Imidazo[4,5-c]pyridine compounds for cancer treatment

Abstract

The present invention relates to formula (I): TIFF2026518208000223.tif49170 (in the formula, R 1 ~R 4 The present invention relates to compounds (A and L as described herein) and pharmaceutically acceptable salts thereof, compositions containing such compounds, and methods of using such compounds.

Description

[Technical Field]

[0001] This invention relates to organic compounds useful for therapy and / or prevention in mammals, particularly to the agonisms of TLR7 and TLR8 useful for the treatment of cancer.

[0002] Field of Invention The present invention relates to novel imidazo[4,5-c]pyridine compounds having Toll-like receptor agonist activity and their derivatives, as well as the manufacture thereof, pharmaceutical compositions containing them, and their potential use as pharmaceuticals for the treatment and / or prevention of cancer. [Background technology]

[0003] Toll-like receptors (TLRs) are a family of transmembrane proteins that recognize pathogen-derived, pathogen-specific, and structurally conserved molecules known as pathogen-associated molecular patterns (PAMPS). They play a crucial role in sensing invading pathogens and subsequently initiating the innate immune response. In humans, there are 10 known members of the TLR family, which are type I transmembrane proteins characterized by an extracellular leucine-rich domain and a cytoplasmic tail containing a conserved Toll / interleukin (IL)-1 receptor (TIR) ​​domain. Within this family, TLR3, TLR7, TLR8, and TLR9 are located within endosomes. In the activated dimeric receptor configuration, TLR7 and TLR8 recognize single-stranded RNA at one ligand-binding site and ribonucleoside degradation products guanosine and uridine (as well as small molecule ligands with related structural motifs) at the second ligand-binding site, respectively (Zhang et al 2016 Immunity 45(4);737-748;Tanji et al 2015 Nat Struct Mol Biol 22:109-115).

[0004] As part of the innate immune system, myeloid cells can respond to infection and abnormal cellular behavior. Myeloid cells are the first to detect pathogens / abnormal cells and eliminate them through various mechanisms such as inflammatory cytokine secretion and phagocytosis. Another crucial function of myeloid cells is the sustained activation of T cells by providing costimulatory signals and antigen presentation to T cells, paving the way for long-lasting immune responses. On the other hand, they also play a vital role in tissue repair and homeostasis by suppressing uncontrolled immune activation. Tumors exploit this property of these cells by recruiting them, where they create a suppressive microenvironment, thereby inhibiting T cells through direct and indirect mechanisms. Tumor-associated myeloid cells can be activated even in a suppressive tumor microenvironment, for example, by delivering the correct signal to TLR agonists. Once activated, they can produce inflammatory cytokines, upregulate activation markers, and thus induce an anti-tumor immune response, ideally leading to a long-lasting adaptive response.

[0005] TLR7 is primarily expressed in plasmacytoid dendritic cells and B cells, and TLR7 agonism leads to the induction of interferon α / β, which plays an essential role in regulating adaptive immune responses (Bao and Liu 2013 Protein Cell 4:40-5). TLR8 is expressed in myeloid dendritic cells, monocytes, macrophages, and neutrophils. Activation of TLR8 induces a pronounced pro-inflammatory cytokine profile characterized by increased production of tumor necrosis factor-α, interleukin-12, and IL-18 (Eigenbrod et al J Immunol, 2015, 195, 1092-1099). Since most antigen-presenting cell types express only one of these two receptors, small molecules with potent agonist activity against both TLR7 and TLR8 receptors are potentially more effective immunoadjuvants than TLR7 agonists alone. Therefore, TLR7 / TLR8 (TLR7 / 8) small molecule agonists with dual bioactivity can offer even greater benefits than more selective TLR7 agonists, eliciting innate immune responses in a wider range of antigen-presenting cells and other important immune cell types, and stimulating effective antitumor responses in cancer.

[0006] In fact, several identified TLR7 / 8 agonists are being investigated for therapeutic purposes. The TLR7 / 8 dual agonist Resiquimod (R-848) is an immunomodulatory topical gel for the treatment of stage cutaneous T-cell lymphoma in Phase II clinical trials at Galderma. BDB-001 is a TLR7 / 8 dual agonist for intravenous treatment of refractory advanced or metastatic solid tumors in anti-PD-1 / anti-PD-L1 therapy in Phase II clinical trials at Seven and Eight Biopharmaceuticals. Despite the success of imiquimod (Aldera) in the treatment of surface basal cell carcinoma, there remains a high unmet clinical need for balanced, potent TLR7 / 8 agonists to expand patient treatment options for a variety of cancers, as well as more potent TLR7 agonists. [Overview of the Initiative]

[0007] Summary of the Invention The present invention relates to a compound of formula (I): TIFF2026518208000002.tif49170(wherein R 1 is H, C 1~6 alkyl or hydroxy C 1~6 alkyl, R 2 is C 1~6 alkyl or C 1~6 alkoxy C 1~6 alkyl, R 3 is C 1~6 alkyl, R 4 is (C 1~6 alkyl)2amino C 1~6 alkyl-substituted 1H-indazolyl, (C 1~6 alkyl)2amino C 1~6 alkyl-substituted 1H-indolyl, C 1~6 alkyl and hydroxy-disubstituted 1H-isoquinolinyl, (C 1~6 alkyl)2amino C 1~6 alkyl, (C 1~6 alkylpiperazinyl)C 1~6 alkyl, amino, C 1~6 alkoxy, C 1~6 alkyl, hydroxy and pyrrolidinyl C 1~6 alkyl, phenyl mono-, di- or trisubstituted by substituents independently selected therefrom, or (C 1~6 alkyl)2amino C 1~6 alkylamino-substituted pyridyl, A is S or Se, L is a bond or C 1~6 alkylene), a novel compound, or a pharmaceutically acceptable salt thereof.

Mode for Carrying Out the Invention

[0008] Detailed description of the invention definition "C 1~6 The term "alkyl" refers to saturated linear or branched alkyl groups containing 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. 1-6 The alkyl groups are methyl, ethyl, and n-propyl.

[0009] "C 1~6 The term "alkylene" refers to a linear or branched saturated divalent hydrocarbon group consisting of 1 to 6 carbon atoms, or a branched saturated divalent hydrocarbon group consisting of 3 to 6 carbon atoms. 1~6 Examples of alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, and hexylene.

[0010] "C 1-6 The term "alkoxy" is C 1-6 Represents alkyl-O-.

[0011] The terms "halogen" and "halo" are used interchangeably herein and mean fluoro, chloro, bromo, or iodine.

[0012] The term "pharmaceutically acceptable salt" refers to a salt that is not biologically or otherwise undesirable. pharmaceutically acceptable salts include both acid addition salts and base addition salts.

[0013] The term "pharmaceutically acceptable acid addition salt" means a pharmaceutically acceptable salt formed by an organic acid selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic acid, and sulfonic acid derivatives, such as an inorganic acid like hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, or phosphoric acid, and an organic acid like an organic acid like formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0014] The term "pharmaceutically acceptable base addition salt" refers to a pharmaceutically acceptable salt formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Examples of pharmaceutically acceptable salts derived from organic non-toxic bases include salts of primary, secondary, and tertiary amines and substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

[0015] The term "pharmaceutically active metabolite" refers to pharmacologically active products produced through the metabolism of a particular compound or a salt thereof in the body. After entering the body, most drugs become substrates for chemical reactions, which can alter their physical properties and biological effects. These metabolic transformations typically affect the polarity of the compounds in this invention and alter how the drug is distributed within and excreted from the body. However, in some cases, the metabolism of a drug is necessary for its therapeutic effect.

[0016] The term "therapeutic dose" means the amount of the compound or molecule of the present invention, when administered to a subject, that (i) treat or prevent a particular disease, symptom, or disorder; (ii) reduce, improve, or eliminate one or more symptoms of a particular disease, symptom, or disorder; or (iii) prevent or delay the onset of one or more symptoms of a particular disease, symptom, or disorder as described herein. The therapeutic dose varies depending on the compound, the condition being treated, the severity of the disease being treated, the age and relative health status of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0017] The term "pharmaceutical composition" means a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable additives, which is administered to a mammal, for example, a human being in need.

[0018] The terms “pharmaceutically acceptable additive,” “pharmaceutically acceptable carrier,” and “therapeutably inactive additive” are interchangeable and refer to any pharmaceutically acceptable component in a pharmaceutical composition that is non-therapeutic and non-toxic to the target of administration, used in the formulation of pharmaceutical products, such as disintegrants, binders, fillers, solvents, buffers, isotonic agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants.

[0019] TLR7 and TLR8 agonists The present invention relates to (i) a compound of formula (I), TIFF2026518208000003.tif49170 (in the formula, R 1 H, C 1~6 Alkyl or hydroxy C 1~6 It is alkyl, R 2 C 1~6 Alkyl or C 1~6 Alkoxy C 1~6 It is alkyl, R 3 C 1~6 It is alkyl, R 4 is, (C 1~6 Alkyl)2-aminoC 1~6 Alkyl-substituted 1H-indazolyl, (C 1~6 Alkyl)2-aminoC 1~6 Alkyl-substituted 1H-indolyl, C 1~6 1H-isoquinolinyl, which is twice substituted with alkyl and hydroxyl groups. (C 1~6 Alkyl)2-aminoC 1~6 Alkyl, (C 1~6 (Alkylpiperazinyl) C 1~6 Alkyl, amino, C 1~6 Alkoxy, C 1~6 Alkyl, hydroxy, and pyrrolidinyl C 1~6 Phenyl compounds that are substituted once, twice, or three times with substituents independently selected from the alkyl group, or (C 1~6 Alkyl)2-aminoC 1~6 It is a pyridyl substituted with an alkylamino, A is S or Se, L is a combination or C 1~6 Compounds (which are alkylenes), or relating to a pharmaceutically acceptable salt thereof.

[0020] Further embodiments of the present invention include (ii)R 1 is H or C 1~6 A compound of formula (I) described in (i), which is alkyl, or a pharmaceutically acceptable salt thereof.

[0021] Further embodiments of the present invention include (iii)R 1 A compound of formula (I) as described in (i) or (ii), or a pharmaceutically acceptable salt thereof, wherein is H or methyl.

[0022] Further embodiments of the present invention include (iv)R 2 The compound is of formula (I) described in any one of (i) to (iii), wherein is butyl or ethoxymethyl.

[0023] Further embodiments of the present invention include (v)R 3 The compound of formula (I) described in any one of (i) to (iv), wherein the compound is methyl, or a pharmaceutically acceptable salt thereof.

[0024] A further embodiment of the present invention is a compound of formula (I) described in any one of (i) to (v) or a pharmaceutically acceptable salt thereof, wherein (vi) A is S.

[0025] Further embodiments of the present invention are compounds of formula (I) described in any one of (i) to (vi) or pharmaceutically acceptable salts thereof, wherein (vii)L is bonded or ethylene.

[0026] Further embodiments of the present invention include (viii)R 4 However, (C 1~6 Alkyl)2-aminoC 1~6 Alkyl, amino, C 1~6 Alkoxy, hydroxy, and pyrrolidinyl C 1~6 A compound of formula (I) described in any one of (i) to (vii) or a pharmaceutically acceptable salt thereof, which is a phenyl compound that is substituted once, twice, or three times with a substituent independently selected from the alkyl group.

[0027] Further embodiments of the present invention are (ix)R 4The compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the phenyl is substituted once, twice, or three times with substituents independently selected from (dimethylamino)methyl, [ethyl(methyl)amino]methyl, [ethyl(propyl)amino]methyl, amino, hydroxy, methoxy, and pyrrolidinylmethyl, according to any one of (i) to (viii).

[0028] Further embodiments of the present invention include (x)R 4 The compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is one of any one of (i) to (ix), which is 2-[4-[(dimethylamino)methyl]-3-hydroxyphenyl]ethyl, 2-[4-[(dimethylamino)methyl]phenyl]ethyl, 2-amino-4-(pyrrolidine-1-ylmethyl)phenyl, 4-[(dimethylamino)methyl]-2,6-dimethoxyphenyl, 4-[(dimethylamino)methyl]-2-hydroxyphenyl, 4-[(dimethylamino)methyl]-3-hydroxyphenyl, 4-[(dimethylamino)methyl]phenyl, 4-[[ethyl(methyl)amino]methyl]phenyl, or 4-[[ethyl(propyl)amino]methyl]phenyl]phenyl.

[0029] Further embodiments of the present invention are compounds of formula (I) described in any one of (xi)(i) to (x), R 1 However, H or C 1-6 It is alkyl, R 2 However, C 1~6 Alkyl or C 1~6 Alkoxy C 1~6 It is alkyl, R 3 However, C 1~6 It is alkyl, R 4 However, (C 1~6 Alkyl)2-aminoC 1~6 Alkyl, amino, C 1~6 Alkoxy, hydroxy, and pyrrolidinyl C 1~6 Phenyl compounds that are substituted once, twice, or three times with substituents independently selected from the alkyl group. A is S, L is a combination or C 1~6 It is alkylene. A compound, or a pharmaceutically acceptable salt thereof.

[0030] Further embodiments of the present invention are compounds of formula (I) described in any one of (xii)(i) to (xi), R 1 However, it is H or methyl, R 2 However, it is butyl or ethoxymethyl, R 3 However, it is methyl, R 4 However, these are 2-[4-[(dimethylamino)methyl]-3-hydroxy-phenyl]ethyl, 2-[4-[(dimethylamino)methyl]phenyl]ethyl, 2-amino-4-(pyrrolidine-1-ylmethyl)phenyl, 4-[(dimethylamino)methyl]-2,6-dimethoxy-phenyl, 4-[(dimethylamino)methyl]-2-hydroxy-phenyl, 4-[(dimethylamino)methyl]-3-hydroxy-phenyl, 4-[(dimethylamino)methyl]phenyl, 4-[[ethyl(methyl)amino]methyl]phenyl, or 4-[[ethyl(propyl)amino]methyl]phenyl, A is S, L is bonded or ethylene. A compound, or a pharmaceutically acceptable salt thereof.

[0031] Another embodiment of the present invention is a compound of formula (I) selected from the following: 7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 1-[4-amino-2-butyl-7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-6-methylimidazo[4,5-c]pyridine-1-yl]-2-methyl-propan-2-ol; 1-[4-amino-7-[4-[(dimethylamino)methyl]phenyl]ceranyl-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-1-yl]-2-methyl-propane-2-ol; 7-[4-[(dimethylamino)methyl]-2,6-dimethoxyphenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 2-(ethoxymethyl)-7-[4-[[ethyl(propyl)amino]methyl]phenyl]sulfanyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 2-(ethoxymethyl)-7-[4-[[ethyl(methyl)amino]methyl]phenyl]sulfanyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-1,6-dimethylimidazo[4,5-c]pyridine-4-amine; 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[(dimethylamino)methyl]phenol; 7-[4-[(dimethylamino)methyl]-3-methoxyphenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 7-[2-[4-[(dimethylamino)methyl]phenyl]ethylsulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 5-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-[(dimethylamino)methyl]phenol; 5-[4-amino-2-(ethoxymethyl)-1,6-dimethylimidazo[4,5-c]pyridine-7-yl]sulfanyl-2-[(dimethylamino)methyl]phenol; 5-[2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]ethyl]-2-[(dimethylamino)methyl]phenol; 2-Butyl-7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 2-butyl-7-[2-[4-[(dimethylamino)methyl]phenyl]ethylsulfanyl]-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 6-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-3-[(dimethylamino)methyl]-2-methylphenol; 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-(diethylaminomethyl)phenol; 7-[[4-[(dimethylamino)methyl]-1H-indole-7-yl]sulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 7-[[4-[(dimethylamino)methyl]-1H-indazole-7-yl]sulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 7-[2-amino-4-[(dimethylamino)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 2-[(4-amino-2-butyl-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl)sulfanyl]-5-[(dimethylamino)methyl]phenol; 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-(pyrrolidine-1-ylmethyl)phenol; 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[(dimethylamino)methyl]-4-methylphenol; 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[1-(dimethylamino)ethyl]phenol; 5-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-[(dimethylamino)methyl]-4-methylphenol; 7-[2-amino-4-(pyrroridine-1-ylmethyl)phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 7-[2-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 7-[3-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 7-[2-amino-6-methoxy-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; N-[5-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-pyridyl]-N',N'-dimethylethane-1,2-diamine; 7-[4-[2-(dimethylamino)ethyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; and 6-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-methyl-3,4-dihydro-1H-isoquinoline-7-ol; or a pharmaceutically acceptable salt thereof.

[0032] Another embodiment of the present invention is a process for preparing a compound according to any one of (xvi)(i) to (xiii), comprising the following steps: a) A compound of formula (III) in the presence of a set of catalyst, ligand, reagent and base: TIFF2026518208000004.tif38170 and WS-L-R which is a compound of formula (II-1) 4 formation step of a compound of formula (I-1) by reaction with (II-1); TIFF2026518208000005.tif46170; b) A compound of formula (XIII) in the presence of an acid: formation step of a compound of formula (I-1) by deprotection of TIFF2026518208000006.tif47170; c) A compound of formula (III) in the presence of a reagent and B(OH)2-L-R which is a compound of formula (II-2) 4 formation step of a compound of formula (I-2) by reaction with (II-2); TIFF2026518208000007.tif48170, comprising any one of the set of catalyst, ligand, reagent and base in step a) being (1) Pd2(dba)3, XantPhos and DIEA (or Cs2CO3), (2) CuI, Mtpy and KOH, (3) Cu2S, Fe and K2CO3 (or Cs2CO3), or (4) TIPSSH, XantPhos Pd G3 and K2CO3 (or Cs2CO3), the acid in step b) being TFA or HCl, the reagent in step c) being SeO2 and KI, W being H, -S-L-R 4 or R a and R a being alkoxycarbonylalkyl, R 1 、R 2 、and R 4However, it relates to a process, defined similarly to any one of (i) to (xii).

[0033] Another embodiment of the present invention is a compound or pharmaceutically acceptable salt described in any one of (i) to (xiii) as produced according to the process of (xv)(xiv).

[0034] Another embodiment of the present invention is a pharmaceutical composition comprising a compound described in any one of (xvi)(i) to (xiii) and a pharmaceutically acceptable additive.

[0035] Another embodiment of the present invention is (xvii) a compound or pharmaceutically acceptable salt described in any one of (i) to (xiii) for use as a therapeutic active substance.

[0036] Another embodiment of the present invention is the use of any one of the compounds described in (i) to (xiii) as agonists of TLR7 and TLR8.

[0037] Another embodiment of the present invention is the use of any one of the compounds described in (i) to (xiii) for the treatment of cancer selected from pancreatic ductal adenocarcinoma, colorectal cancer, melanoma, hepatocellular carcinoma, cholangiocarcinoma, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, head and neck squamous cell carcinoma, adenoid cystic carcinoma, extensive-stage small cell lung cancer, non-small cell lung cancer, muscle-invasive bladder cancer, nodular basal cell carcinoma, and squamous cell carcinoma.

[0038] Another embodiment of the present invention is the use of any one of the compounds described in (i) to (xiii) for preparing an agent for the treatment of cancer selected from (xx) pancreatic ductal adenocarcinoma, colorectal cancer, melanoma, hepatocellular carcinoma, cholangiocarcinoma, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, head and neck squamous cell carcinoma, adenoid cystic carcinoma, extensive-stage small cell lung cancer, non-small cell lung cancer, muscle-invasive bladder cancer, nodular basal cell carcinoma, and squamous cell carcinoma.

[0039] Another embodiment of the present invention is the use of the compound described in either (xix) or (xx), wherein the cancer is selected from pancreatic ductal adenocarcinoma and colorectal cancer.

[0040] Another embodiment of the present invention is a method for treating cancer in which (xxii) cancer is selected from pancreatic ductal adenocarcinoma, colorectal cancer, melanoma, hepatocellular carcinoma, cholangiocarcinoma, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, head and neck squamous cell carcinoma, adenoid cystic carcinoma, extensive-stage small cell lung cancer, non-small cell lung cancer, muscle-invasive bladder cancer, nodular basal cell carcinoma, and squamous cell carcinoma, the method comprising administering a therapeutically effective amount of a compound defined in any one of (i) to (xiii).

[0041] Pharmaceutical composition and administration Another embodiment provides a pharmaceutical composition or pharmaceutically acceptable

[0042] The composition is formulated, administered, and given in a manner consistent with good medical practice. Factors to be considered in this regard include the specific disorder being treated, the specific mammal being treated, the individual patient's clinical symptoms, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to the physician. The “effective dose” of the compound to be administered is determined by these considerations and is the minimum amount necessary to activate the TLR7 / 8 receptor and produce INF-α and other cytokines, although these may be used in the treatment of cancer. For example, such a dose may be below the amount that is toxic to normal cells or the mammal as a whole.

[0043] In one example, the pharmaceutically effective dose of the compound of the present invention administered parenterally per dose is in the range of about 0.01 to 1000 mg / kg, or about 0.01 to 1000 mg / kg patient body weight / day, and the typical initial range of the compound used is 0.3 to 15 mg / kg / day. In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain about 1 to about 1000 mg of the compound of the present invention.

[0044] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, percutaneous, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, and epidural, as well as intranasal administration, and, if desired for local treatment, intra-focal administration. Parenteral administrations include intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration.

[0045] The compounds of the present invention can be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components that are conventional in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and further activators.

[0046] Typical formulations are prepared by mixing the compound of the present invention with a carrier or additive. Suitable carriers and additives are well known to those skilled in the art and are described in detail, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C., Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow enhancers, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives for providing a drug (i.e., the compound of the present invention or its pharmaceutical composition) in an appealing manner or for assisting in the manufacture of a pharmaceutical product (i.e., a pharmaceutical).

[0047] A suitable example of an oral dosage form is a tablet containing about 1 to 1000 mg of the compound of the present invention, comprising about 1 to 1000 mg of anhydrous lactose, about 1 to 1000 mg of croscarmellose sodium, about 1 to 1000 mg of polyvinylpyrrolidone (PVP) K30, and about 1 to 1000 mg of magnesium stearate. The powdered components are first mixed together, and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment. An example of an aerosol formulation can be prepared, for example, by dissolving 1 to 500 mg of the compound of the present invention in a suitable buffer solution, such as phosphate buffer, and optionally adding an isotonic agent, such as a salt of sodium chloride. The solution may be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[0048] Accordingly, one embodiment includes a pharmaceutical composition comprising a compound of formula I or its stereoisomer or a pharmaceutically acceptable salt thereof. A further embodiment includes a pharmaceutical composition comprising a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or additive.

[0049] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of hyperproliferative disorders. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of cancer.

[0050] The following embodiments illustrate typical compositions of the present invention, but serve only as representative examples.

[0051] Composition A The compounds of the present invention can be used as active ingredients in a manner known to the extent of the present invention to produce tablets having the following composition.

[0052] per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Corn starch 25mg Talc 25mg Hydroxypropyl methylcellulose 20 mg 425mg

[0053] Composition B The compounds of the present invention can be used as active ingredients in a manner known to the extent of the present invention to produce capsules having the following compositions.

[0054] per capsule Active ingredient: 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5mg Magnesium stearate 0.5 mg 220.0 mg

[0055] Indications and treatment methods The compounds of the present invention target TLR7 and TLR8. Therefore, the compounds of the present invention are useful in promoting the activation of antigen-presenting cells (APCs), contributing to T cell priming, transport, and invasion, enhancing Th1 and CD8+ T responses, and promoting cancer cell death. The compounds of the present invention are useful in enhancing the innate immune response in myeloid cells expressing TLR7 and TLR8. Alternatively, the compounds of the present invention are useful in activating T cells in tumors where T cells are present but suppressed, for example, by upregulation of costimulatory molecules and production of pro-inflammatory cytokines. More broadly, the compounds may be used to treat non-inflammatory cancer types, such as immune deserts or immune excluded conditions, by enhancing antigen presentation, T cell priming, recruitment / invasion, and tumor death.

[0056] Another embodiment includes a method of treating or preventing cancer in a mammal that requires treatment or prevention, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof. Cancers herein include, but are not limited to, pancreatic ductal adenocarcinoma, colorectal cancer, melanoma, hepatocellular carcinoma, cholangiocarcinoma, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, head and neck squamous cell carcinoma, adenoid cystic carcinoma, advanced small cell lung cancer, non-small cell lung cancer, muscle-invasive bladder cancer, nodular basal cell carcinoma, squamous cell carcinoma, and other progressive solid tumors.

[0057] Synthesis The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds and their starting materials are provided in the following schemes and examples. All substituents, particularly R 1 ~R 4 are as defined above unless otherwise specified. Further, unless otherwise specified, all reactions, reaction conditions, abbreviations, and symbols have meanings well known to those skilled in organic chemistry.

[0058] Scheme 1 JPEG2026518208000008.jpg183170 wherein W is H, -S-L-R 4 or R a and R a is alkoxycarbonylalkyl.

[0059] The compounds of formula (I-1) and (I-2) can be prepared according to Scheme 1.

[0060] The compound of formula (X) is prepared by substituting the compounds of formula (XII) and formula (XI) in the presence of a suitable base such as NH3 or DIEA. The compound of formula (X) is converted to the compound of formula (IX) by introducing a 2,4-dimethoxyphenyl)methyl protecting group. The compound of formula (IX) can be reduced with a reducing agent, such as Pd / C containing H2, Pd(OH)2 containing H2, and Fe containing NH4Cl, to obtain the compound of formula (VIII). The compound of formula (VI) is obtained by condensation of the compound of formula (VIII) with the compound of formula (VII) in the presence of a suitable base such as DIEA and NEt3. The compound of formula (V) is prepared by the reaction of the compound of formula (VI) in the presence of a suitable base such as NaOH and KOH. The compound of formula (IV) is obtained by deprotection of the compound of formula (V) in the presence of a suitable acid such as TFA and HCl. When the compound of formula (IV) is iodized, the compound of formula (III) is obtained in the presence of a suitable reagent such as NIS.

[0061] The compound of formula (I-1) can be prepared by coupling the compound of formula (III) and the compound of formula (II-1) in the presence of a suitable catalyst such as Pd2(dba)3, a suitable ligand such as XantPhos, and a suitable base such as DIEA or Cs2CO3. The compound of formula (I-1) can also be prepared by coupling the compound of formula (III) and the compound of formula (II-1) in the presence of a suitable catalyst such as CuI, a suitable ligand such as Mtpy, and a suitable base such as KOH. The compound of formula (I-1) can also be prepared by coupling the compound of formula (III) and the compound of formula (II-1) in the presence of a suitable reagent such as Cu2S or Fe, and a suitable base such as K2CO3 and Cs2CO3. Alternatively, the compound of formula (I-1) can be prepared by coupling the compound of formula (III) with the compound of formula (II-3) in a suitable solvent, e.g., 1,4-dioxane, in the presence of a suitable reagent, e.g., TIPSSH, a suitable catalyst, e.g., XantPhos Pd G3, and suitable bases, e.g., K2CO3 and Cs2CO3.

[0062] The compound of formula (I-2) can be prepared by the reaction of the compound of formula (III) with the compound of formula (II-2) in the presence of suitable reagents, such as SeO2 and KI.

[0063] Scheme 2 In the TIFF2026518208000009.tif194170 formula, W is H, -SLR 4 or R a And R a It is an alkoxycarbonylalkyl.

[0064] The compound of formula (I-1) can also be prepared according to scheme 2.

[0065] The compound of formula (XXI) is obtained by iodination in the presence of I2 and suitable reagents such as HIO4 to obtain the compound of formula (XX). The compound of formula (XIX) is prepared by treating the compound of formula (XX) with phenyl dichlorophosphate. The compound of formula (XVIII) is prepared by the reaction of the compound of formula (XIX) with the compound of formula (XI) in the presence of a suitable base such as NH3 or DIEA. The compound of formula (XVIII) is converted to the compound of formula (XVII) by the introduction of a 2,4-dimethoxyphenyl)methyl protecting group. The compound of formula (XVII) can be reduced with a reducing agent, such as Pd / C and H2, Pd(OH)2 and H2, or Fe and NH4Cl to obtain the compound of formula (XVI). The compound of formula (XV) is obtained by condensation of the compound of formula (XVI) with the compound of formula (VII) and suitable bases such as DIEA and NEt3. The compound of formula (XIV) is prepared by the reaction of the compound of formula (XV) in the presence of a suitable base such as NaOH.

[0066] The compound of formula (I-1) can be prepared by coupling the compound of formula (XIV) and the compound of formula (II-1) in the presence of suitable reagents such as Cu2S and Fe and suitable bases such as K2CO3 and Cs2CO3, followed by deprotection in the presence of suitable acids such as TFA and HCl.

[0067] The compounds of the present invention can be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as (chiral) HPLC or SFC. In another embodiment, the compound of formula (I) can be obtained according to the scheme described above by using the corresponding chiral starting material.

[0068] The present invention also relates to a process for preparing a compound of formula (I), the process comprising the following steps: a) Compound of formula (III) in the presence of a set of catalyst, ligand, reagent and base: TIFF2026518208000010.tif38170 and the compound WS-LR of formula (II-1) 4 Compound of formula (I-1) obtained by reaction with (II-1): Formation process for TIFF2026518208000011.tif46170; b) Compound of formula (XIII) in the presence of an acid: The deprotection process for forming the compound of formula (I-1) in TIFF2026518208000012.tif47170; c) Compound (III) and compound (II-2), B(OH)2-LR, in the presence of the reagent. 4 Compound of formula (I-2) formed by reaction with (II-2): Formation process of TIFF2026518208000013.tif48170, It includes one of the following: The set of catalyst, ligand, reagent and base in step a) may be, for example, (1) Pd2(dba)3, XantPhos and DIEA (or Cs2CO3), (2) CuI, Mtpy and KOH, (3) Cu2S, Fe and K2CO3 (or Cs2CO3), or (4) TIPSSH, XantPhos Pd G3 and K2CO3 (or 2CO3). The acid in step b) may be, for example, TFA or HCl. The reagents in step c) may be, for example, SeO2 and KI.

[0069] The compound of formula (I) produced by the process described above is also an object of the present invention. [Examples]

[0070] The present invention will be better understood by referring to the following embodiments. However, these should not be construed as limiting the scope of the invention.

[0071] Abbreviation aq.:Aqueous solution BINAP: 1,1'-binaphthyl-2,2'-diphenylphosphine DABCO:1,4-Diazabicyclo[2.2.2]Octane DDQ:2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DIEA: N,N-diethylpropylamine DMAP: 4-dimethylaminopyridine DMB: 2,4-dimethoxybenzyl DMF: Dimethylformamide EC 50 : The molar concentration of the agonist that produces 50% of the agonist's maximum possible response. eq: equivalent methoxy or EA: ethyl acetate FA: Formic acid h or hr (plural): time (multiple hours are possible) HPLC: High-Performance Liquid Chromatography LDA: Lithium diisopropylamide MS (ESI): Mass Spectrometry (Electron Spray Ionization) Mtpy:4'-(4-methoxyphenyl)-2,2':6',2”-terpyridine NEt3: Triethylamine NIS:N-iodosuccinimide NMR: nuclear magnetic resonance obsd.: Measured value Pd2(allyl)2Cl2: Allylpalladium(II) chloride dimer Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium PE: Petroleum ether prep-HPLC: Preparative High-Performance Liquid Chromatography RT or rt: Room temperature sat.: saturation SFC: Supercritical Fluid Chromatography TFA: Trifluoroacetic acid THF: Tetrahydrofuran TIPSSH: Triisopropylsilanthol TLC: Thin-layer chromatography V / V: Volume ratio XantPhos: (9,9-dimethyl-9H-xanthen-4,5-diyl)bis(diphenylphosphine) XantPhos Pd G3:[2'-(amino-κN)[1,1'-biphenyl]-2-yl-κC][[5-(diphenylphosphino)-9,9-dimethyl-9H-xanthene-4-yl]diphenylphosphine-κP](methanesulfonato-κO)palladium XPhos Pd G4:(SP-4-3)-[Dicyclohexyl[2',4',6'-Tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonato-κO)[2'-(methylamino-κN)[1,1'-biphenyl]-2-yl-κC]palladium

[0072] General experimental conditions Intermediate and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and Quad 12 / 25 Cartridge module, ii) ISCO combi-flash chromatography apparatus. Silica gel brands and pore sizes: i) KP-SIL 60Å, particle size: 40-60 μm; ii) CAS registry number: silica gel: 63231-67-4, particle size: 47-60 microns; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore size: 200-300 or 300-400.

[0073] Intermediate and final compounds were purified by preparative HPLC using reversed-phase columns with a Phenomenex Luna C18 (15 μm, 150 × 400 mm) column, a Phenomenex Luna C18 (10 μm, 100 × 250 mm) column, a Phenomenex Luna C18 (10 μm, 80 × 250 mm) column, a Shim-pack C18 (10 μm, 25 × 150 mm) column, a Phenomenex Synergi C18 (10 μm, 25 × 150 mm) column, or a Waters Atlantis T3 (5 μm, 30 × 150 mm) column. Waters AutoP purification system (Sample Manager 2767, Pump 2525, Detectors: Micromass ZQ and UV2487, Solvent system: Acetonitrile and 0.1% ammonium bicarbonate aqueous solution; Acetonitrile and 0.1% FA aqueous solution or Acetonitrile and 0.1% TFA aqueous solution). Alternatively, the Gilson-281 purification system (pump 322, detector: UV156, solvent system: acetonitrile and 0.05% ammonium bicarbonate aqueous solution; acetonitrile and 0.225% FA aqueous solution; acetonitrile and 0.05% HCl aqueous solution; acetonitrile and 0.075% TFA aqueous solution; or acetonitrile and water).

[0074] The LC / MS spectra of the compounds were obtained using LC / MS (Waters® Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ), with the following LC / MS conditions (trial time 3 minutes or 1.5 minutes).

[0075] Acidic conditions I: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile; Acidic conditions II: A: 0.0375% TFA in H2O; B: 0.01875% TFA in acetonitrile; Basic conditions I: A: 0.1% NH3·H2O in H2O; B: Acetonitrile; Basic conditions II: A: 0.025% NH3·H2O in H2O; B: Acetonitrile; Neutral conditions: A: H2O; B: Acetonitrile.

[0076] Mass spectrum (MS): Generally, only the ion showing the primary mass is reported, and unless otherwise specified, the cited mass ion is the positive mass ion (M+H). + That is the case.

[0077] NMR spectra were acquired using a Bruker Avance 400 MHz or Bruker Avance 500 MHz.

[0078] All reactions involving air-sensitive reagents were carried out under an argon atmosphere. Unless otherwise specified, commercially available reagents were used without further purification.

[0079] Preparation Examples Example 1 7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine TIFF2026518208000014.tif38170

[0080] Step 1: Preparation of 2-chloro-6-methyl-3-nitropyridine-4-amine (compound 1a) To a solution of 2,4-dichloro-6-methyl-3-nitropyridine (30.0 g, 144.92 mmol) in 300 mL of THF, NH3 / MeOH (120.0 mL, 840.0 mmol, 7.0 M) was added at 20°C. The mixture was stirred at 50°C for 16 hours. The mixture was then poured into 200 mL of H2O and extracted with EA (3 × 500 mL). The organic layer was washed with brine (3 × 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography to obtain 2-chloro-6-methyl-3-nitropyridine-4-amine (8.3 g, compound 1a) as a pale yellow solid. MS measured value (ESI + )[(M+H) + ]:188.0.

[0081] Step 2: Preparation of N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-6-methyl-3-nitropyridine-2,4-diamine (compound 1b) TIFF2026518208000016.tif48170 A mixture of 2-chloro-6-methyl-3-nitropyridine-4-amine (8.3 g, compound 1a, 44.25 mmol) and DIEA (19.66 mL, 110.62 mmol) in THF (120 mL) was to be mixed with 1-(2,4-dimethoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]methaneamine (15.45 g, 48.67 mmol) at 20°C. The mixture was stirred at 60°C for 16 hours. The reaction mixture was then poured into H2O (200 mL) and extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-6-methyl-3-nitropyridine-2,4-diamine (20.0 g, compound 1b) as a pale yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:469.2.

[0082] Step 3: Preparation of N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-6-methylpyridine-2,3,4-triamine (compound 1c) TIFF2026518208000017.tif48170 A solution of N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-6-methyl-3-nitropyridine-2,4-diamine (15.0 g, compound 1b, 32.02 mmol) in methanol (200 mL) was mixed with Pd / C (4.00 g, 10% supported on activated carbon) under N2 conditions. The reaction mixture was stirred at 25°C for 2 hours under an H2 balloon (15 psi). The reaction mixture was filtered through a Celite pad, and the residue was washed with MeOH (500 mL). The filtrate was concentrated under vacuum to obtain N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-6-methylpyridine-2,3,4-triamine (10.0 g, compound 1c) as a pale yellow oil, which was used directly in the next step without further purification.

[0083] Step 4: Preparation of N-[4-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-methyl-3-pyridyl]-2-ethoxyacetamide (compound 1d) TIFF2026518208000018.tif48170 A mixture of N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-6-methylpyridine-2,3,4-triamine (10.0 g, compound 1c, 22.8 mmol) and DIEA (8.12 mL, 45.61 mmol) in DCM (100 mL) was to be mixed with 2-ethoxyacetyl chloride (2.79 g, 22.8 mmol) at 0°C. The mixture was stirred at 15°C for 12 hours. The mixture was then diluted with H2O (200 mL) and extracted with DCM (2 × 200 mL). The organic layer was washed with brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain N-[4-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-methyl-3-pyridyl]-2-ethoxyacetamide (9.0 g, compound 1d) as a pale yellow oily substance.

[0084] Step 5: Preparation of N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 1e) TIFF2026518208000019.tif50170 To a solution of N-[4-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-methyl-3-pyridyl]-2-ethoxyacetamide (9.0 g, compound 1d, 17.16 mmol) in ethanol (100 mL), NaOH (100.0 mL, 400.0 mmol, 4 M in H2O) was added at 20°C. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was concentrated under vacuum to remove the EtOH. The residue was then diluted with H2O (200 mL) and extracted with EA (3 × 300 mL). The organic layer was washed with brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by trituration from MeOH (50 mL) to obtain N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (6.5 g, compound 1e) as a pale yellow solid. MS measured value (ESI + )[(M+H) + ]:507.3.

[0085] Step 6: Preparation of 2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 1f) A solution of N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (3.0 g, compound 1e, 5.92 mmol) in DCM (30.0 mL) and TFA (30.0 mL) was stirred at 25°C for 12 hours. The mixture was concentrated under vacuum. Saturated NaHCO3 (aqueous solution) was added to adjust the pH to 7. After lyophilization, the residue was washed with DCM / MeOH (150 mL, V / V=10 / 1) and filtered. The filtrate was concentrated under vacuum to obtain 2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (1.0 g, compound 1f) as a yellow oily substance, which was used directly in the next step without further purification.

[0086] Step 7: Preparation of 2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (1 g of compound) TIFF2026518208000021.tif28170 A solution of 2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (1.22 g, compound 1f, 5.92 mmol) in acetic acid (12.0 mL) was mixed with NIS (1.99 g, 8.87 mmol) at 20°C. The mixture was stirred at 20°C for 0.5 hours. The reaction mixture was concentrated under vacuum. The residue was purified by reverse-phase preparative HPLC to obtain 2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (1.96 g, compound 1 g) as a pale yellow solid. MS measured value (ESI + )[(M+H) + ]:333.1.

[0087] Step 8: Preparation of O-(4-formylphenyl)N,N-dimethylcarbamothioate (compound 1h) To a solution of 4-hydroxybenzaldehyde (5.0 g, 40.94 mmol) in DMF (80 mL), DABCO (18.37 g, 163.77 mmol) and dimethylthiocarbamoyl chloride (10.12 g, 81.89 mmol) were added at 20°C. The mixture was stirred at 20°C for 12 hours. The mixture was diluted with H2O (100 mL) and extracted with EA (3 × 100 mL). The organic layer was washed with brine (3 × 100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by recrystallization in MeOH (20 mL) to obtain O-(4-formylphenyl)N,N-dimethylcarbamothioate (5.0 g, compound 1 h) as a white solid. MS measured value (ESI + )[(M+H) + ]:210.1. 1 H NMR(400MHz,CDCl3)δ ppm:10.00(s,1H),7.93(d,J=8.4Hz,2H),7.24(d,J=8.4Hz,2H),3.46(s,3H),3.37(s,3H).

[0088] Step 9: Preparation of S-(4-formylphenyl)N,N-dimethylcarbamothioate (compound 1i) A solution of O-(4-formylphenyl)N,N-dimethylcarbamothioate (2.0 g, compound 1h, 9.56 mmol) in TIFF2026518208000023.tif29170Ph2O (30.0 mL) was stirred at 220°C for 0.5 hours. The mixture was purified by silica gel column chromatography to obtain S-(4-formylphenyl)N,N-dimethylcarbamothioate (1.5 g, compound 1i) as a white solid. 1 H NMR(400MHz,CDCl3)δ ppm:9.96(s,1H),7.81(d,J=8.4Hz,2H),7.61(d,J=8.4Hz,2H),3.04(br s,3H),2.98(br s,3H).

[0089] Step 10: Preparation of S-[4-[(dimethylamino)methyl]phenyl]N,N-dimethylcarbamothioate (compound 1j) TIFF2026518208000024.tif A mixture of S-(4-formylphenyl) N,N-dimethylcarbamothioate (500.0 mg, Compound 1i, 2.39 mmol), dimethylamine hydrochloride (253.28 mg, 3.11 mmol) and acetic acid (43.04 mg, 0.72 mmol) in 29170 DCM (8.0 mL) was stirred at 20 °C for 1 hour. Then, NaBH(OAc)3 (1.01 g, 4.78 mmol) was added to the mixture at 20 °C. The mixture was stirred at 20 °C for 2 hours and then concentrated in vacuo. The residue was purified by silica gel column to give S-[4-[(dimethylamino)methyl]phenyl] N,N-dimethylcarbamothioate (450.0 mg, Compound 1j) as a pale yellow oil. MS found (ESI + ) [(M+H) + : 239.2.

[0090] Step 11: Preparation of 4-[(dimethylamino)methyl]benzenethiol (Compound 1k) TIFF2026518208000025.tif A mixture of S-[4-[(dimethylamino)methyl]phenyl] N,N-dimethylcarbamothioate (440.0 mg, Compound 1j, 1.85 mmol) and KOH (1.03 g, 18.46 mmol) in 17170 methanol (10.0 mL) and water (4.0 mL) was stirred at 80 °C for 2 hours. The pH of the mixture was adjusted to 7 with saturated HCl (3.0 M aqueous solution) and then the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give 4-[(dimethylamino)methyl]benzenethiol (200.0 mg, Compound 1k) as a white solid. MS found (ESI + ) [(M+H) + : 168.0.

[0091] Step 12: Preparation of 7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine (Example 1) TIFF2026518208000026.tif361701,4-Dioxane (2.0 mL), 4-[(dimethylamino)methyl]benzenethiol (29.46 mg, Compound 1k, 0.18 mmol), and 2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine (50.0 mg, Compound 1g, 0.15 mmol) were added with DIEA (0.05 mL, 0.3 mmol), Pd2(dba)3 (27.54 mg, 0.03 mmol), and XantPhos (17.42 mg, 0.03 mmol) at 20 °C. The suspension was degassed in vacuo and purged three times with N2. The suspension was stirred at 100 °C for 4 h under N2. The reaction mixture was filtered through celite. The filtrate was concentrated in vacuo, and the residue was purified by preparative HPLC to give 7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine (20.9 mg, Example 1) as a white solid. MS found (ESI + ) [(M+H) + : 372.1. 1 H NMR (400 MHz, CD3OD) δ ppm: 7.41 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 4.67 (s, 2H), 4.25 (s, 2H), 3.65 - 3.57 (m, 2H), 2.82 (s, 6H), 2.67 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H).

[0092] Example 2 1-[4-Amino-2-butyl-7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-6-methyl-imidazo[4,5-c]pyridin-1-yl]-2-methyl-propan-2-ol TIFF2026518208000027.tif36170

[0093] Step 1: Preparation of 1-[(2-chloro-6-methyl-3-nitro-4-pyridyl)amino]-2-methyl-propan-2-ol (Compound 2a) TIFF2026518208000028.tif35170 A mixture of 2,4-dichloro-6-methyl-3-nitropyridine (17.0 g, 82.12 mmol) and DIEA (21.22 g, 164.24 mmol) in 200 mL of THF was to be dropwise added with 1-amino-2-methylpropan-2-ol (7.32 g, 82.12 mmol) at 0°C. The mixture was stirred at 15°C for 16 hours, then poured into a saturated NH4Cl solution (300 mL), extracted with EA (3 × 200 mL), washed with brine (3 × 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain 1-[(2-chloro-6-methyl-3-nitro-4-pyridyl)amino]-2-methyl-propan-2-ol (7.00 g, compound 2a) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:7.03(br s,1H),6.52(s,1H),3.22(d,J=5.2Hz,2H),2.43(s,3H),1.35(s,6H).

[0094] Step 2: Preparation of 1-[[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-methyl-3-nitro-4-pyridyl]amino]-2-methyl-propan-2-ol (compound 2b) A mixture of 1-[(2-chloro-6-methyl-3-nitro-4-pyridyl)amino]-2-methyl-propan-2-ol (7.00 g, compound 2a, 26.96 mmol), 1-(2,4-dimethoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]methaneamine (10.26 g, 32.35 mmol), and DIEA (6.96 g, 53.91 mmol) in 100 mL of DMF was stirred at 60°C for 12 hours. The mixture was poured into 200 mL of H2O and extracted with EA (3 × 200 mL). The organic layer was washed with brine (3 × 200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column to obtain 1-[[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-methyl-3-nitro-4-pyridyl]amino]-2-methyl-propan-2-ol (12.0 g, compound 2b) as a yellow oily substance.

[0095] Step 3: Preparation of 1-[[3-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-methyl-4-pyridyl]amino]-2-methyl-propan-2-ol (compound 2c) TIFF2026518208000030.tif60170 A solution of 1-[[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-methyl-3-nitro-4-pyridyl]amino]-2-methyl-propan-2-ol (12.0 g, compound 2b, 22.2 mmol) in methanol (500 mL) was to be mixed with Pd(OH)2 / C (2.40 g, 10% supported on activated carbon) under N2 at 20°C. The mixture was degassed under vacuum and purged three times with H2. The mixture was then stirred under an H2 balloon (15 Psi) at 20°C for 0.5 hours. The mixture was filtered through Celite and washed with MeOH (800 mL). The filtrate was concentrated under vacuum to obtain 1-[[3-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-methyl-4-pyridyl]amino]-2-methyl-propan-2-ol (10.0 g, compound 2c) as a brown oily substance. MS measurement value (ESI + )[(M+H) +]:511.3.

[0096] Step 4: Preparation of N-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-[(2-hydroxy-2-methyl-propyl)amino]-6-methyl-3-pyridyl]pentanamide (compound 2d) Compound 2d was prepared in the same manner as in step 4 of Example 1 by using 1-[[3-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-methyl-4-pyridyl]amino]-2-methyl-propan-2-ol (compound 2c) instead of N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-6-methyl-pyridin-2,3,4-triamine (compound 1c), and valeryl chloride instead of 2-ethoxyacetyl chloride. N-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-[(2-hydroxy-2-methyl-propyl)amino]-6-methyl-3-pyridyl]pentanamide (4.7 g, compound 2d) was obtained as a black oil. MS measurement value (ESI + )[(M+H) + ]:595.3.

[0097] Step 5: Preparation of 1-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-2-butyl-6-methylimidazo[4,5-c]pyridine-1-yl]-2-methyl-propan-2-ol (compound 2e) To a solution of N-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-[(2-hydroxy-2-methyl-propyl)amino]-6-methyl-3-pyridyl]pentanamide (4.7 g, compound 2d, 7.9 mmol) in ethanol (30 mL), an aqueous NaOH solution (30.0 mL, 79.03 mmol) was added at 20 °C. The reaction mixture was stirred at 80 °C for 0.5 hours and then extracted with EA (3 × 150 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column to obtain 1-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-2-butyl-6-methylimidazo[4,5-c]pyridine-1-yl]-2-methyl-propan-2-ol (3.2 g, compound 2e) as a yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:577.4.

[0098] Step 6: Preparation of 1-(4-amino-2-butyl-6-methylimidazo[4,5-c]pyridine-1-yl)-2-methylpropan-2-ol (compound 2f) A solution of 1-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-2-butyl-6-methylimidazo[4,5-c]pyridine-1-yl]-2-methyl-propan-2-ol (2.2 g, compound 2e, 3.81 mmol) and TFA (20.0 mL) in DCM (20.0 mL) was stirred at 20°C for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was purified by reverse preparative HPLC to obtain 1-(4-amino-2-butyl-6-methylimidazo[4,5-c]pyridine-1-yl)-2-methyl-propan-2-ol (1.48 g, compound 2f) as a purple oil, which was used directly in the next step without further purification. MS measured value (ESI + )[(M+H) + ]:277.1.

[0099] Step 7: Preparation of 1-(4-amino-2-butyl-7-iodo-6-methylimidazo[4,5-c]pyridine-1-yl)-2-methyl-propan-2-ol (2g of compound) TIFF2026518208000034.tif321702-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 1f) was replaced with 1-(4-amino-2-butyl-6-methylimidazo[4,5-c]pyridine-1-yl)-2-methyl-propan-2-ol (compound 2f), and 2 g of the compound was prepared in the same manner as in Example 1, Step 7. 1-(4-amino-2-butyl-7-iodo-6-methylimidazo[4,5-c]pyridine-1-yl)-2-methyl-propan-2-ol (900.0 mg, compound 2 g) was obtained as a yellow solid. MS measurement value (ESI + )[(M+H) + ]:403.0.

[0100] Step 8: Preparation of 1-[4-amino-2-butyl-7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-6-methylimidazo[4,5-c]pyridine-1-yl]-2-methyl-propan-2-ol (Example 2) TIFF2026518208000035.tif381701,4-Dioxane (3.0 mL) contains a mixture of 1-(4-amino-2-butyl-7-iodo-6-methylimidazo[4,5-c]pyridine-1-yl)-2-methyl-propan-2-ol (150.0 mg, compound 2 g, 0.37 mmol), 4-[(dimethylamino)methyl]benzenethiol (207.91 mg, compound 1 k, 1.24 mmol), and DIEA (321.2 mg, 2.49 mmol), to which XantPhos (143.84 mg, 0.25 mmol) and Pd2(dba)3 (227.4 mg, 0.25 mmol) are added 20 times. oIt was added with C. The suspension was degassed under vacuum and purged three times with N2. The mixture was stirred at 100°C for 16 hours under an N2 atmosphere, and then concentrated under vacuum. The residue was purified by preparative HPLC to obtain 1-[4-amino-2-butyl-7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-6-methylimidazo[4,5-c]pyridine-1-yl]-2-methyl-propan-2-ol (7.8 mg, Example 2) as a white solid. MS measured value (ESI + )[(M+H) + ]:442.4. 1 H NMR(400MHz,CD3OD)δ ppm:7.19(d,J=8.4Hz,2H),6.85(d,J=8.4Hz,2H),3.45(s,2H),3.37-3.32(m,2H),3.05( t,J=7.6Hz,2H),2.54(s,3H),2.25(s,6H),1.83-1.74(m,2H),1.47-1.38(m,2H),1.15(br s,6H),0.96(t,J=7.2Hz,3H).

[0101] Example 3 1-[4-amino-7-[4-[(dimethylamino)methyl]phenyl]ceranyl-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-1-yl]-2-methyl-propane-2-ol TIFF2026518208000036.tif36170

[0102] Step 1: Preparation of N-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-[(2-hydroxy-2-methyl-propyl)amino]-6-methyl-3-pyridyl]-2-ethoxyacetamide (compound 3a) Compound 3a was prepared in the same manner as in Example 1, Step 4 by using 1-[[3-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-methyl-4-pyridyl]amino]-2-methyl-propan-2-ol (compound 2c) instead of N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-6-methyl-pyridyl]amino]-2-methyl-propan-2-ol (compound 2c) instead of N2,N2-bis[(2,4-dimethoxyphenyl)methyl]amino]-4-[(2-hydroxy-2-methyl-propyl)amino]-6-methyl-3-pyridyl]-2-ethoxyacetamide (11.0 g, compound 3a) as a brown oily substance.

[0103] Step 2: Preparation of 1-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-1-yl]-2-methyl-propan-2-ol (compound 3b) TIFF2026518208000038.tif57170 To a solution of N-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-[(2-hydroxy-2-methyl-propyl)amino]-6-methyl-3-pyridyl]-2-ethoxyacetamide (11.0 g, compound 3a, 18.43 mmol) in ethanol (120 mL) and water (40 mL), NaOH (1.49 g, 36.87 mmol) was added at 20 °C. The mixture was stirred at 80 °C for 2 hours. The reaction mixture was then concentrated under vacuum. The residue was diluted with H2 (200 mL) and extracted with EA (3 × 200 mL). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column to obtain 1-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-1-yl]-2-methyl-propan-2-ol (8.00 g, compound 3b) as a yellow oily substance. 1H NMR(400MHz,CDCl3)δ ppm:7.18(d,J=8.4Hz,2H),6.43(d,J=2.0Hz,2H),6.40(s,1H),6.35(dd,J=8.4Hz,2.0Hz,2H),5.24(br s,4H),4.65(s,2H),4.10(s,2H),3.77(s,6H),3.75(s,6H),3.48-3.39(m,2H),2.42(s,3H),1.27(s,6H),1.12(t,J=7.2Hz,3H).

[0104] Step 3: Preparation of 1-[4-amino-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-1-yl]-2-methylpropan-2-ol (compound 3c) A solution of 1-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-1-yl]-2-methylpropan-2-ol (6.00 g, compound 3b, 10.37 mmol) and TFA (50 mL) in DCM (50 mL) was stirred at 20 °C for 1 hour. The mixture was concentrated under vacuum. The residue was purified by reverse preparative HPLC to obtain 1-[4-amino-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-1-yl]-2-methylpropan-2-ol (2.80 g, compound 3c) as a yellow solid. MS measurement value (ESI + )[(M+H) + ]:279.1.

[0105] Step 4: Preparation of 1-[4-amino-7-[4-[(dimethylamino)methyl]phenyl]ceranyl-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-1-yl]-2-methyl-propan-2-ol (Example 3) TIFF2026518208000040.tif38170 A solution of [4-[(dimethylamino)methyl]phenyl]boronic acid (154.36 mg, 0.86 mmol) and 1-[4-amino-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-1-yl]-2-methyl-propan-2-ol (200.0 mg, compound 3c, 0.72 mmol) in DMSO (3.0 mL) is prepared by adding KI (119.27 mg, 0.72 mmol) and SeO2 (95.67 mg, 0.86 mmol) in 20 ml. o It was added with C. The suspension was degassed under vacuum and purged three times with N2. The mixture was stirred at 110°C for 8 hours under an N2 atmosphere. The mixture was filtered through Celite and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC to obtain 1-[4-amino-7-[4-[(dimethylamino)methyl]phenyl]ceranyl-2-(ethoxymethyl)-6-methyl-imidazo[4,5-c]pyridine-1-yl]-2-methyl-propan-2-ol (10.9 mg, Example 3) as a pale yellow solid. MS measured value (ESI + )[(M+H) + ]:492.2. 1 H NMR(400MHz,CD3OD)δ ppm:7.15(d,J=8.4Hz,2H),6.99(d,J=8.4Hz,2H),4.99-4.93(m,2H),3.56-3.49(m,2H),3. 39(s,2H),3.34-3.32(m,2H),2.62(s,3H),2.20(s,6H),1.15(t,J=8.0Hz,3H),1.14(s,6H).

[0106] Example 4 7-[4-[(dimethylamino)methyl]-2,6-dimethoxyphenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine TIFF2026518208000041.tif42170

[0107] Step 1: Preparation of O-(4-formyl-2,6-dimethoxyphenyl)N,N-dimethylcarbamothioate (compound 4a) Compound 4a was prepared in the same manner as in Step 8 of Example 1 by using syringaldehyde instead of 291704-hydroxybenzaldehyde. O-(4-Formyl-2,6-dimethoxy-phenyl) N,N-dimethylcarbamothioate (3.98 g, Compound 4a) was obtained as a white solid. Measured MS value (ESI + ) [(M + H) + : 270.1. 1 H NMR (400 MHz, CDCl3) δ ppm: 9.92 (s, 1H), 7.18 (s, 2H), 3.91 (s, 6H), 3.47 (s, 3H), 3.38 (s, 3H).

[0108] Step 2: Preparation of S-(4-Formyl-2,6-dimethoxy-phenyl) N,N-dimethylcarbamothioate (Compound 4b) A solution of O-(4-Formyl-2,6-dimethoxy-phenyl) N,N-dimethylcarbamothioate (3.98 g, Compound 4a, 14.78 mmol) in Ph2O (60.0 mL) was stirred at 240 °C for 1 hour. The mixture was purified by silica gel column to obtain S-(4-Formyl-2,6-dimethoxy-phenyl) N,N-dimethylcarbamothioate (3.08 g, Compound 4b) as a yellow solid. Measured MS value (ESI + ) [(M + H) + : 270.1. 1 H NMR (400 MHz, CDCl3) δ ppm: 9.98 (s, 1H), 7.13 (s, 2H), 3.96 (s, 6H), 3.20 (br s, 3H), 3.01 (br s, 3H).

[0109] Step 3: Preparation of S-[4-[(Dimethylamino)methyl]-2,6-dimethoxy-phenyl] N,N-dimethylcarbamothioate (Compound 4c) Compound 4c was prepared in the same manner as in Example 1, Step 10, by using S-(4-formyl-2,6-dimethoxy-phenyl)N,N-dimethylcarbamothioate (compound 4b) instead of S-(4-formylphenyl)N,N-dimethylcarbamothioate (compound 1i). S-[4-[(dimethylamino)methyl]-2,6-dimethoxy-phenyl]N,N-dimethylcarbamothioate (1.9 g, compound 4c) was obtained as a yellow solid. MS measured value (ESI + )[(M+H) + ]:299.1.

[0110] Step 4: Preparation of 4-[(dimethylamino)methyl]-2,6-dimethoxybenzenethiol (compound 4d) A mixture of S-[4-[(dimethylamino)methyl]-2,6-dimethoxyphenyl]N,N-dimethylcarbamothioate (1.9 g, compound 4c, 6.37 mmol) and KOH (1.79 g, 31.84 mmol) in water (5.0 mL) and methanol (15 mL) was stirred at 80°C for 2 hours. ° The solution was acidified to pH=6 with an aqueous HCl solution (3.0 M) at C. The mixture was concentrated under vacuum. The residue was purified by reverse preparative HPLC to obtain 4-[(dimethylamino)methyl]-2,6-dimethoxybenzenethiol (2.4 g, compound 4d) as a yellow solid. MS measurement value (ESI + )[(M+H) + ]:228.2.

[0111] Step 5: Preparation of 7-[4-[(dimethylamino)methyl]-2,6-dimethoxyphenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (Example 4) To a mixture of 2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (100.0 mg, 1 g of compound, 0.3 mmol), 4-[(dimethylamino)methyl]-2,6-dimethoxybenzenethiol (82.13 mg, compound 4d, 0.36 mmol), and KOH (33.79 mg, 0.6 mmol), CuI (5.73 mg, 0.03 mmol) and Mtpy (10.22 mg, 0.03 mmol) were added at 20°C. The mixture was stirred under N2 at 110°C for 12 hours. The mixture was then concentrated under vacuum. The residue was purified by preparative HPLC to obtain 7-[4-[(dimethylamino)methyl]-2,6-dimethoxyphenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (5.5 mg, Example 4) as a grayish-white solid. MS measurement value (ESI + )[(M+H) + ]:432.4. 1 H NMR(400MHz,DMSO-d6)δ ppm:11.88(br s,1H),6.58(s,2H),6.26(br s,2H),4.61(s,2H),3.69(s,6H),3.59-3.55(m,2H),3.34(s,2H),2.40(s,3H),2.13(s,6H),1.16(t,J=6.8Hz,3H).

[0112] Example 5 2-(ethoxymethyl)-7-[4-[[ethyl(propyl)amino]methyl]phenyl]sulfanyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine TIFF2026518208000047.tif40170

[0113] Step 1: Preparation of S-[4-[[ethyl(propyl)amino]methyl]phenyl]N,N-dimethylcarbamothioate (compound 5a) Compound 5a was prepared in the same manner as in Example 1, Step 10, by using N-ethylpropylamine instead of dimethylamine hydrochloride. S-[4-[[ethyl(propyl)amino]methyl]phenyl]N,N-dimethylcarbamothioate (1.0 g, compound 5a) was obtained as a pale yellow oil. MS measurement value (ESI + )[(M+H) + ]:281.1.

[0114] Step 2: Preparation of N-ethyl-N-[[4-[[4-[[ethyl(propyl)amino]methyl]phenyl]disulfanyl]phenyl]methyl]propan-1-amine (compound 5b) Compound 5b was prepared in the same manner as in Example 1, Step 11, by using S-[4-[[ethyl(propyl)amino]methyl]phenyl]N,N-dimethylcarbamothioate (compound 5a) instead of S-[4-[(dimethylamino)methyl]phenyl]N,N-dimethylcarbamothioate (compound 1j). N-ethyl-N-[[4-[[4-[[ethyl(propyl)amino]methyl]phenyl]disulfanyl]phenyl]methyl]propan-1-amine (85.0 mg compound 5b) was obtained as a gray oily substance. MS measured value (ESI + )[(M+H) + ]:417.4.

[0115] Step 3: Preparation of 2-(ethoxymethyl)-7-[4-[[ethyl(propyl)amino]methyl]phenyl]sulfanyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (Example 5) Cu2S (32.46 mg, 0.2 mmol) and Fe powder (6.84 mg, 0.12 mmol) were added at 20°C to a mixture of 2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (101.63 mg, 1 g, 0.31 mmol), N-ethyl-N-[[4-[[4-[[ethyl(propyl)amino]methyl]phenyl]disulfanyl]phenyl]methyl]propan-1-amine (85.0 mg, compound 5b, 0.2 mmol), and K2CO3 (28.19 mg, 0.2 mmol). The suspension was degassed under vacuum and purged three times with N2. The mixture was stirred at 110°C for 2 hours under an N2 atmosphere. The reaction mixture was filtered. The filtrate was purified by preparative HPLC to obtain 2-(ethoxymethyl)-7-[4-[[ethyl(propyl)amino]methyl]phenyl]sulfanyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (7.6 mg, Example 5) as a white solid. MS measurement value (ESI + )[(M+H) + ]:414.1. 1 H NMR(400MHz,CD3OD)δ ppm:7.17(d,J=8.4Hz,2H),6.93(d,J=8.4Hz,2H),4.63(s,2H),3.62-3.54(m,2H),3.50(s,2H),2.52(s,3H),2.50-2. 45(m,2H),2.40-2.30(m,2H),1.53-1.43(m,2H),1.20(t,J=7.2Hz,3H),1.02(t,J=7.2Hz,3H),0.84(t,J=7.2Hz,3H).

[0116] Example 6 2-(ethoxymethyl)-7-[4-[[ethyl(methyl)amino]methyl]phenyl]sulfanyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine TIFF2026518208000051.tif40170

[0117] Step 1: Preparation of S-[4-[[ethyl(methyl)amino]methyl]phenyl]N,N-dimethylcarbamothioate (compound 6a) A mixture of S-(4-formylphenyl)N,N-dimethylcarbamothioate (1.0 g, compound 1i, 4.78 mmol), N-ethylmethylamine (0.37 g, 6.21 mmol), and acetic acid (0.09 g, 1.43 mmol) in 10.0 mL of DCM was stirred at 20°C for 12 hours. Then, NaBH(OAc)3 (2.03 g, 9.56 mmol) was added to the mixture at 20°C. The mixture was stirred at 20°C for 2 hours, then filtered through a Celite pad and washed with MeOH (20 mL). The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC to obtain S-[4-[[ethyl(methyl)amino]methyl]phenyl]N,N-dimethylcarbamothioate (1.0 g, compound 6a) as a yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:253.1.

[0118] Step 2: Preparation of N-[[4-[[4-[[ethyl(methyl)amino]methyl]phenyl]disulfanyl]phenyl]methyl]-N-methyl-ethaneamine (compound 6b) Compound 6b was prepared in the same manner as in Example 1, Step 11, by using S-[4-[[ethyl(methyl)amino]methyl]phenyl]N,N-dimethylcarbamothioate (compound 6a) instead of S-[4-[(dimethylamino)methyl]phenyl]N,N-dimethylcarbamothioate (compound 1j). N-[[4-[[4-[[ethyl(methyl)amino]methyl]phenyl]disulfanyl]phenyl]methyl]N-methyl-ethaneamine (74 mg, compound 6b) was obtained as a gray oily substance. MS measured value (ESI + )[(M+H) + ]:361.3.

[0119] Step 3: Preparation of 2-(ethoxymethyl)-7-[4-[[ethyl(methyl)amino]methyl]phenyl]sulfanyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (Example 6) Cu2S (16.77 mg, 0.11 mmol) and Fe powder (3.53 mg, 0.06 mmol) were added at 20°C to a mixture of 2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (35.0 mg, 1 g of compound, 0.11 mmol), N-[[4-[[4-[[ethyl(methyl)amino]methyl]phenyl]disulfanyl]phenyl]methyl]N-methylethaneamine (38.0 mg, compound 6b, 0.11 mmol), and K2CO3 (14.57 mg, 0.11 mmol). The suspension was degassed under vacuum and purged three times with N2. The mixture was stirred at 110°C for 16 hours under an N2 atmosphere. The reaction mixture was diluted with MeOH (5.0 mL), pH was adjusted to 6 at 0°C using FA, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain 2-(ethoxymethyl)-7-[4-[[ethyl(methyl)amino]methyl]phenyl]sulfanyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (7.3 mg, Example 6) as a white solid. MS measurement value (ESI + )[(M+H) + ]:386.1. 1 H NMR(400MHz,CD3OD)δ ppm:7.17(d,J=8.4Hz,2H),6.95(d,J=8.4Hz,2H),4.63(s,2H),3.62-3.54(m,2H),3.45(s,2H) ),2.52(s,3H),2.47-2.41(m,2H),2.15(s,3H),1.20(t,J=7.2Hz,3H),1.08(t,J=7.2Hz,3H).

[0120] Example 7 7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-1,6-dimethylimidazo[4,5-c]pyridine-4-amine TIFF2026518208000055.tif40170

[0121] Step 1: Preparation of N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-1,6-dimethylimidazo[4,5-c]pyridine-4-amine (compound 7a) To a solution of N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (4.0 g, compound 1e, 7.9 mmol) in DMF (40 mL), potassium carbonate (2.18 g, 15.79 mmol) and iodomethane (1.23 mL, 19.74 mmol) were added at 25°C. The mixture was stirred at 25°C for 2 hours, then poured into water (200 mL) and extracted with EA (3 × 150 mL). The organic layer was washed with brine (3 × 100 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated under vacuum to obtain N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-1,6-dimethylimidazo[4,5-c]pyridine-4-amine (4.0 g, compound 7a) as a yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:521.4.

[0122] Step 2: Preparation of 2-(ethoxymethyl)-1,6-dimethylimidazo[4,5-c]pyridine-4-amine (compound 7b) A solution of N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-1,6-dimethylimidazo[4,5-c]pyridine-4-amine (4.0 g, compound 7a, 7.68 mmol) and TFA (40.0 mL) in DCM (40.0 mL) was stirred at 20°C for 2 hours. The reaction mixture was concentrated under vacuum. The pH of the residue was adjusted to 8 with saturated NaHCO3. After lyophilization, the residue was washed with DCM (160 mL) and MeOH (20 mL). The filtrate was concentrated under vacuum to obtain 2-(ethoxymethyl)-1,6-dimethylimidazo[4,5-c]pyridine-4-amine (2.5 g, compound 7b) as a pale yellow solid, which was used directly in the next step without further purification.

[0123] Step 3: Preparation of 2-(ethoxymethyl)-7-iodo-1,6-dimethylimidazo[4,5-c]pyridine-4-amine (compound 7c) TIFF2026518208000058.tif28170 A solution of 2-(ethoxymethyl)-1,6-dimethylimidazo[4,5-c]pyridine-4-amine (2.45 g, compound 7b, 7.33 mmol) in acetic acid (30 mL) was mixed with NIS (3.3 g, 14.66 mmol) at 20°C. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by reverse preparative HPLC to obtain 2-(ethoxymethyl)-7-iodo-1,6-dimethylimidazo[4,5-c]pyridine-4-amine (876.0 mg, compound 7c) as a pale yellow solid. MS measured value (ESI + )[(M+H) + ]:346.9.

[0124] Step 4: Preparation of 7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-1,6-dimethylimidazo[4,5-c]pyridine-4-amine (Example 7) The title compound was prepared in the same manner as in Example 1, Step 12, by using 2-(ethoxymethyl)-7-iodo-1,6-dimethyl-imidazo[4,5-c]pyridine-4-amine (compound 7c) instead of 2-(ethoxymethyl)-7-iodo-1,6-dimethyl-imidazo[4,5-c]pyridine-4-amine (compound 7c) instead of 2-(ethoxymethyl)-7-iodo-1,6-dimethyl-imidazo[4,5-c]pyridine-4-amine (compound 7c). 7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-1,6-dimethyl-imidazo[4,5-c]pyridine-4-amine (31.6 mg, Example 7) was obtained as a white solid. MS measured value (ESI + )[(M+H) + ]:386.2. 1 H NMR(400MHz,CD3OD)δ ppm:7.41(d,J=7.6Hz,2H),7.12(d,J=7.6Hz,2H),4.71(s,2H),4.21(s,2H),3. 99(s,3H),3.63-3.55(m,2H),2.79(s,6H),2.60(s,3H),1.19(t,J=7.2Hz,3H).

[0125] Example 8 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[(dimethylamino)methyl]phenol TIFF2026518208000060.tif41170

[0126] Step 1: Preparation of 5-iodo-6-methyl-3-nitropyridine-2,4-diol (compound 8a) A mixture of 6-methyl-3-nitropyridine-2,4-diol (10.0 g, 58.78 mmol) and HCl (4.51 g, 23.51 mmol) in acetic acid (50 mL), H2SO4 (1.0 mL), and water (20 mL) was stirred at 90°C for 0.5 hours. Then, it was added to mixture I2 at 90°C (5.96 g, 23.51 mmol). The mixture was stirred at 90°C for 1 hour. The mixture was cooled to room temperature, poured into saturated Na2SO3 solution (200 mL), and filtered. The collected solid was washed with H2O (100 mL) and dried in vacuum to obtain 5-iodo-6-methyl-3-nitropyridine-2,4-diol (15.0 g, compound 8a) as a yellow solid. MS measured value (ESI + )[(M+H) + ]:296.9.

[0127] Step 2: Preparation of 2,4-dichloro-5-iodo-6-methyl-3-nitropyridine (compound 8b) A mixture of 5-iodo-6-methyl-3-nitropyridine-2,4-diol (15.0 g, compound 8a, 50.67 mmol) in phenyl dichlorophosphate (150 mL) was stirred at 180 °C for 1 hour. The mixture was cooled to room temperature, poured into H₂O (600 mL), basicized to pH=7 with solid NaHCO₃, and extracted with EA (3 × 300 mL). The organic layer was washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column to obtain 2,4-dichloro-5-iodo-6-methyl-3-nitropyridine (15.0 g, compound 8b) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:2.81(s,3H).

[0128] Step 3: Preparation of 2-chloro-N-[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methyl-3-nitropyridine-4-amine (compound 8c) To a solution of 2,4-dichloro-5-iodo-6-methyl-3-nitropyridine (20.0 g, compound 8b, 60.08 mmol) in 160 mL of THF, DIEA (26.69 mL, 150.19 mmol) and 2,4-dimethoxybenzylamine (9.03 mL, 60.08 mmol) were added at 20°C. The mixture was stirred at 20°C for 16 hours. The mixture was diluted with H2O (200 mL) and extracted with EA (3 × 300 mL). This organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain 2-chloro-N-[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methyl-3-nitropyridine-4-amine (25.0 g, compound 8c) as a yellow solid. MS measurement value (ESI + )[(M+H) + ]:464.0.

[0129] Step 4: Preparation of N2,N2,N4-tris[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methyl-3-nitropyridine-2,4-diamine (compound 8d) Compound 8d was prepared in the same manner as in Example 1, Step 2, by using 2-chloro-N-[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methyl-3-nitropyridine-4-amine (compound 8c) instead of 2-chloro-6-methyl-3-nitropyridine-4-amine (compound 1a). N2,N2,N4-tris[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methyl-3-nitropyridine-2,4-diamine (compound 8d) was obtained as a yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:744.9.

[0130] Step 5: Preparation of N2,N2,N4-tris[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methylpyridine-2,3,4-triamine (compound 8e) To a solution of N2,N2,N4-tris[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methyl-3-nitropyridine-2,4-diamine (25.0 g, compound 8d, 33.58 mmol) in ethanol (150 mL), THF (200 mL), and water (150 mL), Fe (18.75 g, 335.76 mmol) and NH4Cl (17.96 g, 335.76 mmol, 10.0 equivalents) were added at 20°C. The suspension was heated to 70°C and stirred at 70°C for 2.5 hours. The mixture was filtered through a Celite pad and washed with MeOH (5 × 200 mL). The filtrate was concentrated under vacuum. The residue was washed with DCM / MeOH (300 mL, V / V = 10 / 1) and filtered. The filtrate was concentrated under vacuum to obtain N2,N2,N4-tris[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methylpyridine-2,3,4-triamine (20.0 g, compound 8e) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:715.0.

[0131] Step 6: Preparation of N-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-[(2,4-dimethoxyphenyl)methylamino]-5-iodo-6-methyl-3-pyridyl]-2-ethoxyacetamide (compound 8f) Compound 8f was prepared in the same manner as in Example 1, Step 4, by using N2,N2,N4-tris[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methylpyridine-2,3,4-triamine (compound 8e) instead of N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-6-methylpyridine-2,3,4-triamine (compound 8e). N-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-[(2,4-dimethoxyphenyl)methylamino]-5-iodo-6-methyl-3-pyridyl]-2-ethoxyacetamide (10.0 g, compound 8f) was obtained as a brown oily substance, which was used directly in the next step without further purification.

[0132] Step 7: Preparation of N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-7-iodo-6-methylimidazo[4,5-c]pyridine-4-amine (8g of compound) TIFF2026518208000067.tif61170 To a solution of N-[2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-4-[(2,4-dimethoxyphenyl)methylamino]-5-iodo-6-methyl-3-pyridyl]-2-ethoxyacetamide (10.0 g, compound 8f, 12.49 mmol) in ethanol (100 mL) and water (100 mL), add 20 NaOH (5.07 g, 124.89 mmol). o The compound was added with C. The mixture was stirred at 80°C for 12 hours. The mixture was then concentrated under vacuum. The residue was purified by reverse preparative HPLC to obtain N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-7-iodo-6-methylimidazo[4,5-c]pyridine-4-amine (5.00 g, 8 g of compound) as a yellow solid.

[0133] Step 8: Preparation of O-(4-formyl-2-methoxyphenyl)N,N-dimethylcarbamothioate (compound 8h) Compound 8h was prepared in the same manner as in Example 1, Step 8, by using vanillin instead of 4-hydroxybenzaldehyde. O-(4-formyl-2-methoxyphenyl)N,N-dimethylcarbamothioate (5.0 g, compound 8h) was obtained as a pale yellow solid. MS measurement value (ESI + )[(M+H) + ]:240.0. 1 H NMR(400MHz,CDCl3)δ ppm:9.96(s,1H),7.54-7.48(m,2H),7.23(d,J=8.4Hz,1H),3.90(s,3H),3.47(s,3H),3.38(s,3H).

[0134] Step 9: Preparation of S-(4-formyl-2-methoxyphenyl)N,N-dimethylcarbamothioate (compound 8i) Compound 8i was prepared in the same manner as in Example 1, Step 9, by using O-(4-formyl-2-methoxyphenyl)N,N-dimethylcarbamothioate (compound 8h) instead of O-(4-formylphenyl)N,N-dimethylcarbamothioate (compound 1h). S-(4-formyl-2-methoxyphenyl)N,N-dimethylcarbamothioate (4.0 g, compound 8i) was obtained as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:10.00(s,1H),7.69(d,J=7.6Hz,1H),7.49-7.43(m,2H),3.95(s,3H),3.14(s,3H),3.03(s,3H).

[0135] Step 10: Preparation of S-[4-[(dimethylamino)methyl]-2-methoxyphenyl]N,N-dimethylcarbamothioate (compound 8j) Compound 8j was prepared in the same manner as in Example 1, Step 10, by using S-(4-formyl-2-methoxy-phenyl)N,N-dimethylcarbamothioate (compound 8i) instead of S-(4-formylphenyl)N,N-dimethylcarbamothioate (compound 1i). S-[4-[(dimethylamino)methyl]-2-methoxy-phenyl]N,N-dimethylcarbamothioate (2.7g, compound 8j) was obtained as a pale yellow oily substance. MS measured value (ESI + )[(M+H) + ]:269.1.

[0136] Step 11: Preparation of 4-[(dimethylamino)methyl]-2-methoxybenzenethiol (compound 8K) Compound 8k was prepared in the same manner as in Example 1, Step 11, by using S-[4-[(dimethylamino)methyl]-2-methoxy-phenyl]N,N-dimethylcarbamothioate (compound 8j) instead of S-[4-[(dimethylamino)methyl]phenyl]N,N-dimethylcarbamothioate (compound 1j). 4-[(dimethylamino)methyl]-2-methoxy-benzenethiol (300.0 mg, compound 8k) was obtained as a pale yellow oily substance. MS measured value (ESI + )[(M+H) + ]:198.0.

[0137] Step 12: Preparation of 5-[(dimethylamino)methyl]-2-sulfanylphenol (compound 8L) To a solution of 4-[(dimethylamino)methyl]-2-methoxybenzenethiol (300.0 mg, compound 8k, 1.52 mmol) in TIFF2026518208000072.tif17170DCM (5.0 mL), BBr3 (1.14 g, 4.56 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 15°C for 2 hours. The reaction mixture was then quenched with H2O (20 mL) at 5°C and concentrated under vacuum. The residue was purified by preparative HPLC to obtain 5-[(dimethylamino)methyl]-2-sulfanylphenol (270.0 mg, compound 8k) as a pale yellow oil. MS measured value (ESI + )[(M+H) + ]:184.1.

[0138] Step 13: Preparation of 2-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-1-[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-7-yl]sulfanyl-5-[(dimethylamino)methyl]phenol (compound 8m) Compound 8m was prepared in the same manner as in Example 6, Step 3, by using N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-7-iodo-6-methylimidazo[4,5-c]pyridine-4-amine (8g of compound) instead of 2-(ethoxymethyl)-7-iodo-6-methylimidazo[4,5-c]pyridine-4-amine (1g of compound), and 5-[(dimethylamino)methyl]-2-sulfanyl-phenol (8l of compound) instead of N-[[4-[[4-[[ethyl(methyl)amino]methyl]phenyl]disulfanyl]phenyl]methyl]N-methylethaneamine (compound 6b). 2-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-1-[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-7-yl]sulfanyl-5-[(dimethylamino)methyl]phenol (400.0 mg, compound 8 m) phenol was obtained as a yellow solid. MS measurement value (ESI + )[(M+H) + ]:838.2.

[0139] Step 14: Preparation of 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[(dimethylamino)methyl]phenol (Example 8) A solution of 2-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-1-[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-7-yl]sulfanyl-5-[(dimethylamino)methyl]phenol (300.0 mg, compound 8 m, 0.36 mmol) and TFA (5.0 mL) in DCM (5.0 mL) was stirred at 20°C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC to obtain 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[(dimethylamino)methyl]phenol (73.2 mg, Example 8) as a white solid. MS measured value (ESI + )[(M+H) + ]:388.2. 1 H NMR(400MHz,CD3OD)δ ppm:6.77(d,J=1.6Hz,1H),6.58(dd,J=8.0Hz,1.6Hz,1H),6.43(d,J=8.0Hz,1H),4.63(s, 2H),3.58(q,J=6.8Hz,2H),3.34(s,2H),2.53(s,3H),2.20(s,6H),1.21(t,J=6.8Hz,3H).

[0140] Example 9 7-[4-[(dimethylamino)methyl]-3-methoxyphenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine TIFF2026518208000075.tif45170

[0141] Step 1: Preparation of O-(4-formyl-3-methoxyphenyl)N,N-dimethylcarbamothioate (compound 9a) Compound 9a was prepared in the same manner as in Example 1, Step 8, by using 4-hydroxy-2-methoxy-benzaldehyde instead of 4-hydroxybenzaldehyde. O-(4-formyl-3-methoxyphenyl)N,N-dimethylcarbamothioate (11.0 g, compound 9a) was obtained as a yellow solid. MS measurement value (ESI + )[(M+H) + ]:240.1. 1 H NMR(400MHz,CDCl3)δ ppm:10.41(s,1H),7.87(d,J=8.4Hz,1H),6.78-6.72(m,2H),3.93(s,3H),3.47(s,3H),3.36(s,3H).

[0142] Step 2: Preparation of S-(4-formyl-3-methoxyphenyl)N,N-dimethylcarbamothioate (compound 9b) A solution of O-(4-formyl-3-methoxyphenyl)N,N-dimethylcarbamothioate (10.0 g, compound 9a, 41.79 mmol) in TIFF2026518208000077.tif29170Ph2O (50.0 mL) was stirred at 190°C for 6 hours. The mixture was purified by silica gel column chromatography to obtain S-(4-formyl-3-methoxyphenyl)N,N-dimethylcarbamothioate (6.0 g, compound 9b) as a yellow solid. MS measurement value (ESI + )[(M+H) + ]:240.1.

[0143] Step 3: Preparation of 2-methoxy-4-sulfanylbenzaldehyde (compound 9c) Compound 9c was prepared in the same manner as in Example 1, Step 11, by using S-(4-formyl-3-methoxyphenyl)N,N-dimethylcarbamothioate (compound 9b) instead of S-[4-[(dimethylamino)methyl]phenyl]N,N-dimethylcarbamothioate (compound 1j). 2-methoxy-4-sulfanyl-benzaldehyde (700.0 mg, compound 9c) was obtained as a yellow solid. MS measured value (ESI + )[(M+H) + ]:169.2. 1 H NMR(400MHz,CDCl3)δ ppm:10.21(s,1H),7.54(d,J=8.0Hz,1H),7.18(s,1H),6.98(d,J=8.0Hz,1H),6.12(br s,1H),3.89(s,3H).

[0144] Step 4: Preparation of 4-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-methoxybenzaldehyde (compound 9d) Compound 9d was prepared in the same manner as in Example 5, Step 3, by using 2-methoxy-4-sulfanyl-benzaldehyde (compound 9c) instead of N-ethyl-N-[[4-[[4-[[ethyl(propyl)amino]methyl]phenyl]disulfanyl]phenyl]methyl]propan-1-amine (compound 5b). 4-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-methoxy-benzaldehyde (compound 9d) was obtained as a yellow solid. MS measurement value (ESI + )[(M+H) + ]:373.3.

[0145] Step 5: Preparation of 7-[4-[(dimethylamino)methyl]-3-methoxyphenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (Example 9) Dimethylamine hydrochloride (328.4 mg, 4.03 mmol) was added at 20°C to a mixture of 4-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-methoxybenzaldehyde (150.0 mg, compound 9d, 0.4 mmol) and NaOAc (330.38 mg, 4.03 mmol) in methanol (5.0 mL). The mixture was stirred under N2 at 20°C for 12 hours, and then NaBH(OAc)3 (341.43 mg, 1.61 mmol) was added at 20°C. The mixture was stirred for a further 4 hours at 20°C, then filtered through Celite, and the filtrate was purified by preparative HPLC to obtain 7-[4-[(dimethylamino)methyl]-3-methoxyphenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (30.0 mg, Example 9) as a yellow solid. MS measurement value (ESI + )[(M+H) + ]:402.1. 1 H NMR(400MHz,DMSO-d6)δ ppm:12.58(s,1H),7.10(d,J=7.6Hz,1H),6.73(d,J=1.2Hz,1H),6.57(br s,2H),6.34(dd,J=7.6Hz,1.2Hz,1H),4.52(s,2H),3.66(s,3H),3.52-3. 47(m,2H),3.38(s,2H),2.44(s,3H),2.16(s,6H),1.11(t,J=6.8Hz,3H).

[0146] Example 10 7-[2-[4-[(dimethylamino)methyl]phenyl]ethylsulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine TIFF2026518208000081.tif40170

[0147] Step 1: Preparation of [4-(2-bromoethyl)phenyl]methanol (compound 10a) To a solution of methyl 4-(2-bromoethyl)benzoate (1.5 g, 6.17 mmol) in THF (30 mL), diisobutylaluminum hydride (12.96 mL, 12.96 mmol, 1.0 M) was added dropwise at -78°C. The mixture was stirred at 15°C for 2 hours. The reaction product was then quenched at 0°C with saturated aqueous NH4Cl (100 mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain [4-(2-bromoethyl)phenyl]methanol (1.2 g, compound 10a) as a pale yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.34(d,J=8.0Hz,2H),7.22(d,J=8.0Hz,2H),4.68(s,2H),3.58(t,J=7.6Hz,2H),3.18(t,J=7.6Hz,2H).

[0148] Step 2: Preparation of 4-(2-bromoethyl)benzaldehyde (compound 10b) To a solution of [4-(2-bromoethyl)phenyl]methanol (1.0 g, compound 10a, 4.65 mmol) in TIFF2026518208000083.tif17170DCM (30.0 mL), Dess Martin periodinane (2.95 g, 6.97 mmol) was added under N2 at 20°C. The reaction mixture was stirred at 20°C for 4 hours, then filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column to obtain 4-(2-bromoethyl)benzaldehyde (700.0 mg, compound 10b) as a white solid. 1 H NMR(400MHz,CDCl3)δ ppm:10.01(s,1H),7.86(d,J=8.0Hz,2H),7.40(d,J=8.0Hz,2H),3.62(t,J=7.6Hz,2H),3.27(t,J=7.6Hz,2H).

[0149] Step 3: Preparation of 4-[2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]ethyl]benzaldehyde (compound 10c) Triisopropylsilanthol (96.89 mg, 0.51 mmol) and Pd XantPhos G3 (40.44 mg, 0.04 mmol) were added at 20°C to a mixture of 2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (130.0 mg, 1 g of compound, 0.39 mmol) and Cs2CO3 (255.36 mg, 0.78 mmol) in 1,4-dioxane (3.0 mL). The mixture was then degassed three times under N2 and stirred at 100°C for 4 hours under an N2 balloon. The mixture was then cooled to room temperature. Next, 1.0 mL of DMF containing 4-(2-bromoethyl)benzaldehyde (83.4 mg, compound 10b, 0.39 mmol) was added to the mixture under N2 at 20°C. The mixture was stirred at 20°C for 2 hours, then filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column to obtain 4-[2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]ethyl]benzaldehyde (50.0 mg, compound 10c) as a pale yellow oily substance. MS measured value (ESI + )[(M+H) + ]:371.1.

[0150] Step 4: Preparation of 7-[2-[4-[(dimethylamino)methyl]phenyl]ethylsulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (Example 10) A mixture of 4-[2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]ethyl]benzaldehyde (45.0 mg, compound 10c, 0.12 mmol) and dimethylamine hydrochloride (12.88 mg, 0.16 mmol) in TIFF2026518208000085.tif37170DCM (2.0 mL) was stirred at 20°C for 11 hours. Then, NaBH(OAc)3 (51.49 mg, 0.24 mmol) was added to the mixture for 20 minutes. o The mixture was added with C. The mixture was stirred at 20°C for 1 hour. The mixture was then concentrated under vacuum. The residue was purified by preparative HPLC to obtain 7-[2-[4-[(dimethylamino)methyl]phenyl]ethylsulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (23.3 mg, Example 10) as a white solid. MS measurement value (ESI + )[(M+H) + ]:400.2. 1 H NMR(400MHz,CD3OD)δ ppm:7.30(d,J=8.0Hz,2H),7.20(d,J=8.0Hz,2H),4.71(s,2H),4.15(s,2H),3.70-3.61(m,2H) ,3.08(t,J=7.2Hz,2H),2.91(t,J=7.2Hz,2H),2.74(s,6H),2.59(s,3H),1.26(t,J=7.2Hz,3H).

[0151] Example 11 5-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-[(dimethylamino)methyl]phenol TIFF2026518208000086.tif46170

[0152] Step 1: Preparation of S-[4-[(dimethylamino)methyl]-3-methoxyphenyl]N,N-dimethylcarbamothioate (compound 11a) In a solution of S-(4-formyl-3-methoxyphenyl)N,N-dimethylcarbamothioate (2.2 g, compound 9b, 9.19 mmol) in TIFF2026518208000087.tif29170DCM (20.0 mL), Me2NH . HCl (2.99 g, 11.95 mmol) was added at 0°C. The reaction mixture was stirred at 20°C for 2 hours. Then, NaBH(OAc)3 (3.89 g, 18.4 mmol) was added to the mixture at 20°C. The mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with DCM (100 mL), washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by back-preparative HPLC to obtain S-[4-[(dimethylamino)methyl]-3-methoxyphenyl]N,N-dimethylcarbamothioate (1.7 g, compound 11a) as a pale yellow solid.

[0153] Step 2: Preparation of 1-[4-[[4-[(dimethylamino)methyl]-3-methoxyphenyl]disulfanyl]-2-methoxyphenyl]-N,N-dimethylmethaneamine (compound 11b) Compound 11b was prepared in the same manner as in Example 1, Step 11, by using S-[4-[(dimethylamino)methyl]-3-methoxy-phenyl]N,N-dimethylcarbamothioate (Compound 11a) instead of S-[4-[(dimethylamino)methyl]phenyl]N,N-dimethylcarbamothioate (Compound 1j). 1-[4-[[4-[(dimethylamino)methyl]-3-methoxy-phenyl]disulfanyl]-2-methoxy-phenyl]-N,N-dimethylmethaneamine (1.5 g, Compound 11b) was obtained as a colorless oil. MS measurement value (ESI + )[(M+H) + ]:393.2.

[0154] Step 3: Preparation of 2-[(dimethylamino)methyl]-5-[[4-[(dimethylamino)methyl]-3-hydroxyphenyl]disulfanyl]phenol (compound 11c) To a solution of 1-[4-[[4-[(dimethylamino)methyl]-3-methoxyphenyl]disulfanyl]-2-methoxyphenyl]-N,N-dimethylmethaneamine (500.0 mg, compound 11b, 1.27 mmol) in DCM (5.0 mL), BBr3 (957.21 mg, 3.82 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was then quenched dropwise with MeOH (20 mL) at 0°C. The mixture was concentrated under vacuum. The residue was purified by reverse preparative HPLC to obtain 2-[(dimethylamino)methyl]-5-[[4-[(dimethylamino)methyl]-3-hydroxyphenyl]disulfanyl]phenol (460.0 mg, compound 11c) as a brown oil. MS measured value (ESI + )[(M+H) + ]:365.2.

[0155] Step 4: Preparation of 5-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-[(dimethylamino)methyl]phenol (Example 11) The title compound was prepared in the same manner as in Example 5, Step 3, by using 2-[(dimethylamino)methyl]-5-[[4-[(dimethylamino)methyl]-3-hydroxy-phenyl]disulfanyl]phenol (compound 11c) instead of N-ethyl-N-[[4-[[4-[[ethyl(propyl)amino]methyl]phenyl]disulfanyl]phenyl]methyl]propan-1-amine (compound 5b). 5-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-[(dimethylamino)methyl]phenol (10.5 mg, Example 11) was obtained as a white solid. MS measurement value (ESI + )[(M+H) + ]:388.1. 1H NMR(400MHz,CD3OD)δ ppm:6.91(d,J=8.0Hz,1H),6.45(dd,J=8.0Hz,2.0Hz,1H),6.32(d,J=2.0Hz,1H), 4.63(s,2H),3.61-3.55(m,4H),2.52(s,3H),2.29(s,6H),1.21(t,J=7.2Hz,3H).

[0156] Example 12 5-[4-amino-2-(ethoxymethyl)-1,6-dimethylimidazo[4,5-c]pyridine-7-yl]sulfanyl-2-[(dimethylamino)methyl]phenol TIFF2026518208000091.tif46170

[0157] Step 1: Preparation of 2-chloro-5-iodo-6-methyl-3-nitropyridine-4-amine (compound 12a) A solution of 2,4-dichloro-5-iodo-6-methyl-3-nitropyridine (15.0 g, compound 8b, 45.06 mmol) in NH3 / MeOH (50.0 mL, 350.0 mmol, 7.0 M) was stirred at 25°C for 12 hours. The mixture was concentrated under vacuum. The residue was purified by silica gel column to obtain 2-chloro-5-iodo-6-methyl-3-nitropyridine-4-amine (7.00 g, compound 12a) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm:7.08(s,2H),2.57(s,3H).

[0158] Step 2: Preparation of N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methyl-3-nitropyridine-2,4-diamine (compound 12b) Compound 12b was prepared in the same manner as in Example 1, Step 2, by using 2-chloro-5-iodo-6-methyl-3-nitropyridine-4-amine (compound 12a) instead of 2-chloro-6-methyl-3-nitropyridine-4-amine (compound 1a). N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methyl-3-nitropyridine-2,4-diamine (10.0 g, compound 12b) was obtained as a pale red oily substance. 1 H NMR(400MHz,CDCl3)δ ppm:7.09(d,J=8.0Hz,2H),6.67(br s,2H),6.44-6.34(m,4H),4.39(s,4H),3.79(s,6H),3.65(s,6H),2.55(s,3H).

[0159] Step 3: Preparation of N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methylpyridine-2,3,4-triamine (compound 12c) Compound 12c was prepared in the same manner as in Example 8, Step 5, by using N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methyl-3-nitropyridine-2,4-diamine (compound 12b) instead of N2,N2,N4-tris[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methyl-3-nitropyridine-2,4-diamine (compound 8d). N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methylpyridine-2,3,4-triamine (8.4g, compound 12c) was obtained as a light brown solid and was used directly in the next step without further purification.

[0160] Step 4: Preparation of N-[4-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-5-iodo-6-methyl-3-pyridyl]-2-ethoxyacetamide (compound 12d) Compound 12d was prepared in the same manner as in Example 1, Step 4, by using N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methylpyridine-2,3,4-triamine (compound 12c) instead of N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-6-methylpyridine-2,3,4-triamine (compound 1c). N-[4-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-5-iodo-6-methyl-3-pyridyl]-2-ethoxyacetamide (9.20 g, compound 12d) was obtained as a pale yellow oil and used directly in the next step without further purification.

[0161] Step 5: Preparation of N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 12e) Compound 12e was prepared in the same manner as in Example 1, Step 5, by using N-[4-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-5-iodo-6-methyl-3-pyridyl]-2-ethoxyacetamide (compound 12d) instead of N-[4-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-5-iodo-6-methyl-3-pyridyl]-2-ethoxyacetamide (compound 12d) instead of N-[4-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-5-iodo-6-methyl-3-pyridyl]-2-ethoxyacetamide (compound 12d). N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (5.00 g, compound 12e) was obtained as a pale yellow solid. MS measurement value (ESI + )[(M+H) + ]:633.3.

[0162] Step 6: Preparation of N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-7-iodo-1,6-dimethylimidazo[4,5-c]pyridine-4-amine (compound 12f) Compound 12f was prepared in the same manner as in Example 7, Step 1, by using N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 12e) instead of N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 12e). N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-7-iodo-1,6-dimethyl-imidazo[4,5-c]pyridine-4-amine (600.0 mg, compound 12f) was obtained as a pale yellow solid. MS measured value (ESI + )[(M+H) + ]:647.2.

[0163] Step 7: Preparation of 5-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-2-(ethoxymethyl)-1,6-dimethylimidazo[4,5-c]pyridine-7-yl]sulfanyl-2-[(dimethylamino)methyl]phenol (12g of compound) TIFF2026518208000098.tif68170 A mixture of 2-[(dimethylamino)methyl]-5-[[4-[(dimethylamino)methyl]-3-hydroxyphenyl]disulfanyl]phenol (51.31 mg, compound 11c, 0.14 mmol), N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-7-iodo-1,6-dimethylimidazo[4,5-c]pyridine-4-amine (130.0 mg, compound 12f, 0.2 mmol), and K2CO3 (55.58 mg, 0.4 mmol) in DMSO (3.0 mL) is mixed with Fe (11.41 mg, 0.2 mmol) and Cu2S (19.21 mg, 0.12 mmol) for 20 minutes. oThe compound was added with C. The suspension was degassed under vacuum and purged three times with N2. The mixture was stirred at 100°C for 16 hours under an N2 atmosphere. The reaction mixture was purified by reverse preparative HPLC to obtain 5-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-2-(ethoxymethyl)-1,6-dimethyl-imidazo[4,5-c]pyridine-7-yl]sulfanyl-2-[(dimethylamino)methyl]phenol (38.0 mg, 12 g of compound) as a pale red oil. MS measurement value (ESI + )[(M+H) + ]:702.3.

[0164] Step 8: Preparation of 5-[4-amino-2-(ethoxymethyl)-1,6-dimethylimidazo[4,5-c]pyridine-7-yl]sulfanyl-2-[(dimethylamino)methyl]phenol (Example 12) A solution of 5-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-2-(ethoxymethyl)-1,6-dimethyl-imidazo[4,5-c]pyridine-7-yl]sulfanyl-2-[(dimethylamino)methyl]phenol (38.0 mg, 12 g of compound, 0.05 mmol) and TFA (2.0 mL) in DCM (2.0 mL) was stirred at 20°C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC to obtain 5-[4-amino-2-(ethoxymethyl)-1,6-dimethyl-imidazo[4,5-c]pyridine-7-yl]sulfanyl-2-[(dimethylamino)methyl]phenol (5.7 mg, Example 12) as a white solid. MS measured value (ESI + )[(M+H) + ]:402.1. 1 H NMR(400MHz,CD3OD)δ ppm:6.94(d,J=8.0Hz,1H),6.43(dd,J=8.0Hz,2.0Hz,1H),6.29(d,J=2.0Hz,1H),4.69( s,2H),4.00(s,3H),3.61-3.53(m,4H),2.56(s,3H),2.29(s,6H),1.19(t,J=7.2Hz,3H).

[0165] Example 13 5-[2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]ethyl]-2-[(dimethylamino)methyl]phenol TIFF2026518208000100.tif40170

[0166] Step 1: Preparation of methyl 2-(4-formyl-3-methoxyphenyl)acetate (compound 13a) To a solution of 4-bromo-2-methoxybenzaldehyde (15.28 g, 71.06 mmol) in m-xylene (250.0 mL, 71.06 mmol), potassium 3-methoxy-3-oxopropanoate (16.65 g, 106.58 mmol), Pd2(allyl)2Cl2 (519.98 mg, 1.42 mmol), BINAP (2.65 g, 4.26 mmol), and DMAP (868.1 mg, 7.11 mmol) were added at 25°C. The mixture was degassed three times under vacuum using N2. The suspension was stirred under N2 at 140°C for 20 hours. The suspension was concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain methyl 2-(4-formyl-3-methoxyphenyl) acetate (2.09 g, compound 13a) as a yellow oily substance. 1 H NMR(400MHz,CDCl3)δ ppm:10.44(s,1H),7.79(d,J=8.0Hz,1H),6.96(d,J=8.0Hz,1H),6.94(s,1H),3.94(s,3H),3.73(s,3H),3.68(s,2H).

[0167] Step 2: Preparation of methyl 2-[4-[(dimethylamino)methyl]-3-methoxyphenyl]acetate (compound 13b) To a solution of methyl 2-(4-formyl-3-methoxyphenyl) acetate (1.50 g, compound 13a, 7.2 mmol) in TIFF2026518208000102.tif32170DCE (50 mL), dimethylamine (36.02 mL, 72.04 mmol, 2.0 M in MeOH) and acetic acid (865.23 mg, 14.41 mmol) were added in 20 ml. o It was added with C. The mixture was stirred at 20°C for 1 hour. Then, NaBH(OAc)3 (9.16 g, 43.23 mmol) was added to the mixture for 20 minutes. o The mixture was added with C. The mixture was stirred at 20°C for 2 hours. The mixture was concentrated under vacuum, and the residue was purified by back-preparative HPLC to obtain methyl 2-[4-[(dimethylamino)methyl]-3-methoxyphenyl]acetate (907.0 mg, compound 13b) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:7.22(d,J=7.6Hz,1H),6.84(d,J=7.6Hz,1H),6.80(s,1H),3.84(s,3H),3.70(s,3H),3.62(s,2H),3.43(s,2H),2.26(s,6H).

[0168] Step 3: Preparation of 2-[4-[(dimethylamino)methyl]-3-methoxyphenyl]ethanol (compound 13c) To a solution of methyl 2-[4-[(dimethylamino)methyl]-3-methoxyphenyl]acetate (907.0 mg, compound 13b, 3.82 mmol) in THF (10 mL), LiAlH4 (290.0 mg, 7.64 mmol) was added under N2 at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction was then quenched by adding H2O (0.5 mL), NaOH (0.5 mL, 15% wt.), and H2O (1.5 mL) at 0°C. The suspension was stirred at 25°C for 10 minutes and filtered. The filtrate was then dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum to obtain 2-[4-[(dimethylamino)methyl]-3-methoxyphenyl]ethanol (797.0 mg, compound 13c) as a colorless oil, which was used directly in the next step.

[0169] Step 4: Preparation of 5-(2-bromoethyl)-2-[(dimethylamino)methyl]phenol (compound 13d) TIFF2026518208000104.tif301702-[4-[(dimethylamino)methyl]-3-methoxyphenyl]ethanol (797.0 mg, compound 13c, 3.81 mmol) was dissolved in DCM (10 mL) to which BBr3 (11.42 mL, 11.42 mmol, 1.0 M in DCM) was added dropwise at 0°C. The mixture was heated to 25°C and stirred at 25°C for 6 hours. The reaction was then quenched by adding MeOH (20 mL) dropwise at 0°C and concentrated under vacuum. The residue was purified by reverse preparative HPLC to obtain 5-(2-bromoethyl)-2-[(dimethylamino)methyl]phenol (785.0 mg, compound 13d) as a pale yellow oil. MS measured value (ESI + )[(M+H) + ]:257.9.

[0170] Step 5: Preparation of 5-[2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]ethyl]-2-[(dimethylamino)methyl]phenol (Example 13) The title compound was prepared in the same manner as in Example 10, Step 3, by using 5-(2-bromoethyl)-2-[(dimethylamino)methyl]phenol (compound 13d) instead of 4-(2-bromoethyl)benzaldehyde (compound 10b). 5-[2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]ethyl]-2-[(dimethylamino)methyl]phenol (4.19 mg, Example 13) was obtained as a pale yellow solid. MS measurement value (ESI + )[(M+H) + ]:416.1. 1H NMR(400MHz,CD3OD)δ ppm:7.13(d,J=8.0Hz,1H),6.74-6.65(m,2H),4.73(s,2H),4.22(s,2H),3.71-3.62(m,2H),3 .10(t,J=7.6Hz,2H),2.87(t,J=7.6Hz,2H),2.81(s,6H),2.66(s,3H),1.26(t,J=6.8Hz,3H).

[0171] Example 14 2-Butyl-7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine TIFF2026518208000106.tif40170

[0172] Step 1: Preparation of N-[4-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-methyl-3-pyridyl]pentanamide (compound 14a) TIFF2026518208000107.tif48170 A mixture of N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-6-methylpyridine-2,3,4-triamine (compound 1c, 4.56 mmol) and DIEA (1.18 g, 9.12 mmol) in DCM (20 mL) was mixed with valeryl chloride (0.66 g, 5.47 mmol) at 0°C. The mixture was stirred at 25°C for 12 hours. The mixture was then diluted with water (100 mL) and extracted with DCM (2 × 100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain N-[4-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-methyl-3-pyridyl]pentanamide (2.0 g, compound 14a) as a pale yellow oily substance.

[0173] Step 2: Preparation of 2-butyl-N,N-bis[(2,4-dimethoxyphenyl)methyl]-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 14b) TIFF2026518208000108.tif50170 NaOH (1.85 g, 45.61 mmol) was added at 20°C to a solution of N-[4-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-methyl-3-pyridyl]pentanamide (2.38 g, compound 14a, 4.56 mmol) in ethanol (20 mL) and water (10 mL). The mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was then diluted with H2O (100 mL) and extracted with DCM (3 × 100 mL). The filtrate was concentrated under vacuum, and the residue was purified by reverse preparative HPLC to obtain 2-butyl-N,N-bis[(2,4-dimethoxyphenyl)methyl]-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (1.4 g, compound 14b) as a yellow solid. MS measurement value (ESI + )[(M+H) + ]:505.3.

[0174] Step 3: Preparation of 2-butyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 14c) A solution of 2-butyl-N,N-bis[(2,4-dimethoxyphenyl)methyl]-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (1.4 g, compound 14b, 2.77 mmol) and TFA (3.0 mL) in DCM (3.0 mL) was stirred at 20°C for 4 hours. The reaction mixture was concentrated under vacuum. The residue was purified by reverse preparative HPLC to obtain 2-butyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (0.56 g, compound 14c) as a white solid.

[0175] Step 4: Preparation of 2-butyl-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 14d) TIFF2026518208000110.tif28170 To a solution of 2-butyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (0.57g, compound 14c, 2.77 mmol) in acetic acid (6.0 mL), add N-iodosuccinimide (1.25g, 5.55 mmol) for 20 minutes. o The compound was added with C. The mixture was stirred at 20°C for 2 hours, and then concentrated under vacuum. The residue was purified by reverse preparative HPLC to obtain 2-butyl-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (0.43 g, compound 14d) as an orange oil. MS measured value (ESI + )[(M+H) + ]:330.9. 1 H NMR(400MHz,DMSO-d6)δ ppm:13.12(s,1H),11.07(s,1H),8.167(s,1H),2.86(t,J=7.6Hz,2H),2.56(s,3H),1.78-1.69(m,2H),1.40-1.30(m,2H),0.91(t,J=7.2Hz,3H).

[0176] Step 5: Preparation of 2-butyl-7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (Example 14) The title compound was prepared in the same manner as in Example 5, Step 3, by using 2-butyl-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 14d) instead of 2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 1g), and 4-[(dimethylamino)methyl]benzenethiol (compound 1k) instead of N-ethyl-N-[[4-[[4-[[ethyl(propyl)amino]methyl]phenyl]disulfanyl]phenyl]methyl]propan-1-amine (compound 5b). 2-butyl-7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (30.1 mg, Example 14) was obtained as a white solid. MS measurement value (ESI+ )[(M+H) + ]:370.2. 1 H NMR(400MHz,CD3OD)δ ppm:7.17(d,J=8.4Hz,2H),6.95(d,J=8.4Hz,2H),3.44(s,2H),2.82(t,J=7.6Hz,2H), 2.50(s,3H),2.23(s,6H),1.83-1.71(m,2H),1.47-1.28(m,2H),0.94(t,J=7.2Hz,3H).

[0177] Example 15 2-butyl-7-[2-[4-[(dimethylamino)methyl]phenyl]ethylsulfanyl]-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine TIFF2026518208000112.tif37170

[0178] Step 1: Preparation of 4-[2-[(4-amino-2-butyl-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl)sulfanyl]ethyl]benzaldehyde (compound 15a) Compound 15a was prepared in the same manner as in Example 13, Step 5, by using 2-butyl-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 14d) instead of 2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 1g) and 4-(2-bromoethyl)benzaldehyde (compound 10b) instead of 5-(2-bromoethyl)-2-[(dimethylamino)methyl]phenol (compound 13d). 4-[2-[(4-amino-2-butyl-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl)sulfanyl]ethyl]benzaldehyde (45.0 mg, compound 15a) was obtained as a yellow solid.

[0179] Step 2: Preparation of 2-butyl-7-[2-[4-[(dimethylamino)methyl]phenyl]ethylsulfanyl]-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (Example 15) The title compound was prepared in the same manner as in Example 1, Step 10, by using 4-[2-[(4-amino-2-butyl-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl)sulfanyl]ethyl]benzaldehyde (compound 15a) instead of S-(4-formylphenyl)N,N-dimethylcarbamothioate (compound 1i). 2-butyl-7-[2-[4-[(dimethylamino)methyl]phenyl]ethylsulfanyl]-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (5.2 mg, Example 15) was obtained as a pale red solid. MS measurement value (ESI + )[(M+H) + ]:398.2. 1 H NMR(400MHz,CD3OD)δ ppm:7.15(d,J=8.0Hz,2H),7.06(d,J=8.0Hz,2H),3.42(s,2H),2.96(t,J=8.0Hz,2H),2.88(t,J=7.6Hz,2H), 2.79(t,J=8.0Hz,2H),2.55(s,3H),2.21(s,6H),1.87-1.77(m,2H),1.48-1.38(m,2H),0.98(t,J=7.6Hz,3H).

[0180] Example 16 6-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-3-[(dimethylamino)methyl]-2-methylphenol TIFF2026518208000115.tif42170

[0181] Step 1: Preparation of 2-methoxy-4-(methoxymethyl)phenol (compound 16a) TIFF2026518208000116.tif22170 To a solution of 4-hydroxy-3-methoxybenzyl alcohol (10.0 g, 64.87 mmol) in methanol (150 mL), add p-toluenesulfonic acid (0.56 g, 3.24 mmol) for 20 minutes. o The mixture was added with C. The reaction mixture was stirred at 20°C for 6 hours. The mixture was concentrated under vacuum, diluted with saturated NaHCO3 solution (200 mL), and extracted with EA (3 × 200 mL). The organic layer was washed with brine (3 × 200 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column to obtain 2-methoxy-4-(methoxymethyl)phenol (10.0 g, compound 16a) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:6.89-6.81(m,3H),5.76(s,1H),4.38(s,2H),3.89(s,3H),3.37(s,3H).

[0182] Step 2: Preparation of 2-methoxy-4-(methoxymethyl)-3-methylphenol (compound 16b) To a solution of 2-methoxy-4-(methoxymethyl)phenol (9.0 g, compound 16a, 53.51 mmol) in THF (90 mL), n-BuLi (64.21 mL, 160.53 mmol) was slowly added at -10°C. After the addition was complete, the reaction mixture was stirred at 0°C for 2.5 hours. Then, after the reaction mixture was cooled to -10°C, iodomethane (11.56 mL, 187.29 mmol) was added. The reaction mixture was stirred at 0°C for 1.5 hours. Then, the reaction mixture was quenched with water (100 mL) and acidified to pH=7 with aqueous HCl (1.0 M). The mixture was extracted with EA (3 × 150 mL). The organic layer was washed with brine (3 × 100 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain 2-methoxy-4-(methoxymethyl)-3-methylphenol (6.0 g, compound 16b) as a pale yellow oily substance.

[0183] Step 3: Preparation of 4-hydroxy-3-methoxy-2-methylbenzaldehyde (compound 16c) 7.47 g of DDQ (32.93 mmol) was slowly added at 20°C to a solution of 2-methoxy-4-(methoxymethyl)-3-methylphenol (6.0 g, compound 16b, 32.93 mmol) in DCM (75 mL) and water (7.5 mL). The reaction mixture was stirred at 20°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain 4-hydroxy-3-methoxy-2-methylbenzaldehyde (4.5 g, compound 16c) as a white solid.

[0184] Step 4: Preparation of O-(4-formyl-2-methoxy-3-methylphenyl)N,N-dimethylcarbamothioeth 5> (compound 16d) To a solution of 4-hydroxy-3-methoxy-2-methylbenzaldehyde (1.0 g, compound 16c, 6.02 mmol) in DMF (10 mL), DABCO (2.7 g, 24.07 mmol) and dimethylthiocarbamoyl chloride (1.49 g, 12.04 mmol) were added at 20°C. The mixture was stirred at 20°C for 12 hours. The mixture was then diluted with H2O (100 mL) and extracted with EA (3 × 100 mL). The organic layer was washed with brine (3 × 80 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by recrystallization from MeOH (10 mL) to obtain O-(4-formyl-2-methoxy-3-methylphenyl)N,N-dimethylcarbamothioate (500.0 mg, compound 16d) as a pale yellow solid. MS measurement value (ESI + )[(M+H) + ]:254.2.

[0185] Step 5: Preparation of S-(4-formyl-2-methoxy-3-methylphenyl)N,N-dimethylcarbamothioate (compound 16e) A solution of O-(4-formyl-2-methoxy-3-methylphenyl)N,N-dimethylcarbamothioate (2.2 g, compound 16d, 8.68 mmol) in TIFF2026518208000120.tif34170Ph2O (25.0 mL) was stirred at 240°C for 2 hours. The reaction product turned black. The mixture was purified by silica gel column chromatography to obtain S-(4-formyl-2-methoxy-3-methylphenyl)N,N-dimethylcarbamothioate (1.00 g, compound 16e) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:10.27(s,1H),7.62-7.55(m,2H),3.80(s,3H),3.17(s,3H),3.11(s,3H),2.64(s,3H).

[0186] Step 6: Preparation of S-[4-[(dimethylamino)methyl]-2-methoxy-3-methylphenyl]N,N-dimethylcarbamothioate (compound 16f) TIFF2026518208000121.tif34170 To a solution of S-(4-formyl-2-methoxy-3-methylphenyl)N,N-dimethylcarbamothioate (1.0 g, compound 16e, 3.95 mmol) in methanol (10 mL), NaOAc (0.97 g, 11.84 mmol) and dimethylamine hydrochloride (0.97 g, 11.84 mmol) were added at 20°C. The reaction mixture was stirred at 20°C for 12 hours. Then, NaBH(OAc)3 (3.35 g, 15.79 mmol) was added to the mixture at 20°C. The reaction mixture was stirred at 20°C for 2 hours, then concentrated under vacuum. The residue was purified by reverse preparative HPLC to obtain S-[4-[(dimethylamino)methyl]-2-methoxy-3-methylphenyl]N,N-dimethylcarbamothioate (850.0 mg, compound 16f) as a white solid. MS measurement value (ESI + )[(M+H) + ]:283.2.

[0187] Step 7: Preparation of S-[4-[(dimethylamino)methyl]-2-hydroxy-3-methylphenyl]N,N-dimethylcarbamothioate (16g of compound) To a solution of S-[4-[(dimethylamino)methyl]-2-methoxy-3-methylphenyl]N,N-dimethylcarbamothioate (800.0 mg, compound 16 f, 2.83 mmol) in DCM (10 mL), BBr3 (7.08 mL, 7.08 mmol) was added dropwise at 0°C. The mixture was stirred at 25°C for 3 hours. The reaction product was quenched dropwise with MeOH (10 mL) at 0°C. The reaction mixture was concentrated under vacuum, and the residue was purified by reverse preparative HPLC to obtain S-[4-[(dimethylamino)methyl]-2-hydroxy-3-methylphenyl]N,N-dimethylcarbamothioate (650.0 mg, compound 16 g) as a white solid.

[0188] Step 8: Preparation of 3-[(dimethylamino)methyl]-2-methyl-6-sulfanylphenol (compound 16h) To a solution of S-[4-[(dimethylamino)methyl]-2-hydroxy-3-methylphenyl]N,N-dimethylcarbamothioate (590.0 mg, 16 g of compound, 1.88 mmol) in THF (10 mL), LiAlH4 (356.08 mg, 9.38 mmol) was added under N2 at 0°C. The mixture was stirred at 20°C for 0.5 hours. The mixture was quenched at 0°C with H2O (0.4 mL), NaOH (0.4 mL in H2O, 10 M), and H2O (1.2 mL). The reaction mixture was stirred at 20°C for 2 hours. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by reverse preparative HPLC to obtain 3-[(dimethylamino)methyl]-2-methyl-6-sulfanylphenol (250.0 mg, compound 16h) as a light brown solid. MS measurement value (ESI + )[(M+H) + ]:198.3.

[0189] Step 9: Preparation of 6-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-3-[(dimethylamino)methyl]-2-methylphenol (Example 16) TIFF2026518208000124.tif42170 A solution containing 2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (80.0 mg, 1 g of compound, 0.24 mmol) in DMSO (3.0 mL) is mixed with 3-[(dimethylamino)methyl]-2-methyl-6-sulfanylphenol (94.56 mg, 16 h of compound, 0.24 mmol), Cu2S (76.67 mg, 0.48 mmol), Fe (40.32 mg, 0.72 mmol), and K2CO3 (133.16 mg, 0.96 mmol) for 20 minutes. o It was added with C. The suspension was degassed under vacuum and purged three times with N2. The reaction mixture was stirred under N2 at 100°C for 12 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC to obtain 6-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-3-[(dimethylamino)methyl]-2-methylphenol (3.74 mg, Example 16) as a white solid. MS measured value (ESI + )[(M+H) + ]:402.4. 1 H NMR(400MHz,CD3OD)δ ppm:6.73(d,J=8.4Hz,1H),6.52(d,J=8.4Hz,1H),4.65(s,2H),3.98(br s,2H),3.63-3.58(m,2H),2.62(s,6H),2.53(s,3H),2.31(s,3H),1.22(t,J=6.8Hz,3H).

[0190] Example 17 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-(diethylaminomethyl)phenol TIFF2026518208000125.tif38170

[0191] Step 1: Preparation of 2-ethylhexyl 3-(4-formyl-2-hydroxyphenyl)sulfanylpropanoate (compound 17a) To a solution of 3-hydroxy-4-iodobenzaldehyde (10.0 g, 40.32 mmol) in 1,4-dioxane (100 mL), 2-ethylhexyl 3-mercaptopropionate (13.21 g, 60.48 mmol), DIEA (15.63 g, 120.96 mmol), Pd2(dba)3 (1.17 g, 2.02 mmol), and XantPhos (3.69 g, 4.03 mmol) were added at 25°C. The suspension was degassed under vacuum and purged three times with N2. The suspension was heated to 110°C and stirred under N2 at 110°C for 16 hours. The reaction mixture was then filtered through Celite and washed with MeOH (100 mL). The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography and concentrated under vacuum to obtain 2-ethylhexyl 3-(4-formyl-2-hydroxyphenyl)sulfanylpropanoate (7.6 g, compound 17a) as a pale yellow oil. MS measurement value (ESI + )[(M+H) + ]:337.1.

[0192] Step 2: Preparation of 2-ethylhexyl 3-[4-(diethylaminomethyl)-2-hydroxyphenyl]sulfanylpropanoate (compound 17b) TIFF2026518208000127.tif25170 Diethylamine (1.51 g, 20.68 mmol) was added at 20°C to a solution of 2-ethylhexyl 3-(4-formyl-2-hydroxyphenyl)sulfanylpropanoate (700.0 mg, compound 17a, 2.07 mmol) in methanol (10 mL). The reaction mixture was stirred at 20°C for 12 hours, and then NaBH(OAc)3 (4.38 g, 20.68 mmol) was added at 20°C. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by reverse preparative HPLC to obtain 2-ethylhexyl 3-[4-(diethylaminomethyl)-2-hydroxyphenyl]sulfanylpropanoate (150.0 mg, compound 17b) as a pale yellow oil. MS measured value (ESI + )[(M+H) + ]:394.0.

[0193] Step 3: Preparation of 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-(diethylaminomethyl)phenol (Example 17) The title compound was prepared in the same manner as in Example 16, Step 9, by using 2-ethylhexyl 3-[4-(diethylaminomethyl)-2-hydroxyphenyl]sulfanylpropanoate (compound 17b) instead of 3-[(dimethylamino)methyl]-2-methyl-6-sulfanylphenol (compound 16h). 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-(diethylaminomethyl)phenol (25.97 mg, Example 17) was obtained as a white solid. MS measurement value (ESI + )[(M+H) + ]:416.2. 1 H NMR(400MHz,CD3OD)δ ppm:6.80(d,J=1.6Hz,1H),6.60(d,J=8.0Hz,J=1.6Hz,1H),6.45(d,J=8.0Hz,1H),4.63(s,2H),3.62-3 .57(m,2H),3.56(s,2H),2.60-2.54(m,4H),2.53(s,3H),1.21(t,J=6.8Hz,3H),1.06(t,J=7.2Hz,6H).

[0194] Example 18 7-[[4-[(dimethylamino)methyl]-1H-indole-7-yl]sulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine TIFF2026518208000129.tif43170

[0195] Step 1: Preparation of methyl 7-bromo-1H-indole-4-carboxylate (compound 18a) To a solution of methyl 4-bromo-3-nitrobenzoate (10.0 g, 38.46 mmol) in THF (100 mL), vinyl magnesium bromide (115.37 mL, 115.37 mmol) was added dropwise at -40°C. The reaction mixture was stirred at -40°C for 2 hours. The reaction mixture was then quenched by adding saturated NH4Cl (200 mL) dropwise at -40°C. The mixture was warmed to 25°C and stirred at this temperature for 1 hour, then extracted with EA (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography and concentrated under vacuum to obtain methyl 7-bromo-1H-indole-4-carboxylate (2.8 g, compound 18a) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:8.55(s,1H),7.82(d,J=8.0Hz,1H),7.44-7.42(m,2H),7.29-7.27(m,1H),3.99(s,3H).

[0196] Step 2: Preparation of (7-bromo-1H-indole-4-yl)methanol (compound 18b) To a solution of methyl 7-bromo-1H-indole-4-carboxylate (2.80 g, compound 18a, 11.02 mmol) in THF (28 mL), LiAlH4 (836.43 mg, 22.04 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. After 2 hours, H2O (1 mL) and NaOH (1 mL in H2O, 10 M) were added dropwise at 0°C, followed by the addition of H2O (3 mL) and Na2SO4 (30 g). The reaction mixture was stirred at 20°C for 2 hours, then filtered through Celite and washed with DCM / MeOH (100 mL, V / V=1 / 10). The filtrate was concentrated under vacuum, and the residue was purified by reverse preparative HPLC to obtain (7-bromo-1H-indole-4-yl)methanol (2.5 g, compound 18b) as a light brown solid. 1H NMR(400MHz,CD3OD)δ ppm:7.32(d,J=3.2Hz,1H),7.25(d,J=7.6Hz,1H),6.97(d,J=7.6Hz,1H),6.67(d,J=3.2Hz,1H),4.86(s,2H).

[0197] Step 3: Preparation of 7-bromo-1H-indole-4-carbaldehyde (compound 18c) To a solution of (7-bromo-1H-indole-4-yl)methanol (2.5 g, compound 18b, 11.06 mmol) in 30 mL of DCM, MnO2 (14.42 g, 165.88 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered through Celite and washed with 100 mL of DCM. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography and concentrated under vacuum to obtain 7-bromo-1H-indole-4-carbaldehyde (1.5 g, compound 18c) as a pale yellow solid. MS measured value (ESI + )[(M+H) + ]:226.1.

[0198] Step 4: Preparation of 2-ethylhexyl 3-[(4-formyl-1H-indole-7-yl)sulfanyl]propanoate (compound 18d) Compound 18d was prepared in the same manner as in Example 17, Step 1, by using 7-bromo-1H-indole-4-carbaldehyde (compound 18c) instead of 3-hydroxy-4-iodobenzaldehyde. 2-ethylhexyl 3-[(4-formyl-1H-indole-7-yl)sulfanyl]propanoate (2.0 g, compound 18d) was obtained as a pale yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:362.4.

[0199] Step 5: Preparation of 2-ethylhexyl 3-[[4-[(dimethylamino)methyl]-1H-indole-7-yl]sulfanyl]propanoate (compound 18e) Compound 18e was prepared in the same manner as in Example 1, Step 1o by using 2-ethylhexyl 3-[(4-formyl-1H-indole-7-yl)sulfanyl]propanoate (compound 18d) instead of S-(4-formylphenyl)N,N-dimethylcarbamothioate (compound 1i). 2-ethylhexyl 3-[[4-[(dimethylamino)methyl]-1H-indole-7-yl]sulfanyl]propanoate (200.0 mg, compound 18e) was obtained as a light brown oily substance.

[0200] Step 6: Preparation of 7-[[4-[(dimethylamino)methyl]-1H-indole-7-yl]sulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (Example 18) The title compound was prepared in the same manner as in Example 16, Step 9, by using 2-ethylhexyl 3-[[4-[(dimethylamino)methyl]-1H-indole-7-yl]sulfanyl]propanoate (compound 18e) instead of 3-[(dimethylamino)methyl]-2-methyl-6-sulfanylphenol (compound 16h). 7-[[4-[(dimethylamino)methyl]-1H-indole-7-yl]sulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (15.12 mg, Example 18) was obtained as a white solid. MS measurement (ESI + )[(M+H) + ]:411.3. 1H NMR(400MHz,CD3OD)δ ppm:7.34(d,J=3.2Hz,1H),6.82(d,J=7.6Hz,1H),6.64(d,J=3.2Hz,1H),6.47(d,J=7.6Hz,1H),4. 64(s,2H),3.72-3.66(m,2H),3.62-3.55(m,2H),2.53(s,3H),2.25(s,6H),1.20(t,J=7.2Hz,3H).

[0201] Example 19 7-[[4-[(dimethylamino)methyl]-1H-indazole-7-yl]sulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine TIFF2026518208000136.tif44170

[0202] Step 1: Preparation of 6-bromo-2-fluoro-3-iodobenzaldehyde (compound 19a) To a solution of 1-bromo-3-fluoro-4-iodobenzene (10.0 g, 33.23 mmol) in THF (100 mL), LDA (19.94 mL, 39.88 mmol) was added dropwise at -78°C. The mixture was stirred at -78°C for 0.5 hours. Then, DMF (7.29 g, 99.7 mmol) was added dropwise to the mixture at -78°C. The mixture was stirred at -78°C for 2 hours. The mixture was quenched with saturated NH₄Cl (200 mL) at -78°C. The mixture was warmed to 25°C and extracted with siRNA (2 × 400 mL). The organic layer was washed with brine (2 × 200 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography and concentrated under vacuum to obtain 6-bromo-2-fluoro-3-iodobenzaldehyde (7.6 g, compound 19a) as a yellow solid.

[0203] Step 2: Preparation of 4-bromo-7-iodo-1H-indazole (compound 19b) TIFF2026518208000138.tif23170A solution of 6-bromo-2-fluoro-3-iodobenzaldehyde (6.6g, compound 19a, 20.07 mmol) in DMSO (80 mL) is mixed with hydrazine hydrate (7.69 g, 150.5 mmol) for 20 minutes. o The compound was added with C. The mixture was stirred at 130°C for 6 hours. The mixture was diluted with water (150 mL) and extracted with EA (3 × 300 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography and concentrated under vacuum to obtain 4-bromo-7-iodo-1H-indazole (5.90 g, compound 19b) as a white solid. MS measured value (ESI + )[(M+H) + ]:324.9.

[0204] Step 3: Preparation of 2-ethylhexyl 3-[(4-bromo-1H-indazole-7-yl)sulfanyl]propanoate (compound 19c) Compound 19c was prepared in the same manner as in Example 17, Step 1, by using 4-bromo-7-iodo-1H-indazole (compound 19b) instead of 3-hydroxy-4-iodobenzaldehyde. 2-ethylhexyl 3-[(4-bromo-1H-indazole-7-yl)sulfanyl]propanoate (1.60 g, compound 19c) was obtained as a yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:413.1.

[0205] Step 4: Preparation of 4-bromo-7-[(4-bromo-1H-indazole-7-yl)disulfanyl]-1H-indazole (compound 19d) To a solution of 2-ethylhexyl 3-[(4-bromo-1H-indazole-7-yl)sulfanyl]propanoate (800.0 mg, compound 19c, 1.94 mmol) in THF (10.0 mL), t-BuOK (5.81 mL, 5.81 mmol, 1.0 M in THF) was added dropwise at -78°C. The mixture was stirred at -78°C for 1 hour, then warmed to 25°C and adjusted to pH=5 with aqueous HCl (1.0 M). The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and concentrated under vacuum to obtain 4-bromo-7-[(4-bromo-1H-indazole-7-yl)disulfanyl]-1H-indazole (170.0 mg, compound 19d) as a pale yellow solid. MS measurement value (ESI + )[(M+H) + ]:456.9.

[0206] Step 5: Preparation of 7-[(4-bromo-1H-indazole-7-yl)sulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 19e) Compound 19e was prepared in the same manner as in Example 16, Step 9, by using 4-bromo-7-[(4-bromo-1H-indazole-7-yl)disulfanyl]-1H-indazole (compound 19d) instead of 3-[(dimethylamino)methyl]-2-methyl-6-sulfanyl-phenol (compound 16h). 7-[(4-bromo-1H-indazole-7-yl)sulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (60.0 mg, compound 19e) was obtained as a light brown foam. MS measurement value (ESI + )[(M+H) + ]:433.2.

[0207] Step 6: Preparation of 7-[[4-[(dimethylamino)methyl]-1H-indazole-7-yl]sulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (Example 19) TIFF2026518208000142.tif431701,4-Dioxane (1.0 mL) and water (0.2 mL) in a solution of 7-[(4-bromo-1H-indazole-7-yl)sulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (50.0 mg, compound 19e, 0.12 mmol), to which potassium dimethylaminomethyltrifluoroborate (57.12 mg, 0.35 mmol), KOH (32.37 mg, 0.58 mmol), and XPhos Pd G4 (19.86 mg, 0.02 mmol) are added 25 times. o It was added with C. The suspension was degassed under vacuum and purged three times with nitrogen. The mixture was stirred at 100°C for 12 hours under an N2 balloon, then filtered, and the filtrate was concentrated under vacuum. The residue was purified by reverse preparative HPLC and freeze-dried to obtain 7-[[4-[(dimethylamino)methyl]-1H-indazole-7-yl]sulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (8.0 mg, Example 19) as a white solid. MS measured value (ESI + )[(M+H) + ]:412.2. 1 H NMR(400MHz,CD3OD)δ ppm:8.26(s,1H),6.88(d,J=7.2Hz,1H),6.65-6.44(m,1H),4.63(s,2H),3.7 2(s,2H),3.63-3.53(m,2H),2.55(s,3H),2.25(s,6H),1.20(t,J=7.2Hz,3H).

[0208] Example 20 7-[2-amino-4-[(dimethylamino)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine TIFF2026518208000143.tif38170

[0209] Step 1: Preparation of 2-ethylhexyl 3-(4-formyl-2-nitrophenyl)sulfanylpropanoate (compound 20a) To a solution of 4-fluoro-3-nitrobenzaldehyde (8.0 g, 47.31 mmol) in DMF (80 mL), 2-ethylhexyl 3-mercaptopropionate (12.91 mL, 56.77 mmol) and K2CO3 (18.34 g, 141.92 mmol) were added at 25°C. The suspension was stirred at 25°C for 12 hours. The reaction mixture was poured into water (200 mL) and extracted with siRNA (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography and concentrated under vacuum to obtain 2-ethylhexyl 3-(4-formyl-2-nitrophenyl)sulfanylpropanoate (17.0 g, compound 20a) as a yellow oily substance. 1 H NMR(400MHz,CDCl3)δ ppm:10.03(s,1H),8.72(d,J=1.6Hz,1H),8.08(dd,J=8.4Hz,1.6Hz,1H),7.60(d,J=8.4Hz,1H),4.07(dd,J=5.6Hz, 2.0Hz,2H),3.34(t,J=7.6Hz,2H),2.79(t,J=7.6Hz,2H),1.63-1.59(m,1H),1.34-1.25(m,8H),0.92-0.89(m,6H).

[0210] Step 2: Preparation of 2-ethylhexyl 3-[4-[(dimethylamino)methyl]-2-nitrophenyl]sulfanylpropanoate (compound 20b) Compound 20b was prepared in the same manner as in Example 1, Step 10, by using 2-ethylhexyl 3-(4-formyl-2-nitro-phenyl)sulfanylpropanoate (compound 20a) instead of S-(4-formylphenyl)N,N-dimethylcarbamothioate (compound 1i). 2-ethylhexyl 3-[4-[(dimethylamino)methyl]-2-nitro-phenyl]sulfanylpropanoate (2.1 g, compound 20b) was obtained as a pale yellow solid. MS measurement value (ESI + )[(M+H) +]:397.3.

[0211] Step 3: Preparation of 2-ethylhexyl 3-[2-amino-4-[(dimethylamino)methyl]phenyl]sulfanylpropanoate (compound 20c) Compound 20c was prepared in the same manner as in Example 8, Step 5, by using 2-ethylhexyl 3-[4-[(dimethylamino)methyl]-2-nitro-phenyl]sulfanylpropanoate (compound 20b) instead of N2,N2,N4-tris[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methyl-3-nitro-pyridine-2,4-diamine (compound 8d). 2-ethylhexyl 3-[2-amino-4-[(dimethylamino)methyl]phenyl]sulfanylpropanoate (2.0 g, compound 20c) was obtained as a pale yellow oil. MS measurement value (ESI + )[(M+H) + ]:367.3.

[0212] Step 4: Preparation of 7-[2-amino-4-[(dimethylamino)methyl]phenyl]sulfanyl-N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-4-amine (compound 20d) Compound 20d was prepared in the same manner as in Example 16, Step 9, by using 2-ethylhexyl 3-[2-amino-4-[(dimethylamino)methyl]phenyl]sulfanylpropanoate (compound 20c) instead of 3-[(dimethylamino)methyl]-2-methyl-6-sulfanylphenol (compound 16h), and N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-7-iodo-6-methyl-imidazo[4,5-c]pyridine-4-amine (compound 8g) instead of 2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 1g). 7-[2-amino-4-[(dimethylamino)methyl]phenyl]sulfanyl-N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-4-amine (400.0 mg, compound 20d) was obtained as a pale yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:837.5.

[0213] Step 5: Preparation of 7-[2-amino-4-[(dimethylamino)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (Example 20) A solution of 7-[2-amino-4-[(dimethylamino)methyl]phenyl]sulfanyl-N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methyl-imidazo[4,5-c]pyridine-4-amine (400.0 mg, compound 20d, 0.48 mmol) in DCM (5.0 mL) and TFA (20.0 mL) was stirred at 20°C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC and lyophilized to obtain 7-[2-amino-4-[(dimethylamino)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (91.63 mg, Example 20) as a grayish-white solid. MS measured value (ESI + )[(M+H) + ]:387.3. 1 H NMR(400MHz,CD3OD)δ ppm:6.77(d,J=1.6Hz,1H),6.76(d,J=8.0Hz,1H),6.54(dd,J=8.0Hz,1.6Hz,1H),4.65( s,2H),3.61-3.56(m,2H),3.34(s,2H),2.56(s,3H),2.21(s,6H),1.22(t,J=7.2Hz,3H).

[0214] Example 21 2-[(4-amino-2-butyl-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl)sulfanyl]-5-[(dimethylamino)methyl]phenol TIFF2026518208000149.tif38170

[0215] Step 1: Preparation of 2-ethylhexyl 3-[4-[(dimethylamino)methyl]-2-hydroxyphenyl]sulfanylpropanoate (compound 21a) Compound 21a was prepared in the same manner as in Example 1, Step 10, by using 2-ethylhexyl 3-(4-formyl-2-hydroxy-phenyl)sulfanylpropanoate (compound 17a) instead of S-(4-formylphenyl)N,N-dimethylcarbamothioate (compound 1i). 2-ethylhexyl 3-[4-[(dimethylamino)methyl]-2-hydroxy-phenyl]sulfanylpropanoate (6.2g, compound 21a) was obtained as a pale yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:368.3.

[0216] Step 2: Preparation of N-[4-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-5-iodo-6-methyl-3-pyridyl]pentanamide (compound 21b) Compound 21b was prepared in the same manner as in Example 1, Step 4, by using N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-5-iodo-6-methylpyridine-2,3,4-triamine (compound 12c) instead of N2,N2-bis[(2,4-dimethoxyphenyl)methyl]-6-methylpyridine-2,3,4-triamine (compound 12c) and valeryl chloride instead of 2-ethoxyacetyl chloride. N-[4-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-5-iodo-6-methyl-3-pyridyl]pentanamide (2.6g, compound 21b) was obtained as a pale yellow oil and used directly in the next step without further purification. MS measured value (ESI + )[(M+H) + ]:649.3.

[0217] Step 3: Preparation of 2-butyl-N,N-bis[(2,4-dimethoxyphenyl)methyl]-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 21c) Compound 21c was prepared in the same manner as in Example 1, Step 5, by using N-[4-amino-2-[bis[(2,4-dimethoxyphenyl)methyl]amino]-5-iodo-6-methyl-3-pyridyl]pentanamide (compound 21b) instead of6-methyl-3-pyridyl]-2-ethoxyacetamide (compound 1d). 2-butyl-N,N-bis[(2,4-dimethoxyphenyl)methyl]-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine (compound 21c) was obtained as a pale yellow solid. MS measured value (ESI + )[(M+H) + ]:631.2.

[0218] Step 4: Preparation of 2-[[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-2-butyl-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[(dimethylamino)methyl]phenol (compound 21d) Compound 21d was prepared in the same manner as in Example 16, Step 9, by using 2-butyl-N,N-bis[(2,4-dimethoxyphenyl)methyl]-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 21c) instead of 2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 21c) and 2-ethylhexyl3-[4-[(dimethylamino)methyl]-2-hydroxy-phenyl]sulfanylpropanoate (compound 21a) instead of 3-[(dimethylamino)methyl]-2-methyl-6-sulfanylphenol (compound 16h). 2-[[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-2-butyl-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[(dimethylamino)methyl]phenol (200.0 mg, compound 21d) was obtained as a pale yellow solid. MS measurement value (ESI +)[(M+H) + ]:686.4.

[0219] Step 5: Preparation of 2-[(4-amino-2-butyl-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl)sulfanyl]-5-[(dimethylamino)methyl]phenol (Example 21) A solution of 2-[[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-2-butyl-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[(dimethylamino)methyl]phenol (200.0 mg, compound 21d, 0.29 mmol) and TFA (2.0 mL) in DCM (2.0 mL) was stirred at 20°C for 1 hour. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC and lyophilized to obtain 2-[(4-amino-2-butyl-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl)sulfanyl]-5-[(dimethylamino)methyl]phenol (68.15 mg, Example 21) as a white solid. MS measured value (ESI + )[(M+H) + ]:386.2. 1 H NMR(400MHz,CD3OD)δ ppm:6.76(d,J=1.6Hz,1H),6.57(dd,J=8.0Hz,1.6Hz,1H),6.39(d,J=8.0Hz,1H),3.33(s,2H),2.82(t ,J=7.6Hz,2H),2.50(s,3H),2.20(s,6H),1.81-1.71(m,2H),1.44-1.32(m,2H),0.94(t,J=7.2Hz,3H).

[0220] Example 22 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-(pyrrolidine-1-ylmethyl)phenol TIFF2026518208000155.tif38170

[0221] Step 1: Preparation of 2-ethylhexyl 3-[2-hydroxy-4-(pyrrolidine-1-ylmethyl)phenyl]sulfanylpropanoate (compound 22a) Compound 22a was prepared in the same manner as in Example 17, Step 2, by using pyrrolidine instead of diethylamine. 2-ethylhexyl 3-[2-hydroxy-4-(pyrrolidine-1-ylmethyl)phenyl]sulfanylpropanoate (568.0 mg, Compound 22a) was obtained as a yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:394.3. 1 H NMR(400MHz,CDCl3)δ ppm:7.40(dd,J=8.0Hz,1.6Hz,1H),7.09(d,J=1.6Hz,1H),6.91(d,J=8.0Hz,1H),4.08-3.99(m,2H),3.90(s,2H),3.00(t,J=7.2Hz,2H),2. 97-2.91(m,4H),2.57(t,J=7.2Hz,2H),2.01-1.91(m,4H),1.62-1.53(m,1H),1.43-1.34(m,2H),1.34-1.25(m,6H),0.90(t,J=7.2Hz,6H).

[0222] Step 2: Preparation of 5-(pyrrolidine-1-ylmethyl)-2-sulfanylphenol (compound 22b) To a solution of 2-ethylhexyl 3-[2-hydroxy-4-(pyrrolidine-1-ylmethyl)phenyl]sulfanylpropanoate (557.0 mg, compound 22a, 1.42 mmol) in 10 mL of THF, t-BuOK (4.25 mL, 4.25 mmol, 1.0 M in THF) was added dropwise at -78°C. The mixture was stirred at -78°C for 1 hour. The pH of the mixture was then adjusted to 5 at -78°C using FA, and the mixture was concentrated under vacuum. The residue was purified by reverse preparative HPLC and lyophilized to obtain 5-(pyrrolidine-1-ylmethyl)-2-sulfanylphenol (200.0 mg, compound 22b) as a grayish-white solid. MS measured value (ESI +)[(M+H) + ]:210.2.

[0223] Step 3: Preparation of 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-(pyrrolidine-1-ylmethyl)phenol (Example 22) The title compound was prepared in the same manner as in Example 16, Step 9, by using 5-(pyrrolidine-1-ylmethyl)-2-sulfanyl-phenol (compound 22b) instead of 3-[(dimethylamino)methyl]-2-methyl-6-sulfanyl-phenol (compound 16h). 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-(pyrrolidine-1-ylmethyl)phenol (32.1 mg, Example 22) was obtained as a white solid. MS measurement value (ESI + )[(M+H) + ]:414.3. 1 H NMR(400MHz,DMSO-d6)δ ppm:12.45(br s,1H),9.90(br s,1H),6.80(s,1H),6.61-6.39(m,3H),6.10-6.30(m,1H),4.51(s,2H),3.56-3.43 (m,2H),3.34(s,2H),2.44-2.31(m,7H),1.70-1.60(m,4H),1.11(t,J=7.2Hz,3H).

[0224] Example 23 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[(dimethylamino)methyl]-4-methylphenol TIFF2026518208000159.tif38170

[0225] Step 1: Preparation of 4-bromo-5-hydroxy-2-methylbenzaldehyde (compound 23a) TIFF2026518208000160.tif18170 A solution of 5-hydroxy-2-methyl-benzaldehyde (450.0 mg, 3.31 mmol) in methanol (10 mL) was mixed with pyridinium hydrobromide perbromide (1.05 g, 3.31 mmol) at 25°C. The mixture was stirred at 25°C for 1 hour. The mixture was concentrated under vacuum, and the residue was purified by reverse preparative HPLC to obtain 4-bromo-5-hydroxy-2-methyl-benzaldehyde (500.0 mg, compound 23a) as a white solid. MS measured value (ESI + )[(M+H) + ]:215.2.

[0226] Step 2: Preparation of 2-ethylhexyl 3-(4-formyl-2-hydroxy-5-methylphenyl)sulfanylpropanoate (compound 23b) Compound 23b was prepared in the same manner as in Example 17, Step 1, by using 4-bromo-5-hydroxy-2-methyl-benzaldehyde (compound 23a) instead of 3-hydroxy-4-iodobenzaldehyde. 2-ethylhexyl 3-(4-formyl-2-hydroxy-5-methyl-phenyl)sulfanylpropanoate (480.0 mg, compound 23b) was obtained as a yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:353.2.

[0227] Step 3: Preparation of 2-ethylhexyl 3-[4-[(dimethylamino)methyl]-2-hydroxy-5-methylphenyl]sulfanylpropanoate (compound 23c) Compound 23c was prepared in the same manner as in Example 17, Step 2, by using 2-ethylhexyl 3-(4-formyl-2-hydroxy-5-methyl-phenyl)sulfanylpropanoate (compound 23b) instead of 2-ethylhexyl 3-(4-formyl-2-hydroxy-phenyl)sulfanylpropanoate (compound 17a), and dimethylamine hydrochloride instead of diethylamine. 2-ethylhexyl 3-[4-[(dimethylamino)methyl]-2-hydroxy-5-methyl-phenyl]sulfanylpropanoate (380.0 mg, compound 23c) was obtained as an orange oily substance. MS measurement value (ESI + )[(M+H) + ]:382.3.

[0228] Step 4: Preparation of 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[(dimethylamino)methyl]-4-methylphenol (Example 23) The title compound was prepared in the same manner as in Example 16, Step 9, using 2-ethylhexyl 3-[4-[(dimethylamino)methyl]-2-hydroxy-5-methylphenyl]sulfanylpropanoate (compound 23c) instead of 3-[(dimethylamino)methyl]-2-methyl-6-sulfanylphenol (compound 16h). 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[(dimethylamino)methyl]-4-methylphenol (17.3 mg, Example 23) was obtained as a white solid. MS measurement (ESI + )[(M+H) + ]:402.2. 1 H NMR(400MHz,CD3OD)δ ppm:6.83(s,1H),6.41(s,1H),4.64(s,2H),3.98(s,2H),3.63-3.57(m,2H),2.69(s,6H),2.53(s,3H),2.09(s,3H),1.21(t,J=7.2Hz,3H).

[0229] Example 24 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[1-(dimethylamino)ethyl]phenol TIFF2026518208000164.tif42170

[0230] Step 1: Preparation of 1-(3-hydroxy-4-iodophenyl)ethanone (compound 24a) TIFF2026518208000165.tif23170 A solution of 1-(3-hydroxyphenyl)ethanone (5.0 g, 36.72 mmol) in acetic acid (50 mL) was mixed with NIS (9.09 g, 40.4 mmol) at 25°C. The mixture was stirred at 25°C for 1 hour and then diluted with H2O (60 mL). The suspension was stirred at 25°C for 0.5 hours and then filtered. The collected solid was washed with H2O (3 × 30 mL). The solid was dried under vacuum, and the residue was purified by silica gel column chromatography to obtain 1-(3-hydroxy-4-iodophenyl)ethanone (3.89 g, compound 24a) as a white solid. MS measured value (ESI + )[(M+H) + ]:262.9. 1 H NMR(400MHz,CDCl3)δ ppm:7.80(d,J=8.0Hz,1H),7.57(d,J=2.0Hz,1H),7.26(dd,J=8.0Hz,2.0Hz,1H),5.83(br s,1H),2.58(s,3H).

[0231] Step 2: Preparation of 2-ethylhexyl 3-(4-acetyl-2-hydroxyphenyl)sulfanylpropanoate (compound 24b) Compound 24b was prepared in the same manner as in Example 17, Step 1, by using 1-(3-hydroxy-4-iodophenyl)ethanone (compound 24a) instead of 3-hydroxy-4-iodobenzaldehyde. 2-ethylhexyl 3-(4-acetyl-2-hydroxyphenyl)sulfanylpropanoate (1.73 g, compound 24b) was obtained as a yellow solid. MS measurement (ESI + )[(M+H) + ]:353.3. 1 H NMR(400MHz,CDCl3)δ ppm:7.56(d,J=8.0Hz,2H),7.55(d,J=2.0Hz,1H),7.47(dd,J=8.0Hz,2.0Hz,1H),6.99(br s,1H),4.09-4.01(m,2H),3.03(t,J=6.8Hz,2H),2.59(s,3H),2.58-2.54(m,2H) ,1.69-1.48(m,1H),1.40-1.34(m,2H),1.34-1.27(m,6H),0.90(t,J=7.6Hz,6H).

[0232] Step 3: Preparation of 1-[4-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-1-[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-7-yl]sulfanyl-3-hydroxyphenyl]ethanone (compound 24c) Compound 24c was prepared in the same manner as in Example 16, Step 9, by using N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-7-iodo-6-methylimidazo[4,5-c]pyridine-4-amine (8g of compound) instead of 2-(ethoxymethyl)-7-iodo-6-methylimidazo[4,5-c]pyridine-4-amine (8g of compound) and 2-ethylhexyl3-(4-acetyl-2-hydroxy-phenyl)sulfanylpropanoate (compound 24b) instead of 3-[(dimethylamino)methyl]-2-methyl-6-sulfanylphenol (compound 16h). 1-[4-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-1-[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-7-yl]sulfanyl-3-hydroxyphenyl]ethanone (350.0 mg, compound 24c) was obtained as a pale yellow solid. MS measurement value (ESI + )[(M+H) + ]:823.4.

[0233] Step 4: Preparation of 5-(1-aminoethyl)-2-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-1-[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-7-yl]sulfanylphenol (compound 24d) TIFF2026518208000168.tif671701-[4-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-1-[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-7-yl]sulfanyl-3-hydroxyphenyl]ethanone (1.03 g, compound 24c, 1.26 mmol) was dissolved in methanol (15 mL) and NH4OAc (1.45 g, 18.88 mmol) and NaBH3CN (791.07 mg, 12.59 mmol) were added at 25 °C. The suspension was heated to 70 °C, stirred at 70 °C for 12 hours, and then filtered through Celite. The solid was washed with MeOH (20 mL). The filtrate was concentrated under vacuum. The residue was purified by reverse-phase preparative HPLC and lyophilized. The residue was suspended in DCM / MeOH (V / V=10 / 1, 50 mL) and stirred at 20°C for 1 hour. The suspension was filtered, and the filtrate was concentrated under vacuum to obtain 5-(1-aminoethyl)-2-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-1-[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methyl-imidazo[4,5-c]pyridine-7-yl]sulfanylphenol (400.0 mg, compound 24d) as a light brown solid. MS measurement value (ESI + )[(M+H) + ]:824.6.

[0234] Step 5: Preparation of 2-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-1-[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-7-yl]sulfanyl-5-[1-(dimethylamino)ethyl]phenol (compound 24e) To a solution of 5-(1-aminoethyl)-2-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-1-[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-7-yl]sulfanylphenol (400.0 mg, compound 24d, 0.49 mmol) in DCM (5.0 mL), formaldehyde (197.0 mg, 2.43 mmol) and NaBH(OAc)3 (514.42 mg, 2.43 mmol) were added at 20°C. The suspension was stirred at 20°C for 2 hours and then filtered through Celite. The collected solid was washed with MeOH (50 mL). The filtrate was concentrated under vacuum, the residue was purified by reverse preparative HPLC, and the mixture was freeze-dried to obtain 2-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-1-[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-7-yl]sulfanyl-5-[1-(dimethylamino)ethyl]phenol (212.0 mg, compound 24e) as a colorless oil. MS measurement value (ESI + )[(M+H) + ]:852.5.

[0235] Step 6: Preparation of 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[1-(dimethylamino)ethyl]phenol (Example 24) A solution of 2-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-1-[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-7-yl]sulfanyl-5-[1-(dimethylamino)ethyl]phenol (212.0 mg, compound 24e, 0.25 mmol) in TFA (6.0 mL) was stirred at 25°C for 16 hours. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC and freeze-dried to obtain 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[1-(dimethylamino)ethyl]phenol (33.19 mg Example 24) as a white solid. MS measurement value (ESI + )[(M+H) + ]:402.3. 1 H NMR(400MHz,CD3OD)δ ppm:6.76(d,J=1.6Hz,1H),6.58(dd,J=8.0Hz,1.6Hz,1H),6.44(d,J=8.0Hz,1H),4.64(s,2H),3.62-3 .55(m,2H),3.25-3.19(m,1H),2.54(s,3H),2.18(s,6H),1.34(d,J=6.8Hz,3H),1.21(t,J=7.2Hz,3H).

[0236] Example 25 5-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-[(dimethylamino)methyl]-4-methylphenol TIFF2026518208000171.tif43170

[0237] Step 1: Preparation of 2-ethylhexyl 3-(4-formyl-5-hydroxy-2-methyl-phenyl)sulfanylpropanoate (compound 25a) Compound 25a was prepared in the same manner as in Example 17, Step 1, by using 4-bromo-2-hydroxy-5-methyl-benzaldehyde instead of 3-hydroxy-4-iodobenzaldehyde. 2-ethylhexyl 3-(4-formyl-5-hydroxy-2-methyl-phenyl)sulfanylpropanoate (600.0 mg, compound 25a) was obtained as a yellow oily substance.

[0238] Step 2: Preparation of 2-ethylhexyl 3-[4-[(dimethylamino)methyl]-5-hydroxy-2-methylphenyl]sulfanylpropanoate (compound 25b) Compound 25b was prepared in the same manner as in Example 9, Step 5, by using 2-ethylhexyl 3-(4-formyl-5-hydroxy-2-methyl-phenyl)sulfanylpropanoate (compound 25a) instead of TIFF2026518208000173.tif291704-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-methoxy-benzaldehyde (compound 9d). 100.0 mg of compound 25b (2-ethylhexyl 3-[4-[(dimethylamino)methyl]-5-hydroxy-2-methyl-phenyl]sulfanylpropanoate) was obtained as a yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:382.4.

[0239] Step 3: Preparation of 5-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-1-[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-7-yl]sulfanyl-2-[(dimethylamino)methyl]-4-methylphenol (compound 25c) Compound 25c was prepared in the same manner as in Example 16, Step 9, by using N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-7-iodo-6-methylimidazo[4,5-c]pyridine-4-amine (8g of compound) instead of 2-(ethoxymethyl)-7-iodo-6-methylimidazo[4,5-c]pyridine-4-amine (8g of compound) and 2-ethylhexyl3-[4-[(dimethylamino)methyl]-5-hydroxy-2-methyl-phenyl]sulfanylpropanoate (compound 25b) instead of 3-[(dimethylamino)methyl]-2-methyl-6-sulfanylphenol (compound 16h). 5-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-1-[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-7-yl]sulfanyl-2-[(dimethylamino)methyl]-4-methylphenol (50.0 mg, compound 25c) was obtained as a brown solid. MS measured value (ESI + )[(M+H) + ]:852.4.

[0240] Step 4: Preparation of 5-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-[(dimethylamino)methyl]-4-methylphenol (Example 25) A solution of 5-[4-[bis[(2,4-dimethoxyphenyl)methyl]amino]-1-[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-7-yl]sulfanyl-2-[(dimethylamino)methyl]-4-methyl-phenol (45.0 mg, compound 25c) in 2.0 mL of TFA was stirred at 25°C for 2 hours. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC and lyophilized to obtain 5-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-[(dimethylamino)methyl]-4-methyl-phenol (11.0 mg, Example 25) as a white solid. MS measured value (ESI + )[(M+H) + ]:402.1. 1 H NMR(400MHz,CD3OD)δ ppm:6.98(s,1H),5.96(s,1H),4.63(s,2H),3.83(s,2H),3.63-3.55(m,2H),2.51(s,6H),2.50(s,3H),2.37(s,3H),1.21(t,J=7.2Hz,3H).

[0241] Example 26 7-[2-amino-4-(pyrroridine-1-ylmethyl)phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine TIFF2026518208000176.tif38170

[0242] Step 1: Preparation of 2-ethylhexyl 3-[2-nitro-4-(pyrrolidine-1-ylmethyl)phenyl]sulfanylpropanoate (compound 26a) Compound 26a was prepared in the same manner as in Example 20, Step 2, by using pyrrolidine instead of dimethylamine hydrochloride. 2-ethylhexyl 3-[2-nitro-4-(pyrrolidine-1-ylmethyl)phenyl]sulfanylpropanoate (1000.0 mg, compound 26a) was obtained as a pale yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:423.3.

[0243] Step 2: Preparation of 2-ethylhexyl 3-[2-amino-4-(pyrrolidine-1-ylmethyl)phenyl]sulfanylpropanoate (compound 26b) Compound 26b was prepared in the same manner as in Example 20, Step 3, by using 2-ethylhexyl 3-[2-nitro-4-(pyrrolidine-1-ylmethyl)phenyl]sulfanylpropanoate (compound 26a) instead of 2-ethylhexyl 3-[4-[(dimethylamino)methyl]-2-nitro-phenyl]sulfanylpropanoate (compound 20b). 2-ethylhexyl 3-[2-amino-4-(pyrrolidine-1-ylmethyl)phenyl]sulfanylpropanoate (2.0 g, compound 26b) was obtained as a pale yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:393.3.

[0244] Step 3: Preparation of 7-[2-amino-4-(pyrrolidine-1-ylmethyl)phenyl]sulfanyl-N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-4-amine (compound 26c) Compound 26c was prepared in the same manner as in Example 16, Step 9, by using 2-ethylhexyl 3-[2-amino-4-[(dimethylamino)methyl]phenyl]sulfanylpropanoate (compound 26b) instead of 3-[(dimethylamino)methyl]-2-methyl-6-sulfanylphenol (compound 16h), and N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-7-iodo-6-methyl-imidazo[4,5-c]pyridine-4-amine (compound 8g) instead of 2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 1g). 7-[2-amino-4-(pyrroridine-1-ylmethyl)phenyl]sulfanyl-N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-4-amine (180.0 mg, compound 26c) was obtained as a pale yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:863.5.

[0245] Step 4: Preparation of 7-[2-amino-4-(pyrrolidine-1-ylmethyl)phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (Example 26) A solution of 7-[2-amino-4-(pyrroridine-1-ylmethyl)phenyl]sulfanyl-N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-4-amine (180.0 mg, compound 26c, 0.21 mmol) in DCM (2.0 mL) and TFA (10.0 mL) was stirred at 20°C for 12 hours. The reaction mixture was concentrated under vacuum. The crude product was further purified by preparative HPLC and freeze-dried to obtain 7-[2-amino-4-(pyrrolidine-1-ylmethyl)phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (25.82 mg, Example 26) as a white solid. MS measurement value (ESI + )[(M+H) + ]:413.3. 1 H NMR(400MHz,CD3OD)δ ppm:6.81(d,J=1.6Hz,1H),6.77(d,J=8.0Hz,1H),6.57(dd,J=8.0Hz,1.6Hz,1H),4.65(s,2H),3.62- 3.56(m,2H),3.54(s,2H),2.58-2.57(m,4H),2.56(s,3H),1.81-1.79(m,4H),1.22(t,J=7.2Hz,3H).

[0246] Example 27 7-[2-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine TIFF2026518208000181.tif38170

[0247] Step 1: Preparation of 2-ethylhexyl 3-[4-[(4-methylpiperazin-1-yl)methyl]-2-nitrophenyl]sulfanylpropanoate (compound 27a) Compound 27a was prepared in the same manner as in Example 20, Step 2, by using methylpiperazine instead of dimethylamine hydrochloride. 2-Ethylhexyl 3-[4-[(4-methylpiperazine-1-yl)methyl]-2-nitrophenyl]sulfanylpropanoate (900.0 mg, Compound 27a) was obtained as a pale yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:452.3.

[0248] Step 2: Preparation of 2-ethylhexyl 3-[2-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanylpropanoate (compound 27b) Compound 27b was prepared in the same manner as in Example 20, Step 3, by using 2-ethylhexyl 3-[4-[(4-methylpiperazine-1-yl)methyl]-2-nitro-phenyl]sulfanylpropanoate (compound 27a) instead of 2-ethylhexyl 3-[4-[(dimethylamino)methyl]-2-nitro-phenyl]sulfanylpropanoate (compound 20b). 2-ethylhexyl 3-[2-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanylpropanoate (2.0 g, compound 27b) was obtained as a light brown oily substance. MS measurement value (ESI + )[(M+H) + ]:422.6.

[0249] Step 3: Preparation of 7-[2-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-4-amine (compound 27c) Compound 27c was prepared in the same manner as in Example 16, Step 9, by using 2-ethylhexyl 3-[2-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanylpropanoate (compound 27b) instead of 3-[(dimethylamino)methyl]-2-methyl-6-sulfanylphenol (compound 16h), and by using N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-7-iodo-6-methyl-imidazo[4,5-c]pyridine-4-amine (compound 8g) instead of 2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 1g). 7-[2-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-4-amine (200.0 mg, compound 27c) was obtained as a pale yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:892.5.

[0250] Step 4: Preparation of 7-[2-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (Example 27) The title compound was prepared in the same manner as in Example 20, Step 5, by using 7-[2-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-4-amine (compound 27c) instead ofdimethylamino)methyl]phenyl]sulfanyl-N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-4-amine (compound 20d). 7-[2-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (31.92 mg, Example 27) was obtained as a white solid. MS measurement value (ESI + )[(M+H) + ]:442.3. 1 H NMR(400MHz,CD3OD)δ ppm:6.80(d,J=1.6Hz,1H),6.78(d,J=8.0Hz,1H),6.56(dd,J=8.0Hz,1.6Hz,1H),4.65(s,2H),3. 62-3.56(m,2H),3.39(s,2H),2.57(s,3H),2.56-2.41(m,8H),2.31(s,3H),1.23(t,J=7.2Hz,3H).

[0251] Example 28 7-[3-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine TIFF2026518208000186.tif44170

[0252] Step 1: Preparation of 2-ethylhexyl 3-(4-formyl-3-nitrophenyl)sulfanylpropanoate (compound 28a) Compound 28a was prepared in the same manner as in Example 17, Step 1, by using 4-bromo-2-nitrobenzaldehyde instead of 3-hydroxy-4-iodobenzaldehyde. 2-ethylhexyl 3-(4-formyl-3-nitrophenyl)sulfanylpropanoate (2.40 g, compound 28a) was obtained as a yellow oily substance. 1 H NMR(400MHz,DMSO-d6)δ ppm:10.09(s,1H),7.95(d,J=1.6Hz,1H),7.88(d,J=8.0Hz,1H),7.77(dd,J=8.0Hz,1.6Hz,1H),3.96(d,J=5.6Hz,2H),3 .39(t,J=6.8Hz,2H),2.74(t,J=6.8Hz,2H),1.57-1.47(m,1H),1.34-1.26(m,2H),1.25-1.20(m,6H),0.91-0.82(m,6H).

[0253] Step 2: Preparation of 2-ethylhexyl 3-[4-[(4-methylpiperazine-1-yl)methyl]-3-nitrophenyl]sulfanylpropanoate (compound 28b) Compound 28b was prepared in the same manner as in Example 17, Step 2, by using 2-ethylhexyl 3-(4-formyl-3-nitro-phenyl)sulfanylpropanoate (compound 28a) instead of 2-ethylhexyl 3-(4-formyl-2-hydroxy-phenyl)sulfanylpropanoate (compound 17a) and 1-methylpiperazine instead of diethylamine. 2-ethylhexyl 3-[4-[(4-methylpiperazine-1-yl)methyl]-3-nitro-phenyl]sulfanylpropanoate (290.0 mg, compound 28b) was obtained as an orange oily substance. MS measured value (ESI + )[(M+H) + ]:452.3.

[0254] Step 3: Preparation of 2-ethylhexyl 3-[3-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanylpropanoate (compound 28c) Compound 28c was prepared in the same manner as in Example 20, Step 3, by using 2-ethylhexyl 3-[4-[(4-methylpiperazine-1-yl)methyl]-3-nitro-phenyl]sulfanylpropanoate (compound 28b) instead of 2-ethylhexyl 3-[4-[(dimethylamino)methyl]-2-nitro-phenyl]sulfanylpropanoate (compound 20b). 2-ethylhexyl 3-[3-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanylpropanoate (220.0 mg, compound 28c) was obtained as a gray solid. MS measurement value (ESI + )[(M+H) + ]:422.2[(M+H) + ].

[0255] Step 4: Preparation of 7-[3-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-4-amine (compound 28d) Compound 28d was prepared in the same manner as in Example 16, Step 9, using 2-ethylhexyl 3-[3-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanylpropanoate (compound 28c) instead of 3-[(dimethylamino)methyl]-2-methyl-6-sulfanylphenol (compound 16h), and N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-7-iodo-6-methyl-imidazo[4,5-c]pyridine-4-amine (compound 8g) instead of 2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 1g). 7-[3-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-4-amine (200.0 mg, compound 28d) was obtained as a white solid. MS measurement value (ESI + )[(M+H) + ]:892.5.

[0256] Step 5: Preparation of 7-[3-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (Example 28) A solution of 7-[3-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-4-amine (100.0 mg, compound 28d, 0.11 mmol) and TFA (5.0 mL) in TIFF2026518208000191.tif43170DCM (5.0 mL) was stirred at 20°C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC and freeze-dried to obtain 7-[3-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (29.34 mg, Example 28) as a yellow solid. MS measurement value (ESI + )[(M+H) + ]:442.3. 1 H NMR(400MHz,CD3OD)δ ppm:6.88(d,J=8.0Hz,1H),6.37(d,J=1.6Hz,1H),6.36(dd,J=8.0Hz,1.6Hz,1H),4.65(s,2H),3.64-3.56( m,2H),3.48(s,2H),3.26-3.04(m,4H),2.78(s,3H),2.71-2.59(m,4H),2.58(s,3H),1.20(t,J=7.2Hz,3H).

[0257] Example 29 7-[2-amino-6-methoxy-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine TIFF2026518208000192.tif39170

[0258] Step 1: Preparation of (4-formyl-2-methoxy-6-nitrophenyl)trifluoromethanesulfonate (compound 29a) To a solution of 5-nitrovanillin (5.0 g, 25.36 mmol) in 60 mL of DCM, pyridine (3.01 g, 38.04 mmol) and trifluoromethanesulfonic anhydride (7.94 g, 28.15 mmol) were added at 0°C. The reaction mixture was incubated at 0°C for 2 hours. The mixture was diluted with 150 mL of DCM, washed with water (80 mL) and brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography and concentrated under vacuum to obtain (4-formyl-2-methoxy-6-nitrophenyl)trifluoromethanesulfonate (6.9 g, compound 29a) as a white solid. 1 H NMR(400MHz,CDCl3)δ ppm:10.04(s,1H),8.14(d,J=1.6Hz,1H),7.83(d,J=1.6Hz,1H),4.10(s,3H).

[0259] Step 2: Preparation of 2-ethylhexyl 3-(4-formyl-2-methoxy-6-nitrophenyl)sulfanylpropanoate (compound 29b) Compound 29b was prepared in the same manner as in Example 17, Step 1, by using (4-formyl-2-methoxy-6-nitro-phenyl)trifluoromethanesulfonate (compound 29a) instead of 3-hydroxy-4-iodobenzaldehyde. 2-ethylhexyl 3-(4-formyl-2-methoxy-6-nitro-phenyl)sulfanylpropanoate (100.0 mg, compound 29b) was obtained as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm:9.98(s,1H),7.77(s,1H),7.55(s,1H),4.07(s,3H),4.02-3.93(m,2H),3.25(t,J=7. 2Hz, 2H), 2.54 (t, J=7.2Hz, 2H), 1.56-1.52 (m, 1H), 1.34-1.23 (m, 8H), 0.93-0.85 (m, 6H).

[0260] Step 3: Preparation of 2-ethylhexyl 3-[2-methoxy-4-[(4-methylpiperazine-1-yl)methyl]-6-nitrophenyl]sulfanylpropanoate (compound 29c) Compound 29c was prepared in the same manner as in Example 17, Step 2, by using 2-ethylhexyl 3-(4-formyl-2-methoxy-6-nitro-phenyl)sulfanylpropanoate (compound 29b) instead of 2-ethylhexyl 3-(4-formyl-2-hydroxy-phenyl)sulfanylpropanoate (compound 17a) and 1-methylpiperazine instead of diethylamine. 2-ethylhexyl 3-[2-methoxy-4-[(4-methylpiperazine-1-yl)methyl]-6-nitro-phenyl]sulfanylpropanoate (1.0 g, compound 29c) was obtained as a pale yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:482.3.

[0261] Step 4: Preparation of 2-ethylhexyl 3-[2-amino-6-methoxy-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanylpropanoate (compound 29d) Compound 29d was prepared in the same manner as in Example 20, Step 3, by using 2-ethylhexyl 3-[2-methoxy-4-[(4-methylpiperazine-1-yl)methyl]-6-nitro-phenyl]sulfanylpropanoate (compound 29c) instead of 2-ethylhexyl 3-[4-[(dimethylamino)methyl]-2-nitro-phenyl]sulfanylpropanoate (compound 20b). 2-ethylhexyl 3-[2-amino-6-methoxy-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanylpropanoate (230.0 mg, compound 29d) was obtained as a pale red oily substance. MS measurement value (ESI + )[(M+H) + ]:452.3.

[0262] Step 5: Preparation of 7-[2-amino-6-methoxy-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-4-amine (compound 29e) Compound 29e was prepared in the same manner as in Example 16, Step 9, using 2-ethylhexyl 3-[2-amino-6-methoxy-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanylpropanoate (compound 29d) instead of 3-[(dimethylamino)methyl]-2-methyl-6-sulfanylphenol (compound 16h), and N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-7-iodo-6-methyl-imidazo[4,5-c]pyridine-4-amine (compound 8g) instead of 2-(ethoxymethyl)-7-iodo-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (compound 1g). 7-[2-amino-6-methoxy-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-4-amine (230.0 mg, compound 29e) was obtained as a pale yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:922.4.

[0263] Step 6: Preparation of 7-[2-amino-6-methoxy-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (Example 29) A solution of 7-[2-amino-6-methoxy-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-N,N,1-tris[(2,4-dimethoxyphenyl)methyl]-2-(ethoxymethyl)-6-methylimidazo[4,5-c]pyridine-4-amine (220.0 mg, compound 29e, 0.24 mmol) in TIFF2026518208000198.tif38170TFA (2.0 mL) was stirred at 25°C for 2 hours. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC to obtain 7-[2-amino-6-methoxy-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (34.67 mg, Example 29) as a white solid. MS measurement value (ESI + )[(M+H) + ]:472.3. 1 H NMR(400MHz,CD3OD)δ ppm:6.60(s,1H),6.41(s,1H),4.73(s,2H),3.71(s,3H),3.68-3.61(m,2H),3.60-3.32(m, 4H),3.23-2.93(m,4H),2.85(s,3H),2.79(s,3H),2.65-2.22(m,2H),1.29(t,J=7.2Hz,3H).

[0264] Example 30 N-[5-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-pyridyl]-N',N'-dimethylethane-1,2-diamine TIFF2026518208000199.tif41170

[0265] Step 1: Preparation of N-(5-iodo-2-pyridyl)-N',N'-dimethylethane-1,2-diamine (compound 30a) TIFF2026518208000200.tif21170 To a solution of 2-chloro-5-iodopyridine (1 g, 4.18 mmol) in DMSO (10.44 mL), 2-aminoethyl(dimethyl)amine (1.1 g, 1.37 mL, 12.53 mmol) was added. The reaction mixture was stirred at 100°C for 1 hour. The mixture was diluted with H2O (20 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography and concentrated under vacuum to obtain N-(5-iodo-2-pyridyl)-N',N'-dimethylethane-1,2-diamine (163 mg, compound 30a) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ ppm:8.15(d,J=2.0Hz,1H),7.50(dd,J=8.8Hz,2.0Hz,1H),6.19(d,J=8.8Hz,1H),5.07(br s, 1H), 3.28-3.22 (m, 2H), 2.50-2.43 (m, 2H), 2.19 (s, 6H).

[0266] Step 2: Preparation of 6-[2-(dimethylamino)ethylamino]pyridine-3-thiol (compound 30b) TIFF2026518208000201.tif211701,4-Dioxane (5.0 mL) is mixed with N-(5-iodo-2-pyridyl)-N',N'-dimethyl-ethane-1,2-diamine (163 mg, compound 30a, 0.52 mmol) and triisopropylsilanthol (196.22 mg, 1.03 mmol) to which Pd XantPhos G3 (106.48 mg, 0.1 mmol) and Cs2CO3 (335.75 mg, 1.03 mmol) are added 20 times. o The mixture was added with C. The mixture was degassed three times under N2 and stirred at 100°C for 2 hours. The mixture was cooled to room temperature, then filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography to obtain 6-[2-(dimethylamino)ethylamino]pyridine-3-thiol (91.5 mg, compound 30b) as a pale yellow solid. MS measured value (ESI + )[(M+H) +]:197.9.

[0267] Step 3: Preparation of N-[5-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-pyridyl]-N',N'-dimethylethane-1,2-diamine (Example 30) The title compound was prepared in the same manner as in Example 5, Step 3, by using 6-[2-(dimethylamino)ethylamino]pyridine-3-thiol (compound 30b) instead of N-ethyl-N-[[4-[[4-[[ethyl(propyl)amino]methyl]phenyl]disulfanyl]phenyl]methyl]propan-1-amine (compound 5b). N-[5-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-pyridyl]-N',N'-dimethylethane-1,2-diamine (1.5 mg, Example 30) was obtained as a white solid. MS measurement value (ESI + )[(M+H) + ]:402.1. 1 H NMR(400MHz,CD3OD)δ ppm:8.08-8.03(m,1H),7.42-7.37(m,1H),6.49-6.43(m,1H),4.62(s,2H),3.59-3.52(m,4 H),2.82(s,6H),2.64(s,3H),2.13-2.06(m,1H),1.96-1.90(m,1H),1.14(t,J=7.2Hz,3H).

[0268] Example 31 7-[4-[2-(dimethylamino)ethyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine TIFF2026518208000203.tif42170

[0269] Step 1: Preparation of 2-ethylhexyl 3-[4-(2-oxoethyl)phenyl]sulfanylpropanoate (compound 31a) Compound 31a was prepared in the same manner as in Example 17, Step 1, by using 2-(4-bromophenyl)acetaldehyde instead of 3-hydroxy-4-iodobenzaldehyde. 2-ethylhexyl 3-[4-(2-oxoethyl)phenyl]sulfanylpropanoate (1.32 g, compound 31a) was obtained as a yellow oily substance. 1 H NMR(400MHz,CDCl3)δ ppm:9.65(s,1H),7.44-7.30(m,2H),7.19-7.07(m,2H),4.06-3.96(m,2H),3.70-3.63(m,2H), 3.25-3.11(m,2H),2.72-2.58(m,2H),1.63-1.54(m,1H),1.41-1.25(m,8H),0.93-0.84(m,6H).

[0270] Step 2: Preparation of 2-ethylhexyl 3-[4-[2-(dimethylamino)ethyl]phenyl]sulfanylpropanoate (compound 31b) Compound 31b was prepared in the same manner as in Example 17, Step 2, by using 2-ethylhexyl 3-[4-(2-oxoethyl)phenyl]sulfanylpropanoate (compound 31a) instead of 2-ethylhexyl 3-(4-formyl-2-hydroxyphenyl)sulfanylpropanoate (compound 17a), and dimethylamine hydrochloride instead of diethylamine. 2-ethylhexyl 3-[4-[2-(dimethylamino)ethyl]phenyl]sulfanylpropanoate (180.0 mg, compound 31b) was obtained as a yellow oily substance. MS measurement value (ESI + )[(M+H) + ]:366.2.

[0271] Step 3: Preparation of 7-[4-[2-(dimethylamino)ethyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (Example 31) The title compound was prepared in the same manner as in Example 16, Step 9, by using 2-ethylhexyl 3-[4-[2-(dimethylamino)ethyl]phenyl]sulfanylpropanoate (compound 31b) instead of 3-[(dimethylamino)methyl]-2-methyl-6-sulfanylphenol (compound 16h). 7-[4-[2-(dimethylamino)ethyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine (10.33 mg, Example 31) was obtained as a green solid. MS measurement (ESI + )[(M+H) + ]:386.1. 1 H NMR(400MHz,CD3OD)δ ppm:7.18(d,J=8.0Hz,2H),7.02(d,J=8.0Hz,2H),4.64(s,2H),3.65-3.56(m,2H),3. 29-3.25(m,2H),2.98-2.94(m,2H),2.87(s,6H),2.55(s,3H),1.21(t,J=7.2Hz,3H).

[0272] Example 32 6-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-methyl-3,4-dihydro-1H-isoquinoline-7-ol TIFF2026518208000207.tif38170

[0273] Step 1: Preparation of 2-(3-bromo-4-methoxyphenyl)ethaneamine (compound 32a) To a solution of 2-(3-bromo-4-methoxyphenyl)acetonitrile (2.5 g, 11.06 mmol) in THF (25.0 mL), BH3·THF (27.5 mL, 27.5 mmol, 1.0 M in THF) was added dropwise at 0°C. The mixture was stirred at 70°C for 2 hours. The mixture was then cooled to 0°C, and HCl (3.0 mL) and MeOH (10 mL) were added. After stirring at 70°C for a further 2 hours, the mixture was cooled to room temperature, and the pH was adjusted to 9 with aqueous NaOH (10 M). The mixture was diluted with H2O (20 mL) and extracted with EA (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography and concentrated under vacuum to obtain 2-(3-bromo-4-methoxyphenyl)ethaneamine (1.2 g, compound 32a) as a pale yellow oil.

[0274] Step 2: Preparation of methyl N-[2-(3-bromo-4-methoxyphenyl)ethyl]carbamate (compound 32b) To a solution of triphosgene (709.3 mg, 2.39 mmol) in DCM (22.0 mL), 2-(3-bromo-4-methoxyphenyl)ethanamine (1.1 g, compound 32a, 4.78 mmol) was slowly added at 0°C. The mixture was stirred at 0°C for 5 minutes, then NEt3 (987.5 mg, 9.56 mmol) was added, and the mixture was stirred at 0°C for a further 1 hour. Then methanol (5.5 mL) and NEt3 (987.5 mg, 9.56 mmol) were added to the mixture, and the reaction was stirred at room temperature for 1 hour. The mixture was washed with an aqueous solution of NaCl (3 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain methyl N-[2-(3-bromo-4-methoxyphenyl)ethyl]carbamate (1.75 g, compound 32b) as a white solid, which was used directly in the next step without further purification. MS measured value (ESI + )[{ 79 Br}(M+H) + ]:287.9.

[0275] Step 3: Preparation of 6-bromo-7-methoxy-3,4-dihydro-2H-isoquinoline-1-one (compound 32c) A mixture of methyl N-[2-(3-bromo-4-methoxyphenyl)ethyl]carbamate (1.65 g, compound 32b, 5.73 mmol) and phosphorus pentoxide in methanesulfonic acid (13.4 mL / ) was stirred at 90°C for 2 hours. The mixture was then poured into ice water (110 mL) and extracted with EA (3 × 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography to obtain 6-bromo-7-methoxy-3,4-dihydro-2H-isoquinoline-1-one (670 mg, compound 32c) as a white solid. MS measured value (ESI + )[{ 79 Br}(M+H) + ]:255.8.

[0276] Step 4: Preparation of 6-bromo-7-methoxy-2-methyl-3,4-dihydroisoquinoline-1-one (compound 32d) To a solution of 6-bromo-7-methoxy-3,4-dihydro-2H-isoquinoline-1-one (620 mg, compound 32c, 2.42 mmol) in DCM (24.0 mL), NaH (116.4 mg, 2.91 mmol, 60%, dispersion in paraffinic liquid) was slowly added at 0°C. The mixture was stirred at 0°C for 45 minutes, then iodomethane (687.2 mg, 4.84 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction product was then quenched with H2O (20 mL) and extracted with EA (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography to obtain 6-bromo-7-methoxy-2-methyl-3,4-dihydroisoquinoline-1-one (210 mg, compound 32d) as a white solid. MS measurement value (ESI + )[{ 79 Br}(M+H) + ]:269.9.

[0277] Step 5: Preparation of 6-bromo-7-methoxy-2-methyl-3,4-dihydro-1H-isoquinoline (compound 32e) A mixture of 6-bromo-7-methoxy-2-methyl-3,4-dihydroisoquinoline-1-one (210 mg, compound 32d, 0.78 mmol) and BH3·THF (7.77 mL, 7.77 mmol, 1.0 M in THF) was stirred at 70°C for 1 hour. The mixture was then quenched with MeOH and concentrated under vacuum to obtain 6-bromo-7-methoxy-2-methyl-3,4-dihydro-1H-isoquinoline (199 mg, compound 32e) as a white solid, which was used directly in the next step without further purification. MS measured value [{ 79 Br}(M+H) + ]:255.9.

[0278] Step 6: Preparation of 6-bromo-2-methyl-3,4-dihydro-1H-isoquinoline-7-ol (compound 32f) To a solution of 6-bromo-7-methoxy-2-methyl-3,4-dihydro-1H-isoquinoline (70 mg, compound 32e, 0.27 mmol) in DCM (2.7 mL), BBr3 (2.73 mL, 2.73 mmol, 1.0 M in THF) was slowly added at 0°C. The mixture was stirred at room temperature for 3 hours. The mixture was then quenched with MeOH and concentrated under vacuum. DCM (5 mL) and NaOH (10.0 mL, 2 M in H2O) were added to the mixture, and the reaction was stirred at room temperature for 2 hours. The pH of the mixture was adjusted to 7 with acetic acid, and the mixture was extracted with DCM (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 6-bromo-2-methyl-3,4-dihydro-1H-isoquinoline-7-ol (60 mg, compound 32f) as a white solid, which was used directly in the next step without further purification. MS measured value [{ 79 Br}(M+H) + ]:241.9.

[0279] Step 7: Preparation of 2-ethylhexyl 3-[(7-hydroxy-2-methyl-3,4-dihydro-1H-isoquinoline-6-yl)sulfanyl]propanoate (32 g of compound) TIFF2026518208000214.tif371703 Compound 32 g was prepared in the same manner as in Example 17, Step 1, by using 6-bromo-2-methyl-3,4-dihydro-1H-isoquinoline-7-ol (compound 32f) instead of 3-hydroxy-4-iodobenzaldehyde. 2-ethylhexyl 3-[(7-hydroxy-2-methyl-3,4-dihydro-1H-isoquinoline-6-yl)sulfanyl]propanoate (100 mg, compound 32 g) was obtained as a pale yellow solid. MS measurement value (ESI + )[(M+H) + ]:380.2.

[0280] Step 8: Preparation of 6-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-methyl-3,4-dihydro-1H-isoquinoline-7-ol (Example 32) The title compound was prepared in the same manner as in step 9 of Example 16 by using 2-ethylhexyl 3-[(7-hydroxy-2-methyl-3,4-dihydro-1H-isoquinoline-6-yl)sulfanyl]propanoate (compound 32 g) instead of 3-[(dimethylamino)methyl]-2-methyl-6-sulfanylphenol (compound 16 h). 6-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-methyl-3,4-dihydro-1H-isoquinoline-7-ol (36.9 mg, Example 32) was obtained as a pale yellow solid. MS measurement value (ESI + )[(M+H) + ]:400.4. 1H NMR(400MHz,CD3OD)δ=6.49(s,1H),6.30(s,1H),4.55(s,2H),3.99(s,2H),3.51(q,J=7 .2Hz,2H),3.12(t,J=6.4Hz,2H),2.75-2.68(m,5H),2.44(s,3H),1.12(t,J=7.2Hz,3H).

[0281] reference compound Compound SAN-43, disclosed as compound 43 in Prior Art International Publication No. 2022167438, was selected as a reference compound for comparison. TIFF2026518208000216.tif27170

[0282] Example 33 Activity of the compound of the present invention in HEK293-Blue-hTLR7 cell assay and HEK293-Blue--hTLR8 cell assay HEK293-Blue-hTLR7 cell assay: Stable HEK293-Blue-hTLR7 cell lines were purchased from InvivoGen (catalog number: hkb-htlr7, San Diego, California, USA). These cells were designed to study the stimulation of human TLR7 by monitoring NF-κB activation. The SEAP (secreted embryonic alkaline phosphatase) reporter gene was placed under the control of a minimal IFN-β promoter fused to five NF-κB and AP-1 binding sites. SEAP was induced by activating NF-κB and AP-1 by stimulating HEK-Blue hTLR7 cells with a TLR7 ligand. Therefore, reporter expression was regulated by the NF-κB promoter after 20 hours of stimulation of human TLR7. Cell culture supernatant SEAP reporter activity was determined using the QUANTI-Blue (catalog number: rep-qb1, Invivogen, San Diego, California, USA) kit at a wavelength of 650 nm, which is a detection medium that turns purple or blue in the presence of alkaline phosphatase.

[0283] HEK293-Blue-hTLR7 cells were incubated for 24 hours at a density of 250,000-450,000 cells / mL in 180 μL of Dulbecco's Modified Eagle Medium (DMEM) in a 96-well plate containing 4.5 g / L glucose, 100 U / mL penicillin, 100 μg / mL streptomycin, 100 μg / mL Normocin, 1% (V / V) GlutaMAX (trademark), and 10% (V / V) thermo-inactivated fetal bovine serum. The HEK293-Blue-hTLR-7 cells were then incubated with 20 μL of the test compound in serial dilutions in the presence of 1% final DMSO, and incubated in a CO2 incubator at 37°C for 20 hours. Subsequently, 20 μL of the supernatant from each well was mixed with 180 μL of Quanti-blue substrate solution. o The samples were incubated in 1C for 1 hour, and absorbance was read at 620–655 nm using a spectrophotometer. The signaling pathway in which TLR7 activation leads to downstream NF-κB activation is widely accepted, and therefore, similar reporter assays have also been widely used to evaluate TLR7 agonists (Tsuneyasu Kaisho and Takashi Tanaka, Trends in Immunology, Volume 29, Issue 7, July 2008, Pages 329.sci; Hiroaki Hemmi et al, Nature Immunology 3, 196-200 (2002)).

[0284] HEK293-Blue-hTLR8 cell assay: Stable HEK293-Blue-hTLR8 cell lines were purchased from InvivoGen (catalog number: hkb-htlr8, San Diego, California, USA). These cells were designed to study the stimulation of human TLR8 by monitoring NF-κB activation. The SEAP (secreted embryonic alkaline phosphatase) reporter gene was placed under the control of a minimal IFN-β promoter fused to five NF-κB and AP-1 binding sites. SEAP was induced by activating NF-κB and AP-1 by stimulating HEK-Blue hTLR8 cells with a TLR8 ligand. Therefore, reporter expression was regulated by the NF-κB promoter upon stimulation of human TLR8. The activity of the SEAP reporter in the cell culture supernatant was measured at a wavelength of 650 nm using the QUANTI-Blue® kit (catalog number: rep-qb1, Invivogen, San Diego, California, USA), and the detection medium changed from purple to blue in the presence of alkaline phosphatase.

[0285] HEK293-Blue-hTLR8 cells were incubated for 24 hours at a density of 250,000–450,000 cells / mL in 180 μL of Dulbecco's Modified Eagle Medium (DMEM) containing 4.5 g / L glucose, 100 U / mL penicillin, 100 μg / mL streptomycin, 100 μg / mL Normocin, 1% (V / V) GlutaMAX (trademark), and 10% (v / v) thermo-inactivated fetal bovine serum in a 96-well plate. Subsequently, HEK293-Blue-hTLR8 cells were incubated with 20 μL of the test compound added in serial dilutions in the presence of 1% final DMSO, and incubated in a CO2 incubator at 37°C for 20 hours. Next, 20 μL of the supernatant from each well was incubated with 180 μL of Quanti-blue substrate solution at 37°C for 1 hour, and the absorbance was read at 620–655 nm using a spectrophotometer. The signaling pathway in which TLR8 activation leads to downstream NF-κB activation is widely accepted, and therefore, similar reporter assays have also been widely used to evaluate TLR8 agonists.

[0286] The compounds of the present invention were tested for their TLR7 and TLR8 agonism activity in the assay described herein, and the results are listed in Table 1. In addition to significant structural differences compared with the reference compound SAN-43, the examples of the present invention show TLR7 EC 50 It was found to be a dual agonist having TLR7 (0.001 μM~0.048 μM) and TLR8 (0.003 μM~0.082 μM), but compound SAN-43 did not exhibit equivalent TLR7 and TLR8 activity. Furthermore, certain examples of the present invention were found to be equally potent in both TLR7 and TLR8 activity (EC 50 (<0.03 μM). [Table 1]

Claims

1. Equation (I) (In the formula, R １ H, C １～６ Alkyl or hydroxy C １～６ It is alkyl, R ２ C １～６ Alkyl or C １～６ Alkoxy C １～６ It is alkyl, R ３ is C １～６ alkyl, and R ４ is, (C １～６ Alkyl) ２ Amino C １～６ Alkyl-substituted 1H-indazolyl, (C １～６ Alkyl) ２ Amino C １～６ Alkyl-substituted 1H-indolyl, C １～６ 1H-isoquinolinyl, which is twice substituted with alkyl and hydroxyl groups. (C １～６ Alkyl) ２ Amino C １～６ Alkyl, (C １～６ (Alkylpiperazinyl) C １～６ Alkyl, amino, C １～６ Alkoxy, C １～６ Alkyl, hydroxy, and pyrrolidinyl C １～６ Phenyl compounds that are substituted once, twice, or three times with substituents independently selected from the alkyl group, or (C １～６ Alkyl) ２ Amino C １～６ It is a pyridyl substituted with an alkylamino, A is S or Se, L is a combination or C １～６ (It is alkylene.) Compounds thereof, or pharmaceutically acceptable salts thereof.

2. R １ However, H or C １～６ The compound according to claim 1, wherein it is alkyl.

3. R １ The compound according to claim 1 or 2, wherein the compound is H or methyl.

4. R ２ The compound according to any one of claims 1 to 3, wherein the compound is butyl or ethoxymethyl.

5. R ３ The compound according to any one of claims 1 to 4, wherein the compound is methyl.

6. A compound according to any one of claims 1 to 5, wherein A is S.

7. The compound according to any one of claims 1 to 6, wherein L is a bond or ethylene.

8. R ４ However, (C １～６ Alkyl) ２ Amino C １～６ Alkyl, amino, C １～６ Alkoxy, hydroxy, and pyrrolidinyl C １～６ The compound according to any one of claims 1 to 7, wherein the phenyl is substituted once, twice, or three times with a substituent independently selected from the alkyl group.

9. R ４ The compound according to any one of claims 1 to 8, wherein the compound is a phenyl that is substituted once, twice, or three times with a substituent independently selected from (dimethylamino)methyl, [ethyl(methyl)amino]methyl, [ethyl(propyl)amino]methyl, amino, hydroxy, methoxy, and pyrrolidinylmethyl.

10. R ４ The compound according to any one of claims 1 to 8, wherein the compound is 2-[4-[(dimethylamino)methyl]-3-hydroxyphenyl]ethyl, 2-[4-[(dimethylamino)methyl]phenyl]ethyl, 2-amino-4-(pyrrolidine-1-ylmethyl)phenyl, 4-[(dimethylamino)methyl]-2,6-dimethoxyphenyl, 4-[(dimethylamino)methyl]-2-hydroxyphenyl, 4-[(dimethylamino)methyl]-3-hydroxyphenyl, 4-[(dimethylamino)methyl]phenyl, 4-[[ethyl(methyl)amino]methyl]phenyl, or 4-[[ethyl(propyl)amino]methyl]phenyl]phenyl.

11. R １ However, H or C １－６ It is alkyl, R ２ However, C １～６ Alkyl or C １～６ Alkoxy C １～６ It is alkyl, R ３ However, C １～６ It is alkyl, R ４ However, (C １～６ Alkyl) ２ Amino C １～６ Alkyl, amino, C １～６ Alkoxy, hydroxy, and pyrrolidinyl C １～６ Phenyl compounds that are substituted once, twice, or three times with substituents independently selected from the alkyl group. A is S, L is a combination or C １～６ It is alkylene. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. R １ However, it is H or methyl, R ２ However, it is butyl or ethoxymethyl, R ３ However, it is methyl, R ４ However, these are 2-[4-[(dimethylamino)methyl]-3-hydroxyphenyl]ethyl, 2-[4-[(dimethylamino)methyl]phenyl]ethyl, 2-amino-4-(pyrrolidine-1-ylmethyl)phenyl, 4-[(dimethylamino)methyl]-2,6-dimethoxyphenyl, 4-[(dimethylamino)methyl]-2-hydroxyphenyl, 4-[(dimethylamino)methyl]-3-hydroxyphenyl, 4-[(dimethylamino)methyl]phenyl, 4-[[ethyl(methyl)amino]methyl]phenyl, or 4-[[ethyl(propyl)amino]methyl]phenyl]phenyl, A is S, L is a bond or ethylene. The compound according to claim 11, or a pharmaceutically acceptable salt thereof.

13. 7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 1-[4-amino-2-butyl-7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-6-methyl-imidazo[4,5-c]pyridine-1-yl]-2-methyl-propan-2-ol; 1-[4-amino-7-[4-[(dimethylamino)methyl]phenyl]ceranyl-2-(ethoxymethyl)-6-methyl-imidazo[4,5-c]pyridine-1-yl]-2-methyl-propan-2-ol; 7-[4-[(dimethylamino)methyl]-2,6-dimethoxyphenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 2-(ethoxymethyl)-7-[4-[[ethyl(propyl)amino]methyl]phenyl]sulfanyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 2-(ethoxymethyl)-7-[4-[[ethyl(methyl)amino]methyl]phenyl]sulfanyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-1,6-dimethylimidazo[4,5-c]pyridine-4-amine; 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[(dimethylamino)methyl]phenol; 7-[4-[(dimethylamino)methyl]-3-methoxyphenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 7-[2-[4-[(dimethylamino)methyl]phenyl]ethylsulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 5-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-[(dimethylamino)methyl]phenol; 5-[4-amino-2-(ethoxymethyl)-1,6-dimethylimidazo[4,5-c]pyridine-7-yl]sulfanyl-2-[(dimethylamino)methyl]phenol; 5-[2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]ethyl]-2-[(dimethylamino)methyl]phenol; 2-butyl-7-[4-[(dimethylamino)methyl]phenyl]sulfanyl-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 2-butyl-7-[2-[4-[(dimethylamino)methyl]phenyl]ethylsulfanyl]-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 6-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-3-[(dimethylamino)methyl]-2-methylphenol; 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-(diethylaminomethyl)phenol; 7-[[4-[(dimethylamino)methyl]-1H-indole-7-yl]sulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 7-[[4-[(dimethylamino)methyl]-1H-indazole-7-yl]sulfanyl]-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 7-[2-amino-4-[(dimethylamino)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 2-[(4-amino-2-butyl-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl)sulfanyl]-5-[(dimethylamino)methyl]phenol; 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-(pyrrolidine-1-ylmethyl)phenol; 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[(dimethylamino)methyl]-4-methylphenol; 2-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-5-[1-(dimethylamino)ethyl]phenol; 5-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-[(dimethylamino)methyl]-4-methylphenol; 7-[2-amino-4-(pyrroridine-1-ylmethyl)phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 7-[2-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 7-[3-amino-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; 7-[2-amino-6-methoxy-4-[(4-methylpiperazine-1-yl)methyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; N-[5-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-pyridyl]-N',N'-dimethylethane-1,2-diamine; 7-[4-[2-(dimethylamino)ethyl]phenyl]sulfanyl-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-4-amine; and 6-[[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridine-7-yl]sulfanyl]-2-methyl-3,4-dihydro-1H-isoquinoline-7-ol; A compound selected from, or a pharmaceutically acceptable salt thereof.

14. A process for preparing the compound according to any one of claims 1 to 13, comprising the following steps: a) Compound of formula (III) in the presence of a set of catalyst, ligand, reagent and base: And the compound of formula (II-1) is WS-L-R ４ Compound of formula (I-1) obtained by reaction with (II-1): Formation process; b) Compound of formula (XIII) in the presence of an acid: The deprotection process for forming the compound of formula (I-1); c) Compound of formula (III) and compound B(OH) of formula (II-2) in the presence of the reagent ２ -L-R ４ Compound of formula (I-2) obtained by reaction with (II-2): Formation process, Includes one of the following: The set of catalyst, ligand, reagent and base in step a) is (1) Pd ２ (dba) ３ XantPhos and DIEA (or Cs ２ CO ３ (2) CuI, Mtpy and KOH, (3) Cu ２ S, Fe, and K ２ CO ３ (or Cs ２ CO ３ ), or (4) TIPSH, XantPhos Pd G3 and K ２ CO ３ (or Cs ２ CO ３ ) and The acid in step b) is TFA or HCl, The reagent in step c) is SeO ２ and KI, W is H, -S-L-R ４ or R ａ And R ａ However, it is an alkoxycarbonylalkyl, and R １ , R ２ , and R ４ A process, defined in the same manner as any one of claims 1 to 12.

15. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, as produced according to the process described in claim 14.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable additive.

17. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 13 for use as a therapeutically active substance.

18. Use of any one of the compounds described in claims 1 to 13 as agonists for TLR7 and TLR8.

19. Use of a compound according to any one of claims 1 to 13 for the treatment of cancer, wherein the cancer is selected from pancreatic ductal adenocarcinoma, colorectal cancer, melanoma, hepatocellular carcinoma, cholangiocarcinoma, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, head and neck squamous cell carcinoma, adenoid cystic carcinoma, advanced small cell lung cancer, non-small cell lung cancer, muscle-invasive bladder cancer, nodular basal cell carcinoma, and squamous cell carcinoma.

20. Use of a compound according to any one of claims 1 to 13 for preparing a drug for the treatment of cancer, wherein the cancer is selected from pancreatic ductal adenocarcinoma, colorectal cancer, melanoma, hepatocellular carcinoma, cholangiocarcinoma, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, head and neck squamous cell carcinoma, adenoid cystic carcinoma, advanced small cell lung cancer, non-small cell lung cancer, muscle-invasive bladder cancer, nodular basal cell carcinoma, and squamous cell carcinoma.

21. The use according to claim 19 or 20, wherein the cancer is selected from pancreatic ductal adenocarcinoma and colorectal cancer.

22. A method for treating cancer, wherein the cancer is selected from pancreatic ductal adenocarcinoma, colorectal cancer, melanoma, hepatocellular carcinoma, cholangiocarcinoma, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, head and neck squamous cell carcinoma, adenoid cystic carcinoma, extensive-stage small cell lung cancer, non-small cell lung cancer, muscle-invasive bladder cancer, nodular basal cell carcinoma, and squamous cell carcinoma, and the method comprises administering a therapeutically effective amount of any one of claims 1 to 13.

23. The invention as previously described herein.

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