Heterocyclic compounds as STING antagonists

Abstract

The present invention relates to the compound of Formula 1 and STING antagonists, for example, systemic lupus erythematosus (SLE), (monogeneic and digeneic) interferon disorders (including STING-associated vascular disorders that develop in infancy (SAVI), Eicardi-Goutier syndrome (AGS), COPA syndrome, and familial chilblain lupus), type 1 interferon disorders with mutations in DNASE2 or ATAD3A genes, age-related macular degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), diabetes mellitus, obesity, and inflammatory bowel disease. This relates to the use of these as STING antagonists for the treatment of diseases selected from the group consisting of intestinal diseases (IBD), chronic obstructive pulmonary disease (COPD), Bloom 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 exacerbation of chronic liver failure (ACLF), interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), age-related / muscle disorders, sepsis, heart failure, rheumatoid arthritis and osteoarthritis. JPEG2026510538000418.jpg45150

Description

[Technical Field]

[0001] The present invention relates to a compound of formula 1; [ka] and their use as STING antagonists, for example, systemic lupus erythematosus (SLE), (monogeneic and digeneic) interferon disorders (including STING-associated vascular disorders that develop in infancy (SAVI), Eicardi-Goutier syndrome (AGS), COPA syndrome, and familial chilblain lupus), type 1 interferon disorders with DNASE2 or ATAD3A gene mutations, age-related macular degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), diabetes. The use of this product relates to the treatment of diseases selected from the group consisting of obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom 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 exacerbation of chronic liver failure (ACLF), interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), age-related / muscle disorders, sepsis, heart failure, rheumatoid arthritis and osteoarthritis. [Background technology]

[0002] Innate immunity is considered the first-line cellular stress response that defends host cells from invading pathogens and initiates signaling to the adaptive immune system. These processes are triggered by conserved pathogen-associated molecular patterns (PAMPs) sensed by diverse pattern recognition receptors (PRRs), and subsequently by the activation of cytokine and type I interferon gene expression. Major antigen-presenting cells, such as monocytes, macrophages, and dendritic cells, are crucial for producing type I interferons and inducing responses from the T-cell and B-cell adaptive immune systems. Major PRRs detect abnormalities on the cell surface, inside the lysosomal membrane, or within other cellular compartments, i.e., mislocalization, immature, or unmodified nucleic acids (Barbalat et al., Annu. Rev. Immunol. 29, 185-214 (2011)).

[0003] "Cyclic GMP-AMP synthase" C yclic G MP- A MP S Synthase) cGAS cGAS is a major sensor for abnormal double-stranded DNA (dsDNA) caused by pathogens or by the mislocalization or misprocessing of cellular dsDNA in the nucleus or mitochondria (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 between GTP and ATP to form a cyclic dinucleotide GMP-AMP (called cGAMP). cGAMP then acts as an adapter protein "stimulator of interferon genes" fixed to the endoplasmic reticulum membrane. In terferon G enes)( STING It binds to UniProtKB-Q86WV6) and activates it. The activated STING then binds to TANK-binding kinase 1 ( T ANK-b inding k inase 1 )( TBK1 ) recruits and activates, which in turn leads to the transcription factor family, interferon regulators ( i nterferon r egulatory f actor) IRF It phosphorylates ) and induces the expression of cytokines and type I interferon mRNA. cGAMP-mediated STING activation also leads to activation of the NF-κB signaling pathway and downstream production of pro-inflammatory cytokines (Sun et al., Science 339, 786-791 (2013)). Human GoF STING mutations are associated with autoinflammatory syndromes, cutaneous vascular disorders, and pulmonary fibrosis (vascular disorders associated with STING that develop in infancy). S TING- a ssociated v Asculopathy with Onset i It leads to (nfancy) and (SAVI). SAVI patients have highly activated PBMCs and cutaneous fibroblasts, and exhibit upregulation of type 1 IFN signature and expression of NFκB-mediated pro-fibrotic and pro-inflammatory genes (e.g., TNFα, IL-6) (Liu et al., 2014).

[0004] The critical role of STING in dsDNA sensing has been established in various pathogenic bacteria and viruses. In addition, STING is essential in various other biological processes such as cellular senescence (Yang et al., PNAS 114, E4612 (2017), Gluck et al., Nat. Cell Biol. 19, 1061-1070 (2017)), autophagy in the monitoring of potential cancer cells, and recognition of ruptured micronuclei (Mackenzie et al., Nature 548, 461-465 (2017); Harding et al., Nature 548, 466-470 (2017)).

[0005] While the cGAS / STING pathway is crucial for host defense against invading pathogens, cellular stress and genetic factors can also trigger the production of abnormal cellular dsDNA, such as dsDNA production through nuclear or mitochondrial leakage, thus leading to autoinflammatory responses. Aicardi-Gutierrez syndrome (AGS; Crow et al., Nat. Genet. 38, 917-920 (2006)) is a lupus-like severe autoinflammatory immune-mediated disorder resulting from genetic mutations, such as loss-of-function mutations in TREX1, a major DNA exonuclease involved in the degradation of abnormal DNA in the cytosol. Knockout of STING in TREX1-deficient mice prevented autoimmune responses that would be lethal in normal mice, supporting STING as an inducer of interferon disorders (Gall et al., Immunity 36(1), 120-131 (2012); Gao et al., PNAS 112, E5699-E5705 (2015)). Similarly, embryonic lethality caused by deficiency of DNAse2, an endonuclease involved in the degradation of excess DNA within lysosomes during endocytosis, was completely rescued by additional knockout of STING (Ahn et al., PNAS 109, 19386-19391 (2012)). STING inhibitors may offer therapeutic strategies to prevent (monogeneic and digenetic) interferonopathic diseases such as SAVI, AGS, familial lupus frostbite, and COPA. STING inhibitors block inflammation and abnormal tissue remodeling in a cluster of autoimmune and inflammatory diseases, including systemic lupus erythematosus (SLE), systemic sclerosis, dermatomyositis, inflammatory bowel disease, sepsis, Sjögren's syndrome, and atopic dermatitis, as well as in a cluster of fibrotic diseases, including NASH, IPF, and chronic renal fibrosis. STING inhibitors also have indications for additional diseases, such as cancer, heart failure, AMD, retinopathy, glaucoma, aging, muscle disorders, rheumatoid arthritis, osteoarthritis, ALS, Parkinson's disease, and COVID-19 (Decout et al, Nat Rev Immunol. 2021 21:548-569).

[0006] Conventional technology The understanding that inhibiting the STING pathway could lead to therapeutic strategies for preventing autoinflammatory diseases and treating autoimmune diseases has led to efforts to develop STING inhibitors or inhibit the STING signaling pathway. ·WO2019122202 describes, for example, that compounds C-178 or C-176 interfere with the STING signaling pathway in cyclic dinucleotides, such as cGAMP-stimulated HEK293T cells or bone marrow-derived macrophages (BMDMs), and that these compounds are irreversible inhibitors that block palmitoylation of STING at its allosteric site. ·ACS Med Chem Lett. (2019, 10, 1, pp 92-97), Siu et al. described novel cGAMP competitive ligands. Inhibiting the orthosteric site of cGAMP-mediated STING activation is thought to result in the suppression of all STING-mediated activation, in contrast to palmitoylation inhibitors. In this publication, compound 13 or 15 inhibited the HAQ STING variant with moderate IC50s of 84 or 41 nM (substitution assay), and showed low cellular inhibitory activity of approximately 11 μM based on cGAMP-stimulated INFb production in THP1 cells. International patent application WO2019069270 therefore claims a STING modulator that activates or inhibits STING. [Overview of the project]

[0007] Surprisingly, it was found here that the compound described in this patent application is a competitive inhibitor of STING. [Modes for carrying out the invention]

[0008] The present invention relates to a compound of formula 1; [ka] [Wherein, B - A is = C - N - or - N - C =, which means that A is C or N, B is C or N, but A and B are not N at the same time, R1 is

Chemical formula

[0009]

Chemical formula

[0010] Compound of formula 1, [wherein, BA is =CN- or -NC=, which means that A is C or N and B is C or N, but A and B are not N at the same time. R1 is [ka] Selected from, R1 is the connection point to the structure of Equation 1, R2 is C if BA is -NC= 1-6 -alkyl-, C 3-6 -Cycloalkyl-, C 1-6 -Haloalkyl- means, R2 is C when BA = CN- 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- means having R3 is H- or C 1-6 -alkyl, C 3-7 -Cycloalkyl, C 2-6 -Alkenil, C 3-7 -The heterocycloalkyl group may be substituted with a group selected from F-, HO-, Me-, EtO-, and NH2(O)C-. R4 is H-, F-, or HO-. R4 b These are H-, F-, Cl-, Br-, NC-, or HO-. R5 is

[0011] [ka] Selected from, R5 is the bonding point to the structure of Equation 1, Q is -C(R11)(R12)-, -S(O)-, or -S(O)2-, R6 is C 2-6 -It is Alkenil, or C 1-6 - Alkyl, and independently of each other, 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- and may be substituted with one or two substituents selected from the group consisting of; or a heterocycle selected from tetrahydrofuran-, 1,4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, triazole- and may be substituted with one or two substituents selected from the group consisting of C 1-6 -alkyl-, halogen, O=; R7, R8, R9 are C 3-6 -cycloalkyl- and may be substituted with C 1-6 -alkyl- or one or two halogens; or cyclopropylmethyl-, C<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​R13 is carbocyclyl, heterocyclyl, aryl, heteroaryl, preferably C 6-10 -aryl, C 5-10 -heteroaryl, each of which is 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-, and may be substituted with one or two substituents selected from the group consisting of R14 is C 1-6 -haloalkyl-, or C 1-6 -alkyl, 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)-, and may be 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 heterocyclyl, n is preferably 0, 1, 2 or 3.]

[0012] The compound of formula 1, [wherein, B-A is =C-N- or -N-C=, which means that A is C or N, B is C or N, but A and B are not both N at the same time, R1 is

Chemical formula

[0013] [ka] Selected from, R5 is the bonding point to the structure of Equation 1, Q is -C(R11)(R12)-, -S(O)-, or -S(O)2-, R6 is C 2-4 -It is Alkenil, or C 1-4 - Alkyl, and independently of each other, 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 It may be substituted with one or two substituents selected from the group consisting of -alkyl)2(O)P- and (4-methoxyphenyl)methyl-. or A heterocycle selected from tetrahydrofuran-, 1,4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, and triazole-, each independently of the others, C 1-4 It may be substituted with one or two substituents selected from the group consisting of -alkyl-, halogen, and O=. R7, R8, and R9 are C 3-4 -cycloalkyl- and C 1-4 They may be substituted with alkyl groups or one or two halogens. 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 -It is alkyl, linear or branched, HO-, C 1-4 -alkyl-O-,C 1-4 -alkyl-HN-, (C 1-4 It may be substituted with -alkyl)2N- or morpholine-. Or A heterocycle selected from pyrrolidine-, tetrahydrofuran-, and 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 either H- or F. R13 is a carbocyclyl, heterocyclyl, aryl, or heteroaryl, preferably C 6-10 -Aryl, C 5-10 -Heteroaryl, and each is 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 It may be substituted with one or two substituents selected from the group consisting of -S(O)2-, R14 is C 1-4 -haloalkyl-, or C 1-5 -It is alkyl, C 3-4 -Cycloalkyl, C 2-4 -Alkenil-, HO-, C 1-4 -alkyl-O-,H2N-C(O)-,C 1-4 -alkyl-HN-C(O)-,(C 1-4 It may also be substituted with -alkyl)2N-C(O)- 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 heterocyclyl n is preferably 0, 1, 2, or 3.

[0014] Compound of formula 1, [wherein, BA is =CN- or -NC=, which means that A is C or N and B is C or N, but A and B are not N at the same time. R1 is [ka] Selected from, R1 is the connection point to the structure of Equation 1, R2 is C 1-4 -alkyl-, R3 is C 1-4 It is -alkyl- and may be substituted with HO-. or C 3-4 -Cycloalkyl- and may be substituted with methyl- R4 is either H- or F-. R5 is

[0015] [ka] Selected from, R5 is the bonding point to the structure of Equation 1, R6 is C 2-4 -It is Alkenil, or C 1-4 - Alkyl, and independently of each other, C 3-4 -Cycloalkyl-, halogen, HO-, C 1-4 -alkyl-O-, (C 1-4 -alkyl)2N-,NC-,(C 1-4 It may be substituted with one or two substituents selected from the group consisting of -alkyl)2(O)P- and (4-methoxyphenyl)methyl-. or A heterocycle selected from tetrahydrofuran-, 1,4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, and triazole-, each independently of the others, C 1-4 It may be substituted with one or two substituents selected from the group consisting of -alkyl-, halogen, and O=. R7 is C 3-4 -cycloalkyl- and C 1-4 They may be substituted with alkyl groups or one or two halogens. 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, linear or branched, HO-, C 1-4 -alkyl-O-,C 1-4 -alkyl-HN-, (C 1-4It may be substituted with -alkyl)2N- or morpholine-. Or A heterocycle selected from pyrrolidine-, tetrahydrofuran-, and 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 either H- or F. R13 is cyclohexyl-, 3,4-difluorophenyl-, 3-methyl-4N-pyridinyl-, or phenyl-, and at the 4-position is methyl, HO-, F-, Cl-, Br-, R15-(CH2) n It may also be substituted with -O-. R14 is C 1-4 -haloalkyl-, or C 1-5 -It is alkyl, C 3-4 -Cycloalkyl, C 2-4 -Alkenil-, HO-, C 1-4 -alkyl-O-,H2N-C(O)-,(C 1-4 -alkyl)NH-C(O)-, (C 1-4 It may also be substituted with -alkyl)2N-C(O)- 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 preferably 0, 1, or 2.

[0016] Compound of formula 1, [wherein, BA is =CN- or -NC=, which means that A is C or N and B is C or N, but A and B are not N at the same time. R1 is [ka] Selected from, preferably [ka] Therefore, R1 is the connection point to the structure in Equation 1, R2 is methyl- or ethyl-, preferably methyl-. R3 is ethyl-, iso-propyl-, cyclopropyl-, 1-methyl-cyclopropyl-, 1-hydroxy-iso-propyl-, R4 is either H- or F-. R5 is

[0017] [ka] Selected from, R5 is the bonding point to the structure of Equation 1, R6 is C 2-4 -It is Alkenil, or C 1-4 - Alkyl, which may be independently substituted with one or two substituents selected from the group consisting of cyclopropyl-, F-, HO-, H3C-O-, (H3C)2N-, NC-, (H3C)2(O)P-, and (4-methoxyphenyl)methyl-. or A heterocycle selected from tetrahydrofuran-, 1,4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, and triazole-, each of which may be independently substituted with one or two substituents selected from the group consisting of H3C-, F-, and O=. Alternatively, R6 is preferably methyl-, ethyl-, iso-propyl-, or cyclopropyl-. R7 is cyclopropyl-, 1-fluorocyclopropyl-, 2,2-difluorocyclopropyl-, 1-methyl-cyclopropyl-, cyclobutanyl-, cyclopropylmethyl-, F2HC-, F3C-, (iPr)-O-, (H3C)NH-, (H3C)2N-, H3C-S-, or C 1-4 -It is alkyl, linear or branched, and may be substituted with HO-, H3C-O-, H3C-CH2-O-, (H3C)NH-, (H3C)2N- or morpholine-, or A heterocycle selected from pyrrolidine-, tetrahydrofuran-, and 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, preferably H-. R13 is cyclohexyl-, 3,4-difluorophenyl-, 3-methyl-4N-pyridinyl-, or phenyl-, and at the 4-position is methyl, HO-, F-, Cl-, Br-, R15-(CH2) n It may also be substituted with -O-. R14 is FH2C-, FH2C-CH2-, or C 1-5 -Alkyl, may be substituted with cyclopropyl, H2C=CH-, HO-, H3C-O-, H2N-C(O)-, or (H3C)NH-C(O)-. R15 is NC-, (H3C)2N-, (H3C)2(HO)C-, phenyl, or a heterocycle selected from oxetane-, tetrahydropyran-, morpholine-. n is preferably 0, 1, or 2.

[0018] Compound of formula 1, [wherein, BA is =CN- or -NC=, which means that A is C or N and B is C or N, but A and B are not N at the same time. R1 is [ka] Selected from, R1 is the connection point to the structure of Equation 1, R2 is methyl-, R3 is ethyl-, iso-propyl-, cyclopropyl-, 1-methyl-cyclopropyl-, 1-hydroxy-iso-propyl-, R4 is either H- or F-. R5 is

[0019] [ka] Selected from, R5 is the bonding point to the structure of Equation 1, R6 is methyl-, ethyl-, iso-propyl-, cyclopropyl-, R7 is cyclopropyl-, 1-fluorocyclopropyl-, 2,2-difluorocyclopropyl-, 1-methyl-cyclopropyl-, cyclobutanyl-, cyclopropylmethyl-, F2HC-, F3C-, (iPr)-O-, (H3C)NH-, (H3C)2N-, H3C-S-, or C 1-4 -It is alkyl, linear or branched, and may be substituted with HO-, H3C-O-, H3C-CH2-O-, (H3C)NH-, (H3C)2N- or morpholine-, or A heterocycle selected from pyrrolidine-, tetrahydrofuran-, and tetrahydropyran-, R11 is H, HO-, F-, or R14-O-. R12 is H-, R13 is cyclohexyl-, 3,4-difluorophenyl-, 3-methyl-4N-pyridinyl-, or phenyl-, and at the 4-position is methyl, HO-, F-, Cl-, Br-, R15-(CH2)n It may be substituted with -O- R14 is FH2C-, FH2C-CH2-, or C 1-5 -alkyl, and may be substituted with 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 heterocyclic ring selected from oxetane-, tetrahydropyran-, morpholine- n is preferably 0, 1, or 2.

[0020] The compound of formula 1, [wherein, B-A is =C-N- or -N-C=, which means that A is C or N, B is C or N, but A and B are not N at the same time. R1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0021] [Chemistry] [Chemistry] is selected from, and R5 is the point of attachment to the structure of formula 1, which is preferred.

[0022] A compound of formula 1, [wherein, B-A is =C-N- or -N-C=, which means that A is C or N, B is C or N, but A and B are not N at the same time. R1 is, [Chemistry] [Chemistry] [Chemistry] is selected from, and R1 is the point of attachment to the structure of formula 1. R2 is methyl- or ethyl-, preferably methyl-. R3 is ethyl-, iso-propyl-, cyclopropyl-, 1-methyl-cyclopropyl-, ((HO)H2C)(H3C)HC-. R4 is H- or F-. R5 is,

[0023] [Chemistry] [Chemistry] is selected from, and R5 is the point of attachment to the structure of formula 1, which is preferred.

[0024] A compound of formula 1, [wherein, B-A is =C-N- or -N-C=, which means that A is C or N, B is C or N, but A and B are not N at the same time. R1 is, [Chemistry] [ka] Selected from, R1 is the connection point to the structure of Equation 1, R2 is methyl- or ethyl-, preferably methyl-. R3 is ethyl-, iso-propyl-, cyclopropyl-, 1-methyl-cyclopropyl-, ((HO)H2C)(H3C)HC-, R4 is either H- or F-. R5 is

[0025] [ka] [ka] [Selected from, where R5 is a bonding point to the structure of Equation 1] is preferred.

[0026] Compound of formula 1, [wherein, BA is =CN- or -NC=, which means that A is C or N and B is C or N, but A and B are not N at the same time. R1 is [ka] Selected from, R1 is the connection point to the structure of Equation 1, R2 is methyl- or ethyl-, preferably methyl-. R3 is ethyl-, iso-propyl-, cyclopropyl-, 1-methyl-cyclopropyl-, ((HO)H2C)(H3C)HC-, R4 is either H- or F-. R5 is

[0027] [ka] [ka] [Selected from, where R5 is a bonding point to the structure of Equation 1] is preferred.

[0028] Compound of formula 1 [wherein R1 is, [ka] Preferably, R6 and R7 are defined as described above, and R1 is a connection point to the structure of formula 1. Compound of formula 1 [wherein R1 is, [ka] Preferably, R8 is defined as described above, and R1 is a connection point to the structure of Equation 1. Compound of formula 1 [wherein R1 is, [ka] Preferably, R9 and R10 are defined as described above, and R1 is a connection point to the structure of formula 1.

[0029] Compound of formula 1 [wherein R1 is, [ka] Preferably, R9 and R10 are defined as described above, and R1 is a connection point to the structure of formula 1. Compound of formula 1 [wherein R1 is, [ka] [ka] [Selected from, where R1 is a bonding point to the structure of Equation 1] is preferred. Compound of formula 1 [wherein R1 is,

[0030] [ka] [Selected from, where R1 is a bonding point to the structure of Equation 1] is preferred.

[0031] Compound of formula 1 [wherein R1 is, [ka] [ka] [Selected from, where R1 is a bonding point to the structure of Equation 1] is preferred. Compound of formula 1 [wherein R5 is,

[0032] [ka] Preferably, R11, R12, and R13 are defined as described above, and R1 is a bonding point to the structure of formula 1. Compound of formula 1 [wherein R5 is, [ka] And, R11 is HO-, F-, or R14-O-. R12 is H-, R13 is cyclohexyl-, 3,4-difluorophenyl-, 3-methyl-4N-pyridinyl-, or phenyl-, and at the 4-position is methyl, HO-, F-, Cl-, Br-, R15-(CH2) n It may also be substituted with -O-. R14 is FH2C-, FH2C-CH2-, or C 1-5 -Alkyl, may be substituted with cyclopropyl, H2C=CH-, HO-, H3C-O-, H2N-C(O)-, or (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. [It is preferable that R1 is a bonding point to the structure of Equation 1].

[0033] Compound of formula 1 [wherein R5 is, [ka] And, R11 is HO-, R12 is H-, R13 is phenyl-, and at position 4, methyl, HO-, F-, Cl-, Br-, R15-(CH2) n It may also be substituted with -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. [It is preferable that R1 is a bonding point to the structure of Equation 1].

[0034] Compound of formula 1 [wherein R5 is, [ka] And, R11 is HO-, R12 is H-, R13 is phenyl-, and may be substituted at position 4 with methyl, HO-, F-, Cl-, or Br-. [It is preferable that R1 is a bonding point to the structure of Equation 1].

[0035] Compound of formula 1 [wherein R5 is, [ka] It is preferable that it be [that]. Compound of formula 1 [wherein R5 is, [ka] It is preferable that it be [that]. Compound of formula 1 [wherein R5 is,

[0036] [ka] It is preferable that it be [that]. The compound of formula 1a is also preferred. [ka]

[0037] The compound of formula 1b is also preferred. [ka] The compound of formula 1b1 is also preferred. [ka] The compound of formula 1c is also preferred.

[0038] [ka]

[0039] Compounds of formula 1c1 are also preferred. [ka] A compound of formula 1 is preferred, in which BA is =CN- and R3 is isopropyl. A compound of formula 1 is preferred, in which BA is -NC= and R3 is cyclopropyl. Salts of compounds of formula 1, 1a, 1b, 1b1, 1c, or 1c1 are also preferred. Furthermore, pharmaceutically acceptable salts of compounds of formula 1, 1a, 1b, 1b1, 1c, or 1c1 are preferred.

[0040] In preferred embodiments, the present invention relates to the compounds of formulas 1, 1a, 1b, 1b1, 1c, or 1c1 described above and their use as STING antagonists, for example, systemic lupus erythematosus (SLE), (monogeneic and digeneic) interferon disorders (including STING-associated vascular disorders (SAVI), Eicardi-Goutier syndrome (AGS), COPA syndrome, and familial chilblain lupus), type 1 interferon disorders with mutations in the DNASE2 or ATAD3A gene, age-related macular degeneration (AMD), retinopathy, glaucoma, This refers to the use of these drugs for the treatment of diseases selected from the group consisting of amyotrophic lateral sclerosis (ALS), diabetes mellitus, 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 exacerbation of chronic liver failure (ACLF), interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), age-related muscle disorders, sepsis, heart failure, rheumatoid arthritis and osteoarthritis. In more preferred embodiments, the present invention relates to compounds of formulas 1, 1a, 1b, 1b1, 1c, or 1c1 described above for use in the treatment of diseases selected from the group consisting of systemic lupus erythematosus (SLE), (monogeneic and digeneic) interferon disorders, Eicardi-Goutier syndrome, type 1 interferon disorder with mutations in the DNASE2 or ATAD3A gene, age-related macular degeneration (AMD), amyotrophic lateral sclerosis (ALS), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), Bloom syndrome, Sjögren's syndrome, and Parkinson's disease.

[0041] In another, more preferred embodiment, the present invention relates to compounds of formula 1, 1a, 1b, 1b1, 1c, or 1c1 described above for use in the treatment of fibrous diseases selected from the group consisting of systemic sclerosis (SSc), non-alcoholic steatohepatitis (NASH), acute exacerbations of chronic liver failure (ACLF), (monogeneic and digeneic) interferon disorders, and interstitial lung disease (ILD). In another, more preferred embodiment, the present invention relates to compounds of formulas 1, 1a, 1b, 1b1, 1c, or 1c1 described above for use in the treatment of diseases selected from the group consisting of age-related macular degeneration (AMD), retinopathy, glaucoma, aging, muscle disorders, heart failure, COVID-19 / SARS-CoV-2 infection, renal inflammation, renal fibrosis, metabolic disorders, vascular diseases, cardiovascular diseases, diabetes, obesity, and cancer. In another embodiment, the present invention relates to a pharmaceutical composition comprising at least one of the compounds described above and optionally one or more pharmaceutically acceptable carriers and / or excipients.

[0042] In another preferred embodiment, the present invention relates to a combination of a compound of formula 1, 1a, 1b, 1b1, 1c, or 1c1 with one or more activators selected from the group consisting of anti-inflammatory agents, anti-fibrotic agents, anti-allergic agents / antihistamines, bronchodilators, beta-2 agonists / beta mimetic agents, adrenaline agonists, anticholinergic agents, methotrexate, mycophenolate mofetil, leukotriene modulators, JAK inhibitors, anti-interleukin antibodies, nonspecific immunotherapies, such as interferon or other cytokines / chemokines, cytokine / chemokine receptor modulators, Toll-like receptor agonists, immune checkpoint modifiers, anti-TNF antibodies, and anti-BAFF antibodies. [Examples]

[0043] The following examples are illustrative only and are not intended to limit the scope of the present invention. Absolute configurations were defined by X-rays for representative examples in complex with STING protein. [ka] [ka] [ka] [ka]

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

[0044] Common Terms and Definitions Terms not specifically defined herein shall have meanings that would be assigned by those skilled in the art in consideration of this disclosure and the context. However, the following terms, when used herein, shall have the meanings indicated unless otherwise specified, and shall be subject to the following conventions. In the groups, radicals, or parts defined below, the number of carbon atoms is often specified prior to the group, for example, C 1-6 -Alkyl refers to an alkyl group or radical having 1 to 6 carbon atoms. Generally, in groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, and F3C, those skilled in the art can predict the radical bond site to the molecule from the free valence of the group itself. For combined groups containing two or more subgroups, the last named subgroup is the radical bond site, for example, the substituent "aryl-C". 1-3 -Alkilen is C 1-3 - This means the aryl group bonded to the alkyl group, and this C 1-3 - The alkyl group is bonded to the core or group to which the substituent is attached.

[0045] In cases where a compound of the present invention is shown both by its chemical name and by its formula, if there is a conflict between the two, the formula shall prevail. The notation for substituent atoms starts with the atom closest to the core or group to which the substituent is attached. For example, the term "3-carboxypropyl group" refers to the following substituents: [ka] [In the formula, the carboxyl group is bonded to the third carbon atom of the propyl group.] The terms "1-methylpropyl-", "2,2-dimethylpropyl-", or "cyclopropylmethyl-" group refer to the following groups: [ka] It represents. The asterisk can be used in a lower-level expression to indicate a bond that is linked to the core molecule as defined.

[0046] If the claims or specification refer to the fact that residue R# in the illustrated structure is a binding point to the structure of formula 1, then in this context it can also be read as a binding point to the structure of formula 1a, 1b, or 1c. As used herein, the term "substituted" means that one or more hydrogen atoms on a given atom are replaced by a group selected from a defined group of substituents, provided that the substitution does not exceed the standard valence of the given atom and that the substitution results in a stable compound. Similarly, the term "substituted" can be used in relation to a chemical moiety instead of a single atom, for example, "substituted alkyl" or "substituted aryl." Unless otherwise specifically indicated, throughout the entirety of the specification and appended claims, a given chemical formula or name shall encompass tautomers and all stereoisomers, optical isomers and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and racemates thereof, as well as mixtures of distinct enantiomers, mixtures of diastereomers, or any of the aforementioned forms in which such isomers and enantiomers exist, and solvates thereof, e.g., hydrates.

[0047] Unless otherwise specifically indicated, “pharmaceutically acceptable salts” as defined in more detail below also include their solvates, e.g., hydrates. Generally, 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 the use of stereochemically pure starting materials, and / or by stereoselective synthesis. Methods for preparing optically active forms, for example, by dividing a racemate, or by synthesis starting from optically active starting materials, and / or by using chiral reagents, are known in the art. The compounds or intermediates of the present invention, which are pure as enantiomers, can be prepared by asymmetric synthesis, for example, by preparing a suitable diastereomer compound or intermediate that can be separated by known methods (e.g., chromatographic separation or crystallization), and then separating it, and / or by using chiral reagents, such as chiral starting materials, chiral catalysts, or chiral auxiliaries.

[0048] Furthermore, methods for preparing pure compounds as enantiomers from the corresponding racemic mixture are known to those skilled in the art, for example, by chromatographic separation of the corresponding racemic mixture on a chiral stationary phase, or by resolution of the racemic mixture using a suitable resolving agent, for example, by forming a diastereomer salt of the racemic compound using an optically active acid or base, followed by resolution of the salt and release of the desired compound from the salt, or by derivatization of the corresponding racemic compound using an optically active chiral auxiliary reagent, followed by diastereomer separation and removal of the chiral auxiliary, or by kinetic optical resolution of the racemic mixture (e.g., enzymatic resolution), by enantioselective crystallization from an aggregate of enantiomers under suitable conditions, or by (partial) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary. The phrase "pharmaceutically acceptable" is used herein to mean a compound, material, composition, and / or dosage form that is suitable for use in contact with human tissue without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of sound medical judgment, and that is commensurate with a reasonable profit-benefit ratio.

[0049] As used herein, “pharmaceutically acceptable salt” means a derivative of the disclosed compound in which the parent compound has been modified by forming a salt of its acid or base. Examples of pharmaceutically acceptable salts, but not limited to these, include, for example, inorganic or organic salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. For example, such salts include those obtained from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. Further pharmaceutically acceptable salts can be formed with cations obtained from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane.

[0050] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing a basic or acidic moiety. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with a sufficient amount of a suitable base or acid in water, or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Other salts of acids useful for purifying or isolating the compounds of the present invention, such as trifluoroacetates, also constitute part of the present invention. The term halogen refers to fluorine, chlorine, bromine, and iodine.

[0051] "C 1-n The term "-alkyl" (where n is an integer selected from 2, 3, 4, 5, or 6, preferably 4, 5, or 6) refers to an acyclic, saturated, branched, or linear hydrocarbon radical having 1 to n carbon atoms, either alone or in combination with another radical. For example, C 1-5The term -alkyl encompasses radicals such as H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)-, and H3C-CH2-CH(CH2CH3)-. "C 2-m The term "-alkenyl" refers to the group "C 2-m For an alkyl group (where m is an integer selected from 3, 4, 5, or 6, preferably 4, 5, or 6), the term is used when at least two carbon atoms of the group are double-bonded to each other.

[0052] "C 3-k The term "-cycloalkyl" (where k is an integer selected from 3, 4, 5, 7, or 8, preferably selected from 4, 5, or 6) refers to a cyclic, saturated, unbranched hydrocarbon radical having 3 to k carbon atoms, either alone or in combination with another radical. For example, C 3-7 - The term cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "halo" added to an "alkyl," "alkylene," or "cycloalkyl" group (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 selected from fluorine and chlorine, and particularly preferably fluorine. Examples include H2FC-, HF2C-, and F3C-. The term "carbocyclyl" refers to a monocyclic, dicyclic, or tricyclic ring structure consisting of 3 to 14 carbon atoms, either alone or in combination with another radical. The term "carbocyclyl" refers to fully saturated, partially saturated, or aromatic ring systems. The term "carbocyclyl" encompasses condensed, cross-linked, and spirocyclic systems.

[0053] [ka] As used herein, the term "aryl" refers, alone or in combination with another radical, to a carbocyclic aromatic monocyclic group containing six carbon atoms, which is further condensed to a second five- or six-membered carbocyclic group that is optionally aromatic, saturated, or unsaturated. Examples of aryls, but not limited to, include phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenantrenyl, tetrahydronaphthyl, and dihydronaphthyl. The term "heterocyclyl" refers to a saturated or unsaturated monocyclic or polycyclic ring system consisting of 3 to 14 ring atoms, containing one or more heteroatoms selected from N, O, S, SO, or SO2, and optionally including an aromatic ring, none of which are part of an aromatic ring. The term "heterocyclyl" is intended to include all possible isomer forms.

[0054] Therefore, the term “heterocyclyl” includes the following exemplary structures (each form is arbitrarily bonded to any atom via covalent bonds, as long as an appropriate valence is maintained, and not shown as a radical): [ka] [ka] The term "heteroaryl" refers to a monocyclic or polycyclic ring system consisting of 5 to 14 ring atoms, containing one or more heteroatoms selected from N, O, S, SO, or SO2, and including at least one aromatic ring, where at least one of these heteroatoms is part of the aromatic ring. The term "heteroaryl" is intended to include all possible isomer forms.

[0055] Therefore, the term "heteroaryl" includes the following exemplary structures (each form is arbitrarily bonded to any atom via covalent bonds, as long as an appropriate valence is maintained, and not shown as a radical): [ka] Many of the terms assigned above may be used repeatedly in the definitions of formulas or bases, and in each case, independently of each other, they have one of the meanings assigned above. The term "bicyclic ring system" refers to a group consisting of two linked cyclic substructures, including spiro ring systems, fused ring systems, and bridging ring systems.

[0056] Preparation method The following examples are illustrative only and are not intended to limit the scope of the present invention. The term "room temperature" means a temperature of approximately 20°C, for example, 15–25°C. Generally, 1 1H-NMR and / or mass spectra are obtained for the prepared compounds. Flash chromatography or MPLC is performed using commercially available silica gel and is equivalent to silica gel chromatography. The absolute configuration of representative examples is defined by chemical starting materials, single-crystal X-ray structure determination, or protein-ligand X-ray determination. Unless otherwise specified, compounds containing chiral centers have the stereochemistry shown. The stereochemical configuration is determined by the use of chiral starting materials of known stereochemistry, by stereoselective synthesis of known stereochemistry, or by biological activity.

[0057] Scheme 1: General synthesis scheme for patented examples [ka] R4 is H, F, BA is =CN- or -NC=, which means that A is C or N and B is C or N, but A and B are not N at the same time.

[0058] Scheme 2a: Intermediate A: For example, general synthesis of A1, A13, A14, A24 [ka]

[0059] Scheme 2b: intermediate A :for example A2 , A5 , A19~A23 , A25 Alternative synthesis [ka]

[0060] Scheme 2c: intermediate A :for example A4 , A7 Alternative synthesis [ka]

[0061] Scheme 3: Synthesis of intermediates F1-F20, F23-F39, and F49 [ka]

[0062] Scheme 4: Synthesis of intermediates F21 and F22 [ka]

[0063] Scheme 5: Synthesis of imidazole intermediates F40-F47 [ka] All starting materials not listed are either commercially available or those described in the literature.

[0064] Synthesis of intermediates A1-A25: Synthesis of intermediate A1: Step 1: Synthesis of (1R)-2-{[(2-bromo-6-nitrophenyl)methyl]amino}-1-phenylethane-1-ol [ka] (1R)-2-amino-1-phenylethane-1-ol (5.00 g, 17.0 mmol) is dissolved in ACN (20 mL) and DIPEA (8.75 mL, 50.9 mmol). 1-bromo-2-(bromomethyl)-3-nitrobenzene (6.98 g, 50.9 mmol) is slowly added. The reaction mixture is stirred at RT for 2 hours. The reaction mixture is concentrated and purified by flash chromatography (CycH / Â100 / 0~CycH / Â10 / 90) to obtain the desired compound. Analysis (Method A): R t :0.36min, [M+H] + :351 / 353(Br)

[0065] Step 2: Synthesis of (1R)-2-(4-bromo-2H-indazole-2-yl)-1-phenylethane-1-ol [ka] (1R)-2-{[(2-bromo-6-nitrophenyl)methyl]amino}-1-phenylethane-1-ol (5.44 g, 15.5 mmol) is suspended in MeOH (25 mL). Zinc (5.06 g, 77.45 mmol) is added, and then ammonium formate (977 mg, 15.5 mmol) is added dropwise to MeOH (5 mL) over 5 min. The reaction mixture is stirred overnight in RT. The reaction mixture is filtered, washed with MeOH, and the filtrate is concentrated. The residues are ground with water. The precipitate is filtered and recrystallized from ACN to obtain the title compound. Analysis (Method A): R t :0.58min, [M+H] + :317 / 319(Br)

[0066] Synthesis of intermediates A2 and A23: [ka]

[0067] Step 1: Synthesis of 2-(4-bromo-2H-indazole-2-yl)-1-(4-hydroxyphenyl)ethane-1-one [ka] Add 2-bromo-1-(4-hydroxyphenyl)ethane-1-one (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) to DMF / water 3 / 1 (48 mL). Stir the reaction mixture at RT for 5d. Filter the reaction mixture and wash the precipitate with water. Suspend the precipitate in MeOH / DCM / DMF (100 mL / 50 mL / 100 mL) and filter off the aluminum. Concentrate the filtrate and grind the residue with n-heptane (100 mL) to obtain the desired product. Analysis (Method D): R t :0.31min, [M+H] + :331 / 333(Br)

[0068] Step 2: Synthesis of 4-[(1R)-2-(4-bromo-2H-indazole-2-yl)-1-hydroxyethyl]phenol [ka] Under an argon atmosphere, 2-(4-bromo-2H-indazole-2-yl)-1-(4-hydroxyphenyl)ethane-1-one (2.00 g, 5.13 mmol, 85% purity) is dissolved in THF (40 mL). At 0°C, triethylamine formate complex 5:2 (10.73 mL, 25.67 mmol) is added dropwise. After stirring at 0°C for 5 min, chloro([(1S,2S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amide)(mesitylene)ruthenium(II) (0.16 g, 0.26 mmol) is added, and the reaction mixture is stirred overnight at RT. The reaction mixture is diluted with acetone and water and concentrated. The residue is purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 95 / 5) to obtain the desired product A23. Analysis (Method F): R t :0.74min, [M+H] + :333 / 335(Br) Chiral analysis (Method T): R t :3.80min, >98%ee

[0069] Step 3: Synthesis of (1R)-2-(4-bromo-2H-indazole-2-yl)-1-{4-[2-(morpholine-4-yl)ethoxy]phenyl}ethane-1-ol [ka] A mixture of 4-[(1R)-2-(4-bromo-2H-indazole-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 overnight at 70°C. K2CO3 was filtered off, and the filtrate was concentrated. The residue was purified by reverse-phase chromatography (HPLC; ACN / water containing NH3) to obtain compound A2. Analysis (Method H): R t :0.97min, [M+H] + :446 / 448(Br)

[0070] Synthesis of intermediate A3: Step 1: Synthesis of 2-[(benzenesulfinyl)methyl]-4-bromo-2H-indazole [ka] Dissolve 4-bromo-1H-indazole (400 mg, 1.99 mmol) in DMF (5 mL). Add K2CO3 (1.10 g, 7.96 mmol) and chloromethylphenyl sulfoxide (716 mg, 3.98 mmol), and stir the reaction mixture overnight at 50°C. Add K2CO3 (1.10 g, 7.96 mmol), and stir the reaction mixture overnight at 70°C. Filter the reaction mixture, and purify the filtrate by reverse-phase chromatography (HPLC; ACN / water containing TFA) to obtain compound A3. Analysis (Method G): R t :0.90min, [M+H] + :335 / 337(Br)

[0071] Synthesis of intermediates A4 and A14: [ka]

[0072] Step 1: Synthesis of 1-bromo-2-(bromomethyl)-3-nitrobenzene [ka] Dissolve 2-bromo-6-nitrotoluene (50 g, 231 mmol) in DCE (300 mL). Add a suspension of NBS (61.8 g, 347 mmol) in DCE (400 mL) via RT and stir the reaction mixture under reflux. Then, slowly add AIBN (2.66 g, 16.2 mmol) in DCM (35 mL) (syringe pump, pump speed approximately 1 drop per 6 seconds) and stir the reaction mixture overnight under reflux. Concentrate the reaction mixture, dissolve the residue in DCM (500 mL), and wash 3 × with water. Dehydrate the organic layer with MgSO4, filter through a short silica plug, and wash the silica with DCM (50 mL). Concentrate the filtrate and dry under high vacuum to obtain the desired product. TLC: Silica gel, CycH / mmol5 / 1:R f :0.4

[0073] Step 2: Synthesis of [(2-bromo-6-nitrophenyl)methyl][(trimethylsilyl)methyl]amine [ka] (Trimethylsilyl)methylamine (13 mL, 97.1 mmol) and DIPEA (34.00 mL, 196.6 mmol) are dissolved in ACN (200 mL). A solution of 1-bromo-2-(bromomethyl)-3-nitrobenzene (20.00 g, 67.14 mmol) in ACN (200 mL) is added dropwise, and the reaction mixture is stirred at RT for 1 hour. The reaction mixture is concentrated, the residue is dissolved in DCM, and washed with water 3 times. The organic layer is filtered through silica, the silica is washed with DCM, and the filtrate is concentrated to obtain the desired product. Analysis (Method G): R t :0.75min, [M+H] + :317 / 319(Br)

[0074] Step 3: Synthesis of 4-bromo-2-[(trimethylsilyl)methyl]-2H-indazole [ka] [(2-bromo-6-nitrophenyl)methyl][(trimethylsilyl)methyl]amine (18.64 g, 58.75 mmol) is dissolved in MeOH (1.6 L). Zinc (19.2 g, 294 mmol) is added, and ammonium formate (5.55 g, 88.12 mmol) is slowly added dropwise to MeOH (38 mL) over 7 hours at 50°C. The reaction mixture is filtered on Celite, washed with MeOH, and the filtrate is concentrated. The residue is purified by flash chromatography (CycH / Ã88 / 12~CycH / Ã0 / 100) to obtain compound A14. Analysis (Method G): R t :1.18min, [M+H] + :283 / 285(Br)

[0075] Step 4: Synthesis of 2-(4-bromo-2H-indazole-2-yl)-1-(4-methylphenyl)ethane-1-ol [ka] p-Tolualdehyde (103 μL, 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 DMF (2.5 mL) is added dropwise to the reaction mixture via RT, and the mixture is stirred via RT for 2 hours. The reaction mixture is filtered, the filtrate is concentrated under vacuum, diluted with ACN, and purified by reverse-phase chromatography (HPLC; ACN / water / NH4OH) to obtain the desired product. Analysis (Method H): R t :0.94min, [M+H] + :331 / 333(Br)

[0076] Synthesis of intermediate A5: (1R)-2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-2H-indazole-2-yl]-1-phenylethane-1-ol (1R)-2-(4-bromo-5-fluoro-2H-indazole-2-yl)-1-phenylethane-1-ol [ka]

[0077] Step 1: Synthesis of 2-(4-bromo-5-fluoro-2H-indazole-2-yl)-1-phenylethane-1-one [ka] 4-bromo-5-fluoro-1H-indazole (800 mg, 3.72 mmol) and 2-chloro-1-phenylethane-1-one (1.15 g, 7.44 mmol) are combined in a microwave tube, and the reaction mixture is stirred in a microwave at 130°C for 45 minutes. The reaction mixture is purified by reverse-phase chromatography (HPLC; ACN / water / TFA) to obtain the desired compound. Analysis (Method A): R t :0.62min, [M+H] + :333 / 335(Br)

[0078] Step 2: Synthesis of (1R)-2-(4-bromo-5-fluoro-2H-indazole-2-yl)-1-phenylethane-1-ol [ka] Dissolve 2-(4-bromo-5-fluoro-2H-indazole-2-yl)-1-phenylethane-1-one (660 mg, 1.98 mmol) in THF (10 mL). At 0°C, add triethylamine formate complex 5:2 (4.14 mL, 9.91 mmol) dropwise to chloro([(1S,2S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amide), add (mesitylene)ruthenium(II) (61.6 mg, 0.10 mmol), and stir the reaction mixture at RT for 2 hours. Quench the reaction mixture with water, evaporate the THF, and purify the residue by reverse-phase chromatography (HPLC; ACN / water with TFA). Recrystallize the lyophilized fraction from ACN / MeOH to obtain the desired compound A5. Analysis (Method A): R t :0.62min, [M+H] + :335 / 337(Br) Chiral analysis (Method ZD): R t :2.57min, >98%ee

[0079] Synthesis of intermediate A6: Synthesis of ethyl 2-[(1R)-2-(4-bromo-2H-indazole-2-yl)-1-phenylethoxy]acetate [ka] Under an argon atmosphere, (1R)-2-(4-bromo-2H-indazole-2-yl)-1-phenylethane-1-ol (5 g, 15.8 mmol) is dissolved in DCM (140 mL). Rhodium(II) acetate dimer (125 mg, 0.28 mmol) is added, and ethyl diazoethyl (16.6 mL, 158 mmol) is added dropwise to DCM (8 mL) over 24 hours at RT. The reaction mixture is filtered, and the filtrate is purified by reverse-phase chromatography (HPLC; ACN / water with TFA) to obtain the desired compound A6. Analysis (Method F): R t :1.05min, [M+H] + :403 / 405(Br)

[0080] Synthesis of intermediate A7: Step 1: Synthesis of 2-(4-bromo-2H-indazole-2-yl)-1-(3,4-difluorophenyl)ethane-1-ol [ka] 3,4-Difluorbenzaldehyde (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 RT for 2 hours. The reaction mixture was diluted with HOAc and DMF and purified by reverse-phase chromatography (HPLC; ACN / water containing NH3) to obtain the desired compound A7. Analysis (Method G): R t :0.91min, [M+H] + :353 / 355(Br)

[0081] Synthesis of intermediate A8: Step 1: Synthesis of 2-(4-bromo-2H-indazole-2-yl)-1-phenylethane-1-one [ka] Dissolve 4-bromo-2H-indazole (2 g, 10.2 mmol), 2-bromo-1-phenylethane-1-one (4.04 g, 20.3 mmol), and aluminum powder (548 mg, 20.3 mmol; -100 + 325 mesh) in DMF / water 3 / 1 (20 mL). Stir the reaction mixture overnight at 80°C. Filter off the aluminum and wash with DMF. Dilute the filtrate with water and extract with siRNA. Dry the organic layer with (Na2SO4), filter, and concentrate. Grind the residue first with water, then with MeOH. Filter the precipitate to obtain the desired compound. Analysis (Method A): R t :0.60min, [M+H] + :315 / 317(Br)

[0082] Step 2: Synthesis of 4-bromo-2-(2,2-difluoro-2-phenylethyl)-2H-indazole [ka] Dissolve 2-(4-bromo-2H-indazole-2-yl)-1-phenylethane-1-one (1.08 g, 3.41 mmol) in toluene (6 mL) and DCM (6 mL). At 0°C, add DAST (3.93 mL, 30 mmol) dropwise and stir the reaction mixture at RT for 4d. Quench the reaction mixture with a saturated NaHCO3 solution and extract with DCM. Dry the organic layer (Na2SO4), filter, and concentrate. Purify the residue by flash chromatography (CycH / Â70 / 30) to obtain the desired compound A8. Analysis (Method A): R t :0.68min, [M+H] + :337 / 339(Br)

[0083] Synthesis of intermediates A9-A12: [ka] Steps 1-2: Using racemic 2-amino-1-phenylethane-1-ol as the starting material, synthesize intermediate A1 by following a procedure similar to that described for intermediate A1. Step 3: Synthesis of 4-bromo-2-(2-fluoro-2-phenylethyl)-2H-indazole [ka] Dissolve racemic 2-(4-bromo-2H-indazole-2-yl)-1-phenylethane-1-ol (A10, 6.10 g, 17.3 mmol) in DCM (45 mL) and add [bis(2-methoxyethyl)amino]sulfur trifluoride (9.70 mL, 26.3 mmol, 50% in toluene) dropwise. Stir the reaction mixture at RT for 4d. Quench the reaction mixture with a saturated NaHCO3 solution and extract with DCM. Dry the organic layer (Na2SO4), filter, and concentrate. Purify the residue by reverse-phase chromatography (HPLC; ACN / water / formic acid) to obtain the desired product A11. Analysis (Method G): R t :1.12min, [M+H] + :319 / 321(Br)

[0084] [ka] 4-bromo-2-(2-fluoro-2-phenylethyl)-2H-indazole (455 mg) was separated by chiral purification method ZC to obtain 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 min).

[0085] Synthesis of intermediate A13: [ka] Step 1: Synthesis of tert-butyl N-(2-{4-[2-(dimethylamino)ethoxy]phenyl}ethyl) carbamate [ka] Dissolve tert-butyl N-[2-(4-hydroxyphenyl)ethyl]carbamate (7.10 g, 30 mmol) in acetone (70 mL). Add (2-chloroethyl)dimethylamine hydrochloride (5.50 g, 38.2 mmol) and Cs2CO3 (20.00 g, 61.4 mmol), and stir the reaction mixture overnight at 75°C. Filter the reaction mixture and concentrate the filtrate. Purify the residue by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 85 / 15) to obtain the desired product. Analysis (Method H): R t :1.01min, [M+H] + :309

[0086] Step 2: Synthesis of 2-{4-[2-(dimethylamino)ethoxy]phenyl}ethane-1-amine hydrochloride [ka] Dissolve tert-butyl N-(2-{4-[2-(dimethylamine)ethoxy]phenyl}ethyl) carbamate (6.30 g, 20.4 mmol) in dioxane (5 mL). Add 4 M HCl to dioxane (24 mL, 96 mmol) and stir the reaction mixture at RT for 2 hours. Concentrate the reaction mixture to obtain the desired product. Analysis (Method G): R t :0.76min, [M+H] + :209

[0087] Step 3: Synthesis of [(2-bromo-6-nitrophenyl)methyl](2-{4-[2-(dimethylamino)ethoxy]phenyl}ethyl)amine [ka] 1-Bromo-2-(bromomethyl)-3-nitrobenzene (900 mg, 3.05 mmol) and 2-{4-[2-(dimethylamino)ethoxy]phenyl}ethane-1-amine hydrochloride (800 mg, 3.27 mmol) are dissolved in ACN (10 mL). DIPEA (3.50 mL, 20.3 mmol) is added, and the reaction mixture is stirred overnight under RT. The reaction mixture is concentrated and purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 65 / 35) to obtain the desired product. Analysis (Method G): R t :0.63min, [M+H] + :422 / 424(Br)

[0088] Step 4: Synthesis of (2-{4-[2-(4-bromo-2H-indazole-2-yl)ethyl]phenoxy}ethyl)dimethylamine [ka] [(2-bromo-6-nitrophenyl)methyl](2-{4-[2-(dimethylamine)ethoxy]phenyl}ethyl)amine (1.20 g, 2.56 mmol) is suspended in MeOH. Zinc (836 mg, 12.8 mmol) and ammonium formate (110 mg, 1.74 mmol) are added, and the reaction mixture is stirred overnight in RT. The reaction mixture is filtered, washed with MeOH, and the filtrate is concentrated. The residue is purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 72 / 28) to obtain intermediate A13. Analysis (Method G): R t :0.83min, [M+H] + :388 / 390(Br)

[0089] Synthesis of intermediates A15-A18: [ka] Using A13 and 4-chlorobenzaldehyde as starting materials, synthesize A15 following a procedure similar to that described for intermediate A4 (step 4). Step 1: Synthesis of 4-bromo-2-[2-(4-chlorophenyl)-2-fluoroethyl]-2H-indazole

[0090] [ka] Dissolve 2-(4-bromo-2H-indazole-2-yl)-1-(4-chlorophenyl)ethane-1-ol (1.23 g, 3.50 mmol) in DCM (20 mL). At 0°C, add [bis(2-methoxyethyl)amino]sulfur trifluoride (2.28 mL, 5.25 mmol, 50% in THF) dropwise and stir the reaction mixture at RT for 2.5 hours. Quench the reaction mixture, basicize it with a 2 M solution of Na2CO3, and extract it with DCM. Wash the organic layer with a saturated solution of NaHCO3, dry it (Na2SO4), filter it, and concentrate it. Purify the residue by reverse-phase chromatography (HPLC; ACN / water with TFA) to obtain the desired product. Analysis (Method F): R t :1.10min, [M+H] + :353 / 355(Br) [ka]

[0091] Step 2: Synthesis of 4-bromo-2-[(2R)-2-(4-chlorophenyl)-2-fluoroethyl]-2H-indazole 4-bromo-2-[2-(4-chlorophenyl)-2-fluoroethyl]-2H-indazole (750 mg, 2.12 mmol) was separated by chiral purification method ZB to obtain 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 Obtain 0.79 min.

[0092] Synthesis of intermediate A19: Step 1: Synthesis of 2-(4-bromo-2H-indazole-2-yl)-1-cyclohexylethane-1-one [ka] Dissolve 4-bromo-1H-indazole (500 mg, 2.54 mmol) in ACN (8 mL). Add K2CO3 (877 mg, 6.34 mmol) and 2-bromo-1-cyclohexylethane-(cyclohexyletan)1-one (521 mg, 2.54 mmol), and stir the reaction mixture overnight at 50°C. Purify the reaction mixture by reverse-phase chromatography (HPLC; ACN / water containing NH3) to obtain the desired product. Analysis (Method G): R t :1.13min, [M+H] + :321 / 323(Br)

[0093] Step 2: Synthesis of 2-(4-bromo-2H-indazole-2-yl)-1-cyclohexylethane-1-ol [ka] 2-(4-bromo-2H-indazole-2-yl)-1-cyclohexylethane-1-one (200 mg, 0.62 mmol) is dissolved in THF (3 mL) and MeOH (3 mL). At 0°C, sodium borohydride (23.6 mg, 0.62 mmol) is added, and the reaction mixture is stirred at 0°C for 2 hours. The reaction mixture is quenched with 1 M HCl and stirred at RT for 15 minutes. The reaction mixture is then basicized with a saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer is dried (Na2SO4), filtered, and concentrated to obtain the desired product A19. Analysis (Method G): R t :1.13min, [M+H] + :323 / 325(Br)

[0094] Synthesis of intermediate A20: Step 1: Synthesis of 1-[4-(benzyloxy)phenyl]-2-(4-bromo-2H-indazole-2-yl)ethane-1-one [ka] 4-Bromo-1H-indazole (3.5 g, 17.8 mmol) and 1-[4-(benzyloxy)phenyl]-2-chloroethane-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 ground with ACN, the resulting solid was collected, and extracted between DCM and an aqueous solution of Na2CO3. The organic phase was concentrated, and a 2:1 mixture of ACN / siRNA was ground to obtain the desired product. Analysis (Method A): R t :0.78min, [M+H] + :421 / 435(Br)

[0095] Step 2: Synthesis of (1R)-1-[4-(benzyloxy)phenyl]-2-(4-bromo-2H-indazole-2-yl)ethane-1-ol [ka] 1-[4-(benzyloxy)phenyl]-2-(4-bromo-2H-indazole-2-yl)ethane-1-one (2.05 g, 4.86 mmol) was dissolved in THF (100 mL), and triethylamine formate complex 5:2 (10, 15 mL) and chloro([(1S,2S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amide)(mesitylene)ruthenium(II) (181 mg) were added. The mixture was stirred overnight in RT. The mixture was concentrated and extracted with DCM / Na2CO3 aqueous solution. The organic phase was concentrated to obtain the desired product A20. Analysis (Method A): R t :0.75min, [M+H] + :423 / 425(Br) Chiral HPLC (Method V): >98% ee

[0096] Synthesis of intermediate A21: Synthesis of 2-(4-bromo-2H-indazole-2-yl)-1-(2-methylpyridine-4-yl)ethane-1-ol [ka] 4-bromo-2-[(trimethylsilyl)methyl]-2H-indazole (500 mg, 1.76 mmol) and 1-methyl-1H-pyrazole-4-carbaldehyde (231 mg, 2.1 mmol) were dissolved in 4 mL of DMF, CsF (227 mg, 1.5 mmol) was added, and the mixture was stirred at RT for 1.5 hours. The mixture was then diluted with HOAc and DMF and purified by preparative reverse-phase HPLC (Sunfire C18, ACN / water containing formic acid) to obtain the desired product A21. Analysis (Method G): R t :0.84min, [M+H] + :321 / 323(Br)

[0097] Synthesis of intermediate A22: Synthesis of 2-(4-bromo-2H-indazole-2-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethane-1-ol [ka] 4-bromo-2-[(trimethylsilyl)methyl]-2H-indazole (500 mg, 1.76 mmol) and 2-methylpyridine-4-carboaldehyde (290 mg, 2.39 mmol) were dissolved in 1.8 mL of DMF, and CsF (286 mg, 1.765 mmol) was added. The mixture was stirred at RT for 3 hours. The mixture was then diluted with HOAc and DMF and purified by preparative reverse-phase HPLC (Sunfire C18, ACN / water containing formic acid) to obtain the desired product A22. Analysis (Method G): R t :0.72min, [M+H] + :332 / 334(Br)

[0098] Synthesis of intermediate A24 Step 1: (1R)-2-{[(2-bromo-6-nitrophenyl)methyl]amino}-1-(4-fluorophenyl)ethane-1-ol [ka] (1R)-2-amino-1-(4-fluorophenyl)ethane-1-ol hydrochloride (292 mg, 1.08 mmol) is dissolved in ACN (5 mL) and DIPEA (0.525 mL, 3.05 mmol). 1-bromo-2-(bromomethyl)-3-nitrobenzene (300 mg, 1.02 mmol) is added dropwise. The reaction mixture is stirred at RT for 2 hours. The reaction mixture is concentrated and purified by reverse-phase chromatography to obtain the desired product. Analysis (Method G): R t :0.73min, [M+H] + :369 / 371(Br)

[0099] Step 2: Synthesis of (1R)-2-(4-bromo-2H-indazole-2-yl)-1-(4-fluorophenyl)ethane-1-ol [ka] (1R)-2-{[(2-bromo-6-nitrophenyl)methyl]amino}-1-(4-fluorophenyl)ethane-1-ol (338 mg, 0.96 mmol) is suspended in MeOH (5 mL). Zinc (300 mg, 4.6 mmol) is added, followed by the dropwise addition of ammonium formate (57.7 mg, 0.92 mmol) in MeOH (3 mL). The reaction mixture is stirred at RT for 2d. The reaction mixture is filtered through Celite, washed with MeOH, and the filtrate is concentrated. The residue is dissolved in DMF and purified by preparative reverse-phase HPLC to obtain the desired product A24. Analysis (Method G): R t :1.022min, [M+H] + :335 / 337(Br)

[0100] Synthesis of intermediate A25 Step 1: Synthesis of 2-(4-bromo-2H-indazole-2-yl)-1-{4-[2-(dimethylamino)ethoxy]phenyl}ethane-1-one [ka] 2-Chloro-1-{4-[2-(dimethylamino)ethoxy]phenyl}ethane-1-ontrifluate (1.5 g, 3.75 mmol) and 4-bromo-1H-indazole (0.739 g, 3.75 mmol) are heated at 140°C for 90 min. After cooling, the mixture is purified by preparative reverse-phase HPLC (Sunfire C18, ACN / water containing TFA) to obtain the desired product. Analysis (Method B): R t :0.60min, [M+H] + :402 / 404(Br)

[0101] Step 2: Synthesis of (1R)-2-(4-bromo-2H-indazole-2-yl)-1-{4-[2-(dimethylamino)ethoxy]phenyl}ethane-1-ol [ka] Dissolve 2-(4-bromo-2H-indazole-2-yl)-1-{4-[2-(dimethylamino)ethoxy]phenyl}ethane-1-one (0.85 g, 1.65 mmol, as trifluate) in THF (20 mL) and cool in a water / ice bath. Within 5 min, add triethylamine formate complex 5:2 (3.44 mL, 8.32 mmol). Then, after 5 min, add chloro([(1S,2S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amide)(mesitylene)ruthenium(II) (51 mg, 0.082 mmol) and stir the mixture at RT for 3.5 h. Then add 60 mL of MeTHF and 5 mL of 2 M Na2CO3 aqueous solution to separate the organic phase, dehydrate with Na2SO4 to obtain the desired product A25. Analysis (Method C): R t :0.61min, [M+H] + :404 / 406(Br)

[0102] Synthesis of intermediates B1-B20: Synthesis of (1R)-1-phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-2-yl]ethane-1-ol (B1) [ka] (1R)-2-(4-bromo-2H-indazole-2-yl)-1-phenylethane-1-ol (A1, 10 g, 31.5 mmol) is dissolved in dioxane (200 mL). Bis(pinacolato)diborone (9.61 g, 37.8 mmol), potassium acetate (8.03 g, 82 mmol), and Pd(dppf)Cl2×DCM (2.00 g, 2.45 mmol) are added RT, and the reaction mixture is stirred overnight at 80°C. After cooling the reaction mixture to RT, the formed precipitate is filtered and washed with 3 × 20 mL of dioxane. The filtrate is concentrated, the residue is suspended, and it is ground overnight in CycH. The precipitate is filtered, washed with 2 × 20 mL of CycH, and dried overnight in an oven at 50°C to obtain the desired product B1. Analysis (Method G): R t :1.12min, [M+H] + :365

[0103] Synthesis of (1R)-2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol (B2) and {2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazole-4-yl}boronic acid (B3) [ka] (1R)-2-(4-bromo-2H-indazole-2-yl)-1-phenylethane-1-ol (7.50 g, 23.7 mmol) is dissolved in dioxane (60 mL). Bis(neopentyl glycolate)diborone (8.01 g, 35.5 mmol) and potassium acetate (7.00 g, 71.3 mmol) are added, and the mixture is purged with nitrogen. Pd(dppf)Cl2×DCM (0.71 g, 0.87 mmol) is added, and the reaction mixture is stirred at 85°C for 4.5 hours. After the reaction mixture is cooled to RT, it is filtered through Celite and thiol resin, and the filtrate is concentrated. The residue is diluted with DCM, and the organic phase is washed with 2× water and brine. The organic layer is dried with (Na2SO4), filtered, and evaporated. The residue was ground with diethyl ether, the resulting precipitate was filtered, and the mixture was dried overnight in an oven at 50°C to obtain compound B2. Analysis (Method G): R t :0.77min, [M+H] + :351 The filtrate is concentrated, and the residue is purified by reverse-phase chromatography (HPLC; Sunfire, ACN / water containing TFA) to obtain compound B3. Analysis (Method G): R t :0.66min, [M+H] + :283

[0104] Synthesis of {2-[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]-2H-indazole-4-yl}boronic acid (B4) [ka] (1R)-2-(4-bromo-2H-indazole-2-yl)-1-(4-fluorophenyl)ethane-1-ol (50 mg, 0.149 mmol), KOAc (38 mg), complex with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (1:1) (12.2 mg), and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (37 mg) are suspended in 1 mL of dioxane and heated at 100°C for 2 hours. The mixture is filtered and then purified by reverse-phase preparative HPLC to obtain the desired product B4. Analysis (Method G): R t :0.78min, [M+H] + :301

[0105] Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(trimethylsilyl)methyl]-2H-indazole (B5) [ka] (1R)-2-(4-bromo-2H-indazole-2-yl)-1-(4-fluorophenyl)ethane-1-ol (1.5 g, 5.3 mmol), KOAc (1.6 g), complex with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (1:1) (460 mg), and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (2.9 g) are suspended in 12 mL of dioxane and heated overnight at 90°C. The mixture is filtered through Celite and charcoal and washed with dioxane. The organic phase is concentrated and purified by silica chromatography CycH / siRNA to obtain the desired product B5. Analysis (Method G): R t :1.23min, [M+H] + :331

[0106] Synthesis of (1R)-1-{4-[2-(morpholine-4-yl)ethoxy]phenyl}-2-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-2-yl]ethane-1-ol (B6) [ka] Under an argon atmosphere, (1R)-2-(4-bromo-2H-indazole-2-yl)-1-{4-[2-(morpholine-4-yl)ethoxy]phenyl}ethane-1-ol (89.3 mg, 0.20 mmol) is dissolved in dioxane (4 mL). Bis(pinacolato)diborone (50.8 mg, 0.20 mmol), potassium acetate (51 mg, 0.52 mmol), and Pd(dppf)Cl2×DCM (16.3 mg, 0.02 mmol) are added, and the reaction mixture is stirred at 95°C for 2 hours. The formed precipitate is filtered off, washed with dioxane, and the filtrate is concentrated to obtain the desired product B6. Analysis (Method G): R t :0.87min, [M+H] + :494

[0107] Synthesis of (1R)-1-[4-(benzyloxy)phenyl]-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-2-yl]ethane-1-ol (B7) [ka] Under an argon atmosphere, (1R)-1-[4-(benzyloxy)phenyl]-2-(4-bromo-2H-indazole-2-yl)ethane-1-ol (400 mg, 0.95 mmol) is dissolved in dioxane (10 mL). Bis(pinacolato)diborone (480 mg, 1.89 mmol), potassium acetate (278 mg, 2.8 mmol), and Pd(dppf)Cl2×DCM (77 mg) are added, and the reaction mixture is stirred at 90°C for 17 hours. The mixture is diluted with methanol and filtered over cellulose. Using CycH / siRNA as the eluent, the concentrated filtrate is purified by MPLC to obtain the desired product B7. Analysis (Method A): R t :0.79min, [M+H] + :471

[0108] Synthesis of 2-[(benzenesulfinyl)methyl]-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2H-indazole (B8) [ka] Under an argon atmosphere, 2-[(benzenesulfinyl)methyl]-4-bromo-2H-indazole (150 mg, 0.45 mmol) is dissolved in dioxane (2.5 mL). Bis(neopentyl glycolate)diborone (152 mg, 0.67 mmol), potassium acetate (131.8 mg, 1.34 mmol), and Pd(dppf)Cl2×DCM (97 mg, 0.12 mmol) are added, and the reaction mixture is stirred at 100 °C for 2 hours. The reaction mixture is filtered, and the filtrate is concentrated to obtain the desired product B8. This is used in the next step without purification. Analysis (Method G): R t :0.68min, [M+H] + :301 (mass of corresponding boronic acid)

[0109] Synthesis of 2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2H-indazole-2-yl]-1-(4-methylphenyl)ethane-1-ol (B9) [ka] Under an argon atmosphere, 2-(4-bromo-2H-indazole-2-yl)-1-(4-methylphenyl)ethane-1-ol (120 mg, 0.36 mmol) is dissolved in dioxane (2.5 mL). Bis(neopentyl glycolate)diborone (123 mg, 0.54 mmol), potassium acetate (107 mg, 1.09 mmol), and Pd(dppf)Cl2×DCM (78.4 mg, 0.096 mmol) are added, and the reaction mixture is stirred at 100°C for 2 hours. The reaction mixture is filtered, and the filtrate is concentrated to obtain the desired product. This is used in the next step without purification. Analysis (Method G): R t :0.75min, [M+H] + :297 (mass of corresponding boronic acid)

[0110] Synthesis of {2-[2-hydroxy-2-(2-methylpyridine-4-yl)ethyl]-2H-indazole-4-yl}boronic acid (B10) [ka] Under an argon atmosphere, 2-(4-bromo-2H-indazole-2-yl)-1-(2-methylpyridine-4-yl)ethane-1-ol (A21, 221 mg, 0.665 mmol) is dissolved in dioxane (3 mL). Bis(neopentyl glycolate)diborone (180 mg, 0.796 mmol), potassium acetate (196 mg, 2 mmol), and Pd(dppf)Cl2×DCM (54 mg) are added, and the reaction mixture is stirred at 90°C for 3 hours. The reaction mixture is filtered, diluted with HOAc, and purified by reverse-phase preparative HPLC to obtain the desired product B10. Analysis (Method G): R t :0.75min, [M+H] + :298

[0111] Synthesis of 1-(1-methyl-1H-pyrazole-4-yl)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-2-yl]ethane-1-ol (B11) [ka] Under an argon atmosphere, 2-(4-bromo-2H-indazole-2-yl)-1-(1-methyl-1H-pyrazole-4-yl)ethane-1-ol (A1, 118 mg, 0.367 mmol) is dissolved in dioxane (2.5 mL). Bis(pinacolato)diborone (373 mg, 1.47 mmol), potassium acetate (108 mg, 1 mmol), and Pd(dppf)Cl2×DCM (30 mg) are added, and the reaction mixture is stirred at 90°C for 4 hours. The reaction mixture is filtered, then concentrated, and purified with MPLC (silica, DCM / MeOH) to obtain the desired product B11. Analysis (Method G): R t :0.94min, [M+H] + :369

[0112] Synthesis of (1R)-2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-2H-indazole-2-yl]-1-phenylethane-1-ol (B12) [ka] Under an argon atmosphere, (1R)-2-(4-bromo-5-fluoro-2H-indazole-2-yl)-1-phenylethane-1-ol (A5, 608 mg, 1.81 mmol) is dissolved in dioxane (8 mL). Bis(neopentyl glycolate)diborone (1.23 g, 5.44 mmol), potassium acetate (890 mg, 9.07 mmol), and Pd(dppf)Cl2×DCM (74 mg, 0.09 mmol) are added, and the reaction mixture is stirred at 80°C for 3 hours, then stirred overnight in RT. After cooling the reaction mixture to RT, it is filtered through a thiol resin, and the filtrate is concentrated. The residue is diluted with water and extracted with siRNA. The organic layer is dried (Na2SO4), filtered, and concentrated. The residue is crystallized over cold MeOH to obtain product B12. Analysis (Method A): R t :0.39min, [M+H] + :301 (mass of corresponding boronic acid)

[0113] Synthesis of {2-[(2R)-2-(2-ethoxy-2-oxoethoxy)-2-phenylethyl]-2H-indazole-4-yl}boronic acid (B13) [ka] Under an argon atmosphere, ethyl 2-[(1R)-2-(4-bromo-2H-indazole-2-yl)-1-phenylethoxy]acetate (A6, 1.93 g, 4.79 mmol) is dissolved in dioxane (25 mL). Bis(neopentyl glycolate)diborone (1.19 g, 5.26 mmol), potassium acetate (1.64 g, 16.8 mmol), and Pd(dppf)Cl2×DCM (0.30 g, 0.37 mmol) are added, and the reaction mixture is stirred at 90 °C for 1.5 hours. The reaction mixture is diluted with DCM and filtered. The filtrate is concentrated, and the residue is purified by reverse-phase chromatography (HPLC; ACN / water with TFA) to obtain the desired product B13. Analysis (Method F): R t :0.72min, [M+H] + :369

[0114] Synthesis of 4-[(1R)-1-hydroxy-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-2-yl]ethyl]phenol (B14) [ka] Under an argon atmosphere, 4-[(1R)-2-(4-bromo-2H-indazole-2-yl)-1-hydroxyethyl]phenol (A23, 1.45 g, 4.35 mmol) is dissolved in dioxane (40 mL). Bis(pinacolato)diborane (1.11 g, 4.35 mmol), potassium acetate (1.28 g, 13.1 mmol), and Pd(dppf)Cl2×DCM (355 mg, 0.44 mmol) are added, and the reaction mixture is stirred at 90°C for 2 hours. The reaction mixture is diluted with ethyl acetate and water, and MetS-thiol scavenger resin (for catalyst removal) and activated carbon are added, and the reaction mixture is stirred for 5 minutes. This is then filtered, washed, and extracted with ethyl acetate. The organic layer is dried (Na2SO4), filtered, and concentrated. The residue is ground with ethyl acetate / CycH 1 / 1. The precipitate is filtered, washed with  / CycH 1 / 1, and dried to obtain 840 mg of product. The filtrate is purified by flash chromatography (CycH /  75 / 25 to CycH /  25 / 75) to obtain product B14. Analysis (Method A): R t :0.56min, [M+H] + :381

[0115] Synthesis of {2-[2-(3,4-difluorophenyl)-2-hydroxyethyl]-2H-indazole-4-yl}boronic acid (B15) [ka] (1R)-2-(4-bromo-2H-indazole-2-yl)-1-(3,4-difluorophenyl)ethane-1-ol (A7, 1300 mg, 0.37 mmol), bis(neopentyl glycolate)diborone (116 mg, 0.51 mmol), potassium acetate (113 mg, 1.15 mmol), and Pd(dppf)Cl2×DCM (40 mg, 0.05 mmol) are dissolved in dioxane (4 mL), and the reaction mixture is stirred overnight at 85°C. The reaction mixture is filtered and purified by reverse-phase chromatography (HPLC; ACN / water with TFA) to obtain the desired product B15. Analysis (Method G): R t:0.81min, [M+H] + :319

[0116] Synthesis of [2-(2,2-difluoro-2-phenylethyl)-2H-indazole-4-yl]boronic acid (B16) [ka] Under an argon atmosphere, 4-bromo-2-(2,2-difluoro-2-phenylethyl)-2H-indazole (A8, 677 mg, 2.01 mmol), bis(neopentyl glycolate)diborone (1.36 g, 6.02 mmol), potassium acetate (985 mg, 10 mmol), and Pd(dppf)Cl2×DCM (82 mg, 0.10 mmol) are dissolved in dioxane (9 mL), and the reaction mixture is stirred at 80°C for 3 hours. The reaction mixture is filtered through a thiol scavenger resin with ACN, and the filtrate is evaporated. The residue is purified by reverse-phase chromatography (HPLC; ACN / water containing TFA) to obtain the desired product B16. Analysis (Method A): R t :0.46min, [M+H] + :303

[0117] Synthesis of 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-[(2R)-2-fluoro-2-phenylethyl]-2H-indazole (B17) [ka] Under an argon atmosphere, 4-bromo-2-[(2R)-2-fluoro-2-phenylethyl]-2H-indazole (100 mg, 0.31 mmol), bis(neopentyl glycolate)diborone (77.9 mg, 0.345 mmol), potassium acetate (92.3 mg, 0.940 mmol), and Pd(dppf)Cl2×DCM (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 over (Na2SO4), filtered, and concentrated to obtain the desired product B17. This was used in the next step without further purification. Analysis (Method F): R t :0.67min, [M+H] + :285 (mass of corresponding boronic acid)

[0118] Synthesis of [2-(2-{4-[2-(dimethylamino)ethoxy]phenyl}ethyl)-2H-indazole-4-yl]boronic acid (B18) [ka] (2-{4-[2-(4-bromo-2H-indazole-2-yl)ethyl]phenoxy}ethyl)dimethylamine (A13, 1.00 g, 2.32 mmol) is dissolved in dioxane (7 mL). Bis(neopentyl glycolate)diborone (628 mg, 2.78 mmol), potassium acetate (683 mg, 6.95 mmol), and Pd(dppf)Cl2×DCM (151 mg, 0.19 mmol) are added, and the reaction mixture is stirred overnight at 90°C. The reaction mixture is filtered, and the residue is purified by reverse-phase chromatography (HPLC; ACN / water with TFA) to obtain the title compound B18. Analysis (Method G): R t :0.67min, [M+H] + :354

[0119] Synthesis of {2-[(2R)-2-(4-chlorophenyl)-2-fluoroethyl]-2H-indazole-4-yl}boronic acid (B19) [ka] Under an argon atmosphere, 4-bromo-2-[(2R)-2-(4-chlorophenyl)-2-fluoroethyl]-2H-indazole (A17, 340 mg, 0.96 mmol) is dissolved in dioxane (10 mL). Bis(neopentyl glycolate)diborone (239 mg, 1.06 mmol), potassium acetate (245 mg, 2.5 mmol), and Pd(dppf)Cl2xDCM (78.5 mg, 0.096 mmol) are added, and the reaction mixture is stirred at 100 °C for 2 hours. The reaction mixture is filtered through a thiol scavenger resin, and the residue is purified by reverse-phase chromatography (HPLC; ACN / water containing TFA) to obtain the title compound B19. Analysis (Method F): R t :0.78min, [M+H] + :319

[0120] Synthesis of 1-cyclohexyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-2-yl]ethane-1-ol (B20) [ka] Under an argon atmosphere, 2-(4-bromo-2H-indazole-2-yl)-1-cyclohexylethane-1-ol (A19, 133 mg, 0.41 mmol) and bis(neopentyl glycolate)diborone (125.4 mg, 0.49 mmol) are dissolved in dioxane (1.5 mL). Potassium acetate (121.2 mg, 1.23 mmol) and Pd(dppf)Cl2×DCM (33.6 mg, 0.04 mmol) are added, and the reaction mixture is stirred overnight at 85°C. The reaction mixture is concentrated and purified by flash chromatography (CycH / Â 100 / 0~CycH / Â 50 / 50) to obtain the title compound B20. Analysis (Method G): R t :1.19min, [M+H] + :371

[0121] Synthesis of {2-[(2R)-2-(4-fluorophenyl)-2-hydroxyethyl]-2H-indazole-4-yl}boronic acid (B21) [ka] Under an argon atmosphere, (1R)-2-(4-bromo-2H-indazole-2-yl)-1-(4-fluorophenyl)ethane-1-ol (A24, 100 mg, 0.298 mmol) and bis(neopentyl glycolate)diborone (74 mg, 0.33 mmol) are dissolved in dioxane (2 mL). Potassium acetate (76 mg, 1 mmol) and Pd(dppf)Cl2×DCM (25 mg) are added, and the reaction mixture is stirred overnight at 95°C. The reaction mixture is filtered, diluted with HOAc, and purified by preparative reverse-phase HPLC to obtain product B21. Analysis (Method G): R t :0.77min, [M+H] + :301

[0122] Synthesis of {2-[(2R)-2-{4-[2-(dimethylamino)ethoxy]phenyl}-2-hydroxyethyl]-2H-indazole-4-yl}boronic acid (B22) [ka] Under an argon atmosphere, (1R)-2-(4-bromo-2H-indazole-2-yl)-1-{4-[2-(dimethylamino)ethoxy]phenyl}ethane-1-ol (A25, 80 mg, 0.196 mmol) and bis(neopentyl glycolate)diborone (49 mg, 0.22 mmol) are dissolved in dioxane (1.5 mL). Potassium acetate (68 mg, 0.7 mmol) and Pd(dppf)Cl2×DCM (16 mg) are added, and the reaction mixture is stirred at 90°C for 2 hours. The reaction mixture is diluted with DCM, filtered through Celite, and then purified by preparative reverse-phase HPLC (Sunfire C18, ACN / water with TFA) to obtain the desired product B22. Analysis (Method A): R t :0.28min, [M+H] + :370

[0123] Synthesis of intermediate C Synthesis of intermediate C1: Step 1: Synthesis of 2-acetyl-3-methylbutanenitrile [ka] The solution of diisopropylamine (177 mL, 1.25 mol) in T (1.17 L) is cooled to -78°C. 2.5 M N-butyllithium is added to hexane (469 mL, 1.17 mol), and the reaction mixture is warmed to 0°C and stirred for 1 hour at 0°C. The reaction mixture is cooled to -78°C, and while maintaining a temperature below -65°C, 3-methyl-butyronitrile (81.8 mL, 0.782 mol) in 80 mL of THF is added dropwise. The reaction mixture is stirred for 1 hour at -78°C. Then, acetic anhydride (88.7 mL, 0.938 mol) in 80 mL of THF is added dropwise over 30 minutes. The reaction mixture is warmed to 0°C for 1 hour, and then warmed at 15°C for 0.5 hours. The reaction mixture is quenched with citric acid (10%, 200 mL) and extracted with toluene. The organic layer is dried (Na2SO4), filtered, and concentrated to obtain the desired product. This is then used in the next step without further purification. Analysis (TLC):R f :0.3 (20% siRNA / petroleum ether)

[0124] Step 2: Synthesis of 5-methyl-4-(propan-2-yl)-1H-pyrazole-3-amine [ka] 2-acetyl-3-methylbutanenitrile (80 g, 0.64 mol) is dissolved in EtOH (352 mL). Glacial acetic acid (47.6 mL, 0.83 mol) and hydrazine monohydrate (49.6 mL, 1.02 mol) are added, and the reaction mixture is stirred overnight at 80°C. After cooling to 0°C, the pH is carefully adjusted to 9 with a saturated NaHCO3 solution. The reaction mixture is then diluted with water and extracted with 3 × RINKAN. The organic layer is washed with brine, dried (Na2SO4), filtered, and concentrated to obtain the desired product. Analysis (Method C): R t :0.36min, [M+H] + :140

[0125] Step 3: Synthesis of 3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole [ka] Dissolve 5-methyl-4-(propan-2-yl)-1H-pyrazole-3-amine (1 g, 7.2 mmol) in ACN (8 mL). Add sodium nitrite (0.59 g, 8.6 mmol) under ice / acetone cooling and stir the reaction mixture at -5°C for 30 min. Then add KI (1.55 g, 9.34 mmol) and stir the reaction mixture at 0°C for 1.5 h. Quench the reaction mixture with Na2S2O3 and dilute with Me-THF (10 mL) and water (10 mL). After stirring for 1 h, separate the layers. Wash the organic layer with brine, dry it with (Na2SO4), and concentrate it to obtain 1.6 g of the desired product C1. Analysis (Method A): R t :0.52min, [M+H] + :251

[0126] Alternative synthesis of intermediate C1 Step 1: Synthesis of 5-iodo-3-methyl-4-(propan-2-yl)-1H-pyrazole [ka] Dissolve 3-methyl-4-(propan-2-yl)-1H-pyrazole (10 g, 80.5 mmol) in ACN (150 mL). Add NIS (25 g, 111 mmol) and stir the reaction mixture overnight at 80°C. Filter the reaction mixture and evaporate the filtrate. Quench the residue with a semi-saturated Na2S2O3 solution and extract three times with DCM. Dry the combined organic layers (Na2SO4), filter, and concentrate. Purify the crude product by flash chromatography (CycH / siRNA 95 / 5~CycH / siRNA 76 / 24) to obtain intermediate C1. Analysis (Method G): Rt :0.93min, [M+H] + :251

[0127] Synthesis of intermediate C2 Step 1: Synthesis of 2-cyclopropyl-3-oxobutanenitrile [ka] To a stirred solution of 2-cyclopropylacetonitrile (3.7 mL; 40 mmol) in THF (20 mL), LDA (2 M, 6.44 g, 60 mmol) is added dropwise over 20 min at -78°C. The reaction mixture is stirred at -78°C for 1 hour. A solution of acetic anhydride (4.5 mL) in THF is added dropwise over 20 min, and the mixture is stirred at 0°C for 1 hour. The mixture is quenched with saturated citric acid and extracted with diethyl ether (3 × 20 mL). The organic layer is dried (Na₂SO₄), filtered, and concentrated to obtain the title compound. This compound is used in the next step without further purification. Analysis (TLC):R f :0.7, 10% siRNA in hexane

[0128] Step 2: Synthesis of 5-methyl-4-(cyclopropanyl)-1H-pyrazole-3-amine [ka] Dissolve 2-cyclopropyl-3-oxobutanenitrile (4.9 g, 40 mmol) in EtOH (18 mL). Add glacial acetic acid (3 mL, 51.4 mmol) and hydrazine monohydrate (3.15 mL, 64.9 mol), and stir the reaction mixture overnight at 80°C. After cooling to 0°C, adjust the pH to 9 with a saturated NaHCO3 solution. Then, dilute the reaction mixture with water and extract with 4 × RINKAN. Wash the organic layer with brine, dry it with (Na2SO4), filter it, and concentrate it to obtain the desired product. Analysis (Method A): R t :0.26min, [M+H] + :138

[0129] Step 3: Synthesis of 3-iodo-5-methyl-4-(cyclopropanyl)-1H-pyrazole [ka] Dissolve 5-methyl-4-(cyclopropanyl)-1H-pyrazole-3-amine (5.17 g, 37.6 mmol) in ACN (108 mL) and cool to 0°C. Carefully add acetic acid (6.5 mL, 112 mmol), followed by dropwise addition of potassium iodide (11.2 mL, 93.9 mmol dissolved in 54 mL of water). Stir the mixture at 0°C for 10 min, then add tert-butylnitrite (11.2 mL, 94 mmol, dissolved in ACN) dropwise. Stir the mixture at °C for 10 min, followed by stirring at RT for 1 hour. Adjust the reaction mixture pH to 8 by adding aqueous saturated sodium bicarbonate and extract with ELISA. Wash the organic phase with 0.5 M, 200 mL of Na2S2O3 and brine, then dehydrate with Na2SO4. Next, the EtOAC / CycH mixture is used as the eluent, and the concentrated organic phase is purified by flash column chromatography to obtain the desired product C2. Analysis (Method C): R t :0.57min, [M+H] + :249

[0130] Synthesis of intermediate C3 Step 1: Synthesis of 5-cyclopropyl-1-methyl-1H-imidazole [ka] Under an argon atmosphere, 5-bromo-1-methyl-1H-imidazole (7.50 g, 46.6 mmol), cyclopropyl zinc bromide (132 mL, 65.90 mmol, 0.5 M in THF), and Pd(dppf)Cl2 (2.20 g, 3.01 mmol) were mixed together, and the reaction mixture was stirred at 70°C for 20 hours. The reaction mixture was concentrated, and the residue was purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to obtain the desired product. Analysis (Method C): R t:0.31min, [M+H] + :one two three

[0131] Step 2: Synthesis of 5-cyclopropyl-1,2-dimethyl-1H-imidazole [ka] Under an argon atmosphere, 5-cyclopropyl-1-methyl-1H-imidazole (1 g, 8.12 mmol) is dissolved in THF (15.00 mL) and cooled to -78°C. n-BuLi (6.1 mL, 9.8 mmol, 1.6 M) is added dropwise, and the reaction mixture is stirred at -78°C for 30 min. Then MeI (663 μL, 10.6 mmol) is added dropwise, and the reaction mixture is stirred at -78°C for 1 h. The reaction mixture is quenched with a semisaturated NH4Cl solution and stirred for 10 min. 2 mL of aqueous NH4OH (25%) is added, and the mixture is stirred for 30 min. The layers are separated, and the aqueous layer is extracted with 3 × siRNA. The combined organic layers are dried (Na2SO4), filtered, and evaporated to obtain intermediate C3. Analysis (Method H): R t :0.72min, [M+H] + :137

[0132] Synthesis of intermediate C4: 1,2-dimethyl-5-(propan-2-yl)-1H-imidazole [ka] Dissolve 5-isopropyl-1-methyl-1H-imidazole (1 g, 8.05 mmol) in THF (25 mL) and cool to -65°C. Then slowly add 5.4 mL of BuLi (1.6 M, 8.64 mmol). After 30 minutes, add MeI (0.8 mL, 12.9 mmol) and warm the mixture to room temperature. Add water and aqueous ammonia (1 mL) with stirring, then add aqueous NH4Cl solution and extract the mixture with Â. Purify by silica gel chromatography using DCM:MeOH 9 / 1 plus ammonia to obtain the desired product C4. Analysis (Method H): R t :0.76min, [M+H]+ :139

[0133] Synthesis of intermediate C5: 3,4-diethyl-5-iodo-1H-pyrazole [ka] Dissolve 4,5-diethyl-1H-pyrazole-3-amine (916 mg, 6.58 mmol) in concentrated HCl (10 mL), and slowly add sodium nitrite (1.62 g, dissolved in 10 mL of water) over 30 min at 0°C. Slowly add potassium iodide (4.41 g, dissolved in 4 mL of water), and stir the mixture overnight at room temperature. Dilute the mixture with water, extract with TBME, wash the organic phase with sodium thiosulfate solution, and concentrate. Dissolve the crude product in acetonitrile, and collect the resulting solid to obtain the desired product C5. Analysis (Method A): R t :0.53min, [M+H] + :251

[0134] Synthesis of intermediate C6: Methyl 2-(3-iodo-5-methyl-1H-pyrazole-4-yl)acetate Step 1: Synthesis of methyl 2-(5-methyl-1H-pyrazole-4-yl)acetate [ka] Dissolve 2-(5-methyl-1H-pyrazole-4-yl)acetic acid (1 g, 7.14 mmol) in DCM (20 mL) and MeOH (10 mL), cool to -8°C, slowly add trimethylsilyldiazomethane (6.07 mL, 12.3 mmol in hexane), and stir the mixture for 2 hours. Concentrate the mixture and use it as the crude product (g) in the next step.

[0135] Step 2: Synthesis of methyl 2-(3-iodo-5-methyl-1H-pyrazole-4-yl)acetate [ka] Methyl 2-(5-methyl-1H-pyrazole-4-yl)acetate (1.1 g) is dissolved in 10 mL of ACN, NIS (1.284 g, 5.7 mmol) is added, and the mixture is stirred overnight at 80°C. The mixture is then filtered, concentrated, and purified by silica gel chromatography using a CycH / siRNA gradient to obtain the desired product C6. Analysis (Method H): R t :0.75min, [M+H] + :281

[0136] Synthesis of intermediate D Synthesis of intermediate D1: 1-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]propan-2-one [ka] Dissolve 5-iodo-3-methyl-4-(propan-2-yl)-1H-pyrazole (C1, 2.90 g, 11.6 mmol) in ACN (60 mL), and add K2CO3 (4.01 g, 29 mmol) and chloroacetone (1.85 mL, 23.2 mmol). Stir the reaction mixture at 50°C for 2 hours. Add chloroacetone (0.2 mL) and stir the reaction mixture at 50°C for 1 hour. Filter the reaction mixture, wash with ACN, and evaporate the filtrate. Purify the residue by flash chromatography (CycH / Â 90 / 10 to CycH / Â 60 / 40) to obtain product D1. Analysis (Method F): R t :0.82min, [M+H] + :307 The intermediates summarized in the table below can be obtained by following a procedure similar to the one described for intermediate D1.

[0137] [Table 1-1] [Table 1-2] [Table 1-3]

[0138] Synthesis of intermediate D13: 2-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-1-(oxolan-3-yl)ethane-1-one [ka] Step 1: Synthesis of oxolane-3-carbonyl chloride [ka] Dissolve oxolane-3-carboxylic acid (2 g, 17.2 mmol) in DCM (50 mL). Add DMF (24 μL, 0.295 mmol), then add oxalyl chloride (2.14 mL, 25 mmol) dropwise at 0°C, and stir the reaction mixture at RT for 3 hours. Filter the reaction mixture, wash with 10 mL of DCM, and concentrate the filtrate to obtain the product. This product is used in the next step without further purification.

[0139] Step 2: Synthesis of 2-chloro-1-(oxolan-3-yl)ethane-1-one [ka] Dissolve oxolane-3-carbonyl chloride (484 mg, 3.6 mmol) in THF (2 mL) and ACN (2 mL). Add trimethylsilyldiazomethane (3.06 g, 7.92 mmol, 2 M) dropwise and stir the reaction mixture overnight in RT. Quench the reaction mixture at 0°C with 4 M HCl in dioxane (2.70 mL, 10.8 mmol) and stir in RT for 3 hours. Concentrate the reaction mixture to obtain the product, which is used in the next step without further purification. Analysis Rt(EI):3.58min

[0140] Step 3: Synthesis of 2-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-1-(oxolan-3-yl)ethane-1-one [ka] Intermediate D13 is obtained by reacting 2-chloro-1-(oxolan-3-yl)ethane-1-one, intermediate C1, and K2CO3 in DMF with intermediate D1, following a procedure similar to that described for intermediate D1, at 80°C for 2 hours. Analysis (Method G): R t :1.03min, [M+H] + :363 The intermediates summarized in the table below can be obtained by following a reaction sequence similar to that described for intermediate D13.

[0141] [Table 2-1] [Table 2-2]

[0142] Synthesis of intermediate D19: 3-Hydroxy-1-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-3-methylbutan-2-one Step 1: Synthesis of 1-bromo-3-hydroxy-3-methylbutan-2-one [ka] Dissolve 3-hydroxy-3-methylbutan-2-one (500 mg, 4.9 mmol) in acetic acid (2 mL). Add bromine (0.25 mL, 4.9 mmol) in acetic acid (3 mL) dropwise, and stir the reaction mixture at RT for 2 hours. Concentrate the reaction mixture to obtain the product. Use this product in the next step without further purification.

[0143] Step 2: Synthesis of 3-hydroxy-1-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-3-methylbutan-2-one [ka] 5-iodo-3-methyl-4-(propan-2-yl)-1H-pyrazole (intermediate C1) (150 mg, 0.60 mmol) is 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) are added, and the reaction mixture is stirred overnight at 50°C. The reaction mixture is purified by reverse-phase chromatography (HPLC; ACN / water containing TFA) to obtain product D19. Analysis (Method G): R t :1.02min, [M+H] + :351

[0144] Synthesis of intermediate D20: 1-[(tert-butyldiphenylsilyl)oxy]-3-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]propan-2-ol [ka] Step 1: Synthesis of 3-iodo-5-methyl-1-(propa-2-en-1-yl)-4-(propan-2-yl)-1H-pyrazole [ka] Dissolve 5-iodo-3-methyl-4-(propan-2-yl)-1H-pyrazole (intermediate C1) (5.0 g, 19.9 mmol) in ACN (50 mL), and add K2CO3 (6.9 g, 49.8 mmol) and allyl bromide (4.87 g, 40 mmol). Stir the reaction mixture overnight at 50°C. Filter the reaction mixture, wash with ACN, and evaporate the filtrate. Purify the residue by flash chromatography (CycH / Â 90 / 10 to CycH / Â 60 / 40) to obtain the desired product. Analysis (Method H): R t :1.09min, [M+H] + :291

[0145] Step 2: Synthesis of 3-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]propan-1,2-diol [ka] 3-iodo-5-methyl-1-(propan-2-en-1-yl)-4-(propan-2-yl)-1H-pyrazole (3.32 g, 11.4 mmol) is dissolved in THF (45 mL). At 0°C, aqueous osmium tetroxide (4.2 mL, 0.68 mmol, 4% in water) is added dropwise. Then N-methyl-morpholine-N-oxide (2.01 g, 17.2 mmol) is added, and the reaction mixture is stirred overnight at RT. The reaction mixture is quenched with a semisaturated Na2S2O3 solution (10 mL) and stirred at RT for 1 hour. THF is evaporated in vacuo. The aqueous residue is extracted several times with siRNA. The combined organic layers are washed with brine, dried (Na2SO4), filtered, and concentrated to obtain the product. Analysis (Method G): R t :0.76min, [M+H] + :325

[0146] Step 3: Synthesis of 1-[(tert-butyldiphenylsilyl)oxy]-3-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]propan-2-ol [ka] Dissolve 3-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]propan-1,2-diol (3.70 g, 11.4 mmol) and imidazole (2.49 g, 36.5 mmol) in DCM (35 mL). Add tert-butyl(chloro)diphenylsilane (3.56 mL, 13.7 mmol) and stir the reaction mixture at RT for 2 hours. Dilute the reaction mixture with water and extract with DCM. Dry the organic layer over (Na2SO4), filter, and concentrate. Purify the residue by flash chromatography (CycH / Â 93 / 7~CycH / Â 40 / 60) to obtain the desired product. Analysis (Method G): R t :1.21min, [M+H] + :563

[0147] Step 4: Synthesis of 1-[(tert-butyldiphenylsilyl)oxy]-3-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]propan-2-one [ka] Dissolve 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) in DCM (60 mL). Add DMP (5.43 g, 12.8 mmol) and stir the reaction mixture at RT for 2 hours. Concentrate the reaction mixture and purify the residue by flash chromatography (CycH / siRNA 100 / 0 to CycH / siRNA 60 / 40) to obtain intermediate D20. Analysis (Method G): R t :1.21min, [M+H] + :561

[0148] Synthesis of imidazole intermediates D21-D25: Synthesis of 1-(5-cyclopropyl-1-methyl-1H-imidazole-2-yl)-3-methylbutan-2-one (D21) [ka] Dissolve 5-cyclopropyl-1,2-dimethyl-1H-imidazole (2.55 g, 18.7 mmol) in THF (120 mL). Add n-BuLi (17.5 mL, 28 mmol, 1.6 M) dropwise at -78°C and stir the reaction mixture for 1 hour at -78°C. Then add methyl isobutyrate (3.54 mL, 28 mmol) dropwise and stir the reaction mixture for 1 hour at -78°C. Quench the reaction mixture with a saturated NH4Cl solution and extract with 3 × siRNA. Dry the combined organic layers (Na2SO4), filter, concentrate, and purify by silica gel chromatography (gradient: DCM / MeOH 100 / 0~94 / 4) to obtain the desired product D21. Analysis (Method C): R t :0.45min, [M+H] + :207

[0149] Synthesis of 1-cyclopropyl-2-(5-cyclopropyl-1-methyl-1H-imidazole-2-yl)ethane-1-one (D22) [ka] 5-Cyclopropyl-1,2-dimethyl-1H-imidazole (700 mg, 5.14 mmol) is dissolved in THF (7 mL). At -78°C, n-BuLi (6.42 mL, 10.28 mmol, 1.6 M) is added dropwise, and the reaction mixture is stirred at -78°C for 30 min. Then, ethylcyclopropanecarboxylate (1.10 mL, 9.25 mmol) is added dropwise, and the reaction mixture is stirred at -78°C for 30 min, then brought to RT. The reaction mixture is quenched with a saturated NH4Cl solution and extracted with 3 × DCM / IPA 8 / 2. The combined organic layers are dried (Na2SO4), filtered, and concentrated to obtain product D22. Analysis (Method C): R t :0.45min, [M+H] + :205

[0150] The intermediates summarized in the table below can be obtained by following a procedure similar to the one described for intermediate D22. [Table 3]

[0151] Synthesis of intermediate D24: 4-bromo-5-cyclopropyl-2-{6-ethyl-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole Step 1: Synthesis of 5-cyclopropyl-1-methyl-1H-imidazole-2-carbaldehyde [ka] Under an argon atmosphere, 5-cyclopropyl-1-methyl-1H-imidazole (6.30 g, 51.6 mmol) is dissolved in THF (63 mL). At -78°C, n-BuLi (38.7 mL, 61.9 mmol, 1.6 M) is added dropwise, and the reaction mixture is stirred at -78°C for 1 hour. Then DMF (5.03 mL, 61.9 mmol) is added dropwise, and the reaction mixture is stirred at -78°C for 30 minutes. The reaction mixture is quenched with saturated NH4Cl solution and water. Then it is extracted with 3 × diethyl ether. The combined organic layers are dried (Na2SO4), filtered, and concentrated to obtain the product. This is used in the next step without further purification. Analysis (Method C): R t :0.35min, [M+H] + :151

[0152] Step 2: Synthesis of 4-bromo-5-cyclopropyl-1-methyl-1H-imidazole-2-carboaldehyde [ka] Dissolve 5-cyclopropyl-1-methyl-1H-imidazole-2-carboaldehyde (17.8 g, 94.8 mmol) in DCM (300 mL). Add NBS (16.9 g, 94.8 mmol) at 0°C and stir the reaction mixture at 0°C for 1 hour. Wash the reaction mixture with a 0.5 M solution of Na2S2O3, water, and brine. Dry the organic layer (Na2SO4), filter, and concentrate. Purify the residue by flash chromatography (CycH / Â 100 / 0 to CycH / Â 50 / 50) to obtain the product. Analysis (Method C): R t :0.49min, [M+H] + :229 / 231(Br)

[0153] Step 3: Synthesis of 4-bromo-5-cyclopropyl-1-methyl-2-[(1E)-2-nitrobuta-1-en-1-yl]-1H-imidazole [ka] Dissolve 4-bromo-5-cyclopropyl-1-methyl-1H-imidazole-2-carboaldehyde (10.1 g, 40.7 mmol) in nitropropane (18.1 mL, 203 mmol). Add ammonium acetate (6.27 g, 81.4 mmol) and stir the reaction mixture at 60°C for 4 days. Quench the reaction mixture with a semisaturated NaCl solution and extract with 3× siRNA. Dry the combined organic layers (Na2SO4), filter, and concentrate to obtain the product. Use this product in the next step without further purification. Analysis (Method C): R t :0.76min, [M+H] + :300 / 302(Br)

[0154] Step 4: Synthesis of 1-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazole-2-yl)butan-2-one [ka] Iron powder (11.16 g, 0.200 mol) is suspended in acetic acid (150 mL), and the mixture is heated to 60°C. 4-bromo-5-cyclopropyl-1-methyl-2-[(1E)-2-nitrobuta-1-en-1-yl]-1H-imidazole (12 g, 0.040 mol) is slowly added dropwise from acetic acid (50 mL), and the reaction mixture is stirred at 60°C for 1.5 hours, then stirred 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 ethyl acetate and basicized with a 2 M solution of Na2CO3. Charcoal is added, and the reaction mixture is filtered through Celite. The layers are separated, the organic layer is dried (Na2SO4), filtered, and concentrated. The residue is purified by flash chromatography (CycH / ethyl 20 / 80~CycH / ethyl 0 / 100) to obtain product D24. Analysis (Method F): R t :0.46min, [M+H] + :271 / 273(Br)

[0155] Synthesis of intermediate D25: Synthesis of 2-(5-cyclopropyl-1-methyl-1H-imidazole-2-yl)-1-(2,2-difluorocyclopropyl)ethane-1-one Step 1: [ka] Dissolve 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) in DCM (40 mL), cool the mixture to 0°C, then slowly add DIPEA (20 mL), and stir the mixture overnight at RT. Then cool the mixture again to 0°C and add 4 M HCl (35 mL). Separate the organic phase, concentrate, purify the product by silica gel chromatography (DCM), and evaporate the combined fraction at 35°C / 90 mbar to obtain the desired product. Analysis:ESI[M] + :166

[0156] Step 2: [ka] 5-Cyclopropyl-1,2-dimethyl-1H-imidazole (150 mg, 1.1 mmol) is dissolved in THF (4 mL), cooled to -78°C, and BuLi (0.76 mL, 1.6 M) is slowly added. After 15 min, 2,2-difluoro-N-methoxy-N-methylcyclopropane-1-carboxamide (250 mg, 1.1 mmol, dissolved in 0.5 mL of THF) is added, and the mixture is stirred for 30 min. Then aqueous NH4Cl solution is added, and the mixture is extracted with siRNA. The organic phase is concentrated and purified by preparative HPLC to obtain intermediate D25. Analysis (Method G): R t :0.65min, [M+H] + :241

[0157] Synthesis of intermediate E Synthesis of intermediate E1: 3-amino-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-4-carboaldehyde Step 1: Synthesis of ethyl 3-amino-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-4-carboxylate [ka] A solution of NaOEt was prepared (using 4.08 g Na (177 mmol) and 100 mL of EtOH), to which [(4-methoxyphenyl)methyl]hydrazine hydrochloride (11.2 g, 59 mmol) was added. Then, a solution of ethyl(2Z)-2-cyano-3-ethoxypropa-2-enoate (10 g, 59 mmol) in THF (50 mL) was added dropwise over 45 min at 0°C under argon. The reaction mixture was stirred at 0°C for 90 min. The reaction mixture was quenched with 4 M HCl in dioxane (29.6 mL, 118 mmol) and concentrated and dried. The residue was then dissolved in siRNA and washed with a saturated NaHCO3 solution. The aqueous layer was extracted with siRNA. The combined organic layers were dried (Na2SO4), filtered, and concentrated to obtain the product. Analysis (Method Q): R t :1.55min, [MH] -- :274

[0158] Step 2: Synthesis of {3-amino-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-4-yl}methanol [ka] Dissolve ethyl 3-amino-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-4-carboxylate (16.3 g, 56.3 mmol, 95% purity) in THF (81.5 mL), and add LiAlH4 (2 M in THF, 28.1 mL, 56.3 mmol) dropwise over 30 min at -7°C. Stir the reaction mixture at RT for 3 hours. Quench the reaction mixture with 2V THF / H2O 8 / 2 and 1V saturated aqueous Na2SO4 solution, and stir at RT for 30 min. Filter the reaction mixture through Celite and wash with MeOH and DCM / MeOH. Dry the filtrate (Na2SO4), filter, concentrate, and evaporate simultaneously with toluene to obtain the product. Analysis (Method Q): R t :1.34min, [M+H] + :234

[0159] Step 3: Synthesis of 3-amino-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-4-carboaldehyde [ka] {3-amino-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-4-yl}methanol (13.1 g, 50.5 mmol, 90% purity) is dissolved in ACN (131 mL) and water (26.2 mL), then MnO2 (34.2 g, 354 mmol) is added, and the reaction mixture is stirred at RT for 2 hours. The reaction mixture is filtered through Celite and washed with DCM / acetone. The filtrate is concentrated and dried, and the residue is ground with MTBE to obtain product E1. TLC: Silica gel, DCM / MeOH 95 / 5:Rf :0.55 Analysis (Method Q): R t : 1.55 min

[0160] Synthesis of intermediate E2: Step 1: Synthesis of 3-amino-1-[3-(morpholine-4-yl)propyl]-1H-pyrazole-4-carbonitrile [ka] Dissolve 3-amino-4-cyanopyrazole (2 g, 18.5 mmol) in ACN (20 mL) and add K2CO3 (3.2 g, 23.2 mmol). Add 4-(3-chloropropyl)morpholine (3.60 g, 22 mmol) from ACN (10 mL) dropwise at 70°C and stir the reaction mixture for 2.5 hours at 70°C. Filter the reaction mixture and purify the filtrate by reverse-phase chromatography (HPLC; ACN / water containing NH3) to obtain the product. Analysis (Method C): R t :0.27min, [M+H] + :236

[0161] Step 2: Synthesis of 3-amino-1-[3-(morpholine-4-yl)propyl]-1H-pyrazole-4-carbaldehyde [ka] Under an argon atmosphere, 3-amino-1-[3-(morpholine-4-yl)propyl]-1H-pyrazole-4-carbonitrile (0.50 g, 2.13 mmol) is suspended in toluene (5 mL), and DIBALH (5.80 mL, 6.38 mmol, 1.1 M in CycH) is added dropwise at -70°C. The reaction mixture is stirred at -70°C for 20 min. The reaction mixture is then warmed to -10°C and quenched with aqueous HCl (2.66 mL, 10.6 mmol, 4 M). The reaction mixture is stirred at RT for 30 min. NH4OH (1 mL, 28%) and ACN are added, and the reaction product is filtered through cellulose. The filtrate is concentrated and purified by reverse-phase chromatography (HPLC; ACN / water containing NH3) to obtain product E2. Analysis (Method D): R t :0.26min, [M+H] + :239

[0162] Synthesis of intermediate E3: Synthesis of 3-amino-1-methyl-1H-pyrazole-4-carboaldehyde [ka] DIBALH in 1M hexane (515 mL; 0.52 mol) is slowly added to a suspension of 3-amino-1-methyl-1H-pyrazole-4-carbonitrile (21.6 g; 0.18 mol) in toluene (432 mL) under argon at -78°C. After addition, the solution is stirred for 20 mins, then warmed to RT. The reaction mixture is slowly poured at 0°C into 4M aqueous HCl (177 mL; 0.71 mol) and stirred for 1 hour.

[0163] The pH was adjusted to approximately 9 with potassium carbonate, and the mixture was extracted with IPA / DCM 25 / 75 (1750 mL), concentrated, and intermediate E3 was obtained. 1 H-NMR (DMSO-d6, 300MHz): d=9.61 (1H, s), 8.03 (1H, s), 5.66 (2H, s, br), 3.64 (3H, s)

[0164] Synthesis of intermediate F Synthesis of intermediate F1: 3-iodo-1-{2-[(4-methoxyphenyl)methyl]-6-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole [ka] Dissolve 1-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]propan-2-one (D1) (5 g, 16.3 mmol) in EtOH (75 mL), add piperidine (4.03 mL, 40.8 mmol), and heat the reaction mixture under reflux. Add 3-amino-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-4-carboaldehyde (E1) (3.40 g, 14.7 mmol) at 80°C and stir the mixture at this temperature overnight. Concentrate the reaction mixture and purify the residue by flash chromatography (DCM / acetone 90 / 10, homogeneous concentration) to obtain intermediate F1. TLC: Silica gel, DCM / acetone 90 / 10:R f :0.20 Analysis (Method A): R t :0.71min, [M+H] + :502

[0165] Synthesis of intermediate F2: [ka] 1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole Dissolve 1-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]propan-2-one (D1) (2.7 g, 8.82 mmol) and 3-amino-1-methyl-1h-pyrazole-4-carboaldehyde (E3) (1.1 g, 8.82 mmol) in EtOH, add piperidine (2.18 mL, 22.1 mmol), and stir the reaction mixture in a sealed vial at 80°C for 4 hours. Concentrate the reaction mixture, and purify the residue by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to obtain intermediate F2. Analysis (Method F): R t :0.79min, [M+H] + :396 The intermediates summarized in the table below can be obtained by following a procedure similar to the one described for intermediate F2.

[0166] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5]

[0167] Synthesis of intermediate F21: 1-{6-chloro-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole [ka] Step 1: Synthesis of 5-bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine [ka] To a solution of 5-bromo-2H-pyrazolo[3,4-b]pyridine (10 g, 0.050 mol) cooled on ice in dry THF (100 mL), add 1.0 M sodium bis(trimethylsilyl)amide solution in THF (75.8 mL, 0.076 mol) and iodomethane (9.43 mL, 0.151 mol). Heat the resulting mixture to RT and stir for 2 hours. Add DCM (150 mL) and 1 M NH4Cl (150 mL) to the reaction mixture. Extract the aqueous layer with DCM. Dry the combined organic layers over (Na2SO4), filter, and concentrate. Purify the residue by flash chromatography (hexane / siRNA 100 / 0 to hexane / siRNA 0 / 100) to obtain the product. Analysis (Method S): R t :1.01min, [M+H]+ :212 / 214(Br)

[0168] Step 2: Synthesis of 5-bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine-7-ium-7-oleate [ka] 5-Bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine (5 g, 23.6 mmol) is suspended in DCM (160 mL), and MCPBA (10 g, 43.5 mmol, 75% purity) is added. The reaction mixture is stirred overnight in RT. The mixture is then filtered, and the filtrate is evaporated. A saturated NaHCO3 solution is added to the residue, and this mixture is extracted with DCM and a small amount of MeOH. The combined organic phase is dried (Na2SO4), filtered, and concentrated. The residue is ground with MTBE, the precipitate is filtered, and the mixture is dried overnight in an oven at 50°C to obtain the product. Analysis (Method H): R t :0.48min, [M+H] + :228 / 230(Br)

[0169] Step 3: Synthesis of 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridine-7-ium-7-oleate [ka] 5-Bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine-7-ium-7-oleate (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) are dissolved in NMP (5 mL). Under a nitrogen atmosphere, K2CO3 (1.64 g, 11.8 mmol), trans-(1R,2R)-N,N'-bismethyl-1,2-cyclohexanediamine (0.50 mL, 3.17 mmol) and copper(I) iodide (601 mg, 3.16 mmol) are added, and the reaction mixture is stirred in a sealed vial at 105°C for 13 hours. The reaction mixture is filtered, washed with MeOH, and the filtrate is concentrated. The residue is purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 86 / 14) to obtain the desired product. Analysis (Method H): R t :0.88min, [M+H] + :398

[0170] Step 4: Synthesis of 1-{6-chloro-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole [ka] 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridine-7-ium-7-oleate (554.0 mg, 1.12 mmol, 80% purity) is dissolved in ACN (5 mL). POCl3 (500 μL, 5.31 mmol) is added, and the reaction mixture is stirred at 50°C for 45 min. The reaction mixture is concentrated, and the residue is purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to obtain the desired product F21. Analysis (Method H): R t :1.04min, [M+H] + :416

[0171] Synthesis of intermediate F22: 1-{6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole [ka] Dissolve 1-{6-chloro-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (60.0 mg, 0.12 mmol, 80% purity) in EtOH (2.0 mL). Add LiHMDS (400 μL, 0.40 mmol), stir the reaction mixture at 40°C for 3d, and stir overnight at 60°C. Quench the reaction mixture with a few drops of water and concentrate. Purify the residue by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 80 / 20) to obtain product F22. Analysis (Method H): R t :1.08min, [M+H] + :426 The intermediates summarized in the table below can be obtained by following a procedure similar to that described for intermediate F22.

[0172] [Table 5-1] [Table 5-2]

[0173] Synthesis of intermediate F28: Step 1: Synthesis of 1-(6-{[(tert-butyldiphenylsilyl)oxy]methyl}-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl)-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole [ka] 1-[(Tert-butyldiphenylsilyl)oxy]-3-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]propan-2-one (3.98 g, 7.10 mmol) and 3-amino-1-methyl-1H-pyrazole-4-carboaldehyde (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 overnight at 100°C. The reaction mixture was concentrated to obtain the product, which was used in the next step without further purification.

[0174] Step 2: Synthesis of {5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridine-6-yl}methanol [ka] Dissolve 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) in THF (40 mL). Add TBAF (8.5 mL, 8.5 mmol, 1 M) and stir the reaction mixture at RT for 1.5 hours. Concentrate the reaction mixture and purify the residue by reverse-phase chromatography (HPLC; ACN / water with TFA) to obtain product F28. Analysis (Method G): R t :0.93min, [M+H] + :412

[0175] Synthesis of intermediate F29: Step 1: Synthesis of 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridine-6-carbaldehyde [ka] {5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridine-6-yl}methanol (F28) (100 mg, 0.24 mmol) is dissolved in DCM (2 mL). DMP (155 mg, 0.37 mmol) is added, and the reaction mixture is stirred at RT for 2 hours. The reaction mixture is concentrated, and the residue is purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 60 / 40) to obtain the product. Analysis (Method G): R t :0.84min, [M+H] + :410

[0176] Step 2: Synthesis of 1-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridine-6-yl}ethane-1-ol [ka] Dissolve 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridine-6-carboaldehyde (125 mg, 0.21 mmol) in THF (2 mL). At 0°C, add methylmagnesium bromide (0.22 mL, 3 M in diethyl ether, 0.66 mmol) dropwise, stir the reaction mixture at 0°C for 10 min, and stir at RT for 2 h. Quench the reaction mixture with a saturated NH4Cl solution and extract with 2 × siRNA. Wash the combined organic layers with brine, dry with (Na2SO4), filter, and concentrate. Purify the residue by reverse-phase chromatography (HPLC; ACN / water with NH3) to obtain product F29. Analysis (Method H): R t :0.99min, [M+H] + :426

[0177] Synthesis of intermediate F30: 3-iodo-5-methyl-1-[2-methyl-6-(methylsulfanyl)-2H-pyrazolo[3,4-b]pyridine-5-yl]-4-(propan-2-yl)-1H-pyrazole [ka] Dissolve 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridine-7-ium-7-oleate (30 mg, 0.08 mmol, see synthesis F21, step 4) in ACN (2 mL). Add POCl3 (36 μL, 0.378 mmol) and stir the reaction mixture at 60°C for 45 min. Concentrate the reaction mixture and dissolve the residue in DMF (2 mL). Add NaH (18 mg, 0.41 mmol, 55%) and sodium methanethiolate (24 mg, 0.34 mmol) and stir the reaction mixture overnight at RT. Quench the reaction mixture with water and purify by reverse-phase chromatography (HPLC; ACN / water with NH3) to obtain product F30. Analysis (Method H): R t :1.07min, [M+H] + :428

[0178] Synthesis of intermediates F31 and F32: 4-({5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridine-6-yl}methyl)morpholine [ka]

[0179] Step 1: Synthesis of {5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridine-6-yl}methylmethanesulfonic acid [ka] {5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridine-6-yl}methanol (F28, 200 mg, 0.49 mmol) and TEA (149 μL, 1.07 mmol) are dissolved in DCM (2 mL). Methanesulfonyl chloride (45 μL, 0.58 mmol) is added, and the reaction mixture is stirred at RT for 1 hour. The reaction mixture is diluted with DCM and washed with saturated NaHCO3 solution. The organic layer is dried (Na2SO4), filtered, and concentrated to obtain intermediate F31. Analysis (Method G): R t :0.85min, [M+H] + :490

[0180] Step 2: Synthesis of 4-({5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridine-6-yl}methyl)morpholine [ka] {5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridine-6-yl}methylmethanesulfonic acid (F31) (60 mg, 0.12 mmol) is dissolved in THF (1 mL). Morpholine (53 μL, 0.61 mmol) is added, and the reaction mixture is stirred at RT for 1 hour. The reaction mixture is purified by reverse-phase chromatography (HPLC; ACN / water containing NH3) to obtain intermediate F32. Analysis (Method H): Rt:1.02min, [M+H]+:481 The intermediates summarized in the table below can be obtained by following a procedure similar to the one described for intermediate F32.

[0181] [Table 6]

[0182] Synthesis of intermediate F35: 4-(3-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-6-methyl-2H-pyrazolo[3,4-b]pyridine-2-yl}propyl)morpholine Synthesis of 4-(3-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-6-methyl-2H-pyrazolo[3,4-b]pyridine-2-yl}propyl)morpholine [ka] 3-amino-1-[3-(morpholine-4-yl)propyl]-1H-pyrazole-4-carboaldehyde (E2, 115 mg, 0.48 mmol) is dissolved in EtOH (2 mL). Piperidine (122 μL, 1.23 mmol) and 1-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]propan-2-one (D1, 150 mg, 0.49 mmol) are added, and the reaction mixture is stirred at 80°C for 6 hours, followed by stirring at RT for 8 hours. The reaction mixture is acidified with HOAc (2 mL) and TFA (0.5 mL), diluted with water, and purified by reverse-phase chromatography (HPLC; ACN / water with TFA) to obtain product F35. Analysis (Method F): R t :0.62min, [M+H] + :509

[0183] Synthesis of intermediate F36: 6-Cyclopropyl-5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridine-7-ium-7-oleate [ka] Dissolve 1-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (F4) (600 mg, 1.42 mmol) in DCM (3 mL). Add methyltrioxolenium (VII) (71 mg, 0.28 mmol) and H2O2 (890 μL, 15.7 mmol, 50%) at 0°C, and stir the reaction mixture at 0°C for 3 hours, then stir overnight at RT. Dilute the reaction mixture with DCM and water. Separate the organic phase, dry it (Na2SO4), filter it, and concentrate it. Purify the residue by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to obtain product F36. Analysis (Method A): R t :0.57min, [M+H] + :438

[0184] Synthesis of intermediate F37: 1-[6-(difluoromethyl)-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl]-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole Step 1: Synthesis of 5-bromo-6-(difluoromethyl)-2-methyl-2H-pyrazolo[3,4-b]pyridine [ka] 5-Bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine (1 g, 4.7 mmol) and zinc difluoromethanesulfinate (3.48 g, 11.8 mmol) are 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) are added, and the reaction mixture is stirred over RT over the weekend. The reaction mixture is diluted with water, and the layers are separated. The aqueous layer is extracted with DCM, and the combined organic layers are dried (Na2SO4), filtered, and concentrated. The residue is purified by reverse-phase chromatography (HPLC; ACN / water with TFA) to obtain the product. Analysis (Method H): R t :0.84min, [M+H]+ :262 / 264(Br)

[0185] Step 2: Synthesis of 6-(difluoromethyl)-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methyl-2H-pyrazolo[3,4-b]pyridine [ka] Under an argon atmosphere, 5-bromo-6-(difluoromethyl)-2-methyl-2H-pyrazolo[3,4-b]pyridine (270 mg, 1.03 mmol) is dissolved in dioxane (10 mL). Bis(neopentyl glycolate)diborone (512 mg, 2.27 mmol), potassium acetate (313 mg, 3.19 mmol), and Pd(dppf)Cl2xDCM (84 mg, 0.10 mmol) are added, and the reaction mixture is stirred at 80°C for 2 hours. After cooling the reaction mixture to RT, it is filtered through a thiol-scavenging resin, and the filtrate is concentrated. The residue is purified by reverse-phase chromatography (HPLC; ACN / water with TFA) to obtain the product. Analysis (Method G): R t :0.38min, [M+H] + :296 (mass of corresponding boronic acid)

[0186] Step 3: Synthesis of 1-[6-(difluoromethyl)-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl]-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole [ka] 6-(difluoromethyl)-5-(5,5-dimethyl-1,3,2-dioxaborinan-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 is described in intermediate A1, step 1) (60 mg, 0.24 mmol) are 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) are added, and the reaction mixture is stirred in an open flask at RT for 2 hours. The reaction mixture is quenched with aqueous ammonia and extracted with 2 × DCM. The organic layer is dried (Na2SO4), filtered, and concentrated. The residue is purified by reverse-phase chromatography (HPLC; ACN / water containing TFA) to obtain intermediate F37. Analysis (Method G): R t :1.08min, [M+H] + :432

[0187] Synthesis of intermediate F38: 1-[8-cyclopropyl-3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl]-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole Step 1: Synthesis of 2-chloro-4-fluoro-3-iodopyridine [ka] Under an argon atmosphere, LDA (5.44 mL, 10.9 mmol, 2 M) is cooled to -78°C. 2-chloro-4-fluoropyridine (1.00 mL, 9.9 mmol) is added dropwise to THF (25 mL), and the reaction mixture is stirred at -78°C for 1 hour. Then, iodine (2.59 g, 9.9 mmol) is added dropwise to THF (35 mL), and the reaction mixture is stirred at -78°C for 30 minutes. The reaction mixture is quenched with a saturated Na2CO3 solution and extracted with MTBE. The organic layer is washed with Na2S2O3 and brine, dried (Na2SO4), filtered, and concentrated. The residue is purified by reverse-phase chromatography (HPLC; ACN / water with TFA) to obtain the product. Analysis (Method A): R t :0.51min, [M+H] + :258

[0188] Step 2: Synthesis of 2-chloro-3-cyclopropyl-4-fluoropyridine [ka] Under an 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) are mixed. Then PEPPSI(TM)-IPR (210 mg, 0.31 mmol) is added, and the reaction mixture is stirred at 50°C for 1 hour. The reaction mixture is quenched with a saturated NaHCO3 solution and extracted by DCM. The organic layer is washed with brine, dried (Na2SO4), filtered, and concentrated. The residue is purified by flash chromatography (100% DCM) to obtain the product. Analysis (Method A): R t :0.54min, [M+H] + :171 / 173(Cl)

[0189] Step 3: Synthesis of 2-chloro-3-cyclopropyl-4-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]pyridine [ka] Dissolve 3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (1.17 g, 4.66 mmol) and 2-chloro-3-cyclopropyl-4-fluoropyridine (762 mg, 4.44 mmol) in DMF (30 mL). Add K2CO3 (1.23 g, 8.9 mmol), stir the reaction mixture at 100°C for 3 hours, and stir over the weekend in RT. Purify the reaction mixture by reverse-phase chromatography (HPLC; ACN / water with TFA) to obtain the product. Analysis (Method A): R t :0.77min, [M+H] + :402 / 404(Cl)

[0190] Step 4: Synthesis of 3-cyclopropyl-2-hydrazinyl-4-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]pyridine [ka] 2-Chloro-3-cyclopropyl-4-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]pyridine (513 mg, 1.28 mmol) is dissolved in EtOH (3 mL). Hydrazine (11.5 mL, 11.5 mmol, 1 M in THF) is added, and the reaction mixture is stirred in a microwave at 150°C for 5 hours. The reaction mixture is purified by reverse-phase chromatography (HPLC; ACN / water with TFA) to obtain the product. Analysis (Method A): R t :0.50min, [M+H] + :398

[0191] Step 5: Synthesis of 1-[8-cyclopropyl-3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-7-yl]-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole [ka] Dissolve 3-cyclopropyl-2-hydrazinyl-4-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]pyridine (40 mg, 0.07 mmol) in 2,2-difluoroacetic acid (300 μL, 4.77 mmol). Stir the reaction mixture in a microwave at 120°C for 2 hours. Purify the reaction mixture by reverse-phase chromatography (HPLC; ACN / water with TFA) to obtain product F38. Analysis (Method A): R t :0.69min, [M+H] + :458 The intermediates summarized in the table below can be obtained by following a procedure similar to that described for intermediate F38 (steps 3-5).

[0192] [Table 7]

[0193] Synthesis of intermediate F40: 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole Step 1: Synthesis of 5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole [ka] 1-Cyclopropyl-2-(5-Cyclopropyl-1,2-dimethyl-1H-imidazole-4-yl)ethane-1-one (D22) (1.40 g, 5.48 mmol, 80% purity) and 3-amino-1-[(4-methoxyphenyl)methyl]-1H-pyrazole-4-carboaldehyde (E1) (1.65 g, 7.13 mmol) are dissolved in EtOH (35 mL). Piperidine (1.62 mL, 16.5 mmol) is added, and the reaction mixture is stirred overnight at 80°C. The reaction mixture is concentrated and evaporated simultaneously with 3×toluene. The residue is purified by flash chromatography (DCM / acetone 100 / 0 to DCM / acetone 30 / 70) to obtain the product. Analysis (Method Q): R t :1.40min, [M+H] + :400

[0194] Step 2: Synthesis of 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole [ka] Dissolve 5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole (0.60 g, 1.5 mmol) in DCM (21 mL). Add NBS (0.29 g, 1.65 mmol) at 0°C and stir the reaction mixture at RT for 30 min. Quench the reaction mixture with a saturated Na2S2O3 solution and extract with DCM. Wash the organic layer with a saturated K2CO3 solution, dry with (Na2SO4), filter, and concentrate. Purify the residue by flash chromatography (DCM / acetone 100 / 0 to DCM / acetone 90 / 10) to obtain product F40. Analysis (Method R): R t :3.82min, [M+H] + :478 / 480(Br)

[0195] Synthesis of intermediate F41: 4-bromo-5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridine-5-yl]-1H-imidazole Step 1: [ka] 1-(5-cyclopropyl-1-methyl-1H-imidazole-2-yl)-3-methylbutan-2-one (1.28 g, 5 mmol), 3-amino-1-methyl-1h-pyrazole-4-carbaldehyde (684 mg, 5.5 mmol), and piperidine (984 μL, 10 mmol) are dissolved in ethanol and heated overnight at 95°C. The mixture is then purified by reverse-phase preparative HPLC (Xbridge C18, ACN / water containing NH3) to obtain the desired product. Analysis (Method A): R t :0.32min, [M+H] + :296

[0196] Step 2: [ka] Dissolve 5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridine-5-yl]-1H-imidazole (2.04 g, 6.9 mmol) in DCM (21 mL). Add NBS (1.23 g, 6.9 mmol) at 0°C, and after 15 min, stir the reaction mixture at RT for 1 hour. Quench the reaction mixture with a saturated NaHCO3 solution, separate the phases, and extract the aqueous phase with DCM. Dry the combined organic phases (Na2SO4), filter, and concentrate. Purify the residue by flash chromatography (siRNA / MeOH 100 / 0 to siRNA / MeOH 95 / 5) to obtain the desired product F41. Analysis (Method A): R t :0.44min, [M+H] + :374 / 376(Br) The intermediates summarized in the table below can be obtained by following a procedure similar to the one described for intermediate F41.

[0197] [Table 8]

[0198] Synthesis of intermediate F45: 5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazole-2-yl)-6-(difluoromethoxy)-2-methyl-2H-indazole [ka] Step 1: Synthesis of 4-(difluoromethoxy)-1-methyl-2-nitrobenzene [ka] Dissolve KOH (14.7g, 262 mmol) in 1 / 1 ACN / water (100 mL), add 4-methyl-3-nitrophenol (2g, 13.06 mmol), and freeze the reaction mixture in a dry ice / acetone bath. Once frozen solid, add bromodifluoromethyldiethylphosphonate (3.77 mL, 21.2 mmol) on top, and let the reaction mixture stand at this temperature for 10 minutes. Then remove the ice bath. After 1.5 hours, once the reaction mixture has slowly thawed, resume stirring and warm to 10°C to complete the reaction. Dilute the reaction mixture with diethyl ether and water and stir vigorously. Extract with 2× diethyl ether, dry the combined organic layer (Na2SO4), filter, and concentrate. Pass the residue through a small silica gel plug (CycH / siRNA 90 / 10 → CycH / siRNA 0 / 100) to obtain the product. Analysis (Method F): R t :0.86 minutes

[0199] Step 2: Synthesis of 5-(difluoromethoxy)-2-methylaniline [ka] Dissolve 4-(difluoromethoxy)-1-methyl-2-nitrobenzene (1.8 g, 8.86 mmol) in EtOH (25 mL), add ammonium formate (2.45 g, 17.7 mmol) and palladium-supported carbon (1.60 g, 10%), and stir the reaction mixture overnight at 85°C in a sealed vial. Filter the reaction mixture and concentrate it. Purify the residue by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to obtain the product. Analysis (Method F): R t :0.52min, [M+H] + :174

[0200] Step 3: Synthesis of 4-bromo-5-(difluoromethoxy)-2-methylaniline [ka] Dissolve 5-(difluoromethoxy)-2-methylaniline (1.12 g, 6.47 mmol) in chloroform (51.5 mL). Add NBS (1.15 g, 6.47 mmol) at 0°C and stir the reaction mixture overnight at 4-6°C. Concentrate the reaction mixture and purify the residue by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to obtain the product. Analysis (Method F): R t :0.83min, [M+H] + :252 / 254(Br)

[0201] Step 4: Synthesis of 5-bromo-6-(difluoromethoxy)-2H-indazole [ka] To boron trifluoride etherate (1.45 mL, 11.8 mmol) in DCM (18.8 mL), 4-bromo-5-(difluoromethoxy)-2-methylaniline (1.98 g, 7.84 mmol) in DCM (11 mL) is added under an argon atmosphere at -78°C, followed by dropwise addition of tert-butylnitrite (1.12 mL, 9.4 mmol). The reaction mixture is heated to RT and stirred for 22 hours. Potassium acetate (1.46 g, 14.9 mmol) and 18-crown-6 (104 mg, 0.39 mmol) are added to the above solution of the diazonium salt in DCM. After stirring at RT for 1.5 hours, the mixture is filtered and the solid is washed with DCM. The filtrate is concentrated and purified by flash chromatography (CycH / siRNA 100 / 0 to CycH / siRNA 0 / 100) to obtain the product. Analysis (Method F): R t :0.78min, [M+H] + :263 / 265(Br)

[0202] Step 5: Synthesis of 5-bromo-6-(difluoromethoxy)-2-methyl-2H-indazole [ka] Dissolve 5-bromo-6-(difluoromethoxy)-2H-indazole (960 mg, 3.07 mmol, 84% purity) in 19 mL of ethyl acetate. Add trimethyloxonium tetrafluoroborate (589 mg, 3.99 mmol) and stir the reaction mixture overnight in RT. Quench the reaction mixture by adding 10% NaHCO3 solution dropwise until a basic pH is reached. Extract the reaction mixture with DCM. Dry the organic layer over (Na2SO4), filter, and concentrate. Purify the residue by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to obtain the product. Analysis (Method F): R t :0.79min, [M+H] + :277 / 279(Br)

[0203] Step 6: Synthesis of 6-(difluoromethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole [ka] Under an argon atmosphere, 700 mg, 2.53 mmol of 5-bromo-6-(difluoromethoxy)-2-methyl-2H-indazole is dissolved in 18 mL of dioxane. Bis(pinacolato)diborone (0.74 g, 2.91 mmol), potassium acetate (744 mg, 7.58 mmol), and Pd(dppf)Cl2 × DCM (206 mg, 0.25 mmol) are added, and the reaction mixture is stirred at 90°C for 3 hours. The reaction mixture is diluted with DCM and water and filtered on Celite. The layers are separated, the organic layer is dried (Na2SO4), filtered, and concentrated. The residue is purified by reverse-phase chromatography (HPLC; ACN / water with TFA) to obtain the product. Analysis (Method F): R t :0.90min, [M+H] + :325

[0204] Step 7: Synthesis of 5-cyclopropyl-1-methyl-1H-imidazole [ka] Under an argon atmosphere, 5-bromo-1-methyl-1H-imidazole (7.50 g, 46.6 mmol), cyclopropyl zinc bromide (132 mL, 66 mmol, 0.5 M in THF), and Pd(dppf)Cl2 (2.20 g, 3 mmol) were mixed together, and the reaction mixture was stirred at 70°C for 20 hours. The reaction mixture was concentrated, and the residue was purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to obtain the product. Analysis (Method C): R t :0.31min, [M+H] + :one two three

[0205] Step 8: Synthesis of 2,4-dibromo-5-cyclopropyl-1-methyl-1H-imidazole [ka] Dissolve 5-cyclopropyl-1-methyl-1H-imidazole (9.20 g, 52.7 mmol) in ACN (200 mL). Gradually add NBS (18.8 g, 105 mmol) at -5°C, and stir the reaction mixture at -5°C for 30 min, then stir at RT for 4 hours. Quench the reaction mixture by adding saturated Na2S2O3 solution (40 mL, 4.4 M). Filter the formed precipitate and wash with ACN. Extract the filtrate with ethyl acetate, dry the organic layer (Na2SO4), filter, and concentrate. Purify the residue by flash chromatography (CycH / ethyl 95 / 5 to CycH / ethyl 65 / 35) to obtain the product. Analysis (Method F): R t :0.77min, [M+H] + :279 / 281 / 283(2×Br)

[0206] Step 9: Synthesis of 5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazole-2-yl)-6-(difluoro-methoxy)-2-methyl-2H-indazole [ka] Under an argon atmosphere, 2,4-dibromo-5-cyclopropyl-1-methyl-1H-imidazole (108 mg, 0.39 mmol) and 6-(difluoromethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (150.05 mg, 0.46 mmol) were dissolved in dioxane (3.6 mL). Cs2CO3 (377 mg, 1.16 mmol) and Pd(PPh3)4 (44.6 mg, 0.04 mmol) were added, and the reaction mixture was stirred overnight at 80°C. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 85 / 15). The combined fraction was concentrated, and the residue was ground with CycH to obtain product F45. Analysis (Method F): R t:0.61min, [M+H] + :397 / 399(Br)

[0207] Synthesis of intermediate F46: 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2-propyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole Step 1: Synthesis of 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole [ka] 4-Bromo-5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole (F40) (574 mg, 1.20 mmol) and anisole (264 μL, 2.40 mmol) are dissolved in DCE (5 mL) and TFA (3 mL). The reaction mixture is stirred at 60°C over the weekend. The reaction mixture is concentrated and purified by reverse-phase chromatography (HPLC; ACN / water / TFA). The fractions are combined and the solvent is evaporated. The aqueous residue is neutralized with 2 M K2CO3 solution. The precipitate formed is filtered, washed with water, and dried in an oven to obtain the product. Analysis (Method H): R t :0.96min, [M+H] + :358 / 360(Br)

[0208] Step 2: Synthesis of 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2-propyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole [ka] 4-bromo-5-cyclopropyl-2-{6-cyclopropyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole (358 mg, 1 mmol) is dissolved in ACN (5 mL). K2CO3 (346 mg, 2.50 mmol) and 1-bromopropane (91 μL, 1 mmol) are added, and the reaction mixture is stirred overnight at 60°C. The reaction mixture is filtered and purified by reverse-phase chromatography (HPLC; C18, ACN / water containing NH3) to obtain product F46. Analysis (Method H): R t :1.01min, [M+H] + :400 / 402(Br)

[0209] Synthesis of intermediate F47: 4-bromo-5-cyclopropyl-2-{6-ethyl-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole [ka] Dissolve 1-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazole-2-yl)butan-2-one (5.51 g, 20.3 mmol) in EtOH (60 mL). Add 3-amino-1-methyl-1-H-pyrazole-4-carbaldehyde (2.80 g, 22.4 mmol) and piperidine (4.02 mL, 40.6 mmol), and stir the reaction mixture overnight at 90°C. Filter the reaction mixture and purify it by reverse-phase chromatography (HPLC; Xbridge-C18, ACN / water containing NH3) to obtain product F47. Analysis (Method F): R t :0.55min, [M+H] + :360 / 362(Br)

[0210] Synthesis of intermediate F48: 1-{3,8-dimethylimidazo[1,2-a]pyridine-7-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole Step 1: Synthesis of 7-fluoro-3,8-dimethylimidazo[1,2-a]pyridine [ka] 4-Fluoro-3-methylpyridine-2-amine (300 mg, 2.4 mmol), 2-bromo-1,1-dimethoxypropane (1.6 mL, 11.9 mmol), and p-toluol sulfonic acid (82 mg, 0.48 mmol) are dissolved in 12 mL of acetonitrile and heated at 80°C for 2 days. The mixture is then diluted with DCM and purified by preparative flash column chromatography to obtain 330 mg of 7-fluoro-3,8-dimethylimidazo[1,2-a]pyridine. Analysis (Method C): R t :0.41min, [M+H] + :165

[0211] Step 2: Synthesis of 1-{3,8-dimethylimidazo[1,2-a]pyridine-7-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole [ka] 3-iodo-4-isopropyl-5-methyl-1H-pyrazole (C1) (450 mg, 1.8 mmol) is dissolved in NMP (1 mL), then NaH (157 mg) is added, and the mixture is stirred for 5 minutes. 7-fluoro-3,8-dimethylimidazo[1,2-a]pyridine (295 mg, 1.8 mmol) is added, and the mixture is placed in a microwave at 170°C for 16 hours. After cooling, the mixture is diluted with ACN / water, filtered, and purified by preparative HPLC to obtain intermediate F48. Analysis (Method C): R t :0.69min, [M+H] + :395

[0212] Synthesis of intermediate F49: 2-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-3-iodo-5-methyl-1H-pyrazole-4-yl)propan-1-ol Step 1: Synthesis of ethyl 2-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-3-iodo-5-methyl-1H-pyrazole-4-yl)propanoate [ka] Ethyl-2-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}3-iodo-5-methyl-1H-pyrazole-4-yl) acetate (138 mg, 0.31 mmol) is 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) are added, and the mixture is slowly warmed to RT, with stirring continued at RT for 1 hour. NH4Cl aqueous solution (15 mL) is added, and the mixture is extracted with 3 × ELISA. The organic phase is dried (Na2SO4) and concentrated. The product is used in the next step without further purification. Analysis (Method G): R t :0.81min, [M+H] + :454

[0213] Step 2: Synthesis of 2-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}3-iodo-5-methyl-1H-pyrazole-4-yl)propanoic acid [ka] Ethyl 2-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-3-iodo-5-methyl-1H-pyrazole-4-yl)propanoate (68 mg, 0.15 mmol) is dissolved in THF (2 mL) and NaOH (94 μL, 4 M, 0.375 mmol). Two drops of methanol are then added, and the mixture is stirred at 50°C for 3 hours. The mixture is then neutralized with HCl (4 M), concentrated, dissolved in water / DMF, and purified by preparative HPLC to obtain the desired product. Analysis (Method G): R t :0.65min, [M+H] + :426

[0214] Step 3: Synthesis of 2-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-3-iodo-5-methyl-1H-pyrazole-4-yl)propan-1-ol [ka] 102 mg, 0.24 mmol of 2-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-3-iodo-5-methyl-1H-pyrazole-4-yl)propanoic acid was suspended in 2 mL of THF and 200 μL of DMF. Then, 101 μL, 0.72 mmol of triethylamine and 86 mg, 0.528 mmol of CDI were added, and the mixture was stirred at RT for 45 min. The mixture was then cooled in an ice bath, and NaBH4 (32 mg, 0.84 mmol) and water were added. The mixture was stirred for 2 hours while being heated to RT. The mixture was concentrated, then dissolved in DMF / water, and purified by preparative HPLC to obtain product F49. Analysis (Method G): R t :0.66min, [M+H] + :412

[0215] Synthesis of intermediate F50: 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-2,6-dimethyl-1H-1,3-benzodiazole Step 1: Synthesis of 1-(5-chloro-2-methyl-4-nitrophenyl)-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole [ka] 600 mg, 2.4 mmol of 3-iodo-4-isopropyl-5-methyl-1H-pyrazole is dissolved in 15 mL of DMF, and K2CO3 and 909 mg, 4.8 mmol of 4-chloro-2-fluoro-5-nitrotoluene are added. The mixture is stirred at 100°C for 2 hours. The mixture is then purified by preparative HPLC to obtain the desired product. Analysis (Method G): R t:1.26min, [M+H] + :420

[0216] Step 2: Synthesis of 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-4-methyl-2-nitroaniline [ka] 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 hours, and the mixture was purified by preparative HPLC to obtain the desired product. Analysis (Method H): R t :1.18min, [M+H] + :401

[0217] Step 3: Synthesis of 4-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-5-methylbenzene-1,2-diamine [ka] 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-4-methyl-2-nitroaniline (372 mg, 0.93 mmol) is dissolved in HOAc (10 mL), and iron powder (260 mg) is added. Then HCl (4 M, 3 × 1.1 mL) is added, and the mixture is stirred at 60°C for 3 hours. The mixture is purified by preparative HPLC to obtain the desired product. Analysis (Method G): R t :0.89min, [M+H] + :371

[0218] Step 4: Synthesis of 5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-2,6-dimethyl-1H-1,3-benzodiazole [ka] 4-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-5-methylbenzene-1,2-diamine (132 mg, 0.3 mmol) and {[(tert-butoxy)carbonyl]amino}acetic acid (53 mg, 0.3 mmol) are dissolved in DMF (2 mL), then HATU (114 mg, 0.3 mmol) and DIPEA (206 μL, 1.2 mmol) are added, and the mixture is stirred at RT for 2 hours. The mixture is filtered through basic aluminum oxide, then washed with DMF / MeOH 9:1, and concentrated. The mixture is dissolved in HOAc (3 mL) and heated at 85°C for 2 hours. The mixture is then purified by preparative HPLC (ACN / water containing C18, NH3) to obtain the desired product F50. Analysis (Method G): R t :0.89min, [M+H] + :395

[0219] Synthesis of intermediate F51: 5-(4-bromo-5-cyclopropyl-1-methyl-1H-imidazole-2-yl)-6-(trifluoromethoxy)-2-methyl-2H-indazole Step 1: Synthesis of 4-bromo-5-(difluoromethoxy)-2-methylaniline [ka] Dissolve 5-(trifluoromethoxy)-2-methylaniline (656 mg) in chloroform (25 mL). Add NBS (611 mg) at 0°C and stir the reaction mixture at 0°C for 1 hour. Quench the reaction mixture with Na2S2O3 (0.5 M solution) and dilute with DCM. Separate the phases, concentrate the organic layer, and purify it by flash chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10) to obtain the product. Analysis (Method F): R t :0.96min, [M+H] + :270 / 272(Br)

[0220] Step 2: Synthesis of 5-bromo-6-(trifluoromethoxy)-2H-indazole [ka] To 0.53 mL, 4.3 mmol of boron trifluoride etherate in 8 mL of DCM, 1.98 g, 7.84 mmol of 4-bromo-5-(trifluoromethoxy)-2-methylaniline in 11.25 mL of DCM was added at -78°C under an argon atmosphere, followed by dropwise addition of t-butyl nitrite (0.41 mL, 3.4 mmol). The reaction mixture was heated to RT 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 RT 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 obtain the product. Analysis (Method F): R t :0.88min, [M+H] + :281 / 283(Br)

[0221] Step 3: Synthesis of 5-bromo-6-(trifluoromethoxy)-2-methyl-2H-indazole [ka] Dissolve 5-bromo-6-(trifluoromethoxy)-2H-indazole (500 mg, 1.6 mmol) in  (10 mL). Add trimethyloxonium tetrafluoroborate (308 mg, 2.1 mmol) and stir the reaction mixture at RT for 1 hour. Quench the reaction mixture by adding 10% NaHCO3 solution dropwise until a basic pH is reached. Dilute the reaction mixture with DCM and pass it through a phase separator. Adsorb the organic layer onto extrelute and purify it with MPLC (DCM / MeOH 100 / 0 → DCM / MeOH 90 / 10) to obtain the product. Analysis (Method F): R t :0.93min, [M+H] + :295 / 297(Br)

[0222] Step 4: Synthesis of 6-(difluoromethoxy)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole [ka] Under an argon atmosphere, 5-bromo-6-(trifluoromethoxy)-2-methyl-2H-indazole (614 mg, 2.1 mmol) is dissolved in dioxane (12 mL), bis(pinacolato)diborone (0.79 g, 3.1 mmol), potassium acetate (614 mg, 6.2 mmol), and Pd(dppf)Cl2×DCM (170 mg, 0.21 mmol) are added, and the reaction mixture is stirred at 90°C for 2 hours. The cooled reaction mixture is then filtered through a Pd scavenger cartridge, the cartridge is rinsed with methanol, and the filtrate is concentrated. The residue is purified by flash column chromatography (Â / CycH 30 / 70~100 / 0) to obtain the product. Analysis (Method A): R t :0.71min, [M+H] + :343

[0223] Step 5: Synthesis of 5-(4-bromo-5-isopropyl-1-methyl-1H-imidazole-2-yl)-6-(trifluoromethyl(triifluorometh)-oxy)-2-methyl-2H-indazole [ka] Under an argon atmosphere, 2,4-dibromo-5-isopropyl-1-methyl-1H-imidazole (54 mg, 0.19 mmol, synthesized similarly to that 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). Cs2CO3 (188 mg, 0.58 mmol) and Pd(PPh3)4 (22 mg, 0.0.02 mmol) were added by RT, and the reaction mixture was stirred at 80°C for 18 hours. The reaction mixture was injected onto ice, and the resulting solid was isolated. The solid was dissolved in dichloromethane and adsorbed onto Extrelut. The mixture is purified by flash column chromatography (DCM / MeOH 100 / 0 to DCM / MeOH 90 / 10 gradient). The combined fraction is concentrated to obtain the desired product F51. Analysis (Method F): R t :0.72min, [M+H] + :415 / 417(Br)

[0224] 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: Synthesis of intermediate G1: ((1R)-2-[4-(5-methyl-1-{6-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol Step 1: Synthesis of (1R)-2-[4-(1-{2-[(4-methoxyphenyl)methyl]-6-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol

[0225] [ka] Under an argon atmosphere, 3-iodo-1-{2-[(4-methoxyphenyl)methyl]-6-methyl-2H-pyrazolo[3,4-b]pyridine-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-indazole-2-yl]ethane-1-ol (B1) (1.64 g, 4.06 mmol, 90% purity) are dissolved in dioxane (28 mL). Add an aqueous solution of K3PO4 (4.61 mL, 9.23 mmol, 2 M) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate (XPhos Pd G3, 187 mg, 0.22 mmol), and stir the reaction mixture overnight at 90°C. Then add SiliaMetS Thiol to the reaction mixture and stir for 15 min. Next, remove the solid by filtration. Concentrate the filtrate and grind it with MTBE. Filter off the solid as the first batch of the title compound. Concentrate the filtrate and purify it by flash chromatography (siRNA / MeOH 100 / 0 to siRNA / MeOH 90 / 10) to obtain the second batch of the title compound. Analysis (Method A): R t :0.68min, [M+H] + :612

[0226] Step 2: Synthesis of (1R)-2-[4-(5-methyl-1-{6-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol [ka] (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-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol (1.70 g, 2.50 mmol) and anisole (0.55 mL, 5 mmol) are dissolved in DCE (30 mL). TFA (20 mL, 259 mmol) is added, and the reaction mixture is stirred at 50°C for 3 days. The reaction mixture is concentrated, and the residue is purified by reverse-phase chromatography (HPLC; ACN / water with TFA) to obtain 755 mg of the product. Analysis (Method H): R t :0.68min, [M+H] + :492

[0227] Synthesis of Example 1: (1R)-2-[4-(5-methyl-1-{6-methyl-2-[2-(morpholine-4-yl)ethyl]-2H-pyrazolo[3,4-b]pyridine-5-yl}-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol [ka] (1R)-2-[4-(5-methyl-1-{6-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol (300 mg, 0.61 mmol) is dissolved in ACN (5 mL) and DMF (3 mL), and K2CO3 (253 mg, 1.83 mmol) and 4-(2-bromoethyl)morpholine hydrobromide (218 mg, 0.79 mmol) are added. The reaction mixture is stirred overnight in RT. The reaction mixture is purified by reverse-phase chromatography (HPLC; ACN / water containing NH3) to obtain Example 1. Analysis (Method H): R t :0.94min, [M+H] + :605 The intermediates and examples summarized in the table below are obtained by using intermediate G1 and following a procedure similar to that described for Example 1.

[0228] [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7] [Table 9-8] [Table 9-9] [Table 9-10] [Table 9-11] [Table 9-12]

[0229] Synthesis of Example 3: (1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenyl(1- 2 H) Ethane-1-ol [ka]

[0230] Step 1: Synthesis of 2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-one [ka] (1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-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 RT for 5 hours. The reaction mixture was concentrated and purified by reverse-phase chromatography (HPLC; C18, ACN / water containing TFA) to obtain the product. Analysis (Method G): R t :0.96min, [M+H] + :504

[0231] Step 2: 2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenyl(1- 2 H) Synthesis of ethane-1-ol [ka] Dissolve 2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-one (280 mg, 0.56 mmol) in THF (5 mL) and MeOH (5 mL). Add sodium borode deuteride (52 mg, 1.11 mmol) and stir the reaction mixture at RT for 30 min. Quench the reaction mixture with water and extract with DCM. Dry the organic layer (Na2SO4), filter, and concentrate to obtain the product. Analysis (Method G): R t :0.93min, [M+H] + :507

[0232] Step 3: (1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenyl(1- 2 H) Synthesis of ethane-1-ol [ka] 2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenyl(1- 2 H) Ethane-1-ol (149 mg, 0.29 mmol) was separated by chiral purification method W to obtain compound (1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenyl(1- 2 H) Ethane-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]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenyl(1- 2 H) Ethane-1-ol is obtained. Analysis (Method W): R t (3.78 min).

[0233] 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, and 102 Synthesis of Example 5: (1R)-2-[4-(1-{6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol

[0234] Step 1: Synthesis of (1R)-2-[4-(1-{2-[(4-methoxyphenyl)methyl]-6-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol [ka] 1-{6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-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-indazole-4-yl}boronic acid (B3) (52 mg, 0.15 mmol) are dissolved in dioxane (1 mL). Cs2CO3 (112 mg), water (100 μL), and Pd(dppf)Cl2×DCM (10 mg) are added, and the reaction mixture is stirred overnight at 85°C. The mixture is then filtered, diluted with ACN and HOAc, and purified by reverse-phase HPLC to obtain the desired product Example 5. Analysis (Method G): R t :0.98min, [M+H] + :536

[0235] The intermediates and examples summarized in the table below are obtained by following a procedure similar to that described for intermediate G1, step 1. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] [Table 10-7] [Table 10-8] [Table 10-9] [Table 10-10] [Table 10-11] [Table 10-12] [Table 10-13] [Table 10-14] [Table 10-15] [Table 10-16] [Table 10-17] [Table 10-18] [Table 10-19] [Table 10-20] [Table 10-21] [Table 10-22] [Table 10-23]

[0236] Synthesis of intermediate G2, Examples 10, 11, 28, 33, 61 and 104 Synthesis of intermediate G2:(1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole-4-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol Step 1: (1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole-4-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol [ka] Under an argon atmosphere, 5-(4-bromo-5-cyclopropyl-1-methylimidazole-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-indazole-2-yl]ethane-1-ol (B1) (508 mg, 1.25 mmol) are dissolved in dioxane (10 mL). Add an aqueous solution of K3PO4 (1 mL, 2 M) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate (XPhos Pd G3, 44.2 mg, 0.05 mmol), and stir the reaction mixture at 90°C for 1 hour. Then remove the solid by filtration. Concentrate the filtrate to obtain the product. Use this product in the next step without further purification. Analysis (Method H): R t :1.1min, [M+H] + :636

[0237] Step 2: Synthesis of (1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole-4-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol [ka] (1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole-4-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol (600 mg, 0.94 mmol) and anisole (207 μL, 1.88 mmol) are dissolved in DCE (20 mL). TFA (5 mL) is added, and the reaction mixture is stirred at 70°C over the weekend. The reaction mixture is concentrated, and the residue is purified by reverse-phase chromatography (HPLC; ACN / water with TFA) to obtain intermediate G2. Analysis (Method H): R t :1, 03min, [M+H] + :516

[0238] Synthesis of Examples 10 and 61: (1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-[2-(morpholine-4-yl)ethyl]-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole-4-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol (10) and (1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-ethenyl-2H-pyrazolo[3,4-b]pyridin-5-yl}-1-methyl-1H-imidazole-4-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol (61)

[0239] [ka] ((1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole-4-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol (40 mg, 0.08 mmol) and 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 overnight at 40°C. Then morpholine (34 μL, 0.39 mmol) was added, and the mixture was stirred for 4 hours at 80°C, then an additional morpholine (50 μL) was added, and the mixture was stirred overnight at 80°C. The mixture was then diluted with water, filtered, and purified by reverse-phase chromatography (HPLC; ACN / water with NH3) to obtain the title compound. Analysis (Method H): R t :1.01min, [M+H] + :629 (Example 10) Analysis (Method H): R t :1.02min, [M+H] + :542 (Example 61)

[0240] Synthesis of Example 11: (1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-[3-(morpholine-4-yl)propyl]-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole-4-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol

[0241] [ka] ((1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole-4-yl)-2H-indazole-2-yl]-1-phenylethane-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 overnight at 40°C. The mixture was then diluted with water / ACN (2 mL), filtered, and purified by reverse-phase chromatography (HPLC; C18, ACN / water containing NH3) to obtain Example 11. Analysis (Method H): R t :1.01min, [M+H] + :643

[0242] The intermediates and examples summarized in the table below are obtained by using intermediate G2 and following a procedure similar to that described for Example 11. [Table 11-1] [Table 11-2]

[0243] Synthesis of Examples 8, 27, 30, 52, 63, 66, 74, 78, 79, 81, and 85: Synthesis of Example 8: 2-[(1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethoxy]ethane-1-ol [ka] (1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol (102) (25.3 mg, 0.05 mmol) is dissolved in DMF (1 mL). NaH (6.6 mg, 0.15 mmol, 55% purity) is added, and the reaction mixture is stirred at RT for 10 min. Then 2-(2-chloroethoxy)tetrahydro-2H-pyran (32.9 mg, 0.20 mmol) is added, and the reaction mixture is stirred at RT overnight. The reaction mixture is purified by reverse-phase chromatography (HPLC; ACN / water / TFA). To remove the THP protecting group, the residue is dissolved in TFA (1 mL) and stirred at 50°C for 30 min. The reaction mixture was concentrated and purified by reverse-phase chromatography (HPLC; ACN / water containing TFA) to obtain the title compound. Analysis (Method G): R t :1.01min, [M+H] + :550

[0244] The examples summarized in the table below can be obtained by following a procedure similar to that described for Example 8. [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5]

[0245] Synthesis of Example 36: 2-[(1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethoxy]-N-methylacetamide Step 1: Synthesis of ethyl 2-[(1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethoxy]acetate

[0246] [ka] {2-[(2R)-2-(2-ethoxy-2-oxoethoxy)-2-phenylethyl]-2H-indazole-4-yl}boronic acid (300 mg, 0.82 mmol), 1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole (300 mg), Cs2CO3 (0.74 g), and a complex (100 mg) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (ii) and dichloromethane (1:1) are suspended in dioxane (8 mL) and water (2 mL). The mixture is stirred under an argon atmosphere at 80°C for 3 hours. The mixture is concentrated, and HOAc, ACN, and water are added. The mixture is filtered, and the filtrate is purified by reverse-phase preparative HPLC to obtain the product. Analysis (Method F): R t :0.95min, [M+H] + :592

[0247] Step 2: Synthesis of 2-[(1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethoxy]acetic acid

[0248] [ka] Ethyl 2-[(1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethoxy]acetate (375 mg, 0.53 mmol) is dissolved in EtOH (3 mL). NaOH (2.65 mL, 2.65 mmol, 1 M) is added, and the reaction mixture is stirred at RT for 1.25 h. The reaction mixture is diluted with water, and TFA (0.5 mL) is added. The reaction mixture is concentrated, the residue is diluted with water (5 mL) and brine (5 mL), and extracted with DCM (10 mL). The organic layer is dried (Na2SO4), filtered, and concentrated to obtain intermediate G3. Analysis (Method F): R t :0.83min, [M+H] + :564

[0249] Step 3: Synthesis of 2-[(1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethoxy]-N-methylacetamide

[0250] [ka] Dissolve 2-[(1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethoxy]acetic acid (50 mg, 0.074 mmol) in DMF (1 mL). Add DIPEA (26.8 μL, 0.15 mmol) and HATU (32.3 mg, 0.085 mmol), and stir the reaction mixture in RT for 10 min. Then add methylamine (74 μL, 0.15 mmol, 2 M in THF), and stir the reaction mixture in RT overnight. Purify the reaction mixture by reverse-phase chromatography (HPLC; ACN / water containing NH3) to obtain Example 36. Analysis (Method C): R t :0.65min, [M+H] + :577

[0251] The examples summarized in the table below can be obtained by following a procedure similar to that described for Example 36. [Table 13]

[0252] Synthesis of Example 40: (1R)-2-[4-(1-{2-[3-(3,3-difluoropyrrolidine-1-yl)propyl]-6-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol [ka]

[0253] Step 1: Synthesis of (1R)-2-(4-{1-[2-(3-chloropropyl)-6-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl]-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl}-2H-indazole-2-yl)-1-phenylethane-1-ol (1R)-2-[4-(5-methyl-1-{6-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol (200 mg, 0.41 mmol), 1-bromo-3-chloropropane (80.2 μM, 0.814 mmol), and K2CO3 (281 mg) are suspended in ACN (5 mL) and stirred overnight at 60°C. The mixture is filtered and purified by preparative reverse-phase chromatography to obtain the desired product. Analysis: (Method G):R t :1.10min, [M+H] + :568 / 570(Cl)

[0254] Step 2: Synthesis of (1R)-2-[4-(1-{2-[3-(3,3-difluoropyrrolidin-1-yl)propyl]-6-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol [ka] (1R)-2-(4-{1-[2-(3-chloropropyl)-6-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl]-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl}-2H-indazole-2-yl)-1-phenylethane-1-ol (15 mg, 0.03 mmol) is dissolved in ACN (2 mL). K2CO3 (14.6 mg, 0.11 mmol) and 3,3-difluoropyrrolidine × HCl (13.6 mg, 0.096 mmol) are added, and the reaction mixture is stirred overnight at 90°C. The reaction mixture is purified by reverse-phase chromatography (HPLC; ACN / water containing NH3) to obtain Example 40. Analysis: (Method H):R t :1.10min, [M+H] + :639

[0255] Synthesis of Example 41: 4-{4-[(1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole-4-yl)-2H-indazole-2-yl]-1-hydroxyethyl]phenoxy}-2-methylbutan-2-ol [ka] 4-[(1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole-4-yl)-2H-indazole-2-yl]-1-hydroxyethyl]phenol (30 mg, 0.06 mmol) is 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) are added, and the reaction mixture is stirred at 60°C for 4 hours. The reaction mixture is purified by reverse-phase chromatography (HPLC; ACN / water containing NH3) to obtain Example 41. Analysis (Method H): R t :0.99min, [M+H] + :632

[0256] Synthesis of Examples 68, 69, and 90: [ka] 4-[(1R)-2-[4-(5-cyclopropyl-2-{6-cyclopropyl-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-1-methyl-1H-imidazole-4-yl)-2H-indazole-2-yl]-1-hydroxyethyl]phenol (Example 55) (30 mg, 0.06 mmol) is dissolved in DMF (1 mL). K2CO3 (69.1 mg, 0.50 mmol) and 4-bromomethyltetrahydropyran (39.4 mg, 0.22 mmol) are added, and the reaction mixture is stirred overnight at 60°C. The reaction mixture is purified by reverse-phase chromatography (HPLC; ACN / water containing TFA) to obtain Example 68. Analysis (Method G): R t :0.87min, [M+H] + :644 The examples summarized in the table below can be obtained by following a procedure similar to that described for Example 68. [Table 14]

[0257] Synthesis of Example 88: 1-(4-bromophenyl)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]ethane-1-ol

[0258] Step 1: Synthesis of (4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2-[(trimethylsilyl)methyl]-2H-indazole) [ka] 5-(3-iodo-4-isopropyl-5-methylpyrazole-1-yl)-2,6-dimethylpyrazolo[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) are suspended in dioxane (1 mL). Cs2CO3 (346 mg), Pd(dppf)Cl2 (28 mg, 1:1 complex with DCM) and water (150 μL) are added, and the mixture is stirred overnight at 80°C. The mixture is filtered, diluted with MeOH and HOAc, and purified by preparative HPLC (ACN / water with TFA) to obtain the desired product. Analysis (Method G): R t :1.09min, [M+H] + :472

[0259] Step 2: Synthesis of 1-(4-bromophenyl)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]ethane-1-ol [ka] (4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(propan-2-yl)-1H-pyrazole-3-yl)-2-[(trimethylsilyl)methyl]-2H-indazole) (84 mg, 0.18 mmol) and 4-bromobenzaldehyde (90 mg, 0.49 mmol) are dissolved in DMF (1 mL). CsF (30 mg, 0.20 mmol) is added, and the reaction mixture is stirred at RT for 4 hours. The reaction mixture is purified by reverse-phase chromatography (HPLC; ACN / water containing TFA) to obtain Example 88. Analysis (Method G): R t :1.05min, [M+H] + :584 / 586(Br)

[0260] Synthesis of Example 92: (1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(1-methylcyclopropyl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol Step 1: Synthesis of (1R)-2-[4-(5-methyl-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol [ka] (1R)-1-phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-2-yl]ethane-1-ol (700 mg, 1.9 mmol), 3-iodo-5-methyl-1H-pyrazole (400 mg, 1.9 mmol), and a complex (157 mg) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (ii) and dichloromethane (1:1) were suspended in dioxane (7 mL) and Na2CO3 (2 M, 2.9 mL). The mixture was stirred under an argon atmosphere at 80°C for 4 hours, and then stirred overnight at room temperature. The mixture was then diluted with ACN and purified by preparative HPLC to obtain the desired compound. Analysis (Method A): R t :0.45min, [M+H] + :319

[0261] Step 2: Synthesis of (1R)-2-[4-(4-bromo-5-methyl-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol [ka] (1R)-2-[4-(5-methyl-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol (598 mg, 1.87 mmol) is suspended in ACN (40 mL), and NBS (300 mg, 1.69 mmol) is added over 30 min. The mixture is stirred at RT for 1 hour. The mixture is extracted with Na2S2O3 (0.5 M). The aqueous phase is extracted with n-butanol, the organic phase is combined, and the mixture is concentrated. The residue is dissolved in ACN / MeOH and purified by preparative HPLC. ACN is evaporated from the desired HPLC fraction, and the precipitated product is collected to obtain the product. Analysis (Method A): R t :0.56min, [M+H] + :397 / 399

[0262] Step 3: Synthesis of (1R)-2-{4-[5-methyl-4-(propa-1-en-2-yl)-1H-pyrazole-3-yl]-2H-indazole-2-yl}-1-phenylethane-1-ol [ka] (1R)-2-[4-(4-bromo-5-methyl-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol (305 mg, 0.77 mmol), potassium trifluoro(propa-1-en-2-yl)boranoid (193 mg, 1.3 mmol), Cs2CO3 (750 mg), palladium acetate (12 mg), butyldi-1-adamantylphosphine (62 mg), toluol (10 mL), and water (1 mL) are mixed and stirred overnight at 120°C under an argon atmosphere. The mixture is then filtered through a thiol scavenger resin cartridge and purified by preparative HPLC to obtain the product. Analysis (Method A): R t :0.55min, [M+H] + :359

[0263] Step 4: Synthesis of (1R)-2-{4-[5-methyl-4-(1-methylcyclopropyl)-1H-pyrazole-3-yl]-2H-indazole-2-yl}-1-phenylethane-1-ol [ka] (1R)-2-{4-[5-methyl-4-(propa-1-en-2-yl)-1H-pyrazole-3-yl]-2H-indazole-2-yl}-1-phenylethane-1-ol (215 mg) is dissolved in DCM (15 mL). Diiodomethane (219 μL), followed by diethylzinc (2.7 mL, 1 M in hexane) is added at 0°C, and the mixture is stirred at 0°C for 1 hour. Then, aqueous NH4Cl solution (60 mL) is added, and the mixture is extracted with DCM. The organic phase is dried to (Na2SO4), concentrated, and purified by preparative HPLC to obtain the desired product. Analysis (Method A): R t :0.64min, [M+H]+ :373

[0264] Step 5: Synthesis of 1-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazole-4-yl}-5-methyl-4-(1-methylcyclopropyl)-1H-pyrazole-1-yl)propan-2-one [ka] (1R)-2-{4-[5-methyl-4-(1-methylcyclopropyl)-1H-pyrazole-3-yl]-2H-indazole-2-yl}-1-phenylethane-1-ol (28 mg, 0.075 mmol) is dissolved in ACN (0.6 mL), then K2CO3 (26 mg) and chloroacetone (12 μL) are added, and the mixture is stirred at 50°C for 7 days. During this time, additional chloroacetone (2-4 equivalents) is added to the mixture daily. The mixture is then concentrated and purified by preparative HPLC to obtain the product. Analysis (Method A): R t :0.62min, [M+H] + :429.

[0265] Step 6: Synthesis of (1R)-2-[4-(1-{2,6-dimethyl-2H-pyrazolo[3,4-b]pyridine-5-yl}-5-methyl-4-(1-methylcyclopropyl)-1H-pyrazole-3-yl)-2H-indazole-2-yl]-1-phenylethane-1-ol [ka] 1-(3-{2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazole-4-yl}-5-methyl-4-(1-methylcyclopropyl)-1H-pyrazole-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, purified by preparative HPLC, and subsequently purified by preparative TLC (DCM / MeOH 93 / 7) to obtain Example 92. Analysis (Method A): R t :0.62min, [M+H] + :518.

[0266] Synthesis of Example 96: 2-[(benzenesulfonyl)methyl]-4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-1H-imidazole-4-yl}-2H-indazole [ka] 2-{[(R)-benzenesulfinyl]methyl}-4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridine-5-yl]-1H-imidazole-4-yl}-2H-indazole (15.9 mg, enantiomer eluting in 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 containing TFA) to obtain Example 96. Analysis (Method A): R t :0.47min, [M+H] + :566.

[0267] Example 97: (1R)-2-(4-{5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridine-5-yl]-1H-imidazole-4-yl}-2H-indazole-2-yl)-1-phenylethane-1-ol [ka] 4-bromo-5-cyclopropyl-1-methyl-2-[2-methyl-6-(propan-2-yl)-2H-pyrazolo[3,4-b]pyridine-5-yl]-1H-imidazole (150 mg, 0.32 mmol), {2-[(2R)-2-hydroxy-2-phenylethyl]-2H-indazole-4-yl}boronic acid (108 mg, 0.39 mmol), and 1,1'-bis(di-tert-butylphosphinoferrocene palladium dichloride (21 mg) are suspended in dioxane (2.5 mL). Add Na2CO3 (400 μL, 2M aqueous solution), degas the mixture under vacuum, and flush with argon. Heat the reaction mixture under an argon atmosphere at 80°C for 3 hours. Dilute the mixture with ACN / MeOH, filter through a thiol scavenger resin cartridge, purify by preparative HPLC (Xbridge-C18, ACN / water containing TFA, gradient 10-100% ACN), and perform a second HPLC purification (Xbridge-C18, ACN / water containing NH3, 10-80% ACN) to obtain Example 97. Analysis (Method A): R t :0.46min, [M+H] + :532.

[0268] Synthesis of Example 111: (1R)-2-(4-{5-methyl-1-[2-methyl-6-(pyrroridine-2-yl)-2H-pyrazolo[3,4-b]pyridine-5-yl]-4-(propan-2-yl)-1H-pyrazole-3-yl}-2H-indazole-2-yl)-1-phenylethane-1-ol [ka] Under an argon atmosphere, tert-butyl 2-{5-[3-iodo-5-methyl-4-(propan-2-yl)-1H-pyrazole-1-yl]-2-methyl-2H-pyrazolo[3,4-b]pyridine-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 then Cs2CO3 (0.43 mL, 1 M aqueous solution) was added. Then XPhos Pd G3 (8.3 mg) was added, and the mixture was stirred at 90°C for 4 hours. The mixture was then diluted with ELISA and extracted with water. The organic phase was concentrated and suspended in DCM (2 mL) and TFA (1 mL) for 1 hour at RT. Next, the mixture was concentrated and purified by preparative HPLC to obtain Example 111. Analysis (Method G): R t :0.74min, [M+H] + :561

[0269] List of abbreviations: Acetyl ACN Acetonitrile AIBN 2,2'-Azobis(isobutyronitrile) Boc tert-butyloxycarbonyl CBZ Benzyloxycarbonyl CycH cyclohexane d day DAST Diethylaminosulfur Trifluoride DCE 1,2-Dichloroethane DCM Dichloromethane DEAD Diethyl Azodicarboxylate DIAD (Diisopropyl Azodicarboxylate) DIPEA N,N-diisopropylethylamine DMF (N,N-dimethylformamide) DMP Des-Martin Periodinaan DMSO (Dimethyl Sulfoxide) HCl ethyl acetate EtOH Ethanol h time HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate HPLC (High-Performance Liquid Chromatography) HPLC-MS coupled high-performance liquid chromatography-mass spectrometry IPA Isopropyl Alcohol LC (Reset Chromatography) LC-MS coupled liquid chromatography-mass spectrometry LiHMDS (Lithium-bis(trimethylsilyl)amide) M moles (mol / L) MeI methyl iodide MeTHF 2-methyltetrahydrofuran MeOH methanol min MS mass spectrometry MTBE Methyl-tert-butyl ether n-BuLi (butyllithium) NBS N-bromosuccinimide NIS N-iodosuccinimide NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance PEPPSI(TM)-IPR (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride PdCl2(dtbpf) 1,1'-Bis-(di-tert-butylphosphin-)ferrocene-palladium dichloride Pd(dppf)Cl21,1'-Bis(diphenylphosphin)ferrocenedichloropalladium(II) Pd(PPh3)4 Palladium(0) Tetrakis(Triphenylphosphine) XPhos Pd G3 (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate pet. petroleum R f Retention coefficient RP inverse phase rt room temperature t R Retention time (in HPLC / LC) SFC Supercritical Fluid Chromatography TBAF Tetrabutylammonium Fluoride TBTU O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate TEA (Triethylamine) TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) THP Tetrahydro-2H-pyran TLC (Thin-Layer Chromatography) TMAD N,N,N'N'-Tetramethylazodicarboxamide UV ultraviolet light V Volume

[0270] HPLC method: [Table 15] Column: XBridge BEH C18_2.1 x 30 mm, 1.7 μm; Column temperature: 60°C

[0271] [Table 16] Column: XBridge BEH C18_2.1 x 30mm, 1.7μm; Column temperature: 60℃

[0272] [Table 17] Column: XBridge BEH C18_2.1 x 30mm, 2.5μm; Column temperature: 60℃

[0273] [Table 18] Column: XBridge BEH Phenyl_2.1 x 30mm, 1.7μm; Column temperature: 60℃

[0274] [Table 19] Column: Sunfire C18_2.1 x 30mm, 2.5μm; Column temperature: 60℃

[0275] [Table 20] Column: Sunfire C18 (Waters) 2.5μm; 3.0 x 30mm; Column temperature: 60℃

[0276] [Table 21]

[0277] [Table 22] [Table 23]

[0278] [Table 24] Column: Sunfire C18 (Waters) 2.5μm; 3.0 x 30mm; CT: 60℃

[0279] [Table 25]

[0280] [Table 26] Column: Sunfire C18 (Waters) 2.5μm; 3.0 x 30mm; CT: 60℃

[0281] [Table 27]

[0282] [Table 28] Column: XBridge C18_3.0 x 30mm_2.5μm (Waters); Column temperature: 60℃

[0283] [Table 29] Column: XBridge C18_3.0 x 30mm_2.5μm (Waters); Column temperature: 60℃

[0284] [Table 30] Column: XBridge C18_3.0 x 30mm_2.5μm (Waters); Column temperature: 60℃

[0285] [Table 31] Column: Acquity UPLC BEH C18 1.7μm (2.1 x 100 mm); Column temperature: 40℃

[0286] [Table 32] Column: Kinetex XB-C18 2.6 μm (4.6 x 50 mm), 100 Å; Column temperature: 25°C

[0287] [Table 33] Column: Acquity UPLC BEH C18 1.7μm (2.1 x 100mm); Column temperature: 40℃

[0288] [Table 34] Column: CHIRAL ART® Cellulose SB_4.6 x 250mm_5μm; Column temperature: 40℃

[0289] [Table 35] Column: CHIRAL ART® Cellulose SB_4.6 x 250mm_5μm; Column temperature: 40℃ [Table 36] Column: CHIRAL ART® Cellulose SB_4.6 x 250mm_5μm; Column temperature: 40℃

[0290] [Table 37] Column: CHIRAL ART® Cellulose SB_4.6 x 250mm_5μm; Column temperature: 40℃

[0291] [Table 38] Column: CHIRAL ART® Cellulose SB_4.6 x 250mm_5μm; Column temperature: 40℃

[0292] [Table 39] Column: CHIRAL ART® Cellulose SB_4.6 x 250mm_5μm; Column temperature: 40℃

[0293] [Table 40] Column: CHIRAL ART (registered trademark) Cellulose SB_4.6 x 250mm_5μm; Column temperature: 40℃

[0294] [Table 41] Column: CHIRAL ART® Amylose-SA_3 x 100mm_3μm; Column temperature: 40℃ [Table 42] Column: Lux(R) Cellulose-2_3 x 100mm_3μm; Column temperature: 40℃ [Table 43] Column: Chiralpak® IG_4.6 x 250mm_5μm; Column temperature: 40℃ [Table 44] Column: CHIRAL ART® Amylose SA_4.6 x 250mm_5μm; Column temperature: 40℃

[0295] Biological assays The activity of the compounds of the present invention can be demonstrated using the following in vitro STING biochemical assays and cell assays.

[0296] Human STING HTRF binding assay A competitive HTRF assay format (Cisbio 64BDSTGPEG) was used to identify a conjugate to human STING WT (R232). This assay uses a d2-labeled STING ligand, a 6His-tagged human STING protein, and an anti-6His cryptotate-labeled antibody. The compound competes with the STING ligand-d2, thus preventing FRET formation, and can be measured by an EnVision® reader (PerkinElmer).

[0297] Assay Procedure: Compounds were delivered as a 10 mM DMSO solution, which was serially diluted in an Agilent Bravo Workstation and transferred to a 384-well assay plate (Perkin Elmer #6005359) using a Cybiwell dispenser. Typically, eight concentrations were used, with the highest concentration being 10 μM or 1 μM in the final assay volume, followed by an approximately 1:5 dilution step. 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. A cGAMP standard dilution column was prepared according to the manufacturer's instructions and transferred to each assay plate. After transferring compound solution or dilution buffer to the negative (high) and positive (low) controls, 5 μl of the WT R232 human version of human STING protein (cyclic binding domain (residues 138-379), condensed with a 6His tag at the Nter region; 1:50 dilution in detection buffer) was dispensed into all wells except the positive control, with only detection buffer added to the positive control. The plate was centrifuged at 1000 rpm for 20 seconds. Then, using a Multidrop combi dispenser, 10 μl of anti-6His-cryptate antibody / Sting ligand-d2 mix was added to all wells, followed by a further 20 sec / 1000 rpm centrifugation step. After 180 min of plate incubation at room temperature, excitation at 665 / 620 nM (HTRF ratio) was measured using an Envison Reader (PerkinElmer).

[0298] Data Evaluation and Calculation: For data evaluation and calculation, the HTRF ratio was calibrated using a cGAMP calibration curve. Then, the low control measurements were set as the 0% control, and the high control measurements were set as the 100% control. The IC50 value was calculated using a standard four-parameter logistic regression equation. Formula: [y=(ad) / (1+(x / c)^b)+d], where a=low value, d=high value; x=concentration M; c=IC50M; b=slope; The results of this assay are shown in the table below.

[0299] Determination of increased stability of STING proteins against thermal denaturation using differential scanning fluorescence (DSF). The binding affinity of the compound of the present invention can be demonstrated using a thermal shift assay to measure the stability of suitable human STING protein material against thermal denaturation in the presence of the compound. In this assay, the unfolding temperature of the protein is monitored in the presence of a fluorescent dye. This fluorescent dye is embedded in the folded state of the protein and exhibits affinity for the hydrophobic amino acids of the protein that are gradually exposed during unfolding. The dye fluorescence quenches in an aqueous environment and increases as the dye associates with the hydrophobic portions of the unfolding protein. A plot of fluorescence intensity as a function of temperature typically shows a sigmoid curve (differential scanning fluorescence) interpreted by a two-state model of protein unfolding. The inflection point of the curve represents the protein's "melting" temperature (Tm), which is calculated numerically using the Boltzmann equation.

[0300] Methods: The thermal stability of the STING protein was measured at pH 7.5 in an assay buffer containing 20 mM Tris and 150 mM NaCl, using a specific expression construct of the cGAMP-binding domain of wild-type (GRR) human STING, including residues 155–341 and the N-terminal 8×His-tag. The assay was performed on a CFX384 Real-Time System (Bio-Rad) using Hard-Shell® PCR plates, 384 wells, CLR / WHT (catalog number HSP3805, BIO-RAD), and Microseal® 'B' PCR plate adhesive seals (catalog number MSB-1001, BIO-RAD).

[0301] I prepared a SYPRO orange DMSO stock solution (SIGMA S5692-500UL).

[0302] The compound stock solution (10 mM in DMSO) was diluted 1:2 in DMSO to an intermediate compound concentration of 5 mM, and then further diluted 1:40 in assay buffer to obtain a compound concentration of 125 μM and 2.5% DMSO. Next, a fluorescent dye stock solution (5000×SYPRO Orange) was mixed with the target protein and buffer to obtain protein concentrations of 15 μM and 25×SYPRO Orange. 2 μl of this protein-dye mixture was added to 8 μl of the compound solution. The final volume was 10 μL. Wells 3-6 were used as negative controls (proteins containing 2% DMSO). Plates were prepared for dual measurements and centrifuged at 1000 g for 2 min. 160 cycles at 0.5°C were used for the measurements (temperature lamp 15 seconds / cycle, 15°C-95°C).

[0303] The final assay concentrations for characterizing the compound were as follows: 100 μM compound, 3 μM target protein, 5×SYPRO Orange, 2% DMSO in 10 μl. All distribution steps were performed using the HamiltonStar pipetting robot (Hamilton). The dissociation curves were processed using Bio-Rad CFX Manager. The peak type was set to "negative". The compound codes for screening were specified in the plate layout. The average of two repeated TM measurements was taken, and the standard deviation was calculated. If the standard deviation (SD) was > 1.5°C, the measurement was repeated. The ΔTm value was obtained by subtracting the melting point (Tm) obtained for the STING protein alone from the T value obtained for the protein incubated with the ligand.

[0304] Protein Production and Purification: The protein used in the biophysical experiments was recombinant human STING protein, including its cytosolic extracellular domain. A codon-optimized DNA sequence encoding amino acid residues 155-341 (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 STING gene sequence described above. The protein sequences generated for the STING variants used are listed below: His-TEV-hSTING(WT) MHHHHHHHHENLYFQSGVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDRAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEV

[0305] To express recombinant human STING, the above construct was converted to E. coli BL21 DE3 strain and grown in a vibrating flask in LB- medium at 37°C. 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. Proteins were purified by thawing cells in a lysis buffer (20 mM TRIS-HCl, pH 8, 300 mM NaCl, 2 mM mercaptoethanol, 20 mM imidazole, Complete Protease Inhibitor (Roche), and DNase (Roche)). Subsequently, metal affinity purification was performed using Ni-NTA resin and an elution buffer consisting of 20 mM TRIS-HCl, pH 8, 300 mM NaCl, 2 mM mercaptoethanol, and 300 mM imidazole. Size exclusion chromatography was then performed in a 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. The results of this assay are shown in the table below.

[0306] Human whole blood assay (HWBA) To detect STING inhibition in a physiological environment, human whole blood was stimulated with the cyclic dinucleotide cGAMP. Pathway activity was monitored by measuring IFNα2α production. Assay method: The compounds were delivered as a 10 mM DMSO solution, which was serially diluted and transferred to a 96-well cell culture plate (Corning No. 3595) pre-filled with 20 μl of OptiMEM (Gibco #11058-021) per well using an Echo acoustic dispenser. Typically, eight different concentrations were used, with a maximum concentration of 10 μM in the final assay volume, followed by a dilution step of approximately 1:5. The DMSO concentration was set to 0.1% in the final assay volume. The 96-well assay plate contained nine test compounds, a reference compound, and DMSO in the control wells.

[0307] Human whole blood from three or more healthy donors (male or female, not having received drug therapy for 7 days, but excluding contraceptives and thyroxine) was collected concurrently as sodium-citrate blood (e.g., 3.8% in Monovettes (Sarstedt)). Whole blood was kept at room temperature for up to 3 hours after collection before use in the assay. 160 μl of whole blood sample was transferred to each well of a 96-well assay plate filled with compound / OptiMEM. All assay plates were duplicated using blood from different donors. The blood plates were held at room temperature for 60 minutes, continuously shaken at 450 rpm, and covered with lids but not airtight. Immediately before use at room temperature, the 10×cGAMP assay solution was diluted from 2mM stock solution to 1×HBSS. 20 μl of 10×cGAMP / HBSS was added to all compounds and all high control wells, while HBSS alone was added to all low control wells. After covering the assay plate with AERA seals and a lid, the blood plate was kept at room temperature for 30 minutes, then continuously shaken at 450 rpm, followed by overnight incubation in an incubator at 37°C for 22 hours without shaking.

[0308] To detect IFNα-2α in human plasma, biotinylated capture antibody (Antibody set IFNA2, Meso Scale Diagnostics number B21VH-3, including coating and capture antibody) was diluted 1:17.5 in Diluent 100 (Meso Scale Diagnostics number R50AA-4) according to the manufacturer's instructions. 25 μl of the diluted capture antibody was coated onto U-Plex MSD GOLD 96-well Small Spot Streptavidin SECTOR Plates (Meso Scale Diagnostics number L45SA-5). The coated plates were incubated at room temperature for 60 min under continuous shaking at 700 rpm. The MSD IFNα-2α plates were washed three times with 150 μl of washing buffer (1×HBSS, 0.05% Tween).

[0309] The plates were blocked with 100 μl of block solution / well (1×HBSS and 0.2% Tween, 2% BSA) at room temperature for 60 minutes with continuous shaking at 700 rpm. Immediately before continuing the assay with human plasma, the plates were discarded to allow them to dry as much as possible. The whole blood assay plates were 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 pipetting robotics. The plates were sealed with microplate seals and held at room temperature with continuous shaking at 700 rpm for 2 hours. Next, the MSD IFNα-2α plate was washed three times with 150 μl of washing buffer (1×HBSS, 0.05% Tween), and then 25 μl of MSD sulfo-tag IFNα-2α antibody solution (1:100 dilution in diluent 3 (Meso Scale Diagnostics, no. R50AP-2)) was added to each well of the plate. The plate was then sealed with a microplate seal and kept at room temperature with continuous shaking at 700 rpm for 2 hours. Finally, the MSD IFNα-2α plate was washed three times with 150 μl of washing buffer (1×HBSS, 0.05% Tween). 150 μl of 2× Read buffer was added to each well, and the plate was immediately measured using an MSD Sector S600 Reader with the vendor barcode.

[0310] Data Evaluation and Calculation: For data evaluation and calculation, the % control for each well was calculated using the following formula, based on the mean values ​​of the high control (cGAMP-stimulated control) and the low control (unstimulated control): [Count (sample) - Count (low control)) / (Count (high control) - Count (low control))] * 100 The IC50 value was calculated using a standard four-parameter logistic regression equation. Calculation: [y=(ad) / (1+(x / c)^b)+d], where a=low value, d=high value; x=concentration M; c=IC50 M; b=slope; The results of this assay are shown in the table below.

[0311] Human STING reporter gene assay THP1-BlueISG reporter cell lines expressing wild-type STING and an IRF-dependent alkaline phosphatase reporter were used to measure the efficacy of human wild-type STING activators.

[0312] Assay method: Compounds were delivered in 10 mM DMSO solution and sequentially diluted in assay media (RPMI 1640 (Life Technologies, No. A10491-01), 10% FCS (Life Technologies, No. 10500-064), and 1× Pen / Strep solution (Life Technologies, No. 15140-122). Typically, the highest concentration in the final assay volume was 10 or 100 μM, followed by eight different concentrations in 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 1-21), a reference compound (column 22), and DMSO in columns 23 and 24;

[0313] Manufacturer's conditions (Culture medium: RPMI1640 (Life Technologies, No. A10491-01), 10% FCS (Life Technologies, No. 10500-064), 1× Pen / Strep solution (Life Technologies, No. 15140-122), 100 μg / mL Normocin (Life Technologies, No. ant-nr-1), 100 μg / mL Zeocin (Life Cells cultured according to Technologies (No. R25001) were collected, resuspended, and diluted in fresh assay medium. The cells were then seeded in 15 μl of assay medium into assay plates (10,000 cells / well), followed by the addition of 5 μl of pre-diluted compound solution to the wells of the assay plate. Subsequently, 5 μl of assay medium per well was added to the compound-containing wells, followed by incubation at RT for 30 min and incubation at 37°C for 24 h. Next, as controls, 5 μl of assay medium containing DMSO (1% fc) was added to each well. In addition, 5 μl of assay medium alone was added to the negative control (low value), or 5 μl of pre-diluted 2'3'-cGAMP (20 μM f.c.; BIOLOG Life Science Institute, No. C 161 or Invivogen, No. tlrl-nacga23) was added to the positive control (high value).

[0314] Finally, 75 μl of Quanti Blue reagent was added to the plate using a MultiDrop Combi, followed by incubation at 37°C for 30 minutes. Absorbance was measured using an EnVision® reader (PerkinElmer).

[0315] Data Evaluation and Calculation: For data evaluation and calculation, the low control measurements were set as the 100% control, and the high control measurements were set as the 200% control. The EC50 value was calculated using a standard four-parameter logistic regression equation. Calculation: [y=(ad) / (1+(x / c)^b)+d], a=low value, d=high value; x=concentration M; c=IC50 M; b=slope;

[0316] The results of this assay were negative for agonism. The threshold was set higher than 30 μM in this case.

[0317] Characterization data [Table 45] TIFF2026510538000389.tif218146 TIFF2026510538000390.tif177143

[0318] Indications Compounds of formula (I) or formula (I') have been found to be characterized by these ranges of application in the therapeutic field.

[0319] It should be noted that the compounds of the present invention are intended to be used as STING inhibitors based on their pharmaceutically active properties. While the cGAS / STING pathway is important for host defense against invading pathogens, such as viral infections and the invasion of certain intracellular bacteria, cellular stress and genetic factors can also trigger autoinflammatory responses, for example, by causing the production of abnormal cellular dsDNA through leakage from the nucleus or mitochondria. Therefore, STING inhibitors have strong therapeutic potential for use in the treatment of a variety of autoinflammatory and autoimmune diseases.

[0320] STING inhibitors block inflammation and abnormal tissue remodeling in a cluster of autoimmune and inflammatory diseases, including systemic lupus erythematosus (SLE), systemic sclerosis, inflammatory bowel disease, sepsis, Sjögren's syndrome, dermatomyositis, and rheumatoid arthritis, as well as in a cluster of fibrotic diseases, including NASH, IPF, and chronic renal fibrosis. STING inhibitors also have indications for additional diseases, such as cancer, heart failure, AMD, retinopathy, glaucoma, diabetes, obesity, aging, muscle disorders, osteoarthritis, ALS, Parkinson's disease, and COVID-19. An et al., Arthritis Rheumatol. 2017 Apr;69(4):800-807, disclosed that cGAS expression in peripheral blood mononuclear cells (PBMCs) was significantly higher in patients with the autoimmune disease systemic lupus erythematosus (SLE) than in normal controls. Targeted measurement of cGAMP by tandem mass spectrometry detected cGAMP in 15% of the SLE patients tested, but not in either normal controls or rheumatoid arthritis controls. In the comparison between cGAMP-present and cGAMP-absent groups, disease activity was higher in SLE patients with cGAMP.

[0321] • Thim-Uam et al (iScience. 2020 Sep 4;23(9):101530) demonstrated that STING deficiency improved lupus development in Fcgr2b-deficient mice. Prabakaran et al (EBioMedicine. 2021 Apr;66:103314) showed that the STING pathway inhibitor ISD017 blocks STING activity in vivo and improves disease development in a mouse model of lupus. ISD017 treatment also blocks the pathological cytokine response in PBMCs from lupus patients with elevated IFN-I levels. Ryu et al. (Arthritis Rheumatol. 2020 Nov;72(11):1905-1915) showed that in two cohorts of interstitial lung disease associated with systemic sclerosis (SSc-ILD), plasma mtDNA concentration increased, reflecting impaired ventilatory function, and was positively associated with activation of both TLR-9 and cGAS / STING, as well as type I IFN and IL-6 expression. Liu et al. (Rheumatology (Oxford) 2022 Jun 10;keac324.) showed that DNA leakage, STING expression, and vascular inflammation were increased in the skin of SSc patients, and that fibrosis and vascular damage were improved in vitro and in BLM-induced SSc mice by STING deficiency or H151 administration.

[0322] Li et al. have shown that extracellular vesicles containing plasma-derived DNA induce a STING-mediated pro-inflammatory response in dermatomyositis (Theranostics. 2021; 11(15): 7144-7158). Zhou et al. (J Clin Lab Anal. 2022 Oct; 36(10): e24631) describe the correlation between activation of the cGAS-STING pathway and myofibrils atrophy / necrosis in dermatomyositis. Haag et al. (Nature. 2018 Jul;559(7713):269-273) demonstrated that a covalent STING inhibitor attenuated the pathological features of autoinflammatory diseases in TREX1_KO mice. Loss-of-function mutations in TREX1 result in rare monogenic interferon disorders such as Eicardi-Goutierre syndrome (AGS).

[0323] Hu et al. (EBioMedicine. 2019 Mar;41:497-508) showed that STING expression was elevated in peripheral blood mononuclear cells and intestinal biopsies compared to healthy controls in human abdominal sepsis. STING knockout mice mitigated and reduced inflammatory responses, intestinal permeability, and bacterial metastasis in sepsis models. Zeng et al. (ci Transl Med. 2017 Oct 18;9(412):eaan5689) also showed that STING deficiency in mice protected against two sepsis models (LPS model and cecal ligation and puncture model), and that the degree of STING expression in the human intestinal lamina propria correlated with intestinal inflammation in sepsis patients. Inhibition of the ALK-STING pathway protects mice from CLP-induced multimicrobial sepsis.

[0324] In Schuliga et al., Clin. Sci. (Lond). 2020 Apr 17;134(7):889-905, it was reported that autologous DNA sustains fibroblast senescence in IPF lung in a cGAS-dependent manner. Benmerzoug et al. (Nat. Commun. 9, 1-19 (2018)) have shown that STING-dependent sensing of autologous DNA promotes silica-induced pneumonia, which may lead to pulmonary fibrosis. Additional scientific clues linking the cGAS / STING pathway to the causes of metabolic diseases such as non-alcoholic fatty liver disease (NAFLD) and other fibrotic diseases such as non-alcoholic steatohepatitis (NASH) are described in Yu et al., J. Clin. Invest. 2019 Feb 1;129(2):546-555, 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.

[0325] Nascimento et al., Sci. Rep. 2019 Oct 16;9(1):14848, disclosed that the release of autoDNA and STING-dependent sensing promote smoking-induced inflammation in mice, suggesting a link between the cGAS-STING pathway and chronic obstructive pulmonary disease (COPD). Ahn et al. (Cell Rep 2017 21:3873-3884) described the protection of STING-deficient mice in an inflammatory bowel disease model. Martin et al. (Sci Rep 2019 Oct 3; 9:14281) described that in a dextran sulfate sodium (DSS) model of colitis, STING deficiency protected against intestinal inflammation, while STING stimulation exacerbated intestinal inflammation. These publications support STING as a promising therapeutic target for the prevention of inflammatory bowel disease (IBD).

[0326] Kerur et al., Nat. Med. 2018 Jan;24(1):50-61, describe that cGAS plays an important role in atypical inflammasome activation in age-related macular degeneration (AMD). Furthermore, STING inhibitors also have therapeutic potential in cancer treatment (see Hoong et al., Oncotarget. 2020 Jul 28;11(30):2930-2955, and Chen et al., Sci. Adv. 2020 Oct 14;6(42):eabb8941). This is also shown in Bakhoum et el., Nature. 2018 Jan 25;553(7689):467-472: “Chromosomal instability drives metastasis through a cytosolic DNA response”, and Liu et al., Nature. 2018 Nov;563(7729):131-136: “Nuclear cGAS suppresses DNA repair and promotes tumorigenesis”.

[0327] STING inhibitors also have potential in the treatment of obesity and diabetes, as shown in Mao et al., Arterioscler Thromb Vasc Biol (2017) 37(5):920-9. doi: 10.1161 / ATVBAHA.117.309017. In addition, STING inhibitors also have potential as a treatment for 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). Further scientific clues suggest that correlations exist 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).

[0328] Furthermore, STING inhibitors also have potential therapeutic applications 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”. In addition, STING inhibitors have potential therapeutic applications in the treatment of renal inflammation and renal fibrosis, as shown in Chung et al., Cell Metab. 2019 30:784-799: “Mitochondrial Damage and Activation of the STING Pathway Lead to Renal Inflammation and Fibrosis” and Maekawa et al., Cell Rep. 2019 29:1261-1273: “Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury”. Furthermore, STING has been shown to promote aging, apoptosis, and extracellular matrix degradation in osteoarthritis (Guo et al, Cell Death Dis. 2021 Jan 4;12(1):13. doi: 10.1038). Mice with cGAS / STING deactivated exhibit reduced tissue inflammation, improved cardiac / muscular function, and extended lifespan (Dou et al, Nature. 2017 550: 402-406). In addition, in humans, variability in the STING gene is associated with healthy aging, most likely due to a reduction in inflammatory aging (Hamann et al, Gerontology 2019;65:145-154). Taken together, STING inhibitors reduce aging-related inflammation and the accumulation of senescent cells, leading to improvements in age-related diseases such as aging / muscular disorders and osteoarthritis.

[0329] Combined use The compound of Formula 1 can be administered to a patient alone or in combination with one or more other pharmacologically active agents. In preferred embodiments of the present invention, the compound is a PDE4 inhibitor (preferably 1-[[(5R)-2-[4-(5-chloropyrimidine-2-yl)-1-piperidyl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl]amino]cyclobutyl]methanol and [1-[[(5R)-2-[4-(5-chlorophenyl-2-yl)-1-piperidyl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl]amino]cyclobutyl]methanol as disclosed in WO2013 / 026797), an anti-inflammatory agent, an antifibrotic agent, an antiallergic agent / antihistamine, a bronchial agent It can be used in combination with one or more pharmacologically active agents selected from the group of stimulants, beta-2 agonists / beta mimetic drugs, adrenaline agonists, anticholinergics, methotrexate, mycophenolate mofetil, leukotriene modulators, JAK inhibitors, anti-interleukin antibodies, nonspecific immunotherapies such as interferon 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.

[0330] formulation The compounds of the present invention can be administered by any suitable route of administration, including both systemic and topical administration. Systemic administration includes oral, parenteral, transdermal, rectal, and inhalation administration. Parenteral administration refers to routes of administration other than enteral, transdermal, or inhalation, usually by injection or infusion. Parenteral administration includes intravenous, intramuscular, intrasternal, and subcutaneous injection or infusion. Inhalation refers to administration to the patient's lungs, whether through the mouth or nasal passages. Topical administration includes application to the skin. The compounds of the present invention may also be administered via eye drops for the treatment of Sjögren's syndrome.

[0331] Suitable forms for administration include, for example, tablets, capsules, liquids, syrups, emulsions, or inhalation powders or aerosols. In all cases, the content of the pharmaceutically active compound should be in the range of 0.1 to 90% by mass, preferably 0.5 to 50% by mass, of the total composition, i.e., an amount sufficient to achieve the dosage range specified below herein. The preparation may be administered orally in the form of tablets, powders, powders in capsules (e.g., hard gelatin capsules), solutions, or suspensions. When administered by inhalation, the combination of active substances may be provided as a powder, as an aqueous solution or an aqueous ethanol solution, or using a propellant gas preparation. Therefore, preferably, the pharmaceutical formulation is characterized by the content of one or more compounds of formula (I) or formula (I') according to the preferred embodiments described above.

[0332] When the compound of formula (I) or formula (I') is administered orally, this is particularly preferred, and when it is administered once or twice daily, this is also particularly preferred. Suitable tablets can be obtained, for example, by mixing the active substance with known excipients, such as 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, or polyvinyl acetate. The tablets may also contain several layers. Coated tablets can be prepared as appropriate by coating a core, similar to that of a tablet, with a substance commonly used for tablet coatings, such as kollidone or shellac, gum arabic, talc, titanium dioxide, or sugar. To achieve delayed release or to prevent incompatibility, the core may also consist of several layers. Similarly, the tablet coating may consist of several layers to achieve delayed release, possibly using the excipients described above for the tablet.

[0333] The syrup containing the active substance or combination thereof according to the present invention may further contain a sweetener, such as saccharin, cyclamate, glycerol, or sugar, and a flavor enhancer, such as a flavoring agent, such as vanillin or orange extract. These may also contain a suspended adjuvant or thickener, such as sodium carboxymethylcellulose, a humectant, such as a condensate of an aliphatic alcohol and ethylene oxide, or a preservative, such as p-hydroxybenzoate. Capsules containing one or more active substances or combinations of active substances can be prepared, for example, by mixing the active substance with an inert carrier, such as lactose or sorbitol, and filling these into gelatin capsules. Suitable suppositories can be prepared, for example, by mixing with a carrier provided for this purpose, such as a neutral fat or polyethylene glycol or a derivative thereof.

[0334] Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffin (e.g., petroleum fraction), vegetable oils (e.g., peanut 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 inorganic powders (e.g., highly dispersed silicic acid and silicates), sugars (e.g., sucrose, lactose, and glucose), emulsifiers (e.g., lignin, sulfite pulp wastewater, methylcellulose, starch, and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).

[0335] For oral administration, tablets can, of course, contain additives other than the carrier mentioned above, such as sodium citrate, calcium carbonate, and dicalcium phosphate, along with various other additives, such as starch, preferably potato starch, gelatin, etc. Furthermore, lubricants, such as magnesium stearate, sodium lauryl sulfate, and talc, can be used simultaneously in the tableting process. In the case of aqueous suspensions, the active substance can be combined with various flavor enhancers or colorants in addition to the excipients mentioned above.

Claims

1. The compound of formula 1. 【Chemistry 1】 [In the formula, B-A is equal to C-N- or -N-C=, R1 is, 【Chemistry 2】 Selected from, R1 is the connection point to the structure of Equation 1, R2 is C when B-A is -N-C = 1-6 -Alkyl-, C 3-6 -Cycloalkyl-, C 1-6 It has the meaning of -haloalkyl-, When B−A is =C−N−, R2 is C 1-6 -alkyl-, C 3-6 -cycloalkyl-, C 1-6 -haloalkyl-, C 1-6 -alkyl-O-, HO-, H 2 N-, C 1-6 -alkyl-HN-, (C 1-6 -alkyl) 2 and has the meaning of N− R3 is H- or C 1-6 - Alkyl, C 3-7 - Cycloalkyl, C 2-6 - Alkenil, C 3-7 - These are heterocycloalkyl groups, F-, HO-, Me-, EtO-, and NH, respectively. 2 (O) It may be substituted with a group selected from C-, R4 is H-, F-, or HO-. R4 b These are H-, F-, Cl-, Br-, NC-, or HO-. R5 is, 【Transformation 3】 Selected from, R5 is the connection point to the structure of Equation 1, Q is -C(R11)(R12)-, -S(O)-, or -S(O) 2 - and R6 is C 2-6 - It is Alkenil, or C 1-6 - Alkyl, and independently of each other, C 3-6 -Cycloalkyl-, halogen, HO-, C 1-6 -Alkyl-O-, C 1-6 -Alkyl-HN-, (C 1-6 -Alkyl) 2 N-, NC-, (C 1-6 -Alkyl) 2 It may be substituted with one or two substituents selected from the group consisting of (O)P- and (4-methoxyphenyl)methyl-. or A heterocycle selected from tetrahydrofuran-, 1,4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, and triazole-, each independently of the others, C 1-6 It may be substituted with one or two substituents selected from the group consisting of -alkyl-, halogen, and O=. R7, R8, R9 are C 3-6 -Cycloalkyl-, C 1-6 It may be substituted with an alkyl group or 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) 2 N-, C 1-6 It is -alkyl-S-, or C 1-6 - Alkyl, linear or branched, HO-, C 1-6 -Alkyl-O-, C 1-6 -Alkyl-HN-, (C 1-6 -Alkyl) 2 It may be substituted with N- or morpholine-, Or A heterocycle selected from pyrrolidine-, tetrahydrofuran-, and tetrahydropyran-. Or C 1-6 It is -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 consists of carbocyclyl, heterocyclyl, aryl, and heteroaryl, respectively, C 1-6 - Alkyl, C 1-6 -Haloalkyl, HO-, NC-, halogen, R15-(CH 2 ) n -O-, R15-(CH 2 ) n -NH-, (R15-(CH 2 ) n ) 2 -N-, R15-(CH 2 ) n -S(O)-, R15-(CH 2 ) n -S(O) 2 - may be substituted with one or two substituents selected from the group consisting of R14 is C 1-6 - Haloalkyl, or C 1-6 - Alkyl, C 3-6 - Cycloalkyl, C 2-6 -Alkenyl-, HO-, C 1-6 -Alkyl-O-,H 2 N-C(O)-, C 1-6 -Alkyl-HN-C(O)-, (C 1-6 -Alkyl) 2 It may also be substituted with N-C(O)-, R15 is C 1-4 - Alkyl, C 1-6 -Haloalkyl, NC-, C 1-6 -Alkyl-HN-, (C 1-6 -Alkyl) 2 N-, (C 1-6 -Alkyl) 2 (HO)C-, aryl or heterocyclyl, n is 0, 1, 2, or 3.

2. R1 is 【Chemistry 4】 A compound according to claim 1, selected from the following.

3. R3 is H- or C 1-6 - Alkyl, C 3-7 - Cycloalkyl, C 2-5 - Alkenil, C 3-7 - These are heterocycloalkyl groups, F-, HO-, Me-, EtO-, and NH, respectively. 2 (O) It may be substituted with a group selected from C- R4 is H-, F-, or HO-. R4 b However, it is H- or F-, Cl-, Br-, NC-, HO-, R5, 【Transformation 5】 Selected from, R5 is the connection point to the structure of Equation 1, Q is -C(R11)(R12)-, -S(O)-, or -S(O) 2 - and R6 is C 2-4 - It is Alkenil, or C 1-4 -alkyl, independently of one another, C 3-4 -cycloalkyl-, halogen, HO-, C 1-4 -alkyl-O-, C 1-4 -alkyl-HN-(C 1-4 -alkyl) 2 N-, NC-, (C 1-4 -alkyl) 2 (O)P-, (4-methoxyphenyl)methyl- and may be substituted with one or two substituents selected from the group consisting of or A heterocycle selected from tetrahydrofuran-, 1,4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, and triazole-, each independently of the others, C 1-4 It may be substituted with one or two substituents selected from the group consisting of -alkyl-, halogen, and O=. R7, R8, R9 are C 3-4 -Cycloalkyl-, C 1-4 It may be substituted with an alkyl group or 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) 2 N-, C 1-4 -alkyl-S- and or C 1-4 - Alkyl, linear or branched, HO-, C 1-4 -Alkyl-O-, C 1-4 -Alkyl-HN-, (C 1-4 -Alkyl) 2 It may be substituted with N- or morpholine-, Or A heterocycle selected from pyrrolidine-, tetrahydrofuran-, and tetrahydropyran-, Or C 1-4 It is -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 consists of carbocyclyl, heterocyclyl, aryl, and heteroaryl, respectively, C 1-4 - Alkyl, C 1-4 -Haloalkyl, HO-, NC-, halogen, R15-(CH 2 ) n -O-, R15-(CH 2 ) n -NH-, (R15-(CH 2 ) n ) 2 -N-, R15-(CH 2 ) n -S(O)-, R15-(CH 2 ) n -S(O) 2 - may be substituted with one or two substituents selected from the group consisting of R14 is C 1-4 -Haloalkyl- or C 1-5 - Alkyl, C 3-4 - Cycloalkyl, C 2-4 -Alkenyl-, HO-, C 1-4 -Alkyl-O-,H 2 N-C(O)-, C 1-4 -Alkyl-HN-C(O)-, (C 1-4 -Alkyl) 2 It may also be substituted with N-C(O)-, R15 is C 1-4 - Alkyl, C 1-4 -Haloalkyl, NC-, C 1-6 -Alkyl-HN-, (C 1-4 -Alkyl) 2 N-, (C 1-4 -Alkyl) 2 (HO)C-, aryl or heterocyclyl, The compound according to claim 1 or 2, wherein n is 0, 1, 2, or 3.

4. R2 is C 1-4 -Alkyl-, R3 is C 1-4 It is an alkyl group and may be substituted with HO-. or C 3-4 It is a cycloalkyl group and may be substituted with a methyl group. R4 is H- or F-, R5, 【Transformation 6】 Selected from, R5 is the connection point to the structure of Equation 1, R6 is C 2-4 - It is Alkenil, or C 1-4 - Alkyl, and independently of each other, C 3-4 -Cycloalkyl-, halogen, HO-, C 1-4 -Alkyl-O-, (C 1-4 -Alkyl) 2 N-, NC-, (C 1-4 -Alkyl) 2 It may be substituted with one or two substituents selected from the group consisting of (O)P- and (4-methoxyphenyl)methyl-. or A heterocycle selected from tetrahydrofuran-, 1,4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, and triazole-, each independently of the others, C 1-4 It may be substituted with one or two substituents selected from the group consisting of -alkyl-, halogen, and O=. R7 is C 3-4 -Cycloalkyl-, C 1-4 It may be substituted with an alkyl group or 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) 2 N-, C 1-4 It is -alkyl-S-, or C 1-4 - Alkyl, linear or branched, HO-, C 1-4 -Alkyl-O-, C 1-4 -Alkyl-HN-, (C 1-4 -Alkyl) 2 It may be substituted with N- or morpholine-, or A heterocycle selected from pyrrolidine-, tetrahydrofuran-, and tetrahydropyran-, R8 is C 1-4 It is -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-pyridinyl-, or phenyl-, and at position 4, methyl, HO-, F-, Cl-, Br-, R15-(CH 2 ) n It may also be substituted with -O-, R14 is C 1-4 -Haloalkyl- or C 1-5 - Alkyl, C 3-4 - Cycloalkyl, C 2-4 -Alkenyl-, HO-, C 1-4 -Alkyl-O-,H 2 NC(O)-, (C 1-4 -Alkyl)NH-C(O)-,(C 1-4 -Alkyl) 2 It may also be substituted with N-C(O)-, R15 is NC-, (C 1-4 -Alkyl) 2 N-, (C 1-4 -Alkyl) 2 (HO)C-, phenyl, or a heterocycle selected from oxetane-, tetrahydropyran-, and morpholine-, The compound according to claim 1 to 3, wherein n is 0, 1, or 2.

5. R2 is methyl- or ethyl-, R3 is ethyl-, iso-propyl-, cyclopropyl-, 1-methyl-cyclopropyl-, 1-hydroxy-iso-propyl-, R4 is H- or F-, R5, 【Transformation 7】 Selected from, R5 is the connection point to the structure of Equation 1, R6 is C 2-4 - It is Alkenil, or C 1-4 - Alkyl, and independently of each other, cyclopropyl-, F-, HO-, H 3 C-O-, (H 3 C) 2 N-, NC-, (H 3 C) 2 It may be substituted with one or two substituents selected from the group consisting of (O)P- and (4-methoxyphenyl)methyl-. or A heterocycle selected from tetrahydrofuran-, 1,4-dioxane-, pyrrolidine-, piperazine-, morpholine-, pyridine-, pyrazole-, and triazole-, each independently of the others, 3 It may be substituted with one or two substituents selected from the group consisting of C-, F-, and O=. R7 is cyclopropyl-, 1-fluorocyclopropyl-, 2,2-difluorocyclopropyl-, 1-methyl-cyclopropyl-, cyclobutanyl-, cyclopropylmethyl-, F 2 HC-, F 3 C-, (iPr)-O-, (H 3 C) NH-, (H 3 C) 2 N-, H 3 It is C-S-, or C 1-4 - Alkyl, linear or branched, HO-, H 3 C-O-, H 3 C-CH 2 -O-, (H 3 C) NH-, (H 3 C) 2 It may be substituted with N- or morpholine-, or A heterocycle selected from pyrrolidine-, tetrahydrofuran-, and tetrahydropyran-, R8 is F 2 HC-O-, F 3 It is C-O-, R9 is methyl or cyclopropyl, R10 is methyl or F 2 It is C-, R11 is H, HO-, F-, or R14-O-. R12 is H- or F, R13 is cyclohexyl-, 3,4-difluorophenyl-, 3-methyl-4N-pyridinyl-, or phenyl-, and at position 4, methyl, HO-, F-, Cl-, Br-, R15-(CH 2 ) n It may also be substituted with -O-, R14 is FH 2 C-, FH 2 C-CH 2 -, or C 1-5 - Alkyl, cyclopropyl, H 2 C=CH-, HO-, H 3 C-O-, H 2 NC(O)-, (H 3 C) may be substituted with NH-C(O)-, R15 is NC-, (H 3 C) 2 N-, (H 3 C) 2 (HO)C-, phenyl, or a heterocycle selected from oxetane-, tetrahydropyran-, and morpholine-, The compound according to claim 1 to 4, wherein n is 0, 1, or 2.

6. B-A is equal to C-N- or -N-C=, R1 is 【Transformation 8】 Selected from, R1 is the connection point to the structure of Equation 1, R2 is methyl-, R3 is ethyl-, iso-propyl-, cyclopropyl-, 1-methyl-cyclopropyl-, 1-hydroxy-iso-propyl-, R4 is H- or F-, R5, 【Chemistry 9】 Selected from, R5 is the connection point to the structure of Equation 1, R6 is methyl-, ethyl-, iso-propyl-, cyclopropyl-, R7 is cyclopropyl-, 1-fluorocyclopropyl-, 2,2-difluorocyclopropyl-, 1-methyl-cyclopropyl-, cyclobutanyl-, cyclopropylmethyl-, F 2 HC-, F 3 C-, (iPr)-O-, (H 3 C) NH-, (H 3 C) 2 N-, H 3 It is C-S-, or C 1-4 - Alkyl, linear or branched, HO-, H 3 C-O-, H 3 C-CH 2 -O-, (H 3 C) NH-, (H 3 C) 2 It may be substituted with N- or morpholine-, or A heterocycle selected from pyrrolidine-, tetrahydrofuran-, and tetrahydropyran-, R11 is H, HO-, F-, or R14-O-. R12 is H-, R13 is cyclohexyl-, 3,4-difluorophenyl-, 3-methyl-4N-pyridinyl-, or phenyl-, and at position 4, methyl, HO-, F-, Cl-, Br-, R15-(CH 2 ) n It may also be substituted with -O-, R14 is FH 2 C-, FH 2 C-CH 2 -, or C 1-5 - Alkyl, cyclopropyl, H 2 C=CH-, HO-, H 3 C-O-, H 2 NC(O)-, (H 3 C) may be substituted with NH-C(O)-, R15 is NC-, (H 3 C) 2 N-, (H 3 C) 2 (HO)C-, phenyl, or a heterocycle selected from oxetane-, tetrahydropyran-, and morpholine-, The compound according to claim 1 to 5, wherein n is 0, 1, or 2.

7. B-A is equal to C-N- or -N-C=, R1 is 【Chemistry 10-1】 【Chemistry 10-2】 【Chemistry 10-3】 [Chemistry 10-4] 【Transformation 10-5】 【Chemistry 10-6】 Selected from, R1 is the connection point to the structure of Equation 1, R2 is methyl- or ethyl-, R3 is ethyl-, iso-propyl-, cyclopropyl-, 1-methyl-cyclopropyl-, ((HO)H 2 C) (H 3 C) HC-, R4 is H- or F-, R5, 【Chemistry 11-1】 【Chemistry 11-2】 A compound according to claim 1 to 6, wherein R5 is a bonding site to the structure of formula 1, selected from the above.

8. The compound according to claim 1 to 7, wherein the compound of formula 1 is the compound of formula 1a. 【Chemistry 12】

9. The compound according to claim 1 to 7, wherein the compound of formula 1 is the compound of formula 1b. 【Chemistry 13】

10. The compound according to claim 1 to 7, wherein the compound of formula 1 is the compound of formula 1c. 【Chemistry 14】

11. A compound according to claim 1 to 7, selected from the following examples. 【Chemistry 15-1】 【Chemistry 15-2】 【Chemistry 15-3】 【Chemistry 15-4】 【Chemistry 15-5】 【Chemistry 15-6】 【Chemistry 15-7】

12. A salt of the compound of formula 1 according to any one of claims 1 to 11.

13. A pharmaceutically acceptable salt of the 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 diseases treatable by inhibition of STING.

15. Systemic lupus erythematosus (SLE), (monogeneic and bigeneic) interferon disorders (including STING-associated vascular disorders (SAVI) that develop in infancy, Eicardi-Goutier syndrome (AGS), COPA syndrome, and familial chilblain lupus), type 1 interferon disorders with mutations in DNASE2 or ATAD3A genes, age-related macular degeneration (AMD), retinopathy, glaucoma, amyotrophic lateral sclerosis (ALS), diabetes mellitus, obesity, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD) Compounds of formula 1, 1a, 1b, or 1c according to any one of claims 1 to 13, for use in the treatment of diseases selected from the group consisting of Bloom 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 exacerbation of chronic liver failure (ACLF), interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), age-related / muscle disorders, 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 fibrous diseases selected from the group consisting of systemic sclerosis (SSc), non-alcoholic steatohepatitis (NASH), acute exacerbation of chronic liver failure (ACLF), (monogeneic and bigeneic) interferon disorders (including STING-associated vascular disorders (SAVI) that develop in infancy, Eicardi-Goutier syndrome (AGS), COPA syndrome, and familial chilblain lupus), type 1 interferon disorders with mutations in the DNASE2 or ATAD3A gene, 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 the treatment of a disease selected from the group consisting of age-related macular degeneration (AMD), retinopathy, glaucoma, aging, muscle disorders, heart failure, COVID-19 / SARS-CoV-2 infection, renal inflammation, renal fibrosis, metabolic disorders, vascular diseases, cardiovascular diseases, diabetes, obesity, and cancer.

18. A pharmaceutical composition comprising a compound of formula 1, 1a, 1b, or 1c as described in 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 as described in 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, antifibrotic agents, antiallergic agents / antihistamines, bronchodilators, beta-2 agonists / beta mimetic agents, adrenaline agonists, anticholinergic agents, methotrexate, mycophenolate mofetil, leukotriene modulators, JAK inhibitors, anti-interleukin antibodies, nonspecific immunotherapies such as interferon or other cytokines / chemokines, cytokine / chemokine receptor modulators, Toll-like receptor agonists, immune checkpoint modifiers, anti-TNF antibodies, and anti-BAFF antibodies.

Images