Arylamide substituted indazoles 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] Arylamide Substituted Indazoles and the Use Thereof as Medicament

[0002] This application claims priority to the US provisional application 63 / 640390, filed on April 30, 2024.

[0003] Field of the invention

[0004] This invention relates to compounds of formula (I) and their use as STING antagonists e.g. for the treatment of a disease selected from the group consisting of systemic lupus erythematosus (SLE), cutaneous lupus, (monogenic and digenic) interferonopathies (including STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutieres syndrome (AGS), COPA syndrome, and familial chilblain lupus), type 1 interferonopathies with mutations in DNASE2 or ATAD3A genes, age- related macular degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), Huntington disease, Alzheimer's disease, diabetes, obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Niemann-Pick Disease, Type C, ischaemic stroke, myotonic dystrophy type 2, Sjogren's syndrome, Parkinson's disease, heart failure, cancer, systemic sclerosis (SSc), vitiligo, prurigo nodularis, idiopathic inflammatory myopathy, myositis including dermatomyositis, metabolic dysfunction-associated steatotic liver disease (MASLD) (previously referred to as non-alcoholic fatty liver disease (NAFLD), metabolic 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, rheumatoid arthritis and osteoarthritis.

[0005] Background of the invention

[0006] Innate immunity is considered a first line cellular stress response defending the host cell against invading pathogens and initiating signaling to the adaptive immune system. These processes are triggered by conserved pathogen-associated molecular patterns (PAMPs) through sensing by diverse pattern recognition receptors (PRRs) and subsequent activation of cytokine and type I interferon gene expression. The major antigen-presenting cells, such as monocytes, macrophages, and dendritic cells produce type I interferons and are critical for eliciting adaptive T- and B-cell immune system responses. The major PRRs detect aberrant, i.e. mislocalized, immature or unmodified nucleic acids on either the cell surface, the inside of lysosomal membranes or within other cellular compartments (Barbalat et al., Annu. Rev. Immunol. 29, 185-214 (2011)). ^Cyclic GMP-AMP Synthase" (cGAS) is the predominant sensor for aberrant double-stranded DNA (dsDNA) originating from pathogens or mislocalization or misprocessing of nuclear or mitochondrial cellular dsDNA (Sun et al., Science 339, 786-791 (2013); Wu et al., Science 339, 826-830 (2013); Ablasser et al., Nature 498, 380-384 (2013)). Binding of dsDNA to cGAS activates the reaction of GTP and ATP to form the cyclic dinucleotide GMP-AMP (referred to as cGAMP). cGAMP then binds to and activates the endoplasmatic reticulum membrane-anchored adaptor protein, "Stimulator of Interferon Genes" (STING, UniProtKB - Q86WV6). Activated STING recruits and activates TANK- binding kinase 1 (TBK1) which in turn phosporylates the transcription factor family of interferon regulatory factors (IRFs) inducing cytokine and type I interferon mRNA expression. STING activation by cGAMP also leads to activation of NF-kB signaling pathway and downstream production of proinflammatory cytokines (Sun et al., Science 339, 786-791 (2013). Human GoF STING mutants lead to an autoinflammatory syndrome, cutaneous vasculopathy and lung fibrosis (STING-associated vasculopathy with onset in infancy, SAVI). SAVI patients have a highly activated PBMCs and dermal fibroblasts, exhibiting an upregulated type-1 IFN signature and expression of NFicB-mediated profibrotic and proinflammatory genes (e.g. TN Fa, IL-6) (Liu et al., 2014).

[0007] 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)).

[0008] 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- mediated disorder - arises from genetic mutations such as loss-of-function mutations in TREX1, a primary DNA exonuclease responsible for degrading aberrant DNA in cytosol. Knock-out of STING in TREXl-deficient mice prevented otherwise lethal autoimmune responses, supporting STING as driver of interferonopathies (Gall et al., Immunity 36(1), 120-131 (2012); Gao et al., PNAS 112, E5699-E5705 (2015)). Likewise, embryonic lethality caused by deficiency of DNAse2, an endonuclease responsible for degradation of excessive DNA in lysosomes during endocytosis, was completely rescued by additional knock-out of STING (Ahn et al., PNAS 109, 19386-19391 (2012)).

[0009] A STING inhibitor may provide a therapeutic strategy for preventing (monogenic and digenic) interferonopathy diseases such as SAVI, AGS, familial chilblain lupus and COPA. A STING inhibitor will block inflammation and aberrant tissue remodeling in a cluster of autoimmune and inflammatory diseases including systemic lupus erythematosus (SLE), systemic sclerosis, vitiligo, prurigo nodularis, 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 as cancer, heart failure, AMD, retinopathy, glaucoma, aging, decompensated liver cirrhosis, antineutrophil 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. 2021 21:548- 569).

[0010] 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.

[0011] • In WO2019122202 for example, compounds C-178 or C-176 are described interfering with STING signaling pathway in HEK293T cells or bone marrow derived macrophages (BMDMs) stimulated with a cyclic dinucleotide such as e.g. cGAMP which are irreversible inhibitors blocking the palmitoylation of STING at an allosteric site of STING.

[0012] • In ACS Med Chem Lett. (2019, 10, 1, pp 92-97), Siu et all described novel cGAMP competitive ligands. It is believed that inhibiting the orthosteric site of cGAMP mediated STING activation leads to a suppression of all STING mediated activation in contrast to palmitoylation inhibitors. Compound 13 or 15 in this publication inhibits the HAQ STING variant (displacement assay) with a moderate IC50 of 84 or 41 nM and shows low cellular inhibitory activity of about 11 uM based on a cGAMP stimulated IN Fb production in THP1 cells.

[0013] • In International patent application WQ2019069270, claims modulators of STING which either activate or inhibit STING accordingly.

[0014] • In the international patent applications WO23148129 and WO23237457 modulators of STING are disclosed that are relatively large macrocycles with demanding synthesis and handling of the molecules.

[0015] However, inhibitors of the STING receptor for therapeutic use face challenges. For example, it is expected that most inhibitors of the STING receptor binding its ligand binding site similar to the natural ligand, i.e. two molecules in the binding pocket. Yet, for the design of inhibitors of STING receptors this provides the additional challenge that the inhibitor molecules not only need to interact 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.

[0016] Also, the polarity of the inhibitor molecules needs to be optimized on the one hand to allow sufficient crossing of the cell membranes to reach the target, while not enhancing the degradation of the inhibitor.

[0017] Another challenge for a therapeutic inhibitor of STING receptors is that in many STING mediated disease patients are likely to be co-administered with more than one medications to treat the symptoms of said diseases or the diseases itself. The inhibitors of STING should in such a situation not 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.

[0018] Aim of the invention

[0019] It has now been found that compounds of the present invention according to general formula (I), or pharmaceutically acceptable salt thereof, are effective STING inhibitors.

[0020] In addition to the antagonistic property toward STING, the compounds of the present invention provide further advantageous properties as to be viable for human therapy, such as but not limited to: Being optimised for binding of two molecules of the inhibitor to the target's ligand binding pocket, sufficiently easy to synthesize and handle, good bioavailability, good mobility across the cell membrane and good access to the target receptor in the cells, acceptable cytotoxicity and / or genotoxicity, good ligand efficiency, good metabolic stability, low interaction with catabolic processes e.g. by cytochrome p450s or other CYP that are important with respect to possibly coadministered drugs, low degradation by light, e.g. sun light, yet good degradation ex-situ of the inhibitor or its break-down product e.g. in sewage plants.

[0021] .The inhibitors of the invention perform better in one or several of these properties than the inhibitors of the STING receptor available so far. Accordingly, one aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of STING.

[0022] 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 inhibitors of STING having good metabolic stability and potency.

[0023] 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.

[0024] Another aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of STING having good metabolic stability with acceptable cytotoxicity and / or genotoxicity. Another aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of STING having good metabolic stability and low interaction with catabolic processes e.g. by cytochrome p450s or other CYP that are important with respect to possibly co-administered drugs.

[0025] 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.

[0026] 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 target receptor in the cells and good potency.

[0027] Another aspect of the invention refers to compounds according to formula (I), or salts thereof as inhibitors of having good metabolic stability and low interaction with catabolic processes of other pharmaceutical compounds administered overlappingly or simultaneously, including but not limited to further inhibitors of STING, and with acceptable cytotoxicity and / or genotoxicity and optimised in polarity for good mobility across the cell membrane and good access to the target receptor in the cells and good potency and optimised for binding of two molecules of the inhibitor to the target's ligand binding pocket and good ligand efficiency.

[0028] 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. A further aspect of the present invention relates to compounds according to general formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds according to formula (I) or pharmaceutically acceptable salts thereof, for the use in the prevention of and / or treatment of and / or delaying the occurrence of and / or delaying the progression of disorders related to elevated and / or deregulated STING activity. In one aspect of the invention the use is to prevent one or more disorders related to elevated STING activity. Another aspect of the invention the use is to treat one or more disorders related to elevated STING activity. A further aspect the inventive use is to delay the occurrence of one or more disorders related to elevated STING activity. In yet another aspect the inventive compounds and use is to delay the progression one or more disorders related to elevated STING activity, for example but not limited to progression of scleroderma renal crisis (SRC) to end stage renal disease / kidney failure; progression of MAFLD or MASH for example from MAFLD to MASH, or from MASH to Mash with cirrhosis as assessed with the NAFLD Activity Score (NAS) with or without steatosis, activity, and fibrosis (SAF) score and / or progression of Rheumatoid arthritis as assessed via the 2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria for example but not limited to from a point value from 3 to 5 or from a point value 4 to point value 7.

[0029] Another aspect of the invention relates to processes of manufacture of the compounds of the present invention according to general formula (I) or salts thereof, particularly pharmaceutically acceptable salts.

[0030] Other aims of the present invention will become apparent to the skilled man directly from the foregoing and following remarks.

[0031] Detailed description

[0032] In a first aspect the present invention relates to compounds of general formula (I) wherein B-A is selected from the group B-Aaconsisting of =C-N- or -N-C=; this means A is C or N; B is C or N; but A and B are not N at the same time;

[0033] R1is selected from the group Rlaconsisting of wherein R1 is the attaching point to the structure of formula I;

[0034] W is selected from the group Waconsisting of =C— and =N- and =N+-;

[0035] V is selected from the group Vaconsisting of =C— and -N-

[0036] T is selected from the group Taconsisting of -C-, =C— and =N- ;

[0037] R10is selected from the group of R10aconsisting of

[0038] H, HO-, Ci-s-alkyl-, Ci-3-alkyl-S- , Ci-3-alkyl-O-, Cj.s-alkenyl-, amide- and Cs-e-cycloalkyl-, wherein the Ci-3-alkyl-O-group, Cs-e-cycloalkyl- group, amide group and / or the C1-5- alkyl-group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of Ci-3-alkyl-O-, Halogen and HO-;

[0039] R11is selected from the group of Rllaconsisting of H-, HO-, Ci-s-alkyl-, Ci-3-alkyl-O-, and Cs-e-cycloalkyl-, wherein the Ci-3-alkyl-O-group and / or the Ci.5-alkyl-group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of Ci-3-alkyl-O-, Ci.5-Heterocyclyl-, Halogen and HO and wherein the C1-5- Heterocyclyl- groups are optionally substituted with 1 to 5 substituents independently selected from the group consisting of Ci-3-alkyl- and Ci-3-alkyl-O-;

[0040] R12is selected from the group of R12aconsisting of H, HO-, Ci-3-alkyl-, Ci-3-alkyl-O- and

[0041] C3-4-cycloalkyl-, wherein the Ci-3-alkyl-O-group and / or the Ci-3-alkyl-group are optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ci-3-alkyl-O-, Halogen and HO-;

[0042] R13is selected from the group of R13aconsisting of a) H-, H3C- or b) O_if W is =N+-;

[0043] R14is selected from the group of R14aconsisting of H, ci-s-alkyl-7Ci-3-alkyl-O-, and C3-6- cycloalkyl-; wherein the Ci-3-alkyl-O-group and / or the Ci.5-alkyl-group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-3- alkyl-O-, Halogen and H0-;

[0044] R15is selected from the group of R15aconsisting of H, H0-, Ci-5-alkyl-, Ci-3-alkyl-O-, and Cs-e-cycloalkyl-; wherein the Ci-3-alkyl-O-group and / or the Ci.5-alkyl-group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-3- alkyl-O-, Halogen and H0-;

[0045] R2is selected from the group R2aconsisting of H- and Ci-3-alkyl-;

[0046] R3is selected from the group R3aconsisting of

[0047] Ci-3-alkyl- and C3-4 cycloalkyl-, either optionally substituted by 1 to 3 substituents selected from the group consisting of Ci-3-alkyl-, HO- and Halogen-, H3C-O-, F3C-O-, and F2HC-O-;

[0048] R4is selected from the group R4aconsisting of H and Halogen;

[0049] R5is selected from the group R5aconsisting of R9-C(R8)(R7)-CH2- and R9-S(O)-CH2-; R6 is selected from the group R6aconsisting of

[0050] H-, HO- and Halogen-;

[0051] R7is selected from the group R7aconsisting of

[0052] H-, Halogen, HO- and Ci-3-alkyl-O-, H- and Halogen;

[0053] R8is selected from the group R8aconsisting of H- and Halogen-;

[0054] R9is selected from the group R9aconsisting of phenyl, cyclohexyl, heterocyclyl with 6 ring atoms and heteroaryl with 6 ring atoms wherein in the heterocyclyl or the heteroaryl 1 to 3 heteroatoms are present and these are selected from the group consisting of N, O and S, wherein the phenyl, cyclohexyl, heterocyclyl with 6 ring atoms and heteroaryl with 6 ring atoms are substituted with 1 to 3 substituents selected from the group consisting of carboxylic acid , sulfonyl, sulfonamide and / or amide groups, wherein optionally the sulfonyl, sulfonamide and / or amide groups are substituted with 1 to 3 substituents selected from the group consisting of a) Ci-3-alkyl-, b) C1-3- alkyl— O-, c) C3-4-cycloalkyl-, with a) to c) optionally substituted with 1 to 3 substituents selected from HO-, F-, Ci-3-alkyl- and Ci-3-alkyl-O-, and d) halogen, or optionally the sulfonamide and / or amide groups are substituted at the N of the sulfonamide and / or amide with a Cs-s-alkyl-or a Cs-cycloalkyl itself substituted with

[0055] 2 Ci-3-alkyl- to form a heterocycle or heterobicycle with said N, optionally with one carbon atom of the ring structure being replaced by a further heteroatom selected from N or O, wherein said heterocycle or heterobicycle is further optionally substituted with 1 to

[0056] 3 substituents selected independently from HO-, F-, Ci-3-alkyl-, Ci-3-alkyl- itself substituted with 1 to 3 fluorines and Ci-3-alkyl-O-; or a salt thereof, preferably a pharmaceutically acceptable salt. Unless otherwise stated, the groups, residues, and substituents, particularly W, B-A, R1, R2, R3, R4, R5, R6, R7, R8, R9R10, R11, R12, R13, R14and R15are defined as above and hereinafter. If residues, substituents, or groups occur several times in a compound they may have the same or different meanings. Some preferred meanings of groups and substituents of the compounds according to the invention will be given hereinafter.

[0057] In a further embodiment of the present invention

[0058] B-A is selected from the group B-Abconsisting of =C-N-; this means A is N; B is C.

[0059] In a further embodiment of the present invention

[0060] B-A is selected from the group B-Acconsisting of -N-C=; this means A is C; B is N.

[0061] In a preferred embodiment, the compound is a compound of formula (la).

[0062] In another preferred embodiment, the compound is a compound of formula (lb). In a preferred embodiment, the compound is a compound of formula (Ic). In a preferred embodiment, the compound is a compound of formula (Id).

[0063] In a further embodiment of the present invention

[0064] R1is selected from the group Rlbconsisting of wherein R1 is the attaching point to the core structure.

[0065] In a further embodiment of the present invention

[0066] R1is selected from the group Rlcconsisting of wherein R1 is the attaching point to the core structure.

[0067] In a further embodiment of the present invention

[0068] W is selected from the group Wbconsisting of =C— and =N-.

[0069] In a further embodiment of the present invention

[0070] W is selected from the group Wcconsisting of =N-. In a further embodiment of the present invention

[0071] V is selected from the group Vbconsisting of-N-.

[0072] In a further embodiment of the present invention

[0073] T is selected from the group Tbconsisting of =C- .

[0074] In a further embodiment of the present invention

[0075] T is selected from the group Tcconsisting of =N- .

[0076] In a further embodiment of the present invention

[0077] R2is selected from the group R2bconsisting of H- and H3C-.

[0078] In a further embodiment of the present invention

[0079] R2is selected from the group R2cconsisting of H3C-.

[0080] In a further embodiment of the present invention

[0081] R2is selected from the group R2dconsisting of

[0082] H-. R3is selected from the group R3bconsisting of

[0083] Ci-3-alkyl- and cyclopropyl- , either optionally substituted by 1 to 3 substituents selected from the group consisting of H3C-, HO- and F-.

[0084] R3is selected from the group R3cconsisting of and and R3 is the attaching point to the core structure .

[0085] In a further embodiment of the present invention

[0086] R3is selected from the group R3dconsisting of cyclopropyl-. In a further embodiment of the present invention

[0087] R3is selected from the group R3econsisting of isopropyl-.

[0088] In a further embodiment of the present invention

[0089] R4is selected from the group R4bconsisting of H-, CL- and F-.

[0090] In a further embodiment of the present invention

[0091] R4is selected from the group R4cconsisting of

[0092] H-.

[0093] In a further embodiment of the present invention

[0094] R5is selected from the group R5bconsisting of R9-C(R8)(R7)-CH2-.

[0095] In a further embodiment of the present invention R5is selected from the group R5cconsisting of R9-C(R8)(R7)-CH2- with R9comprising a phenyl group substituted with 1 to 2 substituents selected from the group consisting of carboxylic acid , sulfonyl, sulfonamide and / or amide groups, wherein optionally the sulfonyl, sulfonamide and / or amide groups are substituted with 1 to 3 substituents selected from the group consisting of a) Ci-3-alkyl-, b) Ci-3-alkyl-O-, c) C3- 4-cycloalkyl-, d) halogen and e) substituted at the N of the sulfonamide and / or amide with a Cs-s-alkyl-or a Cz-4-alkyl to form a heterocycle or heterobicycle with said N, wherein said heterocycle or heterobicycle is optionally substituted with 1 to 3 substituents selected from HO-, F-, Ci-3-alkyl- and Ci-3-alkyl-O-.

[0096] In a further embodiment of the present invention

[0097] R5is selected from the group R5dconsisting of those structures shown in table A

[0098] Table A

[0099]

[0100] In a further embodiment of the present invention

[0101] R6is selected from the group R6bconsisting of H-, CL- and F-.

[0102] In a further embodiment of the present invention

[0103] R6is selected from the group RScconsisting of H- and F-.

[0104] In a further embodiment of the present invention

[0105] R6is selected from the group Rsdconsisting of

[0106] H-.

[0107] In a further embodiment of the present invention

[0108] R6is selected from the group RSeconsisting of

[0109] F-.

[0110] In a further embodiment of the present invention

[0111] R7is selected from the group R7bconsisting of H-, HO- and Halogen-.

[0112] In a further embodiment of the present invention R7is selected from the group R7cconsisting of H-, HO- and F-.

[0113] In a further embodiment of the present invention

[0114] R8is selected from the group R8bconsisting of H- and F-.

[0115] In a further embodiment of the present invention

[0116] R8is selected from the group R8bconsisting of F-.

[0117] In a further embodiment of the present invention

[0118] R8is selected from the group R8cconsisting of H-.

[0119] In a further embodiment of the present invention

[0120] R9is selected from the group R9bconsisting of phenyl and cyclohexyl either substituted with a substituent selected from the group consisting of carboxylic acid , sulfonyl, sulfonamide and / or amide groups, wherein optionally the sulfonyl, sulfonamide and / or amide groups are substituted with 1 to 3 substituents selected from the group consisting of a) Ci-3-alkyl-, b) Ci-3-alkyl-O-, c) C3-4-cycloalkyl-, d) halogen, preferably fluorine, and e) substituted at the N of the sulfonamide and / or amide with a Cs-s-alkyl-or a Cz-4-alkyl to form a heterocycle or heterobicycle with said N, wherein said heterocycle or heterobicycle is optionally substituted with 1 to 3 substituents selected from HO-, F-, Ci-3-alkyl- and Ci-3-alkyl-O- In a further embodiment of the present invention

[0121] R9is selected from the group R9cconsisting of cyclohexyl and phenyl groups connected to position R5 of the core by a linker of the structure R9-C(R8)(R7)-CH2-R5, wherein R5 denotes the attachment point to the core, and either substituted with a substituent selected from the group consisting of carboxylic acid, sulfonyl, sulfonamide and amide groups that optionally is substituted as shown in table A above.

[0122] In a further embodiment of the present invention

[0123] R10is selected from the group R10bconsisting of

[0124] Ci-3-alkyl-, Cj-s-alkenyl-, Ci-3-alkyl-O-, amide-and C3-4-cycloalkyl-, either optionally substituted with 1 to 3 substituents selected from the group consisting of H3C-CH2-, H3C- and Halogen.

[0125] In a further embodiment of the present invention

[0126] R10is selected from the group R10cconsisting of

[0127] Ci-3-alkyl-, H3C-O- and cyclopropyl, either optionally substituted with 1 to 3 substituents selected from the group consisting of F-, and an amide substituted with 1 to 3 substituents selected from the group consisting of H3C-CH2- and H3C-.

[0128] In a further embodiment of the present invention

[0129] R10is selected from the group R10dconsisting of

[0130] H3C-, H3C-CH2-, (CHsh-C^-, F3C-O- and cyclopropyl, the later optionally substituted with 1 to 2 substituents selected from the group consisting of F-, and amide substituted with 2 substituents selected from the group consisting of H3C-CH2.

[0131] In a further embodiment of the present invention

[0132] R11is selected from the group Rllbconsisting of

[0133] H-, Ci-3-alkyl-, Ci-3-alkyl-O-, and C3-4-cycloalkyl-, wherein the Ci-3-alkyl-O-group and / or the Ci-3-alkyl-group are optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ci-3-alkyl-O-, Ci.5-Heterocyclyl-, Halogen and HO -, and wherein the Ci-5- Heterocyclyl- groups are optionally substituted with 1 to 5 substituents independently selected from the group consisting of Ci-3-alkyl- and Ci-3-alkyl-O-.

[0134] In a further embodiment of the present invention

[0135] R12is selected from the group R12bconsisting of H- and Ci-3-alkyl-.

[0136] In a further embodiment of the present invention

[0137] R12is selected from the group R12cconsisting of H- and H3C-. In a further embodiment of the present invention

[0138] R12is selected from the group R12dconsisting of

[0139] H-.

[0140] In a further embodiment of the present invention

[0141] R13is selected from the group of R13bconsisting of H-. In a further embodiment of the present invention

[0142] R14is selected from the group R14bconsisting of H- and Ci-3-alkyl-.

[0143] In a further embodiment of the present invention R14is selected from the group R14cconsisting of

[0144] H3C-, H3C-CH2-, H3C-CH2-CH2- and (CH3)2-CH2-.

[0145] In a further embodiment of the present invention

[0146] R15is selected from the group R15bconsisting of H- and Ci-3-alkyl-.

[0147] In a further embodiment of the present invention

[0148] R15is selected from the group R15cconsisting of

[0149] H-, H3C-, H3C-CH2-, H3C-CH2-CH2- and (CH3)2-CH2-.

[0150] In a further embodiment of the present invention

[0151] R15is selected from the group R15dconsisting of

[0152] H- and H3C-.

[0153] In a further embodiment of the present invention

[0154] R15is selected from the group R15econsisting of

[0155] H-.

[0156] V, T, B-A, W, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14and R15represents a characterized, individual embodiment for the corresponding substituent as described above. Thus, given the above definitions, individual embodiments of the first aspect of the invention are fully characterized by the term (Vx, Tx, B-Ax, Wx, R1X, R2x, R3X, R4X, R5X, R6X, R7X, R8X, R9x,R10x, Rllx, R12x, R13x, R14xand R15x), 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.

[0157] The following table 1 shows such embodiments E-l to E-14of the compound of general formula (I) or a salt thereof, preferably a pharmaceutically acceptable salt, that are considered preferred. Table 1: Embodiments E-l to E-14 of the invention

[0158] Accordingly, for example E-8 covers compounds of general formula (I),

[0159] Wherein

[0160] B-A is selected from the group B-Aa consisting of =C-N- or -N-C=; this means A is C or N; B is C or N; but A and B are not N at the same time;

[0161] R1is selected from the group Rlbconsisting of wherein R1 is the attaching point to the core structure;

[0162] R2is selected from the group R2aconsisting of

[0163] H- and Ci-3-alkyl-;

[0164] R3is selected from the group R3cconsisting of and and R3 is the attaching point to the core structure ;

[0165] R4is selected from the group R4cconsisting of

[0166] H-;

[0167] R5is selected from the group R5bconsisting of R9-C(R8)(R7)-CH2-;

[0168] R6 is selected from the group R6aconsisting of

[0169] H-, HO- and Halogen-;

[0170] R7is selected from the group R7aconsisting of

[0171] H-, Halogen, HO- and Ci-3-alkyl-O-;H and Halogen;

[0172] R8is selected from the group R8aconsisting of H- and Halogen-;

[0173] R9is selected from the group R9aconsisting of phenyl, cyclohexyl, heterocyclyl with 6 ring atoms and heteroaryl with 6 ring atoms wherein in the heterocyclyl or the heteroaryl 1 to 3 heteroatoms are present and these are selected from the group consisting of N, O and S, wherein the phenyl, cyclohexyl, heterocyclyl with 6 ring atoms and heteroaryl with 6 ring atoms are substituted with 1 to 3 substituents selected from the group consisting of carboxylic acid , sulfonyl, sulfonamide and / or amide groups, wherein optionally the sulfonyl, sulfonamide and / or amide groups are substituted with 1 to 3 substituents selected from the group consisting of a) Ci-3-alkyl-, b) C1-3- alkyl— O-, c) C3-4-cycloalkyl-, with a) to c) optionally substituted with 1 to 3 substituents selected from HO-, F-, Ci-3-alkyl- and Ci-3-alkyl-O-, and d) halogen, or optionally the sulfonamide and / or amide groups are substituted at the N of the sulfonamide and / or amide with a Cs-s-alkyl-or a Cs-cycloalkyl itself substituted with

[0174] 2 Ci-3-alkyl- to form a heterocycle or heterobicycle with said N, optionally with one carbon atom of the ring structure being replaced by a further heteroatom selected from N or O, wherein said heterocycle or heterobicycle is further optionally substituted with 1 to

[0175] 3 substituents selected independently from HO-, F-, Ci-3-alkyl-, Ci-3-alkyl- itself substituted with 1 to 3 fluorines and Ci-3-alkyl-O-;

[0176] R10is selected from the group of R10aconsisting of

[0177] H, HO-, Ci-s-alkyl-, Ci-3-alkyl-S- , Ci-3-alkyl-O-, Cz-3-alkenyl-, amide- and Cs-e-cycloalkyl-, wherein the Ci-3-alkyl-O-group, Cs-e-cycloalkyl- group, amide group and / or the Ci.5-alkyl-group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of Ci-3-alkyl- O-, Halogen and HO-;

[0178] R14is selected from the group R14bconsisting of

[0179] H- and Ci-3-alkyl-;

[0180] R15is selected from the group R15dconsisting of H- and H3C-; or a salt thereof, preferably a pharmaceutically acceptable salt.

[0181] Accordingly, for example E-13 covers compounds of general formula (I), wherein B-A is selected from the group B-Aa consisting of =C-N- or -N-C=; this means A is C or N; B is C or N; but A and B are not N at the same time;

[0182] R1is selected from the group Rlcconsisting of wherein R1 is the attaching point to the core structure;

[0183] T is selected from the group Tbconsisting of =C- ; V is selected from the group Vbconsisting of-N-;

[0184] W is selected from the group Wbconsisting of =C— and =N-;

[0185] R2is selected from the group R2aconsisting of

[0186] H- and Ci-3-alkyl-;

[0187] R3is selected from the group R3bconsisting of

[0188] Ci-3-alkyl- and cyclopropyl- , either optionally substituted by 1 to 3 substituents selected from the group consisting of H3C-, HO- and F-;

[0189] R4is selected from the group R4cconsisting of

[0190] H-;

[0191] R5is selected from the group R5cconsisting of R9-C(R8)(R7)-CH2- with R9comprising a phenyl group substituted with 1 to 2 substituents selected from the group consisting of carboxylic acid , sulfonyl, sulfonamide and / or amide groups, wherein optionally the sulfonyl, sulfonamide and / or amide groups are substituted with 1 to 3 substituents selected from the group consisting of a) Ci-3-alkyl-, b) Ci-3-alkyl-O-, c) C3-4-cycloalkyl-, d) halogen and e) substituted at the N of the sulfonamide and / or amide with a Cs-s-al kyl- or a Cz-4-alkyl to form a heterocycle or heterobicycle with said N, wherein said heterocycle or heterobicycle is optionally substituted with 1 to 3 substituents selected from HO-, F-, Ci-3-alkyl- and Ci-3-alkyl-O-,

[0192] R6is selected from the group Rsbconsisting of

[0193] H-, CL- and F-;

[0194] R7is selected from the group R7cconsisting of H-, HO- and F-; R8is selected from the group R8bconsisting of

[0195] H- and F-;

[0196] R9is selected from the group R9aconsisting of phenyl, cyclohexyl, heterocyclyl with 6 ring atoms and heteroaryl with 6 ring atoms wherein in the heterocyclyl or the heteroaryl 1 to 3 heteroatoms are present and these are selected from the group consisting of N, O and S, wherein the phenyl, cyclohexyl, heterocyclyl with 6 ring atoms and heteroaryl with 6 ring atoms are substituted with 1 to 3 substituents selected from the group consisting of carboxylic acid , sulfonyl, sulfonamide and / or amide groups, wherein optionally the sulfonyl, sulfonamide and / or amide groups are substituted with 1 to 3 substituents selected from the group consisting of a) Ci-3-alkyl-, b) C1-3- alkyl— O-, c) C3-4-cycloalkyl-, with a) to c) optionally substituted with 1 to 3 substituents selected from HO-, F-, Ci-3-alkyl- and Ci-3-alkyl-O-, and d) halogen, or optionally the sulfonamide and / or amide groups are substituted at the N of the sulfonamide and / or amide with a Cs-s-alkyl-or a Cs-cycloalkyl itself substituted with

[0197] 2 Ci-3-alkyl- to form a heterocycle or heterobicycle with said N, optionally with one carbon atom of the ring structure being replaced by a further heteroatom selected from N or O, wherein said heterocycle or heterobicycle is further optionally substituted with 1 to

[0198] 3 substituents selected independently from HO-, F-, Ci-3-alkyl-, Ci-3-alkyl- itself substituted with 1 to 3 fluorines and Ci-3-alkyl-O-;

[0199] R10is selected from the group of R10aconsisting of

[0200] H, HO-, Ci-5-alkyl-, Ci-3-alkyl-S- , Ci-3-alkyl-O-, Cz-3-alkenyl-, amide- and Cs-e-cycloalkyl-, wherein the Ci-3-alkyl-O-group, Cs-e-cycloalkyl- group, amide group and / or the Ci.5-alkyl- group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of Ci-3-alkyl-O-, Halogen and HO-;

[0201] R11is selected from the group of Rllaconsisting of H-, HO-, Ci.5-alkyl-, Ci-3-alkyl-O-, and C3-6- cycloalkyl-, wherein the Ci-3-alkyl-O-group and / or the Ci.5-alkyl-group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of Ci- 3-alkyl-O-, C1-5- Heterocyclyl-, Halogen and HO -, and wherein the C1-5- Heterocyclyl- groups are optionally substituted with 1 to 5 substituents independently selected from the group consisting of Ci-3-alkyl- and Ci-3-alkyl-O-;

[0202] R12is selected from the group R12bconsisting of H- and Ci-3-alkyl-;

[0203] R13is selected from H- and H3C-; or a salt thereof, preferably a pharmaceutically acceptable salt.

[0204] Further preferred are the following compounds listed in table 2 or salt thereof or stereoisomers thereof (the No. refers to the No. assigned to the compound in the experimental section). Each compound of table 2 is represented without indicating the stereochemistry thereof, if any. Specific information concerning stereochemical properties of compounds of table 2 can be taken from the experimental section. In case the final compounds according of said experimental section are salt forms, they can be converted into the neutral compound by conventional methods. Table 2:

[0205]

[0206]

[0207]

[0208] A further embodiment of the present invention covers the compounds of general formula (I), preferably of formula (la), (lb), (Ic) or (Id), particularly the compounds listed in table 2, in form of their pharmaceutically acceptable salts.

[0209] A further embodiment of the present invention refers to pharmaceutical compositions comprising at least one compound according to formula (I), preferably according to formula (la), (lb), (Ic) or (Id), or pharmaceutically acceptable salts thereof, optionally together with at least one inert adjuvant, diluent and / or carrier.

[0210] In a further embodiment, the present invention relates to a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound according to general formula (I), preferably according to formula (la), (lb), (Ic) or (Id) or pharmaceutically acceptable salts thereof, for use as a medicament.

[0211] In a further embodiment, the present invention relates to compounds according to general formula (I), preferably according to formula (la), (lb), (Ic) or (Id) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising compounds according to general formula (I), preferably according to formula (la), (lb), (Ic) or (Id) or pharmaceutically acceptable salts thereof, for use in the prevention , the delaying of the occurrence, the delaying of the progression and / or treatment of diseases or conditions which can be influenced by STING inhibition. Inhibition of the STING protein may not require to be a complete inhibition of the STING proteins within a cell, tissue, organ or the body of a patient to cause the desired positive effects in a patient. A partial inhibition maybe sufficient and possibly desirable in some patients.

[0212] Used terms and definitions

[0213] Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

[0214] In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, Ci.g-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, in groups like HO-, H?N-, (O)S-, (O)?S-, NC- (cyano), HOOC-, F3C- or the like, the skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself. For combined groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent "aryl-Ci-3-alkyl-" means an aryl group which is bound to a Ci-3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.

[0215] 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.

[0216] 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: 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:

[0217] The asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.

[0218] The term "substituted" as used herein, means that one or more hydrogens on the designated atom are replaced by a group selected from a defined group of substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound. Likewise, the term "substituted" may be used in connection with a chemical moiety instead of a single atom, e.g. "substituted alkyl", "substituted aryl" or the like.

[0219] 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 as for instance hydrates.

[0220] Unless specifically indicated, also "pharmaceutically acceptable salts" as defined in more detail below shall encompass solvates thereof such as for instance hydrates.

[0221] In general, substantially pure stereoisomers can be obtained according to synthetic principles known to a person skilled in the field, e.g. by separation of corresponding mixtures, by using stereochemically pure starting materials and / or by stereoselective synthesis. It is known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, e.g. starting from optically active starting materials and / or by using chiral reagents.

[0222] 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. 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 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 conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0223] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio.

[0224] As used herein, "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

[0225] For example, such salts include salts from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, 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, / V-methyl-D-glucamine, potassium, sodium and tris(hydroxymethyl)-aminomethane.

[0226] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.

[0227] Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts) also comprise a part of the invention.

[0228] The term halogen denotes fluorine, chlorine, bromine and iodine.

[0229] The term sulfonamide denotes an organosulfur group with the structure R-S(=O)2-NR'2 that consists of sulfonyl group (O=S=O) connected to an amine group (-NH2), for example drawn like this: wherein one or both hydrogens at the amine group may be substituted by a number of other structures as described herein.

[0230] The term "Ci.n-alkyl-", wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4, 5, or 6, either alone or in combination with another radical, denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term Ci.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)-.

[0231] 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.

[0232] The term "Cs-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. 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:

[0233] 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.

[0234] The term "heterocyclyl" means a saturated or unsaturated mono- or polycyclic ring system optionally comprising aromatic rings, containing one or more heteroatoms selected from N, O, S, SO or SO2 consisting of 3 to 14 ring atoms wherein none of the heteroatoms is part of the aromatic ring. The term "heterocyclyl" is intended to include all the possible isomeric forms.

[0235] 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):

[0236]

[0237] The term "heteroaryl" means a mono- or polycyclic ring system, comprising at least one aromatic ring, containing one or more heteroatoms selected from N, O, S, SO or SO2, consisting of 5 to 14 ring atoms wherein at least one of the heteroatoms is part of an aromatic ring. The term "heteroaryl" is intended to include all the possible isomeric forms. 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):

[0238] 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. 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.

[0239] The term „bicyclic ring systems" means groups consisting of 2 joined cyclic substructures including spirocyclic, fused, and bridged ring systems.

[0240] Synthesis

[0241] The compounds according to the invention may be obtained using methods of synthesis known in principle, known to the one skilled in the art and described in the literature of organic synthesis. Preferably, the compounds are obtained in analogous fashion to the methods of preparation explained more fully hereinafter, in particular as described in the experimental section. In some cases, the order in carrying out the reaction steps may be varied. Variants of the reaction methods that are known to the one skilled in the art but not described in detail here may also be used. Preferably, the compounds are obtained by the following methods according to the invention which are described in more detail hereinafter.

[0242] The following Schemes illustrate generally how to manufacture the compounds of the present invention by way of example. Starting materials may be prepared by methods that are described in the literature or herein, or may be prepared in an analogous or similar manner. Any functional groups in the starting materials or intermediates may be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage within the reaction sequence 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.

[0243] 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 chromatography - mass spectrometry (LC-MS) if desired, and intermediates and products may be purified by chromatography and / or by recrystallization.

[0244] The examples which follow are illustrative and, as recognized by one skilled in the art, particular reagents or conditions could be modified as needed for individual compounds without undue experimentation. Starting materials and intermediates used, in the methods below, are either commercially available or easily prepared from commercially available materials by those skilled in the art.

[0245] Examples and experimental data

[0246] 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.

[0247] The term "room temperature" designate a temperature of about 20 °C, e.g., 15 to 25 °C.

[0248] As a rule,1H-NMR and / or mass spectra have been obtained for the compounds prepared.

[0249] Flash chromatography or MPLC is performed with commercial silica gel and is equivalent to silica gel chromatography.

[0250] 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

[0251] 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.

[0252] Scheme 1: General synthesis scheme for patent examples Intermediates B

[0253] Intermediates A

[0254] G1 = Boronic acids / boronate esters Examples

[0255] Scheme 2a: General synthesis of intermediates A: nterme ate

[0256] Scheme 2b: Alternative synthesis of intermediates A:

[0257] Intermediates A

[0258] Scheme 2c: Alternative synthesis of intermediates A:

[0259] Intermediates A

[0260] Scheme 3: General synthesis of pyrazole intermediates F

[0261]

[0262] Intermediates F

[0263] Scheme 4a: General synthesis of imidazole intermediates F

[0264] Intermediate C Intermediate D

[0265] Intermediate F

[0266] Scheme 4b: Alternative synthesis of Imidazole intermediates F

[0267] Intermediate F All starting materials not described are either commercially available or described in literature.

[0268] Synthesis of intermediates Al - A15:

[0269] Synthesis of intermediate Al, A3 and A8

[0270] Step 1: Synthesis of methyl 4-(l-hydroxy-2-nitroethyl) benzoate

[0271] Nitromethane (2.97 kg, 48.7 mol, 2.63 L) is dissolved in EtOH (160 mL). NaOH (10.0 M, 7.90 mL, 78.9 mmol) is added dropwise and methyl 4-formylbenzoate (800 g, 4.87 mol) is added to the reaction mixture. More NaOH (10.0 M, 7.90 mL, 78.9 mmol) and EtOH (32.0 mL) is added, and the reaction mixture is stirred at 38 °C for 20 h. The reaction mixture is quenched by the addition of water (5.00 L) and extracted with EtOAc (3 x 2.00 L). The combined organic layers are washed with H2O (2.00 L) and brine (3 x 2.00 L), dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain the titled compound.

[0272] Analysis (method A): Rt: 0.97 min, [M+H]+: 226

[0273] Synthesis of methyl 4-(2-amino-l-hydroxyethyl)benzoate

[0274] Methyl 4-(l-hydroxy-2-nitroethyl) benzoate (500 g, 2.22 mol) is dissolved in AcOH (5.00 L). Raney Nickel (50.0 g, 852 mmol) is added, the reaction mixture is degassed 3 times and purged with H2 and stirred at 25 °C for 16 h. The reaction mixture is filtered, and the filtrate is triturated with EtOAc and MTBE at 15 °C for 5 h to obtain the desired compound.

[0275] Analysis (method A): Rt: 0.34 min, [M+H]+: 196

[0276] Step 3: Synthesis of methyl 4-(2-{[(2-bromo-6-nitrophenyl)methyl]amino}-l-hydroxyethyl)benzoate

[0277] Methyl 4-(2-amino-l-hydroxyethyl)benzoate x HOAc (300 g, 1.18 mol) is dissolved in ACN (1.00 L). 1- Bromo-2-(bromomethyl)-3-nitrobenzene (0.40 M, 2.06 L, 0.82 mol) andDIPEA (303 g, 2.35 mol, 409 mL) are added and the reaction mixture is stirred at 15 °C for 16 h. The reaction mixture is diluted with DCM (3.00 L), filtered and the filtrate is concentrated. The residue is purified by column chromatography (SiOj, PE / EtOAc 50 / 1 --> 0 / 1) to obtain the titled compound.

[0278] Analysis (method A): Rt: 0.92 min, [M+H]+: 409

[0279] Step 4: Synthesis of methyl 4-[2-(4-bromo-2H-indazol-2-yl)-l-hydroxyethyl]benzoate

[0280] Methyl 4-(2-{[(2-bromo-6-nitrophenyl)methyl]amino}-l-hydroxyethyl)benzoate (100 g, 244 mmol) is dissolved in MeOH (2.00 L). At 30 °C 4 A molecular sieve and Zn (31.9 g, 488 mmol) are added, and the reaction mixture is stirred at 30 °C for 1 h. Ammoniumformate (10.8 g, 172 mmol) is added, and the reaction mixture is stirred at 30 °C for 16 h. More ammoniumformate (4.62 g, 73.3 mmol) is added to the reaction mixture, and it is stirred at 30 °C for 5 h. Zn (7.99 g, 122 mmol) and ammoniumformate (7.70 g, 122 mmol) are added and the reaction mixture is stirred at 30 °C for 16 h. The reaction mixture is cooled to 15 °C, filtered, and the filtrate is triturated with PE and EtOAc at 15 °C for 2 h to obtain the desired compound as a crude.

[0281] Analysis (method A): Rt: 1.15 min, [M+H]+: 375

[0282] Synthesis of methyl 4-[2-(4-bromo-2H-indazol-2-yl)-l-fluoroethyl]benzoate Methyl 4-[2-(4-bromo-2H-indazol-2-yl)-l-hydroxyethyl]benzoate (100 g, 267 mmol) is dissolved in DCM (2.00 L) and cooled to - 78 °C. Then DAST (51.5 g, 319 mmol, 42.2 mL) is added to the solution at - 78 °C, and the reaction mixture is stirred at 25 °C for 16 h. The reaction mixture is concentrated under reduced pressure. The residue is purified by column chromatography (SiOz, PE / EtOAc 50 / 1 --> 1 / 1) to obtain the desired compound.

[0283] Analysis (TLC on SiO2, PE / EtOAc 2 / 1): Rf: 0.50

[0284] Step 6: Synthesis of methyl 4-[(lR)-2-(4-bromo-2H-indazol-2-yl)-l-fluoroethyl]benzoate

[0285] (intermediate A8)

[0286] Intermediate A8

[0287] Methyl 4-[2-(4-bromo-2H-indazol-2-yl)-l-fluoroethyl]benzoate (125 g, 331 mmol) is dissolved in DCM (250 mL) and ACN (5.00 L) and is separated by chrial SFC (method: column: Chiralpak AS-3, 50 x 4.6 mm, I.D., 3 pm, mobile phase: A: CO2and B: IPA (0.05 % DEA),

[0288] Gradient: from 5 % to 50 % in 1.2 min and hold 50 % for 1 min, then from 50 % to 5 % of

[0289] B for 0.8 min, flow rate: 3.40 mL / min, column temp.: 35 °C, BPR: 1800 psi (12410.563 kPa)). The desired fractions are concentrated under reduced pressure to give the intermediate A8.

[0290] Analysis (SFC method B): Rt: 0.98 min

[0291] Analysis (method C): Rt: 1.04 min, [M+H]+: 377

[0292] Synthesis of 4-[(lR)-2-(4-bromo-2H-indazol-2-yl)-l-fluoroethyl]benzoic acid

[0293] Methyl 4-[(lR)-2-(4-bromo-2H-indazol-2-yl)-l-fluoroethyl]benzoate (intermediate A8) (10.0 g, 26.5 mmol) is suspended in acetone (200 mL). At 0 °C, 2 M aq. NaOH (40.0 mL, 2 M, 80.0 mmol) is added, and the reaction mixture is stirred at 0 °C for 10 min and at 50 °C for 2 h. The reaction mixture is cooled to 0 °C and acidified with HOAc. The formed precipitate is filtered, washed with water, and dried at 55 °C overnight to afford the titled compound.

[0294] Analysis (method D): Rt: 1.10 min, [M+H]+: 363 Synthesis of 4-[(lR)-2-(4-bromo-2H-indazol-2-yl)-l-fluoroethyl]-N,N-dirnethylbenzarnide

[0295] (intermediate A3)

[0296] 4-[(lR)-2-(4-Bromo-2H-indazol-2-yl)-l-fluoroethyl]benzoic acid (12.4g, 34.0 mmol) is dissolved in DMF (50 mL). At 0 °C, dimethylamine (2 M in THF, 26.0 mL, 52.0 mmol), DIPEA (18.0 mL, 105 mmol) and HATU (13.0 g, 34.2 mmol) are added, and the reaction mixture is stirred at 0 °C for 20 min and at rt for 1 h. The reaction mixture is quenched by the addition of ice water, the formed precipitate is filtered, washed with water, and dried at 50 °C overnight to afford the intermediate A3.

[0297] Analysis (method D): Rt: 1.05 min, [M+H]+: 390

[0298] Step 9: Synthesis of 4-[(lR)-2-(4-bromo-3-fluoro-2H-indazol-2-yl)-l-fluoroethyl]-N,N- dimethylbenzamide (intermediate Al)

[0299] 4-[(lR)-2-(4-Bromo-2H-indazol-2-yl)-l-fluoroethyl]-N,N-dimethylbenzamide (intermediate A3) (5.00 g, 11.5 mmol, 90 % purity) is dissolved in ACN (50 mL). Selectfluor (l-(Chloromethyl)-4-fluoro-l,4- diazabicyclo[2.2.2]octane-l,4-diium ditetrafluoroborate) (5.50 g, 15.5 mmol) is added, and the reaction mixture is stirred at 45 °C overnight. The reaction mixture is quenched at 0 °C with an aq. saturated solution of NaHCOs and brine and extracted with EtOAc (3 x). The combined organic layers are dried, filtered, and concentrated. The residue is purified by column chromatography (SiOj, PE / (EtOAc / ACN 9 / 1) 1 / 1 isocratic). The desired fractions are concentrated. The residue is repurified by reversed phase chromatography (HPLC; MeOH / water / TFA) to afford the intermediate Al. Analysis (method D): Rt: 1.03 min, [M+H]+: 408

[0300] Synthesis of intermediate A2 and A5 Synthesis of 4-acetyl-N,N-dimethylbenzamide

[0301] Under an atmosphere or argon, 4-acetylbenzoic acid (3.00 g, 18.3 mmol) is dissolved in DCM (30 mL) and DMF (30.0 pL). Oxalyl chloride (2 M in DCM, 11.9 mL, 23.8 mmol) is added dropwise, and the reaction mixture is stirred at rt for 3 h. The reaction mixture is concentrated and coevaporated with toluene. The residue is suspended in DCM (10 mL), and at 0 °C dimethylamine (2 M in THF, 11.2 mL, 22.5 mmol) and DIPEA (6.00 mL, 35.3 mmol) are added, and the reaction mixture is stirred at rt overnight. The reaction mixture is quenched by the addition of water and washed with 1 M HCI. The organic layer is dried, filtered and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the titled compound.

[0302] Analysis (method E): Rt: 0.48 min, [M+H]+: 192

[0303] Step 2: Synthesis of 4-(2-chloroacetyl)-N,N-dimethylbenzamide

[0304] 4-Acetyl-N,N-dimethylbenzamide (2.70 g, 14.1 mmol) is dissolved in ACN (30 mL). NCS (1.88 g, 14.1 mmol) and p-Toluenesulfonic acid monohydrate (537 mg, 2.82 mmol) are added, and the reaction mixture is stirred at 60 °C for 2 h. The reaction mixture is diluted with EtOAc (120 mL) and an aq saturated solution of NaHCOs (60 mL) and the two layers are extracted. The organic layer is separated, washed with water (2 x) and the aqueous layer is extracted again with EtOAc (2 x). The combined organic layers are dried, filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / NHs) to afford the titled compound.

[0305] Analysis (method F): Rt: 0.41 min, [M+H]+: 226

[0306] Synthesis of 4-[2-(4-bromo-2H-indazol-2-yl)acetyl]-N,N-dimethylbenzamide

[0307] 4-Bromo-lH-indazole (1.62 g, 8.22 mmol) and 4-(2-chloroacetyl)-N,N-dimethylbenzamide (2.06 g,

[0308] 9.13 mmol) are combined and stirred at 130 °C for 1.5 h. After cooling to 50 °C, the reaction mixture is diluted with MeOH and stirred at rt overnight. The formed precipitate is filtered to afford the desired compound.

[0309] Analysis (method E): Rt: 0.79 min, [M+H]+: 386

[0310] Step 4: Synthesis of 4-[2-(4-bromo-2H-indazol-2-yl)-l,l-difluoroethyl]-N,N-dimethylbenzamide

[0311] (intermediate A5)

[0312] 4-[2-(4-Bromo-2H-indazol-2-yl)acetyl]-N,N-dimethylbenzamide (1.21 g, 2.82 mmol, 90 % purity) is dissolved in toluene (7 mL) and DCM (7 mL). At 0 °C, DAST (1.85 mL, 14.1 mmol) is added slowly, and stirred at 0 °C for 10 min and at rt overnight. The reaction mixture is quenched by the addition of an aq. saturated solution of NaHCOs and extracted with DCM. The organic layer is washed with an aq. saturated solution of NaHCOs (2 x), dried, filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate A5.

[0313] Analysis (method F): Rt: 0.63 min, [M+H]+: 408

[0314] Step 5: Synthesis of 4-[2-(4-bromo-3-fluoro-2H-indazol-2-yl)-l,l-difluoroethyl]-N,N- dimethylbenzamide (intermediate A2)

[0315] Intermediate A2

[0316] 4-[2-(4-Bromo-2H-indazol-2-yl)-l,l-difluoroethyl]-N,N-dimethylbenzamide (intermediate A5) (760 mg, 1.86 mmol) is dissolved in ACN (10 mL). Selectfluor (890 mg, 2.51 mmol) is added, and the reaction mixture is stirred at 45 °C for 2 h. The reaction mixture is quenched by the addition of an aq. saturated solution of NaHCOs and extracted with EtOAc (2 x). The combined organic layers are dried, filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; MeOH / water / TFA) to afford the intermediate A2.

[0317] Analysis (method G): Rt: 1.38 min, [M+H]+: 426 Synthesis of intermediate A4

[0318] Step 1: Synthesis of l-bromo-2-(bromomethyl)-3-nitrobenzene

[0319] 2-Bromo-6-nitrotoluene (50 g, 231 mmol) is dissolved in DCE (300 mL). A suspension of NBS (61.8 g, 347 mmol) in DCE (400 mL) is added at RT and the reaction mixture is stirred at reflux. Then AIBN (2.66 g, 16.2 mmol) in DCM (35 mL) is slowly added (syringe pump, pump rate approximately 1 drop per 6 seconds), and the reaction mixture is stirred at reflux overnight. The reaction mixture is concentrated, the residue is dissolved in DCM (500 mL) and washed 3 x with water. The organic layer is dried over MgSO4and 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.

[0320] TLC: silica gel, CycH / EtOAc 5 / 1: Rf: 0.4

[0321] Step 2: Synthesis of [(2-bromo-6-nitrophenyl) methyl] [(trimethylsilyl)methyl] amine

[0322] (Trimethylsilyl)methylamine (13 mL, 97.1 mmol) and DIPEA (34.00 mL, 197 mmol) are dissolved in ACN (200 mL). A solution of l-bromo-2-(bromomethyl)-3-nitrobenzene (20.0 g, 67.1 mmol) in ACN (200 mL) is added dropwise and the reaction mixture is stirred at RT for 1 h. The reaction mixture is concentrated, the residue is dissolved in DCM and washed 3 x with water. The organic layer is filtered through silica, the silica is washed with DCM and the filtrate is concentrated to afford the desired product.

[0323] Analysis (method D): Rt: 0.75 min, [M+H]+: 317

[0324] Step 3: Synthesis of 4-bromo-2-[(trimethylsilyl)methyl]-2H-indazole

[0325] [(2-Bromo-6-nitrophenyl) methyl] [(trimethylsilyl)methyl] amine (18.6 g, 58.8 mmol) is dissolved in MeOH (1.6 L). Zinc (19.2 g, 294 mmol) is added and ammonium formate (5.55 g, 88.1 mmol) in MeOH (38 mL) is slowly added dropwise at 50 °C over 7 h. The reaction mixture is filtered over Celite, washed with MeOH and the filtrate is concentrated. The residue is purified by flash chromatography (SiO2,CycH / EtOAc 88 / 12 --> CycH / EtOAc 0 / 100) to afford the desired compound.

[0326] Analysis (method D): Rt: 1.18 min, [M+H]+: 283

[0327] Step 4: Synthesis of methyl 4-[2-(4-bromo-2H-indazol-2-yl)-l-hydroxyethyl]benzoate

[0328] 4-Bromo-2-[(trimethylsilyl)methyl]-2H-indazole (5.00 g, 17.7 mmol) and methyl 4-formylbenzoate (3.48 g, 21.2 mmol) are dissolved in DMF (25 mL). CsF (2.68 g, 17.7 mmol) is added, and the reaction mixture is stirred at rt overnight. The reaction mixture is added to ice water (500 mL) and stirred 10 min. The formed precipitate is filtered and dried at 50 °C over the weekend to afford the titled compound.

[0329] Analysis (method E): Rt: 0.88 min, [M+H]+: 375

[0330] Step 5: Synthesis of methyl 4-[2-(4-bromo-2H-indazol-2-yl)acetyl]benzoate

[0331] 4-[2-(4-Bromo-2H-indazol-2-yl)-l-hydroxyethyl]benzoate (6.41 g, 17.1 mmol) is dissolved in DCM (150 mL). At 0 °C, DMP (8.26 g, 18.8 mmol) is added, and the reaction mixture is stirred at rt overnight. The reaction mixture is diluted with DCM and washed with an aq. solution of NajSzOs (100 mL) and an aq. saturated solution of NaHCOs. The organic layer is dried, filtered, and concentrated. The residue is crystallized with EtOH. The formed precipitate is a byproduct. The EtOH from the filtrate is mostly concentrated and the residue is stored in the fridge overnight. The formed precipitate is filtered to afford the desired compound.

[0332] Analysis (method F): Rt: 0.65 min, [M+H]+: 373

[0333] Step 6: Synthesis of methyl 4-[(lR)-2-(4-bromo-2H-indazol-2-yl)-l-hydroxyethyl]benzoate

[0334] (intermediate A4)

[0335] Intermediate A4

[0336] Under an atmosphere of argon, methyl 4-[2-(4-bromo-2H-indazol-2-yl)acetyl]benzoate (1.92 g, 5.13 mmol) is dissolved in THF (5 mL). At 0 °C, formic acid triethylamine complex 5:2 (10.7 mL, 25.7 mmol) is added dropwise and then chloro([(lS,2S)-(-)-2-amino-l,2-diphenylethyl](4- toluenesulfonyl)amido)(mesitylene)ruthenium(ll) (160 mg, 0.26 mmol) is added, and the reaction mixture is stirred at rt overnight. The reaction mixture is quenched by the addition of water, and the THF is concentrated. The residue is diluted with DCM and water and is extracted. The organic layer is dried, filtered, and concentrated. The residue is triturated with ACN. The precipitate is filtered and dried at 50 °C to afford the intermediate A4.

[0337] Analysis (method F): Rt: 0.62 min, [M+H]+: 375

[0338] Analysis (method SFC H): Rt: 1.08 min

[0339] Synthesis of intermediate A6

[0340] Step 1 - 7: Synthesis of 4-[(lR)-2-(4-bromo-2H-indazol-2-yl)-l-fluoroethyl]benzoic acid is synthesized analogues to step 1 - 7 of intermediate Al and A3.

[0341] Step 8: Synthesis of 4-bromo-2-[(2R)-2-fluoro-2-[4-(4-methylpiperazine-l-carbonyl)phenyl]ethyl]-2H- indazole (intermediate A6) 4-[(lR)-2-(4-Bromo-2H-indazol-2-yl)-l-fluoroethyl]benzoic acid (2.30 g, 5.76 mmol, 91 % purity) is dissolved in DMF (30 mL). DIPEA (3.94 mL, 23.1 mmol) and HATU (2.41 g, 6.34 mmol) are added, and the reaction mixture is stirred at rt for 15 min. Then 1-methylpiperazine (1.28 mL, 11.5 mmol) is added, and the reaction mixture is stirred at rt overnight. The reaction mixture is diluted with water and EtOAc and is extracted. The organic layer is dried over NajSC , filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate A6.

[0342] Analysis (method F): Rt: 0.46 min, [M+H]+: 445

[0343] Synthesis of intermediate A7

[0344] Step 1 - 3: Synthesis of 4-bromo-2-[(trimethylsilyl)methyl]-2H-indazole is synthesized analogues to step 1 - 3 of intermediate A4.

[0345] Step 4: Synthesis of 2-(4-bromo-2H-indazol-2-yl)-l-(4-methanesulfonylphenyl)ethan-l-ol

[0346] 4-Bromo-2-[(trimethylsilyl)methyl]-2H-indazole (800 mg, 2.82 mmol) and CsF (540 mg, 3.56 mmol) are dissolved in DMF (5 mL). At 0 °C, 4-methanesulfonylbenzaldehyde (700 mg, 3.80 mmol) in DMF (10 mL), is added slowly dropwise (0.5 mL / min), and the reaction mixture is stirred at 0 °C for 20 min. The reaction mixture is added to water. The formed precipitate is filtered, washed with i-PrOH and dried at 45 °C to afford the titled compound.

[0347] Analysis (method D): Rt: 0.92 min, [M+H]+: 395

[0348] Step 5: Synthesis of 4-bromo-2-[2-fluoro-2-(4-methanesulfonylphenyl)ethyl]-2H-indazole (intermediate A7)

[0349] Intermediate A7

[0350] 2-(4-Bromo-2H-indazol-2-yl)-l-(4-methanesulfonylphenyl)ethan-l-ol (200 mg, 0.51 mmol) is dissolved in DCM (4 mL). New DAST (302 mg, 0.68 mmol, 50 %) is added, and the reaction mixture is stirred at rt overnight. The reaction mixture is quenched by the addition of an aq. solution of NaHCOs, and the organic layer is separated. The aqueous layer is extracted with DCM (2 x). The combined organic layers are dried over MgSO4, filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / NHs) to afford the intermediate A7.

[0351] Analysis (method I): Rt: 0.96 min, [M+H]+: 397

[0352] Synthesis of Intermediate A9

[0353] Synthesis of methyl 4-(2-chloroacetyl)benzoate

[0354] Methyl 4-acetylbenzoate (15.0 g, 0.08 mol) is dissolved in ACN (150 mL). NCS (13.5 g, 0.10 mol) and p-Toluenesulfonic acid monohydrate (3.20 g, 0.02 mol) are added, and the reaction mixture is stirred at 60 °C for 4 h. The reaction mixture is filtered, the filtrate is diluted with EtOAc (180 mL) and an aq saturated solution of NaHCOs (90 mL) and the two layers are extracted. The organic layer is separated, washed with water (2 x) and the aqueous layer is extracted again with EtOAc (2 x). The combined organic layers are dried, filtered, and concentrated. The residue is crytallized with EtOH to afford the titled compound.

[0355] Analysis (method F): Rt: 0.49 min, [M+H]+: 213

[0356] Synthesis of methyl 4-[2-(4-bromo-5-fluoro-2H-indazol-2-yl)acetyl]benzoate

[0357] 4-Bromo-5-fluoro-lH-indazole (5.00 g, 23.3 mmol) and methyl 4-(2-chloroacetyl)benzoate (7.42 g, 34.9 mmol) are combined and stirred at 146 °C for 1 h. After cooling to 50 °C, the reaction mixture is diluted with MeOH and purified by column chromatography (SiOj, CycH / EtOAc 100 / 0 --> CycH / EtOAc 60 / 40) to afford the desired compound.

[0358] Analysis (method F): Rt: 0.68 min, [M+H]+: 391

[0359] Synthesis of methyl 4-[(lS)-2-(4-bromo-5-fluoro-2H-indazol-2-yl)-l-hydroxyethyl]benzoate

[0360] Under an atmosphere of argon, methyl 4-[2-(4-bromo-5-fluoro-2H-indazol-2-yl)acetyl]benzoate (5.19 g, 13.3 mmol) is dissolved in THF (55 mL). At 0 °C, formic acid triethylamine complex 5:2 (27.7 mL, 66.3 mmol) is added dropwise and then chloro([(lS,2S)-(-)-2-amino-l,2-diphenylethyl](4- toluenesulfonyl)amido)(mesitylene)ruthenium(ll) (413 mg, 0.66 mmol) is added, and the reaction mixture is stirred at rt for 1 h. The reaction mixture is quenched by the addition of water, and the formed precipitate is filtered, washed with water, and dried to afford the desired compound.

[0361] Analysis (method F): Rt: 0.60 min, [M+H]+: 393

[0362] Analysis (method SFC J): Rt: 1.45 min

[0363] Step 4: Synthesis of methyl 4-[2-(4-bromo-5-fluoro-2H-indazol-2-yl)-l-fluoroethyl]benzoate

[0364] Methyl 4-[(lS)-2-(4-bromo-5-fluoro-2H-indazol-2-yl)-l-hydroxyethyl]benzoate (5.07 g, 12.9 mmol) is dissolved in DCM (150 mL). At 0 °C, new DAST (6.41 mL, 17.4 mmol, 50 %) is added, and the reaction mixture is stirred at rt for 2 h. The reaction mixture is quenched by the addition of an aq. saturated NaHCOs solution. The layers are separated, and the aqueous layer is extracted with DCM. The combined organic layers are dried, filtered, and concentrated. The residue is purified by column chromatography (SiOj, CycH / EtOAc 70 / 30). The desired fractions are combined and concentrated. The residue is triturated with diethyl ether to afford the titled compound.

[0365] Analysis (method SFC K): Rt: 1.43 and 2.30 min, [M+H]+: 395

[0366] Step 5: Synthesis of methyl 4-[(lR)-2-(4-bromo-5-fluoro-2H-indazol-2-yl)-l-fluoroethyl]benzoate

[0367] Methyl 4-[2-(4-bromo-5-fluoro-2H-indazol-2-yl)-l-fluoroethyl]benzoate is separated by chiral SFC (method K) to afford the desired compound. Analysis (method SFC K): Rt: 2.19 min, [M+H]+: 395

[0368] Step 6: Synthesis of 4-[(lR)-2-(4-bromo-5-fluoro-2H-indazol-2-yl)-l-fluoroethyl]benzoic acid

[0369] Methyl 4-[(lR)-2-(4-bromo-5-fluoro-2H-indazol-2-yl)-l-fluoroethyl]benzoate (2.09 g, 5.29 mmol) is dissolved in acetone (90 mL). 1 M NaOH (26.4 mL, 1 M, 26.4 mmol) is added, and the reaction mixture is stirred at rt for 2 h. The reaction mixture is concentrated, diluted with water, and acidified with HOAc. The formed precipitate is filtered, washed with water, and dried to obtain the titled compound.

[0370] Analysis (method F): Rt: 0.61 min, [M+H]+: 381

[0371] Step 7: Synthesis of 4-[(lR)-2-(4-bromo-5-fluoro-2H-indazol-2-yl)-l-fluoroethyl]-N,N- dimethylbenzamide (intermediate A9)

[0372] Intermediate A9

[0373] 4-[(lR)-2-(4-Bromo-5-fluoro-2H-indazol-2-yl)-l-fluoroethyl]benzoic acid (2.13 g, 5.59 mmol) is dissolved in DMF (30 mL). DIPEA (2.87 mL, 16.8 mmol) and HATU (2.12 g, 5.59 mmol) are added, and the reaction mixture is stirred at rt for 15 min. Then dimethyl amine (2 M in THF, 4.19 mL, 8.38 mmol) is added, and the reaction mixture is stirred at rt overnight. It is diluted with water and EtOAc. The organic layer is separated. The aqueous layer is extracted again with EtOAc and the combined organic layers, are washed with water, dried, filtered, and concentrated. The residue is purified by column chromatography (SiOj, DCM / MeOH 100 / 0 --> DCM / MeOH 95 / 5). The desired fractions are combined and concentrated. The residue is triturated with MTBE and crystallized with ACN / MeOH / HjO to afford the intermediate A9.

[0374] Analysis (method F): Rt: 0.61 min, [M+H]+: 408

[0375] Synthesis of intermediate A10

[0376] Step 1: Synthesis of methyl 4-(2-hydroxyethyl)benzoate

[0377] A solution of 2-(4-bromo-phenyl)-ethanol (50.0 g, 249 mmol) in MeOH (500 mL) and THF (200 mL) is degasified with argon. Then Potassium acetate (97.6 g, 995 mmol) and Pd(dppf)CL (5.00 g, 6.12 mmol) are added, and the reaction mixture is purged with CO gas and the reaction is kept at 80 psi (551.581 kPa) under CO gas for 48 h. The reaction mixture is concentrated in vacuo. The crude product is dissolved in EtOAc (1000 mL) washed with water and the organic layer is concentrated. The residue is purified by column chromatography (SiOj, hexane / EtOAc 80 / 20) to obtain the titled compound.

[0378] Analysis (method L): Rt: 2.62 min, [M+H]+: 181

[0379] Step 2: Synthesis of methyl 4-[2-(4-bromo-2H-indazol-2-yl)ethyl]benzoate (intermediate A10)

[0380] Intermediate A10

[0381] To a solution of 4-bromo-lH-indazole (15.0 g, 76.1 mmol) in toluene (500 mL) is added methyl 4-(2- hydroxyethyl)benzoate (15.1 g, 83.7 mmol), TMAD (18.4 g, 107 mmol) and tributyl phosphine (30.8 mL, 122 mmol), and the reaction mixture is stirred at rt overnight. The reaction mixture is washed with water. The aqueous layer is extracted with EtOAc. The combined organic layers are evaporated in vacuo. The crude is purified by column chromatography (SiOj, hexane / EtOAc 80 / 20 --> hexane / EtOAc 70 / 30) to obtain the intermediate A10.

[0382] Analysis (method L): Rt: 3.55 min, [M+H]+: 359

[0383] Synthesis of intermediate All

[0384] Step 1 - 3: Synthesis of 4-bromo-2-[(trimethylsilyl)methyl]-2H-indazole is synthesized analogues to step 1 - 3 of intermediate A4.

[0385] Step 4: Synthesis of 4-formyl-N,N-dimethylbenzene-l-sulfonamide

[0386] 4-Formylbenzene-l-sulfonyl chloride (1.00 g, 4.89 mmol) is dissolved in DCM (5 mL) and pyridine (2 mL, 24.8 mmol). Dimethylamine (2 M in THF, 24.4 mL, 48.9 mmol) is added, and the reaction mixture is stirred at rt overnight. The reaction mixture is quenched by the addition of 0.1 M HCI and water and extracted with DCM. The organic layer is dried, filtered, and concentrated to afford the titled compound.

[0387] Analysis (method D): Rt: 0.71 min, [M+H]+: 214 Synthesis of 4-[2-(4-bromo-2H-indazol-2-yl)-l-hydroxyethyl]-N,N-dimethylbenzene-l- sulfonamide

[0388] 4-Formyl-N,N-dimethylbenzene-l-sulfonamide (445 mg, 2.09 mmol) and CsF (268 mg, 1.77 mmol) are suspended in DMF (5 mL). 4-Bromo-2-[(trimethylsilyl)methyl]-2H-indazole (500 mg, 1.77 mmol) in DMF (5 mL), is added slowly dropwise, and the reaction mixture is stirred at rt for 2 h. The reaction mixture is filtered, concentrated, and purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the desired compound.

[0389] Analysis (method D): Rt: 0.88 min, [M+H]+: 424

[0390] Synthesis of 4-[2-(4-bromo-2H-indazol-2-yl)-l-fluoroethyl]-N,N-dimethylbenzene-l- sulfonamide (intermediate All)

[0391] Intermediate A11

[0392] 4-[2-(4-Bromo-2H-indazol-2-yl)-l-hydroxyethyl]-N,N-dimethylbenzene-l-sulfonamide (250 mg, 0.59 mmol) is dissolved in DCM (4 mL). New DAST (345 pL, 0.80 mmol, 50 %) is added, and the reaction mixture is stirred at rt overnight. Still starting material left. 1 eq. new DAST is added, and it is stirred at rt overnight. The reaction mixture is quenched by the addition of an aq. solution of NaHCOs, and the organic layer is separated. The aqueous layer is extracted with DCM. The combined organic layers are dried, filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate All.

[0393] Analysis (method D): Rt: 0.97 min, [M+H]+: 426 Synthesis of intermediate A12

[0394] 3 Synthesis of 4-bromo-2-[(trimethylsilyl)methyl]-2H-indazole

[0395] Is synthesized analogues to step 1 - 3 of Intermediate A4.

[0396] Step 4: Synthesis of methyl (lr,4rj-4-[2-(4-bromo-2H-indazol-2-yl)-l-hydroxyethyl]cyclohexane-l- carboxylate (intermediate A12)

[0397] Intermediate A12

[0398] 4-Bromo-2-[(trimethylsilyl)rriethyl]-2H-indazole (1.00 g, 3.53 mmol), methyl (lr,4r)-4- formylcyclohexane-l-carboxylate (601 mg, 3.53 mmol) and CsF (536 mg, 3.53 mmol) are suspended in DMF (8 mL), and the reaction mixture is stirred at rt for 3 h. The reaction mixture is diluted with water and extracted with EtOAc. The organic layer is dried, filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate A12. Analysis (method D): Rt: 1.02 min, [M+H]+: 381

[0399] Synthesis of intermediate A13

[0400] 3 Synthesis of 4-bromo-2-[(trimethylsilyl)methyl]-2H-indazole

[0401] Is synthesized analogues to step 1 - 3 of Intermediate A4.

[0402] Step 4: Synthesis of methyl 3-[2-(4-bromo-2H-indazol-2-yl)-l-hydroxyethyl]benzoate

[0403] 4-Bromo-2-[(trimethylsilyl)methyl]-2H-indazole (800 mg, 2.82 mmol), methyl 3-formylbenzoate (464 mg, 2.82 mmol) and CsF (429 mg, 2.82 mmol) are suspended in DMF (8 mL), and the reaction mixture is stirred at rt for 3 h. The reaction mixture is diluted with water and extracted with EtOAc. The organic layer is dried, filtered, and concentrated. The residue is purified by column chromatography (SiOj, CycH / EtOAc 100 / 0 --> CycH / EtOAc 50 / 50) to afford the desired compound.

[0404] Analysis (method D): Rt: 1.01 min, [M+H]+: 375 Step 5: Synthesis of methyl 3-[2-(4-bromo-2H-indazol-2-yl)acetyl]benzoate

[0405] Methyl 3-[2-(4-bromo-2H-indazol-2-yl)-l-hydroxyethyl]benzoate (686 mg, 1.83 mmol) is dissolved in DCM (10 mL). At 0 °C, DMP (1.24 g, 2.93 mmol) is added, and the reaction mixture is stirred at rt for 2 h. The reaction mixture is diluted with DCM and washed with an aq. saturated solution of NaHCOs. The organic layer is dried, filtered, and concentrated. The residue is crystallized with MeOH to afford the desired compound.

[0406] Analysis (method D): Rt: 1.05 min, [M+H]+: 373

[0407] Step 6: Synthesis of methyl 3-[(lR)-2-(4-bromo-2H-indazol-2-yl)-l-hydroxyethyl]benzoate

[0408] (intermediate A13)

[0409] Intermediate A13

[0410] Under an atmosphere of argon, methyl 3-[2-(4-bromo-2H-indazol-2-yl)acetyl]benzoate (242 mg, 0.65 mmol) is dissolved in THF (4 mL). At 0 °C, formic acid triethylamine complex 5:2 (1.35 mL, 3.24 mmol) is added dropwise and then chloro([(lS,2S)-(-)-2-amino-l,2-diphenylethyl](4- toluenesulfonyl)amido)(mesitylene)ruthenium(ll) (20.2 mg, 0.03 mmol) is added, and the reaction mixture is stirred at rt for 2 h. The reaction mixture is quenched by the addition of water, and the THF is concentrated. The residue is diluted with ACN / MeOH and purified by reversed phase chromatography (HPLC; ACN / water / NHs) to afford the desired compound to afford the intermediate A13.

[0411] Analysis (method M): Rt: 0.99 min, [M+H]+: 375

[0412] Analysis (method SFC N): Rt: 4.80 min

[0413] Synthesis of intermediate A14

[0414] Step 1 - 3: Synthesis of 4-bromo-2-[(trimethylsilyl)methyl]-2H-indazole is synthesized analogues to step 1 - 3 of Intermediate A4. Synthesis of methyl 4-formyl-2-methylbenzoate

[0415] 4-Bromo-3-methylbenzaldehyde (500 mg, 2.51 mmol) is dissolved in DMF (2.5 mL) and MeOH (8.0 mL). Pd(dppf)Ck x DCM (0.21 g, 0.25 mmol) is added, and the reaction mixture is stirred under an atmosphere of CO at 90 °C and 15 bar for 20 h. The reaction mixture is filtered, and the filtrate is concentrated. The residue is diluted with water and EtOAc and extracted. The organic layer is dried, filtered, and concentrated. The residue is purified by column chromatography (SiOj, CycH / EtOAc 1 / 0 -> CycH / EtOAc 4 / 1) to afford the desired compound.

[0416] Analysis (method F): Rt: 0.63 min, [M+H]+: 178

[0417] Synthesis of methyl 4-[2-(4-bromo-2H-indazol-2-yl)-l-hydroxyethyl]-2-methylbenzoate

[0418] (intermediate A14)

[0419] Intermediate A14

[0420] 4-Bromo-2-[(trimethylsilyl)methyl]-2H-indazole (405 mg, 1.43 mmol), methyl 4-formyl-2- methylbenzoate (400 mg, 1.68 mmol) and CsF (256 mg, 1.68 mmol) are suspended in DMF (2 mL), and the reaction mixture is stirred at rt for overnight. The reaction mixture is diluted with ice water (75 mL) and extracted with EtOAc (2 x). The combined organic layers are dried, filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate A14.

[0421] Analysis (method F): Rt: 0.64 min, [M+H]+: 389

[0422] Synthesis of intermediate A15

[0423] Step 1 - 5: Synthesis of 4-[2-(4-bromo-2H-indazol-2-yl)-l-hydroxyethyl]-N,N-dimethylbenzene-l- sulfonamide

[0424] Is synthesized analogues to step 1 - 5 of Intermediate All.

[0425] Step 6: Synthesis of 4-[2-(4-bromo-2H-indazol-2-yl)acetyl]-N,N-dimethylbenzene-l-sulfonamide

[0426] 4-[2-(4-Bromo-2H-indazol-2-yl)-l-hydroxyethyl]-N,N-dimethylbenzene-l-sulfonamide (300 mg, 0.71 mmol) is dissolved in DCM (5 mL). DMP (311 mg, 0.71 mmol) is added, and the reaction mixture is stirred at rt overnight. The reaction mixture is diluted with water and extracted with DCM (2 x). The combined organic layers are dried, filtered, and concentrated. The residue is triturated with MeOH to afford the titled compound.

[0427] Analysis (method D): Rt: 0.94 min, [M+H]+: 422

[0428] Step 7: Synthesis of 4-[(lR)-2-(4-bromo-2H-indazol-2-yl)-l-hydroxyethyl]-N,N-dimethylbenzene-l- sulfonamide (intermediate A15)

[0429] Intermediate A15

[0430] Under an atmosphere of argon, 4-[2-(4-bromo-2H-indazol-2-yl)acetyl]-N,N-dimethylbenzene-l- sulfonamide (257 mg, 0.61 mmol) is dissolved in THF (4 mL). At 0 °C, formic acid triethylamine complex 5:2 (1.27 mL, 3.04 mmol) is added dropwise and then chloro([(lS,2S)-(-)-2-amino-l,2- diphenylethyl](4-toluenesulfonyl)amido)(mesitylene)ruthenium(ll) (18.9 mg, 0.03 mmol) is added, and the reaction mixture is stirred at rt for 2 h. The reaction mixture is quenched by the addition of water, and the THF is concentrated. The residue is diluted with ACN / MeOH and purified by reversed phase chromatography (HPLC; ACN / water / NHs) to afford the desired compound to afford the intermediate A15.

[0431] Analysis (method M): Rt: 0.96 min, [M+H]+: 424

[0432] Analysis (method SFC O): Rt: 1.36 min

[0433] Synthesis of intermediates Bl - B18:

[0434] Synthesis of intermediate Bl

[0435] Synthesis of {2-[(2R)-2-[4-(dimethylcarbamoyl)phenyl]-2-fluoroethyl]-3-fluoro-2H-indazol-4- yljboronic acid

[0436] 4-[(lR)-2-(4-Bromo-3-fluoro-2H-indazol-2-yl)-l-fluoroethyl]-N,N-dimethylbenzamide (Al) (150 mg, 0.37 mmol) is dissolved in dioxane (3 mL). Bis(neopentyl glycolato)diboron (103 mg, 0.44 mmol) and potassium acetate (145 mg, 1.48 mmol) are added, and the mixture is purged with argon. Pd(dppf)CI2 x DCM (30.0 mg, 0.04 mmol) is added, and the reaction mixture is stirred at 90 °C for 2.5 h. After the reaction mixture is cooled to RT the reaction mixture is diluted with ACN, filtered, and purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate Bl.

[0437] Analysis (method E): Rt: 0.56 min, [M+H] +: 374

[0438] Synthesis of Intermediate B3

[0439] Synthesis of 4-[(lR)-l-fluoro-2-[3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazol-

[0440] 2-yl]ethyl]-N,N-dimethylbenzamide

[0441] 4-[(lR)-2-(4-Bromo-3-fluoro-2H-indazol-2-yl)-l-fluoroethyl]-N,N-dimethylbenzamide (Al) (570 mg, 1.40 mmol) is dissolved in dioxane (20 mL). Bis(pinacolato)diboron (461 mg, 1.82 mmol) and potassium acetate (548 mg, 5.59 mmol) are added, and the mixture is purged with argon. Pd(dppf)CI2 x DCM (57.0 mg, 0.07 mmol) is added, and the reaction mixture is stirred at 95 °C for 3 h. After the reaction mixture is cooled to RT the reaction mixture is diluted with EtOAc, filtered, and purified by column chromatography (SiOj, PE / EtOAc 90 / 10 --> PE / EtOAc 80 / 20) to afford the intermediate B3.

[0442] Analysis (method D): Rt: 0.80 min, [M+H] +: 456

[0443] The intermediates compiled in the following table are obtained by following a reaction sequence analogous to that described for intermediate Bl and B3.

[0444]

[0445]

[0446] Synthesis of intermediates Cl - C7:

[0447] Synthesis of intermediate Cl Step 1: Synthesis of 5-cyclopropyl-l-methyl-lH-imidazole

[0448] Under an argon atmosphere, 5-bromo-l-methyl-lH-imidazole (7.50 g, 46.6 mmol), cyclopropylzinc bromide (132 mL, 65.90 mmol, 0.5 M in THF) and Pd(dppf)CL (2.20 g, 3.01 mmol) are mixed together, and the reaction mixture is stirred at 70 °C for 20 h. The reaction mixture is concentrated, and the residue is purified by flash chromatography (DCM / MeOH 100 / 0 --> DCM / MeOH 90 / 10) to afford the desired product.

[0449] Analysis (method Q): Rt: 0.31 min, [M+H]+: 123

[0450] Step 2: Synthesis of 5-cyclopropyl-l,2-dimethyl-lH-imidazole (intermediate Cl)

[0451] Intermediate C1

[0452] Under an argon atmosphere, 5-cyclopropyl-l-methyl-lH-imidazole (1 g, 8.12 mmol) is dissolved in THF

[0453] (15.00 mL) and cooled to -78°C. n-BuLi (6.1 mL, 9.8 mmol, 1.6 M) is added dropwise and the reaction mixture is stirred at -78°C for 30 min. Then Mel (663 p.L, 10.6 mmol) is added dropwise and the reaction mixture is stirred at -78°C for 1 h. The reaction mixture is quenched with a half saturated NH4CI solution and stirred for 10 min. 2 mL of aqueous NH4OH (25 %) is added and the mixture is stirred for 30 min. The layers are separated, and the aqueous layer is extracted 3x with EtOAc. The combined organic layers are dried (Na2SO4), filtered and evaporated to afford intermediate Cl.

[0454] Analysis (method M): Rt: 0.72 min, [M+H]+: 137

[0455] Synthesis of intermediate C2

[0456] Step 1: Synthesis of 2-acetyl-3-methylbutanenitrile

[0457] A solution of diisopropylamine (177 mL, 1.25 mol) in T (1.17 L) is cooled to -78°C. N-butyllithium 2.5M in hexane (469 mL, 1.17 mol) is added and the reaction mixture is allowed to warm to 0°C and stirred 1 h at 0°C. The reaction mixture is cooled to -78°C and 3-methyl-butyronitrile (81.8 mL, 0.782 mol) in 80 mL THF is added dropwise, while maintaining the temperature below -65°C. The reaction mixture is stirred at -78°C for lh. After that, a solution of acetic anhydride (88.7 mL, 0.938 mol) in 80 mL THF is added dropwise over 30 min. The reaction mixture is allowed to warm to 0°C for lh, then 15°C for 0.5h. The reaction mixture is quenched with citric acid (10 %, 200 mL) and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated to afford the desired product, which is used without further purification in the next step.

[0458] Analysis (TLC): Rf : 0.3 (20% EtOAc / petrol ether)

[0459] Step 2: Synthesis of 5-methyl-4-(propan-2-yl)-lH-pyrazol-3-amine

[0460] 2-Acetyl-3-methylbutanenitrile (80 g, 0.64 mol) is dissolved in EtOH (352 mL). Glacial acetic acid (47.6 mL, 0.83 mol) and hydrazine monohydrate (49.6 mL, 1.02 mol) are added, and the reaction mixture is stirred at 80 °C overnight. After cooling to 0 °C the pH is carefully adjusted to 9 with a saturated NaHCOs solution. The reaction mixture is then diluted with water and extracted 3 x with EtOAc. The organic layer is washed with brine, dried (Na2SO4), filtered and concentrated to afford the desired product. Analysis (method Q): Rt: 0.36 min, [M+H]+: 140 Step 3: Synthesis of 3-iodo-5-methyl-4-(propan-2-yl)-lH-pyrazole (intermediate C2)

[0461] Intermediate C2

[0462] 5-Methyl-4-(propan-2-yl)-lH-pyrazol-3-amine (1 g, 7.2 mmol) is dissolved in ACN (8 mL). Under cooling with ice / acetone, sodium nitrite (0.59 g, 8.6 mmol) is added, and the reaction mixture is stirred at -5 °C for 30 min. Then KI (1.55 g, 9.34 mmol) is added, and the reaction mixture is stirred at 0 °C for 1.5 h. The reaction mixture is quenched with NajSjOs and is diluted with Me-THF (10 mL) and water (10 mL). After stirring for lh the layers are separated. The organic layer is washed with brine, dried (NajSC ), and concentrated to afford 1.6 g of the intermediate C2.

[0463] Analysis (method F): Rt: 0.52 min, [M+H]+: 251

[0464] Synthesis of intermediate C3

[0465] Synthesis of l,2-dimethyl-5-(propan-2-yl)-lH-imidazole

[0466] Intermediate C3

[0467] 5-lsopropyl-l-methyl-lH-imidazole (1 g, 8.05 mmol) is dissolved in THF (25 mL) and cooled to -65°C. Then 5.4 mL BuLi (1.6M, 8.64 mmol) is added slowly. After 30 min Mel (0.8 mL, 12.9 mmol) is added and the mixture warmed to room temperature; water and aqueous ammonia (ImL) is added under stirring, then aqueous NH4CI solution is added, and the mixture extracted with EtOAc. Purification by silica gel chromatography using DCM:MeOH 9 / 1 plus ammonia yielded the intermediate C3.

[0468] Analysis (method M): Rt: 0.76 min, [M+H]+: 139

[0469] Synthesis of intermediate C4

[0470] Synthesis of 4-cyclopropyl-3-iodo-lH-pyrazole

[0471] Intermediate C4

[0472] 4-Cyclopropyl-lH-pyrazole (300 mg, 2.77 mmol) is dissolved in ACN (3 mL). NIS (687 mg, 3.05 mmol) is added, and the reaction mixture is stirred at 80 °C for 6 h. The reaction mixture is quenched by the addition of an aq. half saturated NajSjOs solution and extracted with DCM. The organic layer is dried, filtered, and concentrated. The residue is purified by column chromatography (SiOj, DCM / MeOH 100 / 0 --> DCM / MeOH 98 / 2) to afford the intermediate C4.

[0473] Analysis (method F): Rt: 0.45 min, [M+H]+: 235

[0474] The intermediates compiled in the following table are obtained by following a procedure analogous to that described for intermediate C4.

[0475] Synthesis of intermediate C5

[0476] Step 1: Synthesis of tert-butyl 4-(propan-2-yl)-lH-pyrazole-l-carboxylate

[0477] 4-(Propan-2-yl)-lH-pyrazole (1.00 g, 9.08 mmol) is dissolved in DCM (10 mL). DMAP (222 mg, 1.82 mmol) and di-tert-butyl dicarbonate (2.58 g, 11.8 mmol) are added, and the reaction mixture is stirred at rt overnight. The reaction mixture is quenched by the addition of 0.1 M HCI (50 mL) and extracted with DCM (3 x 100 mL). The combined organic layers are dried, filtered, and concentrated to afford the titled compound.

[0478] Analysis (method M): Rt: 1.04 min, [M+H-BOC]+: 111 Step 2: Synthesis of 4-(propan-2-yl)-5-(triethylsilyl)-lH-pyrazole (intermediate C5)

[0479] Under an atmosphere of argon, tert-butyl 4-(propan-2-yl)-lH-pyrazole-l-carboxylate (1.90 g, 9.04 mmol) is dissolved in THF (3.62 mL). At - 30 °C, 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex (9.94 mL, 1 M, 9.94 mmol) is added dropwise, and stirred at - 30 °C for 2 h. Then chlorotriethylsilane (1.82 mL, 10.8 mmol) is added, and the reaction mixture is stirred at rt overnight. The reaction mixture is quenched by the addition of an aq. half saturated solution of NaHCOs, filtered, washed with DCM and the layers are separated. The aqueous layer is extracted with DCM (2 x) and the combined organic layers are dried, filtered, and concentrated. The residue is purified by column chromatography (SiOj, CycH / EtOAc 93 / 7 --> CycH / EtOAc 60 / 40) to afford the intermediate C5.

[0480] Analysis (method D): Rt: 1.02 min, [M+H]+: 225

[0481] Synthesis of intermediate C7

[0482] Step 1: Synthesis 4-ethenyl-3-methyl-lH-pyrazole

[0483] Under an atmosphere of argon, 4-iodo-3-methyl-lH-pyrazole (10.0 g, 48.1 mmol), potassium vinyltrifluoroborate (12.9 g, 96.2 mmol) and TEA (13.5 mL, 96.2 mmol) are dissolved in MeOH (100 mL). Pd(dppf)Ck x DCM (1.18 g, 1.44 mmol) is added, and the reaction mixture is stirred at 65 °C overnight. The reaction mixture is diluted with diethyl ether (130 mL), and it is stirred for 1 h at rt. The reaction mixture is filtered, washed with diethyl ether (50 mL), and concentrated (at 50 °C and until 150 mbar). The residue is purified by column chromatography (SiOj, CycH / EtOAc 70 / 30 --> CycH / EtOAc 0 / 100) to afford the titled compound.

[0484] Analysis (method E): Rt: 0.38 min, [M+H]+: 109

[0485] Step 2: Synthesis of benzyl 4-ethenyl-3-methyl-lH-pyrazole-l-carboxylate

[0486] 4-Ethenyl-3-methyl-lH-pyrazole (4.20 g, 31.1 mmol) is dissolved in DCM (50 mL). DIPEA (13.4 mL, 77.7 mmol) and benzyl chloroformate (3 M in toluene, 11.4 mL, 34.2 mmol) are added, and the reaction mixture is stirred at rt overnight. The reaction mixture is diluted with water and DCM and is extracted. The organic layer is dried over NajSC , filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the desired compound.

[0487] Analysis (method F): Rt: 0.63 min, [M+H] +: 243

[0488] Step 3: Synthesis of benzyl 4-(2,2-difluorocyclopropyl)-3-methyl-lH-pyrazole-l-carboxylate

[0489] Under an atmosphere of argon, benzyl 4-ethenyl-3-methyl-lH-pyrazole-l-carboxylate (1.12 g, 4.62 mmol) and NaF (194 mg, 4.62 mmol) are dissolved in Diglyme (30 mL). At 75 °C, trimethylsilyl 2,2- difluoro-2-(fluorosulfonyl)acetate (4.73 mL, 24.0 mmol) is added slowly dropwise, and the reaction mixture is stirred at 75 °C for 1 h. The reaction mixture is quenched by the addition of water (1 mL), and it is concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the desired compound.

[0490] Analysis (method R): Rt: 0.62 min, [M+H] +: 293

[0491] Step 4: Synthesis of 4-(2,2-difluorocyclopropyl)-3-methyl-lH-pyrazole

[0492] Benzyl 4-(2,2-difluorocyclopropyl)-3-methyl-lH-pyrazole-l-carboxylate (1.45 g, 4.96 mmol) is dissolved in 4 M HCI in dioxane (7.44 mL, 29.8 mmol), and stirred at 60 °C for 21 h. The reaction mixture is concentrated and coevaporated with toluene to afford the titled compound.

[0493] Analysis (method E): Rt: 0.44 min, [M+H] +: 159

[0494] Step 5: Synthesis of 4-(2,2-difluorocyclopropyl)-5-iodo-3-methyl-lH-pyrazole (intermediate C7)

[0495] Intermediate C7

[0496] To get the free base, 4-(2,2-Difluorocyclopropyl)-3-methyl-lH-pyrazole x HCI (100 mg, 0.51 mmol) is diluted with an aq. NaHCOs solution and DCM and is extracted. The organic layer is dried, filtered, and concentrated. The free base is dissolved in DMF (5 mL), K2CO3 (249 mg, 1.80 mmol) and I2 (261 mg, 1.03 mmol) in DMF (1 mL) are slowly added, and the reaction mixture is stirred at rt over the weekend. The reaction mixture is quenched by the addition of an aq. solution of Na2S2C>3 and extracted with DCM. The organic layer is dried, filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate C7.

[0497] Analysis (method E): Rt: 0.70 min, [M+H] +: 285

[0498] Synthesis of intermediates DI - D14:

[0499] Synthesis of intermediate DI

[0500] Synthesis of l-(5-cyclopropyl-l-methyl-lH-imidazol-2-yl)-3-methylbutan-2-one

[0501] Intermediate C1 Intermediate D1

[0502] 5-Cyclopropyl-l,2-dimethyl-lH-imidazole (Cl) (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 °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 NH4CI solution and extracted 3x EtOAc. The combined organic layers are dried (NajSC ), filtered and concentrated and purified by silica gel chromatography (gradient: DCM / MeOH 100 / 0 --> 94 / 4) to yield the intermediate DI. Analysis (method Q): Rt: 0.45 min, [M+H]+: 207 The intermediates compiled in the following table are obtained by following a procedure analogous to that described for intermediate DI.

[0503] Synthesis of intermediate D3

[0504] Synthesis of l-[3-iodo-5-methyl-4-(propan-2-yl)-lH-pyrazol-l-yl]propan-2-one

[0505] Intermediate C2 Intermediate D3 5-lodo-3-methyl-4-(propan-2-yl)-lH-pyrazole (C2) (2.90 g, 11.6 mmol) is dissolved in ACN (60 mt), K2CO3 (4.01 g, 29 mmol) and chloroacetone (1.85 mL, 23.2 mmol) are added. The reaction mixture is stirred at 50 °C for 2 h. Chloroacetone (0.2 mL) is added, and the reaction mixture is stirred at 50°C for lh. The reaction mixture is filtered, washed with ACN and the filtrate is evaporated. The residue is purified by flash chromatography (CycH / EtOAc 90 / 10 --> CycH / EtOAc 60 / 40) to afford the intermediate D3.

[0506] Analysis (method E): Rt: 0.82 min, [M+H]+: 307

[0507] The intermediates compiled in the following table are obtained by following a procedure analogous to that described for intermediate D3.

[0508]

[0509] Synthesis of intermediate D4

[0510] Step 1: Synthesis of 5-cyclopropyl-l-methyl-lH-imidazole-2-carbaldehyde

[0511] Under an argon atmosphere, 5-cyclopropyl-l-methyl-lH-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 reaction mixture is stirred at -78 °C for 1 h. Then DMF (5.03 mL, 61.9 mmol) is added dropwise, and the reaction mixture is stirred at -78 °C for 30 min. The reaction mixture is quenched with a saturated NH4CI solution and water. Then it is extracted 3x with diethyl ether. The combined organic layers are dried (NajSC ), filtered and concentrated to afford the product which is used in the next step without further purification.

[0512] Analysis (method Q): Rt: 0.35 min, [M+H]+: 151

[0513] Step 2: Synthesis of 4-bromo-5-cyclopropyl-l-methyl-lH-imidazole-2-carbaldehyde

[0514] 5-Cyclopropyl-l-methyl-lH-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 NajSjOs, water and brine. The organic layer is dried (NajSC ), filtered, and concentrated. The residue is purified by flash chromatography (CycH / EtOAc 100 / 0 --> CycH / EtOAc 50 / 50) to afford the product.

[0515] Analysis (method Q): Rt: 0.49 min, [M+H]+: 229 / 231 (Br)

[0516] Step 3: Synthesis of 4-bromo-5-cyclopropyl-l-methyl-2-[(lE)-2-nitrobut-l-en-l-yl]-lH-imidazole

[0517] 4-Bromo-5-cyclopropyl-l-methyl-lH-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 NaCI solution and is extracted 3 x with EtOAc. The combined organic layers are dried (NajSC ), filtered and concentrated to afford the product which is used without further purification in the next step. Analysis (method Q): Rt: 0.76 min, [M+H]+: 300 / 302 (Br)

[0518] Synthesis of l-(4-bromo-5-cyclopropyl-l-methyl-lH-imidazol-2-yl) butan-2-one ntermediate

[0519] D4)

[0520] Iron powder (11.16 g, 0.200 mol) is suspended in acetic acid (150 mL) and the mixture is heated to 60 °C. 4-Bromo-5-cyclopropyl-l-methyl-2-[(lE)-2-nitrobut-l-en-l-yl]-lH-imidazole (12 g, 0.040 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 NajCOs. Charcoal is added and the reaction mixture is filtered through celite. The layers are separated, and the organic layer is dried (NajSC ), filtered, and concentrated. The residue is purified by flash chromatography (CycH / EtOAc 20 / 80 --> CycH / EtOAc 0 / 100) to afford the intermediate D4.

[0521] Analysis (method E): Rt: 0.46 min, [M+H]+: 271 / 273 (Br)

[0522] Synthesis of intermediate D6

[0523] Step 1: Synthesis of 2,2-difluoro-N-methoxy-N-methylcyclopropane-l-carboxamide

[0524] 2,2-Difluorocyclopropanecarboxylic acid (3.4 g, 27.8 mmol), N,O-dimethyl hydroxylamine hydrochloride (3.6 g, 36.9 mmol) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.4 g , 42.9 mmol) are dissolved in DCM (40 mL), the mixture cooled to 0°C, then DIPEA (20 mL) is slowly added and the mixture stirred overnight at RT. The mixture is then cooled again to 0°C and 4 M HCL (35 mL) is added. The organic phase is separated, concentrated, and the product is purified by silica gel chromatography (DCM), and evaporation of the combined fractions at 35°C / 90 mbar yields the desired product.

[0525] Analysis: ESI [M]+: 166 Synthesis of 2-(5-cyclopropyl-l-methyl-lH-imidazol-2-yl)-l-(2,2-difluorocyclopropyl)ethan-l- one (intermediate D6)

[0526] Intermediate C1 Intermediate D6

[0527] 5-Cyclopropyl-l,2-dimethyl-lH-imidazole (Cl) (150 mg, 1.1 mmol) is dissolved in THF (4mL), cooled to -78°C and BuLi (0.76 mL, 1.6 M) is slowly added. After 15 min, 2,2-difluoro-N-methoxy-N- methylcyclopropane-l-carboxamide (250 mg, 1.1 mmol, dissolved in 0.5 mL THF) is added and the mixture is stirred for 30 min. Then aqueous NH4CI solution is added, and the mixture is extracted with EtOAc. The organic phase is concentrated and purified by preparative HPLC to yield intermediate D6. Analysis (method D): Rt: 0.65 min, [M+H]+: 241

[0528] Synthesis of intermediate D7

[0529] Step 1: Synthesis of 5-cyclopropyl-l-methyl-lH-imidazole

[0530] Under an argon atmosphere, 5-brorno-l-methyl-lH-irnidazole (7.50 g, 46.6 mmol), cyclopropyl zinc bromide (132 mL, 65.9 mmol, 0.5 M in THF) and Pd(dppf)CL (2.20 g, 3.01 mmol) are mixed together, and the reaction mixture is stirred at 70 °C for 20 h. The reaction mixture is concentrated, and the residue is purified by flash chromatography (DCM / MeOH 100 / 0 --> DCM / MeOH 90 / 10) to afford the desired compound.

[0531] Analysis (method Q): Rt: 0.31 min, [M+H]+: 123

[0532] Synthesis of 2, 4-dibromo-5-cyclopropyl-l-methyl-lH-imidazole (intermediate D7)

[0533] Intermediate D7

[0534] 5-Cyclopropyl-l-methyl-lH-imidazole (9.20 g, 52.7 mmol) is dissolved in ACN (200 mL). At - 5 °C NBS (18.8 g, 105 mmol) is added in portions and the reaction mixture is stirred at - 5 °C for 30 min and at RT for 4 h. The reaction mixture is quenched by the addition of a saturated NajSjOs solution (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 (NajSC ), filtered and concentrated. The residue is purified by flash chromatography (CycH / EtOAc 95 / 5 --> CycH / EtOAc 65 / 35) to afford the intermediate D7.

[0535] Analysis (method E): Rt: 0.77 min, [M+H]+: 279

[0536] Synthesis of intermediate D10

[0537] Step 1: Synthesis of methyl 2-[(tert-butyldimethylsilyl)oxy]acetate

[0538] 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 added dropwise, and the reaction mixture is stirred at 0 °C for lh and at RT for 1 h. The reaction mixture is diluted with DCM and washed 2x with 1 M HCI and lx with an aqueous saturated solution of NaHCOs. 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.

[0539] Analysis (TLC silica CycH / EtOAc 9 / 1): Rf: 0.54

[0540] Step 2: Synthesis of l-[(tert-butyldimethylsilyl)oxy]-3-(5-cyclopropyl-l-methyl-lH-imidazol-2- yl)propan-2-one (intermediate D10)

[0541] Intermediate C1

[0542] Intermediate D10 5-Cyclopropyl-l, 2-dimethyl-lH-imidazole (Cl) (3.18 g, 23.3 mmol) is dissolved in THF (45 mL). At - 75 °C n-BuLi (17.5 mL, 28.0 mmol, 1.6 M) is added dropwise and the reaction mixture is stirred at - 75 °C for 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 is quenched with a half saturated NH4CI solution and extracted 2x EtOAc. The combined organic layers are dried (NajSO4), filtered and concentrated to afford the desired intermediate D10.

[0543] Analysis (method D): Rt: 0.78 min, [M+H]+: 309

[0544] Synthesis of intermediates El - E9:

[0545] Synthesis of intermediate El

[0546] Step 1: Synthesis of ethyl 3-amino-l-[(4-rnethoxyphenyl) methyl]-lH-pyrazole-4-carboxylate

[0547] 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 mmol) is added. Then a solution of ethyl (2Z)-2-cyano-3-ethoxyprop-2-enoate (10 g, 59 mmol) in THF (50 mL) is added dropwise over 45 min at 0 °C under Argon. The reaction mixture is stirred at 0 °C for 90 min. The reaction mixture is quenched with 4 M HCI in dioxane (29.6 mL, 118 mmol) and concentrated to dryness. Then the residue is dissolved in EtOAc and washed with a sat. NaHCOs solution. The aqueous layer is extracted with EtOAc. The combined organic layers are dried (NajSO4), filtered and concentrated to afford the product.

[0548] Analysis (method S): Rt: 1.55 min, 274

[0549] Step 2: Synthesis of {3-amino-l-[(4-methoxyphenyl) methyl]-lH-pyrazol-4-yl} methanol

[0550] Ethyl 3-amino-l-[(4-methoxyphenyl) methyl]-lH-pyrazole-4-carboxylate (16.3 g, 56.3 mmol, 95 % purity) is dissolved in THF (81.5 mL), and at -7 °C LiAIH4(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 with 2 V of THF / H2O 8 / 2 and 1 V of aq. sat. Na2SO4solution and stirred 30 min at RT. The reaction mixture is filtered through Celite and washed with MeOH and DCM / MeOH. The filtrate is dried (Na2SO4), filtered, concentrated and co-evaporated with toluene to afford the product.

[0551] Analysis (method S): Rt: 1.34 min, [M+H]+: 234

[0552] Step 3: Synthesis of 3-amino-l-[(4-methoxyphenyl) methyl]-lH-pyrazole-4-carbaldehyde (intermediate El)

[0553] Intermediate E1

[0554] {3-Amino-l-[(4-methoxyphenyl) methyl]-lH-pyrazol-4-yl} methanol (13.1 g, 50.5 mmol, 90 % purity) is dissolved in ACN (131 mL) and water (26.2 mL), then MnC (34.2 g, 354 mmol) is added, and the reaction mixture is stirred at RT for 2h. The reaction mixture is filtered through Celite and washed with DCM / acetone. The filtrate is concentrated to dryness and the residue is triturated with MTBE to afford the intermediate El.

[0555] TLC: silica gel, DCM / MeOH 95 / 5: Rf: 0.55

[0556] Analysis (method S): Rt: 1.55 min

[0557] Synthesis of intermediate E2

[0558] Step 1: Synthesis of 2-methyl-5-(trifluoromethoxy)aniline l-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 residue is purified by flash chromatography (DCM / MeOH 100 / 0 --> DCM / MeOH 90 / 10) to afford the desired compound.

[0559] Analysis (method E): Rt: 0.77 min, [M+H]+: 192 Synthesis of 4-bromo-2-methyl-5-(trifluoromethoxy)aniline

[0560] 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 NajSjOs and diluted and extracted with DCM. The organic layer is dried, filtered, and concentrated. The residue is purified by flash chromatography (DCM / MeOH 100 / 0 --> DCM / MeOH 90 / 10) to afford the desired compound.

[0561] Analysis (method E): Rt: 0.96 min, [M+H]+: 270 / 272 (Br)

[0562] Step 3: Synthesis of 5-bromo-6-(trifluoromethoxy)-2H-indazole

[0563] 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 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.

[0564] Analysis (method E): Rt: 0.88 min, [M+H]+: 281 / 283 (Br)

[0565] 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 stirred at RT for 1 h. The reaction is quenched by the dropwise addition of an 10 % NaHCOs solution 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.

[0566] Analysis (method E): Rt: 0.93 min, [M+H]+: 295 / 297 (Br)

[0567] Step 5: Synthesis of 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6-(trifluoromethoxy)-

[0568] 2H-indazole (intermediate E2)

[0569] Intermediate E2

[0570] 5-Bromo-2-rnethyl-6-(trifluorornethoxy)-2H-indazole (260 mg, 0.88 mmol) is dissolved in dioxane (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)CE x 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 E2.

[0571] Analysis (method F): Rt: 0.69 min, [M+H]+: 343

[0572] Synthesis of intermediate E3

[0573] Step 1: Synthesis of 3-amino-l-[3-(morpholin-4-yl)propyl]-lH-pyrazole-4-carbonitrile

[0574] 3-Amino-4-cyanopyrazole (2 g, 18.5 mmol) is dissolved in ACN (20 mL) and K2CO3 (3.2 g, 23.2 mmol) is added. At 70 °C 4-(3-chloropropyl)morpholine (3.60 g, 22 mmol) in ACN (10 mL) is added dropwise and the reaction mixture is stirred at 70 °C for 2.5 h. The reaction mixture is filtered and the filtrate is purified by reversed phase chromatography (HPLC; ACN / water including NH3) to afford the product. Analysis (method Q): Rt: 0.27 min, [M+H]+: 236

[0575] Step 2: Synthesis of 3-amino-l-[3-(morpholin-4-yl)propyl]-lH-pyrazole-4-carbaldehyde (intermediate

[0576] E3)

[0577] Intermediate E3

[0578] Under an argon atmosphere, 3-amino-l-[3-(morpholin-4-yl)propyl]-lH-pyrazole-4-carbonitrile (0.50 g, 2.13 mmol) is suspended in toluene (5 mL) and at - 70 °C DIBALH (5.80 mL, 6.38 mmol, 1.1 M in CycH) is added dropwise. The reaction mixture is stirred at - 70 °C for 20 min. Then the reaction mixture is warmed to -10 °C and quenched with an aqueous HCI (2.66 mL, 10.6 mmol, 4 M). The reaction mixture is stirred at RT for 30 min. NH4OH (1 mL, 28 %) and ACN is added and the reaction is filtered through cellulose. The filtrate is concentrated and purified by reversed phase chromatography (HPLC; ACN / water including NH3) to afford the intermediate E3.

[0579] Analysis (method T): Rt: 0.26 min, [M+H]+: 239

[0580] Synthesis of intermediate E4 are synthesized analogues to Intermediate E2

[0581] Step 4: Synthesis of 5-bromo-2-[2-(4-methylpiperazin-l-yl)ethyl]-6-(trifluoromethoxy)-2H-indazole

[0582] 5-Bromo-6-(trifluoromethoxy)-2H-indazole (1.00 g, 3.56 mmol) is dissolved in THF (10 mL). At 0 °C, NaH (2.62 g, 11.4 mmol, 60 %) is added and the reaction mixture is stirred for 10 min. Then l-(2- bromoethyl)-4-methylpiperazine x 2 HBr (1.31 g, 3.56 mmol) is added, and the reaction mixture is stirred at rt over the weekend. The reaction is quenched by the dropwise addition of water. It is diluted with EtOAc and extracted. The organic layer is dried, filtered, and concentrated. The crude residue is purified by flash chromatography (SiOj, CycH --> EtOAc 100 / 0 --> CycH / EtOAc 0 / 100 --> EtOAc / MeOH 80 / 20) to afford the desired compound.

[0583] Analysis (method D): Rt: 0.83 min, [M+H]+: 407

[0584] Step 5: Synthesis of 2-[2-(4-methylpiperazin-l-yl)ethyl]-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-6-(trifluoromethoxy)-2H-indazole (intermediate E4)

[0585] 5-Bromo-2-[2-(4-methylpiperazin-l-yl)ethyl]-6-(trifluoromethoxy)-2H-indazole (240 mg, 0.59 mmol) is dissolved in dioxane (15 mL). Bis(pinacolato)diboron (299 mg, 1.18 mmol) and potassium acetate (174 mg, 1.77 mmol) are added, and the mixture is purged with argon. Pd(dppf)CL x DCM (48.1 mg, 0.06 mmol) is added, and the reaction mixture is stirred at 90 °C for 4 h. After the reaction mixture is cooled to RT, it is diluted with MeOH, filtered, and purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate E4.

[0586] Analysis (method D): Rt: 0.89 min, [M+H]+: 455

[0587] Synthesis of intermediate E5

[0588] Step 1: 5-bromo-6-rnethyl-lH-pyrazolo[3,4-b]pyridine 5-Bromo-6-methyl-lH-pyrazolo[3,4-b]pyridin-3-amine (1.00 g, 4.40 mmol) is dissolved in MTBE (50 mL). Isoamyl nitrite (2.37 mL, 17.6 mmol) is added, and the reaction mixture is stirred at rt overnight and then at 55 °C for 5 h. The reaction mixture is added dropwise to an aq. 1 M HCI and basified after with an aq. NaHCOs solution. The layers are separated, and the aqueous layer is extracted with EtOAc. The combined organic layers are dried over Na2SO4, filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the desired compound.

[0589] Analysis (method F): Rt: 0.41 min, [M+H]+: 212

[0590] Step 2: 5-bromo-2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine (intermediate E5)

[0591] 5-Bromo-6-methyl-lH-pyrazolo[3,4-b]pyridine (480 mg, 2.26 mmol) is dissolved in THF (20 mL). At 0 °C, NaHMDS (1 M in THF, 4.53 mL, 4.53 mmol) followed by Mel (419 pL, 6.79 mmol) are added, and the reaction mixture is stirred at rt for 2 h. The reaction mixture is diluted with EtOAc and an aq. solution of NH4CI (1 M). The layers are separated, and the aqueous layer is extracted again with EtOAc (3 x). The combined organic layers are dried over Na2SO4, filtered, and concentrated to afford the intermediate E5.

[0592] Analysis (method E): Rt: 0.51 min, [M+H]+: 226

[0593] Synthesis of intermediate E6

[0594] Step 1: Synthesis of 2-chloro-4-fluoro-3-iodopyridine

[0595] Under an atmosphere of argon, 2-chloro-4-fluoropyridine (1.00 mL, 9.88 mmol), dissolved in THF (25 mL), is added dropwise at - 78 °C to LDA (5.44 mL, 2 M, 10.9 mmol). The reaction mixture is stirred at - 78 °C for 1 h. Then l2(2.59 g, 9.88 mmol), dissolved in THF (35 mL), is added slowly dropwise, and the reaction mixture is stirred at - 78 °C for 0.5 h. The reaction mixture is diluted with MTBE and warmed to rt. It is washed with an aq. saturated solution of Na2CO3. The aqueous layer is extracted with MTBE (3 x). The combined organic layers are washed with Na2S2O3 and brine, dried, filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA). The desired fractions are combined and extracted with DCM to afford the titled compound.

[0596] Analysis (method F): Rt: 0.54 min, [M+H]+: 258

[0597] Step 2: Synthesis of 2-chloro-3-cyclopropyl-4-fluoropyridine (intermediate E6)

[0598] Under an atmosphere of argon, 2-chloro-4-fluoro-3-iodopyridine (300 mg, 1.17 mmol), bromo(cyclopropyl)zinc (0.5 M in THF, 3.03 mL, 1.52 mmol) and PEPPSI (39.6 mg, 0.06 mmol) are combined and stirred at 50 °C for 1 h. The reaction mixture is quenched by the addition of an aq. saturated solution of NaHCOs and extracted with DCM. The organic layer is washed with brine, dried, filtered, and concentrated. The residue is purified by flash chromatography (SiOj, DCM 100 %) to afford the intermediate E6.

[0599] Analysis (method F): Rt: 0.54 min, [M+H]+: 172

[0600] Synthesis of intermediate E7

[0601] Step 1: Synthesis of 5-bromo-2-methyl-2H-pyrazolo[3,4-b]pyridin-7-ium-7-olate

[0602] 5-Bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine (8.00 g, 37.7 mmol) is dissolved in DCM (250 mL). 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 NaHCOs. 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.

[0603] Analysis (method M): Rt: 0.39 min, [M+H]+: 228 / 230 (Br)

[0604] Step 2: Synthesis of 5-bromo-6-chloro-2-methyl-2H-pyrazolo[3,4-b]pyridine

[0605] Under an atmosphere of nitrogen, DMF (20 mL) and Toluene (10 mL) are mixed together, and at 0 °C POCh (261 pL, 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 NaHCOs 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 dried in the air to afford the desired compound.

[0606] Analysis (method I): Rt: 0.80 min, [M+H]+: 246

[0607] Step 3: Synthesis of 5-bromo-6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine

[0608] 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 purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the desired compound. Analysis (method I): Rt: 0.88 min, [M+H]+: 256

[0609] Step 4: Synthesis of {6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}boronic acid (intermediate E7)

[0610] Intermediate E7 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)CE 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 purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate E7.

[0611] Analysis (method I): Rt: 0.64 min, [M+H]+: 222

[0612] Synthesis of intermediate E8

[0613] Synthesis of {2,7-dimethylimidazo[l,2-a]pyridin-6-yl}boronic acid

[0614] Intermediate E8

[0615] 6-Bromo-2,7-dimethylimidazo[l,2-a]pyridine (124 mg, 0.55 mmol) is dissolved in dioxane (4 mL). Bis(neopentyl glycolato)diboron (186 mg, 0.83 mmol) and potassium acetate (162 mg, 1.65 mmol) are added, and the mixture is purged with argon. Pd(dppf)Ck x DCM (119 mg, 0.15 mmol) is added, and the reaction mixture is stirred at 100 °C for 3 h. After the reaction mixture is cooled to RT the formed precipitate is filtered, washed with dioxane and the filtrate is concentrated. The crude residue is purified by reversed phase chromatography (HPLC; ACN / water / TFA) to afford the intermediate E8. Analysis (method D): Rt: 0.33 min, [M+H]+: 191

[0616] Synthesis of intermediate E9

[0617] Synthesis of 3-ethyl-4-iodobenzonitrile

[0618] A suspension of 4-amino-3-ethyl-benzonitrile (20.0 g, 0.14 mol) in H2O (120 mL) is cooled to 0 °C. Cone. HCI (73.6 mL, 0.89 mol, 37 %) is added dropwise while keeping the temperature at 0 °C. The reaction mixture is stirred at 0 °C for 1 h. Then Sodium nitrite (11.3 g, 0.16 mol) in H2O (28.0 mL) is added dropwise keeping the temperature at 0 °C. The reaction mixture is stirred at 0 °C for 1 h. Then, a solution of potassium iodide (27.3 g, 0.16 mol) in H2O (60.0 mL) is added dropwise keeping the temperature below 5 °C. After the addition, the reaction is allowed to warm to rt and stirred overnight at rt. The reaction is quenched by the addition of an aq. sat. NajSjOs and extracted with DCM. The organic layer is dried, filtered, and concentrated to afford the desired compound as a crude.

[0619] Step 2: Synthesis of 3-ethyl-4-iodobenzoic acid

[0620] To a solution of 3-ethyl-4-iodo-benzonitrile (40.0 g, 0.12 mol) in EtOH (600 mL) potassium hydroxide 30 % aqueous solution (341 mL, 2.33 mol) is added and the reaction mixture is stirred at 130 °C for 2 h. EtOH is removed in vacuo and the aqueous layer is acidified with 2 M HCI to pH ~ 2. The obtained solid is collected by filtration, washed with water, pentane, and dried to afford the titled compound. Analysis (method S): Rt: 1.92 min, [M-H] ': 275

[0621] Step 3: Synthesis of N-(2,2-dimethoxyethyl)-3-ethyl-4-iodobenzamide

[0622] To a solution of 3-ethyl-4-iodo-benzoic acid (29.1 g, 105 mmol) in DCM (582 mL) is added 2,2- dimethoxy-ethylamine (11.5 mL) and DIPEA (36.7 mL, 0.21 mol) followed by the addition of HATU (48.1 g). The resulting mixture is stirred overnight at rt. An aq. sat. solution of NH4CI is added and the aqueous layer is extracted with DCM (2 x). The combined organic layers are dried over NajSC , filtered, and concentrated. The crude is purified by flash chromatography (SiOj, hexane / EtOAc 95 / 5 --> hexane / EtOAc 60 / 40) to afford the desired compound.

[0623] Analysis (method S): Rt: 1.88 min, [M+H]+: 332

[0624] Step 4: Synthesis of 7-ethyl-6-iodo-l,2-dihydroisoquinolin-l-one

[0625] Sulfuric acid (54.6 mL, 1.02 mol) is added to N-(2,2-dimethoxy-ethyl)-3-ethyl-4-iodo-benzamide (10.0 g, 27.5 mmol) and the reaction mixture is stirred overnight at 95 °C. The reaction mixture is cooled to rt and poured into ice water. The aqueous layer is extracted with DCM (2 x). The combined organic layers are washed with an aq. sat. solution of NaHCOs, dried over Na2SO4, filtered, and concentrated.

[0626] The residue is triturated with DCM / MTBE and dried to afford the desired compound.

[0627] Step 5: Synthesis of 7-ethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2-dihydroisoquinolin-l- one (intermediate E9)

[0628] A solution of 7-ethyl-6-iodo-2H-isoquinolin-l-one (3.35 g, 11.2 mmol), Bis(pinacolato)diboron (8.53 g, 33.6 mmol) in anhydrous DMF (67.0 mL) is purged with argon for 10 - 15 min, then Pd(dppf)Ck x DCM (0.92 g, 1.12 mmol) and potassium acetate (5.50 g, 56.0 mmol) are added and the reaction mixture is further degassed with argon for 5 - 10 min, and then it is stirred at 95 °C for 18 h. The mixture is allowed to cool to rt and filtered through celite washing with EtOAc. The filtrate is concentrated to dryness and purified by flash chromatography (SiOj, DCM / EtOAc 100 / 0 --> DCM / EtOAc 75 / 25) to afford the intermediate E9.

[0629] Analysis (method S): Rt: 1.94 min, [M+H]+: 300

[0630] Synthesis of intermediates Fl - F24:

[0631] Synthesis of intermediate Fl

[0632] Step 1: Synthesis of 5-cyclopropyl-l-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5- yl]-lH-imidazole

[0633] Intermediate D1 l-(5-Cyclopropyl-l-methyl-lH-imidazol-2-yl)-3-methylbutan-2-one (DI) (1.28 g, 4.97 mmol, 80 % purity), 3-amino-l-methyl-lh-pyrazole-4-carbaldehyde (684 mg, 5.47 mmol), piperidine (984 pL, 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 / NHs) to afford the desired compound.

[0634] Analysis (method F): Rt: 0.32 min, [M+H]+: 296

[0635] Step 2: Synthesis of 4-bromo-5-cyclopropyl-l-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4- b]pyridin-5-yl]-lH-imidazole (intermediate Fl)

[0636] Intermediate F1

[0637] 5-Cyclopropyl-l-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-lH-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 NaHCOs solution, the layers are separated, and the water phase is extracted three times with DCM. The combined organic layers are dried (NajSC ), filtered, and concentrated. The residue is purified by flash chromatography (EtOAc / MeOH 100 / 0 --> EtOAc / MeOH 95 / 5) to afford the intermediate Fl.

[0638] Analysis (method F): Rt: 0.44 min, [M+H]+: 374 / 376 (Br)

[0639] The intermediates compiled in the following table are obtained by following a procedure analogous to that described for intermediate Fl.

[0640]

[0641] Synthesis of intermediate F3

[0642] Synthesis of l-{2,6-dimethyl-2H-pyrazolo[3,4-b] pyridin-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-lH- pyrazole l-[3-lodo-5-methyl-4-(propan-2-yl)-lH-pyrazol-l-yl] propan-2-one (DI) (2.7 g, 8.82 mmol), 3-amino-l- methyl-lh-pyrazole-4-carbaldehyde (1.1 g, 8.82 mmol) are dissolved in EtOH, piperidine (2.18 mL, 22.1 mmol) is added and the reaction mixture is stirred in a closed vial at 80°C for 4 h. The reaction mixture is concentrated, and the residue is purified by flash chromatography (DCM / MeOH 100 / 0 --> DCM / MeOH 90 / 10) to afford intermediate F3.

[0643] Analysis (method E): Rt: 0.79 min, [M+H]+: 396

[0644] The intermediates compiled in the following table are obtained by following a procedure analogous to that described for intermediate F3. Synthesis of intermediate F4

[0645] Synthesis of 4-bromo-5-cyclopropyl-2-{6-ethyl-2-methyl-2H-pyrazolo[3,4-b] pyridin-5-yl}-l-methyl- lH-imidazole l-(4-Bromo-5-cyclopropyl-l-methyl-lH-imidazol-2-yl)butan-2-one (D4) (5.51 g, 20.3 mmol) is dissolved in EtOH (60 mL). 3-Amino-l-methyl-l-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 mixture is filtered and purified by reversed phase chromatography (HPLC; Xbridge-C18, ACN / water including NH3) to afford the intermediate F4.

[0646] Analysis (method E): Rt: 0.55 min, [M+H]+: 360 / 362 (Br)

[0647] Synthesis of intermediate F7

[0648] Step 1: Synthesis of 5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl) methyl]-2H-pyrazolo[3,4-b] pyridin-5-yl}-l-methyl-lH-imidazole

[0649] Intermediate D2 Intermediate E1 l-Cyclopropyl-2-(5-cyclopropyl-l,2-dimethyl-lH-imidazol-4-yl) ethan-l-one (D2) (1.40 g, 5.48 mmol, 80 % purity) and 3-amino-l-[(4-methoxyphenyl) methyl]-lH-pyrazole-4-carbaldehyde (El) (1.65 g, 7.13 mmol) are dissolved in EtOH (35 mL). Piperidine (1.62 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 / Acetone 30 / 70) to afford the product.

[0650] Analysis (method S): Rt: 1.40 min, [M+H]+: 400 Step 2: Synthesis of 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl) methyl]-2H- pyrazolo[3,4-b] pyridin-5-yl}-l-methyl-lH-imidazole

[0651] 5-Cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl) methyl]-2H-pyrazolo[3,4-b] pyridin-5-yl}-l- methyl-lH-imidazole (0.60 g, 1.5 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 with a saturated NajSjOs solution and extracted with DCM. The organic layer is washed with a saturated K2CO3 solution, dried (NajSC ), filtered, and concentrated. The residue is purified by flash chromatography (DCM / Acetone 100 / 0 --> DCM / Acetone 90 / 10) to afford the product.

[0652] Analysis (method U): Rt: 3.82 min, [M+H]+: 478 / 480 (Br)

[0653] Step 3: Synthesis of 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2H-pyrazolo[3,4-b] pyridin-5-yl}-l- methyl-lH-imidazole

[0654] 4-Bromo-5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b] pyridin-5- yl}-l-methyl-lH-imidazole (574 mg, 1.20 mmol) and anisole (264 pL, 2.40 mmol) are dissolved in DCE (5 mL) and TFA (3 mL). The reaction mixture is stirred at 60 °C over the weekend. The reaction mixture is concentrated and purified by reversed phase chromatography (HPLC; ACN / water / TFA). The fractions are combined, and the solvent is evaporated. The aqueous residue is neutralized with a 2 M K2CO3 solution. The formed precipitate is filtered, washed with water, and dried in an oven to afford of the product.

[0655] Analysis (method M): Rt: 0.96 min, [M+H]+: 358 / 360 (Br) Synthesis of 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2-propyl-2H-pyrazolo[3,4-b] pyridin-5- yl}-l-methyl-lH-imidazole (intermediate F7)

[0656] Intermediate F7

[0657] 4-Bromo-5-cyclopropyl-2-{6-cyclopropyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l-methyl-lH-imidazole (358 mg, 1 mmol) is dissolved in ACN (5 mL). K2CO3 (346 mg, 2.50 mmol) and 1-bromopropane (91 pL, 1 mmol) are added and the reaction mixture is stirred at 60 °C overnight. The reaction mixture is filtered and purified by reversed phase chromatography (HPLC; C18, ACN / water including NH3) to afford the intermediate F7.

[0658] Analysis (method M): Rt: 1.01 min, [M+H]+: 400 / 402 (Br)

[0659] Synthesis of intermediate F8

[0660] Synthesis of 5-(4-bromo-5-isopropyl-l-methyl-lH-imidazol-2-yl)-6-(triifluorometh-oxy)-2-methyl-2H- indazole

[0661] Intermediate D7 Intermediate E2 Intermediate F8

[0662] Under an argon atmosphere, 2,4-dibromo-5-isopropyl-l-rnethyl-lH-imidazole (D7) (54 mg, 0.19 mmol) and 6-(trifluoromethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazole (E2) (79 mg, 0.23 mmol) are dissolved in dioxane (1.8 mL). CS2CO3 (188 mg, 0.58 mmol) and Pd PPhsh (22 mg, 0.002 mmol) are added at RT and the reaction mixture is stirred at 80 °C for 18 h. The reaction mixture is poured on ice and the formed solid is isolated. The solid is dissolved in dichloromethane and adsorbed on Extrelut. The mixture is purified by flash column chromatography (DCM / MeOH 100 / 0 --> DCM / MeOH 90 / 10 gradient). The combined fractions are concentrated to yield the desired intermediate F8. Analysis (method E): Rt: 0.72 min, [M+H]+: 415 / 417 (Br)

[0663] The intermediates compiled in the following table are obtained by following a procedure analogous to that described for intermediate F8.

[0664] Synthesis of intermediate F12 Step 1: Synthesis of l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-4-(propan-2-yl)-3-(triethylsilyl)- lH-pyrazole

[0665] I

[0666] 4-(Propan-2-yl)-5-(triethylsilyl)-lH-pyrazole (100 mg, 0.45 mmol) and 5-bromo-2,6-dimethyl-2H- pyrazolo[3,4-b]pyridine (131 mg, 0.58 mmol) are dissolved in dioxane (2 mL). CS2CO3 (290 mg, 0.89 mmol) is added, and the reaction mixture is purged for 2 min with argon. Then Pd-PEPPSO 2Me-IPent

[0667] Cl (37.4 mg, 0.05 mmol) is added, and the reaction mixture is stirred at 165 °C overnight. The reaction mixture is diluted with DMF and purified by reversed phase chromatography (HPLC; C18, ACN / water including NH3) to afford the titled product.

[0668] Analysis (method M): Rt: 1.24 min, [M+H]+: 370

[0669] Step 2: Synthesis of l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-4-(propan-2-yl)-lH- pyrazole (intermediate F12)

[0670] Intermediate F12

[0671] Under an atmosphere of argon, l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-4-(propan-2-yl)-3-

[0672] (triethylsilyl)-lH-pyrazole (52.0 mg, 0.14 mmol) is dissolved in DCM (1 mL). Iodine monochloride (281 pL, 1 M, 0.28 mmol) is added, and the reaction mixture is stirred at rt overnight. The reaction mixture is concentrated, diluted with ACN, and purified by reversed phase chromatography (HPLC; C18,

[0673] ACN / water including TFA) to afford the intermediate F12.

[0674] Analysis (method D): Rt: 0.95 min, [M+H]+: 382

[0675] Synthesis of intermediate F13 Synthesis of 4-bromo-2-(6-{[(tert-butyldirriethylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)-5-cyclopropyl-l-methyl-lH-imidazole l-[(Tert-butyldimethylsilyl)oxy]-3-(5-cyclopropyl-l-methyl-lH-imidazol-2-yl)propan-2-one (D10) (7.85 g, 20.4 mmol, 80 % purity) is dissolved in EtOH (50 mL). 3-Amino-l-methyl-l-H-pyrazole-4- carbaldehyde (2.55 g, 20.4 mmol) and piperidine (5.04 mL, 50.9 mmol) are added and the reaction mixture is stirred at 100 °C overnight. The reaction mixture is filtered and purified by column chromatography (SiOj, DCM / MeOH 100 / 0 --> DCM / MeOH 85 / 15) to afford the titled product.

[0676] Analysis (method M): Rt: 1.07 min, [M+H]+: 398

[0677] Step 2: Synthesis of 4-bromo-2-(6-{[(tert-butyldimethylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl)-5-cyclopropyl-l-methyl-lH-imidazole

[0678] 4-Bromo-2-(6-{[(tert-butyldimethylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5- cyclopropyl-l-methyl-lH-imidazole (6.35 g, 12.8 mmol, 80 % purity) is dissolved in DCM (100 mL). NBS (2.40 g, 13.5 mmol) is added at 0 °C and the reaction mixture is stirred at RT for 15 min. The reaction mixture is quenched with a saturated solution of NaHCOs and a 10 % solution of NajSjOs and extracted with DCM (3 x). The combined organic layers are dried, filtered, and concentrated to afford the product.

[0679] Analysis (method M): Rt: 1.14 min, [M+H]+: 476

[0680] Step 3: Synthesis of [5-(4-bromo-5-cyclopropyl-l-methyl-lH-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4- b]pyridin-6-yl]methanol (intermediate F13)

[0681] 4-Bromo-2-(6-{[(tert-butyldimethylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-5- cyclopropyl-l-methyl-lH-imidazole (7.90 g, 13.3 mmol, 80 % purity) is dissolved in THF (60 mL). TBAF (1 M, 15.9 mL, 15.9 mmol) is added, and the reaction mixture is stirred at rt for 2 h. The reaction mixture is diluted with water, and the THF is concentrated. The aqueous residue is extracted with EtOAc (2 x) and the combined organic layers are washed with brine, dried over NajSC , filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the intermediate F13.

[0682] Analysis (method D): Rt: 0.59 min, [M+H]+: 362

[0683] Synthesis of intermediate F14

[0684] Synthesis of 5-[3-iodo-5-methyl-4-(propan-2-yl)-lH-pyrazol-l-yl]-2-methyl-6-(trifluoromethoxy)-2H- indazole

[0685] Intermediate C2 Intermediate E2 Intermediate F14

[0686] 5-lodo-3-methyl-4-(propan-2-yl)-lH-pyrazole (C2) (100 mg, 0.40 mmol) and 2-methyl-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-6-(trifluoromethoxy)-2H-indazole (E2) (150 mg, 0.44 mmol) are dissolved in ACN (5 mL). Copper (II) acetate (0.20 g, 1.10 mmol) and pyridine (300 pL, 3.80 mmol) are added, and the reaction mixture is stirred at 60 °C under air overnight. The reaction mixture is filtered, washed with ACN, and purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the intermediate F14.

[0687] Analysis (method M): Rt: 1.13 min, [M+H]+: 465 Synthesis of intermediate F16

[0688] Synthesis of 2-chloro-3-cyclopropyl-4-[3-iodo-5-methyl-4-(propan-2-yl)-lH-pyrazol-l- yl]pyridine

[0689] Intermediate C2 Intermediate E6

[0690] 5-lodo-3-methyl-4-(propan-2-yl)-lH-pyrazole (C2) (186 mg, 0.74 mmol) and 2-chloro-3-cyclopropyl-4- fluoropyridine (E6) are dissolved in DMF (3 mL). K2CO3 (187 mg, 1.35 mmol) is added, and the reaction mixture is stirred at 100 °C for 4 h. The reaction mixture is diluted with ACN, filtered, and purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the desired compound.

[0691] Analysis (method F): Rt: 0.77 min, [M+H]+: 402

[0692] Step 2: Synthesis of 3-cyclopropyl-2-hydrazinyl-4-[3-iodo-5-methyl-4-(propan-2-yl)-lH-pyrazol-l- yl]pyridine

[0693] 2-Chloro-3-cyclopropyl-4-[3-iodo-5-methyl-4-(propan-2-yl)-lH-pyrazol-l-yl]pyridine (80.0 mg, 0.20 mmol) is dissolved in EtOH (1 mL). Hydrazine (1 M in THF, 1.79 mL, 1.79 mmol) is added, and the reaction mixture is stirred in the microwave for 20 h at 150 °C. The reaction mixture is concentrated, diluted with ACN, filtered, and purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the desired compound.

[0694] Analysis (method F): Rt: 0.52 min, [M+H]+: 398

[0695] Synthesis of l-{8-cyclopropyl-3-methyl-[l,2,4]triazolo[4,3-a]pyridin-7-yl}-3-iodo-5-methyl-4-

[0696] (propan-2-yl)-lH-pyrazole (intermediate F16)

[0697] Intermediate F16

[0698] 3-Cyclopropyl-2-hydrazinyl-4-[3-iodo-5-methyl-4-(propan-2-yl)-lH-pyrazol-l-yl]pyridine x TFA (36.0 mg, 0.06 mmol) is dissolved in glacial acetic acid (0.3 mL), and the reaction mixture is stirred in the microwave at 150 °C for 2 h. The reaction mixture is diluted with ACN, and purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the intermediate F16.

[0699] Analysis (method F): Rt: 0.55 min, [M+H]+: 422

[0700] Synthesis of intermediate F18

[0701] Synthesis of 5-(4-bromo-5-cyclopropyl-l-methyl-lH-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4- b]pyridine-6-carboxylic acid

[0702] Intermediate F13

[0703] [5-(4-Bromo-5-cyclopropyl-l-methyl-lH-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-6- yl]methanol (F13) (200 mg, 0.55 mmol) is dissolved in DCM (5 mL). MnC (144 mg, 1.66 mmol) is added, and the reaction mixture is stirred at rt overnight. More MnOj (450 mg, 5.19 mmol) is added, and the reaction mixture is stirred at rt for 4 d. The reaction mixture is concentrated, and the residue is purified by column chromatography (SiOj, DCM / MeOH 93 / 7 --> DCM / MeOH 40 / 60). The desired fractions are combined and concentrated. The still crude product is repurified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the desired compound.

[0704] Analysis (method D): Rt: 0.56 min, [M+H]+: 377

[0705] Step 2: Synthesis of 5-(4-bromo-5-cyclopropyl-l-methyl-lH-imidazol-2-yl)-N,N-diethyl-2-methyl-2H- pyrazolo[3,4-b]pyridine-6-carboxamide (intermediate F18)

[0706] Intermediate F18

[0707] 5-(4-Bromo-5-cyclopropyl-l-methyl-lH-imidazol-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridine-6- carboxylic acid (20.0 mg, 0.05 mmol) is dissolved in DCM (1.5 mL) and ACN (1.5 mL). Oxalyl chloride (4.97 pL, 0.06 mmol) and DMF (50 pL) are added, and the reaction mixture is stirred at rt for 45 min. N,O-dimethylhydroxylamine x HCI (10.4 mg, 0.11 mmol) and TEA (37.1 pL, 0.27 mmol) are added, and the reaction mixture is stirred at rt overnight. No conversion. Because of that, the reaction mixture is concentrated, and the residue is dissolved in DMF (1.5 mL). TEA (37.1 pL, 0.27 mmol) and HATU (22.2 mg, 0.06 mmol) are added, and the reaction mixture is stirred at rt overnight. The reaction mixture is purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the intermediate F18.

[0708] Analysis (method I): Rt: 0.84 min, [M+H]+: 431

[0709] Synthesis of intermediate F19

[0710] Step 1: Synthesis of l-{6-ethyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-4-(propan-

[0711] 2-yl)-lH-pyrazole

[0712] Intermediate D11 l-{6-Ethyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-lH-pyrazole

[0713] (Dll) (1.90 g, 5.93 mmol), 3-amino-l-methyl-lh-pyrazole-4-carbaldehyde (817 mg, 6.53 mmol) are dissolved in EtOH (40 mL). Piperidine (1.47 mL, 14.8 mmol) is added, and the reaction mixture is stirred at 80°C overnight. The reaction mixture is concentrated, and the residue is purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the desired compound.

[0714] Analysis (method F): Rt: 0.65 min, [M+H]+: 410 Step 2: Synthesis of 6-ethyl-5-[3-iodo-5-methyl-4-(propan-2-yl)-lH-pyrazol-l-yl]-2-methyl-2H- pyrazolo[3,4-b]pyridin-7-ium-7-olate (intermediate F19)

[0715] Intermediate F19 l-{6-Ethyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-lH-pyrazole (740 mg, 1.81 mmol) is dissolved in DCM (4.5 mL). At 0 °C, methyltrioxorhenium (VII) (90.1 mg, 0.36 mmol) and H2O2 (50 %, 1.13 mL, 19.9 mmol) are added, and the reaction mixture is stirred at 0 °C for 3 h and at rt overnight. The reaction mixture is diluted with water and DCM and is extracted. The organic layer is dried, filtered, and concentrated. The residue is purified by column chromatography (SiO2, DCM / MeOH 100 / 0 -> DCM / MeOH 90 / 10) to afford the intermediate F19.

[0716] Analysis (method F): Rt: 0.57 min, [M+H]+: 426

[0717] Synthesis of Intermediate F24

[0718] Synthesis of 6-(4-brorno-5-cyclopropyl-l-methyl-lH-irnidazol-2-yl)-7-ethyl-2-rnethyl-l,2- dihydroisoquinolin-l-one

[0719] Intermediate F23 Intermediate F24

[0720] To a solution of 6-(4-bromo-5-cyclopropyl-l-methyl-imidazol-2-yl)-7-ethyl-2-methyl-isoquinolin-l-one (F23) (0.12 g, 0.33 mmol) in DMF (2 mL) is added NaH (0.02 g, 0.66 mmol) and the mixture is stirred at rt for 30 min. Then a solution of iodomethane 1 M in DMF (0.49 mL, 0.49 mmol) is added dropwise and the mixture is further stirred at rt for 1 h. Aq. sat. NH4CI solution is added. The formed precipitate is collected by filtration, washed with Et20 and dried to afford the intermediate F24.

[0721] Analysis (method V): Rt: 2.45 min, [M+H]+: 386

[0722] Synthesis of intermediates G1 - Gil: Synthesis of intermediate G1

[0723] Synthesis of 5-(5-cyclopropyl-4-{2-[2-fluoro-2-(4-methanesulfonylphenyl)ethyl]-2H-indazol-4-yl}-l- methyl-lH-imidazol-2-yl)-2-methyl-6-(trifluoromethoxy)-2H-indazole

[0724] Intermediate G1 Under an atmosphere of argon, 5-(4-bromo-5-cyclopropyl-l-methyl-lH-imidazol-2-yl)-2-methyl-6- (trifluoromethoxy)-2H-indazole (F8) (34.0 mg, 0.08 mmol) and {2-[2-fluoro-2-(4- methanesulfonylphenyl)ethyl]-2H-indazol-4-yl}boronic acid (B8) (35.6 mg, 0.10 mmol) are dissolved in dioxane (1.5 mL). CS2CO3 (2 M in water, 123 pL, 0.25 mmol) and Pd(dtbpf)CL (21.4 mg, 0.03 mmol) are added, and the reaction mixture is stirred at 100 °C for 6 h. The reaction mixture is concentrated, and the residue is diluted with ACN, filtered, and purified by reversed phase chromatography (HPLC; C18, ACN / water including NH3) to afford the intermediate Gl.

[0725] Analysis (method I): Rt: 0.82 min, [M+H]+: 653

[0726] The intermediates compiled in the following table are obtained by following a procedure analogous to that described for intermediate Gl.

[0727] Synthesis of intermediate G2 Synthesis of methyl 4-[(lR)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl}-l-methyl-lH-imidazol-4-yl)-2H-indazol-2-yl]-l-fluoroethyl]benzoate Intermediate F2 Intermediate B9

[0728] Under an atmosphere of argon, 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl}-l-methyl-lH-imidazole (F2) (216 mg, 0.58 mmol) and methyl 4-[(lR)-2-[4-(5,5- dimethyl-l,3,2-dioxaborinan-2-yl)-2H-indazol-2-yl]-l-fluoroethyl]benzoate (B9) (238 mg, 0.58 mmol) are dissolved in dioxane (8 mL). K3PO4 (2 M in water, 0.87 mL, 1.74 mmol) and XPhos Pd G3 (49.1 mg, 0.06 mmol) are added, and the reaction mixture is stirred at 90 °C for 2 h. The reaction mixture is purified by reversed phase chromatography (HPLC; C18, ACN / water including NH3) to afford the desired compound.

[0729] Analysis (method M): Rt: 1.06 min, [M+H]+: 590

[0730] Step 2: Synthesis of 4-[(lR)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-

[0731] 5-yl}-l-methyl-lH-imidazol-4-yl)-2H-indazol-2-yl]-l-fluoroethyl]benzoic acid

[0732] Methyl 4-[(lR)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l- methyl-lH-imidazol-4-yl)-2H-indazol-2-yl]-l-fluoroethyl]benzoate (230 mg, 0.39 mmol) is dissolved in acetone (8 mL). Aq. 1 M NaOH (1.95 mL, 1.95 mmol) is added, and the reaction mixture is stirred at rt for 1 h. The acetone is concentrated, and the residue is diluted with water (5 mL). Then it is acidified with 1 M HCI (3 mL). The formed precipitate is filtered, washed with water (3 mL), and dried to afford the desired compound.

[0733] Analysis (method D): Rt: 0.83 min, [M+H]+: 576 Synthesis of 4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l- methyl-lH-imidazol-4-yl)-2-[(2R)-2-{4-[(2R,6S)-2,6-dimethylpiperazine-l-carbonyl]phenyl}-2- fluoroethyl]-2H-indazole (intermediate G2)

[0734] Intermediate G2

[0735] 4-[(lR)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l-methyl-lH- imidazol-4-yl)-2H-indazol-2-yl]-l-fluoroethyl]benzoic acid x HCI (100 mg, 0.16 mmol) and tert-butyl cis-3,5-dimethylpiperazine-l-carboxylate (105 mg, 0.49 mmol) are dissolved in DMF (4 mL). DIPEA (83.8 pL, 0.49 mmol) and HATU (74.5 mg, 0.20 mmol) are added, and the reaction mixture is stirred at 50 °C overnight. It is purified by reversed phase chromatography (HPLC; C18, ACN / water including NH3) to afford the BOC protected intermediate. It is dissolved in DCM / TFA (1 / 1, 4 mL) and stirred at rt for 30 min. The reaction mixture is concentrated and purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the intermediate G2.

[0736] Analysis (method D): Rt: 0.75 min, [M+H]+: 672

[0737] Synthesis of intermediate G3

[0738] Step 1: Synthesis of methyl 4-{2-[4-(5-cyclopropyl-2-{6-ethyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5- yl}-l-methyl-lH-imidazol-4-yl)-2H-indazol-2-yl]ethyl}benzoate

[0739] Under an atmosphere of argon, 4-bromo-5-cyclopropyl-2-{6-ethyl-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl}-l-methyl-lH-imidazole (F4) (2.00 g, 5.55 mmol) and methyl 4-{2-[4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethyl}benzoate (Bll) (2.71 g, 6.66 mmol) are dissolved in dioxane (50 mL). NajCOs (2 M in water, 11.1 mL, 22.2 mmol) and Pd(dtbpf)Ch (300 mg, 0.46 mmol) are added, and the reaction mixture is stirred at 90 °C for 5 h. The reaction mixture is diluted with EtOAc and water and filtered. The layers are separated, and the organic layer is dried over Na2SO4, filtered and concentrated. The residue is crystallized with EtOAc and a small amount of ACN. The precipitate is filtered, washed with ACN, and dried to afford the desired compound.

[0740] Analysis (method E): Rt: 0.62 min, [M+H]+: 560

[0741] Step 2: Synthesis of 4-{2-[4-(5-cyclopropyl-2-{6-ethyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l- methyl-lH-imidazol-4-yl)-2H-indazol-2-yl]ethyl}benzoic acid (intermediate G3)

[0742] Intermediate G3

[0743] Methyl 4-{2-[4-(5-cyclopropyl-2-{6-ethyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l-methyl-lH- imidazol-4-yl)-2H-indazol-2-yl]ethyl}benzoate (900 mg, 1.61 mmol) is dissolved in MeOH (20 mL). Aq.

[0744] 1 M NaOH (6.00 mL, 6.00 mmol) is added, and the reaction mixture is stirred at 50 °C for 4 h. The MeOH is concentrated, and the residue is purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the intermediate G3.

[0745] Analysis (method D): Rt: 0.81 min, [M+H]+: 546

[0746] The intermediates compiled in the following table are obtained by following a procedure analogous to that described for intermediate G3.

[0747] Synthesis of patent Examples:

[0748] Synthesis of example 1 Synthesis of 4-[(lR)-2-(4-{5-cyclopropyl-l-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4- b]pyridin-5-yl]-lH-imidazol-4-yl}-3-fluoro-2H-indazol-2-yl)-l-fluoroethyl]-N,N-dimethylbenzamide (example 1) Intermediate F1 Intermediate B1

[0749] Example 1

[0750] Under an atmosphere of argon, 4-bromo-5-cyclopropyl-l-methyl-2-[2-methyl-6-(propan-2-yl)-2H- pyrazolo[3,4-b]pyridin-5-yl]-lH-imidazole (Fl) (116 mg, 0.31 mmol) and {2-[(2R)-2-[4- (dimethylcarbamoyl)phenyl]-2-fluoroethyl]-3-fluoro-2H-indazol-4-yl}boronic acid (Bl) (116 mg, 0.31 mmol) are dissolved in dioxane (2 mL). K3PO4 (2 M in water, 0.46 mL, 0.92 mmol) and XPhos Pd G3 (40.0 mg, 0.05 mmol) are added, and the reaction mixture is stirred at 80 °C for 3 h. The reaction mixture is diluted with DCM (20 mL) and water (10 mL) and is extracted. The organic layer is dried, filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the example 1.

[0751] Analysis (method E): Rt: 0.57 min, [M+H]+: 623 The examples compiled in the following table are obtained by following a procedure analogous to that described for example 1.

[0752]

[0753]

[0754] Synthesis of examples 10, 15, 17, 18, 24, 25, 51, 56 and 58

[0755] Step 1: Synthesis of methyl 4-[(lR)-2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-

[0756] (propan-2-yl)-lH-pyrazol-3-yl)-2H-indazol-2-yl]-l-hydroxyethyl]benzoate

[0757] Under an atmosphere of argon, l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-4- (propan-2-yl)-lH-pyrazole (F3) (0.75 g, 1.90 mmol) and methyl 4-[(lR)-l-hydroxy-2-[4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethyl]benzoate (B5) (0.80 g, 1.90 mmol) are dissolved in dioxane (8 mL) and water (2 mL). CS2CO3 (1.85 g, 5.69 mmol) and Pd(dppf)Ch (0.23 g, 0.28 mmol) are added, and the reaction mixture is stirred at 80 °C for 3 h. The reaction mixture is diluted with DCM (20 mL) and filtered. The filtrate is concentrated, and the residue is purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the desired compound.

[0758] Analysis (method E): Rt: 0.83 min, [M+H]+: 564 Step 2: Synthesis of 4-[(lR)-2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-

[0759] 2-yl)-lH-pyrazol-3-yl)-2H-indazol-2-yl]-l-hydroxyethyl]benzoic acid (example 51)

[0760] Example 51

[0761] Methyl 4-[(lR)-2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-lH- pyrazol-3-yl)-2H-indazol-2-yl]-l-hydroxyethyl]benzoate x TFA (720 mg, 1.06 mmol) is dissolved in MeOH (30 mL). 1 M NaOH (7.00 mL, 7.00 mmol) is added, and the reaction mixture is stirred at 50 °C for 6 h. The MeOH is concentrated, and the aqueous residue is diluted with 1 M HCI (7 mL). The formed precipitate is filtered and dried to afford the example 51.

[0762] Analysis (method D): Rt: 0.94 min, [M+H]+: 550

[0763] Synthesis of (lR)-l-[4-(3,3-difluoropyrrolidine-l-carbonyl)phenyl]-2-[4-(l-{2,6-dimethyl-2H- pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-lH-pyrazol-3-yl)-2H-indazol-2-yl]ethan-l-ol

[0764] (example 10)

[0765] 4-[(lR)-2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-lH-pyrazol-3- yl)-2H-indazol-2-yl]-l-hydroxyethyl]benzoic acid x HCI (29.3 mg, 0.05 mmol) is dissolved in DMF (1 mL). DIPEA (34.2 pL, 0.20 mmol), 3,3-difluoropyrrolidine x HCI (7.18 mg, 0.05 mmol) and HATU (19.0 mg, 0.05 mmol) are added, and the reaction mixture is stirred at rt overnight. The reaction mixture is purified by reversed phase chromatography (HPLC; C18, ACN / water including NH3) to afford the example 10.

[0766] Analysis (method W): Rt: 0.79 min, [M+H]+: 639 The examples compiled in the following table are obtained by following a procedure analogous to that described for example 10.

[0767] Synthesis of example 16

[0768] Synthesis of 5-(5-cyclopropyl-4-{2-[(2R)-2-fluoro-2-(4-methanesulfonylphenyl)ethyl]-2H-indazol-4-yl}- l-methyl-lH-imidazol-2-yl)-2-methyl-6-(trifluoromethoxy)-2H-indazole

[0769] 5-(5-Cyclopropyl-4-{2-[2-fluoro-2-(4-methanesulfonylphenyl)ethyl]-2H-indazol-4-yl}-l-methyl-lH- imidazol-2-yl)-2-methyl-6-(trifluoromethoxy)-2H-indazole (Gl) (15.0 mg, 0.02 mmol) is purified by chiral separation (SFC; method Aa) to afford 5-(5-cyclopropyl-4-{2-[(2R)-2-fluoro-2-(4- methanesulfonylphenyl)ethyl]-2H-indazol-4-yl}-l-methyl-lH-imidazol-2-yl)-2-methyl-6- (trifluoromethoxy)-2H-indazole (example 16) (Analysis (method Aa): Rt: 6.19 min, [M+H]+: 653) and 5- (5-cyclopropyl-4-{2-[(2S)-2-fluoro-2-(4-methanesulfonylphenyl)ethyl]-2H-indazol-4-yl}-l-methyl-lH- imidazol-2-yl)-2-methyl-6-(trifluoromethoxy)-2H-indazole (Analysis (method Aa): Rt: 3.56 min, [M+H]+: 653).

[0770] Synthesis of example 22

[0771] Synthesis of 4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l-methyl-lH- imidazol-4-yl)-2-[(2R)-2-{4-[(2R,6S)-4-(2,2-difluoroethyl)-2,6-dimethylpiperazine-l-carbonyl]phenyl}-

[0772] 2-fluoroethyl]-2H-indazole

[0773] Intermediate G2 Example 22

[0774] 4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l-methyl-lH-imidazol-4- yl)-2-[(2R)-2-{4-[(2R,6S)-2,6-dimethylpiperazine-l-carbonyl]phenyl}-2-fluoroethyl]-2H-indazole x 2 TFA (G2) (15.0 mg, 0.02 mmol) is dissolved in ACN (1 mL). K2CO3 (9.26 mg, 0.07 mmol) and 1,1-difluoro- 2-iodoethane (11.1 mg, 0.06 mmol) are added, and the reaction mixture is stirred at 50 °C for 19 h. The reaction mixture is purified by reversed phase chromatography (HPLC; C18, ACN / water including NH3) to afford the example 22.

[0775] Analysis (method Z): Rt: 0.94 min, [M+H]+: 736

[0776] Synthesis of examples 29, 32, 35, 36 and 40

[0777] Synthesis of 4-(5-cyclopropyl-2-{6-ethyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l-methyl-lH- imidazol-4-yl)-2-{2-[4-(2,2-dimethylpiperazine-l-carbonyl)phenyl]ethyl}-2H-indazole

[0778] 4-{2-[4-(5-Cyclopropyl-2-{6-ethyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l-methyl-lH-imidazol-4- yl)-2H-indazol-2-yl]ethyl}benzoic acid x TFA (G3) (27.3 mg, 0.05 mmol) is dissolved in DMF (1 mL). DIPEA (34.2 pL, 0.20 mmol), tert-butyl 3,3-dimethylpiperazine-l-carboxylate (21.4 mg, 0.10 mmol) and HATU (19.0 mg, 0.05 mmol) are added, and the reaction mixture is stirred at rt overnight. The reaction mixture is purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the example 29.

[0779] Analysis (method Y): Rt: 0.46 min, [M+H]+: 642 The examples compiled in the following table are obtained by following a procedure analogous to that described for example 29.

[0780] Synthesis of example 33

[0781] Synthesis of 4-[(lR)-2-[4-(5-cyclopropyl-2-{6-hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l- methyl-lH-imidazol-4-yl)-2H-indazol-2-yl]-l-fluoroethyl]-N,N-dimethylbenzamide

[0782] Intermediate G4 Example 33

[0783] 4-[(lR)-2-[4-(5-Cyclopropyl-2-{6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l-methyl-lH- imidazol-4-yl)-2H-indazol-2-yl]-l-fluoroethyl]-N,N-dimethylbenzamide (G4) (10.0 mg, 0.02 mmol) is dissolved in chloroform (0.2 mL). TMSI (9 pL, 0.06 mmol) is added, and the reaction mixture is stirred in a closed vial at rt for 4 d. The reaction mixture is concentrated, and the residue is purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the example 33.

[0784] Analysis (method Ab): Rt: 0.54 min, [M+H]+: 579

[0785] Synthesis of examples 34, 37, 41, 45, 55 and 57

[0786] Step 1: Synthesis of methyl 4-{2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-

[0787] (propan-2-yl)-lH-pyrazol-3-yl)-2H-indazol-2-yl]ethyl}benzoate Intermediate F3 Intermediate B11

[0788] Under an atmosphere of argon, l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-4- (propan-2-yl)-lH-pyrazole (F3) (2.00 g, 5.06 mmol) and methyl 4-{2-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2H-indazol-2-yl]ethyl}benzoate (Bll) (2.47 g, 6.07 mmol) are dissolved in dioxane (20 mL). 1 M CS2CO3 (12.7 mL, 12.7 mmol) and Xphos Crotyl-Pd-CI (341 mg, 0.51 mmol) are added, and the reaction mixture is stirred at 90 °C for 4 h. The reaction mixture is diluted with water and extracted with EtOAc (3 x). The combined organic layers are dried over NajSC , filtered, and concentrated. The residue is purified by reversed phase chromatography (HPLC; C18, ACN / water including NH3) to afford the desired compound.

[0789] Analysis (method M): Rt: 1.06 min, [M+H]+: 548 Step 2: Synthesis of 4-{2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2- yl)-lH-pyrazol-3-yl)-2H-indazol-2-yl]ethyl}benzoic acid (example 42)

[0790] Example 42

[0791] Methyl 4-{2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-lH-pyrazol- 3-yl)-2H-indazol-2-yl]ethyl}benzoate (2.27 g, 4.15 mmol) is dissolved in THF (20 mL). 1 M NaOH (12.4 mL, 12.4 mmol) is added, and the reaction mixture is stirred at 50 °C for 4 h. The reaction mixture is acidified with 1 M HCI (3 eq). The formed precipitate is filtered and dried to afford the example 42. Analysis (method D): Rt: 0.82 min, [M+H]+: 534

[0792] Step 3: Synthesis of N-cyclopropyl-4-{2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-

[0793] 4-(propan-2-yl)-lH-pyrazol-3-yl)-2H-indazol-2-yl]ethyl}benzamide (example 34)

[0794] Example 42 Example 34

[0795] 4-{2-[4-(l-{2,6-Dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-lH-pyrazol-3-yl)- 2H-indazol-2-yl]ethyl}benzoic acid (Ex 42) (26.7 mg, 0.05 mmol) is dissolved in DMF (1 mL). DIPEA (34.2 pL, 0.20 mmol), cyclopropanamine (5.71 mg, 0.10 mmol) and HATU (19.0 mg, 0.05 mmol) are added, and the reaction mixture is stirred at rt overnight. The reaction mixture is purified by reversed phase chromatography (HPLC; C18, ACN / water including NH3) to afford the example 34.

[0796] Analysis (method W): Rt: 0.77 min, [M+H]+: 573

[0797] The examples compiled in the following table are obtained by following a procedure analogous to that described for example 34.

[0798] Synthesis of example 38

[0799] Synthesis of 4-[(lR)-2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)- lH-pyrazol-3-yl)-2H-indazol-2-yl]-l-fluoroethyl]-N,N-dimethylbenzene-l-sulfonamide

[0800] 4-{2-[4-(l-{2,6-Dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-lH-pyrazol-3-yl)-

[0801] 2H-indazol-2-yl]-l-fluoroethyl}-N,N-dimethylbenzene-l-sulfonamide (G5) (16.9 mg, 0.03 mmol) is purified by chiral separation (SFC; method Ac) to afford 4-[(lR)-2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4- b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-lH-pyrazol-3-yl)-2H-indazol-2-yl]-l-fluoroethyl]-N,N- dimethylbenzene-l-sulfonamide (example 38) (Analysis (method Ac): Rt: 5.62 min, [M+H]+: 615) and 4-[(lS)-2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-lH-pyrazol-3- yl)-2H-indazol-2-yl]-l-fluoroethyl]-N,N-dimethylbenzene-l-sulfonamide (Analysis (method Ac): Rt: 3.29 min, [M+H]+: 615).

[0802] Synthesis of example 43

[0803] Synthesis of methyl 4-[(lR)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl}-l-methyl-lH-imidazol-4-yl)-2H-indazol-2-yl]-l-fluoroethyl]benzoate

[0804] Under an atmosphere of argon, 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl}-l-methyl-lH-imidazole (F2) (216 mg, 0.58 mmol) and methyl 4-[(lR)-2-[4-(5,5- dimethyl-l,3,2-dioxaborinan-2-yl)-2H-indazol-2-yl]-l-fluoroethyl]benzoate (B9) (238 mg, 0.58 mmol) are dissolved in dioxane (8 mL). K3PO4 (2 M in water, 0.87 mL, 1.74 mmol) and XPhos Pd G3 (49.1 mg, 0.06 mmol) are added, and the reaction mixture is stirred at 90 °C for 2 h. The reaction mixture is purified by reversed phase chromatography (HPLC; C18, ACN / water including NH3) to afford the desired compound.

[0805] Analysis (method M): Rt: 1.06 min, [M+H]+: 590

[0806] Step 2: Synthesis of 4-[(lR)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-

[0807] 5-yl}-l-methyl-lH-imidazol-4-yl)-2H-indazol-2-yl]-l-fluoroethyl]benzoic acid (example 43)

[0808] Example 43

[0809] Methyl 4-[(lR)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l- methyl-lH-imidazol-4-yl)-2H-indazol-2-yl]-l-fluoroethyl]benzoate (230 mg, 0.39 mmol) is dissolved in acetone (8 mL). Aq. 1 M NaOH (1.95 mL, 1.95 mmol) is added, and the reaction mixture is stirred at rt for 1 h. The acetone is concentrated, and the residue is diluted with water (5 mL). Then it is acidified with 1 M HCI (3 mL). The formed precipitate is filtered, washed with water (3 mL), and dried to afford the example 43.

[0810] Analysis (method D): Rt: 0.83 min, [M+H]+: 576

[0811] Synthesis of example 46

[0812] Synthesis of (lR)-2-[4-(5-cyclopropyl-2-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l-methyl-lH- imidazol-4-yl)-2H-indazol-2-yl]-l-[4-(3-fluoropyrrolidine-l-carbonyl)phenyl]ethan-l-ol

[0813] Intermediate G6 Example 46

[0814] 4-[(lR)-2-[4-(5-Cyclopropyl-2-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l-methyl-lH-imidazol-4- yl)-2H-indazol-2-yl]-l-hydroxyethyl]benzoic acid x TFA (G6) (23.4 mg, 0.04 mmol) is dissolved in DMF

[0815] (1 mL). DIPEA (20.5 pL, 0.12 mmol), 3-fluoropyrrolidine hydrochloride (15.1 mg, 0.12 mmol) and HATU

[0816] (30.4 mg, 0.08 mmol) are added, and the reaction mixture is stirred at rt overnight. The reaction mixture is purified by reversed phase chromatography (HPLC; C18, ACN / water including NH3) to afford the example 46.

[0817] Analysis (method W): Rt: 0.65 min, [M+H]+: 619

[0818] Synthesis of example 47

[0819] Synthesis of 4-[(lR)-l-fluoro-2-{4-[5-methyl-4-(propan-2-yl)-lH-pyrazol-3-yl]-2H-indazol-2- yl}ethyl]-N,N-dimethylbenzamide

[0820] Intermediate B4 Intermediate C2 Under an atmosphere of argon, 3-iodo-5-methyl-4-(propan-2-yl)-lH-pyrazole (C2) (2.26 g, 8.60 mmol) and 4-[(lR)-l-fluoro-2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethyl]-N,N- dimethylbenzamide (B4) (3.60 g, 7.82 mmol) are dissolved in dioxane (48 mL) and DMF (24 mL). K3PO4 (2 M in water, 7.82 mL, 15.6 mmol) and XPhos Pd G3 (180 mg, 0.21 mmol) are added, and the reaction mixture is stirred at 100 °C for 15 h. The reaction mixture concentrated, the residue is diluted with DCM / MeOH 8 / 2 and filtered through a pad of celite. The filtrate is concentrated, and the residue is purified by reversed phase chromatography (HPLC; C18, ACN / water including NH3) to afford the desired compound.

[0821] Analysis (method I): Rt: 0.93 min, [M+H]+: 434

[0822] Step 2: Synthesis of 4-[(lR)-2-[4-(l-{2,7-dimethylimidazo[l,2-a]pyridin-6-yl}-5-methyl-4-(propan-2- yl)-lH-pyrazol-3-yl)-2H-indazol-2-yl]-l-fluoroethyl]-N,N-dimethylbenzamide (example 47)

[0823] 4-[(lR)-l-fluoro-2-{4-[5-methyl-4-(propan-2-yl)-lH-pyrazol-3-yl]-2H-indazol-2-yl}ethyl]-N,N- dimethylbenzamide (50.0 mg, 0.12 mmol) and {2,7-dimethylimidazo[l,2-a]pyridin-6-yl}boronic acid (E8) (24.1 mg, 0.13 mmol) are dissolved in ACN (2 mL). Copper (II) acetate (58.0 mg, 0.32 mmol) and pyridine (86.7 pL, 1.10 mmol) are added, and the reaction mixture is stirred at 60 °C under air overnight. The reaction mixture is filtered, and the residue is purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the example 47.

[0824] Analysis (method M): Rt: 0.96 min, [M+H]+: 578

[0825] Synthesis of example 48

[0826] Synthesis of (lr,4rj-4-{2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)- lH-pyrazol-3-yl)-2H-indazol-2-yl]-l-hydroxyethyl}-N,N-dimethylcyclohexane-l-carboxarnide

[0827] (lr,4r)-4-{2-[4-(l-{2,6-Dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-lH-pyrazol- 3-yl)-2H-indazol-2-yl]-l-hydroxyethyl}cyclohexane-l-carboxylic acid (G7) (31.0 mg, 0.05 mmol) is dissolved in DMF (1.2 mL). DIPEA (23.7 pL, 0.14 mmol), dimethylamine (2 M in THF, 69.4 pL, 0.14 mmol) and HATU (35.2 mg, 0.09 mmol) are added, and the reaction mixture is stirred at rt overnight. The reaction mixture is purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the example 48.

[0828] Analysis (method D): Rt: 0.93 min, [M+H]+: 583

[0829] Synthesis of example 49

[0830] Synthesis of 3-[(lR)-2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)- lH-pyrazol-3-yl)-2H-indazol-2-yl]-l-hydroxyethyl]-N,N-dimethylbenzamide

[0831] Intermediate G8 Example 49

[0832] 3-[(lR)-2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-lH-pyrazol-3- yl)-2H-indazol-2-yl]-l-hydroxyethyl]benzoic acid (G8) (25.0 mg, 0.05 mmol) is dissolved in DMF (1.1 mL). DIPEA (23.3 pL, 0.14 mmol), dimethylamine (2 M in THF, 68.2 pL, 0.14 mmol) and HATU (34.6 mg, 0.09 mmol) are added, and the reaction mixture is stirred at rt overnight. The reaction mixture is purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the example 49.

[0833] Analysis (method D): Rt: 0.92 min, [M+H]+: 577 Synthesis of example 50

[0834] Synthesis of (lR,4r)-4-[(lR)-2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-

[0835] (propan-2-yl)-lH-pyrazol-3-yl)-2H-indazol-2-yl]-l-hydroxyethyl]cyclohexane-l-carboxylic acid

[0836] (lr,4r)-4-{2-[4-(l-{2,6-Dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-lH-pyrazol- 3-yl)-2H-indazol-2-yl]-l-hydroxyethyl}cyclohexane-l-carboxylic acid x TFA (G7) (126 mg, 0.19 mmol) is purified by chiral separation (SFC; method Ad) to afford (lR,4r)-4-[(lR)-2-[4-(l-{2,6-dimethyl-2H- pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-lH-pyrazol-3-yl)-2H-indazol-2-yl]-l- hydroxyethyl]cyclohexane-l-carboxylic acid (example 50) (Analysis (method Ad): Rt: 1.71 min, [M+H]+: 556) and (lS,4r)-4-[(lS)-2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan- 2-yl)-lH-pyrazol-3-yl)-2H-indazol-2-yl]-l-hydroxyethyl]cyclohexane-l-carboxylic acid (Analysis (method Ad): Rt: 1.03 min, [M+H]+: 556).

[0837] Synthesis of example 53

[0838] Synthesis of 4-{2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-lH- pyrazol-3-yl)-2H-indazol-2-yl]-l-hydroxyethyl}-2-methylbenzoic acid

[0839] Methyl 4-{2-[4-(l-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-lH-pyrazol-

[0840] 3-yl)-2H-indazol-2-yl]-l-hydroxyethyl}-2-methylbenzoate (33.0 mg, 0.06 mmol) is dissolved in MeOH

[0841] (1 mL). Aq. 4 M NaOH (0.20 mL, 0.80 mmol) is added, and the reaction mixture is stirred at 80 °C for 1 h. The MeOH is concentrated, and the residue is acidified with 2 M HCI (0.6 mL) and purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the example 53. Analysis (method F): Rt: 0.56 min, [M+H]+: 563

[0842] Synthesis of example 54

[0843] Synthesis of 4-[(lR)-2-[5-chloro-4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4- b]pyridin-5-yl}-l-methyl-lH-imidazol-4-yl)-2H-indazol-2-yl]-l-fluoroethyl]-N,N-dimethylbenzamide

[0844] Intermediate G10 Example 54

[0845] 4-[(lR)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l-methyl-lH- imidazol-4-yl)-2H-indazol-2-yl]-l-fluoroethyl]-N,N-dimethylbenzamide (G10) (30.0 mg, 0.05 mmol, 90 % purity) is dissolved in ACN (1 mL). NCS (6.00 mg, 0.05 mmol) is added, and the reaction mixture is stirred at 55 °C overnight. The reaction mixture is purified by reversed phase chromatography (HPLC; C18, MeOH / water including TFA) to afford the example 54.

[0846] Analysis (method D): Rt: 0.85 min, [M+H]+: 637

[0847] Synthesis of example 59

[0848] Synthesis of (lR)-2-[4-(l-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-

[0849] (propan-2-yl)-lH-pyrazol-3-yl)-2H-indazol-2-yl]-l-[4-(pyrrolidine-l-carbonyl)phenyl]ethan-l-ol

[0850] 4-[(lR)-2-[4-(l-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-lH- pyrazol-3-yl)-2H-indazol-2-yl]-l-hydroxyethyl]benzoic acid (Gil) (23.0 mg, 0.04 mmol) is dissolved in DMF (1 mL). DIPEA (20.7 pL, 0.12 mmol), pyrrolidine (7.10 mg, 0.10 mmol) and HATU (30.4 mg, 0.08 mmol) are added, and the reaction mixture is stirred at rt overnight. The reaction mixture is purified by reversed phase chromatography (HPLC; C18, ACN / water including TFA) to afford the example 59. Analysis (method Y): Rt: 0.87 min, [M+H]+: 629

[0851] Synthesis of example 62

[0852] Synthesis of 4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l-methyl-lH- imidazol-4-yl)-2-[(2R)-2-fluoro-2-(4-methanesulfonylphenyl)ethyl]-2H-indazole

[0853] 4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l-methyl-lH-imidazol-4- yl)-2-[2-fluoro-2-(4-methanesulfonylphenyl)ethyl]-2H-indazole (G12) (9.30 mg, 0.02 mmol) is purified by chiral separation (SFC; method Ae) to afford 4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H- pyrazolo[3,4-b]pyridin-5-yl}-l-methyl-lH-imidazol-4-yl)-2-[(2R)-2-fluoro-2-(4- methanesulfonylphenyl)ethyl]-2H-indazole (example 62) (Analysis (method Ae): Rt: 7.98 min, [M+H]+: 610) and 4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-l-methyl-lH- imidazol-4-yl)-2-[(2S)-2-fluoro-2-(4-methanesulfonylphenyl)ethyl]-2H-indazole (Analysis (method Ae): Rt: 5.69 min, [M+H]+: 610).

[0854] Analytical HPLC methods

[0855] Method A Device description: Shimadzu LC-30 AD&MS 2020; Analytical column: Kinetex 5pm EVO C18 100A; column temperature: 40°C

[0856] Method B AS_IPA_DEA_5_50_34_35_3min

[0857] Device description: Waters UPCC with PDA detector; Analytical column: Chiralpak AS-3 4.6 x 50 mm_3 pm; column temperature: 35°C; back pressure: 1800 psi (12410.563 kPa)

[0858] Method C

[0859] Device description: Agilent 1200; Analytical column: Kinetex C18 2.1 x 50 mm_5 pm; column temperature: 40°C

[0860] Method D ZO18_SO4

[0861] Device description: Agilent 1200; Analytical column: Sunfire (Waters) C18_3.0 x 30 mm_2.5 pm; column temperature: 60°C

[0862] Method E XO18_SO3

[0863] Device description: Waters Acquity; Analytical column: Sunfire (Waters) C18_3.0 x 30 mm_2.5 pm; column temperature: 60°C

[0864] Method F xoi2_soi

[0865] Device description: Waters Acquity; Analytical column: Xbridge (Waters) BEH C18_2.1 x 30 mm_1.7 pm; column temperature: 60°C

[0866] Method G zooi_oo3

[0867] Device description: Agilent 1200; Analytical column: Xbridge (Waters) C18_3.0 x 30 mm_2.5 pm; column temperature: 60°C

[0868] Method H l_IG_25_IPA_NH3_002

[0869] Device description: Agilent 1260 Infinity II SFC; Analytical column: Chiralpak® (Daicel) IG_3 x 100 mm_3 pm; column temperature: 40°C; back pressure: 2175.0 psi (14 996.097 kPa)

[0870] Method I zo2i_soi

[0871] Device description: Agilent 1200; Analytical column: Xbridge (Waters) C18_3.0 x 30 mm_2.5 pm; column temperature: 60°C

[0872] Method J l_C2_20_MEOH_NH3_002

[0873] Device description: Agilent 1260 Infinity II SFC; Analytical column: Lux(R) Cellulose-2 (Phenomenex) 3 x

[0874] 100 mm_3 pm; column temperature: 40°C; back pressure: 2175.0 psi (14 996.097 kPa)

[0875] Method K I_IG_25_MEOH_NH3_002

[0876] Device description: Agilent 1260 Infinity II SFC; Analytical column: Chiralpak® (Daicel) IG_3 x 100 mm_3 pm; column temperature: 40°C; back pressure: 2175.0 psi (14 996.097 kPa)

[0877] Method L

[0878] Device description: Shimadzu Prominance HPLC; Analytical column: Zorbax Ext C18_4.6 x 50 mm_5 pm

[0879] Method M zon_so3

[0880] Device description: Agilent 1200; Analytical column: Xbridge (Waters) C18_3.0 x 30 mm_2.5 pm; column temperature: 60°C

[0881] Method N I_IA_25_MEOH_NH3_OOI

[0882] Device description: Agilent 1260 Infinity II SFC; Analytical column: Chiralpak® (Daicel) IA_4.6 x 250 mm_5 pm; column temperature: 40°C; back pressure: 2175.0 psi (14 996.097 kPa)

[0883] Method O I_C2_35_MEOH_NH3_002

[0884] Device description: Agilent 1260 Infinity II SFC; Analytical column: Lux(R) Cellulose-2 (Phenomenex) 3 x

[0885] 100 mm_3 pm; column temperature: 40°C; back pressure: 2175.0 psi (14 996.097 kPa)

[0886] Method P Device description: Waters Acquity UPLC; Analytical column: YMC Tiart C18_2.1 x 33 mm_3 pm; column temperature: 25°C

[0887] Method Q xoii_sos

[0888] Device description: Waters Acquity; Analytical column: Xbridge (Waters) BEH C18_2.1 x 30 mm_2.5 pm; column temperature: 60°C

[0889] Method R xo23_soi

[0890] Device description: Waters Acquity; Analytical column: XSelect HSS PFP (Waters) 2.1 x 30 mm_1.8 pm; column temperature: 60°C

[0891] Method S SLV-Method-36

[0892] Device description: Waters Acquity; Analytical column: Acquity UPLC BEH (Waters) C18 2.1 x 100 mm_1.7 pm; column temperature: 40°C

[0893] Method T XO15_SO4

[0894] Device description: Waters Acquity; Analytical column: XBridge BEH Phenyl (Waters) 2.1 x 30 mm_1.7 pm; column temperature: 60°C

[0895] Method U SLV-Method-84

[0896] Device description: Dionex UHPLC Ultimate 3000; Analytical column: Kinetex XB-C18 4.6 x 50 mm_2.6 pm (100A); column temperature: 25°C

[0897] Method V SLV-Method-28

[0898]

[0899] Device description: Dionex UHPLC Ultimate 3000; Analytical column: Kinetex XB-C18 4.6 x 50 mm_2.6 pm (100A); column temperature: 25°C

[0900] Method W 004_CAll (004_CA10 und 004_CA02)

[0901] Device description: Waters Acquity; Analytical column: XBridge (Waters) C18_3.0 x 30 mm_2.5 pm; column temperature: 60°C

[0902] Method X zoi2_so4 Device description: Agilent 1200; Analytical column: XBridge (Waters) C18_3.0 x 30 mm_2.5 pm; column temperature: 60°C

[0903] Method Y 003_CA02 (003_CAll und 003_CA10)

[0904] Device description: Waters Acquity; Analytical column: Sunfire (Waters) C18_3.0 x 30 mm_2.5 pm; column temperature: 60°C

[0905] Method Z 008_CAII

[0906] Device description: Waters Acquity; Analytical column: Xbridge (Waters) C18_3.0 x 30 mm_2.5 pm; column temperature: 60°C

[0907] Method Aa i SA 40 IPA NH3 OOI

[0908] Device description: Agilent 1260 Infinity II SFC; Analytical column: Chiral Art® (YMC) Amylose SA_4.6 x

[0909] 250 mm_5 pm; column temperature: 40°C; back pressure: 2175.0 psi (14 996.097 kPa) Method Ab 007_CAII

[0910] Device description: Waters Acquity; Analytical column: Sunfire (Waters) C18_3.0 x 30 mm_2.5 pm; column temperature: 60°C Method Ac I_SB_40_MEOH_NH3_OOI

[0911] Device description: Agilent 1260 Infinity II SFC; Analytical column: Chiral Art® (YMC) Cellulose SB_4.6 x

[0912] 250 mm_5 pm; column temperature: 40°C; back pressure: 2175.0 psi (14 996.097 kPa)

[0913] Method Ad I_SA_30_MEOH_NH3_002

[0914] Device description: Agilent 1260 Infinity II SFC; Analytical column: Chiral Art® (YMC) Amylose SA_3 x 100 mm_3 pm; column temperature: 40°C; back pressure: 2175.0 psi (14 996.097 kPa)

[0915] Method Ae I_SA_40_MEOH_NH3_OOI

[0916] Device description: Agilent 1260 Infinity II SFC; Analytical column: Chiral Art® (YMC) Amylose SA_4.6 x

[0917] 250 mm_5 pm; column temperature: 40°C; back pressure: 2175.0 psi (14996.097 kPa)

[0918] List of abbreviations:

[0919] 4CZIPN l,2,3,5-Tetrakis(carbazol-9-yl)-4,6-dicyanobenzene,2,4,5,6-

[0920] Tetrakis(9H-carbazol-9-yl) isophthalonitrile

[0921] Ac acetyl

[0922] ACN acetonitrile

[0923] Al BN 2,2'-azobis(isobutyronitrile)

[0924] Boc tert-butyloxycarbonyl

[0925] Cbz benzyloxycarbonyl

[0926] CycH cyclohexane d day(s)

[0927] DAST diethylamino sulfur trifluoride

[0928] DCE 1,2-dichloroethane

[0929] DCM dichloromethane

[0930] DEAD diethyl azodicarboxylate

[0931] DIAD diisopropyl azodicarboxylate

[0932] DIPEA N,N-diisopropylethylamine

[0933] DMF N,N-dimethylformamide

[0934] DMP Dess-Martin Periodinane

[0935] DMSO dimethyl sulfoxide

[0936] EtOAc ethyl acetate

[0937] EtOH ethanol h hour(s)

[0938] HATU O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium- hexafluorophosphate

[0939] HPLC high performance liquid chromatography

[0940] HPLC-MS coupled high performance liquid chromatography-mass spectrometry

[0941] IPA isopropyl alcohol

[0942] LC liquid chromatography LC-MS coupled liquid chromatography - mass spectrometry

[0943] LiHMDS Lithium-bis(trimethylsilyl)amide

[0944] M molar (mol / L)

[0945] Mel methyl iodide

[0946] MeTHF 2-methyltetrahydrofuran

[0947] MeOH methanol min minute(s)

[0948] MS mass spectrometry

[0949] MTBE methyl-tertbutyl-ether n-BuLi n-Buthyllithium

[0950] NBS N-Bromosuccinimide

[0951] NIS N-lodosuccinimide

[0952] NMP N-methyl-2-pyrrolidone

[0953] NMR nuclear magnetic resonance

[0954] PEPPSI(TM)-IPR (l,3-Bis(2,6-diisopropylphenyl)imidazolidene) (3-chloropyridyl) pal ladium (I I) dichloride

[0955] PdCI2(dtbpf) l7l'-Bis-(di-tert-butylphosphino-)ferrocene-palladiumdichloride

[0956] Pd(dppf)Ch l,r-bis(diphenylphosphino)ferrocenedichloropalladium(ll)

[0957] PdfPPhah palladium (0) tetrakis(triphenylphosphine)

[0958] XPhos Pd G3 2-Dicyclohexylphosphino-2',4',6'-triisopropyl-l, -biphenyl)[2-(2'- amino-1,1'- biphenyl)]palladium(ll) methanesulfonat pet. petroleum

[0959] Rf retention factor

[0960] RP reverse phase rt room temperature tRretention time (in HPLC / LC)

[0961] SFC supercritical fluid chromatography

[0962] TBAF tetrabutylammonium fluoride

[0963] TBTU O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate

[0964] TEA triethylamine

[0965] TFA trifluoroacetic acid

[0966] THF tetrahydrofuran

[0967] THP tetrahydro-2h-pyran

[0968] TLC thin-layer chromatography

[0969] TMAD N,N,N'N'-Tetramethylazodicarboxamide uv ultraviolet

[0970] V volume

[0971] BIOLOGICAL ASSAYS and DATA

[0972] The activity of the compounds of the invention may be demonstrated using the following in vitro

[0973] STING biochemical and cell assays.

[0974] Human STING HTRF binding assay

[0975] 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 Iigand-d2 and thereby prevents FRET from occurring, which can be measured by an EnVision™ reader (PerkinElmer).

[0976] Assay method: Compounds were delivered as lOmM 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 lOpM or lpM in the final assay volume followed by ~1:5 dilution steps. DMSO concentration was set to 1% in the final assay volume. The 384well assay plate contained 20 test compounds and DMSO in column 23 and 24. A cGAMP standard dilution row was prepared according to the manufacturer and transferred to each assay plate. After transfer of compound solution or dilution buffer for negative (high) and positive (low) controls, 5pl of the human STING protein (cyclic binding domain (residues 138-379) of the WT R232 human version, fused to a 6 His tag at the Nter part; 1:50 dilution in detection buffer) were dispensed to all wells except of the positive control, which received detection buffer only. Plates were the centrifuged for 20 sec at lOOOrpm. After that, lOpI of Anti-6His-Cryptate antibody / Sting Iigand-d2 mix was added to all wells using a Multidrop combi dispenser, followed by another 20sec / 1000rpm centrifugation step. After an incubation of the plates for 180 min at room temperature, excitation at 665 / 620 nM (HTRF ratio) was measured using an Envison Reader (PerkinElmer)

[0977] Data evaluation and calculation: For data evaluation and calculation, HTRF ratios were calibrated using the cGAMP standard curve. After that, the measurement of the low control was set as 0 % control and the measurement of the high control was set as 100% control. The IC50 values were calculated using the standard 4 parameter logistic regression formula. Calculation: [y=(a- d) / (l+(x / c)Ab)+d], a = low value, d = high value; x = cone M; c=IC50 M; b = slope;

[0978] The results of this assay are shown in the characterising data table below. Determination of the increase of stability of STING protein against thermal denaturation, Differential

[0979] Scanning Fluorimetry (DSF)

[0980] The binding affinity of the compounds of the invention may be demonstrated using a thermal shift assay that measures the stability of a suitable protein material of human STING against thermal denaturation in the presence of compounds. In this assay, the unfolding temperature of a protein is monitored in the presence of a fluorescent dye which exhibits affinity for the hydrophobic amino acids of the protein that are buried in its folded state and are gradually exposed during unfolding. Dye 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 Boltzmann equation.

[0981] 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 NaCI at pH7.5.

[0982] 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).

[0983] A DMSO stock solution of SYPRO orange (SIGMA S5692-500UL) was prepared.

[0984] Compound stock solutions (lOmM 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 125pM and 2.5% DMSO.

[0985] 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 lOuL. 3-6 well positions were used as negative control (protein with 2% DMSO). The plates were prepared for duplicate measurement and 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).

[0986] Final Assay concentrations for compound characterization were as follows: lOOuM compound, 3uM target protein, 5x SYPRO Orange, 2% DMSO in lOul. All dispensing steps were performed using a HamiltonStar pipetting robot (Hamilton).

[0987] 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.

[0988] Two replicates of TM measurements were averaged, and the standard deviation was calculated. In cases of SD>1.5 °C the measurement was repeated.

[0989] The melting point (Tm) obtained for STING protein alone was subtracted from T obtained for protein incubated with ligand to generate ATm values.

[0990] Protein production and purification: The protein used for the biophysical experiments was a recombinant human STING protein comprising its cytosolic ectodomain. A codon optimized DNA sequence (for expression in Escherichia coli) encoding amino acid residues 155 to 341 (Swiss Prot Q86WV6) of human STING (WT) was synthesized by GeneArt (Regensburg, Germany) and inserted 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 resulting protein sequence for the used STING variant is listed below:

[0991] His-TEV— hSTING (WT) (SEQ ID NO: 1)

[0992] MHHHHHHHHENLYFQSGVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLS MADPNIRFLDKLPQQTGDRAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKL FCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEV

[0993] 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 p-D-l-thiogalactopyranoside to a final concentration of ImM and cultures shaken overnight. Cell pellets were centrifuged and stored at -70°C until further use.

[0994] Protein was purified by cell thawing in lysis buffer (20mM TRIS-HCI, pH 8, 300mM NaCI, 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-HCI, pH 8, 300mM NaCI, 2mM mercaptoethanol, 300mM imidazole and size exclusion chromatography in running buffer (20mM TRIS-HCI, pH 8, lOOmM NaCI, 2mM DTT). The peak fraction was collected and concentrated to 2.5mg / mL.

[0995] The results of this assay are shown in the characterising data table below.

[0996] Human whole blood assay (HWBA)

[0997] For the detection of STING inhibition in physiological environment human whole blood was stimulated by the cyclic dinucleotide cGAMP. Pathway activity was monitored by measuring the IFNa2a production.

[0998] Assay method: Compounds were delivered as lOmM DMSO solution and serial diluted and transferred to the 96-well Cell culture Plate (Corning #3595), prefilled with 20pl OptiMEM (Gibco #11058-021) in each well, using an Echo acoustic dispenser. Typically, 8 concentrations were used with the highest concentration at lOpM in the final assay volume followed by ~1:5 dilution steps. DMSO concentration was set to 0.1% in the final assay volume. The 96well assay plate contained 9 test compounds, a reference compound and DMSO in control wells.

[0999] Collection of human whole blood from 3 or more healthy donors (male or female, no medication for 7 days, exception contraceptive and thyroxine) as Na-citrate blood (e.g. 3.8% in Monovettes from Sarstedt) is conducted in parallel. Whole blood was kept at room temperature for a maximum of 3 hours after collection until use in the assay.

[1000] 160pl of the whole blood samples were transferred to each well of the 96-well assay plates filled with compound / OptiMEM. All assay plates are prepared as duplicates with blood from different donors. Blood plates were kept at room temperature for 60minutes and continuous shaking with 450rpm, covered with the lid, but not sealed.

[1001] A lOx cGAMP assay solution was diluted from a 2mM stock solution in lxHBSS immediately before use at room temperature. 20pl of the lOx cGAMP / HBSS were added to all compound and all high control wells, whereas HBSS only was added to all low control wells.

[1002] 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. For the detection of IFNa-2a 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 25pl diluted capture antibody. Coated plates were incubated for 60min at room temperature under continuous shaking at 700rpm. MSD IFNa-2a plates were washed three times with 150pl wash buffer (lx HBSS, 0.05% Tween).

[1003] After blocking the plates with lOOpI block solution / well (lx HBSS with 0.2% Tween, 2% BSA) for 60min at room temperature and continuous shaking at 700rpm, plates were emptied as dry as possible by dumping just before continuing with the human plasma. Whole Blood assay plates were centrifuged at 1600rpm for 10 minutes. 25pl of supernatant was transferred with a pipetting robotics from each whole blood plate to the corresponding IFNa-2a plate. Plates were sealed with microplate seals and kept at room temperature again under continuous shaking at 700rpm for two hours. Next MSD IFNa-2a plates were washed three times with 150pl wash buffer (lx HBSS, 0.05% Tween), before adding 25pl MSD SULFO-TAG IFNa-2a Antibody solution (1:100 diluted in Diluent 3 (Meso Scale Diagnostics # R50AP-2) to each well of the plates. Afterwards plates were sealed with microplate seals and kept at room temperature again under continuous shaking at 700rpm for two hours. Finally MSD IFNa-2a plates were washed three times with 150pl wash buffer (lx HBSS, 0.05% Tween). 150pl 2x Read buffer was added to each well and plates were immediately measured with the MSD Sector S600 Reader using the vendor barcode.

[1004] Data evaluation and calculation: For data evaluation and calculation, % control calculation of each well was based on the mean of high (cGAMP stimulated control) and mean of low (unstimulated control) controls by using the following formula:

[1005] [counts(sample) - counts(low)) / (counts(high) - counts(low))]*100

[1006] The IC50 values were calculated using the standard 4 parameter logistic regression formula. Calculation: [y=(a-d) / (l+(x / c)Ab)+d], a = low value, d = high value; x = cone M; c=IC50 M; b = slope;

[1007] The results of this assay are shown in the characterising data table below.

[1008] Human STING reportergene assay A THPl-BluelSG reporter cell line expressing wildtype STING and IRF dependent alkaline phosphatase reporter was used for the potency measurement of activators of human wildtype STING.

[1009] Assay Method: Compounds were delivered lOmM DMSO solution and serially diluted in assay medium (RPMI 1640 (Life Technologies #A10491-01), 10% FCS (Life Technologies #10500-064), lx Pen / Strep solution (Life Technologies #15140-122). Typical ly, 8 concentrations were used with the highest concentration at 10 or 100 pM 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;

[1010] Cells, cultivated according to manufacturer's conditions (culture medium: RPMI 1640 (Life Technologies #A10491-01), 10% FCS (Life Technologies #10500-064), lx Pen / Strep solution (Life Technologies #15140-122), lOOpg / mL Normocin (Life Technologies # ant-nr-1), lOOpg / mL Zeocin (Life Technologies # R25001) were harvested, resuspended and diluted in fresh assay medium. The cells were then seeded in 15pl assay media to the assay plates (10000 cells / well), followed by addition of 5pl prediluted compound solution to wells of the assay plates. Afterwards 5ul per well of assay medium was added to the wells containing compounds, followed by a 30 min incubation at RT and a 24h incubation at 37°C. Then 5ul per well of assay medium with DMSO (1% f.c.) was added to the wells for the controls, plus 5 pl of assay medium alone for negative controls (low values) or 5pl of prediluted 2'3'-cGAMP (20pM f.c.; BIOLOG Life Science Institute # C 161 or Invivogen # tlrl-nacga23) for positive controls (high values).

[1011] Finally 75pl 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).

[1012] Data evaluation and calculation: For data evaluation and calculation, the measurement of the low control was set as 100 % control and the measurement of the high control was set as 200% control. The EC50 values were calculated using the standard 4 parameter logistic regression formula. Calculation: [y=(a-d) / (l+(x / c)Ab)+d], a = low value, d = high value; x = cone M; c=IC50 M; b = slope;

[1013] The results of this assay are negative for agonism, wherein the threshold was set larger than 30 pM.

[1014] Characterising Data Table

[1015] 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.

[1016] 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 70nM. In another preferred embodiment, said IC 50 value is at least and including 0.8nM or at least and including 2nM. In another preferred embodiment said IC50 value is not more than 45nM, more preferably not more than 40nM.

[1017] Further characterization

[1018] Efflux ratio from MDCK-PGP

[1019] The efflux ratio from MDCK-PGP cells is measured using standard methods according to the international patent application published as W024089006 or as in the publication by Dong et al. Pharm Res (2020) 37: 194, https: / / doi.org / 10.1007 / sll095-020-02895-9.

[1020] 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.

[1021] Efflux ratio from CACO2 cells

[1022] The efflux ratio from CACO2 cells is determined using standard methods for example as disclosed in the international patent applications published as WO15048318, WO22254371 and WO24110851, or as in the publication by Dong et al. Pharm Res (2020) 37: 194, https: / / doi.org / 10.1007 / sll095-020- 02895-9.

[1023] 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.

[1024] Inhibition of cytochrome P450 enzymes CYP2D6 and CYP3A4

[1025] 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. 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 W015073310& WO14197345 and the patent US8138188 BB).

[1026] For testing the possible inhibition of the compounds of the invention, demethylation of Dextromethorphan (5 pM) 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.

[1027] 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 W015073310& WO14197345 and the patent US8138188 BB).

[1028] For testing the possible inhibition of the compounds of the invention, hydroxylation of Midazolam (5 pM) by the test compound at five different concentrations or no compound (high control) is assayed at 37°C with human liver microsomes and measured with LC-MS / MS. The IC50 values of the compounds are determined. The IC50 of a positive control inhibitor (ketoconazole) is also determined as a control.

[1029] CYP3A4 and / or CYP2D6 inhibition is observed for the inventive compounds with IC50 values of equal to or greater 1 pmol, preferably equal to or greater 10 pmol and more preferred equal to or greater 20 pmol and even more preferred equal to or greater 25 pmol and most preferred over 30 pmol.

[1030] Measuring clearance from human hepatocytes

[1031] The metabolic degradation of a test compound is assayed in a human hepatocyte suspension using known methods as in the patent application. US2024327429.

[1032] In one embodiment the hepatocyte clearance is lower than 25% Qh [%], preferably equal to or lower than 20 %, 15 %, 10 %, or more preferably at most 8 %.

[1033] Plasma protein binding

[1034] Plasma protein binding of a test compound is assessed with known methods, for example as known from the international patent application W017004537 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 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 pM. The subsequent dialysis solutions are prepared in plasma (supplemented with NaEDTA as anticoagulant), and aliquots of 200 pl test compound dialysis solution in plasma are dispensed into the donor (plasma) chambers. Aliquots of 200 pl 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.

[1035] At the end of the dialysis period, aliquots obtained from donor and acceptor chambers, respectively, are transferred into reaction tubes and processed for HPLC-MS / MS analysis. Analyte concentrations are quantified in aliquots of samples by HPLC-MS / MS against calibration curves.

[1036] Percent bound compound is calculated using the formula: %bound = (plasma concentration - buffer concentration / plasma concentration) x 100

[1037] 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 %.

[1038] Inhibition of STING mutants associated with SAVI by the inventive compounds

[1039] 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 / NEJMoal312625)

[1040] Methods for testing STING activity in THP1 cells with the reporter gene encoding luciferase are known (see the patent publication US2020181153 and references therein). These known methods are 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 STING gene that expresses a constitutively activated protein. The pathway activation is measured using ISG- luciferase reporter gene luminescence. Compound potency is evident by its ability to inhibit the SAVI associated mutant STING proteins and consequently shut down the ISG linked luciferase reporter expression. A subset of the inventive compounds as well as two known STING inhibitors for comparison are tested using THP1 cells with the two known mutants of the STING protein N154S and V155M associated with SAVI. SEQ ID NO: 2 shows the wildtype and these variant positions of the STING protein. The known STING inhibitor SN-011 has previously been reported to inhibit these mutant versions of STING in cell assays (Z. Hong et al, STING inhibitors target the cyclic dinucleotide binding pocket, Proc. Natl. Acad. Sci. U.S.A. 118 (24) e2105465118, https: / / doi.org / 10.1073 / pnas.2105465118 (2021). Used as comparative compounds are SN-011 and another known STING inhibitor H-151 (Haag, S.M., Gulen , M.F., Reymond, L et al. Targeting STING with covalent small-molecule inhibitors. Nature 559, 269-273 (2018). https: / / doi.org / 10.1038 / s41586-018-0287-8).

[1041] Using materials and instruments commercially available and methods similar to the known methods, the luciferase activity in these modified THP1 cells is measured with and without the test compounds. After correction for background and controls, the IC50 values are calculated using the 4- parameter logistic model for the compounds of the invention, as well as for the known STING inhibitors SN-011 and H-151 (see above for details) for comparison.

[1042] As the known inhibitor of STING SN-011 had been reported to inhibit the two mutants of STING tested, the potency of the compounds of the invention in comparison to that of SN-011 is determined. The results are expressed as the ratio of the IC50 value of the compound tested, i.e. the compound of the invention or the second known inhibitor H-151 to the IC 50 value determined for SN-011 in the particular assay. These are normalized to the SN-011 being set to 100% and the others expressed as a percentage number in relation thereto. Table S shows the results, based on multiple repetitions unless otherwise stated.

[1043] Table S

[1044] As can be seen from the results in table S, the other known inhibitor of STING, H-151, requires only a concentration of 10.7 % of the concentration of SN-011 to achieve the same inhibition of the N154S mutant of STING, and only 6.2 % of the concentration of SN-011 for the same inhibition of the second mutant V155M of STING. However, example 1 requires even less, only between 0.1 % and 0.5 % of the concentration of SN-011 to inhibit these STING mutants, which is also superior to the known inhibitor H-151. The example 1 compound is more potent in inhibiting these two SAVI associated mutants of the human STING protein. The compound named example 2 however was less potent as the two known inhibitors of the SAVI mutants tested. Example 2 - as the difference to example 1- contains a Di-fluor group at the second position from the attachment point of R5 to the core structure. Other compounds with such a Dl-fluor group are examples 5, 7 , 12 and 21

[1045] In one embodiment, the IC 50 values of the compounds of the invention to inhibit either or both of the N154S and V155M mutants of the human STING protein are at least O.OlnM, but less than 150nM, preferably less than 120nM and more preferably less than 50nM and even more preferably less than 20nM. In another embodiment, the IC50 values for the compounds of the invention and either or both of these mutants of STING are between at least and including 0.2nM and no more than lOnM, wherein optionally the compound has a carbon atom at the at the second position from the attachment point of R5 to the core structure of formula (I) which has zero fluor atoms or one fluor atom attached.

[1046] 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 not containing a Di-fluoro group at the second position from the attachment point of R5 to the core structure.

[1047] Inhibition of STING in fibroblasts

[1048] As many of the above-mentioned diseases like IPF or SAVI involve fibrosis, it is interesting to check the efficacy of the compounds in fibroblast cells. In an initial test, fibroblasts from human patients suffering from SSc are stimulated with dsDNA and the response with or without the test compounds is assessed. Interestingly, the known STING inhibitors SN-011 and H-151 (for details see above), which had been reported to be effective in other fibroblasts, show very little inhibition in these fibroblasts.

[1049] In one embodiment, the compounds of the invention have an IC 50 value in human SSc fibroblasts of at least O.lnM to no more than 300nM, preferably no more than 150nM and even more preferably no more than lOOnM and most preferably no more than 80nM.

[1050] Inhibition of IP10 production in human monocyte derived dendritic cells after cGAMP stimulation Monocyte derived dendritic cells derived from a specimen of a human donor are cultivated using standard techniques. With the exception of the respective negative controls, the cells are stimulated with cGAMP (Invivogen) in the presence or absence of different concentration of the compounds of the invention. Supernatants are collected and analysed by ELISA for I PIO presence ( I PIO 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 preferably in the range and including 0.03nM to 6.00nM, preferably equal to or less than 4.00nM, and more preferably equal to or less than 3.00nM, and even more preferably equal to or less than 2.5nM. In yet another preferred embodiment the average IC 50 value is between and including 0.07nM and 2.10nM.

[1051] Use in treatment / method of use

[1052] As has been found, the compounds of formula (I) are characterized by their range of applications in the therapeutic field. Preferably, the compounds of the invention are used in diseases that can be treated by the inhibition of STING and / or whose progression can be prevented by the inhibition of STING.

[1053] Particular mention should be made of those applications for which the compounds of the invention are used on the basis of their pharmaceutical activity as STING inhibitors. While the cGAS / STING pathway is important for host defense against invading pathogens, such as viral infection and invasion by some intracellular bacteria, cellular stress and genetic factors may also cause production 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.

[1054] A STING inhibitor of the invention will block in full or in part inflammation and aberrant tissue remodeling in a cluster of autoimmune and inflammatory diseases including systemic lupus erythematosus (SLE), cutaneous lupus, systemic sclerosis, inflammatory bowel disease, sepsis, Sjogren's syndrome, vitiligo, prurigo nodularis, idiopathic inflammatory myopathy, myositis including dermatomyositis, rheumatoid arthritis, as well as a cluster fibrosis diseases including NASH (now referred to as MASH), IPF, chronic kidney fibrosis.

[1055] 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 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. 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, antineutrophil 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.

[1056] • An et al., Arthritis Rheumatol. 2017 Apr;69(4):800-807, disclosed that cGAS expression in peripheral blood mononuclear cells (PBMCs) was significantly higher in patients with the autoimmune disease systemic lupus erythematosus (SLE) than in normal controls. Targeted measurement of cGAMP by tandem mass spectrometry detected cGAMP in 15% of the tested SLE patients, but none of the normal or rheumatoid arthritis controls. Disease activity was higher in SLE patients with cGAMP versus those without cGAMP.

[1057] • Thim-Uam et al (iScience. 2020 Sep 4;23(9):101530) demonstrated that STING deficiency ameliorated lupus development in Fcgr2b-deficient mice. Prabakaran et al (EBioMedicine. 2021 Apr;66:103314) shows that a STING pathway inhibitor ISD017 blocks STING activity in vivo and ameliorates disease development in a mouse model for lupus. ISD017 treatment also blocks pathological cytokine responses in PBMCs from lupus patients with elevated IFN-I levels.

[1058] • Skopelja-Gardner et al reported that ultraviolet B light triggers cGAS / STING-dependent skin and systemic IFN-I signature and could contribute to cutaneous lupus Alzeand fares of disease in patients with SLE (Sci Rep 2020 10:7908 )

[1059] • Ryu et al (Arthritis Rheumatol. 2020 Nov;72(ll):1905-1915) showed that plasma mtDNA concentrations were increased in the 2 Systemic sclerosis-associated interstitial lung disease (SSc-ILD) cohorts, reflective of ventilatory decline, and were positively associated with both TLR-9 and cGAS / STING activation as well as type I IFN and IL-6 expression. Liu et al (Rheumatology (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.

[1060] • Li et al show that plasma-derived DNA containing-extracellular vesicles induce STING-mediated proinflammatory responses in dermatomyositis (Theranostics. 2021; 11(15): 7144-7158). Zhou et al (J Clin Lab Anal. 2022 Oct; 36(10): e24631) describes a correlation between activation of cGAS- STING pathway and myofiber atrophy / necrosis in dermatomyositis. Feng et al. suggested STING could be a potential therapeutic target in idiopathic inflammatory myositis-associated interstitial lung disease (IIM-ILD) (Feng et al., International Immunopharmacology, March 2025, 149, doi:10.1016). It was also reported that the GAS-STING pathway is activated in the muscle biopsies of idiopathic inflammatory myopathy (I IM) patients and its activation may lead to myofiber atrophy and necrosis in 11 M and dermatomyositis patients (Zhou et al., J Clin Lab Anal. 2022;36:e24631.).

[1061] • Haag et al (Nature. 2018 Jul;559(7713):269-273) demonstrated that a covalent STING inhibitor attenuated pathological features of autoinflammatory disease in TREX1_KO mice. Loss of function mutation of TREX1 leads rare monogenic interferonopathies such as Aicardi-Goutieres syndrome (AGS).

[1062] • Hu et al (EBioMedicine. 2019 Mar;41:497-508) showed that in human abdominal sepsis, STING expression was elevated in peripheral blood mononuclear cells and intestinal biopsies compared with healthy controls. In human abdominal sepsis, STING expression was elevated in peripheral blood mononuclear cells and intestinal biopsies compared with healthy controls. STING knockout mice attenuated alleviated inflammatory response, gut permeability, and decreased bacterial translocation in a sepsis model. Zeng et al (ci Transl Med. 2017 Oct 18;9(412):eaan5689) also showed that STING deficiency in mice protected two sepsos modeled (LPS model and cecal ligation and puncture model) and the degree of STING expression in the human intestinal lamina propria correlated with the intestinal inflammation in septic patients. Inhibition of the ALK-STING pathway protects mice against CLP-induced polymicrobial sepsis.

[1063] • In Schuliga et al., Clin. Sci. (Lond). 2020 Apr 17;134(7):889-905, it is described that self-DNA perpetuates IPF lung fibroblast senescence in a cGAS-dependent manner. Benmerzoug et al (Nat. Commun. 9, 1-19 (2018)) shows that STING- dependent sensing of self- DNA drives silica-induced lung inflammation, which can lead to lung fibrosis.

[1064] • Additional scientific hints linking the cause for metabolic diseases such as non-alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), see https: / / easl.eu / news / new_fatty_liver_disease_nomenclature-2, 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 have been described in Yu et al., J. Clin. Invest. 2019 Feb l;129(2):546-555, and in Cho et al., Hepatology. 2018 Oct;68(4): 1331-1346, and in Qiao et al., Metabolism 2018 Apr;81:13-24 doi: 10.1016 / j.metabol.2017.09.010. Epub 2017 Oct 26, Petrasek et al., PNAS 2013 Oct

[1065] 8; 110(41): 16544-9. doi: 10.1073 / pnas.l308331110. Epub 2013 Sep 19 • Nascimento et al., Sci. Rep. 2019 Oct 16;9(1):14848, discloses that self-DNA release and STING- dependent sensing drives inflammation due to cigarette smoke in mice hinting at a link between the cGAS-STING pathway and chronic obstructive pulmonary disease (COPD).

[1066] • Ahn et al (Cell Rep 2017 21:3873-3884) describes that STING-deficient mice protects in an Inflammatory Colitis model. Martin et al (Sci Rep 2019 Oct 3; 9:14281) describes that STING deletion protects while or STING stimulation, exacerbates intestinal inflammation in the dextran sodium sulphate (DSS) model of colitis. These publications support STING as a potential therapeutic target for prevention of inflammatory bowel disease (IBD).

[1067] • Kerur et al., Nat. Med. 2018 Jan;24(l):50-61, describes that cGAS plays a significant role in noncanonical-inflammasome activation in age-related macular degeneration (AMD).

[1068] • Further, the STING inhibitors also have a therapeutic potential in the treatment of cancer (see Hoong et al., Oncotarget. 2020 Jul 28;ll(30):2930-2955, and Chen et al., Sci. Adv. 2020 Oct 14;6(42):eabb8941). Furthermore shown in Bakhoum et el., Nature. 2018 Jan 25;553(7689):467- 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".

[1069] • STING inhibitors have also the potential in the treatment of obesity and diabetes as shown in Mao et al., Arterioscler Thromb Vase Biol (2017) 37(5):920-9. doi: 10.1161 / ATVBAHA.117.309017

[1070] • Additionally, the STING inhibitors have also a therapeutic potential in the treatment of heart failure (King et al, Nat Med 2017 Dec;23(12):1481-1487; Hu et al.,

[1071] Am. J. Physiol. Heart Circ. Physiol. 2020 Jun 1;318(6):H1525-H1537).

[1072] • Further scientific hints at a correlation between Parkinson's disease and the cGAS / STING pathway (Sliter et al., Nature. 2018 Sep;561(7722):258-262), between amyotrophic lateral sclerosis (ALS) and STING (Yu et al, Cell 2020;183:636-649) and between Sjogren's syndrome and the cGAS / STING pathway (Papinska et al., J. Dent. Res. 2018 Jul;97(8):893-900) exist.

[1073] • Furthermore, STING inhibitors have also a therapeutic potential in the treatment of COVID- 19 / SARS-CoV-2 infections as shown in Di Domizio et al., Nature. 2022 Jan 19. doi: 10.1038 / s41586-022-04421-w: "The cGAS-STING pathway drives type I IFN immunopathology in COVID-19", and in Neufeldt et al., Commun Biol. 2022 Jan 12;5(1):45. doi: 10.1038 / s42003-021- 02983-5: "SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS- STING and NF-kappaB". It has also been shown that severe COVID-19 and long COVID are associated with high expression of STING, cGAS and IFN-a (Sci Rep 2024 14:4974).

[1074] • Additionally, STING inhibitors have a therapeutic potential in the treatment of renal inflammation and renal fibrosis as shown in Chung et al., Cell Metab. 2019 30:784-799: "Mitochondrial Damage and Activation of the STING Pathway Lead to Renal Inflammation and Fibrosis", and in Maekawa et al., Cell Rep. 2019 29:1261-1273: "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 2019 30:784-799).

[1075] • Further, two cases of STING GOF mutants have been reported with alopecia symptom indicating STING activation can lead to alopecia (Front Immunol 2019 10:2770. 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).

[1076] • In addition, ANCA vasculitis patients show increased levels of cGAMP and enhanced IFN-I signature. STING deficiency or a STING inhibitor protects a mouse model for ANCA associated pulmonary vasculitis (J Exp Med. 2022 219:e20220759). ANCA pulmonary vasculitis has also been reported in a SAVI patient (STING GOV mutation) (Front Immunol. 2020 11:575219).

[1077] • Furthermore, the lysosomal membrane protein Niemann-Pick type Cl (NPC1) has been identified as a cofactor in the trafficking of STING. Genetic deletion of STING significantly reduced the activation of microglia and relieved the loss of Purkinje neurons in the cerebellum of Npcl- / - 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).

[1078] • Additionally, it has been shown that in myotonic dystrophy type 2 (DM2) disease, patient PBMCs and fibroblasts show elevated type I interferon (IFN) signature which is mediated by the cGAS / STING pathway (Nat Commun. 2024 15:1534).

[1079] • In Huntington's disease (HD), the mutated huntingtin gene induces DNA damage and cytosolic DNA accumulation and activates the cGAS-STING pathway to mediate inflammation and apoptosis (Proc Natl Acad Sci U S A. 2024 121: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).

[1080] • In addition, Xie et al detected binding of cGAS with dsDNA in cytoplasm and the activation of the microglial cGAS-STING pathway in brains of human AD and aged mice. A STING inhibitor suppressed the activation of the cGAS-STING pathway and ameliorated AD pathogenesis in a mouse model of Alzheimer's disease (Nat Aging 20233:202-212).

[1081] • Additionally, during ischemic stroke, tissue damage results in misplaced DNA within the cellular environment activates the cGAS / STING pathway, leading to cytokine production, neuroinflammation, and cell death (Expert Opin Drug Discov 2023 18:1133-1149; Drug Discov Today. 2023 28:103792). STING knockout decreased infarct progression, oedema volume and neuronal damage in mouse stroke model (Stroke Vase Neurol 2023 Jul 3:svn-2023-002320. doi: 10.1136)

[1082] • Further, it has been shown that STING promotes senescence, apoptosis, and extracellular matrix degradation in osteoarthritis (Guo et al, Cell Death Dis. 2021 Jan 4;12(1):13. doi: 10.1038). cGAS / STING null- mice have reduced tissue inflammation, improved heart / muscle function and have an extended lifespan (Dou et al, Nature. 2017550: 402-406). Furthermore, in humans a variation within the STING gene is associated with healthy aging, most likely due to a decreased inflammaging (Hamann et al, Gerontology 2019;65:145-154). Taken together, a STING inhibitor will reduce senescence associated inflammation and senescent cell accumulation and will leads improvement in senescence associated diseases such as aging / muscle disorders and osteoarthritis.

[1083] • Also, it was reported that the STING protein is involved in vitiligo, as the cytosolic mtDNA-cGAS- STING axis of melanocytes plays an important role in oxidative stress-triggered CD8+ T-cell response via melanocyte pyroptosis (Xu et al., Journal of Dermatological Science, 2025, 117(3), March 2025 doi:10.1016). Oxidative stress-induced mitochondrial damage in epidermal cells led to cytosolic mtDNA accumulation, which served as a trigger in activating the cGAS-STING axis in melanocytes resulting in production of IL-ip and IL-18.

[1084] • Prurigo nodularis is a chronic inflammatory skin condition characterized by intensely itchy pruritic nodules on the extremities and trunk that are often a result of persistent scratching. It was reported that both systemic and cutaneous immune responses in patients with PN are skewed toward a Th22 / IL-22 profile (Belzberg et al., Journal of Investigative Dermatology (2021) 141, 2208e2218). Aden et al. reported that IL-22 aggravates epithelial cell death-mediated inflammation through STING activation in intestinal epithelial cells (Aden et al., J. Exp. Med. 2018 Vol. 215: 2868-2886). STING may also play a role in IL22 mediated pathogenic responses in the skin epithelium in Prurigo nodularis.

[1085] The compounds of formula (I) or (la) or (lb) or (Ic), or the salts thereof for use in patients with a disease whose progression can be prevented by the inhibition of STING is an embodiment of the invention.

[1086] In one embodiment, the STING inhibitors of the invention are useful in the prevention of progression, and / or for the treatment of a condition or disease caused by immune dysregulation and involving the STING protein(s). 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.

[1087] In a preferred embodiment, the compounds of the invention for the prevention of progression and / or for the treatment of a disease or condition that involves undesirable STING activation by mutations of the STING protein are those compounds, that show IC50 values of at least O.OOlnM and less than 150nM, preferably less than lOOnM, more preferably less than 50nM, even more preferably less than 20nM when tested for inhibition of any of the mutant N154S or V155M of the STING protein associated with SAVI, preferably both, as described in section BIOLOGICAL ASSAYS AND DATA, and preferably these compounds do not contain a Di-fluoro group at the second position from the attachment point of R5 to the core structure.

[1088] In another embodiment the compounds of the inventions are used as anti-fibrotic agents. An embodiment of the invention is the use of the compounds of the invention in the therapy of interferon-driven inflammatory and / or fibrotic diseases or symptoms, preferably those that are a side effect of an underlying disease that leads to cell damage and cytosolic DNA presence that is not derived from pathogens.

[1089] Combinations

[1090] The compounds of formula 1 may be administered to the patient alone or in combination with one or more other pharmacologically active agents.

[1091] In a preferred embodiment of the invention the compounds may be combined with one or more pharmacologically active agents selected from the group of PDE 4 inhibitors (preferably l-[[(5R)-2-[4- (5-chloropyrimidin-2-yl)-l-piperidyl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4- yl]amino]cyclobutyl] methanol and [l-[[(5R)-2-[4-(5-chlorophenyl-2-yl)-l-piperidyl]-5-oxo-6,7- dihydrothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol as disclosed in WO 2013 / 026797), anti-inflammatory agents, anti-fibrotic agents, anti-allergic agents / anti-histamines, bronchodilators, beta 2 agonists / betamimetics, adrenergic agonists, anticholinergic agents, methotrexate, mycophenolate mofetil, leukotriene modulators, JAK inhibitors, anti-interleukin antibodies, nonlimiting 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-IL-5 antibodies, anti-IL-6 antibodies such as Actemra™, anti-IL-12 antibodies and anti-IL-15 antibodies, non-specific immunotherapeutics such as interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators (i.e. cytokine receptor 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 antiinflammatory agents and / or anti-fibrotic agents in one embodiment is a combination of one or more compounds of the invention with a) one or more known STING inhibitors and / or b) known cGAS 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 or Nerandomilast. Another aspect of the invention is to the combined use of the STING inhibitors of the invention in combination with known cGAS and / or STING inhibitors, for example those disclosed in the international patent applications PCT / EP2023 / 080705, PCT / EP2023 / 080711, PCT / EP2022 / 062496, PCT / EP2022 / 062480, PCT / EP2023 / 079890 or published as WO2021 / 138419, WO2023 / 148129, WO2023 / 237457, WO2024 / 263860, WO2025 / 012195 or W02025 / 017045.

[1092] 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 activating factor (BAFF) antibody or CAR (chimeric antigen receptors) T cells.

[1093] 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).

[1094] 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 infancy (SAVI), Aicardi-Goutieres syndrome (AGS), COPA syndrome, and familial chilblain lupus), type 1 interferonopathies with mutations in DNASE2 or ATAD3A genes, age-related macular degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), Huntington disease, Alzheimer's disease, diabetes, obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Niemann-Pick Disease, Type C, ischaemic stroke, myotonic dystrophy type 2, Sjogren's syndrome, Parkinson's disease, heart failure, cancer, systemic sclerosis (SSc), vitiligo, prurigo nodularis, idiopathic inflammatory myopathy, myositis including dermatomyositis, metabolic dysfunction-associated steatotic liver disease (MASLD) (previously referred to as non-alcoholic fatty liver disease (NAFLD), metabolic 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, rheumatoid arthritis and osteoarthritis.

[1095] Formulations

[1096] The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, intrasternal, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin. The compounds of the invention may be administered via eye drops to treat Sjogren's syndrome.

[1097] Suitable forms for administration are for example tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. The content of the pharmaceutically effective compound(s) in each case should be in the range from 0.1 to 90 wt.%, preferably 0.5 to 50 wt.% of the total composition, i.e. in amounts which are sufficient to achieve the dosage range specified hereinafter.

[1098] 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.

[1099] Preferably, therefore, pharmaceutical formulations are characterized by the content of one or more compounds of formula (I), preferably according to formula (la), (lb), (Ic) or (Id) according to the preferred embodiments above.

[1100] It is particularly preferable if the compounds of formula (I), preferably according to formula (la), (lb), (Ic) or (Id) are administered orally, and it is also particularly preferable if they are administered once or twice a day. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch 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.

[1101] Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example kollidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly, the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

[1102] Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavor enhancer, e.g. a flavoring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p- hydroxybenzoates.

[1103] Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatin capsules. Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethylene glycol or the derivatives thereof.

[1104] Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

[1105] For oral administration the tablets may, of course, contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the 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.

[1106] The inventive use in the prevention of and / or treatment of and / or delaying the occurrence of 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 at least to some extent, although for the overall group of patients the use of the compounds of the invention typically is suitable to delay the occurrence and / or prevent such disorders.

[1107] 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 disorders related to elevated and / or deregulated STING activity, plus in addition one or more compound(s) of the invention.

[1108] 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 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.

[1109] Throughout this description the term disorders is used interchangeably with diseases or conditions.

[1110] A further aspect of the present invention is to a method of preparation of a pharmaceutical composition comprising the compound of the invention for the use in the prevention of and / or treatment of and / or delaying the occurrence of and / or delaying the progression of disorders related to elevated and / or deregulated STING activity, wherein the method comprises the steps of a) producing the inventive compound or a salt thereof, preferably a pharmaceutically acceptable salt thereof, b) optionally adding with one or more inert adjuvant, diluent and / or carrier, c) optionally adding one or more pharmacologically active agents selected from the group of PDE 4 inhibitors (preferably l-[[(5R)-2-[4-(5-chloropyrimidin-2-yl)-l-piperidyl]-5-oxo-6,7-dihydrothieno[3,2- d]pyrimidin-4-yl]amino]cyclobutyl] methanol and [l-[[(5R)-2-[4-(5-chlorophenyl-2-yl)-l-piperidyl]-5- oxo-6, 7-dihydrothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol as disclosed in WO 2013 / 026797), anti-inflammatory agents, anti-fibrotic agents, anti-allergic agents / anti-histamines, bronchodilators, beta 2 agonists / betamimetics, adrenergic agonists, anticholinergic agents, methotrexate, mycophenolate mofetil, leukotriene 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-IL-5 antibodies, anti-IL-6 antibodies such as Actemra™, anti-IL-12 antibodies and / or anti-IL-15 antibodies, non-specific immunotherapeutics such as interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators (i.e. cytokine receptor agonists or antagonists), Toll-like receptor agonists (=TLR agonists), immune checkpoint regulators, anti-TNF antibodies, preferably Humira™, and anti-BAFF agents, preferably Belimumab and / or Etanercept. Another aspect of the invention is to the combined use of one or more of the STING inhibitors of the invention in combination with known cGAS and / or STING inhibitors, and d) optionally formulating into a form for the preferred administration.

Claims

Claims1. A compound of formula (I),whereinB-A is selected from the group B-Aa consisting of =C-N- or -N-C=; this means A is C or N; B is C or N; but A and B are not N at the same time;R1is selected from the group Rlaconsisting ofwherein R1 is the attaching point to the structure of formula I;W is selected from the group Waconsisting of =C— and =N- and =N+-;V is selected from the group Vaconsisting of =C— and -N-T is selected from the group Taconsisting of -C-, =C— and =N- ;R10is selected from the group of R10aconsisting ofH, HO-, Ci-s-alkyl-, Ci-3-alkyl-S- , Ci-3-alkyl-O-, Cj.s-alkenyl-, amide- and Cs-e-cycloalkyl-, wherein the Ci-3-alkyl-O-group, Cs-e-cycloalkyl- group, amide group and / or the C1-5- alkyl-group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of Ci-3-alkyl-O-, Halogen and HO-;R11is selected from the group of Rllaconsisting of H-, HO-, Ci-5-alkyl-, Ci-3-alkyl-O-, and Cs-e-cycloalkyl-; wherein the Ci-3-alkyl-O-group and / or the Ci.5-alkyl-group are optionally substituted with 1 to 5 substituents independently selected from the group consisting of C1-3- alkyl-O-, C1-5- Heterocyclyl-, Halogen and HO and wherein the C1-5- Heterocyclyl- groups are optionally substituted with 1 to 5 substituents independently selected from the group consisting of Ci-s-alkyl- and Ci-s-alkyl-O-;R12is selected from the group of R12aconsisting of H, HO-, Ci-3-alkyl-, Ci-3-alkyl-O- and C3-4-cycloalkyl-; wherein the Ci-3-alkyl-O-group and / or the Ci-3-alkyl-group are optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-3- alkyl-O-, Halogen and HO-;R13is selected from the group of R13aconsisting of a) H-, H3C- or b) O- if W is =N+-;R14is selected from the group of R14aconsisting of H, Ci-5-alkyl-, Ci-3-alkyl-O-, and Cs-e- cycloalkyl-; wherein the Ci-3-alkyl-O-group and / or the Ci-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-;R15is selected from the group of R15aconsisting of H, HO-, Ci-5-alkyl-, Ci-3-alkyl-O-, and Cs-e-cycloalkyl-; wherein the Ci-s-alkyl-O-group and / or the Ci.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 ofH- and Ci-s-alkyl-;R3is selected from the group R3aconsisting ofCi-s-alkyl- and C3-4 cycloalkyl- , either optionally substituted by 1 to 3 substituents selected from the group consisting of Ci-s-alkyl-, HO- and Halogen-, H3C-O-, F3C-O-, and F2HC-O-;R4is selected from the group R4aconsisting of H- and Halogen;R5is selected from the group R5aconsisting of R9-C(R8)(R7)-CH2- and R9-S(O)-CH2-;R6is selected from the group RSaconsisting ofH-, HO- and Halogen-;R7is selected from the group R7aconsisting ofH-, Halogen, HO- and Ci-3-alkyl-O-, H and Halogen;R8is selected from the group R8aconsisting ofH- and Halogen-;R9is selected from the group R9aconsisting of phenyl, cyclohexyl, heterocyclyl with 6 ring atoms and heteroaryl with 6 ring atoms wherein in the heterocyclyl or the heteroaryl 1 to 3 heteroatoms are present and these are selected from the group consisting of N, O and S, wherein the phenyl, cyclohexyl, heterocyclyl with 6 ring atoms and heteroaryl with 6 ring atoms are substituted with 1 to 3 substituents selected from the group consisting of carboxylic acid , sulfonyl, sulfonamide and / or amide groups, wherein optionally the sulfonyl, sulfonamide and / or amide groups are substituted with 1 to 3 substituents selected from the group consisting of a) Ci-3-alkyl-, b) C1-3- alkyl— O-, c) C3-4-cycloalkyl-, with a) to c) optionally substituted with 1 to 3 substituents selected from HO-, F-, Ci-3-alkyl- and Ci-3-alkyl-O-, and d) halogen, or optionally the sulfonamide and / or amide groups are substituted at the N of the sulfonamide and / or amide with a Cs-s-alkyl-or a Cs-cycloalkyl itself substituted with2 Ci-3-alkyl- to form a heterocycle or heterobicycle with said N, optionally with one carbon atom of the ring structure being replaced by a further heteroatom selected from N or O, wherein said heterocycle or heterobicycle is further optionally substituted with 1 to3 substituents selected independently from HO-, F-, Ci-3-alkyl-, Ci-3-alkyl- itself substituted with 1 to 3 fluorines and Ci-3-alkyl-O-; or a salt thereof.

2. A compound according to claim 1, whereinT is selected from the group Tbconsisting of =C-,or a salt thereof.

3. A compound according to claim 1 or 2, whereinW is selected from the group Wbconsisting of =C— and =N-, or a salt thereof.

4. A compound according to one of the claims 1 to 3, whereinR3is selected from the group R3bconsisting ofCi-3-alkyl- and cyclopropyl-, either optionally substituted by 1 to 3 substituents selected from the group consisting of H3C-, HO- and F-, or a salt thereof.

5. A compound according to one of the claims 1 to 4, whereinR4is selected from the group R4bconsisting of H-, CL- and F-; or a salt thereof.

6. A compound according to one of the claims 1 to 5, whereinR5is selected from the group R5bconsisting of R9-C(R8)(R7)-CH2-; or a salt thereof.

7. A compound according to one of the claims 1 to 5, wherein R9is selected from the group R9cconsisting of cyclohexyl and phenyl groups connected to position R5 of the core by a linker of the structure R9-C(R8)(R7)-CH2-R5, wherein R5 denotes the attachment point to the core, either of the cyclohexyl or phenyl groups substituted with a substituent selected from the group consisting of carboxylic acid, sulfonyl, sulfonamide and amide groups that optionally is substituted as shown in table A above.

8. A compound according to one of the claims 1 to 7, wherein the compound of formula (I) is a compound of formula (la)(lb), or a salt thereof.

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

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

11. A compound according to one of the claims 1 to 7 , selected from the following examples:

12. A compound according to one of the claims 1 to 7 , selected from any of the examples 1 to 63.

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

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

15. The compound of formula (I), (la), (lb) or (Ic), according to any of claims 1 to 12 or the salt thereof according to claim 13 for use in the treatment of a disease selected from the group consisting of disease selected from the group consisting of systemic lupus erythematosus (SLE), cutaneous lupus, (monogenic and digenic) interferonopathies (including STING- associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutieres syndrome (AGS), COPA syndrome, and familial chilblain lupus), type 1 interferonopathies with mutations in DNASE2 or ATAD3A genes, age-related macular degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), Huntington disease, Alzheimer's disease, diabetes, obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Niemann-Pick Disease, Type C, ischaemic stroke, myotonic dystrophy type 2, Sjogren's syndrome, Parkinson's disease, heart failure, cancer, systemic sclerosis (SSc), vitiligo, prurigo nodularis, idiopathic inflammatory myopathy, myositis including dermatomyositis, metabolic dysfunction-associated steatotic liver disease (MASLD) (previously referred to as non-alcoholic fatty liver disease (NAFLD), metabolic 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, rheumatoid arthritis andosteoarthritis.

16. Pharmaceutical composition comprising a compound of any of claims 1 to 12 and / or the salt thereof according to claim 14, and optionally one or more pharmaceutically acceptable carriers and / or excipients.

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