Heterocyclic compounds as STING antagonists

Abstract

The present invention relates to compounds of formula 1: # imgabs0 # and their use as STING antagonists, for example, the composition is used for treating diseases selected from the group consisting of systemic lupus erythematosus (SLE), (single and double gene) interferon diseases (including STING-related vascular disease (SAVI), Aicardi-Goutires syndrome (AGS), COPA syndrome and familial chilblain-like lupus, DNASE2 or ATAD3A gene mutated type I interferon disease, age-related macular degeneration (AMD), retinopathy, glaucoma, lupus erythematosus, lupus erythematosus, lupus erythematosus, lupus erythematosus, lupus erythematosus, lupus erythematosus, lupus erythematosus, lupus erythematosus, lupus erythematosus, lupus erythematosus, and lupus erythematosus. Amyotrophic lateral sclerosis (ALS), diabetes, obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom syndrome, sicca syndrome, Parkinson's disease, heart failure and cancer, systemic sclerosis (SSc), dermatomyositis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic plus acute liver failure (ACLF), interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), and the like. , aging / muscle disease, sepsis, heart failure, rheumatoid arthritis, and osteoarthritis.

Description

Technical Field

[0001] The present invention relates to compounds of formula 1:

[0002]

[0003] And its use as a STING antagonist, for example, for the treatment of a disease selected from the following: systemic lupus erythematosus (SLE), (monogenic and digenic) interferonopathies (including STING-associated vasculopathy of infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome and familial pernio-like lupus), type I interferonopathies with mutations in the DNASE2 or ATAD3A genes, age-related macular degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), diabetes, obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Sjogren's syndrome, Parkinson's disease ( disease, heart failure and cancer, systemic sclerosis (SSc), dermatomyositis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), acute-on-chronic liver failure (ACLF), interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), aging / muscle disease, sepsis, heart failure, rheumatoid arthritis, and osteoarthritis. Background Art

[0004] Innate immunity is considered as the first-line cell stress response, which protects host cells from pathogen invasion and initiates signal transduction to the adaptive immune system. These processes are triggered by conservative pathogen-associated molecular patterns (PAMPs) via different pattern recognition receptors (PRR) sensing and then activating cytokines and type I interferon gene expression. Main antigen presenting cells such as monocytes, macrophages and dendritic cells produce type I interferons and are crucial for inducing adaptive T cells and B cell immune system responses. The main PRR detection cell surface, lysosomal membrane inside or other cell compartments in abnormal nucleic acids, that is, mislocalized, immature or unmodified nucleic acids (Barbalat et al., Annu. Rev. Immunol. 29, 185-214 (2011)).

[0005] "Cyclic GMP-AMP Synthase" (cGAS) is a major sensor of aberrant double-stranded DNA (dsDNA) derived 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)). The binding of dsDNA to cGAS activates the reaction of GTP and ATP to form the cyclic dinucleotide GMP-AMP (called cGAMP). cGAMP then binds to and activates the endoplasmic reticulum membrane-anchored adapter protein, "Stimulator of Interferon Genes" (STING, UniProtKB-Q86WV6). Activated STING recruits and activates TANK-binding kinase 1 (TBK1), which in turn phosphorylates the transcription factor family of interferon regulatory factor (IRF), inducing cytokine and type I interferon mRNA expression. Activation of STING by cGAMP also causes activation of the NF-kB signaling pathway and downstream production of proinflammatory cytokines (Sun et al., Science 339, 786-791 (2013)). Human GoF STING mutants produce autoinflammatory syndromes, skin vasculopathy, and pulmonary fibrosis (STING-associated vasculopathy with onset in infancy; SAVI). SAVI patients have highly activated PBMCs and dermal fibroblasts, showing upregulated type I IFN markers and NFκB-mediated expression of profibrotic and proinflammatory genes (e.g., TNFα, IL-6) (Liu et al., 2014).

[0006] The key role of STING in dsDNA sensing has been demonstrated in different pathogenic bacteria and viruses. In addition, STING is crucial in various other biological processes, such as cell senescence (Yang et al., PNAS 114, E4612 (2017), Gluck et al., Nat. Cell Biol. 19, 1061-1070 (2017)), autophagy and recognition of ruptured micronuclei in potential cancer cell monitoring (Mackenzie et al., Nature 548, 461-465 (2017); Harding et al., Nature 548, 466-470 (2017)).

[0007] Although the cGAS / STING pathway is essential for host defense against pathogen invasion, cellular stress and genetic factors can also cause the production of abnormal cellular dsDNA, for example through nuclear or mitochondrial leakage, and thereby trigger autoinflammatory responses. Aicardi-Goutières syndrome (AGS; Crow et al., Nat. Genet. 38, 917-920 (2006))—a lupus-like severe autoinflammatory immune-mediated disorder—is caused by genetic mutations, such as loss-of-function mutations in TREX1, the major DNA exonuclease responsible for degrading abnormal DNA in the cytosol. Knockout of STING in mice lacking TREX1 prevents otherwise lethal autoimmune responses, supporting STING as a driver of interferonopathy (Gall et al., Immunity 36(1), 120-131 (2012); Gao et al., PNAS 112, E5699-E5705 (2015)). Similarly, embryonic lethality caused by lack of DNAse2 (an endonuclease responsible for excessive DNA degradation in lysosomes during endocytosis) was fully rescued by additional knockout of STING (Ahn et al., PNAS 109, 19386-19391 (2012)). STING inhibitors may provide a therapeutic strategy for preventing (monogenic and digenic) interferon diseases such as SAVI, AGS, familial pernio lupus, and COPA. STING inhibitors will block inflammation and abnormal tissue remodeling in a group of autoimmune and inflammatory diseases, including systemic lupus erythematosus (SLE), systemic sclerosis, dermatomyositis, inflammatory bowel disease, sepsis, Sjögren's syndrome, atopic dermatitis, and a group of fibrotic diseases including NASH, IPF, and chronic renal fibrosis. STING inhibitors are also being used in additional diseases such as cancer, heart failure, AMD, retinopathy, glaucoma, aging, muscle diseases, rheumatoid arthritis, osteoarthritis, ALS, Parkinson's disease, and COVID-19 (Decout et al., Nat Rev Immunol. 2021 21:548-569).

[0008] Prior art

[0009] Efforts to develop STING inhibitors or inhibit the STING signaling pathway have been made due to the observation that inhibition of the STING pathway may provide a therapeutic strategy for preventing autoinflammation and treating, for example, autoimmune diseases.

[0010] For example, in WO2019122202, it is described that compounds C-178 or C-176 can interfere with the STING signaling pathway in HEK293T cells or bone marrow-derived macrophages (BMDM) stimulated with cyclic dinucleotides such as cGAMP, and these compounds are irreversible inhibitors that block the palmitoylation of STING at STING ectopic sites.

[0011] In ACS Med Chem Lett. (2019, 10, 1, pp 92-97), Siu et al. describe novel cGAMP competitive ligands. It is believed that inhibition of the orthosteric site of cGAMP-mediated STING activation leads to inhibition of all STING-mediated activation compared to palmitoylation inhibitors. Compounds 13 or 15 in this publication inhibit HAQSTING variants (displacement assay) with a moderate IC50 of 84nM or 41nM, and exhibit low cell inhibitory activity of about 11μM based on cGAMP-stimulated INFb production in THP1 cells.

[0012] In international patent application WO2019069270, it is claimed that modulators of STING are protected, which respectively either activate STING or inhibit STING.

[0013] It has now been found, unexpectedly, that the compounds described in this patent application are competitive inhibitors of STING. DETAILED DESCRIPTION

[0014] The present invention relates to compounds of formula 1:

[0015]

[0016] in

[0017] BA is =CN- or -NC=; this means A is C or N; B is C or N; but A and B are not N at the same time;

[0018] R1 is selected from

[0019]

[0020] and R1 is a connection point with the structure of Formula 1;

[0021] R2, where BA is -NC=, has C 1-6 -alkyl-, C 3-6 -cycloalkyl-, C 1-6 The meaning of -haloalkyl-;

[0022] R2 Where BA is =CN-, it has C 1-6 -alkyl-, C 3-6 -cycloalkyl-, C1-6 -haloalkyl-, C 1-6 -alkyl-O-, HO-, H2N-, C 1-6 -alkyl-HN-, (C 1-6 -alkyl)2N-;

[0023] R3 H- or C 1-6 -alkyl, C 3-7 -Cycloalkyl, C 2-6 -Alkenyl, C 3-7 -heterocycloalkyl, each of which is optionally substituted with a group selected from F-, HO-, Me-, EtO-, NH2(O)C-;

[0024] R4 is H-, F- or HO-;

[0025] R4 b is H-, F-, Cl-, Br-, NC- or HO-;

[0026] R5 is selected from

[0027]

[0028] and R5 is a connection point with the structure of Formula 1;

[0029] Q is -C(R11)(R12)-, -S(O)- or -S(O)2-;

[0030] R6 is C 2-6 -alkenyl,

[0031] or

[0032] C 1-6 -alkyl, which is optionally substituted independently of one another by one or two substituents selected from the group consisting of: C 3-6 -cycloalkyl-, halogen, HO-, C 1-6 -alkyl-O-, C 1-6 -alkyl-HN-, (C 1-6 -alkyl)2N-, NC-, (C 1-6 -alkyl)2(O)P-, (4-methoxyphenyl)methyl-,

[0033] or

[0034] A heterocycle selected from tetrahydrofuran-, 1,4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, triazole-, each of which is optionally substituted independently of one another by one or two substituents selected from the group consisting of: C 1-6 -alkyl-, halogen, O=;

[0035] R7, R8, R9 are C 3-6-cycloalkyl-, which is optionally C 1-6 -alkyl- or one or two halogen-substituted,

[0036] or

[0037] Cyclopropylmethyl-, C 1-6 -haloalkyl-, C 1-6 -alkyl-O-, C 1-6 -alkyl-HN-, (C 1-6 -alkyl)2N-, C 1-6 -alkyl-S-,

[0038] or

[0039] C 1-6 -alkyl, which is linear or branched, which is optionally substituted by HO-, C 1-6 -alkyl-O-, C 1-6 -alkyl-HN-, (C 1-6 -alkyl) 2N- or morpholine-substituted,

[0040] or

[0041] A heterocycle selected from pyrrolidine-, tetrahydrofuran-, tetrahydropyran-;

[0042] or

[0043] C 1-6 -haloalkyl-O-;

[0044] R10 is C 1-6 -alkyl- or C 1-6 -haloalkyl-;

[0045] R11 is H, HO-, halogen- or R14-O-, R14-NH-;

[0046] R12 is H- or F;

[0047] R13 is a carbocyclic group, a heterocyclic group, an aryl group, or a heteroaryl group; preferably C 6-10 -Aryl, C 5-10 -heteroaryl; each of which is optionally substituted with one or two substituents selected from the following: C 1-6 -alkyl, C 1-6 -Haloalkyl, HO-, NC-, halogen, R15-(CH2) n -O-, R15-(CH2) n -NH-, (R15-(CH2) n )2-N-、R15-(CH2) n -S(O)-, R15-(CH2) n -S(O)2-;

[0048] R14 is C 1-6 -haloalkyl- or C 1-6 -alkyl, which is optionally C 3-6 -Cycloalkyl, C 2-6 -Alkenyl-, HO-, C 1-6 -alkyl-O-, H2N-C(O)-, C 1-6 -alkyl-HN-C(O)-, (C 1-6 -alkyl)2N-C(O)-substituted;

[0049] R15 is C 1-4 -alkyl, C 1-6 -haloalkyl, NC-, C 1-6 -alkyl-HN-, (C 1-6 -alkyl)2N-, (C 1-6 -alkyl)2(HO)C-, aryl or heterocyclic;

[0050] n is 0, 1, 2 or 3.

[0051] Preferably, a compound of formula 1 is

[0052] BA is =CN- or -NC=; this means A is C or N; B is C or N; but A and B are not N at the same time;

[0053] R1 is selected from

[0054]

[0055] and R1 is a connection point with the structure of Formula 1;

[0056] R2, where BA is -NC=, has C 1-6 -alkyl-, C 3-6 -cycloalkyl-, C 1-6 The meaning of -haloalkyl-;

[0057] R2 Where BA is =CN-, it has C 1-6 -alkyl-, C 3-6 -cycloalkyl-, C 1-6 -haloalkyl-, C 1-6 -alkyl-O-, HO-, H2N-, C 1-6 -alkyl-HN-, (C 1-6 -alkyl)2N-;

[0058] R3 H- or C 1-6 -alkyl, C 3-7 -cycloalkyl, C 2-6 -Alkenyl, C 3-7- heterocycloalkyl, each of which is optionally substituted by a group selected from F-, HO-, Me-, EtO-, NH2(O)C-;

[0059] R4 is H-, F- or HO-;

[0060] R4 b is H-, F-, Cl-, Br-, NC- or HO-;

[0061] R5 is selected from

[0062]

[0063] and R5 is a connection point with the structure of Formula 1;

[0064] Q is -C(R11)(R12)-, -S(O)- or -S(O)2-;

[0065] R6 is C 2-6 -alkenyl,

[0066] or

[0067] C 1-6 -alkyl, which is optionally substituted independently of one another by one or two substituents selected from the group consisting of: C 3-6 -cycloalkyl-, halogen, HO-, C 1-6 -alkyl-O-, C 1-6 -alkyl-HN-, (C 1-6 -alkyl)2N-, NC-, (C 1-6 -alkyl)2(O)P-, (4-methoxyphenyl)methyl-,

[0068] or

[0069] A heterocycle selected from tetrahydrofuran-, 1,4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, triazole-, each of which is optionally substituted independently of one another by one or two substituents selected from the group consisting of: C 1-6 -alkyl-, halogen, O=;

[0070] R7, R8, R9 are C 3-6 -cycloalkyl-, which is optionally C 1-6 -alkyl- or one or two halogen-substituted,

[0071] or

[0072] Cyclopropylmethyl-, C 1-6 -haloalkyl-, C 1-6 -alkyl-O-, C 1-6 -alkyl-HN-, (C 1-6 -alkyl)2N-, C 1-6 -alkyl-S-,

[0073] or

[0074] C 1-6 -alkyl, which is linear or branched, which is optionally substituted by HO-, C 1-6 -alkyl-O-, C 1-6 -alkyl-HN-, (C 1-6 -alkyl) 2N- or morpholine-substituted,

[0075] or

[0076] A heterocycle selected from pyrrolidine-, tetrahydrofuran-, tetrahydropyran-;

[0077] or

[0078] C 1-6 -haloalkyl-O-;

[0079] R10 is C 1-6 -alkyl- or C 1-6 -haloalkyl-;

[0080] R11 is H, HO-, halogen- or R14-O-, R14-NH-;

[0081] R12 is H- or F;

[0082] R13 is a carbocyclic group, a heterocyclic group, an aryl group, or a heteroaryl group; preferably C 6-10 -Aryl, C 5-10 -heteroaryl; each of which is optionally substituted with one or two substituents selected from the following: C 1-6 -alkyl, C 1-6 -Haloalkyl, HO-, NC-, halogen, R15-(CH2) n -O-, R15-(CH2) n -NH-, (R15-(CH2) n )2-N-、R15-(CH2) n -S(O)-, R15-(CH2) n -S(O)2-;

[0083] R14 is C 1-6 -haloalkyl- or C 1-6 -alkyl, which is optionally C 3-6 -cycloalkyl, C 2-6 -Alkenyl-, HO-, C 1-6 -alkyl-O-, H2N-C(O)-, C 1-6 -alkyl-HN-C(O)-, (C 1-6 -alkyl)2N-C(O)-substituted;

[0084] R15 is C1-4 -alkyl, C 1-6 -haloalkyl, NC-, C 1-6 -alkyl-HN-, (C 1-6 -alkyl)2N-, (C 1-6 -alkyl)2(HO)C-, aryl or heterocyclic;

[0085] n is 0, 1, 2 or 3.

[0086] Preferred is a compound of formula 1, wherein

[0087] BA is =CN- or -NC=; this means A is C or N; B is C or N; but A and B are not N at the same time;

[0088] R1 is selected from

[0089]

[0090] and R1 is a connection point with the structure of Formula 1;

[0091] R2, where BA is -NC=, has C 1-6 -alkyl-, C 3-6 The meaning of -cycloalkyl-;

[0092] R2 Where BA is =CN-, it has C 1-6 -alkyl-, C 3-6 -cycloalkyl-, C 1-6 -alkyl-O-, HO-, H2N-, C 1-6 -alkyl-HN-, (C 1-6 -alkyl)2N-;

[0093] R3 H- or C 1-6 -alkyl, C 3-7 -cycloalkyl, C 2-5 -Alkenyl, C 3-7 - heterocycloalkyl, each of which is optionally substituted by a group selected from F-, HO-, Me-, EtO-, NH2(O)C-;

[0094] R4 is H-, F- or HO-;

[0095] R4 b is H-, F-, Cl-, Br-, NC- or HO-;

[0096] R5 is selected from

[0097]

[0098] and R5 is a connection point with the structure of Formula 1;

[0099] Q is -C(R11)(R12)-, -S(O)- or -S(O)2-;

[0100] R6 is C 2-4 -alkenyl,

[0101] or

[0102] C 1-4 -alkyl, which is optionally substituted independently of one another by one or two substituents selected from the group consisting of: C 3-4 -cycloalkyl-, halogen, HO-, C 1-4 -alkyl-O-, C 1-4 -alkyl-HN-, (C 1-4 -alkyl)2N-, NC-, (C 1-4 -alkyl)2(O)P-, (4-methoxyphenyl)methyl-,

[0103] or

[0104] A heterocycle selected from tetrahydrofuran-, 1,4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, triazole-, each of which is optionally substituted independently of one another by one or two substituents selected from the group consisting of: C 1-4 -alkyl-, halogen, O=;

[0105] R7, R8, R9 are C 3-4 -cycloalkyl-, which is optionally C 1-4 -alkyl- or one or two halogen-substituted,

[0106] or

[0107] Cyclopropylmethyl-, C 1-4 -haloalkyl-, C 1-4 -alkyl-O-, C 1-4 -alkyl-HN-, (C 1-4 -alkyl)2N-, C 1-4 -alkyl-S-,

[0108] or

[0109] C 1-4 -alkyl, which is linear or branched, which is optionally substituted by HO-, C 1-4 -alkyl-O-, C 1-4 -alkyl-HN-, (C 1-4 -alkyl) 2N- or morpholine-substituted,

[0110] or

[0111] A heterocycle selected from pyrrolidine-, tetrahydrofuran-, tetrahydropyran-,

[0112] or

[0113] C 1-4 -haloalkyl-O-;

[0114] R10 is C 1-4 -alkyl- or C 1-4 -haloalkyl-;

[0115] R11 is H, HO-, halogen- or R14-O-, R14-NH-;

[0116] R12 is H- or F;

[0117] R13 is a carbocyclic group, a heterocyclic group, an aryl group, or a heteroaryl group; preferably C 6-10 -Aryl, C 5-10 -heteroaryl; each of which is optionally substituted with one or two substituents selected from the following: C 1-4 -alkyl, C 1-4 -Haloalkyl, HO-, NC-, halogen, R15-(CH2) n -O-, R15-(CH2) n -NH-, (R15-(CH2) n )2-N-、R15-(CH2) n -S(O)-, R15-(CH2) n -S(O)2-;

[0118] R14 is C 1-4 -haloalkyl- or C 1-5 -alkyl, which is optionally C 3-4 -Cycloalkyl, C 2-4 -Alkenyl-, HO-, C 1-4 -alkyl-O-, H2N-C(O)-, C 1-4 -alkyl-HN-C(O)-, (C 1-4 -alkyl)2N-C(O)-substituted;

[0119] R15 is C 1-4 -alkyl, C 1-4 -haloalkyl, NC-, C 1-6 -alkyl-HN-, (C 1-4 -alkyl)2N-, (C 1-4 -alkyl)2(HO)C-, aryl or heterocyclic;

[0120] n is 0, 1, 2 or 3.

[0121] Preferred is a compound of formula 1, wherein

[0122] BA is =CN- or -NC=; this means A is C or N; B is C or N; but A and B are not N at the same time;

[0123] R1 is selected from

[0124]

[0125] and R1 is a connection point with the structure of Formula 1;

[0126] R2 is C 1-4 -alkyl-;

[0127] R3 is C 1-4 -alkyl-, which is optionally substituted with HO-,

[0128] or

[0129] C 3-4 -cycloalkyl-, which is optionally substituted by methyl-;

[0130] R4 is H- or F-;

[0131] R5 is selected from

[0132]

[0133] and R5 is a connection point with the structure of Formula 1;

[0134] R6 is C 2-4 -alkenyl,

[0135] or

[0136] C 1-4 -alkyl, which is optionally substituted independently of one another by one or two substituents selected from the group consisting of: C 3-4 -cycloalkyl-, halogen, HO-, C 1-4 -alkyl-O-, (C 1-4 -alkyl)2N-, NC-, (C 1-4 -alkyl)2(O)P-, (4-methoxyphenyl)methyl-,

[0137] or

[0138] A heterocycle selected from tetrahydrofuran-, 1,4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, triazole-, each of which is optionally substituted independently of one another by one or two substituents selected from the group consisting of: C 1-4 -alkyl-, halogen, O=;

[0139] R7 is C 3-4 -cycloalkyl-, which is optionally C 1-4 -alkyl- or one or two halogen-substituted,

[0140] or

[0141] Cyclopropylmethyl-, C 1-4-haloalkyl-, C 1-4 -alkyl-O-, C 1-4 -alkyl-HN-, (C 1-4 -alkyl)2N-, C 1-4 -alkyl-S-,

[0142] or

[0143] C 1-4 -alkyl, which is linear or branched, which is optionally substituted by HO-, C 1-4 -alkyl-O-, C 1-4 -alkyl-HN-, (C 1-4 -alkyl) 2N- or morpholine-substituted,

[0144] or

[0145] A heterocycle selected from pyrrolidine-, tetrahydrofuran-, tetrahydropyran-;

[0146] R8 is C 1-4 -haloalkyl-O-;

[0147] R9 is C 1-4 -alkyl- or C 3-4 -cycloalkyl-;

[0148] R10 is C 1-4 -alkyl- or C 1-4 -haloalkyl-;

[0149] R11 is H, HO-, halogen- or R14-O-;

[0150] R12 is H- or F;

[0151] R13 is cyclohexyl-, 3,4-difluorophenyl-, 3-methyl-4N-pyridyl-, or phenyl-, which is optionally substituted at the 4-position with methyl, HO-, F-, Cl-, Br-, R15-(CH2) n -O-substitution;

[0152] R14 is C 1-4 -haloalkyl- or C 1-5 -alkyl, which is optionally C 3-4 -cycloalkyl, C 2-4 -Alkenyl-, HO-, C 1-4 -alkyl-O-, H2N-C(O)-, (C 1-4 -alkyl)NH-C(O)-, (C 1-4 -alkyl)2N-C(O)-substituted;

[0153] R15 is NC-, (C 1-4 -alkyl)2N-, (C 1-4-alkyl)2(HO)C-, phenyl, or a heterocycle selected from oxetane-, tetrahydropyran-, morpholine-;

[0154] n is 0, 1 or 2.

[0155] Preferred is a compound of formula 1, wherein

[0156] BA is =CN- or -NC=; this means A is C or N; B is C or N; but A and B are not N at the same time;

[0157] R1 is selected from

[0158]

[0159] Preferably

[0160] and R1 is a connection point with the structure of Formula 1;

[0161] R2 is methyl- or ethyl-, preferably methyl-;

[0162] R3 is ethyl-, isopropyl-, cyclopropyl-, 1-methyl-cyclopropyl-, 1-hydroxy-isopropyl-;

[0163] R4 is H- or F-;

[0164] R5 is selected from

[0165]

[0166] and R5 is a connection point with the structure of Formula 1;

[0167] R6 is C 2-4 -alkenyl,

[0168] or

[0169] C 1-4 -alkyl, which is optionally substituted independently of one another by one or two substituents selected from the group consisting of cyclopropyl-, F-, HO-, H3C-O-, (H3C)2N-, NC-, (H3C)2(O)P-, (4-methoxyphenyl)methyl-,

[0170] or

[0171] A heterocycle selected from tetrahydrofuran-, 1,4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, triazole-, each of which is optionally substituted independently of one another by one or two substituents selected from the group consisting of: H3C-, F-, O=;

[0172] R6 is preferably methyl-, ethyl-, isopropyl-, cyclopropyl-;

[0173] R7 is cyclopropyl-, 1-fluorocyclopropyl-, 2,2-difluorocyclopropyl-, 1-methyl-cyclopropyl-, cyclobutane-, cyclopropylmethyl-, F2HC-, F3C-, (iPr)-O-, (H3C)NH-, (H3C)2N-, H3C-S-,

[0174] or

[0175] C 1-4 - alkyl, which is linear or branched, which is optionally substituted by HO-, H3C-O-, H3C-CH2-O-, (H3C)NH-, (H3C)2N- or morpholine-,

[0176] or

[0177] A heterocycle selected from pyrrolidine-, tetrahydrofuran-, tetrahydropyran-;

[0178] R8 is F2HC-O-, F3C-O-;

[0179] R9 is methyl or cyclopropyl;

[0180] R10 is methyl or F2C-;

[0181] R11 is H, HO-, F- or R14-O-;

[0182] R12 is H- or F; preferably H-;

[0183] R13 is cyclohexyl-, 3,4-difluorophenyl-, 3-methyl-4N-pyridyl-, or phenyl-, which is optionally substituted at the 4-position with methyl, HO-, F-, Cl-, Br-, R15-(CH2) n -O-substitution;

[0184] R14 is FH2C-, FH2C-CH2- or C 1-5 -alkyl, which is optionally substituted by cyclopropyl, H2C=CH-, HO-, H3C-O-, H2N-C(O)-, (H3C)NH-C(O)-;

[0185] R15 is NC-, (H3C)2N-, (H3C)2(HO)C-, phenyl, or a heterocycle selected from oxetane-, tetrahydropyran-, morpholine-;

[0186] n is 0, 1 or 2.

[0187] Preferred is a compound of formula 1, wherein

[0188] BA is =CN- or -NC=; this means A is C or N; B is C or N; but A and B are not N at the same time;

[0189] R1 is selected from

[0190]

[0191] and R1 is a connection point with the structure of Formula 1;

[0192] R2 is methyl-;

[0193] R3 is ethyl-, isopropyl-, cyclopropyl-, 1-methyl-cyclopropyl-, 1-hydroxy-isopropyl-;

[0194] R4 is H- or F-;

[0195] R5 is selected from

[0196]

[0197] and R5 is a connection point with the structure of Formula 1;

[0198] R6 is methyl-, ethyl-, isopropyl-, cyclopropyl-;

[0199] R7 is cyclopropyl-, 1-fluorocyclopropyl-, 2,2-difluorocyclopropyl-, 1-methyl-cyclopropyl-, cyclobutane-, cyclopropylmethyl-, F2HC-, F3C-, (iPr)-O-, (H3C)NH-, (H3C)2N-, H3C-S-,

[0200] or

[0201] C 1-4 - alkyl, which is linear or branched, which is optionally substituted by HO-, H3C-O-, H3C-CH2-O-, (H3C)NH-, (H3C)2N- or morpholine-,

[0202] or

[0203] A heterocycle selected from pyrrolidine-, tetrahydrofuran-, tetrahydropyran-;

[0204] R11 is H, HO-, F- or R14-O-;

[0205] R12 is H-;

[0206] R13 is cyclohexyl-, 3,4-difluorophenyl-, 3-methyl-4N-pyridyl-, or phenyl-, which is optionally substituted at the 4-position with methyl, HO-, F-, Cl-, Br-, R15-(CH2) n -O-substitution;

[0207] R14 is FH2C-, FH2C-CH2- or C 1-5-alkyl, which is optionally substituted by cyclopropyl, H2C=CH-, HO-, H3C-O-, H2N-C(O)-, (H3C)NH-C(O)-;

[0208] R15 is NC-, (H3C)2N-, (H3C)2(HO)C-, phenyl, or a heterocycle selected from oxetane-, tetrahydropyran-, morpholine-;

[0209] n is 0, 1 or 2.

[0210] Preferred is a compound of formula 1, wherein

[0211] BA is =CN- or -NC=; this means A is C or N; B is C or N; but A and B are not N at the same time;

[0212] R1 is selected from

[0213]

[0214]

[0215]

[0216]

[0217] and R1 is a connection point with the structure of Formula 1;

[0218] R2 is methyl- or ethyl-, preferably methyl-;

[0219] R3 is ethyl-, isopropyl-, cyclopropyl-, 1-methyl-cyclopropyl-, ((HO)H2C)(H3C)HC-;

[0220] R4 is H- or F-; R5 is selected from

[0221]

[0222]

[0223] And R5 is the connection point with the structure of Formula 1.

[0224] Preferably, a compound of formula 1 is

[0225] BA is =CN- or -NC=; this means A is C or N; B is C or N; but A and B are not N at the same time;

[0226] R1 is selected from

[0227]

[0228]

[0229] and R1 is a connection point with the structure of Formula 1;

[0230] R2 is methyl- or ethyl-, preferably methyl-;

[0231] R3 is ethyl-, isopropyl-, cyclopropyl-, 1-methyl-cyclopropyl-, ((HO)H2C)(H3C)HC-;

[0232] R4 is H- or F-;

[0233] R5 is selected from

[0234]

[0235]

[0236] And R5 is the connection point with the structure of Formula 1.

[0237] Preferred is a compound of formula 1, wherein

[0238] BA is =CN- or -NC=; this means A is C or N; B is C or N; but A and B are not N at the same time;

[0239] R1 is selected from

[0240]

[0241]

[0242]

[0243] and R1 is a connection point with the structure of Formula 1;

[0244] R2 is methyl- or ethyl-, preferably methyl-;

[0245] R3 is ethyl-, isopropyl-, cyclopropyl-, 1-methyl-cyclopropyl-, ((HO)H2C)(H3C)HC-;

[0246] R4 is H- or F-;

[0247] R5 is selected from

[0248]

[0249]

[0250] And R5 is the connection point with the structure of Formula 1.

[0251] Preferred is a compound of formula 1, wherein

[0252] BA is =CN- or -NC=; this means A is C or N; B is C or N; but A and B are not N at the same time;

[0253] R1 is selected from

[0254]

[0255] and R1 is a connection point with the structure of Formula 1;

[0256] R2 is methyl- or ethyl-, preferably methyl-;

[0257] R3 is ethyl-, isopropyl-, cyclopropyl-, 1-methyl-cyclopropyl-, ((HO)H2C)(H3C)HC-;

[0258] R4 is H- or F-;

[0259] R5 is selected from

[0260]

[0261]

[0262] And R5 is the connection point with the structure of Formula 1.

[0263] Preferred are compounds of formula 1, wherein R1 is

[0264]

[0265] and R6 and R7 are as defined above and R1 is the point of attachment to the structure of Formula 1. Preferred are compounds of Formula 1, wherein R1 is

[0266]

[0267] and R8 is as defined above and R1 is the point of attachment to the structure of Formula 1.

[0268] Preferred are compounds of formula 1, wherein R1 is

[0269]

[0270] and R9 and R10 are as defined above and R1 is the point of attachment to the structure of Formula 1. Preferred are compounds of Formula 1, wherein R1 is

[0271]

[0272] and R9 and R10 are as defined above and R1 is the point of attachment to the structure of Formula 1. Preferred are compounds of Formula 1, wherein R1 is selected from

[0273]

[0274]

[0275] And R1 is the connection point with the structure of Formula 1.

[0276] Preferred are compounds of formula 1, wherein R1 is selected from

[0277]

[0278] And R1 is the connection point with the structure of Formula 1.

[0279] Preferred are compounds of formula 1, wherein R1 is selected from

[0280]

[0281]

[0282] And R1 is the connection point with the structure of Formula 1.

[0283] Preferred are compounds of formula 1, wherein R5 is

[0284]

[0285] and R11, R12 and R13 are as defined above and R1 is the point of attachment to the structure of Formula 1.

[0286] Preferred are compounds of formula 1, wherein R5 is

[0287]

[0288] and

[0289] R11 is HO-, F- or R14-O-;

[0290] R12 is H-;

[0291] R13 is cyclohexyl-, 3,4-difluorophenyl-, 3-methyl-4N-pyridyl-, or phenyl-, which is optionally substituted at the 4-position with methyl, HO-, F-, Cl-, Br-, R15-(CH2) n -O-substitution;

[0292] R14 is FH2C-, FH2C-CH2- or C 1-5 -alkyl, which is optionally substituted by cyclopropyl, H2C=CH-, HO-, H3C-O-, H2N-C(O)-, (H3C)NH-C(O)-;

[0293] R15 is NC-, (H3C)2N-, (H3C)2(HO)C-, phenyl, or a heterocycle selected from oxetane-, tetrahydropyran-, morpholine-;

[0294] n is 0, 1 or 2.

[0295] And R1 is the connection point with the structure of Formula 1.

[0296] Preferred are compounds of formula 1, wherein R5 is

[0297]

[0298] and

[0299] R11 is HO-;

[0300] R12 is H-;

[0301] R13 is phenyl-, which is optionally substituted by methyl, HO-, F-, Cl-, Br-, R15-(CH2) at the 4-position n -O-substitution;

[0302] R15 is NC-, (H3C)2N-, (H3C)2(HO)C-, phenyl, or a heterocycle selected from oxetane-, tetrahydropyran-, morpholine-;

[0303] n is 0, 1 or 2.

[0304] And R1 is the connection point with the structure of Formula 1.

[0305] Preferred are compounds of formula 1, wherein R5 is

[0306]

[0307] and

[0308] R11 is HO-;

[0309] R12 is H-;

[0310] R13 is phenyl-, which is optionally substituted at the 4-position by methyl, HO-, F-, Cl-, or Br-;

[0311] And R1 is the connection point with the structure of Formula 1.

[0312] Preferred are compounds of formula 1, wherein R5 is

[0313]

[0314] Preferred are compounds of formula 1, wherein R5 is

[0315]

[0316] Preferred are compounds of formula 1, wherein R5 is

[0317] Preference is also given to compounds of the formula 1a.

[0318]

[0319] Preference is also given to compounds of the formula 1b.

[0320]

[0321] Preference is also given to compounds of the formula 1b1.

[0322]

[0323] Preferred are also compounds of the formula 1c.

[0324]

[0325] Preference is also given to compounds of the formula 1c1.

[0326]

[0327] Preferred are compounds of formula 1 wherein BA is =CN- and R3 is isopropyl.

[0328] Preferred are compounds of formula 1 wherein BA is -NC= and R3 is cyclopropyl.

[0329] Preferred are also salts of compounds of formula 1, 1a, 1b, 1b1, 1c or 1c1. Furthermore, preferred are pharmaceutically acceptable salts of compounds of formula 1, 1a, 1b, 1b1, 1c or 1c1.

[0330] In a preferred embodiment, the present invention relates to the compounds of formula 1, 1a, 1b, 1b1, 1c or 1c1 mentioned above and their use as STING antagonists, for example, for treating a disease selected from the following: systemic lupus erythematosus (SLE), (monogenic and digenic) interferonopathies (including STING-associated vasculopathy of infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome and familial pernio-like lupus), type I interferonopathies with mutations in the DNASE2 or ATAD3A genes, age-related macular degeneration. (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), diabetes, obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Sjögren's syndrome, Parkinson's disease, heart failure and cancer, systemic sclerosis (SSc), dermatomyositis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), acute-on-chronic liver failure (ACLF), interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), aging / muscle diseases, sepsis, heart failure, rheumatoid arthritis and osteoarthritis.

[0331] In a more preferred embodiment, the present invention relates to a compound of formula 1, 1a, 1b, 1b1, 1c or 1c1 as mentioned above, which is used to treat a disease selected from the following: systemic lupus erythematosus (SLE), (monogenic and digenic) interferon disease, Aicardi-Goutières syndrome, type I interferon disease with DNASE2 or ATAD3A gene mutation, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Sjögren's syndrome and Parkinson's disease.

[0332] In another more preferred embodiment, the present invention relates to a compound of formula 1, 1a, 1b, 1b1, 1c or 1c1 as mentioned above, for use in the treatment of a fibrotic disease selected from the group consisting of systemic sclerosis (SSc), non-alcoholic steatohepatitis (NASH), acute-on-chronic liver failure (ACLF), (monogenic and digenic) interferonopathy, and interstitial lung disease (ILD).

[0333] In another more preferred embodiment, the present invention relates to a compound of formula 1, 1a, 1b, 1b1, 1c or 1c1 as mentioned above, for use in treating a disease selected from the group consisting of age-related macular degeneration (AMD), retinopathy, glaucoma, aging, muscle disease, heart failure, COVID-19 / SARS-CoV-2 infection, renal inflammation, renal fibrosis, metabolic disorders, vascular diseases, cardiovascular diseases, diabetes, obesity and cancer.

[0334] In another embodiment, the present invention relates to a pharmaceutical composition comprising at least one compound as mentioned above and optionally one or more pharmaceutically acceptable carriers and / or excipients.

[0335] In another preferred embodiment, the present invention relates to a combination of a compound of Formula 1, 1a, 1b, 1b1, 1c or 1c1 and one or more active agents selected from the following: anti-inflammatory agents, anti-fibrotic agents, anti-allergic agents / antihistamines, bronchodilators, β2 agonists / β mimetics, adrenergic agonists, anticholinergics, methotrexate, mycophenolate mofetil, leukotriene modifiers, JAK inhibitors, anti-interleukin antibodies, non-specific immunotherapeutics such as interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators, toll-like receptor agonists, immune checkpoint modulators, anti-TNF antibodies, anti-BAFF antibodies.

[0336] Example

[0337] The following examples are for the purpose of illustrating the present invention only and are not intended to limit the scope of the present invention in any way. For a representative example complexed with the STING protein, the absolute configuration was defined by x-ray.

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377] General Terms and Definitions

[0378] Terms that are not specifically defined in this application should be given the meaning that would be given to them by those skilled in the art in view of the disclosure and context. However, unless otherwise specified, as used in this specification, the following terms have the specified meanings and will comply with the following conventions.

[0379] In the groups, radicals or moieties defined below, the number of carbon atoms is usually specified before the radical, e.g. 1-6 Alkyl means an alkyl group or alkyl radical having 1 to 6 carbon atoms. In general, in groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C, etc., one skilled in the art can see the radical attachment point to the molecule from the free valence of the group itself. For a combined group comprising two or more subgroups, the last named subgroup is the radical attachment point, e.g., the substituent "aryl-C 1-3 "Alkylene" means a group bonded to C 1-3 The aryl radical of an alkyl radical, the latter being bonded to the core or to the radical to which the substituent is attached.

[0380] If the compounds of the present invention are described in terms of both a chemical name and a chemical formula, in the event of any inconsistency, the chemical formula shall prevail.

[0381] The numbering of substituent atoms begins with the atom closest to the core or group to which the substituent is attached. For example, the term "3-carboxypropyl group" represents the following substituent:

[0382]

[0383] wherein the carboxyl group is attached to the third carbon atom of the propyl group. The term "1-methylpropyl-", "2,2-dimethylpropyl-" or "cyclopropylmethyl-" group refers to the following groups:

[0384]

[0385] Asterisks may be used in subformulas to indicate bonds to the defined core molecule.

[0386] When the residue R# in the exemplary structures is referred to in the claims or description as the point of attachment to the structure of Formula 1, it is also understood in this context to be the point of attachment to the structure of Formula 1a, 1b or 1c.

[0387] The term "substituted" as used herein means that one or more hydrogens on a designated atom are replaced by a group selected from a defined group of substituents, provided that the normal valence of the designated atom is not exceeded and that the substitution results in a stable compound. Likewise, the term "substituted" may be used in conjunction with chemical moieties rather than individual atoms, such as "substituted alkyl", "substituted aryl", etc.

[0388] Unless otherwise specified, throughout the specification and the appended claims, a given chemical formula or name shall encompass its tautomers and all stereo, optical and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc. . . ) and racemates, as well as mixtures of individual enantiomers in varying proportions, mixtures of diastereomers, or mixtures in any of the aforementioned forms in which such isomers and enantiomers exist, and solvates thereof, such as hydrates.

[0389] Unless otherwise specified, "pharmaceutically acceptable salts" as defined in more detail below shall also encompass solvates thereof, such as hydrates.

[0390] In general, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example 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, for example by resolution of racemic forms or by synthesis (e.g., starting from optically active starting materials and / or by using chiral reagents).

[0391] The enantiomerically pure compounds of the 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 chromatography or crystallization), and / or by using chiral reagents (e.g., chiral starting materials, chiral catalysts or chiral auxiliary agents).

[0392] Furthermore, the person skilled in the art knows how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, for example by chromatographic separation of the corresponding racemic mixtures on a chiral stationary phase; or by resolution of the racemic mixtures using suitable resolving agents, for example by means of formation of diastereomeric salts of the racemic compounds with optically active acids or bases, followed by resolution of these and liberation of the desired compound from the salts; or by derivatization of the corresponding racemic compounds with optically active chiral auxiliary reagents, followed by separation of the diastereomers and removal of the chiral auxiliary groups; or by kinetic resolution of the racemates (e.g. by enzymatic resolution); by enantioselective crystallization under suitable conditions from conglomerates of enantiomorphic crystals; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0393] The phrase "pharmaceutically acceptable" is used in this application to refer to those compounds, substances, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with human tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0394] As used in this application, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which 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.

[0395] For example, such salts include salts from the following acids: 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. In addition, other pharmaceutically acceptable salts can be formed with cations from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucosamine, potassium, sodium and tris(hydroxymethyl)-aminomethane.

[0396] Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing alkaline or acidic moieties by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or free base forms of these compounds with a sufficient amount of appropriate base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile or a mixture thereof.

[0397] In addition to those salts mentioned above, salts of other acids such as trifluoroacetate, which are useful, for example, for purifying or isolating the compounds of the invention, also form part of the invention.

[0398] The term halogen refers to fluorine, chlorine, bromine and iodine.

[0399] The term "C 1-n "alkyl" (wherein n is an integer selected from 2, 3, 4, 5 or 6, preferably 4, 5 or 6) alone or in combination with another group means a non-cyclic, saturated, branched or straight-chain hydrocarbon group having 1 to n C atoms. For example, the term C 1-5-Alkyl encompasses the groups 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-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-, H3C-CH2-CH(CH3)-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0400] If C 2-m At least two carbon atoms of the -alkyl group are bonded to each other via a double bond, then the term "C 2-m -alkenyl" for the group "C 2-m -alkyl", wherein m is an integer selected from 3, 4, 5 or 6, preferably 4, 5 or 6.

[0401] The term "C 3-k -cycloalkyl" (wherein k is an integer selected from 3, 4, 5, 7 or 8, preferably 4, 5 or 6) alone or in combination with another group means a cyclic, saturated, unbranched hydrocarbon group having 3 to k C atoms. For example, the term C 3-7 -Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0402] The term "halo" added to "alkyl", "alkylene" or "cycloalkyl" (saturated or unsaturated) defines an alkyl, alkylene or cycloalkyl group in which one or more hydrogen atoms are replaced by a halogen atom selected from fluorine, chlorine or bromine (preferably fluorine and chlorine, particularly preferably fluorine). Examples include: H2FC-, HF2C-, F3C-.

[0403] The term "carbocyclyl" alone or in combination with another group refers to a monocyclic, bicyclic 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" includes fused, bridged and spiro ring systems.

[0404]

[0405] As used herein, the term "aryl" alone or in combination with another group refers to a carbocyclic aromatic monocyclic group containing 6 carbon atoms, which is optionally further fused to a second five-membered or six-membered carbocyclic group that is aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.

[0406] The term "heterocyclyl" means a saturated or unsaturated monocyclic or polycyclic ring system optionally containing an aromatic ring, which contains one or more heteroatoms selected from N, O, S, SO or SO2 and consists of 3 to 14 ring atoms, wherein none of the heteroatoms is part of an aromatic ring. The term "heterocyclyl" is intended to include all possible isomeric forms.

[0407] Thus, the term "heterocyclyl" includes the following exemplary structures (which are not depicted as radicals because each form may be optionally attached via a covalent bond to any atom as long as proper valence is maintained):

[0408]

[0409]

[0410] The term "heteroaryl" means a monocyclic or polycyclic ring system comprising at least one aromatic ring, containing one or more heteroatoms selected from N, O, S, SO or SO2 and 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 possible isomeric forms.

[0411] Thus, the term "heteroaryl" includes the following exemplary structures (which are not depicted as radicals because each form may be optionally attached via a covalent bond to any atom as long as proper valence is maintained):

[0412]

[0413] Many of the terms given above may be used repeatedly to define chemical formulae or groups and in each case independently of one another have one of the meanings given above.

[0414] The term "bicyclic ring system" refers to a group consisting of two joined cyclic substructures including spiro, fused and bridged ring systems.

[0415] Preparation method

[0416] The following examples are for the purpose of illustrating the present invention only and are not intended to limit the scope of the present invention in any way. The term "room temperature" means a temperature of about 20°C, such as 15 to 25°C. Generally, the prepared compounds have been obtained. 1H-NMR and / or mass spectrometry. Flash chromatography or MPLC is performed with commercially available silica gel and is equivalent to silica gel chromatography. The absolute configuration of representative embodiments is defined via chemical starting materials, single crystal x-ray structure determination, or protein-ligand x-ray determination. Unless otherwise specified, compounds containing chiral centers have the described stereochemistry. Stereochemical identification has been achieved by using chiral starting materials of known stereochemistry, by stereoselective synthesis of known stereochemistry, or by biological activity.

[0417] Scheme 1: General synthesis scheme of patent examples

[0418]

[0419] R4 is H or F;

[0420] BA is =CN- or -NC=; this means A is C or N; B is C or N; but A and B are not N at the same time.

[0421] Scheme 2a: General synthesis of intermediate A: e.g. A1, A13, A14, A24

[0422]

[0423] Scheme 2b: Alternative synthesis of intermediate A: e.g. A2, A5, A19-A23, A25

[0424]

[0425] Scheme 2c: Alternative synthesis of intermediate A: e.g. A4, A7

[0426]

[0427] Scheme 3: Synthesis of intermediates F1-F20, F23-F39, and F49

[0428]

[0429] Scheme 4: Synthesis of intermediates F21 and F22

[0430]

[0431] Scheme 5: Synthesis of imidazole intermediates F40-F47

[0432]

[0433] All starting materials not described were either commercially available or described in the literature.

[0434] Synthesis of intermediates A1-A25:

[0435] Synthesis of intermediate A1:

[0436] Step 1: Synthesis of (1R)-2-{[(2-bromo-6-nitrophenyl)methyl]amino}-1-phenylethan-1-ol

[0437]

[0438] (1R)-2-amino-1-phenyl ethyl-1-ol (5.00 g, 17.0 mmol) was dissolved in ACN (20 mL) and DIPEA (8.75 mL, 50.9 mmol). 1-bromo-2-(bromomethyl)-3-nitrobenzene (6.98 g, 50.9 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by flash chromatography (CycH / EtOAc 100 / 0 to CycH / EtOAc 10 / 90) to obtain the desired compound.

[0439] Analysis (Method A): R t : 0.36 minutes, [M+H] + :351 / 353(Br)

[0440] Step 2: Synthesis of (1R)-2-(4-bromo-2H-indazol-2-yl)-1-phenylethan-1-ol

[0441]

[0442] (1R)-2-{[(2-bromo-6-nitrophenyl)methyl]amino}-1-phenylethan-1-ol (5.44 g, 15.5 mmol) was suspended in MeOH (25 mL). Zinc (5.06 g, 77.45 mmol) was added and then ammonium formate (977 mg, 15.5 mmol) was added dropwise in MeOH (5 mL) over 5 minutes. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered, washed with MeOH and the filtrate was concentrated. The residue was wet-triturated with water. The precipitate was filtered and recrystallized from ACN to give the title compound.

[0443] Analysis (Method A): R t : 0.58 minutes, [M+H] + :317 / 319(Br)

[0444] Synthesis of intermediates A2 and A23:

[0445]

[0446] Step 1: Synthesis of 2-(4-bromo-2H-indazol-2-yl)-1-(4-hydroxyphenyl)ethan-1-one

[0447]

[0448] 2-Bromo-1-(4-hydroxyphenyl)ethyl-1-ketone (5.00 g, 25.4 mmol), 4-bromo-2H-indazole (5.46 g, 25.4 mmol) and aluminum powder (1.37 g, 50.8 mmol, -100+325 mesh) were added to DMF / water 3 / 1 (48 mL). The reaction mixture was stirred at room temperature for 5 days. The reaction mixture was filtered and the precipitate was washed with water. The precipitate was suspended in MeOH / DCM / DMF (100 mL / 50 mL / 100 mL) and aluminum was filtered off. The filtrate was concentrated and the residue was wet-triturated with n-heptane (100 mL) to obtain the desired product.

[0449] Analysis (Method D): R t : 0.31 min, [M+H] + :331 / 333(Br)

[0450] Step 2: Synthesis of 4-[(1R)-2-(4-bromo-2H-indazol-2-yl)-1-hydroxyethyl]phenol

[0451]

[0452] Under argon atmosphere, 2-(4-bromo-2H-indazole-2-yl)-1-(4-hydroxyphenyl)ethan-1-one (2.00 g, 5.13 mmol, 85% purity) was dissolved in THF (40 mL). At 0 ° C, formic acid triethylamine complex 5: 2 (10.73 mL, 25.67 mmol) was added dropwise. After stirring at 0 ° C for 5 minutes, chloro([(1S, 2S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amide)(mesitylene)ruthenium(II) (0.16 g, 0.26 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with acetone and water and concentrated. The residue was purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 95 / 5) to obtain the desired product A23.

[0453] Analysis (Method F): R t : 0.74 minutes, [M+H] + :333 / 335(Br)

[0454] Chiral analysis (method T): R t : 3.80 min, >98% ee

[0455] Step 3: Synthesis of (1R)-2-(4-bromo-2H-indazol-2-yl)-1-{4-[2-(morpholin-4-yl)ethoxy]phenyl}ethan-1-ol

[0456]

[0457] A mixture of 4-[(1R)-2-(4-bromo-2H-indazol-2-yl)-1-hydroxyethyl]phenol (250 mg, 0.75 mmol), 4-(2-chloroethyl)morpholine hydrochloride (279 mg, 1.50 mmol), DIPEA (260 μL, 1.50 mmol) and DMF (8 mL) was stirred at 75 ° C for 4 hours, then K2CO3 (104 mg, 0.75 mmol) and acetone (8 mL) were added, and the reaction mixture was stirred at 70 ° C overnight. K2CO3 was filtered off and the filtrate was concentrated. The residue was purified by reverse phase chromatography (HPLC; ACN / water including NH3) to give compound A2.

[0458] Analysis (Method H): R t : 0.97 minutes, [M+H] + :446 / 448(Br)

[0459] Synthesis of intermediate A3:

[0460] Step 1: Synthesis of 2-[(phenylsulfinyl)methyl]-4-bromo-2H-indazole

[0461]

[0462] 4-Bromo-1H-indazole (400 mg, 1.99 mmol) was dissolved in DMF (5 mL). K2CO3 (1.10 g, 7.96 mmol) and chloromethylphenyl sulfoxide (716 mg, 3.98 mmol) were added, and the reaction mixture was stirred at 50°C overnight. K2CO3 (1.10 g, 7.96 mmol) was added, and the reaction mixture was stirred at 70°C overnight. The reaction mixture was filtered, and the filtrate was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give Compound A3.

[0463] Analysis (Method G): R t : 0.90 min, [M+H] + :335 / 337(Br)

[0464] Synthesis of intermediates A4 and A14:

[0465]

[0466] Step 1: Synthesis of 1-bromo-2-(bromomethyl)-3-nitrobenzene:

[0467]

[0468] 2-bromo-6-nitrotoluene (50g, 231mmol) is dissolved in DCE (300mL). A suspension of NBS (61.8g, 347mmol) in DCE (400mL) is added at room temperature, and the reaction mixture is stirred under reflux. Then the AIBN (2.66g, 16.2mmol) (syringe pump, pump rate is about 1 drop per 6 seconds) in DCM (35mL) is slowly added, and the reaction mixture is stirred overnight under reflux. The reaction mixture is concentrated, and the residue is dissolved in DCM (500mL) and washed with water 3 times. The organic layer is dried with MgSO4 and the short plug of silica is filtered, and the silica is washed with DCM (50ml). The filtrate is concentrated, and it is dried in a high vacuum to obtain the desired product.

[0469] TLC: silica gel, CycH / EtOAc 5 / 1: R f : 0.4

[0470] Step 2: Synthesis of [(2-bromo-6-nitrophenyl)methyl][(trimethylsilyl)methyl]amine

[0471]

[0472] (Trimethylsilyl)methylamine (13mL, 97.1mmol) and DIPEA (34.00mL, 196.6mmol) were dissolved in ACN (200mL). A solution of 1-bromo-2-(bromomethyl)-3-nitrobenzene (20.00g, 67.14mmol) in ACN (200ml) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in DCM and washed 3 times with water. The organic layer was filtered through silica, the silica was washed with DCM and the filtrate was concentrated to give the desired product.

[0473] Analysis (Method G): R t : 0.75 min, [M+H] + :317 / 319(Br)

[0474] Step 3: Synthesis of 4-bromo-2-[(trimethylsilyl)methyl]-2H-indazole

[0475]

[0476] [(2-bromo-6-nitrophenyl)methyl][(trimethylsilyl)methyl]amine (18.64 g, 58.75 mmol) was dissolved in MeOH (1.6 L). Zinc (19.2 g, 294 mmol) was added and ammonium formate (5.55 g, 88.12 mmol) was slowly added dropwise at 50 °C over 7 hours in MeOH (38 mL). The reaction mixture was filtered through celite, washed with MeOH, and the filtrate was concentrated. The residue was purified by flash chromatography (CycH / EtOAc 88 / 12 to CycH / EtOAc 0 / 100) to give compound A14.

[0477] Analysis (Method G): R t : 1.18 minutes, [M+H] + :283 / 285(Br)

[0478] Step 4: Synthesis of 2-(4-bromo-2H-indazol-2-yl)-1-(4-methylphenyl)ethan-1-ol

[0479]

[0480] p-Tolualdehyde (103 μ L, 0.85 mmol) and CsF (107 mg, 0.71 mmol) are suspended in DMF (1.5 mL). A solution of 4-bromo-2-[(trimethylsilyl)methyl]-2H-indazole (200 mg, 0.71 mmol) in DCM (2.5 mL) is added dropwise to the reaction mixture at room temperature and stirred at room temperature for 2 hours. The reaction mixture is filtered, the filtrate is concentrated in vacuo, the filtrate is diluted with ACN and purified by reverse phase chromatography (HPLC; ACN / water / NH4OH) to obtain the desired product.

[0481] Analysis (Method H): R t : 0.94 minutes, [M+H] + :331 / 333(Br)

[0482] Synthesis of Intermediate A5: (1R)-2-[4-(5,5-dimethyl-1,3,2-dioxaborol-2-yl)-5-fluoro-2H-indazol-2-yl]-1-phenylethan-1-ol

[0483] (1R)-2-(4-Bromo-5-fluoro-2H-indazol-2-yl]-1-phenylethan-1-ol

[0484]

[0485] Step 1: Synthesis of 2-(4-bromo-5-fluoro-2H-indazol-2-yl)-1-phenylethan-1-one

[0486]

[0487] 4-Bromo-5-fluoro-1H-indazole (800 mg, 3.72 mmol) and 2-chloro-1-phenylethan-1-one (1.15 g, 7.44 mmol) were combined in a microwave tube and the reaction mixture was stirred in the microwave for 45 minutes at 130° C. The reaction mixture was purified by reverse phase chromatography (HPLC; ACN / water / TFA) to give the desired compound.

[0488] Analysis (Method A): R t : 0.62 minutes, [M+H] + :333 / 335(Br)

[0489] Step 2: Synthesis of (1R)-2-(4-bromo-5-fluoro-2H-indazol-2-yl)-1-phenylethan-1-ol

[0490]

[0491] 2-(4-bromo-5-fluoro-2H-indazol-2-yl)-1-phenylethan-1-one (660 mg, 1.98 mmol) was dissolved in THF (10 mL). Triethylamine formate complex 5:2 (4.14 mL, 9.91 mmol) was added dropwise at 0 ° C. Chloro([(1S, 2S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amide)(mesitylene)ruthenium(II) (61.6 mg, 0.10 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water, THF was evaporated, and the residue was purified by reverse phase chromatography (HPLC; ACN / water including TFA). The freeze-dried fraction was recrystallized with ACN / MeOH to obtain the desired compound A5.

[0492] Analysis (Method A): R t : 0.62 minutes, [M+H] + :335 / 337(Br)

[0493] Chiral analysis (method ZD): R t : 2.57 min, >98% ee

[0494] Synthesis of intermediate A6:

[0495] Synthesis of ethyl 2-[(1R)-2-(4-bromo-2H-indazol-2-yl)-1-phenylethoxy]acetate

[0496]

[0497] Under argon atmosphere, (1R)-2-(4-bromo-2H-indazol-2-yl)-1-phenylethan-1-ol (5 g, 15.8 mmol) was dissolved in DCM (140 mL). Rhodium (II) acetate dimer (125 mg, 0.28 mmol) was added, and ethyl diazoacetate (16.6 mL, 158 mmol) in DCM (8 mL) was added dropwise at room temperature for 24 hours. The reaction mixture was filtered, and the filtrate was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give the desired compound A6.

[0498] Analysis (Method F): R t : 1.05 minutes, [M+H] + :403 / 405(Br)

[0499] Synthesis of intermediate A7:

[0500] Step 1: Synthesis of 2-(4-bromo-2H-indazol-2-yl)-1-(3,4-difluorophenyl)ethan-1-ol

[0501]

[0502] 3,4-difluorobenzaldehyde (351 mg, 2.47 mmol), CsF (268 mg, 1.8 mmol) and 4-bromo-2-[(trimethylsilyl))methyl]-2H-indazole (A14, 500 mg, 1.76 mmol) were suspended in DMF (6 mL) and stirred at room temperature for 2 hours. The reaction mixture was diluted with HOAc and DMF and purified by reverse phase chromatography (HPLC; ACN / water including NH3) to give the desired compound A7.

[0503] Analysis (Method G): R t : 0.91 min, [M+H] + :353 / 355(Br)

[0504] Synthesis of intermediate A8:

[0505] Step 1: Synthesis of 2-(4-bromo-2H-indazol-2-yl)-1-phenylethan-1-one

[0506]

[0507] 4-Bromo-2H-indazole (2g, 10.2mmol), 2-bromo-1-phenylethan-1-one (4.04g, 20.3mmol) and aluminum powder (548mg, 20.3mmol; -100+325 mesh) were dissolved in DMF / water 3 / 1 (20mL). The reaction mixture was stirred at 80°C overnight. The aluminum was filtered out and washed with DMF. The filtrate was diluted with water and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was first wet-triturated with water and then with MeOH. The precipitate was filtered to obtain the desired compound.

[0508] Analysis (Method A): R t : 0.60 min, [M+H] + :315 / 317(Br)

[0509] Step 2: Synthesis of 4-bromo-2-(2,2-difluoro-2-phenylethyl)-2H-indazole

[0510]

[0511] 2-(4-bromo-2H-indazole-2-yl)-1-phenylethyl-1-ketone (1.08g, 3.41mmol) is dissolved in toluene (6mL) and DCM (6mL). DAST (3.93mL, 30mmol) is added dropwise at 0°C, and the reaction mixture is stirred at room temperature for 4 days. The reaction mixture is quenched with NaHCO3 saturated solution and extracted with DCM. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is purified by flash chromatography (CycH / EtOAc 70 / 30) to obtain the required compound A8.

[0512] Analysis (Method A): R t : 0.68 min, [M+H] + :337 / 339(Br)

[0513] Synthesis of intermediates A9 to A12:

[0514]

[0515] Step 1-2: Synthesized by following a similar procedure as described for Intermediate A1 using racemic 2-amino-1-phenylethan-1-ol as starting material.

[0516] Step 3: Synthesis of 4-bromo-2-(2-fluoro-2-phenylethyl)-2H-indazole

[0517]

[0518] 2-(4-bromo-2H-indazol-2-yl)-1-phenylethan-1-ol (A10, 6.10 g, 17.3 mmol) was dissolved in DCM (45 mL) and [bis(2-methoxyethyl)amino]sulfur trifluoride (9.70 mL, 26.3 mmol, 50% in toluene) was added dropwise. The reaction mixture was stirred at room temperature for 4 days. The reaction mixture was quenched with a saturated solution of NaHCO3 and extracted with DCM. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by reverse phase chromatography (HPLC; ACN / water / formic acid) to give the desired product A11.

[0519] Analysis (Method G): R t : 1.12 minutes, [M+H] + :319 / 321(Br)

[0520]

[0521] 4-Bromo-2-(2-fluoro-2-phenylethyl)-2H-indazole (455 mg) was isolated by chiral purification method ZC to give compound 4-bromo-2-[(2R)-2-fluoro-2-phenylethyl]-2H-indazole A9 (--. (Method ZC): R t : 4.52 min) and 4-bromo-2-[(2S)-2-fluoro-2-phenylethyl]-2H-indazole A12-(Analysis: (Method ZC): R t : 3.14 minutes).

[0522] Synthesis of intermediate A13:

[0523]

[0524] Step 1: tert-Butyl N-(2-{4-[2-(dimethylamino)ethoxy]phenyl}ethyl)carbamate

[0525]

[0526] N-[2-(4-hydroxyphenyl)ethyl]t-butyl carbamate (7.10g, 30mmol) is dissolved in acetone (70mL).(2-chloroethyl)dimethylamine hydrochloride (5.50g, 38.2mmol) and CsCO (20.00g, 61.4mmol) are added, and the reaction mixture is stirred at 75°C overnight.The reaction mixture is filtered and the filtrate is concentrated.The residue is purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 85 / 15) to obtain the desired product.

[0527] Analysis (Method H): R t : 1.01 min, [M+H]+ :309

[0528] Step 2: Synthesis of 2-{4-[2-(dimethylamino)ethoxy]phenyl}ethan-1-amine hydrochloride

[0529]

[0530] Tert-butyl N-(2-{4-[2-(dimethylamino)ethoxy]phenyl}ethyl)carbamate (6.30 g, 20.4 mmol) was dissolved in dioxane (5 mL). 4M HCl in dioxane (24 mL, 96 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the desired product.

[0531] Analysis (Method G): R t : 0.76 minutes, [M+H] + :209

[0532] Step 3: Synthesis of [(2-bromo-6-nitrophenyl)methyl](2-{4-[2-(dimethylamino)ethoxy]phenyl}ethyl)amine

[0533]

[0534] 1-Bromo-2-(bromomethyl)-3-nitrobenzene (900 mg, 3.05 mmol) and 2-{4-[2-(dimethylamino)ethoxy]phenyl}ethyl-1-amine hydrochloride (800 mg, 3.27 mmol) were dissolved in ACN (10 mL). DIPEA (3.50 mL, 20.3 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 65 / 35) to give the desired product.

[0535] Analysis (Method G): R t : 0.63 min, [M+H] + :422 / 424(Br)

[0536] Step 4: Synthesis of (2-{4-[2-(4-bromo-2H-indazol-2-yl)ethyl]phenoxy}ethyl)dimethylamine

[0537]

[0538] [(2-bromo-6-nitrophenyl)methyl](2-{4-[2-(dimethylamine)ethoxy]phenyl}ethyl)amine (1.20 g, 2.56 mmol) was suspended in MeOH. Zinc (836 mg, 12.8 mmol) and ammonium formate (110 mg, 1.74 mmol) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, washed with MeOH and the filtrate was concentrated. The residue was purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 72 / 28) to give intermediate A13.

[0539] Analysis (Method G): R t : 0.83 min, [M+H] + :388 / 390(Br)

[0540] Synthesis of intermediates A15 to A18:

[0541]

[0542] A15 was synthesized by following a similar procedure as described for intermediate A4 (step 4) using A13 and 4-chlorobenzaldehyde as starting materials.

[0543] Step 1: Synthesis of 4-bromo-2-[2-(4-chlorophenyl)-2-fluoroethyl]-2H-indazole:

[0544]

[0545] 2-(4-bromo-2H-indazole-2-yl)-1-(4-chlorophenyl)ethan-1-ol (1.23 g, 3.50 mmol) was dissolved in DCM (20 mL). [Bis(2-methoxyethyl)amino]sulfur trifluoride (2.28 mL, 5.25 mmol, 50% in THF) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was quenched and basified with 2M Na2CO3 solution and extracted with DCM. The organic layer was washed with a saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give the desired product.

[0546] Analysis (Method F): R t : 1.10 minutes, [M+H] + :353 / 355(Br)

[0547]

[0548] Step 2: Synthesis of 4-bromo-2-[(2R)-2-(4-chlorophenyl)-2-fluoroethyl]-2H-indazole

[0549] 4-Bromo-2-[2-(4-chlorophenyl)-2-fluoroethyl]-2H-indazole (750 mg, 2.12 mmol) was isolated by chiral purification method ZB to give compound 4-bromo-2-[(2R)-2-(4-chlorophenyl)-2-fluoroethyl]-2H-indazole A17 ((Analytical method ZB): R t : 0.95 min) and 4-bromo-2-[(2S)-2-(4-chlorophenyl)-2-fluoroethyl]-2H-indazole A18 ((Analysis: (Method ZB): R t : 0.79 minutes).

[0550] Synthesis of intermediate A19:

[0551] Step 1: Synthesis of 2-(4-bromo-2H-indazol-2-yl)-1-cyclohexylethan-1-one

[0552]

[0553] 4-Bromo-1H-indazole (500 mg, 2.54 mmol) was dissolved in ACN (8 mL). KCO (877 mg, 6.34 mmol) and 2-bromo-1-cyclohexylethyl-1-one (521 mg, 2.54 mmol) were added and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was purified by reverse phase chromatography (HPLC; ACN / water including NH ) to give the desired product.

[0554] Analysis (Method G): R t : 1.13 minutes, [M+H] + :321 / 323(Br)

[0555] Step 2: Synthesis of 2-(4-bromo-2H-indazol-2-yl)-1-cyclohexylethanol-1-ol

[0556]

[0557] 2-(4-bromo-2H-indazole-2-yl)-1-cyclohexyl ethyl-1-ketone (200mg, 0.62mmol) is dissolved in THF (3mL) and MeOH (3mL). Sodium borohydride (23.6mg, 0.62mmol) is added at 0°C, and the reaction mixture is stirred at 0°C for 2 hours. The reaction mixture is quenched with 1MHCl, and stirred at room temperature for 15 minutes. The reaction mixture is then alkalized with NaHCO3 saturated solution and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated to obtain the desired product A19.

[0558] Analysis (Method G): R t: 1.13 minutes, [M+H] + :323 / 325(Br)

[0559] Synthesis of intermediate A20:

[0560] Step 1: Synthesis of 1-[4-(benzyloxy)phenyl]-2-(4-bromo-2H-indazol-2-yl)ethan-1-one

[0561]

[0562] 4-Bromo-1H-indazole (3.5 g, 17.8 mmol) and 1-[4-(benzyloxy)phenyl]-2-chloroeth-1-one (5.7 g, 19.7 mmol) were heated to 135°C and the molten mixture was stirred for 2 hours. After cooling, the mixture was triturated with ACN, the solid formed was collected and extracted between DCM and aqueous Na2CO3. The organic phase was concentrated and triturated in a mixture of ACN / EtOAc 2:1 to give the desired product.

[0563] Analysis (Method A): R t : 0.78 minutes, [M+H] + :421 / 435(Br)

[0564] Step 2: Synthesis of (1R)-1-[4-(benzyloxy)phenyl]-2-(4-bromo-2H-indazol-2-yl)ethan-1-ol

[0565]

[0566] 1-[4-(Benzyloxy)phenyl]-2-(4-bromo-2H-indazol-2-yl)ethan-1-one (2.05 g, 4.86 mmol) was dissolved in THF (100 mL), triethylamine formate complex 5:2 (10, 15 mL) and chloro([(1S,2S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido)(mesitylene)ruthenium(II) (181 mg) were added, and the mixture was stirred at room temperature overnight. The mixture was concentrated and extracted with DCM / Na2CO3 aqueous solution. The organic phase was concentrated to give the desired product A20.

[0567] Analysis (Method A): R t : 0.75 min, [M+H] + :423 / 425(Br)

[0568] Chiral HPLC (Method V): >98% ee

[0569] Synthesis of intermediate A21:

[0570] Synthesis of 2-(4-bromo-2H-indazol-2-yl)-1-(2-methylpyridin-4-yl)ethan-1-ol

[0571]

[0572] 4-Bromo-2-[(trimethylsilyl)methyl]-2H-indazole (500 mg, 1.76 mmol) and 1-methyl-1H-pyrazole-4-carboxaldehyde (231 mg, 2.1 mmol) were dissolved in 4 mL DMF, CsF (227 mg, 1.5 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The mixture was then diluted with HOAc and DMF and purified by preparative reverse phase HPLC (Sunfire C18, ACN / water including formic acid) to give the desired product A21.

[0573] Analysis (Method G): R t : 0.84 min, [M+H] + :321 / 323(Br)

[0574] Synthesis of intermediate A22:

[0575] Synthesis of 2-(4-bromo-2H-indazol-2-yl)-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-ol

[0576]

[0577] 4-Bromo-2-[(trimethylsilyl)methyl]-2H-indazole (500 mg, 1.76 mmol) and 2-methylpyridine-4-carboxaldehyde (290 mg, 2.39 mmol) were dissolved in 1.8 mL DMF, CsF (286 mg, 1.765 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was then diluted with HOAc and DMF and purified by preparative reverse phase HPLC (Sunfire C18, ACN / water including formic acid) to give the desired product A22.

[0578] Analysis (Method G): R t : 0.72 minutes, [M+H] + :332 / 334(Br)

[0579] Synthesis of intermediate A24

[0580] Step 1: (1R)-2-{[(2-bromo-6-nitrophenyl)methyl]amino}-1-(4-fluorophenyl)ethan-1-ol

[0581]

[0582] (1R)-2-amino-1-(4-fluorophenyl)ethan-1-ol hydrochloride (292 mg, 1.08 mmol) was dissolved in ACN (5 mL) and DIPEA (0.525 mL, 3.05 mmol). 1-bromo-2-(bromomethyl)-3-nitrobenzene (300 mg, 1.02 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by reverse phase chromatography to obtain the desired product.

[0583] Analysis (Method G): R t : 0.73 minutes, [M+H] + :369 / 371(Br)

[0584] Step 2: Synthesis of (1R)-2-(4-bromo-2H-indazol-2-yl)-1-(4-fluorophenyl)ethan-1-ol

[0585] (1R)-2-{[(2-bromo-6-nitrophenyl)methyl]amino}-1-(4-fluorophenyl)ethan-1-ol (338 mg, 0.96 mmol) was suspended in MeOH (5 mL). Zinc (300 mg, 4.6 mmol) was added and then ammonium formate (57.7 mg, 0.92 mmol) was added dropwise in MeOH (3 mL). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was filtered through celite, washed with MeOH and the filtrate was concentrated. The residue was dissolved in DMF and purified by preparative reverse phase HPLC to give the desired product A24.

[0586] Analysis (Method G): R t : 1.022 minutes, [M+H] + :335 / 337(Br)

[0587] Synthesis of intermediate A25

[0588] Step 1: Synthesis of 2-(4-bromo-2H-indazol-2-yl)-1-{4-[2-(dimethylamino)ethoxy]phenyl}ethan-1-one

[0589]

[0590] 2-Chloro-1-{4-[2-(dimethylamino)ethoxy]phenyl}ethan-1-one trifluoromethanesulfonate (1.5 g, 3.75 mmol) and 4-bromo-1H-indazole (0.739 g, 3.75 mmol) were heated at 140° C. for 90 minutes. After cooling, the mixture was purified by preparative reverse phase HPLC (Sunfire C18, ACN / water including TFA) to give the desired product.

[0591] Analysis (Method B): R t : 0.60 min, [M+H] + :402 / 404(Br)

[0592] Step 2: Synthesis of (1R)-2-(4-bromo-2H-indazol-2-yl)-1-{4-[2-(dimethylamino)ethoxy]phenyl}ethan-1-ol

[0593]

[0594] 2-(4-Bromo-2H-indazol-2-yl)-1-{4-[2-(dimethylamino)ethoxy]phenyl}ethan-1-one (0.85 g, 1.65 mmol, as triflate) was dissolved in THF (20 mL) and cooled in a water / ice bath. Triethylamine formate complex 5:2 (3.44 mL, 8.32 mmol) was added over 5 minutes. Then, after 5 minutes, ruthenium(II) chloride ([(1S,2S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido)(mesitylene) (51 mg, 0.082 mmol) was added and the mixture was stirred at room temperature for 3.5 hours. Then, 60 mL of MeTHF and 5 mL of 2M aqueous Na2CO3 were added, and the organic phase was separated and dried over Na2SO4 to give the desired product A25.

[0595] Analysis (Method C): R t : 0.61 min, [M+H] + :404 / 406(Br)

[0596] Synthesis of intermediates B1-B20

[0597] Synthesis of (1R)-1-phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethan-1-ol (B1)

[0598]

[0599] (1R)-2-(4-bromo-2H-indazole-2-yl)-1-phenylethan-1-ol (A1, 10 g, 31.5 mmol) was dissolved in dioxane (200 ml). Bis(pinacol)diboron (9.61 g, 37.8 mmol), potassium acetate (8.03 g, 82 mmol) and Pd(dppf)Cl2×DCM (2.00 g, 2.45 mmol) were added at room temperature, and the reaction mixture was stirred at 80°C overnight. After the reaction mixture was cooled to room temperature, the formed precipitate was filtered and washed with 3×20 mL dioxane. The filtrate was concentrated, and the residue was suspended in CycH and wet-milled in CycH overnight. The precipitate was filtered, washed with 2×20 mL CycH, and dried in an oven at 50°C overnight to obtain the desired product B1.

[0600] Analysis (Method G): R t : 1.12 minutes, [M+H] + :365

[0601] Synthesis of (1R)-2-[4-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol (B2) and {2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}boronic acid (B3)

[0602]

[0603] (1R)-2-(4-bromo-2H-indazole-2-yl)-1-phenylethan-1-ol (7.50 g, 23.7 mmol) was dissolved in dioxane (60 mL). Bis(neopentyl glycolyl)diboron (8.01 g, 35.5 mmol), potassium acetate (7.00 g, 71.3 mmol) were added, and the mixture was purged with nitrogen. Pd(dppf)Cl2 x DCM (0.71 g, 0.87 mmol) was added, and the reaction mixture was stirred at 85 ° C for 4.5 hours. After the reaction mixture was cooled to room temperature, it was filtered through diatomaceous earth and thiol resin (Thiol-Resin), and the filtrate was concentrated. The residue was diluted with DCM, and the organic phase was washed twice with water and brine. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was wet-ground with ether, the formed precipitate was filtered and dried overnight in an oven at 50 ° C to obtain compound B2.

[0604] Analysis (Method G): R t : 0.77 minutes, [M+H] + :351

[0605] The filtrate was concentrated and the residue was purified by reverse phase chromatography (HPLC; Sunfire, ACN / water including TFA) to give Compound B3.

[0606] Analysis (Method G): R t : 0.66 min, [M+H] + :283

[0607] Synthesis of ({2-[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]-2H-indazol-4-yl}boronic acid (B4)

[0608]

[0609] (1R)-2-(4-bromo-2H-indazol-2-yl)-1-(4-fluorophenyl)ethan-1-ol (50 mg, 0.149 mmol), KOAc (38 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (12.2 mg) and 2-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane (37 mg) were suspended in 1 mL of dioxane and heated at 100° C. for 2 hours. The mixture was filtered and then purified by reverse phase preparative HPLC to give the desired product B4.

[0610] Analysis (Method G): R t : 0.78 minutes, [M+H] + :301

[0611] Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(trimethylsilyl)methyl]-2H-indazole (B5)

[0612]

[0613] (1R)-2-(4-bromo-2H-indazol-2-yl)-1-(4-difluorophenyl)ethan-1-ol (1.5 g, 5.3 mmol), KOAc (1.6 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (460 mg) and 2-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-5,5-dimethyl-1,3,2-dioxaborolan (2.9 g) were suspended in 12 mL of dioxane and heated at 90°C overnight. The mixture was filtered through celite and charcoal and washed with dioxane. The organic phase was concentrated and purified by silica gel chromatography CycH / EtOAc to give the desired product B5.

[0614] Analysis (Method G): R t : 1.23 minutes, [M+H] + :331

[0615] Synthesis of (1R)-1-{4-[2-(morpholin-4-yl)ethoxy]phenyl}-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethan-1-ol (B6)

[0616]

[0617] Under argon atmosphere, (1R)-2-(4-bromo-2H-indazol-2-yl)-1-{4-[2-(morpholin-4-yl)ethoxy]phenyl}ethan-1-ol (89.3 mg, 0.20 mmol) was dissolved in dioxane (4 mL). Bis(pinacolato)diboron (50.8 mg, 0.20 mmol), potassium acetate (51 mg, 0.52 mmol) and Pd(dppf)Cl2 x DCM (16.3 mg, 0.02 mmol) were added and the reaction mixture was stirred at 95° C. for 2 hours. The formed precipitate was filtered off, washed with dioxane and the filtrate was concentrated to give the desired product B6.

[0618] Analysis (Method G): R t : 0.87 minutes, [M+H] + :494

[0619] Synthesis of (1R)-1-[4-(Benzyloxy)phenyl]-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethan-1-ol (B7)

[0620]

[0621] Under argon atmosphere, (1R)-1-[4-(benzyloxy)phenyl]-2-(4-bromo-2H-indazole-2-yl)ethan-1-ol (400mg, 0.95mmol) was dissolved in dioxane (10mL). Bis(pinacolato)diboron (480mg, 1.89mmol), potassium acetate (278mg, 2.8mmol) and Pd(dppf)Cl2 x DCM (77mg) were added, and the reaction mixture was stirred at 90°C for 17 hours. The mixture was diluted with methanol and filtered through cellulose. The concentrated filtrate was purified by MPLC using CycH / EtOAc as eluent to obtain the desired product B7.

[0622] Analysis (Method A): R t : 0.79 minutes, [M+H]+ :471

[0623] Synthesis of 2-[(phenylsulfinyl)methyl]-4-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-2H-indazole (B8)

[0624]

[0625] Under argon atmosphere, 2-[(phenylsulfinyl)methyl]-4-bromo-2H-indazole (150 mg, 0.45 mmol) was dissolved in dioxane (2.5 mL). Bis(neopentylglycol)diboron (152 mg, 0.67 mmol), potassium acetate (131.8 mg, 1.34 mmol) and Pd(dppf)Cl2 x DCM (97 mg, 0.12 mmol) were added and the reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to give the desired product B8, which was used in the next step without purification.

[0626] Analysis (Method G): R t : 0.68 min, [M+H] + :301(the mass of the corresponding borous acid)

[0627] Synthesis of 2-[4-(5,5-dimethyl-1,3,2-dioxaborol-2-yl)-2H-indazol-2-yl]-1-(4-methylphenyl)ethan-1-ol (B9)

[0628]

[0629] Under argon atmosphere, 2-(4-bromo-2H-indazol-2-yl)-1-(4-methylphenyl)ethan-1-ol (120 mg, 0.36 mmol) was dissolved in dioxane (2.5 mL). Bis(neopentylglycol)diboron (123 mg, 0.54 mmol), potassium acetate (107 mg, 1.09 mmol) and Pd(dppf)Cl2 x DCM (78.4 mg, 0.096 mmol) were added and the reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to give the desired product, which was used in the next step without purification.

[0630] Analysis (Method G): R t : 0.75 min, [M+H] + :297(the mass of the corresponding borous acid)

[0631] Synthesis of {2-[2-hydroxy-2-(2-methylpyridin-4-yl)ethyl]-2H-indazol-4-yl}boronic acid (B10)

[0632]

[0633] Under argon atmosphere, 2-(4-bromo-2H-indazol-2-yl)-1-(2-methylpyridin-4-yl)ethan-1-ol (A21, 221 mg, 0.665 mmol) was dissolved in dioxane (3 mL). Bis(neopentyl glycolyl)diboron (180 mg, 0.796 mmol), potassium acetate (196 mg, 2 mmol) and Pd(dppf)Cl2 x DCM (54 mg) were added and the reaction mixture was stirred at 90° C. for 3 hours. The reaction mixture was filtered, diluted with HOAc, and purified by reverse phase preparative HPLC to give the desired product B10.

[0634] Analysis (Method G): R t : 0.75 min, [M+H] + :298

[0635] Synthesis of 1-(1-methyl-1H-pyrazol-4-yl)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethan-1-ol (B11)

[0636]

[0637] Under argon atmosphere, 2-(4-bromo-2H-indazol-2-yl)-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-ol (A1, 118 mg, 0.367 mmol) was dissolved in dioxane (2.5 mL). Bis(pinacolato)diboron (373 mg, 1.47 mmol), potassium acetate (108 mg, 1 mmol) and Pd(dppf)Cl2 x DCM (30 mg) were added and the reaction mixture was stirred at 90° C. for 4 hours. The reaction mixture was filtered, then concentrated and purified by MPLC (silica, DCM / MeOH) to give the desired product B11.

[0638] Analysis (Method G): R t : 0.94 minutes, [M+H] + :369

[0639] Synthesis of (1R)-2-[4-(5,5-dimethyl-1,3,2-dioxaborol-2-yl)-5-fluoro-2H-indazol-2-yl]-1-phenylethan-1-ol (B12)

[0640]

[0641] Under argon atmosphere, (1R)-2-(4-bromo-5-fluoro-2H-indazole-2-yl)-1-phenylethan-1-ol (A5, 608mg, 1.81mmol) is dissolved in dioxane (8mL). Bis(neopentyl glycolyl)diboron (1.23g, 5.44mmol), potassium acetate (890mg, 9.07mmol) and Pd(dppf)Cl2 x DCM (74mg, 0.09mmol) are added, and the reaction mixture is stirred at 80°C for 3 hours and stirred at room temperature overnight. After the reaction mixture is cooled to room temperature, it is filtered through a thiol resin, and the filtrate is concentrated. The residue is diluted with water and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is crystallized with cold MeOH to obtain product B12.

[0642] Analysis (Method A): R t : 0.39 min, [M+H] + :301(the mass of the corresponding borous acid)

[0643] Synthesis of {2-[(2R)-2-(2-ethoxy-2-oxoethoxy)-2-phenylethyl]-2H-indazol-4-yl}boronic acid (B13)

[0644]

[0645] Under argon atmosphere, ethyl 2-[(1R)-2-(4-bromo-2H-indazol-2-yl)-1-phenylethoxy]acetate (A6, 1.93 g, 4.79 mmol) was dissolved in dioxane (25 mL). Bis(neopentyl glycolyl)diboron (1.19 g, 5.26 mmol), potassium acetate (1.64 g, 16.8 mmol) and Pd(dppf)Cl2 x DCM (0.30 g, 0.37 mmol) were added and the reaction mixture was stirred at 90 °C for 1.5 hours. The reaction mixture was diluted with DCM and filtered. The filtrate was concentrated and the residue was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give the desired product B13.

[0646] Analysis (Method F): R t : 0.72 minutes, [M+H] + :369

[0647] Synthesis of 4-[(1R)-1-hydroxy-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethyl]phenol (B14)

[0648]

[0649] Under argon atmosphere, 4-[(1R)-2-(4-bromo-2H-indazol-2-yl)-1-hydroxyethyl]phenol (A23, 1.45 g, 4.35 mmol) was dissolved in dioxane (40 mL). Bis(pinacol)diborane (1.11 g, 4.35 mmol), potassium acetate (1.28 g, 13.1 mmol) and Pd(dppf)Cl2 x DCM (355 mg, 0.44 mmol) were added and the reaction mixture was stirred at 90 °C for 2 hours. The reaction mixture was diluted with EtOAc and water, MetS-thiol scavenger resin (for catalyst removal) and activated carbon were added and the reaction mixture was stirred for 5 minutes. It was then filtered, washed and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was triturated with EtOAc / CycH 1 / 1. The precipitate was filtered, washed with EtOAc / CycH 1 / 1 and dried to give 840 mg of product. The filtrate was purified by flash chromatography (CycH / EtOAc 75 / 25 to CycH / EtOAc 25 / 75) to give product B14.

[0650] Analysis (Method A): R t : 0.56 minutes, [M+H] + :381

[0651] Synthesis of {2-[2-(3,4-difluorophenyl)-2-hydroxyethyl]-2H-indazol-4-yl}boronic acid (B15)

[0652]

[0653] (1R)-2-(4-bromo-2H-indazol-2-yl)-1-(3,4-difluorophenyl)ethan-1-ol (A7, 1300 mg, 0.37 mmol), bis(neopentyl glycolyl)diboron (116 mg, 0.51 mmol), potassium acetate (113 mg, 1.15 mmol) and Pd(dppf)Cl2 x DCM (40 mg, 0.05 mmol) were dissolved in dioxane (4 mL), and the reaction mixture was stirred overnight at 85° C. The reaction mixture was filtered and purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give the desired product B15.

[0654] Analysis (Method G): R t : 0.81 min, [M+H] + :319

[0655] Synthesis of [2-(2,2-difluoro-2-phenylethyl)-2H-indazol-4-yl]boronic acid (B16)

[0656]

[0657] Under argon atmosphere, 4-bromo-2-(2,2-difluoro-2-phenylethyl)-2H-indazole (A8, 677 mg, 2.01 mmol), bis(neopentyl glycolyl)diboron (1.36 g, 6.02 mmol), potassium acetate (985 mg, 10 mmol) and Pd(dppf)Cl2 x DCM (82 mg, 0.10 mmol) were dissolved in dioxane (9 mL) and the reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was filtered through a thiol scavenger resin with ACN and the filtrate was evaporated. The residue was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give the desired product B16.

[0658] Analysis (Method A): R t : 0.46 minutes, [M+H] + :303

[0659] Synthesis of 4-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-2-[(2R)-2-fluoro-2-phenylethyl]-2H-indazole (B17)

[0660]

[0661] Under argon atmosphere, 4-bromo-2-[(2R)-2-fluoro-2-phenylethyl]-2H-indazole (100 mg, 0.31 mmol), bis(neopentyl glycolyl)diboron (77.9 mg, 0.345 mmol), potassium acetate (92.3 mg, 0.940 mmol) and Pd(dppf)Cl2 xDCM (29.9 mg, 0.037 mmol) were dissolved in dioxane (2 mL), and the reaction mixture was stirred at 90 ° C for 3 hours. The reaction mixture was diluted with DCM and brine and extracted. The organic layer was dried (Na2SO4), filtered and concentrated to give the desired product B17, which was used in the next step without further purification.

[0662] Analysis (Method F): R t : 0.67 min, [M+H] + :285(the mass of the corresponding borous acid)

[0663] Synthesis of [2-(2-{4-[2-(dimethylamino)ethoxy]phenyl}ethyl)-2H-indazol-4-yl]boronic acid (B18)

[0664]

[0665] (2-{4-[2-(4-bromo-2H-indazol-2-yl)ethyl]phenoxy}ethyl)dimethylamine (A13, 1.00 g, 2.32 mmol) was dissolved in dioxane (7 mL). Bis(neopentyl glycolyl)diboron (628 mg, 2.78 mmol), potassium acetate (683 mg, 6.95 mmol) and Pd(dppf)Cl2 x DCM (151 mg, 0.19 mmol) were added and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was filtered and the residue was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give the title compound B18.

[0666] Analysis (Method G): R t : 0.67 min, [M+H] + :354

[0667] Synthesis of {2-[(2R)-2-(4-chlorophenyl)-2-fluoroethyl]-2H-indazol-4-yl}boronic acid (B19)

[0668]

[0669] 4-Bromo-2-[(2R)-2-(4-chlorophenyl)-2-fluoroethyl]-2H-indazole (A17, 340 mg, 0.96 mmol) was dissolved in dioxane (10 mL) under argon atmosphere. Bis(neopentylglycol)diboron (239 mg, 1.06 mmol), potassium acetate (245 mg, 2.5 mmol) and Pd(dppf)Cl2 x DCM (78.5 mg, 0.096 mmol) were added and the reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was filtered through a thiol scavenger resin and the residue was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give the title compound B19.

[0670] Analysis (Method F): R t : 0.78 minutes, [M+H] + :319

[0671] Synthesis of 1-cyclohexyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethan-1-ol (B20)

[0672]

[0673] Under argon atmosphere, 2-(4-bromo-2H-indazole-2-yl)-1-cyclohexyl eth-1-ol (A19, 133mg, 0.41mmol) and bis(neopentyl glycol) diboron (125.4mg, 0.49mmol) are dissolved in dioxane (1.5mL).Potassium acetate (121.2,1.23mmol) and Pd(dppf)Cl2x DCM (33.6mg, 0.04mmol) are added, and the reaction mixture is stirred at 85°C overnight.The reaction mixture is concentrated and purified by flash chromatography (CycH / EtOAc 100 / 0 to CycH / EtOAc50 / 50) to obtain title compound B20.

[0674] Analysis (Method G): R t : 1.19 minutes, [M+H] + :371

[0675] Synthesis of {2-[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]-2H-indazol-4-yl}boronic acid (B21)

[0676]

[0677] Under argon atmosphere, (1R)-2-(4-bromo-2H-indazol-2-yl)-1-(4-fluorophenyl)ethan-1-ol (A24, 100 mg, 0.298 mmol) and bis(neopentyl glycolyl)diboron (74 mg, 0.33 mmol) were dissolved in dioxane (2 mL). Potassium acetate (76 mg, 1 mmol) and Pd(dppf)Cl2 x DCM (25 mg) were added, and the reaction mixture was stirred at 95° C. overnight. The reaction mixture was filtered, diluted with HOAc and purified by preparative reverse phase HPLC to give the product B21.

[0678] Analysis (Method G): R t : 0.77 minutes, [M+H] + :301

[0679] Synthesis of {2-[(2R)-2-{4-[2-(dimethylamino)ethoxy]phenyl}-2-hydroxyethyl]-2H-indazol-4-yl}boronic acid (B22)

[0680]

[0681] Under argon atmosphere, (1R)-2-(4-bromo-2H-indazol-2-yl)-1-{4-[2-(dimethylamino)ethoxy]phenyl}ethan-1-ol (A25, 80 mg, 0.196 mmol) and bis(neopentyl glycolyl)diboron (49 mg, 0.22 mmol) were dissolved in dioxane (1.5 mL). Potassium acetate (68 mg, 0.7 mmol) and Pd(dppf)Cl2 x DCM (16 mg) were added, and the reaction mixture was stirred at 90° C. for 2 hours. The reaction mixture was diluted with DCM and filtered through celite, then purified by preparative reverse phase HPLC (sunfire C18, ACN / water including TFA) to give the desired product B22.

[0682] Analysis (Method A): R t : 0.28 min, [M+H] + :370

[0683] Synthesis of Intermediate C

[0684] Synthesis of intermediate C1:

[0685] Step 1: Synthesis of 2-acetyl-3-methylbutyronitrile

[0686]

[0687] A solution of diisopropylamine (177mL, 1.25mol) in T (1.17L) was cooled to -78°C. 2.5M n-butyllithium (469mL, 1.17mol) in hexane was added, and the reaction mixture was warmed to 0°C and stirred at 0°C for 1 hour. The reaction mixture was cooled to -78°C, and 3-methyl-butyronitrile (81.8mL, 0.782mol) in 80mL THF was added dropwise while maintaining the temperature below -65°C. The reaction mixture was stirred at 78°C for 1 hour. Thereafter, a solution of acetic anhydride (88.7mL, 0.938mol) in 80mL THF was added dropwise over 30 minutes. The reaction mixture was warmed to 0°C and kept for 1 hour, then warmed to 15°C and kept for 0.5 hour. The reaction mixture was quenched with citric acid (10%, 200mL) and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated to give the desired product which was used in the next step without further purification.

[0688] Analysis (TLC): R f : 0.3 (20% EtOAc / petroleum ether)

[0689] Step 2: Synthesis of 5-methyl-4-(propan-2-yl)-1H-pyrazol-3-amine

[0690]

[0691] 2-Acetyl-3-methylbutyronitrile (80 g, 0.64 mol) was dissolved in EtOH (352 mL). Glacial acetic acid (47.6 mL, 0.83 mol) and hydrazine monohydrate (49.6 mL, 1.02 mol) were added, and the reaction mixture was stirred at 80 ° C overnight. After cooling to 0 ° C, the pH value was carefully adjusted to 9 with a saturated solution of NaHCO. The reaction mixture was then diluted with water and extracted 3 times with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated to obtain the desired product.

[0692] Analysis (Method C): R t : 0.36 minutes, [M+H] + :140

[0693] Step 3: Synthesis of 3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole

[0694]

[0695] 5-methyl-4-(propan-2-yl)-1H-pyrazole-3-amine (1g, 7.2mmol) is dissolved in ACN (8mL). Under cooling with ice / acetone, sodium nitrite (0.59g, 8.6mmol) is added and the reaction mixture is stirred at -5 ℃ for 30 minutes. Then KI (1.55g, 9.34mmol) is added, and the reaction mixture is stirred at 0 ℃ for 1.5 hours. The reaction mixture is quenched with Na2S2O3 and diluted with Me-THF (10mL) and water (10mL). After stirring for 1 hour, separate the layers. The organic layer is washed with salt water, dried (Na2SO4) and concentrated to obtain 1.6g of the required product C1.

[0696] Analysis (Method A): R t : 0.52 minutes, [M+H] + :251

[0697] Alternative synthesis of intermediate C1

[0698] Step 1: Synthesis of 5-iodo-3-methyl-4-(propan-2-yl)-1H-pyrazole

[0699]

[0700] 3-Methyl-4-(propan-2-yl)-1H-pyrazole (10g, 80.5mmol) was dissolved in ACN (150mL). NIS (25g, 111mmol) was added, and the reaction mixture was stirred at 80°C overnight. The reaction mixture was filtered and the filtrate was evaporated. The residue was quenched with Na2S2O3 half-saturated solution and extracted three times with DCM. The combined organic layer was dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (CycH / EtOAc 95 / 5 to CycH / EtOAc 76 / 24) to obtain intermediate C1.

[0701] Analysis (Method G): R t : 0.93 min, [M+H] + :251

[0702] Synthesis of intermediate C2

[0703] Step 1: Synthesis of 2-cyclopropyl-3-oxobutyronitrile

[0704]

[0705] To a stirred solution of 2-cyclopropylacetonitrile (3.7 mL; 40 mmol) in THF (20 mL) was added LDA (2M, 6.44 g, 60 mmol) dropwise over a period of 20 minutes at -78 ° C. The reaction mixture was stirred at -78 ° C for 1 hour. A solution of acetic anhydride (4.5 mL) in THF was added dropwise over 20 minutes, and the mixture was stirred at 0 ° C for 1 hour. The mixture was quenched with saturated citric acid and extracted with diethyl ether (3×20 mL). The organic layer was dried (Na2SO4), filtered and concentrated to give the title compound, which was used in the next step without further purification.

[0706] Analysis (TLC): R f : 0.7, 10% EtOAc in hexanes

[0707] Step 2: Synthesis of 5-methyl-4-(cyclopropenyl)-1H-pyrazol-3-amine

[0708]

[0709] 2-Cyclopropyl-3-oxobutyronitrile (4.9 g, 40 mmol) was dissolved in EtOH (18 mL). Glacial acetic acid (3 mL, 51.4 mmol) and hydrazine monohydrate (3.15 mL, 64.9 mol) were added, and the reaction mixture was stirred at 80 ° C overnight. After cooling to 0 ° C, the pH value was adjusted to 9 with a saturated solution of NaHCO. The reaction mixture was then diluted with water and extracted 4 times with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated to obtain the desired product.

[0710] Analysis (Method A): R t :0.26 minutes, [M+H] + :138

[0711] Step 3: Synthesis of 3-iodo-5-methyl-4-(cyclopropenyl)-1H-pyrazole

[0712]

[0713] 5-methyl-4-(cyclopropenyl)-1H-pyrazole-3-amine (5.17g, 37.6mmol) is dissolved in ACN (108mL) and cooled to 0°C. Acetic acid (6.5mL, 112mmol) is then carefully added, followed by dropwise addition of potassium iodide (11.2mL, 93.9mmol, dissolved in 54mL water). The mixture is stirred at 0°C for 10 minutes, and then tert-butyl nitrite (11.2mL, 94mmol, dissolved in ACN) is added dropwise. The mixture is stirred at ℃ for 10 minutes, and then stirred at room temperature for 1 hour. The reaction mixture is adjusted to pH value of 8 by adding saturated sodium bicarbonate aqueous solution, and extracted with EtOAc. The organic phase is washed with 0.5M, 200mL Na2S2O3 and brine, then dried over Na2SO4. The concentrated organic phase is then purified by flash column chromatography using EtOAC / CycH mixture as eluent to obtain the desired product C2.

[0714] Analysis (Method C): R t : 0.57 minutes, [M+H] + :249

[0715] Synthesis of intermediate C3

[0716] Step 1: Synthesis of 5-cyclopropyl-1-methyl-1H-imidazole

[0717]

[0718] Under argon atmosphere, 5-bromo-1-methyl-1H-imidazole (7.50 g, 46.6 mmol), cyclopropylzinc bromide (132 mL, 65.90 mmol, 0.5 M in THF) and Pd(dppf)Cl (2.20 g, 3.01 mmol) were mixed together and the reaction mixture was stirred for 20 hours at 70° C. The reaction mixture was concentrated and the residue was purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to give the desired product.

[0719] Analysis (Method C): R t : 0.31 min, [M+H] + :123

[0720] Step 2: Synthesis of 5-cyclopropyl-1,2-dimethyl-1H-imidazole

[0721]

[0722] Under argon atmosphere, 5-cyclopropyl-1-methyl-1H-imidazole (1g, 8.12mmol) is dissolved in THF (15.00mL) and cooled to -78 ° C. n-BuLi (6.1mL, 9.8mmol, 1.6M) is added dropwise, and the reaction mixture is stirred at -78 ° C for 30 minutes. Then MeI (663 μL, 10.6mmol) is added dropwise, and the reaction mixture is stirred at -78 ° C for 1 hour. The reaction mixture is quenched with NH4Cl half-saturated solution and stirred for 10 minutes. 2mL NH4OH aqueous solution (25%) is added and the mixture is stirred for 30 minutes. Separate each layer, and extract the aqueous layer 3 times with EtOAc. The combined organic layer is dried (Na2SO4), filtered and evaporated to obtain intermediate C3.

[0723] Analysis (Method H): R t : 0.72 minutes, [M+H] + :137

[0724] Synthesis of intermediate C4: 1,2-dimethyl-5-(propan-2-yl)-1H-imidazole

[0725]

[0726] 5-isopropyl-1-methyl-1H-imidazole (1 g, 8.05 mmol) was dissolved in THF (25 mL) and cooled to -65 °C. Then 5.4 mL of BuLi (1.6 M, 8.64 mmol) was slowly added. After 30 minutes, MeI (0.8 mL, 12.9 mmol) was added and the mixture was warmed to room temperature; water and ammonia (1 mL) were added under stirring, and then NH4Cl aqueous solution was added, and the mixture was extracted with EtOAc. The desired product C4 was obtained by silica gel chromatography using DCM: MeOH 9 / 1 plus ammonia.

[0727] Analysis (Method H): R t : 0.76 minutes, [M+H] + :139

[0728] Synthesis of intermediate C5: 3,4-diethyl-5-iodo-1H-pyrazole

[0729]

[0730] 4,5-diethyl-1H-pyrazole-3-amine (916 mg, 6.58 mmol) was dissolved in concentrated HCl (10 mL), and sodium nitrite (1.62 g, dissolved in 10 mL water) was slowly added at 0 ° C for 30 minutes. Potassium iodide (4.41 g, dissolved in 4 mL water) was slowly added, and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with TBME, and the organic phase was washed with sodium thiosulfate solution and concentrated. The crude product was dissolved in acetonitrile and the solid formed was collected to obtain the desired product C5.

[0731] Analysis (Method A): R t : 0.53 min, [M+H] + :251

[0732] Synthesis of intermediate C6: methyl 2-(3-iodo-5-methyl-1H-pyrazol-4-yl)acetate

[0733] Step 1: Synthesis of methyl 2-(5-methyl-1H-pyrazol-4-yl)acetate

[0734]

[0735] 2-(5-Methyl-1H-pyrazol-4-yl)acetic acid (1 g, 7.14 mmol) was dissolved in DCM (20 mL) and MeOH (10 mL) and cooled to -8°C, trimethylsilyldiazomethane (6.07 mL in hexane, 12.3 mmol) was slowly added, and the mixture was stirred for 2 hours. The mixture was concentrated and used in the next step as a crude product (g).

[0736] Step 2: Synthesis of methyl 2-(3-iodo-5-methyl-1H-pyrazol-4-yl)acetate

[0737]

[0738] Methyl 2-(5-methyl-1H-pyrazol-4-yl)acetate (1.1 g) was dissolved in 10 mL ACN and NIS (1.284 g, 5.7 mmol) was added and the mixture was stirred overnight at 80° C. The mixture was then filtered, concentrated and purified by silica gel chromatography using a CycH / EtOAc gradient to give the desired product C6.

[0739] Analysis (Method H): R t : 0.75 min, [M+H] + :281

[0740] Synthesis of intermediate D

[0741] Synthesis of intermediate D1: 1-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]propan-2-one

[0742]

[0743] 5-iodo-3-methyl-4-(propan-2-yl)-1H-pyrazole (C1, 2.90 g, 11.6 mmol) was dissolved in ACN (60 mL), K2CO3 (4.01 g, 29 mmol) and chloroacetone (1.85 mL, 23.2 mmol) were added. The reaction mixture was stirred at 50 ° C for 2 hours. Chloroacetone (0.2 mL) was added and the reaction mixture was stirred at 50 ° C for 1 hour. The reaction mixture was filtered, washed with ACN and the filtrate was evaporated. The residue was purified by flash chromatography (CycH / EtOAc 90 / 10 to CycH / EtOAc60 / 40) to obtain product D1.

[0744] Analysis (Method F): R t : 0.82 minutes, [M+H] + :307

[0745] The intermediates compiled in the table below were obtained by following a similar procedure as described for intermediate D1.

[0746]

[0747]

[0748]

[0749]

[0750] Synthesis of intermediate D13: 2-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-1-(oxacyclopentan-3-yl)ethan-1-one

[0751]

[0752] Step 1: Synthesis of oxacyclopentane-3-carbonyl chloride

[0753]

[0754] Oxacyclopentane-3-carboxylic acid (2 g, 17.2 mmol) was dissolved in DCM (50 mL). DMF (24 μL, 0.295 mmol) was added, and oxalyl chloride (2.14 mL, 25 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered, washed with 10 mL of DCM, and the filtrate was concentrated to give the product, which was used in the next step without further purification.

[0755] Step 2: Synthesis of 2-chloro-1-(oxacyclopent-3-yl)ethan-1-one

[0756]

[0757] Oxacyclopentane-3-carbonyl chloride (484mg, 3.6mmol) is dissolved in THF (2mL) and ACN (2mL). Trimethylsilyldiazomethane (3.06g, 7.92mmol, 2M) is added dropwise, and the reaction mixture is stirred at room temperature overnight. At 0°C, the reaction mixture is quenched with 4M HCl in dioxane (2.70mL, 10.8mmol) and stirred at room temperature for 3 hours. The reaction mixture is concentrated to obtain the product, which is used in the next step without further purification.

[0758] Analysis Rt (EI): 3.58 minutes

[0759] Step 3: Synthesis of 2-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-1-(oxacyclopentan-3-yl)ethan-1-one

[0760]

[0761] Intermediate D13 was synthesized by following a similar procedure as described for Intermediate D1 using 2-chloro-1-(oxolan-3-yl)ethan-1-one, Intermediate C1, and K2CO3 in DMF at 80°C for 2 hours to give Intermediate D13.

[0762] Analysis (Method G): R t: 1.03 minutes, [M+H] + :363

[0763] The intermediates compiled in the table below were obtained by following a reaction sequence analogous to that described for intermediate D13.

[0764]

[0765]

[0766] Synthesis of intermediate D19:

[0767] 3-Hydroxy-1-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-3-methylbutan-2-one

[0768] Step 1: Synthesis of 1-bromo-3-hydroxy-3-methylbutan-2-one

[0769]

[0770] 3-Hydroxy-3-methylbutan-2-one (500 mg, 4.9 mmol) was dissolved in acetic acid (2 mL). Bromine (0.25 mL, 4.9 mmol) in acetic acid (3 mL) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the product, which was used in the next step without further purification.

[0771] Step 2: Synthesis of 3-hydroxy-1-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-3-methylbutan-2-one

[0772]

[0773] 5-iodo-3-methyl-4-(propan-2-yl)-1H-pyrazole (intermediate c1) (150 mg, 0.60 mmol) was dissolved in ACN (2 mL). K2CO3 (207 mg, 1.50 mmol) and 1-bromo-3-hydroxy-3-methylbutan-2-one (217 mg, 1.20 mmol) were added, and the reaction mixture was stirred at 50°C overnight. The reaction mixture was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give product D19.

[0774] Analysis (Method G): R t : 1.02 minutes, [M+H] + :351

[0775] Synthesis of intermediate D20: 1-[(tert-butyldiphenylsilyl)oxy]-3-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]propan-2-ol

[0776]

[0777] Step 1:

[0778] Synthesis of 3-iodo-5-methyl-1-(prop-2-en-1-yl)-4-(prop-2-yl)-1H-pyrazole

[0779]

[0780] 5-iodo-3-methyl-4-(propan-2-yl)-1H-pyrazole (intermediate C1) (5.0 g, 19.9 mmol) was dissolved in ACN (50 mL), K2CO3 (6.9 g, 49.8 mmol) and allyl bromide (4.87 g, 40 mmol) were added. The reaction mixture was stirred at 50 ° C overnight. The reaction mixture was filtered, washed with ACN and the filtrate was evaporated. The residue was purified by flash chromatography (CycH / EtOAc 90 / 10 to CycH / EtOAc 60 / 40) to obtain the desired product.

[0781] Analysis (Method H): R t : 1.09 minutes, [M+H] + :291

[0782] Step 2: Synthesis of 3-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]propane-1,2-diol

[0783]

[0784] 3-iodo-5-methyl-1-(prop-2-ene-1-yl)-4-(prop-2-yl)-1H-pyrazole (3.32 g, 11.4 mmol) was dissolved in THF (45 mL). Osmium tetroxide aqueous solution (4.2 mL, 0.68 mmol, 4% in water) was added dropwise at 0 ° C. Then N-methyl-morpholine-N-oxide (2.01 g, 17.2 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with Na2S2O3 half-saturated solution (10 mL) and stirred at room temperature for 1 hour. THF was evaporated in vacuo. The aqueous residue was extracted with EtOAc several times. The combined organic layer was washed with brine, dried (Na2SO4), filtered and concentrated to give the product.

[0785] Analysis (Method G): R t : 0.76 minutes, [M+H] +:325

[0786] Step 3: Synthesis of 1-[(tert-butyldiphenylsilyl)oxy]-3-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]propan-2-ol

[0787]

[0788] 3-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]propane-1,2-diol (3.70g, 11.4mmol) and imidazole (2.49g, 36.5mmol) are dissolved in DCM (35mL). Tert-butyl (chloro) diphenylsilane (3.56mL, 13.7mmol) is added, and the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with water and extracted with DCM. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is purified by flash chromatography (CycH / EtOAc 93 / 7 to CycH / EtOAc40 / 60) to obtain the desired product.

[0789] Analysis (Method G): R t : 1.21 minutes, [M+H] + :563

[0790] Step 4: Synthesis of 1-[(tert-butyldiphenylsilyl)oxy]-3-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]propan-2-one

[0791]

[0792] 1-[(tert-butyldiphenylsilyl)oxy]-3-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]propan-2-ol (4.80 g, 8.53 mmol) was dissolved in DCM (60 mL). DMP (5.43 g, 12.8 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by flash chromatography (CycH / EtOAc 100 / 0 to CycH / EtOAc 60 / 40) to give intermediate D20.

[0793] Analysis (Method G): R t : 1.21 minutes, [M+H] + :561

[0794] Synthesis of imidazole intermediates D21-D25:

[0795] Synthesis of 1-(5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-3-methylbutan-2-one (D21)

[0796]

[0797] 5-cyclopropyl-1,2-dimethyl-1H-imidazole (2.55g, 18.7mmol) is dissolved in THF (120mL). n-BuLi (17.5mL, 28mmol, 1.6M) is added dropwise at -78 ° C, and the reaction mixture is stirred at -78 ° C for 1 hour. Then methyl isobutyrate (3.54mL, 28mmol) is added dropwise, and the reaction mixture is stirred at -78 ° C for 1 hour. The reaction mixture is quenched with NH4Cl saturated solution and extracted 3 times with EtOAc. The combined organic layer is dried (Na2SO4), filtered and concentrated and purified by silica gel chromatography (gradient: DCM / MeOH 100 / 0 to 94 / 4) to obtain the desired product D21.

[0798] Analysis (Method C): R t : 0.45 min, [M+H] + :207

[0799] Synthesis of 1-cyclopropyl-2-(5-cyclopropyl-1-methyl-1H-imidazol-2-yl)ethan-1-one (D22)

[0800]

[0801] 5-cyclopropyl-1,2-dimethyl-1H-imidazole (700mg, 5.14mmol) is dissolved in THF (7mL). n-BuLi (6.42mL, 10.28mmol, 1.6M) is added dropwise at -78 ° C, and the reaction mixture is stirred at -78 ° C for 30 minutes. Then ethyl cyclopropanecarboxylate (1.10mL, 9.25mmol) is added dropwise, and the reaction mixture is stirred at -78 ° C for 30 minutes, and then it is brought to room temperature. The reaction mixture is quenched with NH4Cl saturated solution and extracted 3 times with DCM / IPA 8 / 2. The combined organic layer is dried (Na2SO4), filtered and concentrated to obtain product D22.

[0802] Analysis (Method C): R t : 0.45 min, [M+H] + :205

[0803] The intermediates compiled in the table below were obtained by following a similar procedure to that described for intermediate D22.

[0804]

[0805] Synthesis of intermediate D24:

[0806] 4-Bromo-5-cyclopropyl-2-{6-ethyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole

[0807] Step 1: Synthesis of 5-cyclopropyl-1-methyl-1H-imidazole-2-carbaldehyde

[0808]

[0809] Under argon atmosphere, 5-cyclopropyl-1-methyl-1H-imidazole (6.30g, 51.6mmol) is dissolved in THF (63mL). At -78 ° C, n-BuLi (38.7mL, 61.9mmol, 1.6M) is added dropwise and the reaction mixture is stirred at -78 ° C for 1 hour. Then DMF (5.03mL, 61.9mmol) is added dropwise, and the reaction mixture is stirred at -78 ° C for 30 minutes. The reaction mixture is quenched with NH4Cl saturated solution and water. Then the reaction mixture is extracted with ether 3 times. The combined organic layer is dried (Na2SO4), filtered and concentrated to obtain the product, which is used in the next step without further purification.

[0810] Analysis (Method C): R t : 0.35 min, [M+H] + :151

[0811] Step 2: Synthesis of 4-bromo-5-cyclopropyl-1-methyl-1H-imidazole-2-carbaldehyde:

[0812]

[0813] 5-cyclopropyl-1-methyl-1H-imidazole-2-carboxaldehyde (17.8g, 94.8mmol) is dissolved in DCM (300mL). At 0°C, NBS (16.9g, 94.8mmol) is added, and the reaction mixture is stirred at 0°C for 1 hour. The reaction mixture is washed with 0.5M Na2S2O3 solution, water and brine. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is purified by flash chromatography (CycH / EtOAc100 / 0 to CycH / EtOAc 50 / 50) to obtain the product.

[0814] Analysis (Method C): R t : 0.49 min, [M+H] + :229 / 231(Br)

[0815] Step 3: Synthesis of 4-bromo-5-cyclopropyl-1-methyl-2-[(1E)-2-nitrobut-1-en-1-yl]-1H-imidazole

[0816]

[0817] 4-bromo-5-cyclopropyl-1-methyl-1H-imidazole-2-carboxaldehyde (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 days. The reaction mixture is quenched with a half-saturated solution of NaCl and extracted 3 times with EtOAc. The combined organic layer is dried (Na2SO4), filtered and concentrated to obtain the product, which is used in the next step without further purification.

[0818] Analysis (Method C): R t : 0.76 minutes, [M+H] + :300 / 302(Br)

[0819] Step 4: Synthesis of 1-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)butan-2-one

[0820]

[0821] Iron powder (11.16g, 0.200mol) is suspended in acetic acid (150mL) and the mixture is heated to 60°C. 4-bromo-5-cyclopropyl-1-methyl-2-[(1E)-2-nitrobutyl-1-ene-1-yl]-1H-imidazole (12g, 0.040mol) is slowly added dropwise in acetic acid (50mL), and the reaction mixture is stirred at 60°C for 1.5 hours and at 70°C for 2 hours. The hot reaction mixture is filtered, and the solid is washed with acetic acid. The filtrate is diluted with EtOAc and alkalized with 2M NaCO solution. Charcoal is added, the reaction mixture is filtered and passed through diatomaceous earth. Separate the layers, the organic layer is dried (NaSO), filtered and concentrated. The residue is purified by flash chromatography (CycH / EtOAc 20 / 80 to CycH / EtOAc 0 / 100) to obtain product D24.

[0822] Analysis (Method F): R t : 0.46 minutes, [M+H] + :271 / 273(Br)

[0823] Synthesis of intermediate D25:

[0824] Synthesis of 2-(5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-1-(2,2-difluorocyclopropyl)ethan-1-one

[0825] Step 1:

[0826]

[0827] 2,2-Difluorocyclopropanecarboxylic acid (3.4 g, 27.8 mmol), N,O-dimethylhydroxylamine hydrochloride (3.6 g, 36.9 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.4 g, 42.9 mmol) were dissolved in DCM (40 ml), the mixture was cooled to 0 ° C, then DIPEA (20 mL) was slowly added and the mixture was stirred at room temperature overnight. The mixture was then cooled to 0 ° C again and 4M HCL (35 mL) was added. The organic phase was separated, concentrated, the product was purified by silica gel chromatography (DCM), and the combined fractions were evaporated at 35 ° C / 90 mbar to give the desired product.

[0828] Analysis: ESI[M] + :166

[0829] Step 2:

[0830]

[0831] 5-cyclopropyl-1,2-dimethyl-1H-imidazole (150mg, 1.1mmol) is dissolved in THF (4mL), cooled to -78 ° C, and BuLi (0.76mL, 1.6M) is slowly added. After 15 minutes, 2,2-difluoro-N-methoxy-N-methylcyclopropane-1-carboxamide (250mg, 1.1mmol, dissolved in 0.5mL THF) is added and the mixture is stirred for 30 minutes. Then the NH4Cl aqueous solution is added, and the mixture is extracted with EtOAc. The organic phase is concentrated and purified by preparative HPLC to obtain intermediate D25.

[0832] Analysis (Method G): R t : 0.65 min, [M+H] + :241

[0833] Synthesis of Intermediate E

[0834] Synthesis of intermediate E1: 3-amino-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-4-carbaldehyde

[0835] Step 1: Synthesis of ethyl 3-amino-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-4-carboxylate

[0836]

[0837] Prepare a solution of NaOEt (using 4.08g Na (177mmol) and 100mL EtOH), to which [(4-methoxyphenyl) methyl] hydrazine hydrochloride (11.2g, 59mmol) is added. Then under argon, a solution of (2Z)-2-cyano-3-ethoxyprop-2-enoic acid ethyl ester (10g, 59mmol) in THF (50mL) is added dropwise at 0°C for 45 minutes. The reaction mixture is stirred at 0°C for 90 minutes. The reaction mixture is quenched with 4MHCl in dioxane (29.6mL, 118mmol) and concentrated to dryness. Then, the residue is dissolved in EtOAc and washed with a saturated solution of NaHCO. The aqueous layer is extracted with EtOAc. The combined organic layer is dried (NaSO), filtered and concentrated to give the product.

[0838] Analysis (Method Q): R t : 1.55 minutes, [MH] - :274

[0839] Step 2: Synthesis of {3-amino-1-[(4-methoxyphenyl)methyl]-1H-pyrazol-4-yl}methanol

[0840]

[0841] 3-Amino-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (16.3 g, 56.3 mmol, 95% purity) was dissolved in THF (81.5 mL) and LiAlH4 (2M in THF, 28.1 mL, 56.3 mmol) was added dropwise at -7 °C for 30 minutes. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with 2V of THF / H2O 8 / 2 and 1V of a saturated aqueous solution of Na2SO4 and stirred at room temperature for 30 minutes. The reaction mixture was filtered through celite and washed with MeOH and DCM / MeOH. The filtrate was dried (Na2SO4), filtered, concentrated and co-evaporated with toluene to give the product.

[0842] Analysis (Method Q): R t : 1.34 minutes, [M+H] + :234

[0843] Step 3: Synthesis of 3-amino-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-4-carbaldehyde

[0844]

[0845] {3-amino-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-4-yl}methanol (13.1 g, 50.5 mmol, 90% purity) was dissolved in ACN (131 mL) and water (26.2 mL), then MnO2 (34.2 g, 354 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through diatomaceous earth and washed with DCM / acetone. The filtrate was concentrated to dryness and the residue was wet-triturated with MTBE to obtain product E1.

[0846] TLC: silica gel, DCM / MeOH 95 / 5: R f : 0.55

[0847] Analysis (Method Q): R t : 1.55 minutes

[0848] Synthesis of intermediate E2:

[0849] Step 1: Synthesis of 3-amino-1-[3-(morpholin-4-yl)propyl]-1H-pyrazole-4-carbonitrile

[0850]

[0851] 3-Amino-4-cyanopyrazole (2 g, 18.5 mmol) was dissolved in ACN (20 mL) and KCO (3.2 g, 23.2 mmol) was added. 4-(3-Chloropropyl)morpholine (3.60 g, 22 mmol) in ACN (10 mL) was added dropwise at 70° C. and the reaction mixture was stirred at 70° C. for 2.5 hours. The reaction mixture was filtered and the filtrate was purified by reverse phase chromatography (HPLC; ACN / water including NH ) to give the product.

[0852] Analysis (Method C): R t : 0.27 min, [M+H] + :236

[0853] Step 2: Synthesis of 3-amino-1-[3-(morpholin-4-yl)propyl]-1H-pyrazole-4-carbaldehyde

[0854]

[0855] Under argon atmosphere, 3-amino-1-[3-(morpholine-4-yl)propyl]-1H-pyrazole-4-carbonitrile (0.50 g, 2.13 mmol) was suspended in toluene (5 mL) and DIBALH (5.80 mL, 6.38 mmol, 1.1 M in CycH) was added dropwise at -70 ° C. The reaction mixture was stirred at -70 ° C for 20 minutes. The reaction mixture was then warmed to -10 ° C and quenched with HCl aqueous solution (2.66 mL, 10.6 mmol, 4 M). The reaction mixture was stirred at room temperature for 30 minutes. NH4OH (1 mL, 28%) and ACN were added, and the reactant was filtered through cellulose. The filtrate was concentrated and purified by reverse phase chromatography (HPLC; ACN / water including NH3) to obtain product E2.

[0856] Analysis (Method D): R t : 0.26 minutes, [M+H] + :239

[0857] Synthesis of intermediate E3:

[0858] Synthesis of 3-amino-1-methyl-1H-pyrazole-4-carboxaldehyde

[0859]

[0860] Under argon, 1 M DIBALH in hexane (515 mL; 0.52 mol) was slowly added to a suspension of 3-amino-1-methyl-1H-pyrazole-4-carbonitrile (21.6 g; 0.18 mol) in toluene (432 mL) at -78°C. After addition, the solution was stirred for 20 minutes and then warmed to room temperature. The reaction mixture was slowly poured into 4 M aqueous HCl (177 mL; 0.71 mol) at 0°C and stirred for 1 hour.

[0861] The pH was adjusted to pH ca. 9 with potassium carbonate and the mixture was extracted with IPA / DCM 25 / 75 (1750 mL) and concentrated to give Intermediate E3.

[0862] 1 H-NMR (DMSO-d6, 300MHz): d=9.61(1H,s), 8.03(1H,s), 5.66(2H,s,br), 3.64(3H,s)

[0863] Synthesis of Intermediate F

[0864] Synthesis of intermediate F1:

[0865] 3-iodo-1-{2-[(4-methoxyphenyl)methyl]-6-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole

[0866]

[0867] 1-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]propan-2-one (D1) (5 g, 16.3 mmol) was dissolved in EtOH (75 mL), piperidine (4.03 mL, 40.8 mmol) was added and the reaction mixture was heated to reflux. 3-amino-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-4-carbaldehyde (E1) (3.40 g, 14.7 mmol) was added at 80 °C and the mixture was stirred at this temperature overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography (DCM / acetone 90 / 10 isocratic) to give intermediate F1.

[0868] TLC: silica gel, DCM / acetone 90 / 10: R f : 0.20

[0869] Analysis (Method A): R t : 0.71 min, [M+H] + :502

[0870] Synthesis of intermediate F2:

[0871]

[0872] 1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole

[0873] 1-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]propan-2-one (D1) (2.7 g, 8.82 mmol), 3-amino-1-methyl-1H-pyrazole-4-carbaldehyde (E3) (1.1 g, 8.82 mmol) were dissolved in EtOH, piperidine (2.18 mL, 22.1 mmol) was added and the reaction mixture was stirred in a closed vial at 80° C. for 4 hours. The reaction mixture was concentrated and the residue was purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to give intermediate F2.

[0874] Analysis (Method F): R t : 0.79 minutes, [M+H] + :396

[0875] The intermediates compiled in the table below were obtained by following a similar procedure as described for intermediate F2.

[0876]

[0877]

[0878]

[0879]

[0880]

[0881] Synthesis of intermediate F21:

[0882] 1-{6-chloro-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole

[0883]

[0884] Step 1: Synthesis of 5-bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine

[0885]

[0886] 1.0M bis(trimethylsilyl)sodium amide solution (75.8mL, 0.076mol) and iodomethane (9.43mL, 0.151mol) in THF are added to an ice-cooled solution of 5-bromo-2H-pyrazolo[3,4-b]pyridine (10g, 0.050mol) in anhydrous THF (100mL). The resulting mixture is warmed to room temperature and stirred for another 2 hours. DCM (150mL) and 1M NH4Cl (150mL) are added to the reaction mixture. The aqueous layer is extracted with DCM. The combined organic layers are dried (Na2SO4), filtered and concentrated. The residue is purified by flash chromatography (hexane / EtOAc 100 / 0 to hexane / EtOAc 0 / 100) to obtain the product.

[0887] Analysis (Method S): R t : 1.01 min, [M+H] + :212 / 214(Br)

[0888] Step 2: Synthesis of 5-bromo-2-methyl-2H-pyrazolo[3,4-b]pyridin-7-ium-7-olate

[0889]

[0890] 5-Bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine (5g, 23.6mmol) was suspended in DCM (160mL) and MCPBA (10g, 43.5mmol, 75% purity) was added. The reaction mixture was stirred at room temperature overnight. The mixture was then filtered and the filtrate was evaporated. A saturated solution of NaHCO3 was added to the residue, and the mixture was extracted with DCM and a small amount of MeOH. The combined organic phases were dried (Na2SO4), filtered and concentrated. The residue was wet-ground with MTBE, the precipitate was filtered and dried overnight in an oven at 50°C to obtain the product.

[0891] Analysis (Method H): R t : 0.48 minutes, [M+H] + :228 / 230(Br)

[0892] Step 3: Synthesis of 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridin-7-ium-7-olate

[0893]

[0894] 5-Bromo-2-methyl-2H-pyrazolo[3,4-b]pyridin-7-ium-7-olate (1.50 g, 3.95 mmol, 60% purity) and 3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (C1) (1.04 g, 4.14 mmol) were dissolved in NMP (5 mL). Under nitrogen atmosphere, K2CO3 (1.64 g, 11.8 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (0.50 mL, 3.17 mmol) and copper (I) iodide (601 mg, 3.16 mmol) were added and the reaction mixture was stirred in a closed vial at 105°C for 13 hours. The reaction mixture was filtered, washed with MeOH and the filtrate was concentrated. The residue was purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 86 / 14) to give the desired product.

[0895] Analysis (Method H): R t : 0.88 min, [M+H] + :398

[0896] Step 4: Synthesis of 1-{6-chloro-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole

[0897]

[0898] 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridin-7-ium-7-olate (554.0 mg, 1.12 mmol, 80% purity) was dissolved in ACN (5 mL). POCl3 (500 μL, 5.31 mmol) was added and the reaction mixture was stirred at 50 °C for 45 minutes. The reaction mixture was concentrated and the residue was purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to give the desired product F21.

[0899] Analysis (Method H): R t : 1.04 minutes, [M+H] + :416

[0900] Synthesis of intermediate F22: 1-{6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole

[0901]

[0902] 1-{6-chloro-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (60.0 mg, 0.12 mmol, 80% purity) was dissolved in EtOH (2.0 mL). LiHMDS (400 μL, 0.40 mmol) was added, and the reaction mixture was stirred at 40 ° C for 3 days and at 60 ° C overnight. The reaction mixture was quenched with a few drops of water and concentrated. The residue was purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 80 / 20) to give product F22.

[0903] Analysis (Method H): R t : 1.08 minutes, [M+H] + :426

[0904] The intermediates compiled in the table below were obtained by following a similar procedure to that described for intermediate F22.

[0905]

[0906]

[0907] Synthesis of intermediate F28:

[0908] Step 1: Synthesis of 1-(6-{[(tert-butyldiphenylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole

[0909]

[0910] 1-[(tert-Butyldiphenylsilyl)oxy]-3-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]propan-2-one (3.98 g, 7.10 mmol) and 3-amino-1-methyl-1H-pyrazole-4-carbaldehyde (0.89 g, 7.10 mmol) were dissolved in EtOH (20 mL). Piperidine (1.76 mL, 17.8 mmol) was added and the reaction mixture was stirred at 100 °C overnight. The reaction mixture was concentrated to give the product, which was used in the next step without further purification.

[0911] Step 2: Synthesis of {5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl}methanol

[0912]

[0913] 1-(6-{[(tert-butyldiphenylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (4.60 g, 7.08 mmol) was dissolved in THF (40 mL). TBAF (8.5 mL, 8.5 mmol, 1 M) was added and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and the residue was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give the product F28.

[0914] Analysis (Method G): R t : 0.93 min, [M+H] + :412

[0915] Synthesis of intermediate F29:

[0916] Step 1: Synthesis of 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridine-6-carbaldehyde

[0917]

[0918] {5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl}methanol (F28) (100 mg, 0.24 mmol) was dissolved in DCM (2 mL). DMP (155 mg, 0.37 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 60 / 40) to give the product.

[0919] Analysis (Method G): R t : 0.84 min, [M+H] + :410

[0920] Step 2: Synthesis of 1-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl}ethan-1-ol

[0921]

[0922] 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridine-6-carbaldehyde (125 mg, 0.21 mmol) was dissolved in THF (2 mL). Methylmagnesium bromide (0.22 mL, 3M in ether, 0.66 mmol) was added dropwise at 0 ° C, and the reaction mixture was stirred at 0 ° C for 10 minutes and at room temperature for 2 hours. The reaction mixture was quenched with a saturated solution of NH4Cl and extracted twice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by reverse phase chromatography (HPLC; ACN / water including NH3) to give product F29

[0923] Analysis (Method H): R t : 0.99 min, [M+H] + :426

[0924] Synthesis of intermediate F30: 3-iodo-5-methyl-1-[2-methyl-6-(methylthio)-2H-pyrazolo[3,4-b]pyridin-5-yl]-4-(propan-2-yl)-1H-pyrazole

[0925]

[0926] 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridin-7-ium-7-olate (30 mg, 0.08 mmol, see synthesis F21, step 4) was dissolved in ACN (2 mL). POCl3 (36 μL, 0.378 mmol) was added and the reaction mixture was stirred at 60 ° C for 45 minutes. The reaction mixture was concentrated and the residue was dissolved in DMF (2 mL). NaH (18 mg, 0.41 mmol, 55%) and sodium thiomethoxide (24 mg, 0.34 mmol) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and purified by reverse phase chromatography (HPLC; ACN / water including NH3) to give product F30.

[0927] Analysis (Method H): R t : 1.07 minutes, [M+H] + :428

[0928] Synthesis of intermediates F31 and F32:

[0929] 4-({5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl}methyl)morpholine

[0930]

[0931] Step 1: Synthesis of methanesulfonic acid {5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl}methyl ester

[0932]

[0933] {5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl}methanol (F28, 200 mg, 0.49 mmol) and TEA (149 μL, 1.07 mmol) were dissolved in DCM (2 mL). Methanesulfonyl chloride (45 μL, 0.58 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM and washed with a saturated solution of NaHCO. The organic layer was dried (NaSO), filtered and concentrated to give intermediate F31.

[0934] Analysis (Method G): R t : 0.85 min, [M+H] + :490

[0935] Step 2: Synthesis of 4-({5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl}methyl)morpholine

[0936]

[0937] Methanesulfonic acid {5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl}methyl ester (F31) (60 mg, 0.12 mmol) was dissolved in THF (1 mL). Morpholine (53 μL, 0.61 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by reverse phase chromatography (HPLC; ACN / water including NH3) to give intermediate F32.

[0938] Analysis (Method H): R t : 1.02 minutes, [M+H] + :481

[0939] The intermediates compiled in the table below were obtained by following a similar procedure as described for intermediate F32.

[0940]

[0941]

[0942] Synthesis of intermediate F35:

[0943] 4-(3-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-6-methyl-2H-pyrazolo[3,4-b]pyridin-2-yl}propyl)morpholine

[0944] Synthesis of 4-(3-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-6-methyl-2H-pyrazolo[3,4-b]pyridin-2-yl}propyl)morpholine

[0945]

[0946] 3-Amino-1-[3-(morpholin-4-yl)propyl]-1H-pyrazole-4-carboxaldehyde (E2, 115 mg, 0.48 mmol) was dissolved in EtOH (2 mL). Piperidine (122 μL, 1.23 mmol) and 1-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]propan-2-one (D1, 150 mg, 0.49 mmol) were added and the reaction mixture was stirred at 80 ° C for 6 hours and at room temperature for 8 hours. The reaction mixture was acidified with HOAc (2 mL) and TFA (0.5 mL), diluted with water and purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give product F35.

[0947] Analysis (Method F): R t : 0.62 minutes, [M+H] + :509

[0948] Synthesis of intermediate F36: 6-cyclopropyl-5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridin-7-ium-7-olate

[0949]

[0950] 1-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (F4) (600 mg, 1.42 mmol) was dissolved in DCM (3 mL). Methyltrioxorhenium (VII) (71 mg, 0.28 mmol) and H2O2 (890 μL, 15.7 mmol, 50%) were added at 0°C, and the reaction mixture was stirred at 0°C for 3 hours and stirred at room temperature overnight. The reaction mixture was diluted with DCM and water. The organic phase was separated, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to give the product F36.

[0951] Analysis (Method A): R t : 0.57 minutes, [M+H] + :438

[0952] Synthesis of intermediate F37:

[0953] 1-[6-(Difluoromethyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl]-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole

[0954] Step 1: Synthesis of 5-bromo-6-(difluoromethyl)-2-methyl-2H-pyrazolo[3,4-b]pyridine

[0955]

[0956] 5-Bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine (1 g, 4.7 mmol) and zinc difluoromethanesulfinate (3.48 g, 11.8 mmol) were dissolved in DCM (50 mL) and water (10 mL). TFA (351 μL, 4.72 mmol) and tert-butyl hydroperoxide (3.26 mL, 24 mmol, 70% in water) were added and the reaction mixture was stirred at room temperature over the weekend. The reaction mixture was diluted with water and the layers were separated. The aqueous layer was extracted with DCM, and the combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to obtain the product.

[0957] Analysis (Method H): R t : 0.84 min, [M+H] + :262 / 264(Br)

[0958] Step 2: Synthesis of 6-(difluoromethyl)-5-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridine

[0959]

[0960] Under argon atmosphere, 5-bromo-6-(difluoromethyl)-2-methyl-2H-pyrazolo[3,4-b]pyridine (270 mg, 1.03 mmol) was dissolved in dioxane (10 mL). Bis(neopentyl glycolyl)diboron (512 mg, 2.27 mmol), potassium acetate (313 mg, 3.19 mmol) and Pd(dppf)Cl2 x DCM (84 mg, 0.10 mmol) were added and the reaction mixture was stirred at 80 °C for 2 hours. After the reaction mixture was cooled to room temperature, it was filtered through a thiol scavenger resin and the filtrate was concentrated. The residue was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give the product.

[0961] Analysis (Method G): R t : 0.38 minutes, [M+H] + :296(the mass of the corresponding boric acid)

[0962] Step 3: Synthesis of 1-[6-(difluoromethyl)-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl]-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole

[0963]

[0964] 6-(Difluoromethyl)-5-(5,5-dimethyl-1,3,2-dioxaborohexane-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridine (75 mg, 0.25 mmol) and 3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (synthesis described in Intermediate A1 Step 1) (60 mg, 0.24 mmol) were dissolved in DCM (2 mL) and ACN (5 mL). Boric acid (44.5 mg, 0.72 mmol), pyridine (106 μL, 1.34 mmol) and copper (II) acetate (109 mg, 0.60 mmol) were added and the reaction mixture was stirred at room temperature in an open flask for 2 hours. The reaction mixture was quenched with ammonia and extracted twice with DCM. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to afford intermediate F37.

[0965] Analysis (Method G): R t : 1.08 minutes, [M+H] + :432

[0966] Synthesis of intermediate F38:

[0967] 1-[8-cyclopropyl-3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl]-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole

[0968] Step 1: Synthesis of 2-chloro-4-fluoro-3-iodopyridine

[0969]

[0970] Under argon atmosphere, LDA (5.44 mL, 10.9 mmol, 2 M) was cooled to -78 ° C. 2-Chloro-4-fluoropyridine (1.00 mL, 9.9 mmol) in THF (25 mL) was added dropwise, and the reaction mixture was stirred at -78 ° C for 1 hour. Thereafter, iodine (2.59 g, 9.9 mmol) in THF (35 mL) was added dropwise and the reaction mixture was stirred at -78 ° C for 30 minutes. The reaction mixture was quenched with a saturated solution of Na2CO3 and extracted with MTBE. The organic layer was washed with Na2S2O3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give the product.

[0971] Analysis (Method A): R t : 0.51 min, [M+H] + :258

[0972] Step 2: Synthesis of 2-chloro-3-cyclopropyl-4-fluoropyridine:

[0973]

[0974] Under argon atmosphere, 2-chloro-4-fluoro-3-iodopyridine (1.59 g, 6.19 mmol) and bromo(cyclopropyl)zinc (16.1 mL, 8.04 mmol, 0.5 M in THF) were mixed. PEPPSI(TM)-IPR (210 mg, 0.31 mmol) was then added and the reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was quenched with a saturated solution of NaHCO and extracted with DCM. The organic layer was washed with brine, dried (NaSO), filtered and concentrated. The residue was purified by flash chromatography (DCM 100%) to give the product.

[0975] Analysis (Method A): R t : 0.54 minutes, [M+H] + :171 / 173(Cl)

[0976] Step 3: Synthesis of 2-chloro-3-cyclopropyl-4-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]pyridine

[0977]

[0978] 3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (1.17 g, 4.66 mmol), 2-chloro-3-cyclopropyl-4-fluoropyridine (762 mg, 4.44 mmol) were dissolved in DMF (30 mL). K2CO3 (1.23 g, 8.9 mmol) was added and the reaction mixture was stirred at 100°C for 3 hours and at room temperature over the weekend. The reaction mixture was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give the product.

[0979] Analysis (Method A): R t : 0.77 minutes, [M+H] + :402 / 404(Cl)

[0980] Step 4: Synthesis of 3-cyclopropyl-2-hydrazino-4-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]pyridine

[0981]

[0982] 2-Chloro-3-cyclopropyl-4-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]pyridine (513 mg, 1.28 mmol) was dissolved in EtOH (3 mL). Hydrazine (11.5 mL, 11.5 mmol, 1 M in THF) was added and the reaction mixture was stirred at 150 °C in a microwave for 5 hours. The reaction mixture was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give the product.

[0983] Analysis (Method A): R t : 0.50 min, [M+H] + :398

[0984] Step 5: Synthesis of 1-[8-cyclopropyl-3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl]-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole

[0985]

[0986] 3-Cyclopropyl-2-hydrazino-4-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]pyridine (40 mg, 0.07 mmol) was dissolved in 2,2-difluoroacetic acid (300 μL, 4.77 mmol). The reaction mixture was stirred at 120 °C in a microwave for 2 hours. The reaction mixture was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give the product F38.

[0987] Analysis (Method A): Rt : 0.69 min, [M+H] + :458

[0988] The intermediates compiled in the table below were obtained by following a similar procedure as described for intermediate F38 (steps 3 to 5).

[0989]

[0990] Synthesis of intermediate F40: 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole

[0991] Step 1: Synthesis of 5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole

[0992]

[0993] 1-Cyclopropyl-2-(5-cyclopropyl-1,2-dimethyl-1H-imidazole-4-yl)ethan-1-one (D22) (1.40 g, 5.48 mmol, 80% purity) and 3-amino-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-4-carboxaldehyde (E1) (1.65 g, 7.13 mmol) were dissolved in EtOH (35 mL). Piperidine (1.62 mL, 16.5 mmol) was added and the reaction mixture was stirred at 80 ° C overnight. The reaction mixture was concentrated and co-evaporated with toluene 3 times. The residue was purified by flash chromatography (DCM / acetone 100 / 0 to DCM / acetone 30 / 70) to give the product.

[0994] Analysis (Method Q): R t : 1.40 minutes, [M+H] + :400

[0995] Step 2: Synthesis of 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole

[0996]

[0997] 5-Cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole (0.60g, 1.5mmol) was dissolved in DCM (21mL). NBS (0.29g, 1.65mmol) was added at 0°C and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with a saturated solution of Na2S2O3 and extracted with DCM. The organic layer was washed with a saturated solution of K2CO3, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (DCM / acetone 100 / 0 to DCM / acetone 90 / 10) to give product F40.

[0998] Analysis (Method R): R t : 3.82 minutes, [M+H] + :478 / 480(Br)

[0999] Synthesis of intermediate F41: 4-bromo-5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazole

[1000] Step 1:

[1001]

[1002] 1-(5-Cyclopropyl-1-methyl-1H-imidazol-2-yl)-3-methylbutan-2-one (1.28 g, 5 mmol), 3-amino-1-methyl-1H-pyrazole-4-carbaldehyde (684 mg, 5.5 mmol), piperidine (984 μL, 10 mmol) were dissolved in ethanol and heated overnight at 95° C. The mixture was then purified by reverse phase preparative HPLC (Xbridge C18, ACN / water including NH 3) to give the desired product.

[1003] Analysis (Method A): R t : 0.32 minutes, [M+H] + :296

[1004] Step 2:

[1005]

[1006] 5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazole (2.04 g, 6.9 mmol) was dissolved in DCM (21 mL). NBS (1.23 g, 6.9 mmol) was added at 0 ° C, and the reaction mixture was stirred at room temperature for 1 hour after 15 minutes. The reaction mixture was quenched with a saturated solution of NaHCO, each phase was separated, and the aqueous phase was extracted with DCM. The combined organic phases were dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (EtOAc / MeOH 100 / 0 to EtOAc / MeOH 95 / 5) to obtain the desired product F41.

[1007] Analysis (Method A): R t : 0.44 minutes, [M+H] + :374 / 376(Br)

[1008] The intermediates compiled in the table below were obtained by following a similar procedure to that described for intermediate F41.

[1009]

[1010]

[1011] Synthesis of Intermediate F45: 5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-6-(difluoromethoxy)-2-methyl-2H-indazole

[1012]

[1013] Step 1: Synthesis of 4-(difluoromethoxy)-1-methyl-2-nitrobenzene:

[1014]

[1015] KOH (14.7g, 262mmol) is dissolved in ACN / water 1 / 1 (100mL), 4-methyl-3-nitrophenol (2g, 13.06mmol) is added and the reaction mixture is frozen with dry ice / acetone bath. Once frozen into solid, diethylphosphonic acid bromodifluoromethyl ester (3.77mL, 21.2mmol) is added on top and the reaction mixture is kept at this temperature for 10 minutes. Then remove the ice bath. After 1.5 hours, once the reaction has been slowly thawed, stirring is resumed, and it is warming up to 10 ℃, and the reaction is complete. The reaction mixture is diluted with ether and water, and stirred vigorously. It is extracted with ether 2 times, and the combined organic layer is dried (Na2SO4), filtered and concentrated. Make the residue pass through a small silica gel plug (CycH / EtOAc 90 / 10→CycH / EtOAc 0 / 100) to obtain the product.

[1016] Analysis (Method F): R t : 0.86 minutes

[1017] Step 2: Synthesis of 5-(difluoromethoxy)-2-methylaniline:

[1018]

[1019] 4-(Difluoromethoxy)-1-methyl-2-nitrobenzene (1.8 g, 8.86 mmol) was dissolved in EtOH (25 mL), ammonium formate (2.45 g, 17.7 mmol) and palladium / carbon (1.60 g, 10%) were added, and the reaction mixture was stirred overnight at 85 ° C in a sealed vial. The reaction mixture was filtered and concentrated. The residue was purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to give the product.

[1020] Analysis (Method F): R t : 0.52 minutes, [M+H] + :174

[1021] Step 3: Synthesis of 4-bromo-5-(difluoromethoxy)-2-methylaniline

[1022]

[1023] 5-(Difluoromethoxy)-2-methylaniline (1.12 g, 6.47 mmol) was dissolved in chloroform (51.5 mL). NBS (1.15 g, 6.47 mmol) was added at 0° C. and the reaction mixture was stirred at 4° C. to 6° C. overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to give the product.

[1024] Analysis (Method F): R t : 0.83 min, [M+H] + :252 / 254(Br)

[1025] Step 4: Synthesis of 5-bromo-6-(difluoromethoxy)-2H-indazole

[1026]

[1027] Under argon atmosphere, 4- bromo-5- (difluoromethoxy) -2- methylaniline (1.98g, 7.84mmol) was added to the boron trifluoride ether (1.45mL, 11.8mmol) in DCM (18.8mL) at -78 ° C, and then tert-butyl nitrite (1.12mL, 9.4mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 22 hours. Potassium acetate (1.46g, 14.9mmol) and 18- crown ether -6 (104mg, 0.39mmol) were added to the above solution of diazonium salt in DCM. After stirring at room temperature for 1.5 hours, the mixture was filtered and the solid was washed with DCM. The filtrate was concentrated and purified by flash chromatography (CycH / EtOAc100 / 0 to CycH / EtOAc 0 / 100) to obtain the product.

[1028] Analysis (Method F): R t : 0.78 minutes, [M+H] + :263 / 265(Br)

[1029] Step 5: Synthesis of 5-bromo-6-(difluoromethoxy)-2-methyl-2H-indazole

[1030]

[1031] 5-bromo-6-(difluoromethoxy)-2H-indazole (960mg, 3.07mmol, 84% purity) was dissolved in EtOAc (19mL). Trimethyloxonium tetrafluoroborate (589mg, 3.99mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by dropwise addition of 10% NaHCO3 solution until alkaline pH was reached. The reaction mixture was extracted with DCM. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to obtain the product.

[1032] Analysis (Method F): R t : 0.79 minutes, [M+H] + :277 / 279(Br)

[1033] Step 6: Synthesis of 6-(difluoromethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole

[1034]

[1035] Under argon atmosphere, 5-bromo-6-(difluoromethoxy)-2-methyl-2H-indazole (700 mg, 2.53 mmol) was dissolved in dioxane (18 mL), bis(pinacolato)diboron (0.74 g, 2.91 mmol), potassium acetate (744 mg, 7.58 mmol) and Pd(dppf)Cl2 x DCM (206 mg, 0.25 mmol) were added, and the reaction mixture was stirred at 90°C for 3 hours. The reaction mixture was diluted with DCM and water and filtered through celite. The layers were separated, and the organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give the product.

[1036] Analysis (Method F): R t : 0.90 min, [M+H] + :325

[1037] Step 7: Synthesis of 5-cyclopropyl-1-methyl-1H-imidazole

[1038]

[1039] Under argon atmosphere, 5-bromo-1-methyl-1H-imidazole (7.50 g, 46.6 mmol), cyclopropylzinc bromide (132 mL, 66 mmol, 0.5 M in THF) and Pd(dppf)Cl2 (2.20 g, 3 mmol) were mixed together and the reaction mixture was stirred for 20 hours at 70° C. The reaction mixture was concentrated and the residue was purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to give the product.

[1040] Analysis (Method C): R t : 0.31 min, [M+H] + :123

[1041] Step 8: Synthesis of 2,4-dibromo-5-cyclopropyl-1-methyl-1H-imidazole

[1042]

[1043] 5-cyclopropyl-1-methyl-1H-imidazole (9.20g, 52.7mmol) is dissolved in ACN (200mL).At-5 ℃, NBS (18.8g, 105mmol) is added portion by portion, reaction mixture is stirred at-5 ℃ for 30 minutes and stirred at room temperature for 4 hours.By adding Na2S2O3 saturated solution (40mL, 4.4M) reaction mixture is quenched.The formed precipitate is filtered and washed with ACN.Extract filtrate with EtOAc, organic layer is dried (Na2SO4), filtered and concentrated.By flash chromatography (CycH / EtOAc 95 / 5 to CycH / EtOAc 65 / 35) purification of residue, product is obtained.

[1044] Analysis (Method F): R t : 0.77 minutes, [M+H] + :279 / 281 / 283(2x Br)

[1045] Step 9: Synthesis of 5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-6-(difluoro-methoxy)-2-methyl-2H-indazole

[1046]

[1047] Under argon atmosphere, 2,4-dibromo-5-cyclopropyl-1-methyl-1H-imidazole (108mg, 0.39mmol) and 6-(difluoromethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (150.05mg, 0.46mmol) are dissolved in dioxane (3.6mL). CsCO (377mg, 1.16mmol) and Pd(PPh) (44.6mg, 0.04mmol) are added, and the reaction mixture is stirred at 80°C overnight. The reaction mixture is concentrated and purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 85 / 15). The combined fractions are concentrated, and the residue is wet-milled with CycH to obtain product F45.

[1048] Analysis (Method F): R t : 0.61 min, [M+H] + :397 / 399(Br)

[1049] Synthesis of intermediate F46: 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2-propyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole

[1050] Step 1: Synthesis of 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole

[1051]

[1052] 4-Bromo-5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole (F40) (574 mg, 1.20 mmol) and anisole (264 μL, 2.40 mmol) were dissolved in DCE (5 mL) and TFA (3 mL). The reaction mixture was stirred at 60 ° C over the weekend. The reaction mixture was concentrated and purified by reverse phase chromatography (HPLC; ACN / water / TFA). The fractions were combined and the solvent was evaporated. The aqueous residue was neutralized with 2M K2CO3 solution. The formed precipitate was filtered, washed with water and dried in an oven to obtain the product.

[1053] Analysis (Method H): R t : 0.96 minutes, [M+H] + :358 / 360(Br)

[1054] Step 2: Synthesis of 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2-propyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole

[1055]

[1056] 4-Bromo-5-cyclopropyl-2-{6-cyclopropyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole (358 mg, 1 mmol) was dissolved in ACN (5 mL). K2CO3 (346 mg, 2.50 mmol) and 1-bromopropane (91 μL, 1 mmol) were added and the reaction mixture was stirred at 60°C overnight. The reaction mixture was filtered and purified by reverse phase chromatography (HPLC; C18, ACN / water including NH3) to give the product F46.

[1057] Analysis (Method H): R t : 1.01 min, [M+H] + :400 / 402(Br)

[1058] Synthesis of intermediate F47:

[1059] 4-Bromo-5-cyclopropyl-2-{6-ethyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole

[1060]

[1061] 1-(4-Bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)butan-2-one (5.51 g, 20.3 mmol) was dissolved in EtOH (60 mL). 3-Amino-1-methyl-1-H-pyrazole-4-carbaldehyde (2.80 g, 22.4 mmol) and piperidine (4.02 mL, 40.6 mmol) were added and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was filtered and purified by reverse phase chromatography (HPLC; Xbridge-C18, ACN / water including NH 3) to give the product F47.

[1062] Analysis (Method F): R t : 0.55 min, [M+H] + :360 / 362(Br)

[1063] Synthesis of intermediate F48: 1-{3,8-dimethylimidazo[1,2-a]pyridin-7-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole

[1064] Step 1: Synthesis of 7-fluoro-3,8-dimethylimidazo[1,2-a]pyridine

[1065]

[1066] 4-Fluoro-3-methylpyridin-2-amine (300 mg, 2.4 mmol) and 2-bromo-1,1-dimethoxypropane (1.6 mL, 11.9 mmol), p-toluenesulfonic acid (82 mg, 0.48 mmol) were dissolved in 12 mL of acetonitrile and heated at 80° C. for 2 days. The mixture was then diluted with DCM and purified by preparative flash column chromatography to give 330 mg of 7-fluoro-3,8-dimethylimidazo[1,2-a]pyridine.

[1067] Analysis (Method C): R t : 0.41 min, [M+H] + :165

[1068] Step 2: Synthesis of 1-{3,8-dimethylimidazo[1,2-a]pyridin-7-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole

[1069]

[1070] 3-iodo-4-isopropyl-5-methyl-1H-pyrazole (C1) (450 mg, 1.8 mmol) was dissolved in NMP (1 mL), then NaH (157 mg) was added and the mixture was stirred for 5 minutes. 7-fluoro-3,8-dimethylimidazo[1,2-a]pyridine (295 mg, 1.8 mmol) was added and the mixture was placed in a microwave at 170 ° C for 16 hours. After cooling, the mixture was diluted with ACN / water, filtered and purified by preparative HPLC to give intermediate F48.

[1071] Analysis (Method C): R t : 0.69 min, [M+H] + :395

[1072] Synthesis of Intermediate F49: 2-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-1H-pyrazol-4-yl)propan-1-ol

[1073] Step 1: Synthesis of ethyl 2-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-1H-pyrazol-4-yl)propanoate

[1074]

[1075] Intermediate F18

[1076] Ethyl 2-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-1H-pyrazol-4-yl)acetate (138 mg, 0.31 mmol) was dissolved in THF (5 mL) and cooled to -78 ° C. MeI (78 μL, 1.3 mmol) and lithium bis(trimethylsilyl)amide (408 μL, 0.41 mmol) were added, the mixture was slowly warmed to room temperature and continued to stir at room temperature for 1 hour. NH4Cl aqueous solution (15 mL) was added, the mixture was extracted 3 times with EtOAc, and the organic phase was dried (Na2SO4) and concentrated. The product was used in the next step without further purification.

[1077] Analysis (Method G): R t : 0.81 min, [M+H] + :454

[1078] Step 2: Synthesis of 2-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-1H-pyrazol-4-yl)propanoic acid

[1079]

[1080] Ethyl 2-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-1H-pyrazol-4-yl)propanoate (68 mg, 0.15 mmol) was dissolved in THF (2 mL) and NaOH (94 μL, 4 M, 0.375 mmol). Two drops of methanol were then added and the mixture was stirred at 50 ° C for 3 hours. The mixture was then neutralized with HCl (4 M), concentrated, dissolved in water / DMF, and purified by preparative HPLC to give the desired product.

[1081] Analysis (Method G): R t : 0.65 min, [M+H] + :426

[1082] Step 3: Synthesis of 2-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-1H-pyrazol-4-yl)propan-1-ol

[1083]

[1084] 2-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-1H-pyrazol-4-yl)propanoic acid (102 mg, 0.24 mmol) was suspended in THF (2 mL) and DMF (200 μL), then triethylamine (101 μL, 0.72 mmol) and CDI (86 mg, 0.528 mmol) were added, and the mixture was stirred at room temperature for 45 minutes. The mixture was then cooled with an ice bath, NaBH4 (32 mg, 0.84 mmol) and water were added, and the mixture was stirred for 2 hours while warming to room temperature. The mixture was concentrated, then dissolved in DMF / water and purified by preparative HPLC to give product F49.

[1085] Analysis (Method G): R t : 0.66 min, [M+H] + :412

[1086] Synthesis of intermediate F50: 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2,6-dimethyl-1H-1,3-benzodiazole

[1087] Step 1: Synthesis of 1-(5-chloro-2-methyl-4-nitrophenyl)-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole

[1088]

[1089] Intermediate A1

[1090] 3-iodo-4-isopropyl-5-methyl-1H-pyrazole (600 mg, 2.4 mmol) was dissolved in DMF (15 mL), KCO and 4-chloro-2-fluoro-5-nitrotoluene (909 mg, 4.8 mmol) were added and the mixture was stirred for 2 h at 100° C. The mixture was then purified by preparative HPLC to give the desired product.

[1091] Analysis (Method G): R t : 1.26 minutes, [M+H] + :420

[1092] Step 2: Synthesis of 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-4-methyl-2-nitroaniline

[1093]

[1094] 1-(5-Chloro-2-methyl-4-nitrophenyl)-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (900 mg, 2.1 mmol), NMP (12 mL) and concentrated aqueous ammonia (20 mL) were heated at 175 °C for 3 h and the mixture was purified by preparative HPLC to give the desired product.

[1095] Analysis (Method H): R t : 1.18 minutes, [M+H] + :401

[1096] Step 3: Synthesis of 4-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-5-methylbenzene-1,2-diamine

[1097]

[1098] 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-4-methyl-2-nitroaniline (372 mg, 0.93 mmol) was dissolved in HOAc (10 mL) and iron powder (260 mg) was added. HCl (4 M, 3 x 1.1 mL) was then added and the mixture was stirred at 60 °C for 3 hours. The mixture was purified by preparative HPLC to give the desired product.

[1099] Analysis (Method G): R t : 0.89 min, [M+H] + :371

[1100] Step 4: Synthesis of 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2,6-dimethyl-1H-1,3-benzodiazole

[1101]

[1102] 4-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-5-methylbenzene-1,2-diamine (132 mg, 0.3 mmol) and {[(tert-butoxy)carbonyl]amino}acetic acid (53 mg, 0.3 mmol) were dissolved in DMF (2 mL), and HATU (114 mg, 0.3 mmol) and DIPEA (206 μL, 1.2 mmol) were then added, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered through basic alumina, then washed with DMF / MeOH 9:1, and concentrated. The mixture was dissolved in HOAc (3 mL) and heated at 85 ° C for 2 hours. The mixture was then purified by preparative HPLC (C18, ACN / water including NH 3) to give the desired product F50.

[1103] Analysis (Method G): R t : 0.89 min, [M+H] + :395

[1104] Synthesis of Intermediate F51: 5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazol-2-yl)-6-(trifluoromethoxy)-2-methyl-2H-indazole

[1105] Step 1: Synthesis of 4-bromo-5-(difluoromethoxy)-2-methylaniline

[1106]

[1107] 5-(Trifluoromethoxy)-2-methylaniline (656 mg) was dissolved in chloroform (25 mL). NBS (611 mg) was added at 0 ° C, and the reaction mixture was stirred at 0 ° C for 1 hour. The reaction mixture was quenched with Na2S2O3 (0.5M solution) and diluted with DCM. Each phase was separated, the organic layer was concentrated and purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to obtain the product.

[1108] Analysis (Method F): R t : 0.96 minutes, [M+H] + :270 / 272(Br)

[1109] Step 2: Synthesis of 5-bromo-6-(trifluoromethoxy)-2H-indazole

[1110]

[1111] Under argon atmosphere, 4-bromo-5-(trifluoromethoxy)-2-methylaniline (1.98 g, 7.84 mmol) in DCM (11.25 mL) was added to boron trifluoride etherate (0.53 mL, 4.3 mmol) in DCM (8 mL) at -78 ° C, and tert-butyl nitrite (0.41 mL, 3.4 mmol) was then added dropwise. The reaction mixture was warmed to room temperature and stirred for 22 hours. Potassium acetate (531 mg, 5.4 mmol) and 18-crown-6 (38 mg, 0.14 mmol) were added to the above solution of the diazonium salt in DCM. After stirring at room temperature for 2 hours, the mixture was filtered and the solid was washed with DCM. The filtrate was concentrated and the residue was purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to give the product.

[1112] Analysis (Method F): R t : 0.88 min, [M+H] + :281 / 283(Br)

[1113] Step 3: Synthesis of 5-bromo-6-(trifluoromethoxy)-2-methyl-2H-indazole

[1114]

[1115] 5-bromo-6-(trifluoromethoxy)-2H-indazole (500mg, 1.6mmol) is dissolved in EtOAc (10mL). Trimethyloxonium tetrafluoroborate (308mg, 2.1mmol) is added and the reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is quenched by dropwise addition of 10% NaHCO3 solution until alkaline pH is reached. The reaction mixture is diluted with DCM and passed through a phase separator. The organic layer is adsorbed on Extrulute and purified by MPLC (DCM / MeOH 100 / 0→DCM / MeOH 90 / 10) to obtain the product.

[1116] Analysis (Method F): R t : 0.93 min, [M+H] + :295 / 297(Br)

[1117] Step 4: Synthesis of 6-(difluoromethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole

[1118]

[1119] Under argon atmosphere, 5-bromo-6-(trifluoromethoxy)-2-methyl-2H-indazole (614 mg, 2.1 mmol) was dissolved in dioxane (12 mL), bis(pinacolato)diboron (0.79 g, 3.1 mmol), potassium acetate (614 mg, 6.2 mmol) and Pd(dppf)Cl2 x DCM (170 mg, 0.21 mmol) were added, and the reaction mixture was stirred at 90 ° C for 2 hours. The cooled reaction mixture was then filtered through a Pd scavenger cartridge, the cartridge was rinsed with methanol and the filtrate was concentrated. The residue was purified by flash column chromatography (EtOAc / CycH 30 / 70 to 100 / 0) to give the product.

[1120] Analysis (Method A): R t : 0.71 min, [M+H] + :343

[1121] Step 5: Synthesis of 5-(4-bromo-5-isopropyl-1-methyl-1H-imidazol-2-yl)-6-(trifluoromethoxy)-2-methyl-2H-indazole

[1122]

[1123] Under argon atmosphere, 2,4-dibromo-5-isopropyl-1-methyl-1H-imidazole (54 mg, 0.19 mmol, synthesized similarly as described for intermediate F45) and 6-(trifluoromethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (79 mg, 0.23 mmol) were dissolved in dioxane (1.8 mL). CsCO (188 mg, 0.58 mmol) and Pd(PPh) (22 mg, 0.0.02 mmol) were added at room temperature and the reaction mixture was stirred at 80 °C for 18 hours. The reaction mixture was poured onto ice and the solid formed was separated. The solid was dissolved in dichloromethane and adsorbed on Extrelute. The mixture was purified by flash column chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10 gradient). Concentration of the combined fractions gave the desired product F51.

[1124] Analysis (Method F): R t : 0.72 minutes, [M+H] + :415 / 417(Br)

[1125] Synthesis of Intermediate G1 and Examples 1, 2, 4, 6, 7, 10, 11, 12, 14, 16, 18, 21, 24, 28, 31, 32, 33, 37, 39, 43, 45, 56, 61, 62, 67, 70, 77

[1126] Synthesis of intermediate G1: ((1R)-2-[4-(5-methyl-1-{6-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol

[1127] Step 1: Synthesis of (1R)-2-[4-(1-{2-[(4-methoxyphenyl)methyl]-6-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol

[1128]

[1129] Under argon atmosphere, 3-iodo-1-{2-[(4-methoxyphenyl)methyl]-6-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole (F1) (1.85 g, 3.7 mmol) and (1R)-1-phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethan-1-ol (B1) (1.64 g, 4.06 mmol, 90% purity) were dissolved in dioxane (28 mL). K3PO4 aqueous solution (4.61 mL, 9.23 mmol, 2 M) and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II) (XPhos Pd G3, 187 mg, 0.22 mmol) were added and the reaction mixture was stirred at 90 ° C overnight. SiliaMetS thiol was then added to the reaction mixture and stirred for 15 minutes. The solid was then removed by filtration. The filtrate was concentrated and wet-triturated with MTBE; the solid was filtered off as the first batch of title compounds. The filtrate was concentrated and purified by flash chromatography (EtOAc / MeOH 100 / 0 to EtOAc / MeOH 90 / 10) to give a second batch of title compounds.

[1130] Analysis (Method A): R t : 0.68 min, [M+H] + :612

[1131] Step 2: Synthesis of (1R)-2-[4-(5-methyl-1-{6-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol

[1132]

[1133] (1R)-2-[4-(1-{2-[(4-methoxyphenyl)methyl]-6-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol (1.70 g, 2.50 mmol) and anisole (0.55 mL, 5 mmol) were dissolved in DCE (30 mL). TFA (20 mL, 259 mmol) was added and the reaction mixture was stirred at 50 ° C for three days. The reaction mixture was concentrated and the residue was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give 755 mg of the product.

[1134] Analysis (Method H): R t : 0.68 min, [M+H] + :492

[1135] Synthesis of Example 1: (1R)-2-[4-(5-methyl-1-{6-methyl-2-[2-(morpholin-4-yl)ethyl]-2H-pyrazolo[3,4-b]pyridin-5-yl}-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol

[1136]

[1137] (1R)-2-[4-(5-methyl-1-{6-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol (300 mg, 0.61 mmol) was dissolved in ACN (5 mL) and DMF (3 mL), K2CO3 (253 mg, 1.83 mmol) and 4-(2-bromoethyl)morpholine hydrobromide (218 mg, 0.79 mmol) were added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by reverse phase chromatography (HPLC; ACN / water including NH3) to give Example 1.

[1138] Analysis (Method H): R t : 0.94 minutes, [M+H] + :605

[1139] The intermediates and examples compiled in the table below were obtained by following a similar procedure to that described for Example 1 using intermediate G1.

[1140]

[1141]

[1142]

[1143]

[1144]

[1145]

[1146]

[1147]

[1148]

[1149]

[1150]

[1151]

[1152]

[1153] Synthesis of Example 3: (1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenyl(1-2H)ethan-1-ol

[1154]

[1155] Step 1: Synthesis of 2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-one

[1156]

[1157] (1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol (Example 102) (300 mg, 0.59 mmol) was dissolved in DCM (10 mL). DMP (0.58 g, 1.31 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated and purified by reverse phase chromatography (HPLC; C18, ACN / water including TFA) to give the product.

[1158] Analysis (Method G): R t : 0.96 minutes, [M+H] + :504

[1159] Step 2: Synthesis of 2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenyl(1-2H)ethan-1-ol

[1160]

[1161] 2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethyl-1-one (280 mg, 0.56 mmol) was dissolved in THF (5 mL) and MeOH (5 mL). Sodium borodeuteride (52 mg, 1.11 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water and extracted with DCM. The organic layer was dried (Na2SO4), filtered and concentrated to give the product.

[1162] Analysis (Method G): R t : 0.93 min, [M+H] + :507

[1163] Step 3: Synthesis of (1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenyl(1-2H)ethan-1-ol

[1164]

[1165] 2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenyl(1-2H)ethan-1-ol (149 mg, 0.29 mmol) was isolated by chiral purification method W to give compound (1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenyl(1-2H)ethan-1-ol (Example 3) (Analysis (Method W): R t : 4.89 min) and (1S)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenyl(1-2H)ethan-1-ol (Analysis (Method W): R t : 3.78 minutes).

[1166] Synthesis of Examples 4, 5, 9, 13, 15, 17, 19, 20, 22, 23, 26, 29, 34, 35, 38, 42, 46, 47, 48, 49, 50, 51, 53, 54, 57, 58, 59, 60, 64, 65, 71, 72, 73, 75, 76, 80, 83, 84, 86, 87, 89, 91, 97, 102

[1167] Synthesis of Example 5: (1R)-2-[4-(1-{6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol

[1168] Step 1: Synthesis of (1R)-2-[4-(1-{2-[(4-methoxyphenyl)methyl]-6-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol

[1169]

[1170] 1-{6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (F5) (75 mg, 0.12 mmol) and {2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}boronic acid (B3) (52 mg, 0.15 mmol) were dissolved in dioxane (1 mL). Cs2CO3 (112 mg) and water (100 μL) and Pd(dppf)Cl2 xDCM (10 mg) were added, and the reaction mixture was stirred at 85°C overnight. The mixture was then filtered, diluted with ACN and HOAc and purified by reverse phase HPLC to give the desired product Example 5.

[1171] Analysis (Method G): R t : 0.98 minutes, [M+H] + :536

[1172] The intermediates and examples compiled in the table below were obtained by following a procedure similar to that described for intermediate G1, step 1.

[1173]

[1174]

[1175]

[1176]

[1177]

[1178]

[1179]

[1180]

[1181]

[1182]

[1183]

[1184]

[1185]

[1186]

[1187]

[1188]

[1189]

[1190]

[1191]

[1192]

[1193]

[1194] Synthesis of Intermediate G2, Example 10, Example 11, Example 28, Example 33, Example 61 and Example 104

[1195] Synthesis of Intermediate G2: (1R)-2-(4-(5-cyclopropyl-2-{6-cyclopropyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol

[1196] Step 1: (1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol

[1197]

[1198] Under argon atmosphere, 5-(4-bromo-5-cyclopropyl-1-methyl-imidazol-2-yl)-6-cyclopropyl-2-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b]pyridine (F40) (500 mg, 1.05 mmol) and (1R)-1-phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethan-1-ol (B1) (508 mg, 1.25 mmol) were dissolved in dioxane (10 mL). K3PO4 aqueous solution (1 mL, 2M) and (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium (II) (XPhos Pd G3, 44.2 mg, 0.05 mmol) were added and the reaction mixture was stirred at 90 ° C for 1 hour. The solid was then removed by filtration. The filtrate was concentrated to give the product, which was used in the next step without further purification.

[1199] Analysis (Method H): R t: 1.1 minutes, [M+H] + :636

[1200] Step 2: Synthesis of (1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol

[1201]

[1202] (1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol (600 mg, 0.94 mmol) and anisole (207 μL, 1.88 mmol) were dissolved in DCE (20 mL). TFA (5 mL) was added and the reaction mixture was stirred at 70 ° C over the weekend. The reaction mixture was concentrated and the residue was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give Intermediate G2.

[1203] Analysis (Method H): R t : 1.03 minutes, [M+H] + :516

[1204] Synthesis of Example 10 and Example 61: (1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-[2-(morpholin-4-yl)ethyl]-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol (10) and (1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-vinyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol (61)

[1205]

[1206] ((1R)-2-[4-(5-Cyclopropyl-2-{6-cyclopropyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol (40 mg, 0.08 mmol), 1-bromo-2-chloroethane (16 μL, 0.19 mmol) were dissolved in ACN (2 mL), K2CO3 (53 mg) was added, and the mixture was stirred at 40°C overnight. Morpholine (34 μL, 0.39 mmol) was then added, the mixture was stirred at 80°C for 4 hours, and then additional morpholine (50 μL) was added and the mixture was stirred at 80°C overnight. The mixture was then diluted with water, filtered and purified by reverse phase chromatography (HPLC; ACN / water including NH3) to give the title compound.

[1207] Analysis (Method H): R t : 1.01 min, [M+H] + :629 (Example 10)

[1208] Analysis (Method H): R t : 1.02 minutes, [M+H] + :542 (Example 61)

[1209] Synthesis of Example 11: (1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-[3-(morpholin-4-yl)propyl]-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol

[1210]

[1211] ((1R)-2-[4-(5-Cyclopropyl-2-{6-cyclopropyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol (40 mg, 0.08 mmol) and 4-(3-bromopropyl)morpholine 1-bromo-2-chloroethane (25.5 mg, 0.12 mmol) were dissolved in ACN (1.9 mL), K2CO3 (32 mg) was added and the mixture was stirred at 40°C overnight. The mixture was then diluted with water / ACN (2 mL), filtered and purified by reverse phase chromatography (HPLC; C18, ACN / water including NH3) to give Example 11.

[1212] Analysis (Method H): R t : 1.01 min, [M+H] + :643

[1213] The intermediates and examples compiled in the table below were obtained by following a similar procedure to that described for Example 11 using Intermediate G2.

[1214]

[1215]

[1216]

[1217] Synthesis of Embodiments 8, 27, 30, 52, 63, 66, 74, 78, 79, 81, 85:

[1218] Synthesis of Example 8: 2-[(1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethoxy]ethan-1-ol

[1219]

[1220] (1R)-2-[4-(1-{2,6-Dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol (102) (25.3 mg, 0.05 mmol) was dissolved in DMF (1 mL). NaH (6.6 mg, 0.15 mmol, 55% purity) was added and the reaction mixture was stirred at room temperature for 10 minutes. 2-(2-Chloroethoxy)tetrahydro-2H-pyran (32.9 mg, 0.20 mmol) was then added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by reverse phase chromatography (HPLC; ACN / water / TFA). To remove the THP protecting group, the residue was dissolved in TFA (1 mL) and stirred at 50°C for 30 minutes. The reaction mixture was concentrated and purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give the title compound.

[1221] Analysis (Method G): R t : 1.01 min, [M+H] + :550

[1222] The examples compiled in the table below were obtained by following a similar procedure to that described for Example 8.

[1223]

[1224]

[1225]

[1226]

[1227]

[1228]

[1229] Synthesis of Example 36: 2-[(1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethoxy]-N-methylacetamide

[1230] Step 1: Synthesis of ethyl 2-[(1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethoxy]acetate

[1231]

[1232] {2-[(2R)-2-(2-ethoxy-2-oxoethoxy)-2-phenylethyl]-2H-indazol-4-yl}boronic acid (300 mg, 0.82 mmol), 1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (300 mg), Cs2CO3 (0.74 g) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) complex with dichloromethane (1:1) (100 mg) were suspended in dioxane (8 mL) and water (2 mL), and the mixture was stirred at 80 ° C for 3 hours under argon atmosphere. The mixture was concentrated and HOAc, ACN and water were added. The mixture was filtered and the filtrate was purified by reverse phase preparative HPLC to give the product.

[1233] Analysis (Method F): R t : 0.95 min, [M+H] + :592

[1234] Step 2: Synthesis of 2-[(1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethoxy]acetic acid

[1235]

[1236] 2-[(1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethoxy]ethyl acetate (375 mg, 0.53 mmol) was dissolved in EtOH (3 mL). NaOH (2.65 mL, 2.65 mmol, 1 M) was added and the reaction mixture was stirred at room temperature for 1.25 hours. The reaction mixture was diluted with water and TFA (0.5 mL) was added. The reaction mixture was concentrated and the residue was diluted with water (5 mL) and brine (5 mL) and extracted with DCM (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated to give Intermediate G3.

[1237] Analysis (Method F): R t : 0.83 min, [M+H] + :564

[1238] Step 3: Synthesis of 2-[(1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethoxy]-N-methylacetamide

[1239]

[1240] 2-[(1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethoxy]acetic acid (50 mg, 0.074 mmol) was dissolved in DMF (1 mL). DIPEA (26.8 μL, 0.15 mmol) and HATU (32.3 mg, 0.085 mmol) were added and the reaction mixture was stirred at room temperature for 10 minutes. Methylamine (74 μL, 0.15 mmol, 2 M in THF) was then added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by reverse phase chromatography (HPLC; ACN / water including NH3) to give Example 36.

[1241] Analysis (Method C): R t : 0.65 min, [M+H] + :577

[1242] The examples compiled in the table below were obtained by following a similar procedure to that described for Example 36.

[1243]

[1244]

[1245] Synthesis of Example 40: (1R)-2-[4-(1-{2-[3-(3,3-difluoropyrrolidin-1-yl)propyl]-6-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol

[1246]

[1247] Step 1: Synthesis of (1R)-2-(4-{1-[2-(3-chloropropyl)-6-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl]-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl}-2H-indazol-2-yl)-1-phenylethan-1-ol

[1248] (1R)-2-[4-(5-methyl-1-{6-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol (200 mg, 0.41 mmol), 1-bromo-3-chloropropane (80.2 μM, 0.814 mmol) and K2CO3 (281 mg) were suspended in ACN (5 mL) and stirred overnight at 60° C. The mixture was filtered and purified by preparative reverse phase chromatography to give the desired product.

[1249] Analysis: (Method G): R t : 1.10 minutes, [M+H] + :568 / 570(Cl)

[1250] Step 2: Synthesis of (1R)-2-[4-(1-{2-[3-(3,3-difluoropyrrolidin-1-yl)propyl]-6-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol

[1251]

[1252] (1R)-2-(4-{1-[2-(3-chloropropyl)-6-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl]-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl}-2H-indazol-2-yl)-1-phenylethan-1-ol (15 mg, 0.03 mmol) was dissolved in ACN (2 mL). K2CO3 (14.6 mg, 0.11 mmol) and 3,3-difluoropyrrolidine x HCl (13.6 mg, 0.096 mmol) were added, and the reaction mixture was stirred at 90°C overnight. The reaction mixture was purified by reverse phase chromatography (HPLC; ACN / water including NH3) to give Example 40.

[1253] Analysis: (Method H): R t : 1.10 minutes, [M+H] + :639

[1254] Synthesis of Example 41: 4-{4-[(1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1-hydroxyethyl]phenoxy}-2-methylbutan-2-ol

[1255]

[1256] 4-[(1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1-hydroxyethyl]phenol (30 mg, 0.06 mmol) was dissolved in DMF (1 mL). K2CO3 (15.2 mg, 0.11 mmol) and 4-bromo-2-methylbutan-2-ol (45.9 mg, 0.28 mmol) were added, and the reaction mixture was stirred at 60°C for 4 hours. The reaction mixture was purified by reverse phase chromatography (HPLC; ACN / water including NH3) to give Example 41.

[1257] Analysis (Method H): R t : 0.99 min, [M+H] + :632

[1258] Synthesis of Examples 68, 69 and 90:

[1259]

[1260] 4-[(1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazol-4-yl)-2H-indazol-2-yl]-1-hydroxyethyl]phenol (Example 55) (30 mg, 0.06 mmol) was dissolved in DMF (1 mL). K2CO3 (69.1 mg, 0.50 mmol) and 4-bromomethyltetrahydropyran (39.4 mg, 0.22 mmol) were added, and the reaction mixture was stirred at 60°C overnight. The reaction mixture was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give Example 68.

[1261] Analysis (Method G): R t : 0.87 minutes, [M+H] + :644

[1262] The examples compiled in the table below were obtained by following a procedure similar to that described for Example 68.

[1263]

[1264]

[1265] Synthesis of Example 88: 1-(4-bromophenyl)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]ethan-1-ol

[1266] Step 1: Synthesis of (4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2-[(trimethylsilyl)methyl]-2H-indazole)

[1267]

[1268] 5-(3-iodo-4-isopropyl-5-methyl-pyrazol-1-yl)-2,6-dimethyl-pyrazolo[3,4-b]pyridine (140 mg, 0.35 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(trimethylsilyl)methyl]-2H-indazole (71 mg, 0.21 mmol) were suspended in dioxane (1 mL). CsCO (346 mg) and Pd(dppf)Cl (28 mg, 1:1 complex with DCM) and water (150 μL) were added, and the mixture was stirred at 80°C overnight. The mixture was filtered, diluted with MeOH and HOAc and purified by preparative HPLC (ACN / water including TFA) to give the desired product.

[1269] Analysis (Method G): R t : 1.09 minutes, [M+H] + :472

[1270] Step 2: Synthesis of 1-(4-bromophenyl)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]ethan-1-ol

[1271]

[1272] (4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazol-3-yl)-2-[(trimethylsilyl)methyl]-2H-indazole) (84 mg, 0.18 mmol) and 4-bromobenzaldehyde (90 mg, 0.49 mmol) were dissolved in DMF (1 mL). CsF (30 mg, 0.20 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by reverse phase chromatography (HPLC; ACN / water including TFA) to give Example 88.

[1273] Analysis (Method G): R t : 1.05 minutes, [M+H] + :584 / 586(Br)

[1274] Synthesis of Example 92: (1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(1-methylcyclopropyl)-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol

[1275] Step 1: Synthesis of (1R)-2-[4-(5-methyl-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol

[1276]

[1277] (1R)-1-phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl]ethan-1-ol (700 mg, 1.9 mmol), 3-iodo-5-methyl-1H-pyrazole (400 mg, 1.9 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) complex with dichloromethane (1:1) (157 mg) were suspended in dioxane (7 mL) and Na2CO3 (2M, 2.9 mL), and the mixture was stirred at 80°C for 4 hours and at room temperature overnight under an argon atmosphere. The mixture was then diluted with ACN and purified by preparative HPLC to give the desired compound.

[1278] Analysis (Method A): R t : 0.45 min, [M+H] + :319

[1279] Step 2: Synthesis of (1R)-2-[4-(4-bromo-5-methyl-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol

[1280]

[1281] (1R)-2-[4-(5-methyl-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol (598 mg, 1.87 mmol) was suspended in ACN (40 ml), NBS (300 mg, 1.69 mmol) was added over 30 minutes and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with Na2S2O3 (0.5 M). The aqueous phase was extracted with n-butanol and the organic phases were combined and concentrated. The residue was dissolved in ACN / MeOH and purified by preparative HPLC. ACN was evaporated from the desired HPLC fractions and the precipitated product was collected to give the product.

[1282] Analysis (Method A): R t : 0.56 minutes, [M+H] + :397 / 399

[1283] Step 3: Synthesis of (1R)-2-{4-[5-methyl-4-(prop-1-en-2-yl)-1H-pyrazol-3-yl]-2H-indazol-2-yl}-1-phenylethan-1-ol

[1284]

[1285] (1R)-2-[4-(4-bromo-5-methyl-1H-pyrazol-3-yl)-2H-indazol-2-yl]-1-phenylethan-1-ol (305 mg, 0.77 mmol), potassium (prop-1-en-2-yl) trifluoroborate (193 mg, 1.3 mmol), Cs2CO3 (750 mg), palladium acetate (12 mg), butyldi-1-adamantylphosphine (62 mg), toluene (10 mL) and water (1 mL) were mixed and stirred overnight at 120° C. under argon atmosphere. The mixture was then filtered through a thiol scavenger resin cartridge and purified by preparative HPLC to give the product.

[1286] Analysis (Method A): R t : 0.55 min, [M+H] + :359

[1287] Step 4: Synthesis of (1R)-2-{4-[5-methyl-4-(1-methylcyclopropyl)-1H-pyrazol-3-yl]-2H-indazol-2-yl}-1-phenylethan-1-ol

[1288]

[1289] (1R)-2-{4-[5-methyl-4-(prop-1-en-2-yl)-1H-pyrazol-3-yl]-2H-indazol-2-yl}-1-phenylethan-1-ol (215 mg) was dissolved in DCM (15 mL). Diiodomethane (219 μL) was added at 0°C, followed by diethylzinc (2.7 mL, 1 M in hexanes), and the mixture was stirred at 0°C for 1 hour. Aqueous NH4Cl (60 mL) was then added, and the mixture was extracted with DCM. The organic phase was dried (Na2SO4), concentrated, and purified by preparative HPLC to give the desired product.

[1290] Analysis (Method A): R t : 0.64 minutes, [M+H] + :373

[1291] Step 5: Synthesis of 1-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4-(1-methylcyclopropyl)-1H-pyrazol-1-yl)propan-2-one

[1292]

[1293] (1R)-2-{4-[5-methyl-4-(1-methylcyclopropyl)-1H-pyrazol-3-yl]-2H-indazol-2-yl}-1-phenylethan-1-ol (28 mg, 0.075 mmol) was dissolved in ACN (0.6 mL), then KCO (26 mg) and chloroacetone (12 μL) were added, and the mixture was stirred at 50 ° C for 7 days. During this time, additional chloroacetone (2-4 equivalents) was added to the mixture every day. The mixture was then concentrated and purified by preparative HPLC to give the product.

[1294] Analysis (Method A): R t : 0.62 minutes, [M+H] + :429.

[1295] Step 6: Synthesis of (1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-5-methyl-4-(1-methylcyclopropyl)-1H-pyrazol-3-yl)-2H-indazol-2-yl-1-phenylethan-1-ol

[1296]

[1297] 1-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}-5-methyl-4-(1-methylcyclopropyl)-1H-pyrazol-1-yl)propan-2-one (12 mg), 3-amino-1-methyl-1H-pyrazole-4-carbaldehyde (Intermediate E3) (3.5 mg) and piperidine (7 μL) were suspended in ethanol (500 μL) and the mixture was stirred at 80° C. for 3 hours. The mixture was concentrated, dissolved in MeOH and purified by preparative HPLC and then by preparative TLC (DCM / MeOH 93 / 7) to give Example 92.

[1298] Analysis (Method A): R t : 0.62 minutes, [M+H] + :518.

[1299] Synthesis of Example 96: 2-[(phenylsulfonyl)methyl]-4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazol-4-yl}-2H-indazole

[1300]

[1301] 2-{[(R)-Benzenesulfinyl]methyl}-4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazol-4-yl}-2H-indazole (15.9 mg, enantiomer eluted at 0.81 min) was suspended in DCM (1 mL), 3-chloroperbenzoic acid (10 mg) was added at 5°C, and the mixture was stirred for 1 hour. The mixture was diluted with DCM, extracted with Na2CO3 and the organic phase was concentrated. The mixture was purified by preparative HPLC (Xbridge-C18, ACN / water including TFA) to give Example 96.

[1302] Analysis (Method A): R t : 0.47 minutes, [M+H] + :566.

[1303] Example 97: (1R)-2-(4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazol-4-yl}-2H-indazol-2-yl)-1-phenylethan-1-ol

[1304]

[1305] 4-Bromo-5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazole (150 mg, 0.32 mmol), {2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazol-4-yl}boronic acid (108 mg, 0.39 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (21 mg) were suspended in dioxane (2.5 mL). Na2CO3 (400 μL, 2M aqueous solution) was added, and the mixture was degassed in vacuo and flushed with argon. The reaction mixture was heated to 80°C under an argon atmosphere and maintained for 3 hours. The mixture was diluted with ACN / MeOH, filtered through a thiol scavenger resin cartridge, and purified by preparative HPLC (Xbridge-C18, ACN / water including TFA, gradient 10% to 100% ACN) and a second HPLC purification (Xbridge-C18, ACN / water including NH3, 10% to 80% ACN) to give Example 97.

[1306] Analysis (Method A): R t : 0.46 minutes, [M+H] + :532

[1307] Synthesis of Example 111: (1R)-2-(4-{5-methyl-1-[2-methyl-6-(pyrrolidin-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-4-(propan-2-yl)-1H-pyrazol-3-yl}-2H-indazol-2-yl)-1-phenylethan-1-ol

[1308]

[1309] Under argon atmosphere, tert-butyl 2-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazol-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridin-6-yl}pyrrolidine-1-carboxylate (96 mg, 0.17 mmol) and {2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazole-4-yl}boronic acid (59 mg, 0.21 mmol) were suspended in dioxane (2 mL), and CsCO (0.43 mL, 1 M aqueous solution) was then added. XPhos Pd G (8.3 mg) was then added, and the mixture was stirred at 90 ° C for 4 hours. The mixture was then diluted with EtOAc and extracted with water. The organic phase was concentrated and suspended in DCM (2 mL) and TFA (1 mL) at room temperature for 1 hour. The mixture was then concentrated and purified by preparative HPLC to give Example 111.

[1310] Analysis (Method G): R t : 0.74 minutes, [M+H] + :561

[1311] List of abbreviations:

[1312] Ac Acetyl

[1313] ACN Acetonitrile

[1314] AIBN 2,2'-azobis(isobutyronitrile)

[1315] Boc tert-Butyloxycarbonyl

[1316] Cbz benzyloxycarbonyl

[1317] CycH Cyclohexane

[1318] d day

[1319] DAST Diethylaminosulfur trifluoride

[1320] DCE 1,2-Dichloroethane

[1321] DCM Dichloromethane

[1322] DEAD Diethyl azodicarboxylate

[1323] DIAD Diisopropyl azodicarboxylate

[1324] DIPEA N,N-Diisopropylethylamine

[1325] DMF N,N-Dimethylformamide

[1326] DMP Dess-Martin Periodinane

[1327] DMSO Dimethyl sulfoxide

[1328] EtOAc Ethyl acetate

[1329] EtOH

[1330] h hour

[1331] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl Hexafluorophosphate

[1332] HPLC High Performance Liquid Chromatography

[1333] HPLC-MS coupled high performance liquid chromatography-mass spectrometry

[1334] IPA Isopropyl Alcohol

[1335] LC Liquid Chromatography

[1336] LC-MS coupled liquid chromatography-mass spectrometry

[1337] LiHMDS Lithium bis(trimethylsilyl)amide

[1338] M molar concentration (mol / L)

[1339] MeI Methyl iodide

[1340] MeTHF 2-Methyltetrahydrofuran

[1341] MeOH Methanol

[1342] min

[1343] MS

[1344] MTBE Methyl tert-butyl ether

[1345] n-BuLi n-Buthyllithium

[1346] NBS N-Bromosuccinimide

[1347] NIS N-iodosuccinimide

[1348] NMP N-Methyl-2-pyrrolidone

[1349] NMR Nuclear Magnetic Resonance

[1350] PEPPSI(TM)-IPR (1,3-bis(2,6-diisopropylphenyl)imidazolylidene)(3-chloropyridyl)palladium(II) chloride

[1351] PdCl2(dtbpf) 1,1'-Bis-(di-tert-butylphosphino)ferrocenepalladium dichloride

[1352] Pd(dppf)Cl2 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride

[1353] Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0)

[1354] XPhos Pd G3 2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II)

[1355] pet.

[1356] R f Retention Factor

[1357] RP Invert

[1358] rt room temperature

[1359] t R Retention time (HPLC / LC)

[1360] SFC Supercritical Fluid Chromatography

[1361] TBAF Tetrabutylammonium fluoride

[1362] TBTU O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyl Tetrafluoroborate

[1363] TEA Triethylamine

[1364] TFA Trifluoroacetic acid

[1365] THF Tetrahydrofuran

[1366] THP Tetrahydro-2h-pyran

[1367] TLC Thin Layer Chromatography

[1368] TMAD N,N,N'N'-Tetramethylazodicarbonamide

[1369] UV

[1370] V Volume

[1371] HPLC Method:

[1372] Method A

[1373]

[1374] Column: XBridge BEH C18_2.1×30mm, 1.7μm; Column temperature: 60℃

[1375] Method B

[1376]

[1377] Column: XBridge BEH C18_2.1×30mm, 1.7μm; Column temperature: 60℃

[1378] Method C

[1379]

[1380] Column: XBridge BEH C18_2.1×30mm, 2.5μm; Column temperature: 60℃

[1381] Method D

[1382]

[1383] Column: XBridge BEH Phenyl_2.1×30mm, 1.7μm; Column temperature: 60℃

[1384] Method E

[1385]

[1386]

[1387] Column: Sunfire C18_2.1×30mm, 2.5μm; Column temperature: 60°C

[1388] Method F

[1389]

[1390] Column: Sunfire C18 (Waters) 2.5 μm; 3.0×30 mm; column temperature: 60°C

[1391] Method G

[1392]

[1393] Column: Sunfire (Waters) 2.5 μm; 3.0×30 mm; column temperature: 60° C.

[1394] Method H

[1395]

[1396]

[1397] Column: XBridge (Waters); C18_3.0×30mm_2.5μm; Column temperature: 60°C

[1398] Method I

[1399]

[1400] Column: XBridge (Waters); C18_3.0×30mm_2.5μm; Column temperature: 60°C

[1401] Method J

[1402]

[1403] Column: Sunfire C18 (Waters) 2.5 μm; 3.0×30 mm; column temperature: 60°C

[1404] Method K

[1405]

[1406]

[1407] Column: Acquity UPC2 Torus 2-PIC_3.0×100mm_1.7μm; Column temperature: 30°C

[1408] Method L

[1409]

[1410] Column: Sunfire C18 (Waters) 2.5 μm; 3.0×30 mm; column temperature: 60°C

[1411] Method M

[1412] Time (minutes) Carbon dioxide solubility % Methanol solubility % Flow rate [mL / min] 0.00 97 3 1.3 2.5 55 45 1.3 3.5 55 45 1.3 3.51 97 3 1.3 4 97 3 1.3

[1413] Column: Acquity UPC2 Torus 2-PIC_3.0×100mm_1.7μm; Column temperature: 30°C

[1414] Method N

[1415]

[1416] Column: XBridge C18_3.0×30mm_2.5μm (Waters); Column temperature: 60°C

[1417] Method O

[1418]

[1419] Column: XBridge C18_3.0×30mm_2.5μm (Waters); Column temperature: 60°C

[1420] Method P

[1421]

[1422] Column: XBridge C18_3.0×30mm_2.5μm (Waters); Column temperature: 60°C

[1423] Method Q

[1424]

[1425] Column: Acquity UPLC BEH C18 1.7 μm (2.1×100 mm); Column temperature: 40°C

[1426] Method R

[1427]

[1428]

[1429] Column: Kinetex XB-C18 2.6μm (4.6×50mm), Column temperature: 25°C

[1430] Method S

[1431]

[1432] Column: Acquity UPLC BEH C18 1.7 μm (2.1×100 mm); Column temperature: 40°C

[1433] Method T

[1434]

[1435] column: Cellulose SB_4.6×250mm_5μm; column temperature: 40℃

[1436] Method U

[1437]

[1438] Column: CHIRAL Cellulose SB_4.6×250mm_5μm; column temperature: 40℃

[1439] Method V

[1440]

[1441] Column: CHIRAL Cellulose SB_4.6×250mm_5μm; column temperature: 40℃

[1442] Method W

[1443]

[1444] Column: CHIRAL Cellulose SB_4.6×250mm_5μm; column temperature: 40℃

[1445] Method X

[1446]

[1447] Column: CHIRAL Cellulose SB_4.6×250mm_5μm; column temperature: 40℃

[1448] Method Y

[1449]

[1450] Column: CHIRAL Cellulose SB_4.6×250mm_5μm; column temperature: 40℃

[1451] Method Z

[1452]

[1453] Column: CHIRAL Cellulose SB_4.6×250mm_5μm; Column temperature: 40℃ Method ZA

[1454]

[1455] Column: CHIRAL Amylose-SA_3×100mm_3μm; column temperature: 40℃

[1456] Method ZB

[1457]

[1458] Column: Lux(R) Cellulose-2_3×100mm_3μm; Column temperature: 40°C

[1459] Method ZC

[1460]

[1461] column: IG_4.6×250mm_5μm; Column temperature: 40℃

[1462] Method ZD

[1463]

[1464]

[1465] Column: CHIRAL Amylose SA_4.6×250mm_5μm; column temperature: 40℃

[1466] Biological assays

[1467] The following in vitro STING biochemical and cellular assays can be used to demonstrate the activity of compounds of the invention.

[1468] Human STING HTRF binding assay

[1469] Binders to human STING WT (R232) were identified using a competitive HTRF assay format (Cisbio 64BDSTGPEG) using d2-labeled STING ligand, 6His-tagged human STING protein, and an anti-6His cryptate-labeled antibody. Compounds compete with STING ligand-d2, thereby preventing FRET from occurring, which can be detected by EnVision TM Reader (PerkinElmer).

[1470] Assay method: Compounds were delivered as 10 mM DMSO solutions, serially diluted by the Agilent Bravo workbench, and transferred to 384-well assay plates (Perkin Elmer #6005359) using a Cybiwell dispenser. Typically, 8 concentrations were used, with the highest concentration in the final assay volume being 10 μM or 1 μM, followed by approximately 1:5 dilution steps. The DMSO concentration was set to 1% in the final assay volume. The 384-well assay plate contained 20 test compounds and DMSO in columns 23 and 24. The cGAMP standard dilution row was prepared according to the manufacturer and transferred to each assay plate. After transferring the compound solution or dilution buffer for negative (high) and positive (low) controls, 5 μl of human STING protein (WT R232 human version of the ring binding domain (residues 138 to 379), which is fused to a 6His tag at the N-terminal portion; diluted 1:50 in detection buffer) was dispensed into all wells except the positive control, which received only detection buffer. The plate was centrifuged at 1000 rpm for 20 seconds. After that, 10 μl of anti-6His-Cryptate antibody / Sting ligand-d2 mixture was added to all wells using a Multidrop combi dispenser, followed by another 20 sec / 1000 rpm centrifugation step. After incubating the plate at room temperature for 180 minutes, the excitation of 665 / 620 nM (HTRF ratio) was measured using an Envison reader (PerkinElmer).

[1471] Data evaluation and calculations: For data evaluation and calculations, the HTRF ratios were calibrated using the cGAMP standard curve. Thereafter, the measurements of the low control were set as 0% control and the measurements of the high control were set as 100% control. IC50 values ​​were calculated using the standard 4-parameter logistic regression formula. Calculation: [y = (ad) / (1 + (x / c) ^ b) + d], a = low value, d = high value; x = concentration M; c = IC50 M; b = slope.

[1472] The results of this assay are shown in the table below.

[1473] Determine the increased stability of STING protein against thermal denaturation, differential scanning fluorimetry (DSF)

[1474] The binding affinity of the compounds of the invention can be confirmed using a thermal shift assay, which measures the stability of a suitable protein species of human STING against thermal denaturation in the presence of a compound. In this assay, the unfolding temperature of the protein is monitored in the presence of a fluorescent dye that exhibits affinity for the hydrophobic amino acids of the protein, which are buried in its folded state and gradually exposed during the unfolding process. The dye fluorescence is quenched in an aqueous environment and is enhanced when the dye binds to the hydrophobic portion of the unfolded protein. A plot of the fluorescence intensity as a function of temperature generally exhibits an S-shaped curve, which is explained by the two-state model of protein unfolding (differential scanning fluorimetry). The inflection point of the curve represents the "melting" temperature (Tm) of the protein, which is numerically calculated using the Boltzmann equation.

[1475] Methods: The thermal stability of STING protein was measured using a specific expression construct of the cGAMP-binding domain of wild-type (GRR) human STING containing residues 155 to 341 and an N-terminal 8×His tag in an assay buffer containing 20 mM Tris, 150 mM NaCl, pH 7.5.

[1476] Determination of use PCR plate 384 wells CLR / WHT (Catalog No. HSP3805, BIO-RAD), 'B' adhesive seal (Cat. No. MSB-1001, BIO-RAD) and run on a CFX384 Real-Time System (Bio-Rad).

[1477] Prepare a DMSO stock solution of SYPRO orange (SIGMA S5692-500UL).

[1478] Compound stock solutions (10 mM in DMSO) were diluted 1 :2 in DMSO to an intermediate compound concentration of 5 mM and then further diluted 1 :40 in assay buffer to give a compound concentration of 125 μM and 2.5% DMSO.

[1479] Then the fluorescent dye stock solution (5000×SYPRO Orange) was mixed with the target protein and buffer to a concentration of 15 μM protein and 25×SYPRO Orange. 2 μl of this protein-dye mixture was added to 8 μl of compound solution. The final volume was 10 μL. Positions 3 to 6 were used as negative controls (protein containing 2% DMSO). The plate was prepared for repeated measurements and centrifuged at 1000 g for 2 minutes. In the measurement, 160 cycles of 0.5°C were used (temperature ramp rate was 15 seconds / cycle, 15°C to 95°C).

[1480] The final assay concentrations for compound characterization were as follows:

[1481] 100 μM compound, 3 μM target protein, 5×SYPRO Orange, 2% DMSO in 10 μl. All dispensing steps were performed using a HamiltonStar pipetting robot (Hamilton).

[1482] Dissociation curves were processed in Bio-Rad CFX Manager. Peak type was set to "negative". Compound codes for screening were assigned in the plate layout.

[1483] The two replicate measurements of TM were averaged and the standard deviation was calculated. In cases where SD > 1.5 °C, the measurement was repeated.

[1484] The melting point (Tm) obtained for STING protein alone was subtracted from the T obtained for protein incubated with ligand to generate a ΔTm value.

[1485] Protein production and purification: The protein used for biophysical experiments was recombinant human STING protein, which includes its cytoplasmic extracellular domain. A codon-optimized DNA sequence encoding amino acid residues 155 to 341 (Swiss Prot Q86WV6) of human STING (WT) for expression in Escherichia coli was synthesized by GeneArt (Regensburg, Germany) and inserted into the pET17b E. coli expression vector. The protein construct encodes an N-terminal 8×His tag, followed by a tobacco etch virus protease (TEV) cleavage site and the above STING gene sequence. The resulting protein sequences of the STING variants used are listed below: His-TEV—hSTING (WT)

[1486]

[1487] To express recombinant human STING, the above constructs were transformed into E. coli BL21DE3 strain and grown in LB medium at 37°C in a shake flask. Expression was induced by adding isopropyl β-D-1-thiogalactopyranoside to a final concentration of 1 mM and the culture was shaken overnight. The cell pellet was centrifuged and stored at -70°C until further use.

[1488] Proteins were purified by thawing cells in lysis buffer (20 mM TRIS-HCl, pH 8, 300 mM NaCl, 2 mM mercaptoethanol, 20 mM imidazole, complete protease inhibitors (Roche) and DNase (Roche)), followed by metal affinity purification using Ni-NTA resin and elution buffer (composed of 20 mM TRIS-HCl, pH 8, 300 mM NaCl, 2 mM mercaptoethanol, 300 mM imidazole), and size exclusion chromatography in running buffer (20 mM TRIS-HCl, pH 8, 100 mM NaCl, 2 mM DTT). Peak fractions were collected and concentrated to 2.5 mg / mL.

[1489] The results of this assay are shown in the table below.

[1490] Human Whole Blood Assay (HWBA)

[1491] To examine STING inhibition in a physiological setting, whole blood was stimulated with the cyclic dinucleotide cGAMP. Pathway activity was monitored by measuring IFNα2α production.

[1492] Assay method: Compounds were delivered as 10 mM DMSO solutions and serially diluted and transferred to 96-well cell culture plates (Corning #3595) using an Echo acoustic dispenser, each well pre-filled with 20 μl OptiMEM (Gibco, #11058-021). Typically, 8 concentrations were used, with the highest concentration in the final assay volume being 10 μM, followed by approximately 1:5 dilution steps. The DMSO concentration was set to 0.1% in the final assay volume. The 96-well assay plate contained 9 test compounds, a reference compound, and DMSO in the control wells.

[1493] Human whole blood collected as sodium citrate blood (e.g. 3.8% in Monovettes from Sarstedt) from 3 or more healthy donors (male or female, drug-free within 7 days, except contraceptives and thyroxine) was performed in parallel. After collection, the whole blood was kept at room temperature for a maximum of 3 hours until used in the assay.

[1494] 160 μl of whole blood samples were transferred to each well of a 96-well assay plate filled with compound / OptiMEM. All assay plates were prepared in duplicate with blood from different donors. The blood plates were kept at room temperature for 60 minutes and continuously shaken at 450 rpm, covered with a lid but not sealed.

[1495] Dilute 10x cGAMP assay solution from a 2 mM stock solution in 1x HBSS at room temperature just prior to use. Add 20 μl of 10x cGAMP / HBSS to all compound and all high control wells, while add HBSS only to all low control wells.

[1496] After covering the assay plate with an aera seal and lid, the blood plate was kept at room temperature for 30 minutes with continuous shaking at 450 rpm and then incubated overnight in an incubator at 37°C without shaking for 22 hours.

[1497] In order to detect IFNα-2α in human plasma, according to the manufacturer, the biotinylated capture antibody (antibody group IFNA2, Meso Scale Diagnostics#B21VH-3, including coating and capture antibody) was diluted in diluent 100 (Meso Scale Diagnostics#R50AA-4) at 1:17.5. U-Plex MSD GOLD 96-well small spot streptavidin SECTOR plates (Meso Scale Diagnostics#L45SA-5) were coated with 25 μl of the diluted capture antibody. The coated plates were cultured at room temperature under 700 rpm continuous shaking for 60 minutes. The MSDIFNα-2α plates were washed three times with 150 μl of washing buffer (1×HBSS, 0.05% Tween).

[1498] After blocking each plate with 100 μl blocking solution / well (1×HBSS, containing 0.2% Tween, 2% BSA) at room temperature for 60 minutes and continuously shaking at 700 rpm, the plate was emptied as dry as possible by pouring before continuing to use human plasma. The whole blood assay plate was centrifuged at 1600 rpm for 10 minutes. 25 μl of supernatant was transferred from each whole blood plate to the corresponding IFNα-2α plate using a pipetting robot. Each plate was sealed with a microplate seal and kept again for two hours at room temperature under continuous shaking at 700 rpm. Then, the MSD IFNα-2α plate was washed three times with 150 μl wash buffer (1×HBSS, 0.05% Tween), after which 25 μl of MSDSULFO-TAG IFNα-2α antibody solution (1:100 diluted in diluent 3 (Meso Scale Diagnostics#R50AP-2)) was added to each well of the plate. Each plate was then sealed with a microplate sealer and kept again for two hours at room temperature with continuous shaking at 700 rpm. Finally, the MSD IFNα-2α plates were washed three times with 150 μl of wash buffer (1×HBSS, 0.05% Tween). 150 μl of 2× read buffer was added to each well and each plate was immediately measured using an MSD Sector S600 reader using the vendor barcode.

[1499] Data Evaluation and Calculations: For data evaluation and calculations, the % control calculation for each well was based on the mean of the high (cGAMP stimulated controls) and the mean of the low (unstimulated controls) controls by using the following formula:

[1500] [Count(Sample)-Count(Low)) / (Count(High)-Count(Low))]*100

[1501] IC50 values ​​were calculated using a standard 4-parameter logistic regression formula. Calculation: [y = (ad) / (1+(x / c)^b)+d], a = low value, d = high value; x = concentration M; c = IC50 M; b = slope.

[1502] The results of this assay are shown in the table below.

[1503] Human STING reporter gene assay

[1504] The THP1-BlueISG reporter cell line expressing wild-type STING and an IRF-dependent alkaline phosphatase reporter was used for potency measurements of activators of human wild-type STING.

[1505] Assay Method: Compounds were delivered in 10 mM DMSO solution and serially diluted in assay medium (RPMI 1640 (Life Technologies #A10491-01), 10% FCS (Life Technologies #10500-064), 1× Pen / Strep solution (Life Technologies #15140-122)). Typically, 8 concentrations were used, with the highest concentration in the final assay volume being 10 μM or 100 μM, followed by approximately 1:5 dilution steps. The DMSO concentration was set to 1% in the final assay volume. The 384-well assay plate contained 21 test compounds (columns 1 to 21), a reference compound (column 22), and DMSO in columns 23 and 24.

[1506] Cells cultured according to the manufacturer's conditions (culture medium: RPMI 1640 (Life Technologies #A10491-01), 10% FCS (Life Technologies #10500-064), 1× Pen / Strep solution (Life Technologies #15140-122), 100 μg / mL Normocin (Life Technologies #ant-nr-1), 100 μg / mL Zeocin (Life Technologies #R25001)) were harvested, resuspended, and diluted in fresh assay medium. Cells were then seeded into assay plates (10,000 cells / well) in 15 μl of assay medium, and 5 μl of pre-diluted compound solution was then added to the wells of the assay plate. Then, 5 μl of assay medium per well was added to the wells containing the compound, followed by incubation at room temperature for 30 minutes and at 37°C for 24 hours. Then, 5 μl of assay medium containing DMSO (1% fc) per well was added to the control wells, plus 5 μl of assay medium alone for negative control (low value), or plus 5 μl of pre-diluted 2`3`-cGAMP (20 μM fc; BIOLOG Life Science Institute #C 161 or Invivogen #tlrl-nacga23) for positive control (high value).

[1507] Finally, 75 μl of Quanti Blue reagent was added to the plate using a MultiDrop Combi and then incubated at 37°C for 30 minutes. TM The absorbance was measured on a reader (PerkinElmer).

[1508] Data evaluation and calculations: For data evaluation and calculations, the measured value of the low control was set as 100% control and the measured value of the high control was set as 200% control. EC50 values ​​were calculated using the standard 4-parameter logistic regression formula. Calculation: [y = (ad) / (1 + (x / c) ^ b) + d], a = low value, d = high value; x = concentration M; c = IC50 M; b = slope.

[1509] Results from this assay were negative for agonism, with the cutoff set at greater than 30 μM.

[1510] Characterization data

[1511]

[1512]

[1513]

[1514]

[1515]

[1516] Indications

[1517] As has been found, the compounds of formula (I) or (I') are characterized by their various uses in the field of therapy.

[1518] Particularly mention should be made of those applications of the compounds of the invention that are used based on their pharmaceutical activity as STING inhibitors. Although the cGAS / STING pathway is important for host defense against pathogen invasion (e.g., viral infection and invasion of some intracellular bacteria), cellular stress and genetic factors may also lead to the production of abnormal cellular dsDNA (e.g., through nuclear or mitochondrial leakage) and thereby trigger an autoinflammatory response. Therefore, STING inhibitors have a strong therapeutic potential for the treatment of different autoinflammatory and autoimmune diseases.

[1519] STING inhibitors will block inflammation and abnormal tissue remodeling in a group of autoimmune and inflammatory diseases, including systemic lupus erythematosus (SLE), systemic sclerosis, inflammatory bowel disease, sepsis, Sjögren's syndrome, dermatomyositis, rheumatoid arthritis, and a group of fibrotic diseases including NASH, IPF, and chronic renal fibrosis.

[1520] STING inhibitors are also being investigated for other diseases such as cancer, heart failure, AMD, retinopathy, glaucoma, diabetes, obesity, aging, muscle disease, osteoarthritis, ALS, Parkinson's disease, and COVID-19.

[1521] An et al., Arthritis Rheumatol. April 2017; 69(4): 800-807, disclose that cGAS expression in peripheral blood mononuclear cells (PBMC) of patients with the autoimmune disease systemic lupus erythematosus (SLE) is significantly higher than that of normal controls. By combining mass spectrometry-targeted measurement of cGAMP, cGAMP was detected in 15% of the SLE patients tested, but not in normal or rheumatoid arthritis controls. SLE patients with cGAMP have higher disease activity than SLE patients without cGAMP.

[1522] Thim-Uam et al. (iScience, 2020 Sep 4; 23(9): 101530) demonstrated that STING deficiency can improve lupus development in mice lacking Fcgr2b. Prabakaran et al. (EBioMedicine, 2021 Apr; 66: 103314) showed that the STING pathway inhibitor ISD017 blocked STING activity in vivo and improved disease progression in a lupus mouse model. ISD017 treatment also blocked pathological cytokine responses in PBMCs from lupus patients with elevated IFN-I levels.

[1523] Ryu et al. (Arthritis Rheumatol. 2020 Nov;72(11):1905-1915) showed that in 2 systemic sclerosis-related interstitial lung disease (SSc-ILD) cohorts, plasma mtDNA concentrations increased, reflecting decreased ventilation, and were positively correlated with TLR-9 and cGAS / STING activation and 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 the skin of SSc patients, and that STING deficiency or H151 administration improved fibrosis and vascular lesions in vitro and in BLM-induced SSc mice.

[1524] Li et al. showed that extracellular vesicles containing plasma-derived DNA induced STING-mediated proinflammatory responses in dermatomyositis (Theranostics. 2021; 11(15): 7144-7158). Zhou et al. (J Clin Lab Anal. 2022 Oct; 36(10): e24631) described the correlation between activation of the cGAS-STING pathway and muscle fiber atrophy / necrosis in dermatomyositis.

[1525] Haag et al. (Nature. 2018 July; 559(7713): 269-273) demonstrated that covalent STING inhibitors attenuated pathological features of autoinflammatory diseases in TREX1_KO mice. Loss-of-function mutations in TREX1 lead to rare monogenic interferonopathies, such as Aicardi-Goutières syndrome (AGS).

[1526] 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. In a sepsis model, STING knockout mice attenuated inflammatory responses, intestinal permeability, and reduced bacterial translocation. Zeng et al. (ci Transl Med. 2017 Oct 18;9(412):eaan5689) also showed that STING deficiency in mice protected two sepsis models (LPS model and cecal ligation and puncture model), and that the expression level of STING in the human intestinal lamina propria correlated with intestinal inflammation in sepsis patients. Inhibition of the ALK-STING pathway protected mice from CLP-induced polymicrobial sepsis.

[1527] In Schuliga et al., Clin. Sci. (Lond), 2020 Apr 17; 134(7):889-905, it is described that self-DNA perpetuates senescence of IPF lung fibroblasts in a cGAS-dependent manner. Benmerzoug et al. (Nat. Commun. 9, 1-19 (2018)) showed that STING-dependent sensing of self-DNA drives silica-induced lung inflammation, leading to lung fibrosis.

[1528] Other scientific hints linking the etiology of metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) and other fibrotic diseases such as nonalcoholic steatohepatitis (NASH) to the cGAS / STING pathway have been described in Yu et al., J. Clin. Invest. 2019 Feb 1;129(2):546-555, and Cho et al., Hepatology. 2018 Oct;68(4):1331-1346, and Qiao et al., Metabolism, 2018 Apr;81:13-24 doi:10.1016 / j.metabol.2017.09.010, epub 2017 Oct 26.

[1529] Nascimento et al., Sci. Rep. 2019 Oct 16;9(1):14848 discloses that autologous DNA release and STING-dependent sensing drive cigarette smoke-induced inflammation in mice, suggesting a link between the cGAS-STING pathway and chronic obstructive pulmonary disease (COPD).

[1530] Ahn et al. (Cell Rep 2017, 21:3873-3884) described the protective effect of mice lacking STING in an inflammatory colitis model. Martin et al. (Cell Rep 2019 Oct 3; 9:14281) described that STING deficiency was protective in a dextran sodium sulfate (DSS) colitis model, while STING stimulation aggravated intestinal inflammation. These publications support STING as a potential therapeutic target for preventing inflammatory bowel disease (IBD).

[1531] Kerur et al., Nat. Med. 2018 Jan;24(1):50-61, describe that cGAS plays an important role in atypical inflammatory resolving activation in age-related macular degeneration (AMD).

[1532] In addition, STING inhibitors also have therapeutic potential in the treatment of cancer (see Hoong et al., Oncotarget. 2020 July 28; 11(30): 2930-2955, and Chen et al., Sci. Adv. 2020 October 14; 6(42): eabb8941). In addition, it is shown in Bakhoum et al., Nature. 2018 January 25; 553(7689): 467-472: "Chromosomal instability drives metastasis through a cytosolic DNA response", and Liu et al., Nature. 2018 November; 563(7729): 131-136: "Nuclear cGAS suppresses DNA repair and promotes tumorigenesis".

[1533] STING inhibitors also have potential in the treatment of obesity and diabetes, such as Mao et al., Arterioscler Thromb Vasc Biol (2017) 37(5): 920-9. doi: 10.1161 / ATVBAHA.117.309017

[1534] In addition, STING inhibitors also have therapeutic potential in the treatment of heart failure (King et al., Nat Med 2017 Dec;23(12):1481-1487; Hu et al., Am. J. Physiol. Heart Circ. Physiol., 2020 Jun 1;318(6):H1525-H1537).

[1535] Further scientific studies suggest an association 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 Sjögren's syndrome and the cGAS / STING pathway (Papinska et al., J. Dent. Res. 2018 Jul;97(8):893-900).

[1536] In addition, STING inhibitors also have therapeutic potential in the treatment of COVID-19 / SARS-CoV-2 infection, 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 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 NF-kappaB)".

[1537] In addition, STING inhibitors have therapeutic potential in treating renal inflammation and renal fibrosis, as shown in the following documents: Chung et al., Cell Metab. 2019 30:784-799: "Mitochondrial Damage and Activation of the STING Pathway Lead to Renal Inflammation and Fibrosis", and Maekawa et al., Cell Rep. 2019 29:1261-1273: "Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury".

[1538] In addition, STING has been shown to promote 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 knockout mice have reduced tissue inflammation, improved cardiac / muscle function, and extended lifespan (Dou et al., Nature. 2017 550: 402-406). In addition, in humans, variations within the STING gene are associated with healthy aging, most likely due to reduced inflammation (Hamann et al., Gerontology 2019; 65: 145-154). In general, STING inhibitors will reduce aging-related inflammation and senescent cell accumulation, and will improve aging-related diseases such as aging / muscle diseases and osteoarthritis.

[1539] combination

[1540] The compounds of Formula 1 may be administered to a patient alone or in combination with one or more other pharmacologically active agents.

[1541] In a preferred embodiment of the present invention, the compound can be combined with one or more pharmacologically active agents selected from the group consisting of: PDE 4 inhibitors (preferably 1-[[(5R)-2-[4-(5-chloropyrimidin-2-yl)-1-piperidinyl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol and [1-[[(5R)-2-[4-(5-chlorophenyl-2-yl)-1-piperidinyl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol, such as WO 2013 / 026797), anti-inflammatory agents, antifibrotic agents, antiallergic agents / antihistamines, bronchodilators, β2 agonists / β mimetics, adrenergic agonists, anticholinergics, methotrexate, mycophenolate mofetil, leukotriene modifiers, JAK inhibitors, anti-interleukin 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 modulators, anti-TNF antibodies, and anti-BAFF agents.

[1542] Preparation

[1543] The compounds of the present invention can 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 inhalation administration. Parenteral administration refers to administration routes other than enteral, transdermal or inhalation, and is usually administered by injection or infusion. Parenteral administration includes intravenous, intramuscular and subcutaneous injection or infusion. Inhalation refers to administration to the patient's lungs, whether via the mouth or via the nasal passages. Topical administration includes administration to the skin. The compounds of the present invention can be administered via eye drops to treat Sjögren's syndrome.

[1544] Suitable forms for administration are, for example, tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. In each case, the content of the pharmaceutically effective compound should be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight of the total composition, i.e., a content sufficient to achieve the dosage range defined below.

[1545] The preparation can be administered orally in the form of tablets, 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 can be administered as a powder, in the form of an aqueous or ethanolic aqueous solution or using a propellant gas formulation.

[1546] Thus, preferably, the pharmaceutical formulation is characterized by the content of one or more compounds of formula (I) or formula (I') according to the above preferred embodiments.

[1547] It is particularly preferred to administer the compound of formula (I) or formula (I') orally, and it is also particularly preferred to administer it once or twice a day. Suitable tablets can be obtained, for example, by mixing the active substance with known excipients (e.g., inert diluents, such as calcium carbonate, calcium phosphate or lactose; disintegrants, such as corn starch or alginic acid; binders, such as starch or gelatin; lubricants, such as magnesium stearate or talc; and / or agents for delayed release, such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate). The tablet may also contain several layers.

[1548] Thus, coated tablets can be prepared by coating a core similar to that produced for tablets with substances commonly used for tablet coatings, such as polyvinylpyrrolidone (kollidone) or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities, the core may also consist of multiple layers. Similarly, the tablet coating may consist of multiple layers to achieve delayed release, possibly using the excipients mentioned above for tablets.

[1549] According to the invention, syrups containing active substances or combinations thereof may additionally contain sweeteners such as saccharin, cyclamate, glycerol or sugar and flavor enhancers such as flavorings such as vanillin or orange extract. They may also contain suspending adjuvants or thickeners, such as sodium carboxymethylcellulose; wetting agents, such as condensation products of fatty alcohols with ethylene oxide; or preservatives, such as parabens.

[1550] Capsules containing one or more active substances or active substance combinations can be prepared, for example, by mixing the active substances with inert carriers such as lactose or sorbitol and filling them into gelatin capsules. Suitable suppositories can be manufactured, for example, by mixing carriers provided for this purpose, such as neutral fats or polyethylene glycol or its derivatives.

[1551] Excipients that can be used include, for example, water; pharmaceutically acceptable organic solvents, such as paraffins (e.g., petroleum fractions), vegetable oils (e.g., peanut oil or sesame oil), monofunctional or polyfunctional alcohols (e.g., ethanol or glycerol); carriers, such as natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates), sugars (e.g., sucrose, lactose and glucose), emulsifiers (e.g., lignin, sulfite waste liquor, methylcellulose, starch and polyvinyl pyrrolidone) and lubricants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

[1552] Of course, for oral administration, in addition to the above-mentioned carriers, tablets may also contain some additives (e.g. sodium citrate, calcium carbonate and dicalcium phosphate) together with various additives such as starch (preferably potato starch), gelatin, etc. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used simultaneously with tableting. In the case of aqueous suspensions, the active substance may be combined with various flavor enhancers or colorants in addition to the excipients mentioned above.

Claims

1. A compound of formula 1; in BA is =CN- or -NC=; R1 is selected from and R1 is a connection point with the structure of Formula 1; R2 When BA is -NC=, it has C 1-6 -alkyl-, C 3-6 -cycloalkyl-, C 1-6 The meaning of -haloalkyl-; R2 When BA is =CN-, it has C 1-6 -alkyl-, C 3-6 -cycloalkyl-, C 1-6 -haloalkyl-, C 1-6 -alkyl-O-, HO-, H2N-, C 1-6 -alkyl-HN-, (C 1-6 -alkyl)2N-; R3 is H- or C 1-6 -alkyl, C 3-7 -Cycloalkyl, C 2-6 -Alkenyl, C 3-7 - heterocycloalkyl, each of which is optionally substituted with a group selected from F-, HO-, Me-, EtO-, NH2(O)C-; R4 is H-, F- or HO-; R4 b is H-, F-, Cl-, Br-, NC- or HO-; R5 is selected from and R5 is a connection point with the structure of Formula 1; Q is -C(R11)(R12)-, -S(O)- or -S(O)2-; R6 is C 2-6 -alkenyl, or C 1-6 -alkyl, which is optionally substituted independently of one another by one or two substituents selected from: C 3-6 -cycloalkyl-, halogen, HO-, C 1-6 -alkyl-O-, C 1-6 -alkyl-HN-, (C 1-6 -alkyl)2N-, NC-, (C 1-6 -alkyl)2(O)P-, (4-methoxyphenyl)methyl-, or A heterocycle selected from tetrahydrofuran-, 1,4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, triazole-, each of which is optionally substituted independently of one another by one or two substituents selected from the group consisting of: C 1-6 -alkyl-, halogen, O=; R7, R8, R9 are C 3-6 -cycloalkyl-, which is optionally C 1-6 -alkyl- or substituted with one or two halogen atoms, or Cyclopropylmethyl-, C 1-6 -haloalkyl-, C 1-6 -alkyl-O-, C 1-6 -alkyl-HN-, (C 1-6 -alkyl)2N-, C 1-6 -alkyl-S-, or C 1-6 -alkyl, which is linear or branched, which is optionally substituted by HO-, C 1-6 -alkyl-O-, C 1-6 -alkyl-HN-, (C 1-6 -alkyl) 2N- or morpholine-substituted, or A heterocycle selected from pyrrolidine-, tetrahydrofuran-, tetrahydropyran-; or C 1-6 -haloalkyl-O-; R10 is C 1-6 -alkyl- or C 1-6 -haloalkyl-; R11 is H, HO-, halogen- or R14-O-, R14-NH-; R12 is H- or F; R13 is a carbocyclic group, a heterocyclic group, an aryl group, or a heteroaryl group; each of which is optionally substituted with one or two substituents selected from the following: 1-6 -alkyl, C 1-6 -Haloalkyl, HO-, NC-, halogen, R15-(CH2) n -O-, R15-(CH2) n -NH-, (R15-(CH2) n )2-N-、R15-(CH2) n -S(O)-, R15-(CH2) n -S(O)2-; R14 is C 1-6 -haloalkyl or C 1-6 -alkyl, which is optionally C 3-6 -Cycloalkyl, C 2-6 -Alkenyl-, HO-, C 1-6 -alkyl-O-, H2N-C(O)-, C 1-6 -alkyl-HN-C(O)-, (C 1-6 -alkyl)2N-C(O)-substituted; R15 is C 1-4 -alkyl, C 1-6 -haloalkyl, NC-, C 1-6 -alkyl-HN-, (C 1-6 -alkyl)2N-, (C 1-6 -alkyl)2(HO)C-, aryl or heterocyclic; n is 0, 1, 2 or 3.

2. The compound according to claim 1, wherein R1 is selected from 3. The compound according to claim 1 or 2, wherein R3 is H- or C 1-6 -alkyl, C 3-7 -Cycloalkyl, C 2-5 -Alkenyl, C 3-7 - heterocycloalkyl, each of which is optionally substituted by a group selected from F-, HO-, Me-, EtO-, NH2(O)C-; R4 is H-, F- or HO-; R4 b H- or F-, Cl-, Br-, NC-, HO-; R5 is selected from and R5 is a connection point with the structure of Formula 1; Q is -C(R11)(R12)-, -S(O)- or -S(O)2-; R6 is C 2-4 -alkenyl, or C 1-4 -alkyl, which is optionally substituted independently of one another by one or two substituents selected from the group consisting of: C 3-4 -cycloalkyl-, halogen, HO-, C 1-4 -alkyl-O-, C 1-4 -alkyl-HN-, (C 1-4 -alkyl)2N-, NC-, (C 1-4 -alkyl)2(O)P-, (4-methoxyphenyl)methyl-, or A heterocycle selected from tetrahydrofuran-, 1,4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, triazole-, each of which is optionally substituted independently of one another by one or two substituents selected from the group consisting of: C 1-4 -alkyl-, halogen, O=; R7, R8, R9 are C 3-4 -cycloalkyl-, which is optionally C 1-4 -alkyl- or substituted with one or two halogen atoms, or Cyclopropylmethyl-, C 1-4 -haloalkyl-, C 1-4 -alkyl-O-, C 1-4 -alkyl-HN-, (C 1-4 -alkyl)2N-, C 1-4 -alkyl-S-, or C 1-4 -alkyl, which is linear or branched, which is optionally substituted by HO-, C 1-4 -alkyl-O-, C 1-4 -alkyl-HN-, (C 1-4 -alkyl) 2N- or morpholine-substituted, or A heterocycle selected from pyrrolidine-, tetrahydrofuran-, tetrahydropyran-, or C 1-4 -haloalkyl-O-; R10 is C 1-4 -alkyl- or C 1-4 -haloalkyl-; R11 is H, HO-, halogen- or R14-O-, R14-NH-; R12 is H- or F; R13 is a carbocyclic group, a heterocyclic group, an aryl group, or a heteroaryl group; each of which is optionally substituted by one or two substituents selected from the following: 1-4 -alkyl, C 1-4 -Haloalkyl, HO-, NC-, halogen, R15-(CH2) n -O-, R15-(CH2) n -NH-, (R15-(CH2) n )2-N-、R15-(CH2) n -S(O)-, R15-(CH2) n -S(O)2-; R14 is C 1-4 -haloalkyl- or C 1-5 -alkyl, which is optionally C 3-4 -Cycloalkyl, C 2-4 -Alkenyl-, HO-, C 1-4 -alkyl-O-, H2N-C(O)-, C 1-4 -alkyl-HN-C(O)-, (C 1-4 -alkyl)2N-C(O)-substituted; R15 is C 1-4 -alkyl, C 1-4 -haloalkyl, NC-, C 1-6 -alkyl-HN-, (C 1-4 -alkyl)2N-, (C 1-4 -alkyl)2(HO)C-, aryl or heterocyclic; n is 0, 1, 2 or 3.

4. A compound according to any one of claims 1 to 3, wherein R2 is C 1-4 -alkyl-; R3 is C 1-4 -alkyl-, which is optionally substituted with HO-, or C 3-4 -cycloalkyl-, which is optionally substituted by methyl-; R4 is H- or F-; R5 is selected from and R5 is a connection point with the structure of Formula 1; R6 is C 2-4 -alkenyl, or C 1-4 -alkyl, which is optionally substituted independently of one another by one or two substituents selected from the group consisting of: C 3-4 -cycloalkyl-, halogen, HO-, C 1-4 -alkyl-O-, (C 1-4 -alkyl)2N-, NC-, (C 1-4 -alkyl)2(O)P-, (4-methoxyphenyl)methyl-, or A heterocycle selected from tetrahydrofuran-, 1,4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, triazole-, each of which is optionally substituted independently of one another by one or two substituents selected from the group consisting of: C 1-4 -alkyl-, halogen, O=; R7 is C 3-4 -cycloalkyl-, which is optionally C 1-4 -alkyl- or substituted with one or two halogen atoms, or Cyclopropylmethyl-, C 1-4 -haloalkyl-, C 1-4 -alkyl-O-, C 1-4 -alkyl-HN-, (C 1-4 -alkyl)2N-, C 1-4 -alkyl-S-, or C 1-4 -alkyl, which is linear or branched, which is optionally substituted by HO-, C 1-4 -alkyl-O-, C 1-4 -alkyl-HN-, (C 1-4 -alkyl) 2N- or morpholine-substituted, or A heterocycle selected from pyrrolidine-, tetrahydrofuran-, tetrahydropyran-; R8 is C 1-4 -haloalkyl-O-; R9 is C 1-4 -alkyl- or C 3-4 -cycloalkyl-; R10 is C 1-4 -alkyl- or C 1-4 -haloalkyl-; R11 is H, HO-, halogen- or R14-O-; R12 is H- or F; R13 is cyclohexyl-, 3,4-difluorophenyl-, 3-methyl-4N-pyridyl-, or phenyl-, which is optionally substituted at the 4-position with methyl, HO-, F-, Cl-, Br-, R15-(CH2) n -O-substitution; R14 is C 1-4 -haloalkyl- or C 1-5 -alkyl, which is optionally C 3-4 -Cycloalkyl, C 2-4 -Alkenyl-, HO-, C 1-4 -alkyl-O-, H2N-C(O)-, (C 1-4 -alkyl)NH-C(O)-, (C 1-4 -alkyl)2N-C(O)-substituted; R15 is NC-, (C 1-4 -alkyl)2N-, (C 1-4 -alkyl)2(HO)C-, phenyl, or a heterocycle selected from oxetane-, tetrahydropyran-, morpholine-; n is 0, 1 or 2.

5. A compound according to any one of claims 1 to 4, wherein R2 is methyl- or ethyl-; R3 is ethyl-, isopropyl-, cyclopropyl-, 1-methyl-cyclopropyl-, 1-hydroxy-isopropyl-; R4 is H- or F-; R5 is selected from and R5 is a connection point with the structure of Formula 1; R6 is C 2-4 -alkenyl, or C 1-4 -alkyl, which is optionally substituted independently of one another by one or two substituents selected from the group consisting of cyclopropyl-, F-, HO-, H3C-O-, (H3C)2N-, NC-, (H3C)2(O)P-, (4-methoxyphenyl)methyl-, or A heterocycle selected from tetrahydrofuran-, 1,4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, triazole-, each of which is optionally substituted independently of one another by one or two substituents selected from the group consisting of: H3C-, F-, O=; R7 is cyclopropyl-, 1-fluorocyclopropyl-, 2,2-difluorocyclopropyl-, 1-methyl-cyclopropyl-, cyclobutane-, cyclopropylmethyl-, F2HC-, F3C-, (iPr)-O-, (H3C)NH-, (H3C)2N-, H3C-S-, or C 1-4 -alkyl, which is linear or branched, which is optionally substituted by HO-, H3C-O-, H3C-CH2-O-, (H3C)NH-, (H3C)2N- or morpholine-substituted, or A heterocycle selected from pyrrolidine-, tetrahydrofuran-, tetrahydropyran-; R8 is F2HC-O-, F3C-O-; R9 is methyl or cyclopropyl; R10 is methyl or F2C-; R11 is H, HO-, F- or R14-O-; R12 is H- or F; R13 is cyclohexyl-, 3,4-difluorophenyl-, 3-methyl-4N-pyridyl-, or phenyl-, which is optionally substituted at the 4-position with methyl, HO-, F-, Cl-, Br-, R15-(CH2) n -O-substitution; R14 is FH2C-, FH2C-CH2- or C 1-5 -alkyl, which is optionally substituted by cyclopropyl, H2C=CH-, HO-, H3C-O-, H2N-C(O)-, (H3C)NH-C(O)-; R15 is NC-, (H3C)2N-, (H3C)2(HO)C-, phenyl, or a heterocycle selected from oxetane-, tetrahydropyran-, morpholine-; n is 0, 1 or 2.

6. A compound according to any one of claims 1 to 5, wherein BA is =CN- or -NC=; R1 is selected from and R1 is a connection point with the structure of Formula 1; R2 is methyl-; R3 is ethyl-, isopropyl-, cyclopropyl-, 1-methyl-cyclopropyl-, 1-hydroxy-isopropyl-; R4 is H- or F-; R5 is selected from and R5 is a connection point with the structure of Formula 1; R6 is methyl-, ethyl-, isopropyl-, cyclopropyl-; R7 is cyclopropyl-, 1-fluorocyclopropyl-, 2,2-difluorocyclopropyl-, 1-methyl-cyclopropyl-, cyclobutane-, cyclopropylmethyl-, F2HC-, F3C-, (iPr)-O-, (H3C)NH-, (H3C)2N-, H3C-S-, or C 1-4 - alkyl, which is linear or branched, which is optionally substituted by HO-, H3C-O-, H3C-CH2-O-, (H3C)NH-, (H3C)2N- or morpholine-, or A heterocycle selected from pyrrolidine-, tetrahydrofuran-, tetrahydropyran-; R11 is H, HO-, F- or R14-O-; R12 is H-; R13 is cyclohexyl-, 3,4-difluorophenyl-, 3-methyl-4N-pyridyl-, or phenyl-, which is optionally substituted at the 4-position with methyl, HO-, F-, Cl-, Br-, R15-(CH2) n -O-substitution; R14 is FH2C-, FH2C-CH2- or C 1-5 -alkyl, which is optionally substituted by cyclopropyl, H2C=CH-, HO-, H3C-O-, H2N-C(O)-, (H3C)NH-C(O)-; R15 is NC-, (H3C)2N-, (H3C)2(HO)C-, phenyl, or a heterocycle selected from oxetane-, tetrahydropyran-, morpholine-; n is 0, 1 or 2.

7. A compound according to any one of claims 1 to 6, wherein BA is =CN- or -NC=; R1 is selected from and R1 is a connection point with the structure of Formula 1; R2 is methyl- or ethyl-; R3 is ethyl-, isopropyl-, cyclopropyl-, 1-methyl-cyclopropyl-, ((HO)H2C)(H3C)HC-; R4 is H- or F-; R5 is selected from And R5 is the connection point with the structure of Formula 1.

8. The compound according to any one of claims 1 to 7, wherein the compound of formula 1 is a compound of formula 1a 9. The compound according to any one of claims 1 to 7, wherein the compound of formula 1 is a compound of formula 1b 10. The compound according to any one of claims 1 to 7, wherein the compound of formula 1 is a compound of formula 1c 11. A compound according to any one of claims 1 to 7, selected from the following examples 12. A salt of a compound of formula 1 according to any one of claims 1 to 11.

13. A pharmaceutically acceptable salt of a compound of formula 1 according to any one of claims 1 to 11.

14. A compound of formula 1, 1a, 1b or 1c according to any one of claims 1 to 13 for use in the treatment of a disease treatable by inhibition of STING.

15. A compound of formula 1, 1a, 1b or 1c according to any one of claims 1 to 13 for use in treating a disease selected from the group consisting of systemic lupus erythematosus (SLE), (monogenic and digenic) interferonopathies (including STING-associated vasculopathy of infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome and familial lupus pernio), type I interferonopathies with mutations in the DNASE2 or ATAD3A genes, age-related macular degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), diabetes, obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom's syndrome, Sjogren's syndrome, Parkinson's disease, disease), heart failure and cancer, systemic sclerosis (SSc), dermatomyositis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), acute-on-chronic liver failure (ACLF), interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), aging / muscle diseases, sepsis, heart failure, rheumatoid arthritis and osteoarthritis.

16. A compound of formula 1, 1a, 1b or 1c according to any one of claims 1 to 13, for use in the treatment of a fibrotic disease selected from the group consisting of systemic sclerosis (SSc), non-alcoholic steatohepatitis (NASH), acute-on-chronic liver failure (ACLF), (monogenic and digenic) interferonopathies (including STING-associated vasculopathy of infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome and familial lupus pernio), type I interferonopathies with mutations in the DNASE2 or ATAD3A genes, and interstitial lung disease (ILD).

17. A compound of formula 1, 1a, 1b or 1c according to any one of claims 1 to 13 for use in treating a disease selected from the group consisting of age-related macular degeneration (AMD), retinopathy, glaucoma, aging, muscle disease, heart failure, COVID-19 / SARS-CoV-2 infection, renal inflammation, renal fibrosis, metabolic disorders, vascular disease, cardiovascular disease, diabetes, obesity and cancer.

18. A pharmaceutical composition comprising a compound of formula 1, 1a, 1b or 1c according to any one of claims 1 to 13, and optionally one or more pharmaceutically acceptable carriers and / or excipients.

19. A pharmaceutical composition comprising a compound of formula 1, 1a, 1b or 1c according to any one of claims 1 to 13 in combination with one or more active agents selected from the group consisting of: PDE4 inhibitors, anti-inflammatory agents, anti-fibrotic agents, anti-allergic agents / antihistamines, bronchodilators, β2 agonists / β mimetics, adrenergic agonists, anticholinergics, methotrexate, mycophenolate mofetil, leukotriene modifiers, JAK inhibitors, anti-interleukin antibodies, non-specific immunotherapeutics such as interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators, toll-like receptor agonists, immune checkpoint modulators, anti-TNF antibodies, anti-BAFF antibodies.

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