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

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 deacetylases (HDACs) are enzymes that remove the acetyl group from the amino group of the N-terminal lysine tail of histones. They are also known to perform various functions on non-histone proteins, and are involved in important cellular activities such as cell growth cycle regulation, differentiation, and cancer formation. Recently, HDACs have been shown to be overexpressed under adverse environmental conditions, such as hypoxia, low glucose, and tumorigenesis, and to promote cell proliferation by inhibiting the expression of cytostatic factors. Thus, HDACs are recognized as important regulators of tumorigenesis and differentiation. HDACs can be broadly classified into four groups based on their function and DNA sequence similarity. To date, 18 HDACs have been identified. Among them, HDAC8 belongs to class I. While HDACs 1, 2, and 3 are primarily found in the nucleus, HDAC8 is present in both the nucleus and the 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] Currently, FDA-approved HDAC inhibitors 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 Acrotec's Belinostat (belinostat) for peripheral T-cell lymphoma. Most HDAC inhibitors developed to date have only been approved for the treatment of specific cancers, but their effectiveness has been limited and they have caused unnecessary side effects, creating a need for improved, selective HDAC inhibitors. Summary of the Invention [Problem to be solved by the invention]

[0004] One embodiment provides novel 3,4-dihydroquinoxaline-2-carboxamide derivative compounds.

[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 provides a health functional food composition for preventing or ameliorating cancer diseases, comprising a 3,4-dihydroquinoxaline-2-carboxamide derivative compound.

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

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

[0010] Another embodiment provides a use of a 3,4-dihydroquinoxaline-2-carboxamide derivative compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of cancer diseases. [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, unsubstituted or substituted 5-8 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, 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 is 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 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;

[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 may be selected from the group consisting of —OH, halogen, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl, and C 1-8 alkylcarbonyloxy;

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

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

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

[0029] Another embodiment provides a compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in treating cancer diseases.

[0030] Another embodiment provides a use of the compound, its stereoisomer, its hydrate, or its pharmaceutically acceptable salt for use in the manufacture of a medicament for treating cancer diseases. [Effects of the Invention]

[0031] 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. 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. [Brief explanation of the drawings]

[0032] [Figure 1]PCI-34051, a known 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-fluorophenylalanine)-2-hydroxybenzoate were used. 10 shows the results of confirming the growth inhibitory effect of these compounds on prostate cancer cell PC-3 cells 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; the compound of Example 35). [Figure 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 the prostate cancer cell line PC-3 during the administration period. [Figure 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. [Figure 5] 1 shows the results of measuring changes in body weight of 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 the 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 INVENTION

[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. Furthermore, the embodiment of one embodiment is provided to more completely explain the present invention to those skilled in the art. Furthermore, the term "comprising" a certain element throughout the specification does not mean excluding other elements, but may further include other elements, unless otherwise specified.

[0034] Numerical ranges used herein include lower and upper limits, all values ​​within the range, increments logically derived from the form and width of the defined range, all doubly limited values, and all possible combinations of upper and lower limits of numerical ranges limited in different forms. For example, if the content of a composition is limited to 10 to 80% or 20 to 50%, numerical ranges of 10 to 50% or 50 to 80% should also be interpreted as being within the scope of this specification. Unless otherwise specified in this specification, values ​​outside the numerical range that may occur due to experimental error or rounding off 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, unsubstituted or substituted 5-8 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, 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 is 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 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;

[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 may be selected from the group consisting of —OH, halogen, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl, and C 1-8 alkylcarbonyloxy;

[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 two 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, unsubstituted or substituted 5-6 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, 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 is 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 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;

[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 may be 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, unsubstituted or substituted 5-6 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, 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 is 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 substituted with one or more substituents selected from the group consisting of 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 1-5substituted 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;

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

[0060] The substituted 8-10 atom fused heteroaryl may be 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 It is a group substituted with alkylcarbonyloxy or -OC(O)CH3, and among these, it is a group substituted with one or more, two or more, or one or two kinds of substituents.

[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 alkylcarbonyloxy, -OC(O)CH3, or heteroaryl having 5 to 6 atoms and containing one or more heteroatoms selected from the group consisting of 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 among these.

[0063] Alternatively, 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 It is a group substituted with alkylcarbonyloxy or -OC(O)CH3, and among these, it is a group substituted with one or more, two or more, or one or two kinds of substituents.

[0064] In one embodiment, the R 1 teeth, [ka] 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 one or more, two or more, three to five, or four alkyl, -CH3, or -OH groups 3-5 Or specifically, the R 4 teeth, [ka] 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 the R 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, unsubstituted or substituted 5-8 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, 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 is 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 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;

[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 may be selected from the group consisting of —OH, halogen, C 1-8 Alkoxycarbonyl, C 1-8 Alkoxycarbonyl C 1-5 Alkyl, and C 1-8 alkylcarbonyloxy;

[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 example may include any stereoisomer of the compound represented by Chemical Formula 2. For example, the compound represented by Chemical Formula 2 may include a stereoisomeric compound represented by the following Chemical Formula 2A. However, Chemical Formula 2A is merely an example of various stereoisomeric compounds, and is not necessarily limited to the following compound.

[0079] [ka]

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

[0081] [ka]

[0082] At this time, the R 13 , R 23, R 33 and L 13 is the R 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)acetic acid;

[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-carboxylic acid;

[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 Formula 1 can be used in the form of a pharmaceutically acceptable salt, and useful salts include acid addition salts formed with a pharmaceutically acceptable free acid. Acid addition salts can be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid; non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, 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 pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, 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, and benzoate. Acid salts include benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, benzenesulfonates, toluenesulfonates, chlorobenzenesulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, beta-hydroxybutyrates, glycolates, malates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and the like.

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

[0143] According to one embodiment, a method for preparing the compound represented by Chemical Formula 1 is as shown in Reaction Scheme 1 below:

[0144] reacting the compound represented by formula 1A with hydroxide ions (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 formula 1, R 1 Or R 4 and L 1 The above definitions can be applied to the R. Therefore, 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 Chemical Formula 1A with a compound containing hydroxide ions, and for example, a basic compound such as NaOH, KOH, Ba(OH), Ca(OH), NHOH, or Mg(OH) or HO (hydrolysis reaction) may be used, but this is merely an example and is not necessarily limited to the use of the above compounds.

[0149] Another embodiment provides a pharmaceutical composition for preventing or treating cancer, comprising the compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically 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 histone deacetylase 8 (HDAC8), thereby exerting a preventive or therapeutic effect on cancer. The pharmaceutical composition according to one embodiment is effective in selectively inhibiting HDAC8 among HDACs, and can minimize unnecessary side effects, making it 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 pharmaceutically acceptable salt thereof may be used for the treatment or prevention of not only cancer diseases but also other cancers in which an anti-cancer effect is 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 Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral dosage forms. When formulated, it is typically prepared using diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, and the like. These solid dosage forms are prepared by mixing one or more compounds with at least one or more excipients, such as starch, calcium carbonate, sucrose or lactose, and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid dosage forms for oral administration include suspensions, oral solutions, emulsions, syrups, and the like. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients, such as wetting agents, sweeteners, flavoring agents, and preservatives, are also used. Formulations 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 pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and the parenteral administration can be by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

[0155] In this case, to prepare a formulation for parenteral administration, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be mixed with water together with a stabilizer or buffer to prepare a solution or suspension, which may then be packaged in an ampule or vial for unit administration. The composition may be sterilized or may contain auxiliary agents such as preservatives, stabilizers, hydrating agents or emulsifiers, salts or buffers for adjusting osmotic pressure, and other therapeutically useful substances, and may be formulated by conventional mixing, granulating, or coating methods.

[0156] Dosage forms for oral administration include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, and lozenges, which contain, in addition to the active ingredient, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, or glycine) and lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salts, 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 Chemical 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 Chemical Formula 1, its stereoisomer, its hydrate, 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 used with other foods or food ingredients in a conventional manner. The amount of the active ingredient to be added is determined appropriately depending on the intended use (prevention or improvement). Generally, the amount of the compound in a health food may be added in an amount of 0.1 to 90 parts by weight of the total weight of the food. However, in the case of long-term intake for the purposes of health and hygiene or health regulation, the amount may be less than the above range, and since there is no safety issue, 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 the compound, and may contain various flavorings or natural carbohydrates 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 colloidal 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 cancer, comprising administering the compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof to an individual or subject in need thereof.

[0163] An embodiment provides a compound represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in treating cancer diseases.

[0164] An embodiment provides a use of the compound, its stereoisomer, its hydrate, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating cancer disease.

[0165] Examples and experimental examples will be 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 by the method of the following reaction scheme A.

[0167] [ka]

[0168] In the reaction formula A, —R in compound III is a1 to a40 shown below.

[0169] [ka]

[0170] Specific production 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] To a mixture of 6,7-dimethyl-3-oxo-4-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)-3,4-dihydroquinoxaline-2-carboxylic acid (II) in DMF solvent, the same equivalent of arylamine (III, R = a1) was added, followed by the slow addition of 1.2 equivalents of 2-(3H-[1,2,3]triazole[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouranium hexafluorophosphate (HATU) and 5 equivalents of N,N-diisopropylethylamine (DIPEA), followed by stirring at room temperature for 4 hours. The resulting mixture was purified using preparative HPLC (solvent system: acetonitrile, water) to give 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 as in Example 1 was repeated, except that arylamine (III, R=a2) was used instead of arylamine (III, R=a1), to obtain the compound of Example 2 as a yellow solid (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 as in Example 1 was repeated, 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 as in Example 1 was repeated, 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 the compound of Example 7 as a yellow solid (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 the compound of Example 8 as a yellow solid (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 the compound of Example 9 as a yellow solid (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 the compound of Example 10 as a yellow solid (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 the compound of Example 11 as a yellow solid (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 as in Example 1 was repeated, except that arylamine (III, R=a12) was used instead of arylamine (III, R=a1), to obtain the compound of Example 12 as a yellow solid (15 mg, 23.1% yield).

[0206] ESI LC / MS: m / z calcd. for: C 25 H 27 BrNO[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 the compound of Example 13 as a yellow solid (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 procedure as in Example 1 was repeated, except that arylamine (III, R=a14) was used instead of arylamine (III, R=a1), to give 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 give the compound of Example 15 as a yellow solid (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 give the compound of Example 16 as a yellow solid (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 as in Example 1 was repeated, except that arylamine (III, R=a17) was used instead of arylamine (III, R=a1), to give the compound of Example 17 as a yellow solid (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 procedure as in Example 1 was repeated, except that arylamine (III, R=a18) was used instead of arylamine (III, R=a1), to give 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 as in Example 1 was repeated, except that arylamine (III, R=a19) was used instead of arylamine (III, R=a1), to give the compound of Example 19 as a yellow solid (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 the compound of Example 20 as a yellow solid (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 as in Example 1 was repeated, 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 procedure as in Example 1 was repeated, except that arylamine (III, R=a22) was used instead of arylamine (III, R=a1), to give 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 as in Example 1 was repeated, except that arylamine (III, R=a23) was used instead of arylamine (III, R=a1), to give the compound of Example 23 as a yellow solid (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 as in Example 1 was repeated, except that arylamine (III, R=a24) was used instead of arylamine (III, R=a1), to give the compound of Example 24 as a yellow solid (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 as in Example 1 was repeated, except that arylamine (III, R=a25) was used instead of arylamine (III, R=a1), to give the compound of Example 25 as a yellow solid (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 as in Example 1 was repeated, except that arylamine (III, R=a26) was used instead of arylamine (III, R=a1), to give the compound of Example 26 as a yellow solid (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, 400 MHz) 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 as in Example 1 was repeated, except that arylamine (III, R=a27) was used instead of arylamine (III, R=a1), to give the compound of Example 27 as a yellow solid (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 give the compound of Example 28 as a yellow solid (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 give the compound of Example 29 as a yellow solid (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 as in Example 1 was repeated, except that arylamine (III, R=a30) was used instead of arylamine (III, R=a1), to obtain the compound of Example 30 as a yellow solid (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 the compound of Example 31 as a yellow solid (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 as in Example 1 was repeated, except that arylamine (III, R=a32) was used instead of arylamine (III, R=a1), to give the compound of Example 32 as a yellow solid (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 as in Example 1 was repeated, except that arylamine (III, R=a33) was used instead of arylamine (III, R=a1), to give the compound of Example 33 as a yellow solid (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 as in Example 1 was repeated, except that arylamine (III, R=a34) was used instead of arylamine (III, R=a1), to give the compound of Example 34 as a yellow solid (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 as in Example 1 was repeated, except that arylamine (III, R=a35) was used instead of arylamine (III, R=a1), to give the compound of Example 35 as a yellow solid (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 give the compound of Example 36 as a yellow solid (10 mg, 11.68% yield).

[0285] ESI LC / MS: m / z calcd. for: C 23 H 24 BrNO[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 as in Example 1 was repeated, except that arylamine (III, R=a37) was used instead of arylamine (III, R=a1), to give the compound of Example 37 as a yellow solid (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 as in Example 1 was repeated, except that arylamine (III, R=a38) was used instead of arylamine (III, R=a1), to give the compound of Example 38 as a yellow solid (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 as in Example 1 was repeated, except that arylamine (III, R=a39) was used instead of arylamine (III, R=a1), to give the compound of Example 39 as a yellow solid (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 as in Example 1 was repeated, except that arylamine (III, R=a40) was used instead of arylamine (III, R=a1), to obtain the compound of Example 40 as a yellow solid (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 by the method of the following reaction scheme B.

[0299] [ka]

[0300] In the 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, compound VI (R=b1) was used to obtain the compound of Example 41 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 Scheme B, compound VI (R=b2) was used to obtain the compound of Example 42 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 Scheme B, compound VI (R=b3) was used to obtain the compound of Example 43 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. 20 equivalents of 50% aqueous hydroxylamine solution were then added, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, and the resulting residue was filtered through a microfiltrator and purified using preparative HPLC (solvent system: acetonitrile, water) to give 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 formula C.

[0319] [ka]

[0320] In the reaction formula C, —R of compound I is c1 to c7 shown below.

[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, compound I (R=c3) was used to obtain the compound of Example 48 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, compound I (R=c4) was used to obtain the compound of Example 49 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, compound I (R=c5) was used to obtain the compound of Example 50 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, compound I (R=c6) was used to obtain the compound of Example 51 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, compound I (R=c7) was used to obtain the compound of Example 52 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] JPEG0007811659000017.jpg230146JPEG0007811659000018.jpg224145JPEG0007811659000019.jpg231149JPEG0007811659000020.jpg162146

[0346] <Comparative Example>

[0347] As comparative examples, known HDAC8 inhibitors, such as TSA (Trichostatin A), SAHA (suberoylanilide hydroxamic acid), and PCI-34051 (N-hydroxy-1-(4-methoxybenzyl)-1H-indole-6-carboxamide), 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 were subcultured at 80-90% confluency, and only cells that had undergone less 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. A P value of less than 0.05 was 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 in the examples, measurements were performed using a BPS bioscience HDAC Fluorogenic Assay Kit. HDAC substrate 2A was diluted in buffer to a concentration of 20 μM and used for analysis. The compounds in the examples were diluted to 1 mM (1% DMSO concentration) with DMSO to a final concentration of 10 μM, and then diluted 1 / 10 with assay buffer. 5 μL of the diluted compounds in the examples, 5 μL of diluted HDAC substrate 2A, 5 μL of BSA (1 mg / mL), 5 μL of HDAC8 enzyme diluted to the appropriate 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. A blank was run without HDAC8 enzyme. The positive control was 100% HDAC8 enzyme activity with 1% DMSO. Inhibitor controls included TSA, SAHA, and PCI-34051 compounds. Next, 50 μL of 2X HDAC developer was added to each well. After 15 minutes of incubation at room temperature, fluorescence was measured using a microplate reader (Synergy Neo) at excitation wavelengths of 350-380 nm and emission wavelengths of 440-460 nm. The results were calculated by averaging the blank values, subtracting the average blank value from each value, and setting the positive control value to 100.

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

[0358] [Table 2]

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

[0360] To confirm the selective inhibitory effect of the compounds of the examples on HDAC8, inhibitory activity was measured using a BPS bioscience HDAC Fluorogenic Assay Kit. For the assay, HDAC Substrate 3 was diluted in buffer to a concentration of 200 μM and used in the HDAC1, 2, 3, 6, and 10 assays. HDAC Substrate 2A was diluted in buffer to a concentration of 200 μM and used in the HDAC4, 7, 9, and 11 assays. HDAC Substrate 2A was diluted in buffer to a concentration of 20 μM and used in the HDAC8 assay. For the HDAC11 assay, a dedicated buffer included in the kit was used separately, while the same buffer was used for the other assays. The compounds of the examples were diluted to 1 mM (1% DMSO concentration) with DMSO to a final concentration of 10 μM, and then diluted 1 / 10 with assay buffer. 5 μL of the diluted compound of the example, 5 μL of diluted HDAC substrate, 5 μL of BSA (1 mg / mL), 5 μL of HDAC enzyme diluted to each concentration, and 30 μL of assay buffer were added to a black round-bottom 96-well plate and incubated at 37°C for 30 minutes. The blank contained no HDAC enzyme, the positive control contained 1% DMSO (100% enzyme activity), and the inhibitor control contained TSA. 50 μL of 2X HDAC developer was then added to each well. After incubation at room temperature for 15 minutes, fluorescence was measured using a microplate reader (Synergy Neo) at excitation wavelengths of 350-380 nm and emission wavelengths of 440-460 nm. The results 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, a known HDAC8 inhibitor, showed very high inhibitory effects not only on HDAC8 but also on HDAC1, HDAC2, HDAC6, and HDAC10, and also on HDAC3, HDAC4, HDAC7, and HDAC9, and did not show selective inhibitory effects 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 growth inhibitory activity on prostate cancer and liver cancer 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 days 1 and 2 using a CCK-8 assay. 4 The cells were dispensed into a 96-well plate at 1000 cells / mL. After 20 hours, PCI34051, the compounds of Example 27, and Example 35 were added at various concentrations and incubated for 24 and 48 hours in a 37°C, 5% CO2 incubator. After incubation, 10 μL of CCK-8 reagent was added, and absorbance was measured after 1 hour. Absorbance was measured at 450 nm using a microplate reader (BMG Labtech, Offenburg, Germany). The results are shown in Figure 1. PCI-34051, a known HDAC8 inhibitor, was confirmed to inhibit cancer cell viability in a concentration- and time-dependent manner. Compound 27 also effectively reduced prostate cancer cell viability in a concentration- and time-dependent manner, demonstrating superior cancer cell viability inhibition compared to PCI-34051. Compound 35 demonstrated concentration-dependent inhibition of cancer cell viability at 24 hours, even though cell viability recovered after 48 hours.

[0365] Furthermore, the growth inhibitory activity of liver cancer was analyzed. 4 The cells were dispensed into a 96-well plate at 100 cells / ml. After 20 hours, PCI34051, Example 27, and Example 35 were added at various concentrations and incubated at 37°C in a 5% CO2 atmosphere for 24 and 48 hours. After incubation, 100 μL of CellTiter-Glo® Luminescent Cell Viability Assay reagent was added, and luminescence signals were measured 0.5-1 hour later. Luminescence signals were measured using an IVIS (PerkinElmer, Waltham, USA). The hepatoma cell line Huh-7 was treated with PCI-34051 (control), Example 27, and Example 35 at various concentrations, and cell viability was measured using the CellTiter-Glo® Luminescent Cell Viability Assay on day 1. As shown in Figure 6, Examples 27 and 35 demonstrated a concentration-dependent inhibition of cancer cell viability, similar to the control group.

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

[0367] PC-3 cell line was subcutaneously transplanted into nude mice to establish a prostate cancer model, which was then divided into two groups (Group 1: vehicle-administered group (10% DSMO, 30% PEG400, 60% DW) and Group 2: 50 mg / kg of the compound of Example 27-administered group). The drug was orally administered once a day, 12 times a day. To evaluate the therapeutic efficacy, tumors were excised before and after drug administration, and on days 3, 6, 8, 10, 12, and 14, and tumor volumes were 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-administered group (Group 1) showed clear tumor growth up to 14 days after administration, while the group administered with the compound of Example 27 (Group 2) showed a significantly reduced tumor volume growth rate compared to Group 1, and statistical significance was confirmed ( *p<0.05, compared with vehicle).

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

[0369] Furthermore, when the weight of the mice 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 Huh-7 cell lines 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 a day. To evaluate the therapeutic efficacy, 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 and weighed on day 15.

[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, tumors were excised on the 15th day and weighed. Similar to the tumor volume measurement results, the tumor weight in the vehicle group was significantly higher than that in the compound of Example 27 administration group, 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 by the appended claims. Furthermore, 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 2, a stereoisomer thereof, a hydrate thereof, or a salt thereof: 【Chemistry 1】 In the above Chemical Formula 2, R 12 is unsubstituted or substituted C 5-8 cycloalkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-8 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, 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 substituted with one or more substituents selected from the group consisting of 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 alkoxycarbonylC 1-5 alkyl, and C 1-8 alkylcarbonyloxy; the substituted C 6-10 aryl is substituted with one or more substituents selected from the group consisting of 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 alkoxycarbonylC 1-5 alkyl, C 1-8 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 atom heteroaryl is a C 6-10 aryl substituted with a halogen or a halogen; the substituted 8-10 atom fused heteroaryl is substituted with one or more substituents selected from the group consisting of -OH, halogen, C 1-8 alkoxycarbonyl, C 1-8 alkoxycarbonylC 1-5 alkyl, and C 1-8 alkylcarbonyloxy; R 22 and R 32 are each independently —H, halogen, or C 1-10 alkyl; and L 12 is a bond or C 1-10 alkylene.

2. The R12 is unsubstituted or substituted C ５－６ Cycloalkyl, unsubstituted or substituted C ６－８ aryl, unsubstituted or substituted 5-6 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, 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 is alkenyl, The substituted C ５－６ Cycloalkyl includes 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 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 may be 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 a salt thereof, which is substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy.

3. The R12 is unsubstituted or substituted C ５－６ Cycloalkyl, unsubstituted or substituted C ６－８ aryl, unsubstituted or substituted 5-6 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, 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 is alkenyl, The substituted C ５－６ Cycloalkyl includes 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 substituted with one or more substituents selected from the group consisting of 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 may be 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 a salt thereof, which is substituted with one or more substituents selected from the group consisting of alkylcarbonyloxy.

4. The R12 is 【Chemistry 2】 The compound according to claim 1, its stereoisomer, its hydrate or a salt thereof,

5. R22 and R32 each independently represent —H, halogen, or C １－５ The compound according to claim 1, its stereoisomer, its hydrate or a salt thereof, wherein R is alkyl.

6. The L12 is a bond or C １－５ The compound according to claim 1, a stereoisomer thereof, a hydrate thereof or a salt thereof, which is alkylene.

7. The compound represented by Chemical Formula 2 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; (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.

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

9. 9. The pharmaceutical composition for preventing or treating cancer diseases according to claim 8, wherein the cancer disease is selected from the group consisting of prostate cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, colon cancer, skin cancer, head and neck cancer, brain cancer, laryngeal cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer and rectal cancer.

10. The pharmaceutical composition for preventing or treating cancer diseases according to claim 8, wherein the pharmaceutical composition selectively inhibits HDAC8.

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

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