cancer, decompensated liver cirrhosis, heart failure, AMD, retinopathy, glaucoma, diabetes, obesity, aging, muscle disorders, anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis, alopecia, chronic kidney disease; Niemann-Pick Disease, Type C, myotonic dystrophy type 2, Huntington disease, Bloom syndrome, osteoarthritis, ALS, Parkinson’s disease, COVID-19. 20 ^An et al., Arthritis Rheumatol.2017 Apr;69(4):800-807, disclosed that cGAS expression inperipheral blood mononuclear cells (PBMCs) was significantly higher in patients with the autoimmune disease systemic lupus erythematosus (SLE) than in normal controls. Targeted measurement of cGAMP by tandem mass spectrometry detected cGAMP in 15% of the tested 25 SLE patients, but none of the normal or rheumatoid arthritis controls. Disease activity was higher in SLE patients with cGAMP versus those without cGAMP. ^Thim-Uam et al (iScience.2020 Sep 4;23(9):101530) demonstrated that STING deficiencyameliorated lupus development in Fcgr2b-deficient mice. Prabakaran et al (EBioMedicine.2021 Apr;66:103314) shows that a STING pathway inhibitor ISD017 blocks STING activity in vivo and 30 ameliorates disease development in a mouse model for lupus. ISD017 treatment also blocks pathological cytokine responses in PBMCs from lupus patients with elevated IFN-I levels. ^Skopelja-Gardner et al reported that ultraviolet B light triggers cGAS / STING-dependent skin andsystemic IFN-I signature and could contribute to cutaneous lupus Alzeand fares of disease in patients with SLE (Sci Rep 202010:7908 ) 01-3595-WO-1 192 ^Ryu et al (Arthritis Rheumatol.2020 Nov;72(11):1905-1915) showed that plasma mtDNAconcentrations were increased in the 2 Systemic sclerosis–associated interstitial lung disease (SSc-ILD) cohorts, reflective of ventilatory decline, and were positively associated with both TLR-9 and cGAS / STING activation as well as type I IFN and IL-6 expression. Liu et al (Rheumatology 5 (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-mediatedproinflammatory responses in dermatomyositis (Theranostics.2021; 11(15): 7144–7158). Zhou et10 al (J Clin Lab Anal.2022 Oct; 36(10): e24631) describes a correlation between activation of cGAS- STING pathway and myofiber atrophy / necrosis in dermatomyositis. Feng et al. suggested STINGcould be a potential therapeutic target in idiopathic inflammatory myositis-associated interstitiallung disease (IIM–ILD) (Feng et al., International Immunopharmacology, March 2025, 149,doi:10.1016). It was also reported that the GAS-STING pathway is activated in the muscle15 biopsies of idiopathic inflammatory myopathy (IIM) patients and its activation may lead to myofiber atrophy and necrosis in IIM and dermatomyositis patients (Zhou et al., J Clin Lab Anal. 2022;36:e24631.). ^Haag et al (Nature.2018 Jul;559(7713):269-273) demonstrated that a covalent STING inhibitorattenuated pathological features of autoinflammatory disease in TREX1_KO mice. Loss of 20 function mutation of TREX1 leads rare monogenic interferonopathies such as Aicardi-Goutières syndrome (AGS). ^Hu et al (EBioMedicine.2019 Mar;41:497-508) showed that in human abdominal sepsis, STINGexpression was elevated in peripheral blood mononuclear cells and intestinal biopsies compared with healthy controls. In human abdominal sepsis, STING expression was elevated in peripheral 25 blood mononuclear cells and intestinal biopsies compared with healthy controls. STING knockout mice attenuated alleviated inflammatory response, gut permeability, and decreased bacterial translocation in a sepsis model. Zeng et al (ci Transl Med.2017 Oct 18;9(412):eaan5689) also showed that STING deficiency in mice protected two sepsos modeled (LPS model and cecalligation and puncture model) and the degree of STING expression in the human intestinal lamina 30 propria correlated with the intestinal inflammation in septic patients. Inhibition of the ALK-STING pathway protects mice against CLP-induced polymicrobial sepsis. ^In Schuliga et al., Clin. Sci. (Lond).2020 Apr 17;134(7):889-905, it is described that self-DNAperpetuates IPF lung fibroblast senescence in a^cGAS-dependent manner. Benmerzoug et al (Nat. 01-3595-WO-1 193 Commun.9, 1–19 (2018)) shows that STING- dependent sensing of self- DNA drives silica-inducedlung inflammation, which can lead to lung fibrosis. ^Additional scientific hints linking the cause for metabolic diseases such as non-alcoholic fatty liverdisease (NAFLD), now referred to as metabolic dysfunction–associated steatotic liver disease5 (MASLD), see https: / / easl.eu / news / new_fatty_liver_disease_nomenclature-2, https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC10653297 / ), other fibrosing diseases such as non-alcoholic steatohepatitis (NASH) , now referred to as metabolic dysfunction associated steatohepatitis (MASH ), and alcoholic liver disease (ALD) with the cGAS / STING pathway havebeen described in Yu et al., J. Clin. Invest.2019 Feb 1;129(2):546-555, and in Cho et al.,10 Hepatology.2018 Oct;68(4): 1331-1346, and in Qiao et al., Metabolism 2018 Apr;81:13-24 doi: 10.1016 / j.metabol.2017.09.010. Epub 2017 Oct 26, Petrasek et al., PNAS 2013 Oct8;110(41):16544-9. doi: 10.1073 / pnas.1308331110. Epub 2013 Sep 19 ^Nascimento et al., Sci. Rep.2019 Oct 16;9(1):14848, discloses that self-DNA release and STING-dependent sensing drives inflammation due to cigarette smoke in mice hinting at a link between15 the cGAS-STING pathway and chronic obstructive pulmonary disease (COPD). ^Ahn et al (Cell Rep 201721:3873-3884) describes that STING-deficient mice protects in anInflammatory Colitis model. Martin et al (Sci Rep 2019 Oct 3; 9:14281) describes that STING deletion protects while or STING stimulation, exacerbates intestinal inflammation in the dextransodium sulphate (DSS) model of colitis. These publications support STING as a potential 20 therapeutic target for prevention of inflammatory bowel disease (IBD). ^Kerur et al., Nat. Med.2018 Jan;24(1):50-61, describes that cGAS plays a significant role innoncanonical-inflammasome activation in age-related macular degeneration (AMD). ^Further, the STING inhibitors also have a therapeutic potential in the treatment of cancer (seeHoong et al., Oncotarget.2020 Jul 28;11(30):2930-2955, and Chen et al., Sci. Adv.2020 Oct25 14;6(42):eabb8941). Furthermore shown in Bakhoum et el., Nature.2018 Jan 25;553(7689):467- 472: “Chromosomal instability drives metastasis through a cytosolic DNA response”, and in Liu et al., Nature.2018 Nov;563(7729):131-136: “Nuclear cGAS suppresses DNA repair and promotes tumorigenesis“. ^STING inhibitors have also the potential in the treatment of obesity and diabetes as shown in30 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 heartfailure (King et al, Nat Med 2017 Dec;23(12):1481-1487; Hu et al., Am. J. Physiol. Heart Circ. Physiol.2020 Jun 1;318(6):H1525-H1537). 01-3595-WO-1 194 ^Further scientific hints at a correlation between Parkinson’s disease and the cGAS / STINGpathway (Sliter et al., Nature.2018 Sep;561(7722):258-262), between amyotrophic lateralsclerosis (ALS) and STING (Yu et al, Cell 2020;183:636-649) and between Sjogren’s syndrome and the cGAS / STING pathway (Papinska et al., J. Dent. Res.2018 Jul;97(8):893-900) exist.5 ^ Furthermore, STING inhibitors have also a therapeutic potential in the treatment of COVID-19 / SARS-CoV-2 infections as shown in Di Domizio et al., Nature.2022 Jan 19. doi: 10.1038 / s41586-022-04421-w: “The cGAS-STING pathway drives type I IFN immunopathology in COVID-19“, and in Neufeldt et al., Commun Biol.2022 Jan 12;5(1):45. doi: 10.1038 / s42003-021- 02983-5: “SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS- 10 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). ^Additionally, STING inhibitors have a therapeutic potential in the treatment of renalinflammation and renal fibrosis as shown in Chung et al., Cell Metab.201930:784-799: “Mitochondrial Damage and Activation of the STING Pathway Lead to Renal Inflammation and 15 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 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 indicating20 STING activation can lead to alopecia (Front Immunol 201910:2770. doi: 10.3389; Pediatr Rheumatol Online J.202422:9 doi: 10.1186). Blood mitochondrial DNA copy number has been reported as a diagnostic marker and indicator of degree of severity in alopecia areata (J Immunoassay Immunochem 202344:256-268). ^In addition, ANCA vasculitis patients show increased levels of cGAMP and enhanced IFN-I25 signature. STING deficiency or a STING inhibitor protects a mouse model for ANCA associated pulmonary vasculitis (J Exp Med.2022219:e20220759). ANCA pulmonary vasculitis has also been reported in a SAVI patient (STING GOV mutation) (Front Immunol.202011:575219). ^Furthermore, the lysosomal membrane protein Niemann-Pick type C1 (NPC1) has been identifiedas a cofactor in the trafficking of STING. Genetic deletion of STING significantly reduced the30 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). 01-3595-WO-1 195 ^Additionally, it has been shown that in myotonic dystrophy type 2 (DM2) disease, patient PBMCsand fibroblasts show elevated type I interferon (IFN) signature which is mediated by the cGAS / STING pathway (Nat Commun.202415:1534). ^In Huntington’s disease (HD), the mutated huntingtin gene induces DNA damage and cytosolic5 DNA accumulation and activates the cGAS–STING pathway to mediate inflammation and apoptosis (Proc Natl Acad Sci U S A.2024121:e2313652121). Depletion of cGAS in HD neuron cells decreases the expression of inflammatory genes while suppressing the up-regulation of autophagy (Proc Natl Acad Sci 117:15989-15999). ^In addition, Xie et al detected binding of cGAS with dsDNA in cytoplasm and the activation of the10 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). ^Additionally, during ischemic stroke, tissue damage results in misplaced DNA within the cellularenvironment activates the cGAS / STING pathway, leading to cytokine production, 15 neuroinflammation, and cell death (Expert Opin Drug Discov 202318:1133-1149; Drug Discov Today.202328:103792). STING knockout decreased infarct progression, oedema volume and neuronal damage in mouse stroke model (Stroke Vasc Neurol 2023 Jul 3:svn-2023-002320. doi: 10.1136). ^Further, it has been shown that STING promotes senescence, apoptosis, and extracellular matrix20 degradation in osteoarthritis (Guo et al, Cell Death Dis.2021 Jan 4;12(1):13. doi: 10.1038). cGAS / STING null- mice have reduced tissue inflammation, improved heart / muscle function andhave an extended lifespan (Dou et al, Nature.2017550: 402–406). Furthermore, in humans a 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 25 will reduce senescence associated inflammation and senescent cell accumulation and will leads improvement in senescence associated diseases such as aging / muscle disorders and osteoarthritis. ^Also, it was reported that the STING protein is involved in vitiligo, as the cytosolic mtDNA-cGAS-STING axis of melanocytes plays an important role in oxidative stress-triggered CD8+ T-cell30 response via melanocyte pyroptosis (Xu et al., Journal of Dermatological Science, 2025, 117(3),March 2025 doi:10.1016). Oxidative stress-induced mitochondrial damage in epidermal cells led to cytosolic mtDNA accumulation, which served as a trigger in activating the cGAS-STING axis in melanocytes resulting in production of IL-1β and IL-18. 01-3595-WO-1 196 ^Prurigo nodularis is a chronic inflammatory skin condition characterized by intensely itchypruritic nodules on the extremities and trunk that are often a result of persistent scratching. It was reported that both systemic and cutaneous immune responses in patients with PN areskewed toward a Th22 / IL-22 profile (Belzberg et al., Journal of Investigative Dermatology (2021) 5 141, 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.10 The compounds of formula (I) or (Ia), or the salts thereof for use in patients with a disease whoseprogression can be prevented by the inhibition of STING is an embodiment of the invention.In one embodiment, the STING inhibitors of the invention are useful in the prevention of progression, and / or for the treatment of a condition or disease caused by immune dysregulation and involving the 15 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 with deregulated STING mutants, e.g. but not limited to SAVI, or Niemann–Pick disease type C.20 In a preferred embodiment, the compounds of the invention useful in the prevention of progressionand / or for the treatment of a disease or a condition that involves undesirable STING activation bymutations of the STING protein are those compounds, of formula (I) wherein X-Y-Z is =CH-N-N= ;and optionally Wis selected from the group Wc consisting of =N-.25 In another embodiment, the compounds of the invention useful to inhibit mutants associated with SAVI and therefore useful in the prevention of progression and / or for the treatment of a condition caused by immune dysregulation and involving the STING protein(s), are compounds of formula (I), preferably of formula (Ia), and preferably show IC50 values of at least 0.001 nM and less than 150nM, preferably less than 100 nM, more preferably less than 50 nM, even more preferably less than30 20 nM when tested for inhibition of any of the mutant N154S or V155M of the STING proteinassociated with SAVI, preferably both, as described in section BIOLOGICAL ASSAYS AND DATA, and preferably for these compounds 01-3595-WO-1 197 Wis selected from the group Wc consisting of =N-And / or X-Y-Z is =CH-N-N= ;preferably both. In another embodiment the compounds of the inventions are used as anti-fibrotic agents. An 5embodiment of the invention is the use of the compounds of the invention in the therapy ofinterferon-driven inflammatory and / or fibrotic diseases or symptoms, preferably those that are aside effect of an underlying disease that leads to cell damage and cytosolic DNA presence that is notderived from pathogens.10 Combinations The compounds of formula 1 may be administered to the patient alone or in combination with one or more other pharmacologically active agents. In a preferred embodiment of the invention the compounds may be combined with one or more15 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), anti-inflammatory agents, anti-fibrotic agents, anti-allergic agents / anti-histamines, bronchodilators, 20 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™, anti-IL-12 antibodies and anti-IL-15 antibodies, non-specific immunotherapeutics such as interferons25 or other cytokines / chemokines, cytokine / chemokine receptor modulators (i.e. cytokine receptor agonists or antagonists), Toll-like receptor agonists (=TLR agonists), immune checkpoint regulators, anti-TNF antibodies for example but not limited to Humira™ and anti- B-cell activating factor (BAFF)agents e.g. without limitation Belimumab and Etanercept.. Such a combination with anti-inflammatory agents and / or anti-fibrotic agents in one embodiment is a combination of one or more 30 compounds of the invention with a) one or more known STING inhibitors and / or b) known cGAS inhibitors and / or c) anti-inflammatory agents that are not STING inhibitors and / or anti-fibrotic agents that are not STING inhibitors, for example but not limited to Pirfenidon, Nintedanib orNerandomilast. Another aspect of the invention is to the combined use of the STING inhibitors of the 01-3595-WO-1 198 invention in combination with known cGAS and / or STING inhibitors, for example but not limited to those disclosed in the international patent applications PCT / EP2023 / 080705, PCT / EP2023 / 080711, PCT / EP2022 / 062496, PCT / EP2022 / 062480, PCT / EP2023 / 079890 or published as WO2021 / 138419,WO2023 / 148129, WO2023 / 237457, WO2024 / 263860, WO2025 / 012195 or WO2025 / 017045. 5 In a further aspect of the present invention, the one or more other pharmacologically active agents include immunosuppressive drugs, Nonsteroidal anti-inflammatory drug (NSAID), corticosteroids e.g. glucocorticoids, hydroxychloroquine or methotrexate, antibodies for example anti- B-cell activatingfactor (BAFF) antibody or CAR (chimeric antigen receptors) T cells. 10 In another aspect of the present invention, the one or more other pharmacologically active agents are RAAS inhibitors (Renin–Angiotensin–Aldosterone System). In one aspect of the present invention, the one or more other therapeutic substances is a direct renin inhibitor, an Angiotensin- Converting Enzyme (ACE) inhibitor and / or an angiotensin II receptor blocker (ARB). 15 In one embodiment , the invention comprise pharmaceutical compositions comprising one or more compounds of the invention and one or more other pharmacologically active agents for use in the treatment or prevention of progression of a disease selected from the group consisting of disease selected from the group consisting of systemic lupus erythematosus (SLE), cutaneous lupus, (monogenic and digenic) interferonopathies (including STING-associated vasculopathy with onset in 20 infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome, and familial chilblain lupus), type 1 interferonopathies with mutations in DNASE2 or ATAD3A genes, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), Huntington disease, Alzheimer's disease, diabetes, obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom’s syndrome, Niemann-Pick Disease, Type C, ischaemic stroke, myotonic dystrophy type 2, Sjogren’s25 syndrome, Parkinson’s disease, heart failure, cancer, systemic sclerosis (SSc), vitiligo, prurigonodularis, idiopathic inflammatory myopathy, myositis including dermatomyositis, metabolicdysfunction–associated steatotic liver disease (MASLD) (previously referred to as non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction associated steatohepatitis (MASH, previously non-alcoholic steatotic hepatitis (NASH)), compensated and decompensated liver cirrhosis, acute on 30 chronic liver failure (ACLF), alcoholic liver disease (ALD), interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), long COVID, aging / muscle disorders, sepsis, heart failure, anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis, alopecia, chronic kidney disease, rheumatoid arthritis and osteoarthritis. 35 01-3595-WO-1 199 Formulations The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, 5 and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, intrasternal, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin. The10 compounds of the invention may be administered via eye drops to treat Sjogren's syndrome. Suitable forms for administration are for example tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. The content of the pharmaceutically effective compound(s) in each case should be in the range from 0.1 to 90 wt.%, preferably 0.5 to 50 wt.% of the total composition,15 i.e. in amounts which are sufficient to achieve the dosage range specified hereinafter. The preparations may be administered orally in the form of a tablet, as a powder, as a powder in a capsule (e.g. a hard gelatin capsule), as a solution or suspension. When administered by inhalation the active substance combination may be given as a powder, as an aqueous or aqueous-ethanolic solution or using a propellant gas formulation. 20 Preferably, therefore, pharmaceutical formulations are characterized by the content of one or more compounds of formula (I), preferably of formula (Ia), according to the preferred embodiments above. It is particularly preferable if the compounds of formula (I), preferably of formula (Ia), areadministered orally, and it is also particularly preferable if they are administered once or twice a day. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known25 excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose,disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and / or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.30 Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example kollidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly, the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned above for the tablets. 35 01-3595-WO-1 200 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), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineralpowders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate,20 talc, stearic acid and sodium lauryl sulphate). For oral administration the tablets may, of course, contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like. Moreover, lubricants such as 25 magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tableting process. In the case of aqueous suspensions, the active substances may be combined with various flavor enhancers or colorings in addition to the excipients mentioned above. The inventive use in the prevention of and / or treatment of and / or delaying the occurrence of 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 the use of the compounds of the invention, individual patients may still suffer from such disorders atleast to some extent, although for the overall group of patients the use of the compounds of the35 invention typically is suitable to delay the occurrence and / or prevent such disorders. 01-3595-WO-1 201 Prevention or delay is typically identified by comparison with a control patient group or a patient not receiving any compound of the invention, preferably a patient group / patient receiving placebo and standard of care. The treatment group / patient receives standard of care for any other disorder not related to elevated and / or deregulated STING activity, and if applicable the standard of care for 5 disorders related to elevated and / or deregulated STING activity, plus in addition one or more compound(s) of the invention. Identification of a prevention or delay will typically require studies in a large group of patients and control group under controlled conditions, typically in a clinical trial, but the identified prevention or delay normally applies to any individual patient receiving the compound(s) of the invention, whereas 10 the quantity of prevention or delay for the individual patient can be expected by the average value observed in the large group but modified due to individual factors. Therefore, the prevention or delay may be present but smaller than the observed average in large trials, or higher for the individual patient. Throughout this description the term disorders is used interchangeably with diseases or conditions. 15 A further aspect of the present invention is to a method of preparation of a pharmaceutical composition comprising the compound of the invention for the use in the prevention of and / or 20 treatment of and / or delaying the occurrence of and / or delaying the progression of disorders related to elevated and / or deregulated STING activity, wherein the method comprises the steps of a) producing the inventive compound or a salt thereof, preferably a pharmaceutically acceptable salt thereof, b) optionally adding with one or more inert adjuvant, diluent and / or carrier, c) optionally adding one or more pharmacologically active agents selected from the group of PDE 4 inhibitors25 (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), anti-inflammatory agents, anti-fibrotic agents, anti-allergic agents / anti-histamines, bronchodilators, beta 2 agonists / betamimetics, adrenergic agonists, anticholinergic agents, 30 methotrexate, mycophenolate mofetil, leukotriene modulators, JAK inhibitors, anti-interleukin antibodies, preferably anti-IL-23 such as Risankizumab, anti-IL-17 antibodies, anti-IL-1 antibodies,anti-IL-4 antibodies, anti-IL-13 antibodies, anti-lL-5 antibodies, anti-IL-6 antibodies such as Actemra™, anti-IL-12 antibodies and / or anti-IL-15 antibodies, non-specific immunotherapeutics such asinterferons or other cytokines / chemokines, cytokine / chemokine receptor modulators (i.e. cytokine 35 receptor agonists or antagonists), Toll-like receptor agonists (=TLR agonists), immune checkpoint 01-3595-WO-1 202 regulators, anti-TNF antibodies, preferably Humira™, and anti-BAFF agents, preferably Belimumaband / or Etanercept.. Another aspect of the invention is to the combined use of one or more of theSTING inhibitors of the invention in combination with known cGAS and / or STING inhibitors, and d)optionally formulating into a form for the preferred administration. 5

Claims

01-3595-WO-1 203 Claims 1. A compound of formula (I),5wherein X-Y-Z is selected from the group X-Y-Za consisting of =CH-N-N= and -N=C-NH-;W is selected from the group Wa consisting of =CH- and =N-;R1is selected from the group R1aconsisting of C1-5-alkyl-, C1-3-alkyl-O-, and C3-6-cycloalkyl-; wherein the C1-3-alkyl-O-group and / or the C1-5-alkyl-group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-3-alkyl-O-, Halogen and HO-; 10 R2is selected from the group R2aconsisting of C1-3-alkyl-; R3is selected from the group R3aconsisting of C3-6-cycloalkyl- and C1-3-alkyl-, either optionally substituted independently with1 to 3 substituents selected from the group consisting of fluorine, HO-, H3C-O-, F3C-O-, and F2HC-O-; R4is selected from the group R4aconsisting of H and Halogen; R5is selected from the group R5aconsisting of01-3595-WO-1 204, wherein * denotes the attachment point to the core; R6is selected from the group R6aconsisting of C1-5-alkyl- and heterocyclyl-,wherein the C1-5-alkyl- group is optionally substituted with 1 to 5 substituentsindependently of one another selected from the group consisting of C3-6-cycloalkyl-, halogen, HO-, C1-6-alkyl-O-, C1-6-alkyl-HN-, (C1-6-alkyl)2N-, NC-, (C1-6- alkyl)2(O)P-, (4-methoxyphenyl)methyl-, , C1-6-alkyl-, branched C3-6-alkyl-,tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, and morpholinyl, wherein the heterocyclyl-group is optionally substituted independently of one another by one or two substituents selected from the group consisting of C1-6-alkyl-, halogen, O=; R7is selected from the group R7aconsisting of C1-6-alkyl-, C3-5-alkenyl-, C3-6-cycloalkyl-, aryl, heteroaryl and heterocyclyl; wherein the C1-6-alkyl-group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Halogen, HO-, and C1-3- alkyl-O-, wherein the heteroaryl group is optionally substituted with 1 substituent selected from the group consisting of C1-3-alkyl-, wherein the C3-6-cycloalkyl- and / or aryl group is optionally substituted with 1to 3 substituents independently selected from the group consisting of (H3C)2N- C(O)-; R8is selected from the group R8aconsisting of H-, C1-6-alkyl-O- and heterocyclyl-O-;wherein the C1-6-alkyl-O-group is optionally substituted with 1 substituent selected from the group consisting of C1-3-alkyl-O- and (H3C)2N-C(O)-;501-3595-WO-1 205 R9is selected from the group R9aconsisting of H-, C1-3-alkyl- and H2N-C(O)-CH2-;R10is selected from the group R10aconsisting of C1-3-alkyl-, C2-3-alkenyl-, C1-3-alkyl-O-, C1-3-alkyl-S- and C3-6-cycloalkyl-,wherein the C1-3-alkyl-group or the C2-3-alkenyl-group is optionallysubstituted with 1 to 3 substituents selected from the group consisting of Halogen- and C1-3-alkyl-;R11is selected from the group R11aconsisting of C1-3-alkyl-, C2-3-alkenyl-, C1-3-alkyl-O-, C1-3-alkyl-S- and C3-6-cycloalkyl-,wherein the C1-3-alkyl-group or the C2-3-alkenyl-group is optionally substituted with 1 to 3 substituents selected from the group consisting of Halogen-, O= and C1-3-alkyl-, or a salt thereof.

52. A compound according to claim 1, whereinX-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N=,or a salt thereof.

3. A compound according to claims 1 or 2, whereinR1is selected from the group R1bconsisting of H3C-, (H3C)2C-, H3C-CH2-, cyclopropyl-, F3C-O-, F3C-O-, H3C-CH(OH)-, H3C-CH2-CH(OH)-, H3C-CH2-O-, and H3C-O-CH2-CH2-, or a salt thereof. 10 4. A compound according to any one of claim 1 to 3, whereinR4 is selected from the group R4b consisting of H- and F-,or a salt thereof.

5. A compound according to one of the claims 1 to 4, whereinR5is selected from the group R5bconsisting of01-3595-WO-1 206, wherein * denotes the attachment point to the core structure, or a salt thereof.

6. A compound according to one of the claims 1 to 5, whereinR6is selected from the group R6bconsisting of C1-3-alkyl-, or a salt thereof. 5 7. A compound according to one of the claims 1 to 6, wherein the compound of formula (I) is acompound of formula (Ia)or a salt thereof. 10 8. A compound according to one of the claims 1 to 7, whereinW is selected from the group Wc consisting of =N-;X-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N=.R1is selected from the group R1bconsisting of H3C-, (H3C)2C-, H3C-CH2-, cyclopropyl-, F3C-O-, F3C-O-, H3C-CH(OH)-, H3C-CH2- CH(OH)-, H3C-CH2-O-, and H3C-O-CH2-CH2-. R2is selected from the group R2bconsisting of H3C-. R3is selected from the group R3bconsisting of cyclopropyl-. R4is selected from the group R4cconsisting of H-. R5is selected from the group R5cconsisting of01-3595-WO-1 207. R7is selected from the group R7bconsisting of C1-6-alkyl-, C3-5-alkenyl-, C3-6-cycloalkyl-, phenyl, ,, , , ,rein the C1-6-alkyl-group is optionally substitutedwith 1 to 3 substituents independently selected from the group consisting of F-, HO- and H3C-O-.R8is selected from the group R8cconsisting of H-, H3C-O-, H3C-O-CH2-CH2-O-, H3C-CH2-O-, (H3C) 2CH-O-, (H3C) 2N-C(O)-CH2-O-, and, or a salt thereof, preferably a pharmaceutically acceptable salt.

9. A compound according to one of the claims 1 to 8, whereinW is selected from the group Wc consisting of =N-;X-Y-Z is selected from the group X-Y-Zb consisting of =CH-N-N=.R1is selected from the group R1cconsisting of H3C-, (H3C)2C-, H3C-CH2-, cyclopropyl-, F2C-O-, F3C-O-, H3C-CH(OH)-, H3C-CH2- CH(OH)-, H3C-CH2-O-, and H3C-O-CH2-CH2-. R2is selected from the group R2bconsisting of H3C-. R3is selected from the group R3bconsisting of cyclopropyl-. R4is selected from the group R4cconsisting of H-. R5is selected from the group R5dconsisting of01-3595-WO-1 208. R6is selected from the group R6bconsisting of C1-3-alkyl-. R9is selected from the group R9bconsisting of C1-3-alkyl-. R10is selected from the group R10cconsisting of F3C-, F2HC-, F2HC-O-, (CH2) (CH3)C-, H3C-O-, H3C-H2C-, H3C-S- and cyclopropyl,or a salt thereof, preferably a pharmaceutically acceptable salt.

10. A compound according to one of the claims 1 to 6, selected from the following examples:01-3595-WO-1 21201-3595-WO-1 218.

11. A compound according to one of the claims 1 to 6, selected from any of the examples 1 to5 79.

12. A salt, preferably a pharmaceutically acceptable salt, of any of the compounds of claims 10 or11. 10 13. The compound of formula (I) or (Ia), according to any of claims 1 to 12 or the salt thereofaccording to claim 12 for use in the treatment of a disease that can be treated by theinhibition of STING.15 14. The compound of formula (I) or (Ia) according to any of claims 1 to 12 or the salt thereofaccording to claim 12 for use in the treatment of a disease selected from the groupconsisting of systemic lupus erythematosus (SLE), cutaneous lupus, (monogenic and digenic)interferonopathies (including STING-associated vasculopathy with onset in infancy (SAVI),01-3595-WO-1 219 Aicardi-Goutières syndrome (AGS), COPA syndrome, and familial chilblain lupus), type 1interferonopathies with mutations in DNASE2 or ATAD3A genes, age-related macular degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), Huntington disease, Alzheimer's disease, diabetes, obesity, inflammatory bowel disease (IBD), chronic 5 obstructive pulmonary disease (COPD), Bloom’s syndrome, Niemann-Pick Disease, Type C, ischaemic stroke, myotonic dystrophy type 2, Sjogren’s syndrome, Parkinson’s disease, heart failure, cancer, systemic sclerosis (SSc),vitiligo, prurigo nodularis, idiopathic inflammatory myopathy, myositis including dermatomyositis, metabolic dysfunction–associated steatoticliver disease (MASLD) (previously referred to as non-alcoholic fatty liver disease (NAFLD), 10 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) associated vasculitis, alopecia, chronic kidney disease,15 rheumatoid arthritis and osteoarthritis.

15. Pharmaceutical composition comprising a compound of formula (I) or (Ia) according to any ofclaims 1 to 12 and / or the salt thereof according to claim 12, and optionally one or morepharmaceutically acceptable carriers and / or excipients. 20