3, 4-dihydroquinoxaline-2-carboxamide derivative compound and pharmaceutical composition for preventing or treating cancer disease comprising same

Abstract

The present disclosure relates to a 3, 4-dihydroquinoxaline-2-carboxamide derivative compound and a pharmaceutical composition for preventing or treating cancer diseases comprising the same. The compound has an excellent selective inhibition effect on histone deacetylase (HDAC) 8 in HDAC, and thus can be used as a selective inhibitor of HDAC8 or a pharmaceutical composition for preventing or treating cancer diseases.

Description

Technical Field

[0001] The present disclosure relates to 3,4-dihydroquinoxaline-2-carboxamide derivative compounds and pharmaceutical compositions containing the compounds for preventing or treating cancer diseases. Background Art

[0002] Histone deacetylase (hereinafter referred to as HDAC) is an enzyme that removes acetyl groups from the amino group of the N-terminal lysine tail of histones. It is known that it has multiple effects on non-histone proteins and is involved in important cellular activities, such as cell growth cycle regulation, differentiation and cancer formation. In particular, it has recently been found that it is overexpressed under harsh environmental conditions (such as hypoxia, low glucose and cell tumor formation), and by inhibiting the expression of cell proliferation inhibitors, it plays a role in promoting cell proliferation and is considered to be an important regulatory factor in the control of cell differentiation and tumorigenicity. HDAC can be roughly divided into four categories according to its function and DNA sequence similarity, which currently include 18 groups. Among them, HDAC8 belongs to Class I, in which HDAC1, HDAC2 and HDAC3 are mainly found in the nucleus, while HDAC8 is present in both the nucleus and the cytoplasm. HDAC8 is overexpressed in many cancers and has been reported to be associated with a variety of diseases including inflammatory diseases, and is becoming an important target for the treatment of a variety of diseases.

[0003] Currently, FDA-approved HDAC inhibitors include Novartis's multiple myeloma treatment drug "Farydak (panobinostat)", BMS's cutaneous T-cell lymphoma treatment drug "Istodax (romidepsin)", Merck's cutaneous T-cell lymphoma treatment drug "Zolinza (vorinostat)", and Acrotech's peripheral T-cell lymphoma treatment drug "Beleodaq (belinostat)". Most HDAC inhibitors developed so far have been approved for the treatment of specific cancers, but their efficacy is limited and may cause unnecessary side effects, so more improved HDAC selective inhibitors are needed. Summary of the invention Technical goals

[0004] One embodiment aims to provide a novel 3,4-dihydroquinoxaline-2-carboxamide derivative compound.

[0005] Another embodiment is directed to a method for preparing a 3,4-dihydroquinoxaline-2-carboxamide derivative compound.

[0006] Another embodiment is to provide a pharmaceutical composition for preventing or treating cancer diseases, wherein the pharmaceutical composition comprises a 3,4-dihydroquinoxaline-2-carboxamide derivative compound.

[0007] Another embodiment is to provide a health functional food composition for preventing or improving cancer diseases, wherein the health functional food composition comprises a 3,4-dihydroquinoxaline-2-carboxamide derivative compound.

[0008] Another embodiment is directed to a method for treating cancer disease, comprising administering a compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof to an individual or subject in need thereof.

[0009] Another embodiment is to provide a 3,4-dihydroquinoxaline-2-carboxamide derivative compound, a stereoisomer thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof for treating cancer diseases.

[0010] Another embodiment is to provide the use of a 3,4-dihydroquinoxaline-2-carboxamide derivative compound, a stereoisomer thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer diseases. Technical Solution

[0011] One embodiment provides a compound represented by the following Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a salt thereof.

[0012] [Chemical formula 1]

[0013]

[0014] In Chemical Formula 1,

[0015] R 1 is unsubstituted or substituted C 5-8 Cycloalkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted heteroaryl containing 5 to 8 atoms of one or more heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted fused heteroaryl containing 8 to 10 atoms of one or more heteroatoms selected from the group consisting of N, O and S, or C 1-15 Alkenyl,

[0016] Among them, the substituted C 5-8 The cycloalkyl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10Haloalkyl, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl and C 1-8 Alkylcarbonyloxy,

[0017] Substituted C 6-10 The aryl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 6-10 Aryl, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl, C 1-8 alkylcarbonyloxy, and a heteroaryl group of 5 to 8 atoms containing one or more heteroatoms selected from the group consisting of N, O and S,

[0018] The 5 to 8-atom substituted heteroaryl is substituted by halogen, or by a C 6-10 Aryl substituted, and

[0019] The substituted fused heteroaryl of 8 to 10 atoms is substituted by one or more substituents selected from the group consisting of: -OH, halogen, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl and C 1-8 Alkylcarbonyloxy;

[0020] R 2 and R 3 are independently -H, halogen or C 1-10 alkyl;

[0021] R 4 C 1-8 Alkyl, or C substituted with two or more -OH 3-10 Alkyl; and

[0022] L 1 Can be a key or C 1-10 Alkylene.

[0023] Another embodiment provides a method for preparing a compound represented by Chemical Formula 1, the method comprising: as shown in the following reaction scheme 1,

[0024] preparing a compound represented by Chemical Formula 1B by reacting the compound represented by Chemical Formula 1A with hydroxide ions (OH-); and

[0025] The compound represented by Chemical Formula 1 is prepared by reacting the compound represented by Chemical Formula 1B with the compound represented by Chemical Formula 1C.

[0026] [Reaction Scheme 1]

[0027]

[0028] Another embodiment provides a pharmaceutical composition for preventing or treating a cancer disease, the pharmaceutical composition comprising the compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0029] Another embodiment provides a health functional food composition comprising the compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0030] Another embodiment provides a method for treating a cancer disease, comprising administering a compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof to an individual or subject in need thereof.

[0031] Another embodiment provides a compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for treating a cancer disease.

[0032] Another embodiment provides use of the compound, its stereoisomer, its hydrate or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer diseases. Beneficial Effects

[0033] The present disclosure relates to 3,4-dihydroquinoxaline-2-carboxamide derivative compounds and pharmaceutical compositions for preventing or treating cancer diseases comprising the compounds. Since the compounds have an excellent effect of selectively inhibiting HDAC8 among histone deacetylases (HDACs), they can be usefully used as selective inhibitors of HDAC8 or pharmaceutical compositions for preventing or treating cancer diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1The graph shows the results confirming the growth inhibitory effect on prostate cancer cells PC-3, using PCI-34051 (known as an HDAC8 inhibitor), N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide (the compound of Example 27), and N-(4-fluoro-1H-benzo[d]imidazol-2-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide (the compound of Example 35).

[0035] Figure 2 : is a graph showing the results of confirming the anticancer efficacy by measuring the volume of tumors extracted from a mouse model transplanted with a prostate cancer cell line PC-3 during administration of the compound of Example 27.

[0036] Figure 3 This is a graph showing the results of confirming the anticancer efficacy by measuring the weight of tumors extracted from the mouse model 12 days after the administration of the compound of Example 27.

[0037] Figure 4 This is a graph showing the results of observing a decrease in tumor volume by photographing a tumor extracted from a mouse model 12 days after administration of the compound of Example 27.

[0038] Figure 5 This is a graph showing the results of measuring the change in body weight of the mouse model during administration of the compound of Example 27.

[0039] Figure 6 This is a graph showing the results of confirming the growth inhibitory effect on liver cancer cell Huh-7 using the compounds of Example 27 and Example 35.

[0040] Figure 7 is a graph showing data for evaluating the effectiveness of the compound of Example 27 against liver cancer. DETAILED DESCRIPTION

[0041] The embodiments described herein may be modified into various other forms, and the technology according to one embodiment is not limited to the embodiments described below. In addition, an embodiment example is provided to explain the present disclosure more comprehensively to a person of ordinary skill in the art. In addition, unless otherwise expressly stated, throughout the specification, "comprising / containing" or "including" an element means that other elements may be further included without excluding other elements.

[0042] As used herein, the numerical range includes the lower limit and the upper limit and all values ​​within the range, the increments logically derived from the shape and width of the defined range, all double-defined values, and all possible combinations of upper and lower limits of the numerical range defined in different forms. As an example, if the content of the composition is defined as 10% to 80% or 20% to 50%, the numerical range of 10% to 50% or 50% to 80% should also be interpreted as described herein. Unless otherwise specified herein, values ​​outside the numerical range that may appear due to experimental errors or numerical rounding are also included in the defined numerical range.

[0043] Hereinafter, unless otherwise specified herein, "about" may be considered a value within 30%, 25%, 20%, 15%, 10%, or 5% of a specified value.

[0045] One embodiment provides a compound represented by the following Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a salt thereof.

[0046] [Chemical formula 1]

[0047]

[0048] In Chemical Formula 1,

[0049] R 1 is unsubstituted or substituted C 5-8 Cycloalkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted heteroaryl containing 5 to 8 atoms of one or more heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted fused heteroaryl containing 8 to 10 atoms of one or more heteroatoms selected from the group consisting of N, O and S, or C 1-15 Alkenyl,

[0050] Among them, the substituted C 5-8 The cycloalkyl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl and C 1-8 Alkylcarbonyloxy,

[0051] Substituted C 6-10The aryl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 6-10 Aryl, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl, C 1-8 alkylcarbonyloxy, and a heteroaryl group of 5 to 8 atoms containing one or more heteroatoms selected from the group consisting of N, O and S,

[0052] The 5 to 8-atom substituted heteroaryl is substituted by halogen, or by a C 6-10 Aryl substituted, and

[0053] The substituted fused heteroaryl of 8 to 10 atoms is substituted by one or more substituents selected from the group consisting of: -OH, halogen, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl and C 1-8 Alkylcarbonyloxy;

[0054] R 2 and R 3 are each independently -H, halogen, or C 1-10 Alkyl; and

[0055] R 4 C 1-8 Alkyl, or C substituted with two or more -OH 3-10 Alkyl; and

[0056] L 1 For key or C 1-10 Alkylene.

[0057] In one embodiment, the alkyl group, alkoxy group, etc. may include a linear or branched alkyl group or alkoxy group, etc.

[0058] In one embodiment, the halogen may be I, Br, Cl or F.

[0059] In one embodiment, the term "substituted" may mean that one or more, two or more, one or two substituents are substituted with one or more, or two or more types of the listed substituents.

[0060] In one embodiment, a fused heteroaryl may include a ring in which an aryl or cycloalkyl group is fused to a heteroaryl group.

[0061] In one embodiment, R 1 It can be unsubstituted or substituted C 5-6 Cycloalkyl, unsubstituted or substituted C 6-8 aryl, unsubstituted or substituted heteroaryl containing 5 to 6 atoms of one or more heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted fused heteroaryl containing 8 to 10 atoms of one or more heteroatoms selected from the group consisting of N, O and S, or C 5-15 Alkenyl,

[0062] Among them, the substituted C 5-6 The cycloalkyl group may be substituted with one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxycarbonyl C 1-3 Alkyl and C 1-6 Alkylcarbonyloxy,

[0063] Substituted C 6-8 The aryl group may be substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 6-8 Aryl, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxycarbonyl C 1-3 Alkyl, C 1-6 alkylcarbonyloxy, and a heteroaryl group of 5 to 6 atoms containing one or more heteroatoms selected from the group consisting of N, O and S,

[0064] The substituted heteroaryl of 5 to 6 atoms may be substituted by halogen, or by C 6-8 Aryl substituted, and

[0065] The substituted fused heteroaryl of 8 to 10 atoms may be substituted by one or more substituents selected from the group consisting of: -OH, halogen, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxycarbonyl C 1-3 Alkyl and C 1-6 Alkylcarbonyloxy;

[0066] Alternatively, in one embodiment, R 1 It can be unsubstituted or substituted C 5-6 Cycloalkyl, unsubstituted or substituted C 6-8 aryl, unsubstituted or substituted heteroaryl containing 5 to 6 atoms of one or more heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted fused heteroaryl containing 8 to 10 atoms of one or more heteroatoms selected from the group consisting of N, O and S, or C 6-12 Alkenyl,

[0067] Among them, the substituted C 5-6 The cycloalkyl group may be substituted with one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-5 Alkyl, C 1-5 Haloalkyl and C 1-5 Alkoxycarbonyl,

[0068] Substituted C 6-8 The aryl group may be substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Halogenated alkyl, C6 aryl, C 1-5 Alkoxycarbonyl, C 1-5 Alkoxycarbonyl C 1-3 Alkyl, C 1-5 alkylcarbonyloxy, and a heteroaryl group of 5 to 6 atoms containing one or more heteroatoms selected from the group consisting of N, O and S,

[0069] The substituted heteroaryl of 5 to 6 atoms may be substituted by halogen, or by a C6 aryl substituted by halogen, and

[0070] The substituted fused heteroaryl of 8 to 10 atoms may be substituted by one or more substituents selected from the group consisting of: -OH, halogen, C 1-5 Alkoxycarbonyl, C 1-5 Alkoxycarbonyl C 1-3 Alkyl and C 1-5 Alkylcarbonyloxy.

[0071] Alternatively, in one embodiment, the substituted C 5-8 Cycloalkyl or C 5-6 The cycloalkyl group may be substituted by halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-5Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, -CH3, C 1-5 Haloalkyl, C 1-4 Haloalkyl, C 1-3 Haloalkyl, C 1-2 Haloalkyl, C1 haloalkyl, C 1-5 Alkoxy, C 1-5 Alkoxy, C 1-4 Alkoxy, C 1-3 Alkoxy, C 1-2 Alkoxy, -OCH3, C 1-5 Alkoxycarbonyl, C 1-4 Alkoxycarbonyl, C 1-3 Alkoxycarbonyl, C 1-2 Alkoxycarbonyl, -C(O)OCH3, C 1-5 Alkoxycarbonyl C 1-3 Alkyl, C 1-4 Alkoxycarbonyl C 1-2 Alkyl, C 1-3 Alkoxycarbonyl C 1-2 Alkyl, C 1-2 Alkoxycarbonyl C 1-2 Alkyl, -CH2CH2C(O)OCH3, -CH2C(O)OCH3, C 1-5 Alkylcarbonyloxy, C 1-4 Alkylcarbonyloxy, C 1-3 Alkylcarbonyloxy, C 1-2 Alkylcarbonyloxy, or -OC(O)CH3, and may be substituted by one or more, or two or more, or one or two substituents, the substituents being one, or two or more types of the substituents listed.

[0072] Alternatively, in one embodiment, C 6-10 Aryl or C 6-8 The aryl group may be substituted by halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, -CH3, C 1-5 Alkoxy, C 1-5 Alkoxy, C 1-4 Alkoxy, C 1-3 Alkoxy, C 1-2 Alkoxy, -OCH3, C 1-5 Haloalkyl, C 1-4 Haloalkyl, C 1-3 Haloalkyl, C1-2 Haloalkyl, C1 haloalkyl, C6 aryl (phenyl), C 1-5 Alkoxycarbonyl, C 1-4 Alkoxycarbonyl, C 1-3 Alkoxycarbonyl, C 1-2 Alkoxycarbonyl, -C(O)OCH3, C 1-5 Alkoxycarbonyl C 1-3 Alkyl, C 1-4 Alkoxycarbonyl C 1-2 Alkyl, C 1-3 Alkoxycarbonyl C 1-2 Alkyl, C 1-2 Alkoxycarbonyl C 1-2 Alkyl, -CH2CH2C(O)OCH3, -CH2C(O)OCH3, C 1-5 Alkylcarbonyloxy, C 1-4 Alkylcarbonyloxy, C 1-3 Alkylcarbonyloxy, C 1-2 Alkylcarbonyloxy, -OC(O)CH3, or a heteroaryl group of 5 to 6 atoms containing one or more heteroatoms selected from the group consisting of N, O and S, and may be substituted by one or more, or two or more, or one or two substituents, the substituents being one, or two or more types of the substituents listed.

[0073] Alternatively, in one embodiment, the 8 to 10-atom substituted fused heteroaryl may be substituted by: -OH, halogen, C 1-5 Alkoxycarbonyl, C 1-4 Alkoxycarbonyl, C 1-3 Alkoxycarbonyl, C 1-2 Alkoxycarbonyl, -C(O)OCH3, C 1-5 Alkoxycarbonyl C 1-3 Alkyl, C 1-4 Alkoxycarbonyl C 1-2 Alkyl, C 1-3 Alkoxycarbonyl C 1-2 Alkyl, C 1-2 Alkoxycarbonyl C 1-2 Alkyl, -CH2CH2C(O)OCH3, -CH2C(O)OCH3, C 1-5 Alkylcarbonyloxy, C 1-4 Alkylcarbonyloxy, C 1-3 Alkylcarbonyloxy, C 1-2 Alkylcarbonyloxy, or -OC(O)CH3, and may be substituted by one or more, or two or more, or one or two substituents, the substituents being one, or two or more types of the substituents listed.

[0074] In one embodiment, R1 Can be

[0075] In one embodiment, R 2 and R 3 can be independently -H, halogen, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl or -CH3.

[0076] In one embodiment, L 1 Can be key, C 1-5 Alkylene, C 1-4 Alkylene, C 1-3 Alkylene or C 1-2 Alkylene.

[0077] In one embodiment, R 4 Can be C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, -CH3, or C substituted by 1 or more, 2 or more, 3 to 5 or 4 -OH 3-5 Or, more specifically, R 4 Can be

[0078] In one embodiment, the compound represented by Chemical Formula 1 may be a compound represented by the following Chemical Formula 2:

[0079] [Chemical formula 2]

[0080]

[0081] At this time, the R defined above 1 , R 2 , R 3 and L 1 The same applies to R 12 , R 22 , R 32 and L 12 .

[0082] Specifically, for example, R 12 is unsubstituted or substituted C 5-8 Cycloalkyl, unsubstituted or substituted C 6-10aryl, unsubstituted or substituted heteroaryl containing 5 to 8 atoms of one or more heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted fused heteroaryl containing 8 to 10 atoms of one or more heteroatoms selected from the group consisting of N, O and S, or C 1-15 Alkenyl,

[0083] Among them, the substituted C 5-8 The cycloalkyl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl and C 1-8 Alkylcarbonyloxy,

[0084] Substituted C 6-10 The aryl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 6-10 Aryl, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl, C 1-8 alkylcarbonyloxy, and a heteroaryl group of 5 to 8 atoms containing one or more heteroatoms selected from the group consisting of N, O and S,

[0085] The 5 to 8-atom substituted heteroaryl is substituted by halogen, or by a C 6-10 Aryl substituted, and

[0086] The substituted fused heteroaryl of 8 to 10 atoms is substituted by one or more substituents selected from the group consisting of: -OH, halogen, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl and C 1-8 Alkylcarbonyloxy;

[0087] R 22 and R 32 are independently -H, halogen or C 1-10 Alkyl; and

[0088] L12 Can be key or C 1-10 Alkylene.

[0089] One embodiment may include all stereoisomers of the compound represented by Chemical Formula 2. For example, the compound represented by Chemical Formula 2 may include a stereoisomeric compound represented by the following Chemical Formula 2A. However, the following Chemical Formula 2A describes only one example of various stereoisomeric compounds and is not necessarily limited to the following compounds.

[0090] [Chemical Formula 2A]

[0091]

[0092] In one embodiment, the compound represented by Chemical Formula 1 may be a compound represented by Chemical Formula 3 below.

[0093] [Chemical formula 3]

[0094]

[0095] At this time, the R defined above 1 , R 2 , R 3 and L 1 The same applies to R 13 , R 23 , R 33 and L 13 .

[0096] Specifically, for example, R 13 is unsubstituted or substituted C 6-10 aryl, or an unsubstituted or substituted fused heteroaryl group of 8 to 10 atoms containing one or more heteroatoms selected from the group consisting of N, O and S.

[0097] Among them, the substituted C 6-10 The aryl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl and C 1-8 Alkylcarbonyloxy,

[0098] The substituted fused heteroaryl of 8 to 10 atoms is substituted with one or more substituents selected from the group consisting of -OH and halogen;

[0099] R 23 and R33 are independently -H, halogen or C 1-10 Alkyl; and

[0100] L 13 Can be key or C 1-10 Alkylene.

[0101] In one embodiment, the compound represented by Chemical Formula 1 may be any one selected from the following compound group.

[0102] (1) N-(4-methoxybenzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0103] (2) 6,7-dimethyl-N-(4-methylbenzyl)-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0104] (3) 6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-N-(4-(trifluoromethyl)benzyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0105] (4) N-(4-fluorobenzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0106] (5) 6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-N-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0107] (6) N-([1,1'-biphenyl]-4-ylmethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0108] (7) N-(3,5-dichlorobenzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0109] (8) N-(3,4-dichlorobenzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0110] (9) N-(2,4-dichlorophenethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0111] (10) N-(3-(4-bromophenyl)isoxazol-5-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0112] (11) N-(5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0113] (12) N-(3-(4-bromophenyl)-1H-pyrazol-5-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0114] (13) N-(4-(4-bromophenyl)thiazol-2-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0115] (14) N-((E)-3,7-dimethyloct-2,6-dien-1-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0116] (15) methyl 2-(4-((6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)methyl)phenyl)acetate;

[0117] (16) methyl 3-((6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)methyl)benzoate;

[0118] (17) N-(2-(1H-benzo[d]imidazol-2-yl)ethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0119] (18) methyl 4-((6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)methyl)benzoate;

[0120] (19) methyl 2-(3-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)phenyl)acetate;

[0121] (20) methyl 4-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)benzoate;

[0122] (21) N-(3-(1H-benzo[d]imidazol-2-yl)propyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0123] (22) N-((1H-indol-6-yl)methyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0124] (23) N-(4-(1H-imidazol-1-yl)phenyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0125] (24) N-((1H-benzo[d]imidazol-2-yl)methyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0126] (25) N-(3-1H-imidazol-1-yl)propyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0127] (26) N-(3-(1H-indol-1-yl)propyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0128] (27) N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0129] (28) N-(3-(1H-benzo[d]imidazol-1-yl)propyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0130] (29) N-(2-(1H-indol-2-yl)ethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0131] (30) methyl 3-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)-4-methylbenzoate;

[0132] (31) N-(3-(1H-indol-3-yl)propyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0133] (32) N-(1H-indol-5-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0134] (33) 3-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)cyclopentane-1-carboxylic acid methyl ester;

[0135] (34) N-((1H-benzo[d]imidazol-5-yl)methyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0136] (35) N-(4-fluoro-1H-benzo[d]imidazol-2-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0137] (36) N-(4-bromo-1H-benzo[d]imidazol-2-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0138] (37) N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0139] (38) N-(2-(4-fluoro-1H-benzo[d]imidazol-2-yl)ethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0140] (39) N-(4-hydroxy-1H-benzo[d]imidazol-2-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0141] (40) 3-(2-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)ethyl)-1H-indol-5-yl pivalate;

[0142] (41) N-(2-(5-Hydroxy-1H-indol-3-yl)ethyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide;

[0143] (42) N-(2-(4-fluoro-1H-benzo[d]imidazol-2-yl)ethyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide;

[0144] (43) N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide;

[0145] (44) 4-methyl-3-(4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)benzoic acid methyl ester;

[0146] (45) N-(5-(Hydroxycarbamoyl)-2-methylphenyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide;

[0147] (46) N-(3-(2-(hydroxyamino)-2-oxoethyl)phenyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0148] (47) N-(4-(Hydroxycarbamoyl)benzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0149] (48) N-(4-(Hydroxycarbamoyl)phenyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0150] (49) N-(4-(2-(hydroxyamino)-2-oxoethyl)benzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0151] (50) N-(3-(Hydroxycarbamoyl)benzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0152] (51) N-(5-(hydroxycarbamoyl)-2-methylphenyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; and

[0153] (52) N-(3-(Hydroxycarbamoyl)cyclopentyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide.

[0154] In one embodiment, the compound represented by Chemical Formula 1 can be used in the form of a pharmaceutically acceptable salt, and as a salt, an acid addition salt formed from a pharmaceutically acceptable free acid is useful. Acid addition salts can be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc.; non-toxic organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids and alkanedioic acids, aromatic acids, aliphatic sulfonic acids and aromatic sulfonic acids, etc.; organic acids such as trifluoroacetic acid, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. These types of pharmaceutically nontoxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, decanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioic acid salt, hexane-1,6-dioic acid salt, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

[0156] One embodiment provides a method for preparing the compound represented by Chemical Formula 1.

[0157] A method for preparing a compound represented by Chemical Formula 1 according to an embodiment is shown in the following Reaction Scheme 1,

[0158] preparing a compound represented by Chemical Formula 1B by reacting the compound represented by Chemical Formula 1A with hydroxide ions (OH-); and

[0159] The compound represented by Chemical Formula 1 is prepared by reacting the compound represented by Chemical Formula 1B with the compound represented by Chemical Formula 1C.

[0160] [Reaction Scheme 1]

[0161]

[0162] In reaction scheme 1, the above definition can be applied to R 1 To R 4 and L 1Therefore, Chemical Formula 1 may be Chemical Formula 2 or Chemical Formula 3, R 1 To R 3 and L 1 Can be R 12 To R 32 and L 12 , or R 13 To R 33 and L 13 .

[0163] The step of reacting with hydroxide ions is a step of reacting the compound represented by Chemical Formula 1A with a compound containing hydroxide ions. For example, alkaline compounds such as NaOH, KOH, Ba(OH)2, Ca(OH)2, NH4OH, Mg(OH)2, or H2O (hydrolysis reaction) can be used; however, this is only an example and is not limited to the use of the above compounds.

[0165] Another embodiment provides a pharmaceutical composition for preventing or improving a cancer disease, the pharmaceutical composition comprising the compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0166] The cancer disease can be selected from the group consisting of prostate cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, colon cancer, skin cancer, head and neck cancer, brain cancer, laryngeal cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer and rectal cancer.

[0167] In one embodiment, the pharmaceutical composition can selectively inhibit histone deacetylase 8 (HDAC8), and can prevent or treat cancer diseases by selectively inhibiting HDAC8. The pharmaceutical composition according to one embodiment has an excellent effect of selectively inhibiting HDAC8 in HDAC, thereby minimizing unnecessary side effects, and can therefore be used as a substitute for currently known HDAC8 inhibitor compounds (drugs).

[0168] In one embodiment, the composition comprising the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is not limited to the treatment or prevention of cancer diseases, and other cancers that exert anti-cancer effects by selectively inhibiting HDAC8. Therefore, the composition can be a pharmaceutical composition for preventing or treating HDAC8-related cancers, or can be an HDAC8 inhibitor.

[0169] The compound represented by Chemical Formula 1 or its pharmaceutically acceptable salt can be administered by various oral and parenteral preparations during clinical administration. In terms of preparations, conventionally used diluents or excipients (such as fillers, extenders, adhesives, wetting agents, disintegrants and surfactants) are used to prepare. Solid preparations for oral administration include tablets, pills, acid agents, granules and capsules, etc., and such solid preparations can be prepared by mixing at least one or more excipients (such as starch, calcium carbonate, sucrose, lactose and gelatin) in addition to one or more compounds. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to commonly used simple diluents (such as water and liquid paraffin), various excipients such as wetting agents, sweeteners, aromatics and preservatives may also be included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions and emulsions. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils (eg, olive oil) and injectable esters (eg, ethyl oleate) can be used.

[0170] The pharmaceutical composition comprising the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally by subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.

[0171] At this time, in order to prepare a preparation for parenteral administration, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water and a stabilizer or a buffer to prepare a solution or a suspension, which can be prepared in the form of a unit dose of an ampoule or a vial. The composition may be sterile and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifying agents, salts and / or buffers for adjusting osmotic pressure, and other therapeutically useful substances, and may be formulated according to conventional mixing, granulation or coating methods.

[0172] Preparations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsions, syrups, granules, elixirs, lozenges, etc., and in addition to the active ingredient, such preparations also contain diluents (e.g., lactose, glucose, sucrose, mannitol, sorbitol, cellulose and / or glycine) and lubricants (e.g., silicon dioxide, talc, stearic acid and its magnesium or calcium salt and / or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidone, etc., and, depending on the circumstances, may contain disintegrants such as starch, agar, alginic acid or its sodium salt, etc., or effervescent mixtures and / or absorbents, colorants, flavorings and sweeteners.

[0173] Another embodiment provides a selective inhibitor of HDAC8, comprising the compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a salt thereof as an active ingredient.

[0175] Another embodiment provides a health functional food composition for preventing or improving cancer diseases, comprising the compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a salt thereof as an active ingredient.

[0176] The compound represented by Chemical Formula 1 according to one embodiment can be directly added to food, or used together with other foods or food ingredients, and can be used appropriately according to conventional methods. The mixing amount of the active ingredient can be appropriately determined according to the purpose of use (prevention or improvement). In general, the amount of the compound in the health food can be 0.1 parts by weight to 90 parts by weight of the total weight of the food. However, in the case of long-term intake for health and hygiene purposes or health management, the amount may be lower than the above range, and since there is no problem in terms of safety, the active ingredient can be used in an amount exceeding the above range.

[0177] In addition, the health functional food composition according to one embodiment has no particular limitation on other ingredients except the above-mentioned compounds, and may contain various flavoring agents or natural carbohydrates as additional ingredients like ordinary beverages.

[0178] In addition, it may contain various nutrients, vitamins, minerals (electrolytes), flavorings (such as synthetic flavorings and natural flavorings), coloring agents and fillers (cheese, chocolate, etc.), pectin acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.

[0180] One embodiment provides a method for treating a cancer disease, comprising administering a compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof to an individual or subject in need thereof.

[0181] One embodiment provides a compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for treating a cancer disease.

[0182] One embodiment provides use of the compound, its stereoisomer, its hydrate or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer diseases. Example

[0183] Hereinafter, embodiments and experimental examples will be described in detail below. However, the embodiments and experimental examples described below are only illustrative, and the technology described in this specification is not limited thereto.

[0185] The compounds of Examples 1 to 40 were prepared according to Reaction Scheme A below.

[0186] [Reaction Scheme A]

[0187]

[0188] In Reaction Scheme A, -R of Compound III is the following a1 to a40.

[0189]

[0190] Specific methods for preparing Examples 1 to 40 are described below.

[0192] <Example 1> Preparation of N-(4-methoxybenzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0193] After adding an equivalent amount of aromatic amine (III, R = a1) to a mixture of 6,7-dimethyl-3-oxo-4-((2S, 3S, 4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxylic acid (II) in DMF solvent, 1.2 equivalents of 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and 5 equivalents of N,N-diisopropylethylamine (DIPEA) were slowly added, and stirred at room temperature for 4 hours. The resulting mixture was purified using preparative HPLC (solvent system: acetonitrile, water) to obtain the compound of Example 1 as a yellow solid (15 mg, yield 37.4%).

[0194]

[0195] <Example 2> Preparation of 6,7-dimethyl-N-(4-methylbenzyl)-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0196] The compound of Example 2 (6 mg, yield 23.2%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a2) was used instead of aromatic amine (III, R=a1).

[0197]

[0198] <Example 3> Preparation of 6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-N-(4-(trifluoromethyl)benzyl)-3,4-dihydroquinoxaline-2-carboxamide

[0199] The compound of Example 3 (7 mg, yield 24.2%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a3) was used instead of aromatic amine (III, R=a1).

[0200]

[0201] <Example 4> Preparation of N-(4-fluorobenzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0202] The compound of Example 4 (8 mg, yield 30.7%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a4) was used instead of aromatic amine (III, R=a1).

[0203] ESI LC / MS: m / z calcd.for: C 23 H 27 FN3O6[M+H] + : 460.19; found 460.20, 1 H NMR (CD3OD, 400MHz) 7.77 (s, 1H), 7.66 (s, 1H), 7.45-7.41 (m, 2H), 7.08-7.04 (m, 2H), 4.76 (q, J=10.52Hz, 1H), 4.64 ( s, 2H), 4.43 (d, J=12.68Hz, 1H), 4.27-4.25 (m, 1H), 3.82-3.75 (m, 3H), 3.69-3.65 (m, 1H), 2.46 (s, 3H), 2.38 (s, 3H).

[0204] <Example 5> Preparation of (6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-N-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinoxaline-2-carboxamide

[0205] The compound of Example 5 (11 mg, yield 24.2%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a5) was used instead of aromatic amine (III, R=a1).

[0206]

[0207] <Example 6> Preparation of N-([1,1′-biphenyl]-4-ylmethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0208] The compound of Example 6 (5 mg, yield 22.7%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a6) was used instead of aromatic amine (III, R=a1).

[0209]

[0210] <Example 7> Preparation of N-(3,5-dichlorobenzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0211] The compound of Example 7 (6 mg, yield 27.6%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a7) was used instead of aromatic amine (III, R=a1).

[0212]

[0213] <Example 8> Preparation of N-(3,4-dichlorobenzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0214] The compound of Example 8 (11 mg, yield 29.4%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a8) was used instead of aromatic amine (III, R=a1).

[0215]

[0216] <Example 9> Preparation of N-(2,4-dichlorophenethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0217] The compound of Example 9 (8 mg, yield 26.9%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a9) was used instead of aromatic amine (III, R=a1).

[0218]

[0219] <Example 10> Preparation of N-(3-(4-bromophenyl)isoxazol-5-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0220] The compound of Example 10 (6 mg, yield 18.4%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a10) was used instead of aromatic amine (III, R=a1).

[0221]

[0222] <Example 11> Preparation of N-(5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0223] The compound of Example 11 (10 mg, yield 29.9%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a1 1) was used instead of aromatic amine (III, R=a1).

[0224]

[0225] <Example 12> Preparation of N-(3-(4-bromophenyl)-1H-pyrazol-5-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0226] The compound of Example 12 (15 mg, yield 23.1%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a12) was used instead of aromatic amine (III, R=a1).

[0227]

[0228] <Example 13> Preparation of N-(4-(4-bromophenyl)thiazol-2-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0229] The compound of Example 13 (6 mg, yield 17.9%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a13) was used instead of aromatic amine (III, R=a1).

[0230]

[0231] <Example 14> Preparation of N-((E)-3,7-dimethylocta-2,6-dien-1-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0232] The compound of Example 14 (32 mg, yield 66.5%) was obtained as a pale yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a14) was used instead of aromatic amine (III, R=a1).

[0233]

[0234] <Example 15> Preparation of methyl 2-(4-((6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)methyl)phenyl)acetate

[0235] The compound of Example 15 (11 mg, yield 15.09%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a15) was used instead of aromatic amine (III, R=a1).

[0236]

[0237] <Example 16> Preparation of methyl 3-((6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)methyl)benzoate

[0238] The compound of Example 16 (15 mg, yield 21.2%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a16) was used instead of aromatic amine (III, R=a1).

[0239]

[0240]

[0241] <Example 17> Preparation of N-(2-(1H-benzo[d]imidazol-2-yl)ethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0242] The compound of Example 17 (118 mg, yield 55.9%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a17) was used instead of aromatic amine (III, R=a1).

[0243]

[0244]

[0245] <Example 18> Preparation of methyl 4-((6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)methyl)benzoate

[0246] The compound of Example 18 (21 mg, yield 14.8%) was obtained as a pale yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a18) was used instead of aromatic amine (III, R=a1).

[0247]

[0248]

[0249] <Example 19> Preparation of methyl 2-(3-((6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)phenyl)acetate

[0250] The compound of Example 19 (112 mg, yield 52.57%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a19) was used instead of aromatic amine (III, R=a1).

[0251]

[0252]

[0253] <Example 20> Preparation of methyl 4-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)benzoate

[0254] The compound of Example 20 (32 mg, yield 46.6%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a20) was used instead of aromatic amine (III, R=a1).

[0255]

[0256]

[0257] <Example 21> Preparation of N-(3-(1H-benzo[d]imidazol-2-yl)propyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0258] The compound of Example 21 (6 mg, yield 8.3%) was obtained as a pale yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a21) was used instead of aromatic amine (III, R=a1).

[0259]

[0260] <Example 22> Preparation of N-((1H-indol-6-yl)methyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0261] The compound of Example 22 (10 mg, yield 14.67%) was obtained as a pale yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a22) was used instead of aromatic amine (III, R=a1).

[0262]

[0263] <Example 23> Preparation of N-(4-(1H-imidazol-1-yl)phenyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0264] The compound of Example 23 (34 mg, yield 48.5%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a23) was used instead of aromatic amine (III, R=a1).

[0265]

[0266]

[0267] <Example 24> Preparation of N-((1H-benzo[d]imidazol-2-yl)methyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0268] The compound of Example 24 (7.8 mg, yield 14.3%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a24) was used instead of aromatic amine (III, R=a1).

[0269]

[0270] <Example 25> Preparation of N-(3-(1H-imidazol-1-yl)propyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0271] The compound of Example 25 (9 mg, yield 21.9%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a25) was used instead of aromatic amine (III, R=a1).

[0272]

[0273] <Example 26> Preparation of N-(3-(1H-indol-1-yl)propyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0274] The compound of Example 26 (20 mg, yield 43.9%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a26) was used instead of aromatic amine (III, R=a1).

[0275]

[0276] <Example 27> Preparation of N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0277] The compound of Example 27 (8.5 mg, yield 18.8%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a27) was used instead of aromatic amine (III, R=a1).

[0278] ESI LC / MS: m / z calcd.for: C 26 H 30 N4O7[M+H] + : 511.21; found 511.27 1 H NMR (MeOD, 400MHz) δ7.81 (s, 1H), 7.70 (s, 1H), 7.18 (t, J=8.4Hz, 2H), 6.99 (s, 1H), 6.67 (d, J=7.96Hz, 1H), 4.78 (d, J=11.84Hz, 1H), 4.49 (d, J=12.52Hz, 1H), 4.29 (s, 1H), 3.83-3.71 (m, 6H), 3.10-3.05 (m, 2H), 2.50 (s, 3H), 2.41 (s, 3H), 2.83 (s, 2H), 2.50 (s, 3H), 2.41 (s, 3H).

[0279]

[0280] <Example 28> Preparation of N-(3-(1H-benzo[d]imidazol-1-yl)propyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0281] The compound of Example 28 (13 mg, yield 29.8%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a28) was used instead of aromatic amine (III, R=a1).

[0282]

[0283] <Example 29> Preparation of N-(2-(1H-indol-2-yl)ethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0284] The compound of Example 29 (21 mg, yield 49.1%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a29) was used instead of aromatic amine (III, R=a1).

[0285]

[0286] <Example 30> Preparation of methyl 3-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)-4-methylbenzoate

[0287] The compound of Example 30 (24.6 mg, yield 56.3%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a30) was used instead of aromatic amine (III, R=a1).

[0288]

[0289] <Example 31> Preparation of N-(3-(1H-indol-3-yl)propyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0287] The compound of Example 31 (20 mg, yield 44.3%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a31) was used instead of aromatic amine (III, R=a1).

[0291]

[0292] <Example 32> Preparation of N-(1H-indazol-5-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0293] The compound of Example 32 (2.8 mg, yield 6.10%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a32) was used instead of aromatic amine (III, R=a1).

[0294]

[0295] <Example 33> Preparation of methyl 3-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)cyclopentane-1-carboxylate

[0296] The compound of Example 33 (25 mg, yield 46%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a33) was used instead of aromatic amine (III, R=a1).

[0297]

[0298] <Example 34> Preparation of N-((1H-benzo[d]imidazol-5-yl)methyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0299] The compound of Example 34 (6 mg, yield 14.28%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a34) was used instead of aromatic amine (III, R=a1).

[0300]

[0301] <Example 35> Preparation of N-(4-fluoro-1H-benzo[d]imidazol-2-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0302] The compound of Example 35 (14 mg, yield 10.01%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a35) was used instead of aromatic amine (III, R=a1).

[0303]

[0304] <Example 36> Preparation of N-(4-bromo-1H-benzo[d]imidazol-2-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0305] The compound of Example 36 (10 mg, yield 11.68%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a36) was used instead of aromatic amine (III, R=a1).

[0306]

[0307] Preparation of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0308] The compound of Example 37 (50 mg, yield 63.3%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a37) was used instead of aromatic amine (III, R=a1).

[0309]

[0310] <Example 38> Preparation of N-(2-(4-fluoro-1H-benzo[d]imidazol-2-yl)ethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0311] The compound of Example 38 (35 mg, yield 29.2%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a38) was used instead of aromatic amine (III, R=a1).

[0312]

[0313] <Example 39> Preparation of N-(4-hydroxy-1H-benzo[d]imidazol-2-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0314] The compound of Example 39 (2 mg, yield 1.26%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a39) was used instead of aromatic amine (III, R=a1).

[0315]

[0316] <Example 40> Preparation of 3-(2-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)ethyl)-1H-indol-5-yl pivalate

[0317] The compound of Example 40 (6 mg, yield 34.7%) was obtained as a yellow solid in the same manner as in Example 1, except that aromatic amine (III, R=a40) was used instead of aromatic amine (III, R=a1).

[0318]

[0320] The compounds of Examples 41 to 45 were prepared by the method of Reaction Scheme B below.

[0321] [Reaction Scheme B]

[0322]

[0323] In Reaction Scheme B, -R of Compound VI is b1 to b3 below.

[0325] The specific preparation methods of Examples 41 to 45 are described below.

[0327] <Example 41> Preparation of N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide

[0328] In Reaction Scheme B, using Compound VI (R=b1), Example 41 (22 mg, 24% yield) was obtained as a yellow solid.

[0329]

[0330] <Example 42> Preparation of N-(2-(4-fluoro-1H-benzo[d]imidazol-2-yl)ethyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide

[0331] In Reaction Scheme B, using Compound VI (R = b2), Example 42 (28 mg, 38% yield) was obtained as a yellow solid.

[0332]

[0333] <Example 43> Preparation of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide

[0334] In Reaction Scheme B, using Compound VI (R = b3), Example 43 (22 mg, yield 10.5%) was obtained as a yellow solid.

[0335]

[0336] <Example 44> Preparation of methyl 4-methyl-3-(4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)benzoate

[0337] In Reaction Scheme B, methyl 3-amino-4-methylbenzoate was added to Compound V to give Example 44 (102 mg, 62.4% yield) as a yellow solid.

[0338] ESI LC / MS: m / z calcd.for: C 21 H 22 N3O4[M+H] + : 380.16; found 380.03.

[0339] <Example 45> Preparation of N-(5-(hydroxycarbamoyl)-2-methylphenyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide

[0340] After the compound of Example 44 was mixed with THF, the mixture was added to 0.5 equivalents of sodium cyanide and methanol solution. Then, 20 equivalents of 50% aqueous hydroxylamine solution were added, and the resulting mixture was stirred at room temperature for 16 hours. After the resulting mixed solution was concentrated under reduced pressure, the resulting residue was filtered through a microfilter and purified using preparative HLPC (solvent system: acetonitrile, water) to obtain the compound of Example 45 (2.9 mg, yield 13.84%) as a yellow solid.

[0341]

[0343] The compounds of Examples 46 to 52 were prepared by the method of Reaction Scheme C below.

[0344] [Reaction Scheme C]

[0345]

[0346] In Reaction Scheme C, -R of Compound I is c1 to c7 below.

[0347]

[0348] Specific preparation methods of Examples 46 to 52 are described below.

[0350] <Example 46> Preparation of N-(3-(2-(hydroxyamino)-2-oxoethyl)phenyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0351] In Reaction Scheme C, using Compound I (R = c1), Example 46 (7 mg, 46.6% yield) was obtained as a yellow solid.

[0352]

[0353] <Example 47> Preparation of N-(4-(hydroxycarbamoyl)benzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0354] In Reaction Scheme C, using Compound I (R = c2), Example 47 (3.1 mg, 30.9% yield) was obtained as a yellow solid.

[0355]

[0356] <Example 48> Preparation of N-(4-(hydroxycarbamoyl)phenyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0357] In Reaction Scheme C, using Compound I (R = c3), Example 48 (2.4 mg, 15.9% yield) was obtained as a yellow solid.

[0358]

[0359] <Example 49> Preparation of N-(4-(2-(hydroxyamino)-2-oxoethyl)benzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0360] In Reaction Scheme C, using Compound I (R = c4), Example 49 (1.2 mg, 13.2% yield) was obtained as a yellow solid.

[0361] ESI LC / MS: m / z calcd.for: C 25 H 30 N4O8[M+H] + : 515.52; found 515.24. 1 H NMR (CD3OD, 400MHz) 7.81 (s, 1H), 7.70 (s, 1H), 7.39 (d, J = 8.24Hz, 2H), 7.31 (d, J = 8.16Hz, 2H), 4.77 (q, J = 9.96Hz, 1H), 4.67 (s, 2H) , 4.47 (dd, J=13.64, 2.12Hz, 1H), 4.30-4.26 (m, 1H), 3.85-3.76 (m, 3H), 3.71-3.67 (m, 1H), 3.42 (s, 2H), 2.50 (s, 3H), 2.41 (s, 3H).

[0362] <Example 50> Preparation of N-(3-(hydroxycarbamoyl)benzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0363] In Reaction Scheme C, using Compound I (R = c5), Example 50 (1.5 mg, 14.9% yield) was obtained as a yellow solid.

[0364]

[0365] <Example 51> Preparation of N-(5-(hydroxycarbamoyl)-2-methylphenyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0366] In Reaction Scheme C, using Compound I (R = c6), Example 51 (3.2 mg, 21.9% yield) was obtained as a yellow solid.

[0367]

[0368] <Example 52> Preparation of N-(3-(hydroxycarbamoyl)cyclopentyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide

[0369] In Reaction Scheme C, using Compound I (R = c7), Example 52 (1.8 mg, 8.72% yield) was obtained as a yellow solid.

[0370]

[0372] The compounds of Examples 1 to 52 are summarized and presented in Table 1 below.

[0374] Table 1

[0375] <Comparative Example>

[0376] TSA (Trichostatin A), SAHA (suberoylanilide hydroxamic acid), and PCI-34051 (N-hydroxy-1-(4-methoxybenzyl)-1H-indole-6-carboxamide), which are known to inhibit HDAC8, were prepared as comparative examples.

[0377] TSA:

[0378] SAHA:

[0379] PCI-34051:

[0381] Cell culture

[0382] PC-3 (a human prostate cancer cell line) was cultured in RPMI1640 medium (10% fetal bovine serum, 1% penicillin-streptomycin) at 37°C and 5% CO2. All cells in the experiment were subcultured when they reached about 80% to 90% confluence, and only cells that were subcultured no more than 20 times were used.

[0384] Statistical analysis

[0385] All data are presented as mean ± standard deviation (SD) of at least three independent experiments, and the statistical significance of the differences was determined by unpaired Student's test using GrahPad Prism 5. A P value of less than 0.05 was considered statistically significant.

[0387] <Experimental Example 1> HDAC8 inhibitory activity analysis (in vitro) - RFU analysis

[0388] In order to confirm the activity of the compound of the embodiment on the HDAC enzyme, the HDAC fluorescence detection kit of BPS bioscience was used for measurement, and the HDAC substrate 2A was diluted to a concentration of 20 μM in the buffer and used for analysis. The compound of the embodiment was diluted to 1 mM (1% DMSO concentration) with DMSO, and diluted 1 / 10 by the detection buffer to obtain a final concentration of 10 μM for preparation. In a 96-well black round bottom plate, 5 μL of the diluted compound of the embodiment, 5 μL of the diluted HDAC substrate 2A, 5 μL of BSA (1 mg / mL), 5 μL of HDAC8 enzyme diluted to an appropriate concentration and 30 μL of detection buffer were added, and the enzyme reaction was carried out at 37 ° C for 30 minutes. The blank does not contain HDAC8 enzyme; the positive control is 100% of the HDAC8 enzyme activity value under the condition of 1% DMSO; the inhibitor control uses TSA compounds, SAHA compounds and PCI-34051 compounds. Subsequently, 50 μL of 2X HDAC developer was added to each well. After 15 minutes of reaction at room temperature, the fluorescence values ​​at the excitation wavelength of 350-380 nm and the emission wavelength of 440-460 nm were measured with a microplate reader (Synergy Neo). The result value was calculated by averaging the blank values, subtracting the average blank value from all values, and setting the positive control value to 100.

[0389] The results are shown in Table 2 below, which confirms that the 3,4-dihydroquinoxaline-2-carboxamide derivative compounds of the examples exhibit inhibitory activity against HDAC8, and in particular, the compounds of Examples 10, 27, 34, 35, 48, 49 and 51 exhibit inhibitory activity similar to that of known existing HDAC8 inhibitors TSA or SAHA.

[0391] Table 2 RFU(%) RFU(%) DMSO 1 00 TSA 13.83 SAHA 38.57 PCI-34051 I.86 4 85.71 7 54.79 8 85.37 9 66.28 10 16.61 11 63.24 12 58.97 24 42.03 27 7.62 33 69.48 34 34.05 35 8.23 47 53.58 48 10.48 49 35.15 50 51.23 51 5.81 52 41.96

[0392] <Experimental Example 2> Analysis of the Selective Inhibitory Effect on HDAC8

[0393] In order to confirm the selective inhibitory effect of the compounds of the embodiment on HDAC8, the inhibitory activity was measured using the HDAC fluorescence detection kit of BPS bioscience. For analysis, HDAC substrate 3 was diluted to a concentration of 200 μM in buffer and used for HDAC1, HDAC2, HDAC3, HDAC6 and HDAC10 detection; HDAC substrate 2A was diluted to a concentration of 200 μM in buffer and used for HDAC4, HDAC7, HDAC9 and HDAC11 detection; HDAC substrate 2A was diluted to a concentration of 20 μM in buffer and used for HDAC8 detection. For HDAC11 detection, the dedicated buffer contained in the kit was used alone, and the same buffer was used for other detections. The compound of the embodiment was diluted to 1 mM (1% DMSO concentration) with DMSO and diluted 1 / 10 by the detection buffer to obtain a final concentration of 10 μM for preparation. In a 96-well black round bottom plate, 5 μL of the diluted compound of the embodiment, 5 μL of the diluted HDAC substrate, 5 μL of BSA (1 mg / mL), 5 μL of HDAC enzyme diluted to an appropriate concentration and 30 μL of detection buffer were added, and the enzyme reaction was carried out at 37°C for 30 minutes. The blank does not contain HDAC enzyme; the positive control group uses 100% enzyme activity value under the condition of 1% DMSO; the inhibitor control uses TSA compound. Subsequently, 50 μL of 2X HDAC developer was added to each well. After reacting at room temperature for 15 minutes, the fluorescence values ​​at the excitation wavelength of 350-380 nm and at the emission wavelength of 440-460 nm were measured with a microplate reader (SynergyNeo). The result value is calculated by averaging the blank values, subtracting the average blank value from all values, and setting the positive control value for each HDAC enzyme to 100.

[0394] The results are shown in Table 3 below. As a result of the experiment, the known existing HDAC8 inhibitor TSA exhibited very high inhibitory effects not only on HDAC8 but also on HDAC1, HDAC2, HDAC6 and HDAC10, and also exhibited high inhibitory effects on HDAC3, HDAC4, HDAC7 and HDAC9, and thus could not obtain a selective inhibitory effect on HDAC8. On the other hand, the compound of Example 27 exhibited selectivity and excellent inhibitory activity only on HDAC8.

[0396] Table 3 DMSO (%) TSA(%) Example 27 (%) HDAC1 100 1.22 76.23 HDAC2 100 0.70 9I.24 HDAC3 1 00 21.38 73.14 HDAC4 100 18.83 98.24 HDAC6 100 1.11 43.66 HDAC7 100 8.91 91.19 HDAC8 100 11.05 14.05 HDAC9 100 21.46 66.46 HDAC10 100 1.21 87.15 HDAC11 100 59.06 97.30

[0397] <Experimental Example 3> Analysis of prostate cancer and liver cancer cell growth inhibitory activity

[0398] In order to analyze the inhibitory effect of the compounds of the examples on the growth of prostate cancer cells, PC-3 prostate cancer cells were treated with different concentrations of the compounds of Example 27 and Example 35 and PCI-34051, and then the cell viability was confirmed by CCK-8 assay on the first and second days. Specifically, PC-3 cells were cultured at 1×10 4 Cells / mL were distributed into 96-well plates. After 20 hours, different concentrations of PCI-34051, the compound of Example 27, and the compound of Example 35 were added and cultured in a 37°C, 5% CO2 incubator for 24 hours and 48 hours. After the culture, 10 μL of CCK-8 reagent was added and the absorbance was measured after 1 hour. The absorbance was measured at 450 nm using a microplate reader [BMG Labtech (Offenburg, Germany)]. The results are shown in Figure 1 It was confirmed that the known HDAC8 inhibitor PCI-34051 inhibited cancer cell viability in a concentration- and time-dependent manner, and the compound of Example 27 also effectively reduced the viability of prostate cancer cells in a concentration- and time-dependent manner, and showed a cancer cell viability inhibition rate superior to PCI-34051. The compound of Example 35 showed concentration-dependent inhibition of cancer cell viability after 24 hours, although cell viability was restored after 48 hours.

[0399] In addition, the growth inhibitory activity of liver cancer cells was analyzed. Huh-7 liver cancer cells were cultured at 1×10 4 Cells / mL were distributed into a 96-well plate. After 20 hours, different concentrations of PCI-34051, Example 27 and Example 35 were added and cultured at 37°C, 5% CO2 atmosphere for 24 hours and 48 hours. After culture, 100 μL of CellTiter-Glo luminescent cell viability detection reagent was added, and the luminescent signal was measured after 0.5 to 1 hour. The luminescent signal was measured using IVIS [PerkinElmer, (Waltham, USA)]. After the liver cancer cell line Huh-7 was treated with different concentrations of PCI-34051 (control), Example 27 and Example 35, the cell viability was confirmed on the first day using the CellTiter-Glo luminescent cell viability detection method. As a result, Figure 6 As shown, Example 27 and Example 35, like the control group, showed concentration-dependent inhibition of cancer cell viability.

[0401] <Experimental Example 4> Analysis of anticancer effects on prostate cancer and liver cancer

[0402] A prostate cancer model was established by subcutaneously transplanting PC-3 cell lines into nude mice, and the mice were divided into two groups (Group 1: vehicle administration group (10% DMSO, 30% PEG400, 60% DW), Group 2: 50 mg / kg Example 27 compound administration group). The drug was orally administered once a day for a total of 12 times. To evaluate the therapeutic efficacy, tumors were removed before drug administration and on the 3rd, 6th, 8th, 10th, 12th and 14th days after drug administration, and the tumor volume was measured. The tumor volume (mm 3 ) to calculate (tumor volume (mm 3 )=(A×B 2 ) / 2, where A = tumor long axis, B = tumor short axis), the results are shown in Figure 2 The vehicle-administered group (Group 1) showed significant tumor growth within 14 days after administration, while the Example 27 compound-administered group (Group 2) showed a significantly reduced tumor volume growth rate compared to Group 1, and statistical significance was confirmed (*p<0.05, compared to the vehicle).

[0403] At the same time, on the 12th day after drug administration, the tumor was removed and its weight was measured. The results are shown in Figure 3 , and took photos of the removed tumor, shown in Figure 4 The vehicle-administered group (Group 1) had significantly higher tumor weight than the Example 27 compound-administered group (Group 2), and statistical significance was also confirmed (***p<0.0005, compared with the vehicle).

[0404] Furthermore, when the body weight of the mice was examined during drug administration, no rapid weight loss was found ( Figure 5 ).

[0405] In addition, a liver cancer model was established by subcutaneously transplanting the Huh-7 cell line into nude mice. After the liver cancer model was established, the mice were divided into two groups (Group 1: vehicle administration group, Group 2: 50 mg / kg Example 27 compound administration group). The drug was administered once a day for a total of 12 times. To evaluate the therapeutic efficacy, tumor volume was measured before drug administration and on the 4th, 7th, 10th, 13th and 15th days after drug administration. The tumor volume (mm) was measured as follows: 3 ) to calculate (tumor volume (mm 3 )=(A×B 2 ) / 2, where A = tumor long axis, B = tumor short axis). Body weight was measured before administration and on the 4th, 7th, 10th, 13th and 15th day after drug administration during drug administration. Tumors were removed on the 15th day after drug treatment and body weight was measured.

[0406] As a result, the vehicle-administered group still showed significant tumor growth on day 15 after administration, but the 50 mg / kg Example 27 compound-administered group showed a tumor growth inhibitory effect, and statistical significance was confirmed (**p<0.005, compared with the vehicle) ( Figure 7 A). On the 15th day after drug administration, the tumor was removed and its weight was measured. Similar to the results of tumor volume measurement, the tumor weight of the vehicle group was significantly higher than that of the Example 27 compound administration group, and it was confirmed to be statistically significant (***p<0.0005, compared with the vehicle) ( Figure 7 B and Figure 7 C). No rapid weight loss was observed during drug administration ( Figure 7 D).

[0408] Although the present disclosure is described in detail through preferred embodiments and experimental examples, the scope of the present disclosure is not limited to the specific embodiments and should be interpreted according to the appended claims. In addition, those skilled in the art should understand that various modifications and variations can be made without departing from the scope of the present disclosure.

Claims

1. A compound represented by the following chemical formula 1, a stereoisomer thereof, a hydrate thereof or a salt thereof: [Chemical formula 1] in, In Chemical Formula 1, R 1 is unsubstituted or substituted C 5-8 Cycloalkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted heteroaryl containing 5 to 8 atoms of one or more heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted fused heteroaryl containing 8 to 10 atoms of one or more heteroatoms selected from the group consisting of N, O and S, or C 1-15 Alkenyl, Among them, the substituted C 5-8 The cycloalkyl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl and C 1-8 Alkylcarbonyloxy, Substituted C 6-10 The aryl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 6-10 Aryl, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl, C 1-8 alkylcarbonyloxy, and a heteroaryl group of 5 to 8 atoms containing one or more heteroatoms selected from the group consisting of N, O and S, The 5 to 8-atom substituted heteroaryl is substituted by halogen, or by a C 6-10 Aryl substituted, and The substituted fused heteroaryl of 8 to 10 atoms is substituted by one or more substituents selected from the group consisting of: -OH, halogen, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl and C 1-8 Alkylcarbonyloxy; R 2 and R 3 are each independently -H, halogen, or C 1-10 alkyl; R 4 C 1-8 Alkyl, or C substituted with two or more -OH 3-10 Alkyl; and L 1 For key or C 1-10 Alkylene.

2. The compound according to claim 1, its stereoisomer, its hydrate or its salt, wherein R 1 is unsubstituted or substituted C 5-6 Cycloalkyl, unsubstituted or substituted C 6-8 aryl, unsubstituted or substituted heteroaryl containing 5 to 6 atoms of one or more heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted fused heteroaryl containing 8 to 10 atoms of one or more heteroatoms selected from the group consisting of N, O and S, or C 5-15 Alkenyl, Among them, the substituted C 5-6 The cycloalkyl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxycarbonyl C 1-3 Alkyl and C 1-6 Alkylcarbonyloxy, Substituted C 6-8 The aryl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 6-8 Aryl, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxycarbonyl C 1-3 Alkyl, C 1-6 alkylcarbonyloxy, and a heteroaryl group of 5 to 6 atoms containing one or more heteroatoms selected from the group consisting of N, O and S, The 5- to 6-atom substituted heteroaryl is substituted by halogen, or by a C 6-8 Aryl substituted, and The substituted fused heteroaryl of 8 to 10 atoms is substituted by one or more substituents selected from the group consisting of: -OH, halogen, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxycarbonyl C 1-3 Alkyl and C 1-6 Alkylcarbonyloxy.

3. The compound according to claim 1, its stereoisomer, its hydrate or its salt, wherein R 1 is unsubstituted or substituted C 5-6 Cycloalkyl, unsubstituted or substituted C 6-8 aryl, unsubstituted or substituted heteroaryl containing 5 to 6 atoms of one or more heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted fused heteroaryl containing 8 to 10 atoms of one or more heteroatoms selected from the group consisting of N, O and S, or C 6-12 Alkenyl, Among them, the substituted C 5-6 The cycloalkyl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-5 Alkyl, C 1-5 Haloalkyl and C 1-5 Alkoxycarbonyl, Substituted C 6-8 The aryl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Halogenated alkyl, C6 aryl, C 1-5 Alkoxycarbonyl, C 1-5 Alkoxycarbonyl C 1-3 Alkyl, C 1-5 alkylcarbonyloxy, and a heteroaryl group of 5 to 6 atoms containing one or more heteroatoms selected from the group consisting of N, O and S, The 5- to 6-atom substituted heteroaryl is substituted by halogen, or is substituted by a C6 aryl substituted by halogen, and The substituted fused heteroaryl of 8 to 10 atoms is substituted by one or more substituents selected from the group consisting of: -OH, halogen, C 1-5 Alkoxycarbonyl, C 1-5 Alkoxycarbonyl C 1-3 Alkyl and C 1-5 Alkylcarbonyloxy.

4. The compound according to claim 1, its stereoisomer, its hydrate or its salt, wherein R 1 for 5. The compound according to claim 1, its stereoisomer, its hydrate or its salt, wherein R 2 and R 3 are independently -H, halogen or C 1-5 alkyl.

6. The compound according to claim 1, its stereoisomer, its hydrate or its salt, wherein L 1 is key or C 1-5 Alkylene.

7. The compound according to claim 1, its stereoisomer, its hydrate or its salt, wherein R 4 C 1-5 Alkyl, or C substituted with 3 to 5 -OH 3-8 alkyl.

8. The compound according to claim 1, its stereoisomer, hydrate or salt thereof, wherein The compound represented by Chemical Formula 1 is a compound represented by the following Chemical Formula 2: [Chemical formula 2] Wherein, in Chemical Formula 2, R 12 is unsubstituted or substituted C 5-8 Cycloalkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted heteroaryl containing 5 to 8 atoms of one or more heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted fused heteroaryl containing 8 to 10 atoms of one or more heteroatoms selected from the group consisting of N, O and S, or C 1-15 Alkenyl, Among them, the substituted C 5-8 The cycloalkyl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl and C 1-8 Alkylcarbonyloxy, Substituted C 6-10 The aryl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 6-10 Aryl, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl, C 1-8 alkylcarbonyloxy, and a heteroaryl group of 5 to 8 atoms containing one or more heteroatoms selected from the group consisting of N, O and S, The 5 to 8-atom substituted heteroaryl is substituted by halogen, or by a C 6-10 Aryl substituted, and The substituted fused heteroaryl of 8 to 10 atoms is substituted by one or more substituents selected from the group consisting of: -OH, halogen, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl and C 1-8 Alkylcarbonyloxy; R 22 and R 32 are independently -H, halogen or C 1-10 Alkyl; and L 12 For key or C 1-10 Alkylene.

9. The compound according to claim 1, its stereoisomer, its hydrate or its salt, wherein The compound represented by Chemical Formula 1 is a compound represented by the following Chemical Formula 3: [Chemical formula 3] Among them, in chemical formula 3, R 13 is unsubstituted or substituted C 6-10 aryl, or an unsubstituted or substituted fused heteroaryl group of 8 to 10 atoms containing one or more heteroatoms selected from the group consisting of N, O and S, Among them, the substituted C 6-10 The aryl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-10 Alkyl, C 1-10 Haloalkyl, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl and C 1-8 Alkylcarbonyloxy, The substituted fused heteroaryl of 8 to 10 atoms is substituted with one or more substituents selected from the group consisting of -OH and halogen; R 23 and R 33 are independently -H, halogen or C 1-10 Alkyl; and L 13 For key or C 1-10 Alkylene.

10. The compound according to claim 1, its stereoisomer, its hydrate or its salt, wherein The compound represented by Chemical Formula 1 is any one selected from the following compound groups: (1) N-(4-methoxybenzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (2) 6,7-dimethyl-N-(4-methylbenzyl)-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (3) 6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-N-(4-(trifluoromethyl)benzyl)-3,4-dihydroquinoxaline-2-carboxamide; (4) N-(4-fluorobenzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (5) 6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-N-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinoxaline-2-carboxamide; (6) N-([1,1'-biphenyl]-4-ylmethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (7) N-(3,5-dichlorobenzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (8) N-(3,4-dichlorobenzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (9) N-(2,4-dichlorophenethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (10) N-(3-(4-bromophenyl)isoxazol-5-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (11) N-(5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (12) N-(3-(4-bromophenyl)-1H-pyrazol-5-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (13) N-(4-(4-bromophenyl)thiazol-2-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (14) N-((E)-3,7-dimethyloct-2,6-dien-1-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (15) methyl 2-(4-((6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)methyl)phenyl)acetate; (16) methyl 3-((6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)methyl)benzoate; (17) N-(2-(1H-benzo[d]imidazol-2-yl)ethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (18) methyl 4-((6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)methyl)benzoate; (19) methyl 2-(3-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)phenyl)acetate; (20) methyl 4-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)benzoate; (21) N-(3-(1H-benzo[d]imidazol-2-yl)propyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (22) N-((1H-indol-6-yl)methyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (23) N-(4-(1H-imidazol-1-yl)phenyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (24) N-((1H-benzo[d]imidazol-2-yl)methyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (25) N-(3-1H-imidazol-1-yl)propyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (26) N-(3-(1H-indol-1-yl)propyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (27) N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (28) N-(3-(1H-benzo[d]imidazol-1-yl)propyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (29) N-(2-(1H-indol-2-yl)ethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (30) methyl 3-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)-4-methylbenzoate; (31) N-(3-(1H-indol-3-yl)propyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (32) N-(1H-indol-5-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (33) 3-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)cyclopentane-1-carboxylic acid methyl ester; (34) N-((1H-benzo[d]imidazol-5-yl)methyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (35) N-(4-fluoro-1H-benzo[d]imidazol-2-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (36) N-(4-bromo-1H-benzo[d]imidazol-2-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (37) N-(2-(5-chloro-1H-indol-3-yl)ethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (38) N-(2-(4-fluoro-1H-benzo[d]imidazol-2-yl)ethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (39) N-(4-hydroxy-1H-benzo[d]imidazol-2-yl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (40) 3-(2-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)ethyl)-1H-indol-5-yl pivalate; (41) N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide; (42) N-(2-(4-fluoro-1H-benzo[d]imidazol-2-yl)ethyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide; (43) N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide; (44) 4-methyl-3-(4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)benzoic acid methyl ester; (45) N-(5-(Hydroxycarbamoyl)-2-methylphenyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide; (46) N-(3-(2-(hydroxyamino)-2-oxoethyl)phenyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (47) N-(4-(Hydroxycarbamoyl)benzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (48) N-(4-(Hydroxycarbamoyl)phenyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (49) N-(4-(2-(hydroxyamino)-2-oxoethyl)benzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (50) N-(3-(Hydroxycarbamoyl)benzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; (51) N-(5-(hydroxycarbamoyl)-2-methylphenyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide; and (52) N-(3-(Hydroxycarbamoyl)cyclopentyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide.

11. A method for preparing a compound represented by Chemical Formula 1, the method comprising: As shown in the following reaction scheme 1, preparing a compound represented by Chemical Formula 1B by reacting the compound represented by Chemical Formula 1A with hydroxide ions (OH-); as well as The compound represented by Chemical Formula 1 is prepared by reacting the compound represented by Chemical Formula 1B with the compound represented by Chemical Formula 1C, [Reaction Scheme 1] Wherein, in reaction scheme 1, R 1 is unsubstituted or substituted C 5-8 Cycloalkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted heteroaryl containing 5 to 8 atoms of one or more heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted fused heteroaryl containing 8 to 10 atoms of one or more heteroatoms selected from the group consisting of N, O and S, or C 1-15 Alkenyl, Among them, the substituted C 5-8 The cycloalkyl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl and C 1-8 Alkylcarbonyloxy, Substituted C 6-10 The aryl group is substituted by one or more substituents selected from the group consisting of halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 6-10 Aryl, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl, C 1-8 alkylcarbonyloxy, and a heteroaryl group of 5 to 8 atoms containing one or more heteroatoms selected from the group consisting of N, O and S, The 5 to 8-atom substituted heteroaryl is substituted by halogen, or by a C 6-10 Aryl substituted, and The substituted fused heteroaryl of 8 to 10 atoms is substituted by one or more substituents selected from the group consisting of: -OH, halogen, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl and C 1-8 Alkylcarbonyloxy; R 2 and R 3 are independently -H, halogen or C 1-10 alkyl; R 4 C 1-8 Alkyl, or C substituted with two or more -OH 3-10 Alkyl; and L 1 For key or C 1-10 Alkylene.

12. A pharmaceutical composition for preventing or treating cancer diseases, comprising the compound according to claim 1, its stereoisomer, its hydrate or a pharmaceutically acceptable salt thereof as an active ingredient.

13. The pharmaceutical composition according to claim 12, wherein The cancer disease is selected from the group consisting of prostate cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, colon cancer, skin cancer, head and neck cancer, brain cancer, laryngeal cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer and rectal cancer.

14. The pharmaceutical composition according to claim 12, wherein The pharmaceutical composition selectively inhibits histone deacetylase 8 (HDAC8).

15. A health functional food composition for preventing or improving cancer diseases, comprising the compound according to claim 1, its stereoisomer, its hydrate or a pharmaceutically acceptable salt thereof as an active ingredient.

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