Small molecule compounds for controlling endosomal toll-like receptors and autoimmune disease therapeutic agents using the same

Abstract

The present invention relates to an antagonistic small molecule compound having a function of inhibiting an endosome toll-like receptor (TLR), and more particularly to: a small molecule compound for inhibiting a TLR3 / 7 / 8 / 9 signaling pathway; a composition for inhibiting a toll-like receptor comprising the small molecule compound; and a composition for preventing or treating an autoimmune disease, an inflammatory disease, or a viral disease. The compound according to the present invention shows very significant results in a systemic lupus erythematosus animal model, which not only prevents TNF-α secretion induced by poly I:C (TLR3 agonist), imiquimod (TLR7 agonist), TL8-506 (TLR8 agonist), or ODN2395 (TLR9 agonist), but also inhibits the production of inflammatory cytokines. This indicates that the compound can also be used for preventing or treating TLR3, TLR7, TLR8, or TLR9-related autoimmune diseases, inflammatory diseases, and viral diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to an antagonistic small molecule compound having inhibitory activity against endosomal Toll-like receptors (TLRs), and more particularly to a small molecule compound inhibiting the signaling pathway of Toll-like receptors 3 / 7 / 8 / 9, a composition for inhibiting Toll-like receptors comprising the same, and a composition for preventing or treating an autoimmune disease, an inflammatory disease, or a viral disease comprising the same. BACKGROUND

[0002] The innate (or inborn) immunity is the first line of defense against bacterial infection in the mammalian immune system, and is activated upon recognition of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) by pattern recognition receptors such as Toll-like receptors (TLRs). Examples include triacyl lipoproteins (e.g., Pam3CSK4) recognized by TLR1 / 2 (Takeuchi, O. et al., J. Immunol. 169:10-14 (2002)), diacyl lipoproteins (e.g., Pam2CSK4) recognized by TLR2 / 6 (Takeuchi, O. et al., Int. Immunol. 13:933-940 (2001)), lipopolysaccharide (LPS) recognized by TLR4 (Poltorak, A. et al., Science 282:2085-2088 (1998)), bacterial flagellin recognized by TLR5 (Poltorak, A. et al., Science 282:2085-2088 (1998)), viral double-stranded RNA (dsRNA) recognized by TLR3 (Poltorak, A. et al., Science 282:2085-2088 (1998)), viral single-stranded RNA (ssRNA) recognized by TLR7 and TLR8 (Diebold, S. S. et al., Science 303:1529-1531 (2004); Heil, F. et al., Science 303:1526-1529 (2004)), unmethylated CpG-containing oligodeoxynucleotides (ODNs) recognized by TLR9 (Hemmi, H. et al., Nature 408:740-745 (2000)), etc.

[0003] TLRs play a key role in innate immune responses, and are classified into extracellular TLRs, including TLR1, TLR2, TLR4, TLR5, TLR6, and TLR11, which act on the plasma membrane, and intracellular TLRs, including TLR3, TLR7, TLR8, and TLR9, which act in cells such as endosomes. Structurally, TLRs have a leucine-rich repeat (LRR) site at the N-terminus of the extracellular domain, which is recognized by a ligand or a helper molecule, and a Toll / interleukin 1 receptor (TIR) domain at the C-terminus, which delivers a signal to the intracellular portion.

[0004] In particular, TLR3, TLR7, TLR8, and TLR9 detect exogenous single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), and CpG DNA exposed from endosomes of extracellular invading pathogens, or recognize endogenous ssRNA or DNA fragments exposed from damaged tissues due to necrosis or apoptosis in tissues resulting from abnormal responses, thereby amplifying inflammatory cytokines through a signaling process. Generally, TLR7 and TLR8 recognize ssRNA from influenza or damaged cells, while TLR9 detects CpG DNA fragments produced from the genomes of bacteria and viruses or damaged tissues, and TLR3 recognizes dsRNA as an intermediate product of viral multiplication, thereby activating the innate immune response. Due to the known roles of TLRs, research using TLRs as targets for treating immune-related diseases is actively being conducted worldwide.

[0005] In the MyD88 (myeloid differentiation primary response 88)-dependent signaling of TLR7 / 8 / 9, a dimer is formed with the corresponding ligand, and the TIR domain of the TLR binds to the TIR domain of MyD88 to form a complex, thereby activating the signaling pathway (Hemmi, H. et al., Nat. Immunol. 3, 196-200, (2002)). The activated TLR signal induces the activation of NF-κB, its migration to the nucleus, and the activation of MAPK, and expresses interferon alpha (IFNα) and IFN-inducible genes. The activation of NF-κB and MAPK causes the secretion of inflammatory cytokines such as TNFα, IL-1β (interleukin 1β), and IL-6. The MyD88-independent signaling process of TLR3 is initiated by binding between the TIR domain of TLR3 and the TIR domain of TRIF (TIR domain-containing adaptor-inducing interferon beta), and type 1 interferons are secreted due to the activation of interferon regulatory factors (IRFs). In addition, TLR activity produces oxidative stressors such as NO and ROS in macrophages.

[0006] TLRs (TLR3, TLR7, TLR8, and TLR9) in the membrane of endosomes play an important role in protecting a host from various viral and bacterial infections. In particular, the expression of TLR7, TLR8, and TLR9 is essential for sustained defense against pathogenic components or autoantigens released from damaged or stressed tissues / cells (Demaria, O. et al., J. Clin. Invest. 120:3651-3662 (2010)). Dysfunction of these TLRs that detect nucleic acids is associated with several autoimmune pathologies such as psoriasis and systemic lupus erythematosus (SLE) (Vincent, FB et al., Nat. Rev. Rheumatol. 10:365-373 (2014)). However, the etiology of these diseases is still unclear (Krieg, A.M. and Vollmer, J., Immunol. Rev. 220:251-269 (2007); Terhorst, D. et al., J. Immunol. 195:4953-4961 (2015)). Thus, there is an increasing need for developing novel antagonists that inhibit the progression of endosomal TLR-mediated diseases.

[0007] As described above, TLRs can serve as targets for treating various diseases such as autoimmune diseases, inflammatory diseases, viral diseases, and cancers, and thus there has been an active research on TLR-targeting substances and pharmaceutical compositions for treating TLR-related diseases.

[0008] Accordingly, as a result of intensive efforts to develop TLR-targeting substances and pharmaceutical compositions for treating TLR-related diseases, the present inventors found that a novel compound comprising a compound defined as “SK” inhibits the secretion of cytokines by inhibiting the TLR signaling pathway induced by the activation of TLR3, TLR7, TLR8, or TLR9, and completed the present application based on this finding.

[0009] The information described in the background techniques is only for the purpose of increasing the understanding of the background of the present application, and it should not be interpreted to include information that is well known to those skilled in the art to which the present application pertains. SUMMARY

[0010] An object of the present application is to provide a small molecule compound having an inhibitory effect on TLR (Toll-like receptor) function, and a composition for inhibiting TLR (Toll-like receptor) comprising the same.

[0011] Another object of the present application is to provide a composition for preventing or treating an autoimmune disease, an inflammatory disease, or a viral disease, the composition comprising the small molecule compound for inhibiting TLR or the composition.

[0012] Still another object of the present application is to provide a method for preventing or treating an autoimmune disease, an inflammatory disease, or a viral disease, the method including administration of the small molecule compound or the composition for inhibiting TLR.

[0013] Still another object of the present application is to provide a method for preventing or treating an autoimmune disease, an inflammatory disease, or a viral disease, the method including administration of the small molecule compound or the composition for inhibiting TLR.

[0014] Still another object of the present application is to provide a method for preventing or treating an autoimmune disease, an inflammatory disease, or a viral disease, the method including administration of the small molecule compound or the composition for inhibiting TLR.

[0015] To achieve the above object, the present application provides a compound represented by the following formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0016] [Formula 1]

[0017]

[0018] wherein R1 to R6 are the same as or different from each other, and each is independently a hydrogen atom, a halogen atom, a linear or branched alkyl group, an amino group, an alkyl amine, a heterocyclic amine, a nitrile group, a nitro group, a nitroso group, a hydroxyl group, a cycloalkyl group, a benzyl group, a haloalkyl group, an allyl group, an alkoxy group, an alkoxyalkyl group, an alkylcarbonyl group, a cycloalkylcarbonyl group, an arylcarbonyl group, an alkylarylcarbonyl group, an alkoxycarbonyl group, a cycloalkyloxy group, an aryl group, a heteroaryl group, a heterocycloalkyl group, an aryloxy group, an alkoxyheteroaryl group, a heteroaryloxyalkyl group, an alkylheteroaryl group, an alkylaryl group, an arylalkyl group, an alkylheteroaryl group, an alkyl ester, an alkyl ether, an alkyl amide, or an acryloyl group, or

[0019] R2 and R3 are connected to each other to form a substituted or unsubstituted cycloalkane or arene, or

[0020] R5 and R6 are connected to each other to form a substituted or unsubstituted cycloalkane or arene,

[0021] wherein the alkyl group, the alkyl amine, the heterocyclic amine, the alkoxy group, the alkoxyalkyl group, the alkyl ester, the alkyl ether, or the alkyl amide is C 1-30 the cycloalkyl group is C 3-30 the allyl group is C 2-30 the aryl group is C 6-30 and the heteroaryl group and the heterocycloalkyl group contain a heteroatom selected from fluorine, oxygen, sulfur, and nitrogen.

[0022] In addition, the present application provides a composition for inhibiting Toll-like receptor (TLR), the composition comprising a compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0023] In addition, the present application provides a composition for preventing or treating an autoimmune disease, an inflammatory disease, or a viral disease, the composition comprising the compound for inhibiting TLR or the composition.

[0024] In addition, the present application provides a method for preventing or treating an autoimmune disease, an inflammatory disease, or a viral disease, the method comprising administering the compound for inhibiting TLR or the composition.

[0025] In addition, the present application provides a use of the compound for inhibiting TLR or the composition for preventing or treating an autoimmune disease, an inflammatory disease, or a viral disease.

[0026] In addition, the present application provides a use of the compound for inhibiting TLR or the composition for manufacturing a medicament for preventing or treating an autoimmune disease, an inflammatory disease, or a viral disease. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 The overall computational screening workflow and the initial evaluation of the activity on TLR7 and TLR9 of the product SK01 are shown.

[0028] Figure 1 A shows the quantitative structure-activity relationship modeling and steps of the ligand screening method according to the present application, wherein the first step is divided into several sub-steps described in the orange boxes, Figure 1 B shows the inhibition of TNF-a induced by the TLR7 agonist Imiquimod (IMQ), Figure 1 C is a graph showing the inhibition of TNF-a secretion induced by the TLR9 agonist ODN2395, wherein cells were treated with SK01 for 1 hour, followed by IMQ (3.61 mM) or ODN2395 (0.5 mM) for 4 hours, and the secretion of TNF-a was detected by ELISA, Figure 1 D is a graph showing the evaluation of the cytotoxicity of SK01 in the mouse macrophage cell line RAW 264.7, wherein cells were treated with 20 mM or 50 mM SK01 for 24 hours, and cell viability was tested by MTT assay, Figure 1E is a graph showing the evaluation of the agonistic activity of SK01, where cells were treated with the ligand for 24 hours, the secretion of TNF-a was monitored by ELISA, the cytokine induction caused by ODN 2395 (0.5 mM) is shown for comparison, the experiments were performed in triplicate, and the difference shown as mean ± SEM was evaluated by two-tailed Student's t-test (*p < 0.05, **p < 0.01).

[0029] Figure 2 The main comparative inhibitory activity of SK01 and its structural derivatives (SK02-SK20) against TLR9 is shown.

[0030] Figure 3 The main comparative inhibitory activity of SK01 and its structural derivatives (SK02-SK20) against TLR9 is shown. Figure 2 The evaluation of the activity of the six derivatives of SK01 that show the main activity against TLR7 and TLR9 is shown in Table 1.

[0031] Figure 3 A is a graph showing the inhibitory activity of SK01 derivatives against TLR7 activation, where RAW 264.7 cells were treated with 2 mM or 5 mM inhibitor for 1 hour, then treated with the TLR7 agonist IMQ for 4 hours, Figure 3 B is a graph showing the inhibitory activity of SK01 derivatives against TLR9 activation, where RAW 264.7 cells were treated with 0.5 mM or 2 mM inhibitor for 1 hour, then treated with the TLR9 agonist ODN 2395 for 4 hours, and the secretion of TNF-a in all experiments was monitored by ELISA, Figure 3 C shows the two-dimensional structure of the ligands that exhibit TLR7 / 9 inhibitory activity in cell-based assays, where SK01 was identified as the initial lead, and its derivative SK16 was found to be an effective inhibitor for both TLR7 and TLR9, and Figure 3 D shows the SMILES string, IUPAC name, and molecular weight of the active ligands.

[0032] Figure 4 is a graph showing the in vitro efficacy of SK01, SK16, and HCQ.

[0033] Figure 4 A is a graph showing the comparative evaluation of the cytotoxicity induced by SK01, SK16, and HCQ, where RAW264.7 cells were exposed to increasing concentrations (12.5, 25, 50, 100, and 200 mM) of ligands for 24 hours, and cell viability was monitored by the MTT assay, and the graph shows the LC 50Furthermore, by performing nonlinear regression analysis on each concentration-response curve using GraphPad Prism 7 (GraphPad software, USA), the LC50 indicating 50% cell viability (in RAW 264.7 cells) was determined. 50 , Figure 4 B is a graph showing the TLR3-dependent inhibition (%) of TNF-α secretion induced by the TLR3 agonist poly-I:C. Figure 4 C is a graph used to determine the TLR7-dependent inhibition (%) of TNF-α secretion induced by the TLR7 agonist IMQ. Figure 4 D is a graph used to determine the TLR9-dependent inhibition (%) of TNF-α secretion induced by the TLR9 agonist ODN2395. Figure 4 B. Figure 4 C and Figure 4 In D, RAW 264.7 cells were treated with a predetermined concentration of inhibitor for 1 hour, then stimulated with IMQ or ODN2395 for 4 hours and with poly-I:C for 24 hours. TNF-α secretion was measured by ELISA, and the values ​​were averaged and displayed as a ratio based on the negative control (untreated, set at 0%) and the positive control (agonist only; set at 100% (highest value for each case)). IC50 was obtained using nonlinear regression analysis performed using GraphPad Prism 7 (GraphPad software, USA). 50 This is the point where TNF-α secretion is inhibited by 50%, and Figure 4 E shows that through Figure 4 A to Figure 5 LC obtained in D 50 and IC 50 The therapeutic index for each drug for each type of TLR was derived.

[0034] Figure 5 This is a diagram showing the effect of SK01 on the signal transmission path of the same source TLR.

[0035] Figure 5 A to Figure 5 C demonstrates the inhibitory activity of SK01 against TLRs (TLR1 / 2, TLR2 / 6, and TLR4) exposed on the cell surface, and Figure 5 D to Figure 6G shows the inhibitory activity of SK01 against endosomal TLRs (TLR3, TLR7, TLR8 and TLR9), where RAW 264.7 cells were treated with negative control, positive control (ligand only), additional positive control (ligand and 0.25% DMSO) or SK01 at predetermined concentrations for 1 hour, then stimulated with TLR-specific agonists for 4 or 24 hours (only for TLR3), for TLR8, a human monocytic cell line (THP-1) was used and THP-1 cells were treated with phorbol 12-myristate 13-acetate for 48 hours to induce cell differentiation, then treated with SK01 for 1 hour and with TLR8 agonist TL8-506 for 4 hours, and the levels of TNF-a secretion were measured by ELISA.

[0036] Figure 6 is a graph showing the effect of SK16 on the signaling pathways of homologous TLRs.

[0037] Figure 6 A to Figure 6 C shows the inhibitory activity of SK16 on cell surface TLRs (TLR1 / 2, TLR2 / 6 and TLR4), and Figure 6 D to Figure 6 G shows the inhibitory activity of SK16 on endosomal TLRs (TLR3, TLR7, TLR8 and TLR9), where RAW 264.7 cells were treated with control (-), DMSO 0.25% or SK16 at predetermined concentrations for 1 hour, then stimulated with specific TLR agonists for 4 or 24 hours (only for TLR3), for TLR8, a human monocytic cell line (THP-1) was used and THP-1 cells were treated with phorbol 12-myristate 13-acetate (PMA) for 48 hours to induce cell differentiation, followed by treatment with SK16 for 1 hour and with TLR8 agonist TL8-506 for 4 hours, and the levels of TNF-a secretion were measured by ELISA, Figure 7 H shows the activity of signaling factors that transduce the signal under TLR9, where a negative control group was set up without treatment with any substance, a positive control group was set up by administering SK16 to the RAW 264.7 cell line at each time point, the cells were treated with SK16 for 1 hour, followed by treatment with TLR9 agonist for 15 or 30 minutes, and after quantifying the prepared samples, the activity of the signaling factors was determined by protein electrophoresis.

[0038] Figure 8 is a graph showing the cytotoxicity of the inhibitor candidates SK21 to SK82 (including SK16).

[0039] Figure 9Figure 1 is a graph showing the inhibition of TLR7 by inhibitor candidates SK21 to SK82, including SK16.

[0040] Figure 10 Figure 2 is a graph showing the inhibition of TLR9 by inhibitor candidates SK21 to SK82, including SK16.

[0041] Figure 11 Figure 3 is a table comparing the LC 50 , IC 50 and TI (therapeutic index) measured between 13 SK substances, including SK16, showing effective inhibitory activity against TLR7 and TLR9, and hydroxychloroquine (HCQ).

[0042] Figure 12 Figure 4 is a graph showing the inhibitory effect of SK41, SK50, SK58 and SK64 against surface TLRs (TLR1 / 2, TLR2 / 6, TLR4 and TLR5).

[0043] Figure 13 Figure 5 is a graph showing the inhibitory effect of SK41, SK50, SK58 and SK64 against TLR3 and TLR8 as endosomal TLRs.

[0044] Figure 14 Figure 6 is an image showing the appearance change after oral administration once a day for 3 weeks (oral administration 2 weeks after onset; 60 mg / Kg for HCQ, 30 mg / Kg for the SK series) in a mouse lupus model (MRL / Fas lpr or MRL / lpr) animal experiment.

[0045] Figure 15 Figure 7 is a graph showing the monitoring results of the average body weight of the mouse experimental groups during the lupus animal experiment.

[0046] Figure 16 Figure 8 is a graph showing the weight of the spleen and lymph nodes collected at the end of the lupus animal experiment (40 days after oral administration).

[0047] Figure 17 Figure 9 is a graph showing the results of an enzyme-linked immunosorbent assay for analyzing the concentration of anti-nuclear antibodies (ANA) and C3 complement in the plasma collected at the end of the lupus animal experiment.

[0048] Example 1-1: In silico screening (in silico programming in virtual experiment) for endosomal TLR inhibiting molecules Figure 10 is an image showing the appearance change after oral administration once a day for 4 weeks (oral administration 3 weeks after onset; 15 mg / Kg for HCQ; 15 mg / Kg for the SK series) in a mouse lupus model (MRL / Fas lpr animal experiment. Detailed Implementation

[0049] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art to which this invention pertains. Generally, the nomenclature used herein is well-known in the art and is commonly used.

[0050] Innate immunity plays a crucial role in inducing adaptive immune responses against invading pathogens and endogenous / exogenous toxic molecules. Simultaneously, self-recognition of nucleic acids via endosomal TLRs is involved in the pathogenesis of systemic autoimmune diseases such as RA or SLE (Marshak-Rothstein, A. Nat Rev Immunol 2006, 6, 823-35). A preliminary lead compound, SK01, was identified as an effective downregulator of excessive immune production because TLRs transmit signals via multiple redundant pathways involving universal downstream adaptors or kinases. A derivative (SK16) exhibiting in vitro efficacy equivalent to HCQ (a known endosomal TLR inhibitor) was identified through further experiments using a structure with 80% or higher identity. Recently, several chemical or biological agents have been developed for the treatment of autoimmune and inflammatory diseases; however, none have been successfully formulated into drugs due to early safety concerns (NCT00547014) or ineffectiveness in late-stage clinical trials (Rice, TW et al., Crit Care Med 2010, 38, 1685-94). The only TLR antagonists approved for the treatment of SLE and RA are the antimalarial drugs HCQ, chloroquine, and quinacrine (Rynes, RIBr J Rheumatol 1997, 36, 799-805). These drugs block the endosome acidification required for nucleic acid binding to TLRs or their accumulation around TLRs, thereby effectively inhibiting the production of pro-inflammatory cytokines in plasmacytoid dendritic cells and peripheral blood mononuclear cells. However, their efficacy can be greatly enhanced based on known intermolecular interactions studied through structure-activity relationships. Therefore, there is a need to develop novel antagonists with direct receptor binding capabilities.

[0051] The present invention is based on the finding that the primary lead SK01 and its potent derivative SK16, which are two small molecules identified using computers, specifically inhibit the function of endosomal TLR3 / 7 / 9 in RAW 264.7 cells, and that novel compounds, including compounds defined as SK23, SK24, SK29, SK36, SK39, SK40, SK41, SK50, SK52, SK54, SK55, SK58, SK59, SK60, SK61, SK62, SK63, SK64, SK65, SK69, SK70, SK71, SK72, SK74, SK75, SK81 and SK82 based on SK16, inhibit the secretion of cytokines by inhibiting the TLR signaling pathway induced by TLR3, TLR7, TLR8 and / or TLR9 activation. This indicates that these compounds have a therapeutic effect on autoimmune, inflammatory or viral diseases such as systemic lupus erythematosus and psoriasis caused by TLR3, TLR7, TLR8 and / or TLR9 activation.

[0052] Thus, in one aspect, the present invention relates to a compound represented by the following formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0053] [Formula 1]

[0054]

[0055] wherein R1 to R6 are the same as or different from each other, and each is independently a hydrogen atom, a halogen atom, a linear or branched alkyl group, an amino group, an alkylamine, a heterocyclic amine, a nitrile group, a nitro group, a nitroso group, a hydroxyl group, a cycloalkyl group, a benzyl group, a haloalkyl group, an allyl group, an alkoxy group, an alkoxyalkyl group, an alkylcarbonyl group, a cycloalkylcarbonyl group, an arylcarbonyl group, an alkylarylcarbonyl group, an alkoxycarbonyl group, a cycloalkyloxy group, an aryl group, a heteroaryl group, a heterocycloalkyl group, an aryloxy group, an alkoxyheteroaryl group, a heteroaryloxyalkyl group, an alkylheteroaryl group, an alkylaryl group, an arylalkyl group, an alkylheteroaryl group, an alkyl ester, an alkyl ether, an alkyl amide, or an acryloyl group, or

[0056] R2 and R3 are connected to each other to form a substituted or unsubstituted cycloalkane or arene, or

[0057] R5 and R6 are connected to each other to form a substituted or unsubstituted cycloalkane or arene,

[0058] wherein the alkyl group, the alkylamine, the heterocyclic amine, the alkoxy group, the alkoxyalkyl group, the alkyl ester, the alkyl ether, or the alkyl amide is C 1-30 the cycloalkyl group is C 3-30 the allyl group is C 2-30 the aryl group is C 6-30and the heteroaryl and the heterocycloalkyl contain a heteroatom selected from the group consisting of fluorine, oxygen, sulfur and nitrogen.

[0059] In the present application, the alkyl, the alkylamine and the heterocyclic amine are preferably C 1-15 , more preferably C 1-10 , and most preferably C 1-7 .

[0060] As used herein, the term "C 1-30 alkyl" means a monovalent straight-chain or branched saturated hydrocarbon moiety having from 1 to 30 carbon atoms and containing only carbon and hydrogen atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, and the like. Examples of "branched alkyl" include isopropyl, isobutyl, t-butyl, and the like.

[0061] As used herein, the term "C 1-30 alkoxy" means a functional group of formula -O-C 1-30 alkyl and includes, but is not limited to, methoxy, ethoxy, isopropoxy, t-butoxy, and the like.

[0062] Specific examples of the term "halogen" (or "halo") include fluorine (F), chlorine (CI), bromine (Br), and iodine (I).

[0063] As used herein, the term "amino" means a functional group in which one hydrogen atom is removed from ammonia, and includes amine groups in which one or more hydrogen atoms are replaced by a residue, such as a hydrocarbon. The amine group can include primary, secondary, or tertiary alkyl amines, depending on the number of alkyl groups substituted. The term "heterocyclic amine" means a heterocyclic compound, which is an amine containing nitrogen in the ring.

[0064] As used herein, the term "C 6-30 aryl" means a compound comprising at least one ring having a shared pi-electron system, such as a monocyclic or fused ring polycyclic group (i.e., having rings that share adjacent pairs of carbon atoms). That is, unless otherwise defined herein, aryl can include phenyl or biaryl groups, such as naphthyl groups. According to one embodiment of the present application, the aryl group is an aromatic ring having from 6 to 30 carbon atoms.

[0065] As used herein, the term "C 3-30 cyclic alkyl" means a cyclic saturated hydrocarbon moiety having from 5 to 6 carbon atoms and containing only carbon and hydrogen atoms. Examples of cyclic alkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, and the like.

[0066] Unless otherwise defined, as used herein, the term "heteroaryl" refers to an aromatic ring having 5 or 6 ring atoms and containing 1 to 4 heteroatoms selected from N, O, and S, or a bicyclic ring having a heteroaryl ring fused to a benzene ring or another heteroaryl ring. Examples of monocyclic heteroaryl groups include, but are not limited to, thiazolyl, oxazolyl, thiophene, furanyl, pyrrole, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, triazolyl, triazinyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyrazinyl, and similar groups. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, azaindolyl, dihydroindolyl, benzothiophene, benzofuranyl, benzimidazolyl, benzooxazolyl, benzoisooxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, purinyl, furanopyridyl, and similar groups.

[0067] As used herein, the term "heterocyclic alkyl" refers to a saturated or partially unsaturated carbon ring having 5 to 9 ring atoms, and containing 1 to 3 heteroatoms selected from N, O, and S in addition to the carbon atoms. For example, a heterocyclic alkyl can be azahexacyclic butyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolyl, imidazoalkyl, oxazolyl, isoxazolyl, thiazoalkyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azaheptanyl, diazaheptanyl, homopiperazinyl, oxazaheptanyl, dihydroindolyl, dihydrofuranyl, dihydroimidazolinyl, dihydrooxazolyl, tetrahydropyridinyl, dihydropyranyl, dihydrobenzofuranyl, benzodioxacyclopentenyl, or benzodioxane.

[0068] As used herein, R1 to R6 can be substituents selected from, but not limited to, the following substituents.

[0069] R1:

[0070] R2:

[0071] R3:

[0072] R2 and R3:

[0073]

[0074] R4:

[0075] R5:

[0076] R6:

[0077] R5 and R6:

[0078] In the present application, the compound represented by Formula 1 can be a compound represented by any one selected from the group consisting of Formulas 1-1 to 1-34:

[0079] [Formula 1-1]

[0080]

[0081] [Formula 1-2]

[0082]

[0083] [Formula 1-3]

[0084]

[0085] [Formula 1-4]

[0086]

[0087] [Formula 1-5]

[0088]

[0089] [Formula 1-6]

[0090]

[0091] [Formula 1-7]

[0092]

[0093] [Formula 1-8]

[0094]

[0095] [Formula 1-9]

[0096]

[0097] [Formula 1-10]

[0098]

[0099] [Formula 1-11]

[0100]

[0101] [Formula 1-12]

[0102]

[0103] [Formula 1-13]

[0104]

[0105] [Formula 1-14]

[0106]

[0107] [Formula 1-15]

[0108]

[0109] [Formula 1-16]

[0110]

[0111] [Formula 1-17]

[0112]

[0113] [Formula 1-18]

[0114]

[0115] [Formula 1-19]

[0116]

[0117] [Formula 1-20]

[0118]

[0119] [Formula 1-21]

[0120]

[0121] [Formula 1-22]

[0122]

[0123] [Formula 1-23]

[0124]

[0125] [Formula 1-24]

[0126]

[0127] [Formula 1-25]

[0128]

[0129] [Formula 1-26]

[0130]

[0131] [Formula 1-27]

[0132]

[0133] [Formula 1-28]

[0134]

[0135] [Formula 1-29]

[0136]

[0137] [Formula 1-30]

[0138]

[0139] [Formula 1-31]

[0140]

[0141] [Formula 1-32]

[0142]

[0143] [Formula 1-33]

[0144]

[0145] [Formula 1-34]

[0146]

[0147] Here, the compound of Formula 1-1 is named “SK01”, the compound of Formula 1-2 is named “SK09”, the compound of Formula 1-3 is named “SK11”, the compound of Formula 1-4 is named “SK13”, the compound of Formula 1-5 is named “SK14”, the compound of Formula 1-6 is named “SK16”, and the compound of Formula 1-7 is named “SK19” (Table 1).

[0148] [Table 1]

[0149]

[0150]

[0151]

[0152] Further, in the present specification, the compound of Formula 1-8 is named as "SK23", the compound of Formula 1-9 is named as "SK24", the compound of Formula 1-10 is named as "SK29", the compound of Formula 1-11 is named as "SK36", the compound of Formula 1-12 is named as "SK39", the compound of Formula 1-13 is named as "SK40", the compound of Formula 1-14 is named as "SK41", the compound of Formula 1-15 is named as "SK50", the compound of Formula 1-16 is named as "SK52", the compound of Formula 1-17 is named as "SK54", the compound of Formula 1-18 is named as "SK55", the compound of Formula 1-19 is named as "SK58", the compound of Formula 1-20 is named as "SK59", the compound of Formula 1-21 is named as "SK60", the compound of Formula 1-22 is named as "SK61", the compound of Formula 1-23 is named as "SK62", the compound of Formula 1-24 is named as "SK63", the compound of Formula 1-25 is named as "SK64", the compound of Formula 1-26 is named as "SK65", the compound of Formula 1-27 is named as "SK69", the compound of Formula 1-28 is named as "SK70", the compound of Formula 1-29 is named as "SK71", the compound of Formula 1-30 is named as "SK72", the compound of Formula 1-31 is named as "SK74", the compound of Formula 1-32 is named as "SK75", the compound of Formula 1-33 is named as "SK33", and the compound of Formula 1-34 is named as "SK34" (Table 2).

[0153] [Table 2]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168] The compound according to the present application can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed from a pharmaceutically acceptable free acid can be used as the salt. The free acid can be an inorganic acid or an organic acid. The inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like, and the organic acid includes citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, and the like.

[0169] The compound according to the present application includes any salt, isomer, hydrate, and solvate that can be prepared by a conventional method, as well as a pharmaceutically acceptable salt.

[0170] In addition, the compound according to the present application can be prepared in a crystalline or amorphous form. When the compound of Formula 1 is prepared in a crystalline form, it can be optionally hydrated or solvated.

[0171] In the present application, the compound represented by Formula 1 exhibits an effect of inhibiting the secretion of inflammatory cytokines such as TNF-α by inhibiting the TLR3, TLR7, TLR8, or TLR9 signaling pathway.

[0172] Accordingly, in another aspect, the present application relates to a composition for inhibiting a Toll-like receptor (TLR), the composition comprising a compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0173] The compound represented by Formula 1 can be a compound represented by any one selected from Formula 1-1 to Formula 1-34, but is not limited thereto.

[0174] In the present application, the compound can inhibit the signaling pathway of at least one TLR selected from TLR3, TLR7, TLR8, and TLR9, which are endosomal TLRs.

[0175] As used herein, the term "inhibit" refers to a phenomenon in which biological activity or signaling activity is degraded due to some defect, imbalance, or other reason, and can include partial or complete blocking, reduction, or prevention of TLR activity, delay of activation, inactivation, or down-regulation.

[0176] As used herein, the term "inhibitor" refers to a molecule that partially or completely inhibits the effect on other molecules, such as receptors or intracellular mediators, by any mechanism. In the present context, the composition for inhibiting TLR has the same meaning as TLR inhibitor.

[0177] As used herein, the term "TLR3, TLR7, TLR8 or TLR9 inhibitor" refers to a substance capable of directly or indirectly or substantially interfering with, reducing or inhibiting the biological activity of TLR3, TLR7, TLR8 or TLR9, and preferably refers to a substance which binds to the TLR3, TLR7, TLR8 or TLR9 receptor and neutralizes its activity to block the TLR3, TLR7, TLR8 or TLR9 signaling pathway, and thereby reduces the secretion of NF-κB (nuclear factor kappa light chain enhancer of activated B cells), MAPK (mitogen-activated protein kinase), inflammatory cytokines, NO and ROS.

[0178] According to one embodiment of the present application, SK23, SK24, SK29, SK36, SK39, SK40, SK41, SK50, SK52, SK54, SK55, SK58, SK59, SK60, SK61, SK62, SK63, SK64, SK65, SK69, SK70, SK71, SK72, SK74, SK75, SK81 and SK82 inhibit the overactivation of cytokines such as TNF-α (tumor necrosis factor-α) by inhibiting the TLR signaling pathway induced by the activation of TLR3, TLR7, TLR8 or TLR9. Therefore, these substances have an excellent effect of reducing inflammatory cytokines (improving inflammatory reactions), and thus can be used as a composition for preventing or treating autoimmune diseases, inflammatory diseases and viral diseases caused by the activation of TLR3, TLR7, TLR8 or TLR9.

[0179] As used herein, the term "TLR3" refers to a protein classified as a Toll-like receptor (TLR) as a family of transmembrane proteins serving as a monitor for infection by pathogens, is a protein encoded by the TLR3 gene, and is also referred to as "CD283" or "IIAE2". TLR3 recognizes double-stranded RNA or poly I:C to activate the innate immune system.

[0180] As used herein, the term "TLR7" refers to a protein classified as a Toll-like receptor (TLR) as a family of transmembrane proteins serving as a monitor for infection by pathogens, is a protein encoded by the TLR7 gene, and is also referred to as "UNQ248 / PRO285". TLR7 recognizes ssRNA (single-stranded RNA) of RNA viruses or synthetic small molecules such as imidazoquinolines, loxoribine and brincidolamine to activate the innate immune system.

[0181] As used herein, the term "TLR8" refers to a protein classified as a Toll-like receptor (TLR) of a family of transmembrane proteins that serve as sentinels for infection by pathogens, is a protein encoded by the TLR8 gene, and is also known as "CD288 (cluster of differentiation 288)" or "UNQ249 / PRO286". TLR8 is activated by single-stranded viral RNA, phagocytic bacterial RNA that enters cells through phagocytosis, or by a synthetic small molecule, TL8-506.

[0182] As used herein, the term "TLR9" refers to a protein classified as a Toll-like receptor (TLR) of a family of transmembrane proteins that serve as sentinels for infection by pathogens, is a protein encoded by the TLR9 gene, and is also known as "CD289" or "UNQ5798 / PRO19605". TLR9 recognizes unmethylated CpG oligodeoxynucleotide DNA fragments from bacteria or DNA viruses to activate the innate immune system.

[0183] As used herein, the term "TLR signaling pathway" refers to a signaling pathway through a TLR, which can be a reaction dependent on a complex formed by a TLR and an adaptor protein MyD88 (for TLR7 / 8 / 9) or a complex formed by a TLR and an adaptor protein TRIF (for TLR3), and functions to transmit a signal. Activated TLR7 / 8 / 9 activates NF-κB through a Myd88-dependent signaling process, transmits it to the nucleus, and induces activation of MAPK. Activation of NF-κB and MAPK leads to secretion of inflammatory cytokines such as TNF-α, IL-1β, and IL-6, and production of oxidative stressors such as nitric oxide (hereinafter referred to as NO) and reactive oxygen species (hereinafter referred to as ROS) in macrophages. In addition, TLR3 activates TRIF, interferon regulatory factor (IRF), and NF-κB, thereby inducing a MyD88-independent signaling process and secretion of type 1 interferon.

[0184] According to one embodiment of the present application, the compound of Formula 1 according to the present application has an excellent effect of inhibiting the TLR3, TLR7, TLR8, and TLR9 signaling pathways, and is useful as a composition for preventing or treating autoimmune diseases, inflammatory diseases, and viral diseases caused by the TLR3, TLR7, TLR8, or TLR9 signaling pathways.

[0185] Accordingly, in another aspect, the present application relates to a composition for preventing or treating an autoimmune disease, an inflammatory disease, or a viral disease, the composition comprising the compound (an isomer thereof or a pharmaceutically acceptable salt thereof) for inhibiting a Toll-like receptor (TLR) or the composition.

[0186] In another aspect, the present application relates to a method for preventing or treating an autoimmune disease, an inflammatory disease, or a viral disease, the method comprising administering the compound (an isomer thereof or a pharmaceutically acceptable salt thereof) or the composition for inhibiting Toll-like receptor (TLR).

[0187] In another aspect, the present application relates to the use of the compound (an isomer thereof or a pharmaceutically acceptable salt thereof) or the composition for inhibiting Toll-like receptor (TLR) for preventing or treating an autoimmune disease, an inflammatory disease, or a viral disease.

[0188] In another aspect, the present application relates to the use of the compound (an isomer thereof or a pharmaceutically acceptable salt thereof) or the composition for inhibiting Toll-like receptor (TLR) in the manufacture of a medicament for preventing or treating an autoimmune disease, an inflammatory disease, or a viral disease.

[0189] In the present application, the compound represented by Formula 1 can be a compound represented by any one selected from Formula 1-1 to Formula 1-34, but is not limited thereto.

[0190] In the present application, the autoimmune disease or the inflammatory disease is selected from the group consisting of psoriasis, systemic lupus erythematosus (SLE), skin rash, photosensitive dermatosis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, discoid lupus erythematosus, malaria, oral ulcer, nephritis, cytopenia, vasculitis, serositis, inflammatory bowel disease (IBD), diabetes, multiple sclerosis, scleroderma, pemphigus, atopic dermatitis, urethritis, cystitis, arteriosclerosis, allergic disease, rhinitis, asthma, acute pain, chronic pain, periodontitis, gingivitis, gout, myocardial infarction, congestive heart failure, hypertension, angina pectoris, gastric ulcer, cerebral infarction, Down's syndrome, obesity, dementia, depression, schizophrenia, tuberculosis, sleep disorder, sepsis, burn, pancreatitis, Parkinson's disease, and stroke, but is not limited thereto.

[0191] As used herein, the term "autoimmune disease" refers to a disease caused by a process in which a problem occurs in inducing or maintaining self-tolerance, resulting in an immune response to self-antigens and thus attacking the organism's own tissues. The term "self-tolerance" refers to immune unresponsiveness, meaning no harmful reaction to potentially antigenic substances that make up the self. Autoimmune diseases include diseases caused by the breakdown of self-tolerance, in which the adaptive immune system responds to self-antigens and mediates cellular and tissue damage. In certain embodiments, the autoimmune disease is caused at least in part by a humoral immune response.

[0192] Autoimmune diseases associated with the present application include systemic lupus erythematosus, insulin-dependent diabetes mellitus, multiple sclerosis, autoimmune encephalomyelitis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, discoid lupus erythematosus, photosensitive dermatosis, autoimmune arthritis, myasthenia gravis, thyroiditis, experimental uveitis, Hashimoto's thyroiditis, primary myxedema, thyrotoxicosis, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, early menopause, male infertility, childhood diabetes, Goodpasture's syndrome, pemphigus vulgaris, bullous pemphigoid, sympathetic ophthalmia, phacogenic uveitis, autoimmune hemolytic anemia, idiopathic leukocytosis, primary biliary cirrhosis, chronic active hepatitis Hbs-ve, latent cirrhosis, ulcerative colitis, Sjogren's syndrome, scleroderma, Wegener's granulomatosis, polymyositis / dermatomyositis, and discoid LE, but are not limited thereto.

[0193] In addition, non-limiting examples of autoimmune diseases include acute disseminated encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, allergic asthma, allergic rhinitis, alopecia areata, amyloidosis, ankylosing spondylitis, antibody-mediated transplant rejection, anti-GBM / anti-TBM nephritis, antiphospholipid antibody syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune dysautonomia, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency syndrome, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy in diabetes, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticarial, axonal and neuronal neuropathies, Balo disease, Behcet's disease, bullous pemphigoid, cardiomyopathy, Castleman's disease, celiac disease, Chagas disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome, cicatricial pemphigoid / benign mucosal pemphigoid, Crohn's disease, Cogan syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST disease, essential mixed cryoglobulinemia, demyelinating neuropathies, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis (GPA), Graves' disease, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis, hypogammalglobulinemia, hypergammalglobulinemia, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, immunoregulatory lipoproteins, inclusion body myositis, inflammatory bowel disease, insulin-dependent diabetes mellitus (Type 1), interstitial cystitis, juvenile arthritis, juvenile diabetes, Kawasaki syndrome, Lambert-Eaton syndrome, lupus, Lyme disease, Marfan syndrome, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, multiple sclerosis, myasthenia gravis, myositis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, Sjogren's syndrome, stiff person syndrome, systemic lupus erythematosus (SLE), Takayasu's arteritis, temporal arteritis, thrombocytopenic purpura, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, uveitis, uveo-retinal syndromes, and vasculitis.syndrome), leukopenia vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus (SLE), Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), monoclonal gammopathy of undetermined significance (MGUS), Mooren's ulcer, Mucha-Habermanndisease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devic's disease), neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus infection), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), unilateral facial atrophy, Parsonnage-Turner syndrome, pars planitis (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, type I, type II, and type III autoimmune polyglandular syndromes, polymyalgia rheumatica, polymyositis, post myocardial infarction syndrome, post pericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure red cell anemia, Raynaud's phenomenon, reflex sympathetic dystrophy, Rett syndrome, relapsing polychondritis, restless leg syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff person syndrome, subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vesiculobullous dermatosis, vitiligo, Waldenstrom's macroglobulinemia (WM), and Wegener's granulomatosis (granulomatosis with polyangiitis; GPA).

[0194] As used herein, the term "inflammatory disease" refers to a disease caused by inflammatory substances (inflammatory cytokines) such as TNFa, IL-1, IL-6, prostaglandins, leukotrienes, or NO secreted by immune cells (such as macrophages) due to over-excitation of the immune system by a harmful stimulus (such as an inflammation-inducing factor or radiation). An "inflammatory disease" can be an acute or chronic inflammatory condition, and can be caused by infectious or non-infectious causes.

[0195] Inflammatory diseases of the present application include psoriasis, asthma, eczema, allergy, rheumatoid arthritis, psoriatic arthritis, contact dermatitis, atopic dermatitis, acne, atopic rhinitis, allergic dermatitis, chronic rhinosinusitis, seborrheic dermatitis, gastritis, gout, gouty arthritis, ulcer, chronic bronchitis, pulmonary inflammation, Crohn's disease, ulcerative colitis, ankylosing spondylitis, sepsis, vasculitis, bursitis, lupus, polymyalgia rheumatica, temporal arteritis, multiple sclerosis, solid cancer, Alzheimer's disease, arteriosclerosis, obesity, malaria, and viral infection, but are not limited thereto.

[0196] In addition, non-limiting examples of inflammatory diseases include atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthritis osteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatitis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Goodpasture's disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory skin disease, usual interstitial pneumonia (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of vasculitis (temporal arteritis and polyarteritis nodosa), inflammatory skin disease, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonitis, airway inflammation, adult respiratory distress syndrome (ARDS), encephalitis, anaphylaxis, asthma, hay fever, allergy, acute hypersensitivity reactions, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), allograft rejection, host versus graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dermatitis, endocarditis, endometritis, enteritis, enterocolitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myocarditis, nephritis, lymphadenitis, oophoritis, orchitis, osteitis, otitis media, pancreatitis, parotitis, pericarditis, pharyngitis, nephritis, phlebitis, pneumonitis, proctitis and proctodynia, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, cystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, vasculitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, depression, cerebral pia arachnoiditis, and cerebral encephalopathy. In certain embodiments, the inflammatory disease is selected from atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory arthritis, and myocarditis.

[0197] In the present invention, the viral disease encompasses any viral disease including all virus groups consisting of ssRNA, dsRNA, dsDNA and ssDNA. ssRNA viruses include Astroviridae (positive ssRNA; human astrovirus), Caliciviridae (positive ssRNA; norovirus), Picornaviridae (positive ssRNA; coxsackievirus, hepatitis A, poliovirus, rhinovirus), Coronaviridae (positive ssRNA; severe acute respiratory syndrome virus, SARS-CoV-2), Flaviviridae (positive ssRNA; hepatitis C virus, yellow fever virus, dengue virus, West Nile virus TBE virus), Togaviridae (positive ssRNA; rubella virus), Hepeviridae (positive ssRNA; hepatitis E virus), Retroviridae (ssRNA-RT; human immunodeficiency virus HIV), Orthomyxoviridae (negative ssRNA; orthomyxovirus), Arenaviridae (negative ssRNA; Lassa virus), Bunyaviridae (negative ssRNA; Crimean-Congo hemorrhagic fever, hantavirus), Filoviridae (negative ssRNA; Ebola virus, Marburg virus), Paramyxoviridae (negative ssRNA; measles virus, mumps virus, parainfluenza virus, respiratory syncytial virus), Rhabdoviridae (negative ssRNA; rabies virus), and hepatitis D (negative ssRNA), dsRNA viruses include Reoviridae (dsRNA; rotavirus, orbivirus, coltivirus, banna virus), Adenoviridae (dsDNA; adenovirus) and Herpesviridae (dsDNA; herpes simplex virus 1, herpes simplex virus 2, varicella-zoster virus, Epstein-Barr virus, human cytomegalovirus, KSHV), Papillomaviridae (dsDNA; human papillomavirus), Polyomaviridae (dsDNA; BK virus, JC virus), Poxviridae (dsDNA; smallpox), and Hepadnaviridae (dsDNA-RT; hepatitis B virus), and ssDNA viruses include Parvoviridae (ssDNA; parvovirus B19). The viral disease can be selected from viral diseases caused by this virus group, but is not limited thereto.

[0198] Examples of viral diseases include, but are not limited to, common cold, influenza (influenza), chickenpox, shingles, herpes simplex, infectious mononucleosis, cytomegalovirus infection, measles, mumps, rubella, parvovirus infection, polio, viral hemorrhagic fever, yellow fever, dengue fever, rabies, AIDS, and Covid-19.

[0199] As used herein, the term "prevention" means any action of inhibiting or delaying any effect of an autoimmune disease, an inflammatory disease and / or a viral disease by administering a pharmaceutical composition comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. As used herein, the term "treatment" means any action of alleviating or completely curing symptoms of an autoimmune disease, an inflammatory disease and / or a viral disease by administering a pharmaceutical composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0200] The composition for preventing or treating an autoimmune disease, an inflammatory disease and / or a viral disease according to the present application can comprise only a pharmaceutically effective amount of a compound represented by Formula 1, or in addition to the compound, at least one pharmaceutically acceptable carrier, excipient or diluent. The term "pharmaceutically effective amount" means an amount sufficient to prevent, alleviate and treat symptoms of an autoimmune disease, an inflammatory disease and / or a viral disease.

[0201] The term "pharmaceutically acceptable" used herein means physiologically acceptable when administered to humans without causing ordinary allergic reactions such as gastrointestinal disorders or dizziness or reactions similar thereto. Examples of the carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In addition, the composition can further comprise a filler, an anti-aggregation agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and a preservative.

[0202] The term "carrier" as used herein means a substance that facilitates the addition of a compound to cells or tissues.

[0203] The term "diluent" as used herein is defined as a substance that stabilizes the biological activity of the subject compound and dilutes in water to dissolve the compound.

[0204] In addition, the composition of the present application can comprise one or more active ingredients known to have a therapeutic effect on an autoimmune disease, an inflammatory disease and / or a viral disease, as well as a compound represented by Formula 1.

[0205] The composition of the present application can be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a non-human mammal. The formulation can be in the form of a powder, granules, tablets, emulsions, syrups, aerosols, soft gelatin capsules or hard gelatin capsules, sterile injection solutions or sterile powders.

[0206] The composition of the present application can be administered by various routes including oral, transdermal, subcutaneous, intravenous or intramuscular administration, and the dose of the active ingredient depends on various factors such as the administration route, the age, sex and body weight of the patient, and the severity of the disease of the patient. The composition according to the present application can be administered in combination with known compounds having an effect of preventing, ameliorating or treating the symptoms of autoimmune diseases, inflammatory diseases and / or viral diseases.

[0207] Unless otherwise defined, all terms and abbreviations used in the present specification can be interpreted as having the meanings commonly understood by those skilled in the art to which the present application pertains.

[0208] Hereinafter, the present application will be described in more detail with reference to the following examples. However, it will be apparent to those skilled in the art that the following examples are provided only for illustrating the present application, and should not be construed as limiting the scope of the present application.

[0209] Example 1: Materials and Methods

[0210] Design of novel compounds Example 1-2: Cell culture and seeding

[0211] First, a multi-conformational library of screening compounds was prepared using molecules from ChemBridge, Chemspace, Mcule, MOE Leadlike, MolPort, ZINC Druglike, and ZINC Leadlike chemical databases. Ligand structures were washed using MOE washing protocol. Briefly, salts and broken fragments were removed, protonation state at pH 6.5 was calculated, and energy was minimized. Duplicate conformations were removed, and then a BIT:MACCS fingerprint similarity search (80% similarity cutoff) was performed against a list of known TLR3 / 7 / 8 / 9 inhibitors reported in the literature. Ligands were screened based on pharmacophore models of high activity antagonists of the screen. Next, using MOE software (Molecular Operating Environment (MOE), 2013.08; Chemical Computing Group ULC, 1010 rue Sherbrooke Ouest, Suite 910, Montreal, QC, Canada H3A 2R7, 2017 (2013)), ligands that satisfy the pharmacophore constraints were docked into the R848 binding site of TLR7 (PDB ID: 5GMH (Zhang, Z. et al. Immunity 45, 737-748 (2016)). Docked poses were re-ranked based on S-score (binding affinity) implemented in London DG scoring function. The resulting docked poses were re-scored by a steered fitting method and “GBVI / WSA dG” force field refinement. Finally, to determine TLR3 / 7 / 8 / 9 inhibitory activity in cell-based assays, a set of top ligands (SK02-SK20) were fixed. Based on the compounds with effectiveness, a series of novel compounds were designed and synthesized.

[0212] Example 1-3: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay

[0213] RAW 264.7 cells were purchased from Korean Cell Line Bank and cultured in Dulbecco’s modified Eagle’s medium containing 10% FBS (Gibco), 1% penicillin and streptomycin solution (Hyclone).

[0214] For cytotoxicity assay and TLR1 / 2, TLR2 / 6, TLR3, TLR4, TLR7, TLR8, and TLR9 ligand screening, cells were seeded at a density of 2 x 10 4 cells / well into 96-well cell culture plates and incubated overnight (approximately 18-24 hours).

[0215] The THP-1 cell line, a human monocytic cell line derived from acute leukemia, was obtained from Professor Changhee Seo of Ajou University College of Medicine (Suwon, Korea). The cells were cultured in RPMI1640 (HyClone Laboratories, Inc., San Angelo, TX, USA) containing 10% FBS (Gibco), 1% penicillin and streptomycin solution (Hyclone) and then differentiated into M0 macrophages using 80 nM phorbol 12-myristate 13-acetate (PMA; Sigma-Aldrich Co., St. Louis, MO, USA) for 24 hours.

[0216] For TLR5 ligand screening, the cells were seeded in a 96-well cell culture plate at a density of 1 x 10 5 cells / well and incubated overnight (about 18 hours).

[0217] During the experiment, both the RAW 264.7 cell line and the THP-1 cell line were maintained in a humidified incubator (5% CO2, 37°C), and the medium of RAW 264.7 was changed every day, and the medium of THP-1 was changed every 2 days.

[0218] Example 1-4: Enzyme-linked immunosorbent assay (ELISA)

[0219] RAW 264.7 cells were seeded in a 96-well cell culture plate at a density of 2 x 10 4 cells / well and stabilized overnight in a humidified incubator. Each well was treated with a test compound or a negative control (dimethyl sulfoxide; DMSO). The plate was left to stand in the incubator for 24 hours. Then, the medium of the 96-well culture dish was discarded, and 500 μg / ml of MTT solution (InvivoGen Ltd.) was added to each well. After 3 hours of incubation, the solution was removed, and the residue was incubated in DMSO (Biosesang Co. Ltd., Korea) for 30 minutes to completely dissolve the formazan dye. The absorbance at a wavelength of 595 nm was measured with a microplate colorimetric reader, and was normalized based on the untreated control. All cultures were performed under the same conditions as the cell culture described above.

[0220] Example 1-5: Protein electrophoresis

[0221] To determine the inhibitory activity of the test ligands, RAW 264.7 cells were pre-treated with each candidate compound for 1 hour and then treated with Pam3CSK4 (synthetic triacyl lipopeptide; TLR1 / 2, Invitrogen), FSL-1 (synthetic diacyl lipoprotein, TLR2 / 6, 100 ng / ml), lipopolysaccharide (LPS, TLR4, Sigma Aldrich), Imiquimod (IMQ, TLR7, Invitrogen) and ODN2395 (CpG type C repeat motif DNA oligo (5'-tcgtcgttttcggcgcgcgccg-3), TLR9, Bioneer) ligands for 4 hours and with Poly I:C (I:C repeat motif double stranded RNA, TLR3, Invitrogen) and TL8-506 (TLR8, Invitrogen) for 24 hours. After TLR activation, supernatants were diluted in appropriate ratios in order to measure in a standard dose range, transferred to pre-coated 96-well assay plates and then treated for mouse TNF-α secretion levels using a mouse TNF-α ELISA kit (Invitrogen) according to the manufacturer's instructions.

[0222] To determine the inhibitory activity of the test ligands against TLR5, differentiated THP-1 cells were pre-treated with each compound for 1 hour and then treated with FLA-ST (E. coli-derived flagellin, TLR5, Invitrogen) for 4 hours. After TLR activation, supernatants were diluted and transferred to pre-coated 96-well assay plates and the levels of human TNF-α secretion were measured using a human TNF-α ELISA kit (Invitrogen) according to the manufacturer's instructions.

[0223] Example 1-7: Statistical analysis

[0224] RAW 264.7 cells were plated at 2 x 10 6Cells were plated at a density of 1 cell / well in 60 mm cell culture dishes and allowed to stabilize for 2 days and experiments were performed. Cells were treated with antagonists for 1 hour and stimulated with TLR9 agonists for 15 and 30 minutes. Cell lysates were obtained by treated protease and phosphatase inhibitor cocktail (Thermo Fisher Scientific, Inc.) and Mammalian Protein Extraction Reagent (M-PER; Thermo Fisher Scientific, Inc.). All samples were quantified by a Benzoquinolinecarboxylic Acid assay (Sigma-Aldrich, Co.) using SoftMax Pro 5.3 software (Molecular Devices, Inc.). During the experiment, membranes were treated with specific primary antibodies, phosphorylated JNK, phosphorylated p38-MAPK, JNK, ERK 1 / 2, p38-MAPK, ΙκΒα (Cell Signaling Technology, Inc., Danvers, MA, USA), phosphorylated ERK 1 / 2 and β-actin (Santa Cruz Biotechnology, Inc., Dallas, TX, USA). Proteins were then treated with HRP-conjugated anti-rabbit or anti-mouse IgG (Thermo Fisher Scientific, Inc.) antibodies and protein levels were detected using a chemiluminescent substrate (SuperSignal West Pico PLUS, Thermo Fisher Scientific, Inc.) and a luminescence detection system (Fusion Solo S, Vilber, France). TM West PicoPLUS,Thermo Fisher Scientific,Inc.) and a luminescence detection system (Fusion Solo S, Vilber, France).

[0225] Examples 1-6: LC 50 (50% lethal concentration), IC 50 (50% inhibitory concentration), and TI (therapeutic index) analysis

[0226] To plot the concentration-dependent LC 50 curves, cells were treated with SK series ligands at different concentrations and at the highest concentration of 200 μΜ (the highest concentration that can be treated within the level of 0.5% DMSO). Then, cell viability and toxicity responses after treatment with ligands were measured by MTT assay as described in Examples 1-3. Cell viability in each graph was normalized from negative control (100%; untreated) to positive control (test ligand at the highest concentration) and LC 50 was determined by nonlinear regression (Graph Pad Prism 7.0). To plot the concentration-dependent IC 50Curves, pre-treated with SK series ligands at different concentrations and up to 50 μΜ (twice the initial concentration). Cell responses mediated by TLR7 and TLR9 (level of TNF-a secretion) were analyzed by ELISA as described in examples 1-4. The cytokine level in each graph was normalized from the negative control (untreated) to the positive control (treated with ligand) and the IC50 was determined by non-linear regression (Graph Pad Prism 7.0). 50 .

[0227] Then, LC 50 and IC 50 were applied to the following function to calculate TI.

[0228]

[0229] Example 2-1: Analysis and purification conditions

[0230] Statistical analysis was performed using a two-tailed Student's t-test in Microsoft Excel software. LC 50 and IC 50 calculations were performed with the GraphPad Prism program.

[0231] Example 2: Synthesis of novel compounds

[0232] Example 2-2: Synthesis procedure

[0233] 1) HPLC analysis conditions (Method A; (A) in Table 2 above)

[0234] Instrument name: Shimadzu

[0235] Column: YMC-pack pro C18, 150 x 4.6 mm i.d., 5 μm, 40 °C

[0236] Mobile phase: 5%→100% acetonitrile / H2O + 0.1% trifluoroacetic acid

[0237] Analysis time: 9 min, flow rate: 1 mL / min

[0238] UV detector: 254 nm

[0239] 2) HPLC analysis conditions (Method B; (B) in Table 2 above)

[0240] Instrument name: Thermo Scientific Ultimate 3000 RSLC

[0241] Column: 2.6 μM biphenyl 100 x 2.1 mm

[0242] Mobile phase: 5%→ 100% acetonitrile / H2O + 0.1% trifluoroacetic acid

[0243] Analysis time: 9 min, flow rate: 0.7 mL / min

[0244] UV detector: 254 nm

[0245] 3) LC-MS analysis conditions

[0246] Instrument name: Shimadzu LCMS-2020

[0247] Column: ACE Excel2 C18, 75 x 2.1 mm

[0248] Mobile phase: acetonitrile / H2O + 0.1% trifluoroacetic acid

[0249] Flow rate: 0.5 mL / min

[0250] UV detector: 254 nm

[0251] 4) MPLC purification conditions

[0252] Instrument name:

[0253] UV detector: 254 nm

[0254] 5) Prep HPLC purification conditions

[0255] Instrument name: Gilson GX-281, 321 pump, UV / VIS-155

[0256] Column: 10 μM C18 (2) 250 x 21.2 mm

[0257] Mobile phase: acetonitrile / 0.1% trifluoroacetic acid H2O

[0258] Flow rate: 15 mL / min

[0259] UV detector: 254 nm

[0260] 6) 1 H NMR

[0261] Instrument name: Bruker Avance (400 MHz)

[0262] Example 3-1: Animal breeding and drug administration

[0263] [Experimental Example 1] N-(1-(3-(dimethylamino)propyl)-2,3-dimethyl-1,5,6,7,8,9- hexahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-4-yl)acetamide

[0264]

[0265] Step 1: 2-Amino-1-(3-(dimethylamino)propyl)-4,5-dimethyl-1H-pyrrole-3-carbonitrile

[0266]

[0267] N1,N1-dimethylpropane-1,3-diamine (5.68 mL, 45.4 mmol) and 3-hydroxybutan-2-one (4 g, 45.4 mmol) were dissolved in toluene (60 mL) and to this was added concentrated hydrochloric acid (0.05 mL, 2.27 mmol) at room temperature. The reaction mixture was stirred at reflux for 1 hour, cooled to room temperature, and then malononitrile (3.0 g, 45.4 mmol) was added thereto. Then, the reaction mixture was stirred at reflux for 1 hour. After the completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was separated and purified by amine silica gel chromatography (0% to 50% ethyl acetate / hexane) to obtain the target compound (8.14 g, 81%, yellow solid).

[0268] Step 2: 1-(3-(dimethylamino)propyl)-2,3-dimethyl-1,5,6,7,8,9-hexahydrocyclohepta[b]pyrrolo[3,2- e]pyridin-4-amine

[0269]

[0270] Cycloheptanone (1.07 mL, 9.08 mmol) was dissolved in dichloroethane (25 mL), and then aluminum chloride (1.21 g, 9.08 mmol) was added thereto. The resulting mixture was stirred at room temperature for 10 minutes, 2-amino-1-(3-(dimethylamino)propyl)-4,5-dimethyl-1H-pyrrole-3-carbonitrile (1.0 g, 4.54 mmol) prepared in Step 1 was added thereto, and the reaction mixture was stirred at reflux for 3 hours. The resulting mixture was cooled to room temperature, an aqueous sodium bicarbonate solution was added dropwise thereto to terminate the reaction, and the product was washed with brine and extracted using a mixed solution (10% methanol / dichloromethane). The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was separated and purified by amine silica gel chromatography (0% to 30% ethyl acetate / hexane) to obtain the target compound (1.1 g, 77%, light yellow solid).

[0271] Step 3: N-(l-(3-(dimethylamino)propyl)-2,3-dimethyl-l,5,6,7,8,9- hexahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-4-yl)acetamide

[0272]

[0273] The compound 1-(3-(dimethylamino)propyl)-2,3-dimethyl-l,5,6,7,8,9- hexahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-4-amine prepared in Step 2 (30 mg, 0.095 mmol) was dissolved in dichloromethane (1 mL), then acetyl chloride (0.014 mL, 0.191 mmol) and triethylamine (0.027 mL, 0.191 mmol) were added thereto at 0 °C. Then, the reaction mixture was stirred at room temperature for 2 hours. To this was added a supersaturated aqueous solution of sodium bicarbonate dropwise to terminate the reaction, then the mixture was extracted with dichloromethane and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was separated and purified by silica gel chromatography (0% - 30% methanol / dichloromethane) to obtain the target compound (10.2 mg, 30%, yellowish solid).

[0274] 1 H NMR (400 MHz, MeOD) δ 4.24 (t, J = 7.3 Hz, 2H), 3.14 - 3.05 (m, 2H), 2.84 - 2.76 (m, 2H), 2.39 (dd, J = 9.7, 5.5 Hz, 2H), 2.36 (s, 3H), 2.25 (d, J = 4.1 Hz, 8H), 2.21 (s, 3H), 1.97 - 1.83 (m, 4H), 1.76 - 1.61 (m, 4H); 357 [M+H] + ; LCMS, m / z 612 [M+H] + ; HPLC t R 4.105 min (Method A).

[0275] [Experimental Example 2] The target compound (N-(l-(3-(dimethylamino)propyl)- 2,3-dimethyl-l,5,6,7,8,9-hexahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-4-yl)-2,2,2- trifluoroacetamide) was obtained in a similar manner to Experimental Example 1.

[0276] [Experimental Examples 3, 4 and 5] The target compound (1-(3-(benzyl(methyl)amino)propyl)-2,3-dimethyl-1,5,6,7,8,9-hexahydrocyclohepta[b]pyrrolo[3,2- e]pyridin-4-amine; 2,3-dimethyl-1-(3-(methylamino)propyl)-1,5,6,7,8,9- hexahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-4-amine; 3-(4-amino-2,3-dimethyl- 6,7,8,9-tetrahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-1(5H)-yl)-N,N-dimethylpropanamide) was obtained in a similar manner to Steps 1 to 2 of Experimental Example 1 described above.

[0277] [Experimental Example 6] N-acetyl-N-(1-(3-(benzyl(methyl)amino)propyl)-2,3-dimethyl-1,5,6,7,8,9-hexahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-4-yl)acetamide

[0278]

[0279] N-acetyl-N-(1-(3-(benzyl(methyl)amino)propyl)-2,3-dimethyl-1,5,6,7,8,9- hexahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-4-yl)acetamide (7.0 mg, 11.5%, yellow solid) was obtained in a similar manner to Steps 1 to 2 of Experimental Example 1 described above.

[0280] 1H NMR (400 MHz, CDC13) δ 7.35 - 7.26 (m, 5H), 4.23 (t, J = 7.4 Hz, 2H), 3.63 (s, 2H), 3.13 - 3.07 (m, 2H), 2.70 - 2.59 (m, 2H), 2.56 (t, J = 7.2 Hz, 2H), 2.31 (s, 3H), 2.27 (s, 6H), 2.07 (s, 3H), 2.04 (s, 3H), 2.02 - 1.98 (m, 2H), 1.86 - 1.80 (m, 2H), 1.75 - 1.69 (m, 2H), 1.64 - 1.59 (m, 2H); LCMS, m / z 475 [M+H] + ; HPLC t R 5.641 min (Method A).

[0281] [Experimental Example 7] The target compound (3-(4-acetylamino-2,3-dimethyl-6,7,8,9-tetrahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-1(5H)-yl)-N,N-dimethylpropanamide) was obtained in a similar manner to Experimental Example 1 described above.

[0282] [Experimental Example 8] The target compound (3-(4-(N-acetylglycylamino)-2,3-dimethyl-6,7,8,9-tetrahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-1(5H)-yl)-N,N-dimethylpropanamide) was obtained in a similar manner to Experimental Example 6 described above.

[0283] [Experimental Example 9] 1-(3-(dimethylamino)propyl)-2-methyl-1,5,6,7,8,9-hexahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-4-amine

[0284]

[0285] Step 1: 2-(2-oxopropyl)malononitrile

[0286]

[0287] Propiolonitrile (4.4 g, 66.60 mmol) was dissolved in tetrahydrofuran (100 mL) and to this was added a solution of 1 M potassium tert-butoxide in tetrahydrofuran (66 mL, 66.60 mmol) at 0 °C. The resulting mixture was stirred for 30 seconds and to this was added 1-(chloroprop)-2-one (4.7 ml, 59.03 mmol) followed by stirring for 30 seconds. After completion of the reaction, distilled water was added dropwise at 0 °C to quench the reaction and the product was washed with brine and extracted with dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel chromatography (0% - 20% ethyl acetate in hexane) to obtain the target compound (2.7 g, 33%, white solid).

[0288] Step 2: 2-Amino-1-(3-(dimethylamino)propyl)-5-methyl-1H-pyrrole-3-carbonitrile

[0289]

[0290] Step 1: 2-(2-oxopropyl)propanedinitrile

[0291] Step 3: 1-(3-(dimethylamino)propyl)-2-methyl-1,5,6,7,8,9-hexahydrocyclohepta[b]pyrrolo[3,2- e]pyridin-4-amine

[0292]

[0293] Cycloheptanone (0.33 mL, 2.76 mmol) was dissolved in toluene (3 mL) to which was added aluminum chloride (368 mg, 2.76 mmol). The mixture was stirred at room temperature for 10 minutes to which was added 2-amino-1-(3-(dimethylamino)propyl)-5-methyl-1H-pyrrole-3-carbonitrile (285 mg, 1.38 mmol) prepared in Step 2 above and the reaction mixture was stirred at reflux for 2 hours. The mixture was cooled to room temperature and to which was added dropwise a supersaturated aqueous solution of sodium bicarbonate to quench the reaction and the product was washed with brine and extracted with dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was separated and purified by silica gel chromatography (0% - 100% ethyl acetate mixture (1% triethylamine)) to obtain the target compound (315 mg, 75%, yellow syrup).

[0294] 1 H NMR (400 MHz, CDC13) δ 5.96 (s, 1H), 4.19 (t, J = 7.2 Hz, 2H), 4.11 (s, 2H), 3.02-2.99 (m, 2H), 2.70-2.66 (m, 2H), 2.40 (s, 3H), 2.30 (t, J = 7.2 Hz, 2H), 2.22 (s, 6H), 1.97-1.91 (m, 2H), 1.89-1.75 (m, 2H), 1.70-1.60 (m, 6H); LCMS, m / z 301 [M+H] + ; HPLC t R 4.144 min (Method A).

[0295] [Experimental Example 10] The target compound (N-(1-(3-(dimethylamino)propyl)-2,3-dimethyl-1,5,6,7,8,9-hexahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-4-yl)-2,2-difluoropropionamide) was obtained in a similar manner to Experimental Example 1.

[0296] [Experimental Example 11] 3-Bromo-1-(3-(dimethylamino)propyl)-2-methyl-1,5,6,7,8,9-hexahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-4-amine

[0297]

[0298] Step 1: 3-Bromo-1-(3-(dimethylamino)propyl)-2-methyl-1,5,6,7,8,9-hexahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-4-amine

[0299]

[0300] The 1 -(3-(dimethylamino)propyl)-2-methyl- 1,5,6,7,8,9-hexahydrocyclohepta[b]pyrrolo[3,2- e]pyridin-4-amine (65 mg, 0.21 mmol) prepared in Step 3 of Experimental Example 9 above was dissolved in acetonitrile and to this was added N-bromosuccinimide (46 mg, 0.25 mmol) at 0 °C followed by stirring at 0 °C for 1 hour. After completion of the reaction, the reaction mixture was diluted in dichloroethane and the solid was filtered. The filtrate was concentrated and then separated and purified by preparative HPLC (0.1% trifluoroacetic acid H20 / acetonitrile). The obtained trifluoroacetate salt compound was neutralized with an oversaturated aqueous solution of sodium bicarbonate to obtain the target compound (9 mg, 11%, yellow solid).

[0301] 1 H NMR (400 MHz, CDC13) δ 4.86 (s, 2H), 4.20 (t, J = 7.3 Hz, 2H), 2.98-2.96 (m, 2H), 2.63-2.60 (m, 2H), 2.35 (s, 3H), 2.28 (t, J = 7.3 Hz, 2H), 2.21 (s, 6H), 1.92-1.81 (m, 4H), 1.70-1.59 (m, 4H); LCMS, m / z 380 [M+H] + ; HPLC t R 4.215 min (Method A).

[0302] [Experimental Examples 12, 13] The target compounds (3-chloro- 1 -(3-(dimethylamino)propyl)-2-methyl- 1,5,6,7,8,9-hexahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-4-amine; 1 -(3-(dimethylamino)propyl)-3-iodo-2-methyl- 1,5,6,7,8,9-hexahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-4-amine) were obtained in a similar manner to Experimental Example 9, Steps 1 to 2.

[0303] [Experimental Examples 14, 15, 16, 17, 18] The target compounds (1-(3-methoxypropyl)-2,3-dimethyl-1,5,6,7,8,9-hexahydrocyclohepta[b]pyrrolo[3,2- e]pyridin-4-amine; 1-(2-methoxyethyl)-2,3-dimethyl-1,5,6,7,8,9-hexahydrocyclohepta[b]pyrrolo[3,2- e]pyridin-4-amine; 1-(3-(dimethylamino)propyl)-2,3-dimethyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3- b]quinolin-4-amine; 1-(3-(dimethylamino)propyl)-2,3-dimethyl-1,5,6,7-tetrahydrocyclopenta[b]pyrrolo[3,2- e]pyridin-4-amine; 1-(3-(dimethylamino)propyl)-2,3-dimethyl-6-phenyl-1H-pyrrolo[2,3-b]pyridin-4-amine) were obtained in a similar manner to Steps 1 to 2 of Experimental Example 1.

[0304] [Experimental Example 19] 1-(3-(dimethylamino)propyl)-2-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinolin-4-amine

[0305]

[0306] Step 1: 1-(3-(dimethylamino)propyl)-2-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinolin-4-amine

[0307]

[0308] Cyclohexanone (50 μL, 0.48 mmol) was dissolved in toluene (1 mL), to which was then added aluminum chloride (64 mg, 0.48 mmol). The mixture was stirred at room temperature for 10 minutes, to which was added 2-amino-1-(3-(dimethylamino)propyl)-5-methyl-1H-pyrrole-3-carbonitrile (285 mg, 1.38 mmol) prepared in Step 2 above, and the reaction mixture was stirred at reflux for 2 hours. The mixture was cooled to room temperature, to which was added a supersaturated aqueous solution of sodium bicarbonate dropwise to terminate the reaction, and the product was washed with brine and extracted with dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0% to 100% ethyl acetate mixed solution (1% triethylamine) / hexane) to obtain the target compound (28 mg, 40%, white solid).

[0309] 1H NMR (400 MHz, CDC13) δ 5.97 (s, 1H), 4.18 (t, J = 7.3 Hz, 2H), 4.10 (s, 2H), 2.93-2.90 (m, 2H), 2.56-2.53 (m, 2H), 2.40 (s, 3H), 2.29 (t, J = 7.3 Hz, 2H), 2.21 (s, 6H), 1.97-1.86 (m, 6H); LCMS, m / z 287 [M+H] + ; HPLC t R 4.022 min (Method A).

[0310] [Experimental Examples 20, 21] The target compounds (1-(3-(dimethylamino)propyl)-6-ethyl-2,5-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-amine; 1-(3-(dimethylamino)propyl)-2-methyl-5,6,7,8,9,10-hexahydro-1H-cycloocta[b]pyrrolo[3,2-e]pyridin-4-amine) were obtained in a similar manner to Step 1 of Experimental Example 19.

[0311] [Experimental Example 22] 1-(2-(dimethylamino)ethyl)-2-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinolin-4-amine

[0312]

[0313] Step 1: 2-amino-1-(2-(dimethylamino)ethyl)-5-methyl-1H-pyrrole-3-carbonitrile

[0314]

[0315] The 2-(2-oxopropyl)malononitrile (1 g, 8.2 mmol) prepared in Step 2 of Experimental Example 9 was dissolved in ethanol (5 mL), to which concentrated hydrochloric acid (3 drops) was added at room temperature, and further N,N-dimethylethane-1,3-diamine (1.07 ml, 9.84 mmol) was added thereto. The reaction mixture was stirred at reflux for 2 hours. After the completion of the reaction, distilled water was added dropwise at 0°C to terminate the reaction, and the product was washed with brine and extracted with dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was separated and purified by silica gel chromatography (0% to 50% ethyl acetate / hexane) to obtain the target compound (524 mg, 33%, brown solid).

[0316] Step 2: 1-(2-(dimethylamino)ethyl)-2-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinolin-4-amine

[0317]

[0318] Cyclohexanone (53 μL, 0.52 mmol) was dissolved in toluene (1 mL), then 2-amino-1-(2-(dimethylamino)ethyl)-5-methyl-1H-pyrrole-3-carbonitrile (50 mg, 0.26 mmol) prepared in Step 1 of Experimental Example 22 above and aluminum chloride (69 mg, 0.52 mmol) were added thereto. The reaction mixture was stirred at reflux for 2 hours. After completion of the reaction, a supersaturated aqueous solution of sodium bicarbonate was added dropwise at 0°C to terminate the reaction, and the product was washed with brine and extracted with dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0% to 100% ethyl acetate mixture (1% triethylamine) / hexane) to obtain the target compound (36 mg, 51%, white solid).

[0319] 1 H NMR (400 MHz, CDCl3) δ 5.97 (s, 1H), 4.25 (t, J = 7.2 Hz, 2H), 4.10 (s, 2H), 2.93-2.90 (m, 2H), 2.59 (t, J = 7.2 Hz, 2H), 2.55-2.52 (m, 2H), 2.40 (s, 3H), 2.30 (s, 6H), 1.90-1.85 (m, 4H); LCMS, m / z 273 [M+H] + ; HPLC t R 3.947 min (Method A).

[0320] [Experimental Example 23] The target compound (1-(2-(dimethylamino)ethyl)-2-methyl-1,5,6,7,8,9-hexahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-4-amine) was obtained in a similar manner to Step 3 of Experimental Example 9.

[0321] [Experimental Example 24] 1-Benzyl-2,3-dimethyl-1,5,6,7,8,9-hexahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-4-amine

[0322]

[0323] Step 1: tert-Butyl (1-(benzo[d][1,3]dioxol-5-yl(methyl)amino)-1 -oxo-3- phenylpropan-2-yl)carbamate

[0324] 1 H NMR (400 MHz, CDC13) δ 7.26 - 7.14 (m, 3H), 7.02 (d, J = 7.1 Hz, 2H), 5.41 (s, 2H), 4.42 (br s, 2H), 3.01 - 2.96 (m, 2H), 2.70 - 2.63 (m, 2H), 2.43 (s, 3H), 2.11 (s, 3H), 1.88 - 1.82 (m, 2H), 1.73 - 1.64 (m, 4H); LCMS, m / z 320 [M+H] + ; HPLC t R 4.956 min (Method A).

[0325] [Example 25] 2-(2-(4-amino-2,3-dimethyl-5,6,7,8-tetrahydro-1 H-pyrrolo[2,3- b]quinolin-1 -yl)acetamido)-N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenylpropanamide

[0326]

[0327] Step 1 : tert-Butyl (1-(benzo[d][1,3]dioxol-5-yl(methyl)amino)-1 -oxo-3- phenylpropan-2-yl)carbamate

[0328]

[0329] Tert-butyl (1-(benzo[d][1,3]dioxol-5-yl(methyl)amino)-1-oxo-3- phenylpropan-2-yl)carbamate (1.2 g, 80%, yellow oil) was obtained using a similar method to reference [Patent WO 2012 / 65062A (18 May 2012; page 49)].

[0330] Step 2: 2-Amino-N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenylpropanamide

[0331]

[0332] Tert-butyl (1-(benzo[d][1,3]dioxol-5-yl(methyl)amino)-1-oxo-3- phenylpropan-2-yl)carbamate (1.2 g, 3.01 mmol) prepared in Step 1 above was dissolved in dichloromethane (10 mL), then trifluoroacetic acid (5 mL, 64.9 mmol) was added at room temperature. The reaction mixture was stirred for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure without further purification to obtain the target compound as a trifluoroacetate salt (1.24 g, 100%, brown oil).

[0333] Step 3: N-(benzo[d][1,3]dioxol-5-yl)-2-(2-bromoacetamido)-N-methyl-3- phenylpropanamide

[0334]

[0335] 2-Amino-N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenylpropanamide (0.5 g, 1.676 mmol) prepared in Step 2 above was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (0.878 mL, 5.028 mmol) and bromoacetyl bromide (1.015 g, 5.03 mmol) were added thereto at 0°C. The mixture was stirred at 0°C for 30 minutes, and then the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was diluted with distilled water and extracted with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0% - 60% ethyl acetate / hexane) to obtain the target compound (0.27 g, 38%, yellowish solid).

[0336] Step 4: 2-(2-(4-amino-2,3-dimethyl-5,6,7,8-tetrahydro-lH-pyrrolo[2,3-b]quinolin-l- yl)acetamido)-N-(benzo[d][l,3]dioxol-5-yl)-N-methyl-3-phenylpropanamide

[0337]

[0338] Step 4: 2-(2-(4-amino-2,3-dimethyl-5,6,7,8-tetrahydro-lH-pyrrolo[2,3-b]quinolin-l- yl)acetamido)-N-(benzo[d][l,3]dioxol-5-yl)-N-methyl-3-phenylpropanamide

[0339] 1 H NMR (400 MHz, CDC13) δ 7.19 - 7.10 (m, 3H), 6.83 (br s, 2H), 6.68 (d, J = 8.0 Hz, 1H), 5.98 (s, 2H), 4.88 - 4.74 (m, 2H), 4.65 (q, J = 7.0 Hz, 1H), 3.10 (s, 3H), 3.07 - 2.94 (m, 2H), 2.92 - 2.81 (m, 1H), 2.77 - 2.63 (m, 3H), 2.36 (s, 3H), 2.19 (s, 3H), 1.74 - 1.58 (m, 4H), 1.49 - 1.40 (m, 2H), 1.37 - 1.28 (m, 2H); LCMS, m / z 582 [M+H] + ; HPLC t R 5.808 min (Method A).

[0340] [Experimental Examples 26, 27] The target compounds (2-(2-(4-amino-2,3-dimethyl-5,6,7,8,9,10-hexahydro-1H-cycloocta[b]pyrrolo[3,2-e]pyridin-1-yl)acetamido)-N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenylpropanamide; 2-(2-(4-amino-2,3-dimethyl-6,7,8,9-tetrahydrocyclohepta[b]pyrrolo[3,2-e]pyridin-1(5H)-yl)acetamido)-N-(benzo[d][1,3]dioxol-5-yl)-N-methyl-3-phenylpropanamide) were obtained in a similar manner to Experimental Example 25.

[0341] [Experimental Example 28] N-(3-(11-amino-1,2,3,4-tetrahydro-6H-indolo[2,3-b]quinolin-6-yl)propyl)-5-methyl-3-phenylisoxazole-4-carboxamide

[0342]

[0343] Step 1: N-(3-chloropropyl)-5-methyl-3-phenylisoxazole-4-carboxamide

[0344]

[0345] Step 1: N-(3-chloropropyl)-5-methyl-3-phenylisoxazole-4-carboxamide 5-methyl-3-phenylisoxazole-4-carboxylic acid (0.5 g, 2.461 mmol) was dissolved in dimethylformamide (7 mL) and to this was added 3-chloroprop-1-amine hydrochloride (0.416 g, 3.20 mmol), EDCI (0.708 g, 3.69 mmol) and DMAP (0.15 g, 1.23 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, washed with brine and the extracted organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel chromatography (0% to 10% methanol / dichloromethane) to obtain the target compound (0.27 g, 39%, white solid).

[0346] Step 2: 2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinoline-11-amine

[0347]

[0348] 2,3,4,6-Tetrahydro-lH-indolo[2,3-b]quinoline-ll-amine (0.25 g, 33%, yellow solid) was obtained in a similar manner as the reference [Yang, Xiaobo et al. Advanced Synthesis and Catalysis, 2010, vol. 352, #6, p. 1035-1038].

[0349] Step 3: N-(3-(l l-amino- 1,2,3,4-tetrahydro-6H-indolo[2,3-b]quinolin-6-yl)propyl)-5- methyl-3-phenylisoxazole-4-carboxamide

[0350]

[0351] Step 2: N-(3-(l l-amino- 1,2,3,4-tetrahydro-6H-indolo[2,3-b]quinolin-6-yl)propyl)-5- methyl-3-phenylisoxazole-4-carboxamide

[0352] 1 H NMR (400 MHz, CDC13) δ 8.68 (t, J = 6.0 Hz, 1H), 7.81 - 7.73 (m, 3H), 7.46 - 7.37 (m, 4H), 7.33 (d, J = 8.0 Hz, 1H), 7.25 - 7.19 (m, 1H), 4.70 (br s, 2H), 4.12 - 4.03 (m, 2H), 3.14 (dd, J = 11.8, 6.1 Hz, 2H), 2.67 (s, 3H), 2.53 (t, J = 6.2 Hz, 2H), 2.42 (t, J = 6.2 Hz, 2H), 2.02 - 1.94 (m, 2H), 1.89 - 1.82 (m, 2H), 1.79 - 1.72 (m, 2H); LCMS, m / z 480 [M+H] + ; HPLC t R 5.561 min (Method A).

[0353] [Experimental Example 29] 2,3-Dimethyl-l-(2-nitrobenzyl)-5,6,7,8-tetrahydro-lH-pyrrolo[2,3-b]quinolin-4-amine

[0354]

[0355] Step 1: 2,3-Dimethyl-5,6,7,8-tetrahydro-lH-pyrrolo[2,3-b]quinolin-4-amine

[0356]

[0357] Cyclohexanone (1.53 mL, 14.79 mmol) was dissolved in toluene (6 mL), then aluminum chloride (1.97 g, 14.79 mmol) and 2-amino-4,5-dimethyl-lH-pyrrole-3-carbonitrile (1 g, 7.39 mmol) were added thereto. The reaction mixture was stirred at reflux for 3 hours. After the completion of the reaction, a supersaturated aqueous solution of sodium bicarbonate was added dropwise at 0°C to terminate the reaction, and the product was washed with brine and extracted with dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was separated and purified by silica gel chromatography (0% to 50% ethyl acetate / hexane) to obtain the target compound (271 mg, 17%, brown solid).

[0358] Step 2: 2,3-Dimethyl-l-(2-nitrobenzyl)-5,6,7,8-tetrahydro-lH-pyrrolo[2,3-b]quinolin-4-amine

[0359]

[0360] 2,3-Dimethyl-5,6,7,8-tetrahydro-lH-pyrrolo[2,3-b]quinolin-4-amine (200 mg, 0.92 mmol) prepared in Step 1 was dissolved in dimethylformamide (3 mL), then sodium hydroxide (80 mg, 1.11 mmol) was added thereto at 0°C. The mixture was allowed to stand at 0°C for 30 minutes, then 2-nitrobenzyl bromide (300 mg, 1.39 mmol) was added thereto. The mixture was warmed to room temperature and stirred for 1 hour. After the completion of the reaction, ice water was added dropwise thereto at 0°C to terminate the reaction. The reaction product was extracted with ethyl acetate, then washed with brine. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0% to 100% ethyl acetate mixed solution (1% triethylamine) / hexane) to obtain the target compound (172 mg, 55%, brown solid).

[0361] 1H NMR (400 MHz, CDC13) δ 7.64 (dd, J = 8.0, 1.4 Hz, 1H), 7.32-7.27 (m, 1H), 7.26-7.21 (m, 1H), 6.90-6.85 (m, 1H), 3.93 (s, 2H), 3.86 (d, J = 15.1 Hz, 1H), 3.39 (d, J = 15.1 Hz, 1H), 2.80 (t, J = 5.8 Hz, 2H), 2.37 (t, J = 5.9 Hz, 2H), 2.33 (s, 3H), 1.85-1.70 (m, 2H), 1.44 (s, 3H), 1.30-1.15 (m, 2H); LCMS, m / z 351 [M+H] + ; HPLC t R 4.736 min (Method A).

[0362] [Experimental Example 30] 6-(3-(dimethylamino)propyl)-9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine

[0363]

[0364] Step 1: N-(2-bromo-4-methoxyphenyl)-2,2,2-trifluoroacetamide

[0365]

[0366] To a solution of 2-bromo-4-methoxyaniline (10 g, 49.49 mmol) in dichloromethane (30 mL), triethylamine (13.8 mL, 98.98 mmol) and trifluoroacetic anhydride (7.6 mL, 54.44 mmol) were added slowly at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction was quenched by slow addition of saturated aqueous NaHC03solution to the mixture, followed by extraction with dichloromethane and washing with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (15.6 g, 100%, brown solid).

[0367] Step 2: 2-amino-5-methoxy-1H-indole-3-carbonitrile

[0368]

[0369] N-(2-bromo-4-methoxyphenyl)-2,2,2-trifluoroacetamide (1 g, 3.35 mmol) prepared in Step 1 was dissolved in a solution of dimethylsulfoxide in distilled water (1 / 1) (10 mL) and charged with N2gas, to which propiolonitrile (266 mg, 4.02 mmol) was added, followed by potassium carbonate (924 mg, 6.7 mmol), n-proline (77 mg, 0.67 mmol), and copper iodide (63 mg, 0.033 mmol). The reaction mixture was stirred at 60 °C for 15 hours. After completion of the reaction, the mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure, diluted with distilled water, extracted with ethyl acetate, and washed with brine. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0% - 50% ethyl acetate / hexane) to obtain the target compound (412 mg, 65%, gray solid).

[0370] Step 3: 9-methoxy-2,3,4,6-tetrahydro-1H-indazolo[2,3-b]quinoline-11-amine

[0371]

[0372] Cyclohexanone (1.2 ml, 11.05 mmol) was dissolved in dichloroethane (7 mL), to which aluminum chloride (1.47 g, 11.05 mmol) was added. Then, 2-amino-5-methoxy-1H-indazole-3-carbonitrile (1.38 g, 7.37 mmol) prepared in Step 2 was added thereto, and the reaction mixture was stirred at reflux for 5 hours. The mixture was cooled to room temperature, and a supersaturated aqueous solution of sodium bicarbonate was added dropwise thereto to terminate the reaction, followed by extraction with a 10% methanol / dichloromethane mixed solution and washing with brine. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0% - 50% ethyl acetate / hexane) to obtain the target compound (1.61 g, 81%, white solid).

[0373] Step 4: 6-(3-(dimethylamino)propyl)-9-methoxy-2,3,4,6-tetrahydro-1H-indazolo[2,3-b]quinoline-11-amine

[0374]

[0375] Step 3: 9-Methoxy-2,3,4,6-tetrahydro-lH-indolo[2,3-b]quinolin-l l-amine (1 g, 3.74 mmol) prepared in step 3 was dissolved in dimethylformamide (7 mL) and then sodium hydroxide (500 mg, 18.7 mmol) was added to it at 0 °C. The reaction mixture was stirred for 30 min and then 3-bromo-N,N-dimethylpropan-1-amine hydrobromide (1.3 g, 7.48 mmol) was added to it. The reaction mixture was allowed to warm slowly to room temperature and then it was allowed to react for 15 h. The reaction was quenched by adding ice water drop wise to the mixture at 0 °C and the mixture was extracted with ethyl acetate and washed with brine. The extracted organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0% - 100% ethyl acetate mixture (1% triethylamine) / hexane) to obtain the target compound (695 mg, 53%, yellow solid).

[0376] 1 H NMR (400 MHz, CDC13) δ 7.36 (d, J = 8.8 Hz, 1H), 7.33 (s, 1H), 7.04 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 4.66 (s, 2H), 4.41 (t, J = 7.0 Hz, 2H), 3.92 (s, 3H), 2.98-2.95 (m, 2H), 2.62-2.59 (m, 2H), 2.45-2.41 (m, 2H), 2.30 (s, 6H), 2.10-1.89 (m, 6H); LCMS, m / z 353 [M+H] + ; HPLC t R 4.276 min (Method A).

[0377] [Experimental Example 31] The target compound (12-(3-(dimethylamino)propyl)-9-methoxy-6,12-dihydro-5H-benzo[h]indolo[2,3-b]quinolin-7-amine) was obtained in a similar manner to Step 3 of Experimental Example 30 described above.

[0378] [Experimental Example 32] The target compound (6-(3-(dimethylamino)propyl)-2,3,4,6-tetrahydro-lH-indolo[2,3-b]quinolin-l l-amine) was obtained in a similar manner to Experimental Example 30 described above.

[0379] [Experimental Example 33] The target compound (6-benzyl-2,3,4,6-tetrahydro-lH-indolo[2,3-b]quinolin-l l-amine) was obtained in a similar manner to Step 3 of Experimental Example 28.

[0380] [Experimental Example 34] 9-Methoxy-6-(3-(methylamino)propyl)-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinoline-11-amine

[0381]

[0382] Step 1: (3-(11-amino-9-methoxy-1,2,3,4-tetrahydro-6H-indolo[2,3-b]quinoline-6-yl)propyl)(methyl)carbamate tert-butyl

[0383]

[0384] The 9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinoline-11-amine (50 mg, 0.18 mmol) prepared in step 3 of Experimental Example 30 above was dissolved in dimethylformamide (1 mL), and then sodium hydroxide (15 mg, 0.37 mmol) was added to it at 0 °C. The reaction product was stirred for 30 minutes, and then (3-bromopropyl)(methyl)carbamate tert-butyl hydrobromide (58 mg, 0.28 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction was terminated by adding ice water dropwise to the mixture at 0 °C, and then the mixture was extracted with ethyl acetate and washed with brine. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0%-100% ethyl acetate mixture (1% triethylamine) / hexane) to obtain the target compound (47 mg, 57%, white solid).

[0385] Step 2: 9-Methoxy-6-(3-(methylamino)propyl)-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinoline-11-amine

[0386]

[0387] The tert-butyl (3-(11-amino-9-methoxy-1,2,3,4-tetrahydro-6H-indolo[2,3-b]quinoline-6-yl)propyl)(methyl)carbamate (47 mg, 0.10 mmol) prepared in step 1 above was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (200 μL) was added to it at room temperature, followed by stirring for 2 hours. After the reaction was complete, the reaction product was neutralized with a supersaturated aqueous solution of sodium bicarbonate, extracted with dichloromethane, and washed with water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound (39 mg, 99%, white solid).

[0388] 1H NMR (400 MHz, CDC13) δ 7.35 (d, J = 2.3 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.05 (dd, J = 8.8, 2.3 Hz, 1H), 4.68 (s, 2H), 4.43 (t, J = 6.4 Hz, 2H), 3.92 (s, 3H), 2.94 (t, J = 5.9 Hz, 2H), 2.60 (t, J = 5.9 Hz, 2H), 2.48 (t, J = 6.4 Hz, 2H), 2.41 (s, 3H), 2.14 - 2.04 (m, 2H), 1.97 - 1.84 (m, 4H); LCMS, m / z 339 [M+H] + ; HPLC t R 4.271 min (Method A).

[0389] [Experimental Example 35] The target compound (6-(3-(methylamino)propyl)-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine) was obtained in a similar manner to Experimental Example 34.

[0390] [Experimental Example 36] 9-Methoxy-6-(4-methylpent-3-en-1-yl)-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine

[0391]

[0392] Step 1: 9-Methoxy-6-(4-methylpent-3-en-1-yl)-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine

[0393]

[0394] The 9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine (30 mg, 0.11 mmol) prepared in Step 3 of the above Experimental Example 30 was dissolved in dimethylformamide (1 mL), and then sodium hydroxide (20 mg, 0.44 mmol) was added thereto at 0°C. The reaction mixture was stirred for 30 minutes, and then 5-bromo-2-methylpentan-2-ol (22 mg, 0.13 mmol) was added thereto. The reaction mixture was slowly warmed to room temperature, and then stirred for 5 hours. The reaction was terminated by dropwise addition of ice water to the mixture at 0°C, and then the mixture was extracted with ethyl acetate and washed with brine. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (0% to 100% ethyl acetate mixed solution (1% triethylamine) / hexane) to obtain the target compound (4 mg, 12%, white solid).

[0395] 1 H NMR (400 MHz, CDC13) δ 7.35 (d, J = 2.3 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.03 (dd, J = 8.7, 2.3 Hz, 1H), 5.23 (t, J = 7.3 Hz, 1H), 4.61 (s, 2H), 4.37-4.27 (m, 2H), 3.92 (s, 3H), 2.99 (d, J = 5.8 Hz, 2H), 2.61 (t, J = 5.8 Hz, 2H), 2.63-2.45 (m, 2H), 1.95-1.90 (m, 4H), 1.64 (s, 3H), 1.53 (s, 3H); LCMS, m / z 350 [M+H] + ; HPLC t R 4.350 min (Method A).

[0396] [Experimental Example 37] 4-(11-amino-9-methoxy-1,2,3,4-tetrahydro-6H- indolo[2,3-b]quinolin-6-yl)butanoic acid ethyl ester

[0397]

[0398] Step 1: 4-(11-amino-9-methoxy-1,2,3,4-tetrahydro-6H-indolo[2,3-b]quinolin-6- yl)butanoic acid ethyl ester

[0399]

[0400] The 9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine (100 mg, 0.39 mmol) prepared in Step 3 of Experimental Example 30 above was dissolved in dimethylformamide (3 mL) and sodium hydroxide (30 mg, 0.74 mmol) was added thereto at 0°C. The reaction mixture was stirred for 30 minutes, and then 4-bromobutanoic acid ethyl ester (102 mg, 0.56 mmol) was added thereto. The reaction mixture was slowly warmed to room temperature, and then stirred for 3 hours. The reaction was terminated by dropwise addition of ice water to the mixture at 0°C, and then the mixture was extracted with ethyl acetate and washed with brine. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (0% to 100% ethyl acetate mixture (1% triethylamine) / hexane) to obtain the target compound (18 mg, 12%, white solid).

[0401] 1H NMR (400 MHz, CDC13) δ 7.35 (s, 1H), 7.34 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 1H), 4.62 (s, 2H), 4.42 (t, J = 6.9 Hz, 2H), 4.10 (q, J = 6.9 Hz, 2H), 3.92 (s, 3H), 2.96 (t, J = 5.8 Hz, 2H), 2.61 (t, J = 5.8 Hz, 2H), 2.32 (q, J = 7.3 Hz, 2H), 2.35-2.15 (m, 2H), 2.00-1.90 (m, 4H), 1.23 (t, J = 7.3 Hz, 3H); LCMS, m / z 382 [M+H] + ; HPLC t R 5.430 min (Method A).

[0402] [Experimental Example 38] 6-(3-(dimethylamino)propyl)-9-methyl-2,3,4,6-tetrahydro-1H- indolo[2,3-b]quinolin-11-amine

[0403]

[0404] Step 1: N-(2-bromo-4-methylphenyl)-2,2,2-trifluoroacetamide

[0405]

[0406] Step 1: N-(2-bromo-4-methylphenyl)-2,2,2-trifluoroacetamide 2-bromo-4-methylphenylamine (1 g, 5.37 mmol) was dissolved in dichloroethane, and then triethylamine (1.5 mL, 10.75 mmol) and trifluoroacetic anhydride (0.91 mL, 6.45 mmol) were added thereto at 0°C. The resulting mixture was stirred at 0°C for 30 minutes, and at room temperature for 2 hours. The mixture was cooled to 0°C, and a supersaturated aqueous solution of sodium bicarbonate was slowly added dropwise to terminate the reaction. Then, the reaction product was extracted with dichloromethane and washed with distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel chromatography (0% to 5% methanol / dichloromethane) to obtain the target compound (1.25 g, 82%, ivory-colored solid).

[0407] Step 2: 2-amino-5-methyl-1H-indole-3-carbonitrile

[0408]

[0409] N-(2-bromo-4-methoxyphenyl)-2,2,2-trifluoroacetamide (1.25 g, 4.43 mmol) prepared in Step 1 was dissolved in a solution of dimethylsulfoxide in distilled water (1 / 1) and charged with N2gas, to which propiolonitrile (266 mg, 4.02 mmol) was added, followed by propiolonitrile (0.35 g, 5.32 mmol), potassium carbonate (1.225 g, 8.86 mmol), n-proline (0.102 g, 0.886 mmol), and copper iodide (0.084 g, 0.443 mmol). The reaction mixture was stirred at 60 °C for 4 hours. After completion of the reaction, the mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure, diluted with distilled water, extracted with ethyl acetate, and washed with brine. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0% - 10% methanol / dichloromethane) to obtain the target compound (0.75 g, 95%, deep yellow solid).

[0410] Step 3: 9-methyl-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinoline-11-amine

[0411]

[0412] Cyclohexanone (0.665 mL, 6.43 mmol) was dissolved in dichloroethane (10 mL), to which aluminum chloride (1.07 g, 8.03 mmol) was added. Then, 2-amino-5-methoxy-1H-indole-3-carbonitrile (0.55 g, 3.21 mmol) prepared in Step 2 was added thereto, and the reaction mixture was stirred at reflux for 5 hours. The mixture was cooled to room temperature, and a supersaturated aqueous solution of sodium bicarbonate was added dropwise thereto to terminate the reaction, followed by extraction with a 10% methanol / dichloromethane mixed solution and washing with brine. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (0% - 5% methanol / dichloromethane) to obtain the target compound (0.65 g, 89%, yellow solid).

[0413] Step 4: 6-(3-(dimethylamino)propyl)-9-methyl-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinoline-11-amine

[0414]

[0415] Step 3. Preparation of 9-methyl-2,3,4,6-tetrahydro-lH-indolo[2,3- b]quinolin-l l-amine. The 9-methyl-2,3,4,6-tetrahydro-lH-indolo[2,3-b]quinoline- 11 -carbonitrile (40 mg, 0.159 mmol) prepared in Step 2 was dissolved in dimethylformamide (1 mL) and then sodium hydroxide (9.5 mg, 0.179 mmol) was added to it at 0 °C. The reaction mixture was stirred for 1 h and then 3-chloro-N,N- dimethylpropyl- 1 -amine hydrochloride (0.03 g, 0.191 mmol) was added to it. The reaction mixture was allowed to warm slowly to room temperature and then stirred for 1 h. Separately, sodium hydroxide (6.4 mg, 0.159 mmol) was added to it and then stirred for 16 h. The reaction was quenched by the dropwise addition of ice water to the mixture at 0 °C and the mixture was extracted with ethyl acetate and washed with brine. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0% - 80% ethyl acetate mixture (10% ammonia water) / hexane) to obtain the target compound (33.6 mg, 63%, yellow solid).

[0416] 1 H NMR (400 MHz, CDC13) δ 7.61 (s, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 4.68 (s, 2H), 4.44 (t, J = 6.9 Hz, 2H), 2.98 (t, J = 5.8 Hz, 2H), 2.77 (s, 2H), 2.61 (t, J = 5.9 Hz, 2H), 2.53 (s, 3H), 2.46 (t, J = 7.0 Hz, 2H), 2.31 (s, 6H), 2.16 - 2.05 (m, 2H), 1.99 - 1.85 (m, 4H); LCMS, m / z 337 [M+H] + ; HPLC t R 4.354 min (Method A).

[0417] [Experimental Examples 39, 40, 41, 42, 43, 44, 45] The target compounds (6-(3-(dimethylamino)propyl)-9-fluoro-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine; 9-chloro-6-(3-(dimethylamino)propyl)-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine; 6-(3-(dimethylamino)propyl)-9-(trifluoromethoxy)-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine; 11-amino-6-(3-(dimethylamino)propyl)-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinoline-9-carbonitrile; 6-(3-(dimethylamino)propyl)-9-(trifluoromethyl)-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine; 11-amino-6-(3-(dimethylamino)propyl)-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinoline-9-carboxylic acid methyl ester; 6-(3-(dimethylamino)propyl)-8-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine) were obtained in a similar manner to Experimental Example 38.

[0418] [Experimental Example 46] 1-((6-(3-(dimethylamino)propyl)-9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-yl)amino)propan-2-ol

[0419]

[0420] Step 1: 1-((6-(3-(dimethylamino)propyl)-9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-yl)amino)propan-2-ol

[0421]

[0422] The 6-(3-(dimethylamino)propyl)-9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine (50 mg, 0.15 mmol) prepared in Experimental Example 30 was dissolved in 2-methyloxirane (2 ml, excess), and lithium perchlorate (160 mg, 1.61 mmol) was added thereto, followed by stirring at 50°C for 2 hours. After completion of the reaction, the reaction product was cooled to room temperature, and then concentrated under reduced pressure. The residue was separated and purified by preparative HPLC (0.1% trifluoroacetic acid H2O / acetonitrile). The obtained trifluoroacetate compound was neutralized with an oversaturated aqueous sodium bicarbonate solution to obtain the target compound (35 mg, 60%, white solid).

[0423] 1 H NMR (400 MHz, DMSO) δ 7.88 (d, J = 2.2 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 6.96 (dd, J = 8.9, 2.2 Hz, 1H), 6.13 (s, 2H), 5.58 (s, 1H), 4.35 - 4.20 (m, 2H), 4.17 (s, 1H), 3.85 (s, 3H), 3.06 (d, J = 6.4 Hz, 6H), 2.85 - 2.75 (m, 2H), 1.90 - 1.75 (m, 4H), 1.06 (d, J = 6.3 Hz, 3H); LCMS, m / z 411 [M+H] + ; HPLC t R 4.255 min (Method A).

[0424] [Experimental Examples 47, 48] The target compounds (11-amino-6-(3- (dimethylamino)propyl)-9-methoxy-3,3-dimethyl-2,3,4,6-tetrahydro-lH-indolo[2,3- b]quinolin-l-one; 11-amino-6-(3-(dimethylamino)propyl)-9-methoxy-3-phenyl- 2,3,4,6-tetrahydro-lH-indolo[2,3-b]quinolin-l-one) were obtained in a similar manner to Experimental Example 38.

[0425] [Experimental Examples 49, 50] The target compounds (9-(benzyloxy)-6-(3- (dimethylamino)propyl)-2,3,4,6-tetrahydro-lH-indolo[2,3-b]quinolin-l l-amine; 6-(3- (dimethylamino)propyl)-9-isopropoxy-2,3,4,6-tetrahydro-lH-indolo[2,3-b]quinolin-l l- amine) were obtained in a similar manner to Experimental Example 30.

[0426] [Experimental Example 51] 11-amino-6-(3-(dimethylamino)propyl)-2,3,4,6- tetrahydro-lH-indolo[2,3-b]quinolin-9-ol

[0427]

[0428] Step 1: 11-amino-6-(3-(dimethylamino)propyl)-2,3,4,6-tetrahydro-lH-indolo[2,3- b]quinolin-9-ol

[0429]

[0430] The 6-(3-(dimethylamino)propyl)-9-isopropoxy-2,3,4,6-tetrahydro-lH- indolo[2,3-b]quinolin-l l-amine (50 mg, 0.13 mmol) prepared in Experimental Example 50 above was dissolved in dichloromethane (1 mL), aluminum chloride (87 mg, 0.65 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, a supersaturated aqueous solution of sodium bicarbonate was added dropwise thereto to terminate the reaction. The reaction mixture was extracted with dichloromethane, and then washed with brine. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel chromatography (0% to 20% methanol / dichloromethane) to obtain the target compound (22 mg, 50%, white solid).

[0431] 1 H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 6.82 (dd, J = 8.6, 2.2 Hz, 1H), 5.87 (s, 2H), 4.23 (t, J = 7.0 Hz, 2H), 3.40-3.10 (m, 4H), 2.80-2.75 (m, 2H), 2.71-2.18 (t, J = 7.0 Hz, 2H), 2.11 (s, 6H), 1.87-1.71 (m, 4H); LCMS, m / z 339 [M+H] + ; HPLC t R 3.975 min (Method A).

[0432] [Experimental Example 52] N1-(7-(3-(dimethylamino)propyl)-9,10,11,12- tetrahydro-7H-benzo[4,5]indolo[2,3-b]quinolin-13-yl)-N3,N3-dimethylpropane-1,3- diamine

[0433]

[0434] 9,10,11,12-Tetrahydro-7H-benzo[4,5]indolo[2,3-b]quinoline-13-amine (50 mg, 0.17 mmol) prepared in a similar manner as described in Experimental Example 34 above was dissolved in dimethylformamide (2 mL), then sodium hydroxide (56 mg, 1.38 mmol) was added thereto at 0°C. The reaction mixture was stirred for 30 minutes, then 3-chloro-N,N-dimethylpropan-1-amine hydrochloride (220 mg, 1.38 mmol) was added thereto. The reaction mixture was slowly warmed to room temperature, then stirred for 15 hours. The mixture was terminated by dropwise addition of ice water at 0°C, then the mixture was extracted with ethyl acetate and washed with brine. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (0% - 100% ethyl acetate mixed solution (1% triethylamine) / hexane) to obtain the target compound (48 mg, 60%, yellow syrup).

[0435] 1 H NMR (400 MHz, DMSO) δ 9.24 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.58 (dd, J = 7.0 Hz, 7.0 Hz, 1H), 7.39 (dd, J = 7.0 Hz, 7.0 Hz, 1H), 5.45 (t, J = 6.7 Hz, 1H), 4.51 (t, J = 7.1 Hz, 2H), 3.10 - 3.02 (m, 2H), 2.95 - 2.85 (m, 2H), 2.82 - 2.75 (m, 2H), 2.23 (t, J = 6.7 Hz, 2H), 2.13 (s, 6H), 2.05 (t, J = 6.7 Hz, 2H), 1.98 (s, 6H), 1.95 - 1.80 (m, 6H), 1.62 - 1.52 (m, 2H); LCMS, m / z 458 [M+H] + ; HPLC t R 4.175 min (Method A).

[0436] [Experimental Example 53] 5-(11-amino-9-methoxy-1,2,3,4-tetrahydro-6H-indolo[2,3-b]quinolin-6-yl)-2-methylpentan-2-ol

[0437]

[0438] Step 1: 5-(11-amino-9-methoxy-1,2,3,4-tetrahydro-6H-indolo[2,3-b]quinolin-6-yl)pentan-2-one

[0439]

[0440] Step 3: 5-(11-amino-9-methoxy-1,2,3,4-tetrahydro-6H-indolo[2,3- b]quinolin-6-yl)-2-methylpentan-2-ol

[0441] Step 2: 5-(11-amino-9-methoxy-1,2,3,4-tetrahydro-6H-indolo[2,3- b]quinolin-6-yl)-2-methylpentan-2-ol

[0442]

[0443] Step 1 : 5-(11-amino-9-methoxy-1,2,3,4-tetrahydro-6H-indolo[2,3- b]quinolin-6-yl)pentan-2-one

[0444] 1H NMR (400 MHz, CDC13) δ 7.36 (d, J = 2.3 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.05 (dd, J = 8.8, 2.3 Hz, 1H), 4.70 (s, 2H), 4.57 (t, J = 6.3 Hz, 2H), 3.92 (s, 3H), 2.98 (t, J = 6.0 Hz, 2H), 2.61 (t, J = 6.0 Hz, 2H), 2.05 - 1.85 (m, 6H), 1.40 - 1.34 (m, 2H), 1.19 (s, 6H); LCMS, m / z 368 [M+H] + ; HPLC t R 5.251 min (Method A).

[0445] [Experimental Example 54] The target compound (7-(3-(dimethylamino)propyl)-9,10,11,12-tetrahydro-7H-benzo[4,5]indolo[2,3-b]quinoline-13-amine) was obtained in a similar manner to Experimental Example 30.

[0446] [Experimental Example 55] 2,3-Dimethyl-1-(3-(methylamino)propyl)-5,6,7,8,9,10-hexahydro-1H-cycloocta[b]pyrrolo[3,2-e]pyridin-4-amine

[0447]

[0448] Step 1: 2,3-Dimethyl-5,6,7,8,9,10-hexahydro-1H-cycloocta[b]pyrrolo[3,2-e]pyridin-4-amine

[0449]

[0450] Dissolve 2-amino-4,5-dimethyl-1H-pyrrole-3-carbonitrile (1 g, 7.39 mmol) in dichloroethane (5 mL) and add to it cyclooctanone (1.46 mL, 11.09 mmol) and aluminum chloride (1.48 g, 11.09 mmol). Stir the reaction mixture under reflux for 15 hours, then cool to room temperature and add to it a supersaturated aqueous solution of sodium bicarbonate dropwise to terminate the reaction. Then, extract the reaction product with dichloromethane and wash with brine. Dry the extracted organic layer over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the obtained residue and purify by silica gel chromatography (0% - 10% methanol / dichloromethane) to obtain the target compound (718 mg, 39%, brown solid).

[0451] Step 2: tert-Butyl (3-(4-amino-2,3-dimethyl-5,6,7,8,9,10-hexahydro-lH- cycloocta[b]pyrrolo[3,2-e]pyridin-l-yl)propyl)(methyl)carbamate

[0452]

[0453] Step 2: tert-Butyl (3-(4-amino-2,3-dimethyl-5,6,7,8,9,10-hexahydro-lH- cycloocta[b]pyrrolo[3,2-e]pyridin-l-yl)propyl)(methyl)carbamate

[0454] Step 3: 2,3-Dimethyl-l-(3-(methylamino)propyl)-5,6,7,8,9,10-hexahydro-lH- cycloocta[b]pyrrolo[3,2-e]pyridin-4-amine

[0455]

[0456] Step 2: tert-Butyl (3-(4-amino-2,3-dimethyl-5,6,7,8,9,10-hexahydro-lH- cycloocta[b]pyrrolo[3,2-e]pyridin-l-yl)propyl)(methyl)carbamate

[0457] 1H NMR (400 MHz, CDC13) δ 4.60 (s, 2H), 4.26-4.15 (m, 2H), 2.88-2.79 (m, 2H), 2.81-2.65 (m, 4H), 2.61 (s, 3H), 2.42 (s, 3H), 2.26 (s, 3H), 2.24-2.15 (m, 2H), 1.80-1.64 (m, 4H), 1.50-1.45 (m, 2H), 1.37-1.28 (m, 2H); LCMS, m / z 315 [M+H] + ; HPLC t R 4.446 min (Method A).

[0458] [Experimental Example 56] 1-Isobutyl-2,3-dimethyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinolin-4-amine

[0459]

[0460] Dissolve 2,3-dimethyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinolin-4-amine (50 mg, 0.23 mmol) prepared in step 1 of Experimental Example 29 in dichloroethane (1 mL) and add sodium hydroxide (14 mg, 0.34 mmol) thereto at 0°C. Stir the mixture at 0°C for 30 minutes, and then add 1-bromo-2-methylpropane (37 μL, 0.34 mmol) thereto. Warm the mixture to room temperature, and then stir for 15 hours. Cool the mixture to 0°C, and add ice water dropwise to terminate the reaction. Then, extract the reaction product with dichloromethane and wash with distilled water. Dry the extracted organic layer over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate the obtained residue and purify by silica gel chromatography (0% to 50% ethyl acetate / hexane) to obtain the target compound (22 mg, 35%, white solid).

[0461] 1 H NMR (400 MHz, CDC13) δ 4.31 (s, 2H), 3.91 (d, J = 7.6 Hz, 2H), 2.88 (t, J = 6.0 Hz, 2H), 2.50 (t, J = 6.0 Hz, 2H), 2.42 (s, 3H), 2.26 (s, 3H), 2.25-2.15 (m, 1H) 1.93-1.78 (m, 4H), 0.86 (d, J = 6.7 Hz, 6H); LCMS, m / z 272 [M+H] + ; HPLC t R 5.419 min (Method A).

[0462] [Experimental Example 57] The target compound (2,3-dimethyl-l-(pyridin-2- ylmethyl)-5,6,7,8-tetrahydro-lH-pyrrolo[2,3-b]quinolin-4-amine) was obtained in a similar manner to Experimental Example 56.

[0463] [Experimental Example 58] The target compound (10-(3-(dimethylamino)propyl)-8,9- dimethyl-6,10-dihydro-5H-benzo[h]pyrrolo[2,3-b]quinolin-7-amine) was obtained in a similar manner to Experimental Example 29.

[0464] [Experimental Example 59] 2,3-Dimethyl-l-phenyl-5,6,7,8-tetrahydro-lH-pyrrolo[2,3- b]quinolin-4-amine

[0465]

[0466] Step 1: 2-Amino-4,5-dimethyl-l-phenyl-lH-pyrrole-3-carbonitrile

[0467]

[0468] Step 1: 2-Amino-4,5-dimethyl-l-phenyl-lH-pyrrole-3-carbonitrile

[0469] Step 2: 2,3-Dimethyl-l-phenyl-5,6,7,8-tetrahydro-lH-pyrrolo[2,3-b]quinolin-4-amine

[0470]

[0471] Cyclohexanone (48 μL, 0.47 mmol) was dissolved in dichloroethane (1 mL) to which was added aluminum chloride (63 mg, 0.47 mmol). The mixture was stirred at room temperature for 10 minutes to which was further added 2-amino-4,5-dimethyl-l-phenyl-lH-pyrrole-3-carbonitrile (50 mg, 0.23 mmol) prepared in Step 1 and the reaction mixture was stirred at reflux for 15 hours. The mixture was cooled to room temperature to which was added dropwise a supersaturated aqueous solution of sodium bicarbonate to quench the reaction and the reaction product was washed with brine and extracted with dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated and purified by preparative HPLC (0.1% trifluoroacetic acid H2O / acetonitrile). The obtained trifluoroacetate compound was neutralized with a supersaturated aqueous solution of sodium bicarbonate to obtain the target compound (7 mg, 11%, brown solid).

[0472] 1 H NMR (400 MHz, CDC13) δ 7.47 (dd, J = 7.6, 7.6 Hz, 2H), 7.42 - 7.30 (m, 3H), 4.40 (s, 2H), 2.79 (t, J = 6.2 Hz, 2H), 2.57 - 2.43 (m, 2H), 2.49 (s, 3H), 2.13 (s, 3H), 1.90 - 1.77 (m, 6H); LCMS, m / z 292 [M+H] + ; HPLC t R 5.397 min (Method A).

[0473] [Experimental Example 60] The target compound (2,3-dimethyl-l-(pyridin-3-yl)-5,6,7,8-tetrahydro-lH-pyrrolo[2,3-b]quinolin-4-amine) was obtained in a similar manner to Experimental Example 59.

[0474] [Experimental Examples 61, 62] The target compounds (6-(3-(dimethylamino)propyl)-8-methyl-2,3,4,6-tetrahydro-lH-indolo[2,3-b]quinolin-l l-amine; 8-chloro-6-(3-(dimethylamino)propyl)-2,3,4,6-tetrahydro-lH-indolo[2,3-b]quinolin-l l-amine) were obtained in a similar manner to Experimental Example 38.

[0475] Example 3: Systemic lupus erythematosus mouse model experiment

[0476] Example 3-2: Analysis of systemic lupus erythematosus mouse model samples

[0477] MRL / lpr (or MRL / Faslpr) mice (14 weeks old, 36-40 g female) lpr) Mice (purchased from the Jackson Laboratory, USA, through Orient Bio) were used for the lupus treatment effect experiment, and were bred in accordance with the breeding and ethics guidelines of the Laboratory Animal Research Center of the Asia University Medical Center. Prior to the experiment, 4 to 5 animals were randomly allocated to each of the negative control group (vehicle), the positive control group (HCQ), and the experimental compound groups (SK41, SK50, SK58, and SK64) for blinding, and each of the SK41, SK50, SK58, and SK64 compounds was completely dissolved in a vehicle consisting of 10% ethanol (ethyl alcohol), 40% polyethylene glycol 400, and 50% sterile distilled water, and the solution was then orally administered to the experimental animals.

[0478] As for the administration method, the same amount of vehicle was administered only for the negative control group, 15-60 MPK (15-60 mg / Kg) HCQ was administered daily for the positive control group, and SK41, SK50, SK58, and SK64 were administered in an amount of 15-30 MPK (15-30 mg / Kg) daily for the experimental compound groups, and the administration was started from when the experimental mice were 14 weeks old, for 40 days.

[0479] As for the sample collection method, the body weight of the experimental mice was measured at 3-day intervals, and on the day of the expiration of 40 days, the mice were inhaled anesthetized and euthanized using IFRAN liquid (Hana Pharmaceutical, Korea; ingredient name: isoflurane), and then blood, kidneys, spleen, and axillary and inguinal lymph nodes were collected therefrom.

[0480] Figure 1

[0481] The blood sample was collected from the heart of the anesthetized mouse, serum was extracted therefrom using a serum separation tube and a centrifuge (4,000 rpm, 10 minutes, 4℃), and the blood concentration of ANA (anti-nuclear antibody, MyBioSourse, USA), which is an indicator molecule of the severity of lupus, and C3 complement (MyBioSourse, USA), which is an indicator molecule of comprehensive inflammation, was measured by enzyme-linked immunosorbent assay (ELISA).

[0482] Immediately after extraction, the organs were treated with an RNA stabilizer (RNA stabilizing reagent, Germany, QUIAGEN) to preserve the condition and prepare the sample, the organs were imaged and weighed to determine whether the organs were damaged and measure the degree of immune organ hypertrophy, and the sum of the weights of a pair of axillary lymph nodes and a pair of inguinal lymph nodes was recorded as the weight of the lymph nodes.

[0483] Example 4: Identification of a lead substance based on TLR7 / 9 inhibitory activity

[0484] The putative binding mode and interaction mode of SK01 with TLR7 was predicted by molecular docking. The R848 bound crystal structure of TLR7 (PDB ID: 5GMH) was used for docking assays as the inhibitor did not show activity against TLR8 and the small molecule binding cavity on TLR3 and TLR9 was not determined by X-ray crystallography. The receptor was washed by removing non-essential elements including water molecules and heteroatoms, except for the bound agonist R848. Protonation was achieved in the presence of Amber12:EHT force field. Energy minimization was performed until the root mean square (RMS) gradient reached 0.1 The residues surrounding R848 were defined as the ligand binding site and docking was performed using microplate similarity placement and affinity dG scoring function. The docking hits were scored again using Amber12:EHT force field and GBVI / WSA dG scoring function. The best scoring poses with lower RMS deviation from R848 were selected to visualize the binding mode of the ligand and intermolecular interactions. The potential inhibitory capacity on TLR7 / TLR9 activation was confirmed by ELISA to identify a small molecule compound called “SK01” Figure 2

[0485] To identify ligands with 80% or higher structural similarity (i.e., Tanimoto metric, cutoff = 0.8) to SK01, the MolPort database (https: / / www.molport.com / shop / index) was searched to find the SK01 structure. A total of 100 derivatives were downloaded as SDF files and processed in MOE. The ligands were washed using the sdwash protocol of MOE and energy minimized. Assuming that SK01 must bind to the extracellular domain of the receptor to exert its inhibitory activity, all ligands except SK01 were docked in the small molecule binding cavity (R848) of the TLR7 structure. The docking poses were ranked according to the calculated binding affinity designated as S-score. Ligands with higher affinity to TLR7 than SK01 were selected for experimental validation of activity. The inhibitory capacity of selected SK02 to SK20 candidates against TLR9 was tested at 5 mM Figure 3 and based on this, six compounds were selected to determine the inhibitory activity of regular SK01 at lower concentrations (2 mM and 5 mM) Figure 4 to Figure 6 This approach showed that among the structural analogs of SK01, SK16 exhibited the best inhibitory activity Figure 7 and was further modified on this basis.

[0486] Example 5: Identification of potential inhibitors of endosomal TLRs

[0487] ​To select potential inhibitory molecules against TLR3 / TLR7 / TLR8 / TLR9 activation, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell viability assay was first performed after treatment with a set of ligands from SK21 to SK82 at a concentration of 20 μΜ Figure 8 ), and their inhibitory activity was evaluated by ELISA assay to monitor the level of TNF-α secretion in RAW 264.7 cells. Experimental ligands from SK21 to SK82 were applied to RAW 264.7 cells at 0.5 μΜ or 2 μΜ, and stimulated with imiquimod (TLR7, 1 μg / ml) and OND2395 (TLR9, 0.5 μΜ). Among the tested ligands, SK23, SK24, SK29, SK36, SK39, SK40, SK41, SK50, SK52, SK54, SK55, SK58, SK59, SK60, SK61, SK62, SK63, SK64, SK65, SK69, SK70, SK71, SK72, SK 74, SK75, SK81 and SK82 exhibited significant inhibitory activity against TLR7 and TLR9 in a dose-dependent manner Figure 9 and Figure 10 ).

[0488] To verify the potential of 13 compounds among the significant candidates identified in the initial screening phase as specific novel drugs, LC 50 and IC 50 of TLR7 and TLR9 of each compound and positive control HCQ were measured. The therapeutic index calculated using these two values is shown in the table Figure 11 ). Compared to HCQ, all 13 compounds initially selected had higher inhibitory concentrations in TLR7 and TLR9, and 4 candidates with lower toxicity (LC 50 ) and superior TI (SK41, SK50, SK58 and SK64) were selected from among them.

[0489] To determine the inhibitory activity of SK41, SK50, SK58 and SK64 against various TLR signaling pathways, RAW264.7 cells were incubated with each of the compounds and then stimulated with different TLR agonists. The TLR agonists used herein are Pam3CSK4 (TLR1 / 2), FSL-1 (TLR2 / 6), LPS (TLR4) and FLA-ST (TLR5) for cell surface TLRs and poly I:C (TLR3) and TL8-506 (TLR8) for endosomal TLRs. The results of the measurement of TNF-a secretion levels using ELISA indicated that SK41, SK50, SK58 and SK64 did not exhibit specific inhibitory activity against cell surface TLRs: TLR1 / 2, TLR2 / 6, TLR4 and TLR5 Figure 12 ), but exhibited strong inhibitory activity against endosomal TLRs: TLR3 and TLR8 Figure 13 .

[0490] Example 6: Confirmation of SK derivatives exhibiting therapeutic effects in MRL / lpr lupus disease mouse model

[0491] SK41, SK50, SK58 and SK64 were selected as test substances to verify efficacy through in vivo animal experiments, and then animal experiments were performed in an MRL / lpr mouse model, which is a naturally occurring lupus animal model. A group administered with only a vehicle (Vehicle) and a group administered with HCQ were added as experimental control groups, and HCQ is known as an endosomal TLR inhibitor. Body weight changes of all mice were monitored at 3-day intervals during the entire period, which was used as an index for evaluation of long-term administration toxicity due to administration of test substances. As a result, all administration groups did not exhibit changes in body weight, which means that visual therapeutic effects (SK41, SK58 and SK64 are superior to HCQ) or changes thereof are independent of toxicity when SK41, SK50, SK58 and SK64 are administered Figure 14 and Figure 15 ).

[0492] After 40 days of administration, the mice were euthanized, and samples of the spleen, lymph nodes and kidneys were collected therefrom. No clear visual changes were observed in the spleen. The appearance of lymph nodes in which antigens in lymph fluid cause an immune response was observed. As a result, the SK58 experimental group was relatively good, while all SK41 experimental groups had small inguinal lymph node sizes. The weights of the spleen and lymph nodes of each mouse were measured, and the results indicated that the spleen and lymph node swelling of the SK58 experimental group was relatively small Figure 16 ).

[0493] Anti-nuclear antibodies (decreased to normal) and C3 complement (increased to normal) (they are molecular markers of lupus disease) in the plasma collected from the heart of mice immediately after euthanizing the mice were tracked, and as a result, significant results were obtained in SK41 and SK58 ( Figure 13 to Figure 16 ). Especially, the SK58 experimental group contained low anti-nuclear antibodies and high C3 complement compared to the negative control group treated with only a vehicle and the positive control group treated with HCQ, which means it has a high potential as an effective candidate.

[0494] Figure 17 The results were obtained by treating with twice the dose of HCQ (60 mg / Kg) of the SK series dose (30 mg / Kg), and Figure 17 The results were obtained by administering 15 mg / Kg, which is the same daily dose as HCQ (a competitive substance) for direct comparison of therapeutic effects. SK41 and SK58 exhibit superior visual (apparent) cure effects to HCQ ( ​ ).

[0495] The results of the determination of inhibitory activity against TLR7 and TLR9 at a low concentration showed that SK23, SK24, SK29, SK36, SK39, SK40, SK41, SK50, SK52, SK54, SK55, SK58, SK59, SK60, SK61, SK62, SK63, SK64, SK65, SK69, SK70, SK71, SK72, SK74, SK75, SK81, and SK82 were identified as effective novel compounds, and all of these substances significantly reduced the level of TLR7 / TLR9-mediated TNF-α secretion, thereby indicating that they are effective inhibitors of TLR7 / 9 signaling. In addition, SK41, SK50, SK58, and SK64 did not exhibit inhibitory activity against TLR1 / 2, TLR2 / 6, TLR4, or TLR5 in the cell surface TLR signaling pathway, but exhibited specific inhibitory activity against TLR3 and TLR8. This indicates that SK24, SK29, SK36, SK39, SK40, SK41, SK50, SK52, SK54, SK55, SK58, SK59, SK60, SK61, SK62, SK63, SK64, SK65, SK69, SK70, SK71, SK72, SK74, SK75, SK81, and SK82 all have the effect of controlling endosomal TLRs.

[0496] Industrial applicability

[0497] The novel compounds according to the present application can block the secretion of TNF-α induced by poly I:C (TLR3 agonist), imiquimod (TLR7 agonist), TL8-506 (TLR8 agonist) or ODN 2395 (TLR9 agonist) and inhibit the production of inflammatory cytokines, and are thus particularly useful for the prevention or treatment of TLR3, TLR7, TLR8 or TLR9 related autoimmune diseases, inflammatory diseases and viral diseases, including systemic lupus erythematosus and psoriasis.

[0498] While particular configurations of the application have been described in detail herein, it will be appreciated by those skilled in the art that the foregoing description is provided for illustration purposes only and should not be construed in a limiting sense. Thus, the scope of the present application is best delineated by the appended claims and equivalents thereof.

Claims

1. A compound represented by any one selected from the group consisting of the following formulae 1-8 to 1-12 and 1-14 to 1-34: [Formula 1-8] [Formula 1-9] [Formula 1-10] [Formula 1-11] [Formula 1-12] [Formula 1-14] [Formula 1-15] [Formula 1-16] [Formula 1-17] [Formula 1-18] [Formula 1-19] [Formula 1-20] [Formula 1-21] [Formula 1-22] [Formula 1-23] [Formula 1-24] [Formula 1-25] [Formula 1-26] [Formula 1-27] [Formula 1-28] [Formula 1-29] [Formula 1-30] [Formula 1-31] [Formula 1-32] [Formula 1-33] [Formula 1-34] or a pharmaceutically acceptable salt thereof.

2. A composition for inhibiting a Toll-like receptor (TLR), the composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. A composition for inhibiting a Toll-like receptor (TLR), the composition comprising a compound represented by any one selected from the group consisting of the following formulae 1-1 to 1-34: [Formula 1-1] [Formula 1-2] [Formula 1-3] [Formula 1-4] [Formula 1-5] [Formula 1-6] [Formula 1-7] [Formula 1-8] [Formula 1-9] [Formula 1-10] [Formula 1-11] [Formula 1-12] [Formula 1-13] [Formula 1-14] [Formula 1-15] [Formula 1-16] [Formula 1-17] [Formula 1-18] [Formula 1-19] [Formula 1-20] [Formula 1-21] [Formula 1-22] [Formula 1-23] [Formula 1-24] [Formula 1-25] [Formula 1-26] [Formula 1-27] [Formula 1-28] [Formula 1-29] [Formula 1-30] [Formula 1-31] [Formula 1-32] [Formula 1-33] [Formula 1-34] or a pharmaceutically acceptable salt thereof.

4. Use of the composition according to claim 2 in the manufacture of a medicament for inhibiting a signaling pathway of at least one TLR selected from the group consisting of TLR3, TLR7, TLR8 and TLR9.

5. A pharmaceutical composition comprising, as an active ingredient, the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing or treating an autoimmune disease, an inflammatory disease or a viral disease. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 7. Use according to claim 6, wherein the autoimmune or inflammatory disease is selected from psoriasis, systemic lupus erythematosus SLE, skin rash, photosensitive dermatosis, rheumatoid arthritis, juvenile rheumatoid arthritis, discoid lupus erythematosus, malaria, mouth ulcer, nephritis, cytopenia, vasculitis, serositis, inflammatory bowel disease IBD, multiple sclerosis, scleroderma, pemphigus, atopic dermatitis, urethritis, cystitis, allergic disease, rhinitis, asthma, periodontitis, gingivitis, gout, gastric ulcer, sepsis and pancreatitis, and the viral disease is selected from viral influenza, varicella, herpes zoster, herpes simplex, infectious mononucleosis, cytomegalovirus infection, measles, mumps, rubella, parvovirus infection, poliomyelitis, viral hemorrhagic fever, yellow fever, dengue fever, rabies, AIDS and Covid-19.

8. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of Down syndrome, dementia, depression, schizophrenia, sleep disorders, Parkinson's disease, diabetes, obesity, tuberculosis, congestive heart failure, angina pectoris, myocardial infarction, arteriosclerosis, cerebral infarction, hypertension, stroke, acute or chronic pain.

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