Ligand compound for ubiquitin ligase and protac molecule comprising same

Abstract

The present invention relates to a ligand compound for a ubiquitin ligase and a proteolysis targeting chimera (PROTAC) molecule comprising same and, more specifically, to a compound acting as a ligand for a E3 ubiquitin ligase or a prodrug thereof, and a PROTAC heterobifunctional molecule comprising same.

Description

Ligand compound of ubiquitin ligase and PROTAC molecule containing same

[0001] The present invention relates to a ligand compound of ubiquitin ligase and a PROTAC (proteolysis targeting chimera) molecule comprising the same, and more particularly, to a compound acting as a ligand of E3 ubiquitin ligase or a prodrug thereof, and a PROTAC heterobifunctional molecule comprising the same.

[0002] The N-end rule states that the lifetime of a protein depends on the characteristics of its N-terminal residue. The N-terminal residue that destabilizes the protein is called an N-degron, and is divided into type 1 and type 2. Type 1 N-degrons contain basic amino acid residues that can be positively charged, such as arginine (Arg), lysine (Lys), and histidine (His), while type 2 N-degrons contain hydrophobic amino acid residues, such as phenylalanine (Phe), tryptophan (Trp), tyrosine (Tyr), leucine (Leu), or isoleucine (Ile) (Varshavsky, A. et al. Protein Science 2011, 20, 1298-1345).

[0003] In mammals, seven isoforms of ubiquitin protein ligase E3 component N-recognin (UBR) proteins, which commonly contain the evolutionarily well-conserved UBR box, are known (see Fig. 1; Kim, JG et al. Int. J. Mol. Sci. 2021, 22, 8323). In addition to the UBR box, UBR proteins contain RING, HECT, F-box, or PHD domains that bind to the E2 enzyme of other E3 ligases. Among the UBR protein isoforms, UBR1, UBR2, UBR4, and UBR5 proteins bind to type 1 N-degrons (Tasaki, T. et al. J. Biol. Chem. 2009, 284, 1884-1895; Nillegoda, NB et al. Mol. Biol. Cell 2010, 21, 2102-2116).

[0004] The protein crystal structures of the UBR box of human UBR1, UBR2 and yeast UBR1 are known, and the UBR box contains three Zn cations, and Zn 2+There are two zinc finger motifs capable of coordinating ions and two binding pockets capable of recognizing the first and second amino acid residues of the N-degron (Choi, WS et al. Nat. Struct. Mol. Biol. 2010, 17, 1175-1181; Matta-Camacho, E. et al. Nat. Struct. Mol. Biol. 2010, 17, 1182-1187; Munoz-Escobar, J. Structure 2017, 25, 719-729). The first binding pocket is composed of aspartic acid (Asp), threonine (Thr), and phenylalanine (Phe) residues, which form a negatively charged protein surface and allow strong interactions with type 1 N-degrons, which have positively charged basic residues, through hydrogen bonding and charge-charge interactions. The second binding pocket also allows selective recognition of N-degrons through interactions with specific residues, such as serine (Ser), valine (Val), phenylalanine (Phe), and threonine (Thr).

[0005] The UBR box of the UBR protein recognizes N-degrons and plays a crucial role in cellular protein degradation. Ligand compounds that bind to the UBR box can participate in protein degradation pathways. Furthermore, UBR proteins are known to play essential regulatory roles in numerous signaling pathways, including G-protein signaling, apoptosis, and inflammation. Dysregulation in these signaling pathways can lead to disease states such as cancer and neurodegeneration.

[0006] In G-protein-coupled receptors (GPCRs), heterotrimeric G proteins are known to dissociate into downstream subunits by external ligands or signal mediators, and downstream signaling pathways are stimulated by activated GTP-bound proteins. Regulator of G-protein signaling (RGS) proteins, which play a key role in this signaling cascade, undergo arginylation of their N-terminal residues through metabolism and ubiquitination by UBR1 and UBR2, leading to protein degradation (Lee, MJ et al. Proc. Natl. Acad. Sci. USA 2005, 102, 15030-15035). Therefore, it has been reported that inhibition of the function of UBR1 and UBR2 stabilizes RGS proteins, promotes hydrolysis of GTP-binding subunits, inactivates G-protein signaling, and impairs neurodevelopment and cardiovascular development (Sjogren, B. et al. Mol. Pharmacol. 2010, 78, 550-557; Davydov, IV et al. J. Biol. Chem. 2000, 275, 22931-22941). Dysregulation of the apoptotic process, which maintains homeostasis by selectively eliminating damaged or abnormal cells, can lead to cancer and neurodegenerative diseases. Knockdown experiments using siRNA (small interfering RNA) have shown that depletion of UBR1, UBR2, UBR4, and UBR5 increases apoptosis in various cancer cells (Leboeuf, D. et al. Mol. Ther. 2020, 28, 1092-1104).Additionally, RIPK1 (receptor-interacting serine / threonine-protein kinase 1), known as a pro-apoptotic fragment, is known to be ubiquitinated by UBR protein and promote cell survival (Zhang, A. et al. Nat. Commun. 2019, 10, 4158).

[0007] Inflammation is a protective response induced by the well-conserved innate immune system to protect against pathogens, damaged cells, or harmful stimuli. Some inflammatory fragments contain unstable N-terminal residues, leading to their degradation via the N-degron pathway, such as UBR1, UBR2, UBR4, and UBR5. Indeed, knockdown of UBR1, UBR2, UBR4, and UBR5 via siRNA significantly increased IL-1β secretion (Leboeuf, D. Biomolecules 2020, 10, 903), suggesting that UBR E3 ligases are also involved in inflammatory responses.

[0008] Meanwhile, a proteolysis targeting chimera (PROTAC) is a heterobifunctional molecule consisting of a ligand for a target protein and a ligand that binds to an E3 ubiquitin ligase, linked via a linker. PROTACs simultaneously bind to both proteins, bringing the target protein into close proximity to the E3 ubiquitin ligase. This allows the E3 ubiquitin ligase to recognize the target protein as a substrate, triggering polyubiquitination and subsequent proteasomal degradation. This principle allows for the effective removal of specific proteins from cells. Therefore, PROTACs can be used as chemical probes for studying the function of target proteins and, furthermore, hold great potential as therapeutic agents for diseases. However, despite these advantages, the current use of PROTAC technology has limitations. One of these limitations is the limited number of cell types and tissues that can be targeted. Although there are over 600 E3 ubiquitin ligases in the human body, only a few, such as cereblon (CRBN) and Von Hippel-Lindau tumor suppressor (VHL), are currently used as E3 ubiquitin ligases in the PROTAC design.

[0009] Accordingly, the present invention has as a technical problem a compound or a prodrug thereof that can efficiently act as a ligand of an E3 ubiquitin ligase by binding to the UBR box of a UBR protein.

[0010] In addition, the present invention has as another technical object to provide a PROTAC (proteolysis targeting chimera) heterobifunctional molecule comprising a ligand compound of the E3 ubiquitin ligase or a prodrug thereof.

[0011] To solve the above technical problem, the present invention provides a compound of the following chemical formula 1 or a prodrug thereof:

[0012] [Chemical Formula 1]

[0013]

[0014]

[0015] In the above chemical formula 1, R1, R2, R3, R4, R5, R6, R7, R8, L1, L2, L3, m, n and p are as defined herein.

[0016]

[0017] In addition, to solve the above other technical problems, the present invention provides a chimeric compound of the following chemical formula 2:

[0018] [Chemical Formula 2]

[0019]

[0020]

[0021] In the above chemical formula 2, A and B are as defined herein, and A and B are chemically linked by a linker.

[0022] The compound according to the present invention or a prodrug thereof can act as a ligand for an efficient E3 ubiquitin ligase, thereby efficiently degrading a target protein by the ubiquitin-proteasome system of a cell in a PROTAC (proteolysis targeting chimera) technology utilizing the compound.

[0023] Figure 1 shows the seven isoforms of ubiquitin protein ligase E3 component n-recognin (UBR) proteins.

[0024] Figure 2 is a graph showing a competitive fluorescence polarization analysis method.

[0025] Figure 3 shows LC and Mass analysis data of PROTAC of Example 167.

[0026] Figure 4 is a graph showing the results of measuring the binding affinity of the compound of Example 113 and the PROTAC of Example 167 to the UBR1 protein in Experimental Example 2.

[0027] Figure 5 shows the results of evaluating the BRD4 protein decomposition ability of PROTAC of Example 167 in Experimental Example 3 (BRD4: bromodomain-containing protein 4, GAPDH: glyceraldehyde-3-phosphate dehydrogenase).

[0028] Figure 6 shows the results of evaluating the decomposition ability of BRD4 protein in Experimental Example 4 (JQ1: BET bromodomain inhibitor, MG132: proteasome inhibitor, BRD4: bromodomain-containing protein 4, GAPDH: glyceraldehyde-3-phosphate dehydrogenase).

[0029] Figure 7 shows LC and Mass analysis data of the PROTAC prodrug of Example 168.

[0030] Figure 8 shows the results of evaluating the ability of the PROTAC and the PROTAC prodrug of Example 168 to decompose BRD4 protein in which the compound of Example 100 and the BRD4 ligand were linked via a linker in Experimental Example 5 (BRD4: bromodomain-containing protein 4, GAPDH: glyceraldehyde-3-phosphate dehydrogenase).

[0031] The present invention is described in more detail below.

[0032]

[0033] According to one aspect of the present invention, a compound of the following chemical formula 1 or a prodrug thereof is provided:

[0034] [Chemical Formula 1]

[0035]

[0036]

[0037] In the above chemical formula 1,

[0038] R1 and R2 are each independently -H, -D, alkyl, deuterated alkyl or haloalkyl;

[0039] R3 is -DEG; wherein D is a direct bond or alkylene; E is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocycloalkylene, heterocycloalkenylene, or heteroarylene; wherein said alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocycloalkylene, heterocycloalkenylene or heteroarylene is optionally -D, halo, hydroxy, thiol (-SH), amino, nitro, cyano, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkylthio, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkenyl, alkynyl, cycloalkyl, may be substituted with one or more substituents selected from heterocycloalkyl, aryl and heteroaryl; G is amino, heteroaryl, , or and; here R9, R 10 and R 11 are each independently -H, alkyl or haloalkyl; or R9 and R 10 These can be interconnected to form a ring structure;

[0040] R4 and R6 are each independently -H, -D, alkyl, deuterated alkyl or haloalkyl;

[0041] L1 is -C-, -CH-, cycloalkylene, heterocyclylene, cycloalkenylene, heterocycloalkenylene, arylene or heteroarylene; or may form a ring structure together with the N atom to which R4 and L1 are bonded;

[0042] R5 is -H, -D, halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, aryl-alkoxy or heteroaryl-alkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, aryl-alkoxy or heteroaryl-alkyl is optionally -D, hydroxy, thiol, amino, halo, nitro, cyano, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl-oxy, heterocycloalkyl-oxy, aryl-oxy, heteroaryl-oxy, alkoxyalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, carboxy, alkoxyoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, Alkylcarbonyl, alkylcarbonylalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and may be substituted with one or more substituents selected from; wherein R 12 and R 13 are each independently -H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, cycloalkenyl-alkyl, heterocycloalkyl-alkyl, heterocycloalkenyl-alkyl, aryl-alkyl or heteroaryl-alkyl; or R 12 Wow R 13These can be connected to each other to form a ring structure; q is 0, 1, 2, 3, 4, 5, 6 or 7; or when L1 is -C- and m is 2, R5 and L1 can be connected together to form a cycloalkyl or heterocycloalkyl;

[0043] L2 may be a direct bond, or when n is 0, R4 and L2 may be connected to each other with the N atom to which they are bonded to form a ring structure; wherein said ring may be optionally substituted with one or more substituents selected from -D, hydroxy, amino, halo, nitro, cyano, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl-oxy, heterocycloalkyl-oxy, aryl-oxy, heteroaryl-oxy, alkoxyalkyl, aminoalkyl, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

[0044] L3 is a direct bond, -C-, -CH-, -CH2-, cycloalkylene, heterocycloalkylene, unsaturated carbocyclylene, unsaturated heterocyclylene, arylene or heteroarylene; or can form a ring structure together with the N atom to which R6 and L3 are bonded;

[0045] R7 is halo, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl-oxy, cycloalkyl-alkyl, cycloalkyl-alkoxy, cycloalkenyl-oxy, cycloalkenyl-alkyl, cycloalkenyl-alkoxy, heterocycloalkyl-oxy, heterocycloalkyl-alkyl, heterocycloalkyl-alkoxy, heterocycloalkenyl-oxy, heterocycloalkenyl-alkyl, heterocycloalkenyl-alkoxy, aryl, aryl-oxy, aryl-alkyl, aryl-alkoxy, heteroaryl, heteroaryl-oxy, heteroaryl-alkyl, heteroaryl-alkoxy or and here R 14 and R 15 are each independently -H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, cycloalkenyl-alkyl, heterocycloalkyl-alkyl, heterocycloalkenyl-alkyl, aryl-alkyl or heteroaryl-alkyl; or R 14 Wow R 15These can be interconnected to form a ring structure; r is 0, 1, 2, 3, 4, 5, 6 or 7; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, cycloalkenyl-alkyl, heterocycloalkyl-alkyl, heterocycloalkenyl-alkyl, aryl-alkyl or heteroaryl-alkyl is optionally -D, hydroxy, thiol, amino, halo, nitro, cyano, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl-oxy, heterocycloalkyl-oxy, aryl-oxy, heteroaryl-oxy, alkoxyalkyl, aminoalkyl, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, may be substituted with one or more substituents selected from dialkylaminocarbonylalkyl, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

[0046] When L3 is -C- and p is 2, R7 and L3 may be linked together to form cycloalkyl or heterocycloalkyl;

[0047] R8 is -H, , , , , , , , , , or and here R 16 Inland R 31are each independently -H, hydroxy, nitro, cyano, azido(-N3), halo, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthio, alkylthioalkyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkylamino, dialkylamino, dialkylaminoalkyl, aminoalkoxy-alkyl, alkylcarbonyl, aryl, heteroaryl, cycloalkyl-alkyl, cycloalkenyl-alkyl, heterocycloalkyl-alkyl, heterocycloalkenyl-alkyl, aryl-alkyl, heteroaryl-alkyl, partially unsaturated heterocyclyl, or partially unsaturated heterocyclyl-alkyl;The above alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, cycloalkenyl-alkyl, heterocycloalkyl-alkyl, heterocycloalkenyl-alkyl, aryl-alkyl, heteroaryl-alkyl, partially unsaturated heterocyclyl and partially unsaturated heterocyclyl-alkyl are optionally -D, halo, hydroxy, thiol, amino, nitro, cyano, azido, carboxy, oxo, aminocarbonyl, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl-oxy, heterocycloalkyl, haloalkyl, heterocycloalkyl-oxy, aryl-oxy, heteroaryl-oxy, alkylthio, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, Heteroarylamino, alkoxycarbonyl, cycloalkyl-oxycarbonyl, heterocycloalkyl-oxycarbonyl, aryl-oxycarbonyl, heteroaryl-oxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, alkylcarbonyl, cycloalkylcarbonyl, heterocycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, sulfo(-SO3H), alkoxy-sulfonyl(SO2), aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, carboxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, which may be substituted with one or more substituents selected from alkoxycarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, alkylcarbonylalkyl, sulfoalkyl, alkoxysulfonylalkyl, aminosulfonylalkyl, alkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, cycloalkenyl-alkyl, heterocycloalkyl-alkyl, heterocycloalkenyl-alkyl, aryl-alkyl and heteroaryl-alkyl;s is 0, 1, 2, 3, 4, 5,6 or 7;

[0048] n is 0 or 1;

[0049] m is 0, 1, or 2;

[0050] p is 0, 1, 2, 3 or 4;

[0051] However, if L1 is -C- or -CH-, L3 is not a direct bond or -CH-; L2 and L3 are not direct bonds at the same time;

[0052] The above heterocycloalkylene, heterocycloalkenylene, heteroarylene, heterocycloalkyl, heteroaryl, heterocyclylene, heterocyclyl and partially unsaturated heterocyclyl have one or more heteroatoms selected from N, O and S.

[0053]

[0054] Unless otherwise specified, the following terms used in the present invention have the meanings set forth below. Any undefined term has the meaning understood in the art.

[0055]

[0056] In the present invention, the term “-D” means deuterium.

[0057] In the present invention, the term “halo” or “halogen”, when used alone or in combination with other additional terms (e.g., haloalkyl), means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0058] In the present invention, the term “hydroxy” group means -OH.

[0059] In the present invention, the term “nitro” group means -NO2.

[0060] In the present invention, the term “cyano group” means -CN.

[0061] In the present invention, the term “thiol” group means -SH.

[0062] In the present invention, the term “oxy” means -O-.

[0063] In the present invention, the term “carboxy” group means -C(=O)OH.

[0064] In the present invention, the term “carbonyl” group means -C(=O)-.

[0065] In the present invention, the term “sulfonyl” means -S(=O)2-.

[0066] The term “amino” in the present invention may refer to a primary, secondary, or tertiary amino group, alone or in combination, bonded via a nitrogen atom. In the present invention, the secondary amino group may refer to one having an alkyl substituent, and the tertiary amino group may refer to one having two similar or different alkyl substituents.

[0067] In the present invention, the term “azido” means -N3.

[0068] As used herein, the term “alkyl”, when used alone or in combination with other additional terms (e.g., haloalkyl), means a radical of a straight or branched saturated aliphatic hydrocarbon group having, for example, 1 to 7 carbon atoms or 1 to 5 carbon atoms. Typical examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, and 1,2-dimethylpropyl.

[0069] In the present invention, the term “deuterated alkyl” means an alkyl group having one or more deuterium atoms.

[0070] In the present invention, the term “alkenyl” means a radical of an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, for example, having 2 to 7 carbon atoms or 2 to 5 carbon atoms.

[0071] In the present invention, the term “alkynyl” means a radical of an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, for example, having 2 to 7 carbon atoms or 2 to 5 carbon atoms.

[0072] In the present invention, the term “alkoxy” means an alkyloxy (-O-alkyl group), for example, an alkyloxy having 1 to 7 carbon atoms or 1 to 5 carbon atoms.

[0073] In the present invention, the term “alkylthio” means an -S-alkyl group, for example, an -S-alkyl group having 1 to 7 or 1 to 5 carbon atoms.

[0074] In the present invention, the term “alkylene” means a radical of a divalent straight-chain or branched-chain saturated aliphatic hydrocarbon group having, for example, 1 to 7 carbon atoms or 1 to 5 carbon atoms.

[0075] In the present invention, the term “alkynylene” means a radical of an aliphatic hydrocarbon group containing at least one carbon-carbon double bond of two valences, for example, having 2 to 7 carbon atoms or 2 to 5 carbon atoms.

[0076] In the present invention, the term “alkynylene” means a radical of an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond of two valences, for example, having 2 to 7 carbon atoms or 2 to 5 carbon atoms.

[0077] In the present invention, the term “hydroxyalkyl” means an alkyl group substituted with hydroxy.

[0078] As used herein, the term “cycloalkyl” refers to a saturated aliphatic hydrocarbon radical having, for example, 3 to 10 carbon atoms or 3 to 8 carbon atoms in a ring shape. Typical examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl may include a bridged structure, a fused structure, or a spiro structure.

[0079] The term “cycloalkenyl” in the present invention means a radical of a partially unsaturated aliphatic hydrocarbon group having a cyclic shape, for example, 3 to 10 carbon atoms or 3 to 8 carbon atoms, and one carbon-carbon double bond.

[0080] The term “heterocycloalkyl” in the present invention means a radical of a saturated aliphatic hydrocarbon group containing one or more heteroatoms selected from N, O and S as a reducing group, for example, a 4 to 12 membered or a 4 to 10 membered group. The heterocycloalkyl may include a bridged structure, a fused structure or a spiro structure.

[0081] The term “partially unsaturated heterocyclyl” as used herein means a cyclic, for example, 4 to 12-membered or 4 to 10-membered, partially unsaturated hydrocarbon group containing one or more heteroatoms selected from N, O and S as a reducing group. The partially unsaturated heterocyclyl may include a bridged structure, a fused structure or a spiro structure.

[0082] In the present invention, the term “aryl” means an aromatic hydrocarbon having, for example, 6 to 12 or 6 to 10 carbon atoms, and specific examples include, but are not limited to, phenyl and naphthyl.

[0083] In the present invention, the term “heteroaryl” means, for example, a 5- to 12-membered or 5- to 10-membered aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S as a reducing group and forming a single or fused ring that can be fused with benzo or cycloalkyl.

[0084]

[0085] In the present invention, the term “prodrug” includes a form in which the compound of the above chemical formula 1 is converted in vivo to exhibit the same effect, and can be prepared according to a method known in the art, and there are no particular limitations thereto. For example, the prodrug can be provided in the form of, but is not limited to, carbamates, esters, N-Mannich adducts, phosphates, phosphonooxymethylethers, phosphoramidates, acylsulfonamides, amides, sulfenamides, imines, azo conjugates, N-acyloxyalkylamines, etc.

[0086]

[0087] According to one specific example of the present invention, in the chemical formula 1

[0088] R1 and R2 are each independently -H, -D, C1-C7 alkyl, deuterated C1-C7 alkyl or halo-C1-C7 alkyl;

[0089] R3 is -DEG; where D is a direct bond or C1-C7 alkylene; E is C1-C7 alkylene, C2-C7 alkenylene, C2-C7 alkynylene, C3-C 10 Cycloalkylene, C3-C 10 Cycloalkenylene, C6-C 12 Arylene, 4 to 12 membered heterocycloalkylene, 4 to 12 membered heterocycloalkenylene or 5 to 12 membered heteroarylene; wherein said alkylene, alkenylene, alkynylene, cycloalkylene. Cycloalkenylene, arylene, heterocycloalkylene, heterocycloalkenylene or heteroarylene is optionally -D, halo, hydroxy, thiol, amino, nitro, cyano, C1-C7 alkyl, halo-C1-C7 alkyl, deuterated C1-C7 alkyl, hydroxy-C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkoxy, C1-C7 alkoxy-C1-C7 alkyl, C1-C7 alkylthio, C1-C7 alkylamino, di(C1-C7 alkyl)amino, amino-C1-C7 alkyl, C1-C7 alkylamino-C1-C7 alkyl, di(C1-C7 alkyl)amino-C1-C7 alkyl, aminocarbonyl, C1-C7 alkylaminocarbonyl, di(C1-C7 alkyl)aminocarbonyl, Aminocarbonyl-C1-C7 alkyl, C1-C7 alkylaminocarbonyl-C1-C7 alkyl, di(C1-C7 alkyl)aminocarbonyl- C1-C7 alkyl, carboxy, C1-C7 alkoxycarbonyl, carboxy-C1-C7 alkyl, C1-C7 alkoxycarbonyl-C1-C7 alkyl, C1-C7 alkylcarbonyl, C1-C7 alkylcarbonyl-C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C 10 Cycloalkyl, 4 to 12 membered heterocycloalkyl, C6-C 12 may be substituted with 1 to 4 substituents selected from aryl and 5 to 12 membered heteroaryl; G is amino, 5 to 12 membered heteroaryl, , or and; here R9, R 10 and R 11are each independently -H, C1-C7 alkyl or halo-C1-C7 alkyl; or R9 and R 10 These can be interconnected to form a ring structure;

[0090] R4 and R6 are each independently -H, -D, C1-C7 alkyl, deuterated C1-C7 alkyl or halo-C1-C7 alkyl;

[0091] L1 is -C-, -CH-, C3-C 10 Cycloalkylene, 4 to 12 membered heterocyclylene, C3-C 10 Cycloalkenylene, 4 to 12 membered heterocycloalkenylene, C6-C 12 Arylene or 5 to 12 membered heteroarylene; or can form a ring structure together with the N atom to which R4 and L1 are bonded;

[0092] R5 is -H, -D, halo, C1-C7 alkyl, halo-C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, 4 to 12 membered heterocycloalkyl, 4 to 12 membered heterocycloalkenyl, C6-C 12 Aryl, 5 to 12 membered heteroaryl, C3-C 10 Cycloalkyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkyl-C1-C7 alkyl, C6-C 12 Aryl-C1-C7 alkyl or 5 to 12 membered heteroaryl-C1-C7 alkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, aryl-alkoxy or heteroaryl-alkyl is optionally -D, hydroxy, thiol, amino, halo, nitro, cyano, C1-C7 alkyl, halo-C1-C7 alkyl, deuterated C1-C7 alkyl, hydroxy-C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkoxy, C3-C 10Cycloalkyl-oxy, 4 to 12 membered heterocycloalkyl-oxy, C6-C 12 Aryl-oxy, 5 to 12 membered heteroaryl-oxy, C1-C7alkoxy-C1-C7alkyl, aminocarbonyl, C1-C7alkylaminocarbonyl, di(C1-C7alkyl)aminocarbonyl, aminocarbonyl-C1-C7alkyl, C1-C7alkylaminocarbonyl-C1-C7alkyl, di(C1-C7alkyl)aminocarbonyl-C1-C7alkyl, carboxy, C1-C7alkoxycarbonyl, carboxy-C1-C7alkyl, C1-C7alkoxycarbonyl-C1-C7alkyl, C1-C7alkylcarbonyl, C1-C7alkylcarbonyl-C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C3-C 10 Cycloalkyl, 4 to 12 membered heterocycloalkyl, C6-C 12 Aryl, 5 to 12 membered heteroaryl and may be substituted with 1 to 4 substituents selected from; wherein R 12 and R 13 are each independently -H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, 4 to 12 membered heterocycloalkyl, 4 to 12 membered heterocycloalkenyl, C6-C 12 Aryl, 5 to 12 membered heteroaryl, C3-C 10 Cycloalkyl-C1-C7 alkyl, C3-C 10 Cycloalkenyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkenyl-C1-C7 alkyl, C6-C 12 Aryl-C1-C7 alkyl or 5 to 12 membered heteroaryl-C1-C7 alkyl; or R 12 Wow R 13 These can be linked to each other to form a ring structure; q is 0, 1, 2, 3, 4, 5, 6 or 7; or when L1 is -C- and m is 2, R5 and L1 are linked together to form C3-C 10It can form a cycloalkyl or a 4 to 12 membered heterocycloalkyl;

[0093] L2 may be a direct bond, or when n is 0, R4 and L2 may be connected to each other with the N atom to which they are bonded to form a ring structure; wherein the ring is optionally -D, hydroxy, amino, halo, nitro, cyano, C1-C7 alkyl, halo-C1-C7 alkyl, deuterated C1-C7 alkyl, hydroxy-C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkyl-oxy, C3-C 10 Cycloalkyl-oxy, 4 to 12 membered heterocycloalkyl-oxy, C6-C 12 Aryl-oxy, 5 to 12 membered heteroaryl-oxy, C1-C7alkoxy-C1-C7alkyl, amino-C1-C7alkyl, C1-C7alkylamino, di(C1-C7alkyl)amino, C1-C7alkylamino-C1-C7alkyl, di(C1-C7alkyl)amino-C1-C7alkyl, aminocarbonyl, C1-C7alkylaminocarbonyl, di(C1-C7alkyl)aminocarbonyl, aminocarbonyl-C1-C7alkyl, C1-C7alkylaminocarbonyl-C1-C7alkyl, di(C1-C7alkyl)aminocarbonyl-C1-C7alkyl, carboxy, C1-C7alkoxycarbonyl, carboxy-C1-C7alkyl, C1-C7alkoxycarbonyl-C1-C7alkyl, C2-C7alkenyl, C2-C7 alkynyl, C3-C 10 Cycloalkyl, 4 to 12 membered heterocycloalkyl, C6-C 12 Aryl, C6-C 12 which may be substituted with 1 to 4 substituents selected from aryl-C1-C7 alkyl and 5 to 12 membered heteroaryl;

[0094] L3 is a direct bond, -C-, -CH-, -CH2-, C3-C 10 Cycloalkylene, 4 to 12 membered heterocycloalkylene, unsaturated C3-C 10 Carbocyclylene, unsaturated 4 to 12 membered heterocyclylene, C6-C 12Arylene or 5 to 12 membered heteroarylene; or may form a ring structure together with the N atom to which R6 and L3 are bonded;

[0095] R7 is halo, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, halo-C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkoxy, hydroxy-C1-C7 alkyl, C3-C 10 Cycloalkyl-oxy, C3-C 10 Cycloalkyl-C1-C7 alkyl, C3-C 10 Cycloalkyl-C1-C7alkoxy, C3-C 10 Cycloalkenyl-oxy, C3-C 10 Cycloalkenyl-C1-C7 alkyl, C3-C 10 Cycloalkenyl-C1-C7alkoxy, 4 to 12 membered heterocycloalkyl-oxy, 4 to 12 membered heterocycloalkyl-C1-C7alkyl, 4 to 12 membered heterocycloalkyl-C1-C7alkoxy, 4 to 12 membered heterocycloalkenyl-oxy, 4 to 12 membered heterocycloalkenyl-C1-C7alkyl, 4 to 12 membered heterocycloalkenyl-C1-C7alkoxy, C6-C 12 Aryl, C6-C 12 Aryl-oxy, C6-C 12 Aryl-C1-C7 alkyl, C6-C 12 Aryl-C1-C7alkoxy, 5 to 12 membered heteroaryl, 5 to 12 membered heteroaryl-oxy, 5 to 12 membered heteroaryl-C1-C7alkyl, 5 to 12 membered heteroaryl-C1-C7alkoxy or and here R 14 and R 15 are each independently -H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, 4 to 12 membered heterocycloalkyl, 4 to 12 membered heterocycloalkenyl, C6-C 12 Aryl, 5 to 12 membered heteroaryl, C3-C 10 Cycloalkyl-C1-C7 alkyl, C3-C10 Cycloalkenyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkenyl-C1-C7 alkyl, C6-C 12 Aryl-C1-C7 alkyl or 5 to 12 membered heteroaryl-C1-C7 alkyl; or R 14 Wow R 15 These can be linked to each other to form a ring structure; r is 0, 1, 2, 3, 4, 5, 6 or 7; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, cycloalkenyl-alkyl, heterocycloalkyl-alkyl, heterocycloalkenyl-alkyl, aryl-alkyl, aryl-alkoxy or heteroaryl-alkyl is optionally -D, hydroxy, thiol, amino, halo, nitro, cyano, C1-C7 alkyl, halo-C1-C7 alkyl, deuterated C1-C7 alkyl, hydroxy-C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkoxy, C3-C 10 Cycloalkyl-oxy, 4 to 12 membered heterocycloalkyl-oxy, C6-C 12 Aryl-oxy, 5 to 12 membered heteroaryl-oxy, C1-C7alkoxy-C1-C7alkyl, amino-C1-C7alkyl, C1-C7alkylamino, di(C1-C7alkyl)amino, C1-C7alkylamino-C1-C7alkyl, di(C1-C7alkyl)amino-C1-C7alkyl, aminocarbonyl, C1-C7alkylaminocarbonyl, di(C1-C7alkyl)aminocarbonyl, aminocarbonyl-C1-C7alkyl, C1-C7alkylaminocarbonyl-C1-C7alkyl, di(C1-C7alkyl)aminocarbonyl-C1-C7alkyl, carboxy, carboxy-C1-C7alkyl, C1-C7alkoxycarbonyl, C1-C7alkoxycarbonyl-C1-C7alkyl, C1-C7 alkoxycarbonyl-C1-C7 alkyl, C1-C7 alkylcarbonyl, C1-C7 alkylcarbonyl-C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C 10 Cycloalkyl, 4 to 12 membered heterocycloalkyl, C6-C 12which may be substituted with 1 to 4 substituents selected from aryl and 5 to 12 membered heteroaryl;

[0096] When L3 is -C- and p is 2, R7 and L3 are connected together to form C3-C 10 can form a cycloalkyl or a 4 to 12 membered heterocycloalkyl;

[0097] R8 is -H, , , , , , , , , , or and here R 16 Inland R 31 are each independently -H, hydroxy, nitro, cyano, azido(-N3), halo, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, C1-C7 alkoxy-C1-C7 alkyl, C1-C7 alkylthio, C1-C7 alkylthio-C1-C7 alkyl, halo-C1-C7 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, 4 to 12 membered heterocycloalkyl, 4 to 12 membered heterocycloalkenyl, C1-C7 alkylamino, di(C1-C7 alkyl)amino, di(C1-C7 alkyl)amino-C1-C7 alkyl, amino-C1-C7 alkoxy-C1-C7 alkyl, C1-C7 alkylcarbonyl, C6-C 12 Aryl, 5 to 12 membered heteroaryl, C3-C 10 Cycloalkyl-C1-C7 alkyl, C3-C 10 Cycloalkenyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkenyl-C1-C7 alkyl, C6-C 12Aryl-C1-C7 alkyl, 5 to 12 membered heteroaryl-C1-C7 alkyl, partially unsaturated 4 to 12 membered heterocyclyl or partially unsaturated 4 to 12 membered heterocyclyl-C1-C7 alkyl; The above alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, cycloalkenyl-alkyl, heterocycloalkyl-alkyl, heterocycloalkenyl-alkyl, aryl-alkyl, heteroaryl-alkyl, partially unsaturated heterocyclyl and partially unsaturated heterocyclyl-alkyl are optionally -D, halo, hydroxy, thiol, amino, nitro, cyano, azido, carboxy, oxo, aminocarbonyl, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl-oxy, 4 to 12 membered heterocycloalkyl, halo-C1-C7 alkyl, 4 to 12 membered heterocycloalkyl-oxy, C6-C 12 Aryl-oxy, 5 to 12 membered heteroaryl-oxy, C1-C7 alkylthio, C1-C7 alkylamino, di(C1-C7 alkyl)amino, C3-C 10 Cycloalkylamino, 4 to 12 membered heterocycloalkylamino, C6-C 12 Arylamino, 5-12 membered heteroarylamino, C1-C7 alkoxycarbonyl, C3-C 10 Cycloalkyl-oxycarbonyl, 4 to 12 membered heterocycloalkyl-oxycarbonyl, C6-C 12 Aryl-oxycarbonyl, 5 to 12 membered heteroaryl-oxycarbonyl, C1-C7 alkylaminocarbonyl, di(C1-C7 alkyl)aminocarbonyl, C3-C 10 Cycloalkylaminocarbonyl, 4 to 12 membered heterocycloalkylaminocarbonyl, C6-C 12 Arylaminocarbonyl, 5 to 12 membered heteroarylaminocarbonyl, C1-C7 alkylcarbonyl, C3-C 10 Cycloalkylcarbonyl, 4 to 12 membered heterocycloalkylcarbonyl, C6-C 12Arylcarbonyl, 5-12 membered heteroarylcarbonyl, sulfo, C1-C7 alkoxy-sulfonyl, aminosulfonyl, C1-C7 alkylaminosulfonyl, di(C1-C7 alkyl)aminosulfonyl, C3-C 10 Cycloalkylaminosulfonyl, 4 to 12 membered heterocycloalkylaminosulfonyl, C6-C 12 Arylaminosulfonyl, 5 to 12 membered heteroarylaminosulfonyl, carboxy-C1-C7 alkyl, amino-C1-C7 alkyl, C1-C7 alkylamino-C1-C7 alkyl, di(C1-C7 alkyl)amino-C1-C7 alkyl, C1-C7 alkoxy-C1-C7 alkyl, C1-C7 alkoxycarbonyl-C1-C7 alkyl, C1-C7 alkylaminocarbonyl-C1-C7 alkyl, di(C1-C7 alkyl)aminocarbonyl-C1-C7 alkyl, C1-C7 alkylcarbonyl-C1-C7 alkyl, sulfo-C1-C7 alkyl, C1-C7 alkoxysulfonyl-C1-C7 alkyl, aminosulfonyl-C1-C7 alkyl, C1-C7 alkylaminosulfonyl-C1-C7 alkyl, Di(C1-C7 alkyl)aminosulfonyl-C1-C7 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, 4 to 12 membered heterocycloalkenyl, C6-C 12 Aryl, 5 to 12 membered heteroaryl, C3-C 10 Cycloalkyl-C1-C7 alkyl, C3-C 10 Cycloalkenyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkenyl-C1-C7 alkyl, C6-C 12 which may be substituted with one or more substituents selected from aryl-C1-C7 alkyl and 5 to 12 membered heteroaryl-C1-C7 alkyl; s is 0, 1, 2, 3, 4, 5,6 or 7;

[0098] n is 0 or 1;

[0099] m is 0, 1, or 2;

[0100] p is 0, 1, 2, 3 or 4;

[0101] However, if L1 is -C- or -CH-, L3 is not a direct bond or -CH-; L2 and L3 are not direct bonds at the same time;

[0102] The above heterocycloalkylene, heterocycloalkenylene, heteroarylene, heterocycloalkyl, heteroaryl, heterocyclylene, heterocyclyl and partially unsaturated heterocyclyl have 1 to 4 heteroatoms selected from N, O and S.

[0103]

[0104] According to one specific example of the present invention, in the above chemical formula 1, R1 and R2 are each independently -H or C1-C5 alkyl.

[0105] According to one specific example of the present invention, in the above chemical formula 1, R3 is -DEG; wherein D is C1-C5 alkylene; and E is C1-C5 alkylene, C6-C 10 Arylene or a 5 to 10 membered heterocycloalkylene having 1 to 3 N atoms; G is amino, 5 to 10 membered heteroaryl, , or and; here R7, R8 and R9 is each independently -H, C1-C5 alkyl or halo-C1-C5 alkyl.

[0106] According to one specific example of the present invention, in the above chemical formula 1, R4 and R6 are each independently -H or C1-C5 alkyl.

[0107] According to one specific example of the present invention, in the above chemical formula 1, L1 is -C-, -CH-, C4-C8 cycloalkylene, C4-C8 cycloalkenylene or C6-C 10 or may form a 4 to 10 membered heterocycloalkyl together with the N atom to which R4 and L1 are bonded;

[0108] R5 is halo, C1-C5 alkyl, halo-C1-C5 alkyl, C6-C 10Aryl, 5-8 membered heteroaryl, C3-C8 cycloalkyl-C1-C5 alkyl, C6-C 10 Aryl-C1-C5 alkyl or 5 to 8 membered heteroaryl-C1-C5 alkyl; wherein said aryl is optionally selected from the group consisting of hydroxy, halo, halo-C1-C5 alkyl, C1-C5 alkoxy and C6-C 10 may be substituted with 1 to 3 substituents selected from aryl; when L1 is -C- and m is 2, R5 and L1 may be linked together to form C3-C8 cycloalkyl or 4 to 10 membered heterocycloalkyl.

[0109] According to one specific example of the present invention, in the above chemical formula 1, L2 is a direct bond, or when n is 0, R4 and L2 can be connected to each other together with the N atom to which they are bonded to form a 4 to 10 membered heterocycloalkyl, wherein the heterocycloalkyl is optionally C1-C5 alkyl and C6-C 10 It may be substituted with 1 to 3 substituents selected from aryl-C1-C5 alkyl.

[0110] According to one specific example of the present invention, in the above chemical formula 1, L3 is a direct bond, -CH-, -CH2-, C4-C8 cycloalkylene, unsaturated C4-C8 carbocyclylene or C6-C 10 Arylene; or R6 and L3 may form a 4 to 10 membered heterocycloalkyl together with the N atom to which they are bonded.

[0111] According to one specific example of the present invention, in the above formula 1, R7 is halo, C1-C5 alkyl, halo-C1-C5 alkyl, C1-C5 alkoxy, hydroxy-C1-C5 alkyl, C3-C8 cycloalkyl-oxy, C3-C8 cycloalkyl-C1-C5 alkyl, C3-C8 cycloalkyl-C1-C5 alkoxy, C6-C 10 Aryl, C6-C 10 Aryl-C1-C5 alkyl, C6-C 10 Aryl-oxy, C6-C 10Aryl-C1-C5 alkoxy, 5 to 8 membered heteroaryl-C1-C5 alkyl, unsaturated 4 to 10 membered heterocyclyl or unsaturated C4-C 10 Carbocyclyl-oxy; wherein said aryl, aryl-alkyl or aryl-alkoxy is optionally halo, cyano, C1-C5 alkyl, halo-C1-C5 alkyl, C1-C5 alkoxy and C6-C 10 It may be substituted with one to three substituents selected from aryl.

[0112] According to one specific example of the present invention, in the above chemical formula 1, R8 is halo, hydroxy, 4 to 10 membered heterocycloalkyl, , , , , or and here R 17 Inland R 23 and R 31 are each independently -H, hydroxy, C1-C7 alkyl, C2-C5 alkenyl, halo-C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkoxy-C1-C5 alkyl, C1-C5 alkylthio-C1-C5 alkyl, di(C1-C5 alkyl)amino-C1-C5 alkyl, amino-C1-C5 alkoxy-C1-C5 alkyl, C1-C5 alkylcarbonyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C5 alkyl, C3-C8 cycloalkenyl-C1-C5 alkyl, 4 to 10 membered heterocycloalkyl, 4 to 10 membered heterocycloalkyl-C1-C5 alkyl, partially unsaturated 4 to 10 membered heterocyclyl-C1-C5 alkyl, C6-C 10 Aryl or C6-C 10 Aryl-C1-C5 alkyl; wherein said heterocycloalkyl or heterocycloalkyl-C1-C5 alkyl is optionally selected from the group consisting of hydroxy, halo, oxo, C1-C5 alkyl, halo-C1-C5 alkyl, 4 to 10 membered heterocycloalkyl-C1-C5 alkyl and C6-C 10Aryl-C1-C5alkyl may be substituted with 1 to 3 substituents selected from; wherein said aryl or aryl-alkyl is optionally selected from hydroxy, halo, C1-C5alkyl, halo-C1-C5alkyl, aminosulfonyl, 4 to 10 membered heterocycloalkyl and C6-C 10 It may be substituted with 1 to 3 substituents selected from aryl-C1-C5 alkyl.

[0113]

[0114] Representative compounds of the chemical formula 1 according to the present invention may include, but are not limited to, the following compounds:

[0115] (1S,3R)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-3-((S)-2-amino-5-guanidinopentanamido)cyclohexanecarboxamide;

[0116] (1S,3R)-N-((S)-1-amino-3-(4-fluorophenyl)-1-oxopropan-2-yl)-3-((S)-2-amino-5-guanidinopentanamido)cyclohexanecarboxamide;

[0117] N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-3-((S)-2-amino-5-guanidinopentanamido)benzamide;

[0118] (S)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-1-((S)-2-amino-5-guanidinopentanoyl)piperidine-3-carboxamide;

[0119] (R)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-1-((S)-2-amino-5-guanidinopentanoyl)piperidine-3-carboxamide;

[0120] (1S,3R)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-3-((S)-2-amino-5-guanidinopentanamido)cyclopentanecarboxamide;

[0121] (1R,3S)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-3-((S)-2-amino-5-guanidinopentanamido)cyclopentanecarboxamide;

[0122] (1S,4R)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-4-((S)-2-amino-5-guanidinopentanamido)cyclopent-2-encarboxamide;

[0123] (1S,3R)-3-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)cyclohexane-1-carboxamide;

[0124] (1S,3R)-N-((S)-1-amino-3-(4-fluorophenyl)-1-oxopropan-2-yl)-3-((S)-2-amino-3-(4-guanidinophenyl)propanamido)cyclohexane-1-carboxamide;

[0125] rel-(1S,3R)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-3-((S)-2-amino-5-guanidinopentanamido)cyclohexanecarboxamide;

[0126] rel-(1S,3S)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-3-((S)-2-amino-5-guanidinopentanamido)cyclohexanecarboxamide;

[0127] (1S,3R)-3-((S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-3-cyclohexylpropanamido)cyclohexanecarboxamide;

[0128] 3-((S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-3-cyclohexylpropanamido)benzamide;

[0129] (R)-1-((S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-3-cyclohexylpropanoyl)piperidine-3-carboxamide;

[0130] (1S,3R)-3-((S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-3-cyclohexylpropanamido)cyclopentanecarboxamide;

[0131] (1R,4s)-4-((S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-3-cyclohexylpropanamido)cyclopent-2-enecarboxamide;

[0132] (1S,3R)-3-((S)-2-amino-3-(4-guanidinophenyl)propanamido)cyclohexane-1-carboxamide;

[0133] (S)-3-(2-amino-3-(4-guanidinophenyl)propanamido)benzamide;

[0134] (S)-1-((S)-2-amino-3-(4-guanidinophenyl)propanoyl)piperidine-3-carboxamide;

[0135] (1S,3R)-3-((S)-2-amino-3-(4-guanidinophenyl)propanamido)cyclopentane-1-carboxamide;

[0136] (1R,4S)-4-((S)-2-amino-3-(4-guanidinophenyl)propanamido)cyclohexane-1-carboxamide;

[0137] (1R,2S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)cyclohexanecarboxamide;

[0138] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)benzamide;

[0139] (S)-2-(2-amino-3-(4-guanidinophenyl)propanamido)benzamide;

[0140] (1S,2R)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)cyclopentanecarboxamide;

[0141] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-((4-fluorobenzyl)oxy)benzamide;

[0142] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-methoxybenzamide;

[0143] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-ethoxybenzamide;

[0144] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-isopropoxybenzamide;

[0145] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-isobutoxybenzamide;

[0146] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(cyclobutylmethoxy)benzamide;

[0147] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(cyclopentylmethoxy)benzamide;

[0148] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(cyclohexylmethoxy)benzamide;

[0149] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-cyclopropoxybenzamide;

[0150] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-cyclobutoxybenzamide;

[0151] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(cyclopentyloxy)benzamide;

[0152] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(cyclohexyloxy)benzamide;

[0153] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-phenoxybenzamide;

[0154] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(benzyloxy)benzamide;

[0155] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-((4-chlorobenzyl)oxy)benzamide;

[0156] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(naphthalen-1-ylmethoxy)benzamide;

[0157] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)benzamide;

[0158] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(4-fluorophenoxy)benzamide;

[0159] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-((2,3-dihydro-1H-inden-2-yl)oxy)benzamide;

[0160] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-((4-bromo-2-fluorobenzyl)oxy)benzamide;

[0161] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(naphthalen-2-ylmethoxy)benzamide;

[0162] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(4-methylphenethoxy)benzamide;

[0163] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(2,4-dichlorophenethoxy)benzamide;

[0164] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-((4-(trifluoromethyl)benzyl)oxy)benzamide;

[0165] 4-((S)-2-((S)-2-amino-5-(3-methylguanidino)pentanamido)-3-cyclohexylpropanamido)-3-phenoxybenzamide;

[0166] 4-((S)-2-((S)-2-amino-5-(3,3-dimethylguanidino)pentanamido)-3-cyclohexylpropanamido)-3-phenoxybenzamide;

[0167] 4-((S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-3-cyclohexylpropanamido)-3-phenoxybenzamide;

[0168] 4-((S)-2-((S)-2-amino-5-ureidopentanamido)-3-cyclohexylpropanamido)-3-phenoxybenzamide;

[0169] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(3-fluorophenoxy)benzamide;

[0170] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(2-fluorophenoxy)benzamide;

[0171] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(4-chlorophenoxy)benzamide;

[0172] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(3-chlorophenoxy)benzamide;

[0173] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(2-chlorophenoxy)benzamide;

[0174] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(p-tolyloxy)benzamide;

[0175] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(m-tolyloxy)benzamide;

[0176] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(o-tolyloxy)benzamide;

[0177] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(4-(trifluoromethyl)phenoxy)benzamide;

[0178] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(3-(trifluoromethyl)phenoxy)benzamide;

[0179] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(2-(trifluoromethyl)phenoxy)benzamide;

[0180] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(4-cyanophenoxy)benzamide;

[0181] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(3-cyanophenoxy)benzamide;

[0182] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(2-cyanophenoxy)benzamide;

[0183] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(4-methoxyphenoxy)benzamide;

[0184] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(3-methoxyphenoxy)benzamide;

[0185] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(2-methoxyphenoxy)benzamide;

[0186] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(3,4-dimethoxyphenoxy)benzamide;

[0187] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(2,4-dimethoxyphenoxy)benzamide;

[0188] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(benzo[d][1,3]dioxol-5-yloxy)benzamide;

[0189] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(naphthalen-1-yloxy)benzamide;

[0190] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(naphthalen-2-yloxy)benzamide;

[0191] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(4-hydroxyphenoxy)benzamide;

[0192] (S)-4-(2-amino-5-guanidinopentanamido)-3-phenoxybenzamide;

[0193] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)hexamido)-3-(3-chlorophenoxy)benzamide;

[0194] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-4,4-dimethylpentanamido)-3-(3-chlorophenoxy)benzamide;

[0195] (S)-4-(1-(2-amino-5-guanidinopentanamido)cyclopropanecarboxamido)-3-(3-chlorophenoxy)benzamide;

[0196] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclopropylpropanamido)-3-(3-chlorophenoxy)benzamide;

[0197] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-2-phenylacetamido)-3-(3-chlorophenoxy)benzamide;

[0198] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-(pyridin-3-yl)propanamido)-3-(3-chlorophenoxy)benzamide;

[0199] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-(thiophen-2-yl)propanamido)-3-(3-chlorophenoxy)benzamide;

[0200] 4-((1S,3R)-3-((S)-2-amino-5-guanidinopentanamido)cyclohexanecarboxamido)-3-(3-chlorophenoxy)benzamide;

[0201] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)benzamide;

[0202] 4-((1S,3R)-3-((S)-2-amino-5-guanidinopentanamido)cyclohexanecarboxamido)benzamide;

[0203] 4-((1S,3R)-3-((S)-2-amino-3-(4-guanidinophenyl)propanamido)cyclohexanecarboxamido)benzamide;

[0204] 3-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-2-(3-chlorophenoxy)benzamide;

[0205] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-2-(3-chlorophenoxy)benzamide;

[0206] 3-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-4-(3-chlorophenoxy)benzamide;

[0207] 3-((S)-2-((S)-2-amino-5-guanidinopentanamido)-2-phenylacetamido)-2-(3-chlorophenoxy)benzamide;

[0208] 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-2-phenylacetamido)-2-(3-chlorophenoxy)benzamide;

[0209] 3-((S)-2-((S)-2-amino-5-guanidinopentanamido)-2-phenylacetamido)-4-(3-chlorophenoxy)benzamide;

[0210] 4-((S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-3-cyclohexylpropanamido)-3-(3-chlorophenoxy)benzamide;

[0211] 4-((S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-2-phenylacetamido)-3-(3-chlorophenoxy)benzamide;

[0212] 4-((S)-2-((S)-2-amino-3-(3-guanidinophenyl)propanamido)-2-phenylacetamido)-3-(3-chlorophenoxy)benzamide;

[0213] 4-((S)-2-((S)-2-amino-3-(2-guanidinophenyl)propanamido)-2-phenylacetamido)-3-(3-chlorophenoxy)benzamide;

[0214] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)benzamide;

[0215] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-(4-fluorophenoxy)benzamide;

[0216] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-3-(cyclohexylmethoxy)benzamide;

[0217] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-3-(cyclohexyloxy)benzamide;

[0218] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-3-(3-chlorophenoxy)benzamide;

[0219] 2-(4-((S)-2-amino-3-(4-guanidinophenyl)propanoyl)-3-methylpiperazin-1-yl)acetamide;

[0220] 2-(4-((S)-2-amino-3-(4-guanidinophenyl)propanoyl)-3-propylpiperazin-1-yl)acetamide;

[0221] 2-(4-((S)-2-amino-3-(4-guanidinophenyl)propanoyl)-3-isobutylpiperazin-1-yl)acetamide;

[0222] 2-(4-((S)-2-amino-3-(4-guanidinophenyl)propanoyl)-3-benzylpiperazin-1-yl)acetamide;

[0223] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((3-fluorobenzyl)oxy)benzamide;

[0224] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-chlorobenzyl)oxy)benzamide;

[0225] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-(cyclohexyloxy)benzamide;

[0226] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-(cyclohexylmethoxy)benzamide;

[0227] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-(2-cyclohexylethoxy)benzamide;

[0228] (S)-4-(2-amino-3-(1-carbamimidoylpiperidin-4-yl)propanamido)-2-((4-fluorobenzyl)oxy)benzamide;

[0229] (S)-4-(2-amino-3-(1-carbamimidoylpiperidin-4-yl)propanamido)-2-(2-cyclohexylethoxy)benzamide;

[0230] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-isopropylbenzamide;

[0231] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(cyclohexylmethyl)-2-((4-fluorobenzyl)oxy)benzamide;

[0232] (S)-N-allyl-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)benzamide;

[0233] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-isopentylbenzamide;

[0234] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(2-(cyclohex-1-en-1-yl)ethyl)-2-((4-fluorobenzyl)oxy)benzamide;

[0235] 4-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-((tetrahydrofuran-3-yl)methyl)benzamide;

[0236] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-cyclopentyl-2-((4-fluorobenzyl)oxy)benzamide;

[0237] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-cyclohexyl-2-((4-fluorobenzyl)oxy)benzamide;

[0238] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(4-morpholinophenyl)benzamide;

[0239] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(2-(methylthio)ethyl)benzamide;

[0240] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-phenethylbenzamide;

[0241] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(4-methoxybenzyl)benzamide;

[0242] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-neopentylbenzamide;

[0243] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(4-(tert-butyl)benzyl)-2-((4-fluorobenzyl)oxy)benzamide;

[0244] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-((4-fluorobenzyl)oxy)benzamide;

[0245] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(4-(trifluoromethyl)benzyl)benzamide;

[0246] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(naphthalen-2-ylmethyl)benzamide;

[0247] 4-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-((tetrahydrofuran-2-yl)methyl)benzamide;

[0248] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-hexylbenzamide;

[0249] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(3-methylbenzyl)benzamide;

[0250] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(3-chloropropyl)-2-((4-fluorobenzyl)oxy)benzamide;

[0251] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(4-fluorophenethyl)benzamide;

[0252] 4-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(1-phenylethyl)benzamide;

[0253] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-isobutylbenzamide;

[0254] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-benzyl-2-((4-fluorobenzyl)oxy)benzamide;

[0255] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(2-methoxyethyl)benzamide;

[0256] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-cyclobutyl-2-((4-fluorobenzyl)oxy)benzamide;

[0257] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-propylbenzamide;

[0258] 4-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-N-(sec-butyl)-2-((4-fluorobenzyl)oxy)benzamide;

[0259] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(2-cyclohexylethyl)-2-((4-fluorobenzyl)oxy)benzamide;

[0260] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(3-(2-oxopyrrolidin-1-yl)propyl)benzamide;

[0261] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(4-chlorobenzyl)-2-((4-fluorobenzyl)oxy)benzamide;

[0262] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(3-(dimethylamino)propyl)-2-((4-fluorobenzyl)oxy)benzamide;

[0263] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(4-sulfamoylphenethyl)benzamide;

[0264] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(2-(tert-butoxy)ethyl)-2-((4-fluorobenzyl)oxy)benzamide;

[0265] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(4-hydroxybenzyl)benzamide;

[0266] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(piperidin-4-yl)benzamide;

[0267] (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(1-benzylpiperidin-4-yl)-2-((4-fluorobenzyl)oxy)benzamide;

[0268] (S)-2-(2-cyclohexylethoxy)-4-(2,6-diaminohexanamido)benzamide; and

[0269] (S)-4-(2-amino-3-(1H-imidazol-4-yl)propanamido)-2-(2-cyclohexylethoxy)benzamide;

[0270] (S)-2-amino-N-(4-bromo-3-(2-cyclohexylethoxy)phenyl)-3-(4-guanidinophenyl)propanamide;

[0271] (S)-N-(4-acetamido-3-(2-cyclohexylethoxy)phenyl)-2-amino-5-guanidinopentanamide;

[0272] (S)-2-amino-N-(4-bromophenyl)-3-(4-guanidinophenyl)propanamide;

[0273] (S)-2-amino-N-(3-bromophenyl)-3-(4-guanidinophenyl)propanamide;

[0274] (S)-2-amino-3-(4-guanidinophenyl)-N-(4-hydroxyphenyl)propanamide;

[0275] (S)-2-amino-N-(4-(2-(2-aminoethoxy)ethoxy)phenyl)-3-(4-guanidinophenyl)propanamide;

[0276] (S)-2-amino-N-(2-((3-bromo-5-(2-cyclohexylethoxy)phenyl)amino)-2-oxoethyl)-3-(4-guanidinophenyl)propanamide;

[0277] (S)-2-amino-N-(3-(2-cyclohexylethoxy)-5-(piperazin-1-yl)phenyl)-3-(4-guanidinophenyl)propanamide;

[0278] (S)-2-amino-N-(3-((2-(2-aminoethoxy)ethyl)amino)-5-(2-cyclohexylethoxy)phenyl)-3-(4-guanidinophenyl)propanamide;

[0279] (S)-2-amino-N-(3-amino-5-(2-cyclohexylethoxy)phenyl)-3-(4-guanidinophenyl)propanamide; and

[0280] (S)-2-Amino-N-(3-(3-(2-aminoethoxy)prop-1-yn-1-yl)-5-(2-cyclohexylethoxy)phenyl)-3-(4-guanidinophenyl)propanamide.

[0281]

[0282] The names of the above compounds are described according to the nomenclature provided by PerkinElmer's ChemDraw Professional software (version 21.0.0.28).

[0283]

[0284] According to another aspect of the present invention, a chimeric compound of the following chemical formula 2 is provided:

[0285] [Chemical Formula 2]

[0286]

[0287]

[0288] In the above chemical formula 2,

[0289] A is a ubiquitin ligase binding moiety (ULM) and is a compound of the above chemical formula 1 or a prodrug thereof;

[0290] B is a protein target moiety (PTM);

[0291] A and B are chemically linked by a linker.

[0292]

[0293] In the above chemical formula 2, any linker used in the production of PROTAC in the relevant field can be used, and there are no special limitations thereto. For example, the linker can be a compound having the structure of the following chemical formula 3,

[0294] [Chemical Formula 3]

[0295]

[0296]

[0297] In the above chemical formula 3,

[0298] Y1 does not exist, or , , , , , , , , , , , , , , , , cycloalkylene, cycloalkenylene, heterocycloalkylene, heterocycloalkenylene, arylene, heteroarylene, bridged cyclclylene, fused cyclylene, spiro-cyclylene, poly-cyclylene, bridged heterocyclclylene, fused heterocyclylene, spiro-heterocyclylene and poly-heterocyclylene; wherein R'" and R"" are each independently -H, -D, halo, hydroxy, amino, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, alkylthio, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl-oxo, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, carboxyalkyl, or alkoxycarbonyl; n is an integer from 1 to 20;

[0299] Y2 is - does not exist, or , , , , , , , , , , , , , , , , cycloalkylene, cycloalkenylene, heterocycloalkylene, heterocycloalkenylene, arylene, heteroarylene, bridged cyclclylene, fused cyclylene, spiro-cyclylene, poly-cyclylene, bridged heterocyclclylene, fused heterocyclylene, spiro-heterocyclylene and poly-heterocyclylene; wherein R'" and R"" are each independently -H, -D, halo, hydroxy, amino, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, alkylthio, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl-oxo, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, carboxyalkyl, or alkoxycarbonyl; n is an integer from 1 to 20;

[0300] Y3 does not exist, or , , , , , , , , , , , , , , , , cycloalkylene, cycloalkenylene, heterocycloalkylene, heterocycloalkenylene, arylene, heteroarylene, bridged cyclclylene, fused cyclylene, spiro-cyclylene, poly-cyclylene, bridged heterocyclclylene, fused heterocyclylene, spiro-heterocyclylene and poly-heterocyclylene; wherein R'" and R"" are each independently -H, -D, halo, hydroxy, amino, cyano, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, alkylthio, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl-oxo, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, carboxyalkyl, or alkoxycarbonyl; n is an integer from 1 to 20.

[0301] For example, a linker having the structure shown below may be used, and as another specific example, the linker is as described and defined in International Publication Nos. WO 2016 / 149668 A1, WO 2020 / 051564 A1, WO 2023 / 076161 A1, which are incorporated herein by reference, but are not limited thereto.

[0302] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

[0303]

[0304] In the above chemical formula 2, B, which is a protein target moiety (PTM), can be any target protein ligand used in the production of PROTAC in the art, and there are no special limitations thereon.

[0305] For example, compounds targeting BET bromodomain-containing proteins such as those shown in Table 1 below may be used, but are not limited thereto.

[0306] [Table 1]

[0307]

[0308]

[0309] For example, kinase and phosphatase inhibitor compounds such as those shown in Table 2 below may be used, but are not limited thereto.

[0310] [Table 2]

[0311]

[0312]

[0313]

[0314] For example, compounds targeting JAK (Janus kinase) family proteins, such as those shown in Table 3 below, may be used, but are not limited thereto.

[0315] [Table 3]

[0316]

[0317]

[0318] For example, compounds targeting PARP-1 (poly [ADP-ribose] polymerase 1) such as those shown in Table 4 below may be used, but are not limited thereto.

[0319] [Table 4]

[0320]

[0321]

[0322] For example, compounds targeting the focal adhesion kinase (FAK) protein, such as those shown in Table 5 below, may be used, but are not limited thereto.

[0323] [Table 5]

[0324]

[0325]

[0326] For example, but not limited to, compounds targeting the RAF (rapidly accelerated fibrosarcoma) receptor (kinase) as shown in Table 6 below may be used.

[0327] [Table 6]

[0328]

[0329]

[0330] For example, compounds targeting the androgen receptor (AR) such as those shown in Table 7 below may be used, but are not limited thereto.

[0331] [Table 7]

[0332]

[0333]

[0334] For example, compounds targeting the estrogen receptor (ER) such as those shown in Table 8 below may be used, but are not limited thereto.

[0335] [Table 8]

[0336]

[0337]

[0338] For example, compounds targeting BTK (Bruton tyrosine kinase) inhibitors such as those shown in Table 9 below may be used, but are not limited thereto.

[0339] [Table 9]

[0340]

[0341]

[0342] For example, compounds targeting heat shock protein 90 (HSP90) inhibitors such as those shown in Table 10 below may be used, but are not limited thereto.

[0343] [Table 10]

[0344]

[0345]

[0346] For example, compounds targeting HDM2 / MDM2 (human double minute 2 / mouse double minute 2) inhibitors such as those shown in Table 11 below may be used, but are not limited thereto.

[0347] [Table 11]

[0348]

[0349]

[0350] For example, immunosuppressive compounds such as those shown in Table 12 below may be used, but are not limited thereto.

[0351] [Table 12]

[0352]

[0353]

[0354] Example

[0355] Hereinafter, the present invention will be described in more detail by the following examples, which are provided for illustrative purposes only and the present invention is not limited thereto.

[0356]

[0357] The definitions of abbreviations used in the examples below are as follows.

[0358]

[0359]

[0360] Examples 1 to 166: Synthesis of ligands for E3 ubiquitin ligases

[0361] The UBR1 ligand was prepared through the following solid phase synthesis.

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369] Rink amide MBHA resin (50 mg, 0.52 mmol / g loading, 0.026 mmol, 1.0 equiv.) was placed in a 5.0 mL fritted syringe and incubated with DMF for 2 h at room temperature. After removing the Fmoc protecting group with 20% piperidine (v / v) in DMF (0.5 mL) for 20 min, the resin was treated with HATU (0.078 mmol, 3 equiv.), HOAt (0.078 mmol, 3 equiv.), DIPEA (0.156 mmol, 6 equiv.), and the Fmoc-protected amino acid (0.078 mmol, 3 equiv.) (Method AB). After the amide coupling reaction at room temperature for 2 h, the reaction mixture was discarded, and the resin was washed with DMF (3×), MeOH (3×), CH2Cl2 (3×), and DMF (3×). This process was repeated to obtain the desired compound. After removing the Fmoc protecting group, the compound on the resin was cleaved by treating with 1.0 mL of a cleavage cocktail (95% TFA, 2.5% TIPS, and 2.5% DDW) at room temperature for 3 h, and the compound was purified using reverse-phase column chromatography (C18 Silica Kelp, YL9100 GPC system) (solvent A: DDW with 0.1% TFA added, solvent B: ACN with 0.1% TFA added; gradient). The compound was analyzed by LC (Agilent 1220 LC system Ontario, CA, USA) and MALDI-TOF MS (Autoflex Speed ​​LRF, Bruker, Billerica, MA, USA). The purified compound was lyophilized to obtain a white solid, and Examples 1 to 26 were synthesized using the above synthetic method.

[0370]

[0371] Rink amide MBHA resin (50 mg, 0.52 mmol / g loading, 0.026 mmol, 1.0 equiv.) was placed in a 5.0 mL fritted syringe and incubated in DMF for 2 h at room temperature. After removing the Fmoc protecting group with 20% piperidine (v / v) in DMF (0.5 mL) for 20 min, the resin was treated with HATU (0.078 mmol, 3 equiv.), HOAt (0.078 mmol, 3 equiv.), DIPEA (0.156 mmol, 6 equiv.), and fluoronitrobenzoic acid (0.078 mmol, 3 equiv.) (Method C). After the amide coupling reaction at room temperature for 3 h, the reaction mixture was discarded, and the resin was washed with DMF (3×), MeOH (3×), CH2Cl2 (3×), and DMF (3×). Afterwards, R1-OH (1.04 mmol, 40 equiv.) and Cs2CO3 (1.04 mmol, 40 equiv.) in DMF (0.5 mL) were treated at 60°C for 6 hours to carry out the alcohol substitution reaction. Next, SnCl2 (1.56 mmol, 60 equiv.) in DMF (0.5 mL) was reacted at room temperature overnight. After washing the resin with DMF (3x), MeOH (3x), DCM (3x), and DMF (3x), the amide coupling reaction was carried out by treating the beads with HOAt (0.078 mmol, 3 equiv.), EDC (0.078 mmol, 3 equiv.), 2,6-lutidine (0.156 mmol, 6 equiv.), Fmoc-protected amino acid (0.078 mmol, 3 equiv.) in DMF (0.5 mL) at room temperature for 2 h. After treating with 20% piperidine, HATU (0.078 mmol, 3 equiv.), HOAt (0.078 mmol, 3 equiv.), DIPEA (0.156 mmol, 6 equiv.), Fmoc-protected amino acid (0.078 mmol, 3 equiv.) in DMF (0.5 mL) was added.) was treated on the resin. After removing the Fmoc protecting group, the compound on the resin was cleaved by treating with 1.0 mL of a cleavage cocktail (95% TFA, 2.5% TIPS, and 2.5% DDW) at room temperature for 3 hours, and the compound was purified using reverse-phase column chromatography (C18 Silica Kelp, YL9100 GPC system) (solvent A: DDW with 0.1% TFA added, solvent B: ACN with 0.1% TFA added; gradient). The purification and analysis methods of the compound were the same as in the above examples, and the purified compound was obtained as a white solid by lyophilization, and Examples 27 to 104 and Examples 109 to 115 were synthesized through the above synthetic method.

[0372]

[0373] Rink amide MBHA resin (50 mg, 0.52 mmol / g loading, 0.026 mmol, 1.0 equiv.) was placed in a 5.0 mL fritted syringe and incubated in DMF for 2 h at room temperature. The Fmoc protecting group was removed with 20% piperidine (v / v) in DMF (0.5 mL) for 20 min, followed by treatment with BAA (0.52 mmol, 20 equiv.) and DIC (0.52 mmol, 20 equiv.) in DMF (0.5 mL) at room temperature for 30 min (Method D). Subsequently, the amine substitution reaction was performed by treatment with R1-substituted piperazine (0.52 mmol, 20 equiv.) in DMF for 2 h at room temperature. After washing the resin with DMF (3x), MeOH (3x), CH2Cl2 (3x), and DMF (3x), HATU (0.078 mmol, 3 equiv.), HOAt (0.078 mmol, 3 equiv.), DIPEA (0.156 mmol, 6 equiv.), and Fmoc-protected amino acid (0.078 mmol, 3 equiv.) were added to the resin. After removing the Fmoc protecting group, the compound on the resin was cleaved by treating with 1.0 mL of cleavage cocktail (95% TFA, 2.5% TIPS, and 2.5% DDW) for 3 h at room temperature, and the compound was purified using reversed-phase column chromatography (C18 Silica Gel, YL9100 GPC system) (Solvent A: DDW with 0.1% TFA, Solvent B: ACN with 0.1% TFA; Gradient). The purification and analysis methods of the compounds were the same as in the above examples, and the purified compounds were freeze-dried to obtain white solids, and Examples 105 to 108 were synthesized using the above synthetic method.

[0374]

[0375] PAL resin (50 mg, 0.92 mmol / g loading, 0.046 mmol, 1.0 equiv.) was placed in a 4.0 mL vial and THF was added and left for 2 h. After all THF was removed, the resin was treated with primary amine (0.23 mmol, 5.0 equiv.) together with 1.0 mL of THF at room temperature for 2 h. The solution was then treated with NaBH(OAc)3 (0.32 mmol, 7.0 equiv.) and AcOH (0.46 mmol, 10 equiv.) at room temperature for 12 h. The reaction mixture was transferred to a 5.0 mL fritted syringe, and the resin was washed with THF (3×), MeOH (3×), CH2Cl2 (3×), and DMF (3×). HATU (0.138 mmol, 3.0 equiv.), HOAt (0.138 mmol, 3.0 equiv.), DIPEA (0.276 mmol, 6.0 equiv.), and 4-fluoro nitrobenzoic acid (0.138 mmol, 3.0 equiv.) were treated on the resin. After the amide coupling reaction at room temperature for 3 h, the reaction mixture was discarded, and the resin was washed with DMF (3x), MeOH (3x), CH2Cl2 (3x), and DMF (3x). Next, SnCl2 (2.76 mmol, 60 equiv.) in DMF (0.5 mL) was reacted at room temperature overnight. The resin was washed with DMF (3x), MeOH (3x), DCM (3x), and DMF (3x), and then treated with Fmoc-protected amino acid (0.230 mmol, 5 equiv.). After amide coupling reaction at room temperature for 2 h, the reaction mixture was discarded, and the resin was washed with DMF (3x), MeOH (3x), CH2Cl2 (3x), and DMF (3x). This process was repeated to obtain the desired compound. After removal of the Fmoc protecting group, 1.0 mL of cleavage cocktail (95% TFA, 2.5% TIPS, and 2.The compound on the resin was cleaved by treating with 5% DDW and purified using reverse phase column chromatography (C18 silica gel, YL9100 GPC system) (solvent A: DDW with 0.1% TFA added, solvent B: ACN with 0.1% TFA added; gradient). The compound was analyzed by LC (Agilent 1220 LC system Ontario, CA, USA) and MALDI-TOF MS (Autoflex Speed ​​LRF, Bruker, Billerica, MA, USA). The purified compound was freeze-dried to obtain a white solid, and Examples 116 to 155 were synthesized using the above synthetic method.

[0376]

[0377]

[0378]

[0379]

[0380] Iron powder (Fe, 7.0 equiv.) and ammonium chloride (NH₄Cl, 10 equiv.) were added to 3-bromo-1-nitrobenzene (1.0 equiv.) or 4-bromo-1-nitrobenzene (1.0 equiv.), and the mixture was stirred at 80°C overnight in a mixture of ethanol and water (1:1, v / v). After the reaction, Fmoc-Phe(4-Boc2-guanidino)-OH (1.2 equiv.), HATU (1.2 equiv.), and DIEA (3.0 equiv.) were added to the resulting 3-bromoaniline or 4-bromoaniline solution, and the mixture was reacted in DMF at room temperature for 2 hours to synthesize the amide conjugate. After removing the Boc and Fmoc protecting groups, the compound was purified using reverse-phase column chromatography (C18 silica gel, YL9100 GPC system) (solvent A: DDW with 0.1% TFA, solvent B: ACN with 0.1% TFA; gradient). The compound was analyzed by LC (Agilent 1220 LC system Ontario, CA, USA) and MALDI-TOF MS (Autoflex Speed ​​LRF, Bruker, Billerica, MA, USA). The purified compound was freeze-dried to obtain a white solid, and Examples 158 and 159 were synthesized using the above synthetic method.

[0381]

[0382] Iron powder (Fe, 7.0 equiv.) and ammonium chloride (NH₄Cl, 10.0 equiv.) were added to 4-nitrophenol (1.0 equiv.), and reduced in a solvent of ethanol and water (1:1, v / v) at 80°C for 4 h by stirring. To the resulting 4-aminophenol solution, Fmoc-Phe(4-Boc2-guanidino)-OH (1.2 equiv.), HATU (1.2 equiv.), and DIEA (3.0 equiv.) were added in a solvent of DMF, and the reaction was carried out at room temperature for 2 h to synthesize an amide derivative. After removing the Boc and Fmoc protecting groups, the compound was purified using reverse-phase column chromatography (C18 silica gel, YL9100 GPC system) (solvent A: DDW with 0.1% TFA, solvent B: ACN with 0.1% TFA; gradient). The compound was analyzed by LC (Agilent 1220 LC system Ontario, CA, USA) and MALDI-TOF MS (Autoflex Speed ​​LRF, Bruker, Billerica, MA, USA). The purified compound was freeze-dried to obtain a white solid, and Example 160 was synthesized using the above synthetic method.

[0383]

[0384] 4-Nitrophenol (1.0 eq.) was added to tert-butyl (2-(2-bromoethoxy)ethyl)carbamate (1.0 equiv.) and K2CO3 (4.0 equiv.) in DMF solvent and reacted at 40°C overnight to form an ether bond intermediate. Iron powder (Fe, 10.0 equiv.) and ammonium chloride (NH₄Cl, 10.0 equiv.) were added to the ether intermediate and reacted at 80°C for 4 hours in a mixed solvent of ethanol and water (1:1, v / v) to form an amine. Fmoc-Phe(4-Boc2-guanidino)-OH (1.2 equiv.), HATU (1.2 equiv.), and DIEA (3.0 equiv.) were added to the reduced ether amine intermediate in DMF, and the reaction was performed at room temperature for 2 hours to obtain the final amide derivative. After the Boc and Fmoc protecting groups were removed, the compound was purified using reverse-phase column chromatography (C18 silica gel, YL9100 GPC system) (solvent A: DDW with 0.1% TFA added, solvent B: ACN with 0.1% TFA added; gradient). The compound was analyzed by LC (Agilent 1220 LC system Ontario, CA, USA) and MALDI-TOF MS (Autoflex Speed ​​LRF, Bruker, Billerica, MA, USA). The purified compound was lyophilized to obtain a white solid, and Example 161 was synthesized using the above synthetic method.

[0385]

[0386]

[0387]

[0388]

[0389] 2-Bromo-5-nitrophenol (1.0 equiv.) or 3-bromo-5-nitrophenol (1.0 equiv.) was added (2-bromoethyl)cyclohexane (1.5 equiv.) and K2CO3 (3.0 equiv.), and the mixture was stirred at 50°C for 16 hours in DMF to synthesize an alkyl aryl ether derivative. Next, the intermediate was added to a mixed solvent of DCM and water (1:1, v / v) together with K2CO3 (15.0 equiv.), Na2S2O4 (10.0 equiv.), and tetrabutylammonium hydrogen sulfate (TBAHS, 0.2 equiv.), and stirred three times for 1 hour each at room temperature to reduce the nitro group to obtain an aryl amine compound. Afterwards, Fmoc-Phe(4-Boc2-guanidino)-OH (1.2 equiv.), HATU (1.2 equiv.), and DIPEA (3.0 equiv.) were added to the generated amine in DMF solvent and reacted at room temperature for 2 hours to form an amide conjugate. After the Boc protecting group was removed from the generated compound under acidic conditions, the Fmoc protecting group was also removed under basic conditions. Afterwards, the compound was purified using reversed-phase column chromatography (C18 Silica Kelp, YL9100 GPC system) (solvent A: DDW with 0.1% TFA added, solvent B: ACN with 0.1% TFA added; gradient). The compound was analyzed by LC (Agilent 1220 LC system Ontario, CA, USA) and MALDI-TOF MS (Autoflex Speed ​​LRF, Bruker, Billerica, MA, USA). The purified compound was freeze-dried to obtain a white solid, and Examples 156 and 162 were synthesized using the above synthetic method.

[0390]

[0391] An alkyl aryl ether derivative was synthesized by adding (2-bromoethyl)cyclohexane (1.5 equiv.) and K2CO3 (3.0 equiv.) to 2-bromo-5-nitrophenol (1.0 equiv.) in DMF solvent and stirring at 50℃ for 16 h. To the resulting aryl ether compound, tert-butyl carbamate (1.2 equiv.), Pd(OAc)₂ (3 mol%), XPhos (9 mol%), and Cs2CO3 (1.4 equiv.) were added in dioxane solvent and reacted at 100℃ for 4 h to obtain a C-N bond-forming derivative. After removing the Boc protecting group from this compound by treating it with trifluoroacetic acid (50% in DCM), acetylation was performed by reacting it with 5% acetic anhydride in DCM at room temperature for 30 min. Subsequently, K2CO3 (15.0 equiv.), Na2S2O4 (10.0 equiv.), and TBAHS (0.2 equiv.) were added to a DCM / H₂O mixed solvent, and the nitro group was reduced three times for 1 hour each at room temperature. To the resulting amine compound, Fmoc-Arg(Pbf)-OH (1.2 equiv.), HATU (1.2 equiv.), and DIPEA (4.0 equiv.) were added in DMF, and the reaction was performed at room temperature for 2 hours to synthesize an amide conjugate. Subsequently, the Fmoc and Pbf protecting groups were removed under basic and acidic conditions, respectively, to obtain an aryl ether-based arginine derivative as the final product. Subsequently, the compound was purified using reverse-phase column chromatography (C18 silica gel, YL9100 GPC system) (solvent A: DDW with 0.1% TFA, solvent B: ACN with 0.1% TFA; gradient). The compound was analyzed by LC (Agilent 1220 LC system Ontario, CA, USA) and MALDI-TOF MS (Autoflex Speed ​​LRF, Bruker, Billerica, MA, USA).The purified compound was freeze-dried to obtain a white solid, and Example 157 was synthesized using the above synthetic method.

[0392]

[0393] An alkyl aryl ether derivative was synthesized by adding (2-bromoethyl)cyclohexane (1.5 equiv.) and K2CO3 (3.0 equiv.) to 3-bromo-5-nitrophenol (1.0 equiv.) in DMF solvent and stirring at 50°C for 16 hours. To the resulting aryl ether compound, tert-butyl piperazine-1-carboxylate (1.2 equiv.) or tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (1.2 equiv.) or tert-butyl carbamate (1.2 equiv.), Pd(OAc)₂ (3 mol%), XPhos (9 mol%), and Cs2CO3 (1.4 equiv.) were added in dioxane solvent and reacted at 100°C for 4 hours to obtain a CN bond-forming derivative. Subsequently, K2CO3 (15.0 equiv.), Na2S2O4 (10.0 equiv.), and TBAHS (0.2 equiv.) were added to a DCM / H₂O mixed solvent, and the nitro group was reduced three times for 1 hour each at room temperature. To the resulting amine compound, Fmoc-Phe(4-Boc2-guanidino)-OH (1.2 equiv.), HATU (1.2 equiv.), and DIPEA (4.0 equiv.) were added in DMF, and the reaction was allowed to proceed at room temperature for 2 hours to synthesize an amide conjugate. Subsequently, the Fmoc and Pbf protecting groups were removed under basic and acidic conditions, respectively. Afterwards, the compound was purified using reversed-phase column chromatography (C18 Silica Kelp, YL9100 GPC system) (solvent A: DDW with 0.1% TFA added, solvent B: ACN with 0.1% TFA added; Gradient). Compounds were analyzed by LC (Agilent 1220 LC system Ontario, CA, USA) and MALDI-TOF MS (Autoflex Speed ​​LRF, Bruker, Billerica, MA, USA).The purified compound was freeze-dried to obtain a white solid, and Examples 163, 164 and 165 were synthesized using the above synthetic method.

[0394]

[0395] An alkyl aryl ether derivative was synthesized by adding (2-bromoethyl)cyclohexane (1.5 equiv.) and K2CO3 (3.0 equiv.) to 3-bromo-5-nitrophenol (1.0 equiv.) in DMF solvent and stirring at 50°C for 16 h. The resulting aryl ether compound was subjected to Sonogashira reaction using tert-butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate (1.2 equiv.), CuI (0.05 equiv.), Pd2(PPh3)2Cl2 (0.03 equiv.), and PPh₃ (0.06 equiv.) as catalysts in a triethylamine / DMF (3:1, v / v) mixed solvent at 70°C for 12 h. Subsequently, K2CO3 (15.0 equiv.), Na2S2O4 (10.0 equiv.), and TBAHS (0.2 equiv.) were added to a DCM / H₂O mixed solvent, and the nitro group was reduced three times for 1 hour each at room temperature. To the resulting amine compound, Fmoc-Phe(4-Boc2-guanidino)-OH (1.2 equiv.), HATU (1.2 equiv.), and DIPEA (4.0 equiv.) were added in DMF, and the reaction was allowed to proceed at room temperature for 2 hours to synthesize an amide conjugate. Subsequently, the Fmoc and Pbf protecting groups were removed under basic and acidic conditions, respectively. Afterwards, the compound was purified using reversed-phase column chromatography (C18 Silica Kelp, YL9100 GPC system) (solvent A: DDW with 0.1% TFA added, solvent B: ACN with 0.1% TFA added; Gradient). The compound was analyzed by LC (Agilent 1220 LC system Ontario, CA, USA) and MALDI-TOF MS (Autoflex Speed ​​LRF, Bruker, Billerica, MA, USA). The purified compound was lyophilized to obtain a white solid, and Example 166 was synthesized using the above synthetic method.

[0396]

[0397] The above synthesis results are summarized and shown in Table 13.

[0398] [Table 13]

[0399] [Correction pursuant to Rule 91, June 16, 2025]

[0400] [Correction pursuant to Rule 91, June 16, 2025]

[0401] [Correction pursuant to Rule 91, June 16, 2025]

[0402] [Correction pursuant to Rule 91, June 16, 2025]

[0403] [Correction pursuant to Rule 91, June 16, 2025]

[0404] [Correction pursuant to Rule 91, June 16, 2025]

[0405] [Correction pursuant to Rule 91, June 16, 2025]

[0406] [Correction pursuant to Rule 91, June 16, 2025]

[0407] [Correction pursuant to Rule 91, June 16, 2025]

[0408] [Correction pursuant to Rule 91 16.06.2025]d

[0409] [Correction pursuant to Rule 91, June 16, 2025]

[0410] [Correction pursuant to Rule 91, June 16, 2025]

[0411] [Correction pursuant to Rule 91, June 16, 2025]

[0412] [Correction pursuant to Rule 91, June 16, 2025]

[0413] [Correction pursuant to Rule 91, June 16, 2025]

[0414] [Correction pursuant to Rule 91, June 16, 2025]

[0415] [Correction pursuant to Rule 91, June 16, 2025]

[0416] [Correction pursuant to Rule 91, June 16, 2025]

[0417] [Correction pursuant to Rule 91, June 16, 2025]

[0418] [Correction pursuant to Rule 91, June 16, 2025]

[0419] [Correction pursuant to Rule 91, June 16, 2025]

[0420] [Correction pursuant to Rule 91 16.06.2025]d

[0421] [Correction pursuant to Rule 91, June 16, 2025]

[0422] [Correction pursuant to Rule 91, June 16, 2025]

[0423] [Correction pursuant to Rule 91, June 16, 2025]

[0424] [Correction pursuant to Rule 91, June 16, 2025]

[0425] [Correction pursuant to Rule 91, June 16, 2025]

[0426] [Correction pursuant to Rule 91, June 16, 2025]

[0427] [Correction pursuant to Rule 91, June 16, 2025]

[0428] [Correction pursuant to Rule 91, June 16, 2025]

[0429] [Correction pursuant to Rule 91, June 16, 2025]

[0430] [Correction pursuant to Rule 91, June 16, 2025]

[0431] [Correction pursuant to Rule 91, June 16, 2025]

[0432]

[0433] Experimental Example 1: Competitive Fluorescence Polarization Assay

[0434] Competitive fluorescence polarization analysis was performed to evaluate the binding affinity of the ligand compounds. Fluorescently labeled RLNalS (K d = 125 nM) was incubated with the UBR Box domain of UBR1 (300 nM) in binding buffer (20 mM Tris-HCl pH 7.6, 150 mM NaCl, 1 mM TCEP-HCl, 0.01% Tween 20), and then treated with various concentrations of compounds (Fig. 2). After incubation for an additional 1 hour, the polarization of fluorescence was measured using a Tecan F200 Microplate reader (Excitation: 485 nm; Emission: 535 nm). IC was calculated using nonlinear regression. 50 Determine the value and use the following equation Y = Bottom+(Top-Bottom) / (1+(X / IC 50 )) was fitted using GraphPad Prism 7 software. The results of measuring the binding affinity of the example compounds to the UBR1 protein are shown in Table 14.

[0435] [Table 14]

[0436]

[0437]

[0438]

[0439] Example 167: Synthesis of PROTAC in which the compound of Example 113 and a bromodomain-containing protein 4 (BRD4) ligand are linked via a linker

[0440]

[0441]

[0442] PAL resin (100 mg, 0.91 mmol / g loading, 0.091 mmol, 1.0 equiv.) was placed in a 4 mL vial, and 13-amino-5,8,11-trioxa-2-azatridecanoic acid 1,1-dimethylethyl ester (0.455 mmol, 5 equiv.) and AcOH (0.455 mmol, 5 equiv.) in THF were added to the beads at room temperature for 2 h. Then, NaBH(OAc)3 (0.455 mmol, 5 equiv.) was added and reacted overnight. After washing the resin with DCM (3x), MeOH (3x), and DMF (3x), the amide coupling reaction was performed by treating the beads with HBTU (0.455 mmol, 5 equiv.), HOBt (0.455 mmol, 5 equiv.), DIPEA (0.91 mmol, 10 equiv.), 2-fluoro-4-nitrobenzoic acid (0.455 mmol, 5 equiv.) in DMF (1 mL) at room temperature for 3 h. The resin was washed with DMF (3x), MeOH (3x), DCM (3x), and DMF (3x), and then the alcohol substitution reaction was performed by treating 2-cyclohexylethanol (3.64 mmol, 40 equiv.), Cs2CO3 (3.64 mmol, 40 equiv.) in DMF (1 mL) at 60 °C for 6 h. Next, SnCl2 (5.46 mmol, 60 equiv.) in DMF (1 mL) was reacted overnight at room temperature. The resin was washed with DMF (3x), MeOH (3x), DCM (3x), and DMF (3x), and then HOAt (0.273 mmol, 3 equiv.), EDC (0.273 mmol, 3 equiv.), 2,6-lutidine (0.546 mmol, 6 equiv.), Fmoc-Phe(guanidine)-OH (0.273 mmol, 3 equiv.)) in DMF (1 mL) was treated on the beads at room temperature for 2 hours to carry out the amide coupling reaction. Afterwards, 2 mL of cleavage cocktail (95% TFA, 2.5% TIPS, 2.5% DDW) was treated to cleave the resinous compound and purified by reverse phase HPLC. The purified compound was lyophilized to obtain a light brown solid. The obtained compound was treated on the beads with a solution of HATU (0.182 mmol, 2.0 eq), HOAt (0.182 mmol, 2.0 eq), DIPEA (0.364 mmol, 4.0 eq), JQ1 carboxylic acid (0.091 mmol, 1.0 eq) in DMF for 2 hours at room temperature, and then piperidine was added to obtain a final 20% piperidine in DMF solution. After reacting at room temperature for 30 minutes, purification was performed using reverse-phase HPLC. The purification and analysis methods of the synthesized compound were the same as in the above examples, and the purified compound, 4-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-N-(1-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-2-(2-cyclohexylethoxy)benzamide, was freeze-dried to obtain an off-white solid (Fig. 3).

[0443]

[0444] Experimental Example 2: Competitive FP Assay of the Compound of Example 113 and the PROTAC of Example 167 against the UBR1 protein

[0445] To evaluate the binding affinity of the compound of Example 113 and the PROTAC of Example 167 for the UBR1 protein, a competitive fluorescence polarization assay was performed. The analysis was performed in the same manner as in Experimental Example 1 above. The PROTAC of Example 167 had a K of 124 nM for the UBR Box domain of the UBR1 protein. i It was combined with the value, and although the binding affinity was somewhat reduced compared to that of the compound of Example 113, which is a UBR1 ligand, it was still confirmed to be at an excellent level (K i = 17 nM). This indicates that the PROTAC of Example 167 can form a ternary complex with the UBR1 protein and the BRD4 protein with an excellent level of binding affinity. The results of the binding affinity measurement of the compound of Example 113 and the PROTAC of Example 167 for the UBR1 protein are shown in Figure 4.

[0446]

[0447] Experimental Example 3: Confirmation of BRD4 protein degradation by PROTAC of Example 167

[0448] PC-3 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and penicillin-streptomycin at 37°C with 5% CO2.

[0449] To evaluate the BRD4 protein degradation ability of PROTAC of Example 167, human prostate cancer PC-3 cells were treated with DMSO or various concentrations of PROTAC compounds. PC-3 cells were seeded in 6-well plates and cultured at 37°C for 24 hours, and then treated with DMSO or PROTAC compounds in Opti-MEM medium for 48 hours. Before cell lysis, cells were washed twice with cold Dulbecco's phosphate-buffered saline (DPBS). Next, cells were treated with lysis buffer (50 mM Tris-HCl pH 7.4, 150 mM NaCl, 1% Triton X, 0.1% SDS, 0.5% sodium deoxycholate, 1x protease inhibitor cocktail) to lyse the cells and placed on ice. The cell lysate was then centrifuged at 13,000 rpm for 15 minutes at 4°C. The supernatant was collected and the protein concentration was determined using Pierce TM The 660 nm Assay Reagent was used. 6x SDS loading buffer was added to the cell lysate and heated at 95°C for 5 minutes. Equal amounts of protein were loaded onto SDS-PAGE and transferred to PVDF membranes. The PVDF membranes were blocked with 5% skim milk in TBST (Tris-buffered saline containing 0.01% Tween-20) and treated with primary antibodies at 4°C for 15 hours. After incubation with HRP-conjugated secondary antibodies for 1 hour at room temperature, Western blot images were obtained with ECL solution. The PROTAC of Example 167 reduced the intracellular BRD4 protein expression level by approximately 50% at a concentration of approximately 50 nM, and exhibited stronger BRD4 protein degradation activity as the concentration increased (Fig. 5).

[0450]

[0451] Experimental Example 4: Confirmation of target protein degradation through the proteasome-mediated pathway of PROTAC of Example 167 and formation of a ternary complex with BRD4 and UBR1 proteins.

[0452] To determine whether the PROTAC of Example 167 induces BRD4 protein degradation through the proteasome-mediated pathway, the PROTAC of Example 167 (500 nM) was treated alone or together with the proteasome inhibitor MG-132 (5 μM). PC-3 cells were seeded in 6-well plates and cultured at 37°C for 24 h, and then treated with the compound in Opti-MEM medium. Afterwards, the cells were washed twice with cold DPBS to lyse the cells, and the lysis buffer was applied to the cells and placed on ice. The cell lysate was centrifuged at 13,000 rpm for 15 min at 4°C, and the supernatant was collected and the protein concentration was determined using Pierce TMThe 660 nm Assay Reagent was used. Afterwards, 6x SDS loading buffer was added to the cell lysate and heated at 95°C for 5 minutes. The same amount of protein was loaded onto SDS-PAGE and transferred to a PVDF membrane, followed by blocking with 5% skim milk in TBST. After incubation with primary and secondary antibodies in the same manner as described above, Western blot images were obtained with ECL solution. When the PROTAC of Example 167 was treated with the proteasome inhibitor MG-132, no BRD4 degradation effect was observed, thereby proving that the degradation of BRD4 by the PROTAC of Example 167 is via the proteasome-mediated pathway. In addition, to confirm whether the PROTAC of Example 167 induces BRD4 protein degradation by forming a ternary complex with the BRD4 protein and UBR1 protein, PC-3 cells were treated with the PROTAC of Example 167 (500 nM) and JQ1 (10 μM) or the compound of Example 113 (10 μM), and the amount of intracellular BRD4 was measured by Western blot. When the PROTAC of Example 167 was treated with JQ1 (10 μM) or the compound of Example 113 (10 μM), no BRD4 degradation effect was observed, thereby proving that the degradation of BRD4 by the PROTAC of Example 167 is due to the formation of a ternary complex with the BRD4 protein and UBR1 protein (Fig. 6).

[0453]

[0454] Example 168: Prodrug synthesis of PROTAC in which the compound of Example 100 and a bromodomain-containing protein 4 (BRD4) ligand are linked via a linker

[0455]

[0456]

[0457] PAL resin (100 mg, 0.91 mmol / g loading, 0.091 mmol, 1.0 equiv.) was placed in a 4.0 mL vial, and 13-amino-5,8,11-trioxa-2-azatridecanoic acid 1,1-dimethylethyl ester (13-amino-5,8,11-trioxa-2-azatridecanoic acid 1,1-dimethylethyl ester) (0.46 mmol, 5.0 equiv.) and AcOH (0.46 mmol, 5.0 equiv.) in THF were added to the beads at room temperature for 2 h. Then, NaBH(OAc)3 (0.46 mmol, 5.0 equiv.) was added and the mixture was reacted overnight. After washing the resin with DCM (3x), MeOH (3x), and DMF (3x), the amide coupling reaction was performed by treating the beads with HBTU (0.46 mmol, 5.0 equiv.), HOBt (0.46 mmol, 5.0 equiv.), DIPEA (0.91 mmol, 10 equiv.), and 2-fluoro-4-nitrobenzoic acid (0.46 mmol, 5.0 equiv.) in DMF (1.0 mL) at room temperature for 3 h. The resin was washed with DMF (3x), MeOH (3x), DCM (3x), and DMF (3x), and then treated with 4-fluorobenzyl alcohol (3.6 mmol, 40 equiv.), Cs2CO3 (3.6 mmol, 40 equiv.) in DMF (1.0 mL) at 60 °C for 6 h to initiate the alcohol substitution reaction. Next, SnCl2 (5.5 mmol, 60 equiv.) in DMF (1.0 mL) was reacted overnight at room temperature. The resin was washed with DMF (3x), MeOH (3x), DCM (3x), and DMF (3x), and then treated with HOAt (0.27 mmol, 3.0 equiv.), EDC (0.27 mmol, 3.0 equiv.), 2,6-lutidine (0.55 mmol, 6.The beads were treated with Fmoc-Phe(guanidine)-OH (0.27 mmol, 3.0 equiv.) in DMF (1.0 mL) at room temperature for 2 h to initiate the amide coupling reaction. Afterwards, the resinous compound was cleaved by treating with 2.0 mL of cleavage cocktail (95% TFA, 2.5% TIPS, 2.5% DDW) and purified by reverse-phase HPLC. The purified compound was lyophilized to obtain a light brown solid. The obtained compound was treated with beads at room temperature for 2 hours with a solution of HATU (0.18 mmol, 2.0 eq), HOAt (0.18 mmol, 2.0 eq), DIPEA (0.36 mmol, 4.0 eq), and JQ1 carboxylic acid (0.091 mmol, 1.0 eq) in DMF, and then piperidine was added to obtain a final 20% piperidine in DMF solution. After reacting at room temperature for 30 minutes, purification was performed using reverse-phase HPLC. The purified compound was lyophilized to obtain an off-white solid. Afterwards, the obtained compound (2.2 mg, 0.002 mmol, 1.0 equiv.) was treated with a solution of 1-((2,5-dioxopyrrolidin-1-yloxy)carbonyloxy)ethyl isobutyrate (0.002 mmol, 1.0 equiv.) and DIPEA (0.008 mmol, 4.0 equiv.) in dry DMF, reacted at room temperature for 2 hours, and then purified using reverse phase HPLC.The purification and analysis methods of the synthesized compound were the same as in the above examples, and the purified compound was freeze-dried to obtain 1-((((S)-1-((4-((1-((R)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)carbamoyl)-3-((4-fluorobenzyl)oxy)phenyl)amino)-3-(4-guanidinophenyl)-1-oxopropan-2-yl)carbamoyl)oxy)ethylisobutyrate as an off-white solid (Fig. 7).

[0458]

[0459] Experimental Example 5: Confirmation of BRD4 protein degradation by prodrug of Example 168

[0460] To evaluate the BRD4 protein degradation ability of the synthesized Example 168 prodrug, human prostate cancer PC-3 cells were treated with DMSO or various concentrations of protac compounds. PC-3 cells were seeded in 6-well plates and cultured at 37°C for 24 hours, and then treated with DMSO or protac compounds in Opti-MEM medium for 48 hours. Before cell lysis, cells were washed twice with cold Dulbecco's phosphate-buffered saline (DPBS). Next, cells were treated with lysis buffer (50 mM Tris·HCl pH 7.4, 150 mM NaCl, 1% Triton X, 0.1% SDS, 0.5% sodium deoxycholate, 1x protease inhibitor cocktail) to lyse the cells and then placed on ice. The cell lysate was then centrifuged at 13,000 rpm for 15 minutes at 4°C. Collect the supernatant and measure the protein concentration using Pierce TMThe 660 nm Assay Reagent was used. 6x SDS loading buffer was added to the cell lysate and heated at 95°C for 5 minutes. Equal amounts of protein were loaded onto SDS-PAGE and transferred to PVDF membranes. The PVDF membranes were blocked with 5% skim milk in TBST (Tris-buffered saline containing 0.01% Tween-20) and treated with primary antibodies for 15 hours at 4°C. After incubation with HRP-conjugated secondary antibodies for 1 hour at room temperature, Western blot images were obtained with ECL solution (Fig. 8).

Claims

1. A compound of the following chemical formula 1 or a prodrug thereof: [Chemical Formula 1] In the above chemical formula 1, R1 and R2 are each independently -H, -D, alkyl, deuterated alkyl or haloalkyl; R3 is -DEG; wherein D is a direct bond or alkylene; E is alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocycloalkylene, heterocycloalkenylene, or heteroarylene; wherein said alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heterocycloalkylene, heterocycloalkenylene or heteroarylene is optionally -D, halo, hydroxy, thiol (-SH), amino, nitro, cyano, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkylthio, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkenyl, alkynyl, cycloalkyl, may be substituted with one or more substituents selected from heterocycloalkyl, aryl and heteroaryl; G is amino, heteroaryl, , or and; here R9, R 10 and R 11 are each independently -H, alkyl or haloalkyl; or R9 and R 10 These can be interconnected to form a ring structure; R4 and R6 are each independently -H, -D, alkyl, deuterated alkyl or haloalkyl; L1 is -C-, -CH-, cycloalkylene, heterocyclylene, cycloalkenylene, heterocycloalkenylene, arylene or heteroarylene; or may form a ring structure together with the N atom to which R4 and L1 are bonded; R5 is -H, -D, halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, aryl-alkoxy or heteroaryl-alkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, aryl-alkoxy or heteroaryl-alkyl is optionally -D, hydroxy, thiol, amino, halo, nitro, cyano, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl-oxy, heterocycloalkyl-oxy, aryl-oxy, heteroaryl-oxy, alkoxyalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, carboxy, alkoxyoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, Alkylcarbonyl, alkylcarbonylalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and may be substituted with one or more substituents selected from; wherein R 12 and R 13 are each independently -H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, cycloalkenyl-alkyl, heterocycloalkyl-alkyl, heterocycloalkenyl-alkyl, aryl-alkyl or heteroaryl-alkyl; or R 12 Wow R 13 These can be connected to each other to form a ring structure; q is 0, 1, 2, 3, 4, 5, 6 or 7; or when L1 is -C- and m is 2, R5 and L1 can be connected together to form a cycloalkyl or heterocycloalkyl; L2 may be a direct bond, or when n is 0, R4 and L2 may be connected to each other with the N atom to which they are bonded to form a ring structure; wherein said ring may be optionally substituted with one or more substituents selected from -D, hydroxy, amino, halo, nitro, cyano, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl-oxy, heterocycloalkyl-oxy, aryl-oxy, heteroaryl-oxy, alkoxyalkyl, aminoalkyl, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; L3 is a direct bond, -C-, -CH-, -CH2-, cycloalkylene, heterocycloalkylene, unsaturated carbocyclylene, unsaturated heterocyclylene, arylene or heteroarylene; or can form a ring structure together with the N atom to which R6 and L3 are bonded; R7 is halo, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl-oxy, cycloalkyl-alkyl, cycloalkyl-alkoxy, cycloalkenyl-oxy, cycloalkenyl-alkyl, cycloalkenyl-alkyl-oxy, heterocycloalkyl-oxy, heterocycloalkyl-alkyl, heterocycloalkyl-alkoxy, heterocycloalkenyl-oxy, heterocycloalkenyl-alkyl, heterocycloalkenyl-alkyl-oxy, aryl, aryl-oxy, aryl-alkyl, aryl-alkoxy, heteroaryl, heteroaryl-oxy, heteroaryl-alkyl, heteroaryl-alkoxy or and here R 14 and R 15 are each independently -H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, cycloalkenyl-alkyl, heterocycloalkyl-alkyl, heterocycloalkenyl-alkyl, aryl-alkyl or heteroaryl-alkyl; or R 14 Wow R 15 These can be interconnected to form a ring structure; r is 0, 1, 2, 3, 4, 5, 6 or 7; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, cycloalkenyl-alkyl, heterocycloalkyl-alkyl, heterocycloalkenyl-alkyl, aryl-alkyl, aryl-alkoxy or heteroaryl-alkyl is optionally -D, hydroxy, thiol, amino, halo, nitro, cyano, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl-oxy, heterocycloalkyl-oxy, aryl-oxy, heteroaryl-oxy, alkoxyalkyl, aminoalkyl, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, which may be substituted with one or more substituents selected from alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; When L3 is -C- and p is 2, R7 and L3 may be linked together to form cycloalkyl or heterocycloalkyl; R8 is -H, , , , , , , , , , or and here R 16 Inland R 31 are each independently -H, hydroxy, nitro, cyano, azido(-N3), halo, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthio, alkylthioalkyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkylamino, dialkylamino, dialkylaminoalkyl, aminoalkoxy-alkyl, alkylcarbonyl, aryl, heteroaryl, cycloalkyl-alkyl, cycloalkenyl-alkyl, heterocycloalkyl-alkyl, heterocycloalkenyl-alkyl, aryl-alkyl, heteroaryl-alkyl, partially unsaturated heterocyclyl, or partially unsaturated heterocyclyl-alkyl;The above alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, cycloalkenyl-alkyl, heterocycloalkyl-alkyl, heterocycloalkenyl-alkyl, aryl-alkyl, heteroaryl-alkyl, partially unsaturated heterocyclyl and partially unsaturated heterocyclyl-alkyl are optionally -D, halo, hydroxy, thiol, amino, nitro, cyano, azido, carboxy, oxo, aminocarbonyl, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl-oxy, heterocycloalkyl, haloalkyl, heterocycloalkyl-oxy, aryl-oxy, heteroaryl-oxy, alkylthio, alkylamino, dialkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, Heteroarylamino, alkoxycarbonyl, cycloalkyl-oxycarbonyl, heterocycloalkyl-oxycarbonyl, aryl-oxycarbonyl, heteroaryl-oxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, alkylcarbonyl, cycloalkylcarbonyl, heterocycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, sulfo(-SO3H), alkoxy-sulfonyl(SO2), aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, carboxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, which may be substituted with one or more substituents selected from alkoxycarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, alkylcarbonylalkyl, sulfoalkyl, alkoxysulfonylalkyl, aminosulfonylalkyl, alkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, cycloalkenyl-alkyl, heterocycloalkyl-alkyl, heterocycloalkenyl-alkyl, aryl-alkyl and heteroaryl-alkyl;s is 0, 1, 2, 3, 4, 5,6 or 7; n is 0 or 1; m is 0, 1, or 2; p is 0, 1, 2, 3 or 4; However, if L1 is -C- or -CH-, L3 is not a direct bond or -CH-; L2 and L3 are not direct bonds at the same time; The above heterocycloalkylene, heterocycloalkenylene, heteroarylene, heterocycloalkyl, heteroaryl, heterocyclylene, heterocyclyl and partially unsaturated heterocyclyl have one or more heteroatoms selected from N, O and S.

2. In paragraph 1, R1 and R2 are each independently -H, -D, C1-C7 alkyl, deuterated C1-C7 alkyl or halo-C1-C7 alkyl; R3 is -DEG; where D is a direct bond or C1-C7 alkylene; E is C1-C7 alkylene, C2-C7 alkenylene, C2-C7 alkynylene, C3-C 10 Cycloalkylene, C3-C 10 Cycloalkenylene, C6-C 12 Arylene, 4 to 12 membered heterocycloalkylene, 4 to 12 membered heterocycloalkenylene or 5 to 12 membered heteroarylene; wherein said alkylene, alkenylene, alkynylene, cycloalkylene. Cycloalkenylene, arylene, heterocycloalkylene, heterocycloalkenylene or heteroarylene is optionally -D, halo, hydroxy, thiol, amino, nitro, cyano, C1-C7 alkyl, halo-C1-C7 alkyl, deuterated C1-C7 alkyl, hydroxy-C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkoxy, C1-C7 alkoxy-C1-C7 alkyl, C1-C7 alkylthio, C1-C7 alkylamino, di(C1-C7 alkyl)amino, amino-C1-C7 alkyl, C1-C7 alkylamino-C1-C7 alkyl, di(C1-C7 alkyl)amino-C1-C7 alkyl, aminocarbonyl, C1-C7 alkylaminocarbonyl, di(C1-C7 alkyl)aminocarbonyl, Aminocarbonyl-C1-C7 alkyl, C1-C7 alkylaminocarbonyl-C1-C7 alkyl, di(C1-C7 alkyl)aminocarbonyl- C1-C7 alkyl, carboxy, C1-C7 alkoxycarbonyl, carboxy-C1-C7 alkyl, C1-C7 alkoxycarbonyl-C1-C7 alkyl, C1-C7 alkylcarbonyl, C1-C7 alkylcarbonyl-C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C 10 Cycloalkyl, 4 to 12 membered heterocycloalkyl, C6-C 12 may be substituted with 1 to 4 substituents selected from aryl and 5 to 12 membered heteroaryl; G is amino, 5 to 12 membered heteroaryl, , or and; here R9, R 10 and R 11 are each independently -H, C1-C7 alkyl or halo-C1-C7 alkyl; or R9 and R 10 These can be interconnected to form a ring structure; R4 and R6 are each independently -H, -D, C1-C7 alkyl, deuterated C1-C7 alkyl or halo-C1-C7 alkyl; L1 is -C-, -CH-, C3-C 10 Cycloalkylene, 4 to 12 membered heterocyclylene, C3-C 10 Cycloalkenylene, 4 to 12 membered heterocycloalkenylene, C6-C 12 Arylene or 5 to 12 membered heteroarylene; or can form a ring structure together with the N atom to which R4 and L1 are bonded; R5 is -H, -D, halo, C1-C7 alkyl, halo-C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, 4 to 12 membered heterocycloalkyl, 4 to 12 membered heterocycloalkenyl, C6-C 12 Aryl, 5 to 12 membered heteroaryl, C3-C 10 Cycloalkyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkyl-C1-C7 alkyl, C6-C 12 Aryl-C1-C7 alkyl or 5 to 12 membered heteroaryl-C1-C7 alkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, aryl-alkyl, aryl-alkoxy or heteroaryl-alkyl is optionally -D, hydroxy, thiol, amino, halo, nitro, cyano, C1-C7 alkyl, halo-C1-C7 alkyl, deuterated C1-C7 alkyl, hydroxy-C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkoxy, C3-C 10 Cycloalkyl-oxy, 4 to 12 membered heterocycloalkyl-oxy, C6-C 12 Aryl-oxy, 5 to 12 membered heteroaryl-oxy, C1-C7alkoxy-C1-C7alkyl, aminocarbonyl, C1-C7alkylaminocarbonyl, di(C1-C7alkyl)aminocarbonyl, aminocarbonyl-C1-C7alkyl, C1-C7alkylaminocarbonyl-C1-C7alkyl, di(C1-C7alkyl)aminocarbonyl-C1-C7alkyl, carboxy, C1-C7alkoxycarbonyl, carboxy-C1-C7alkyl, C1-C7alkoxycarbonyl-C1-C7alkyl, C1-C7alkylcarbonyl, C1-C7alkylcarbonyl-C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C3-C 10 Cycloalkyl, 4 to 12 membered heterocycloalkyl, C6-C 12 Aryl, 5 to 12 membered heteroaryl and may be substituted with 1 to 4 substituents selected from; wherein R 12 and R 13 are each independently -H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, 4 to 12 membered heterocycloalkyl, 4 to 12 membered heterocycloalkenyl, C6-C 12 Aryl, 5 to 12 membered heteroaryl, C3-C 10 Cycloalkyl-C1-C7 alkyl, C3-C 10 Cycloalkenyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkenyl-C1-C7 alkyl, C6-C 12 Aryl-C1-C7 alkyl or 5 to 12 membered heteroaryl-C1-C7 alkyl; or R 12 Wow R 13 These can be linked to each other to form a ring structure; q is 0, 1, 2, 3, 4, 5, 6 or 7; or when L1 is -C- and m is 2, R5 and L1 are linked together to form C3-C 10 It can form a cycloalkyl or a 4 to 12 membered heterocycloalkyl; L2 may be a direct bond, or when n is 0, R4 and L2 may be connected to each other with the N atom to which they are bonded to form a ring structure; wherein the ring is optionally -D, hydroxy, amino, halo, nitro, cyano, C1-C7 alkyl, halo-C1-C7 alkyl, deuterated C1-C7 alkyl, hydroxy-C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkyl-oxy, C3-C 10 Cycloalkyl-oxy, 4 to 12 membered heterocycloalkyl-oxy, C6-C 12 Aryl-oxy, 5 to 12 membered heteroaryl-oxy, C1-C7alkoxy-C1-C7alkyl, amino-C1-C7alkyl, C1-C7alkylamino, di(C1-C7alkyl)amino, C1-C7alkylamino-C1-C7alkyl, di(C1-C7alkyl)amino-C1-C7alkyl, aminocarbonyl, C1-C7alkylaminocarbonyl, di(C1-C7alkyl)aminocarbonyl, aminocarbonyl-C1-C7alkyl, C1-C7alkylaminocarbonyl-C1-C7alkyl, di(C1-C7alkyl)aminocarbonyl-C1-C7alkyl, carboxy, C1-C7alkoxycarbonyl, carboxy-C1-C7alkyl, C1-C7alkoxycarbonyl-C1-C7alkyl, C2-C7alkenyl, C2-C7 alkynyl, C3-C 10 Cycloalkyl, 4 to 12 membered heterocycloalkyl, C6-C 12 Aryl, C6-C 12 which may be substituted with 1 to 4 substituents selected from aryl-C1-C7 alkyl and 5 to 12 membered heteroaryl; L3 is a direct bond, -C-, -CH-, -CH2-, C3-C 10 Cycloalkylene, 4 to 12 membered heterocycloalkylene, unsaturated C3-C 10 Carbocyclylene, unsaturated 4 to 12 membered heterocyclylene, C6-C 12 Arylene or 5 to 12 membered heteroarylene; or may form a ring structure together with the N atom to which R6 and L3 are bonded; R7 is halo, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, halo-C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkoxy, hydroxy-C1-C7 alkyl, C3-C 10 Cycloalkyl-oxy, C3-C 10 Cycloalkyl-C1-C7 alkyl, C3-C 10 Cycloalkyl-C1-C7alkoxy, C3-C 10 Cycloalkenyl-oxy, C3-C 10 Cycloalkenyl-C1-C7 alkyl, C3-C 10 Cycloalkenyl-C1-C7alkoxy, 4 to 12 membered heterocycloalkyl-oxy, 4 to 12 membered heterocycloalkyl-C1-C7alkyl, 4 to 12 membered heterocycloalkyl-C1-C7alkoxy, 4 to 12 membered heterocycloalkenyl-oxy, 4 to 12 membered heterocycloalkenyl-C1-C7alkyl, 4 to 12 membered heterocycloalkenyl-C1-C7alkoxy, C6-C 12 Aryl, C6-C 12 Aryl-oxy, C6-C 12 Aryl-C1-C7 alkyl, C6-C 12 Aryl-C1-C7alkoxy, 5 to 12 membered heteroaryl, 5 to 12 membered heteroaryl-oxy, 5 to 12 membered heteroaryl-C1-C7alkyl, 5 to 12 membered heteroaryl-C1-C7alkoxy or and here R 14 and R 15 are each independently -H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, 4 to 12 membered heterocycloalkyl, 4 to 12 membered heterocycloalkenyl, C6-C 12 Aryl, 5 to 12 membered heteroaryl, C3-C 10 Cycloalkyl-C1-C7 alkyl, C3-C 10 Cycloalkenyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkenyl-C1-C7 alkyl, C6-C 12 Aryl-C1-C7 alkyl or 5 to 12 membered heteroaryl-C1-C7 alkyl; or R 14 Wow R 15 These can be connected to each other to form a ring structure; r is 0, 1, 2, 3, 4, 5, 6 or 7; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, cycloalkenyl-alkyl, heterocycloalkyl-alkyl, heterocycloalkenyl-alkyl, aryl-alkyl, aryl-alkoxy or heteroaryl-alkyl is optionally -D, hydroxy, thiol, amino, halo, nitro, cyano, C1-C7 alkyl, halo-C1-C7 alkyl, deuterated C1-C7 alkyl, hydroxy-C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkoxy, C3-C 10 Cycloalkyl-oxy, 4 to 12 membered heterocycloalkyl-oxy, C6-C 12 Aryl-oxy, 5 to 12 membered heteroaryl-oxy, C1-C7alkoxy-C1-C7alkyl, amino-C1-C7alkyl, C1-C7alkylamino, di(C1-C7alkyl)amino, C1-C7alkylamino-C1-C7alkyl, di(C1-C7alkyl)amino-C1-C7alkyl, aminocarbonyl, C1-C7alkylaminocarbonyl, di(C1-C7alkyl)aminocarbonyl, aminocarbonyl-C1-C7alkyl, C1-C7alkylaminocarbonyl-C1-C7alkyl, di(C1-C7alkyl)aminocarbonyl-C1-C7alkyl, carboxy, carboxy-C1-C7alkyl, C1-C7alkoxycarbonyl, C1-C7alkoxycarbonyl-C1-C7alkyl, C1-C7 alkoxycarbonyl-C1-C7 alkyl, C1-C7 alkylcarbonyl, C1-C7 alkylcarbonyl-C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C 10 Cycloalkyl, 4 to 12 membered heterocycloalkyl, C6-C 12 which may be substituted with 1 to 4 substituents selected from aryl and 5 to 12 membered heteroaryl; When L3 is -C- and p is 2, R7 and L3 are connected together to form C3-C 10 can form a cycloalkyl or a 4 to 12 membered heterocycloalkyl; R8 is -H, , , , , , , , , , or and here R 16 Inland R 31 are each independently -H, hydroxy, nitro, cyano, azido(-N3), halo, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, C1-C7 alkoxy-C1-C7 alkyl, C1-C7 alkylthio, C1-C7 alkylthio-C1-C7 alkyl, halo-C1-C7 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, 4 to 12 membered heterocycloalkyl, 4 to 12 membered heterocycloalkenyl, C1-C7 alkylamino, di(C1-C7 alkyl)amino, di(C1-C7 alkyl)amino-C1-C7 alkyl, amino-C1-C7 alkoxy-C1-C7 alkyl, C1-C7 alkylcarbonyl, C6-C 12 Aryl, 5 to 12 membered heteroaryl, C3-C 10 Cycloalkyl-C1-C7 alkyl, C3-C 10 Cycloalkenyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkenyl-C1-C7 alkyl, C6-C 12 Aryl-C1-C7 alkyl, 5 to 12 membered heteroaryl-C1-C7 alkyl, partially unsaturated 4 to 12 membered heterocyclyl or partially unsaturated 4 to 12 membered heterocyclyl-C1-C7 alkyl; The above alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkyl-alkyl, cycloalkenyl-alkyl, heterocycloalkyl-alkyl, heterocycloalkenyl-alkyl, aryl-alkyl, heteroaryl-alkyl, partially unsaturated heterocyclyl and partially unsaturated heterocyclyl-alkyl are optionally -D, halo, hydroxy, thiol, amino, nitro, cyano, azido, carboxy, oxo, aminocarbonyl, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl-oxy, 4 to 12 membered heterocycloalkyl, halo-C1-C7 alkyl, 4 to 12 membered heterocycloalkyl-oxy, C6-C 12 Aryl-oxy, 5 to 12 membered heteroaryl-oxy, C1-C7 alkylthio, C1-C7 alkylamino, di(C1-C7 alkyl)amino, C3-C 10 Cycloalkylamino, 4 to 12 membered heterocycloalkylamino, C6-C 12 Arylamino, 5-12 membered heteroarylamino, C1-C7 alkoxycarbonyl, C3-C 10 Cycloalkyl-oxycarbonyl, 4 to 12 membered heterocycloalkyl-oxycarbonyl, C6-C 12 Aryl-oxycarbonyl, 5 to 12 membered heteroaryl-oxycarbonyl, C1-C7 alkylaminocarbonyl, di(C1-C7 alkyl)aminocarbonyl, C3-C 10 Cycloalkylaminocarbonyl, 4 to 12 membered heterocycloalkylaminocarbonyl, C6-C 12 Arylaminocarbonyl, 5 to 12 membered heteroarylaminocarbonyl, C1-C7 alkylcarbonyl, C3-C 10 Cycloalkylcarbonyl, 4 to 12 membered heterocycloalkylcarbonyl, C6-C 12 Arylcarbonyl, 5-12 membered heteroarylcarbonyl, sulfo, C1-C7 alkoxy-sulfonyl, aminosulfonyl, C1-C7 alkylaminosulfonyl, di(C1-C7 alkyl)aminosulfonyl, C3-C 10 Cycloalkylaminosulfonyl, 4 to 12 membered heterocycloalkylaminosulfonyl, C6-C 12 Arylaminosulfonyl, 5 to 12 membered heteroarylaminosulfonyl, carboxy-C1-C7 alkyl, amino-C1-C7 alkyl, C1-C7 alkylamino-C1-C7 alkyl, di(C1-C7 alkyl)amino-C1-C7 alkyl, C1-C7 alkoxy-C1-C7 alkyl, C1-C7 alkoxycarbonyl-C1-C7 alkyl, C1-C7 alkylaminocarbonyl-C1-C7 alkyl, di(C1-C7 alkyl)aminocarbonyl-C1-C7 alkyl, C1-C7 alkylcarbonyl-C1-C7 alkyl, sulfo-C1-C7 alkyl, C1-C7 alkoxysulfonyl-C1-C7 alkyl, aminosulfonyl-C1-C7 alkyl, C1-C7 alkylaminosulfonyl-C1-C7 alkyl, Di(C1-C7 alkyl)aminosulfonyl-C1-C7 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, 4 to 12 membered heterocycloalkenyl, C6-C 12 Aryl, 5 to 12 membered heteroaryl, C3-C 10 Cycloalkyl-C1-C7 alkyl, C3-C 10 Cycloalkenyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkyl-C1-C7 alkyl, 4 to 12 membered heterocycloalkenyl-C1-C7 alkyl, C6-C 12 which may be substituted with one or more substituents selected from aryl-C1-C7 alkyl and 5 to 12 membered heteroaryl-C1-C7 alkyl; s is 0, 1, 2, 3, 4, 5,6 or 7; n is 0 or 1; m is 0, 1, or 2; p is 0, 1, 2, 3 or 4; However, if L1 is -C- or -CH-, L3 is not a direct bond or -CH-; L2 and L3 are not direct bonds at the same time; A compound or a prodrug thereof, wherein the heterocycloalkylene, heterocycloalkenylene, heteroarylene, heterocycloalkyl, heteroaryl, heterocyclylene, heterocyclyl and partially unsaturated heterocyclyl have 1 to 4 heteroatoms selected from N, O and S.

3. In paragraph 1, A compound or a prodrug thereof, wherein R1 and R2 are each independently -H or C1-C5 alkyl.

4. In paragraph 1, R3 is -DEG; where D is C1-C5 alkylene; E is C1-C5 alkylene, C6-C 10 Arylene or a 5 to 10 membered heterocycloalkylene having 1 to 3 N atoms; G is amino, 5 to 10 membered heteroaryl, , or and; here R7, R8 and A compound or a prodrug thereof, wherein each R9 is independently -H, C1-C5 alkyl or halo-C1-C5 alkyl.

5. In paragraph 1, A compound or a prodrug thereof, wherein R4 and R6 are each independently -H or C1-C5 alkyl.

6. In paragraph 1, L1 is -C-, -CH-, C4-C8cycloalkylene, C4-C8cycloalkenylene or C6-C 10 or may form a 4 to 10 membered heterocycloalkyl together with the N atom to which R4 and L1 are bonded; R5 is halo, C1-C5 alkyl, halo-C1-C5 alkyl, C6-C 10 Aryl, 5-8 membered heteroaryl, C3-C8 cycloalkyl-C1-C5 alkyl, C6-C 10 Aryl-C1-C5 alkyl or 5 to 8 membered heteroaryl-C1-C5 alkyl; wherein said aryl is optionally selected from the group consisting of hydroxy, halo, halo-C1-C5 alkyl, C1-C5 alkoxy and C6-C 10 A compound or a prodrug thereof, wherein R5 and L1 may be substituted with one to three substituents selected from aryl; and when L1 is -C- and m is 2, R5 and L1 may be connected together to form a C3-C8 cycloalkyl or a 4 to 10 membered heterocycloalkyl.

7. In paragraph 1, When L2 is a direct bond, or n is 0, R4 and L2 may be connected to each other together with the N atom to which they are bonded to form a 4 to 10 membered heterocycloalkyl, wherein the heterocycloalkyl is optionally C1-C5 alkyl and C6-C 10 A compound or a prodrug thereof, characterized in that it can be substituted with one to three substituents selected from aryl-C1-C5 alkyl.

8. In paragraph 1, L3 is a direct bond, -CH-, -CH2-, C4-C8 cycloalkylene, unsaturated C4-C8 carbocyclylene or C6-C 10 A compound or a prodrug thereof, characterized in that it is arylene; or can form a 4 to 10 membered heterocycloalkyl together with the N atom to which R6 and L3 are bonded.

9. In paragraph 1, R7 is halo, C1-C5 alkyl, halo-C1-C5 alkyl, C1-C5 alkoxy, hydroxy-C1-C5 alkyl, C3-C8 cycloalkyl-oxy, C3-C8 cycloalkyl-C1-C5 alkyl, C3-C8 cycloalkyl-C1-C5 alkoxy, C6-C 10 Aryl, C6-C 10 Aryl-C1-C5 alkyl, C6-C 10 Aryl-oxy, C6-C 10 Aryl-C1-C5 alkoxy, 5 to 8 membered heteroaryl-C1-C5 alkyl, unsaturated 4 to 10 membered heterocyclyl or unsaturated C4-C 10 Carbocyclyl-oxy; wherein said aryl, aryl-alkyl or aryl-alkoxy is optionally halo, cyano, C1-C5 alkyl, halo-C1-C5 alkyl, C1-C5 alkoxy and C6-C 10 A compound or a prodrug thereof, characterized in that it can be substituted with one to three substituents selected from aryl.

10. In paragraph 1, R8 is halo, hydroxy, 4 to 10 membered heterocycloalkyl, , , , , or and here R 17 Inland R 23 and R 31 are each independently -H, hydroxy, C1-C7 alkyl, C2-C5 alkenyl, halo-C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkoxy-C1-C5 alkyl, C1-C5 alkylthio-C1-C5 alkyl, di(C1-C5 alkyl)amino-C1-C5 alkyl, amino-C1-C5 alkoxy-C1-C5 alkyl, C1-C5 alkylcarbonyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C5 alkyl, C3-C8 cycloalkenyl-C1-C5 alkyl, 4 to 10 membered heterocycloalkyl, 4 to 10 membered heterocycloalkyl-C1-C5 alkyl, partially unsaturated 4 to 10 membered heterocyclyl-C1-C5 alkyl, C6-C 10 Aryl or C6-C 10 Aryl-C1-C5 alkyl; wherein said heterocycloalkyl or heterocycloalkyl-C1-C5 alkyl is optionally selected from the group consisting of hydroxy, halo, oxo, C1-C5 alkyl, halo-C1-C5 alkyl, 4 to 10 membered heterocycloalkyl-C1-C5 alkyl and C6-C 10 Aryl-C1-C5alkyl may be substituted with 1 to 3 substituents selected from; wherein said aryl or aryl-alkyl is optionally selected from hydroxy, halo, C1-C5alkyl, halo-C1-C5alkyl, aminosulfonyl, 4 to 10 membered heterocycloalkyl and C6-C 10 A compound or a prodrug thereof, characterized in that it can be substituted with one to three substituents selected from aryl-C1-C5 alkyl.

11. A compound or a prodrug thereof, characterized in that the compound of formula 1 in paragraph 1 is selected from the following group: (1S,3R)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-3-((S)-2-amino-5-guanidinopentanamido)cyclohexanecarboxamide; (1S,3R)-N-((S)-1-amino-3-(4-fluorophenyl)-1-oxopropan-2-yl)-3-((S)-2-amino-5-guanidinopentanamido)cyclohexanecarboxamide; N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-3-((S)-2-amino-5-guanidinopentanamido)benzamide; (S)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-1-((S)-2-amino-5-guanidinopentanoyl)piperidine-3-carboxamide; (R)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-1-((S)-2-amino-5-guanidinopentanoyl)piperidine-3-carboxamide; (1S,3R)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-3-((S)-2-amino-5-guanidinopentanamido)cyclopentanecarboxamide; (1R,3S)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-3-((S)-2-amino-5-guanidinopentanamido)cyclopentanecarboxamide; (1S,4R)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-4-((S)-2-amino-5-guanidinopentanamido)cyclopent-2-encarboxamide; (1S,3R)-3-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)cyclohexane-1-carboxamide; (1S,3R)-N-((S)-1-amino-3-(4-fluorophenyl)-1-oxopropan-2-yl)-3-((S)-2-amino-3-(4-guanidinophenyl)propanamido)cyclohexane-1-carboxamide; rel-(1S,3R)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-3-((S)-2-amino-5-guanidinopentanamido)cyclohexanecarboxamide; rel-(1S,3S)-N-((S)-1-amino-3-(naphthalen-1-yl)-1-oxopropan-2-yl)-3-((S)-2-amino-5-guanidinopentanamido)cyclohexanecarboxamide; (1S,3R)-3-((S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-3-cyclohexylpropanamido)cyclohexanecarboxamide; 3-((S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-3-cyclohexylpropanamido)benzamide; (R)-1-((S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-3-cyclohexylpropanoyl)piperidine-3-carboxamide; (1S,3R)-3-((S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-3-cyclohexylpropanamido)cyclopentanecarboxamide; (1R,4S)-4-((S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-3-cyclohexylpropanamido)cyclopent-2-enecarboxamide; (1S,3R)-3-((S)-2-amino-3-(4-guanidinophenyl)propanamido)cyclohexane-1-carboxamide; (S)-3-(2-amino-3-(4-guanidinophenyl)propanamido)benzamide; (S)-1-((S)-2-amino-3-(4-guanidinophenyl)propanoyl)piperidine-3-carboxamide; (1S,3R)-3-((S)-2-amino-3-(4-guanidinophenyl)propanamido)cyclopentane-1-carboxamide; (1R,4s)-4-((S)-2-amino-3-(4-guanidinophenyl)propanamido)cyclohexane-1-carboxamide; (1R,2S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)cyclohexanecarboxamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)benzamide; (S)-2-(2-amino-3-(4-guanidinophenyl)propanamido)benzamide; (1S,2R)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)cyclopentanecarboxamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-((4-fluorobenzyl)oxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-methoxybenzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-ethoxybenzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-isopropoxybenzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-isobutoxybenzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(cyclobutylmethoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(cyclopentylmethoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(cyclohexylmethoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-cyclopropoxybenzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-cyclobutoxybenzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(cyclopentyloxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(cyclohexyloxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-phenoxybenzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(benzyloxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-((4-chlorobenzyl)oxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(naphthalen-1-ylmethoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-((3,5-bis(trifluoromethyl)benzyl)oxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(4-fluorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-((2,3-dihydro-1H-inden-2-yl)oxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-((4-bromo-2-fluorobenzyl)oxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(naphthalen-2-ylmethoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(4-methylphenethoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(2,4-dichlorophenethoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-((4-(trifluoromethyl)benzyl)oxy)benzamide; 4-((S)-2-((S)-2-amino-5-(3-methylguanidino)pentanamido)-3-cyclohexylpropanamido)-3-phenoxybenzamide; 4-((S)-2-((S)-2-amino-5-(3,3-dimethylguanidino)pentanamido)-3-cyclohexylpropanamido)-3-phenoxybenzamide; 4-((S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-3-cyclohexylpropanamido)-3-phenoxybenzamide; 4-((S)-2-((S)-2-amino-5-ureidopentanamido)-3-cyclohexylpropanamido)-3-phenoxybenzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(3-fluorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(2-fluorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(4-chlorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(3-chlorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(2-chlorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(p-tolyloxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(m-tolyloxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(o-tolyloxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(4-(trifluoromethyl)phenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(3-(trifluoromethyl)phenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(2-(trifluoromethyl)phenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(4-cyanophenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(3-cyanophenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(2-cyanophenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(4-methoxyphenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(3-methoxyphenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(2-methoxyphenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(3,4-dimethoxyphenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(2,4-dimethoxyphenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(benzo[d][1,3]dioxol-5-yloxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(naphthalen-1-yloxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(naphthalen-2-yloxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-3-(4-hydroxyphenoxy)benzamide; (S)-4-(2-amino-5-guanidinopentanamido)-3-phenoxybenzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)hexamido)-3-(3-chlorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-4,4-dimethylpentanamido)-3-(3-chlorophenoxy)benzamide; (S)-4-(1-(2-amino-5-guanidinopentanamido)cyclopropanecarboxamido)-3-(3-chlorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclopropylpropanamido)-3-(3-chlorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-2-phenylacetamido)-3-(3-chlorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-(pyridin-3-yl)propanamido)-3-(3-chlorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-(thiophen-2-yl)propanamido)-3-(3-chlorophenoxy)benzamide; 4-((1S,3R)-3-((S)-2-amino-5-guanidinopentanamido)cyclohexanecarboxamido)-3-(3-chlorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)benzamide; 4-((1S,3R)-3-((S)-2-amino-5-guanidinopentanamido)cyclohexanecarboxamido)benzamide; 4-((1S,3R)-3-((S)-2-amino-3-(4-guanidinophenyl)propanamido)cyclohexanecarboxamido)benzamide; 3-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-2-(3-chlorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-2-(3-chlorophenoxy)benzamide; 3-((S)-2-((S)-2-amino-5-guanidinopentanamido)-3-cyclohexylpropanamido)-4-(3-chlorophenoxy)benzamide; 3-((S)-2-((S)-2-amino-5-guanidinopentanamido)-2-phenylacetamido)-2-(3-chlorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-5-guanidinopentanamido)-2-phenylacetamido)-2-(3-chlorophenoxy)benzamide; 3-((S)-2-((S)-2-amino-5-guanidinopentanamido)-2-phenylacetamido)-4-(3-chlorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-3-cyclohexylpropanamido)-3-(3-chlorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-2-phenylacetamido)-3-(3-chlorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-3-(3-guanidinophenyl)propanamido)-2-phenylacetamido)-3-(3-chlorophenoxy)benzamide; 4-((S)-2-((S)-2-amino-3-(2-guanidinophenyl)propanamido)-2-phenylacetamido)-3-(3-chlorophenoxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-(4-fluorophenoxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-3-(cyclohexylmethoxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-3-(cyclohexyloxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-3-(3-chlorophenoxy)benzamide; 2-(4-((S)-2-amino-3-(4-guanidinophenyl)propanoyl)-3-methylpiperazin-1-yl)acetamide; 2-(4-((S)-2-amino-3-(4-guanidinophenyl)propanoyl)-3-propylpiperazin-1-yl)acetamide; 2-(4-((S)-2-amino-3-(4-guanidinophenyl)propanoyl)-3-isobutylpiperazin-1-yl)acetamide; 2-(4-((S)-2-amino-3-(4-guanidinophenyl)propanoyl)-3-benzylpiperazin-1-yl)acetamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((3-fluorobenzyl)oxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-chlorobenzyl)oxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-(cyclohexyloxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-(cyclohexylmethoxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-(2-cyclohexylethoxy)benzamide; (S)-4-(2-amino-3-(1-carbamimidoylpiperidin-4-yl)propanamido)-2-((4-fluorobenzyl)oxy)benzamide; (S)-4-(2-amino-3-(1-carbamimidoylpiperidin-4-yl)propanamido)-2-(2-cyclohexylethoxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-isopropylbenzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(cyclohexylmethyl)-2-((4-fluorobenzyl)oxy)benzamide; (S)-N-allyl-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-isopentylbenzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(2-(cyclohex-1-en-1-yl)ethyl)-2-((4-fluorobenzyl)oxy)benzamide; 4-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-((tetrahydrofuran-3-yl)methyl)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-cyclopentyl-2-((4-fluorobenzyl)oxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-cyclohexyl-2-((4-fluorobenzyl)oxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(4-morpholinophenyl)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(2-(methylthio)ethyl)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-phenethylbenzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(4-methoxybenzyl)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-neopentylbenzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(4-(tert-butyl)benzyl)-2-((4-fluorobenzyl)oxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-((4-fluorobenzyl)oxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(4-(trifluoromethyl)benzyl)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(naphthalen-2-ylmethyl)benzamide; 4-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-((tetrahydrofuran-2-yl)methyl)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-hexylbenzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(3-methylbenzyl)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(3-chloropropyl)-2-((4-fluorobenzyl)oxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(4-fluorophenethyl)benzamide; 4-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(1-phenylethyl)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-isobutylbenzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-benzyl-2-((4-fluorobenzyl)oxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(2-methoxyethyl)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-cyclobutyl-2-((4-fluorobenzyl)oxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-propylbenzamide; 4-((S)-2-amino-3-(4-guanidinophenyl)propanamido)-N-(sec-butyl)-2-((4-fluorobenzyl)oxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(2-cyclohexylethyl)-2-((4-fluorobenzyl)oxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(3-(2-oxopyrrolidin-1-yl)propyl)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(4-chlorobenzyl)-2-((4-fluorobenzyl)oxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(3-(dimethylamino)propyl)-2-((4-fluorobenzyl)oxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(4-sulfamoylphenethyl)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(2-(tert-butoxy)ethyl)-2-((4-fluorobenzyl)oxy)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(4-hydroxybenzyl)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-2-((4-fluorobenzyl)oxy)-N-(piperidin-4-yl)benzamide; (S)-4-(2-amino-3-(4-guanidinophenyl)propanamido)-N-(1-benzylpiperidin-4-yl)-2-((4-fluorobenzyl)oxy)benzamide; (S)-2-(2-cyclohexylethoxy)-4-(2,6-diaminohexanamido)benzamide; (S)-4-(2-amino-3-(1H-imidazol-4-yl)propanamido)-2-(2-cyclohexylethoxy)benzamide; (S)-2-amino-N-(4-bromo-3-(2-cyclohexylethoxy)phenyl)-3-(4-guanidinophenyl)propanamide; (S)-N-(4-acetamido-3-(2-cyclohexylethoxy)phenyl)-2-amino-5-guanidinopentanamide; (S)-2-amino-N-(4-bromophenyl)-3-(4-guanidinophenyl)propanamide; (S)-2-amino-N-(3-bromophenyl)-3-(4-guanidinophenyl)propanamide; (S)-2-amino-3-(4-guanidinophenyl)-N-(4-hydroxyphenyl)propanamide; (S)-2-amino-N-(4-(2-(2-aminoethoxy)ethoxy)phenyl)-3-(4-guanidinophenyl)propanamide; (S)-2-amino-N-(2-((3-bromo-5-(2-cyclohexylethoxy)phenyl)amino)-2-oxoethyl)-3-(4-guanidinophenyl)propanamide; (S)-2-amino-N-(3-(2-cyclohexylethoxy)-5-(piperazin-1-yl)phenyl)-3-(4-guanidinophenyl)propanamide; (S)-2-amino-N-(3-((2-(2-aminoethoxy)ethyl)amino)-5-(2-cyclohexylethoxy)phenyl)-3-(4-guanidinophenyl)propanamide; (S)-2-amino-N-(3-amino-5-(2-cyclohexylethoxy)phenyl)-3-(4-guanidinophenyl)propanamide; and (S)-2-Amino-N-(3-(3-(2-aminoethoxy)prop-1-yn-1-yl)-5-(2-cyclohexylethoxy)phenyl)-3-(4-guanidinophenyl)propanamide.

12. Chimeric compound of the following chemical formula 2: [Chemical Formula 2] In the above chemical formula 2, A is a compound according to any one of claims 1 to 11 or a prodrug thereof, wherein A is a ubiquitin ligase binding moiety (ULM); B is a protein target moiety (PTM); A and B are chemically linked by a linker.

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