PDK1 modulator compound and composition containing same

Abstract

The present invention provides a 3-phosphoinositide-dependent protein kinase 1 (PDK1) modulator compound. The PDK1 modulator compound according to the present invention, is provided as a compound represented by chemical formula 1, or a solvate, hydrate, prodrug, stereoisomer or pharmaceutically acceptable salt thereof, and regulates, inhibits or antagonizes the activity of PDK1, and thus can be used for anticancer, antifibrosis, anti-aging and reverse aging, or treatment or prevention of Alzheimer's disease or autoimmune disease. In addition, the present invention provides a composition for anticancer, antifibrosis, anti-aging and reverse aging, or treatment, prevention or alleviation of Alzheimer's disease or autoimmune disease, containing the PDK1 modulator compound and a salt thereof as active ingredients, and provides a method, in which the compound and a salt thereof are administered to a subject, for anticancer, antifibrosis, anti-aging and reverse aging, or treatment, prevention or alleviation of Alzheimer's disease or autoimmune disease.

Description

PDK1 modulator compound and composition containing the same

[0001] The present invention relates to a PDK1 modulator compound and a composition comprising the same, and more particularly, to a use thereof for treating or preventing anticancer, antifibrotic, anti-aging, reverse aging, Alzheimer's disease, or autoimmune diseases by modulating, inhibiting, or antagonizing the activity of PDK1 (3-phosphoinositide-dependent protein kinase 1).

[0002] In addition, the present invention relates to a composition for preventing or improving anticancer, antifibrotic, anti-aging, anti-aging, Alzheimer's disease, or autoimmune disease, comprising the PDK1 modulator compound and its salt as an active ingredient.

[0003] In addition, the present invention relates to a method for treating, preventing, or improving cancer or autoimmune disease by administering the compound and its salt to a subject.

[0004] - Priority Information -

[0005] This application claims the benefit of Korean Application No. 10-2024-0053033, filed April 19, 2024 (earlier application), and Korean Application No. 10-2025-0051925, filed April 21, 2025, which are incorporated herein by reference in their entirety.

[0006]

[0007] PDK1 (3-phosphoinositide-dependent protein kinase 1), also known as PDPK1, is one of the kinases included in the 'PI3K-PDK1-AKT-mTOR' pathway and acts as a central regulator of the AGC kinase family, which includes AKT, SGK, PLK, S6K, and RSK, and are essential for cell growth, survival, and metabolism.

[0008] PDK1 is composed of an N-terminal catalytic domain (kinase domain, PDK1-PKD) and a C-terminal pleckstrin homology domain (PH domain, PDK1-PHD), and is known to play a key role in directly or indirectly regulating the activity of various kinases within the 'PI3K-PDK1-AKT-mTOR' pathway (Belham, Christopher, Shilan Wu, and Joseph Avruch, Curr. Biol., 1999, 9(3):R94-96, see Fig. 1).

[0009] Activated PI3-K (Phosphoinositide 3-kinase) converts PIP2 to PIP3, which sequentially induces exposure of serine and threonine on AKT (Adenosin kinase terminal / Protein Kinase B).

[0010] AKT in this state is activated in the presence of PDK1 and regulates downstream signaling pathways, including mammalian target of rapamycin (mTOR).

[0011] In particular, phosphorylation of mTOR sequentially activates and inactivates S6K (Ribosomal protein S6 kinase) and 4E-BP1 (Eukaryotic translation initiation factor, 4E-binding protein 1), leading to the initiation of ribosomal protein synthesis and protein translation.

[0012] Meanwhile, among immune cells, activation of AKT by PDK1 in T cells leads to the activation of mTORC1, known as a positive regulator of follicular helper T cells (Tfh) cells, and NFκB, one of the key factors in the T cell signaling system, is also activated by the signaling system. (Sun Zhen et al., ELife, 2021, 10:e61406, see Fig. 2)

[0013] Because of this importance, kinases within the PI3K-PDK1-AKT-mTOR pathway are being utilized as targets for the development of immunosuppressive and anticancer drugs.

[0014] Among them, PDK1 is a key kinase that coordinates the entire signal transduction system by regulating the activity of various kinases involved in the inflammatory response and the development and growth of cancer, and is attracting attention as a major target for drug development.

[0015] By binding the inhibitor of the present invention to the allosteric site of PDK1, it can effectively block abnormal activation of the PI3K / Akt / mTOR signaling pathway, thereby inducing a biological effect of inhibiting cell survival, growth, or pathophysiological responses related to fibrosis.

[0016] The compound of the present invention can exhibit non-competitive inhibition by binding to a separate allosteric site, rather than the substrate binding site (active site) of PDK1. This binding induces a change in the overall structural arrangement of PDK1 or the conformational structure of the active site, preventing the enzymatic reaction from occurring even when the substrate binds. Therefore, the compound has the characteristic of effectively blocking the downstream signaling pathway by inhibiting the phosphorylation activity of PDK1 regardless of substrate binding.

[0017] In particular, in relation to cancer, PDK1 (3-Phosphoinositide-dependent protein kinase-1) is overexpressed in various cancer types, and is closely related to the malignant progression of cancer by promoting tumor growth, invasiveness, and metastasis, and increasing resistance to apoptosis.

[0018] Several preclinical models have reported that PDK1 inhibition is effective in suppressing tumor growth, and this effect extends beyond simple tumor cell effects to modulating the tumor microenvironment (TME).

[0019] PDK1 regulates the function of immune cells, cancer-associated fibroblasts (CAFs), and vascular endothelial cells within the TME, and can activate various signaling pathways that induce immune evasion mechanisms.

[0020] If this is suppressed, the tumor-specific immune response can be restored, which can enhance the anti-tumor effect, and the mechanism of inducing the activity of immune cells by regulating the metabolic competition between immune cells and tumor cells is also attracting attention.

[0021] Additionally, PDK1 plays a key role in angiogenesis.

[0022] It promotes the creation of new blood vessels through linkage with VEGF (vascular endothelial growth factor) signals, thereby activating the supply of oxygen and nutrients to the tumor.

[0023] Therefore, PDK1 inhibition can be used as a strategy to block angiogenesis and create an unfavorable environment for tumor growth.

[0024] From a therapeutic perspective, PDK1 inhibition is known to exhibit particularly potent synergistic effects in combination treatment strategies, rather than as monotherapy. Combinations with PI3K, AKT, and mTOR inhibitors are prime examples. Because PDK1 acts as an upstream regulator of these signaling pathways, combined inhibition can induce a more potent antitumor response. Furthermore, combination strategies with antibody-drug conjugates (ADCs) and immuno-oncology agents are also being studied, with PDK1 inhibition attracting particular attention as a strategy for overcoming resistance to existing treatments.

[0025] Meanwhile, PDK1 has also been reported to regulate autophagy, and a pathway that inhibits autophagy through interaction with mTOR has been identified. In cancer cells, autophagy can act in the direction of either cell survival or death, and inducing autophagy through PDK1 inhibition can impair cancer cell viability. Furthermore, PDK1 is involved in histone modification and gene expression regulation, exerting a significant influence on the transcriptome of cancer cells.

[0026] In particular, PDK1 overexpression has been reported to be associated with poor prognosis and reduced treatment response in breast, pancreatic, and lung cancers. In this respect, PDK1 is not simply a tumor growth factor, but rather a key molecule that comprehensively regulates cancer initiation, progression, immune evasion, and treatment resistance. Combination therapy targeting PDK1 is considered a highly promising next-generation anticancer strategy.

[0027] Meanwhile, in particular, in relation to immunity, PDK1 has been identified as essential for NF-κB signaling and T cell activation through TCR and CD28 signaling.

[0028] Because PDK1 deficiency increases cell cycle progression and B cell apoptosis and impairs B cell maturation and IgG synthesis, modulation of PDK1 may be a target for immunotherapeutic strategies.

[0029] PDK1 inhibitors are expected to be very useful in autoimmune diseases such as systemic lupus erythematosus (SLE), which is an autoimmune disease characterized by abnormal T cells, overactive B cells, and production of large amounts of autoantibodies.

[0030] Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease caused by excessive proliferation of fibroblasts and abnormal accumulation of extracellular matrix (ECM), particularly collagen, within lung tissue. This leads to decreased lung elasticity, impaired gas exchange, and ultimately, overall respiratory function decline. The PI3K / Akt signaling pathway, which plays a central role in the pathophysiology of fibrosis, is known to regulate cell survival, proliferation, migration, and metabolism, as well as act as a global regulator of the fibrotic response. Specifically, studies have shown that activation of this pathway is closely associated with fibroblast proliferation and increased expression of collagen I and III in an animal model of bleomycin-induced pulmonary fibrosis, and that these responses are effectively inhibited by PI3K inhibitors.

[0031] PDK1 is a key factor that directly phosphorylates Akt within the PI3K / Akt pathway, functioning as an upstream regulatory node in this pathway. Therefore, selective inhibition of PDK1 suppresses fibroblast survival and proliferation and blocks the progression of fibrosis. Furthermore, PDK1 inhibition suppresses crosstalk with TGF-β1 signaling, a key inducer of fibrosis, thereby reducing α-SMA expression and ECM accumulation.

[0032] In addition, it has been reported to inhibit early stages of fibrotic reactions, such as epithelial-mesenchymal transition (EMT) and fibroblast mobility, and to alleviate inflammatory signals by reducing the production of reactive oxygen species (ROS).

[0033] These mechanisms are commonly involved not only in pulmonary fibrosis but also in fibrosis in various organs. For example, the PDK1-related pathway has been observed to contribute to the progression of fibrosis in systemic sclerosis-related interstitial lung disease (SSc-ILD) and radiation-induced pulmonary fibrosis.

[0034] In the case of liver fibrosis, there is also research showing that chronic inflammation induces collagen accumulation in nonalcoholic steatohepatitis (NASH) or viral hepatitis (types B and C), and that inhibition of PDK1 alleviates fibrosis in liver tissue.

[0035] In renal fibrosis, activation of the TGF-β / PI3K / PDK1 pathway, which is related to ECM production, has been confirmed in chronic kidney disease (CKD) or diabetic nephropathy, and in cardiac fibrosis, PDK1 is involved in regulating cardiomyocyte survival and fibroblast activation in heart failure or hypertrophic cardiomyopathy.

[0036] In addition, retinal fibrosis (PVR) is associated with decreased photoreceptor function and increased risk of blindness, which has also been suggested to be modifiable through inhibition of the PI3K / PDK1 pathway.

[0037] The role of PDK1 as one of the signaling pathways involved in fibroblast hyperactivation in pancreatic fibrosis and skin fibrosis (e.g., keloids, systemic sclerosis) is also receiving increasing attention.

[0038] Thus, PDK1 inhibitors commonly modulate pathological fibrotic pathways in various organ fibrosis, demonstrating potential for development as multi-organ antifibrotic agents.

[0039] On the other hand, in relation to aging, PDK1 activity is increased in the aging state of human dermal fibroblasts.

[0040] There is a paper that shows that regulating PDK1 partially reverses senescence by reducing the expression of p21, p16, and SA-β-gal, which are characteristics of senescent cells, and PDK1 inhibition is known to decrease the activity of the AKT and mTOR pathways, which contributes to reducing intracellular stress responses and SASP (senescence-associated secretory phenotype).

[0041] PDK1 is overactivated in senescent cells, and its regulation has been reported to reduce markers of cellular senescence and induce rejuvenation to a youthful state.

[0042] Therefore, PDK1 is suggested as a promising target for aging control and anti-aging treatment.

[0043] Alzheimer's disease (AD) is a representative degenerative neurodegenerative disease associated with aging, characterized by memory loss and cognitive dysfunction, and the number of patients is continuously increasing.

[0044] The pathophysiology of AD is known to involve a complex interaction of amyloid beta (Aβ) accumulation, Tau protein hyperphosphorylation, neuronal cell death, and inflammatory responses.

[0045] PDK1 is a key regulator of the PI3K / Akt pathway, and its overactivation in AD has been reported to promote Aβ production by increasing the expression of γ-secretase and reduce the non-amyloid pathway by inhibiting the activity of α-secretase (TACE).

[0046] Chronic activation of the PDK1 / Akt pathway may favor neuronal death rather than survival, and this tendency is known to become more pronounced with aging.

[0047] Some studies have confirmed that inhibiting PDK1 activity alleviates Aβ-induced neurotoxicity and promotes the non-amyloid pathway by increasing TACE activity.

[0048] In addition, a reduction in neuroinflammatory response and improvement in cognitive function have also been reported, and thus PDK1 is evaluated to have potential as a new therapeutic target.

[0049] In addition, PDK1 (3-Phosphoinositide-dependent protein kinase-1) is a central regulator of the PI3K / Akt signaling pathway, and regulates biological processes essential for tumor progression, such as cell survival, proliferation, motility, invasiveness, and angiogenesis, by inducing the activation of various AGC kinases, including Akt, S6K, and PKC.

[0050] In particular, PDK1 increases the motility and invasiveness of cancer cells by inducing epithelial-mesenchymal transition (EMT) in tumor cells, which plays an important role in the early stages of cancer metastasis.

[0051] In fact, Du et al. reported in their Oncogene (2016) paper that in the MMTV-PyMT breast cancer mouse model with a deletion of the PDK1 gene, the number of tumor lung metastases was significantly reduced, cell motility and invasiveness were inhibited, and the expression pattern of EMT-related markers was changed.

[0052] Furthermore, PDK1 inhibition was shown to simultaneously block various pathways involved in creating a metastatic environment by suppressing the expression of VEGF, an angiogenesis-related factor, and inhibiting the activity of p-Akt and mTOR signaling.

[0053] PDK1 is a key factor inducing angiogenesis through the PI3K / Akt / mTOR / HIF-1α / VEGF axis, and this pathway is closely related to pathological angiogenesis in the eye.

[0054] In fact, choroidal neovascularization is the main pathogenic mechanism in wet age-related macular degeneration (wAMD), intraretinal ischemic neovascularization is the main pathogenic mechanism in diabetic retinopathy (DR) and retinal vein occlusion (RVO), and vascular and fibrotic proliferation is the main pathogenic mechanism in retinal proliferative diseases.

[0055] Here, VEGF is utilized as an important therapeutic target.

[0056] Therefore, by inhibiting PDK1 and thereby reducing VEGF expression, abnormal angiogenesis in these ophthalmic diseases can be effectively suppressed, and PDK1 inhibitors can be applied as useful therapeutic tools in the ophthalmic field as well.

[0057] Accordingly, the applicant of the present invention focused his interest and research on anticancer efficacy, immunosuppressive efficacy, antifibrotic efficacy, and anti-aging efficacy by inhibiting the activity of PDK1.

[0058]

[0059] The technical problem to be solved by the present invention is to provide a compound having an excellent treatment, prevention, or improvement effect on cancer or autoimmune disease.

[0060] As a result, the compound of chemical formula 1 was developed and the present invention was completed.

[0061] In addition, the present invention aims to provide a compound or salt thereof having an excellent effect in treating, preventing, or improving cancer or autoimmune disease.

[0062] According to the present invention, the compound of chemical formula 1 or a salt thereof has an excellent effect of killing cancer cells or inhibiting tumor growth and proliferation due to its PDK1 inhibitory, regulating, or antagonistic ability, and is highly safe for the human body.

[0063] Therefore, it can be usefully utilized for the prevention, treatment or improvement of cancer.

[0064] In addition, the compound of chemical formula 1 or a salt thereof according to the present invention having excellent PDK1 inhibitory ability not only inhibits the proliferation of T cells but also induces the death of B cells, thereby exhibiting a strong immunosuppressive function, and thus can be usefully used for the treatment or prevention of autoimmune diseases that form autoantibodies in addition to transplant rejection.

[0065] In addition, the PDK1 inhibitor of the present invention can effectively block the metastatic process of tumors by inhibiting EMT of cancer cells, reducing mobility and invasiveness, inhibiting angiogenesis, and inhibiting Akt / mTOR signaling, and thus can be utilized as a useful therapeutic means that can exhibit metastasis inhibition and therapeutic effects in various solid cancers such as breast cancer, lung cancer, and pancreatic cancer.

[0066]

[0067] In order to solve the above-described technical problem, the present invention provides a compound represented by Chemical Formula 1, or a solvate, hydrate, prodrug, stereoisomer, or pharmaceutically acceptable salt thereof.

[0068] <Chemical Formula 1>

[0069] Z 1 -Prd-CONH-R 10

[0070] Here, Z 1is -NH2 (or -NHR1, wherein R1 is benzene or a benzene derivative; Compound 59), -SH, a methylthio group, a benzoyl group, a benzyloxy group, an alkyl group substituted with a halogen, a benzimidazole group, -OH, -SH, a halogen, -NO2, -CF3, a C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C3-C10 arylalkyl (Ar-(CH2)n-), a C5-C10 aryl (Ar-), a C3-C10 alkylaryl ((CH2)n-Ar-), a C3-C10 cycloalkyl, a C3-C10 heteroaryl or a C3-C10 heterocycloalkyl, or is unsubstituted or substituted, a C5-C10 aryl or a C3-C10 heteroaryl,

[0071] Prd is pyridine or benzene,

[0072] -CONH- is an amide bond,

[0073] R 10 is a C8-C14 alkyl, C8-C14 alkenyl or C8-C14 alkynyl group, wherein one, two or three hydrogen atoms of the terminal carbon are substituted with halogen (fluorine, chlorine, bromine, iodine), morpholine or an analogue thereof, piperazine or an analogue thereof, thiomorpholine or an analogue thereof, pyrrolidine or an analogue thereof, piperidine or an analogue thereof, 3,4-dihydro-2H-benzo[b][1,4]oxazine or an analogue thereof, pyrimidine or an analogue thereof, pyrazine or an analogue thereof, or a functional group of Table 1.

[0074] Table 1

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085] In the present invention, terms such as alkyl, alkenyl, and alkynyl are intended to include both straight-chain (also referred to as linear) and branched-chain (also referred to as branched).

[0086] For example, the term alkyl refers to an unbranched or branched saturated hydrocarbon chain.

[0087] In some embodiments, alkyl may have 1 to 6 carbon atoms ((C1-C6)alkyl), 8 to 14 carbon atoms ((C8-C14)alkyl).

[0088] More specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, 3-hexyl, and 3-methyl pentyl.

[0089] When naming an alkyl moiety having a particular number of carbon atoms, all geometric isomers having that number of carbon atoms can be included. For example, butyl can include n-butyl, sec-butyl, isobutyl, and t-butyl, and propyl can include n-propyl and isopropyl.

[0090] Unless specifically stated otherwise in the specification, the alkyl chain may be optionally substituted with one or more substituents, such as those described herein.

[0091] The term “halogen” as used in the present invention means fluorine, chlorine, bromine or iodine.

[0092] The term “alkoxy” used in the present invention means ‘oxygen (O)-alkyl’.

[0093] The term “hetero” as used in the present invention means a heteroatom selected from oxygen, nitrogen and sulfur.

[0094] The term "cycloalkyl" as used in the present invention means an alkyl that forms a ring.

[0095] The term "heterocycloalkyl" used in the present invention means a cycloalkyl in which a heteroatom is included within the ring.

[0096] The term “arylalkyl” used in the present invention means alkyl having an aryl group.

[0097] The term “alkylaryl” used in the present invention means an aryl having an alkyl group.

[0098] The term "analog" used in the present invention means a structure having a similar chemical structure, a structure in which the ring size is changed, a structure substituted with a heteroatom, a structure in which a substituent (such as an alkyl) is replaced, or a structure in which a double bond is created or eliminated to change the degree of saturation. For example, an analog of morpholine may have a structure in which the ring size is changed from 6 atoms to 5 or 7 atoms, a structure in which oxygen (O) or nitrogen (N) is replaced with sulfur (S), or a structure in which nitrogen (N) or oxygen (O) is replaced with a substituent (such as an alkyl).

[0099] The term "salt" used in the present invention can be prepared by a method conventional in the art, and for example, it can form a salt with an inorganic acid such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, carbonic acid, etc., or a salt of these acids with an organic acid such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin), or it can form a metal salt thereof by reacting with an alkali metal ion such as sodium or potassium, or it can form another type of salt by reacting with an ammonium ion, but is not limited thereto.

[0100] The hydrates, isomers, solvates, prodrugs, and crystalline forms of the compounds according to the present invention are included in the compounds of the present invention, despite the difference in terminology, within the range in which the original PDK1 regulatory ability or inhibitory or antagonistic ability properties of the compounds are expressed.

[0101] The term “isomer” used in the present invention includes stereoisomers, enantiomers, diastereomers, tautomers, geometric isomers, etc.

[0102] The term "solvate" as used in the present invention means an aggregate or complex of a compound of the present invention and one or more solvent molecules, wherein the solvent includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.

[0103] The term "hydrate" as used in the present invention means a solvate in which the solvent molecule is water.

[0104] The term “crystal form” used in the present invention means a form in which identical molecules form different crystal structures.

[0105] According to the present invention, the R 10The alkyl, alkenyl or alkynyl having 8 to 14 carbon atoms may be for the purpose of exerting an allosteric effect.

[0106] According to the present invention, if the number of carbon atoms is 7 or less, it is difficult to exert an immunosuppressive effect, and if it is 15 or more, it may be difficult to form an allosteric bond or to be absorbed in the body.

[0107] According to the present invention, the compound of formula 1 according to the present invention may be at least one selected from the group consisting of:

[0108] 2-Amino-N-(12-fluoro-dodecyl)-nicotinamide, 4'-methyl-biphenyl-2-carboxylic acid (12-fluoro-dodecyl)-amide, 2-amino-N-dodecylnicotinamide, 2-bromo-N-(12-fluoro-dodecyl)-nicotinamide, 2-amino-N-[12-(3,4-dihydro-1H-isoquinolin-2-yl)-dodecyl]-nicotinamide, N-(12-fluoro-dodecyl)-3-(3-trifluoromethyl-phenylamino)-isonicotinamide, 4-chloro-N-(12-fluoro-dodecyl)-nicotinamide, 2-amino-N-(12-morpholin-4-yl-dodecyl)-nicotinamide, 2-Amino-N-(8-fluoro-octyl)-nicotinamide, N-(12-fluoro-dodecyl)-2-mercapto-nicotinamide, 2-amino-N-(10-morpholin-4-yl-decyl)-nicotinamide, biphenyl-2-carboxylic acid (12-fluoro-dodecyl)-amide, 1H-indole-4-carboxylic acid (12-fluoro-dodecyl)-amide, 3-hydroxy-pyridine-2-carboxylic acid (12-fluoro-dodecyl)-amide, 3-benzoyl-pyridine-2-carboxylic acid (12-fluoro-dodecyl)-amide, isoquinoline-1-carboxylic acid (12-fluoro-dodecyl)-amide, 2-(4-Chloro-phenoxy)-N-(12-fluoro-dodecyl)-nicotinamide, N-(12-fluoro-dodecyl)-2-methylsulfanyl-nicotinamide, 2-amino-N-(10-fluoro-decyl)-nicotinamide, 3-(12-fluoro-dodecylcarbamoyl)-pyridin-2-yl-ammonium chloride, 2-amino-N-(11-fluoro-undecyl)-nicotinamide, 3-(11-fluoro-undecylcarbamoyl)-pyridin-2-yl-ammonium chloride, N-(12-fluoro-dodecyl)-2-hydroxy-nicotinamide, 4-amino-N-(12-fluoro-dodecyl)-nicotinamide, 3-amino-N-(12-fluoro-dodecyl)-isonicotinamide, N-(12-fluoro-dodecyl)-2-trifluoromethyl-nicotinamide, N-(12-fluoro-dodecyl)-3-iodo-isonicotinamide, 2-amino-N-(12-thiomorpholin-4-yl-dodecyl)nicotinamide or 2-amino-N-(12-(piperazin-1-yl)dodecyl)nicotinamide.

[0109] Additionally, according to the present invention, the compound may include at least one selected from the group consisting of the following chemical formulas:

[0110] Chemical formulas 2 to 39, 43 to 64, 67 to 71, 73, 76, 88 to 118, 121 to 217.

[0111] The present invention may be a compound characterized in that it is used to inhibit, antagonize, or regulate PDK1 (3-phosphoinositide-dependent protein kinase 1) as the above-described compound or a pharmaceutically acceptable salt thereof.

[0112] The present invention provides a method for inhibiting PDK1, comprising the step of contacting an effective amount of the compound described above or a pharmaceutically acceptable salt thereof with a subject containing PDK1 (3-phosphoinositide-dependent protein kinase 1) to inhibit PDK1.

[0113] In the above method, the subject may be treated in vivo or in vitro.

[0114] The present invention provides a method for inhibiting PDK1, characterized in that it comprises a step of contacting a cell containing PDK1 (3-phosphoinositide-dependent protein kinase 1) with an effective amount of the compound or a pharmaceutically acceptable salt thereof, thereby inhibiting PDK1.

[0115] In the above method, the cells may be handled in vivo or in vitro.

[0116] The present invention provides a method for antagonizing PDK1, characterized in that it comprises a step of antagonizing PDK1 by contacting an effective amount of the above-described compound or a pharmaceutically acceptable salt thereof with a target object containing PDK1 (3-phosphoinositide-dependent protein kinase 1).

[0117] In the above method, the subject may be treated in vivo or in vitro.

[0118] The present invention provides a method for antagonizing PDK1, characterized by comprising a step of contacting a cell containing PDK1 (3-phosphoinositide-dependent protein kinase 1) with an effective amount of a compound or a pharmaceutically acceptable salt thereof to antagonize PDK1.

[0119] In the above method, the cells may be treated in vivo or in vitro.

[0120] The present invention provides a method for treating cancer, which comprises administering to a subject suffering from cancer a therapeutically effective amount of a compound used for inhibiting, antagonizing, or regulating PDK1 (3-phosphoinositide-dependent protein kinase 1) or a pharmaceutically acceptable salt thereof.

[0121] According to one embodiment of the present invention, a method for treating an autoimmune disease is provided, which comprises administering to a subject suffering from an autoimmune disease a therapeutically effective amount of a compound used for inhibiting, antagonizing, or regulating PDK1 (3-phosphoinositide-dependent protein kinase 1) or a pharmaceutically acceptable salt thereof.

[0122] According to one embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof may be included as an active ingredient.

[0123] According to one embodiment of the present invention, the pharmaceutical composition may non-competitively regulate PDK1 activity.

[0124] According to one embodiment of the present invention, the PDK1 regulation may be performed through allosteric binding.

[0125] According to one embodiment of the present invention, the pharmaceutical composition may inhibit proliferation and survival signals of lymphocytes by blocking the PDK1-related pathway.

[0126] According to one embodiment of the present invention, the pharmaceutical composition may be used for autoimmune diseases, immune hypersensitivity reactions, chronic inflammatory diseases, and lymphocyte-related hyperproliferative diseases occurring in immune cells, macrophages, T cells, B cells, or plasma cells.

[0127] According to one embodiment of the present invention, the immune hypersensitivity reaction disease may be at least one of chronic urticaria, asthma, atopic dermatitis, allergic rhinitis, or serum sickness.

[0128] According to one embodiment of the present invention, the pharmaceutical composition may be used to prevent or treat rejection immune responses after transplantation or to treat lymphoproliferative diseases.

[0129] According to one embodiment of the present invention, the pharmaceutical composition may exhibit an effect of reducing immunoglobulin production.

[0130] According to one embodiment of the present invention, the pharmaceutical composition may have an effect of reducing lymph node enlargement, autoantibodies, inflammatory cytokine production, etc.

[0131] According to one embodiment of the present invention, the pharmaceutical composition may inhibit metastasis of cancer cells.

[0132] According to one embodiment of the present invention, the pharmaceutical composition may exhibit an anti-aging or reverse-aging effect.

[0133] According to one embodiment of the present invention, the pharmaceutical composition may be characterized by a decrease in intracellular β-galactosidase activity or an increase in Ki-67 expression.

[0134] According to one embodiment of the present invention, the pharmaceutical composition may have a use for treating a fibrotic disease.

[0135] According to one embodiment of the present invention, the fibrotic disease may be pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated interstitial lung disease (SSc-ILD), radiation-induced pulmonary fibrosis, liver fibrosis, renal fibrosis, cardiac fibrosis, retinal fibrosis, pancreatic fibrosis, or skin fibrotic disease.

[0136] According to one embodiment of the present invention, the pharmaceutical composition may have an effect of reducing α-SMA expression and collagen accumulation.

[0137] According to one embodiment of the present invention, the pharmaceutical composition may be used to inhibit or antagonize PDK1 (3-phosphoinositide-dependent protein kinase 1) expression.

[0138] According to one embodiment of the present invention, the pharmaceutical composition may be used for treating cancer or solid tumor cancer.

[0139] According to one embodiment of the present invention, the solid tumor cancer is glioma, glioblastoma, medulloblastoma, meningioma, pituitary adenoma, optic glioma, spinal cord tumor, Schwannoma, brain metastases, primary CNS lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, large cell carcinoma, malignant mesothelioma, tracheal cancer, laryngeal cancer, pharyngeal cancer, Nasal cavity cancer, oral cancer, tongue cancer, salivary gland cancer, laryngeal cancer, pharyngeal cancer, nasal cavity cancer, paranasal sinus cancer, thyroid cancer, parathyroid cancer, olfactory neuroblastoma, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, inflammatory breast cancer, triple-negative breast cancerPapillary carcinoma, Mucinous carcinoma, Tubular carcinoma, Medullary carcinoma, Metastatic breast cancer, Esophageal cancer, Gastric cancer, Small intestine cancer, Colon cancer, Rectal cancer, Hepatocellular carcinoma, Cholangiocarcinoma, Gallbladder cancer, Pancreatic cancer, Anal cancer, Renal cell carcinoma, Urothelial carcinoma, Bladder cancer, Ureteral cancer, Urethral cancer, Prostate cancer, Testicular cancer, Penile cancer, Adrenocortical cancer carcinoma), Pheochromocytoma, Endometrial cancer, Cervical cancer, Uterine sarcoma, Ovarian cancer, Fallopian tube cancer, Vaginal cancer, Vulvar cancer, Hydatidiform mole, Choriocarcinoma, Germinoma, Testicular cancer, Penile cancer, Prostate cancer, Epididymal cancer, Seminal vesicle cancer, Urethral cancer,Germinoma, Choriocarcinoma, Teratoma, Leydig cell tumor, Osteosarcoma, Chondrosarcoma, Ewing sarcoma, Fibrosarcoma, Synovial sarcoma, Liposarcoma, Rhabdomyosarcoma, Leiomyosarcoma, Desmoid tumor, Giant cell tumor of bone, Skin cancer, Melanoma, Basal cell carcinoma, Squamous cell carcinoma, Kaposi's sarcoma, Neuroendocrine tumor, Gastrointestinal It may be a gastrointestinal stromal tumor (GIST), retinoblastoma, Wilms tumor, or neuroblastoma.

[0140] According to the present invention, the pharmaceutical composition may be used for treating blood cancer.

[0141] According to one embodiment of the present invention, the blood cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma, cutaneous T-cell lymphoma (CTCL), plasmablastic lymphoma, Burkitt lymphoma, multiple myeloma, myelodysplastic syndromes (MDS), or It may be a myeloproliferative neoplasm (MPN).

[0142] According to one embodiment of the present invention, the autoimmune disease is systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren's syndrome, multiple sclerosis, inflammatory bowel disease (Crohn's disease or ulcerative colitis), psoriatic arthritis, autoimmune hemolytic anemia, immune thrombocytopenia (ITP). Glomerulitis, systemic lupus erythematosus (SLE), glomerulitis, ankylosing spondylitis, myastenia gravis, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic sclerosis, pernicious anemia, autoimmune anemia, infammatory bowel disease, insulin-dependent diabetes mellitus (IDDM), type 1 diabetes, Graves disease, Graves hyperthyroidism, Kikuchi disease, hemophagocytic lymphohistiocytosis, adult onset Still's disease, Behcet disease, immune It may be immune thrombocytopenia (ITP), alopecia areata, IgG4-related diseases, psoriasis, asthma, or transplant rejection.

[0143] According to the present invention, the pharmaceutical composition may be used for preventing or treating Alzheimer's disease.

[0144] According to the present invention, the above prevention or treatment may be by inhibiting the activity of PDK1 (phosphoinositide-dependent kinase-1).

[0145] According to the present invention, the pharmaceutical composition may suppress intraocular pathological angiogenesis by suppressing the activity of PDK1.

[0146] According to the present invention, the pathological angiogenesis may be caused by macular degeneration, diabetic retinopathy, retinal vein occlusion, or retinal proliferative disease.

[0147] According to the present invention, a pharmaceutical composition comprising the above-described compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided.

[0148] Another aspect of the present invention provides a pharmaceutical composition for treating or preventing cancer or an autoimmune disease, comprising a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0149] In the pharmaceutical composition according to the present invention, unless specifically stated otherwise, related terms are understood to have the same meaning as the terms described above.

[0150] The term "treatment" used in the present invention means all that is achieved by improving, alleviating, reversing, or completely curing cancer or an autoimmune disease by administering a composition according to the present invention.

[0151] The term "prevention" used in the present invention means all things that suppress, delay, prevent, etc. the occurrence or recurrence of cancer or autoimmune disease by administration of the composition according to the present invention.

[0152] The pharmaceutical composition of the present invention can be administered to a subject in need of prevention or treatment of cancer or an autoimmune disease by containing an effective amount of the compound, an isomer thereof, a solvate thereof, a hydrate thereof, a crystal form thereof, or a salt thereof.

[0153] As used herein, the term "administration" means physically introducing a composition to a subject using any of a variety of methods and delivery systems known to those of ordinary skill in the art.

[0154] The above administration may be performed, for example, by oral administration, or by intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral administration, such as by injection or infusion, but is not limited thereto.

[0155] The frequency of the above administrations may be, for example, single, multiple, and over one or more extended periods.

[0156] The pharmaceutical composition of the present invention can be formulated as a preparation for oral administration or parenteral administration according to the administration route described above.

[0157] As used herein, the term "subject" includes a human or any non-human animal, which non-human animal may be a vertebrate, such as a primate, dog, cow, horse, pig, rodent, such as a mouse, rat, guinea pig, etc.

[0158] In this specification, the term “subject” is used interchangeably with “individual” and “patient.”

[0159] In particular, the subject to whom the compound or composition according to the present invention is administered may be a cancer patient, or a cancer patient suffering from an autoimmune disease or at a high risk of developing an autoimmune disease.

[0160] Additionally, the subject to whom the compound or composition according to the present invention is administered may be a patient with an autoimmune disease, or a patient with an autoimmune disease who is suffering from cancer or has a high risk of developing cancer.

[0161] Additionally, the effective amount may be a “therapeutically effective amount” or a “prophylactically effective amount”.

[0162] The term "therapeutically effective amount" means any amount of a drug or therapeutic agent, when used alone or in combination with other therapeutic agents, that can result in a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to disease affliction.

[0163] The term "prophylactically effective amount" means any amount that inhibits the occurrence or recurrence of a disease in a subject.

[0164] The level of the above effective dose may be determined based on factors including the severity of the subject's condition, age, sex, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrent medications, and other factors well known in the medical field.

[0165] In addition, the dosage of the pharmaceutical composition may vary depending on the age, sex, weight, route of administration, severity of disease, etc. of the subject, and specifically, depending on the symptoms of the subject, 0.1 to 100 mg / kg of the composition of the present invention may be administered once or several times a day, or at intervals of several days to several months.

[0166] In addition, the term 'pharmaceutically acceptable salt' used in the present invention refers to a salt that is acceptable for administration to a subject.

[0167] Such salts having counter ions are understood to have acceptable mammalian safety for a given dosing regimen.

[0168] These salts may also be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids, and may include organic and inorganic counter ions.

[0169] The neutral form of the compound described in the present invention can be converted into the corresponding salt form by contacting the compound with a base or acid and isolating the resulting salt.

[0170] Additionally, the terms 'pharmaceutically acceptable excipient', 'pharmaceutically acceptable diluent', 'pharmaceutically acceptable carrier' and 'pharmaceutically acceptable adjuvant' are used interchangeably and mean an excipient, diluent, carrier or adjuvant that is generally safe, non-toxic and not biologically or otherwise undesirable and useful in preparing pharmaceutical compositions, and includes excipients, diluents, carriers and adjuvants that are acceptable for veterinary use and human pharmaceutical use.

[0171] The phrase 'pharmaceutically acceptable excipient' includes any one or more excipients, diluents, carriers and / or auxiliaries.

[0172] Additionally, the term 'pharmaceutical composition' is meant to include a composition suitable for administration to a subject such as a mammal, particularly a human.

[0173] In general, a 'pharmaceutical composition' is sterile and preferably free from contaminants that could induce an undesirable reaction within the subject (i.e., the compound(s) of the pharmaceutical composition are of pharmaceutical grade).

[0174] The pharmaceutical composition may be processed for administration to a subject or patient in need thereof via a number of different routes of administration, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intratracheal, intramuscular, subcutaneous, and the like.

[0175] In addition, the pharmaceutical composition may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.

[0176] Carriers, excipients and diluents that may be included in the composition include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

[0177] Additionally, the pharmaceutical composition may be administered in combination with other therapeutic agents.

[0178] In this case, the pharmaceutical composition of the present invention and the other therapeutic agent may be administered simultaneously, sequentially, or separately.

[0179] The above other therapeutic agents may be, but are not limited to, drugs such as compounds and proteins that have the effect of preventing, treating, and improving cancer or autoimmune diseases.

[0180] Additionally, the pharmaceutical composition may be formulated to be administered simultaneously, sequentially, or separately with other therapeutic agents.

[0181] For example, the compound, its isomer, solvate, hydrate, crystalline form or salt and another therapeutic agent may be administered simultaneously in one formulation, or may be administered simultaneously, sequentially or separately in separate formulations.

[0182] For simultaneous, sequential or separate administration, the compound, its isomer, solvate, hydrate, crystalline form or salt thereof and other therapeutic agents included in the pharmaceutical composition of the present invention may be formulated separately in separate containers or formulated together in the same container.

[0183] In addition, the compound, its isomer, solvate, hydrate, crystal form or salt and other therapeutic agents included in the pharmaceutical composition of the present invention may be the same or different from each other in terms of pharmaceutically effective amount, administration time, administration interval, administration route, treatment period, etc.

[0184] Another aspect of the present invention provides a method for treating or preventing cancer or an autoimmune disease, comprising administering to a subject a compound represented by chemical formula 1 or a salt thereof.

[0185] In the method for treating or preventing cancer or autoimmune disease according to the present invention, unless specifically stated otherwise, related terms are understood to have the same meaning as the terms described above.

[0186] Additionally, in the method for treating or preventing cancer or autoimmune disease according to the present invention, the compound or its salt may be administered to the subject simultaneously, sequentially, or separately with other agents.

[0187] The above “simultaneous” administration means administering the compound or its salt and another therapeutic agent at the same time as one preparation, or administering the compound or its salt and another therapeutic agent at the same time as separate preparations, in which case the routes of administration may be different from each other.

[0188] The above "sequential" administration means administering the compound or its salt and the other therapeutic agent relatively consecutively, allowing for the minimum possible time between administrations.

[0189] The above “individual” administration means administering the compound or its salt and other therapeutic agents at regular intervals.

[0190]

[0191] According to the present invention, the compound of chemical formula 1 or a salt thereof has an excellent effect of killing cancer cells or inhibiting tumor growth and proliferation due to its PDK1 inhibitory, regulating, or antagonistic ability, and is highly safe for the human body.

[0192] Therefore, it can be usefully utilized for the prevention, treatment or improvement of cancer.

[0193] In addition, the compound of chemical formula 1 or a salt thereof according to the present invention having excellent PDK1 inhibitory ability not only inhibits the proliferation of T cells but also induces the death of B cells, thereby exhibiting a strong immunosuppressive function, and thus can be usefully used for the treatment or prevention of autoimmune diseases that form autoantibodies in addition to transplant rejection.

[0194] In addition, by selectively inhibiting PDK1, it can suppress the survival and proliferation of fibroblasts and block the progression of fibrosis, so it can be usefully used for the treatment or prevention of fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) or nonalcoholic steatohepatitis (NASH).

[0195] Additionally, PDK1 inhibition may be useful for anti- or reverse-aging by reducing the activity of the AKT and mTOR pathways.

[0196] Additionally, it can be useful for the treatment or prevention of Alzheimer's disease by alleviating neurotoxicity caused by Aβ by inhibiting PDK1 activity and promoting the non-amyloid pathway by increasing the activity of TACE.

[0197] In addition, the present invention can effectively block the metastasis process of tumors by inhibiting EMT of cancer cells, reducing mobility and invasiveness, inhibiting angiogenesis, and inhibiting Akt / mTOR signaling, and thus can exhibit metastasis inhibition and therapeutic effects in various solid cancers such as breast cancer, lung cancer, and pancreatic cancer.

[0198]

[0199] Figure 1 is a conceptual diagram of the PDK1 domain map, showing the PKD, PHD, and PIF domains.

[0200] Figure 2 is a schematic diagram showing PDK1 and its downstream signaling pathways in mouse spleen-derived T cells.

[0201] Figure 3 is a graph showing the results of flow cytometry analysis according to the present invention.

[0202] Figure 4 shows the IC for inhibition of PDK1 kinase activity of enzyme kinetics analysis for compounds according to the present invention. 50 This is a graph showing the values,

[0203] Figure 5 is a graph showing the results of measuring the reaction rate according to the change in substrate concentration for the compound according to the present invention.

[0204] Figure 6 is a graph showing the results of analyzing stained cells of the compound according to the present invention through flow cytometry.

[0205] Figure 7 is a photograph of mice subcutaneously implanted with human B cell lymphoma cell line SU-DHL-8 (ATCC, Cat. #CRL-2961) to test the anticancer efficacy of the compound according to the present invention.

[0206] Figure 8 shows a photograph taken 14 days after administering the compound according to the present invention to the mice of Figure 7, along with the date of passage and the measured size.

[0207] Figure 9 is a graph showing that the weight change of mice of the compound according to the present invention is constant over time (day).

[0208] Figure 10 is a schedule showing the psoriasis treatment schedule of mice administered the compound according to the present invention.

[0209] Figure 11 is a photograph of the skin of mice taken 8 days after administration of the compound according to the present invention to determine the degree of psoriasis treatment.

[0210] Figure 12 is a photograph of the skin thickness of mice taken 8 days after administration of the compound according to the present invention to determine the degree of psoriasis treatment.

[0211] Figure 13 is a graph showing the results of measuring the PASI (Psoriasis Area and Severity Index) score to evaluate the therapeutic effect of psoriasis-induced mice administered the compound according to the present invention.

[0212] Figure 14 is a graph showing the results of analyzing the concentration of psoriasis-related cytokines (IL-17A) in the heart serum of mice administered the compound according to the present invention.

[0213] Figure 15 is a graph showing the results of measuring the body weight of mice with lupus disease administered the compound according to the present invention.

[0214] Figure 16 is a graph showing the results of analyzing the protein concentration in urine of mice with lupus disease that were administered the compound according to the present invention using 'Quick Start™ Bradford 1x Dye Reagent (Bio-Rad, Cat. #5000205)'.

[0215] Figure 17 is a graph showing the results of measuring the concentration of antinuclear antibodies (Anti-dsDNA Ab) using the 'Mouse Anti-dsDNA IgG ELISA Kit (Alpha Diagnostic International, Cat. #5120)' for serum isolated from mice administered the compound according to the present invention.

[0216] Figure 18 is a graph showing the results of measuring the concentration of total IgG using 'IgG (Total) Mouse Uncoated ELISA Kit (Invitrogen, Cat. #88-50400)' for serum isolated from mice administered the compound according to the present invention.

[0217] Figure 19 is a graph showing the results of staining mouse spleen cells administered with a compound according to the present invention and analyzing them through flow cytometry.

[0218] Figure 20 is a graph showing the results of gene expression analysis on cytokines in the kidney to confirm the effect on the systemic immune response of lupus mice administered the compound according to the present invention.

[0219] Figure 21 is a drawing showing the results of observation after sectioning and staining to confirm the effect on the kidney tissue of lupus mice administered with the compound according to the present invention.

[0220] Figure 22 is a photograph of immunofluorescence staining performed to confirm the degree of IgG deposition in the kidney tissue of a lupus mouse administered the compound according to the present invention, observed under a fluorescence microscope.

[0221] Figures 23 and 24 are photographs showing the relief of hair loss symptoms on the face of lupus mice administered with a compound according to the present invention. Figure 23 is a photograph taken after GO15F was treated with 30 mg / kg for 2 months, or 60 days, and Figure 24 is a photograph taken after GO15F, GO48, and GO88 were administered for 14 days and the skin was removed to observe the tissue.

[0222] Figure 25 is a photograph taken using an optical microscope after performing Ki-67 immunohistochemistry (IHC) staining to confirm the cell proliferation activity of hair follicles in the skin tissue of a lupus mouse administered with a compound according to the present invention.

[0223] Figure 26 is a photograph of the foot of a rheumatoid mouse administered with a compound according to the present invention.

[0224] Figure 27 is a photograph of joint tissues extracted and observed to confirm the degree of rheumatoid arthritis in mice administered the compound according to the present invention.

[0225] Figure 28 is a photograph of joint tissue extracted and observed to confirm the degree of rheumatoid arthritis in mice administered the compound according to the present invention.

[0226] Figure 29 is a graph showing the results of analysis using the IL-17A, TNF-α Mouse ELISA kit on the serum of rheumatoid mice administered with the compound according to the present invention.

[0227] Figure 30 is a photograph taken under a microscope after staining to evaluate the metastasis inhibition effect of the compound according to the present invention on the HCT-116 colon cancer cell line.

[0228] Figure 31 is a photograph taken at different times of a mouse in which a human-derived colon cancer cell line was subcutaneously transplanted.

[0229] Figure 32 is a drawing showing the results of evaluating the tumor growth inhibition efficacy of a human-derived colon cancer cell line of a compound according to the present invention in mice subcutaneously transplanted therein.

[0230] Figure 33 is a graph showing the results of measuring the total IgG concentration in the serum of normal mice and mice that induced a sensitized animal model, and expressing it as a relative concentration value.

[0231] Figure 34 is a graph showing the results of analyzing changes in B cell subtypes in spleen cells of mice to confirm the effect of administration of a compound according to the present invention on changes in the proportion of immune cells in the body of sensitized mice.

[0232] Figure 35 is a graph showing the results of analyzing changes in T cell subtypes in spleen cells of mice to confirm the effect of administration of a compound according to the present invention on changes in the proportion of immune cells in the body of sensitized mice.

[0233] Figure 36 is a graph showing the results of measuring the total IgG concentration in the serum of normal mice and mice that induced a sensitized animal model, and expressing it as a relative concentration value.

[0234] Figure 37 is a graph showing the results of administering a compound according to the present invention to a skin grafted mouse, isolating immune cells from the spleen, and analyzing the ratio of CD3 and B220 positive cells within each cell using a flow cytometer.

[0235] Figure 38 is a photograph of a skin grafted mouse administered with a compound according to the present invention.

[0236] Figure 39 is a drawing showing the results of treating NHDF (Normal Human Dermal Fibroblast, Promocell) cells with a compound according to the present invention and analyzing β-galactosidase activity and Ki-67 expression.

[0237] Figure 40 is a drawing showing the results of treating NHDF (Normal Human Dermal Fibroblast, Promocell) cells with a compound according to the present invention and applying it to a FACS analyzer to observe the fluorescence expression of Ki-67.

[0238] Figure 41 is a photograph of the establishment of a mouse model for pulmonary fibrosis.

[0239] Figure 42 is a photograph of a compound according to the present invention administered to a mouse with pulmonary fibrosis, and the extracted lungs were stained, pathologically analyzed, and taken.

[0240] Figure 43 is a photograph taken after administering a compound according to the present invention to a mouse with pulmonary fibrosis, performing immunohistochemical (IHC) staining on the extracted lung, and analyzing the results.

[0241] Figure 44 is a drawing showing the results of treating human lung fibroblast MRC-5 cells with a compound according to the present invention, extracting proteins, transferring them to PVDF membranes, and performing Western blot analysis.

[0242] Figure 45 is a drawing showing the experimental method and schedule of atopic mice administered with a compound according to the present invention.

[0243] Figure 46 is a photograph showing the extent of skin lesions on the back of atopic mice administered with a compound according to the present invention.

[0244] Figure 47 shows the results of analyzing the pathological tissue through H&E and Toluidine Blue staining related to the back area of ​​atopic mice administered the compound according to the present invention.

[0245] Figure 48 is a graph obtained through comparative analysis of binding affinity between PDK1 and GO88 using Microscale Thermophoresis (MST) according to the invention.

[0246]

[0247] Hereinafter, the present invention will be described in more detail by examples.

[0248] However, these examples are intended to exemplify the present invention, and the scope of the present invention is not limited by these examples.

[0249] In addition, a person having ordinary knowledge in the relevant technical field may make various modifications and changes to the present invention within a scope that does not detract from the spirit of the present invention.

[0250] Terms not specifically defined herein should be understood to have the meanings commonly used in the technical field to which the present invention belongs.

[0251] Also, unless the context specifically defines otherwise, the singular includes the plural, and the plural includes the singular.

[0252] Manufacturing example

[0253] Compounds corresponding to the examples and comparative examples of the present invention were prepared according to the following reaction scheme 1. Compounds with different substituents were also prepared through similar steps, but not all of them are specified in this specification.

[0254] Anyone with ordinary knowledge in the relevant technical field can easily prepare compounds with different substituents by referring to the representative examples below.

[0255]

[0256]

[0257]

[0258] Looking at the reaction scheme 1 in detail, a carboxylic acid derivative (1.0 equiv.), 12-aminododecan-1-ol (1.5 equiv.), HATU (2.0 equiv.), and DIPEA (2.0 equiv.) were added to a round flask, dissolved in DMF, and stirred for 3 hours. After the reaction was completed, Step 1 was completed through reverse phase purification using MPLC under the conditions of H2O (0.1% formic acid) and acetonitrile. In a round flask, PPh3 (2.8 equiv.) was dissolved in CH2Cl₂, and CBr4 (1.4 equiv.) was added. After 10 minutes, the product of Step 1 was added, stirred for 1 hour, and after the reaction was completed, the product of Step 2, secondary amine derivative (3.0 equiv.), was added to a round flask. After adding K2CO₃ (10.0 equiv.) and dissolving it in acetonitrile, stirring for 24 hours, and after completion of the reaction, purification through amine column chromatography (CH2Cl₂ / MeOH) can be performed to obtain the product of Step 3.

[0259] Therefore, the compounds below can be easily prepared by substituting the bromine (product after step 2) substituted at the end of the above reaction scheme 1 with a terminal group.

[0260] This can be performed with similar reactions 2, 3, and 4 as Step 3 of Reaction Scheme 1.

[0261] Compounds such as PBK-2024-007, which can be easily manufactured using the reaction formulas above, can be seen.

[0262] Additionally, in the case where the reaction is benzene rather than a pyridine ring, reaction scheme 5 can be used similarly.

[0263] Add carboxylic acid derivative (1.0 equiv.), 12-aminododecan-1-ol (1.5 equiv.), HATU (2.0 equiv.), and DIPEA (2.0 equiv.) to a round flask, dissolve in DMF, and stir for 3 hours.

[0264] After the reaction is completed, step 1 can be completed and product 1 can be obtained through reverse phase purification under H2O (0.1% formic acid) and acetonitrile conditions using MPLC.

[0265] In a round flask, dissolve PPh3 (2.8 equiv.) in CH2Cl₂, add CBr4 (1.4 equiv.), and after 10 minutes, add product 1 and stir for 1 hour.

[0266] After the reaction is complete, product 2 can be obtained by purification through silica gel column chromatography (Hexane / Ethyl acetate).

[0267] Add product 2, secondary amine derivative (3.0 equiv.), and K2CO₃ (10.0 equiv.) to a round flask, dissolve in acetonitrile, and stir for 24 hours.

[0268] After the reaction is complete, product 3 can be obtained by purification through amine column chromatography (CH2Cl₂ / MeOH).

[0269]

[0270] The chemical structure, properties, identification data, molecular weight, etc. of the compounds manufactured based on the reaction formulas shown above are as follows.

[0271] Various compound examples

[0272] The chemical structure, properties, identification data, molecular weight, etc. of the compounds manufactured in this way are represented as follows.

[0273] In the following, the chemical structure of the compound is listed first, followed by the compound's identification information.

[0274] Chemical structure of the compound

[0275]

[0276] Compound identification information

[0277] 2. Compound 2: 2-amino-N-(12-morpholin-4-yl-dodecyl)-nicotinamide (also used as GO48)

[0278] <Chemical Formula 2>

[0279] (A chemical structural formula like this can be called a 'chemical formula', and the number can be the same as the compound number. For example, since it is compound 2, it can be referred to or written as 'chemical formula 2', and the same method is applied below.)

[0280] White solid, 1H NMR (400 MHz, CDCl3) δ 8.13 (dd, J=4.79, 1.75Hz, 1H), 7.55(dd, J=7.69, 1.76 Hz, 1H), 6.57(dd, J=7.64, 4.86Hz, 1H), 6.28(s, 2H), 5.99(s,1H), 3.70(t, J=4.67 Hz, 4H), 3.41-3.36(m, 2H), 2.41 (t, J=4.25Hz, 4H), 2.29(dd, J=8.77, 6.75Hz, 2H), 1.58(t, J=7.29, 2H), 1.46(t, J=7.29Hz, 2H), 1.37-1.25(m, 16H) Ms calcd for C 22 H 38 N4O2: 390.57.

[0281]

[0282] 3. Compound 3: 2-Amino-N-[12-(3,4-dihydro-1H-isoquinolin-2-yl)-dodecyl]-nicotinamide (nicknamed GO51)

[0283] <Chemical Formula 3>

[0284] White, 1 H NMR (400 MHz, cdcl3) δ 8.13 (dd, J=4.73, 1.76Hz, 1H), 7.55 (dd, J=7.69, 1.77Hz, 1H), 7.09 (dq, J=6.07, 2.99Hz, 3H), 6.99(dd, J=5.04, 2.83H, 1H), 6.57(dd, J=7.72, 4.97Hz, 1H), 6.27(d, J=0.56Hz, 2H), 5.97(t, J= 1.40Hz, 1H), 3.60(s, 2H), 3.39 (td, J=7.15, 5.84Hz, 2H) 2.89(t, J=5.90, 2H), 2.70(t, J=5.96Hz, 2H), 2.47(dd, J=8.65, 6.77Hz, 2H) 1.62-1.54(m, 2H), 1.37-1.24(m, 18H) Ms calcd for C27H40N4O: 436.64

[0285]

[0286] 4. Compound 4: 2-amino-N-(12-thiomorpholin-4-yl-dodecyl)-nicotinamide (nicknamed GO77)

[0287] <Chemical Formula 4>

[0288] White-yellow solid, 1 H NMR (400 MHz, CDCl3) δ 8.12 (dd, J=4.86, 1.75Hz, 1H), 7.55 (dd, J=7.68, 1.75Hz, 1H), 6.57 (dd, J=7.68, 4.86Hz, 1H), 6.28 (s, 2H), 6.02 (s, 1H), 3.41-3.36(m, 2H), 2.66(d, J=1.72Hz, 8H), 2.31 (d, J=15.47Hz 2H), 1.57 ( t, J=7.19Hz, 2H), 1.44-1.25(m, 18H), Ms calcd for C 22 H 38 N4OS: 406.63.

[0289]

[0290] 5. Compound 5: 2-amino-N-(12-(piperazin-1-yl)dodecyl)-nicotinamide (nicknamed GO78)

[0291] <Chemical Formula 5>

[0292] White solid, 1 H NMR (400 MHz, cdcl3) δ 8.12 (dd, J=4.87, 1.74Hz, 1H), 7.55 (dd, J=7.69, 1.72Hz, 1H), 6.57 (dd, J=7.67, 4.86Hz, 1H), 6.38 (d, J=0.36Hz, 2H), 6.02(s, 1H), 3.41-3.36 (m, 2H), 2.45-2.28 (m, 10H), 1.85 ( s, 3H), 1.57 (t, J=7.18Hz, 2H), 1.47-1.25 (m, 18H), Ms calcd for C 23 H 41 N5O: 403.62.

[0293]

[0294] 6. Compound 6: 12-[4-(2-methylpropyl)piperazin-1-yl]dodecyl-N-(6-aminopurin-2-yl)carboxamide (nicknamed GO79)

[0295] <Chemical Formula 6>

[0296] White solid, 1 H NMR (400 MHz, CDCl3) δ 8.13 (dd, J=4.85, 1.77Hz, 1H), 7.55 (dd, J=7.69, 1.76Hz, 1H), 6.58 (d, J=4.84Hz, 1H), 6.28 (s, 2H), 6.03 (s, 1H), 3.38 (td, J=7.15, 5.80Hz, 2H), 2.48-2.38(m, 6H), 1.78-1.74 (m, 4H), 1.60-1.47(m, 4H), 1.37-1.22(m,16), Ms calcd for C 25 H 45 N5O: 431.67.

[0297]

[0298] 7. Compound 7: 12-[4-(2-methoxy-2-oxoethyl)piperazin-1-yl]dodecyl-N-(6-aminopurin-2-yl)carboxamide (nicknamed GO80)

[0299] <Chemical Formula 7>

[0300] White solid, 1 H NMR (400 MHz, CDCl3) δ 8.13 (t, J=2.46Hz, 1H), 7.54 (s, 1H), 6.57 (dd, J=7.63, 4.83Hz, 1H), 6.28 (s, 2H), 6.02 (s, 1H), 3.43-3.38(m, 6H), 2.32 (dt, J=20.10, 6.32Hz, 6H), 1.58 (t, J=7.12Hz, 2H), 1.44-1.25(m, 2H), 1.26 (d, J=28.73Hz, 18H), 1.03 (d, 27H), Ms calcd for C 27 H 47 N5O3: 489.71.

[0301]

[0302] 8. Compound 8: 12-(piperazin-1-yl)dodecyl-N-(6-aminopurin-2-yl)carboxamide (nicknamed GO81)

[0303] <Chemical Formula 8>

[0304] White solid, 1 H NMR (400 MHz, CDCl3) δ 8.13 (dd, J=4.90, 1.75Hz, 1H), 7.55 (dd, J=7.70, 1.72Hz, 1H), 6.57 (dd, J=7.66, 4.88Hz, 1H), 6.27 (s, 2H), 5.99 (s, 1H), 3.41-3.36(m, 2H), 2.86 (d, J=11.65, 2H), 2.25 (dd, J=9.16, 6.66Hz, 2H), 1.85(td, J=11.56, 1.64Hz, 3H), 1.58 (td, J=13.93, 6.70Hz, 4H), 1.37-1.21 (m, 20H), 0.89 (d, J=6.28Hz, 3H), Ms calcd for C 24 H 42 N4O: 402.63.

[0305]

[0306] 9. Compound 9: 12-(4-hydroxypiperidin-1-yl)dodecyl-N-(6-aminopurin-2-yl)carboxamide (nicknamed GO83)

[0307] <Chemical Formula 9>

[0308] White solid, 1H NMR (400 MHz, CDCl3) δ 8.12 (dd, J=4.81, 1.64Hz, 1H), 7.55 (dd, J=7.65, 1.57Hz, 1H), 6.56 (dd, J=7.64, 4.86Hz, 1H), 6.28 (s, 2H), 6.01 (s, 1H), 3.38(q, J=6.55Hz, 2H), 2.83(d, J=11.23Hz, 1H), 2.61 (ddd, J=12.79, 10.32, 5.81Hz, 1H), 2.30 (ddd, J=12.82, 10.18, 5.58Hz, 1H), 2.23 (t, J=5.90Hz, 1H), 2.11(td, J=11.09, 2.94Hz, 1H), 1.59-1.25(m. 26H), 1.03(d, J=6.23Hz, 3H), Ms calcd for C 24 H 42 N4O: 402.63.

[0309]

[0310] 10. Compound 10: 12-(4-hydroxypiperazin-1-yl)dodecyl-N-(6-aminopurin-2-yl)carboxamide (nicknamed GO85)

[0311] <Chemical Formula 10>

[0312] White-yellow solid, 1 H NMR (400 MHz, cdcl3) δ 8.13(dd, J=4.83, 1.62Hz, 1H), 7.56(dd, J=7.64, 1.54Hz, 1H), 6.57(dd, J=7.63, 4.86Hz, 1H), 6.28(s, 2H), 6.04(s, 1H), 3.48(d, J=6.36Hz, 2H), 3.38(q, J=6.55Hz, 2H), 3.03(d, J=10.74Hz, 2H), 2.37(t, J=7.82Hz, 2H), 2.03-1.94(m, 2H), 1.76-1.74(m, 7H); 1.42-1.20(m, 18H), Ms calcd for C 24 H 42 N4O2: 418.63.

[0313]

[0314] 11. Compound 11: 12-[4-(2,2-dimethylmorpholin-4-yl)]dodecyl-N-(6-aminopurin-2-yl)carboxamide (nicknamed GO86)

[0315] <Chemical Formula 11>

[0316] White solid, 1 H NMR (400 MHz, cdcl3) δ 8.12(dd, J=4.76, 1.70Hz, 1H), 7.55(dd, J=7.70, 1.74Hz, 1H), 6.57(dd, J=7.77, 5.03Hz, 1H), 6.28(s, 2H), 6.02(s, 1H), 3.68-3.64(m, 2H), 3.41-3.36(m, 2H), 2.74-2.71(m, 2H), 2.28-2.25(m, 2H), 1.78(s, 2H), 1.65(t, J=10.86Hz, 2H), 1.57(t, J=7.15Hz, 2H), 1.45(s, 2H), 1.33-1.25(m, 14H), 1.13(d, J=6.31Hz, 6H), Ms calcd for C 24 H 42 N4O2: 418.63.

[0317]

[0318] 12. Compound 12: tert-Butyl 3-(8-(2-aminonicotinamido)octyl)-4-methylpiperazine- 1-carboxylate (nicknamed KMC-003P)

[0319] <Chemical Formula 12>

[0320] Off-white solid, ¹H NMR (400 MHz, CDCl3: δ = 9.68 (s, 1H), 8.85 (t, J = 5.3 Hz, 1H), 8.30 (d, J = 7.7 Hz, 1H), 8.10 (dd, J = 1.5, 5.9 Hz, 2H), 6.87 (dd, J = 6.0, 7.5 Hz, 1H), 3.20 (dd, J = 6.7, 13.1 Hz, 4H), 3.08-3.00 (m, 1H), 2.78 (s, 3H), 1.88-1.78 (m, 1H), 1.62-1.48 (m, 4H), 1.42 (s, 9H), 1.28 (s, 12H), Ms calcd for C 24 H 41 N5O3: 447.62.

[0321]

[0322] 13. Compound 13: 12-(4-hydroxypiperidin-1-yl)dodecyl-N-(6-aminopurin-2-yl)carboxamide (nicknamed GO87)

[0323] <Chemical Formula 13>

[0324] White-yellow solid, 1 H NMR (400 MHz, CDCl3) δ 8.13(dd, J=4.83, 1.53Hz, 1H), 7.56(dd, J=7.64, 1.65Hz, 1H), 6.57(dd, J=7.67, 4.93Hz, 1H), 6.29(s, 2H), 6.08(t, J=1.07Hz, 1H), 6.02-5.94(m, 1H), 3.39-3.34(m, 4H), 3.10(s, 2H), 2.62(t, J=5.39Hz, 2H), 2.38(t, J=7.47Hz, 2H), 1.57(d, J=7.26Hz, 2H), 1.46(s, 2H), 1.32-1.25(m, 16H), Ms calcd for C 22 H 37 N5O2: 403.57.

[0325]

[0326] 14. Compound 14: 2-amino-N-(12-(piperazin-1-yl)dodecyl)nicotinamide (hereinafter referred to as GO88)

[0327] <Chemical Formula 14>

[0328] White-yellow solid, 1 H NMR (400 MHz, cdcl3) δ 8.12(dd, J+4.79, 1.61Hz, 1H), 7.55(dd, J=7.68, 1.71Hz, 1H), 6.56(dd, J=7.73, 4.98Hz, 1H), 6.28(s, 2H), 6.05(s, 1H), 3.37(q, J=6.57Hz, 2H), 2.88(t, J=4.91Hz, 4H), 2.40(s, 4H), 2.31-2.27(m, 2H), 1.57(t, J=7.16Hz, 2H), 1.48-1.43(m, 2H), 1.26(d, J=27.82Hz, 17), Ms calcd for C 22 H 39 N5O: 389.59.

[0329]

[0330] 15. Compound 15: 12-[4-(2-hydroxyethyl)piperazin-1-yl]dodecyl-N-(6-aminopurin-2-yl)carboxamide (nicknamed GO89)

[0331] <Chemical Formula 15>

[0332] White solid, 1 H NMR (400 MHz, cdcl3) δ 8.13(dd, J=4.85, 1.77Hz, 1H), 7.55 (dd, J=7.69, 1.76Hz, 1H), 6.58(d, J=4.84Hz, 1H), 6.28 (s, 2H), 6.03 (s, 1H), 3.38 (td, J=7.15, 5.80Hz, 2H), 2.48-2.38(m, 6H), 1.78-1.74 (m, 4H), 1.60-1.47(m, 4H), 1.37-1.22(m,16), Ms calcd for C 22 H 38 N4O: 347.57.

[0333]

[0334] 16. Compound 16: 2-Amino-N-(12-(octahydroisoquinolin-2(1H)-yl)dodecyl) nicotinamide (hereinafter referred to as PBK-2024-003)

[0335] <Chemical Formula 16>

[0336] White-yellow solid, ¹H NMR (400 MHz, DMSO): δ = 8.38 (t,J= 5.5 Hz, 1H), 8.24 (d,J= 1.5 Hz, 1H), 8.05 (dd,J= 1.8, 4.8 Hz, 1H), 7.85 (dd,J= 1.8, 7.7) Hz, 1H), 7.03 (s, 2H), 6.56 (dd,J= 4.8, 7.7 Hz, 1H), 3.95 (s, 9H), 3.19 (q,J= 6.6 Hz, 2H), 3.10-2.97 (m, 1H), 2.91-2.82 (m, 1H), 2.07 (s, 1H), 1.65 (s, 3H), 1.59-1.43 (m, 6H), 1.31-1.21 (m, 18H), 0.92-0.87 ppm (m, 3H), Ms calcd for C 27 H 46 N4O: 442.69.

[0337]

[0338] 17. Compound 17: 2-Amino-N-(12-(3,4-dihydroisoquinolin-2(1H)-yl)dodecyl) nicotinamide (2-Amino-N-[12-(3,4-dihydro-1H-isoquinolin-2-yl)-dodecyl]-nicotinamide) (hereinafter referred to as PBK-2024-004)

[0339] <Chemical Formula 17>

[0340] White solid, ¹H NMR (400 MHz, CDCl3):δ= 8.15 (s, 1H), 7.60 (d,J= 7.7 Hz, 1H), 7.18-7.11 (m, 3H), 7.06-7.02 (m, 1H), 6.60 (dd,J= 4.8, 7.5 Hz, 1H), 6.33 (t,J= 18.1 Hz, 2H), 6.09 (s, 1H), 3.80 (s, 2H), 3.44-3.36 (m, 2H), 3.00-2.89 (m, 6H), 2.68-2.61 (m, 3H), 1.39-1.24 ppm (m, 15H), Ms calcd for C 27 H 40 N4O: 436.64.

[0341]

[0342] 18. Compound 18: 2-amino-N-(12-(piperidin-1-yl)dodecyl)nicotinamide (PBK-2024-005)

[0343] <화학식18>

[0344] White solid, ¹H NMR (400 MHz, CDCl3):δ= 8.15 (dd,J= 1.6, 4.8 Hz, 1H), 7.59 (dd,J= 1.6, 7.7 Hz, 1H), 6.60 (dd,J= 4.9, 7.7 Hz, 1H), 6.32 (s, 2H), 6.06 (s, 1H), 3.44-3.37 (m, 2H), 2.54-2.34 (m, 6H), 1.28 ppm (s, 18H), Ms calcd for C 23 H 40 N4O: 388.60.

[0345]

[0346] 19. Compound19: 2-Amino-N-(12-(3-(dimethylamino)pyrrolidin-1-yl)dodecyl)nicotinamide (PBK-2024-006)

[0347] <화학식19>

[0348] Brown solid, ¹H NMR (400 MHz, CDCl3):δ= 8.15 (dd,J= 1.8, 4.9 Hz, 1H), 7.58 (dd,J= 1.8, 7.7 Hz, 1H), 6.60 (dd,J= 4.9, 7.7 Hz, 1H), 6.29 (s, 2H), 6.06-6.02 (m, 1H), 3.44-3.37 (m, 2H), 3.02-2.77 (m, 4H), 2.24 (s, 12H), 2.09-1.97 (m, 3H), 1.80-1.70 ppm (m, 1H), Ms calcd for C 24 H 43 N5O: 417.64.

[0349]

[0350] 20. Compound20: 2-Amino-N-(12-(pyrrolidin-1-yl)dodecyl)nicotinamide (PBK-2024-007)

[0351] <화학식20>

[0352] White solid, ¹H NMR (400 MHz, DMSO):δ= 8.38 (t,J= 5.3 Hz, 1H), 8.06-8.03 (m, 1H), 7.84 (d,J= 7.7 Hz, 1H), 7.02 (s, 2H), 6.56 (dd,J= 4.8, 7.7 Hz, 1H), 2.40-2.29 (m, 6H), 1.65 (t,J= 3.2 Hz, 4H), 1.53-1.37 (m, 6H), 1.24 ppm (s, 18H), Ms calcd for C 22 H 38 N4O: 374.57.

[0353]

[0354] 21. Compound21: 2- Amino - N - (12-(2,6-dimethylmorpholino) dodecyl) nicotinamide (PBK-2024-008)

[0355] <화학식21>

[0356] White solid, ¹H NMR (400 MHz, CDCl3):δ= 8.15 (dd,J= 1.8, 4.8 Hz, 1H), 7.58 (dd,J= 1.8, 7.7 Hz, 1H), 6.60 (dd,J= 4.9, 7.7 Hz, 1H), 6.29 (s, 2H), 6.04 (s, 1H), 3.86-3.80 (m, 2H), 3.44-3.37 (m, 2H), 2.86-2.84 (m, 2H), 2.39 (s, 2H), 1.64-1.55 (m, 6H), 1.32-1.24 (m, 18H), 1.17 ppm (d,J= 6.4 Hz, 6H), Ms calcd for C 24 H 42 N4O2: 418.63.

[0357]

[0358] 22. 화합물22: 2-Amino-N-(12-(3,3-dimethylpyrrolidin-1-yl)dodecyl) nicotinamide (PBK-2024-009이라 별칭함)

[0359] <화학식22>

[0360] Brown solid, ¹H NMR (400 MHz, CDCl3):δ= 8.15 (dd,J= 1.8, 4.8 Hz, 1H), 7.58 (dd,J= 1.8, 7.7 Hz, 1H), 6.60 (dd,J= 4.9, 7.7 Hz, 1H), 6.29 (s, 2H), 6.04 (s, 1H), 3.86-3.80 (m, 2H), 3.44-3.37 (m, 2H), 2.86-2.84 (m, 2H), 2.39 (s, 2H), 1.64-1.55 (m, 6H), 1.32-1.24 (m, 18H), 1.17 ppm (d,J= 6.4 Hz, 6H), Ms calcd for C 24 H 42 N4O: 402.64.

[0361]

[0362] 23. Compound 23: N-(12-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)dodecyl)nicotinamide (PBK-2024-010)

[0363] <화학식23>

[0364] White solid, ¹H NMR (400 MHz, DMSO):δ= 8.37 (s, 1H), 8.05 (dd,J= 1.8, 4.7 Hz, 1H), 7.85 (dd,J= 1.8, 7.7 Hz, 1H), 7.03 (s, 2H), 6.60-6.54 (m, 1H), 2.95-2.82 (m, 3H), 2.71 (d,J= 10.4 Hz, 1H), 2.30-2.22 (m, 3H), 2.10-1.85 (m, 6H), 1.70-1.59 (m, 6H), 1.27-1.21 ppm (m, 24H), Ms calcd for C 25 H 43 N4O: 429.63.

[0365]

[0366] 24. Compound 24: 2-Amino-N-(12-(3-methylpyrrolidin-1-yl)dodecyl)nicotinamide (PBK-2024-012)

[0367] <화학식24>

[0368] White-yellow solid, 1H NMR (400 MHz, CDCl3)δ8.15 (dd, J = 1.7, 4.9 Hz, 1H), 7.59 (dd, J = 1.7, 7.7 Hz, 1H), 6.60 (dd, J = 4.9, 7.6 Hz, 1H), 6.31 (s, 2H), 6.06 (s, 1H), 3.40 (q, J = 6.7 Hz, 2H), 2.95 - 2.90 (m, 1H), 2.81 - 2.81 (m, 1H), 2.54 - 2.42 (m, 3H), 2.35 - 2.26 (m, 1H), 2.10 - 2.01 (m, 2H), 1.62 - 1.53 (m, 5H), 1.34 - 1.24 (m, 16H), 1.04 (d, J = 6.8 Hz, 3H), Ms calcd for C 23 H 40 N4O: 388.60.

[0369]

[0370] 25. 화합물25: 2-Amino-N-(12-(1,1-dioxidothiomorpholino)dodecyl) nicotinamide (PBK-2024-013이라 별칭함)

[0371] <화학식25>

[0372] White solid, 1 H NMR (400 MHz, CDCl3)δ8.05 (dd, J = 1.5, 5.2 Hz, 1H), 7.75 - 7.72 (m, 1H), 6.98 (s, 2H), 6.66 (dd, J = 5.3, 7.6 Hz, 1H), 6.27 (s, 1H), 3.41 (q, J = 6.8 Hz, 2H), 3.11 - 3.05 (m, 4H), 3.03 - 2.98 (m, 4H), 2.51 (t, J = 7.5 Hz, 2H), 1.65 - 1.57 (m, 2H), 1.48 - 1.46 (m, 2H), 1.31 - 1.25 (m, 16H), Ms calcd for C 22 H 38 N4O3S: 438.63.

[0373]

[0374] 26. Compound26: 2- Amino - N - (12-(3-fluoropyrrolidin-1-yl) dodecyl) nicotinamide (PBK-2024-014)

[0375] <화학식26>

[0376] White-yellow solid, 1 H NMR (400 MHz, CDCl3)δ8.15 (dd, J = 1.7, 4.9 Hz, 1H), 7.58 (dd, J = 1.7, 7.7 Hz, 1H), 6.60 (dd, J = 4.9, 7.7 Hz, 1H), 6.31 (s, 2H), 6.03 (s, 1H), 5.27 - 5.13 (m, 1H), 3.44 - 3.37 (m, 2H), 2.97 - 2.84 (m, 2H), 2.56 - 2.56 (m, 2H), 2.24 - 2.03 (m, 2H), 1.63 - 1.55 (m, 6H), 1.36 - 1.24 (m, 16H), Ms calcd for C 22 H 37 FN4O: 392.56.

[0377]

[0378] 27. Compound27: 2-Amino-N-(12-(4-(4-fluorobenzyl)piperazin-1-yl)dodecyl)nicotinamide (PBK-2024-015)

[0379] <화학식27>

[0380] White solid, ¹H NMR (400 MHz, CDCl3): δ = 8.15 (dd, J = 1.8, 4.9 Hz, 1H), 7.58 (dd, J = 1.6, 7.7 Hz, 1H), 7.02-6.97 (m, 2H), 6.60 (dd, J = 4.8, 7.7 Hz, 1H), 6.31 (s, 2H), 6.06 (s, 1H), 3.50-3.37 (m, 6H), 2.55-2.41 ppm (m, 12H), Ms calcd for C 29 H 44 FN5O: 497.70.

[0381]

[0382] 28. Compound28: 2-Amino-N-(12-(4-(4-methoxybenzyl)piperazin-1-yl)dodecyl)nicotinamide (PBK-2024-016)

[0383] <화학식28>

[0384] White solid, ¹H NMR (400 MHz, CDCl3):δ= 8.15 (dd,J= 1.8, 4.9 Hz, 1H), 7.58 (dd,J= 1.8, 7.7 Hz, 1H), 6.85 (d,J= 8.7 Hz, 2H), 6.60 (dd,J= 4.8, 7.7 Hz, 1H), 6.31 (s, 2H), 6.05-6.01 (m, 1H), 3.80 (s, 3H), 3.49-3.37 (m, 4H), 2.77-2.37 (m, 9H), 1.27 ppm (s, 18H), Ms calcd for C 30 H 47 N5O2: 509.74.

[0385]

[0386] 29. Compound29: 2-Amino-N-(12-(1-methylhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)dodecyl)nicotinamide (이하 PBK-2024-018은라 별칭함)

[0387] <화학식29>

[0388] White solid, 1 H NMR (400 MHz, CDCl3)δ8.14 (1H, dd, J = 1.8, 4.9 Hz), 7.64 (1H, dd, J = 1.7, 7.7 Hz), 6.60 (1H, dd, J = 4.9, 7.7 Hz), 6.36-6.24 (3H, m), 3.44-3.36 (2H, m), 3.19-3.05 (3H, m), 2.92-2.90 (1H, m), 2.81-2.69 (3H, m), 2.59-2.53 (1H, m), 2.36-2.28 (2H, m), 1.98-1.77 (4H, m), 1.66-1.51 (4H, m), 1.41-1.22 (19H, m). 443.68, Ms calcd for C 26 H 45 N5O: 443.67.

[0389]

[0390] 30. 화합물30: tert-Butyl 4-(12-(2-aminonicotinamido) dodecyl)-2,5-dimethylpiperazine-1-carboxylate (이하 PBK-2024-020이라 별칭함)

[0391] <화학식30>

[0392] White solid, 1H NMR (400 MHz, DMSO-d6)δ8.39 (t, J = 5.3 Hz, 1H), 8.05 (dd, J = 1.8, 4.8 Hz, 1H), 7.85 (dd, J = 1.8, 7.7 Hz, 1H), 7.03 (s, 2H), 6.56 (dd, J = 4.8, 7.7 Hz, 1H), 4.09 - 4.05 (m, 2H), 3.50 (d, J = 12.9 Hz, 1H), 3.19 (q, J = 6.6 Hz, 2H), 3.11 (dd, J = 3.3, 13.0 Hz, 1H), 2.86 - 2.84 (m, 1H), 2.33 - 2.26 (m, 1H), 2.26 - 2.19 (m, 2H), 1.51 - 1.47 (m, 2H), 1.38 (s, 9H), 1.26 - 1.22 (m, 16H), 1.13 (d, J = 6.7 Hz, 3H), 0.80 (d, J = 6.5 Hz, 3H), Ms calcd for C 29 H 51 N5O3: 517.76.

[0393]

[0394] 31. 화합물31: 2-Amino-N-(12-(thiazolidin-3-yl)dodecyl)nicotinamide) (이하 PBK-2024-021이라 별칭함)

[0395] <화학식31>

[0396] White solid, 1H NMR (400 MHz, CDCl3)δ8.01 (dd, J = 1.7, 5.1 Hz, 1H), 7.65 (dd, J = 1.7, 7.7 Hz, 1H), 6.61 - 6.52 (m, 3H), 6.36 - 6.34 (m, 1H), 4.02 (s, 2H), 3.36 - 3.29 (m, 2H), 3.05 (t, J = 6.3 Hz, 2H), 2.84 (t, J = 6.3 Hz, 2H), 2.36 (t, J = 7.6 Hz, 2H), 1.56 - 1.50 (m, 2H), 1.50 - 1.43 (m, 2H), 1.26 - 1.17 (m, 16H), Ms calcd for C 21 H 36 N4O5S: 392.61.

[0397]

[0398] 32. 화합물32: 2-Amino-N-(12-(3-methoxypyrrolidin-1-yl) dodecyl) nicotinamide ( 이하 PBK-2024-024이라 별칭함)

[0399] <화학식32>

[0400] White solid, ¹H NMR (400 MHz, CDCl3):δ= 8.15 (dd,J= 1.7, 4.8 Hz, 1H), 7.59 (dd,J= 1.6, 7.7 Hz, 2H), 6.60 (dd,J= 4.9, 7.7 Hz, 1H), 6.31 (s, 2H), 6.10 (s, 1H), 4.00-3.94 (m, 1H), 3.40 (dd,J= 7.1, 13.1 Hz, 2H), 3.29 (s, 3H), 3.12-3.02 (m, 1H), 2.79-2.59 (m, 6H), 2.15-2.02 (m, 2H), 1.91 (dd,J= 6.1, 7.0 Hz, 2H), 1.34-1.24 ppm (m, 21H), Ms calcd for C 23 H 40 N4O2: 404.60.

[0401]

[0402] 33. Compound 33: 2-Amino-N-(12-(4-(2-(dimethylamino)ethyl)piperazin-1-yl) dodecyl) nicotinamide (PBK-2024-025이라 별칭함)

[0403] <화학식33>

[0404] White solid, ¹H NMR (400 MHz, CDCl3):δ= 8.15 (dd,J= 1.7, 4.8 Hz, 1H), 7.59 (dd,J= 1.6, 7.7 Hz, 1H), 6.60 (dd,J= 4.9, 7.7 Hz, 1H), 6.32 (s, 2H), 6.05 (s, 1H), 3.43-3.37 (m, 2H), 2.59-2.52 (m, 12H), 2.39 (t,J= 7.8 Hz, 2H), 2.32 (s, 6H), 2.15 (d,J= 6.9 Hz, 2H), 2.07-2.00 (m, 3H), 1.27 ppm (s, 18H), Ms calcd for C 26 H 48 N6O: 460.71.

[0405]

[0406] 34. Compound34: 2-Amino-N-(12-(cyclohexyl(methyl)amino)dodecyl)nicotinamide (PBK-2024-026)

[0407] <화학식34>

[0408] White solid, ¹H NMR (400 MHz, CDCl3):δ= 8.15 (dd,J= 1.8, 4.9 Hz, 1H), 7.59 (dd,J= 1.6, 7.7 Hz, 1H), 6.60 (dd,J= 4.9, 7.7 Hz, 1H), 6.31 (s, 2H), 6.07 (s, 1H), 3.40 (dd,J= 7.2, 13.1 Hz, 2H), 2.51 (s, 4H), 2.33 (s, 3H), 2.03 (d,J= 7.2 Hz, 1H), 1.87 (s, 3H), 1.68-1.53 (m, 6H), 1.27 (s, 24H), 1.15-1.05 ppm (m, 2H)), Ms calcd for C 25 H 48 N6O: 416.65.

[0409]

[0410] 35. 화합물35: 2-Amino-N-(12-(2-methylpiperazin-1-yl) dodecyl) nicotinamide (PBK-2024-029이라 별칭함)

[0411] <화학식35>

[0412] White solid, ¹H NMR (400 MHz, CDCl3):δ= 8.15 (dd,J= 1.6, 4.9 Hz, 1H), 7.59 (dd,J= 1.6, 7.7 Hz, 1H), 6.60 (dd,J= 4.9, 7.7 Hz, 1H), 6.32 (s, 2H), 6.09 (s, 1H), 4.23 (s, 1H), 3.82 (d,J= 13.4 Hz, 1H), 3.44-3.37 (m, 2H), 3.22-3.13 (m, 1H), 2.86-2.68 (m, 2H), 2.41-2.14 (m, 3H), 2.10-1.73 (m, 2H), 1.64-1.55 (m, 2H), 0.96-0.71 ppm (m, 1H)), Ms calcd for C 23 H 41 N5O: 403.62.

[0413]

[0414] 36. Compound36: 2-Amino-N-(12-(2,5-dimethylpiperazin-1-yl)dodecyl)nicotinamide hydrochloride(PBK-2024-030)

[0415] <화학식36>

[0416] White solid, ¹H NMR (400 MHz, DMSO): δ = 10.25 (d, J = 4.8 Hz, 1H), 10.00-9.91 (m, 1H), 8.99 (s, 1H), 8.42 (d, J = 7.2 Hz, 3H), 8.18 (d, J = 5.5 Hz, 1H), 6.97 (t, J , 1.53 (s, 3H), 1.43-1.23 (m, 24H), 1.17 (t, J = 7.1 Hz, 2H) ppm., Ms calcd for C 24 H 44 ClN5O: 454.10.

[0417]

[0418] 37. Compound37: (S)-2-Amino-N-(12-(2-methylpiperazin-1-yl)dodecyl)nicotinamide hydrochloride (PBK-2024-032)

[0419] <화학식37>

[0420] White solid, ¹H NMR (400 MHz, CDCl3):δ= 9.03 (1H, t,J= 5.3 Hz), 8.44 (3H, dd,J= 1.3, 7.6 Hz), 8.18 (1H, dd,J= 1.5, 6.1 Hz), 6.96 (1H, dd,J= 6.1, 7.5 Hz), 4.03 (1H, ddd,J= 7.1, 7.1, 7.1 Hz), 3.30-3.19 (12H, m), 3.10-2.98 (6H, m), 1.99 (1H, s), 1.65 (3H, s), 1.55-1.44 (3H, m), 1.38 (4H, d,J= 6.5 Hz), , Ms calcd for C 23 H 42 ClN5O: 440.07.

[0421]

[0422] 38. 화합물38: 2-Amino-N-(12-(4-(pyridin-4-yloxy)piperidin-1-yl)dodecyl) nicotinamide (이하 PBK-2024-033이라 별칭함)

[0423] <화학식38>

[0424] White solid, ¹H NMR (400 MHz, CDCl3):δ= 8.44 (dd,J= 1.5, 4.9 Hz, 3H), 8.15 (dd,J= 1.7, 4.8 Hz, 1H), 7.62 (dd,J= 1.7, 7.7 Hz, 1H), 6.80 (dd,J= 1.5, 4.9 Hz, 3H), 6.60 (dd,J= 4.9, 7.7 Hz, 1H), 6.31 (s, 1H), 6.21 (s, 1H), 4.71-4.52 (m, 1H), 3.44-3.37 (m, 3H), 2.92-2.77 (m, 4H), 2.63-2.57 (m, 3H), 2.39-2.29 (m, 3H), 2.09-2.00 (m, 3H), 1.38-1.24 ppm (m, 21H), Ms calcd for C 28 H 43 N5O2: 481.69.

[0425]

[0426] 39. Compound 39: 2-Amino-N-(12-(4-methylazepan-1-yl) dodecyl) nicotinamide (hereinafter referred to as PBK-2024-034)

[0427] <Chemical Formula 39>

[0428] White solid, ¹H NMR (400 MHz, CDCl3):δ= 8.15 (dd,J= 1.6, 4.9 Hz, 1H), 7.63 (dd,J= 1.6, 7.7 Hz, 1H), 6.60 (dd,J= 4.9, 7.7 Hz, 1H), 6.31 (s, 1H), 6.21 (s, 1H), 3.40 (dd,J= 7.1, 13.1 Hz, 2H), 3.03-2.86 (m, 9H), 2.66 (t,J= 8.0 Hz, 2H), 2.52 (s, 3H), 2.05 (t,J= 12.8 Hz, 2H), 1.28 ppm (s, 18H), Ms calcd for C 25 H 44 N4O: 416.65.

[0429]

[0430] 43. Compound 43: N-(12-((3,5-dimethylimidazolidin-2-yl)dodecyl)pyrido[2,3-d]pyrimidin-7-amine (hereinafter referred to as GO92)

[0431] <Chemical Formula 43>

[0432] White solid, ¹H NMR (400 MHz, cdcl3) δ 8.13( dd, J=4.85, 1.74Hz, 1H), 7.55(dd, J=7.67, 1.71Hz, 1H), 6.57(dd, J=7.64, 4.85, 1H), 6.27 (s, 2H), 5.99(d, J=0.45Hz, 1H), 3.41-3.36(m, 2H), 2.91 (ddd, J=9.79, 6.63, 2.91Hz, 2H), 2.78 (dd, J=11.01, 1.68Hz, 2H), 2.27 (dd, J=8.90, 6.78Hz, 2H), 1.60-1.45 ( m, 6H), 1.37-1.25 (m, 16H), 1.02(d, J=6.36Hz 6H), Ms calcd for C 24 H 43 N5O: 417.63.

[0433]

[0434] 44. 화합물44: 2- Amino -N- (12 - (4 -(4 - nitrophenyl)piperidin - 1 - yl) dodecyl) nicotinamide (이하 PBK-2025-001이라 별칭함)

[0435] <화학식44>

[0436] White solid, ¹H NMR (400 MHz, CDCl3):δ= 8.18 (d,J= 8.6 Hz, 2H), 8.14 (dd,J= 1.7, 5.1 Hz, 1H), 7.63 (dd,J= 1.9, 8.0 Hz, 1H), 7.44 (d,J= 9.2 Hz, 2H), 6.60 (dd,J= 5.2, 7.9 Hz, 1H), 6.31 (s, 2H), 6.20 (s, 1H), 3.50 (s, 2H), 3.40 (q,J= 7.0 Hz, 3H), 2.79 (s, 4H), 2.54 (s, 4H), 1.98 (d,J= 15.8 Hz, 2H), 1.81 (s, 2H), 1.64-1.57 (m, 2H), 1.31 ppm (d,J= 32.8 Hz, 21H), Ms calcd for C29 H 43 N5O3: 509.68.

[0437]

[0438] 45. Compound 45: 2-Amino -N- (12-( 3- (dimethylamino) azepan - 1 - yl) dodecyl) nicotinamide (hereinafter referred to as PBK-2025-002)

[0439] <Chemical Formula 45>

[0440] Brown semi-liquid, 1 H NMR (400 MHz, CDCl3): δ= 8.07 (dd,J= 1.6, 4.9 Hz, 1H), 7.55 (dd,J= 1.6, 7.7 Hz, 1H), 6.52 (dd,J= 4.9, 7.7 Hz, 1H), 6.26 (s, 2H), 6.17 (s, 1H), 3.36-3.29 (m, 2H), 2.78-2.65 (m, 2H), 2.61-2.39 (m, 6H), 2.25 (s, 6H), 1.76 (dd,J= 4.7, 8.2 Hz, 1H), 1.20 ppm (s, 15H), Ms calcd for C 26 H 47 N5O: 445.70.

[0441]

[0442] 46. ​​Compound 46: 2-Amino -N- (12- (hexahydrocyclopenta[c]pyrrol-2 (1H)-yl) dodecyl) nicotinamide (hereinafter referred to as PBK-2025-004)

[0443] <Chemical Formula 46>

[0444] White solid, ¹H NMR (400 MHz, CDCl3):δ= 8.15 (dd,J= 1.8, 4.9 Hz, 1H), 7.63 (dd,J= 1.7, 7.7 Hz, 1H), 6.60 (dd,J= 4.9, 7.7 Hz, 1H), 6.30 (s, 2H), 6.21 (s, 1H), 3.43-3.23 (m, 4H), 2.79 (s, 2H), 2.63-2.23 (m, 4H), 1.73-1.49 (m, 10H), 1.40-1.23 ppm (m, 18H), Ms calcd for C 25 H 42 N4O: 414.64.

[0445]

[0446] 47. 화합물47: 2 - Amino - N- (12 - ( 4 - hydroxypiperidin - 1 - yl)dodecyl)nicotinamide (이하 PBK-2025-011이라 별칭함)

[0447] <화학식47>

[0448] White solid, ¹H NMR (400 MHz, CDCl3):δ= 8.14 (dd,J= 1.7, 4.8 Hz, 1H), 7.63 (dd,J= 1.5, 7.7 Hz, 1H), 6.60 (dd,J= 4.9, 7.7 Hz, 1H), 6.32 (s, 2H), 6.24 (s, 1H), 3.87 (s, 1H), 3.44-3.36 (m, 2H), 2.95 (s, 2H), 2.53-2.10 (m, 9H), 1.74-1.68 (m, 2H), 1.68-1.57 (m, 4H), 1.40-1.23 ppm (m, 18H), Ms calcd for C 23 H 40 N4O2: 404.60.

[0449]

[0450] 48. Compound 48: 2-Amino-N-(12-(4-hydroxypiperidin-1-yl)dodecyl)nicotinamide (hereinafter referred to as PBK-2025-012)

[0451] <Chemical Formula 48>

[0452] White solid, ¹H NMR (400 MHz, CDCl3):δ= 8.23-8.14 (m, 3H), 7.62 (dd,J= 1.6, 7.8 Hz, 1H), 6.99-6.93 (m, 2H), 6.60 (dd,J= 4.8, 7.7 Hz, 1H), 6.31-6.16 (m, 3H), 4.66 (s, 1H), 3.44-2.91 (m, 6H), 2.70 (s, 2H), 2.47 (d,J= 7.4 Hz, 2H), 2.07-2.01 (m, 2H), 1.65-1.55 (m, 2H), 1.39-1.23 ppm (m, 18H), Ms calcd for C 29 H 43 N5O4: 525.69.

[0453]

[0454] 49. Compound 49: tert-Butyl(S)-(1-(12-(2-aminonicotinamido) dodecyl) pyrrolidin-3-yl)carbamate (hereinafter referred to as PBK-2025-013)

[0455] <Chemical Formula 49>

[0456] White solid, ¹H NMR (400 MHz, CDCl3):δ= 8.15 (dd,J= 1.8, 4.8 Hz, 1H), 7.62 (dd,J= 1.7, 7.7 Hz, 1H), 6.60 (dd,J= 4.9, 7.7 Hz, 1H), 6.33 (s, 2H), 6.18 (s, 1H), 4.43-4.30 (m, 1H), 3.44-3.37 (m, 3H), 3.23-3.08 (m, 1H), 2.96-2.90 (m, 1H), 2.79 (s, 3H), 2.46-2.31 (m, 1H), 2.07-1.97 (m, 1H), 1.72 (s, 2H), 1.38-1.26 ppm (m, 18H), Ms calcd for C 27 H 47 N5O3: 489.69.

[0457]

[0458] 50. 화합물50: (S)- 2 - Amino- N - (12-(3-aminopyrrolidin-1-yl)dodecyl) nicotinamide hydrochloride ( 이하 PBK-2025-014이라 별칭함)

[0459] <화학식50>

[0460] White solid, ¹H NMR (400 MHz, DMSO):δ= 9.06 (t,J= 4.8 Hz, 1H), 8.77-8.43 (m, 5H), 8.19 (dd,J= 1.4, 6.1 Hz, 1H), 6.97 (dd,J= 6.1, 7.5 Hz, 1H), 4.05-3.65 (m, 3H), 3.27-3.18 (m, 5H), 2.34-2.12 (m, 2H), 1.67 (s, 2H), 1.51 (t,J= 6.5 Hz, 2H), 1.27 ppm (s, 15), Ms calcd for C 22 H 40 ClN5O: 426.05.

[0461]

[0462] 51. Compound51: 2-Amino-N-(12-(4-(p-tolyloxy)piperidin-1-yl)dodecyl)nicotinamide (PBK-2025-015)

[0463] <화학식51>

[0464] White solid, ¹H NMR (400 MHz, CDCl3): δ = 8.15 (dd, J = 1.8, 4.9 Hz, 1H), 7.62 (dd, J = 1.6, 7.7 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.82-6.77 (m, 2H), 6.60 (dd, J = 4.9, 7.7 Hz, 1H), 6.32 (s, 1H), 6.20 (s, 1H), 4.47 (s, 1H), 3.40 (q, J = 6.8 Hz, 2H), 2.98 (s, 3H), 2.68 (s, 2H), 2.31 (d, J = 23.0 Hz, 3H), 2.01 (s, 2H), 1.76 (s, 2H), 1.65-1.56 (m, 2H), 1.29 ppm (d, J = 16.1 Hz, 20H), Ms calcd for C 30 H 46 N4O2: 494.71.

[0465]

[0466] 52. Compound52: 2-Amino-N-(12-(3-fluoroazetidin-1-yl)dodecyl)nicotinamide

[0467] <화학식52>

[0468] White solid, 1H NMR (400 MHz, CDCl3)δ8.16 (dd, J = 1.7, 4.9 Hz, 1H), 7.57 (dd, J = 1.7, 7.7 Hz, 1H), 6.60 (dd, J = 4.9, 7.7 Hz, 1H), 6.30 (s, 2H), 6.01 (s, 1H), 5.11 (dq, J = 26.0, 22.7 Hz, 1H), 3.71 - 3.62 (m, 2H), 3.40 (td, J = 5.0, 10.1 Hz, 2H), 3.13 - 3.02 (m, 2H), 2.46 (t, J = 7.1 Hz, 2H), 1.64 - 1.55 (m, 2H), 1.27 (s, 18H), Ms calcd for C 21 H 35 FN4O: 378.53.

[0469]

[0470] 53. 화합물53: 2-Amino-N-(12-(tert-butyl(methyl) amino) dodecyl) nicotinamide (이하 PBK-2025-017이라 별칭함)

[0471] <화학식53>

[0472] White solid, 1 H NMR (400 MHz, CDCl3)δ8.15 (dd, J = 1.8, 4.9 Hz, 1H), 7.57 (dd, J = 1.7, 7.7 Hz, 1H), 6.60 (dd, J = 4.9, 7.7 Hz, 1H), 6.30 (s, 2H), 6.02 (s, 1H), 3.40 (td, J = 5.0, 10.1 Hz, 2H), 2.30 (t, J = 7.6 Hz, 2H), 2.20 (s, 3H), 1.64 - 1.55 (m, 2H), 1.44 - 1.43 (m, 2H), 1.28 (s, 16H), 1.05 (s, 9H), Ms calcd for C 23 H 42 N4O: 390.62.

[0473]

[0474] 54. Compound 54: 2-Amino-N-(12-(4-(2-hydroxyethyl)piperazin-1-yl)dodecyl) nicotinamide (hereinafter referred to as PBK-2025-018)

[0475] <Chemical Formula 54>

[0476] White solid, ¹H NMR (400 MHz, CDCl3):δ= 8.15 (dd,J= 1.7, 4.8 Hz, 1H), 7.62 (dd,J= 1.7, 7.7 Hz, 1H), 6.60 (dd,J= 4.9, 7.7 Hz, 1H), 6.33-6.16 (m, 3H), 3.71-3.66 (m, 2H), 3.44-3.36 (m, 2H), 2.78-2.63 (m, 12H), 2.56-2.48 (m, 3H), 1.63-1.57 (m, 4H), 1.41-1.23 ppm (m, 18H), Ms calcd for C 24 H 43 N5O2: 433.64.

[0477]

[0478] 55. Compound 55: 2-Amino-N-(12-(4-(p-tolyl)piperidin-1-yl)dodecyl) nicotinamide (hereinafter referred to as PBK-2025-023)

[0479] <Chemical Formula 55>

[0480] White solid, ¹H NMR (400 MHz, CDCl3):δ= 8.14 (dd,J= 1.7, 4.8 Hz, 1H), 7.63 (dd,J= 1.5, 7.7 Hz, 1H), 7.17-7.11 (m, 5H), 6.59 (dd,J= 4.9, 7.7 Hz, 1H), 6.34 (s, 2H), 6.22 (s, 1H), 3.44-3.34 (m, 6H), 2.66-2.59 (m, 4H), 2.32 (s, 9H), 1.91 (d,J= 13.1 Hz, 2H), 1.65-1.55 (m, 3H), 1.32-1.24 ppm (m, 21H), Ms calcd for C 30 H 46 N4O: 478.73.

[0481]

[0482] 56. Compound 56: 2-Amino-N-(12-(3,5-dimethyl-4H-1,2,4-triazol-4-yl) dodecyl)nicotinamide (hereinafter referred to as PBK-2025-048)

[0483] <Chemical Formula 56>

[0484] Clear liquid, ¹H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 5.2 Hz, 1H), 7.59 (d, J = 7.1 Hz, 1H), 6.57-6.50 (m, 3H), 3.88 (t, J = 7.3 Hz, 2H), 3.37-3.31 (m, 2H), 2.32 (s, 3H), 2.25 (s, 3H), 1.77-1.68 (m, 2H), 1.56-1.49 ppm (m, 2H), Ms calcd for C 22 H 36 N6O: 400.57.

[0485]

[0486] 57. Compound 57: 2-Amino-N-(12-fluoro-dodecyl)-nicotinamide (hereinafter referred to as GO15F)

[0487] <Chemical Formula 57>

[0488] White solid, 1H NMR (400 MHz, CDCl3) δ 8.14 (dd, J=4.73, 1.66Hz, 1H), 7.55(dd, J=7.67, 1.55Hz, 1H), 6.58(dd, J=7.59, 4.85Hz, 1H), 6.28(d, J= 0.71Hz, 2H), 5.97(d, J= 1.38Hz, 1H), 4.48(t, J= 6.23Hz, 1H), 4.36 (t, J=6.18Hz, 1H), 3.39(q, J=6.77Hz, 2H), 1.74-1.55 (m, 4H), 1.41-1.27 (m, 16H) MS calcd for C18H30FN3O2: 323.24.

[0489]

[0490] 58. Compound 58: 2-Bromo-N-(12-fluoro-dodecyl)-nicotinamide (hereinafter referred to as CS06-005-F)

[0491] <Chemical Formula 58>

[0492] Dark yellow solid, 1H NMR (400 ㎒, Chloroform-d) δ 8.35 (dd, J = 4.6, 2.0 ㎐, 1H), 7.85 (dd, J = 7.6, 2.0 ㎐, 1H), 7.28 (dd, J = 7.6, 4.7 ㎐, 1H), 6.16 (s, 1H), 4.43 (t, J = 6.2 Hz, 1H), 4.31 (t, J = 6.2 Hz, 1H), 3.40 (td, J = 7.1, 5.8 Hz, 2H), 1.69- 1.48 (m, 4H), 1.35- 1.04 (m, 16H) Ms calcd for C 18 H 28 BrFN2O: 387.34.

[0493]

[0494] 59. Compound 59: N-(12-fluoro-dodecyl)-3-(3-trifluoromethyl-phenylamino)-isonicotinamide (hereinafter referred to as PBK-069-F)

[0495] <Chemical Formula 59>

[0496] Off-white solid, 1H NMR (400㎒, Chloroform-d)δ7.44- 7.29 (m, 5H), 7.27 (s, 1H), 7.20 (d, J = 7.5㎐, 1H), 6.93- 6.81 (m, 1H), 4.49 (t, J = 6.2㎐, 1H), 4.37 (t, J = 6.2㎐, 1H), 3.42 (q, J = 6.7㎐, 2H), 1.75-1.55(m,4H),1.48-1.12(m,16H), Ms calcd for C 25 H 35 F4N3O: 467.53.

[0497]

[0498] 60. Compound 60: 4-chloro-N-(12-fluoro-dodecyl)-nicotinamide (hereinafter referred to as PBK-048-F)

[0499] <Chemical Formula 60>

[0500] Brown solid, 1H NMR (400 ㎒, Methanol-d4) δ 8.57- 8.48 (m, 2H), 7.58 (d, J = 5.4 ㎐, 1H), 4.46 (t, J = 6.1 ㎐, 1H), 4.34 (t, J = 6.1 ㎐, 1H), 3.38 (t, J = 7.0 Hz, 2H), 1.65 (dtd, J = 21.9, 9.0, 8.6, 6.5 Hz, 4H), 1.32 (s, 17H), Ms calcd for C 18 H 28 BrFN2O: 342.88.

[0501]

[0502] 61. Compound 61: 2-Amino-N-(8-fluoro-octyl)-nicotinamide (hereinafter referred to as GO15-F-8)

[0503] <Chemical Formula 61>

[0504] White solid, 1H NMR (400 MHz, CDCl3) δ 8.13 (dd, J= 4.80, 1.72Hz, 1H), 7.55(dd, J=7.69, 1.75 Hz, 1H), 6.57(dd, J=7.71, 4.95Hz, 1H), 6.29(s, 2H), 6.00(s,1H), 4.48(t, J=6.15 Hz, 1H), 4.36(t, J=6.15Hz, 1H), 3.42-3.37 (m, 2H), 1.72-1.55(m, 4H), 1.40-1.24 (m, 8H), MS calcd for C 14 H 22 FN3O: 267.35.

[0505]

[0506] 62. Compound 62: N-(12-fluoro-dodecyl)-2-mercapto-nicotinamide (hereinafter referred to as GO59)

[0507] <Chemical Formula 62>

[0508] Yellow solid, 1H NMR (400 MHz, CDCl3) δ 10.62(d, J=4.4Hz, 1H), 8.84 (dd, J=7.49, 1.85Hz, 1H), 7.67 (dd, J=6.04, 1.82Hz, 1H), 6.95(dd, J=7.61, 6.10Hz, 1H), 4.47(t, J=6.20Hz, 1H), 4.36(t, J=6.23Hz, 1H), 3.513.46(m, 2H), 1.72-1.61(m, 4H), 1.46-1.23(m, 16H), Ms calcd for C 18 H 29 FN2OS: 340.50.

[0509]

[0510] 63. Compound 63: 2-amino-N-(10-morpholin-4-yl-decyl)-nicotinamide (hereinafter referred to as GO50)

[0511] <Chemical Formula 63>

[0512] White solid, 1H NMR (400 MHz, CDCl3) δ 8.14 (dd, J= 4.94, 1.78Hz, 1H), 7.55(dd, J=7.64, 1.74Hz, 1H), 6.58(dd, J=7.63, 4.86Hz, 1H), 6.27(s, 2H), 3.70(t, J=4.68Hz, 4H), 3.42-3.37(m, 2H), 3.41-3.37(m, 2H), 2.41 (t, J=4.30Hz, 4H), 2.30(dd, J=8.77, 6.73Hz, 2H), 1.57(s 2H), 1.46(d, J=1.22Hz, 2H); 1.36-1.28(m, 12H), Ms calcd for C 20 H 34 N4O2: 362.52.

[0513]

[0514] 64. Compound 64: 3-Hydroxy-pyridine-2-carboxylic acid (12-fluoro-dodecyl)-amide (hereinafter referred to as GO62)

[0515] <Chemical Formula 64>

[0516] White solid, 1H NMR (400 MHz, CDCl3)δ12.67(s, 1H), 9.14(s, 1H), 8.10(dd, J=4.48, 1.33Hz, 1H), 7.47(dd, J=8.47, 4.36Hz, 1H), 7.35(dd, J=8.47, 1.37Hz, 1H), 4.43(t, J=6.14Hz, 1H), 4.31(t, J=6.13Hz, 1H), 3.24(t, J=6.90Hz, 2H), 1.64-1.49(m, 4H), 1.29-1.13(m, 16H), Ms calcd for C 18 H 29 FN2O2: 324.44.

[0517]

[0518] 67. Compound 67: N-(12-fluoro-dodecyl)-2-methylsulfanyl-nicotinamide (hereinafter referred to as PBK-058-F)

[0519] <Chemical Formula 67>

[0520] Off-white solid, 1H NMR (400 ㎒, Methanol-d4) δ 9.27 (dd, J = 4.9, 1.7 Hz, 1H), 8.44 (dd, J = 7.6, 1.8 Hz, 1H), 7.90 (dd, J = 7.6, 4.9 Hz, 1H), 5.18 (dt, J = 47.7, 6.1 Hz, 2H), 4.09 (d, J = 1.6 Hz, 3H), 3.30 (s, 3H), 2.44 (ddt, J = 32.8, 14.4, 6.8 Hz, 4H), 2.11 (s, 15H), Ms calcd for C 19 H 31 FN2O2S: 354.53.

[0521]

[0522] 68. Compound 68: 2-amino-N-(10-fluoro-decyl)-nicotinamide (hereinafter referred to as GO44)

[0523] <Chemical Formula 68>

[0524] Pale-yellow sold, 1H NMR (400 MHz, CDCl3) δ 8.13 (dd, J= 4.81, 1.72Hz, 1H), 7.55(dd, J=7.70, 1.75 Hz, 1H), 6.57(dd, J=7.70, 4.93Hz, 1H), 6.29(s, 2H), 6.01(s, 1H), 4.47(t, J=6.19 Hz, 1H), 4.35(t, J=6.18Hz, 1H), 3.41-3.36 (m, 2H), 1.73-1.55(m, 4H), 1.40-1.24 (m, 12H), Ms calcd for C 16 H 26 FN3O: 295.4.

[0525]

[0526] 69. Compound 69: 3-(12-Fluoro-dodecylcarbamoyl)-pyridin-2-yl-ammonium chloride (hereinafter referred to as GO15-F-salt)

[0527] <Chemical Formula 69>

[0528] White sold, 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 2H), 8.19 (d, J=7.43Hz, 1H), 7.69 (d, J=5.89Hz, 1H), 7.35(s, 1H), 6.79 (t, J=6.85Hz, 1H), 4.48 (t, J=6.18Hz, 1H), 4.36 (t, J=6.19Hz, 1H), 3.44-3.39 (m, 2H), 1.72-1.59 (m, 4H), 1.39-1.27(m, 16H), Ms calcd for C 18 H 31 ClFN3O: 359.91.

[0529]

[0530] 70. Compound 70: 2-amino-N-(11-fluoro-undecyl)-nicotinamide (hereinafter referred to as GO45)

[0531] <Chemical Formula 70>

[0532] White solid, 1H NMR (400 MHz, CDCl3) δ 7.55 (dd, J=7.64, 1.73Hz, 1H), 4.58(dd, J=7.63, 4.79Hz, 1H), 6.58(dd, J=7.63, 4.79Hz, 1H), 6.27(s, 2H) 5.98(s,1H), 4.48(t, J=6.20Hz, 1H), 4.36 (t, J=6.18Hz, 1H), 3.42-3.37(m, 2H), 1.74-1.55(m, 4H), 1.41-1.28(m, 14H), Ms calcd for C 17 H 28 FN3O: 309.43.

[0533]

[0534] 71. Compound 71: 3-(11-Fluoro-undecylcarbamoyl)-pyridin-2-yl-ammonium chloride (hereinafter referred to as GO45-salt)

[0535] <Chemical Formula 71>

[0536] White solid, 1H NMR (400 MHz, CDCl3) δ 8.50(s, 3H), 8.39(d, J=7.23Hz, 1H), 7.86(s, 1H), 7.68 (d, J=5.92Hz, 1H), 6.80(t, J=6.72Hz, 1H), 4.47(t, J=6.18Hz, 1H), 4.35(t, J=6.17Hz, 1H), 3.39(q, J=6.67Hz, 2H), 1.73-1.60(m, 4H), 1.40-1.23(m, 14H), Ms calcd for C 17 H 29 ClFN4O: 345.89.

[0537]

[0538] 73. Compound 73: 4-amino-N-(12-fluoro-dodecyl)-nicotinamide (hereinafter referred to as GO60)

[0539] <Chemical Formula 73>

[0540] White solid, 1H NMR (400 MHz, CDCl3) δ 8.48(s, 1H), 8.10(d, J=5.81Hz, 1H), 6.49(d, J= 5.84Hz, 2H), 6.38(s, 1H), 6.18(s, 2H), 4.47(t, J=6.20Hz, 1H) 4.35(t, J=6.20Hz, 1H), 3.39(q, J=6.57Hz, 2H), 1.73-1.57(m, 4H) 1.36-1.26(m, 16H), Ms calcd for C 18 H 30 FN3O: 323.46.

[0541]

[0542] 76. Compound 76: N-(12-fluoro-dodecyl)-3-iodo-isonicotinamide (hereinafter referred to as GO73)

[0543] <Chemical Formula 76>

[0544] White solid, 1H NMR (400 MHz, CDCl3) δ 8.95(s, 1H), 8.55(d, J=4.76Hz, 1H), 7.30-7.29(m, 1H), 5.86(s, 1H), 4.47(t, J=6.20, Hz, 1H), 4.35(t, J=6.19Hz, 1H), 3.46-3.41(m, 2H), 1.73-1.59(m, 4H), 1.43-1.22(m, 16H), Ms calcd for C 18 H 28 FIN2O: 434.34.

[0545]

[0546] 77. Compound 77 (C1): 2-bromo-N-(10-cyano-decyl)benzamide (hereinafter referred to as PBK-CNB-1)

[0547] <Chemical Formula 77>

[0548] Yellow oil, 1H NMR (400 ㎒, Chloroform-d) δ 7.59- 7.52 (m, 2H), 7.35 (td, J = 7.5, 1.2 ㎐, 2H), 5.99 (s, 1H), 3.47- 3.42 (m, 2H), 2.34 (t, J = 7.1 Hz, 3H), 1.67- 1.62 (m, 4H), 1.32 (d, J = 10.3 Hz, 12H), MS calcd for C 18 H 25 BrN2O: 365.32.

[0549]

[0550] 78. Compound 78 (C2): 2-amino-N-(3-morpholin-4-yl-propyl)nicotinamide (hereinafter referred to as GO35)

[0551] <Chemical Formula 78>

[0552] Yellow solid, 1H NMR (500 MHz, cdcl3) δ 8.16-8.09 (m, 2H), 7.64(dd, J=7.64, 1.50Hz, 1H), 6.59(dd, J=7.63, 4.86Hz, 1H), 6.37(s, 2H), 3.68(t, J=4.48Hz, 4H), 3.51(q, J=5.49Hz, 2H), 2.57-2.50(m, 6H), 1.77(dt, J=11.73, 5.88Hz, 2H), MS calcd for C 13 H 20 N4O2: 264.16.

[0553]

[0554] 79. Compound 79 (C3): 2-amino-N-(10-cyano-decyl)-nicotinamide (hereinafter referred to as CNA)

[0555] <Chemical Formula 79>

[0556] Yellow solid, 1H NMR (400 MHz, Chloroform-d) δ 8.05 (dd, J = 4.9, 1.8 Hz, 1H), 7.56 (dd, J = 7.7, 1.8 Hz, 1H), 6.54 (dd, J = 7.6, 4.9 Hz, 1H), 6.39 (s, 2H), 6.12 (t, J = 5.8 Hz, 1H), 3.33 (td, J = 7.4, 5.8 Hz, 2H), 2.27 (t, J = 7.1 Hz, 2H), 1.56 (d, J = 35.6 Hz, 4H), 1.39- 1.21 (m, 12H), MS calcd for C 17 H 26 N4O: 302.42.

[0557]

[0558] 80. Compound 80 (C4): 12-(2-bromo-benzoylamino)-dodecanoic acid ethyl ester (hereinafter referred to as CS06-010-2)

[0559] <Chemical Formula 80>

[0560]

[0561] 81. Compound 81 (C5): 12-(2-bromo-benzoylamino)-dodecanoic acid (hereinafter referred to as CS06-010-3)

[0562] <Chemical Formula 81>

[0563] 82. Compound 82 (C6): 12-[(3-bromo-pyridine-4-carbonyl)-amino]-dodecanoic acid ethyl ester (hereinafter referred to as CS06-010-4)

[0564] <Chemical Formula 82>

[0565]

[0566] 83. Compound 83 (C7): 12-[(3-bromo-pyridine-4-carbonyl)-amino]-dodecanoic acid (hereinafter referred to as CS06-010-5)

[0567] <Chemical Formula 83>

[0568]

[0569] 88. Compound 88: N -(12 -(3H -[1,2,3]triazolo[4,5 -b]pyridin-3-yl)dodecyl)-2-aminonicotinamide (hereinafter referred to as PBK-2025-069)

[0570] <Chemical Formula 88>

[0571] White-yellow solid, ¹H NMR (400 MHz, CDCl3):δ= 8.68-8.55 (m, 1H), 8.26-8.10 (m, 1H), 7.97-7.94 (m, 1H), 7.61-7.57 (m, 1H), 7.24 (q,J= 4.2 Hz, 1H), 6.60 (d,J= 8.1 Hz, 2H), 6.49 (dt,J= 0.9, 6.4 Hz, 1H), 6.22 (d,J= 23.5 Hz, 1H), 4.63 (q,J= 7.4 Hz, 2H), 3.31-3.24 (m, 2H), 2.05-1.91 (m, 2H), 1.52-1.42 (m, 2H), 1.19 ppm (d,J= 41.6 Hz, 18H), Ms calcd for C 23 H 33 N7O: 423.57.

[0572]

[0573] 89. Compound 89: 2-Amino-N-(12-(indolin-1-yl)dodecyl)nicotinamide (hereinafter referred to as PBK-2025-070)

[0574] <Chemical Formula 89>

[0575] Yellow oil, ¹H NMR (400 MHz, CDCl3): δ = 8.29 (s, 1H), 8.00 (dd, J = 1.7, 5.1 Hz, 1H), 7.60 (dd, J = 1.7, 7.7 Hz, 1H), 7.26 (t, J = 2.9 Hz, 2H), 7.24 (s, 2H), 7.22-7.17 (m, 3H), 6.75 (s, 2H), 6.51 (dd, J = 5.0, 7.7 Hz, 1H), 6.28 (s, 1H), 4.41 (s, 4H), 3.36-3.29 (m, 2H), 3.07-3.01 (m, 2H), 1.79-1.71 (m, 2H), 1.57-1.49 (m, 2H), 1.31-1.15 ppm (m, 18H), Ms calcd for C 26 H 38 N4O: 422.62.

[0576]

[0577] 90. Compound 90: 5-Phenyl-N-(12-(piperazin-1-yl)dodecyl)furan-2-carboxamide hydrochloride (hereinafter referred to as PBK-2025-085)

[0578] <Chemical Formula 90>

[0579] White-yellow solid, ¹H NMR (400 MHz, DMSO):δ= 11.66 (s, 1H), 9.64 (s, 2H), 8.25-8.20 (m, 1H), 7.76-7.67 (m, 1H), 7.30 (t,J= 10.5 Hz, 2H), 3.64 (s, 5H), 3.29-3.08 (m, 7H), 2.95-2.89 (m, 2H), 1.68 (s, 2H), 1.42-1.38 (m, 2H), 1.27-1.14 ppm (m, 21H), Ms calcd for C 27 H 42 ClN3O2: 476.10.

[0580]

[0581] 91. Compound91:N-(12-(4-methylpiperazin-1-yl)dodecyl)-1H-benzo[d]imidazole-5-carboxamide

[0582] <화학식91>

[0583] Yellow solid, 1 H NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), 8.13 (bs, 1H), 7.77 (d,J= 8.6 Hz, 1H), 7.66 (d,J= 8.6 Hz, 1H), 3.40 (t,J= 7.2 Hz, 2H), 2.52 (bs, 8H), 2.38-2.34 (m, 2H), 2.29 (s, 3H), 1.65 (p,J= 7.2 Hz, 2H), 1.53-1.48 (m, 2H), 1.43-1.31 (m, 16H), Ms calcd for C 25 H 41 N5O: 427.63.

[0584]

[0585] 92. Compound92: ethyl 1-(12-(2-aminonicotinamido)dodecyl)piperidine-3-carboxylate

[0586] <화학식92>

[0587] Oil, Yield: 29%, 1 H NMR (400 MHz, CDCl3) δ8.17 (dd,J= 4.8, 1.4 Hz, 1H), 7.59 (dd,J= 7.7, 1.5 Hz, 1H), 6.62 (dd,J= 7.6, 4.8 Hz, 1H), 6.32 (s, 2H), 6.04 (s, 1H), 4.15 (q,J= 7.1 Hz, 2H), 3.43 (dd,J= 13.2, 7.0 Hz, 2H), 3.05 (d,J= 7.1 Hz, 1H), 2.83 (s, 1H), 2.61 (s, 1H), 2.37 (s, 2H), 2.16 (d,J= 10.2 Hz, 1H), 2.02 (dd,J= 28.1, 8.5 Hz, 2H), 1.75 (dd,J= 9.7, 3.6 Hz, 2H), 1.62 (dt,J= 14.5, 7.2 Hz, 3H), 1.51 (d,J= 8.8 Hz, 2H), 1.44 - 1.25 (m, 19H). MS calcd for C 26 H 44 N4O3(M+H) + :460, found 461

[0588]

[0589] 93. 화합물93: methyl 1-(12-(2-aminonicotinamido)dodecyl)piperidine-4-carboxylate (이하 K-PB-2라 별칭한다)

[0590] <화학식93>

[0591] Oil, Yield: 32%, 1H NMR (400 MHz, CDCl3) δ8.16 (dd,J= 4.8, 1.5 Hz, 1H), 7.66 - 7.56 (m, 1H), 6.61 (dd,J= 7.6, 4.9 Hz, 1H), 6.32 (s, 2H), 6.11 (s, 1H), 3.70 (s, 3H), 3.42 (dd,J= 13.3, 6.8 Hz, 2H), 3.01 - 2.88 (m, 2H), 2.40 (d,J= 7.0 Hz, 3H), 2.26 - 2.08 (m, 2H), 2.02 (dd,J= 21.2, 9.4 Hz, 2H), 1.94 - 1.78 (m, 2H), 1.70 - 1.59 (m, 2H), 1.56 (d,J= 12.0 Hz, 2H), 1.32 (d,J= 28.8 Hz, 16H). MS calcd for C 25 H 42 N4O3(M+H) + :446, found 447

[0592]

[0593] 94. 화합물94: 2-amino-N-(12-(4-methoxypiperidin-1-yl)dodecyl)nicotinamide (이하 K-PB-3이라 별칭한다)

[0594] <화학식94>

[0595] Oil, Yield: 29%, 1H NMR (400 MHz, CDCl3) δ8.16 (dd,J= 4.7, 1.5 Hz, 1H), 7.65 - 7.54 (m, 1H), 6.61 (dd,J= 7.6, 4.9 Hz, 1H), 6.33 (s, 2H), 6.20 (s, 1H), 3.42 (dd,J= 13.1, 7.0 Hz, 1H), 3.35 (s, 3H), 2.95 (s, 2H), 2.36 - 2.19 (m, 2H), 2.03 (t,J= 12.7 Hz, 2H), 1.90 (s, 2H), 1.76 (s, 2H), 1.61 (dd,J= 14.2, 7.0 Hz, 2H), 1.47 - 1.25 (m, 16H). MS calcd for C 24 H 42 N4O2(M+H) + :418, found 419

[0596]

[0597] 95. 화합물95: 2-amino-N-(12-(4-(2-methoxyethyl)piperazin-1-yl)dodecyl)nicotinamide (이하 K-PB-4 라 별칭한다)

[0598] <화학식95>

[0599] Oil, Yield: 28%, 1H NMR (400 MHz, CDCl3) δ8.17 (dd,J= 4.9, 1.7 Hz, 1H), 7.60 (dd,J= 7.7, 1.7 Hz, 1H), 6.61 (dd,J= 7.7, 4.9 Hz, 1H), 6.32 (s, 2H), 6.06 (s, 1H), 3.53 (t,J= 5.6 Hz, 2H), 3.42 (dd,J= 13.0, 7.1 Hz, 2H), 3.37 (s, 3H), 2.62 (dd,J= 7.2, 3.9 Hz, 8H), 2.42 (dd,J= 9.1, 6.7 Hz, 2H), 2.25 (dd,J= 16.5, 9.0 Hz, 2H), 1.62 (dt,J= 14.7, 7.4 Hz, 2H), 1.53 (s, 2H), 1.32 (d,J= 29.2 Hz, 16H). MS calcd for C 25 H 45 N5O2(M+H) + :447, found 448

[0600]

[0601] 96. 화합물96: N-(12-(allyl(methyl)amino)dodecyl)-2-aminonicotinamide ( 이하 K-PB-5 라 별칭한다)

[0602] <화학식96>

[0603] Oil, Yield: 36%, 1H NMR (400 MHz, CDCl3) δ8.08 (d,J= 4.8 Hz, 2H), 7.50 (d,J= 7.6 Hz, 2H), 6.53 (dd,J= 7.6, 4.9 Hz, 1H), 6.23 (s, 4H), 5.93 (s, 2H), 5.79 (ddt,J= 16.7, 10.2, 6.5 Hz, 2H), 5.13 - 5.00 (m, 4H), 3.33 (dd,J= 13.2, 6.8 Hz, 4H), 2.91 (d,J= 6.5 Hz, 4H), 2.28 - 2.21 (m, 4H), 2.13 (s, 6H), 1.52 (dd,J= 14.4, 7.2 Hz, 5H), 1.38 (d,J= 6.6 Hz, 5H), 1.23 (d,J= 27.8 Hz, 16H). MS calcd for C 22 H 38 N4O(M+H) + :374, found 375

[0604]

[0605] 97. 화합물97: 2-amino-N-(12-(4-formylpiperazin-1-yl)dodecyl)nicotinamide (이하 K-PB-6 이라 별칭한다)

[0606] <화학식97>

[0607] White solid, Yield: 46%, 1H NMR (400 MHz, CDCl3) δ8.08 (dd,J= 4.8, 1.7 Hz, 1H), 7.95 (s, 1H), 7.50 (dd,J= 7.7, 1.7 Hz, 1H), 6.52 (dd,J= 7.7, 4.9 Hz, 1H), 6.23 (s, 2H), 5.97 (s, 1H), 3.53 - 3.45 (m, 2H), 3.40 - 3.26 (m, 4H), 2.42 - 2.30 (m, 4H), 2.30 - 2.24 (m, 2H), 1.53 (dt,J= 14.7, 7.3 Hz, 2H), 1.47 - 1.36 (m, 2H), 1.23 (d,J= 27.1 Hz, 16H). MS calcd for C 23 H 39 N5O2(M+H) + :417, found 418

[0608]

[0609] 98. 화합물98: 2-amino-N-(12-(ethylamino)dodecyl)nicotinamide (이하 K-PB-7 이라 별칭한다)

[0610] <화학식98>

[0611] Oil, Yield: 25%, 1 H NMR (400 MHz, CDCl3) δ8.08 (dd,J= 4.8, 1.8 Hz, 1H), 7.50 (dd,J= 7.7, 1.7 Hz, 1H), 6.52 (dd,J= 7.7, 4.9 Hz, 1H), 6.22 (s, 2H), 5.94 (s, 1H), 3.39 - 3.25 (m, 2H), 2.62 - 2.47 (m, 4H), 1.53 (dt,J= 14.8, 7.3 Hz, 2H), 1.45 - 1.37 (m, 2H), 1.23 (d,J= 27.9 Hz, 16H), 1.03 (t,J= 7.1 Hz, 3H). MS calcd for C 20 H 36 N4O(M+H) + :348, found 349

[0612]

[0613] 99. Compound 99: 2-amino-N-(12-(4-(cyclopropanecarbonyl)piperazin-1-yl) dodecyl) nicotinamide (hereinafter referred to as K-PB-8)

[0614] <Chemical Formula 99>

[0615] Oil, Yield: 35%, 1 H NMR (400 MHz, CDCl3) δ8.17 (dd,J= 4.8, 1.6 Hz, 1H), 7.60 (dd,J= 7.7, 1.6 Hz, 1H), 6.61 (dd,J= 7.6, 4.9 Hz, 1H), 6.33 (s, 2H), 6.09 (s, 1H), 3.69 (d,J= 18.8 Hz, 4H), 3.42 (dd,J= 13.1, 7.0 Hz, 2H), 2.45 (d,J= 25.0 Hz, 4H), 2.36 (dd,J= 13.0, 5.2 Hz, 2H), 1.75 (ddd,J= 12.7, 8.1, 4.7 Hz, 1H), 1.62 (dt,J= 14.7, 7.3 Hz, 2H), 1.51 (s, 2H), 1.32 (d,J= 26.6 Hz, 16H), 1.02 - 0.97 (m, 2H), 0.80 - 0.73 (m, 2H). MS calcd for C 26 H 43 N5O2(M+H) + :457, found 458

[0616]

[0617] 101. Compound 101: tert-Butyl (1-(12-(2-aminonicotinamido) dodecyl) piperidin-4-yl) carbamate (hereinafter referred to as K-PB-10)

[0618] <Chemical Formula 101>

[0619] yellow oil, Yield: 44%, 1H NMR (400 MHz, CDCl3) δ10.36 (s, 2H), 8.01 (s, 1H), 8.00 (d,J= 5.7 Hz, 1H), 7.33 (s, 1H), 6.75 (d,J= 15.2 Hz, 1H), 6.71 (t,J= 9.0 Hz, 1H), 3.72 (m, 4H), 3.61 (d,J= 13.8 Hz, 2H), 3.43 - 3.38 (m, 2H), 3.14 (m, 4H), 2.93 (dd,J= 10.3, 6.0 Hz, 2H), 2.74 (d,J= 10.5 Hz, 1H), 1.47 (d,J= 6.7 Hz, 18H), 1.43 (s, 9H). MS calcd for C 28 H 49 N5O3(M+H) + : 503, found 504

[0620]

[0621] 102. 화합물102: 2-Amino-N-(12-(4,4-dimethylpiperidin-1-yl)dodecyl)nicotinamide (이하 K-PB-11이라 별칭한다)

[0622] <화학식102>

[0623] White solid, Yield: 17%, 1 H NMR (400 MHz, CDCl3) δ8.15 (s, 1H), 7.63 (d,J= 7.5 Hz, 1H), 6.65 - 6.56 (m, 1H), 6.32 (s, 2H), 6.20 (s, 1H), 3.52 - 3.33 (m, 4H), 2.97 - 2.88 (m, 2H), 2.86 - 2.69 (m, 2H), 2.10 - 1.99 (m, 4H), 1.88 - 1.83 (m, 2H), 1.38 - 1.27 (m, 18H), 1.05 (s, 6H). MS calcd for C 25 H 44 N4O (M+H) + : 416, found 417

[0624]

[0625] 103. Compound 103: Ethyl 1-(12-(2-aminonicotinamido)dodecyl)piperidine-4-carboxylate (hereinafter referred to as K-PB-12)

[0626] <Chemical Formula 103>

[0627] White solid, Yield: 47.6%, 1 H NMR (400 MHz, CDCl3) δ8.15 (dd,J= 4.9, 1.8 Hz, 1H), 7.60 (dd,J= 7.7, 1.7 Hz, 1H), 6.59 (dd,J= 7.7, 4.9 Hz, 1H), 6.30 (s, 2H), 6.12 (s, 1H), 4.14 (q,J= 7.1 Hz, 2H), 3.40 (td,J= 7.2, 5.9 Hz, 2H), 2.98 (s, 2H), 2.49 (s, 2H), 2.40 (s, 2H), 2.04 (s, 2H), 1.93 (s, 2H), 1.65 - 1.55 (m, 4H), 1.34 (s, 2H), 1.34 - 1.22 (m, 18H), MS calcd for C 26 H 44 N4O3(M+H) + : 460, found 461

[0628]

[0629] 104. Compound 104: 2-Amino-N-(12-(4-isopropylpiperazin-1-yl)dodecyl) nicotinamide (hereinafter referred to as K-PB-13)

[0630] <Chemical Formula 104>

[0631] White solid, Yield: 42%, 1H NMR (400 MHz, CDCl3) δ8.15 (dd,J= 4.8, 1.7 Hz, 1H), 7.59 (dd,J= 7.7, 1.7 Hz, 1H), 6.59 (dd,J= 7.6, 4.9 Hz, 1H), 6.30 (s, 2H), 6.08 (s, 1H), 3.40 (dd,J= 13.1, 7.1 Hz, 2H), 2.83 (s, 1H), 2.73 (s, 8H), 2.45 - 2.39 (m, 2H), 1.63 - 1.57 (m, 2H), 1.30 (d,J= 29.4 Hz, 18H), 1.14 (s, 3H), 1.12 (s, 3H)., MS calcd for C 25 H 45 N5O (M+H) + : 431, found 432

[0632]

[0633] 105. 화합물105: 2-Amino-N-(12-(4-bromo-3-methyl-1H-pyrazol-1-yl)dodecyl)nicotinamide (이하 K-PB-14 이라 별칭한다)

[0634] <화학식105>

[0635] Yellow solid, Yield: 23%, 1 H NMR (400 MHz, CDCl3) δ8.15 (d,J= 4.8 Hz, 1H), 7.56 (d,J= 7.6 Hz, 1H), 7.26 (d,J= 0.9 Hz, 1H), 6.59 (dd,J= 7.2, 5.3 Hz, 1H), 6.29 (s, 2H), 6.00 (s, 1H), 4.01 (dt,J= 12.1, 7.2 Hz, 2H), 3.40 (dd,J= 13.3, 6.6 Hz, 2H), 2.22 (s, 3H), 1.85 - 1.73 (m, 2H), 1.61 - 1.56 (m, 2H), 1.36 - 1.21 (m, 16H)., MS calcd for C 22 H 34 BrN5O (M+H)+ : 464, found 465

[0636]

[0637] 106. Compound 106: 2-Amino-N-(12-(6-iodo-1H-indol-1-yl)dodecyl)nicotinamide (hereinafter referred to as K-PB-15)

[0638] <Chemical Formula 106>

[0639] Brown oil, Yield: 39%, 1 H NMR (400 MHz, CDCl3) δ8.14 (d,J= 4.7 Hz, 1H), 7.68 (s, 1H), 7.56 (d,J= 7.6 Hz, 1H), 7.36 (d,J= 1.3 Hz, 1H), 7.01 (d,J= 3.1 Hz, 1H), 6.59 (dd,J= 7.6, 4.9 Hz, 1H), 6.44 (dd,J= 3.1, 0.6 Hz, 1H), 6.33 (s, 2H), 6.00 (s, 1H), 4.05 (t,J= 7.2 Hz, 2H), 3.40 (dd,J= 13.0, 7.0 Hz, 2H), 1.83 - 1.78 (m, 2H), 1.60 (dd,J= 14.1, 7.3 Hz, 2H), 1.38 - 1.22 (m, 18H)., MS calcd for C 26 H 35 IN4O (M+H) + : 546, found 547

[0640]

[0641] 107. Compound 107: 2-Amino-N-(12-(4-(difluoromethyl)piperidin-1-yl)dodecyl)nicotinamide (hereinafter referred to as K-PB-16)

[0642] <Chemical Formula 107>

[0643] Yellow solid, Yield: 72%, 1H NMR (400 MHz, CDCl3) δ8.15 (dd,J= 4.9, 1.7 Hz, 1H), 7.57 (dd,J= 7.7, 1.7 Hz, 1H), 6.60 (dd,J= 7.7, 4.8 Hz, 1H), 6.29 (s, 2H), 6.00 (s, 1H), 3.40 (dd,J= 13.0, 7.1 Hz, 2H), 3.03 (s, 2H), 2.36 (s, 2H), 1.94 (s, 2H), 1.80 (d,J= 7.1 Hz, 2H), 1.75 (d,J= 7.1 Hz, 1H), 1.61 (d,J= 7.1 Hz, 4H), 1.37 - 1.35 (m, 1H), 1.35 - 1.23 (m, 18H)., MS calcd for C 24 H 40 F2N4O (M+H) + : 438, found 439

[0644]

[0645] 108. 화합물108:N-(12-(6-Azaspiro[2.5]octan-6-yl)dodecyl)-2-aminonicotinamide (이하 K-PB-17 이라 별칭한다)

[0646] <화학식108>

[0647] White solid, Yield: 39%, 1 H NMR (400 MHz, CDCl3) δ 8.12 (d,J= 3.5 Hz, 1H), 7.74 (d,J= 7.6 Hz, 1H), 6.61 (dd,J= 7.6, 4.9 Hz, 1H), 6.44 (s, 2H), 6.39 (s, 1H), 3.60 - 3.49 (m, 2H), 3.41 (dd,J= 13.2, 7.0 Hz, 2H), 3.01 - 2.94 (m, 2H), 2.81 - 2.68 (m, 3H), 1.93 (s, 4H), 1.35 - 1.25 (m, 18H), 0.54 (s, 2H), 0.36 (s, 2H)., MS calcd for C 25 H 42N4O (M+H) + : 414, found 415

[0648]

[0649] 109. Compound 109: 2-Amino-N-(12-(4-chloro-5-iodo-1H-pyrrolo[2,3-b]pyridin-1-yl)dodecyl) nicotinamide (hereinafter referred to as K-PB-18)

[0650] <Chemical Formula 109>

[0651] Yellow solid, Yield: 36%, 1 H NMR (400 MHz, CDCl3) δ8.54 (s, 1H), 8.14 (d,J= 4.8 Hz, 1H), 7.56 (d,J= 7.7 Hz, 1H), 7.19 (d,J= 3.4 Hz, 1H), 6.61 - 6.55 (m, 1H), 6.52 (dd,J= 3.5, 0.9 Hz, 1H), 6.31 (s, 2H), 6.03 (s, 1H), 4.24 (t,J= 7.1 Hz, 2H), 3.42 - 3.37 (m, 2H), 1.61 - 1.57 (m, 2H), 1.33 - 1.22 (m, 18H)., MS calcd for C 25 H 33 ClIN5O (M+H) + : 581, found 582

[0652]

[0653] 110. Compound 110: 2-amino-N-(12-((2S,6R)-2,6-dimethylmorpholino)dodecyl)nicotinamide (hereinafter referred to as K-PB-19)

[0654] <Chemical Formula 110>

[0655] Yellow solid, Yield: 80%, 1H NMR (400 MHz, CDCl3) δ8.15 (dd, J = 4.9, 1.8 Hz, 1H), 7.57 (dd, J = 7.7, 1.7 Hz, 1H), 6.59 (dd, J = 7.7, 4.9 Hz, 1H), 6.29 (s, 2H), 5.99 (s, 1H), 3.77 - 3.63 (m, 2H), 3.40 (td, J = 7.2, 5.9 Hz, 2H), 2.76 (d, J = 11.1 Hz, 2H), 2.36 - 2.25 (m, 2H), 1.76 - 1.43 (m, 12H), 1.40 - 1.27 (m, 10H), 1.17 (s, 3H), 1.15 (s, 3H)., MS calcd for C 24 H 42 N4O2(M+H) + : 418, found 419

[0656]

[0657] 111. 화합물111: tert-butyl-4-(12-(2-aminonicotinamido)dodecyl) piperazine-1-carboxylate ( 이하 K-PB-20 이라 별칭한다)

[0658] <화학식111>

[0659] Yellow solid, Yield: 55%, 1 H NMR (400 MHz, CDCl3) δ8.15 (dd, J = 4.9, 1.8 Hz, 1H), 7.57 (dd, J = 7.7, 1.7 Hz, 1H), 6.59 (dd, J = 7.7, 4.9 Hz, 1H), 6.29 (s, 2H), 6.01 (s, 1H), 3.51 - 3.33 (m, 6H), 2.43 - 2.34 (m, 4H), 2.34 - 2.28 (m, 2H), 1.69 - 1.53 (m, 6H), 1.52 - 1.42 (m, 11H), 1.40 - 1.27 (m, 12H)., MS calcd for C 27 H 47N5O3(M+H) + : 489, found 490

[0660]

[0661] 113. Compound 113: 2-amino-N-(12-(4-(cyclohexylmethyl)piperazin-1-yl)dodecyl)nicotinamide (hereinafter referred to as K-PB-22)

[0662] <Chemical Formula 113>

[0663] Yellow solid, Yield: 87%, 1 H NMR (400 MHz, CDCl3) δ8.15 (dd, J = 4.9, 1.8 Hz, 1H), 7.59 (dd, J = 7.7, 1.7 Hz, 1H), 6.60 (dd, J = 7.7, 4.9 Hz, 1H), 6.30 (s, 2H), 6.06 (s, 1H), 3.46 - 3.34 (m, 2H), 3.00 - 2.41 (m, J = 38.6 Hz, 10H), 2.21 (s, 2H), 1.80 - 1.42 (m, 14H), 1.42 - 1.26 (m, 12H), 1.16 (ddd, J = 12.5, 8.0, 2.4 Hz, 3H), 0.87 (dd, J = 22.4, 10.7 Hz, 2H)., MS calcd for C 29 H 51 N5O (M+H) + : 485, found 486

[0664]

[0665] 114. Compound 114: 2-amino-N-(12-(4,4-difluoropiperidin-1-yl)dodecyl)nicotinamide (hereinafter referred to as K-PB-23)

[0666] <Chemical Formula 114>

[0667] Yellow solid, Yield: 33%, 1H NMR (400 MHz, CDCl3) δ8.18 (dd, J = 4.8, 1.7 Hz, 1H), 7.59 (dd, J = 7.6, 1.3 Hz, 1H), 6.62 (dd, J = 7.6, 4.9 Hz, 1H), 6.31 (s, 2H), 6.01 (s, 1H), 3.43 (dd, J = 13.4, 6.7 Hz, 2H), 2.61 - 2.48 (m, 4H), 2.42 - 2.34 (m, 2H), 2.08 - 1.95 (m, 4H), 1.67 - 1.45 (m, 10H), 1.44 - 1.30 (m, 10H)., MS calcd for C 23 H 38 F2N4O (M+H) + : 424, found 425

[0668]

[0669] 115. 화합물115: 2-amino-N-(12-(4-fluoropiperidin-1-yl)dodecyl)nicotinamide (이하 K-PB-24 라 별칭한다)

[0670] <화학식115>

[0671] Yellow solid, Yield: 64%, 1 H NMR (400 MHz, CDCl3) δ8.15 (dd, J = 4.9, 1.8 Hz, 1H), 7.59 (dd, J = 7.7, 1.7 Hz, 1H), 6.60 (dd, J = 7.7, 4.9 Hz, 1H), 6.30 (s, 2H), 6.05 (s, 1H), 4.84 (d, J = 48.9 Hz, 2H), 3.45 - 3.34 (m, 2H), 2.92 - 2.57 (m, J = 72.2 Hz, 5H), 2.31 (s, 2H), 2.04 (s, 2H), 1.83 - 1.28 (m, J = 113.7, 70.4, 15.8 Hz, 20H)., MS calcd for C 23 H 39 FN4O (M+H)+ : 406, found 407

[0672]

[0673] 116. Compound 116: Methyl-1-(12-(2-aminonicotinamido)dodecyl)pyrrolidine-3-carboxylate (hereinafter referred to as K-PB-25)

[0674] <Chemical Formula 116>

[0675] Yellow solid, Yield: 29%, 1 H NMR (400 MHz, CDCl3) δ8.18 (dd, J = 4.9, 1.8 Hz, 1H), 7.60 (dd, J = 7.7, 1.7 Hz, 1H), 6.62 (dd, J = 7.7, 4.9 Hz, 1H), 6.32 (s, 2H), 6.05 (s, 1H), 3.73 (s, 3H), 3.49 - 3.36 (m, 2H), 3.17 (s, 2H), 2.79 (s, 1H), 2.62 (s, 2H), 2.29 - 2.11 (m, J = 28.5 Hz, 2H), 1.78 - 1.44 (m, 12H), 1.42 - 1.29 (m, 10H)., MS calcd for C 24 H 40 N4O3(M+H) + : 432, found 433

[0676]

[0677] 117. Compound 117: tert-butyl-(R)-(1-(12-(2-aminonicotinamido)dodecyl)piperidin-3-yl)carbamate (hereinafter referred to as K-PB-26)

[0678] <Chemical Formula 117>

[0679] Yellow solid, Yield: 32%, 1H NMR (400 MHz, CDCl3) δ8.17 (dd, J = 4.9, 1.8 Hz, 1H), 7.60 (dd, J = 7.7, 1.7 Hz, 1H), 6.62 (dd, J = 7.7, 4.9 Hz, 1H), 6.32 (s, 2H), 6.05 (s, 1H), 5.03 (s, 1H), 3.77 (s, 1H), 3.43 (dd, J = 13.0, 7.2 Hz, 2H), 2.57 - 2.23 (m, 6H), 1.80 - 1.53 (m, 12H), 1.47 (s, 12H), 1.42 - 1.29 (m, J = 12.8, 5.9 Hz, 9H)., MS calcd for C 28 H 49 N5O3(M+H) + : 503, found 504

[0680]

[0681] 118. 화합물118: 2-chloro-N-(12-(4-methylpiperazin-1-yl)dodecyl)nicotinamide ( 이하 K-PB-31 이라 별칭한다)

[0682] <화학식118>

[0683] White solid, Yield: 32%, 1 H NMR (400 MHz, CDCl3) δ8.46 (dd,J= 4.8, 2.0 Hz, 1H), 8.11 (dd,J= 7.6, 2.0 Hz, 1H), 7.35 (dd,J= 7.6, 4.8 Hz, 1H), 6.47 (s, 1H), 3.58 (s, 8H), 3.51 - 3.45 (m, 2H), 3.04 - 2.98 (m, 2H), 1.77 - 1.68 (m, 2H), 1.64 (dt,J= 14.6, 7.2 Hz, 2H), 1.45 - 1.20 (m, 16H)., MS calcd for C 23 H 39 ClN4O (M+H) + : 422, found 423

[0684]

[0685] 121. Compound 121: 2-fluoro-N-(12-(4-methylpiperazin-1-yl)dodecyl) nicotinamide (hereinafter referred to as K-PB-40)

[0686] <Chemical Formula 121>

[0687] White solid, Yield: 35% 1 H NMR (400 MHz, CDCl3) δ8.58 (ddd,J= 9.8, 7.5, 2.1 Hz, 1H), 8.36 - 8.28 (m, 1H), 7.36 (ddd,J= 7.4, 4.8, 2.4 Hz, 1H), 6.84 (s, 1H), 3.58 (s, 8H), 3.48 (td,J= 7.1, 1.2 Hz, 2H), 3.05 - 2.98 (m, 2H), 2.84 (s, 3H), 1.79 - 1.56 (m, 4H), 1.43 - 1.18 (m, 16H)., MS calcd for C 23 H 39 FN4O (M+H) + : 406, found 407

[0688]

[0689] 122. Compound 122: 2-Amino-N-(12-(3,3-difluoroazetidin-1-yl)dodecyl) nicotinamide (hereinafter referred to as K-PB-44)

[0690] <Chemical Formula 122>

[0691] Yellow solid, Yield: 35%, 1H NMR (400 MHz, CDCl3) δ8.15 (dd,J= 4.8, 1.6 Hz, 1H), 7.57 (dd,J= 7.6, 1.5 Hz, 1H), 6.59 (dd,J= 7.6, 4.9 Hz, 1H), 6.30 (s, 2H), 6.02 (s, 1H), 3.53 (t,J= 12.1 Hz, 4H), 3.40 (dd,J= 13.2, 6.9 Hz, 2H), 2.52 (t,J= 7.1 Hz, 2H), 1.60 (dt,J= 14.6, 7.2 Hz, 2H), 1.37 - 1.25 (m, 18H)., MS calcd for C 21 H 34 F2N4O (M+H) + : 396, found 397

[0692]

[0693] 123. 화합물123: 2-Amino-N-(12-(6-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl) dodecyl)nicotinamide (이하 K-PB-45라 별칭한다)

[0694] <화학식123>

[0695] White solid, Yield: 19%, 1 H NMR (400 MHz, CDCl3) δ8.14 (s, 1H), 7.96 (d,J= 8.5 Hz, 1H), 7.90 (s, 1H), 7.61 (d,J= 7.5 Hz, 1H), 7.04 (d,J= 8.6 Hz, 1H), 6.60 (dd,J= 6.3, 5.2 Hz, 1H), 6.41 (s, 2H), 6.10 (s, 1H), 4.40 (t,J= 7.0 Hz, 2H), 3.43 - 3.38 (m, 2H), 2.10 - 1.93 (m, 2H), 1.66 - 1.53 (m, 2H), 1.36 - 1.19 (m, 16H)., MS calcd for C 24 H 33 ClN6O (M+H) +: 457, found 458

[0696]

[0697] 124. Compound 124: 2-Amino-N-(12-(4-(4-methylpiperazin- 1- yl)piperidin-1-yl)dodecyl) nicotinamide (hereinafter referred to as K-PB-46)

[0698] <Chemical Formula 124>

[0699] White solid, Yield: 82%, 1 H NMR (400 MHz, CDCl3) δ8.15 (d,J= 4.8 Hz, 1H), 7.57 (d,J= 7.6 Hz, 1H), 6.62 - 6.55 (m, 1H), 6.30 (s, 2H), 6.02 (s, 1H), 3.40 (dd,J= 13.3, 6.5 Hz, 2H), 2.99 (d,J= 11.4 Hz, 2H), 2.60 (s, 4H), 2.46 (s, 4H), 2.28 (s, 3H), 2.27 - 2.22 (m, 1H), 1.90 (m, 4H), 1.79 (d,J=12.1 Hz, 2H), 1.60 (t,J= 7.4 Hz, 4H), 1.46 (m, 2H), 1.30 (m, 16H)., MS calcd for C 28 H 50 N6O (M+H) + : 486, found 487

[0700]

[0701] 125. Compound 125: 2-Amino-N-(12-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)dodecyl)nicotinamide (hereinafter referred to as K-PB-47)

[0702] <Chemical Formula 125>

[0703] White solid, Yield: 40%, 1H NMR (400 MHz, CDCl3) δ8.13 (s, 1H), 7.57 (d,J= 25.3 Hz, 1H), 6.59 (s, 1H), 6.55 (s, 1H), 6.51 (s, 1H), 6.31 (s, 2H), 6.16 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.39 (m, 2H), 2.97 (m, 2H), 2.97 (m, 1H), 2.73 (m, 1H), 1.74 (s, 3H), 1.59 (m, 4H), 1.26 (m, 18H)., MS calcd for C 29 H 44 N4O3(M+H) + : 496, found 497

[0704]

[0705] 126. 화합물126: 2-amino-N-(12-(3-methoxypyrrolidin-1-yl)dodecyl) nicotinamide (이하 K-PB-48 이라 별칭한다)

[0706] <화학식126>

[0707] Oil, Yield: 13%, 1 H NMR (400 MHz, CDCl3) δ8.16 (d,J= 4.1 Hz, 1H), 7.61 (t,J= 22.1 Hz, 1H), 6.62 (dd,J= 7.1, 5.1 Hz, 1H), 6.28 (d,J= 40.1 Hz, 2H), 6.20 (s, 1H), 4.10 (s, 1H), 3.87 - 3.60 (m, 2H), 3.42 (dd,J= 13.3, 6.6 Hz, 2H), 3.34 (d,J= 0.8 Hz, 3H), 3.15 - 2.83 (m, 4H), 2.23 (dd,J= 12.0, 5.2 Hz, 2H), 1.84 (dd,J= 14.8, 7.4 Hz, 2H), 1.62 (dd,J= 14.3, 7.1 Hz, 2H), 1.47 - 1.23 (m, 16H). MS calcd for C 23 H 40N4O2(M+H) + :404, found 405

[0708]

[0709] 127. Compound 127: 2-amino-N-(12-(2-oxooxazolidin-3-yl)dodecyl) nicotinamide (hereinafter referred to as K-PB-49)

[0710] <Chemical Formula 127>

[0711] Oil, Yield: 15%, 1 H NMR (400 MHz, CDCl3) δ8.17 (d,J= 4.7 Hz, 1H), 7.61 (d,J= 7.6 Hz, 1H), 6.62 (dd,J= 7.6, 4.9 Hz, 1H), 6.32 (s, 2H), 6.11 (s, 1H), 4.34 (t,J= 8.0 Hz, 2H), 3.57 (t,J= 8.0 Hz, 2H), 3.43 (dd,J= 13.4, 6.7 Hz, 2H), 3.27 (t,J= 7.3 Hz, 2H), 1.58 (dd,J= 15.3, 7.4 Hz, 4H), 1.31 (d,J=14.0 Hz, 16H). MS calcd for C 21 H 34 N4O3(M+H) + :390, found 391

[0712]

[0713] 128. Compound 128: 2-amino-N-(12-((tetrahydrofuran-3-yl)amino)dodecyl) nicotinamide (hereinafter referred to as K-PB-50)

[0714] <Chemical Formula 128>

[0715] Oil, Yield: 22%, 1H NMR (400 MHz, CDCl3) δ8.17 (dd,J= 4.8, 1.4 Hz, 1H), 7.60 (dd,J= 7.7, 1.7 Hz, 1H), 6.62 (dd,J= 7.6, 4.9 Hz, 1H), 6.33 (s, 2H), 6.07 (s, 1H), 3.96 (dd,J= 14.7, 8.1 Hz, 1H), 3.88 - 3.73 (m, 2H), 3.68 (dd,J= 9.2, 3.9 Hz, 1H), 3.52 - 3.46 (m, 1H), 3.43 (dd,J= 13.4, 6.6 Hz, 2H), 2.72 - 2.58 (m, 2H), 2.18 - 2.03 (m, 4H), 1.82 (ddd,J= 12.5, 7.7, 4.2 Hz, 1H), 1.68 - 1.50 (m, 4H), 1.43 - 1.26 (m, 16H). MS calcd for C 22 H 38 N4O2(M+H) + :390, found 391

[0716]

[0717] 129. 화합물129: 2-amino-N-(12-(2,5-dihydro-1H-pyrrol-1-yl)dodecyl) nicotinamide (이하 K-PB-51이라 별칭한다)

[0718] <화학식129>

[0719] Oil, Yield: 30%, 1H NMR (400 MHz, CDCl3) δ8.17 (dd,J= 4.8, 1.7 Hz, 1H), 7.69 - 7.55 (m, 1H), 6.62 (dd,J= 7.7, 4.9 Hz, 1H), 6.32 (s, 2H), 6.14 (dd,J= 13.8, 11.7 Hz, 1H), 5.82 (s, 2H), 3.73 (d,J= 30.7 Hz, 4H), 3.43 (dd,J= 13.0, 7.1 Hz, 2H), 2.87 - 2.69 (m, 2H), 1.62 (dt,J= 14.6, 7.2 Hz, 4H), 1.31 (d,J= 16.1 Hz, 16H). MS calcd for C 22 H 36 N4O(M+H) + :372, found 373

[0720]

[0721] 130. 화합물130: N-(12-(2-aminonicotinamido)dodecyl)-N-formylalanine (이하 K-PB-52라 별칭한다)

[0722] <화학식130>

[0723] Oil, Yield: 18%, 1 H NMR (400 MHz, CDCl3) δ8.21 (s, 1H), 8.16 (dd,J= 14.7, 11.5 Hz, 1H), 7.63 - 7.54 (m, 1H), 6.62 (dd,J= 7.6, 4.9 Hz, 1H), 6.29 (d,J= 30.3 Hz, 2H), 6.07 (s, 1H), 4.76 - 4.63 (m, 1H), 4.18 (t,J= 6.7 Hz, 2H), 3.43 (dd,J= 13.1, 7.0 Hz, 2H), 1.75 - 1.60 (m, 4H), 1.48 (t,J= 8.4 Hz, 3H), 1.30 (s, 16H). MS calcd for C 22 H 36 N4O4(M+H) + :420, found 421

[0724]

[0725] 131. Compound 131: 1-(2-aminopyridin-3-yl)-14-(8-oxa-3-azabicyclo[3.2.1] octan- 3-yl)tetradecan-1-one (hereinafter referred to as K-PB-53)

[0726] <Chemical Formula 131>

[0727] White soild, Yield: 35%, 1 H NMR (400 MHz, CDCl3) δ8.17 (dd,J= 4.8, 1.7 Hz, 1H), 7.59 (dd,J= 7.7, 1.7 Hz, 1H), 6.61 (dd,J= 7.7, 4.9 Hz, 1H), 6.32 (s, 2H), 6.04 (s, 1H), 4.28 (dd,J= 4.3, 2.1 Hz, 2H), 3.46 - 3.31 (m, 2H), 2.58 (dd,J= 10.0, 0.9 Hz, 2H), 2.26 (dd,J= 12.5, 4.6 Hz, 4H), 1.95 (dt,J= 7.8, 3.6 Hz, 2H), 1.84 (dd,J= 7.3, 4.3 Hz, 2H), 1.62 (dt,J= 14.7, 7.3 Hz, 2H), 1.50 - 1.27 (m, 18H). MS calcd for C 24 H 40 N4O2(M+H) + :416, found 417

[0728]

[0729] 132. Compound 132: 1-(2-aminopyridin-3-yl)-14-(isobutyl(methyl)amino) tetradecan-1-one (hereinafter referred to as K-PB-54)

[0730] <Chemical Formula 132>

[0731] Oil, Yield: 32%, 1H NMR (400 MHz, CDCl3) δ8.07 (d,J= 3.7 Hz, 1H), 7.53 (dt,J= 15.4, 7.7 Hz, 1H), 6.53 (dd,J= 7.6, 4.9 Hz, 1H), 6.23 (s, 2H), 6.06 (s, 1H), 3.33 (dd,J= 13.1, 7.0 Hz, 2H), 2.70 - 2.57 (m, 2H), 2.48 (s, 3H), 2.44 (d,J= 7.1 Hz, 2H), 1.88 (ddd,J= 20.3, 13.7, 6.9 Hz, 1H), 1.63 - 1.48 (m, 4H), 1.35 - 1.17 (m, 16H), 0.94 (d,J= 6.6 Hz, 6H). MS calcd for C 23 H 42 N4O (M+H) + :390, found 391

[0732]

[0733] 133. 화합물133: 1-(2-aminopyridin-3-yl)-14-(methyl(propyl)amino) tetradecan-1-one (이하 K-PB-55라 별칭한다)

[0734] <화학식133>

[0735] Oil, Yield: 26%, 1 H NMR (400 MHz, CDCl3) δ8.08 (d,J= 3.5 Hz, 1H), 7.53 (dd,J= 7.7, 1.7 Hz, 1H), 6.53 (dd,J= 7.7, 4.9 Hz, 1H), 6.23 (s, 2H), 6.02 (s, 1H), 3.33 (dd,J= 13.0, 7.1 Hz, 2H), 2.54 (dd,J= 16.0, 10.0 Hz, 4H), 2.39 (s, 3H), 1.63 - 1.47 (m, 6H), 1.34 - 1.19 (m, 16H), 0.88 (t,J= 7.4 Hz, 3H). MS calcd for C 22 H 40 N4O (M+H) +:376, found 377

[0736]

[0737] 134. Compound 134: 1-(2-aminopyridin-3-yl)-14-(2-(hydroxymethyl)pyrrolidin-1- yl)tetradecan-1-one (hereinafter referred to as K-PB-56)

[0738] <Chemical Formula 134>

[0739] Oil, Yield: 20%, 1 H NMR (400 MHz, CDCl3) δ8.17 (dd,J= 4.8, 1.5 Hz, 1H), 7.62 (dt,J= 9.1, 4.6 Hz, 1H), 6.62 (dd,J= 7.6, 4.9 Hz, 1H), 6.33 (s, 2H), 6.15 (s, 1H), 3.81 (dd,J= 12.1, 3.3 Hz, 1H), 3.71 (dd,J= 12.1, 5.1 Hz, 1H), 3.54 (s, 1H), 3.42 (dt,J= 12.6, 6.3 Hz, 2H), 3.12 - 2.96 (m, 2H), 2.68 - 2.55 (m, 2H), 2.08 - 1.96 (m, 2H), 1.96 - 1.85 (m, 2H), 1.79 (s, 1H), 1.62 (dt,J= 14.6, 7.4 Hz, 4H), 1.29 (s, 16H). MS calcd for C 23 H 40 N4O2(M+H) + :404, found 405

[0740]

[0741] 147. Compound 147: 1-(2-aminopyridin-3-yl)-14-((2-(methylamino)ethyl) amino)tetradecan-1-one (hereinafter referred to as K-PB-57)

[0742] <Chemical Formula 147>

[0743] Oil, Yield: 27%, 1H NMR (400 MHz, CDCl3) δ8.17 (dd,J= 4.9, 1.8 Hz, 1H), 7.59 (dt,J= 18.1, 9.0 Hz, 1H), 6.61 (dd,J= 7.7, 4.9 Hz, 1H), 6.32 (s, 2H), 6.12 (s, 1H), 3.48 - 3.35 (m, 2H), 2.78 (t,J= 6.2 Hz, 2H), 2.51 - 2.38 (m, 2H), 2.34 (dd,J= 21.7, 14.1 Hz, 2H), 2.29 - 2.18 (m, 3H), 1.61 (dd,J= 14.6, 7.4 Hz, 2H), 1.46 (dd,J= 16.9, 10.2 Hz, 2H), 1.32 (d,J= 27.7 Hz, 18H). MS calcd for C 21 H 39 N5O (M+H) + :377, found 378

[0744]

[0745] 148. 화합물148: N-(14-(2-aminopyridin-3-yl)-14-oxotetradecyl)-2,2,2 -trifluoroacetamide (이하 K-PB-58이라 별칭한다)

[0746] <화학식148>

[0747] Oil, Yield: 19%, 1 H NMR (400 MHz, CDCl3) δ8.17 (dd,J= 4.9, 1.7 Hz, 1H), 7.60 (dd,J= 7.7, 1.7 Hz, 1H), 6.62 (dd,J= 7.7, 4.9 Hz, 1H), 6.36 (s, 1H), 6.31 (s, 2H), 6.05 (s, 1H), 3.40 (ddd,J= 19.3, 13.3, 6.9 Hz, 4H), 1.61 (dd,J= 15.1, 7.1 Hz, 4H), 1.31 (d,J= 14.4 Hz, 16H). MS calcd for C 20 H 31 F3N4O2(M+H) +:416, found 417

[0748]

[0749] 149. Compound 149: 1-(2-aminopyridin-3-yl)-14-(3-hydroxypiperidin-1-yl) tetradecan-1-one (hereinafter referred to as K-PB-59)

[0750] <Chemical Formula 149>

[0751] Oil, Yield: 17%, 1 H NMR (400 MHz, CDCl3) δ8.17 (dd,J= 4.9, 1.8 Hz, 1H), 7.61 (dd,J= 7.7, 1.7 Hz, 1H), 6.62 (dd,J= 7.7, 4.9 Hz, 1H), 6.33 (s, 2H), 6.09 (s, 1H), 3.96 (s, 1H), 3.46 - 3.37 (m, 2H), 2.64 (s, 2H), 2.52 - 2.44 (m, 2H), 2.03 (dd,J= 12.5, 6.8 Hz, 2H), 1.93 (s, 2H), 1.73 - 1.54 (m, 6H), 1.33 (d,J= 29.0 Hz, 16H). MS calcd for C 23 H 40 N4O2(M+H) + :404, found 405

[0752]

[0753] 150. Compound 150: methyl 2-(1-(12-(2-aminonicotinamido)dodecyl) piperidin-4-yl)acetate (hereinafter referred to as K-PB-60)

[0754] <Chemical Formula 150>

[0755] Oil, Yield: 16%, 1H NMR (400 MHz, CDCl3) δ8.17 (d,J= 4.8 Hz, 1H), 7.63 (d,J= 7.6 Hz, 1H), 6.62 (dd,J= 7.6, 4.9 Hz, 1H), 6.32 (s, 2H), 6.16 (s, 1H), 3.70 (s, 3H), 3.43 (dd,J= 13.3, 6.8 Hz, 2H), 3.36 (s, 2H), 2.74 (s, 2H), 2.47 (s, 2H), 2.34 (d,J= 6.6 Hz, 2H), 2.01 (dd,J= 17.9, 11.8 Hz, 3H), 1.88 (s, 2H), 1.77 (s, 2H), 1.62 (dd,J= 14.1, 7.0 Hz, 2H), 1.31 (d,J= 17.5 Hz, 16H). MS calcd for C 26 H 44 N4O3(M+H) + :460, found 461

[0756]

[0757] 151. 화합물151: 3-(14-(2-aminopyridin-3-yl)-14-oxotetradecyl) oxazolidine-2,4-dione (이하 K-PB-61이라 별칭한다)

[0758] <화학식151>

[0759] Oil, Yield: 44%, 1 H NMR (400 MHz, CDCl3) δ8.17 (dd,J= 4.8, 1.6 Hz, 1H), 7.59 (dd,J= 7.6, 1.5 Hz, 1H), 6.61 (dd,J= 7.6, 4.9 Hz, 1H), 6.32 (s, 2H), 6.07 (s, 1H), 4.70 (s, 2H), 3.55 (dd,J= 19.2, 11.8 Hz, 2H), 3.42 (dd,J= 13.0, 7.0 Hz, 2H), 1.64 (ddd,J= 28.3, 14.1, 6.9 Hz, 4H), 1.30 (d,J= 16.4 Hz, 16H). MS calcd for C 21 H 32N4O4(M+H) + :404, found 405

[0760]

[0761] 152. Compound 152: 1-(2-aminopyridin-3-yl)-14-(ethyl(methyl)amino) tetradecan-1-one (hereinafter referred to as K-PB-62)

[0762] <Chemical Formula 152>

[0763] Oil, Yield: 13%, 1 H NMR (400 MHz, CDCl3) δ8.26 - 8.14 (m, 1H), 7.65 (dd,J= 7.7, 1.5 Hz, 1H), 6.62 (dd,J= 7.6, 4.9 Hz, 1H), 6.34 (s, 2H), 6.21 (s, 1H), 3.43 (dd,J= 13.2, 7.0 Hz, 2H), 3.09 (d,J= 7.3 Hz, 2H), 2.98 - 2.88 (m, 2H), 2.73 (s, 3H), 2.03 (dd,J= 15.1, 9.2 Hz, 2H), 1.84 (s, 2H), 1.44 (t,J= 7.3 Hz, 3H), 1.32 (d,J= 24.8 Hz, 16H). MS calcd for C 21 H 38 N4O (M+H) + :362, found 363

[0764]

[0765] 153. Compound 153: 1-(2-aminopyridin-3-yl)-14-(methyl(oxetan-3-yl)amino) tetradecan-1-one (hereinafter referred to as K-PB-63)

[0766] <Chemical Formula 153>

[0767] Oil, Yield: 42%, 1H NMR (400 MHz, CDCl3) δ8.14 (dd,J= 4.9, 1.7 Hz, 1H), 7.59 (dd,J= 7.7, 1.7 Hz, 1H), 6.59 (dd,J= 7.7, 4.9 Hz, 1H), 6.39 (d,J= 43.8 Hz, 2H), 6.18 (s, 1H), 4.62 (p,J= 6.4 Hz, 4H), 3.53 (p,J= 6.7 Hz, 1H), 3.44 - 3.36 (m, 2H), 2.21 - 2.14 (m, 2H), 2.11 (s, 3H), 1.66 - 1.55 (m, 2H), 1.42 (dd,J= 13.8, 7.2 Hz, 2H), 1.31 (d,J= 26.1 Hz, 16H). MS calcd for C 22 H 38 N4O2(M+H) + :390, found 391

[0768]

[0769] 154. 화합물154: 1-(2-aminopyridin-3-yl)-14-(2-(2-hydroxyethyl) piperidin-1-yl)tetradecan-1-one (이하 K-PB-64라 별칭한다)

[0770] <화학식154>

[0771] Oil, Yield: 36%, 1H NMR (400 MHz, CDCl3) δ8.06 (dd,J= 4.8, 1.5 Hz, 1H), 7.94 (s, 1H), 7.58 (dd,J= 7.6, 1.4 Hz, 1H), 6.53 (dd,J= 7.6, 4.9 Hz, 1H), 6.26 (s, 2H), 3.88 (s, 1H), 3.77 - 3.61 (m, 1H), 3.41 (s, 2H), 3.33 (dd,J= 13.0, 7.0 Hz, 2H), 2.89 (s, 4H), 2.81 (s, 4H), 1.93 (d,J= 17.7 Hz, 2H), 1.80 (d,J= 8.2 Hz, 4H), 1.58 - 1.50 (m, 2H), 1.35 - 1.14 (m, 16H), MS calcd for C 25 H 44 N4O2(M+H) + :432, found 433

[0772]

[0773] 155. 화합물155: 1-(2-aminopyridin-3-yl)-14-(2-methylmorpholino) tetradecan-1-one (이하 K-PB-65라 별칭한다)

[0774] <화학식155>

[0775] Oil, Yield: 56%, 1H NMR (400 MHz, CDCl3) δ8.15 (dd,J= 4.9, 1.7 Hz, 1H), 7.59 (dd,J= 7.7, 1.7 Hz, 1H), 6.59 (dd,J= 7.7, 4.9 Hz, 1H), 6.33 (s, 2H), 6.12 (s, 1H), 3.85 (ddd,J= 11.3, 3.3, 1.4 Hz, 1H), 3.73 - 3.59 (m, 2H), 3.45 - 3.35 (m, 2H), 2.74 (ddd,J= 20.6, 11.3, 1.7 Hz, 2H), 2.35 - 2.28 (m, 2H), 2.08 (td,J= 11.5, 3.4 Hz, 1H), 1.77 (dd,J= 11.0, 10.3 Hz, 1H), 1.60 (dt,J= 14.7, 7.4 Hz, 2H), 1.51 - 1.43 (m, 2H), 1.31 (d,J= 26.3 Hz, 16H), 1.15 (d,J= 6.3 Hz, 3H). MS calcd for C 23 H 40 N4O2(M+H) + :404, found 405

[0776]

[0777] 156. 화합물156: 1-(2-aminopyridin-3-yl)-14-((2-hydroxyethyl)(methyl) amino)tetradecan-1-one (이하 K-PB-66이라 별칭한다)

[0778] <화학식156>

[0779] Oil, Yield: 18%, 1H NMR (400 MHz, CDCl3) δ8.17 (d,J= 4.8 Hz, 1H), 7.61 (d,J= 7.7 Hz, 1H), 6.62 (dd,J= 7.6, 4.9 Hz, 1H), 6.33 (s, 2H), 6.11 (s, 1H), 3.83 - 3.71 (m, 2H), 3.43 (dd,J= 13.2, 6.8 Hz, 2H), 2.85 - 2.77 (m, 2H), 2.72 - 2.62 (m, 2H), 2.51 (s, 3H), 2.09 - 1.98 (m, 1H), 1.62 (dt,J= 14.6, 7.3 Hz, 4H), 1.31 (d,J= 11.2 Hz, 16H). MS calcd for C 21 H 38 N4O2(M+H) + :378, found 377

[0780]

[0781] 157. 화합물157: 2-amino-N-(12-(2,2,6,6-tetramethylpiperidin-1-yl) dodecyl) nicotinamide (이하 K-PB-67이라 별칭한다)

[0782] <화학식157>

[0783] Light yellow solid, Yield: 43% 1 H NMR (400 MHz, CDCl3) δ8.14 (d,J= 4.8 Hz, 1H), 7.72 - 7.49 (m, 1H), 6.59 (dd,J= 7.6, 4.9 Hz, 1H), 6.30 (s, 2H), 3.40 (dd,J= 13.4, 6.8 Hz, 2H), 2.99 - 2.67 (m, 2H), 1.79 - 1.61 (m, 18H), 1.43 - 1.20 (m, 20H)., MS calcd for C 27 H 48 N4O (M+H) + : 444, found 445

[0784]

[0785] 158. Compound 158: (2S,3aS,7aS)-1-(12-(2-aminonicotinamido)dodecyl) octahydro -1H-indole-2-carboxylic acid (hereinafter referred to as K-PB-68)

[0786] <Chemical Formula 158>

[0787] Colorless oil, Yield: 27% 1 H NMR (400 MHz, MeOD) δ8.03 (dd,J= 5.0, 1.8 Hz, 1H), 7.85 (dd,J= 7.7, 1.8 Hz, 1H), 6.65 (dd,J= 7.7, 5.0 Hz, 1H), 3.98 (dd,J= 9.5, 6.3 Hz, 1H), 3.57 (dd,J= 12.5, 6.0 Hz, 1H), 3.30 - 3.23 (m, 2H), 3.17 - 3.05 (m, 1H), 2.56 - 2.38 (m, 2H), 2.15 - 2.05 (m, 1H), 1.97 - 1.81 (m, 1H), 1.78 - 1.68 (m, 1H), 1.68 - 1.50 (m, 8H), 1.43 - 1.28 (m, 18H)., MS calcd for C 27 H 44 N4O3(M+H) + : 472, found 473

[0788]

[0789] 159. Compound 159: 3-(12-(2-aminonicotinamido)dodecyl)thiazolidine-2-carboxylic acid (hereinafter referred to as K-PB-69)

[0790] <Chemical Formula 159>

[0791] White solid, Yield: 20% 1H NMR (400 MHz, CDCl3) δ8.17 (dd,J= 4.8, 1.5 Hz, 1H), 7.59 (dd,J= 7.7, 1.4 Hz, 1H), 6.62 (dd,J= 7.6, 4.9 Hz, 1H), 6.32 (s, 2H), 6.03 (s, 1H), 4.94 (s, 1H), 4.27 - 4.11 (m, 2H), 3.74 - 3.62 (m, 1H), 3.43 (dd,J= 13.2, 6.9 Hz, 2H), 3.15 - 2.98 (m, 2H), 2.94 - 2.78 (m, 1H), 1.70 - 1.58 (m, 4H), 1.44 - 1.15 (m, 16H)., MS calcd for C 22 H 36 N4O3S (M+H) + : 436, found 437

[0792]

[0793] 160. 화합물160: 1-(12-(2-aminonicotinamido)dodecyl)piperidine-3- carboxylic acid (이하 K-PB-70 이라 별칭한다)

[0794] <화학식160>

[0795] Colorless oil, Yield: 16% 1H NMR (400 MHz, CDCl3) δ8.14 (dd,J= 4.9, 1.8 Hz, 1H), 7.60 (dd,J= 7.7, 1.7 Hz, 1H), 6.59 (dd,J= 7.7, 4.9 Hz, 1H), 6.32 (s, 2H), 6.17 (s, 1H), 3.40 (dd,J= 13.0, 7.1 Hz, 2H), 3.26 - 3.16 (m, 1H), 3.13 - 3.00 (m, 1H), 2.74 - 2.69 (m, 1H), 2.55 (t,J= 7.6 Hz, 2H), 2.43 - 2.33 (m, 1H), 2.32 - 2.15 (m, 1H), 2.12 - 1.96 (m, 1H), 1.96 - 1.81 (m, 1H), 1.75 - 1.66 (m, 2H), 1.65 - 1.54 (m, 4H), 1.41 - 1.20 (m, 16H)., MS calcd for C 24 H 40 N4O3(M+H) + : 432, found 433

[0796]

[0797] 161. 화합물161: 2-amino-N-(12-((3-methyloxetan-3-yl)amino)dodecyl) nicotinamide (이하 K-PB-71 이라 별칭한다)

[0798] <화학식161>

[0799] White solid, Yield: 61% 1H NMR (400 MHz, MeOD) δ8.03 (dd,J= 5.0, 1.8 Hz, 1H), 7.84 (dd,J= 7.7, 1.8 Hz, 1H), 6.65 (dd,J= 7.7, 5.0 Hz, 1H), 4.62 (d,J= 6.4 Hz, 2H), 4.40 (d,J= 6.8 Hz, 2H), 3.35 - 3.31 (m, 2H), 2.73 - 2.59 (m, 2H), 1.64 - 1.53 (m, 4H), 1.51 (s, 3H), 1.40 - 1.29 (m, 16H)., MS calcd for C 22 H 38 N4O2(M+H) + : 390, found 391

[0800]

[0801] 162. 화합물162: 2-Amino-N-(12-(2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidin -5-yl)dodecyl)nicotinamide (이하 K-PB-72라 별칭한다)

[0802] <화학식162>

[0803] Yellow oil, Yield: 13%, 1 H NMR (400 MHz, CDCl3) δ 8.17 (dd,J= 5.0, 1.7 Hz, 1H), 7.62 (dd,J= 7.6, 1.6 Hz, 1H), 7.11 (s, 1H), 6.68 (s, 2H), 6.60 (dd,J= 7.6, 5.0 Hz, 1H), 6.37 (d,J= 2.9 Hz, 1H), 6.12 (s, 1H), 4.37 (t,J= 7.2 Hz, 2H), 3.45 - 3.40 (m, 2H), 1.59 (dt,J= 13.9, 7.0 Hz, 4H), 1.27 (m, 16H)., MS calcd for C 24 H 32 Cl-2N6O2(M+H) + : 491, found 492

[0804]

[0805] 163. Compound 163: 2-Amino-N-(12-(4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl) dodecyl) nicotinamide (hereinafter referred to as K-PB-73)

[0806] <Chemical Formula 163>

[0807] Yellow oil, Yield: 30%, 1 H NMR (400 MHz, CDCl3) δ 9.31 (s, 2H), 8.23 ​​(d,J= 5.3 Hz, 1H), 7.96 (dd,J= 7.5, 1.6 Hz, 1H), 7.78 (dd,J= 6.2, 1.6 Hz, 1H), 7.27 (s, 1H), 7.11 (d,J= 5.3 Hz, 1H), 6.73 (dd,J= 7.5, 6.2 Hz, 1H), 6.58 (d,J= 3.5 Hz, 1H), 6.53 (t,J= 5.3 Hz, 1H), 4.31 - 4.25 (m, 2H), 3.41 (dd,J=13.1, 7.1 Hz, 2H), 1.91 - 1.80 (m, 2H), 1.64 - 1.56 (m, 2H), 1.33 - 1.22 (m, 16H)., MS calcd for C 25 H 34 NClN5O3(M+H) + : 456, found 457

[0808]

[0809] 164. Compound 164: 2- Amino-N- [2-(2-hydroxyethylamino) dodecyl] nicotinamide) (hereinafter referred to as K-PB-74)

[0810] <Chemical Formula 164>

[0811] White solid, Yield: 71%, 1H NMR (400 MHz, MeOD) δ8.31 (dd,J= 7.6, 1.5 Hz, 1H), 8.02 (dd,J= 6.2, 1.5 Hz, 1H), 6.95 (dd,J= 7.5, 6.3 Hz, 1H), 3.87 - 3.70 (m, 2H), 3.36 (t,J= 7.3 Hz, 2H), 3.14 - 3.09 (m, 2H), 3.05 - 2.98 (m, 2H), 1.68 (d,J= 7.7 Hz, 2H), 1.65 - 1.56 (m, 2H), 1.45 - 1.28 (m, 16H). MS calcd for C 20 H 36 N4O2(M+H) + : 364.28, found 365.25

[0812]

[0813] 165. Compound 165: 2-Amino-N-[12-(3-hydroxypyrrolidin-1-yl)dodecyl] nicotinamide (hereinafter referred to as K-PB-75)

[0814] <Chemical Formula 165>

[0815] White solid, Yield: 63%, 1H NMR (400 MHz, MeOD) δ8.32 (dd,J= 7.6, 1.6 Hz, 1H), 8.02 (dd,J= 6.2, 1.6 Hz, 1H), 6.96 (dd,J= 7.5, 6.3 Hz, 1H), 3.88 (dd,J= 12.2, 3.7 Hz, 1H), 3.75 - 3.61 (m, 2H), 3.57 (dd,J= 6.1, 3.6 Hz, 1H), 3.37 (dd,J= 12.7, 5.5 Hz, 3H), 3.15 (dt,J= 11.3, 8.1 Hz, 1H), 3.10 - 2.99 (m, 1H), 2.28 - 2.15 (m, 1H), 2.11 (ddd,J= 10.7, 7.7, 3.7 Hz, 1H), 2.06 - 1.95 (m, 1H), 1.94 - 1.84 (m, 1H), 1.73 (dd,J= 15.2, 7.4 Hz, 2H), 1.61 (dd,J= 14.1, 6.9 Hz, 2H), 1.45 - 1.28 (m, 16H). MS calcd for C 23 H 40 N4O2(M+H) + : 404.31, found 405.30

[0816]

[0817] 166. 화합물166: 2-Amino-N-[12-(4-methoxypyrrolidin-1-yl)dodecyl] nicotinamide (이하 K-PB-76이라 별칭한다)

[0818] <화학식166>

[0819] White solid, Yield: 74%, 1H NMR (400 MHz, MeOD) δ8.33 (dd,J= 7.6, 1.6 Hz, 1H), 8.02 (dd,J= 6.2, 1.6 Hz, 1H), 6.96 (dd,J= 7.5, 6.3 Hz, 1H), 3.74 - 3.60 (m, 3H), 3.56 (dd,J= 11.7, 7.7 Hz, 1H), 3.43 (s, 3H), 3.40 - 3.33 (m, 3H), 3.16 (dt,J= 11.3, 8.1 Hz, 1H), 3.10 - 2.98 (m, 1H), 2.29 - 2.18 (m, 1H), 2.18 - 2.06 (m, 1H), 1.99 (tt,J= 15.2, 7.8 Hz, 1H), 1.87 (dt,J= 14.4, 7.2 Hz, 1H), 1.73 (d,J= 6.9 Hz, 2H), 1.67 - 1.56 (m, 2H), 1.35 (d,J= 16.0 Hz, 16H). MS calcd for C 24 H 42 N4O2(M+H) + : 418.33, found 419.35

[0820]

[0821] 167. 화합물167: 2-Amino-N-[12-(4-hydroxypiperidin-1-yl)dodecyl] nicotinamide (이하 K-PB-77이라 별칭한다)

[0822] <화학식167>

[0823] White solid, Yield: 35%, 1H NMR (400 MHz, MeOD) δ8.33 (dd,J= 7.6, 1.5 Hz, 2H), 8.02 (dd,J= 6.2, 1.5 Hz, 2H), 6.96 (dd,J= 7.5, 6.3 Hz, 2H), 3.37 (dd,J= 17.2, 9.9 Hz, 4H), 3.21 (td,J= 11.6, 6.3 Hz, 2H), 3.13 - 3.05 (m, 2H), 1.82 (dd,J= 9.6, 4.0 Hz, 4H), 1.74 (d,J= 8.0 Hz, 2H), 1.67 - 1.57 (m, 2H), 1.35 (d,J= 20.6 Hz, 16H), 1.29 (s, 3H). MS calcd for C 24 H 42 N4O2(M+H) + : 418.33, found 419.35

[0824]

[0825] 168. 화합물168: 2-Amino-N-[12-{4-(cyclohexanecarbonyl)piperazin-1-yl} dodecyl] nicotinamide (이하 K-PB-78이라 별칭한다)

[0826] <화학식168>

[0827] White solid, Yield: 69%, 1 H NMR (400 MHz, MeOD) δ8.36 (dd,J= 7.6, 1.6 Hz, 1H), 8.02 (dd,J= 6.3, 1.6 Hz, 1H), 6.98 (dd,J= 7.5, 6.4 Hz, 1H), 4.22 (s, 1H), 3.72 - 3.44 (m, 3H), 3.40 - 3.33 (m, 3H), 3.19 - 3.11 (m, 3H), 2.99 (d,J= 14.1 Hz, 1H), 2.71 - 2.60 (m, 1H), 1.77 (dd,J= 21.2, 12.7 Hz, 7H), 1.61 (dd,J= 14.2, 7.0 Hz, 2H), 1.53 - 1.14 (m, 22H).MS calcd for C 29 H49 N5O2(M+H) + : 499.38, found 500.40

[0828]

[0829] 169. Compound 169: 2-Amino-N-[12-{1-benzoyl-2,5-dihydro-1H-pyrrol-2-one-3-yl} dodecyl] nicotinamide (hereinafter referred to as K-PB-79)

[0830] <Chemical Formula 169>

[0831] White solid, Yield: 59%, 1 H NMR (400 MHz, MeOD) δ8.33 (dd,J= 7.5, 1.2 Hz, 1H), 8.02 (dd,J= 6.2, 1.5 Hz, 1H), 7.60 (d,J= 7.9 Hz, 2H), 7.36 (t,J= 8.0 Hz, 2H), 7.16 (t,J= 7.4 Hz, 1H), 6.97 (dd,J= 7.4, 6.4 Hz, 1H), 4.34 - 4.22 (m, 1H), 3.88 - 3.70 (m, 1H), 3.39 - 3.33 (m, 3H), 3.22 (ddd,J= 16.2, 14.8, 7.6 Hz, 2H), 2.70 - 2.58 (m, 1H), 2.29 - 2.03 (m, 3H), 1.79 - 1.68 (m, 2H), 1.60 (dd,J= 14.2, 7.0 Hz, 2H), 1.32 (d,J= 19.2 Hz, 16H). MS calcd for C 29 H 43 N5O2(M+H) + : 493.34, found 494.35

[0832]

[0833] 170. Compound 170: 2-Amino-N-[12-[(3S)-3-hydroxypyrrolidin-1-yl]dodecyl]nicotinamide) (hereinafter referred to as K-PB-80)

[0834] <Chemical Formula 170>

[0835] White solid, Yield: 64%, 1 H NMR (400 MHz, MeOD) δ8.32 (dd,J= 7.6, 1.5 Hz, 1H), 8.04 (dd,J= 6.2, 1.5 Hz, 1H), 6.97 (dd,J= 7.5, 6.3 Hz, 1H), 4.57 (s, 1H), 3.76 (s, 2H), 3.50 (s, 1H), 3.41 - 3.35 (m, 2H), 3.19 (m, 3H), 2.14 (m,J= 67.7 Hz, 2H), 1.74 (s, 2H), 1.63 (dd,J= 14.1, 7.0 Hz, 2H), 1.37 (d,J= 16.5 Hz, 16H). MS calcd for C 22 H 38 N4O2(M+H) + : 390.29, found 391.30

[0836]

[0837] 171. Compound171: 2-Amino-N-[12-{4-(acetamido)piperidin-1-yl}dodecyl]nicotinamide)

[0838] <화학식171>

[0839] White solid, Yield: 46%, 1H NMR (400 MHz, MeOD) δ8.35 (dd,J= 7.6, 1.5 Hz, 1H), 8.02 (dd,J= 6.3, 1.6 Hz, 1H), 6.98 (dd,J= 7.5, 6.3 Hz, 1H), 4.02 (s, 1H), 3.58 (dd,J= 28.7, 10.0 Hz, 2H), 3.36 (t,J= 7.3 Hz, 3H), 3.20 - 3.03 (m, 2H), 2.85 (t,J= 12.5 Hz, 1H), 2.62 (t,J= 11.3 Hz, 1H), 2.18 - 1.99 (m, 2H), 1.96 (s, 3H), 1.88 - 1.46 (m, 5H), 1.44 - 1.24 (m, 16H). MS calcd for C 25 H 43 N5O2(M+H) + : 445.34, found 446.30

[0840]

[0841] 172. 화합물172: 2-Amino-N-[12-(4-(2-hydroxyethyl)piperidin-1-yl) dodecyl] nicotinamide (이하 K-PB-82라 별칭한다)

[0842] <화학식172>

[0843] White solid, Yield: 23%, 1H NMR (400 MHz, MeOD) δ8.34 (dd,J= 7.6, 1.5 Hz, 1H), 8.02 (dd,J= 6.3, 1.5 Hz, 1H), 6.97 (dd,J= 7.5, 6.4 Hz, 1H), 3.63 (t,J= 6.4 Hz, 2H), 3.56 (d,J= 12.4 Hz, 2H), 3.36 (t,J= 7.2 Hz, 2H), 3.11 - 3.00 (m, 2H), 3.00 - 2.85 (m, 2H), 2.00 (d,J= 14.3 Hz, 2H), 1.82 - 1.66 (m, 3H), 1.61 (dd,J= 14.0, 6.9 Hz, 2H), 1.52 (dd,J= 13.1, 6.5 Hz, 2H), 1.45 (d,J= 14.4 Hz, 2H), 1.42 - 1.27 (m, 16H). MS calcd for C 25 H 44 N4O2(M+H) + : 432.34, found 433.35

[0844]

[0845] 173. 화합물173: 2-Amino-N-[12-{4-[1-(benzimidazol-1-yl)acetyl]piperazin-1-yl}dodecyl]nicotinamide (이하 K-PB-83이라 별칭한다)

[0846] <화학식173>

[0847] White solid, Yield: 47%, 1H NMR (400 MHz, MeOD) δ8.29 (dd,J= 7.6, 1.5 Hz, 1H), 8.03 (dd,J= 6.2, 1.5 Hz, 1H), 7.22 - 7.06 (m, 4H), 6.95 (dd,J= 7.5, 6.2 Hz, 1H), 6.05 (s, 1H), 4.06 (s, 2H), 3.64 (s, 2H), 3.40 - 3.33 (m, 4H), 2.94 (s, 2H), 2.69 - 2.54 (m, 1H), 1.83 (s, 2H), 1.70 - 1.54 (m, 2H), 1.39 (d,J= 33.3 Hz, 16H).MS calcd for C 30 H 42 N6O2(M+H) + : 518.33, found 519.35

[0848]

[0849] 174. compound174: 2-Amino-N-[12-{4-[(3,5-dimethylbenzoyl)amino]piperidin- 1 - yl}dodecyl]nicotinamide (이하 K-PB-84라 별치파다)

[0850] <화학식174>

[0851] White solid, Yield: 46%, 1H NMR (400 MHz, MeOD) δ8.29 (dd,J= 7.6, 1.4 Hz, 1H), 8.02 (dd,J= 6.1, 1.4 Hz, 1H), 7.23 - 7.07 (m, 3H), 6.94 (dd,J= 7.5, 6.2 Hz, 1H), 4.06 (d,J= 10.9 Hz, 1H), 3.70 (d,J= 10.7 Hz, 1H), 3.39 - 3.33 (t, 2H), 3.15 (dd,J= 20.6, 11.8 Hz, 3H), 2.40 (d,J= 14.9 Hz, 1H), 2.22 (s, 6H), 2.01 (dd,J= 19.7, 14.4 Hz, 3H), 1.92 - 1.67 (m, 4H), 1.60 (dd,J= 14.1, 6.9 Hz, 2H), 1.47 - 1.23 (m, 16H). MS calcd for C 32 H 49 N5O2(M+H) + : 535.38, found 536.40

[0852]

[0853] 175. 화합물175: 2-Amino-N-[12-(4-(2-hydroxyethyl)piperidin-1-yl) dodecyl]nicotinamide (이하 K-PB-85라 별칭한다)

[0854] <화학식175>

[0855] White solid, Yield: 61%, 1H NMR (400 MHz, MeOD) δ8.32 (dd,J= 7.6, 1.5 Hz, 1H), 8.03 (dd,J= 6.2, 1.5 Hz, 1H), 6.96 (dd,J= 7.5, 6.3 Hz, 1H), 3.98 (dd,J= 12.5, 3.4 Hz, 1H), 3.58 (dd,J= 12.5, 1.9 Hz, 1H), 3.48 (d,J= 12.2 Hz, 1H), 3.39 - 3.33 (m, 2H), 3.24 - 3.11 (m, 2H), 3.11 - 2.99 (m, 1H), 1.97 - 1.53 (m, 11H), 1.48 - 1.20 (m, 16H). MS calcd for C 24 H 42 N4O2(M+H) + : 418.33, found 419.30

[0856]

[0857] 176. 화합물176: 2-Amino-N-[12-(3-hydroxypyrrolidin-1-yl)dodecyl] nicotinamide (이하 K-PB-86이라 별칭한다)

[0858] <화학식176>

[0859] White solid, Yield: 63%, 1 H NMR (400 MHz, MeOD) δ8.32 (dd,J= 7.6, 1.5 Hz, 1H), 8.04 (dd,J= 6.2, 1.5 Hz, 1H), 6.97 (dd,J= 7.5, 6.3 Hz, 1H), 4.57 (s, 1H), 3.76 (s, 2H), 3.50 (s, 1H), 3.41 - 3.35 (m, 2H), 3.19 (m, 3H), 2.14 (m,J= 67.7 Hz, 2H), 1.74 (s, 2H), 1.63 (dd,J= 14.1, 7.0 Hz, 2H), 1.37 (d,J= 16.5 Hz, 16H). MS calcd for C 22 H 38 N4O2(M+H) +: 390.29, found 391.30

[0860]

[0861] 177. Compound 177: 2-amino-N-(12-(6-nitro-3,4-dihydroisoquinolin-2(1H)-yl) dodecyl)nicotinamide (hereinafter referred to as K-PB-87)

[0862] <Chemical Formula 177>

[0863] Yellow solid, Yield: 49%, 1 H NMR (400 MHz, CDCl3) δ9.43 (s, 2H), 8.18 - 8.11 (m, 2H), 8.01 (dd, J = 7.6, 1.5 Hz, 1H), 7.86 (dd, J = 6.2, 1.6 Hz, 1H), 7.34 (d, J = 8.5) Hz, 1H), 6.74 (dd, J = 7.5, 6.2 Hz, 1H), 6.56 - 6.51 (m, 1H), 4.81 (s, 2H), 4.17 (s, 2H), 3.84 (s, 2H), 3.45 (dd, J = 13.2, 6.9 Hz, 4H), 3.30 - 3.06 (m, 4H), 1.91 - 1.80 (m, 2H), 1.68 - 1.56 (m, 2H), 1.46 - 1.25 (m, 12H)., MS calcd for C 27 H 39 N5O3(M+H) + : 481, found 482

[0864]

[0865] 178. Compound 178: 2-amino-N-(12-(7-nitro-3,4-dihydroisoquinolin-2(1H)-yl) dodecyl)nicotinamide (hereinafter referred to as K-PB-88)

[0866] <Chemical Formula 178>

[0867] Yellow solid, Yield: 50%, 1H NMR (400 MHz, CDCl3) δ8.18 (dd, J = 4.8, 1.8 Hz, 1H), 8.00 (dd, J = 8.4, 2.4 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.59 (dd, J = 7.7, 1.7 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.62 (dd, J = 7.7, 4.9 Hz, 1H), 6.31 (s, 2H), 6.01 (s, 1H), 3.71 (s, 2H), 3.48 - 3.37 (m, 2H), 3.01 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 5.9 Hz, 2H), 2.59 - 2.51 (m, 2H), 1.66 - 1.57 (m, 8H), 1.43 - 1.31 (m, J = 12.0 Hz, 12H)., MS calcd for C 27 H 39 N5O3(M+H) + : 481, found 482

[0868]

[0869] 179. 화합물179: 2-amino-N-(12-(4-iodo-1H-pyrazol-1-yl)dodecyl) nicotinamide (이하 K-PB-89라 별칭한다)

[0870] <화학식179>

[0871] Yellow solid, Yield: 20%, 1H NMR (400 MHz, CDCl3) δ9.31 (s, 2H), 7.93 (dd, J = 7.5, 1.6 Hz, 1H), 7.87 (dd, J = 6.1, 1.6 Hz, 1H), 7.52 (s, 1H), 7.44 (s, 1H), 6.75 (dd, J = 7.5, 6.2 Hz, 1H), 6.23 (s, 1H), 4.13 (t, J = 7.2 Hz, 2H), 3.45 (dd, J = 13.1, 7.1 Hz, 2H), 1.90 - 1.80 (m, 2H), 1.63 (dt, J = 14.9, 7.6 Hz, 2H), 1.44 - 1.18 (m, 16H). MS calcd for C 21 H 32 IN5O (M+H) + : 497, found 498

[0872]

[0873] 180. Compound 180: 2-amino-N-(12-(4-phenylpiperazin-1-yl)dodecyl)nicotinamide (이하 K-PB-90

[0874] <화학식180>

[0875] Yellow solid, Yield: 11%, 1H NMR (400 MHz, CDCl3) δ8.15 (dd, J = 4.8, 1.7 Hz, 1H), 7.57 (dd, J = 7.7, 1.7 Hz, 1H), 7.29 - 7.27 (m, J = 2.0 Hz, 1H), 7.25 - 7.23 (m, J = 2.3 Hz, 1H), 6.93 (d, J = 7.9 Hz, 2H), 6.86 (t, J = 7.0 Hz, 1H), 6.59 (dd, J = 7.7, 4.9 Hz, 1H), 6.29 (s, 2H), 6.00 (s, 1H), 3.41 (dd, J = 13.0, 7.1 Hz, 2H), 3.24 (s, 4H), 2.64 (s, 4H), 2.41 (s, 2H), 1.64 - 1.55 (m, 8H), 1.39 - 1.26 (m, 12H)., MS calcd for C 28 H 43 N5O (M+H) + : 465, found 466

[0876]

[0877] 181. 화합물181: (R)-2-amino-N-(12-(2-methylmorpholino)dodecyl) nicotinamide (이하 K-PB-91 이라 별칭한다)

[0878] <화학식181>

[0879] Yellow Oil, Yield: 28%, 1H NMR (400 MHz, CDCl3) δ8.18 (dd, J = 4.9, 1.8 Hz, 1H), 7.59 (dd, J = 7.7, 1.7 Hz, 1H), 6.62 (dd, J = 7.6, 4.9 Hz, 1H), 6.31 (s, 2H), 6.01 (s, 1H), 3.87 (ddd, J = 11.3, 3.2, 1.4 Hz, 1H), 3.72 (dd, J = 11.4, 2.4 Hz, 1H), 3.69 - 3.63 (m, 1H), 3.43 (td, J = 7.2, 5.9 Hz, 2H), 2.76 (dd, J = 21.1, 11.4 Hz, 2H), 2.37 - 2.29 (m, 2H), 2.14 - 2.05 (m, 1H), 1.83 - 1.74 (m, 1H), 1.67 - 1.58 (m, 8H), 1.53 - 1.47 (m, 2H), 1.44 - 1.30 (m, 10H), 1.17 (d, J = 6.3 Hz, 3H)., MS calcd for C 23 H 40 N4O2(M+H) + : 404, found 405

[0880]

[0881] 182. 화합물182: 2-amino-N-(12-((naphthalen-2-ylmethyl)amino)dodecyl) nicotinamide (이하 K-PB-92 이라 별칭한다)

[0882] <화학식182>

[0883] White solid, Yield: 35%, 1H NMR (400 MHz, CDCl3) δ9.50 (s, 2H), 9.19 (s, 1H), 8.05 (d, J = 6.3 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.82 - 7.76 (m, 2H), 7.70 (d, J = 4.8 Hz, 1H), 7.56 (dd, J = 11.1, 4.1 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.46 (d, J = 6.2 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.06 - 6.97 (m, 1H), 6.67 - 6.60 (m, 1H), 4.26 (s, 2H), 3.38 (dd, J = 13.1, 6.8 Hz, 2H), 2.85 (s, 2H), 1.58 (td, J = 14.0, 6.8 Hz, 4H), 1.37 - 1.16 (m, 15H), 0.91 - 0.80 (m, 2H)., MS calcd for C 29 H 40 N4O (M+H) + : 460, found 461

[0884]

[0885] 183. 화합물183: 2-amino-N-(12-((2-methyl-1,2,3,4-tetrahydroisoquinolin- 6-yl) amino) dodecyl)nicotinamide (이하 K-PB-93이라 별칭한다)

[0886] <화학식183>

[0887] Yellow solid, Yield: 57%, 1H NMR (400 MHz, MeOD) δ8.35 (dd, J = 7.6, 1.6 Hz, 1H), 8.04 (dd, J = 6.3, 1.6 Hz, 1H), 7.03 - 6.96 (m, 2H), 6.79 (dd, J = 8.2, 2.3 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 4.47 (q, J = 14.8 Hz, 2H), 3.73 - 3.64 (m, 2H), 3.38 (dd, J = 12.1, 4.8 Hz, 4H), 3.16 (dd, J = 5.7, 4.0 Hz, 2H), 3.12 (s, 3H), 1.88 (dt, J = 12.5, 7.0 Hz, 2H), 1.66 - 1.61 (m, 2H), 1.41 - 1.30 (m, 16H)., MS calcd for C 28 H 43 N5O (M+H) + : 465, found 466

[0888]

[0889] 184. 화합물184: 2-amino-N-(12-((1-(naphthalen-1-yl)ethyl)amino)dodecyl) nicotinamide (이하 K-PB-94라 별칭한다)

[0890] <화학식184>

[0891] White solid, Yield: 47%, 1H NMR (400 MHz, CDCl3) δ10.00 (s, 1H), 9.27 (s, 2H), 8.09 (d, J = 6.6 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.98 - 7.91 (m, 2H), 7.82 (d, J = 5.6 Hz, 1H), 7.68 - 7.56 (m, 3H), 6.96 (t, J = 5.3 Hz, 1H), 6.78 - 6.70 (m, 1H), 5.25 (s, 1H), 3.42 (dd, J = 13.1, 6.8 Hz, 2H), 2.89 - 2.79 (m, 1H), 2.73 - 2.63 (m, J = 17.9, 9.3 Hz, 1H), 1.81 (d, J = 6.7 Hz, 3H), 1.72 - 1.55 (m, 4H), 1.39 - 1.13 (m, 15H), 0.93 - 0.81 (m, 2H)., MS calcd for C 30 H 42 N4O (M+H) + : 474, found 475

[0892]

[0893] 185. 화합물185: 2-amino-N-(12-(3,4-dihydroquinolin-1(2H)-yl)dodecyl) nicotinamide (이하 K-PB-95라 별칭한다)

[0894] <화학식185>

[0895] Green oil, Yield: 19%, 1H NMR (400 MHz, CDCl3) δ9.42 (s, 2H), 7.99 (dd, J = 7.6, 1.4 Hz, 1H), 7.84 (dd, J = 6.2, 1.5 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 7.4 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.82 (t, J = 7.2 Hz, 1H), 6.74 (dd, J = 7.4, 6.2 Hz, 1H), 6.46 (s, 1H), 3.45 (dd, J = 13.1, 7.1 Hz, 2H), 3.41 - 3.35 (m, 2H), 3.32 - 3.23 (m, 2H), 2.84 (t, J = 6.5 Hz, 2H), 2.10 - 1.98 (m, 2H), 1.73 - 1.55 (m, 4H), 1.45 - 1.01 (m, 16H)., MS calcd for C 27 H 40 N4O (M+H) + : 436, found 437

[0896]

[0897] 186. 화합물186: 2-amino-N-(12-(benzo[d][1,3]dioxol-5-ylamino)dodecyl) nicotinamide (이하 K-PB-96이라 별칭한다)

[0898] <화학식186>

[0899] Yellow solid, Yield: 43%, 1H NMR (400 MHz, CDCl3) δ9.28 (s, 2H), 8.10 (dd, J = 7.6, 1.6 Hz, 1H), 7.81 (dd, J = 6.2, 1.6 Hz, 1H), 6.97 (t, J = 5.5 Hz, 1H), 6.87 (td, J = 4.5, 2.2 Hz, 2H), 6.80 - 6.72 (m, 2H), 6.03 (s, 2H), 3.43 (dd, J = 13.1, 7.0 Hz, 2H), 3.22 - 3.12 (m, 2H), 1.66 (ddd, J = 21.5, 18.6, 11.2 Hz, 4H), 1.41 - 1.20 (m, 15H), 0.94 - 0.79 (m, J = 12.7, 8.3, 5.5 Hz, 2H)., MS calcd for C 25 H 36 N4O3(M+H) + : 440, found 441

[0900]

[0901] 187. 화합물187: 2-amino-N-(12-(quinolin-6-ylamino)dodecyl)nicotinamide (이하 K-PB-97이라 별칭한다)

[0902] <화학식187>

[0903] Yellow solid, Yield: 48%, 1H NMR (400 MHz, MeOD) δ9.67 (s, 1H), 8.55 (d, J = 6.9 Hz, 1H), 8.48 (dd, J = 7.0, 1.5 Hz, 1H), 8.27 (dd, J = 7.6, 1.6 Hz, 1H), 8.04 (dd, J = 6.0, 1.6 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.38 (dd, J = 7.8, 0.8 Hz, 1H), 6.94 (dd, J = 7.6, 6.1 Hz, 1H), 4.72 - 4.65 (m, 2H), 3.39 - 3.34 (m, 4H), 2.11 (dt, J = 14.4, 7.2 Hz, 2H), 1.62 (dt, J = 14.7, 7.4 Hz, 2H), 1.47 - 1.29 (m, 14H)., MS calcd for C 27 H 37 N5O (M+H) + : 447, found 448

[0904]

[0905] 189. 화합물189: ethyl 1-(14-(2-aminopyridin-3-yl)-14-oxotetradecyl) piperidine- 2-carboxylate (이하 K-PB-99라 별칭한다)

[0906] <화학식189>

[0907] Oil, Yield: 59%, 1H NMR (400 MHz, CDCl3) δ8.16 (dd,J= 4.9, 1.8 Hz, 1H), 7.59 (dd,J= 7.7, 1.7 Hz, 1H), 6.60 (dd,J= 7.7, 4.9 Hz, 1H), 6.32 (s, 2H), 6.09 (s, 1H), 4.28 - 4.14 (m, 2H), 3.49 - 3.35 (m, 2H), 3.17 - 2.96 (m, 2H), 2.51 (ddd,J= 12.4, 9.5, 6.6 Hz, 1H), 2.26 (ddd,J= 12.3, 9.5, 6.1 Hz, 1H), 2.18 - 2.07 (m, 1H), 1.88 - 1.69 (m, 3H), 1.69 - 1.55 (m, 4H), 1.49 (t,J= 10.3 Hz, 2H), 1.42 - 1.32 (m, 4H), 1.32 - 1.22 (m, 16H). MS calcd for C 26 C 44 N4O3(M+H) + : 460, found 461

[0908]

[0909] 190. 화합물190: 2-amino-N-(12-(isopropyl(methyl)amino)dodecyl) nicotinamide (이하 K-PB-100이라 별칭한다)

[0910] <화학식190>

[0911] Oil, Yield: 14%, 1H NMR (400 MHz, CDCl3) δ8.07 (dd,J= 4.8, 1.7 Hz, 1H), 7.55 (dd,J= 7.7, 1.7 Hz, 1H), 6.53 (dd,J= 7.7, 4.9 Hz, 1H), 6.24 (s, 2H), 6.10 (s, 1H), 3.38 - 3.28 (m, 2H), 2.78 (s, 2H), 2.53 (s, 3H), 1.96 (d,J= 6.9 Hz, 1H), 1.77 (s, 2H), 1.53 (dd,J= 14.4, 7.1 Hz, 5H), 1.28 (d,J=6.6 Hz, 6H), 1.20 (s, 16H). MS calcd for C 22 C 40 N4O (M+H) + : 376, found 377

[0912]

[0913] 191. Compound 191: N1-cyclohexyl-N2-(12-(4-methylpiperazin-1-yl)dodecyl)phthalamide (nicknamed KP-01)

[0914] <Chemical Formula 191>

[0915] Yellow, 1 H NMR (400 MHz, CDCl3) δ 7.63 - 7.54 (m, 2H), 7.50 - 7.42 (m, 2H), 6.76 (s, NH), 6.55 (s, NH), 3.91 (d,J= 9.9 Hz, 1H), 3.38 (dd,J= 12.5, 5.9 Hz, 2H), 2.59 (bs, 8H), 2.46 - 2.37 (m, 2H), 2.35 (s, 3H), 1.97 (d,J= 10.8 Hz, 2H), 1.74 (d,J= 12.8 Hz, 2H), 1.65 - 1.48 (m, 5H), 1.45 - 1.20 (m, 21H) Ms calcd for C31H52N4O2: 512.78

[0916]

[0917] 192. Compound 192: 2-(1H-imidazol-2-yl)-N-(12-(4-methylpiperazin-1-yl)dodecyl)benzamide (nicknamed KP-06)

[0918] <Chemical Formula 192>

[0919] White, 1 H NMR (400 MHz, CD3OD) δ 7.77 (d, J= 7.8 Hz, 1H), 7.57-7.46 (m, 3H), 7.14 (s, 2H), 3.35-3.28 (m, 2H, overlapped with CD3OD peak), 2.56 (bs, 8H), 2.43-2.39 (m, 2H), 2.32 (s, 3H), 1.56-1.50 (m, 4H), 1.33-1.30 (m, 16H). Ms calcd for C27H43N5O: 453.67

[0920]

[0921] 193. Compound 193: N-(12-(4-methylpiperazin-1-yl)dodecyl)-2-(1H-pyrrol-1-yl)benzamide (nicknamed KP-07)

[0922] <Chemical Formula 193>

[0923] Brown, 1 H NMR (400 MHz, CD3OD) δ 7.53 (td,J= 7.7, 1.7 Hz, 1H), 7.49 (dd,J= 7.7, 1.6 Hz, 1H), 7.43-7.38 (m, 2H), 6.90 (t,J= 2.1 Hz, 2H), 6.23 (t,J= 2.1 Hz, 2H), 3.16 (t,J= 7.1 Hz, 2H), 2.81 (bs, 8H), 2.65-2.61 (m, 2H), 2.49 (s, 3H), 1.62-1.55 (m, 2H), 1.43-1.19 (m, 18H) Ms calcd for C28H44N4O: 452.69

[0924]

[0925] 194. Compound 194: N-(12-(4-methylpiperazin-1-yl)dodecyl)-[1,1'-biphenyl]-2-carboxamide (nicknamed KP-08)

[0926] <Chemical Formula 194>

[0927] White, 1 H NMR (400 MHz, CD3OD) δ 7.52-7.25 (m, 9H), 3.12 (t,J= 7.0 Hz, 2H), 2.87 (bs, 8H), 2.71-2.67 (m, 2H), 2.53 (s, 3H), 1.63-1.55 (m, 2H), 1.35-1.20 (m, 16H), 1.12-1.04 (m, 2H). Ms calcd for C30H45N3O: 463.71

[0928]

[0929] 195. Compound 195: N-(12-(4-methylpiperazin-1-yl)dodecyl)-[2,2'-bipyridine]-4-carboxamide (nicknamed KP-10)

[0930] <Chemical Formula 195>

[0931] White, 1 H NMR (400 MHz, CD3OD) δ 8.78 (dd,J= 5.1, 0.9 Hz, 1H), 8.70-8.68 (m, 2H), 8.38 (dt,J= 8.0, 0.9 Hz, 1H), 7.96 (td,J= 7.8, 1.7 Hz, 1H), 7.75 (dd,J= 5.1, 1.7 Hz, 1H), 7.46 (ddd,J= 7.5, 4.8, 1.1 Hz, 1H), 3.42 (t,J= 7.2 Hz, 2H), 2.60 (bs, 8H), 2.46-2.42 (m, 2H), 2.35 (s, 3H), 1.66 (p,J= 7.0 Hz, 2H), 1.56-1.49 (m, 2H), 1.44-1.29 (m, 16H) Ms calcd for C28H43N5O: 465.69

[0932]

[0933] 196. Compound 196: 2-Benzyl-N-(12-(4-methylpiperazin-1-yl)dodecyl)benzamide (aka KP-21)

[0934] Compound 196

[0935] White, 1 H NMR (400 MHz, CD3OD) δ 7.36-7.32 (m, 2H), 7.27-7.20 (m, 4H), 7.15-7.11 (m, 3H), 4.14 (s, 2H), 3.25 (t,J= 7.0 Hz, 2H), 2.50 (bs, 8H), 2.37-2.33 (m, 2H), 2.28 (s, 3H), 1.52-1.46 (m, 4H), 1.32-1.30 (m, 16H) Ms calcd for C31H47N3O: 477.74

[0936]

[0937] 197. Compound 197: 3-Amino-2-iodo-N-(12-(4-methylpiperazin-1-yl)dodecyl)benzamide (nicknamed KP-23)

[0938] <Chemical Formula 197>

[0939] White, 1 H NMR (400 MHz, CD3OD) δ 7.12 (dd,J= 8.0, 7.3 Hz, 1H), 6.81 (dd,J= 8.1, 1.5, 1H), 6.57 (dd, 7.3, 1.5 Hz, 1H), 3.33 (m, 2H, overlapped with CD3OD peak), 2.54 (bs, 8H), 2.41-2.37 (m, 2H), 2.31 (s, 3H), 1.62 (p,J= 7.2 Hz, 2H), 1.56-1.50 (m, 2H), 1.45-1.29 (m, 16H) Ms calcd for C24H41IN4O: 528.52

[0940]

[0941] 198. Compound 198: 2,3-dichloro-N-(12-(4-methylpiperazin-1-yl)dodecyl)isonicotinamide (aka KP-25)

[0942] <Chemical Formula 198>

[0943] White, 1 H NMR (400 MHz, CD3OD) δ 8.37 (dd,J= 4.8, 0.8 Hz, 1H), 7.38 (dd,J= 4.9, 0.8 Hz, 1H), 3.37 (t,J= 7.0 Hz, 2H), 2.68 (bs, 8H), 2.53-2.49 (m, 2H), 2.40 (s, 3H), 1.65-1.51 (m, 4H), 1.44-1.29 (m, 16H) Ms calcd for C23H38Cl2N4O: 457.48

[0944]

[0945] 199. Compound 199: 3-chloro-N-(12-(4-methylpiperazin-1-yl)dodecyl)isonicotinamide (aka KP-26)

[0946] <Chemical Formula 199>

[0947] White, 1 H NMR (400 MHz, CD3OD) δ 8.67 (s, 1H), 8.57 (d,J= 4.9 Hz, 1H), 7.46 (d,J= 4.9 Hz, 1H), 3.39 (t,J= 7.0 Hz, 2H), 2.54 (bs, 8H), 2.41-2.37 (m, 2H), 2.31 (s, 3H), 1.64 (p,J= 7.1 Hz, 2H), 1.57-1.50 (m, 2H), 1.46-1.31 (m, 16H) Ms calcd for C23H39ClN4O: 423.04

[0948]

[0949] 200. Compound 200: 2-methoxy-N-(12-(4-methylpiperazin-1-yl)dodecyl)nicotinamide (nicknamed KP-27)

[0950] <Chemical Formula 200>

[0951] White, 1 H NMR (400 MHz, CD3OD) δ 8.30 (dd,J= 4.9, 2.0 Hz, 1H), 8.27 (dd,J= 7.6, 2.0 Hz, 1H), 7.12 (dd, 7.5, 4.9 Hz, 1H), 4.09 (s, 3H), 3.42 (t,J= 7.1 Hz, 2H), 2.53 (bs, 8H), 2.40-2.36 (m, 2H), 2.31 (s, 3H), 1.64 (p,J= 7.1 Hz, 2H), 1.56-1.48 (m, 2H), 1.44-1.31 (m, 16H) Ms calcd for C24H42N4O2: 418.63

[0952]

[0953] 201. Compound 201: 3,5-dichloro-N-(12-(4-methylpiperazin-1-yl)dodecyl)isonicotinamide (aka KP-28)

[0954] <Chemical Formula 201>

[0955] White, 1 H NMR (400 MHz, CD3OD) δ 8.49 (s, 2H), 3.29 (t,J= 6.9 Hz, 2H), 2.41 (bs, 8H), 2.28-2.24 (m, 2H), 2.19 (s, 3H), 1.53 (p,J= 7.2 Hz, 2H), 1.45-1.36 (m, 2H), 1.36-1.19 (m, 16H) Ms calcd for C23H38Cl2N4O: 457.48

[0956]

[0957] 202. Compound 202: 5-methyl-N-(12-(4-methylpiperazin-1-yl)dodecyl)picolinamide (nicknamed KP-29)

[0958] <Chemical Formula 202>

[0959] White, 1H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 7.99 (d,J= 8.0 Hz, 1H), 7.77 (d,J= 8.1 Hz, 1H), 3.42 (t,J= 7.2 Hz, 2H), 2.52 (bs, 8H), 2.43 (s, 3H), 2.43-2.35 (m, 2H), 2.30 (s, 3H), 1.64 (p,J= 7.2 Hz, 2H), 1.56-1.48 (m, 2H), 1.42-1.32 (m, 16H) Ms calcd for C24H42N4O: 402.63

[0960]

[0961] 203. Compound 203: 5-Fluoro-N-(12-(4-methylpiperazin-1-yl)dodecyl)picolinamide (aka KP-30)

[0962] <Chemical Formula 203>

[0963] White, 1 H NMR (400 MHz, CD3OD) δ 8.54 (d,J= 2.8 Hz, 1H), 8.17 (dd,J=8.7, 4.5 Hz, 1H), 7.75 (td, 8.6, 2.9 Hz, 1H), 3.42 (t,J= 7.1 Hz, 2H), 2.53 (bs, 8H), 2.39-2.35 (m, 2H), 2.30 (s, 3H), 1.64 (p,J= 7.3 Hz, 2H), 1.56-1.50 (m, 2H), 1.42-1.32 (m, 16H) Ms calcd for C23H39FN4O: 406.59

[0964]

[0965] 204. Compound 204: 5-methoxy-N-(12-(4-methylpiperazin-1-yl)dodecyl)picolinamide (aka KP-31)

[0966] <Chemical Formula 204>

[0967] White, 1H NMR (400 MHz, CD3OD) δ 8.18 (d,J= 2.8 Hz, 1H), 7.94 (d,J= 8.7 Hz, 1H), 7.36 (dd,J= 8.7, 2.9 Hz, 1H), 3.83 (s, 3H), 3.29 (t,J= 7.0 Hz, 2H), 2.41 (bs, 8H), 2.27-2.23 (m, 2H), 2.18 (s, 3H), 1.52 (p,J= 7.2 Hz, 2H), 1.44-1.36 (m, 2H), 1.29-1.20 (m, 16H) Ms calcd for C24H42N4O2: 418.63

[0968]

[0969] 207. Compound 207: 3-(2-methyl-1H-imidazol-1-yl)-N-(12-(4-methylpiperazin-1-yl)dodecyl)benzamide (nicknamed KP-53)

[0970] <Chemical Formula 207>

[0971] White, 1 H NMR (400 MHz, CD3OD) δ 7.93 (d,J= 7.8 Hz, 1H), 7.83 (s, 1H), 7.65 (t,J= 7.9 Hz, 1H), 7.59 (dq,J= 7.9, 1.0 Hz, 1H), 7.23 (d,J= 1.2 Hz, 1H), 7.00 (d,J= 1.2 Hz, 1H), 3.39 (t,J= 7.2 Hz, 2H), 2.51 (bs, 8H), 2.38-2.34 (m, 5H), 2.29 (s, 3H), 1.63 (p,J= 7.2 Hz, 2H), 1.54-1.46 (m, 2H), 1.41-1.29 (m, 16H) Ms calcd for C28H45N5O: 467.70

[0972]

[0973] 208. Compound 208: N-(12-(4-methylpiperazin-1-yl)dodecyl)-4-(1H-1,2,4-triazol-5-yl)benzamide (nicknamed KP-54)

[0974] <Chemical Formula 208>

[0975] White, 1 H NMR (400 MHz, CD3OD) δ 7.72 (d,J= 8.6 Hz, 2H), 7.43 (d,J= 8.6 Hz, 2H), 7.05 (s, 1H), 3.37 (t,J= 7.1 Hz, 2H), 2.49 (bs, 8H), 2.35-2.32 (m, 2H), 2.27 (s, 3H), 1.62 (p,J= 7.1 Hz, 2H), 1.53-1.47 (m, 2H), 1.39-1.30 (m, 16H) Ms calcd for C26H42N6O: 454.66

[0976]

[0977] 209. Compound 209: 3-amino-N-(12-(4-methylpiperazin-1-yl)dodecyl)isonicotinamide (aka KP-61)

[0978] <Chemical Formula 209>

[0979] White, 1 H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.75 (d,J= 5.3 Hz, 1H), 7.33 (d,J= 5.3 Hz, 1H), 3.33 (t,J= 7.2 Hz, 2H, overlapped with CD3OD peak), 2.50 (bs, 8H), 2.37-2.33 (m, 2H), 2.28 (s, 3H), 1.61 (p,J= 7.2 Hz, 2H), 1.54-1.46 (m, 2H), 1.40-1.31 (m, 16H) Ms calcd for C23H41N5O: 403.62

[0980]

[0981] 210. Compound 210: 2-hydroxy-N-(12-(4-methylpiperazin-1-yl)dodecyl)nicotinamide (aka KP-62)

[0982] <Chemical Formula 210>

[0983] White, 1H NMR (400 MHz, CD3OD) δ 8.45 (dd,J= 7.2, 2.2 Hz, 1H), 7.66 (dd,J= 6.3, 2.2 Hz, 1H), 6.56 (dd,J= 7.2, 6.2 Hz, 1H), 3.40 (t,J= 7.0 Hz, 2H), 2.50 (bs, 8H), 2.37-2.33 (m, 2H), 2.28 (s, 3H), 1.61 (p,J= 7.2 Hz, 2H), 1.54-1.47 (m, 2H), 1.42-1.31 (m, 16H). Ms calcd for C23H40N4O2: 404.60

[0984]

[0985] 211. Compound 211: 4-amino-N-(12-(4-methylpiperazin-1-yl)dodecyl)nicotinamide (aka KP-63)

[0986] <Chemical Formula 211>

[0987] White, 1 H NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), 7.87 (d,J= 5.9 Hz, 1H), 6.55 (d,J= 6.0 Hz, 1H), 3.25-3.23 (m, 2H, overlapped with CD3OD peak), 2.40 (bs, 8H), 2.27-2.23 (m, 2H), 2.18 (s, 3H), 1.50 (p,J= 7.0 Hz, 2H), 1.44-1.37 (m, 2H), 1.29-1.19 (m, 16H) Ms calcd for C23H41N5O: 403.62

[0988]

[0989] 212. Compound 212: 4-amino-N-(12-(4-methylpiperazin-1-yl)dodecyl)nicotinamide (aka KP-64)

[0990] <Chemical Formula 212>

[0991] White, 1H NMR (400 MHz, CD3OD) δ 8.75 (d,J= 4.6 Hz, 1H), 7.95 (d,J= 7.9 Hz, 1H), 7.70 (dd,J= 7.8, 4.8 Hz, 1H), 3.35 (t, 7.1 Hz, 2H), 2.69 (bs, 8H), 2.55-2.51 (m, 2H), 2.41 (s, 3H), 1.62-1.53 ​​(m, 4H), 1.42-1.33 (m, 16H). Ms calcd for C24H39F3N4O: 456.60

[0992]

[0993] 213. Compound 213: 2-Amino-N-(12-(4-methylpiperazin-1-yl)dodecyl)-4-(trifluoromethyl)benzamide (nicknamed KP-65)

[0994] <Chemical Formula 213>

[0995] White, 1 H NMR (400 MHz, CD3OD) δ 7.53 (d,J= 8.2 Hz, 1H), 7.01 (s, 1H), 6.81 (d,J= 8.2 Hz, 1H), 3.33 (t,J= 7.1 Hz, 2H, overlapped with CD3OD peak), 2.49 (bs, 8H), 2.36-2.32 (m, 2H), 2.28 (s, 3H), 1.61 (p,J= 7.0 Hz, 2H), 1.54-1.46 (m, 2H), 1.40-1.31 (m, 16H) Ms calcd for C25H41F3N4O: 470.63

[0996]

[0997] 214. Compound 214: N-(12-(4-methylpiperazin-1-yl)dodecyl)-2-phenoxybenzamide (nicknamed KP-66)

[0998] <Chemical Formula 214>

[0999] White, 1H NMR (400 MHz, CD3OD) δ 7.81 (dd,J= 7.8, 1.8 Hz, 1H), 7.44 (ddd,J= 8.3, 7.3, 1.7 Hz, 1H), 7.40-7.35 (m, 2H), 7.23 (td,J= 7.7, 1.1 Hz, 1H), 7.15 (tt,J= 7.4, 1.1 Hz, 1H), 7.03-7.00 (m, 2H), 6.92 (dd,J= 8.4, 1.0 Hz, 1H), 3.33 (t,J= 7.0 Hz, 2H, overlapped with CD3OD peak), 2.50 (bs, 8H), 2.37-2.33 (m, 2H), 2.28 (s, 3H), 1.53-1.45 (m, 4H), 1.32-1.22 (m, 16H) Ms calcd for C30H45N3O2: 479.71

[1000]

[1001] 216. Compound 216: 4-(tert-butyl)-2-ethoxy-N-(12-(4-methylpiperazin-1-yl)dodecyl)benzamide (nicknamed KP-68)

[1002] <Chemical Formula 216>

[1003] White, 1 H NMR (400 MHz, CDCl3) δ 7.71 (dd,J= 7.6, 1.3 Hz, 1H), 7.47 (td,J= 7.5, 1.5 Hz, 1H), 7.44 - 7.33 (m, 7H), 5.17 (s, NH), 3.13 (dd,J= 12.9, 6.9 Hz, 2H), 2.75 (bs, 8H), 2.58 - 2.50 (m, 2H), 2.44 (s, 3H), 1.62 - 1.49 (m, 2H), 1.31 - 1.09 (m, 16H), 1.01 - 0.95 (m, 2H) Ms calcd for C30H53N3O2: 487.77

[1004]

[1005] 217. Compound 217: 4-Bromo-2-fluoro-N-(12-(4-methylpiperazin-1-yl)dodecyl)benzamide (nicknamed KP-69)

[1006] <Chemical Formula 217>

[1007] Pale yellow solid, 1 H NMR (400 MHz, CD3OD) δ 7.52 - 7.47 (m, 1H), 7.41 - 7.33 (m, 2H), 3.27 (t,J= 7.1 Hz, 2H), 2.40 (bs, 8H), 2.27 - 2.23 (m, 2H), 2.18 (s, 3H), 1.51 (p,J= 7.1 Hz, 2H), 1.43 - 1.36 (m, 2H), 1.30 - 1.17 (m, 16H) Ms calcd for C24H39BrFN3O: 484.50

[1008]

[1009] 218. Compound 218: 2,6-Dimethoxy-N-(12-(4-methylpiperazin-1-yl) dodecyl) benzamide (hereinafter referred to as PBK-2025-052)

[1010] <Chemical Formula 218>

[1011] white solid, ¹H NMR (400 MH z, CDCl3):δ= 8.06 (d,J= 8.7 Hz, 1H), 7.63 (s, 1H), 7.14 (s, 1H), 6.47 (dd,J= 2.4, 8.8 Hz, 1H), 6.35 (d,J= 2.3 Hz, 1H), 3.81 (s, 3H), 3.72 (s, 3H), 3.34-3.27 (m, 2H), 2.65-2.38 (m, 6H), 2.27 (t,J= 7.8 Hz, 3H), 2.21 (s, 4H), 1.50-1.43 (m, 2H), 1.15 ppm (s, 18H), Chemical Formula: C26H45N3O3, MW: 447.66

[1012]

[1013] 219. Compound219: 3-Chloro-2-methyl-N-(12-(4-methylpiperazin-1-yl)dodecyl)benzamide

[1014] <화학식 219>

[1015] white solid, ¹H NMR (400 MHz, CDCl3):δ= 7.40 (d,J= 11.0 Hz, 1H), 7.24-7.13 (m, 2H), 5.78 (s, 1H), 3.46-3.38 (m, 2H), 2.56 (s, 9H), 2.46-2.32 (m, 9H), 1.65-1.48 (m, 4H), 1.34-1.23 ppm (m, 18H). Chemical Formula: C25H42ClN3O, MW: 436.08

[1016]

[1017] 220. Compound 220: 2,3,4,5,6- Pentafluoro-N-(12-(piperazin-1-yl)dodecyl)benzamide hydrochloride

[1018] <화학식220>

[1019] white solid, ¹H NMR (400 MHz, DMSO):δ= 11.80 (s, 1H), 9.77 (s, 2H), 8.97 (s, 1H), 3.65 (s, 2H ), 3.53-3.45 (m, 4H), 3.30-3.20 (m, 5H), 3.08 (s, 3H), 1.69 (s, 2H), 1.52-1.46 (m, 2H), 1.29 ppm (s, 20H). Chemical Formula: C2 3H35ClF5N3O, MW: 500.00

[1020]

[1021] 221. Compound 221: N-(12-( 2H-benzo[d][1,2,3]triazol-2-yl)dodecyl)-2-aminoni cotinamide (hereinafter referred to as PBK-2025-136)

[1022] <Chemical Formula 221>

[1023] white solid, ¹H NMR (400 MHz, CDCl3): δ = 8.09 (dd, J = 1.5, 5.0 Hz, 1H), 7.86 (dd, J = 3.1, 6.5 Hz, 2H), 7.66 (dd, J = 1.6, 7.7 Hz, 1H), 7.38 (dd, J = 3.1, 6.6 Hz, 2H), 6.62 (dd, J = 5.0, 7.7 Hz, 3H), 6.26 (s, 1H), 4.72 (t, J = 7.2 Hz, 2H), 3.43-3.36 (m, 2H), 2.15-2.07 (m, 2H), 1.64-1.56 (m, 2H), 1.38-1.22 ppm (m, 21H). Chemical Formula: C24H34N6O, MW: 422.58

[1024]

[1025] 222. Compound 222: N-(12-(1H-benzo[d][1,2,3]triazol-1-yl)dodecyl)-2-aminonicotinamide (hereinafter referred to as PBK-2025-137)

[1026] <Chemical Formula 222>

[1027] white solid, ¹H NMR (400 MHz, CDCl3): δ = 8.10 (dd, J = 1.7, 4.9 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 1.6, 7.7 Hz, 1H), 7.56-7.47 (m, 2H), 7.37 (t, J = 7.4 Hz, 1H), 6.59 (q, J = 4.1 Hz, 1H), 6.50 (s, 2H), 6.44 (s, 1H), 4.64 (t, J = 7.1 Hz, 2H), 3.40 (dd, J = 7.0, 13.1 Hz, 2H), 2.00 (dq, J = 7.1, 7.1 Hz, 2H), 1.64-1.55 (m, 2H), 1.37-1.21 ppm (m, 18H).Chemical Formula: C24H34N6O, M.W.: 422.58

[1028]

[1029] 223. 화합물223: N-(12-(1H-tetrazol-1-yl)dodecyl)-2-a minonicotinamide (이하 PBK-2025-138 이라 별칭한다)

[1030] <화학식2 23>

[1031] white solid, ¹H NMR (400 MHz, CDCl3):δ= 8.50 (s, 1H), 8.01 (d,J= 4.1 Hz, 1H), 7.81 (d,J= 6.3 Hz, 1H), 7.06 (s, 2H), 6.67 (q,J= 4.5 Hz, 1H), 6.54 (s, 1H), 4.65 (t,J= 6.9 Hz, 2H), 3.41 (q,J= 6.7 Hz, 2H), 2.06- 1.98 (m, 2H), 1.65-1.56 (m, 2H), 1.36-1.23 ppm (m, 24H). Chemical Formula: C19H31N7O, M.W.: 373.51

[1032]

[1033] 224. Compound224:N-(12-(2H-tetrazol-2-yl)dodecyl)-2-aminonicotinamide

[1034] <화학식224>

[1035] white solid, ¹H NMR (400 MHz, CDCl3):δ= 8.50 (s, 1H), 8.01 (d,J= 4.1 Hz, 1H), 7.81 (d,J= 6.3 Hz, 1H), 7.06 (s, 2H), 6.67 (q,J= 4.5 Hz, 1H), 6.54 (s, 1H), 4.65 (t,J= 6.9 Hz, 2H), 3.41 (q,J= 6.7 Hz, 2H), 2.06- 1.98 (m, 2H), 1.65-1.56 (m, 2H), 1.36-1.23 ppm (m, 24H). Chemical Formula: C19H31N7O, MW: 373.51

[1036]

[1037] 225. Compound 225: 2,4,6-Trimethyl-N-(12-(4-methylpiperazin-1-yl)dodecyl)benzamide hydrochloride (hereinafter referred to as PBK-2025-141)

[1038] <화학식225>

[1039] white solid, ¹H NMR (400 MHz, MeO D):δ= 6.86 (s, 2H), 3.81 (d,J= 27.7 Hz, 2H), 3.57-3.55 (m, 2H), 3.48 (s, 1H), 3.01 (s, 3H), 2.26-2.24 (m, 9H), 1.83-1.75 (m, 2H), 1.64-1.56 (m, 2H), 1.40-1.31 ppm (m, 18H). Chemical Formula: C27H48ClN3O, MW: 466.15

[1040]

[1041] Experimental Example 1: PDK1 regulatory efficacy experiment

[1042] To evaluate the PDK1 inhibitory efficacy of a series of compounds according to the present invention, the relative enzyme activity (% activity) was analyzed at a single concentration (30 μM).

[1043] All experiments were performed using the 'PDK1 Kinase Enzyme System and ADP-Glo TM Kinase assay (Promega, Cat # V9681) was performed.

[1044] All materials used in the experiment were diluted with 1x reaction solution (6 mM Tris-HCl, 6 mM MgCl2, 6 mM NaCl, 1 mM DTT, pH 7.5).

[1045] PDK1 was diluted 0.12-fold using 1x reaction solution and added 5 μL per well.

[1046] For samples containing both ATP and substrate (PDKtide), ATP and substrate were diluted 0.0625-fold and 0.25-fold, respectively, with 1x reaction solution, so that 10 μL of the mixture was added per well.

[1047] For samples with ATP but no substrate, ATP was diluted 0.0625 times with 1x reaction solution and 10 μL of the mixture was added to each well.

[1048] 96-well white plate (LUMITRAC TM 600 μClear TM The mixture was added to a 96-well Microplate (Bottom High-Binding, Greiner Bio-One, Cat. # 655094) according to the experimental conditions as shown in Table 2 and reacted at room temperature for 60 minutes.

[1049] PDK1 + DMSO + substrate (PDKtide) PDK1 + DMSO PDK1 + compound + substrate (PDKtide) 30 ng PDK1 (μL) 10.00 10.00 10.00 100 μM ATP + 2 μg PDKtide (μL) 10.000 10.00 100 μM ATP (μL) 0.00 10.000 30 μM compound (μL) 0.000 00 5.00 5% DMSO (μL) 5.00 5.000 00 Total volume (μL) 25.00 25.00 25.00

[1050] - Check the relative enzyme activity level (% activity) -

[1051] 25 μL of ADP-Glo ​​in each well TM After adding the reagent, react at room temperature for 40 minutes to remove the remaining ATP, then add 50 μL of Kinase Detection Reagent and react at room temperature for 60 minutes. During this process, care was taken to avoid exposing the plate to light, and the luminescence of each well was measured using a luminometer (Plate-reading luminometer, SpectraMax M2e, Molecular Devices).

[1052] For the measurement values ​​of each well, the 'average of values ​​for wells containing both PDK1 and substrate and DMSO' was calculated as 100%, and the 'average of values ​​for wells containing only PDK1 and DMSO' was calculated as 0%. All values ​​were normalized and summarized in Table 3.

[1053] As a result, it was confirmed that the compound according to the present invention can regulate PDK1 by effectively inhibiting it at a single concentration.

[1054] Here, regulation means inhibition, but it can also be understood as antagonism.

[1055] That is, it can be understood that the compound drug of the present invention blocks other agents (e.g., RSK, etc.) from activating PDK1.

[1056] In another sense, it can be said that the drugs of the present invention have an antagonistic effect by binding to the RSK binding site at the allosteric site and inhibiting PDK1 activity.

[1057] PDK1 inhibition potency (% activity) at a single concentration (30 μM) Compound No. Drug name % activity Compound No. Drug name % activity2GO4818.82116K-PB-2515.843GO5114.29117K-PB-267.574GO772.41118K-PB-3132.765GO780.41121K-PB-4028.106GO792.211 22K-PB-4418.117GO800.31123K-PB-4519.758GO813.99124K-PB-4619.569GO833.11125K-PB-4714.8110GO850.73126K-PB-4813.5011GO 862.53127K-PB-4922.1212KMC-003P5.35128K-PB-507.6513GO872.10129K-PB-516.9614GO882.01130K-PB-5224.1915GO8910.41131K-P B-536.6316PBK-2024-00340.75132K-PB-5410.2117PBK-2024-00415.02133K-PB-5513.7918PBK-2024-00519.51134K-PB-5626.5619PBK- 2024-00618.01147K-PB-5711.3320PBK-2024-00713.13148K-PB-587.3521PBK-2024-00818.20149K-PB-594.0122PBK-2024-00935.4515 0K-PB-6011.1723PBK-2024-01012.77151K-PB-6121.9424PBK-2024- 01216.63152K-PB-6213.4925PBK-2024-01316.11153K-PB-6315.932 6PBK-2024-01411.35154K-PB-648.3827PBK-2024-01519.89155K-PB-654.3928PBK-2024-01619.51156K-PB-6619.1729PBK-2024-01811 .02157K-PB-6710.9430PBK-2024-0206.95158K-PB-6822.7131PBK-2 024-02110.34159K-PB-6915.1632PBK-2024-02439.00160K-PB-709.0333PBK-2024-02516.00161K-PB-7111.7734PBK-2024-02630.70162K-PB-7221.9635PBK-2024-02932.34163K-PB-7323.8036PBK-2024-03024.07164K-PB-745.9837PBK-2024-03220.37165K-PB-7519.6338PBK-2024-03314.03166K-PB-7618.2439PBK-2024-03442.00167K-PB-7710.1943GO921.04168K-PB-7813.2844PBK-2025-0013.14169K-PB-797.4045PBK-2025-0024.45170K-PB-807.9246PBK-2025-0042.99171K-PB-818.8447PBK-2025-0112.02172K-PB-8210.0648PBK-2025-0123.24173K-PB-8319.3449PBK-2025-0133.35174K-PB-8418.4550PBK-2025-0143.21175K-PB-8515.5151PBK-2025-0153.18176K-PB-8610.7752PBK-2025-0167.25177K-PB-8732.9453PBK-2025-0172.56178K-PB-8830.6154PBK-2025-01814.65179K-PB-8923.5755PBK-2025-02316.35180K-PB-9016.3956PBK-2025-0487.82181K-PB-9115.7357GO15-F10.72182K-PB-9224.5158CS06-005F19.33183K-PB-9323.9859PBK-069-F22.92184K-PB-9434.7560PBK-048-F28.52185K-PB-9527.2861GO15-F-824.15186K-PB-9630.6962GO5935.83187K-PB-9738.5063GO5010.60188K-PB-9864GO6241.77189K-PB-9913.2367PBK-058-F28.51190K-PB-10027.568GO4428.20191KP-0111.9069GO15-F-salt10.27192KP-0614.7570GO4530.58193KP-0712.7871GO45-salt21.14194KP-0815.4473GO6010.60195KP-1013.0876GO7334.52196KP-2119.5177PBK-CNB -161.70197KP-2321.9478GO3573.05198KP-2520.5579CNA51.64199KP-2628.4288PBK-2025-06918.28200KP-2721.6689PBK-2025-070 3.29201KP-2826.1490PBK-2025-08519.72202KP-2919.9091KP-163.45203KP-3020.7592K-PB-13.94204KP-3124.1893K-PB-23.88207 KP-5319.5394K-PB-33.90208KP-5418.9995K-PB-43.79209KP-6120.6896K-PB-53.95210KP-6225.7097K-PB-66.86211KP-6321.4498K -PB-715.89212KP-6431.8799K-PB-89.56213KP-6523.72101K-PB-1016.03214KP-6620.60102K-PB-114.06216KP-6818.95103K-PB-1 23.99217KP-6925.20104K-PB-132.93218PBK-2025-05211.90105K-PB-1426.93219PBK-2025-08323.98106K-PB-1529.67220PBK-2025 -11521.68107K-PB-1612.70221PBK-2025-13622.70108K-PB-1727.10222PBK-2025-13719.25109K-PB-1830.88223PBK-2025-13821.3 4110K-PB-1918.00224PBK-2025-13923.22111K-PB-203.95225PBK-2025-14125.43113K-PB-224.23114K-PB-234.96115K-PB-244.73.

[1058]

[1059] - Quantitative evaluation of inhibition of PDK1 kinase activity -

[1060] That is, referring to the table below, in the present invention, an in vitro kinase assay system was constructed to quantitatively evaluate inhibition of PDK1 kinase activity, and the activity of novel PDK1 inhibitor candidates was compared and analyzed using this system.

[1061] Specifically, after reacting with a certain concentration of ATP (100 μM), substrate (PDKtide, 0.5 μg / μL), and PDK1 enzyme (30 ng), the difference in ATP consumption between the group treated with each candidate compound and the DMSO control group was measured through luciferase-based luminescence signal (RLU).

[1062] Based on the correlation between the luminescence signal and the ATP-to-ADP conversion rate, the candidate substances of the present invention were found to induce a significant decrease in ATP consumption compared to DMSO, thereby effectively inhibiting substrate phosphorylation of PDK1.

[1063] This suggests that the compounds of the present invention have a mechanism of action that inhibits the enzymatic activity of PDK1 and exhibit superior inhibitory activity compared to existing compounds.

[1064] - Confirmed inhibition of phosphorylation -

[1065] In addition, to confirm whether the compound according to the present invention inhibits phosphorylation of PDK1 (phosphoinositide-dependent kinase 1) in cancer cells, flow cytometry was performed using a human B cell lymphoma cell line, SU-DHL-8 (ATCC CRL-2961).

[1066] SU-DHL-8 cells were cultured in RPMI-1640 medium (containing 10% FBS, 100 U / mL penicillin, and 100 μg / mL streptomycin) at a cell concentration of 1 × 10 6The cells were adjusted to cells / mL and dispensed into a 12-well plate. After stabilizing the cells, they were treated with the compound of the present invention and cultured for 24 hours.

[1067] After drug treatment, cells were harvested and subjected to Fc receptor blockade, followed by fixation and permeabilization using the Intracellular Staining Kit (Cat. No. BD554715) from BD Biosciences. Subsequently, intracellular pPDK1 was stained using a pPDK1-PE fluorescently labeled antibody (BD Biosciences).

[1068] Afterwards, the stained cells were analyzed using a flow cytometer, and as a result, the compound GO15F of the present invention had an inhibitory effect on the phosphorylation of PDK1 compared to the control group, but GO48, GO86, and GO88 showed stronger inhibition of PDK1.

[1069] These FACS results are presented in bar graph format in Figure 3.

[1070] Referring to the drawing, the vertical axis represents the phosphorylation level of PDK1 (phospho-PDK1 expression level), and the horizontal axis represents the treatment conditions for each concentration of each compound.

[1071] As a result of treating with compounds of the present invention at various concentrations, the phosphorylation level of PDK1 tended to decrease with concentration compared to the control group. In particular, GO48, GO86, and GO88 showed high inhibitory effects even at low concentrations, confirming excellent activity. This indicates that the compounds have excellent efficacy in regulating PDK1 phosphorylation.

[1072] These results show that the compound of the present invention is associated with an inhibitory effect on the activity of PDK1 kinase, and that the activity of the kinase is inhibited by inhibiting the phosphorylation of PDK1.

[1073] Since it can contribute to the treatment of various diseases by regulating the signal transduction pathway involving PDK1, it is believed that the compound of the present invention can serve as the basis for a new therapeutic strategy targeting PDK1.

[1074] Additionally, enzyme kinetics analysis was performed to quantitatively analyze the effect of the compound of the present invention on the enzyme activity of PDK1 (3-Phosphoinositide-dependent protein kinase-1) and to confirm the inhibition pattern.

[1075] Prior to analysis, the half-inhibitory concentration (IC) of the compounds of the present invention, GO15F, GO86, and GO88, for inhibition of PDK1 kinase activity 50 ) The values ​​were calculated and the results are shown in Figure 4.

[1076] As a result, the IC50 values ​​of GO15F, GO86, and GO88 of the compounds of the present invention were confirmed to be 380.3 nM, 11.33 nM, and 12.98 nM, respectively.

[1077] Through this, it was confirmed that the compound according to the present invention has excellent inhibitory ability against PDK1.

[1078] - Confirmation of allosteric site inhibition -

[1079] ADP-Glo ​​from Promega TM A kinase assay kit was used, and changes in enzyme activity according to the concentration of the reaction substrate (ATP and peptide substrate) and the concentration of the compound of the present invention were measured.

[1080] The compound of the present invention was treated at concentrations of GO15F (500, 1000, 2000 nM), GO86 (15, 30, 60 nM), and GO88 (6.25, 12.5, 25 nM), and the reaction rate according to the change in substrate concentration at each concentration was measured, and the results are shown in Figure 5.

[1081] Based on the measured reaction rate, a Lineweaver-Burk plot was created to analyze the changes in Km and Vmax.

[1082] The Lineweaver-Burk plot displays the reciprocal of the reaction rate (1 / V) on the vertical axis and the reciprocal of the substrate concentration (1 / [S]) on the horizontal axis, allowing analysis of the Km and Vmax of the enzymatic reaction in the form of a straight line.

[1083] As a result, Vmax decreased as the concentration of the active substance increased, but there was no significant change in Km.

[1084] Through this, it was easily confirmed that the compound of the present invention acted as a non-competitive inhibitor for PDK1.

[1085] These results indicate that the compound of the present invention inhibits PDK1 activity without competing with the substrate, thereby effectively contributing to the regulation of overactivity of the PDK1-related signal transduction pathway.

[1086]

[1087] Experimental Example 2: Verification of T cell proliferation inhibition effect

[1088] In order to verify the T cell proliferation inhibitory effect of the compound according to the present invention, the following experiment was performed based on flow cytometry analysis using carboxyfluorescein diacetate succinimidyl ester (CFSE), a fluorescent dye that covalently binds to intracellular molecules.

[1089] The spleen was removed from 7-week-old C57BL / 6 mice, mashed, and single cells were separated using a strainer (40 μM pore size, SPL). Then, red blood cells were removed using ACK (Ammonium-Chloride-Potassium) lysis buffer to isolate only white blood cells.

[1090] CD90.2 microbeads (130-121-278, Miltenyi Biotech.) were added here and reacted at 4°C for 20 minutes. Then, only the T cells in the spleen were finally separated using the MACS Magnetic Stand and LS column.

[1091] T cells isolated from spleen cells were resuspended in 1 mL of free media (RPMI-1640 + 200 U / mL penicillin + 200 μg / mL streptomycin), and 0.3 μL of CFSE (10 mM) was added and reacted at 37°C for 5 minutes.

[1092] Afterwards, 10 mL of free media was added to stop the reaction and centrifuged to obtain a cell pellet.

[1093] Add RPMI 1640 medium containing 10% FBS, 100 U / mL penicillin, and 100 μg / mL streptomycin to suspend the cells, and seed them at 2 x 10 per well in a 96-well plate. 5 The cells were divided into cells and treated with CD3 and CD28 antibodies (0.5 μg / mL each) to activate T cells.

[1094] Compounds diluted in DMSO were treated in three wells each at concentrations of 10 nM, 100 nM, 1 μM, 10 μM, 30 μM, and 50 μM, and incubated for 3 days in a 37°C, 5% CO2 incubator, and then read using a FACS canto instrument.

[1095] The proliferation inhibition rate (%) of the resulting T cells is shown in Table 4.

[1096] It can be seen that the compound belonging to the chemical formula 1 of the present invention has an excellent effect of inhibiting the proliferation of T cells, whereas the compound corresponding to the comparative group has no effect or a very low effect of inhibiting the proliferation of T cells.

[1097] The proliferation inhibition rate (%) was calculated using the following formula:

[1098] Proliferation inhibition rate (%) = 100-((fluorescence intensity of compound+CD3+CD28 treated sample) ÷ (fluorescence intensity of control substance (DMSO+CD3CD28) treated sample)) × 100

[1099] That is, referring to Table 4 below, when T cells isolated from mouse spleen were treated with the compound of the present invention, stimulated with anti-CD3 and anti-CD28 antibodies, and CFSE analysis was performed, it was confirmed that T cell proliferation was significantly inhibited in the group treated with the compound of the present invention dissolved in DMSO compared to the control group treated with only DMSO.

[1100] This suggests that the compounds of the present invention have an action principle and function of regulating the proliferation of immune cells by participating in a signal transduction pathway related to the activation or proliferation of T cells, and thus have an excellent effect of regulating immune responses or suppressing excessive immune activity.

[1101] Proliferation inhibition rate (%) Concentration drug Name50μM30μM10μM1μM100nM10nMPBK-069-F99.8278.36-8.320.000.000.00CS06-005-F95.7978.8920.031.921.78-4.38PBK-048-F100.00100.0063.556.858.77-1.92PBK-058-F100.0073.81-3.830.000.000.00GO15-F100.00100.00100.0016.20-5.28-9.32GO358.764.510.68-3.73-4.19-7.1 4GO15-F-salt99.2089.9465.367.14-4.66-4.04GO15-F-893.1685.4234 .85-5.75-6.37-10.25GO48100.00100.00100.000.000.00-1.47GO50100. 00100.00100.0011.164.85-9.84GO51100.00100.0088.330.000.004.99 GO5889.4818.9516.186.44-0.27-6.03GO59100.00100.00-18.490.000.0 00.00GO60100.00100.0084.767.405.75-6.44GO6297.0080.438.946.99 8.63-4.11GO7397.7823.66-4.950.000.000.00GO5889.4818.9516.180. 000.000.00PBK-CNB-132.203.802.0915.34-3.971.51CNA34.6927.8810 .997.121.23-2.19GO77100.00100.00100.00100.00100.002.70GO78100. 00100.00100.00100.00100.00-27.49GO79100.00100.00100.00100.001 00.00-18.46GO80100.00100.00100.00100.00100.005.14GO81100.00100 .00100.00100.0032.454.55GO83100.00100.00100.00100.00100.0038. 33GO85100.00100.00100.00100.00100.00100.00GO86100.00100.00100.00100.00100.00-25.47GO87100.00100.0081.15100.001.719.13GO88100.0098.9585.09100.00100.0017.83GO89100.00100.00100.00100.00100.00-0.40PBK-2024-003100.00100.00100.00100.00-2.934.13PBK-2024-004100.00100.00100.00100.00-14.000.00PBK-2024-005100.00100.00100.00100.0076.131.87PBK-2024-006100.00100.00100.00100.00100.00-14.40PBK-2024-007100.00100.00100.00100.00100.003.46PBK-2024-008100.00100.00100.00100.00100.00-13.87PBK-2024-009100.00100.00100.00100.00100.00-0.80PBK-2024-010100.00100.00100.00100.00100.00-12.80PBK-2024-012100.00100.00100.00100.00100.00-7.33PBK-2024-013100.00100.00100.00100.0089.43-2.67PBK-2024-014100.00100.00100.00100.00100.002.13PBK-2024-015100.00100.00100.00100.0083.332.27PBK-2024-016100.00100.00100.00100.00100.00-0.27PBK-2024-018100.00100.00100.00100.00100.004.15PBK-2024-020100.00100.00100.00100.00100.001.34PBK-2024-021100.00100.00100.00100.0077.158.01PBK-2024-024100.00100.00100.00100.00100.000.29PBK-2024-025100.00100.00100.00100.00100.00-36.05PBK-2024-026100.00100.00100.00100.00100.002.08PBK-2024-029100.00100.00100.00100.00100.008.33PBK-2024-030100.00100.00100.00100.00100.00-38.89PBK-2024-032100.00100.00100.00100.0033.33-4.14PBK-2024-033100.00100.00100.00100.00100.00-33.51PBK-2024-034100.00100.00100.00100.00100.00-58.92GO92100.00100.00100.00100.00100.00-10.80PBK-2025-001100.00100.00100.00100.00100.00-6.21PBK-2025-002100.00100.00100.00100.00100.000.16PBK-2025-004100.00100.00100.00100.00100.00-10.52PBK-2025-011100.00100.00100.00100.00100.00-28.82PBK-2025-012100.00100.00100.00100.00100.00-18.31PBK-2025-013100.00100.00100.00100.00100.00-22.61PBK-2025-014100.00100.00100.00100.00100.00-7.48PBK-2025-015100.00100.00100.00100.0016.100.77PBK-2025-016100.00100.00100.00100.0013.7711.34PBK-2025-017100.00100.00100.00100.00100.00-26.59PBK-2025-018100.00100.00100.00100.00100.00-43.03PBK-2025-023100.00100.00100.00100.00100.0089.67PBK-2025-048100.00100.00100.0081.112.91-2.51PBK-2025-069100.00100.00100.0056.264.29-3.22PBK-2025-070100.00100.00100.00100.00100.00-3.34PBK-2025-085100.00100.00100.0066.18-2.03-8.27KP-16100.00100.00100.00100.00100.00-14.62K-PB-01100.00100.00100.00100.00100.00-9.65K-PB-02100.00100.00100.00100.00100.00-12.87K-PB-03100.00100.00100.00100.00100.00-25.44K-PB-04100.00100.00100.00100.00100.0094.37K-PB-05100.00100.00100.00100.00100.00-0.58K-PB-06100.00100.00100.00100.0040.643.51K-PB-07100.00100.00100.00100.00-3.95-4.82K-PB-08100.00100.00100.00100.00100.00-12.13K-PB-09100.00100.00100.00100.007.602.92K-PB-10100.00100.00100.00100.00100.00-0.15K-PB-11100.00100.00100.00100.00100.00-4.53K-PB-12100.00100.00100.00100.00100.00-6.43K-PB-13100.00100.00100.00100.00100.00100.00K-PB-14100.00100.00100.0038.898.336.73K-PB-15100.00100.00100.000.44-1.900.44K-PB-16100.00100.00100.00100.00100.00-35.23K-PB-17100.00100.00100.00100.0028.510.88K-PB-18100.00100.00100.0020.918.480.15K-PB-19100.00100.00100.00100.00100.00-36.70K-PB-20100.00100.00100.00100.00100.000.00K-PB-22100.00100.00100.00100.00100.0011.11K-PB-23100.00100.00100.00100.0026.17-18.27K-PB-24100.00100.00100.00100.00100.00-11.40K-PB-25100.00100.00100.00100.0026.17-1.90K-PB-26100.00100.00100.00100.00100.00-15.79K-PB-31100.0088.6034.5012.574.824.24K-PB-40100.00100.0030.000.000.000.00K-PB-44100.00100.00100.0080.000.000.00K-PB-45100.00100.00100.0048.364.78-2.54K-PB-46100.00100.00100.0030.0020.000.00K-PB-47100.00100.00100.00100.00100.00-4.48K-PB-48100.00100.00100.00100.00100.000.00K-PB-49100.00100.00100.0015.0710.30-2.24K-PB-50100.00100.00100.00100.00100.00-7.16K-PB-51100.00100.00100.00100.0090.000.00K-PB-52100.00100.0085.4313.58-5.22-4.33K-PB-53100.00100.00100.00100.00100.00-6.12KP-01100.00100.0093.267.390.000.00KP-06100.00100.0099.810.96-0.84-3.25KP-07100.00100.00100.0011.964.875.02KP-08100.00100.00100.00-1.68-2.40-4.09KP-10100.00100.00100.00-7.832.811.77KP-21100.00100.00100.0012.304.055.21KP-23100.00100.0097.9916.3510.277.81KP-25100.00100.00100.0020.129.415.35KP-26100.00100.0040.000.000.000.00KP-27100.00100.0080.000.000.000.00KP-28100.00100.0078.448.546.667.24KP-29100.00100.00100.0018.9613.174.05KP-30100.00100.00100.006.801.1 6-4.49KP-31100.00100.0095.0112.30-0.14-2.60KP-4097.9989.329.844.343.62 11.14KP-53100.00100.00100.00-3.04-3.91-5.35KP-54100.00100.00100.0010.5 6-0.582.46KP-61100.00100.0084.5218.811.59-1.45KP-62100.00100.0042.842. 75-3.18-4.34KP-63100.00100.0090.019.70-0.87-2.17KP-64100.0071.7820.55 -4.34-3.91-2.89KP-65100.00100.00100.008.546.37-0.14KP-66100.00100.0010 0.0017.3712.162.32KP-68100.00100.00100.0013.022.322.03PBK-2025-052100. 00100.00100.0012.402.741.31PBK-2025-083100.00100.0066.473.482.18-5.37.

[1102]

[1103] Experimental Example 3: Evaluation of anticancer efficacy against cancer cell lines

[1104] To evaluate the anticancer efficacy of the compound according to the present invention against cancer cell lines, the following experiments were performed.

[1105] The human B lymphoma cell line SU-DHL-8 (Cat. # CRL-2961) purchased from ATCC was cultured in RPMI-1640 medium containing 10% FBS, 100 U / mL penicillin, and 100 μg / mL streptomycin.

[1106] Afterwards, each cell culture solution was recovered, centrifuged at 1,300 rpm for 5 minutes, and the supernatant was removed. The cells were resuspended in the same medium and dispensed at 90 μL per well into a 96-well plate (Costar 96 well cell culture plate, Corning) to achieve the final conditions as shown in Table 5.

[1107] After treating the plate with 10 μL of the compound according to the present invention or the control group (DMSO) at different concentrations (0.05, 0.1, 0.5, 1, 10, 30, 50 μM), the plate was cultured at 37°C for 48 hours in a 5% CO2 incubator.

[1108] Afterwards, 10 μL of CCK-8 was added to each well and cultured again at 37°C for 4 hours in a 5% CO2 incubator. The absorbance was measured at 450 nm, and the relative cell viability compared to cells not treated with the drug is shown in Table 6.

[1109] Human breast cancer cell line MCF-7, human lung cancer cell line A549, human colon cancer cell line HCT-116, human pancreatic cancer cell line AsPC-1, glioblastoma cell line A172, melanoma cell line Malme-3M, gastric cancer cell line SNU-719, and bladder cancer cell line T24 were obtained from the Korea Cell Line Bank and cultured in RPMI-1640 medium containing 10% FBS.

[1110] Similarly, human cervical cancer cell line HeLa and renal cancer cell line ACHN, respectively, received from the Korea Cell Line Bank, were cultured in DMEM medium containing 10% FBS, 100 U / mL penicillin, and 100 μg / mL streptomycin.

[1111] Human head and neck cancer cell line Fadu and osteosarcoma cell line Saos-2 were cultured in MEM medium containing 10% FBS, 100 U / mL penicillin, and 100 μg / mL streptomycin.

[1112] Afterwards, each stabilized cell was recovered through Trypsin-EDTA treatment, centrifuged at 1,200 rpm for 3 minutes, the supernatant was removed, resuspended in the same medium, and dispensed at 100 μL per well into a 96-well plate (Costar 96 well cell culture plate, Corning) to achieve the final conditions as shown in Table 5.

[1113] After culturing the cells at 37°C in a 5% CO2 incubator, stabilization of each cell was confirmed after 24 hours. Each plate was washed with 200 μL / well of PBS and 50 μL of culture solution was treated per well.

[1114] After treating the plate with 50 μL of the compound according to the present invention or the control group (DMSO) at different concentrations (0, 10, 30, 50 μM), the plate was cultured at 37°C for 48 hours in a 5% CO2 incubator.

[1115] Afterwards, 10 μL of CCK-8 was added to each well, and the wells were incubated again at 37°C for 2 hours in a 5% CO2 incubator. The absorbance was measured at 450 nm, and the relative cell viability compared to cells not treated with the drug was shown in Tables 7 to 19.

[1116] Cell line culture medium conditions Final cell number SU-DHL-8 (Human B lymphocyte) RPMI with 10% FBS, 100 U / mL penicillin, 100 μg / mL streptomycin 2 × 10 4 cells / wellMCF-7(Human Breast Cancer)2×10 4 cells / wellHCT-116(Human Colorectal Carcinoma)3.5×10 4 cells / wellMalme-3M(Human melanoma)5×10 3 cells / wellSNU-719(Human gastric cancer)5×103 cells / wellT24(Human bladder cancer)5×10 3 cells / wellAsPC-1(Human pancreatic cancer)5×10 3 cells / wellA172(Human glioblastoma)5×10 3 cells / wellKMS12PE(Human multiple myeloma)5×10 4 cells / wellKMS26(Human multiple myeloma)5×10 4 cells / wellKMS34(Human multiple myeloma)5×10 4 cells / wellHeLa(Human Cervical Carcinoma)DMEM with 10% FBS, 100U / mL penicillin,100μg / mL streptomycin1.5×10 4 cells / wellACHN(Human kidney cnacer)5×10 3 cells / wellSaos-2(Human Osteosarcoma)MEM with 10% FBS, 100U / mL penicillin,100μg / mL streptomycin5×10 3 cells / wellFadu(Human Head and Neck cancer)5×10 3 cells / well

[1117] That is, when the survival rate of untreated cells treated with the control group (DMSO) is 100%, it refers to the relative cell survival rate in the groups treated with each drug at different concentrations.

[1118] Based on the results, it was verified that the compound according to the present invention has cancer cell killing efficacy.

[1119] In order to evaluate the anticancer activity of the compound according to the present invention with a cell viability of less than 50% at 1 μM, concentration-dependent cell viability was measured for various human-derived cancer cell lines (SU-DHL-8 and 12 other types), and a significant decrease in cell viability was observed in the group treated with the compound according to the present invention compared to the DMSO control group.

[1120] This suggests that the compound of the present invention exhibits anticancer activity through a cytotoxic mechanism of action, such as inhibiting a signal transduction pathway related to the survival and proliferation of cancer cells or inducing apoptosis, and is judged to have a universal and excellent cytotoxic efficacy against various types of cancer.

[1121] Relative cell viability (%) Human B Lymphocyte cell line, SU-DHL-8. Concentration Drug name 50μM 30μM 10μM 1μM GO 48 24.67 25.29 26.01 31.02 GO 50 27.92 29.14 29.8 232.96 GO 51 23.47 24.66 25.67 29.13 GO 59 19.3 122.9 124.90 32.48 GO 600.910.98 5.03 11.92 GO 626.336.5 114.08 23.28 GO 637.389 6315.2017.92 Kmedi-87-F1.344.104.93 15.42 GO 15 salt11.9415.5118.7530.47GO774.454.685.497.58GO783.674.635.878.80GO793.944.666.397.83GO80 3.173.484.165.17GO814.495.076.4910.82GO833.143.364.195.32GO854.865.526.217.37GO863.294.82 6.097.63KMC-003P1.131.643.797.60GO880.321.163.319.28PBK-2024-0034.945.986.567.33PBK-2024 -0045.215.696.1110.58PBK-2024-0053.444.094.505.28PBK-2024-0065.085.987.518.51PBK-2024-007 3.684.895.347.74PBK-2024-008-0.223.707.689.64PBK-2024-0091.672.452.856.46PBK-2024-0101.9 79.1715.7116.11PBK-2024-0110.521.573.289.85PBK-2024-012-0.240.621.658.38PBK-2024-0130.950 .111.269.73PBK-2024-014-0.990.051.041.70PBK-2024-0150.562.034.976.24PBK-2024-016-1.550.33 2.825.46PBK-2024-017-1.01-0.180.230.94PBK-2024-0181.031.251.863.85PBK-2024-0197.809.4616.8418.14PBK-2024-0201.061.862.607.90PBK-2024-0210.231.004.365.57PBK-2024-0241.451.973.013.48PBK-2024-0252.663.354.3210.08PBK-2024-0261.372.453.113.63PBK-2024-029-0.640.420.641.18PBK-2024-0304.255.9813.9317.42PBK-2024-0322.323.174.456.38PBK-2024-0331.421.793.304.16PBK-2024-0344.276.248.4111.48PBK-2025-0011.412.544.916.14PBK-2025-002-1.310.531.271.91PBK-2025-004-0.922.082.444.80PBK-2025-0118.339.4010.0311.70PBK-2025-0128.639.2210.4211.96PBK-2025-0134.097.488.028.93PBK-2025-0144.316.188.189.20PBK-2025-0150.480.891.983.48PBK-2025-0169.1510.1411.5914.24PBK-2025-0172.072.784.025.59PBK-2025-0182.233.264.056.42PBK-2025-0230.971.104.929.36PBK-2025-0480.0011.2019.6032.40PBK-2025-0692.235.065.9812.58PBK-2025-070-0.860.480.821.33PBK-2025-0851.942.485.947.19GO15-F11.9415.6318.7519.00GO15-F-821.0142.0336.4148.82GO15-F-salt0.771.0515.1627.80GO44-5.64-2.9015.2716.05GO45-0.571.454.945.01GO45-salt0.752.044.055.57GO921.582.3411.9322.61KP-161.591.843.123.93K-PB-4031.1129.0428.9934.89K-PB-4435.7032.9331.9131.84K-PB-4548.8344.5942.1742.24K-PB-4631.7232.1030.7030.43K-PB-4742.7142.0442.5741 .97K-PB-4830.4432.3231.9833.03K-PB-5134.2735.0533.9934.26K-PB-5342.4642.7142.1344.80.

[1122] Relative cell viability (%) Human cervical carcinoma cell line, HeLa Concentration Drug name 50μM 30μM 10μM 1μM GO 5 10.73 1.07 3.26 16.44

[1123] Relative cell viability (%) Human Breast Cancer cell line, MCF-7 Concentration Drug name 50μM 30μM 10μM 1μM GO 511.954.029.1035.36

[1124] Relative cell viability (%) Human Colorectal Carcinoma cell line, HCT-116 Concentration Drug name 50μM 30μM 10μM 1μM GO 858.90 10.07 12.04 13.03 GO 86 25.26 24.78 24.91 21.36 GO 887.6 19.38 12.31 14.20 GO 899.08 10.00 11.46 12.07 PBK-2024-010 12.96 14.00 14 .6313.08PBK-2024-02111.9912.3113.2011.61PBK-2024-0267.0910.4412.46 13.78PBK-2025-01611.8412.7113.3133.57PBK-2025-0177.919.3012.3310.94

[1125] Relative cell viability (%) Human Kidney Cancer cell line, ACHN Concentration Drug name 50μM 30μM 10μM 1μM GO 7 8 28.30 29.23 30.02 29.50 GO 8 9 30.30 30.56 30.00 31.67 PBK-2024-004 33.05 35.10 33.60 35.03 PBK-2025-017 26.79 33.16 32.98 36.73

[1126] Relative cell viability (%) Human Pancreas Adenocarcinoma cell line, AsPC-1 Concentration Drug name 50μM 30μM 10μM 1μM GO 85 35.83 40.2 141.10 40.40 GO 88 30.49 36.76 45.39 43.06 GO 89 41.48 44.15 42.80 40.88 PBK-2024-004 33.19 35.65 38.13 43.44 PBK-2024-010 42.0042 .6844.5542.38PBK-2024-02136.6439.4341.0440.83PBK-2024-02635.8939.0240. 2739.48PBK-2025-01743.1443.4543.5944.59PBK-2025-07017.8017.8119.1830.32

[1127] Relative cell viability (%) Human Melanoma cancer cell, Malme-3M Concentration Drug name 50μM 30μM 10μM 1μM GO 855.976.036.196.00 GO 8638.8736.8037.4044.06 GO 8815.8616.2731.2343.71 PBK-2024-0269.8911.1826.7747.03 PBK-2025-01712.03 19.3931.3541.11

[1128]

[1129] Relative cell viability (%) Human gastric cancer cells, SNU-719 Concentration of drug Name50μM30μM10μM1μMGO8541.0746.6447.7546.06GO8845.5544.4147.8049.89PBK-2024-00325.5933.5936.9037.13PBK-2024-01035.5740.3935.8736.14PBK-2024-02631.6138.0836.0439.45PBK-2025-01634.9535.5235.9141.25PBK-2025-01724.9831.6135.5035.93

[1130]

[1131] Relative cell viability (%) Human Bladder cancer cell, T24 Concentration Drug name 50μM 30μM 10μM 1μM GO 78 29.32 29.73 30.42 28.34 GO 859.11 10.36 10.78 10.57 GO 86 29.34 30.42 31.17 28.15 GO 887.479.22 11.019.88 GO 898.759.579.297.92 PBK-202 4-0109.469.5310.0810.04PBK-2024-0216.927.587.067.59PBK-2024-0266.646 .907.797.49PBK-2025-0029.049.9510.989.91PBK-2025-0177.237.557.638.87

[1132]

[1133] Relative cell viability (%) Human Osteosarcoma, Saos-2 Concentration Drug name 50μM 30μM 10μM 1μM GO 782.60 19.77 33.69 28.36 GO 85-9.49 42.94 53.92 6.85 GO 86 36.73 16.00 24.98 36.73 GO 880.00 16.31 34.17 47.09

[1134] Relative cell viability (%) Human Head and Neck cancer, Fadu Concentration Drug name 50μM 30μM 10μM 1μM GO 780.99 4.936.634.18 GO 864.788.519.682.08 GO 887.08 57.64 73.257.05 GO 899.44 41.53 29.274.15 PBK-2024-003 2.798.66 11.26 31.30 PBK-2024-004 3.312.300.22 29.18 PBK-2025-001-0.70 2.94 5.891.22 PBK-2025-002 18. 1859.9874.1129.84PBK-2025-0115.027.3419.9110.04PBK-2025-01231.3726.7028.8732.04PBK-2025-0147.0523.4226 .5520.78PBK-2025-0157.6910.5617.3024.93PBK-2025-0179.5627.9239.9737.43PBK-2025-01818.6532.4133.0324.97

[1135] Relative cell viability (%) Human multiple myeloma, KMS12PE Concentration Drug name 50μM 30μM 10μM 1μM GO 15F--41.72-

[1136] Relative cell viability (%) Human multiple myeloma, KMS26 Concentration Drug name 50μM 30μM 10μM 1μM GO 15 F-43.15 44.43-GO86---31.19

[1137] Relative cell viability (%) Human multiple myeloma, KMS34 Concentration Drug name 50μM 30μM 10μM 1μM GO 86---26.19

[1138] Experimental Example 4: Apoptosis Experiment on Cancer Cell Lines

[1139] To confirm whether the compound of the present invention induces apoptosis in cancer cells, the following experiment was performed using the human B lymphoma cell line SU-DHL-8 (ATCC, Cat. # CRL-2961).

[1140] The above cell line was cultured at 37°C under 5% CO₂ conditions using cells within 10 to 15 passages in RPMI-1640 medium containing 10% fetal bovine serum (FBS), 100 U / mL penicillin, and 100 μg / mL streptomycin.

[1141] The cell culture was recovered and centrifuged at 1,300 rpm for 5 minutes. The supernatant was removed and resuspended in the same medium. 1.5 mL was dispensed per well of a 6-well plate, resulting in a final concentration of 1 × 10 6 Adjusted to be cell / well.

[1142] Afterwards, each well was treated with the compound of the present invention at a final concentration of 30 μM, and the control group was treated with 0.2% DMSO, and then cultured for 24 hours under conditions of 37°C and 5% CO₂.

[1143] After collecting the cultured cells, fluorescent staining was performed using FITC Annexin Apoptosis Detection Kit I (BD Biosciences) according to the manufacturer's instructions.

[1144] The stained cells were analyzed by flow cytometry and are shown in Figure 6.

[1145] Annexin V used here recognizes and binds to phosphatidylserine (PS), a phospholipid of the outer cell membrane, which is exposed to the outside of the cell in the early stage of cell death, and PI (propium iodide) is a dye that penetrates into late apoptotic or necrotic cells with damaged cell membranes and binds to nucleic acids.

[1146] Therefore, the combined use of Annexin V and PI can distinguish between live cells, early apoptotic cells, late apoptotic cells, and necrotic cells, allowing for a high degree of reliance on distinguishing the stages of apoptosis.

[1147] The degree of cell death is determined by Annexin V High / PI High , Annexin V High / PI Low and Annexin V Low / PI High The sum of the percentage of cells located in the region (%) is displayed as a bar graph.

[1148] As a result, it was confirmed that the apoptosis rate significantly increased in the group treated with the compound of the present invention compared to the control group, which suggests that the compound induces apoptosis in B lymphoma cells.

[1149] Through these results, it can be seen that various compounds according to the present invention can be utilized as anticancer agents.

[1150] That is, when the compound according to the present invention is treated on lymphoma cancer cells, as confirmed in Experimental Example 1, the compound of the present invention inhibits the cell survival mechanism and induces cell death by inhibiting intracellular PDK1 (3-Phosphoinositide-dependent protein kinase-1) signal transduction.

[1151] Therefore, as a result, it was confirmed that early and late apoptosis accompanied by external exposure of phosphatidylserine and cell membrane damage were effectively induced.

[1152] This suggests that the compound according to the present invention can perform an effective action in treating lymphoma by selectively blocking the survival mechanism of lymphoma cells through PDK1.

[1153]

[1154] Experimental Example 5: Experiment to verify the anticancer efficacy of B-cell lymphoma in vivo.

[1155] In order to verify the anticancer efficacy of the compound according to the present invention in vivo, an animal model (mouse xenograft tumor model) was established in which the human B cell lymphoma cell line SU-DHL-8 (ATCC, Cat. #CRL-2961) was subcutaneously transplanted.

[1156] For this purpose, 7-week-old normal mice (BALB / c nude mice, female) were acclimatized in an animal room for more than a week and then 8×10 6 Tumors were induced by subcutaneously injecting 100 μL PBS containing SU-DHL-8 cells into the back, and tumors were confirmed to develop subcutaneously after approximately 14 days.

[1157] This is shown in Figure 7.

[1158] In order to verify the therapeutic efficacy of the compound according to the present invention, a tumor growth inhibition experiment was conducted using the animal model in which the human B lymphoma cell line, SU-DHL-8, was subcutaneously transplanted.

[1159] The initial tumor volume of each animal model was approximately 100 mm 3 From the time of reaching the target, GO48 (0.5 mg / kg), GO88 (0.5 mg / kg), a compound according to the present invention, or a control substance (vehicle) was intratumorally injected once a day at a dose of 30 mg / kg for 12 days.

[1160] During the entire experimental period, the weight of each mouse was measured twice a week to check for toxicity such as weight loss due to drug administration. The size of the tumor was measured in each direction using a vernier caliper and then divided by 0.5×(width) 2 ×(length) (unit: mm) 3 ) was calculated using the formula.

[1161] As a result, when GO48 and GO88 were administered to subcutaneous cancer animal models, the following phenomena were commonly observed.

[1162] First, in mice administered the compound according to the present invention, tumor growth was suppressed after 14 days, and in mice belonging to the group administered the control substance vehicle or not administered the substance, tumor growth was confirmed to continue to increase without any therapeutic effect.

[1163] Pictures of these mice are shown in Figure 8.

[1164] Additionally, the same pattern was confirmed in the actual measurement results using a vernier caliper.

[1165] In addition, no decrease in body weight was observed in the rats administered the compound according to the present invention until the end of the experiment, confirming that no change in body weight was observed due to drug toxicity.

[1166] This is shown in Figure 9.

[1167] Accordingly, based on this, it was verified that the compound according to the present invention exhibits excellent cancer treatment efficacy in the body when cancer exists under the skin.

[1168] That is, referring to the above results, it can be judged that the compounds according to the present invention inhibit the activity of PDK1 (3-Phosphoinositide-dependent protein kinase-1) or antagonize it, thereby inhibiting the signal transduction pathway mediated by PDK1, and thereby effectively inhibiting cell proliferation, survival, tumor formation, etc.

[1169] Through these in vivo actions, it was shown that the compound according to the present invention had a significant effect on tumor growth inhibition and size reduction, thereby confirming that it has an excellent effect as a composition for anticancer treatment.

[1170]

[1171] Experimental Example 6: Experiment to verify the therapeutic effect on psoriasis in vivo.

[1172] In order to verify the therapeutic effect of the compound according to the present invention on psoriasis, an animal model of psoriasis was constructed as follows, and the compound according to the present invention was injected to evaluate the alleviation of skin lesions and the changes in immune cells.

[1173] To establish an animal model of psoriasis, BALB / c (7-week-old, female, 20 g) were purchased from Hana Biotech Co., Ltd. and allowed to adapt to the breeding environment for one week.

[1174] The schedule for establishing a psoriasis animal model is shown in Figure 10.

[1175] Afterwards, the hair on the back of the mouse was first removed with a hair remover, and then completely removed a second time using hair removal cream (Nicrine cream (80% thioglycolic acid, Ildong Pharmaceutical)). Then, the mouse was raised for 24 hours to check for skin damage.

[1176] In order to verify the psoriasis prevention and treatment effect of the compound according to the present invention, the experimental group was formed as follows:

[1177] [Normal control group that did not induce psoriasis (Normal, Not Treatment), control group that only induced psoriasis (Psoriasis, Not Treatment), vehicle control group that induced psoriasis and administered the injection solvent intraperitoneally (Psoriasis, Vehicle), experimental group that induced psoriasis and administered the compound of the present invention intraperitoneally (GO85, GO86, GO88, GO89, PBK-2024-010, PBK-2024-026, PBK-2025-002, PBK-2025-004, PBK-2025-016, PBK-2025-017, PBK-2025-023)].

[1178] Also, as can be seen in Table 20, each group that induced psoriasis had Aldara 　Psoriasis was induced by applying cream (Imiquimod, 250 mg / package) once a day, 62.5 mg per animal, for 7 consecutive days.

[1179] In order to comparatively evaluate the psoriasis occurrence prevention and treatment effect of the compound according to the present invention, for the group administered the drug, a given dose of the compound per mouse was completely dissolved in DMSO corresponding to 10% of the total administered dose, and then diluted in a solvent mixed with Cremophor EL, PEG 400, and distilled water to prepare a final ratio of DMSO:Cremophor EL:PEG 400:distilled water of 1:1:4:4 (v / v / v / v).

[1180] The prepared test solution was administered intraperitoneally to each mouse once daily at 100 μL, starting 24 hours after hair removal. For the vehicle control group, only the same solvent (DMSO: Cremophor EL: PEG 400: distilled water = 1:1:4:4 (v / v / v / v)) excluding the compound was administered intraperitoneally to each mouse once daily at 100 μL.

[1181] GroupImiquimod 62.5 mgInterventionNumber of mouseNormalXHair removal only (no medication)4Psoriasis_NT(Not treated)OHair removal only (no medication)4Psoriasis_VehicleOSolvent (DMSO:cremophorEL:PEG 400:distilled water)= 1:1:4:4 (v / v / v / v)100 μl / intraperitoneal administration once daily4Psoriasis_GO85OSolvent (DMSO:cremophorEL:PEG 400:distilled water)= 1:1:4:4 (v / v / v / v) + 1mg / kg GO85100 μl / intraperitoneal administration once daily4Psoriasis_GO86OSolvent (DMSO:cremophorEL:PEG 400:distilled water)= 1:1:4:4 (v / v / v / v) + 2.5mg / kg GO86 100 μl / Intraperitoneal administration once a day 4Psoriasis_GO88O solvent (DMSO:cremophorEL:PEG 400: distilled water) = 1:1:4:4 (v / v / v / v) + 0.25mg / kg GO88 100 μl / Intraperitoneal administration once a day 4Psoriasis_GO89O solvent (DMSO:cremophorEL:PEG 400: distilled water) = 1:1:4:4 (v / v / v / v) + 2.5mg / kg GO89 100 μl / Intraperitoneal administration once a day 4Psoriasis_PBK-2024-010O solvent (DMSO:cremophorEL:PEG 400: distilled water) = 1:1:4:4 (v / v / v / v) + 0.5 mg / kg PBK-2024-010 100 μl / Intraperitoneal administration once daily 4Psoriasis_PBK-2024-026O Solvent (DMSO:cremophorEL:PEG 400: Distilled water) = 1:1:4:4 (v / v / v / v) + 0.5 mg / kg PBK-2024-026 100 μl / Intraperitoneal administration once daily 4Psoriasis_PBK-2025-002O Solvent (DMSO:cremophorEL:PEG 400: Distilled water) = 1:1:4:4 (v / v / v / v) + 0.5 mg / kg PBK-2025-002 100 μl / Intraperitoneal administration once a day 4Psoriasis_PBK-2025-004O Solvent (DMSO:cremophorEL:PEG 400: distilled water) = 1:1:4:4 (v / v / v / v) + 0.5 mg / kg PBK-2025-004 100 μl / Intraperitoneal administration once a day 4Psoriasis_PBK-2025-016O Solvent (DMSO:cremophorEL:PEG 400: distilled water) = 1:1:4:4 (v / v / v / v) + 0.5 mg / kg PBK-2025-016 100 μl / Intraperitoneal administration once a day 4Psoriasis_PBK-2025-017O Solvent (DMSO:cremophorEL:PEG 400:distilled water) = 1:1:4:4 (v / v / v / v) + 0.5 mg / kg PBK-2025-017100 μl / intraperitoneal administration once daily4Psoriasis_PBK-2025-023OSolvent (DMSO:cremophorEL:PEG 400:distilled water) = 1:1:4:4 (v / v / v / v) + 0.5 mg / kg PBK-2025-023100 μl / intraperitoneal administration once daily4.

[1182] The body weights of each group of mice were measured on days 1, 4, and 8 after the start of injection and induction of psoriasis, and the degree of erythema, thickness, and scaling of the skin on the back of the mice were observed every day from days 1 to 8.

[1183] On the 8th day, mice were sacrificed, and skin tissue from the back was collected, stained with H&E, and subjected to histopathological analysis.

[1184] As a result, hyperkeratosis, parakeratosis, irregular acanthosis, and inflammatory cell infiltration were significantly observed in the skin tissues of the group that only induced psoriasis (Psoriasis, Not Treatment) and the group that induced psoriasis and administered the injection solvent (Psoriasis, Vehicle), whereas these symptoms were mild or barely observed in the group that administered the compound of the present invention.

[1185] This is shown in Figure 11.

[1186] Referring to Figure 11, the skin pathology tissue of mice induced with psoriasis was analyzed using H&E staining. In the control group (Psoriasis, Not Treatment, and Vehicle), significant thickening of the epidermis along with irregular acanthosis and infiltration of inflammatory cells were observed.

[1187] On the other hand, referring to Figure 12, it was confirmed that in the group administered the compound of the present invention, the thickness of the epidermis was reduced, and the degree of inflammatory cell infiltration and acanthosis were also alleviated.

[1188] Figure 12 is a photograph of the skin thickness of mice taken 8 days after administration of the compound according to the present invention to determine the degree of psoriasis treatment.

[1189] Taken together, these results readily demonstrate that this compound effectively suppresses the chronic inflammatory and epidermal proliferative responses that accompany psoriasis.

[1190] To evaluate the therapeutic effect in a psoriasis-induced mouse model, the Psoriasis Area and Severity Index (PASI) score was measured.

[1191] The PASI score was scored from 0 (none) to 4 (severe) based on three items: erythema, scaling, and skin thickness. The scores for each item were added up to obtain a total score (12 points) to compare the treatment effects.

[1192] Observations were conducted at the same time every day, and the same observer visually judged each item and recorded the scores, and the results are shown in Figure 13.

[1193] Referring to Figure 13, the Psoriasis score continuously increased over time in the group that only induced psoriasis (Psoriasis, Not Treatment) and the group that induced psoriasis and administered the injection solvent (Psoriasis, Vehicle).

[1194] However, in the group administered the compound of the present invention, the Psoriasis score increased until the 5th day and was maintained thereafter, confirming the effect of suppressing the worsening of psoriasis symptoms.

[1195] After the experiment (day 8), the mice were anesthetized and blood was collected through the heart.

[1196] The collected blood was allowed to coagulate at room temperature and then centrifuged at 3,000 rpm for 10 minutes to separate the serum from the upper layer.

[1197] Using the collected serum, the concentration of IL-17A was analyzed using the IL-17A Mouse ELISA kit (BioLegend) according to the manufacturer's manual in the GO86, GO88, and GO89 administration groups, which were evaluated to have excellent effects on improving skin diseases.

[1198] The results are shown in Fig. 14.

[1199] All samples were measured in duplicate, and absorbance was measured at 450 nm using a Microplate Reader.

[1200] Referring to Figure 14, the serum IL-17A concentrations in the group that only induced psoriasis (Psoriasis, Not Treatment) and the group that induced psoriasis and administered the injection solvent (Psoriasis, Vehicle) were significantly increased compared to the normal group.

[1201] On the other hand, in the experimental group administered the composition of the present invention, the serum IL-17A concentration was significantly reduced (p<0.001).

[1202] This suggests that the compound according to the present invention has physiological activity capable of inhibiting the secretion of IL-17A, a psoriasis-related cytokine.

[1203] That is, referring to the above results, it was found that the compounds according to the present invention suppress the expression of IL-17, a major cytokine that induces an inflammatory response in skin tissue, thereby controlling excessive immune response and inflammatory response and alleviating abnormal keratin formation.

[1204] These results suggest that the compound of the present invention has excellent efficacy as a therapeutic candidate that can effectively suppress the progression of IL-17-mediated inflammatory skin diseases, particularly psoriasis.

[1205]

[1206] Experimental Example 7: Efficacy in treating systemic lupus erythematosus

[1207] In order to verify the therapeutic efficacy of the compound according to the present invention on systemic lupus erythematosus, a lupus animal model was established and a therapeutic efficacy verification experiment was performed.

[1208]

[1209] (1) Establishment of a lupus animal model and changes in spleen size

[1210] MRL / MpJ-Faslpr / J (hereinafter referred to as MRL / lpr) used in this experiment is one of the representative animal models for systemic lupus erythematosus (SLE), and is known to form various autoantibodies, including antinuclear antibodies, due to the lpr (lymphoproliferation) gene.

[1211] Typically, female MRL / lpr develop systemic lupus erythematosus around 12 weeks of age, and approximately 50% of the individuals are reported to have died by 30 weeks of age.

[1212] In the present invention, 9 weeks of age after birth were considered as the stage before the onset of the disease, and 23 weeks or older were considered as the stage after the onset of the disease, and the efficacy verification experiment using the model was applied.

[1213] To secure experimental subjects, 6-week-old male and female MRL / lpr mice were imported from The Jackson Laboratory and underwent a one-week acclimatization process in an SPF (Specific Pathogen Free) facility maintained at a temperature of 21–24°C, humidity of 40–60%, and a 12-hour light / dark cycle (lights on: 07:00 / lights off: 19:00).

[1214] Thereafter, female and male MRL / lpr mice were mated at a ratio of 2:1 in the same facility, and the resulting female mice were administered 30 mg / kg of the compound of the present invention, GO15F, or vehicle, intraperitoneally or orally once a day from the time they reached 10 weeks of age until they reached 23 weeks of age.

[1215] Urine samples were collected from each individual once a week and used for analytical experiments.

[1216] When MRL / lpr mice reached 23 weeks of age, necropsy was performed on each individual, and serum, kidneys, and spleen were isolated and used for analytical tests.

[1217] As a result of measuring the size and weight of the isolated spleen, it was observed that the spleen tended to enlarge due to the progression of lupus disease, and it was confirmed that the size and weight of the spleen were relatively reduced in the group administered the compound according to the present invention.

[1218] Figure 15 is a graph showing the results of measuring the body weight of mice with lupus disease administered a compound according to the present invention, and this was referenced.

[1219] Through this, it was verified that by administering the compound according to the present invention, an overactivated autoimmune response was controlled in a lupus animal model, and accordingly, the size of an enlarged spleen was normalized.

[1220]

[1221] (2) Measurement of proteinuria

[1222] Protein concentrations in urine obtained weekly from the control or experimental groups were analyzed using 'Quick Start™ Bradford 1x Dye Reagent (Bio-Rad, Cat. #5000205)'.

[1223] After adding 5 μl of urine sample diluted with distilled water and 250 μl of 1x dye reagent to each well of a 96-well plate and reacting, the absorbance was measured at 595 nm.

[1224] As a result, it was confirmed that in the MRL / lpr mice belonging to the control group, the increase in the concentration of protein in urine was large, whereas in the group administered with GO15F, a compound of the present invention, the concentration was significantly lower than in the control group.

[1225] This is shown in Figure 16.

[1226] Through this, it was confirmed that the compound of the present invention has the effect of alleviating the deterioration of renal function caused by lupus and suppressing the production of proteinuria, and it is further judged that it can suppress the progression of lupus nephritis.

[1227]

[1228] (3) Measurement of antinuclear antibodies (Anti-dsDNA IgG)

[1229] The concentration of antinuclear antibody (Anti-dsDNA Ab) was measured using the 'Mouse Anti-dsDNA IgG ELISA Kit (Alpha Diagnostic International, Cat. #5120)' in serum isolated at the time of autopsy of a lupus animal model.

[1230] The serum of each mouse was diluted 1 / 5000 times with Working Sample Diluent (WSD) and Low NSB Sample Diluent (LNSD), and 100 μl of the diluted serum was applied to the anti-dsDNA-coated well and reacted at room temperature for 60 minutes.

[1231] Afterwards, each well was washed four times with 200 μl of washing solution (washing buffer), 100 μl of anti-Mouse IgG-HRP antibody was added to each well, and the reaction was allowed to proceed at room temperature for 30 minutes.

[1232] Afterwards, each well was washed four times with 200 μl of washing solution, and 100 μl of 3,3',5,5' Tetramethylbenzidine (TMB) substrate solution was added to each well.

[1233] After checking the degree to which the well containing the standard solution turned blue, the reaction was stopped by adding 100 μl of stop solution after 15 minutes.

[1234] After the reaction was completed, the optical density (OD) was measured at 450 nm.

[1235] As a result, it was confirmed that the concentration of anti-dsDNA IgG in the blood of mice was significantly lower in the experimental group administered GO15F compared to the control group MRL / lpr.

[1236] This is shown in Figure 17.

[1237] Through this, it was confirmed that the compound according to the present invention exhibits a significant effect of inhibiting the production of antinuclear antibodies in a lupus animal model.

[1238]

[1239] (4) Measurement of total IgG concentration in serum

[1240] The concentration of total IgG was measured using the 'IgG (Total) Mouse Uncoated ELISA Kit (Invitrogen, Cat. #88-50400)' in serum isolated at the time of autopsy of the lupus animal model.

[1241] 100 μl of capture antibody (anti-mouse IgG) diluted 1 / 250 times in coating buffer was added to each well of a 96-well plate (Nunc™ MaxiSorp™ ELISA Plates, Uncoated, BioLegend, Cat. #423501) and incubated at 4°C for 16 hours.

[1242] Afterwards, each well was washed twice with 400 μl of washing solution, 250 μl of blocking buffer was added, and the reaction was resumed at room temperature. After 2 hours of reaction, each well was washed twice with 400 μl of washing solution.

[1243] Each well was sequentially filled with 90 μl of assay solution (assay buffer), 10 μl of serum diluted in assay solution, and 50 μl of detection antibody diluted 1 / 250 times, and then reacted at room temperature for 2 hours.

[1244] Afterwards, each well was washed twice with 400 μl of washing solution, and 100 μl of TMB substrate solution was added to each well.

[1245] After checking the degree to which the well containing the standard solution turned blue, the reaction was stopped by adding 100 μl of stop solution after 15 minutes.

[1246] After the reaction was completed, the optical density (OD) was measured at 450 nm.

[1247] As a result, it was confirmed that the total IgG concentration in the blood of mice was significantly lower in the experimental group administered GO15F compared to the MRL / lpr control group.

[1248] This is shown in Figure 18.

[1249] Through this, it was confirmed that the compound according to the present invention exhibits pharmacological efficacy in effectively suppressing excessive formation of total IgG in lupus, an autoimmune disease.

[1250]

[1251] (5) Measurement of changes in the proportion of immune cells in the spleen of a lupus animal model

[1252] To determine the effect of GO15F administration on the change in the proportion of immune cells in the body of a lupus animal model, the spleens of mice administered with each compound were removed, cells were extracted, and then suspended in MACS buffer (autoMACS Washing Solution, Miltenyi Biotec., Cat. #130-092-987).

[1253] For flow cytometry analysis, 5 × 10 spleen cells from each mouse were collected in FACS tubes (5 mL round tube, Falcon, Cat. #352052). 5After dispensing each cell, each tube was treated with 1 μg / mL of anti-mouse CD16 / CD32 (InVivoPlus anti-mouse CD16 / CD32, BioXCell, Cat. #BP0307) for 30 minutes to prevent nonspecific binding of antibodies, and then centrifuged at 1,500 rpm for 5 minutes and resuspended in 100 μL of MACS buffer.

[1254] Afterwards, the experiment was conducted as follows depending on the type of immune cell to be confirmed.

[1255] For B cells, each FACS tube was stained with 1 μg / mL FITC-conjugated anti-B220 antibody (eBioscience™, Cat. #11-0452-81) at 4°C for 30 minutes and then washed with 2 mL of MACS buffer.

[1256] Afterwards, each tube was centrifuged at 1,500 rpm for 5 minutes, the supernatant was discarded, and the sedimented cells were fixed using 200 L of 2% formaldehyde solution.

[1257] For T cells, each FACS tube was stained with 1 μg / mL PerCP-Cy5.5-conjugated anti-CD3 (Biolegend, Cat. #100218) at 4°C for 30 min.

[1258] Afterwards, each tube was washed with 2 mL of MACS buffer, centrifuged at 1,500 rpm for 5 minutes, the supernatant was discarded, and the sedimented cells were fixed using 200 μL of 2% formaldehyde solution.

[1259] For macrophages, each FACS tube was stained with 1 μg / mL PE-conjugated anti-CD11b antibody (Biolegend, Cat. #101207) and PerCP-Cy5.5-conjugated anti-F4 / 80 (Biolegend, Cat. #123128) at 4°C for 30 minutes, and then washed with 2 mL of MACS buffer.

[1260] Afterwards, each tube was centrifuged at 1,500 rpm for 5 minutes, the supernatant was discarded, and the sedimented cells were fixed using 200 L of 2% formaldehyde solution.

[1261] The results of flow cytometry analysis performed by staining each immune cell through the above process are shown in Figure 19.

[1262] Referring to Figure 19, it was confirmed that the increased B cells, T cells, and macrophages due to the aggravation of the symptoms of lupus, an autoimmune disease, were reduced by administering GO15F.

[1263] Through this, it was determined that the administration of the compound according to the present invention suppressed PDK1, thereby controlling the hyperactivity of B cells, T cells, and macrophages in the spleen cells of a lupus animal model, and that it has excellent functionality as an autoimmune treatment agent.

[1264]

[1265] (6) Measurement of changes in cytokine expression levels in the kidney

[1266] In order to confirm the effect of administration of compound GO15F according to the present invention on the systemic immune response of a lupus animal model, gene expression analysis for cytokines in kidney tissue (1) was performed.

[1267] Each kidney tissue was treated with TRIzol TMTotal RNA was isolated using Invitrogen (Cat. #15596018). 1 μg of RNA from each mouse was quantified using a microdispersible spectrophotometer (ThermoFisher Scientific, ND2000) and cDNA was synthesized.

[1268] The cDNA of each synthesized mouse was quantified at a concentration of 50 ng using a micro-spectrophotometer, and qPCR was performed for cytokines 'IL-2, IL-6, IL-10, IL-17, TNF-α, IFN-γ' using a SYBR green probe (CFX96, BIO-RAD).

[1269] Cytokine primers for performing qPCR used a pair of forward and reverse gene primers that can complementarily bind to the base sequence of each mRNA.

[1270] As a result of analyzing the amount of cytokine mRNA expression in the renal tissue of the control group and drug-administered group, it was confirmed that the expression of mRNA for 'IL-2, IL-6, IL-10, IL-17, TNF-α, and IFN-γ' among the cytokines was significantly suppressed as the drug was administered.

[1271] This is shown in Figure 20.

[1272] Referring to FIG. 20, it was found that administration of the compound according to the present invention suppresses mRNA expression of 'IL-2, IL-6, IL-10, IL-17, TNF-α, IFN-γ', which are major cytokines involved in the inflammatory response and exacerbation of the disease in the renal tissue of a lupus animal model, thereby controlling excessive immune response and inflammatory response.

[1273]

[1274] (7) Renal pathology tissue staining

[1275] To determine the effect of drug administration on the kidney tissue of MRL / lpr mice, the tissues were fixed in 10% neutral buffered formalin at room temperature, dehydrated through stepwise infiltration with ethanol, and embedded using xylene and paraffin.

[1276] The blocked tissue was sectioned into 4 μm thick sections using a microtome, deparaffinized, and then treated with water and stained.

[1277] Hematoxylin & Eosin staining, PAS staining, and Masson trichrome staining were performed for pathological evaluation of the tissue, respectively.

[1278] As a result, in the kidney tissue of MRL / lpr mice, which corresponds to the control group, it was observed that mesangial cells proliferated and the glomerular capillary space was occluded, whereas in mice administered GO15F, the glomerular capillary space was well maintained.

[1279] This is shown in Figure 21.

[1280] Through this, it was confirmed that the compound according to the present invention exhibits an effect of reducing glomerular inflammation of renal tissue in a lupus animal model.

[1281]

[1282] (8) Kidney tissue IgG immunofluorescence staining

[1283] To determine the extent of IgG deposition in the renal tissue of MRL / lpr mice, immunofluorescence staining was performed using anti-IgG antibody on paraffin-embedded kidney tissue sections, and the staining results were confirmed using a fluorescence microscope.

[1284] As a result, high IgG deposition was observed in the kidney tissue of MRL / lpr mice belonging to the control group, whereas the level of IgG deposition was confirmed to be significantly lower in the group administered GO15F, a compound of the present invention.

[1285] This is shown in Figure 22.

[1286] Through this, it was confirmed that administration of the compound according to the present invention effectively suppresses the deposition of IgG that induces an inflammatory response in the glomeruli of renal tissue, ultimately leading to alleviation of lupus disease.

[1287] In addition, it was confirmed that the compound of the present invention exhibits a therapeutic effect in an animal model of systemic lupus erythematosus, and in the process, has a pharmacological effect of suppressing excessive proliferation of immune cells.

[1288]

[1289] (9) Hair loss treatment

[1290] GO15F, a compound of the present invention, was administered intraperitoneally once a day at a dose of 30 mg / kg to 23-week-old female MRL / lpr mice exhibiting systemic lupus erythematosus and hair loss symptoms on the face.

[1291] As a result, hair began to grow on the face of the mouse three days after compound administration, and after two months of administration, prominent hair growth was observed over the entire face.

[1292] This is shown in the photo in Figure 23.

[1293] Additionally, when compounds GO15F (30 mg / kg), GO48 (1 mg / kg), and GO88 (0.5 mg / kg) were administered intraperitoneally once a day to 41-week-old female MRL / lpr mice, it was confirmed that facial hair grew in these mice over time.

[1294] This is shown in Figure 24.

[1295] - Confirmation of hair follicle cell proliferation -

[1296] In order to confirm the proliferation activity of hair follicle cells in the skin tissue of these mice, the mice were sacrificed 14 days after administration of the compound of the present invention, and Ki-67 immunohistochemistry (IHC) staining was performed.

[1297] To this end, the extracted skin tissue was fixed in formalin and made into a paraffin block, and the tissue sections made into slides were stained using a Ki-67 specific antibody.

[1298] As a result, it was confirmed that the Ki-67 positive reaction in cells surrounding hair follicles increased compared to the control group (NT) administered the compound of the present invention, and the proliferation activity of hair follicle cells significantly increased.

[1299] This is attached to Fig. 25.

[1300] In addition, the number of hair follicles observed significantly increased along with the increase in Ki-67 positivity, suggesting that this compound contributes to the activation of hair follicle regeneration and proliferation.

[1301] In conclusion, it is believed that the compound according to the present invention induces proliferation of hair follicle cells, increases the number of hair follicles, and actually causes hair growth in the skin of 41-week-old MRL / lpr mice with hair loss due to old age and inflammation, thereby restoring damaged hair follicle function or activating cell proliferation.

[1302] Therefore, it can be judged that the compound of the present invention is involved in the treatment of effectively improving hair loss symptoms caused by inflammation in systemic lupus erythematosus, and since these results are a phenomenon observed in aged lupus mice, it is judged that the compound according to the present invention has the potential to be used in anti-aging or reverse-aging treatment through inhibition of PDK1.

[1303] Experimental Example 8: Experiment to verify the therapeutic effect on rheumatism in vivo.

[1304] In order to verify the therapeutic effect of the compound according to the present invention on rheumatism, an animal model of rheumatism was constructed as follows, and the compound according to the present invention was injected to evaluate the aspects of alleviation of foot swelling and joint damage.

[1305] To establish a rheumatoid mouse animal model, DBA / 1 (7 weeks old, 20 g, male) was purchased from Hana Biotech Co., Ltd. and allowed to adapt to the breeding environment for one week.

[1306] Afterwards, 100 ul of an ampoule containing a 1:1 mixture of bovine type 2 collagen 2 mg / ml (Chondrex, #20022) and Complete Freunds Adjuvant (CFA) 1 mg / ml (Chondrex, #7008) was injected subcutaneously into the tail of mice to induce rheumatism in mice except for the Normal group.

[1307] After 3 weeks, 100 μl of an ampoule containing a 1:1 mixture of bovine type 2 collagen 2 mg / ml (Chondrex, #20022) and Incomplete Freunds Adjuvant (IFA) (Chondrex, #7002) was injected subcutaneously into the tail of the mice.

[1308] Afterwards, it was confirmed that the swelling of the feet increased to a certain amount, and an experimental group was set up to verify the rheumatism treatment effect of the compound according to the present invention.

[1309] In order to compare the rheumatism treatment effect of the compound according to the present invention, for the group receiving the drug, the compound at a set dose per mouse was completely dissolved in DMSO corresponding to 10% of the administered dose, and then diluted in a Cremophor EL-PEG 400-distilled water mixture so that the final ratio of DMSO:Cremophor EL:PEG 400:distilled water was 1:1:4:4 (v / v / v / v, volume ratio).

[1310] The details are summarized and attached in Table 29 below.

[1311] The injection solution was injected intraperitoneally once a day at 100 μL per mouse when the paw swelling reached a certain level.

[1312] For the vehicle administration group, 100 μL of the injection solution excluding the drug (DMSO: Cremophor EL: PEG 400: distilled water = 1:1:4:4 (v / v / v / v)) was injected intraperitoneally once a day.

[1313] GroupInduction of Rheumatoid arthritisInterventionNumber of mouseNormalXNo treatment4Rheumatoid arthritis_NT(Not treated)ONo treatment4Rheumatoid arthritis_VehicleOSolvent (DMSO:cremophorEL:PEG 400:distilled water)= 1:1:4:4 (v / v / v / v)100 μl / Intraperitoneal administration once daily4Rheumatoid arthritis_GO15FOSolvent (DMSO:cremophorEL:PEG 400:distilled water)= 1:1:4:4 (v / v / v / v) + 30mg / kg GO15F100 μl / Intraperitoneal administration once daily4Rheumatoid arthritis_GO48OSolvent (DMSO:cremophorEL:PEG 400:distilled water)= 1:1:4:4 (v / v / v / v) + 0.5mg / kg GO48100 μl / Intraperitoneal administration once a day4Rheumatoid arthritis_GO77O solvent (DMSO:cremophorEL:PEG 400: distilled water) = 1:1:4:4 (v / v / v / v) + 0.5mg / kg GO77100 μl / Intraperitoneal administration once a day4Rheumatoid arthritis_GO78O solvent (DMSO:cremophorEL:PEG 400: distilled water) = 1:1:4:4 (v / v / v / v) + 1mg / kg GO78100 μl / Intraperitoneal administration once a day4Rheumatoid arthritis_GO86O solvent (DMSO:cremophorEL:PEG 400: distilled water) = 1:1:4:4 (v / v / v / v) + 2.5mg / kg GO86100 μl / Intraperitoneal administration once a day Intraperitoneal administration 4 Rheumatoid arthritis_GO88O solvent (DMSO: cremophorEL: PEG 400: distilled water) = 1:1:4:4 (v / v / v / v) + 0.5mg / kg GO88 100 μl / Intraperitoneal administration once a day 4

[1314] At 21 days after the start of injection, the paw thickness of the mice in each group was measured.

[1315] This is shown in Figure 26.

[1316] As a result, in the group in which only rheumatism was induced (CIA, Not Treatment) and the group in which rheumatism was induced and the injection solvent was injected into the peritoneal cavity (CIA, Vehicle), not only severe paw swelling but also severe infiltration of inflammatory cells was observed, but it was confirmed that such symptoms were mild in mice administered the compound according to the present invention.

[1317] In addition, in the results of actual measurement of foot thickness using a vernier caliper, it was observed that the swelling of the foot was reduced in the group administered the compound of the present invention compared to the control group, NT and Vehicle groups.

[1318] The measurement results are shown in Fig. 27.

[1319] - Joint observation -

[1320] After the experiment, the ankle joint tissues of the experimental animals in which rheumatoid arthritis was induced were removed, fixed in 10% neutral formalin, decalcified, and paraffin blocks were made. The tissues were then sectioned into 5 μM thicknesses and stained with H&E and Safranin O.

[1321] As a result of H&E staining, the control group, Not treat and Vehicle groups showed hypertrophy of the ankle joint area compared to the Normal group, infiltration of numerous inflammatory cells, and damage to cartilage and bone tissue was confirmed.

[1322] This is shown in Figure 28.

[1323] On the other hand, in the group administered the compound of the present invention, hypertrophy of cartilage tissue and infiltration of inflammatory cells were significantly reduced, and damage to cartilage and bone tissue was minimized, showing a relatively well-preserved appearance of the tissue.

[1324] In addition, as a result of Safranin O staining, in the control group, the staining intensity was significantly reduced or lost due to loss of proteoglycan in the cartilage, but in the group administered with the composition of the present invention, strong red staining was maintained, and it was confirmed that the cartilage layer structure was also well maintained, and the proteoglycan content was preserved.

[1325] - Confirmed cytokine suppression -

[1326] After the experiment (day 8), the mice were anesthetized and blood was collected through the heart.

[1327] The collected blood was allowed to coagulate at room temperature and then centrifuged at 3,000 rpm for 10 minutes to separate the serum from the upper layer.

[1328] The collected serum was analyzed using a commercially available IL-17A, TNF-α Mouse ELISA kit (BioLegend, 436204, 430916) according to the manufacturer's manual.

[1329] The analysis results are shown in Figure 29.

[1330] All samples were measured in duplicate, and absorbance was measured at 450 nm using a Microplate Reader.

[1331] As a result of the analysis, the serum concentrations of IL-17A and TNF-α were high in the group that only induced rheumatism (Not Treatment) and the group that induced rheumatism and administered an injection solvent (Vehicle), but were relatively decreased in the experimental group that administered the compound of the present invention (*: p<0.05, **: p<0.01, ***: p<0.001), suggesting that the compound of the present invention has physiological activity capable of suppressing the secretion of IL-17A and TNF-α, which are rheumatism-related cytokines.

[1332] That is, this is a result demonstrating that the composition of the present invention effectively suppresses joint damage and inflammatory responses at the tissue level through reduction of inflammatory cytokines in an animal model induced with rheumatoid arthritis, suggesting that the compound of the present invention effectively acts to alleviate the pathological progression of rheumatoid arthritis.

[1333] These results provide evidence that the compound of the present invention may be used as a pharmaceutical composition for preventing or treating rheumatoid arthritis in the future.

[1334]

[1335] Experimental Example 9: Metastasis inhibition experiment for colon cancer cell lines

[1336] In order to evaluate the metastasis inhibition effect of the compound according to the present invention on the HCT-116 colon cancer cell line, an invasion assay using Matrigel was performed to evaluate the cell invasion ability.

[1337] First, Matrigel was sufficiently thawed on ice with RPMI-1640 medium without FBS, and then diluted with DMEM at a ratio of 1:20.

[1338] 100 μl of the diluted Matrigel mixture was applied to the upper chamber, and 750 μl of RPMI-1640 without FBS was added to the lower chamber.

[1339] Afterwards, it was kept in a 37°C incubator for 1 hour to allow Matrigel to solidify.

[1340] After coating was completed, the Matrigel mixture in the upper chamber was removed using a pipette and washed with RPMI without FBS.

[1341] Human-derived colon cancer cell line HCT-116, obtained from the Korea Cell Line Bank, was cultured in RPMI-1640 medium containing 10% FBS.

[1342] Afterwards, each stabilized cell was recovered through Trypsin-EDTA treatment, centrifuged at 1,200 rpm for 3 minutes, the supernatant was removed, resuspended in the same medium, and the medium in the lower chamber was replaced with 750 μl of RPMI-1640 supplemented with 10% FBS, and 5 × 10 4 Cells were applied to the upper chamber under the condition of cells / well.

[1343] After the cells were attached, they were cultured for 24 hours, and then, using RPMI-1640 without FBS, the compounds according to the present invention (G078, G085, G086, G088, G089, PBK-2024-010, PBK-2025-010, PBK-2025-013, PBK-2025-016) and the control substance DMSO were diluted, and the medium in the upper chamber was removed and replaced.

[1344] Additionally, the culture was continued by replacing the medium in the lower chamber with RPMI-1640 containing fresh FBS.

[1345] After an additional 24 hours, the medium was removed and 1 ml of methanol was added to fix it for 10 minutes.

[1346] Afterwards, 1 ml of Hematoxylin was added and reacted for 5 minutes, 1 ml of Eosin was added and reacted for 30 seconds, and then washed with distilled water (DW).

[1347] After staining was completed, the remaining cells inside the upper chamber were removed, and finally, the infiltrated cells were observed under a microscope, photographed, and the degree of infiltration was analyzed.

[1348] This picture is shown in Figure 30.

[1349] Referring to Figure 30, the results of staining the infiltrated cells were shown, and it was confirmed that the number of infiltrated cells was reduced in the compound (GO78, GO85, GO86, GO88, GO89, PBK-2024-010, PBK-2025-010, PBK-2025-013, PBK-2025-016) treatment group of the present invention compared to the DMSO treatment group used as a control group.

[1350] This is a result of confirming through an invasion assay that the compound of the present invention inhibits the invasion ability of cancer cells at the cellular level, and it was confirmed that the compound effectively acts to reduce the invasiveness of cancer cells.

[1351] Through this, it can be seen that the compound of the present invention can be utilized as a composition for inhibiting cancer metastasis.

[1352]

[1353] Experimental Example 10: In vivo evaluation of anticancer efficacy against human colon cancer

[1354] In order to verify the efficacy of the compound according to the present invention, whose therapeutic efficacy has been verified at the cancer cell level, in vivo, an animal model (mouse xenograft tumor model) was constructed in which a human-derived colon cancer cell line, HCT116 (Korea Cell Line Bank; KCLB, Cat. # 10247), was subcutaneously transplanted.

[1355] For this purpose, 7-week-old normal mice (BALB / c nude mice, female) were acclimatized in an animal room for more than a week and then 5×10 6 Tumors were induced by subcutaneously injecting 100 μL of PBS containing HCT116 cells into the dorsal side of the mouse, and tumors were confirmed to develop subcutaneously after approximately 14 days.

[1356] This is shown in Figure 31.

[1357] - Confirmed tumor growth inhibition -

[1358] In order to verify the therapeutic efficacy of the compound according to the present invention, a tumor growth inhibition experiment was conducted using the animal model in which a human-derived colon cancer cell line (HCT116) was subcutaneously transplanted.

[1359] The initial tumor volume of each animal model was approximately 100 mm 3 From the time point reached, GO48 (0.5 mg / kg), GO78 (1 mg / kg), GO86 (5 mg / kg), a compound according to the present invention, or a control substance (vehicle) was administered intraperitoneally once a day for 1 day.

[1360] This is shown in Figure 32.

[1361] Figure 32 is a drawing showing the results of an experiment on tumor growth inhibition of mice in which human-derived colon cancer cell lines were subcutaneously transplanted after administration of a compound according to the present invention. During the entire experimental period, the weight of each mouse was measured twice a week to confirm toxicity such as weight loss due to drug administration. The size of the tumor was measured in each direction using a vernier caliper and then divided by 0.5×(width). 2 ×(length) (unit: mm) 3 ) was calculated using the formula.

[1362] Referring to Figure 32, the following common phenomena could be explained when GO48 (0.5 mg / kg), GO78 (1 mg / kg), and GO86 (5 mg / kg) were administered to subcutaneous cancer animal models.

[1363] First, in mice administered the compound according to the present invention, tumor growth was suppressed after 14 days, and in the group of mice administered the control substance vehicle, tumor growth was observed to continuously increase without any therapeutic effect.

[1364] In addition, the tumor growth inhibition effect was quantitatively evaluated by measuring the weight of the extracted tumor. It was confirmed that the size and weight of the extracted tumor were reduced in the group administered the compound of the present invention compared to the control group, and a clear difference in size could be confirmed with the naked eye through photography.

[1365] In addition, no decrease in body weight was observed in the rats administered the compound according to the present invention until the end of the experiment, confirming that no change in body weight was observed due to drug toxicity.

[1366] Therefore, it is believed that the compound according to the present invention will have a therapeutic effect on colon cancer.

[1367]

[1368] Experimental Example 11: Immunosuppression Mechanisms in a Sensitized Animal Model

[1369] In order to verify the antibody production inhibitory effect of the compound according to the present invention, a sensitized animal model was constructed as follows, and experimental groups were set as shown in Table 30 to evaluate the concentration of total IgG in serum and the changes in each immune cell in the spleen.

[1370] Group Sensitization animal model induction dose and daily administration frequencyNormalX No compound or control substance administeredNTO No compound or control substance administeredVehicle Administer 100 ul of solvent intraperitoneally once a day (Solvent: DMSO, Cremophor EL, PEG400, DW mixed in a volume ratio of 1:1:4:4, respectively)GO15F Administer intraperitoneally once a day at a concentration of 30 mg / kg (dissolve in 100 ul of solvent of the same composition as the vehicle and inject)GO7 Administer intraperitoneally once a day at a concentration of 81 mg / kg (dissolve in 100 ul of solvent of the same composition as the vehicle and inject)GO8 Administer intraperitoneally once a day at a concentration of 80.5 mg / kg (dissolve in 100 ul of solvent of the same composition as the vehicle and inject)

[1371] To establish a sensitized mouse animal model, C57BL / 6 and BALB / c (7 weeks old, 20 g, Female) were purchased from Hana Biotech Co., Ltd. and allowed to adapt to the breeding environment for one week.

[1372] After one week, spleen cells from BALB / c mice were isolated, suspended in PBS, and injected into C57BL / 6 mice at a density of 1×10 per mouse. 7 The process of intraperitoneal injection was repeated three times at two-week intervals to induce sensitization in animal models.

[1373] Six weeks after the first splenocyte injection, blood was collected from C57BL / 6 mice, and the total amount of IgG in the serum was measured using the following method to confirm the establishment of a mouse sensitization model.

[1374] The mouse blood was centrifuged at 4000 rpm for 10 minutes to separate the supernatant, and the concentration of total IgG in the serum was measured using the IgG (Total) Mouse Uncoated ELISA Kit (Invitrogen, Cat. # 88-50400).

[1375] Capture antibody (anti-mouse IgG) diluted 1 / 250 times in coating buffer was added to a 96-well plate (Nunc TM MaxiSorp TM 100 μl was added to each well of ELISA Plates, Uncoated, BioLegend, Cat. # 423501) and incubated at 4°C for 16 hours.

[1376] Afterwards, each well was washed twice with 400 μl of washing solution, 250 μl of blocking buffer was added, and the reaction was resumed at room temperature. After 2 hours of reaction, each well was washed twice with 400 μl of washing solution.

[1377] Each well was sequentially filled with 90 μl of assay solution (assay buffer), 10 μl of serum diluted in assay solution, and 50 μl of detection antibody diluted 1 / 250 times, and then reacted at room temperature for 2 hours.

[1378] Afterwards, each well was washed twice with 400 μl of washing solution, and 100 μl of TMB substrate solution was added to each well. After confirming the degree to which the well containing the standard solution turned blue, the reaction was stopped after 15 minutes by adding 100 μl of stop solution.

[1379] After the reaction was completed, the optical density (OD) was measured at 450 nm, and the results are shown in Figure 33.

[1380] Figure 33 is a graph showing the results of measuring the total IgG concentration in the serum of normal mice and mice that were induced with a sensitized animal model, and expressing this as a relative concentration value.

[1381] At this time, the relative concentration value means the relative value of the concentration of IgG in the sample serum compared to the concentration of IgG in the serum of a normal mouse, expressed as a percentage.

[1382] The serum IgG concentration of mice injected with antigen (spleen cells of BalB / c mice) (Sensitized mice) was approximately 3×10 higher than that of mice not injected with antigen (Normal mice). 5 It was confirmed that an adaptive immune induction animal model was successfully established based on this.

[1383] Afterwards, the compound of the present invention or a control substance was intraperitoneally injected once a day into the sensitized animal model, and 8 days after the start of administration, the antigen (1×10 7The spleen cells of BalB / c mice were injected intraperitoneally to induce antibody production and immune cell activation. 3 days after administration, 11 days later, all mice were necropsied, and the serum and spleen were separated and used for analysis tests.

[1384] In order to confirm the effect of administration of the compound of the present invention on changes in the proportion of immune cells in the body of a sensitized animal model, spleen cells from mice administered with each compound were extracted and suspended in MACS buffer (autoMACS Washing Solution, Miltenyi Biotec., Cat. # 130-092-987).

[1385] For flow cytometry analysis, 5×10 spleen cells from each mouse were placed in a FACS tube (5 mL round tube, Falcon, Cat. # 352052). 5 After dispensing each cell, each tube was treated with 1 μg / mL of anti-mouse CD16 / CD32 (InVivoPlus anti-mouse CD16 / CD32, BioXCell, Cat. # BP0307) for 30 minutes to prevent nonspecific binding of antibodies, and then centrifuged at 1,500 rpm for 5 minutes and resuspended in 100 μL of MACS buffer.

[1386] Afterwards, depending on the type of immune cell to be identified, each spleen cell was stained with an antibody to a marker combined with fluorescence of different wavelengths, and then flow cytometry analysis was performed.

[1387] Figures 34 and 35 are graphs showing the results of analyzing changes in B cell and T cell subtypes in spleen cells following administration of a compound or control substance according to the present invention to a sensitized animal model, respectively.

[1388] Referring to the B cell analysis results according to Figure 34, CD45 + CD138 in a cell population selected based on + B220 +, CD138 + B220 - The proportion of cells was significantly reduced, and each cell group corresponded to differentiated plasma cells and their progenitor cells, which are closely related to the production of autoantibodies.

[1389] Also, GL7 + CD38 - / B220 + and GL7 + CD38 + / B220 + The cells also showed a marked decrease in number, and these cells are germinal center B cells, a group of cells involved in antigen-specific responses, antibody class switching, and memory B cell formation.

[1390] These results indicate that the compound of the present invention relatively reduced the number of B cell subtypes associated with pathological antibody production and B cell hyperactivation.

[1391] It is believed that this compound can be used as a therapeutic agent that can control pathological B cell responses in diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), IgG4-related diseases, allograft rejection (AMR), and multiple myeloma, where autoantibodies and pathological antibodies are major pathological factors.

[1392] On the other hand, referring to the T cell analysis results according to Figure 35, CD44 + CD4 + / CD4 + (memory helper T cells), CD44 + CD8 + / CD8 + (Memory cytotoxic T cells) cells were reduced.

[1393] Also, CD4 + RORγt + / CD4 + cells (Th17 cells) and PD-1 + CXCR5 + / CD4 +Cells (T follicular helper cells) were also significantly reduced.

[1394] Th17 cells play an important role in autoimmune and inflammatory diseases through the secretion of inflammatory cytokines (e.g., IL-17), and Tfh cells are involved in inducing antibody production by B cells.

[1395] On the other hand, CD4 has the function of maintaining immune homeostasis and suppressing autoimmunity. + Foxp3 + / CD4 + Regulatory T cells (Treg) did not show a significant decrease by compound treatment.

[1396] These results indicate that the compound of the present invention significantly reduced the proportion of T cell subtypes that play an important role in inflammatory and autoimmune pathology.

[1397] Therefore, this compound is expected to have the potential as an immunomodulatory agent that can selectively act on diseases caused by overactivation of Th17 and Tfh cells, such as inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE).

[1398] - Measurement of total IgG concentration in serum -

[1399] Figure 36 is a graph showing the results of measuring the total IgG concentration in the serum obtained during the autopsy of a sensitized animal model and in the serum of normal mice, and expressing this as a relative concentration value.

[1400] Based on this, it was confirmed that the concentration of IgG in the serum of mice administered the compound according to the present invention was significantly lower than that of mice administered the control substance, and that the actual antibody production amount was reduced.

[1401] Based on the above, it was confirmed that the compound according to the present invention suppresses the activity of specific immune cells involved in the formation of antibodies, thereby ultimately inhibiting the production of antibodies.

[1402] That is, it is believed that the compound of the present invention can be utilized as an immune modulatory substance that can be effectively applied to various immune-related diseases such as autoimmune diseases, inflammatory diseases, transplant rejection, GVHD, and cancer diseases by selectively reducing pathologically activated cell groups among B cell and T cell subtypes.

[1403]

[1404] Experimental Example 12: In vivo skin graft immunosuppression efficacy experiment

[1405] In order to evaluate the immunosuppressive effect of the compound according to the present invention, a skin graft animal model was constructed, and the efficacy of the compound was analyzed in the model.

[1406] First, 7-week-old female BALB / c mice weighing approximately 20 g were used as donors, and female C57BL / 6 mice of the same age and weight were used as recipients. All experimental animals were supplied by Hana Biotech Co., Ltd.

[1407] Before the experiment, the animals were acclimated for one week in a breeding facility under SPF conditions and then used in the experiment. The breeding environment was maintained at a temperature of 22±2℃, a relative humidity of 55±10%, and a 12-hour day / night cycle.

[1408] To establish a skin graft model, anesthesia was induced in C57BL / 6 mice by intraperitoneal injection of an anesthetic solution consisting of ketamine, rumpun, and PBS in a volume ratio of 1:1:3.

[1409] After removing and disinfecting the dorsal hair of an anesthetized mouse, full-thickness skin was excised using an 8-mm diameter punch. Then, skin of the same size collected from a donor mouse (BALB / c) was transplanted.

[1410] In the test group, the compounds GO15F (20 mg / kg) and GO88 (0.15 mg / kg) of the present invention were administered intraperitoneally twice a day at 12-hour intervals starting 2 days before transplantation, and administration was continued in the same manner after transplantation.

[1411] The control group was administered only vehicle in the same manner.

[1412] For immune cell analysis, mice from each group were sacrificed on the 9th day after transplantation, and cells were isolated from the spleen.

[1413] Isolated splenocytes were suspended in MACS buffer (Miltenyi Biotec., Cat. # 130-092-987) and placed in FACS tubes at 5 × 10 5 After dispensing each cell, anti-mouse CD16 / CD32 (BioXCell, Cat. # BP0307) was reacted at a concentration of 1 μg / mL for 30 minutes to block nonspecific antibody binding.

[1414] Afterwards, PerCP / Cyanine5.5 anti-CD3 (Biolegend, Cat. #100218), an antibody to label T cells, and FITC anti-mouse B220 (eBioscience), an antibody to label B cells TM , Cat. # 11-0452-81) for 30 minutes each, centrifuged at 1,500 rpm for 5 minutes, and resuspended in 100 μL of MACS buffer.

[1415] Afterwards, the proportion of CD3 and B220 positive cells in each cell was analyzed using a flow cytometer.

[1416] The results are shown in Figure 37.

[1417] Through this, the change in the relative ratio of T cells and B cells according to treatment with the compound of the present invention was quantitatively evaluated.

[1418] Figure 37 visualizes these results as a bar graph, where the vertical axis represents the proportion (%) of T cells and B cells within spleen cells, and the horizontal axis indicates each experimental group (e.g., NT, GO15F, etc.) separately.

[1419] As a result, in the control group (not treated, NT) that only performed skin grafting, splenic T cells (CD3 + ) and B cells (B220 + ) were observed to have increased in all cases.

[1420] On the other hand, the group administered the compound of the present invention showed a decrease in the ratio of T cells and B cells, and through this, it was confirmed that the compound of the present invention exhibits an effect of suppressing immune cell activity in a transplant animal model.

[1421] In addition, in the group administered 0.15 mg / kg of GO88 among the compounds of the present invention twice a day, it was observed that the grafts were bright red and blood flow was maintained well in 3 out of 5 animals on the 10th day after transplantation and in 1 out of 5 animals on the 15th day, indicating that the engraftment status was stably maintained.

[1422] These results suggest that GO88 is effective in delaying immune rejection of grafts.

[1423] Figure 38 is a photograph of a skin grafted mouse administered a compound according to the present invention.

[1424] Through the above results, it was confirmed that the immune response induced during a living body transplant is effectively controlled by administration of the compound according to the present invention, thereby showing the effect of alleviating or preventing graft rejection.

[1425] In particular, the compound of the present invention is believed to contribute to inhibiting the activation of immune cells such as T cells and B cells by inhibiting or antagonizing the phosphorylation of PDK1.

[1426] This mechanism of action is thought to play an important role in promoting graft engraftment and extending graft survival by suppressing excessive proliferation of immune cells.

[1427] Therefore, it can be seen that the compound of the present invention acts as an immunomodulatory substance that effectively controls the activity of immune cells by inhibiting or antagonizing the functional activity of PDK1 and alleviates immune rejection response to the graft.

[1428] It is believed that the compound of the present invention, when administered in an appropriate therapeutically effective amount, can be used as a therapeutic agent that can improve the survival rate of grafts in situations requiring immune regulation, such as organ transplantation and tissue transplantation.

[1429]

[1430] Experimental Example 13: Anti-aging and anti-aging effects in NHDF cells

[1431] In order to confirm the anti-aging and reverse-aging effects of GO15F, a compound of the present invention, a NHDF (Normal Human Dermal Fibroblast, Promocell) cell model in which aging was induced by treatment with doxorubicin was constructed, and β-galactosidase activity and Ki-67 expression were analyzed for the cells.

[1432] - Anti-aging efficacy confirmed -

[1433] First, NHDF cells were seeded at 1 × 10⁴ cells per well in a 12-well plate and stabilized for 24 hours.

[1434] Afterwards, the stabilized cells were treated with the compound GO15F (0.01, 1 μM) of the present invention, respectively, and pre-incubated for 24 hours.

[1435] After pretreatment, the medium was removed, and GO15F was treated in a medium containing Doxorubicin (100 ng / ml) and IGF-1 (100 ng / ml) and cultured for 7 days.

[1436] During this process, fresh media was replaced every two days.

[1437] After the culture was completed, the cells were washed with PBS, fixed with 1× Fixation buffer for 15 minutes, washed again with PBS, and then 300 μL of 1× working SA-β-gal buffer was added to each well, followed by reaction in a 37°C incubator for 24 hours.

[1438] After the reaction was completed, the cells were washed with PBS, and the fluorescence level of the blue-stained β-gal-positive cells was observed and photographed using an optical microscope.

[1439] This is shown in Figure 39.

[1440] Referring to Figure 39, compared to the control group in which β-galactosidase activity increased by Doxorubicin and IGF-1 treatment, the number of β-gal positive cells was confirmed to be reduced in the GO15F treatment group, suggesting that GO15F may have an anti-aging effect through inhibition of the cellular aging mechanism.

[1441] - Increased cell proliferation capacity -

[1442] In addition, in order to confirm the effect of the compound of the present invention (GO15F) on proliferation activity in senescence-induced NHDF (Normal Human Dermal Fibroblast) cells, Ki-67 expression was measured through FACS analysis.

[1443] First, NHDF cells were seeded at 1 × 10⁴ cells per well in a 12-well plate and stabilized for 24 h. Then, GO15F was treated at a concentration of 0.01 μM for 24 h. After pretreatment, the medium was removed, and GO15F (0.01 μM) was added to medium containing doxorubicin (100 ng / ml) and IGF-1 (100 ng / ml), and cultured for 7 days, with fresh media replaced every 2 days.

[1444] After incubation was completed, cells were detached with Trypsin-EDTA, washed once with PBS, and centrifuged at 1,500 rpm for 3 minutes.

[1445] Afterwards, the cells were fixed for 15 minutes with 1× Fixation buffer, washed with PBS, and reacted with blocking buffer for 1 hour.

[1446] After blocking, Ki-67 antibody was diluted 1:100 and reacted at room temperature for 1 hour, washed three times with PBS (1,500 rpm, 3 minutes), and Alexa Fluor 488-conjugated secondary antibody was reacted at room temperature for 1 hour, and washed three times with PBS.

[1447] Finally, the prepared cells were applied to a FACS analyzer to measure cells showing fluorescence expression of Ki-67.

[1448] This is shown in Figure 40.

[1449] As a result, it was confirmed that the number of cells expressing Ki-67 increased in the group treated with the compound of the present invention compared to the control group in which Ki-67 expression was significantly reduced by Doxorubicin and IGF-1.

[1450] Through this, it is judged that the compound of the present invention has the function of inhibiting cell aging and inducing reverse aging by reducing the accumulation of β-galactosidase positive cells in a cell aging-inducing environment and simultaneously increasing Ki-67 expression to restore the cell's proliferative ability.

[1451] Based on these actions, it is believed that this compound has the potential to be utilized as a PDK1 inhibitor for anti-aging or reverse-aging.

[1452]

[1453] Experimental Example 14: Experimental study on the efficacy of inhibiting pulmonary fibrosis in vivo and in vitro.

[1454] In order to evaluate the therapeutic efficacy of the compound according to the present invention on pulmonary fibrosis, an animal model in which pulmonary fibrosis was induced through intratracheal administration of bleomycin was established.

[1455] To this end, 8-week-old male Balb / c mice were anesthetized with general anesthesia using isoflurane (2-3% isoflurane in oxygen). The neck area was disinfected and the skin was incised to expose the trachea.

[1456] A 100 μL solution of 5 mg / kg diluted Bleomycin (Sigma-Aldrich, USA) was directly administered into the exposed trachea using a microsyringe (27G needle).

[1457] This appearance was photographed and pasted in Figure 41.

[1458] Two days before administration of bleomycin, the compound of the present invention or a comparative drug was injected intraperitoneally at a given concentration and dose, and administration was continued once a day for a total of 14 days.

[1459] The experimental groups included Normal, Bleomycin-only treatment group (BLM), and BLM + GO88 (0.2 mg / kg), which is a group simultaneously treated with BLM and the compound of the present invention.

[1460] After 10 days, the mice were humanely euthanized using carbon dioxide gas, the trachea was incised, and PBS was injected into the trachea to remove blood in the lungs.

[1461] Lung tissues washed with PBS were excised and fixed in a 4% paraformaldehyde solution for 24 hours. Paraffin blocks and tissue sections were prepared. The prepared sections were subjected to pathological analysis using H&E, Masson's trichrome, and Sirius red staining.

[1462] This is shown in Figure 42.

[1463] Figure 42 is a photograph of a lung extracted after administering a compound according to the present invention to a mouse with pulmonary fibrosis, staining the lung, and pathologically analyzing the lung.

[1464] H&E staining results showed that tissue damage, including loss of alveolar structure and infiltration of numerous inflammatory cells, was observed in the BLM-only treatment group.

[1465] On the other hand, in the group administered the compound of the present invention, the alveolar structure was relatively well maintained, and it was confirmed that inflammatory cell infiltration was also reduced.

[1466] In addition, when analyzing collagen deposition, an indicator of fibrosis, using Masson's trichrome and Sirius red staining, the area of ​​collagen fibers stained blue and red was significantly increased in the BLM treatment group.

[1467] However, this collagen deposition was significantly reduced in the GO15F and GO88 treatment groups.

[1468] - Confirmation of inhibition of α-SMA expression -

[1469] Additionally, immunohistochemical (IHC) staining for α-smooth muscle actin (α-SMA), an activation indicator of lung fibroblasts, was performed.

[1470] This is shown in Figure 43.

[1471] Figure 43 is a photograph taken after administering a compound according to the present invention to a mouse with pulmonary fibrosis, performing immunohistochemical (IHC) staining on the extracted lung, and analyzing the results.

[1472] Referring to Figure 43, in the BLM alone treatment group, the expression of α-SMA positive cells in lung tissue was significantly increased, suggesting activation of fibroblasts and formation of myofibroblasts.

[1473] In contrast, α-SMA expression was significantly suppressed in the GO15F and GO88 administration groups compared to the BLM alone treatment group.

[1474] - Confirmed direct action on fibrosis-related mechanisms -

[1475] In addition, in order to confirm that the compound of the present invention directly acts on the fibrosis-related mechanism, an in vitro experiment was performed using human lung fibroblast MRC-5 cell line (Korea Cell Line Bank).

[1476] First, MRC-5 cells were seeded at 5 × 10 per well in a 6-well plate. 3 The cells were divided into groups and stabilized for 24 hours.

[1477] Afterwards, an untreated group, a group treated with TGF-β (5 ng / ml) alone, and an experimental group treated with TGF-β and GO88, a compound of the present invention, at concentrations of 0.5 μM and 1 μM, respectively, were formed.

[1478] After drug treatment for 24 hours in each group, the cell medium was removed and washed twice with cold PBS, and each group was treated with RIPA lysis buffer containing phosphatase inhibitor and protease inhibitor to extract proteins.

[1479] The extracted protein was reacted at 4°C for 30 minutes, centrifuged at 13,000 rpm for 15 minutes, and the supernatant was collected. The total protein concentration was measured using the BCA protein quantification method.

[1480] Afterwards, the proteins were separated through SDS-PAGE, transferred to PVDF membrane, and Western blot analysis was performed.

[1481] The expression level of Collagen I, a marker related to pulmonary fibrosis, was confirmed, and GAPDH was used as an endogenous control.

[1482] This is shown in Figure 44.

[1483] Referring to Figure 44, in the TGF-β treatment group, protein expression of Collagen I was significantly increased compared to the untreated group, but in the group treated with GO88 in parallel, protein expression of Collagen1 was suppressed in a concentration-dependent manner.

[1484] This result suggests that the compound GO88 of the present invention effectively inhibits the fibrosis mechanism induced by TGF-β, demonstrating its potential for use as a preventive or therapeutic agent for pulmonary fibrosis.

[1485] In summary, these results suggest that the compound of the present invention (GO88) alleviates lung damage by suppressing inflammatory and fibrotic reactions in lung tissue, inhibits fibroblast activation by reducing α-SMA expression, and prevents excessive accumulation of Collagen I in tissue.

[1486] In addition, the present compound was confirmed to effectively inhibit the increase in Collagen I expression in MRC-5 cells induced by TGF-β, suggesting the possibility of regulating fibrosis-related mechanisms at the cellular level as well as the tissue level.

[1487] Therefore, the compound of the present invention can be usefully utilized as a pharmaceutical composition for preventing or treating various fibrotic diseases including pulmonary fibrosis.

[1488]

[1489] Experimental Example 15: Establishment of an Autoimmune Disease Model (Atopy) and Verification of Treatment Efficacy

[1490] In order to verify the therapeutic effect of the compound according to the present invention on atopic dermatitis (AD), an atopic animal model was constructed as follows, and the compound according to the present invention was injected to evaluate the alleviation of skin lesions.

[1491] To establish an atopic mouse animal model, BALB / c (7 weeks old, 20 g, Female) were purchased from Hana Biotech Co., Ltd. and allowed to adapt to the breeding environment for one week.

[1492] Afterwards, the hair on the back of the mouse was first removed with a hair remover, and then completely removed with a hair removal cream (Nicrine Cream (80% thioglycolic acid, Ildong Pharmaceutical)). The mouse was kept for 24 hours to check for any wounds on the back.

[1493] Thereafter, in order to verify the atopy prevention and treatment effect of the compound according to the present invention, experimental groups were set up as a group that did not induce atopy (Normal, Not Treatment (NT)), a group that only induces atopy (AD, NT), a group that induces atopy and injected the injection solvent into the peritoneal cavity (AD, Vehicle), and a group that induces atopy and injected the compound according to the present invention into the peritoneal cavity (AD, compound of the present invention (GO15F, GO48, GO77, GO86, GO88)).

[1494] In order to induce atopy in mice, 200ul of 1% DNCB was applied locally to the skin once a day for 3 days to check for atopic lesions, 3 times in total, followed by a 4-day rest period. Then, 200ul of 0.5% DNCB was applied to the same area once every other day for 2 weeks, 7 times in total, to induce atopy.

[1495] At the same time, in order to compare the atopy occurrence prevention and treatment effect of the compound according to the present invention, for the group receiving the drug, the compound at a set dose per mouse was completely dissolved in DMSO corresponding to 10% of the administered dose, and then diluted in a Cremophor EL-PEG 400-distilled water mixture so that the final ratio of DMSO:Cremophor EL:PEG 400:distilled water was 1:1:4:4 (v / v / v / v).

[1496] The injection solution was administered intraperitoneally once a day to each mouse at 100 μL 24 hours after hair removal. In the vehicle administration group, 100 μL of the injection solution excluding the drug (DMSO: Cremophor EL: PEG 400: Distilled water = 1:1:4:4 (v / v / v / v)) was administered intraperitoneally once a day.

[1497] At 14 days after the start of injection, the degree of skin lesions on the back of the mice in each group was observed, and the pathological tissues of the relevant areas were analyzed through H&E and Toluidine Blue staining, and the related results are attached to Figures 46 and 47.

[1498] Referring to Figure 46, in the group in which only atopic dermatitis was induced (AD, NT) and in the group in which atopy was induced and the injection solvent was injected intraperitoneally (AD, Vehicle), hyperkeratosis accumulation was severely observed, but in the mice administered the compound according to the present invention, it was observed that hyperkeratosis accumulation was reduced.

[1499] Referring to Figure 47, the skin tissue of atopic dermatitis-induced mice was observed through H&E staining, and the control group (NT and Vehicle) showed increased epidermal thickness and increased infiltration of inflammatory cells compared to the normal control group (Normal).

[1500] Additionally, Toluidine Blue staining observed a significant increase in the number of mast cells in the dermis.

[1501] On the other hand, in the group administered the compound according to the present invention, epidermal hyperplasia was significantly alleviated, and a decrease in mast cell accumulation was confirmed in Toluidine Blue staining.

[1502] As a result, it was confirmed that the compound according to the present invention suppresses the inflammatory response of atopic dermatitis and has an effect of alleviating hyperkeratosis and mast cell accumulation.

[1503] It is believed that this compound may act as an effective substance for treating atopic dermatitis.

[1504]

[1505] Experimental Example 16: Binding Affinity Test with PDK1 Using MST

[1506] Microscale Thermophoresis (MST) analysis was performed to quantitatively measure the binding affinity between PDK1 protein and substrate peptide (PDKTide) or our own small molecule compound (GO88).

[1507] The target proteins for analysis were the full-length (PDK1-FL) protein and the Protein Kinase Domain (PKD) fragment of human PDK1, each expressed through a baculovirus expression system using an insect cell line (Sf9).

[1508] The harvested cells were then disrupted with lysis buffer and purified to a purity of over 90% through Ni-NTA affinity chromatography and Superdex 200 Increase 10 / 300 GL size exclusion chromatography (Cytiva). The purity of the purified protein was confirmed through SDS-PAGE and Coomassie Brilliant Blue staining.

[1509] The purified protein was fluorescently labeled using the Monolith NT™ RED-NHS protein fluorescent labeling kit (NanoTemper).

[1510] Specifically, a 20 μM concentration of protein was dissolved in PBS (pH 7.4) buffer, mixed with a fluorescent reagent, and reacted under dark conditions at room temperature for 30 minutes, after which the buffer was exchanged with MST analysis buffer (50 mM HEPES, 150 mM NaCl, 1 mM DTT, 0.05% Tween-20, pH 7.5).

[1511] The fluorescently labeled protein was diluted to a final concentration of 20 nM, then mixed with the ligand (GO88, 10 nM-1 mM) serially diluted to various concentrations, and reacted at room temperature for 30 minutes in the presence or absence of ATP or ADP (final concentration 1 mM).

[1512] The sample for which the reaction was completed was injected into a capillary dedicated to MST (NanoTemper) and analyzed under laser intensity conditions using Monolith NT.115 equipment (NanoTemper).

[1513] The laser irradiation time was 30 seconds and the total measurement time was approximately 40 seconds.

[1514] The measured data were analyzed using MO.Affinity Analysis software (NanoTemper), and the dissociation constant (Kd) was calculated from the binding curve.

[1515] This is shown in Figure 48.

[1516] Figure 48 is a graph obtained through comparative analysis of binding affinity between PDK1 and GO88 using Microscale Thermophoresis (MST) according to the invention.

[1517] For reference, the binding between PDK1-PKD protein and GO88 was measured to have a dissociation constant (Kd) of approximately 371 nM in the presence of ATP, indicating an intermediate level of binding affinity.

[1518] On the other hand, the binding between full-length PDK1 and GO88 had a Kd of approximately 58.4 nM, indicating a binding affinity that was approximately 6 times stronger than that of the PKD fragment.

[1519] These results suggest that GO88 may exhibit high binding affinity through interaction with specific domains of PDK1 (e.g., PIF domain) or binding through allosteric sites, and that it may act as a non-competitive inhibitor as binding is maintained even in the presence of ATP.

[1520]

[1521] PDK1 of the present invention is a protein that plays an important role in regulating various biological processes such as cell growth, death, metastasis, and metabolic regulation, and has been a major research subject in the development of cancer treatment agents. At the same time, it can also play an important role in the development of autoimmune disease treatment agents. Therefore, the present invention, which can fundamentally regulate this, can be used in various meaningful ways in new anticancer and autoimmune fields.

Claims

1. A compound characterized by comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof: <Chemical Formula 1> Z 1 -Prd-CONH-R 10 Here, Z 1 is -NH2 (or -NHR1, wherein R1 is benzene or a benzene derivative; Compound 59), -SH, a methylthio group, a benzoyl group, a benzyloxy group, an alkyl group substituted with a halogen, a benzimidazole group, -OH, -SH, a halogen, -NO2, -CF3, a C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C3-C10 arylalkyl (Ar-(CH2)n-), a C5-C10 aryl (Ar-), a C3-C10 alkylaryl ((CH2)n-Ar-), a C3-C10 cycloalkyl, a C3-C10 heteroaryl or a C3-C10 heterocycloalkyl, or is unsubstituted or substituted, a C5-C10 aryl or a C3-C10 heteroaryl, Prd is pyridine or benzene, -CONH- is an amide bond, R 10 is a C8-C14 alkyl, C8-C14 alkenyl or C8-C14 alkynyl, wherein one, two or three hydrogen atoms of the terminal carbon are substituted with halogen (fluorine, chlorine, bromine, iodine), morpholine or an analogue thereof, piperazine or an analogue thereof, thiomorpholine or an analogue thereof, pyrrolidine or an analogue thereof, piperidine or an analogue thereof, 3,4-dihydro-2H-benzo[b][1,4]oxazine or an analogue thereof, pyrimidine or an analogue thereof, pyrazine or an analogue thereof, or a functional group described in Table 1.

2. In paragraph 1, The above R 10 A compound characterized in that the alkyl, alkenyl or alkynyl group has 8 to 14 carbon atoms and exhibits the effect of non-competitive inhibition of phosphorylation of PDK1.

3. In paragraph 2, A compound characterized in that if the number of carbon atoms is 7 or less, it is difficult to exert an immunosuppressive effect, and if the number of carbon atoms is 15 or more, it is difficult to form an alternative stereoisomer bond or to be absorbed in the body.

4. In paragraph 1, The compound is characterized in that it comprises at least one of the following substances: 2-Amino-N-(12-fluoro-dodecyl)-nicotinamide, 4'-methyl-biphenyl-2-carboxylic acid (12-fluoro-dodecyl)-amide, 2-amino-N-dodecylnicotinamide, 2-bromo-N-(12-fluoro-dodecyl)-nicotinamide, 2-amino-N-[12-(3,4-dihydro-1H-isoquinolin-2-yl)-dodecyl]-nicotinamide, N-(12-fluoro-dodecyl)-3-(3-trifluoromethyl-phenylamino)-isonicotinamide, 4-chloro-N-(12-fluoro-dodecyl)-nicotinamide, 2-amino-N-(12-morpholin-4-yl-dodecyl)-nicotinamide, 2-Amino-N-(8-fluoro-octyl)-nicotinamide, N-(12-fluoro-dodecyl)-2-mercapto-nicotinamide, 2-amino-N-(10-morpholin-4-yl-decyl)-nicotinamide, biphenyl-2-carboxylic acid (12-fluoro-dodecyl)-amide, 1H-indole-4-carboxylic acid (12-fluoro-dodecyl)-amide, 3-hydroxy-pyridine-2-carboxylic acid (12-fluoro-dodecyl)-amide, 3-benzoyl-pyridine-2-carboxylic acid (12-fluoro-dodecyl)-amide, isoquinoline-1-carboxylic acid (12-fluoro-dodecyl)-amide, 2-(4-Chloro-phenoxy)-N-(12-fluoro-dodecyl)-nicotinamide, N-(12-fluoro-dodecyl)-2-methylsulfanyl-nicotinamide, 2-amino-N-(10-fluoro-decyl)-nicotinamide, 3-(12-fluoro-dodecylcarbamoyl)-pyridin-2-yl-ammonium chloride, 2-amino-N-(11-fluoro-undecyl)-nicotinamide, 3-(11-fluoro-undecylcarbamoyl)-pyridin-2-yl-ammonium chloride, N-(12-fluoro-dodecyl)-2-hydroxy-nicotinamide, 4-amino-N-(12-fluoro-dodecyl)-nicotinamide, 3-amino-N-(12-fluoro-dodecyl)-isonicotinamide, N-(12-Fluoro-dodecyl)-2-trifluoromethyl-nicotinamide, N-(12-Fluoro-dodecyl)-3-iodo-isonicotinamide, 2-amino-N-(12-thiomorpholin-4-yl-dodecyl)nicotinamide and 2-amino-N-(12-(piperazin-1-yl)dodecyl)nicotinamide.

5. In paragraph 1, A compound characterized in that the compound is at least one selected from the group consisting of chemical formulas 2 to 20.

6. In paragraph 1, A compound characterized in that the compound is at least one selected from the group consisting of chemical formulas 21 to 40.

7. In paragraph 1, A compound characterized in that the compound is at least one selected from the group consisting of chemical formulas 43 to 60.

8. In paragraph 1, A compound characterized in that the compound is at least one selected from the group consisting of chemical formulas 61 to 64, 67 to 71, 73, and 76.

9. In paragraph 1, A compound characterized in that the compound is at least one selected from the group consisting of chemical formulas 88 to 99.

10. In paragraph 1, A compound characterized in that the compound is at least one selected from the group consisting of chemical formulas 101 to 118.

11. In paragraph 1, A compound characterized in that the compound is at least one selected from the group consisting of chemical formulas 121 to 134.

12. In paragraph 1, A compound characterized in that the compound is at least one selected from the group consisting of chemical formulas 147 to 160.

13. In paragraph 1, A compound characterized in that the compound is at least one selected from the group consisting of chemical formulas 161 to 180.

14. In paragraph 1, A compound characterized in that the compound is at least one selected from the group consisting of chemical formulas 181 to 190.

15. In paragraph 1, A compound characterized in that the compound is at least one selected from the group consisting of chemical formulas 191, 214, 216 to 225.

16. A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, characterized in that it is used to inhibit, antagonize, or regulate PDK1 (3-phosphoinositide-dependent protein kinase 1).

17. A method for inhibiting PDK1, comprising the step of contacting an effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof with a subject containing PDK1 (3-phosphoinositide-dependent protein kinase 1) to inhibit PDK1.

18. In paragraph 17, A method characterized in that the above object is handled in vivo or in vitro.

19. A method for inhibiting PDK1, characterized by comprising a step of contacting a cell containing PDK1 (3-phosphoinositide-dependent protein kinase 1) with an effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, thereby inhibiting PDK1.

20. In paragraph 19, A method characterized in that the above cells are handled in vivo or in vitro.

21. A method for antagonizing PDK1, characterized by comprising the step of contacting an effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof with a subject containing PDK1 (3-phosphoinositide-dependent protein kinase 1) to antagonize PDK1.

22. In paragraph 21, A method characterized in that the above object is handled in vivo or in vitro.

23. A method for antagonizing PDK1, characterized by comprising the step of contacting a cell containing PDK1 (3-phosphoinositide-dependent protein kinase 1) with an effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, thereby antagonizing PDK1.

24. In paragraph 23, A method characterized in that the above cells are handled in vivo or in vitro.

25. A method for treating cancer, comprising administering to a subject suffering from cancer a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof used for inhibiting, antagonizing, or regulating PDK1 (3-phosphoinositide-dependent protein kinase 1) of Article 16.

26. A method for treating an autoimmune disease, comprising administering to a subject suffering from an autoimmune disease a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof used for inhibiting, antagonizing, or regulating PDK1 (3-phosphoinositide-dependent protein kinase 1) of Article 16.

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof as an active ingredient.

28. In paragraph 27, The pharmaceutical composition is characterized in that it non-competitively regulates PDK1 activity.

29. In paragraph 27, A pharmaceutical composition characterized in that the above PDK1 regulation is performed through allosteric binding.

30. In paragraph 27, The pharmaceutical composition is characterized in that it inhibits proliferation and survival signals of lymphocytes by blocking the PDK1-related pathway.

31. In paragraph 27, The pharmaceutical composition is characterized in that it is used for the treatment of autoimmune diseases, immune hypersensitivity reactions, chronic inflammatory diseases, and lymphocyte-related hyperproliferative diseases occurring in immune cells, macrophages, T cells, B cells, or plasma cells.

32. In paragraph 27, A pharmaceutical composition characterized in that the above-mentioned immune hypersensitivity reaction disease is at least one of chronic urticaria, asthma, atopic dermatitis, allergic rhinitis, or serum sickness.

33. In paragraph 27, A pharmaceutical composition characterized in that the above pharmaceutical composition is used for preventing or treating rejection immune response after transplantation or for treating lymphoproliferative disease.

34. In paragraph 27, A pharmaceutical composition characterized in that the pharmaceutical composition exhibits an effect of reducing immunoglobulin production.

35. In paragraph 27, A pharmaceutical composition characterized in that the pharmaceutical composition exhibits an effect of reducing lymph node enlargement, autoantibodies, and inflammatory cytokine production.

36. In paragraph 27, The above pharmaceutical composition is characterized in that it inhibits metastasis of cancer cells.

37. In Article 27, A pharmaceutical composition characterized in that the above pharmaceutical composition exhibits an anti-aging or reverse-aging effect.

38. In paragraph 27, A pharmaceutical composition characterized in that the above pharmaceutical composition is characterized by a decrease in intracellular β-galactosidase activity or an increase in Ki-67 expression.

39. In paragraph 27, A pharmaceutical composition characterized in that the above pharmaceutical composition has a use for treating a fibrotic disease.

40. In paragraph 39, A pharmaceutical composition characterized in that the above fibrotic disease is pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), systemic sclerosis-related interstitial lung disease (SSc-ILD), radiation-induced pulmonary fibrosis, liver fibrosis, renal fibrosis, cardiac fibrosis, retinal fibrosis, pancreatic fibrosis, or skin fibrotic disease.

41. In paragraph 27, The pharmaceutical composition is characterized in that it exhibits an effect of reducing α-SMA expression and collagen accumulation.

42. In paragraph 27, The pharmaceutical composition is characterized in that the above pharmaceutical composition is used for inhibiting or antagonizing PDK1 (3-phosphoinositide-dependent protein kinase 1) activity.

43. In paragraph 27, A pharmaceutical composition characterized in that the above pharmaceutical composition is used for the treatment of cancer or solid tumor cancer.

44. In paragraph 43, The above solid tumor cancers include glioma, glioblastoma, medulloblastoma, meningioma, pituitary adenoma, optic glioma, spinal cord tumor, schwannoma, brain metastases, primary CNS lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, large cell carcinoma, malignant mesothelioma, tracheal cancer, laryngeal cancer, pharyngeal cancer, nasal cavity cancer, Oral cancer, tongue cancer, salivary gland cancer, laryngeal cancer, pharyngeal cancer, nasal cavity cancer, paranasal sinus cancer, thyroid cancer, parathyroid cancer, olfactory neuroblastoma, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, inflammatory breast cancer, triple-negative breast cancer, papillary carcinoma,Mucinous carcinoma, tubular carcinoma, medullary carcinoma, metastatic breast cancer, esophageal cancer, gastric cancer, small intestine cancer, colon cancer, rectal cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic cancer, anal cancer, renal cell carcinoma, urothelial carcinoma, bladder cancer, ureteral cancer, urethral cancer, prostate cancer, testicular cancer, penile cancer, adrenocortical carcinoma, Pheochromocytoma, Endometrial cancer, Cervical cancer, Uterine sarcoma, Ovarian cancer, Fallopian tube cancer, Vaginal cancer, Vulvar cancer, Hydatidiform mole, Choriocarcinoma, Germinoma, Testicular cancer, Penile cancer, Prostate cancer, Epididymal cancer, Seminal vesicle cancer, Urethral cancer, Germinoma,Choriocarcinoma, Teratoma, Leydig cell tumor, Osteosarcoma, Chondrosarcoma, Ewing sarcoma, Fibrosarcoma, Synovial sarcoma, Liposarcoma, Rhabdomyosarcoma, Leiomyosarcoma, Desmoid tumor, Giant cell tumor of bone, Skin cancer, Melanoma, Basal cell carcinoma, Squamous cell carcinoma, Kaposi's sarcoma, Neuroendocrine tumor, Gastrointestinal stromal tumor A pharmaceutical composition characterized by being a tumor, GIST), retinoblastoma, Wilms tumor or neuroblastoma.

45. In paragraph 27, A pharmaceutical composition characterized in that the above pharmaceutical composition is used for treating blood cancer.

46. ​​In paragraph 45, The above blood cancers include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma, cutaneous T-cell lymphoma (CTCL), plasmablastic lymphoma, Burkitt lymphoma, multiple myeloma, myelodysplastic syndromes (MDS), or A pharmaceutical composition characterized by being a myeloproliferative neoplasm (MPN).

47. In paragraph 27, The above autoimmune diseases include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren's syndrome, multiple sclerosis, inflammatory bowel disease (Crohn's disease or ulcerative colitis), psoriatic arthritis, autoimmune hemolytic anemia, and immune thrombocytopenia (ITP). Glomerulitis, systemic lupus erythematosus (SLE), glomerulitis, ankylosing spondylitis, myastenia gravis, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic sclerosis, pernicious anemia, autoimmune anemia, infammatory bowel disease, insulin-dependent diabetes mellitus (IDDM), type 1 diabetes, Graves disease, Graves hyperthyroidism, Kikuchi disease, hemophagocytic lymphohistiocytosis, adult onset Still's disease, Behcet disease, immune A pharmaceutical composition characterized by thrombocytopenia (ITP), alopecia areata, IgG4-related disease, psoriasis, asthma or transplant rejection.

48. In paragraph 27, A pharmaceutical composition characterized in that the above pharmaceutical composition is used for the purpose of preventing or treating Alzheimer's disease.

49. In paragraph 48, The above prevention or treatment is a pharmaceutical composition characterized by inhibiting the activity of PDK1 (phosphoinositide-dependent kinase-1).

50. In paragraph 27, The pharmaceutical composition is characterized in that it inhibits pathological angiogenesis in the eye by inhibiting the activity of PDK1.

51. In paragraph 50, A pharmaceutical composition characterized in that the above pathological neovascularization is caused by macular degeneration, diabetic retinopathy, retinal vein occlusion or retinal proliferative disease.

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