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

Abstract

The present invention 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 effect of selectively inhibiting HDAC8 among histone deacetylases (HDACs), and is therefore useful as a selective inhibitor of HDAC8 or a pharmaceutical composition for preventing or treating cancer diseases.

Description

[Technical field]

[0001] The present invention relates to a 3,4-dihydroquinoxaline-2-carboxamide derivative compound and a pharmaceutical composition containing the same for preventing or treating cancer diseases. [Background technology]

[0002] Histone deacetylase (HDAC) is an enzyme that removes the acetyl group from the amino group of the N-terminal lysine tail of histones. It is known to have various functions even in non-histone proteins, and is involved in important cellular activities such as cell growth cycle regulation, differentiation, and cancer formation. In particular, it has been recently revealed that HDACs are overexpressed under adverse environmental conditions such as hypoxia, low glucose, and cell tumorigenesis, and play a role in promoting cell proliferation by inhibiting the expression of cell growth inhibitors, and are recognized as important regulators of cell tumorigenesis and differentiation. HDACs can be broadly classified into four groups based on their function and DNA sequence similarity, and 18 HDACs have been identified so far. Among them, HDAC8 belongs to class I in terms of classification, and while HDAC1, 2, and 3 are mainly found in the nucleus, HDAC8 is present in both the nucleus and cytoplasm. HDAC8 has been reported to be overexpressed in various cancers and to be associated with various diseases, including inflammatory diseases, and has emerged as an important target for the treatment of various diseases.

[0003] HDAC inhibitors currently approved by the FDA include Novartis' Farydak (panobinostat) for multiple myeloma, BMS' Istodax (romidepsin) for cutaneous T-cell lymphoma, Merck's Zolinza (vorinostat) for cutaneous T-cell lymphoma, and Acrotech's Belostat (belinostat) for peripheral T-cell lymphoma. Most HDAC inhibitors developed so far have only been approved for the treatment of specific cancers, but their effectiveness is limited and they cause unnecessary side effects, so there is a need for improved selective HDAC inhibitors. Summary of the Invention [Problem to be solved by the invention]

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

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

[0006] Another embodiment provides a pharmaceutical composition for preventing or treating cancer diseases, comprising a 3,4-dihydroquinoxaline-2-carboxamide derivative compound.

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

[0008] Another embodiment of the present invention 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 pharma- ceutically 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 pharma- ceutically acceptable salt thereof for use in the treatment of cancer disease.

[0010] Another embodiment is to provide a use of a 3,4-dihydroquinoxaline-2-carboxamide derivative compound, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of cancer disease. [Means for solving the problem]

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

[0012] [ka]

[0013] In the above Chemical Formula 1,

[0014] R 1 is unsubstituted or substituted C 5-8 Cycloalkyl, unsubstituted or substituted C 6-10 aryl, an unsubstituted or substituted 5-8 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, an unsubstituted or substituted 8-10 atom fused heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, or C 1-15 alkenyl,

[0015] The substituted C 5-8Cycloalkyl is 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 substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy;

[0016] The substituted C 6-10 Aryl is 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 and one or more substituents selected from the group consisting of alkylcarbonyloxy and heteroaryl having 5 to 8 atoms and containing one or more heteroatoms selected from the group consisting of N, O, and S;

[0017] The substituted 5-8 atom heteroaryl is a halogen or a C substituted with a halogen. 6-10 the aryl is substituted;

[0018] The substituted 8-10 atom fused heteroaryl is selected from the group consisting of -OH, halogen, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl, and C 1-8 substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy;

[0019] R 2 and R 3are each independently -H, halogen, or C 1-10 is alkyl;

[0020] R 4 is C 1-8 C substituted with 2 or more alkyl or -OH 3-10 is alkyl; and

[0021] L 1 is a bond, or C 1-10 It is alkylene.

[0022] In another embodiment, when according to the following reaction scheme 1,

[0023] reacting the compound represented by formula 1A with hydroxide ion (OH-) to prepare a compound represented by formula 1B; and

[0024] The present invention provides a method for producing a compound represented by Chemical Formula 1, as shown in Reaction Scheme 1 below, comprising reacting a compound represented by Chemical Formula 1B with a compound represented by Chemical Formula 1C to produce a compound represented by Chemical Formula 1.

[0025] [ka]

[0026] In another embodiment, there is provided a pharmaceutical composition for preventing or treating cancer disease, comprising the compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0027] Another embodiment provides a health functional food composition comprising the compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0028] Another embodiment provides a method for treating a cancer disease, comprising administering the compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof to an individual or subject in need thereof.

[0029] Another embodiment provides a compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer disease.

[0030] Another embodiment provides the use of the compound, its stereoisomer, its hydrate or its pharma- ceutically acceptable salt for the manufacture of a medicament for the treatment of a cancer disease. Effect of the Invention

[0031] The present invention 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 effect of selectively inhibiting HDAC8 among histone deacetylases (HDACs), and is therefore useful as a selective inhibitor of HDAC8 or a pharmaceutical composition for preventing or treating cancer diseases. [Brief description of the drawings]

[0032] [Figure 1]PCI-34051, known as an HDAC8 inhibitor, and 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-fluorophenyl)-2-(2-phenylpropanediol) were used. 13 shows the results of confirming the growth inhibitory effect of these prostate cancer cells PC-3 using 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 (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; compound of Example 35). [Diagram 2] 1 shows the results of confirming the anti-cancer efficacy of the compound of Example 27 by measuring the volume of tumors excised from a mouse model implanted with prostate cancer cell line PC-3 during the administration period. [Diagram 3] 1 shows the results of confirming the anti-cancer efficacy of the compound of Example 27 by measuring the weight of the tumor excised from the mouse model 12 days after administration. [Figure 4] 1 shows the results of observing the reduction in tumor volume by taking photographs of tumors excised from mouse models 12 days after administration of the compound of Example 27. [Diagram 5] 1 shows the results of measuring the weight change in a mouse model during the administration period of the compound of Example 27. [Figure 6]1 shows the results of confirming the growth inhibitory effects of the compounds of Example 27 and Example 35 on liver cancer cell line Huh-7. [Figure 7] 1 shows data evaluating the efficacy of the compound of Example 27 against liver cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] The embodiments described herein may be modified into various other forms, and the technology according to one embodiment is not limited to the embodiment described below. Moreover, the embodiment of one embodiment is provided to more completely explain the present invention to those skilled in the art. Furthermore, the term "including" a certain element in the entire specification means that it does not exclude other elements, but may further include other elements, unless otherwise specified to the contrary.

[0034] Numerical ranges used herein include lower and upper limits and all values ​​within the range, increments logically derived from the form and width of the range defined, all values ​​that are doubly limited, and all possible combinations of upper and lower limits of numerical ranges that are limited in different forms. For example, if the content of a composition is limited to 10-80% or 20-50%, the numerical ranges of 10-50% or 50-80% should also be interpreted as being described in the present specification. In the present specification, unless otherwise specified, values ​​outside the numerical range that may occur due to experimental error or rounding of values ​​are also included in the defined numerical range.

[0035] Hereinafter, unless otherwise defined, "about" is considered to mean a value within 30%, 25%, 20%, 15%, 10% or 5% of the specified value.

[0036] One embodiment provides a compound represented by the following Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a salt thereof:

[0037] [ka]

[0038] In the above Chemical Formula 1,

[0039] R 1 is unsubstituted or substituted C 5-8 Cycloalkyl, unsubstituted or substituted C 6-10 aryl, an unsubstituted or substituted 5-8 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, an unsubstituted or substituted 8-10 atom fused heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, or C 1-15 alkenyl,

[0040] The substituted C 5-8 Cycloalkyl is 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 substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy;

[0041] The substituted C 6-10 Aryl is 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 and one or more substituents selected from the group consisting of alkylcarbonyloxy and heteroaryl having 5 to 8 atoms and containing one or more heteroatoms selected from the group consisting of N, O, and S;

[0042] The substituted 5-8 atom heteroaryl is a halogen or a C substituted with a halogen. 6-10 the aryl is substituted;

[0043] The substituted 8-10 atom fused heteroaryl is selected from the group consisting of -OH, halogen, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl, and C 1-8 substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy;

[0044] R 2 and R 3 are each independently -H, halogen, or C 1-10 is alkyl;

[0045] R 4 is C 1-8 C substituted with 2 or more alkyl or -OH 3-10 is alkyl; and

[0046] L 1 is a bond, or C 1-10 It is alkylene.

[0047] In one embodiment, the alkyl, alkoxy, etc. may include straight or branched chain alkyl or alkoxy, etc.

[0048] In one embodiment, the halogen is I, Br, Cl, or F.

[0049] In one embodiment, the term "substituted" means that one or more, two or more, or one or two of the listed substituents are substituted.

[0050] In one embodiment, the fused heteroaryl may include a ring in which an aryl or cycloalkyl is fused to a heteroaryl.

[0051] In one embodiment, the R 1 is unsubstituted or substituted C 5-6 Cycloalkyl, unsubstituted or substituted C 6-8 aryl, an unsubstituted or substituted 5-6 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, an unsubstituted or substituted 8-10 atom fused heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, or C 5-15 alkenyl,

[0052] The substituted C 5-6 Cycloalkyl is 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 substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy;

[0053] The substituted C 6-8 Aryl is 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 and one or more substituents selected from the group consisting of alkylcarbonyloxy and heteroaryl having 5 to 6 atoms and containing one or more heteroatoms selected from the group consisting of N, O, and S;

[0054] The substituted 5-6 atom heteroaryl is a halogen or a C substituted with a halogen. 6-8the aryl is substituted;

[0055] The substituted 8-10 atom fused heteroaryl is selected from the group consisting of -OH, halogen, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxycarbonyl C 1-3 Alkyl, and C 1-6 It is substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy.

[0056] Or, in one embodiment, the R 1 is unsubstituted or substituted C 5-6 Cycloalkyl, unsubstituted or substituted C 6-8 aryl, an unsubstituted or substituted 5-6 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, an unsubstituted or substituted 8-10 atom fused heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, or C 6-12 alkenyl,

[0057] The substituted C 5-6 Cycloalkyl is halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-5 Alkyl, C 1-5 Haloalkyl and C 1-5 alkoxycarbonyl;

[0058] The substituted C 6-8 Aryl is halogen, -CONH-OH, -CH2-CONH-OH, -CH2CH2-CONH-OH, C 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Haloalkyl, C6 aryl, C 1-5 Alkoxycarbonyl, C 1-5 Alkoxycarbonyl C 1-3 Alkyl, C 1-5and one or more substituents selected from the group consisting of alkylcarbonyloxy and heteroaryl having 5 to 6 atoms and containing one or more heteroatoms selected from the group consisting of N, O, and S;

[0059] The substituted 5-6 atom heteroaryl is a C6 aryl substituted with halogen or halogen;

[0060] The substituted 8-10 atom fused heteroaryl is selected from the group consisting of -OH, halogen, C 1-5 Alkoxycarbonyl, C 1-5 Alkoxycarbonyl C 1-3 Alkyl, and C 1-5 It is substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy.

[0061] Or, in one embodiment, the substituted C 5-8 Cycloalkyl or C 5-6 Cycloalkyl is 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 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 C1-2 Alkyl, C 1-3 Alkoxycarbonyl C 1-2 Alkyl, C 1-2 Alkoxycarbonyl C 1-2 Alkyl, -CH2CH2C(0)OCH3, -CH2C(O)OCH3, C 1-5 Alkylcarbonyloxy, C 1-4 Alkylcarbonyloxy, C 1-3 Alkylcarbonyloxy, C 1-2 Alkylcarbonyloxy or -OC(O)CH3 are substituted, and among these, one or more kinds of substituents are substituted by one or more, two or more, or one or two.

[0062] Or, in one embodiment, the C 6-10 Aryl or C 6-8 Aryl is 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, C 1-2 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 1-2Alkoxycarbonyl C 1-2 Alkyl, -CH2CH2C(0)OCH3, -CH2C(O)OCH3, C 1-5 Alkylcarbonyloxy, C 1-4 Alkylcarbonyloxy, C 1-3 Alkylcarbonyloxy, C 1-2 It is a substituted heteroaryl having 5 to 6 atoms and containing one or more heteroatoms selected from the group consisting of alkylcarbonyloxy, -OC(O)CH3, or N, O, and S, and is substituted with one or more, two or more, or one or two, of one or two types of substituents.

[0063] In one embodiment, the substituted 8-10 atom fused heteroaryl is selected from the group consisting of -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(0)OCH3, -CH2C(O)OCH3, C 1-5 Alkylcarbonyloxy, C 1-4 Alkylcarbonyloxy, C 1-3 Alkylcarbonyloxy, C 1-2 Alkylcarbonyloxy or -OC(O)CH3 are substituted, and among these, one or more kinds of substituents are substituted by one or more, two or more, or one or two.

[0064] In one embodiment, the R 1 teeth, [ka] It is.

[0065] In one embodiment, the R 2 and R 3 are each independently -H, halogen, or C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, or -CH3.

[0066] In one embodiment, the L 1 is a bond, C 1-5 Alkylene, C 1-4 Alkylene, C 1-3 Alkylene, or C 1-2 It is alkylene.

[0067] In one embodiment, the R 4 is C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 C substituted with 1 or more, 2 or more, 3 to 5, or 4 alkyl, -CH3, or -OH groups 3-5 Or specifically, R 4 teeth, [ka] It is.

[0068] In one embodiment, the compound represented by Chemical Formula 1 is a compound represented by Chemical Formula 2 below.

[0069] [ka]

[0070] At this time, the R 12 , R 22 , R 32 and L 12 is R as defined above. 1 , R 2 , R 3 and L 1can be applied in a similar manner.

[0071] Specifically, for example, R 12 is unsubstituted or substituted C 5-8 Cycloalkyl, unsubstituted or substituted C 6-10 aryl, an unsubstituted or substituted 5-8 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, an unsubstituted or substituted 8-10 atom fused heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, or C 1-15 alkenyl,

[0072] The substituted C 5-8 Cycloalkyl is 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 substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy;

[0073] The substituted C 6-10 Aryl is 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 and one or more substituents selected from the group consisting of alkylcarbonyloxy and heteroaryl having 5 to 8 atoms and containing one or more heteroatoms selected from the group consisting of N, O, and S;

[0074] The substituted 5-8 atom heteroaryl is a halogen or a C substituted with a halogen. 6-10 the aryl is substituted;

[0075] The substituted 8-10 atom fused heteroaryl is selected from the group consisting of -OH, halogen, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl, and C 1-8 substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy;

[0076] R 22 and R 32 are each independently -H, halogen, or C 1-10 is alkyl; and

[0077] L 12 is a bond, or C 1-10 It is alkylene.

[0078] An 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 stereoisomer compound represented by the following Chemical Formula 2A. However, Chemical Formula 2A is only one example of various stereoisomer compounds, and is not necessarily limited to the following compound.

[0079] [ka]

[0080] In one embodiment, the compound represented by Formula 1 is a compound represented by Formula 3 below.

[0081] [ka]

[0082] At this time, the R 13 , R 23, R 33 and L 13 is R as defined above. 1 , R 2 , R 3 and L 1 can be applied in a similar manner.

[0083] Specifically, for example, R 13 is unsubstituted or substituted C 6-10 aryl or an unsubstituted or substituted 8-10 atom fused heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S;

[0084] The substituted C 6-10 Aryl is 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 substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy;

[0085] The substituted 8-10 atom fused heteroaryl is substituted with one or more substituents selected from the group consisting of -OH and halogen;

[0086] R 23 and R 33 are each independently -H, halogen, or C 1-10 is alkyl; and

[0087] L 13 is a bond, or C 1-10 It is alkylene.

[0088] In one embodiment, the compound represented by Chemical Formula 1 is any one selected from the following compound group:

[0089] (1) N-(4-methoxybenzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0090] (2) 6,7-dimethyl-N-(4-methylbenzyl)-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0091] (3) 6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-N-(4-(trifluoromethyl)benzyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0092] (4) N-(4-fluorobenzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0093] (5) 6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-N-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0094] (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;

[0095] (7) N-(3,5-dichlorobenzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0096] (8) N-(3,4-dichlorobenzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0097] (9) N-(2,4-dichlorophenethyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0098] (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;

[0099] (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;

[0100] (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;

[0101] (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;

[0102] (14) 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;

[0103] (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)acetic acid;

[0104] (16) Methyl 3-((6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)methyl)benzoate;

[0105] (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;

[0106] (18) Methyl 4-((6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)methyl)benzoate;

[0107] (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;

[0108] (20) Methyl 4-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)benzoate;

[0109] (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;

[0110] (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;

[0111] (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;

[0112] (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;

[0113] (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;

[0114] (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;

[0115] (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;

[0116] (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;

[0117] (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;

[0118] (30) Methyl 3-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamido)-4-methylbenzoate;

[0119] (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;

[0120] (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;

[0121] (33) Methyl 3-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide)cyclopentane-1-carboxylate;

[0122] (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;

[0123] (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;

[0124] (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;

[0125] (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;

[0126] (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;

[0127] (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;

[0128] (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-ylpivalic acid;

[0129] (41) N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide;

[0130] (42) N-(2-(4-fluoro-1H-benzo[d]imidazol-2-yl)ethyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide;

[0131] (43) N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide;

[0132] (44) Methyl 4-methyl-3-(4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)benzoate;

[0133] (45) N-(5-(hydroxycarbamoyl)-2-methylphenyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide;

[0134] (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;

[0135] (47) N-(4-(hydroxycarbamoyl)benzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0136] (48) N-(4-(hydroxycarbamoyl)phenyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0137] (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;

[0138] (50) N-(3-(hydroxycarbamoyl)benzyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide;

[0139] (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

[0140] (52) N-(3-(hydroxycarbamoyl)cyclopentyl)-6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide.

[0141] In one embodiment, the compound represented by Chemical Formula 1 may be used in the form of a pharma- ceutically acceptable salt, and the salt may be an acid addition salt formed with a pharma- ceutically acceptable free acid. The acid addition salt may be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid, non-toxic organic acids such as aliphatic mono- and di-carboxylates, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, and alkanedioates, aromatic acids, and aliphatic and aromatic sulfonic acids, and organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and fumaric acid. Such pharma- ceutically non-toxic salt types include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4-dioate, hexane-1,6-dioate, benzoate, benzoic acid ... These include phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

[0142] One embodiment provides a method for preparing the compound represented by Formula 1.

[0143] According to an embodiment, a method for preparing the compound represented by Chemical Formula 1 may be carried out as shown in Reaction Scheme 1 below:

[0144] reacting the compound represented by formula 1A with hydroxide ion (OH-) to prepare a compound represented by formula 1B; and

[0145] reacting the compound represented by Chemical Formula 1B with the compound represented by Chemical Formula 1C to prepare the compound represented by Chemical Formula 1;

[0146] [ka]

[0147] In the above reaction scheme 1, R 1 Or R 4 and L 1 The above definitions can be applied. Therefore, the above formula 1 can be used in the formula 2 or formula 3, and the R 1 Or R 3 and L 1 is R 12 Or R 32 and L 12 or R 13 Or R 33 and L 13 It is also.

[0148] The step of reacting with hydroxide ions is a step of reacting the compound represented by Formula 1A with a compound containing hydroxide ions, and for example, a basic compound such as NaOH, KOH, Ba(OH)2, Ca(OH)2, NH4OH, Mg(OH)2, or H2O (hydrolysis reaction) can be used, but this is merely an example and is not necessarily limited to the use of only the above compounds.

[0149] In another embodiment, there is provided a pharmaceutical composition for preventing or treating cancer disease, comprising the compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0150] The cancer disease may 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.

[0151] In one embodiment, the pharmaceutical composition can selectively inhibit HDAC8 (histone deacetylase 8), and by selectively inhibiting HDAC8, can exert a preventive or therapeutic effect on cancer diseases. Since the pharmaceutical composition according to one embodiment has an excellent effect of selectively inhibiting HDAC8 among HDACs, it can minimize unnecessary side effects, and is therefore useful as an alternative to compounds (drugs) currently known as HDAC8 inhibitors.

[0152] In one embodiment, the composition comprising the compound represented by Formula 1 or a pharma- ceutically acceptable salt thereof may be used for the treatment or prevention of not only cancer diseases but also other cancers in which anti-cancer effects are exerted by selectively inhibiting HDAC8. Thus, the composition is a pharmaceutical composition for the prevention or treatment of HDAC8-related cancers or an HDAC8 inhibitor.

[0153] The compound represented by Chemical Formula 1 or a pharma- ceutically acceptable salt thereof is administered in various oral and parenteral dosage forms during clinical administration. When formulated, it is prepared using a diluent or excipient such as a typical filler, extender, binder, wetting agent, disintegrant, or surfactant. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations are prepared by mixing one or more compounds with at least one or more excipients, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral liquids, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients, such as wetting agents, sweeteners, flavorings, and preservatives, are included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0154] The pharmaceutical composition containing the compound represented by Chemical Formula 1 or a pharma- ceutical acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration can be by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

[0155] In this case, in order to prepare a formulation for parenteral administration, the compound represented by Chemical Formula 1 or a pharma- ceutically acceptable salt thereof may be mixed with a stabilizer or buffer in water to prepare a solution or suspension, which may then be prepared in an ampule or vial for unit administration. The composition may be sterilized or contain preservatives, stabilizers, hydrating agents or emulsifying agents, auxiliary agents such as salts or buffers for osmotic pressure adjustment, and other therapeutically useful substances, and may be formulated by a conventional mixing, granulation, or coating method.

[0156] Dosage forms for oral administration include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, and troches, and these dosage forms contain, in addition to the active ingredient, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, or glycine), lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salt, or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidine, and may optionally contain disintegrants or boiling mixtures or absorbents such as starch, agar, alginic acid, or its sodium salt, colorants, flavors, and sweeteners.

[0157] Another embodiment provides a selective inhibitor of HDAC8, comprising the compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a salt thereof as an active ingredient.

[0158] Another embodiment provides a health functional food composition for preventing or improving cancer disease, comprising the compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a salt thereof as an active ingredient.

[0159] The compound represented by Chemical Formula 1 according to one embodiment may be added directly to food or may be used together with other food or food ingredients, and may be used appropriately in a conventional manner. The amount of the active ingredient to be mixed may be determined appropriately depending on the purpose of use (for prevention or improvement). In general, the amount of the compound in a health food may be added in an amount of 0.1 to 90 parts by weight based on the total weight of the food. However, in the case of long-term intake for the purpose of health and hygiene or health regulation, the amount is within the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount greater than the above range.

[0160] In addition, the health functional food composition according to one embodiment is not particularly limited in terms of other ingredients other than containing the above-mentioned compound, and may contain various flavorings or natural carbohydrates, etc. as additional ingredients, like ordinary beverages.

[0161] Additionally, it may contain various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic and natural flavors, colorants and fillers (cheese, chocolate, etc.), pectinic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated beverages, etc.

[0162] In one embodiment, there is provided a method for treating a cancer disease, comprising administering the compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof to an individual or subject in need thereof.

[0163] An embodiment provides a compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer disease.

[0164] An embodiment provides the use of said compound, its stereoisomer, its hydrate or its pharma- ceutically acceptable salt for use in the manufacture of a medicament for the treatment of a cancer disease.

[0165] Examples and experimental examples are specifically illustrated below. However, the examples and experimental examples described below are only a partial list, and the technology described in this specification is not limited thereto.

[0166] The compounds of Examples 1 to 40 were prepared according to the method of the following Reaction Scheme A.

[0167] [ka]

[0168] In the above reaction formula A, -R in compound III is the following a1 to a40.

[0169] [ka]

[0170] Specific manufacturing methods of Examples 1 to 40 are described below.

[0171] 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

[0172] After adding the same equivalent of arylamine (III, R = a1) to the 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, 2-(3H-[1,2,3]triazole[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouranium hexafluorophosphate (HATU) 1.2 equivalents and N,N-diisopropylethylamine (DIPEA) 5 equivalents were gradually added and stirred at room temperature for 4 hours. The resulting mixture was purified using preparative HLPC (solvent system: acetonitrile, water) to obtain the compound of Example 1 as a yellow solid (15 mg, 37.4% yield).

[0173] ESI LC / MS:m / z calcd.for:C 24 H 29 N3O7[M+H] + :472.71;found 472.25. 1H NMR (CD3OD, 400MHz) δ7.74(s, 1H), 7.63(s, 1H), 7.32(d, J=8.56Hz, 2H), 6.89(d, J=8.64Hz, 2H), 4.74(q, J=9.92Hz, 1H), 4 .58(s, 2H), 4.41(d, J=13.96Hz, 1H), 4.27-4.24(m, 1H), 3.82-3.76(m, 6H), 3.68-3.64(m, 1H), 2.45(s, 3H), 2.36(s, 3H).

[0174] <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

[0175] The same method was repeated in Example 1, except that arylamine (III, R=a2) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 2 (6 mg, 23.2% yield).

[0176] ESI LC / MS:m / z calcd.for:C 24 H 29 N3O6[M+H] + :456.21;found 456.01. 1 H NMR (CD3OD, 400MHz) δ 7.74(s, 1H), 7.63(s, 1H), 7.28(d, J=7.84Hz, 2H), 7.15(d, J=7.8Hz, 2H), 4.74(q, J=9.96Hz, 1H), 4.60(s, 2H), 4.41( d, J=13.92Hz, 1H), 4.27-4.24(m, 1H), 3.83-3.74(m, 3H), 3.69-3.64(m, 1H), 2.44(s, 3H), 2.36(s, 3H), 2.31(s, 3H).

[0177] <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

[0178] The same method as in Example 1 was repeated, except that arylamine (III, R=a3) was used instead of arylamine (III, R=a1), to obtain the compound of Example 3 as a yellow solid (7 mg, 24.2% yield).

[0179] ESI LC / MS:m / z calcd.for:C 24 H 27 F3N3O6[M+H] + :510.19;found 510.20. 1 H NMR(CD3OD, 400MHz)δ 7.97(s, 2H), 7.76(s, 1H), 7.67-7.59(m, 3H), 4.82-4.78(m, 1H), 4.75(s, 2H), 4.45(d, J=13.9 6Hz, 1H), 4.29-4.26(m, 1H), 3.83-3.75(m, 3H), 3.69-3.65(m, 1H), 2.46(s, 3H), 2.38(s, 3H).

[0180] <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

[0181] The same method was repeated in Example 1, except that arylamine (III, R=a4) was used instead of arylamine (III, R=a1), to obtain the compound of Example 4 as a yellow solid (8 mg, 30.7% yield).

[0182] ESI LC / MS:m / z calcd.for:C 23 H 27 FN3O6[M+H] + :460.19;found 460.20. 1 H NMR(CD3OD, 400MHz)δ 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).

[0183] <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

[0184] The same method as in Example 1 was repeated, except that arylamine (III, R=a5) was used instead of arylamine (III, R=a1), to obtain the compound of Example 5 as a yellow solid (11 mg, 24.2% yield).

[0185] ESI LC / MS:m / z calcd.for:C 24 H 27 F3N3O6[M+H] + :510.19;found 510.20.1 H NMR(CD3OD, 400MHz)δ 7.75-7.73(m, 2H), 7.69(d, J=7.24Hz, 1H), 7.65(s, 1H), 7.59-7.52(m, 2H), 4.81-4.78(m, 1H), 4.73(s, 2H), 4.43(d, J=13.88Hz, 1H), 4.28-4.26(m, 1H), 3.83-3.77(m, 3H), 3.69-3.65(m, 1H), 2.46(s, 3H), 2.37(s, 3H).

[0186] <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

[0187] The same method was repeated in Example 1, except that arylamine (III, R=a6) was used instead of arylamine (III, R=a1), to obtain the compound of Example 6 as a yellow solid (5 mg, 22.7% yield).

[0188] ESI LC / MS:m / z calcd.for:C 29 H 32 N3O6[M+H] + :518.23;found 518.20. 1H NMR (CD3OD, 400MHz) δ 7.78(s, 1H), 7.67(s, 1H), 7.60-7.58(m, 4H), 7.48(d, J=8.04Hz, 2H), 7.42(t, J=7.4Hz, 2H), 7.32(t, J=7.32Hz, 1H), 4.79(q, J=9.9 6Hz, 1H), 4.71(s, 2H), 4.45(d, J=13.88Hz, 1H), 4.30-4.26(m, 1H), 3.83-3.75(m, 3H), 3.69-3.64(m, 1H), 2.47(s, 3H), 2.38(s, 3H).

[0189] <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

[0190] The same method as in Example 1 was repeated, except that arylamine (III, R=a7) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 7 (6 mg, 27.6% yield).

[0191] ESI LC / MS:m / z calcd.for:C 23 H 26 Cl2N3O6[M+H] + :510.12;found 510.15. 1 H NMR (CD3OD, 400MHz) δ 7.77(s, 1H), 7.68(s, 1H), 7.38-7.33(m, 3H), 4.80(q, J=10.96Hz, 1H), 4.63(s, 2H), 4.44(d, J =13.2Hz, 1H), 4.29(br, 1H), 3.83-3.78(m, 3H), 3.68-3.65(m, 1H), 2.47(s, 3H), 2.38(s, 3H).

[0192] <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

[0193] The same method as in Example 1 was repeated, except that arylamine (III, R=a8) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 8 (11 mg, 29.4% yield).

[0194] ESI LC / MS:m / z calcd.for:C 23 H 26 Cl2N3O6[M+H] + :510.12;found 510.15. 1 H NMR (CD3OD, 400MHz) δ 7.77(s, 1H), 7.67(s, 1H), 7.58(s, 1H), 7.48(d, J=8.28Hz, 1H), 7.34(d, J=8.24Hz, 1H), 4.79(q, J=9.92Hz, 1H), 4.63 (s, 2H), 4.44(d, J=13.92Hz, 1H), 4.30-4.26(m, 1H), 3.83-3.75(m, 3H), 3.70-3.65(m, 1H), 2.47(s, 3H), 2.38(s, 3H).

[0195] <Example 9> (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

[0196] The same method as in Example 1 was repeated, except that arylamine (III, R=a9) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 9 (8 mg, 26.9% yield).

[0197] ESI LC / MS:m / z calcd.for:C 24 H 28 Cl2N3O6[M+H] + :524.14;found 524.15. 1 H NMR (CD3OD, 400MHz) δ 7.78(s, 1H), 7.68(s, 1H), 7.44(s, 1H), 7.38(d, J=8.24Hz, 1H), 7.27(d, J=8.16Hz, 1H), 4.79(q, J=10.28Hz, 1H ), 4.46(d, J=13.68Hz, 1H), 4.28-4.25(m, 1H), 3.83-3.67(s, 6H), 3.11-3.08(m, 2H), 2.48(s, 3H), 2.39(s, 3H).

[0198] <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

[0199] The same method as in Example 1 was repeated, except that arylamine (III, R=a10) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 10 (6 mg, 18.4% yield).

[0200] ESI LC / MS:m / z calcd.for:C 25 H 26 BrN4O7[M+H] + :573.10;found 574.99. 1 H NMR (CD3OD, 400MHz) δ 7.84(br, 1H), 7.82-7.80(m, 2H), 7.75(s, 1H), 7.71-7.69(m, 2H), 7.48(s, 1H), 4.56-4.5 3(m, 1H), 4.34(br, 1H), 3.85-3.80(m, 4H), 3.72-3.67(m, 1H), 2.78(s, 3H), 2.41(s, 3H).

[0201] <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

[0202] The same method as in Example 1 was repeated, except that arylamine (III, R=a11) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 11 (10 mg, 29.9% yield).

[0203] ESI LC / MS:m / z calcd.for:C 24 H 25 BrNOS[M+H] + :590.06;found 591.90. 1 H NMR (CD3OD, 400MHz) δ 7.88(d, J=8.52Hz, 2H), 7.82(s, 1H), 7.75(s, 1H), 7.70(d, J=8.56Hz, 2H), 4.59-4.55(m, 1H), 4.37-4.34(m, 1H), 3.86-3.81(m, 3H), 3.73-3.69(m, 2H), 2.49(s, 3H), 2.40(s, 3H).

[0204] <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

[0205] The same method was repeated in Example 1, except that arylamine (III, R=a12) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 12 (15 mg, 23.1% yield).

[0206] ESI LC / MS:m / z calcd.for:C 25 H 27 BrNO6[M+H] + :572.11;found 573.95. 1 H NMR (DMSO-d6, 400MHz) δ 7.74-7.71(m, 3H), 7.66-7.64(m, 3H), 7.06(s, 1H), 4.66(q, J=10.2Hz, 1H), 4.28(d , J=12Hz, 1H), 4.15(d, J=9.44Hz, 1H), 3.64-3.49(m, 4H), 2.40(s, 3H), 2.34(s, 3H).

[0207] <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

[0208] The same method as in Example 1 was repeated, except that arylamine (III, R=a13) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 13 (6 mg, 17.9% yield).

[0209] ESI LC / MS:m / z calcd.for:C 25 H 26 BrN4O6S[M+H] + :589.08;found 591.0. 1 H NMR (DMSO-d6, 400MHz) δ 7.89(d, J=8.56Hz, 2H), 7.85(s, 1H), 7.75(s, 1H), 7.69(s, 1H), 7.62(d, J=8.6Hz, 2H), 4.70-4. 64(m, 1H), 4.56-4.51(m, 1H), 4.34-4.31(m, 1H), 3.64-3.61(m, 4H), 2.42(s, 3H), 2.35(s, 3H).

[0210] <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

[0211] The same method was used as in Example 1, except that arylamine (III, R=a14) was used instead of arylamine (III, R=a1), to obtain the compound of Example 14 as a bright yellow solid (32 mg, 66.5% yield).

[0212] ESI LC / MS:m / z calcd.for:C 26 H 38N3O6[M+H] + :488.27;found 488.05. 1 H NMR (CD3OD, 400MHz) δ7.76(s, 2H), 5.36(s, 1H), 5.13(s, 1H), 4.48(m, 1H), 4.29(s, 1H), 4.03(s, 2H), 3.85(m, 3H), 3.72(m, 1H), 2 49(s, 3H), 2.40(s, 3H), 2.15(m, 2H), 2.09(m, 2H), 1.77(s, 3H), 1.68(s, 3H), 1.62(s, 3H).

[0213] <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

[0214] The same method as in Example 1 was repeated, except that arylamine (III, R=a15) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 15 (11 mg, 15.09% yield).

[0215] ESI LC / MS:m / z calcd.for:C 26 H 31 N3O8[M+H] + :514.54;found 514.21. 1H NMR (CD3OD, 400MHz) δ 7.79(s, 1H), 7.68(s, 1H), 7.38(d, J=8.0Hz, 2H), 7.27(d, J=8.04Hz, 2H), 4.77(q, J=9.92Hz, 1H), 4.66(s, 2H), 4.46(dd, J=14 , 2.52Hz, 1H), 4.30-4.26(m, 1H), 3.85-3.76(m, 3H), 3.71-3.69(m, 1H), 3.68(s, 3H), 3.65(s, 2H), 2.48(s, 3H), 2.39(s, 3H).

[0216] <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

[0217] The same method as in Example 1 was repeated, except that arylamine (III, R=a16) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 16 (15 mg, 21.2% yield).

[0218] ESI LC / MS:m / z calcd.for:C 25 H 29 N3O8[M+H] + :500.15;found 500.25. 1H NMR (CD3OD, 400MHz) δ 7.98(s, 1H), 7.84(d, J=7.8Hz, 1H), 7.70(s, 1H), 7.59-7.58(m, 2H), 7.38(t, J=7.76Hz, 1H), 4.69(q, J=9.88Hz, 1H), 4.66(s, 2H), 4.37(dd, J=14.04, 2.64Hz, 1H), 4.20-4.16(m, 1H), 3.80(s, 3H), 3.74-3.66(m, 3H), 3.60-3.56(m, 1H), 2.38(s, 3H), 2.30(s, 3H).

[0219] 13 C NMR(CD3OD, 100MHz) δ 168.54, 157.13, 145.61, 145.05, 140.53, 135.55, 134.07, 133.74, 132.85, 132.07, 130.09 , 129.91, 129.66, 117.37, 75.25, 74.36, 71.32, 64.99, 52.82, 46.47, 44.31, 21.03, 19.31.

[0220] <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

[0221] The same method was repeated in Example 1, except that arylamine (III, R=a17) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 17 (118 mg, 55.9% yield).

[0222] ESI LC / MS:m / z calcd.for:C 25 H 29 N5O6[M+H]+ :496.52;found 496.25. 1 H NMR (DMSO-d6, 400MHz) δ 12.29(s, 1H), 9.27(t, J=5.72Hz, 1H), 7.64(s, 1H), 7.60(s, 1H), 7.54(d, J=7.76Hz, 1H), 7.43(d, J=6.84Hz, 1H), 7.15-7.09(m, 2H), 4.98-4.81(m, 2H), 4.66(d, J=6.2Hz, 1-OH), 4.59(q, J=10.08H) z, 1-OH), 4.48-4.46(m, 1-OH), 4.22(dd, J=13.6, 2.08Hz, 1-OH), 4.13-4.09(m, 1H), 3.77(q, J=7. 12Hz, 2H), 3.64-3.59(m, 3H), 3.45-3.41(m, 1H), 3.10(t, J=7.2Hz, 2H), 2.38(s, 3H), 2.32(s, 3H).

[0223] 13 C NMR (DMSO-d6, 100MHz) δ 163.74, 154.42, 153.09, 148.41, 142.23, 133.10, 132.51, 130.89, 130.26, 122.04, 121.36 , 118.68, 116.57, 111.32, 74.19, 73.12, 69.10, 63.89, 44.96, 37.75, 29.16, 20.76, 19.10.

[0224] <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

[0225] The same method was used as in Example 1, except that arylamine (III, R=a18) was used instead of arylamine (III, R=a1), to obtain the compound of Example 18 as a bright yellow solid (21 mg, 14.8% yield).

[0226] ESI LC / MS:m / z calcd.for:C 25 H 29 N3O8[M+H] + :500.51;found 500.15. 1 H NMR (CD3OD, 400MHz) δ 8.01(d, J=6.88Hz, 2H), 7.80(s, 1H), 7.70(s, 1H), 7.54(t, J=8.32Hz, 1H), 4.78(q, J=9.84Hz, 1H), 4.76(s, 2H), 4.38( dd.

[0227] 13 C NMR(CD3OD, 100MHz) δ 166.93, 463.65, 144.05, 143.79, 143.55, 134.00, 132.47, 131.25, 130.47, 129.94, 12 8.94, 127.25, 115.79, 73.67, 72.78, 69.73, 63.41, 51.18, 44.87, 42.74, 19.44, 17.73.

[0228] <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

[0229] The same method was repeated in Example 1, except that arylamine (III, R=a19) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 19 (112 mg, 52.57% yield).

[0230] ESI LC / MS:m / z calcd.for:C 25 H 29 N3O8[M+H] + :500.51;found 500.10. 1 H NMR (DMSO-d6, 400MHz) δ 11.13(s, 1H), 7.69(s, 1H), 7.65-7.62(m, 3H), 7.35-7.31(m, 1H), 7.03(d, J =7.6Hz, 1H), 4.99(s, 1H), 4.84(s, 1H), 4.69(d, J=6.28Hz, 1H), 4.65(q, J=10 .04Hz, 1H), 4.49-4.47(s, 1H), 4.26(d, J=13.68Hz, 1H), 4.17-4.15(m, 1H), 3 .70(s, 2H), 3.63-3.60(m, 6H), 3.46-3.44(m, 1H), 2.40(s, 3H), 2.34(s, 3H).

[0231] 13 C NMR (DMSO-d6, 100MHz)177.97, 162.23, 154.33, 148.92, 142.42, 138.94, 135.67, 133.26, 132.58, 130.88, 130.28, 129.48, 125.56, 120.81, 118.55, 116.66, 74.20, 73.15, 69.20, 63.91, 52.22, 45.02, 20.79, 19.11.

[0232] <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

[0233] The same method as in Example 1 was repeated, except that arylamine (III, R=a20) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 20 (32 mg, 46.6% yield).

[0234] ESI LC / MS:m / z calcd.for:C 24 H 27 N3O8[M+H] + :486.48;found 486.20. 1 H NMR (DMSO-d6, 400MHz) δ 11.41(s, 1H), 7.99(d, J=8.72Hz, 2H), 7.86(d, J=8.76Hz, 2H), 7.70(s, 1H), 7.66(s, 1H), 5.01(s, 1H), 4.85(s, 1H), 4.70(d, J=6.28Hz, 1H), 4.65(q, J=10 .12Hz, 1H), 4.51-4.48(m, 1H), 4.26(d, J=13.68Hz, 1H), 4.17-4.15(m, 1H), 3 .86(s, 3H), 3.65-3.61(m, 3H), 3.46-3.42(m, 1H), 2.41(s, 3H), 2.34(s, 3H).

[0235] 13C NMR (DMSO-d6, 100MHz) δ 177.22, 162.75, 154.19, 148.76, 143.17, 142.63, 133.35, 132.64, 130.96, 130.83, 130 .29, 125.22, 119.54, 116.69, 74.19, 73.14, 69.19, 63.90, 52.45, 45.04, 20.81, 19.10.

[0236] <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

[0237] The same method was used as in Example 1, except that arylamine (III, R=a21) was used instead of arylamine (III, R=a1), to obtain the compound of Example 21 as a bright yellow solid (6 mg, 8.3% yield).

[0238] ESI LC / MS:m / z calcd.for:C 26 H 31 N5O6[M+H] + :510.55;found 510.20. 1 H NMR (CD3OD, 400MHz) δ 7.75(s, 1H), 7.69-7.65(m, 3H), 7.46-7.43(m, 2H), 4.79-7.63(m, 2H), 4.46-4.40(m, 1H), 4.28-4.25(m, 1H), 3.87-3.79(m, 2H), 3.73-3.65(m, 3H), 3.01(s, 1H), 2.88(s, 1H), 2.50(s, 3H), 2.42(s, 3H), 2.36-2.32(m, 2H).

[0239] <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

[0240] The same method was used as in Example 1, except that arylamine (III, R=a22) was used instead of arylamine (III, R=a1), to obtain the compound of Example 22 as a bright yellow solid (10 mg, 14.67% yield).

[0241] ESI LC / MS:m / z calcd.for:C 25 H 28 N4O6[M+H] + :481.51;found 481.20. 1 H NMR (CD3OD, 400MHz) δ 7.68(s, 1H), 7.60(m, 1H), 7.48(d, J=8.08Hz, 1H), 7.47-7.34(m, 2H), 7.22-7.21(m, 1H), 7.04(d, J=8.12Hz, 1H), 4 .79-4.60(m, 4H), 4.37(dd, J=13.88, 2.04Hz, 1H), 4.27-4.18(m, 2H), 3.83-3.65(m, 6H), 2.42(s, 3H), 2.33(s, 3H).

[0242] <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

[0243] The same method was repeated in Example 1, except that arylamine (III, R=a23) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 23 (34 mg, 48.5% yield).

[0244] ESI LC / MS:m / z calcd.for:C 25 H 27 N5O6[M+H] + :494.51;found 494.15. 1 H NMR (DMSO-d6, 400MHz) δ 11.12(s, 1H), 8.23(s, 1H), 7.87-7.84(m, 2H), 7.73-7.72(m, 2H), 7.68-7.66 (m, 3H), 7.10(s, 1H), 5.01(s, 1H), 4.86(s, 1H), 4.70(d, J=6.33Hz, 1H), 4.66( d, J=13.67Hz, 1H), 4.50-4.48(m, 1H), 4.26(dd, J=13.76, 2.08Hz, 1H), 4.18- 4.15(m, 1H), 3.66-3.62(m, 3H), 3.47-3.44(m, 1H), 2.41(s, 3H), 2.34(s, 3H).

[0245] 13C NMR (DMSO-d6, 100MHz) δ 162.34, 154.25, 148.82, 142.53, 137.58, 135.91, 133.31, 132.62, 130.85, 130.25, 121.19, 12 1.08, 118.49, 116.69, 74.20, 73.16, 69.19, 66.94, 63.91, 45.02, 36.24, 31.35, 20.80, 19.12.

[0246] <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

[0247] The same method was repeated in Example 1, except that arylamine (III, R=a24) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 24 (7.8 mg, 14.3% yield).

[0248] ESI LC / MS:m / z calcd.for:C 24 H 27 N5O6[M+H] + :482.50;found 482.19. 1 H NMR (CD3OD, 400MHz) δ7.80(s, 1H), 7.74(s, 1H), 7.69-7.66(m, 2H), 7.46-7.43(m, 2H), 5.09(s, 2H), 4.82(s, 1H), 4 .53(dd, J=14.04, 2.44Hz, 1H), 4.34-4.30(m, 1H), 3.86-3.79(m, 3H), 3.73-3.68(m, 1H), 2.51(s, 3H), 2.41(s, 3H).

[0249] <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

[0250] The same method was repeated in Example 1, except that arylamine (III, R=a25) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 25 (9 mg, 21.9% yield).

[0251] ESI LC / MS:m / z calcd.for:C 22 H 29 N5O6[M+H] + :460.22;found 460. 1 H NMR(MeOD, 400MHz)δ 8.00(s, 1H), 7.79(q, J=12.24Hz, 3H), 7.59(s, 1H), 7.70(d, J=8.56Hz, 2H), 4.43(t, J=6.8Hz, 2H), 3.83- 3.80(m, 2H), 3.56-3.50(m, 2H), 3.01(s, 3H), 2.88(s, 3H), 2.51(s, 3H), 2.42(s, 3H), 2.30-2.28(m, 2H).

[0252] <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

[0253] The same method was repeated in Example 1, except that arylamine (III, R=a26) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 26 (20 mg, 43.9% yield).

[0254] ESI LC / MS:m / z calcd.for:C 27 H 32 N4O6[M+H] + :509.24;found 509.30. 1 H NMR (MeOD, 400MHz) δ 7.78(s, 1H), 7.70(s, 1H), 7.52(dd, J=22.72, 7.88Hz, 2H), 7.29(d, J=0.7 2Hz, 1H), 7.16-7.12(m, 1H), 7.01-6.97(m, 1H), 6.44(q, J=0.72Hz, 1H), 4 .35(t, J=6.84Hz, 3H), 3.84-3.83(m, 3H), 3.82-3.80(m, 3H), 3.75(t, J=6 .6Hz, 2H), 3.49(q, J=6.72Hz, 2H), 2.83(s, 2H), 2.50(s, 3H), 2.41(s, 3H).

[0255] <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

[0256] The same method was repeated in Example 1, except that arylamine (III, R=a27) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 27 (8.5 mg, 18.8% yield).

[0257] ESI LC / MS:m / z calcd.for:C 26 H 30 N4O7[M+H] + :511.21;found 511.27. 1 H NMR(MeOD, 400MHz)δ 7.81(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=12.5 2Hz, 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).

[0258] 13 C NMR (DMSO-d6, 100MHz) δ 163.56, 154.42, 150.67, 148.65, 133.04, 132.50, 131.27, 130.90, 130.29, 128.29, 123.69, 116 .55, 112.14, 111.77, 111.02, 102.69, 74.22, 73.13, 69.12, 63.90, 44.91, 25.64, 20.76, 19.12.

[0259] <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

[0260] The same method as in Example 1 was repeated, except that arylamine (III, R=a28) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 28 (13 mg, 29.8% yield).

[0261] ESI LC / MS:m / z calcd.for:C 26 H 31 N5O6[M+H] + :510.23;found 510.30. 1 H NMR(MeOD, 400MHz)δ 8.06(d, J=8.08Hz, 1H), 7.86(dd, J=7.6, 2.2Hz, 1H), 7.79(s, 1H), 7.72-7.64(m, 3H), 4.83(d, J=3.2Hz, 1H), 4.80-4.67(m, 3H), 4.65-4.60(m, 1H), 4.58-4.47(m, 1H), 4.33-4.30(m, 1H), 3.84-3.81(m, 2H), 3.62(t, J=6.16Hz, 3H), 2.51(s, 3H), 2.42(s, 3H).

[0262] <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

[0263] The same method as in Example 1 was repeated, except that arylamine (III, R=a29) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 29 (21 mg, 49.1% yield).

[0264] ESI LC / MS:m / z calcd.for:C 26 H 30 N4O7[M+H]+ :495.26;found 495.22. 1 H NMR(MeOD, 400MHz)δ 7.79(s, 1H), 7.69(s, 1H), 7.45(d, J=7.76Hz, 1H), 7.31(d, J=8.04Hz, 1H), 7.05-7.01(m, 1H), 6.97(q, J=0.92Hz, 1H) , 4.49(dd, J=14.0, 2.48Hz, 1H), 4.30-4.26(m, 1H), 3.88-3.69(m, 6H), 3.15-3.12(m, 2H), 2.49(s, 3H), 2.40(s, 3H).

[0265] <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

[0266] The same method was repeated in Example 1, except that arylamine (III, R=a30) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 30 (24.6 mg, 56.3% yield).

[0267] ESI LC / MS:m / z calcd.for:C 25 H 29 N3O8[M+H] + :500.27;found 500.20. 1H NMR(DMSO, 400MHz)δ 8.70(d, J=1.68Hz, 1H), 7.77(s, 1H), 7.71(q, J=1.72Hz, 2H), 7.45(d, J=8.00Hz, 1H), 5.03(d, J=4.56Hz, 1H), 4.87(q, J=4.48Hz, 1H), 4.74-4.7 0(m, 2H), 4.49-4.47(m, 1H), 4.31-4.28(m, 1H), 4.18-4.17(m, 1H), 3.6 3(d, J=3.92Hz, 3H), 2.68-2.66(m, 3H), 2.36(s, 3H), 2.33-2.31(m, 3H).

[0268] <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

[0269] The same method as in Example 1 was repeated, except that arylamine (III, R=a31) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 31 (20 mg, 44.3% yield).

[0270] ESI LC / MS:m / z calcd.for:C 27 H 32 N4O6[M+H] + :509.29;found 509.24. 1H NMR(MeOD, 400MHz)δ 7.65(s, 1H), 7.61(s, 1H), 7.53(d, J=8.00Hz, 1H), 7.34(d, J=8.08Hz, 1H), 7.16(d, J=2 .24Hz, 1H), 6.96-6,91(m, 1H), 4.97(d, J=4.68Hz, 1H), 4.85-4.82(m, 1H), 4.67-4.58( m, 2H), 4.47(t, J=5.54Hz, 1H), 4.24-4.21(m, 1H), 4.13-4.12(m, 1H), 3.64-3.61(m, 3H) ), 3.60-3.59(m, 1H), 2.79(t, J=7.4Hz, 1H), 2.68(d, J=7.24Hz, 2H), 1.92-1.88(m, 2H).

[0271] <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

[0272] The same method was repeated in Example 1, except that arylamine (III, R=a32) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 32 (2.8 mg, 6.10% yield).

[0273] ESI LC / MS:m / z calcd.for:C 23 H 25 N5O6[M+H] + :468;found 468.18. 1H NMR(DMSO, 400MHz)δ 8.30(s, 1H), 8.09(s, 1H), 7.76-7.66(m, 2H), 7.56-7.50(m, 2H), 4.69-4.63(m, 2H), 4.29-4.27(m, 1H), 4.17-4.15 (m, 1H), 3.65-3.62(m, 4H), 2.89(s, 2H), 2.73-2.66(m, 6H), 2.41(s, 5H), 2.35(s, 4H), 2.34-2.31(m, 6H)(Mixture form:purity:80%).

[0274] <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

[0275] The same method was repeated in Example 1, except that arylamine (III, R=a33) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 33 (25 mg, 46% yield).

[0276] ESI LC / MS:m / z calcd.for:C 23 H 31 N3O8[M+H] + :478.22;found 478.21. 1H NMR(DMSO, 400MHz)δ 7.64(s, 1H), 7.60(s, 1H), 7.79(s, 1H), 4.63-4.57(m, 1H), 4.28-4.20(m, 2H), 4.12-4.10(m, 1H), 4.65-4.60(m, 1H), 3.62(s, 7H) , 2.89-2.87(m, 1H), 2.39(s, 3H), 2.33-2.27(m, 5H), 1.98-1.95(m, 1H), 1.90-1.86(m, 2H), 1.71-1.68(m, 1H), 1.61-1.58(m, 1H).

[0277] <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

[0278] The same method was repeated in Example 1, except that arylamine (III, R=a34) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 34 (6 mg, 14.28% yield).

[0279] ESI LC / MS:m / z calcd.for:C 24 H 27 N5O6[M+H] + :482.24;found 482.20. 1 H NMR(DMSO, 400MHz)δ 7.79-7.76(m, 2H), 7.64(d, J=10.1Hz, 2H), 7.53-7.51(m, 1H), 4.69-4.60(m, 3H), 4.25-4.2 1(m, 1H), 4.14(d, J=10.2Hz, 1H), 3.63-3.60(m, 3H), 2.89(s, 1H), 2.39(s, 3H), 2.33(s, 3H).

[0280] <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

[0281] The same method was repeated in Example 1, except that arylamine (III, R=a35) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 35 (14 mg, 10.01% yield).

[0282] ESI LC / MS:m / z calcd.for:C 23 H 24 FN5O6[M+H] + :486.12;found 486.17. 1 H NMR(MeOD, 400MHz)δ 7.87(s, 1H), 7.78(s, 1H), 7.38(d, J=8.36Hz, 1H), 7.22-7.17(m, 1H), 7.00-6.95(m, 1H), 4.63-4.59(m, 2H), 4.39-4.3 3(m, 1H), 3.88-3.86(m, 3H), 3.75-3.72(m, 1H), 3.84-3.81(m, 2H), 3.62(t, J=6.16Hz, 3H), 2.51(s, 3H), 2.43(s, 3H).

[0283] <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

[0284] The same method as in Example 1 was repeated, except that arylamine (III, R=a36) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 36 (10 mg, 11.68% yield).

[0285] ESI LC / MS:m / z calcd.for:C 23 H 24 BrNO6[M+H] + :548.10;found 548.09. 1 H NMR(MeOD, 400MHz)δ 7.81(s, 1H), 7.77(s, 1H), 7.79(s, 1H), 7.66(d, J=8.16Hz, 1H), 7.58(d, J=7.88Hz, 1H), 7.34-7.32(m, 1H), 4.43(d, J=9 .28Hz, 1H), 3.90-3.86(m, 3H), 3.77-3.74(m, 1H), 3.50-3.48(m, 1H), 3.15(t, J=1.68Hz, 1H), 2.47(s, 3H), 2.38(s, 3H).

[0286] <Example 37> 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

[0287] The same method was repeated in Example 1, except that arylamine (III, R=a37) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 37 (50 mg, 63.3% yield).

[0288] ESI LC / MS:m / z calcd.for:C 26 H 29 ClN4O6[M+H] + :529.17;found 529.18. 1 H NMR(DMSO, 400MHz)δ 7.66(s, 2H), 7.61(s, 1H), 7.37-7.33(m, 2H), 7.72-7.64(m, 3H), 7.08(d, J=1.88Hz, 1H), 4.64-4.53(m, 1 H), 3.64-3.54(m, 4H), 2.95-2.92(m, 2H), 2.75(s, 3H), 2.67(d, J=1.92Hz, 1H), 2.39(s, 3H), 2.33(s, 3H).

[0289] <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

[0290] The same method was repeated in Example 1, except that arylamine (III, R=a38) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 38 (35 mg, 29.2% yield).

[0291] ESI LC / MS:m / z calcd.for:C 25 H 28 FN5O6[M+H] + :514.08;found 514.21. 1 H NMR(MeOD, 400MHz)δ 7.79-7.76(m, 1H), 7.61(s, 1H), 7.55-7.53(d, 2H), 7.40-7.35(m, 1H), 4.73-4.68(m, 1H), 4.33-4.30(m, 1H), 4.24-4. 22(m, 1H), 4.02(d, J=3.8Hz, 2H), 3.86-3.78(m, 3H), 3.72-3.69(m, 1H), 3.60-3.57(m, 2H), 2.48(s, 3H), 2.34(s, 3H).

[0292] <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

[0293] The same method was repeated in Example 1, except that arylamine (III, R=a39) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 39 (2 mg, 1.26% yield).

[0294] ESI LC / MS:m / z calcd.for:C 23 H 25 N5O7[M+H] + :483.99;found 484.18. 1 H NMR(MeOD, 400MHz)δ 7.92(s, 1H), 7.84(s, 1H), 7.31(t, J=7.92Hz, 1H), 7.21(d, J=8.04Hz, 1H), 6.91(d, J=8.04Hz, 1H), 4. 13(q, J=7.20Hz, 1H), 3.86(s, 3H), 3.18(s, 1H), 3.01(s, 2H), 2.55(s, 3H), 2.46(s, 3H), 2.33(s, 2H).

[0295] <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

[0296] The same method was repeated in Example 1, except that arylamine (III, R=a40) was used instead of arylamine (III, R=a1), to obtain a yellow solid compound of Example 40 (6 mg, 34.7% yield).

[0297] ESI LC / MS:m / z calcd.for:C 31 H 38 N4O8[M+H] + :595.17;found 595.27. 1 H NMR (MeOD, 400MHz) δ7.82(s, 1H), 7.70(s, 1H), 7.35-7.37(m, 1H), 7.25-7.21(m, 2H), 6.75(d, J=8.24Hz, 1H), 4.57(d, J=7.32Hz) , 1H), 4.46-4.42(m, 1H), 4.13(d, J=3.64Hz, 1H), 3.82-3.76(m, 6H), 3.12-3.08(m, 2H), 2.48(s, 3H), 2.41(s, 3H), 1.29(s, 9H).

[0298] The compounds of Examples 41 to 45 were prepared according to the method of the following Reaction Scheme B.

[0299] [ka]

[0300] In the above reaction formula B, -R of compound VI is the following b1 to b3.

[0301] [ka]

[0302] Specific production methods of Examples 41 to 45 are described below.

[0303] <Example 41> Preparation of N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide

[0304] In the above Reaction Formula B, when compound VI (R=b1) was used, the compound of Example 41 was obtained as a yellow solid (22 mg, 24% yield).

[0305] ESI LC / MS:m / z calcd.for:C 22 H 22 N4O3[M+H] + :391.85;found 391.17. 1 H NMR(DMSO, 400MHz)δ 7.67(s, 1H), 7.45(s, 1H), 7.14(q, J=4.72Hz, 2H), 6.88(d, J=2.0Hz, 1H), 6.61(q, J=2.1 6Hz, 1H), 3.55(s, 3H), 3.54-3.52(m, 2H), 2.88-3.84(m, 2H), 2.42(s, 3H), 2.33(s, 3H).

[0306] <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

[0307] In the above Reaction Formula B, when compound VI (R=b2) was used, the compound of Example 42 was obtained as a yellow solid (28 mg, 38% yield).

[0308] ESI LC / MS:m / z calcd.for:C 21 H 20 FN5O2[M+H] + :394.05;found 394.16. 1 H NMR(DMSO, 400MHz)δ 7.74-7.71(m, 1H), 7.63(s, 1H), 7.79(s, 1H), 7.60(d, J=9.08Hz, 1H), 7.47(s, 1H), 7.30(t, J= 9.00Hz, 1H), 3.82-3.80(m, 2H), 3.64(s, 4H), 2.67(d, J=1.8Hz, 1H), 2.42(s, 3H), 2.33(s, 3H).

[0309] <Example 43> Preparation of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide

[0310] In the above Reaction Formula B, when compound VI (R=b3) was used, the compound of Example 43 was obtained as a yellow solid (22 mg, 10.5% yield).

[0311] ESI LC / MS:m / z calcd.for:C 22 H 21 ClN4O2[M+H] + :409.02;found 409.14. 1 H NMR(DMSO, 400MHz)δ 7.67(s, 1H), 7.65(d, J=1.84Hz, 1H), 7.45(s, 1H), 7.37(d, J=8.6Hz, 1H), 7.32(s, 1H), 7.08-7.0 5(m, 1H), 3.65(s, 1H), 3.59(t, J=7.16Hz, 2H), 2.97(t, J=7.16Hz, 2H), 2.43(s, 3H), 2.34(s, 3H).

[0312] <Example 44> Preparation of methyl 4-methyl-3-(4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)benzoate

[0313] In the above-mentioned Reaction Formula B, methyl 3-amino-4-methylbenzoate was added to compound V to obtain the compound of Example 44 as a yellow solid (102 mg, 62.4% yield).

[0314] ESI LC / MS:m / z calcd.for:C 21 H 22 N3O4[M+H] + :380.16;found 380.03.

[0315] <Example 45> Preparation of N-(5-(hydroxycarbamoyl)-2-methylphenyl)-4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamide

[0316] The compound of Example 44 was mixed with THF, and the mixture was added to a solution of 0.5 equivalents of sodium cyanide and methanol. Then, 20 equivalents of 50% aqueous hydroxylamine was added, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuum, and the resulting residue was filtered with a microfiler and purified using a preparative HLPC (solvent system: acetonitrile, water) to obtain the compound of Example 45 as a yellow solid (2.9 mg, 13.84% yield).

[0317] ESI LC / MS:m / z calcd.for:C 20 H 20 N4O4[M+H] + :381.05;found 381.15. 1 H NMR(MeOD, 400MHz)δ 8.40(s, 1H), 7.80(d, J=8.16Hz, 1H), 7.55(s, 1H), 7.47(d, 3H), 7.36(d, J=8. 10Hz, 1H), 3.73(s, 3H), 2.67(s, 1H), 2.33(s, 6H), 2.29(s, 1H), 1.24(s, 2H).

[0318] The compounds of Examples 46 to 52 were prepared by the method of the following Reaction Scheme C.

[0319] [ka]

[0320] In the above reaction formula C, -R of compound I is the following c1 to c7.

[0321] [ka]

[0322] Specific production methods of Examples 46 to 52 are described below.

[0323] <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

[0324] In the above Reaction Formula C, compound I (R=c1) was used to obtain the compound of Example 46 as a yellow solid (7 mg, 46.6% yield).

[0325] ESI LC / MS:m / z calcd.for:C 24 H 28 N4O8[M+H] + :501.50;found 501.20. 1 H NMR (CD3OD, 400MHz) δ 11.13(s, 1H), 7.70(s, 1H), 7.68-7.64(m, 2H), 7.46(s, 1H), 7.22(t, J=7.8Hz, 1H), 6.99(d, J=7.64Hz, 1H), 4.67(q, J=10.24Hz, 1H) ), 4.28(d, J=11.72Hz, 1H), 4.15(d, J=9.56Hz, 1H), 3.65-3.61(m, 3H), 3.47-3.45(s, 1H), 3.10(s, 2H), 2.40(s, 3H), 2.33(s, 3H).

[0326] <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

[0327] In the above Reaction Formula C, compound I (R=c2) was used to obtain the compound of Example 47 as a yellow solid (3.1 mg, 30.9% yield).

[0328] ESI LC / MS:m / z calcd.for:C 24 H 28 N4O8[M+H] + :501.50;found 501.23. 1 H NMR (CD3OD, 400MHz) δ 7.82-7.80(m, 2H), 7.77-7.75(m, 1H), 7.71-7.70(m, 1H), 7.53(d, J=8.2Hz, 1H), 7.45(d, J=8.4Hz, 1H), 4.75(s, 1H), 4.72( s, 2H), 4.49(dd, J=13.96, 2.6Hz, 1H), 4.31-4.28(m, 1H), 3.85-3.78(m, 3H), 3.72-3.67(m, 1H), 2.50(s, 3H), 2.41(s, 3H).

[0329] <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

[0330] In the above Reaction Formula C, when compound I (R=c3) was used, the compound of Example 48 was obtained as a yellow solid (2.4 mg, 15.9% yield).

[0331] ESI LC / MS:m / z calcd.for:C 23 H 26 N4O8[M+H] + :487.47;found 487.20. 1 H NMR (CD3OD, 400MHz) δ 7.91-7.88(m, 2H), 7.83-7.79(m, 3H), 7.72(s, 1H), 4.53(dd, J=14, 2.6Hz, 2H), 4. 35-4.31(m, 1H), 3.86-3.79(m, 3H), 3.72-3.68(m, 1H), 2.49(s, 3H), 2.41(s, 3H).

[0332] <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

[0333] In the above Reaction Formula C, when compound I (R=c4) was used, the compound of Example 49 was obtained as a yellow solid (1.2 mg, 13.2% yield).

[0334] ESI LC / MS:m / z calcd.for:C 25 H 30 N4O8[M+H] + :515.52;found 515.24. 1H NMR (CD3OD, 400MHz) δ 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).

[0335] <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

[0336] In the above Reaction Formula C, when compound I (R=c5) was used, the compound of Example 50 was obtained as a yellow solid (1.5 mg, 14.9% yield).

[0337] ESI LC / MS:m / z calcd.for:C 24 H 28 N4O8[M+H] + :501.50;found 501.17. 1 H NMR (CD3OD, 400MHz) δ 7.84-7.79(m, 2H), 7.73-7.66(m, 2H), 7.64-7.59(m, 1H), 7.46(t, J=7.68Hz, 1H), 4.80-4.71(m, 3H), 4.58(s, 1H), 4 .47(dd, J=13.92, 2.48Hz, 1H), 4.29-4.26(m, 1H), 3.83-3.75(m, 3H), 3.69-3.65(m, 1H), 2.48(s, 3H), 2.39(s, 3H).

[0338] <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

[0339] In the above Reaction Formula C, when compound I (R=c6) was used, the compound of Example 51 was obtained as a yellow solid (3.2 mg, 21.9% yield).

[0340] ESI LC / MS:m / z calcd.for:C 24 H 28 N4O8[M+H] + :501.50;found 501.21. 1 H NMR (CD3OD, 400MHz) δ8.62(s, 1H), 7.83(s, 1H), 7.71(s, 1H), 7.49(dd, J=7.84, 1.72Hz, 1H), 7.36(d, J=7.96Hz, 1H), 4.58(s, 1H), 4.55(dd, J=14.04, 2.52Hz, 1H), 4.38-4.34(m, 1H), 3.86-3.81(m, 3H), 3.73-3.69(m, 1H), 2.46(s, 3H), 2.45(s, 3H), 2.38(s, 3H).

[0341] <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

[0342] In the above Reaction Formula C, when compound I (R=c7) was used, the compound of Example 52 was obtained as a yellow solid (1.8 mg, 8.72% yield).

[0343] ESI LC / MS:m / z calcd.for:C 22 H 30 N4O8[M+H] + :479.22;found 479.21. 1 H NMR(MeOD, 400MHz)δ 7.80(s, 1H), 7.70(s, 1H), 7.79(s, 1H), 4.53-4.48(m, 2H), 4.31-4.28(m, 1H), 3.87-3.73(m, 3H), 3.71-3.68(m, 1H), 3. 32(s, 1H), 2.74-2.70(m, 1H), 2.49(s, 3H), 2.41-2.32(m, 4H), 2.16-2.12(m, 1H), 2.02-1.96(m, 2H), 1.90-1.84(m, 2H).

[0344] The compounds of Examples 1 to 52 are summarized in Table 1 below.

[0345] [Table 1] JPEG2025510702000018.jpg230146JPEG2025510702000019.jpg224145JPEG2025510702000020.jpg231149JPEG2025510702000021.jpg162146

[0346] <Comparative Example>

[0347] As comparative examples, TSA (Trichostatin A), SAHA (suberoylanilide hydroxamic acid), and PCI-34051 (N-hydroxy-1-(4-methoxybenzyl)-1H-indole-6-carboxamide), which are known to be HDAC8 inhibitors, were prepared.

[0348] [ka]

[0349] [ka]

[0350] [ka]

[0351] cell culture

[0352] PC-3, a human prostate cancer cell line, was cultured in RPMI1640 (10% fetal bovine serum, 1% penicillin streptomycin) medium at 37°C and 5% CO2. All cells in the experimental process were subcultured when they reached a density of 80-90%, and only cells that had not been cultured for more than 20 passages were used.

[0353] statistical analysis

[0354] All data are presented as the mean ± standard deviation (SD) from at least three independent experiments, and the statistical significance of differences was determined by unpaired Student's test using GrahPad Prism 5. P values ​​less than 0.05 were considered statistically significant.

[0355] <Experimental Example 1> HDAC8 inhibitory activity analysis (in vitro) - RFU analysis

[0356] To confirm the HDAC enzyme activity of the compounds of the examples, the HDAC Fluorogenic assay kit from BPS bioscience was used to measure the activity. HDAC substrate 2A was diluted in buffer to a concentration of 20 μM and used for analysis. The compounds of the examples were diluted to 1 mM (1% DMSO concentration) using DMSO to a final concentration of 10 μM, and then diluted 1 / 10 with assay buffer. 5 μL of the diluted compounds of the examples, 5 μL of HDAC substrate 2A prepared by dilution, 5 μL of BSA (1 mg / mL), 5 μL of HDAC8 enzyme prepared by dilution according to the concentration, and 30 μL of assay buffer were placed in a black round-bottom 96-well plate, and the enzyme reaction was carried out at 37° C. for 30 minutes. The blank did not contain HDAC8 enzyme, the positive control was 100% HDAC8 enzyme activity value with 1% DMSO, and the inhibitor control used TSA, SAHA, and PCI-34051 compounds. Then, 50μL of 2X HDAC developer was added to each well. After 15 minutes of reaction at room temperature, the fluorescence intensity was measured at excitation 350-380nm and emission 440-460nm wavelengths using a microplate reader (Synergy Neo). The results were calculated by averaging the blank values, subtracting the average blank value for each value, and setting the positive control value to 100.

[0357] The results are shown in Table 2 below. From the results, it was confirmed that the 3,4-dihydroquinoxaline-2-carboxamide derivative compounds of the Examples exhibited inhibitory activity against HDAC8, and in particular, the compounds of Examples 10, 27, 34, 35, 48, 49, and 51 exhibited inhibitory activity similar to that of TSA or SAHA, which are known as existing HDAC8 inhibitors.

[0358] [Table 2]

[0359] <Experimental Example 2> Analysis of selective inhibition effect on HDAC8

[0360] In order to confirm the selective inhibitory effect of the compounds of the examples on HDAC8, the inhibitory activity was measured using the HDAC Fluorogenic assay kit of BPS bioscience. For the analysis, HDAC substrate 3 was diluted in buffer to a concentration of 200 μM and used in HDAC1, 2, 3, 6, and 10 assays, HDAC substrate 2A was diluted in buffer to a concentration of 200 μM and used in HDAC4, 7, 9, and 11 assays, and HDAC substrate 2A was diluted in buffer to a concentration of 20 μM and used in HDAC8 assay. For the HDAC11 assay, a dedicated buffer included in the kit was used separately, and the same buffer was used in the remaining assays. The compounds of the examples were diluted to 1 mM (1% DMSO concentration) using DMSO to a final concentration of 10 μM, and then diluted 1 / 10 with assay buffer to prepare the compounds. 5μL of the diluted compound of the Example, 5μL of diluted HDAC substrate, 5μL of BSA (1mg / ml), 5μL of HDAC enzyme diluted to each concentration, and 30μL of assay buffer were added to a black round-bottom 96-well plate, and the enzyme reaction was carried out at 37℃ for 30 minutes. Blank did not contain HDAC enzyme, positive control used 100% enzyme activity value with 1% DMSO, and inhibitor control used TSA compound. Then, 50μL of 2X HDAC developer was added to each well. After reacting at room temperature for 15 minutes, fluorescence values ​​at excitation 350-380nm and emission 440-460nm wavelengths were measured using a Microplate reader (Synergy Neo). The result values ​​were 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.

[0361] The results are shown in Table 3 below. As a result of the experiment, TSA, which is known as an existing HDAC8 inhibitor, showed a very high inhibitory effect not only on HDAC8 but also on HDAC1, HDAC2, HDAC6, and HDAC10, and also showed a high inhibitory effect on HDAC3, HDAC4, HDAC7, and HDAC9, and did not show a selective inhibitory effect on HDAC8. On the other hand, the compound of Example 27 was selective only for HDAC8 and showed excellent inhibitory activity.

[0362] [Table 3]

[0363] <Experimental Example 3> Analysis of the inhibitory activity on the growth of prostate cancer and hepatoma cells

[0364] To analyze the inhibitory effect of the compounds of the above examples on the growth of prostate cancer cells, prostate cancer cells PC-3 were treated with the compounds of Examples 27 and 35 and PCI-34051 at various concentrations, and the cell viability was confirmed on the first and second days using a CCK-8 assay. 4 The cells / mL were dispensed into a 96-well plate, and after 20 hours, PCI34051, Example 27, and Example 35 compounds were added at different concentrations and incubated in a 37°C, 5% CO2 incubator for 24 and 48 hours. After incubation, 10μL CCK-8 reagent was added, and the absorbance was measured after 1 hour. The absorbance was measured at 450nm using a microplate reader [BMG Labtech (Offenburg, Germany)]. The results are shown in Figure 1. It was confirmed that PCI-34051, known as an HDAC8 inhibitor, inhibits 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, showing a better cancer cell viability inhibition rate than PCI-34051. The compound of Example 35 showed a concentration-dependent cancer cell viability inhibition rate at 24 hours, even if the cell viability was restored after 48 hours.

[0365] Furthermore, the hepatoma growth inhibitory activity was analyzed. 4 After 20 hours, PCI34051, Example 27 and Example 35 were added at different concentrations and cultured at 37°C in a 5% CO2 atmosphere for 24 and 48 hours. After the culture, 100μL CellTiter-Glo® Luminescent Cell Viability Assay reagent was added, and luminescence signals were measured after 0.5-1 hour. Luminescence signals were measured using IVIS [PerkinElmer, (Waltham, USA)]. After treating hepatoma cell line Huh-7 with PCI-34051 (control group), Example 27 and Example 35 at various concentrations, cell viability was confirmed on the first day using CellTiter-Glo® Luminescent Cell Viability Assay. As a result, as shown in FIG. 6, Example 27 and Example 35 showed a concentration-dependent cancer cell viability inhibition rate, as with the control group.

[0366] <Experimental Example 4> Analysis of anti-cancer effects against prostate cancer and liver cancer

[0367] A prostate cancer model was established by subcutaneously implanting PC-3 cell lines into nude mice, and then the mice were divided into two groups (Group 1: vehicle administration group (10% DSMO, 30% PEG400, 60% DW), Group 2: 50 mg / kg of the compound of Example 27 administration group). The drug was orally administered once a day, 12 times. To evaluate the therapeutic efficacy, tumors were excised before and after drug administration, and on days 3, 6, 8, 10, 12, and 14, and the tumor volume was measured. Tumor volume (mm 3 ) was calculated as follows (tumor volume, mm 3 )=(AXB 2 ) / 2, A = tumor long axis, B = tumor shortening), and the results are shown in Figure 2. The vehicle administration group (Group 1) showed clear tumor growth up to 14 days after administration, while the tumor volume growth rate was significantly reduced in the group administered with the compound of Example 27 (Group 2) compared to Group 1, and statistical significance was confirmed ( *p<0.05, compared with vehicle).

[0368] On the 12th day after drug administration, the tumors were excised and weighed. The results are shown in FIG. 3, and the excised tumors were photographed and shown in FIG. 4. The tumor weight in the vehicle-administered group (Group 1) was definitely higher than that in the compound of Example 27-administered group (Group 2), and the statistical significance was also confirmed ( *** p<0.0005, compared with vehicle).

[0369] Furthermore, when the mouse body weight was checked during the drug administration period, no sudden weight loss was observed (Figure 5).

[0370] Furthermore, a liver cancer model was established by subcutaneously transplanting the Huh-7 cell line into nude mice. After establishing the liver cancer model, the mice were divided into two groups (Group 1: vehicle administration group, Group 2: 50 mg / kg of the compound of Example 27 administration group). The drug was administered intraperitoneally once a day, 12 times. To evaluate the therapeutic efficacy, the tumor volume was measured before drug administration, and on days 4, 7, 10, 13, and 15 after drug administration. Tumor size (mm 3 ) was calculated as follows (tumor size (mm 3 )=(AXB 2 ) / 2, A = tumor long axis, B = tumor shortening). During the drug administration period, body weight was measured before administration, after drug administration, and on days 4, 7, 10, 13, and 15. After drug treatment, tumors were excised on the 15th day and weighed.

[0371] As a result, the vehicle-administered group showed clear tumor growth up to 15 days after administration, but the group administered 50 mg / kg of the compound of Example 27 showed a tumor growth inhibitory effect, and the statistical significance of this effect was confirmed ( ** p<0.005, compared with vehicle) (FIG. 7A). After drug administration, the tumors were excised on the 15th day and weighed. As with the tumor volume measurement results, the tumor weight in the vehicle group was definitely higher than that in the group administered with the compound of Example 27, and statistical significance was also confirmed ( ***p<0.0005, compared with vehicle) (FIGS. 7B and 7C). No rapid weight loss was observed during the drug administration period (FIG. 7D).

[0372] Although the present invention has been described in detail through preferred embodiments and experimental examples, the scope of the present invention is not limited to the specific embodiments, but should be interpreted according to the appended claims. In addition, those skilled in the art should understand that many modifications and variations are possible without departing from the scope of the present invention.

Claims

1. A compound represented by the following chemical formula 1, a stereoisomer thereof, a hydrate thereof, or a salt thereof: 【Chemistry 1】 In the above Chemical Formula 1, R １ is unsubstituted or substituted C ５－８ Cycloalkyl, unsubstituted or substituted C ６－１０ aryl, an unsubstituted or substituted 5-8 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, an unsubstituted or substituted 8-10 atom fused heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, or C １－１５ alkenyl, The substituted C ５－８ Cycloalkyl is halogen, -CONH-OH, -CH ２ -CONH-OH, -CH ２ CH ２ -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 substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy; The substituted C ６－１０ Aryl is halogen, -CONH-OH, -CH ２ -CONH-OH, -CH ２ CH ２ -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 substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy and heteroaryl having 5 to 8 atoms and containing one or more heteroatoms selected from the group consisting of N, O and S; The substituted 5-8 heteroaryl is a halogen or a C substituted with a halogen. ６－１０ the aryl is substituted; The substituted 8-10 atom fused heteroaryl is selected from the group consisting of -OH, halogen, C １－８ Alkoxycarbonyl, C １－８ Alkoxycarbonyl C １－５ Alkyl, and C １－８ substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy; R ２ and R ３ are each independently -H, a halogen, or C １－１０ is alkyl; R ４ is C １－８ C substituted with two or more alkyl or -OH ３－１０ is alkyl; and L １ is a bond, or C １－１０ It is alkylene.

2. The R １ is unsubstituted or substituted C ５－６ Cycloalkyl, unsubstituted or substituted C ６－８ aryl, an unsubstituted or substituted 5-6 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, an unsubstituted or substituted 8-10 atom fused heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, or C ５－１５ alkenyl, The substituted C ５－６ Cycloalkyl is halogen, -CONH-OH, -CH ２ -CONH-OH, -CH ２ CH ２ -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 substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy; The substituted C ６－８ Aryl is halogen, -CONH-OH, -CH ２ -CONH-OH, -CH ２ CH ２ -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 substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy and heteroaryl having 5 to 6 atoms and containing one or more heteroatoms selected from the group consisting of N, O and S; The substituted 5-6 atom heteroaryl is a halogen or a C substituted with a halogen. ６－８ the aryl is substituted; The substituted 8-10 atom fused heteroaryl is selected from the group consisting of -OH, halogen, C １－６ Alkoxycarbonyl, C １－６ Alkoxycarbonyl C １－３ Alkyl, and C １－６ The compound according to claim 1, its stereoisomer, its hydrate or its salt, wherein one or more substituents selected from the group consisting of alkylcarbonyloxy are substituted.

3. The R １ is unsubstituted or substituted C ５－６ Cycloalkyl, unsubstituted or substituted C ６－８ aryl, an unsubstituted or substituted 5-6 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, an unsubstituted or substituted 8-10 atom fused heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, or C ６－１２ alkenyl, The substituted C ５－６ Cycloalkyl is halogen, -CONH-OH, -CH ２ -CONH-OH, -CH ２ CH ２ -CONH-OH,C １－５ Alkyl, C １－５ Haloalkyl, and C １－５ alkoxycarbonyl; The substituted C ６－８ Aryl is halogen, -CONH-OH, -CH ２ -CONH-OH, -CH ２ CH ２ -CONH-OH,C １－５ Alkyl, C １－５ Alkoxy, C １－５ Haloalkyl, C ６ Aryl, C １－５ Alkoxycarbonyl, C １－５ Alkoxycarbonyl C １－３ Alkyl, C １－５ substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy and heteroaryl having 5 to 6 atoms and containing one or more heteroatoms selected from the group consisting of N, O and S; The substituted 5-6 atom heteroaryl is a halogen or a C substituted with a halogen. ６ the aryl is substituted; The substituted 8-10 atom fused heteroaryl is selected from the group consisting of -OH, halogen, C １－５ Alkoxycarbonyl, C １－５ Alkoxycarbonyl C １－３ Alkyl, and C １－５ The compound according to claim 1, its stereoisomer, its hydrate or its salt, wherein one or more substituents selected from the group consisting of alkylcarbonyloxy are substituted.

4. The R １ teeth, 【Chemistry 2】 The compound according to claim 1, its stereoisomer, its hydrate or a salt thereof,

5. The R ２ and R ３ are each independently -H, a halogen, or C １－５ The compound according to claim 1, its stereoisomer, its hydrate or its salt, wherein R is an alkyl group.

6. Said L １ is a bond, or C １－５ The compound according to claim 1, wherein the alkylene is a stereoisomer, a hydrate or a salt thereof.

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

8. The compound represented by Chemical Formula 1 is a compound represented by Chemical Formula 2 below. The compound according to claim 1, its stereoisomer, its hydrate, or a salt thereof: 【Chemistry 3】 In the above Chemical Formula 2, R １２ is unsubstituted or substituted C ５－８ Cycloalkyl, unsubstituted or substituted C ６－１０ aryl, an unsubstituted or substituted 5-8 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, an unsubstituted or substituted 8-10 atom fused heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, or C １－１５ alkenyl, The substituted C ５－８ Cycloalkyl is halogen, -CONH-OH, -CH ２ -CONH-OH, -CH ２ CH ２ -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 substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy; The substituted C ６－１０ Aryl is halogen, -CONH-OH, -CH ２ -CONH-OH, -CH ２ CH ２ -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 substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy and heteroaryl having 5 to 8 atoms and containing one or more heteroatoms selected from the group consisting of N, O and S; The substituted 5-8 heteroaryl is a halogen or a C substituted with a halogen. ６－１０ the aryl is substituted; The substituted 8-10 atom fused heteroaryl is selected from the group consisting of -OH, halogen, C １－８ Alkoxycarbonyl, C １－８ Alkoxycarbonyl C １－５ Alkyl, and C １－８ substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy; R ２２ and R ３２ are each independently -H, a halogen, or C １－１０ is alkyl; and L １２ is a bond, or C １－１０ It is alkylene.

9. The compound represented by Chemical Formula 1 is a compound represented by Chemical Formula 3 below. The compound according to claim 1, its stereoisomer, its hydrate, or a salt thereof: 【Chemistry 4】 In the above Chemical Formula 3, R １３ is unsubstituted or substituted C ６－１０ aryl or an unsubstituted or substituted 8-10 atom fused heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S; The substituted C ６－１０ Aryl is halogen, -CONH-OH, -CH ２ -CONH-OH, -CH ２ CH ２ -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 substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy; The substituted 8-10 atom fused heteroaryl is substituted with one or more substituents selected from the group consisting of -OH and halogen; R ２３ and R ３３ are each independently -H, a halogen, or C １－１０ is alkyl; and L １３ is a bond, or C １－１０ It is alkylene.

10. The compound represented by the formula 1 is any one selected from the following compound group, the compound according to claim 1, its stereoisomer, its hydrate, or a salt thereof: (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-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; (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)acetic acid; (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)acetic acid; (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) Methyl 3-(6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxamide)cyclopentane-1-carboxylic acid; (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-ylpivalic acid; (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) Methyl 4-methyl-3-(4,6,7-trimethyl-3-oxo-3,4-dihydroquinoxaline-2-carboxamido)benzoate; (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. As shown in the following reaction scheme 1: reacting the compound represented by formula 1A with hydroxide ions (OH-) to prepare a compound represented by formula 1B; reacting a compound represented by formula 1B with a compound represented by formula 1C to prepare a compound represented by formula 1; A method for preparing a compound represented by formula 1, comprising: 【Chemistry 5】 In the reaction scheme 1, R １ is unsubstituted or substituted C ５－８ Cycloalkyl, unsubstituted or substituted C ６－１０ aryl, an unsubstituted or substituted 5-8 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, an unsubstituted or substituted 8-10 atom fused heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, or C １－１５ alkenyl, The substituted C ５－８ Cycloalkyl is halogen, -CONH-OH, -CH ２ -CONH-OH, -CH ２ CH ２ -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 substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy; The substituted C ６－１０ Aryl is halogen, -CONH-OH, -CH ２ -CONH-OH, -CH ２ CH ２ -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 substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy and heteroaryl having 5 to 8 atoms and containing one or more heteroatoms selected from the group consisting of N, O and S; The substituted 5-8 heteroaryl is a halogen or a C substituted with a halogen. ６－１０ the aryl is substituted; The substituted 8-10 atom fused heteroaryl is selected from the group consisting of -OH, halogen, C １－８ Alkoxycarbonyl, C １－８ Alkoxycarbonyl C １－５ Alkyl, and C １－８ substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy; R ２ and R ３ are each independently -H, a halogen, or C １－１０ is alkyl; R ４ is C １－８ C substituted with two or more alkyl or -OH ３－１０ is alkyl; and L １ is a bond, or C １－１０ It is alkylene.

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

13. The pharmaceutical composition for preventing or treating cancer diseases 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, gastric 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 for preventing or treating a cancer disease according to claim 12, wherein the pharmaceutical composition selectively inhibits HDAC8.

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

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