Compounds as UBR box domain ligands

Abstract

This specification relates to compounds as ligands for UBR box domains. This specification provides small molecule compounds that bind to UBR box domains. Furthermore, this specification provides compositions for inhibiting substrate binding to UBR box domains, pharmaceutical compositions for treating UBR-related diseases, and uses thereof, comprising ligand compounds that bind to UBR box domains.

Description

Technology Field

[0001] [Cross-reference to related applications]

[0002] This application claims the benefit and priority of U.S. provisional application serial number 63 / 015,945 filed on April 27, 2020, the entirety of which is incorporated herein by reference.

[0003] [Technology Field]

[0004] The present specification discloses compounds as UBR box domain ligands. The UBR box domain is a domain commonly found within the UBR (Ubiquitin protein ligase E3 component n-recognin) protein of the N-end rule pathway. The UBR box domain is known to be the domain to which a substrate binds. The UBR box domain is essential for binding to the N-terminal residue of a substrate to form a multi-ubiquitin chain on the substrate, and it is known that the substrate is degraded through this process.

[0005] This specification relates to a compound that acts as a ligand binding to the UBR box domain. Background Technology

[0006] Cells regulate the quantity and function of proteins in vivo through protein degradation. In this process, proteins in vivo can be degraded in a manner dependent on the sequence of their N-terminal residues, and this degradation pathway is known as the N-end rule pathway. In other words, the N-end rule pathway is a protein degradation system that uses the N-terminus of a specific protein as a degradation signal. The aforementioned N-end rule pathway may involve the following protein degradation processes.

[0007] In eukaryotes, N-recogninin recognizes the N-terminal degradation signal of a protein, and said N-recogninin can degrade the protein by binding ubiquitin to the target protein. At this time, said N-terminal degradation signal may include residues having a positive charge at the N-terminus (Type 1; e.g., arginine, lysine, histidine) or large hydrophobic residues (Type 2; phenylalanine, leucine, tryptophan, isoleucine, tyrosine). The inventors first discovered or cloned N-recogninins UBR 1, UBR2, UBR3, and UBR5 and revealed that they possess a UBR box domain as a substrate recognition domain (Tasaki et al. 2005). At this time, the ubiquitinated substrate formed by the binding of N-recogninin to an N-end rule ligand is delivered to the proteasome and degraded into a short peptide. In this process, specific N-terminal residues (Nt-Arg, Nt-His, Nt-Lys, Nt-Trp, Nt-Phe, Nt-Tyr, Nt-Leu, Nt-Leu) are essential determinants for binding because they provide most of the hydrogen bonds required when N-lecogniz targets N-end rule substrates (Sriram and Kwon, 2010).

[0008] The above UBR stands for Ubiquitin protein ligase E3 component n-recognin, and UBR is an N-recogninin that recognizes the N-terminal degradation signal of a protein. It is known that at least seven types of UBR, UBR 1 to 7, exist in mammals. Furthermore, the UBR box domain, which is common to all UBRs, is a zinc finger motif with a size of approximately 70 residues and is known to be a highly conserved substrate-binding domain. [Kwon et al., 1998; Xie and Varshavsky, 1999; Kwak et al., 2004; Varshavsky, 1996; Varshavsky, 1997; Kwon et al., 2011; and Zenker et al., 2014].

[0009] In other words, UBR is an N-lecognizant associated with the N-terminal pathway rule, which is a protein degradation pathway, and the UBR box domain within the UBR is a substrate binding domain. Specifically, among the above UBRs 1 to 7, UBR1, UBR2, UBR3, and UBR5 are known to act as ubiquitin protein ligase E3 and possess a RING domain or a HECT domain. Substrates of the N-terminal rule that bind to the above UBR are degraded by the ubiquitin proteasome pathway. Specifically, the UBR box domain within the above UBR recognizes the N-terminal amino acid of the substrate and degrades the substrate via the proteasome pathway by ubiquitinizing the substrate through the RING domain or the HECT domain. For example, if misfolded proteins are left in a cell for a long time, they can aggregate and block proteasomes or impair other cellular functions, so they are degraded via the ubiquitin proteasome pathway (Ji and Kwon, 2017).

[0010] In other words, the UBR box domain plays a crucial role in intracellular protein degradation pathways through the recognition of N-terminal degradation signals. Therefore, ligands binding to the UBR box domain can influence intracellular protein degradation pathways.

[0011] This specification relates to compounds as ligands that bind to a UBR box domain associated with an intracellular protein degradation pathway, as described above. The problem to be solved

[0012] The present specification provides a small molecule compound that binds to a UBR box domain. The UBR box domain comprises a UBR box domain within UBR 1 to 7. The small molecule compound can function as a ligand suitable for binding to the UBR box domain.

[0013] In one embodiment, the present specification provides a composition for inhibition of UBR box domain substrate binding comprising a ligand compound that binds to a UBR box domain.

[0014] In a specific embodiment, the present specification provides a pharmaceutical composition for treating UBR-related diseases comprising a ligand compound that binds to a UBR box domain, and the use thereof.

[0015] In a more specific embodiment, the present specification provides a therapeutic pharmaceutical composition comprising a ligand compound that binds to a UBR box domain, and includes diseases known to be related to the UBR box and UBR proteins, such as muscular dystrophy (Becker, Congennital, Duchenne, Distal, Emery-Dreifuss, Facioscapulohumeral, Limb-girdle, myotonic, ocuophargyngeal) (muscular dystrophy), muscle wasting diseases mediated by muscle loss or degradation including sarcopenia or cancer cachexia, as well as liposarcoma, cystic fibrosis, Johanson-Blizzard syndrome, urethral obstruction sequence, autoimmune pancreatitis, or Usher syndrome, as well as diseases mediated by excessive protein degradation. It provides a use for this. means of solving the problem

[0016] The present specification provides a compound having the structure of Formula 1 or a salt thereof.

[0017] [Chemical Formula 1]

[0018]

[0019] Here, X1 is optionally a phenyl, cycloalkyl, or heterocyclyl substituted or unsubstituted with one or more R2s;

[0020] Each R2 is independently alkyl, alkoxy, amino, aminoalkyl, -NO2, Selected from =O, -NHC2H4OH, -C(=NH)NH2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)OH, phenyl, or heterocycloalkyl;

[0021] X4 is optionally a phenyl, cycloalkyl, or heterocyclyl substituted or unsubstituted with one or more R3s;

[0022] Each R3 is independently selected from alkyl, alkoxy, amino, halo, hydroxyl, alkylamino, dialkylamino, -NO2, -CONR'R'', -CO2R', -NHCOR', phenyl, or heterocycloalkyl;

[0023] Each R' and R'' is independently -H or alkyl;

[0024] X2 is SO2, or CR a R b And;

[0025] R a and R b Each is independently H or CH3;

[0026] X3 is NH or CH2;

[0027] B1 is CH2 or NH;

[0028] A1 is CH2 or NH.

[0029] At this time, in one embodiment, in the above Chemical Formula 1,

[0030] -X2-B1-X3 is selected from the group consisting of -SO2-NH-NH, -SO2-NH-CH2, -SO2-CH2-NH, and -CH2-NH-NH, and

[0031] The above X1 is optionally a phenyl, cycloalkyl, or heterocyclyl substituted or unsubstituted with one or more R2s;

[0032] Each R2 is independently selected from alkyl, alkoxy, amino, aminoalkyl, -NO2, =O, -NHC2H4OH, -C(=NH)NH2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)OH, phenyl, or heterocycloalkyl;

[0033] The above X4 is optionally a phenyl, cycloalkyl, or heterocyclyl substituted or unsubstituted with one or more R3s;

[0034] Each R3 is selected from alkyl, alkoxy, amino, halo, hydroxyl, alkylamino, dialkylamino, -NO2, -CONR'R'', -CO2R', -NHCOR', phenyl, or heterocycloalkyl; wherein each R' and R'' is independently -H or alkyl;

[0035] A1 is CH2 or NH, and

[0036] I is an integer of 0 or 1.

[0037] In a specific embodiment, each of the X1 and X4 is independently substituted or unsubstituted phenyl, cycloalkyl, or heterocyclyl; wherein each of the X1 and X4 may be independently substituted or unsubstituted phenyl, cyclohexyl, cyclopentyl, furanyl, thiazolyl, 1H-pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, indolinyl, 1H-indolinyl, 1H-indolyl, 1H-indazolyl, isoindolinyl, indolin-2-onyl, 2,3-dihydro-1H-indenyl, and 1H-pyrrolopyridinyl.

[0038] In this case, as in one embodiment, each of the above R2 may be independently selected from methyl, ethyl, amino, aminoalkyl, amino(hydroxyalkyl), methoxy, ethoxy, -C(=NH)NH2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)OH, phenyl, pyrrolidinyl, piperazinyl, piperidinyl, and morpholinyl.

[0039] In this case, in one embodiment, each of the above R3 is independently selected from hydroxyl, fluoro, chloro, bromo, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, alkylamino, dialkylamino, -NO2, -C(=O)NH2, -CO2R', -NHCOR', -CONR'R'' and phenyl;

[0040] Each R' and R'' is independently -H or alkyl.

[0041] In one embodiment, the formula 1 provides a compound of formula 1-1 or a salt thereof:

[0042] [Chemical Formula 1-1]

[0043] .

[0044] At this time, the above A1 is CH2 or NH, and

[0045] I is an integer of 0 or 1.

[0046] In this case, as an example, the above formula 1 provides a compound of formula 1-2 or a salt thereof:

[0047] [Chemical Formula 1-2]

[0048] .

[0049] In this case, as an example, the above formula 1 provides a compound of formula 1-3 or a salt thereof:

[0050] [Chemical Formula 1-3]

[0051] .

[0052] In this case, as one embodiment, the above formula 1 provides a compound of formula 1-4 or a salt thereof.

[0053] [Chemical Formula 1-4]

[0054]

[0055] At this time, in the above chemical formulas 1-1, 1-2, 1-3 and 1-4,

[0056] In one embodiment,

[0057] At this time, X1 is a phenyl, cycloalkyl, or heterocyclic alkyl optionally substituted or unsubstituted with one or more R2s, wherein each of the R2s is independently selected from alkyl, alkoxy, amino, aminoalkyl, -NO2, =O, -NHC2H4OH, -C(=NH)NH2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)OH, phenyl, or heterocyclic alkyl;

[0058] X4 is a phenyl, cycloalkyl, or heterocyclic phenyl optionally substituted or unsubstituted with one or more R3s; wherein each R3 is independently selected from alkyl, alkoxy, amino, halo, hydroxyl, alkylamino, dialkylamino, -NO2, -CONR'R'', -CO2R', -NHCOR', phenyl, or heterocyclic alkyl;

[0059] Each R' and R'' is independently -H or alkyl.

[0060] In a specific embodiment, each of the X1 and X4 is independently substituted or unsubstituted phenyl, cycloalkyl, or heterocyclyl; wherein each of the X1 and X4 may be independently substituted or unsubstituted phenyl, cyclohexyl, cyclopentyl, furanyl, thiazolyl, 1H-pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, indolinyl, 1H-indolinyl, 1H-indolyl, 1H-indazolyl, isoindolinyl, indolin-2-onyl, 2,3-dihydro-1H-indenyl, and 1H-pyrrolopyridinyl.

[0061] In this case, as in one embodiment, each of the above R2 may be independently selected from methyl, ethyl, amino, aminoalkyl, amino(hydroxyalkyl), methoxy, ethoxy, -C(=NH)NH2, -C(=O)NH2, -C(=O)OH, phenyl, pyrrolidinyl, piperazinyl, piperidinyl, and morpholinyl.

[0062] In this case, as a specific example, the above R2 provides a compound that is an amino acid or a salt thereof.

[0063] At this time, in one embodiment, the X1 is

[0064] or Provides a phosphorus compound or its salt.

[0065] In this case, in one embodiment, each of the above R3 is independently selected from hydroxyl, fluoro, chloro, bromo, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, alkylamino, dialkylamino, -NO2, -C(=O)NH2, -CO2R', -NHCOR', -CONR'R'' and phenyl;

[0066] Each R' and R'' is independently -H or alkyl.

[0067] In this case, as a specific example, R3 provides a compound that is a hydroxyl or a salt thereof.

[0068] At this time, in one embodiment, the X4 is , or Provides a phosphorus compound or its salt.

[0069] At this time, as an example,

[0070] The above compound may be a compound selected from below or a salt thereof:

[0071] N -(4-hydroxybenzoyl)-4-methylbenzenesulfonohydrazide;

[0072] 4-amino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide;

[0073] 4-amino- N -(4-hydroxybenzoyl)-3-morpholinobenzenesulfonohydrazide;

[0074] N -(4-hydroxybenzoyl)-2-oxoindoline-5-sulfonohydrazide;

[0075] N -(4-hydroxybenzoyl)indolin-5-sulfonohydrazide;

[0076] N '-([1,1'-biphenyl]-4-carbonyl)-4-aminobenzenesulfonohydrazide;

[0077] N '-([1,1'-biphenyl]-3-carbonyl)-4-aminobenzenesulfonohydrazide;

[0078] 3-amino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide;

[0079] 4-(1-aminoethyl)- N -(4-hydroxybenzoyl)benzenesulfonohydrazide;

[0080] 3,5-diamino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide;

[0081] N -(4-hydroxybenzoyl)-4-((2-hydroxyethyl)amino)benzenesulfonohydrazide;

[0082] N -(4-hydroxybenzoyl)-4-methoxybenzenesulfonohydrazide;

[0083] 4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)benzimideamide;

[0084] 4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)benzamide;

[0085] 6-amino- N '-(4-hydroxybenzoyl)-[1,1'-biphenyl]-3-sulfonohydrazide;

[0086] 4-(2-((4-aminophenyl)sulfonyl)hydrazine-1-carbonyl)benzamide;

[0087] 4-amino- N '-(1 H -Indole-3-carbonyl)benzenesulfonohydrazide;

[0088] 4-amino- N -(4-hydroxybenzoyl)-3-(pyrrolidine-1-yl)benzenesulfonohydrazide;

[0089] N-(4-hydroxybenzoyl)-4-nitro-3-(pyrrolidin-1-yl)benzenesulfonohydrazide;

[0090] 4-amino- N -(4-hydroxybenzoyl)-3-(piperidine-1-yl)benzenesulfonohydrazide;

[0091] N -(4-hydroxybenzoyl)-1 H -Pyrazole-4-sulfonohydrazide;

[0092] N -(4-hydroxybenzoyl)indolin-4-sulfonohydrazide;

[0093] N -(4-hydroxybenzoyl)-1 H -Indole-4-sulfonohydrazide;

[0094] 2-((4-aminophenyl)sulfonyl)- N -Phenylhydrazine-1-carboxamide;

[0095] 4-amino- N '-(1 H -Indole-4-carbonyl)-3-morpholinobenzenesulfonohydrazide;

[0096] 4-amino- N -(Indolin-4-carbonyl)benzenesulfonohydrazide;

[0097] 4-amino- N -(4-hydroxybenzoyl)-3-(peparazine-1-yl)benzenesulfonohydrazide;

[0098] 4-amino- N -(2,3-dehydro-1 H -Indene-2-carbonyl)benzenesulfonohydrazide;

[0099] 4-amino- N -(isoindolin-2-carbonyl)benzenesulfonohydrazide;

[0100] N -(4-hydroxybenzoyl)-1 H -Indole-2-sulfonohydrazide;

[0101] 4-amino- N -(2-phenylacetyl)benzenesulfonohydrazide;

[0102] N -(4-hydroxybenzoyl)-1 H -Indazole-3-sulfonohydrazide;

[0103] 4-amino- N -(Indolin-6-carbonyl)benzenesulfonohydrazide;

[0104] 4-amino- N -(Indolin-3-carbonyl)benzenesulfonohydrazide;

[0105] N -(4-hydroxybenzoyl)piperidine-4-sulfonohydrazide;

[0106] 4-amino- N -(Indolin-6-carbonyl)-3-morpholinobenzenesulfonohydrazide;

[0107] 4-amino- N -(Piperazine-1-carbonyl)benzenesulfonohydrazide;

[0108] 4-amino-3-morpholino- N -(Piperazine-1-carbonyl)benzenesulfonohydrazide;

[0109] N'-(4-hydroxybenzoyl)-2-methylthiazole-4-sulfonohydrazide;

[0110] (1 S ,4 S )-4-amino- N -(4-hydroxybenzoyl)cyclohexane-1-sulfonohydrazide;

[0111] (1 R ,4 R )-4-amino- N -(4-hydroxybenzoyl)cyclohexane-1-sulfonohydrazide;

[0112] 4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)-5-methylfuran-2-carboxylic acid;

[0113] N -(4-hydroxybenzoyl)pyrrolidine-3-sulfonohydrazide;

[0114] N -(4-hydroxybenzoyl)-1 H -pyrrolo[2,3-b ]Pyridine-2-sulfonohydrazide;

[0115] 2-((4-aminophenyl)sulfonyl)-N-(3-hydroxyphenyl)hydrazine-1-carboxamide;

[0116] 2-((4-amino-3-morpholinophenyl)sulfonyl)-N-phenylhydrazine-1-carboxamide;

[0117] N -(4-aminobenzyl)-4-hydroxybenzohydrazide;

[0118] 4-hydroxy-N'-(4-methoxybenzyl)benzohydrazide;

[0119] N'-(4-aminobenzyl)-2,3-dihydro-1H-indene-2-carbohydrazide;

[0120] 4-amino- N -(2-(4-hydroxyphenyl)-2-oxoethyl)benzenesulfonamide;

[0121] 4-amino-N-(2-(4-hydroxyphenyl)-2-oxoethyl)-3-morpholinobenzenesulfonamide;

[0122] 3,5-diamino-N-(2-(4-hydroxyphenyl)-2-oxoethyl)benzenesulfonamide;

[0123] N-(((4-aminophenyl)sulfonyl)methyl)-4-hydroxybenzamide;

[0124] 4-hydroxy-N-(((4-methoxyphenyl)sulfonyl)methyl)benzamide; and

[0125] N-(((4-aminophenyl)sulfonyl)methyl)-[1,1'-biphenyl]-4-carboxamide.

[0126] In another aspect of the present application, a pharmaceutical composition for treating UBR-related diseases comprising the said compound or a pharmaceutically acceptable salt thereof, and a method for treating UBR-related diseases using the same are provided.

[0127] At this time, as an example, The above UBR-related diseases may be selected from muscular dystrophy (Becker, Congennital, Duchenne, Distal, Emery-Dreifuss, Facioscapulohumeral, Limb-girdle, myotonic, ocuophargyngeal), muscle wasting diseases mediated by muscle loss or breakdown including sarcopenia or cancer cachexia, as well as liposarcoma, cystic fibrosis, Johanson-Blizzard syndrome, urethral obstruction sequence, autoimmune pancreatitis, or Usher syndrome caused by excessive protein breakdown. Effects of the invention

[0128] One invention disclosed in this specification provides a ligand compound with a higher binding affinity to a UBR box domain.

[0129] The binding of UBR box domain substrates can be inhibited through UBR box domain ligand compounds, and various applications utilizing this property can be provided. For example, UBR-related diseases (e.g., myasthenia) can be treated through UBR box domain ligand compounds. Brief explanation of the drawing

[0130] Figure 1 shows the experimental results of confirming whether muscle actin is a substrate of the Arg / N-degron pathway using immunoblotting. Figure 2 is the experimental result of confirming whether the degradation of R-nsp4, which needs to be degraded by binding to UBR1, is inhibited by using an in vitro transcriptional translation method (compounds 2, 3, 7, 12, 14, 16). Figure 3 is the experimental result of confirming whether compounds (compounds 2 and 3) bind to UBR1 and inhibit the degradation of RGS4, a substrate of UBR proteins in embryonic kidney cells that need to be degraded, using an immunoblotting method. Figure 4 is the experimental result of confirming whether compounds (compounds 1, 2, 3, 4, 5, 6, 7, 16) inhibit the degradation of actin, which is the substrate of UBR proteins in muscle cells, using immunoblotting. Figure 5 is the experimental result of confirming whether compounds (compounds 35, 36, 37, 38, 39, 43, 44, 45, 46, 47) inhibit actin degradation in muscle cells using immunoblotting. Figure 6 shows the experimental results of confirming whether compounds (compounds 8, 9, 18, 19, 20, 21, 22, 23, 24) inhibit actin degradation in muscle cells using immunoblotting. Figure 7 shows the experimental results of confirming whether compounds (compounds 25, 26, 27, 28, 32, 33, 34) inhibit actin degradation in muscle cells using immunoblotting. Figure 8 shows the experimental results of confirming whether compounds (compounds 41, 42) inhibit actin degradation in muscle cells using immunoblotting. Figure 9 shows the experimental results of confirming whether compounds (compounds 12, 13, 14, 15, 17, 29, 30, 31) inhibit actin degradation in muscle cells using immunoblotting. Figures 10 and 11 are experimental results confirming the intracellular UBR1, 2, 3, and 5 binding efficacy of the compound (compound 2) using an immunoblotting method. Figures 12 to 19 show the results of Microscale Thermophoresis (MST) experiments to confirm whether compounds (compounds 1, 2, 5, 8, 9, 11, 12, 13) bind to UBR1. Specific details for implementing the invention

[0131] Hereinafter, the content of the invention will be described in more detail through specific embodiments and examples with reference to the attached drawings. It should be noted that the attached drawings include some embodiments of the invention, but not all embodiments. The content of the invention disclosed by this specification may be implemented in various ways and is not limited to the specific embodiments described herein. A person skilled in the art to which the invention disclosed in this specification belongs would be able to conceive of many variations and other embodiments of the content of the invention disclosed in this specification. Therefore, the content of the invention disclosed in this specification is not limited to the specific embodiments described herein, and variations and other embodiments thereof should be understood to be included within the scope of the claims.

[0132] Definition of Terms

[0133] The definitions of key terms used in this specification are as follows.

[0134] UBR (Ubiquitin protein ligase E3 component n-recognin)

[0135] As used in this specification, the term UBR stands for Ubiquitin protein ligase E3 component n-recognin. The UBR is an N-recognizant that recognizes the N-terminal residue of a protein, and it is known that at least seven types of UBR 1 to 7 exist in mammals. The UBR is an N-recognizant and is associated with the N-terminal rule pathway, which is a protein degradation pathway in vivo. Specifically, the UBR recognizes the N-terminal degradation signal (N-degron) of a protein and is involved in the process in which a substrate protein is degraded through the ubiquitin proteasome pathway.

[0136] UBR box domain

[0137] As used herein, the term UBR box domain refers to a domain present within a UBR protein that is a zinc finger motif. The UBR protein comprises UBR 1 to 7 proteins. The UBR box domain is known as a domain to which a substrate protein binds. Compounds as UBR box domain ligands disclosed herein can bind to the UBR box domain and inhibit the binding of the UBR box domain substrate. Furthermore, compounds as UBR box domain ligands disclosed herein can affect intracellular protein degradation pathways.

[0138] RING domain

[0139] The term RING domain as used in this specification is known to exist within the UBR 1, 2, and 3 proteins. The RING domain may also be referred to as the RING ubiquitination domain. The RING domain is a domain present within the protein and is a zinc finger motif. The RING domain plays an important role in the process of ubiquitin in E2 being transferred to a substrate protein, and the RING domain enables the process of ubiquitin being transferred to the substrate protein to occur in a one-step manner.

[0140] HECT domain

[0141] The term HECT domain as used in this specification is known to exist within the UBR 5 protein. The HECT domain may also be referred to as the HECT ubiquitination domain. The HECT domain is a domain that plays an important role in the process of ubiquitin in E2 being transferred to the substrate protein. Ubiquitin in E2 is transferred to the HECT domain and then transferred to the substrate protein. In other words, the HECT domain plays a role in causing the process of ubiquitin being transferred to the substrate protein to occur in two steps.

[0142] zinc finger motif

[0143] As used herein, the term zinc finger motif refers to a protein structural motif in which one or more zinc ions are present to stabilize the structure of a protein. The UBR box domain and the RING domain of this specification are zinc finger motifs.

[0144] ligand

[0145] As used in this specification, the term "ligand" refers to a substance that specifically binds to a protein. The protein includes an enzyme or a receptor; if the protein is an enzyme, the ligand may refer to a substrate that binds to the enzyme, and if the protein is a receptor, the ligand may refer to a hormone that binds to the receptor.

[0146] The compounds provided in this specification as UBR box domain ligands refer to compounds that bind to a UBR box domain. In one embodiment, the compound refers to a compound that binds to a UBR box domain within a UBR protein. In a specific embodiment, the compound refers to a compound that binds to a UBR box domain present in one or more proteins among UBR1 to 7. However, it is not limited thereto.

[0147] The compounds provided in this specification as UBR box domain ligands can act competitively with the substrate of the UBR box domain. That is, the compounds can inhibit the binding of the substrate to the UBR box domain. Additionally, the compounds can inhibit the degradation of the substrate by inhibiting the binding of the substrate.

[0148] aminoalkyl

[0149] As used in this specification, the term aminoalkyl means an alkyl moiety substituted with an amino group. The aminoalkyl group includes -CH(NH2)CH3 and -CH2(NH2).

[0150] Cycloalkyl and heterocycloalkyl

[0151] As used herein, the term cycloalkyl refers to a carbocyclic group containing one or more saturated ring structures and includes bicyclic groups. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0152] Heterocycloalkyl means a ring structure comprising one or more heteroatoms selected from P, N, O, and S in addition to the ring-carbon atom in the above cycloalkyl.

[0153] heterocyclyl

[0154] As used herein, the term heterocyclil refers to an unsaturated, saturated, or partially unsaturated monocyclil, bicyclic, or tricyclic group having 2 to 14 cyclic carbon atoms and comprises one or more heteroatoms selected from P, N, O, and S in addition to the cyclic carbon atoms. The heterocyclil comprises a heterocycloalkyl. In various embodiments, the heterocyclic group is attached to another moiety via a carbon or heteroatom and optionally substituted on the carbon or heteroatom. Examples of heterocyclyls are azetidinyl, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, isoindolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, and isoindolyl. Isoquinolyl, isothiazoyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl,Pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, Pyridin-2-only, pyrrolidinyl, pyrrolopyridinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl,Includes dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, etc.

[0155] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. All publications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0156] The specific details of the invention are disclosed below.

[0157] I. UBR Box Domain

[0158] 1. Overview

[0159] The compounds provided in this specification as UBR box domain ligands bind to the UBR box domain. The UBR box domain is known as a domain to which an N-terminal residue sequence or an N-terminal degradation signal binds. The domain is associated with the process of protein degradation by the N-terminal pathway law. Therefore, the compounds can influence the protein degradation process through the N-terminal pathway.

[0160] 2. N-end rule pathway

[0161] Cells regulate the amount of protein through protein degradation. It is known that this protein degradation process proceeds through the recognition of degrons, which are protein degradation signals. Specifically, protein degradation is regulated in a dependency on the N-terminal residue sequence of a protein, and the protein degradation signals present at the N-terminus are collectively referred to as N-degrons. These N-degrons include residues with a positive charge at the N-terminus (e.g., arginine, lysine, histidine) or large hydrophobic residues (phenylalanine, leucine, tryptophan, isoleucine, tyrosine). Based on this correlation, where the half-life of a protein is determined by the amino acid residue present at its N-terminus, the term "N-end rule" has been used.

[0162] 3. UBR Box Domain

[0163] In the above N-terminal rule pathway, N-degrons are recognized by N-recognizants, and UBR (Ubiquitin protein ligase E3 component n-recognin) has been identified as an N-recognizant. It is known that the UBR recognizes N-terminal residue sequences or N-terminal degradation signals through its UBR box domain. That is, the UBR recognizes protein degradation signals through its UBR box domain, and the protein degradation process proceeds through this.

[0164] The protein degradation process by the above UBR may include the following: The UBR box domain recognizes a substrate having an N-terminal degradation signal, ubiquitin binds to the substrate, and the ubiquitin-bound substrate can be degraded by a proteasome. That is, the substrate having an N-terminal degradation signal can be degraded by the ubiquitin proteasome system (UPS).

[0165] II. UBR Box Domain Ligand

[0166] 1. Overview

[0167] 1) The compounds of this specification reflect the structure of the UBR box domain and the binding characteristics with the N-terminal pathway substrate.

[0168] The compounds as UBR box domain ligands disclosed in this specification were designed considering the structure of the UBR box domain and the binding mode between the UBR box domain and the N-terminal pathway substrate.

[0169] Various amino acids present in the UBR box domain interact with and bind to amino acids of the N-terminal pathway substrate through ionic interactions, hydrogen bonds, hydrophobic interactions, etc. By analyzing these binding modes, the present specification provides a small molecule compound capable of forming a suitable binding mode with the UBR box domain. Furthermore, the present specification provides compounds according to the following chemical formulas 1 to 55.

[0170] 2) The compound of this specification has a core structure that binds well to the UBR box domain.

[0171] In this specification, as described above, the binding mode between the UBR box domain and the amino acid of the N-terminal pathway substrate was analyzed, and the core structure of the compound was derived. The compound provided in this specification may have the structure of [Formula 1] below, derived based on the core structure of the compound. [Formula 1] is as follows:

[0172] [Chemical Formula 1]

[0173] .

[0174] In this specification, various compounds are designed and provided based on the above [Chemical Formula 1]. At this time, X1, X2, X3, B1, A1, B 1, Candidates for X4 were derived by considering the binding mode with the UBR box domain. A more detailed description of various compounds based on the above [Formula 1] is provided below.

[0175] 2. Chemical Formula 1

[0176]

[0177] [Chemical Formula 1]

[0178] 1) X2, B1, X3 and A1

[0179] ① X2

[0180] In Chemical Formula 1 above, X2 may be a structure that induces a bending structure within the compound disclosed herein. The bending structure may help X1 of the compound disclosed herein to smoothly maintain charge-charge interactions, hydrogen bonding, or hydrophobic activity with the UBR box domain, thereby enhancing bond strength. Accordingly, in one embodiment, X2 may be one of various structures capable of inducing a bending structure. In a specific embodiment, X2 may be SO2 or CR a R b It may be. In this case, the above R a and R b Each can be independently selected from H or CH2. Furthermore, X2 may be CH2, CH(CH3), or C(CH3)2. In another specific embodiment, X2 may be SO2.

[0181] ② B1, X3 and A1

[0182] In the above chemical formula 1, A1 may be CH2 or NH as one example.

[0183] In the above chemical formula 1, B1 may be CH2 or NH as one example.

[0184] In the above chemical formula 1, X3 may be CH2 or NH as one example.

[0185] In this case, as an example, if B1 in the above chemical formula 1 is CH2, X3 may not be CH2.

[0186] However, it is not limited to this.

[0187] ③ Examples of X2, B1, X3 and A1

[0188] The above chemical formula 1 may have a structure selected from below as an example:

[0189] [Chemical Formula 1-1] [Chemical Formula 1-2]

[0190] , ,

[0191] [Chemical Formula 1-3] [Chemical Formula 1-4]

[0192] , ,

[0193] [Chemical Formula 1-5] [Chemical Formula 1-6]

[0194] , ,

[0195] [Chemical Formula 1-7] [Chemical Formula 1-8]

[0196] , ,

[0197] [Chemical Formula 1-9] [Chemical Formula 1-10]

[0198] , ,

[0199] [Chemical Formula 1-11] [Chemical Formula 1-12]

[0200] , ,

[0201] [Chemical Formula 1-13] [Chemical Formula 1-14]

[0202] , ,

[0203] [Chemical Formula 1-15] [Chemical Formula 1-16]

[0204] , ,

[0205] [Chemical Formula 1-17] [Chemical Formula 1-18]

[0206] , ,

[0207] [Chemical Formula 1-19] [Chemical Formula 1-20]

[0208] , ,

[0209] [Chemical Formula 1-21] [Chemical Formula 1-22]

[0210] , ,

[0211] [Chemical Formula 1-23] [Chemical Formula 1-24]

[0212] , ,

[0213] [Chemical Formula 1-25] [Chemical Formula 1-26]

[0214] , ,

[0215] [Chemical Formula 1-27] [Chemical Formula 1-28]

[0216] , ,

[0217] [Chemical Formula 1-29] [Chemical Formula 1-30]

[0218] , ,

[0219] [Chemical Formula 1-31] ​​[Chemical Formula 1-32]

[0220] , ,

[0221] [Chemical Formula 1-33] [Chemical Formula 1-34]

[0222] , ,

[0223] [Chemical Formula 1-35] [Chemical Formula 1-36]

[0224] , ,

[0225] [Chemical Formula 1-37] [Chemical Formula 1-38]

[0226] , ,

[0227] [Chemical Formula 1-39] [Chemical Formula 1-40]

[0228] , ,

[0229] [Chemical Formula 1-41] [Chemical Formula 1-42]

[0230] , ,

[0231] [Chemical Formula 1-43] [Chemical Formula 1-44]

[0232] , ,

[0233] [Chemical Formula 1-45]

[0234] .

[0235] As a specific example, in the above chemical formula 1,

[0236] -X2-B1-X3 is selected from the group consisting of -SO2-NH-NH, -SO2-NH-CH2, -SO2-CH2-NH, and -CH2-NH-NH, and

[0237] A1 is CH2 or NH, and

[0238] I is an integer of 0 or 1.

[0239] The above chemical formula 1 may have a structure selected from below as a specific example:

[0240] [Chemical Formula 1-1]

[0241] ,

[0242] [Chemical Formula 1-2]

[0243] ,

[0244] [Chemical Formula 1-3]

[0245] ,

[0246] [Chemical Formula 1-4]

[0247] .

[0248] 2) X1

[0249] As a result of performing a complex structural analysis of the UBR boxes and N-degrons of UBR1 and UBR2 and a molecular docking study with a compound having the core structure of Chemical Formula 1, X1 in the above Chemical Formula 1 is X1 corresponds to the side chain of the first residue (N1) of the N-degron and is expected to bind to a negatively charged-surrounded region. Accordingly, in one embodiment, X1 in Formula 1 may have a ring structure containing a moiety that carries a charge or forms hydrogen bonds. In a specific embodiment, X1 may be a ring structure having a planar structure containing a moiety that carries a charge or forms hydrogen bonds. Additionally, when the compound is used in combination with other substances, X1 in Formula 1 may include a structure capable of binding to a linker.

[0250] In one embodiment, X1 may be a phenyl, cycloalkyl, or heterocyclyl optionally substituted or unsubstituted with one or more R2s. In a specific embodiment, X1 may be selected from phenyl, cyclohexyl, cyclopentyl, furanyl, thiazolyl, 1H-pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, indolinyl, 1H-indolinyl, 1H-indolyl, 1H-indazolyl, isoindolinyl, indolin-2-onyl, 2,3-dihydro-1H-indenyl, and 1H-pyrrolopyridinyl optionally substituted or unsubstituted with one or more R2s. In this case, each R2 is independently an alkyl, alkoxy, amino, aminoalkyl, -NO2, It may be selected from =O, -NHC2H4OH, -C(=NH)NH2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)OH, phenyl, or heterocycloalkyl. In one embodiment, each R2 may be independently selected from methyl, ethyl, amino, aminoalkyl, amino(hydroxyalkyl), methoxy, ethoxy, -C(=NH)NH2, -C(=O)NH2, -C(=O)OH, phenyl, pyrrolidinyl, piperazinyl, piperidinyl, and morpholinyl. In a specific embodiment, R2 may be amino.

[0251] In a more specific example, the above X1 can be selected from the following structures:

[0252] , ,

[0253] , ,

[0254] , ,

[0255] , ,

[0256] , ,

[0257] , ,

[0258] , ,

[0259] , ,

[0260] , ,

[0261] , ,

[0262] , ,

[0263] , ,

[0264] , ,

[0265] , ,

[0266] .

[0267] In a more specific embodiment, the above X1 can be selected from the following structures:

[0268] , .

[0269] 3) X4

[0270] In Chemical Formula 1 above, X4 corresponds to the side chain of the second residue (N2) of the N-degron and may have a ring or chain structure to fill the bonding space when combined with a UBR box. In this case, as in one embodiment, the ring or chain structure may have a moiety that carries a charge or forms hydrogen bonds to increase the bonding strength. Additionally, X4 may include a structure capable of performing the role of bonding with a linker when the compound of this specification is subsequently combined with other materials.

[0271] In one embodiment, X4 may be a phenyl, cycloalkyl, or heterocyclyl that is optionally substituted with or unsubstituted with one or more R3s. In a specific embodiment, X4 may be selected from phenyl, cyclohexyl, cyclopentyl, furanyl, thiazolyl, 1H-pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, indolinyl, 1H-indolinyl, 1H-indolyl, 1H-indazolyl, isoindolinyl, indolin-2-onyl, 2,3-dihydro-1H-indenyl, and 1H-pyrrolopyridinyl that are optionally substituted with or unsubstituted with one or more R3s. In this case, each R3 may be independently selected from alkyl, alkoxy, amino, halo, hydroxyl, alkylamino, dialkylamino, -NO2, -CONR'R'', -CO2R', -NHCOR', phenyl, or heterocycloalkyl. In one embodiment, each R3 may be independently selected from hydroxyl, fluoro, chloro, bromo, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, alkylamino, dialkylamino, -NO2, -C(=O)NH2, -CO2R', -NHCOR', -CONR'R'', and phenyl. In a specific embodiment, R3 may be hydroxyl. In this case, each R' and R'' may be independently -H or alkyl.

[0272] As a more specific example, the X4 can be selected from the following:

[0273] , ,

[0274] , ,

[0275] , ,

[0276] , ,

[0277] , ,

[0278] , ,

[0279] , ,

[0280] , ,

[0281] , ,

[0282] , ,

[0283] , ,

[0284] , ,

[0285] , ,

[0286] , ,

[0287] , ,

[0288] , ,

[0289] , ,

[0290] , ,

[0291] , ,

[0292] , ,

[0293] , ,

[0294] , ,

[0295] , ,

[0296] , ,

[0297] .

[0298] In a more specific example, the X4 can be selected from the following:

[0299] , ,

[0300] .

[0301] The compounds disclosed in this specification may exist in the form of stereoisomers or salts thereof, and such isomers or salts of the compounds are included within the scope of this specification.

[0302] III. Specific Examples of Compounds as UBR Box Domain Ligands

[0303] 1. Specific examples of compounds

[0304] The following describes specific embodiments of the compounds disclosed herein. The specific embodiments below are exemplary structures for the ease of understanding of the compounds disclosed herein, and the scope of the compounds disclosed herein is not limited by the embodiments below.

[0305] As a specific example, the compound disclosed herein may have the structure of [Chemical Formula 1-1]:

[0306] [Chemical Formula 1-1]

[0307] .

[0308] In this case, A1 in the above compound is CH2 or NH, and I is an integer of 0 or 1.

[0309] The above X1 and X4 are Table of Contents II. UBR Box Domain Ligands 2) It applies in the same way as described in X1 and 3)X4.

[0310] As a more specific example, specific example compounds for [Chemical Formula 1-1] can be selected from below.

[0311] Specific example compounds for chemical formula [1-1] Compound number compound 1 N -(4-hydroxybenzoyl)-4-methylbenzenesulfonohydrazide 2 4-amino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide 3 4-amino- N -(4-hydroxybenzoyl)-3-morpholinobenzenesulfonohydrazide 4 N -(4-hydroxybenzoyl)-2-oxoindolin-5-sulfonohydrazide 5 N -(4-hydroxybenzoyl)indolin-5-sulfonohydrazide 6 N '-([1,1'-biphenyl]-4-carbonyl)-4-aminobenzenesulfonohydrazide 7 N '-([1,1'-biphenyl]-3-carbonyl)-4-aminobenzenesulfonohydrazide 8 3-amino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide 9 4-(1-aminoethyl)- N -(4-hydroxybenzoyl)benzenesulfonohydrazide 10 3,5-diamino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide 11 N -(4-hydroxybenzoyl)-4-((2-hydroxyethyl)amino)benzenesulfonohydrazide 13 N -(4-hydroxybenzoyl)-4-methoxybenzenesulfonohydrazide 14 4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)benzimideamide 15 4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)benzamide 17 6-amino- N -(4-hydroxybenzoyl)-[1,1'-biphenyl]-3-sulfonohydrazide 18 4-(2-((4-aminophenyl)sulfonyl)hydrazine-1-carbonyl)benzamide 20 4-amino- N '-(1 H -Indole-3-carbonyl)benzenesulfonohydrazide 21 4-amino- N -(4-hydroxybenzoyl)-3-(pyrrolidine-1-yl)benzenesulfonohydrazide 22 N -(4-hydroxybenzoyl)-4-nitro-3-(pyrrolidine-1-yl)benzenesulfonohydrazide 23 4-amino- N -(4-hydroxybenzoyl)-3-(piperidine-1-yl)benzenesulfonohydrazide 24 N -(4-hydroxybenzoyl)-1 H -Pyrazole-4-sulfonohydrazide 25 N -(4-hydroxybenzoyl)indolin-4-sulfonohydrazide 26 N -(4-hydroxybenzoyl)-1 H -Indol-4-Sulfonohydrazid 27 2-((4-aminophenyl)sulfonyl)- N -phenylhydrazine-1-carboxamide 28 4-amino- N '-(1 H -Indole-4-carbonyl)-3-morpholinobenzenesulfonohydrazide 29 4-amino- N -(Indolin-4-carbonyl)benzenesulfonohydrazide 30 4-amino- N -(4-hydroxybenzoyl)-3-(peparazine-1-yl)benzenesulfonohydrazide 31 4-amino- N -(2,3-dehydro-1 H -Indene-2-carbonyl)benzenesulfonohydrazide 32 4-amino- N -(isoindolin-2-carbonyl)benzenesulfonohydrazide 33 N -(4-hydroxybenzoyl)-1 H -Indol-2-Sulfonohydrazid 34 4-amino- N -(2-phenylacetyl)benzenesulfonohydrazide 35 N -(4-hydroxybenzoyl)-1 H -Indazole-3-sulfonohydrazide 36 4-amino- N -(Indolin-6-carbonyl)benzenesulfonohydrazide 37 4-amino- N -(Indolin-3-carbonyl)benzenesulfonohydrazide 38 N -(4-hydroxybenzoyl)piperidine-4-sulfonohydrazide 39 4-amino- N -(Indolin-6-carbonyl)-3-morpholinobenzenesulfonohydrazide 40 4-amino- N -(Piperazine-1-carbonyl)benzenesulfonohydrazide 41 4-amino-3-morpholino- N -(Piperazine-1-carbonyl)benzenesulfonohydrazide 42 N'-(4-hydroxybenzoyl)-2-methylthiazole-4-sulfonohydrazide 43 (1 S ,4 S )-4-amino- N -(4-hydroxybenzoyl)cyclohexane-1-sulfonohydrazide 44 (1 R ,4 R )-4-amino- N -(4-hydroxybenzoyl)cyclohexane-1-sulfonohydrazide 45 4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)-5-methylfuran-2-carboxylic acid 46 N -(4-hydroxybenzoyl)pyrrolidine-3-sulfonohydrazide 47 N -(4-hydroxybenzoyl)-1 H -pyrrolo[2,3- b ]Pyridin-2-sulfonohydrazide 52 2-((4-aminophenyl)sulfonyl)-N-(3-hydroxyphenyl)hydrazine-1-carboxamide 53 2-((4-amino-3-morpholinophenyl)sulfonyl)-N-phenylhydrazine-1-carboxamide

[0312] In another specific example, the compound disclosed herein may have the structure of [Formula 1-2]: [Formula 1-2]

[0313] .

[0314] At this time, in the above compound, X1 and X4 are 2) of Table of Contents II. UBR Box Domain Ligands It applies in the same way as described in X1 and 3)X4.

[0315] Specific example compounds for [Chemical Formula 1-2] can be selected from the following.

[0316] Specific example compounds for chemical formula [1-2] Compound number compound 19 N -(4-aminobenzyl)-4-hydroxybenzohydrazide 48 4-hydroxy-N'-(4-methoxybenzyl)benzohydrazide 49 N'-(4-aminobenzyl)-2,3-dihydro-1H-indene-2-carbohydrazide

[0317] In another specific example, the compound disclosed herein may have the structure of [Formula 1-3]: [Formula 1-3]

[0318] .

[0319] At this time, in the above compound, X1 and X4 are 2) of Table of Contents II. UBR Box Domain Ligands It applies in the same way as described in X1 and 3)X4.

[0320] Specific example compounds for [Chemical Formula 1-3] can be selected from below.

[0321] Specific example compounds for chemical formula [1-3] Compound number compound 12 4-amino- N -(2-(4-hydroxyphenyl)-2-oxoethyl)benzenesulfonamide 50 4-amino-N-(2-(4-hydroxyphenyl)-2-oxoethyl)-3-morpholinobenzenesulfonamide 51 3,5-Diamino-N-(2-(4-hydroxyphenyl)-2-oxoethyl)benzenesulfonamide

[0322] In another specific example, the compound disclosed herein may have the structure of [Formula 1-4]:

[0323] [Chemical Formula 1-4]

[0324] .

[0325] Specific example compounds for [Chemical Formula 1-4] can be selected from the following.

[0326] Specific example compounds for chemical formula [1-4] Compound number compound 16 N -(((4-aminophenyl)sulfonyl)methyl)-4-hydroxybenzamide 54 4-hydroxy-N-(((4-methoxyphenyl)sulfonyl)methyl)benzamide 55 N-(((4-aminophenyl)sulfonyl)methyl)-[1,1'-biphenyl]-4-carboxamide

[0327] In this case, the compound may be considered in the form of one of its possible isomers or a mixture thereof. For example, all stereoisomers, including enantiomers and diastereomers, or mixtures thereof (e.g., racemic mixtures) may be considered.

[0328] 2. Salt of the above compound

[0329] The compounds disclosed herein may be considered in the form of their salts. The salts include pharmaceutically acceptable salts. The salts disclosed herein include acid addition salts or basic addition salts. Exemplary acids forming the salts include hydrochloric acid, sulfuric acid, phosphoric acid, glycolic acid, lactic acid, pyruvate, citric acid, succinic acid, glutaric acid, etc., and exemplary bases forming the salts include lithium, sodium, potassium, calcium, magnesium, methylamine, trimethylamine, etc., provided, however, that they are not limited thereto and may be readily selected by those skilled in the art.

[0330] IV. Uses of Compounds

[0331] 1. Inhibition of UBR box domain substrate binding

[0332] A composition for inhibition of UBR box domain substrate binding

[0333] The compounds disclosed herein may be used in the preparation of compositions for inhibiting the binding of UBR box domain substrates. In one embodiment, a composition containing the compounds disclosed herein may be used to bind to UBR box domains to inhibit the binding of UBR box domain substrates. In another embodiment, a composition containing the compounds may be used to prevent the degradation of a substrate that binds to and degrades the UBR box domain. In a specific embodiment, a composition containing the compounds may be used to prevent a substrate that binds to the UBR box domain from being degraded by the ubiquitin-proteasome pathway.

[0334] In a specific embodiment, a composition comprising the compound disclosed herein may be used to inhibit the binding of a substrate having an N-terminal residue that binds to a UBR box domain. In a specific embodiment, it may be used to inhibit the binding of a substrate having an N-terminal residue, such as arginine (Arg), lysine (Lys), histidine (His), tryptophan (Trp), phenylalanine (Phe), tyrosine (Tyr), leucine (Leu), and isoleucine (Ile). However, it is not limited thereto and may be used to inhibit the binding of a substance known in the art as a substrate of a UBR box domain.

[0335] Referring to the examples, it can be seen that the compound disclosed herein inhibits the degradation of a substrate by binding to UBR (see FIGS. 1 to 19).

[0336] 2. Treatment of UBR-related diseases

[0337] The compound or salt thereof described in this specification has the property of binding to the UBR box domain. That is, it is a compound that functions as a ligand that binds to the UBR box domain. Therefore, by using such a compound, the degradation of proteins that are degraded by binding to the UBR box domain in the body can be inhibited, and UBR-related diseases can be treated using this mechanism.

[0338] 1) Pharmaceutical composition

[0339] The compounds disclosed in this specification may be used in the manufacture of pharmaceutical compositions for treating targets in need thereof.

[0340] In this case, the treatment includes having the effect of improving symptoms of a specific medical condition or delaying the progression of a disease. In this case, the subject includes humans and non-human animals. In this case, the pharmaceutical composition may include pharmaceutically acceptable carriers, excipients, and / or additives together with the compound. The pharmaceutically acceptable carriers, excipients, and / or additives include, but are not limited to, water, saline solution, glycol, glycerol, animal and vegetable fats, oils, starch, etc., and include all pharmaceutically acceptable carriers, excipients, and / or additives known in the art.

[0341] 2) Treatment methods

[0342] The present specification provides a treatment method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject in need thereof. In this case, the administration of said compound or pharmaceutically acceptable salt thereof may have the effect of improving symptoms of a specific medical condition or delaying the progression of a disease compared to a subject who has not received the administration. In this case, said subject includes humans and non-human animals.

[0343] - UBR-related diseases

[0344] In one embodiment, the present specification provides a treatment method comprising administering the compound or a pharmaceutically acceptable salt thereof to a subject having a UBR-related disease. That is, the compound disclosed herein or a pharmaceutically acceptable salt thereof may be used to treat a UBR-related disease. In a specific embodiment, the compound or a pharmaceutically acceptable salt thereof may be used to treat a specific disease that can be treated by inhibiting the degradation of a protein that is degraded through binding to a UBR box domain.

[0345] The specific diseases mentioned above include muscular dystrophy (Becker, Congennital, Duchenne, Distal, Emery-Dreifuss, Facioscapulohumeral, Limb-girdle, myotonic, ocuophargyngeal), muscle wasting diseases mediated by muscle loss or degradation including sarcopenia or cancer cachexia, as well as liposarcoma, cystic fibrosis, Johanson-Blizzard syndrome, urethral obstruction sequence, autoimmune pancreatitis, or Usher syndrome mediated by excessive protein degradation.

[0346] In one embodiment, the compound or a pharmaceutically acceptable salt thereof may be used to treat muscle loss mediated by UBR. For example, rapid loss of muscle mass associated with disease states such as cancer, sepsis, and hyperthyroidism is known to be associated with increased degradation of proteins within the muscle, which is associated with the activation of the ubiquitin proteasome system. In this case, it is known that ubiquitin binding increases specifically through the activation of the N-terminal rule pathway, resulting in muscle loss [ALFRED L. GOLDBERG et al. 1998, 1999]. Accordingly, the compound disclosed herein or a pharmaceutically acceptable salt thereof may be used to treat said diseases by preventing the activation of the muscle loss pathway through binding to the UBR box domain. However, the specific diseases mentioned above include all diseases known in the art as UBR-related diseases, provided that they are not limited thereto.

[0347] V. Examples

[0348] Example 1. Compound Synthesis

[0349] List of compounds number Compound name 1 N -(4-hydroxybenzoyl)-4-methylbenzenesulfonohydrazide 2 4-amino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide 3 4-amino- N -(4-hydroxybenzoyl)-3-morpholinobenzenesulfonohydrazide 4 N -(4-hydroxybenzoyl)-2-oxoindolin-5-sulfonohydrazide 5 N -(4-hydroxybenzoyl)indolin-5-sulfonohydrazide 6 N '-([1,1'-biphenyl]-4-carbonyl)-4-aminobenzenesulfonohydrazide 7 N '-([1,1'-biphenyl]-3-carbonyl)-4-aminobenzenesulfonohydrazide 8 3-amino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide 9 4-(1-aminoethyl)- N -(4-hydroxybenzoyl)benzenesulfonohydrazide 10 3,5-diamino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide 11 N -(4-hydroxybenzoyl)-4-((2-hydroxyethyl)amino)benzenesulfonohydrazide 12 4-amino- N -(2-(4-hydroxyphenyl)-2-oxoethyl)benzenesulfonamide 13 N -(4-hydroxybenzoyl)-4-methoxybenzenesulfonohydrazide 14 4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)benzimideamide 15 4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)benzamide 16 N -(((4-aminophenyl)sulfonyl)methyl)-4-hydroxybenzamide 17 6-amino- N -(4-hydroxybenzoyl)-[1,1'-biphenyl]-3-sulfonohydrazide 18 4-(2-((4-aminophenyl)sulfonyl)hydrazine-1-carbonyl)benzamide 19 N -(4-aminobenzyl)-4-hydroxybenzohydrazide 20 4-amino- N '-(1 H -Indole-3-carbonyl)benzenesulfonohydrazide 21 4-amino- N -(4-hydroxybenzoyl)-3-(pyrrolidine-1-yl)benzenesulfonohydrazide 22 N -(4-hydroxybenzoyl)-4-nitro-3-(pyrrolidine-1-yl)benzenesulfonohydrazide 23 4-amino- N -(4-hydroxybenzoyl)-3-(piperidine-1-yl)benzenesulfonohydrazide 24 N -(4-hydroxybenzoyl)-1 H -Pyrazole-4-sulfonohydrazide 25 N -(4-hydroxybenzoyl)indolin-4-sulfonohydrazide 26 N -(4-hydroxybenzoyl)-1 H -Indol-4-Sulfonohydrazid 27 2-((4-aminophenyl)sulfonyl)- N -phenylhydrazine-1-carboxamide 28 4-amino- N '-(1 H -Indole-4-carbonyl)-3-morpholinobenzenesulfonohydrazide 29 4-amino- N -(Indolin-4-carbonyl)benzenesulfonohydrazide 30 4-amino- N -(4-hydroxybenzoyl)-3-(peparazine-1-yl)benzenesulfonohydrazide 31 4-amino- N -(2,3-dehydro-1 H -Indene-2-carbonyl)benzenesulfonohydrazide 32 4-amino- N -(isoindolin-2-carbonyl)benzenesulfonohydrazide 33 N -(4-hydroxybenzoyl)-1 H -Indol-2-Sulfonohydrazid 34 4-amino- N -(2-phenylacetyl)benzenesulfonohydrazide 35 N -(4-hydroxybenzoyl)-1 H -Indazole-3-sulfonohydrazide 36 4-amino- N -(Indolin-6-carbonyl)benzenesulfonohydrazide 37 4-amino- N -(Indolin-3-carbonyl)benzenesulfonohydrazide 38 N -(4-hydroxybenzoyl)piperidine-4-sulfonohydrazide 39 4-amino- N -(Indolin-6-carbonyl)-3-morpholinobenzenesulfonohydrazide 40 4-amino- N -(Piperazine-1-carbonyl)benzenesulfonohydrazide 41 4-amino-3-morpholino- N -(Piperazine-1-carbonyl)benzenesulfonohydrazide 42 N'-(4-hydroxybenzoyl)-2-methylthiazole-4-sulfonohydrazide 43 (1 S ,4 S )-4-amino- N -(4-hydroxybenzoyl)cyclohexane-1-sulfonohydrazide 44 (1 R ,4 R )-4-amino- N -(4-hydroxybenzoyl)cyclohexane-1-sulfonohydrazide 45 4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)-5-methylfuran-2-carboxylic acid 46 N -(4-hydroxybenzoyl)pyrrolidine-3-sulfonohydrazide 47 N -(4-hydroxybenzoyl)-1 H -pyrrolo[2,3- b ]Pyridin-2-sulfonohydrazide 48 4-hydroxy-N'-(4-methoxybenzyl)benzohydrazide 49 N'-(4-aminobenzyl)-2,3-dihydro-1H-indene-2-carbohydrazide 50 4-amino-N-(2-(4-hydroxyphenyl)-2-oxoethyl)-3-morpholinobenzenesulfonamide 51 3,5-Diamino-N-(2-(4-hydroxyphenyl)-2-oxoethyl)benzenesulfonamide 52 2-((4-aminophenyl)sulfonyl)-N-(3-hydroxyphenyl)hydrazine-1-carboxamide 53 2-((4-amino-3-morpholinophenyl)sulfonyl)-N-phenylhydrazine-1-carboxamide 54 4-hydroxy-N-(((4-methoxyphenyl)sulfonyl)methyl)benzamide 55 N-(((4-aminophenyl)sulfonyl)methyl)-[1,1'-biphenyl]-4-carboxamide

[0350] 1 ¹H NMR spectra were recorded at Bruker Avance III 400 MHz and Bruker Fourier 300 MHz, and TMS was used as an internal standard. LCMS was measured using a quadrupole mass spectrometer on an Agilent 1260 HPLC and 6120 MSD. (ES Column operating in (+) or (-) ionization mode: C18 (50 χ 4.6 mm, 5 μm); T = 30 o C; Flow rate = 1.5 mL / min; Detected wavelengths: 220 nm, 254 nm)

[0351] Experimental Example 1-1. Compound 1 ( N Preparation of -(4-hydroxybenzoyl)-4-methylbenzenesulfonohydrazide)

[0352]

[0353] Step 1) Synthesis of A2

[0354] A1 A mixture of (methyl 4-hydroxybenzoate, 2.00 g, 13 mmol, 1.0 eq) and hydrazine monohydrate (20 mL) 100 o It was stirred at C for 16 hours. The solvent was concentrated under reduced pressure to obtain the crude product, which was purified using a flash column (DCM / MeOH=50 / 1~1 / 1). A2 (4-hydroxybenzohydrazide, 2.0 g, yield 60%) was obtained as a white solid.

[0355] 1 1 H NMR (DMSO- d 6, 400 MHz): δ 9.49 (s, 1H), 7.67-7.69 (m, 2H), 6.76-6.79 (m, 2H), 4.38 (br s, 2H).

[0356] Step 2) Synthesis of Compound 1

[0357] In pyridine (5 mL) A2 A mixture of (4-hydroxybenzohydrazide, 0.3 g, 1.97 mmol, 1.0 eq) and 4-methylbenzenesulfonyl chloride (0.3 g, 1.57 mmol, 0.8 eq) was 80 o It was stirred at C for 16 hours. Subsequently, 1N HCl was added to the mixture until pH=3, and it was extracted with EA (20 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to obtain the crude product (400 mg). Approximately 130 mg of the crude product was purified by prep-HPLC. The collected fraction was concentrated to remove most of the CH3CN. The remaining fraction was freeze-dried to obtain Compound 1 ( N -(4-hydroxybenzoyl)-4-methylbenzenesulfonohydrazide, 50 mg, 24.8% yield) was obtained as a white solid.

[0358] 1 HNMR (DMSO- d 6, 400 MHz): δ 10.38 (s, 1H), 10.09 (s, 1H), 9.76 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 2.35 (s, 3H).

[0359] LCMS; Mass Calcd.:306.3; MS Found: 306.9.

[0360] Experimental Example 1-2. Compound 2 (4-amino- N Preparation of -(4-hydroxybenzoyl)benzenesulfonohydrazide)

[0361]

[0362] Step 1) Synthesis of A3

[0363] In pyridine (5 mL) A2 A mixture of (4-hydroxybenzohydrazide, 0.3 g, 1.97 mmol, 1.0 eq) and 4-nitrobenzene-1-sulfonyl chloride (0.35 g, 1.57 mmol, 0.8 eq) was 80 o It was stirred at C for 16 hours. Subsequently, 1N HCl was added until the mixture reached pH=3, and it was extracted with EA (20 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to obtain the crude product. A3 ( N -(4-hydroxybenzoyl)-4-nitrobenzenesulfonohydrazide, 370 mg) was obtained as a yellow solid.

[0364] LCMS; Mass Calcd.:337.1; MS Found: 337.6 [MS], 359.6[MS+22].

[0365] Step 2) Synthesis of Compound 2

[0366] In EtOH (10 mL) A3 ( N A mixture of -(4-hydroxybenzoyl)-4-nitrobenzenesulfonohydrazide, 150 mg, 0.45 mmol, 1.0 eq) and 5% Pd / C (200 mg, 50% in water) 10 o It was stirred with an H2 balloon at C for 4 hours. Subsequently, the mixture was filtered and the filtrate concentrated to obtain the crude product, which was purified by prep-HPLC. The collected fraction was concentrated to remove most of the CH3CN. The residual fraction was freeze-dried to obtain compound 2 (4-amino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide), 50 mg, yield 36.6%) was obtained as a white solid.

[0367] 1 HNMR (DMSO- d 6, 400 MHz): δ 10.31 (s, 1H), 10.06 (s, 1H), 9.13 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.08 Hz, 2H), 6.50 (d, J = 8.8 Hz, 2H), 5.95 (s, 2H).

[0368] LCMS; Mass Calcd.:307.3; MS Found: 307.9.

[0369] Experimental Example 1-3. Compound 3 (4-amino- N Preparation of -(4-hydroxybenzoyl)-3-morpholinobenzenesulfonohydrazide)

[0370]

[0371] Step 1) A4 synthesis

[0372] In pyridine (5 mL) A23-fluoro-4-nitrobenzene-1-sulfonyl chloride (790 mg, 3.29 mmol, 1.0 eq) in pyridine (3 mL) was added dropwise to a mixture of (4-hydroxybenzohydrazide, 500 mg, 3.29 mmol, 1.0 eq). Subsequently, the mixture 25 o It was stirred at C for 3 hours. The solution was poured into water (30 mL). The mixture was extracted with EA (30 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to obtain the crude product, which was purified by a flash column (DCM / MeOH=50 / 1–30 / 1). A4 (3-fluoro- N -(4-hydroxybenzoyl)-4-nitrobenzenesulfonohydrazide, 500 mg, 42.8%) was obtained as a white solid.

[0373] 1 HNMR (DMSO- d 6, 400 MHz): δ 10.55 (s, 1H), 10.49 (s, 1H), 10.14 (s, 1H), 8.32 (t, J = 8.0 Hz, 1H), 7.98 (d, J = 10.4 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H).

[0374] Step 2) Synthesis of A5

[0375] In DMF (10 mL) A4 (3-fluoro- N K2CO3 (486 mg, 3.52 mmol, 2.5 eq) was added to a mixture of -(4-hydroxybenzoyl)-4-nitrobenzenesulfonohydrazide, 500 mg, 1.41 mmol, 1.0 eq) and morpholine (184 mg, 2.11 mmol, 1.5 eq) at a concentration of 25 o It was added at C. Subsequently, the mixture was 25 oIt was stirred at C for 16 hours. The solution was poured into water (30 mL). The mixture was extracted with EA (30 mL x 3). The combined organic layer was washed with water (50 mL x 3) and brine, dried and concentrated with Na2SO4 to obtain the crude product, which was purified by a flash column (DCM / MeOH = 50 / 1–30 / 1) A5 ( N -(4-hydroxybenzoyl)-3-morpholino-4-nitrobenzenesulfonohydrazide, 180 mg, 30.3%) was obtained as a white solid.

[0376] 1 HNMR (DMSO- d 6, 400 MHz): δ 10.51 (s, 1H), 10.24 (s, 1H), 10.14 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.60-7.62 (m, 3H), 7.52 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 2H), 3.64 (t, J = 4.8 Hz, 4H), 2.90-2.94 (m, 4H).

[0377] Step 3) Synthesis of Compound 3

[0378] In EtOH (10 mL) A5 ( N In a mixture of '-(4-hydroxybenzoyl)-3-morpholino-4-nitrobenzenesulfonohydrazide, 180 mg, 0.427 mmol, 1.0 eq), Pd / C (200 mg) 25 o It was added at C. Subsequently, the mixture was 25 o It was stirred under an H2 balloon at C for 4 hours. The solution was filtered, the filtrate was concentrated, and purified by prep-HPLC. Compound 3 (4-amino- N -(4-hydroxybenzoyl)-3-morpholinobenzenesulfonohydrazide, 40 mg, 23.9%) was obtained as a white solid. (TLC: N / A)

[0379] 1 HNMR (DMSO- d 6, 400 MHz): δ 10.35 (d, J = 3.6 Hz, 1H), 10.06 (s, 1H), 9.20 (d, J = 4.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.23-7.28 (m, 2H), 6.76 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 8.4 Hz, 1H), 5.63 (s, 2H), 3.69 (t, J = 4.4 Hz, 4H), 2.62 (t, J = 4.4 Hz, 4H).

[0380] LCMS; Mass Calcd.:392.4; MS Found: 393.

[0381] Experimental Example 1-4. Compound 4 ( N Preparation of -(4-hydroxybenzoyl)-2-oxoindoline-5-sulfonohydrazide)

[0382]

[0383] Step 1) Synthesis of A7

[0384] Chlorosulfonic acid (0.88 g, 7.52 mmol, 1.0 eq) and A6 A mixture of (indolin-2-one, 1.0 g, 7.52 mmol, 1.0 eq) 25 o It was stirred at C for 1.5 hours and then 68 o It was stirred at C for 1 hour. The mixture was cooled and carefully poured into water. The formed precipitate was collected by filtration, washed with water, and dried under vacuum. A7 (2-oxoindolin-5-sulfonyl chloride, 0.7 g, crude) was obtained as a pink solid.

[0385] 1 HNMR (DMSO- d6, 400 MHz): δ10.47 (br s, 1H), 7.44-7.46 (m, 2H), 6.75 (d, J = 8.8 Hz, 1H), 3.47 (s, 2H).

[0386] Step 2) Synthesis of Compound 4

[0387] In pyridine (10 mL) A2 (4-hydroxybenzohydrazide, 0.20 g, 1.32 mmol, 1.0 eq) and A7 A mixture of (2-oxoindolin-5-sulfonyl chloride, 0.30 g, 1.32 mmol, 1.0 eq) 30 o It was stirred at C for 5 hours. The mixture was poured into water. The formed precipitate was collected by filtration, washed with water, and dried under vacuum. The solid was 30 in DCM o It was stirred at C for 30 minutes. The mixture was filtered and the filter cake was dried. Compound 4 ( N -(4-hydroxybenzoyl)-2-oxoindolin-5-sulfonohydrazide 50 mg (11%) was obtained as a pink solid.

[0388] 1 HNMR (DMSO- d 6, 400 MHz): δ 10.79 (br s, 1H), 10.35 (br s, 1H), 10.11 (br s, 1H), 9.62 (br s, 1H), 7.63-7.66 (m, 2H), 7.57 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 2H), 3.51 (s, 2H).

[0389] LCMS; Mass Calcd.: 347.3; MS Found: 347.8.

[0390] Experimental Example 1-5. Compound 5 ( N' - Preparation of (4-hydroxybenzoyl)indolin-5-sulfonohydrazide)

[0391]

[0392] Step 1) Synthesis of A8

[0393] In pyridine (10 mL) A2 A mixture of (4-hydroxybenzohydrazide, 293 mg, 1.93 mmol, 1.0 eq) and 1-acetylindoline-5-sulfonyl chloride (500 mg, 1.93 mmol, 1.0 eq) 30 o It was stirred at C for 5 hours. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated. A8 (1-acetyl- N -(4-hydroxybenzoyl)indolin-5-sulfonohydrazide, 500 mg, crude) was obtained as a yellow solid.

[0394] Step 2) Synthesis of Compound 5

[0395] In THF (10 mL) A8 (1-acetyl- N A mixture of '-(4-hydroxybenzoyl)indolin-5-sulfonohydrazide, 200 mg, 0.53 mmol, 1.0 eq) and 2N HCl (6 mL) 50 o It was stirred at C for 5 hours. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated. The crude product was purified by prep-HPLC and freeze-dried to obtain Compound 5 ( N -(4-hydroxybenzoyl)indolin-5-sulfonohydrazide, 50 mg, 28.2%) was obtained as a white solid.

[0396] 1 HNMR (DMSO- d 6, 400 MHz): δ 10.30 (br s, 1H), 10.05 (br s, 1H), 9.14 (br s, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.33-7.36 (m, 2H), 6.77 (d, J = 8.4 Hz, 2H), 6.37-6.40(m, 2H), 3.51 (t, J = 8.4 Hz, 2H), 2.90 (t, J = 8.4 Hz, 2H).

[0397] LCMS; Mass Calcd.: 333.3; MS Found: 333.8.

[0398] Experimental Example 1-6. Compound 6 ( N Preparation of '-([1,1'-biphenyl]-4-carbonyl)-4-aminobenzenesulfonohydrazide)

[0399]

[0400] Step 1) Synthesis of A10

[0401] Methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate in a solution of bromobenzene (400 mg, 2.5 mmol) in dioxane A9 , 801 mg, 3.0 mmol), K3PO4 (541 mg, 7.5 mmol), and Pd(dppf)Cl2-CH2Cl2 (208 mg, 0.25 mmol) were added at room temperature. The mixture was 100 o It was stirred at C for 12 hours. After the reaction was complete, the reaction mixture was cooled. The reaction mixture was filtered through Celite and then extracted with ethyl acetate. The organic layer was dried with anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (Hex / EA = 3 / 1) A10 (Methyl [1,1'-biphenyl]-4-carboxylate, 160 mg, yield: 45%) was obtained as a white solid.

[0402] 1H NMR (DMSO-d6, 600 MHz) δ (ppm): 8.05-8.03 (m, 2H), 7.84-7.83 (m, 2H), 7.76-7.74 (m, 2H), 7.52-7.50 (m, 2H), 7.50-7.42 (m, 1H), 3.87 (s, 3H); LCMS Calcd m / z for C 14 H 12 O2[M+H] + 213.25 Found 213.

[0403] Step 2) Synthesis of A11

[0404] In hydrazine monohydrate (8 mL) A10 A solution of (methyl [1,1'-biphenyl]-4-carboxylate, 160 mg, 0.70 mmol) is 100 o It was stirred at C for 16 hours. After the reaction was complete, the reaction mixture was cooled, then concentrated under reduced pressure, and then purified by flash column chromatography (DCM / MeOH = 15 / 1) to obtain the crude product, A11 ([1,1'-biphenyl]-4-carbohydrazide, 152 mg, theoretical yield: 100%) was obtained as a white solid. LCMS Calcd m / z for C 13 H 12 N2O [M+H] + 213.25 Found 213.

[0405] Step 3) Synthesis of A12

[0406] In pyridine (5 mL) A11 4-nitrosulfonyl chloride (143 mg, 0.60 mmol) was added to a solution of ([1,1'-biphenyl]-4-carbohydrazide, 152 mg, 0.70 mmol). The mixture was refluxed for 12 hours. After the reaction was complete, the resulting mixture was cooled and evaporated to remove pyridine and purified by flash column chromatography (DCM / MeOH = 15 / 1) to obtain the crude product, A12 ( N'-([1,1'-biphenyl]-4-carbonyl)-4-nitrobenzenesulfonohydrazide, 60 mg, yield: 21%) was obtained as a yellow solid. LCMS Calcd m / z for C 19 H 15 N3O5S [M+H] + 398.41 Found 398.

[0407] Step 4) Synthesis of Compound 6

[0408] In THF:MeOH = 3:1 (12 mL) A12 ( N Zn (99 mg, 1.5 mmol) and NH4Cl (81 mg, 1.5 mmol) were added to a solution of -([1,1'-biphenyl]-4-carbonyl)-4-nitrobenzenesulfonohydrazide (60 mg, 0.15 mmol). The mixture was stirred at room temperature for 12 hours. After the reaction was complete, ethyl acetate was added. The mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM / MeOH = 15 / 1) Compound 6 (N'-([1,1'-biphenyl]-4-carbonyl)-4-aminobenzenesulfonohydrazide, 10 mg, yield: 20%) was obtained as a white solid.

[0409] 1H NMR (DMSO-d6, 600 MHz) δ (ppm): δ 10.64 (br s, 1H), 9.32 (br s, 1H), 7.79-7.77 (m, 2H), 7.74-7.70 (m, 4H), 7.49 (t, 2H), 7.45-7.39 (m, 3H), 6.51 (d, J = 6.0 Hz, 2H), 5.96 (s, 1H), 6.52 (d, J = 5.0 Hz, 2H); LCMS Calcd m / z for C 19 H 17 N3O3S [M+H] + 368.42 Found 368.

[0410] Experimental Example 1-7. Compound 7 ( N Preparation of '-([1,1'-biphenyl]-3-carbonyl)-4-aminobenzenesulfonohydrazide)

[0411]

[0412] Step 1) Synthesis of A14

[0413] Methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate in a solution of bromobenzene (400 mg, 2.5 mmol) in dioxane A13 , 801 mg, 3.0 mmol), K3PO4 (541 mg, 7.5 mmol), and Pd(dppf)Cl2-CH2Cl2 (208 mg, 0.25 mmol) were added at room temperature. The mixture was 100 o It was stirred at C for 12 hours. After the reaction was complete, the reaction mixture was cooled. The mixture was filtered through Celite and then extracted with ethyl acetate. The organic layer was dried with anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (Hex / EA = 3 / 1) A14 (Methyl [1,1'-biphenyl]-3-carboxylate, 160 mg, yield: 49%) was obtained as a white solid.

[0414] 1H NMR (DMSO-d6, 600 MHz) δ (ppm): 8.18 (t, J = 1.8 Hz, 1H), 7.97-7.95 (m, 2H), 7.71-7.70 (m, 2H), 7.63 (t, J = 7.7 Hz, 1H), 7.52-7.49 (m, 2H), 7.43-7.41 (m, 1H), 3.89 (s, 3H); LCMS Calcd m / z for C 14 H 12 O2[M+H] + 213.25 Found 213.

[0415] Step 2) Synthesis of A15

[0416] Hydrazine monohydrate (8 mL) A14 A solution of (methyl [1,1'-biphenyl]-3-carboxylate, 160 mg, 7.5 mmol) is 100 oIt was stirred at C for 16 hours. After the reaction was complete, the reaction mixture was cooled, then concentrated under reduced pressure, and subsequently purified by flash column chromatography (DCM / MeOH = 15 / 1) to obtain the crude product. A15 ([1,1'-biphenyl]-3-carbohydrazide, 200 mg, yield: 100%) was obtained as a yellow solid.

[0417] LCMS Calcd m / z for C 13 H 12 N2O [M+H] + 213.25 Found 213.

[0418] Step 3) Synthesis of A16

[0419] In pyridine (7 mL) A15 4-nitrosulfonyl chloride (2.5 mL) was added to a solution of ([1,1'-biphenyl]-3-carbohydrazide, 200 mg, 0.90 mmol). The mixture was refluxed for 12 hours. After the reaction was complete, the resulting mixture was cooled and evaporated to remove pyridine, and then purified by flash column chromatography (DCM / MeOH = 15 / 1) to obtain the crude product, A16 ( N '-([1,1'-biphenyl]-3-carbonyl)-4-nitrobenzenesulfonohydrazide, 102 mg, yield: 53%) was obtained as an ivory-colored solid.

[0420] LCMS Calcd m / z for C 19 H 15 N3O5S [M+H] + 398.41 Found 398.

[0421] Step 4) Synthesis of Compound 7

[0422] In THF:MeOH = 3:1 (10 mL) A16 ( NZn (168 mg, 2.5 mmol) and NH4Cl (137 mg, 2.5 mmol) were added to a solution of -([1,1'-biphenyl]-3-carbonyl)-4-nitrobenzenesulfonohydrazide, 102 mg, 0.25 mmol). The mixture was stirred at room temperature for 12 hours. After the reaction was complete, ethyl acetate was added. The mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM / MeOH = 15 / 1) Compound 7 ( N '-([1,1'-biphenyl]-3-carbonyl)-4-aminobenzenesulfonohydrazide, 14 mg, yield: 14%, purity: 96.8%) was obtained as a white solid.

[0423] 1H NMR (DMSO-d6, 600 MHz) δ (ppm): δ 10.71 (br s, 1H), 9.37 (br s, 1H), 7.97 (s, 1H), 7.83 (d, J = 6.0 Hz, 1H), 7.72 (d, J = 6.0 Hz, 2H), 7.65 (d, J = 6.0 Hz, 1H), 7.54-7.49 (m, 3H), 7.45 (d, J = 6.0 Hz, 2H), 7.42 (t, 1H), 6.52 (d, J = 6.0 Hz, 2H), 5.97 (s, 2H); ESI-MS Calcd m / z for C 19 H 17 N3O3S [M+H] + 368.42 Found 368.

[0424] Experimental Example 1-8. Compound 8 (3-amino- N Preparation of -(4-hydroxybenzoyl)benzenesulfonohydrazide)

[0425]

[0426] Step 1) Synthesis of A17

[0427] In pyridine (8 mL) A23-nitrosulfonyl chloride (168 mg, 1.08 mmol) was added to a solution of (200 mg, 0.90 mmol). The mixture was refluxed for 12 hours. After the reaction was complete, the resulting mixture was cooled and evaporated to remove pyridine, and then purified by flash column chromatography (DCM / MeOH = 15 / 1) to obtain the crude product, A17 ( N -(4-hydroxybenzoyl)-3-nitrobenzenesulfonohydrazide, 129 mg, yield: 43%) was obtained as an ivory solid. LCMS Calcd m / z for C 13 H 11 N3O6S [M+H] + 338.31 Found 338.

[0428] Step 2) Synthesis of Compound 8

[0429] In THF:MeOH = 3:1 (10 mL) A17 ( N Zn (250 mg, 3.8 mmol) and NH4Cl (204 mg, 3.8 mmol) were added to a solution of -(4-hydroxybenzoyl)-3-nitrobenzenesulfonohydrazide (129 mg, 0.38 mmol). The mixture was stirred at room temperature for 12 hours. After the reaction was complete, ethyl acetate was subsequently added. The mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM / MeOH = 15 / 1) Compound 8 (3-amino- N-(4-hydroxybenzoyl)benzenesulfonohydrazide, 25 mg, yield: 21%, purity: 98.0%) was obtained as a white solid. 1H NMR (DMSO-d6, 600 MHz) δ (ppm): δ 10.36 (br s, 1H), 10.06 (br s, 1H), 9.53 (br s, 1H), 7.59 (d, J = 12 Hz, 2H), 7.11-7.08 (t, J = 9.0) Hz, 1H), 7.02 (s, 1H) 6.90 (d, J = 6.0 Hz, 1H), 6.77 (d, J = 6.0 Hz, 1H), 6.71 (d, J = 12 Hz, 1H), 5.49 (s, 2H); LCMS Calcd m / z for C 13 H 13 N3O4S [M+H] + 308.32 Found 308.

[0430] Experimental Example 1-9. Compound 9 (4-(1-aminoethyl)- N Preparation of -(4-hydroxybenzoyl)benzenesulfonohydrazide)

[0431]

[0432] Step 1) Synthesis of A18

[0433] In pyridine (5 mL) A2 A mixture of (4-hydroxybenzohydrazide, 500 mg, 3.29 mmol, 1.0 eq) and 4-acetylbenzene-1-sulfonyl chloride (717 mg, 3.29 mmol, 1.0 eq) 25 o It was stirred at C for 3 hours. The mixture was cooled and carefully poured into water. The mixture was extracted with EA (50 mL x 2). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, and concentrated. A18 (4-acetyl-N'-(4-hydroxybenzoyl)benzenesulfonohydrazide, 0.5 g, crude) was obtained as a brown solid.

[0434] LCMS Calcd m / z for C 15 H 14 N2O5S [M+H] +335.3 Found 335.

[0435] Step 2) Synthesis of Compound 9

[0436] In MeOH (5 mL) A18 A mixture of (4-acetyl-N'-(4-hydroxybenzoyl)benzenesulfonohydrazide, 200 mg, 0.60 mmol, 1.0 eq), NH4OAc (461 mg, 5.98 mmol, 10 eq), and sodium cyanoborohydride (188 mg, 2.99 mmol, 5 eq) 60 o It was stirred at C for 16 hours. The mixture was concentrated, purified by prep-HPLC, and freeze-dried. Compound 9 (4-(1-aminoethyl)- N -(4-hydroxybenzoyl)benzenesulfonohydrazide, 55 mg, 24%) was obtained as a white solid.

[0437] 1 HNMR (DMSO- d 6, 400 MHz): δ 10.37 (br s, 2H), 8.28 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.57 (dd, J = 11.2, 8.8 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 4.22 (q, J = 6.8 Hz, 1H), 1.33 (d, J = 6.4 Hz, 3H).

[0438] LCMS; Mass Calcd.: 335.3(C 15 H 17 N3O4S); MS Found: 336.

[0439] Experimental Example 1-10. Compound 10 (3,5-diamino- N Preparation of -(4-hydroxybenzoyl)benzenesulfonohydrazide)

[0440]

[0441] Step 1) Synthesis of A20

[0442] 3,5-dinitroaniline in concentrated HCl (10 mL) ( A19 NaNO2 (226 mg, 3.28 mmol, 1.2 eq) in H2O (2 mL) was added to a mixture of , 500 mg, 2.73 mmol, 1.0 eq). o Added at C. The mixture is 0 o It was stirred at C for 0.5 hours. SOCl2 (1.30 g, 10.9 mmol, 4.0 eq) was added to a mixture of CuCl (27 mg, 0.27 mmol, 0.1 eq) in H2O (10 mL) at 0 o It was added at C. Subsequently, the diazo salt solution was 0 o Added dropwise at C. The mixture is 0 o It was stirred at C for 3 hours and then poured into water. The formed precipitate was collected by filtration and dried under vacuum. A20 (3,5-dinitrobenzenesulfonyl chloride, 0.5 g, crude) was obtained as a yellow solid.

[0443] Step 2) Synthesis of A21

[0444] In pyridine (5 mL) A20 (3,5-dinitrobenzenesulfonyl chloride, 175 mg, 0.66 mmol, 1.0 eq) and A2 A mixture of (4-hydroxybenzohydrazide, 100 mg, 0.66 mmol, 1.0 eq) 60 o It was stirred at C for 16 hours. The mixture was cooled and carefully poured into water. The mixture was extracted with EA (50 mL x 2). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, and concentrated. A21 ( N -(4-hydroxybenzoyl)-3,5-dinitrobenzenesulfonohydrazide, 0.1 g, crude) was obtained as a pink solid.

[0445] Step 3) Compound 10(3,5-diamino- N Synthesis of -(4-hydroxybenzoyl)benzenesulfonohydrazide)

[0446] In EtOH (5 mL) A21 ( N A mixture of -(4-hydroxybenzoyl)-3,5-dinitrobenzenesulfonohydrazide, 0.1 g, 0.26 mmol, 1.0 eq) and 10% Pd / C (0.1 g) was stirred under an H2 balloon at room temperature for 3 hours. The reaction mixture was filtered, and the filter cake was washed with EA (50 mL x 2). The combined filtrates were concentrated to obtain the crude product and stirred in MeOH (5 mL) for 10 minutes. The mixture was filtered, and the filter cake was dried under vacuum. Compound 10 (3,5-diamino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide, 27 mg, 32%) was obtained as a yellow solid.

[0447] 1 HNMR (DMSO- d 6, 400 MHz): δ 10.20 (br s, 1H), 10.04 (br s, 1H), 9.19 (br s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 6.26 (d, J = 1.6 Hz, 2H), 5.94 (s, 1H), 5.10 (s, 4H).

[0448] LCMS; Mass Calcd.: 322.3(C 13 H 14 N4O4S); MS Found: 323 [MS+1].

[0449] Experimental Example 1-11. Compound 11 ( N Preparation of -(4-hydroxybenzoyl)-4-((2-hydroxyethyl)amino)benzenesulfonohydrazide)

[0450]

[0451] In AcOH / H2O=1:1 (4 mL) Compound 2 (4-amino- NA mixture of -(4-hydroxybenzoyl)benzenesulfonohydrazide, 500 mg, 1.63 mmol, 1.0 eq) and oxirane (72 mg, 1.63 mmol, 1.0 eq) 25 o It was stirred at C for 4 hours. Subsequently, NaHCO3 was added to the mixture until pH=8, and it was extracted with EA (50 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to obtain the crude product, which was purified by prep-TLC. Compound 11 ( N -(4-hydroxybenzoyl)-4-((2-hydroxyethyl)amino)benzenesulfonohydrazide, 50 mg, yield 8.8%) was obtained as a white solid.

[0452] 1 HNMR (DMSO- d 6, 400 MHz): δ 7.56 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H), 6.45 (t, J = 5.2 Hz, 1H), 3.53 (t, J = 6.0 Hz, 2H), 3.12 (q, J = 6.0 Hz, 2H).

[0453] LCMS; Mass Calcd.:351.3; MS Found: 351.8 [MS+1].

[0454] Experimental Example 1-12. Compound 12 (4-amino- N Preparation of (2-(4-hydroxyphenyl)-2-oxoethyl)benzenesulfonamide)

[0455]

[0456] Step 1) Synthesis of A23

[0457] In EtOH (40 mL) A22Br2 (2.83 g, 17.7 mmol, 1.0 eq) was added to a mixture of (1-(4-(benzyloxy)phenyl)ethane-1-one, 4.0 g, 17.7 mmol, 1.0 eq). o It was added at C. The mixture is 30 o It was stirred at C for 30 minutes. The mixture was poured into PE and stirred for 30 minutes. The mixture was filtered, and the filter cake was dried. A23 (1-(4-(benzyloxy)phenyl)-2-bromoethane-1-one, 2.5 g, 46.3%) was obtained as a white solid.

[0458] Step 2) Synthesis of A24

[0459] In DCM (20 mL) A23 A mixture of (1-(4-(benzyloxy)phenyl)-2-bromoethane-1-one, 2.0 g, 6.55 mmol, 1.0 eq) and HMTA (1.38 g, 9.83 mmol, 1.5 eq) was 10 o It was stirred at C for 2 hours. Subsequently, the mixture was filtered, and the filter cake was dissolved in EtOH (15 mL) and concentrated HCl (5 mL). The mixture was 85 o It was stirred at C for 2 hours. The mixture was filtered and the filter cake was dried. A24 (2-amino-1-(4-(benzyloxy)phenyl)ethane-1-one hydrochloride, 2.0 g (crude) was obtained as a white solid.

[0460] 1 HNMR (CD3OD, 400 MHz): δ 8.03 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 7.2 Hz, 2H), 7.34-7.42 (m, 3H), 7.17 (d, J = 8.8 Hz, 2H), 5.23 (s, 2H), 4.55 (s, 2H).

[0461] Step 3) Synthesis of A25

[0462] In DCM (20 mL)A24 (2-amino-1-(4-(benzyloxy)phenyl)ethane-1-one hydrochloride, A mixture of 2.00 g, 7.20 mmol, 1.0 eq), 4-nitrobenzene-1-sulfonyl chloride (1.60 g, 7.20 mmol, 1.0 eq), and TEA (2.19 g, 21.6 mmol, 3.0 eq) was 20 o It was stirred at C for 1 hour. The mixture was poured into water and extracted with DCM. The organic layer was washed with water and brine, dried and concentrated with Na2SO4 to obtain the crude product, and stirred at PE for 30 minutes. The mixture was filtered and into a filter cake. A25 (N-(2-(4-(benzyloxy)phenyl)-2-oxoethyl)-4-nitrobenzenesulfonamide, 1.0 g, 35.8% for 2 steps) was obtained as a white solid.

[0463] 1 HNMR (CD3Cl, 400 MHz): δ 8.36 (d, J = 8.8 Hz, 2H), 8.10 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.37-7.43 (m, 5H), 7.03 (d, J = 8.4 Hz, 2H), 5.86 (t, J = 4.0 Hz, 1H), 5.16 (s, 2H), 4.49 (d, J = 4.0 Hz, 2H).

[0464] Step 4) Synthesis of Compound 12

[0465] In EtOH (10 mL) A25 A mixture of (N-(2-(4-(benzyloxy)phenyl)-2-oxoethyl)-4-nitrobenzenesulfonamide, 200 mg, 0.47 mmol, 1.0 eq) and Pd / C (150 mg, 50% in water) 25 oIt was stirred under an H2 balloon at C for 4 hours. Subsequently, the mixture was filtered, concentrated, purified by prep-HPLC, and freeze-dried. Compound 12 (4-amino- N -(2-(4-hydroxyphenyl)-2-oxoethyl)benzenesulfonamide, 69 mg, yield 48.0%) was obtained as a white solid.

[0466] 1 HNMR (DMSO- d 6, 400 MHz): δ 10.43 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.32 (t, J = 5.6 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 8.8 Hz, 2H), 5.91 (s, 2H), 4.19 (d, J = 5.6 Hz, 2H).

[0467] LCMS; Mass Calcd.:306.3; MS Found: 307 [MS+1].

[0468] Experimental Example 1-13. Compound 13 ( N Preparation of -(4-hydroxybenzoyl)-4-methoxybenzenesulfonohydrazide)

[0469]

[0470] In DMF (6 mL) A2Triethylamine (0.11 mL, 0.76 mmol) and 4-methoxybenzenesulfonyl chloride (124 mg, 0.60 mmol) were added to a solution of 4-hydroxybenzohydrazide (100 mg, 0.66 mmol). The mixture was maintained at room temperature for 12 hours. After the reaction was complete, the reaction mixture was evaporated and extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM / MeOH = 5 / 1) and Compound 13 (N'-(4-hydroxybenzoyl)-4-methoxybenzenesulfonohydrazide, 25 mg, yield: 12%, purity: 96.9%) was obtained as a white solid.

[0471] 1H NMR (DMSO-d6, 600 MHz) δ (ppm): δ 10.37 (br s, 1H), 10.07 (br s, 1H), 9.64 (br s, 1H), 7.73 (d, J = 12 Hz, 2H), 7.57 (d, J = 6.0 Hz, 2H), 7.03 (d, J = 6.0 Hz, 2H), 6.76 (d, J = 6.0 Hz, 2H), 3.80 (s, 3H); LCMS Calcd m / z for C 14 H 14 N2O5S [M+H] + 323.3 Found 323.

[0472] Experimental Example 1-14. Preparation of Compound 14 (4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)benzimide)

[0473]

[0474] Step 1) Synthesis of A26

[0475] In pyridine (10 mL) A2 4-cyanobenzene-1-sulfonyl chloride (1.33 g, 6.57 mmol, 1.0 eq) in pyridine (3 mL) was added dropwise to a mixture of (4-hydroxybenzohydrazide, 1.00 g, 6.57 mmol, 1.0 eq). Subsequently, the mixture 25 oIt was stirred at C for 3 hours. The solution was poured into water (50 mL). The mixture was extracted with EA (50 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to obtain the crude product, which was purified by a flash column (PE / EA=1 / 1). A26 (4-cyano- N -(4-hydroxybenzoyl)benzenesulfonohydrazide, 1.40 g, 67.1%) was obtained as a white solid.

[0476] 1 HNMR (DMSO- d 6, 400 MHz): δ 10.49 (s, 1H), 10.27 (s, 1H), 10.14 (s, 1H), 8.02-8.04 (m, 2H), 7.97-7.99 (m, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H).

[0477] Step 2) Synthesis of Compound 14

[0478] In HCl / EtOH (5 mL, 6 mol / L) A26 (4-cyano- N A mixture of '-(4-hydroxybenzoyl)benzenesulfonohydrazide, 200 mg, 0.63 mmol, 1.0 eq)' 25 o It was stirred at C for 3 hours. The solution was concentrated and added to MeOH. The mixture was concentrated again. The residue was added to MeOH (10 mL) and then to NH4OAc (485 mg, 6.30 mmol, 10 eq). The mixture was 25 o It was stirred at C for 16 hours. The mixture was concentrated, purified by prep-HPLC, and freeze-dried. Compound 14 (4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)benzimideamide, 26 mg, 10.8%) was obtained as a white solid.

[0479] 1 HNMR (DMSO- d6, 400 MHz): δ 8.43 (s, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H).

[0480] LCMS; Mass Calcd.:334; MS Found: 334.8 [MS+1].

[0481] Experimental Example 1-15. Preparation of Compound 15 (4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)benzamide).

[0482]

[0483] DMSO my A26 (4-cyano- N Cooled (0 of '-(4-hydroxybenzoyl)benzenesulfonohydrazide, 210 mg, 0.66 mmol) o C) Hydrogen peroxide, 35% w / w aq. Soln. (0.42 mL, 4.8 mmol) and potassium carbonate (30 mg, 0.20 mmol) were added to the solution. The reaction was heated to room temperature and stirred for 12 hours. After the reaction was complete, the reaction mixture was evaporated and extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 5 / 1) and Compound 15 (4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)benzamide, 20 mg, yield: 10%, purity: 96.5%) was obtained as a white solid.

[0484] 1H NMR (DMSO-d6, 600 MHz) δ (ppm): δ 10.44 (br s, 1H), 10.10 (br s, 1H), 10.03 (br s, 1H), 8.15 (br s, 1H), 7.96 (d, J = 6.0 Hz, 2H), 7.87 (d, J = 10 Hz, 2H), 7.59 (br s, 1H), 7.57 (d, J = 6.0 Hz, 2H), 6.76 (d, J = 6.0 Hz, 2H); LCMS Calcd m / z for C 14 H 13 N3O5S [M+H] + 336.33 Found 336.

[0485] Experimental Example 1-16. Compound 16 ( N - Preparation of (((4-aminophenyl)sulfonyl)methyl)-4-hydroxybenzamide)

[0486]

[0487] Step 1) Synthesis of A28

[0488] In DMF (40 mL) A27 K2CO3 (6.05 g, 43.8 mmol, 1.5 eq) and BnBr (4.99 g, 29.2 mmol, 1.0 eq) were added to a mixture of (4-hydroxybenzamide, 4.0 g, 29.2 mmol, 1.0 eq). The mixture was 60 o It was stirred at C for 16 hours. The mixture was poured into water and extracted with EA. The organic layer was washed with water and brine, dried with Na2SO4, and concentrated. A28 (4-(benzyloxy)benzamide, 6.0 g, 90.5%) was obtained as a white solid.

[0489] Step 2) Synthesis of A29

[0490] In THF / H2O (40 mL, v / v=1 / 1) A28A mixture of (4-(benzyloxy)benzamide, 4.0 g, 17.6 mmol, 1.0 eq), K2CO3 (0.24 g, 1.76 mmol, 0.1 eq), and HCOH (1.43 g, 17.6 mmol, 37% in water, 1.0 eq) was 65 o It was stirred at C for 16 hours. Subsequently, the mixture was concentrated and filtered. The filter cake was dried. A29 (4-(benzyloxy)- N -(hydroxymethyl)benzamide, 4.0 g, crude) was obtained as a white solid.

[0491] Step 3) Synthesis of A30

[0492] In TFA (20 mL) A29 (4-(benzyloxy)- N A mixture of -(hydroxymethyl)benzamide, 4.00 g, 15.6 mmol, 1.0 eq) and 4-nitrobenzenethiol (2.41 g, 15.6 mmol, 1.0 eq) 20 o It was stirred at C for 1 hour. The mixture was concentrated, added to water, and aq. NaHCO3. The pH was adjusted to 8. The mixture was extracted with EA. The organic layer was washed with brine, dried with Na2SO4, and concentrated. A30 (4-(benzyloxy)- N -(((4-nitrophenyl)thio)methyl)benzamide, 2.0 g, 32.6% for 2 steps) was obtained as a white solid.

[0493] Step 4) Synthesis of A31

[0494] In DCM (20 mL) A30 (4-(benzyloxy)- N A mixture of -(((4-nitrophenyl)thio)methyl)benzamide, 500 mg, 1.27 mmol, 1.0 eq) and m-CPBA (656 g, 3.80 mmol, 3.0 eq) 20 oIt was stirred at C for 16 hours. The mixture was poured with aq. Na2O3S2 and extracted. The organic layer was washed with aq. NaHCO3 and brine, dried with Na2SO4, and concentrated. A31 (4-(benzyloxy)- N -(((4-nitrophenyl)sulfonyl)methyl)benzamide, 300 mg, crude) was obtained as a white solid.

[0495] 1 HNMR (DMSO- d 6, 400 MHz): δ 9.39 (t, J = 6.4 Hz, 1H), 8.42 (d, J = 8.8 Hz, 2H), 8.14 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.34-7.46 (m, 5H), 7.08 (d, J = 8.8 Hz, 2H), 5.17 (s, 2H), 5.00 (d, J = 6.4 Hz, 2H).

[0496] Step 5) Synthesis of Compound 16

[0497] In EtOH (10 mL) A31 (4-(benzyloxy)- N A mixture of -(((4-nitrophenyl)sulfonyl)methyl)benzamide, 300 mg, 0.47 mmol, 1.0 eq) and Pd / C (150 mg, 50% in water) 25 o The mixture was stirred under an H2 balloon at C for 2 hours. Subsequently, the mixture was filtered, concentrated, purified by prep-HPLC, and freeze-dried to obtain Compound 16 (N-(((4-aminophenyl)sulfonyl)methyl)-4-hydroxybenzamide, 35 mg, yield 9.0% for 2 steps) was obtained as a white solid.

[0498] 1 HNMR (DMSO- d6, 400 MHz): δ 10.15 (br s, 1H), 9.06 (t, J = 6.4 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 8.8 Hz, 2H), 6.12 (s, 2H), 4.65 (d, J = 6.4 Hz, 2H).

[0499] LCMS ; Mass Calcd.:306; MS Found: 307 [MS+1].

[0500] Experimental Example 1-17. Compound 17 (6-amino- N Preparation of '-(4-hydroxybenzoyl)-[1,1'-biphenyl]-3-sulfonohydrazide)'

[0501]

[0502] Step 1) Synthesis of A33

[0503] In toluene (10 mL) A32 A mixture of (3-bromo-4-nitroaniline, 1 g, 4.61 mmol, 1.0 eq), phenylboronic acid (0.56 g, 4.61 mmol, 1.0 eq), Pd(dppf)Cl2 (337 mg, 0.09 mmol, 0.1 eq), and AcOK (1.14 g, 13.8 mmol, 3.0 eq) for 16 hours at 90 o It was stirred under N2 at C. The mixture was poured into water (30 mL) and extracted with EA (30 mL x 2). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated. The crude product was purified using a flash column (PE / EA = 30 / 1–10 / 1) and A33 (6-nitro-[1,1'-biphenyl]-3-amine, 1 g, crude) was obtained as a yellow solid.

[0504] Step 2) Synthesis of A34

[0505] In AcOH (10 mL) and concentrated HCl (5 mL) A33 In a mixture of (6-nitro-[1,1'-biphenyl]-3-amine, 500 mg, 2.33 mmol, 1.0 eq), NaNO2 (193 mg, 2.8 mmol, 1.2 eq) in H2O (2 mL) was 0 o Added dropwise at C. The mixture is 0 o It was stirred at C for 0.5 hours. SOCl2 (1.39 g, 11.6 mmol, 5.0 eq) was added to a mixture of CuCl (31.3 mg, 0.23 mmol, 0.1 eq) in H2O (10 mL) at 0 o It was added at C. Subsequently, the diazo salt solution was 0 o Added dropwise at C. The mixture is 0 o It was stirred at C for 3 hours and then poured with water. The formed precipitate was collected by filtration and dried under vacuum. A34 (6-nitro-[1,1'-biphenyl]-3-sulfonyl chloride, 400 mg, 57.6%) was obtained as a yellow solid.

[0506] 1 HNMR (DMSO- d 6, 400 MHz): δ 7.98 (d, J = 8.4 Hz, 1H), 7.78-7.80 (m, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.44-7.50 (m, 3H), 7.32-7.34 (m, 2H).

[0507] Step 3) Synthesis of A35

[0508] In pyridine (5 mL) A34 A mixture of (6-nitro-[1,1'-biphenyl]-3-sulfonyl chloride, 200 mg, 0.67 mmol, 1.0 eq) and 4-hydroxybenzohydrazide (122 mg, 0.81 mmol, 1.2 eq) 30 oIt was stirred at C for 0.5 hours. The mixture was carefully poured into water. The mixture was extracted with EA (50 mL x 2). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, and concentrated. A35 ( N -(4-hydroxybenzoyl)-6-nitro-[1,1'-biphenyl]-3-sulfonohydrazide, 200 mg, crude) was obtained as a brown solid.

[0509] Step 4) Synthesis of Compound 17

[0510] In EtOH (10 mL) A35 ( N A mixture of '-(4-hydroxybenzoyl)-6-nitro-[1,1'-biphenyl]-3-sulfonohydrazide, 200 mg, 0.48 mmol, 1.0 eq) and 10% Pd / C (200 mg) 30 o It was stirred under an H2 balloon at C for 3 hours. The reaction mixture was filtered, and the filter cake was washed with EA (50 mL x 2). The combined filtrate was concentrated to obtain the crude product, which was purified by prep-HPLC and freeze-dried to obtain compound 17 (6-amino- N -(4-hydroxybenzoyl)-[1,1'-biphenyl]-3-sulfonohydrazide, 45 mg, 17.5% for 2 steps) was obtained as a white solid.

[0511] 1 HNMR (DMSO- d 6, 400 MHz): δ 10.39 (s, 1H), 10.09 (s, 1H), 9.32 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.32-7.59 (m, 5H), 7.23 (d, J = 6.4 Hz, 2H), 6.73-6.79 (m, 3H), 5.64 (s, 2H).

[0512] LCMS; Mass Calcd.: 383; MS Found: 384 [MS+1].

[0513] Experimental Example 1-18. Preparation of Compound 18 (4-(2-((4-aminophenyl)sulfonyl)hydrazine-1-carbonyl)benzamide).

[0514]

[0515] Step 1) Synthesis of A37

[0516] Cooled (0 methyl 4-(chlorocarbonyl)benzoate (A36, 1.5 g, 7.5 mmol) in DCM o C) An ammonia solution (25–30%) (1.8 mL, 15 mmol) was added to the solution. The reaction was heated to room temperature and stirred for 4 hours. After the reaction was complete, the reaction mixture was evaporated and then water was added. The formed precipitate was collected by filtration. The filter cake was washed with water and dried. A37 (Methyl 4-carbamoylbenzoate, 1.0 g, 74%) was obtained as a white solid. LCMS Calcd m / z for C9H9NO3[M+H] + 152.17 Found 152.

[0517] Step 2) Synthesis of A38

[0518] In MeOH (10 mL) A37 A solution of (methyl 4-carbamoylbenzoate, 1 g, 6.6 mmol) and hydrazine monohydrate (10 mL) 80 o It was stirred at C for 16 hours. The solvent was concentrated under reduced pressure to obtain the crude product, which was purified using a flash column (DCM / MeOH = 10 / 1) and A38 (4-(hydrazine carbonyl)benzamide, 600 mg, yield: 60%) was obtained as a white solid.

[0519] 1H NMR (DMSO-d6, 600 MHz) δ (ppm): δ 9.87 (s, 1H), 8.06 (s, 1H), 7.92-7.91 (m, 2H), 7.87-7.86 (m, 2H), 7.48 (s, 1H), 4.55 (brs, 2H).

[0520] Step 3) Synthesis of A39

[0521] In DMF (7 mL) A38 TEA (0.55 mL, 3.9 mmol) and 4-methoxybenzenesulfonyl chloride (676 mg, 3.0 mmol) were added to a solution of 4-(hydrazine carbonyl)benzamide (600 mg, 3.3 mmol). The mixture was maintained at room temperature for 12 hours. After the reaction was complete, the reaction mixture was evaporated and extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM / MeOH = 10 / 1) and A39 (4-(2-((4-nitrophenyl)sulfonyl)hydrazine-1-carbonyl)benzamide, 366 mg, yield: 30%) was obtained as a white solid. LCMS Calcd m / z for C 14 H 12 N4O6S [M+H] + 365.33 Found 365.

[0522] Step 4) Synthesis of Compound 18

[0523] In THF:MeOH = 3:1 (10 mL) A39 Zn (657 mg, 10 mmol) and NH4Cl (537 mg, 10 mmol) were added to a solution of (4-(2-((4-nitrophenyl)sulfonyl)hydrazine-1-carbonyl)benzamide, 366 mg, 1.0 mmol) at a concentration of 60 o Added at C for 5 hours. After the reaction was complete, the reaction mixture was cooled, and then ethyl acetate was added. The mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM / MeOH = 15 / 1) and Compound 18(4-(2-((4-aminophenyl)sulfonyl)hydrazine-1-carbonyl)benzamide, 10 mg, 4.51 mmol, yield: 3%, purity: 97.0%) was obtained as a white solid.

[0524] 1H NMR (DMSO-d6, 600 MHz) δ (ppm): δ 10.68 (br s, 1H), 9.38 (br s, 1H), 8.06 (s, 1H), 7.90 (d, J = 6.0 Hz, 2H), 7.73 (d, J = 6.0 Hz, 2H), 7.05 (s, 1H), 7.44 (d, J = 6.0 Hz, 2H), 6.51 (d, J = 6.0 Hz, 2H), 5.97 (s, 2H); LCMS Calcd m / z for C 14 H 14 N4O4S [M+H] + 335.35 Found 335.

[0525] Experimental Example 1-19. Compound 19 ( N Preparation of -(4-aminobenzyl)-4-hydroxybenzohydrazide)

[0526]

[0527] Step 1) Synthesis of A40

[0528] In DMF (10 mL) A2 Triethylamine (0.46 mL, 3.2 mmol) and 1-(bromomethyl)-4-nitrobenzene (545 mg, 2.5 mmol) were added to a solution of (500 mg, 3.2 mmol). The mixture was maintained at room temperature for 12 hours. After the reaction was complete, the reaction mixture was evaporated and extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM / MeOH = 5 / 1) and A40 (4-hydroxy- N -(4-nitrobenzyl)benzohydrazide, 410 mg, yield: 44%) was obtained as a yellow solid. LCMS Calcd m / z for C14 H 13 N3O4[M+H] + 288.28 Found 288.

[0529] Step 2) Synthesis of Compound 19

[0530] In THF:MeOH = 3:1 (12 mL) A40 (4-hydroxy- N Zn (933 mg, 14 mmol) and NH4Cl (764 mg, 14 mmol) were added to a solution of -(4-nitrobenzyl)benzohydrazide (410 mg, 1.4 mmol). The mixture was stirred at room temperature for 12 hours. After the reaction was complete, ethyl acetate was subsequently added. The mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM / MeOH = 15 / 1) and Compound 19 ( N -(4-aminobenzyl)-4-hydroxybenzohydrazide, 6 mg, yield: 16%, purity: 95.0%) was obtained as a white solid.

[0531] 1H NMR (DMSO-d6, 600 MHz) δ (ppm): δ 10.03 (br s, 1H), 9.80 (br s, 1H), 7.67 (d, J = 6.0 Hz, 2H), 7.00 (d, J = 6.0 Hz, 2H), 6.77 (d, J = 6.0) Hz, 2H), 6.51 (d, J = 6.0 Hz, 2H), 4.97 (bs, 3H), 3.72 (bs, 2H); LCMS Calcd m / z for C 14 H 15 N3O2[M+H] + 258.29 Found 258.

[0532] Experimental Example 1-20. Compound 20 (4-amino- N '-(1 H Synthesis of -indole-3-carbonyl)benzenesulfonohydrazide)

[0533]

[0534] Step 1) Synthesis of A42

[0535] In pyridine (5 mL) A41 (1 H 4-nitrobenzene-1-sulfonyl chloride (632 mg, 2.85 mmol, 1.0 eq) in pyridine (5 mL) was added dropwise to a mixture of indole-3-carbohydrazide (500 mg, 2.85 mmol, 1.0 eq). Subsequently, the mixture 10 o It was stirred at C for 2 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to obtain the crude product, which was purified by a flash column (DCM / MeOH = 50 / 1 to 30 / 1). A42 ( N '-(1 H- Indole-3-carbonyl)-4-nitrobenzenesulfonohydrazide (0.9 g, yield 87.5%) was obtained as a yellow solid. (TLC: DCM / MeOH = 20 / 1, Rf = 0.5)

[0536] Step 2) Synthesis of Compound 20

[0537] In MeOH (10 mL) A42 ( N '-(1 H- Pd / C (100 mg) was added to a mixture of indole-3-carbonyl)-4-nitrobenzenesulfonohydrazide, 300 mg, 0.83 mmol, 1.0 eq). Subsequently, the mixture 10 o It was stirred under an H2 balloon at C for 2 hours. The solution was filtered, the filtrate was purified by prep-HPLC, and freeze-dried. Compound 20 (4-amino- N '-(1 H -Indole-3-carbonyl)benzenesulfonohydrazide, 30 mg, yield 10.9%) was obtained as a yellow solid.

[0538] 1 HNMR (DMSO- d 6, 400 MHz): δ 11.62 (d,J = 2.8 Hz, 1H), 9.98 (s, 1H), 9.11 (d, J = 3.2 Hz, 1H), 8.00 (d, J = 2.8 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.40-7.46 (m, 3H), 7.05-7.16 (m, 2H), 6.51 (d, J = 8.8 Hz, 2H), 5.89 (br s, 2H).

[0539] LCMS ; Mass Calcd.:330; MS Found: 331.1 [MS+1].

[0540] Experimental Examples 1-21 and 1-22. Compound 21 (4-amino-N'-(4-hydroxybenzoyl)-3-(pyrrolidin-1-yl)benzenesulfonohydrazide) and Compound 22 ( N Preparation of -(4-hydroxybenzoyl)-4-nitro-3-(pyrrolidine-1-yl)benzenesulfonohydrazide)

[0541]

[0542] Step 1) Synthesis of Compound 22

[0543] In DMF (10 mL) A4 (3-fluoro- N Pyrrolidine (96 mg, 1.35 mmol, 1.2 eq) was added to a mixture of -(4-hydroxybenzoyl)-4-nitrobenzenesulfonohydrazide, 400 mg, 1.13 mmol, 1.0 eq) and K2CO3 (389 mg, 2.81 mmol, 2.5 eq). o It was added at C. Subsequently, the mixture was 25 o It was stirred at C for 16 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to obtain the crude product, which was purified by flash column (DCM / MeOH=50 / 1–30 / 1) to obtain Compound 22 ( N -(4-hydroxybenzoyl)-4-nitro-3-(pyrrolidin-1-yl)benzenesulfonohydrazide, 176 mg, yield 38.5%) was obtained as a yellow solid.

[0544] 1 HNMR (DMSO- d 6, 400 MHz): δ 10.48 (s, 1H), 10.14 (s, 2H), 7.86 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 1.6 Hz, 1H), 7.11-7.13 (m, 1H), 6.78 (d, J = 8.8 Hz, 2H), 3.64 (t, J = 6.0 Hz, 4H), 1.86 (t, J = 6.0 Hz, 4H).

[0545] Step 2) Synthesis of Compound 21

[0546] In MeOH (5 mL) Compound 22 ( N Pd / C (30 mg) was added to a mixture of -(4-hydroxybenzoyl)-4-nitro-3-(pyrrolidine-1-yl)benzenesulfonohydrazide, 100 mg, 0.54 mmol, 1.0 eq). Subsequently, the mixture 10 o It was stirred under an H2 balloon at C for 16 hours. The solution was filtered, and the filtrate was concentrated to obtain the crude product, which was stirred in MeOH (5 mL) and DMSO (0.5 mL) for 5 minutes. The mixture was filtered, and the filter cake was washed with MeOH and dried. Compound 21 (4-amino-N'-(4-hydroxybenzoyl)-3-(pyrrolidin-1-yl)benzenesulfonohydrazide, 30 mg, yield 32.4%) was obtained as a grayish-white solid.

[0547] 1 HNMR (DMSO- d 6, 400 MHz): δ 10.34 (s, 1H), 10.06 (s, 1H), 9.13 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.17 (t, J = 1.6 Hz, 2H), 6.76 (d,J = 8.8 Hz, 2H), 6.61 (d, J = 8.4 Hz, 1H), 5.47 (s, 2H), 2.80 (s, 4H), 1.77 (s, 4H).

[0548] LCMS ; Mass Calcd.:330; MS Found: 331.1 [MS+1].

[0549] Experimental Example 1-23. Compound 23 (4-amino- N Synthesis of (-(4-hydroxybenzoyl)-3-(piperidine-1-yl)benzenesulfonohydrazide)

[0550]

[0551] Step 1) Synthesis of A43

[0552] In DMF (10 mL) A4 (3-fluoro- N Piperidine (115 mg, 1.35 mmol, 1.2 eq) was added to a mixture of -(4-hydroxybenzoyl)-4-nitrobenzenesulfonohydrazide, 400 mg, 1.13 mmol, 1.0 eq) and K2CO3 (389 mg, 2.81 mmol, 2.5 eq). o It was added at C. Subsequently, the mixture was 25 o It was stirred at C for 16 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to obtain the crude product, which was purified by a flash column (DCM / MeOH=50 / 1–30 / 1). A43 ( N -(4-hydroxybenzoyl)-4-nitro-3-(piperidin-1-yl)benzenesulfonohydrazide, 240 mg, yield 50.7%) was obtained as a yellow solid.

[0553] 1 HNMR (DMSO- d 6, 400 MHz): δ 10.53 (s, 1H), 10.21 (s, 1H), 10.15 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.62 (d,J = 8.8 Hz, 2H), 7.56 (d, J = 1.6 Hz, 1H), 7.40-7.43 (m, 1H), 6.79 (d, J = 8.8 Hz, 2H), 2.88 (t, J = 5.2 Hz, 4H), 1.50-1.51 (m, 6H).

[0554] Step 2) Synthesis of Compound 23

[0555] In MeOH (5 mL) A43 ( N Pd / C (30 mg) was added to a mixture of -(4-hydroxybenzoyl)-4-nitro-3-(piperidine-1-yl)benzenesulfonohydrazide, 100 mg, 0.24 mmol, 1.0 eq). Subsequently, the mixture 10 o It was stirred under an H2 balloon at C for 16 hours. The solution was filtered, the filtrate was purified by prep-HPLC, and freeze-dried. Compound 23 (4-amino- N -(4-hydroxybenzoyl)-3-(piperidine-1-yl)benzenesulfonohydrazide, 25 mg, yield 26.9%) was obtained as a yellow solid.

[0556] 1 HNMR (DMSO- d 6, 400 MHz): δ10.37 (d, J = 4.0 Hz, 1H), 10.07 (s, 1H), 9.17 (d, J = 4.0 Hz, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.2-7.25 (m, 2H), 6.77 (d, J = 7.2 Hz, 2H), 6.64 (d, J = 8.4 Hz, 1H), 5.51 (s, 2H), 2.55 (s, 4H), 1.55-1.60 (m, 4H), 1.45 (s, 2H).

[0557] LCMS ; Mass Calcd.:390; MS Found: 390.8 [MS+1].

[0558] Experimental Example 1-24. Compound 24 ( N -(4-hydroxybenzoyl)-1 H Synthesis of -pyrazol-4-sulfonohydrazide)

[0559]

[0560] Step 1) Synthesis of A44

[0561] 1 in chlorosulfonic acid (5 mL) H - A solution of pyrazole (1 g, 14.7 mmol, 1.0 eq) is 100 o It was stirred overnight at C. The above solution was poured into water (30 mL) and extracted with EA (30 mL * 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated. A44 (1 H -Pyrazole-4-sulfonyl chloride, 340 mg, yield 14%) was obtained as a grayish-white solid.

[0562] 1 HNMR (CDCl3, 400 MHz): 8.22 (s, 2H), 7.92 (s, 1H).

[0563] Step 2) Synthesis of Compound 24

[0564] In pyridine (20 mL) A44 (1 H -Pyrazole-4-sulfonyl chloride, 100 mg, 0.6 mmol, 1.0 eq) and A2 A mixture of (4-hydroxybenzohydrazide, 109 mg, 0.72 mmol, 1.2 eq) 80 o It was stirred overnight at C. The solution was poured into water (30 mL) and extracted with EA (30 mL * 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to obtain the crude product. The residue was purified by prep-HPLC. Compound 24 ( N -(4-hydroxybenzoyl)-1 H-Pyrazole-4-sulfonohydrazide, 60 mg) was obtained as a grayish-white solid.

[0565] 1 HNMR (DMSO- d 6, 400 MHz): 13.4 (s, 1H), 10.39 (s, 1H), 10.1 (s, 1H), 9.5 (s, 1H), 8.47-7.63 (m, 2H), 7.62 (d, 2H), 6.78 (d, 2H).

[0566] Experimental Examples 1-25 and 1-26. Compound 25 ( N -(4-hydroxybenzoyl)indolin-4-sulfonohydrazide) and compound 26 ( N -(4-hydroxybenzoyl)-1 H Preparation of -Indole-4-Sulfonohydrazide)

[0567]

[0568] Step 1) Synthesis of A46

[0569] In THF (10 mL) and Et2O (10 mL) A45 (4-Bromo-1 H - In a solution of indole (1.0 g, 5.10 mmol, 1.0 eq), NaH (204 mg, 5.10 mmol, 60% in mineral oil, 1.0 eq) is 0 o It was added at C. After stirring for 15 minutes, the mixture was -78 o It was cooled to C, and t-BuLi (7.9 mL, 10.2 mmol, 1.3 M in THF, 2.0 eq) was slowly added. After 30 minutes, SO2 (gas, 1 L) was -78 o It was added slowly at C. The mixture was heated to room temperature and stirred overnight. The mixture of acetic acid (307 mg, 5.10 mmol, 1.0 eq) in Et2O (15 mL) was 0 o It was added at C. The mixture was 0 for 30 minutes. o It was stirred at C and then filtered. The filter cake was rapidly washed with Et2O. The solid was suspended in Et2O (15 mL), and 0 oIt was cooled to C and NCS (682 g, 5.10 mmol, 1.0 eq) was carefully added. The resulting suspension was rapidly stirred for 30 minutes and then filtered. The filter cake was washed with Et2O. The combined filtrate was concentrated A46 (1 H -Indole-4-sulfonyl chloride, 420 mg, crude) was obtained as a brown solid.

[0570] Step 2) Synthesis of Compound 26

[0571] In pyridine (30 mL) A46 (1 H -Indole-4-sulfonyl chloride, 420 mg, 1.95 mmol, 1.0 eq) and 4-hydroxybenzohydrazide ( A2 A mixture of , 297 mg, 1.95 mmol, 1.0 eq) 25 o It was stirred at C for 30 minutes. The solution was poured into water (30 mL). The formed solid was collected by filtration, and the filter cake was washed with water. The crude product was purified by prep-HPLC and freeze-dried. Compound 26 ( N -(4-hydroxybenzoyl)-1 H -Indole-4-sulfonohydrazide, 200 mg, yield 31.0%) was obtained as a white solid.

[0572] 1 HNMR (DMSO- d 6, 400 MHz): δ 11.48 (s, 1H), 10.30 (s, 1H), 10.04 (s, 1H), 9.52 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.49-7.52 (m, 4H), 7.16 (t, J = 8.0 Hz, 1H), 6.85 (t, J = 2.0 Hz, 1H), 6.73 (dd, J = 6.8, 2.0 Hz, 2H).

[0573] LCMS ; Mass Calcd.:331.3; MS Found: 331.9 [MS+1].

[0574] Step 3) Synthesis of Compound 25

[0575] In TFA (5 mL) and DCM (5 mL) Compound 26 ( N -(4-hydroxybenzoyl)-1 H NaBH3CN (89 mg, 1.43 mmol, 3.0 eq) in a mixture of -indole-4-sulfonohydrazide (150 mg, 0.48 mmol, 1.0 eq) o It was added at C. The mixture is 10 o It was stirred at C for 30 minutes. The solution was poured into water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to obtain a crude product, which was purified by prep-HPLC and freeze-dried. Compound 25 ( N -(4-hydroxybenzoyl)indolin-4-sulfonohydrazide, 30 mg, yield 20.0%) was obtained as a gray solid.

[0576] 1 HNMR (DMSO- d 6, 400 MHz): δ 10.35 (d, J = 2.8 Hz, 1H), 10.09 (s, 1H), 9.62 (d, J = 2.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 6.97-6.99 (m, 1H), 6.93 (d, J = 6.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 7.2 Hz, 1H), 3.39-3.44 (m, 2H), 3.27-3.32 (m, 2H).

[0577] LCMS ; Mass Calcd.:333; MS Found: 333.8 [MS+1].

[0578] Experimental Example 1-27. Compound 27 (2-((4-aminophenyl)sulfonyl)- N Preparation of -phenylhydrazine-1-carboxamide)

[0579]

[0580] Step 1) Synthesis of A47

[0581] Tert-butyl hydrazine carboxylate (1.8 g, 13.6 mmol, 1.0 eq) in pyridine (5 mL) was added dropwise to a mixture of 4-nitrobenzenesulfonyl chloride (3 g, 13.5 mmol, 1.0 eq) in pyridine (25 mL). Subsequently, the mixture 10 o It was stirred at C for 2 hours. The solution was poured into water (100 mL) and stirred for 1 hour. The formed solid was collected by filtration and dried. A47 ( tert -Butyl 2-((4-nitrophenyl)sulfonyl)hydrazine-1-carboxylate, 3.0 g, yield 69.7%) was obtained as a yellow solid.

[0582] 1 HNMR (CDCl3, 400 MHz): δ 8.35 (d, J = 8.4 Hz, 2H), 8.13 (dd, J = 7.2, 2.0 Hz, 2H), 6.79 (s, 1H), 6.68 (s, 1H), 1.25 (s, 9H).

[0583] Step 2) Synthesis of A48

[0584] In MeOH (30 mL) A47 ( tert MeOH / HCl (30 mL, 6 mol / L) was added to a mixture of β-butyl 2-((4-nitrophenyl)sulfonyl)hydrazine-1-carboxylate, 3 g, 9.45 mmol, 1.0 eq). Subsequently, the mixture 10 o It was stirred at C for 2 hours. The above solution was concentrated and A48(4-nitrobenzenesulfonohydrazide hydrochloride, 2.0 g, yield 83.4%) was obtained as a yellow solid.

[0585] 1 HNMR (DMSO- d 6, 400 MHz): δ 8.45-8.48 (m, 2H), 8.15 (d, J = 8.8 Hz, 2H).

[0586] Step 3) Synthesis of A49

[0587] In THF (20 mL) A48 DIEA (764 mg, 5.91 mmol, 3.0 eq) and isocyanatobenzene (235 mg, 1.97 mmol, 1.0 eq) were added to a mixture of (4-nitrobenzenesulfonohydrazide hydrochloride, 500 mg, 1.97 mmol, 1.0 eq). o It was added at C. Subsequently, the mixture was 10 o It was stirred at C for 2 hours. The solution was poured into water (80 mL). The formed solid was filtered, and the filter cake was stirred in EA (20 mL) for 30 minutes. Subsequently, the mixture was filtered again, and the filter cake was dried. A49 (2-((4-nitrophenyl)sulfonyl)- N -Phenylhydrazine-1-carboxamide, 340 mg, yield 51.3%) was obtained as a white solid.

[0588] 1 HNMR (DMSO- d 6, 400 MHz): δ 10.09 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 8.40-8.43 (m, 2H), 8.09 (dd, J = 7.2, 2.0 Hz, 2H), 7.34 (t, J = 8.0 Hz, 2H), 7.21 (t, J = 8.0 Hz, 1H), 6.94 (t, J = 7.2 Hz, 1H).

[0589] Step 4) Synthesis of Compound 27

[0590] In MeOH (30 mL) A49 (2-((4-nitrophenyl)sulfonyl)- N A mixture of phenylhydrazine-1-carboxamide (340 mg, 1.01 mmol, 1.0 eq) and Pd / C (200 mg) 10 o It was stirred under an H2 balloon at C for 15 hours. The solution was filtered, and the filtrate was concentrated to obtain the crude product, which was stirred in MeOH (5 mL) for 30 minutes. The mixture was filtered, and the filter cake was dried under vacuum. Compound 27 (2-((4-aminophenyl)sulfonyl)- N -phenylhydrazine-1-carboxamide, 50 mg (yield 16.2%) was obtained as a white solid.

[0591] 1 HNMR (DMSO- d 6, 400 MHz): δ 9.12 (s, 1H), 8.41 (s, 1H), 8.15 (s, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.22 (t, J = 8.0 Hz, 2H), 6.94 (t, J = 7.2 Hz, 1H), 6.60 (d, J = 8.8 Hz, 2H), 6.04 (s, 2H).

[0592] LCMS ; Mass Calcd.:306; MS Found: 306.9.

[0593] Experimental Example 1-28. Compound 28 (4-amino- N '-(1 H Preparation of -indole-4-carbonyl)-3-morpholinobenzenesulfonohydrazide)

[0594]

[0595] Step 1) Synthesis of A51

[0596] In N2H4H2O (10 mL) A50 (methyl 1 H A mixture of -indole-4-carboxylate, 1.00 g, 5.71 mmol, 1.0 eq) 100 o It was stirred at C for one hour. The solution was poured with water and extracted with EA (30 mL x 3). The combined organic layer was dried with Na2SO4 and concentrated. A51 (1H-indole-4-carbohydrazide, 500 mg, crude) was obtained as a yellow solid.

[0597] Step 2) Synthesis of A52

[0598] In pyridine (2 mL) A51 3-fluoro-4-nitrobenzene-1-sulfonyl chloride (175 mg, 0.57 mmol, 1.0 eq) in pyridine (2 mL) was added dropwise to a mixture of (1H-indole-4-carbohydrazide, 100 mg, 0.57 mmol, 1.0 eq). Subsequently, the mixture 10 o It was stirred at C for 3 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL x 3). The combined organic layer was washed with 1N HCl (30 mL x 2) and brine, dried with Na2SO4, and concentrated. A52 (3-fluoro- N '-(1 H -Indole-4-carbonyl)-4-nitrobenzenesulfonohydrazide, 200 mg, crude) was obtained as a yellow solid.

[0599] Step 3) Synthesis of A53

[0600] In DMF (5 mL) A52 (3-fluoro- N '-(1 H-Indole-4-carbonyl)-4-nitrobenzenesulfonohydrazide, 200 mg, 0.52 mmol, 1.0 eq) and K2CO3 (183 mg, 1.30 mmol, 2.5 eq) were mixed with 10 morpholine (54 mg, 0.62 mmol, 1.2 eq). o It was added at C. Subsequently, the mixture was 25 o It was stirred at C for 16 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated. A53 ( N '-(1 H -Indole-4-carbonyl)-3-morpholino-4-nitrobenzenesulfonohydrazide, 100 mg, crude) was obtained as a yellow solid.

[0601] Step 4) Synthesis of Compound 28

[0602] In EtOH (5 mL) A53 ( N '-(1 H Fe (61.6 mg, 1.10 mmol, 5.0 eq) and sat. aq. NH4Cl (3 mL) were added to a mixture of -indole-4-carbonyl)-3-morpholino-4-nitrobenzenesulfonohydrazide, 100 mg, 0.22 mmol, 1.0 eq. o It was stirred at C for 3 hours. The solution was filtered, the filtrate was purified by prep-HPLC, and freeze-dried. Compound 28 (4-amino- N '-(1 H -Indole-4-carbonyl)-3-morpholinobenzenesulfonohydrazide, 20 mg, yield 21.5%) was obtained as a white solid.

[0603] 1 HNMR (DMSO- d 6, 400 MHz): δ11.30 (s, 1H), 10.34 (s, 1H), 9.35 (d, J = 4.0 Hz, 1H), 7.54 (d,J = 8.4 Hz, 1H), 7.43 (t, J = 2.4 Hz, 1H), 7.30-7.35 (m, 3H), 7.11 (t, J = 7.6 Hz, 1H), 6.65-6.67 (m, 2H), 5.60 (br s, 2H), 3.64 (t, J = 4.0 Hz, 4H), 2.60 (t, J = 4.0 Hz, 4H).

[0604] LCMS ; Mass Calcd.:415; MS Found: 415.9 [MS+1].

[0605] Experimental Example 1-29. Compound 29 (4-amino- N Preparation of '-(Indolin-4-Carbonyl)Benzenesulfonohydrazide)

[0606]

[0607] Step 1) Synthesis of A54

[0608] In pyridine (5 mL) A51 (1 H 4-nitrobenzene-1-sulfonyl chloride (505 mg, 2.29 mmol, 1.0 eq) in pyridine (5 mL) was added dropwise to a mixture of indole-4-carbohydrazide (400 mg, 2.29 mmol, 1.0 eq). Subsequently, the mixture 10 o It was stirred at C for 3 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated. A54 ( N '-(1 H -Indole-4-carbonyl)-4-nitrobenzenesulfonohydrazide, 300 mg, crude) was obtained as a yellow solid.

[0609] Step 2) Synthesis of A55

[0610] In DCM (5 mL) A54 ( N '-(1 HIn a mixture of -indole-4-carbonyl)-4-nitrobenzenesulfonohydrazide, 300 mg, 0.83 mmol, 1.0 eq), TFA (1.5 mL) and NaBH3CN (157 mg, 2.49 mmol, 3.0 eq) were added. o It was added at C. Subsequently, the mixture was 10 o It was stirred at C for 45 minutes. The above solution was poured into water (30 mL) and sat. aq. NaHCO3 The pH was adjusted to 7. The mixture was filtered, the filter cake was washed with MTBE, and dried under vacuum. A55 ( N -(Indolin-4-carbonyl)-4-nitrobenzenesulfonohydrazide, 150 mg, crude) was obtained as a yellow solid.

[0611] Step 3) Synthesis of Compound 29

[0612] In MeOH (5 mL) A55 ( N A mixture of '-(indolin-4-carbonyl)-4-nitrobenzenesulfonohydrazide, 150 mg, 0.41 mmol, 1.0 eq) and Pd / C (100 mg) 10 o It was stirred under an H2 balloon at C for 2 hours. The solution was filtered, and the filtrate was concentrated to obtain the crude product, which was stirred in MeOH (10 mL) for 30 minutes. The mixture was filtered, and the filter cake was dried under vacuum. Compound 29 (4-amino- N -(Indolin-4-carbonyl)benzenesulfonohydrazide, 40 mg, yield 29.1%) was obtained as a white solid.

[0613] 1 HNMR (DMSO- d 6, 400 MHz): δ10.28 (d, J = 3.6 Hz, 1H), 9.28 (d, J = 3.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.03 (t, J= 8.0 Hz, 1H), 6.83 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.53 (d, J = 8.8 Hz, 2H), 3.42 (t, J = 8.4 Hz, 2H), 2.96 (t, J = 8.4 Hz, 2H).

[0614] LCMS ; Mass Calcd.:332; MS Found: 332.8 [MS+1].

[0615] Experimental Example 1-30. Preparation of Compound 30 (4-amino-N'-(4-hydroxybenzoyl)-3-(piperazine-1-yl)benzenesulfonohydrazide).

[0616]

[0617] Step 1) Synthesis of A56

[0618] In DMF (5 mL) A4 (3-fluoro- N tert-butylpiperazine-1-carboxylate (315 mg, 1.69 mmol, 1.2 eq) was added to a mixture of -(4-hydroxybenzoyl)-4-nitrobenzenesulfonohydrazide, 500 mg, 1.41 mmol, 1.0 eq) and K2CO3 (290 mg, 2.10 mmol, 1.5 eq). o It was added at C. Subsequently, the mixture was 10 o It was stirred at C for 16 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to obtain the crude product, which was purified by a flash column (DCM / MeOH=50 / 1–30 / 1). A56 ( tert -Butyl 4-(5-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)-2-nitrophenyl)piperazine-1-carboxylate, 310 mg, crude) was obtained as a yellow solid.

[0619] Step 2) Synthesis of A57

[0620] In EtOH (3 mL) A56 ( tert sat. aq. NH4Cl (3 mL) and Fe (135 mg, 2.41 mmol, 5.0 eq) were added to a mixture of butyl 4-(5-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)-2-nitrophenyl)piperazine-1-carboxylate, 250 mg, 0.48 mmol, 1.0 eq). Subsequently, the mixture 85 o It was stirred at C for 1 hour. The solution was filtered, and the filtrate was poured into water (30 mL) and extracted with EA (30 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated. A57 ( tert -Butyl 4-(2-amino-5-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)phenyl)piperazine-1-carboxylate, 210 mg, crude) was obtained as a yellow solid.

[0621] Step 3) Synthesis of Compound 30

[0622] In DCM (5 mL) A57 ( tert TFA (0.5 mL) was added to a mixture of butyl 4-(2-amino-5-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)phenyl)piperazine-1-carboxylate, 270 mg, 0.55 mmol, 1.0 eq). o It was added at C. Subsequently, the mixture was 10 o It was stirred at C for 3 hours. The solution was concentrated to obtain a crude product, which was purified by prep-HPLC and freeze-dried to obtain a crude product. The crude product was stirred in MeOH (2.5 mL) and CH3CN (2.5 mL) for 5 minutes. The mixture was filtered, and the filter cake was washed with MeOH and dried. Compound 30 (4-amino- N -(4-hydroxybenzoyl)-3-(piperazine-1-yl)benzenesulfonohydrazide, 20 mg, yield 9.30%) was obtained as a white solid.

[0623] 1 HNMR (DMSO- d 6, 400 MHz): δ 7.57 (d, J = 8.0 Hz, 2H), 7.21-7.25 (m, 2H), 6.76 (d, J = 8.0 Hz, 2H), 6.64 (d, J = 8.4 Hz, 1H), 5.54 (s, 2H), 2.78 (s, 4H), 2.54 (s, 4H).

[0624] LCMS ; Mass Calcd.:391; MS Found: 392.1 [MS+1].

[0625] Experimental Example 1-31. Compound 31 (4-amino- N -(2,3-dehydro-1 H Preparation of -Indene-2-Carbonyl)Benzenesulfonohydrazide)

[0626]

[0627] Step 1) Synthesis of A59

[0628] In MeOH (50 mL) A58 (2,3-dehydro-1 H H2SO4 (5 mL) was added dropwise to a mixture of -indene-2-carboxylic acid (5.0 g, 30.8 mmol, 1.0 eq). Subsequently, the mixture 70 o It was stirred at C for 12 hours. The solution was poured into water (60 mL) and extracted with EA (60 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated. A59 (methyl 2,3-dihydro-1 H -Indene-2-carboxylate, 5.3 g, yield 97.5%) was obtained as a yellow oil.

[0629] Step 2) Synthesis of A60

[0630] In MeOH (30 mL) A59 (methyl 2,3-dihydro-1 HN2H4·H2O (8.56 g, 171 mmol, 10 eq) was added dropwise to a mixture of -indene-2-carboxylate (3.0 g, 17.1 mmol, 1.0 eq). Subsequently, the mixture was 80 o It was stirred at C for 12 hours. The above solution was concentrated and A60 (2,3-dehydro-1 H -Indene-2-carbohydrazide, 2.0 g, yield 87.5%) was obtained as a yellow solid.

[0631] 1 HNMR (DMSO-d6, 400 MHz): δ 9.13 (s, 1H), 7.18-7.20 (m, 2H), 7.11-7.13 (m, 2H), 4.25 (br s, 2H), 3.01-3.11 (m, 5H).

[0632] Step 3) Synthesis of A61

[0633] In pyridine (20 mL) A60 (2,3-dehydro-1 H 4-nitrobenzene-1-sulfonyl chloride (2.52 g, 11.4 mmol, 1.0 eq) was partially added to a mixture of -indene-2-carbohydrazide (2 g, 11.4 mmol, 1.0 eq). Subsequently, the mixture 10 o It was stirred at C for 2 hours. The solution was poured into water (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated. A61 ( N -(2,3-dehydro-1 H -indene-2-carbonyl)-4-nitrobenzenesulfonohydrazide (1.4 g, yield 34.1%) was obtained as a yellow solid. (TLC: DCM / MeOH =10 / 1, Rf=0.5)

[0634] Step 4) Synthesis of Compound 31

[0635] In MeOH (10 mL) A61 ( N-(2,3-dehydro-1 H Pd / C (100 mg) was added to a mixture of -indene-2-carbonyl)-4-nitrobenzenesulfonohydrazide, 200 mg, 0.83 mmol, 1.0 eq). Subsequently, the mixture 10 o It was concentrated under an H2 balloon at C for 12 hours. The solution was filtered, the filtrate was purified by prep-HPLC, and freeze-dried. Compound 31 (4-amino- N -(2,3-dehydro-1 H -Indene-2-carbonyl)benzenesulfonohydrazide, 80 mg, yield 43.6%) was obtained as a white solid.

[0636] 1 HNMR (CD3OD, 400 MHz): δ 7.55 (dd, J = 6.8, 2.0 Hz, 2H), 7.07-7.12 (m, 4H), 6.65 (dd, J = 6.8, 2.0 Hz, 2H), 2.92-3.03 (m, 5H).

[0637] LCMS ; Mass Calcd.:331; MS Found: 331.8 [MS+1].

[0638] Experimental Example 1-32. Preparation of Compound 32 (4-amino-N'-(isoindolin-2-carbonyl)benzenesulfonohydrazide)

[0639]

[0640] Step 1) Synthesis of A63

[0641] In dichloromethane (10 mL) A62Triethylamine (2 mL) and 4-nitrophenyl chloroformate (1.68 g, 8.4 mmol) were added to a mixture of isoindoline (1.00 g, 8.4 mmol, 1.0 eq). The mixture was stirred at room temperature for 16 hours. The solution was poured into water (30 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layer was dried and concentrated with Na2SO4. The product was added to tetrahydrofuran (10 mL) and N2H4H2O (2 mL). The mixture was 60 o It was stirred at C for 16 hours. The solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried and concentrated with sodium sulfate (Na2SO4). A63 (Isoindolin-2-carbohydrazide, 600 mg, crude) was obtained as a yellow solid. (TLC: DCM / MeOH = 10 / 1, Rf=0.6)

[0642] LCMS ; Mass Calcd.:177.2; MS Found: 178.2 [MS+1].

[0643] Step 2) Synthesis of A64

[0644] In pyridine (10 mL) A63 4-nitrobenzene-1-sulfonyl chloride (750 mg, 3.39 mmol, 1.0 eq) in pyridine (5 mL) was added dropwise to a mixture of (isoindolin-2-carbohydrazide, 600 mg, 3.39 mmol, 1.0 eq). Subsequently, the mixture 10 o It was stirred at C for 3 hours. The solution was poured into water (50 mL) and extracted with EA (50 mL x 3). The combined organic layer was washed with 1N HCl (50 mL x 2) and brine, dried with Na2SO4, and concentrated. A64 (N'-(isoindolin-2-carbonyl)-4-nitrobenzenesulfonohydrazide, 200 mg, crude) was obtained as a yellow solid. (TLC: DCM / MeOH = 20 / 1, Rf = 0.5)

[0645] LCMS ; Mass Calcd.:362.3; MS Found: 363.1 [MS+1].

[0646] Step 3) Synthesis of Compound 32 (4-amino-N'-(isoindolin-2-carbonyl)benzenesulfonohydrazide)

[0647] In ethanol (10 mL) A64 Fe (154 mg, 2.75 mmol, 5.0 eq) and sat. aq. NH4Cl (6 mL) were added to a mixture of (200 mg, 0.55 mmol, 1.0 eq). Subsequently, the mixture was 85 o It was stirred at C for 3 hours. The solution was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by prep-HPLC and freeze-dried. Compound 32 (4-amino-N'-(isoindolin-2-carbonyl)benzenesulfonohydrazide, 20 mg, yield 11.0%) was obtained as a white solid.

[0648] 1HNMR (DMSO-d6, 400 MHz): δ 8.64 (s, 1H), 8.53 (s, 1H), 7.41-7.44 (m, 2H), 7.29-7.31 (m, 4H), 6.51-6.54 (m, 2H), 5.93 (s, 2H), 4.51 (s, 4H).

[0649] LCMS; Mass Calcd.:332; MS Found: 333 [MS+1].

[0650] Experimental Example 1-33. Preparation of Compound 33 (N'-(4-hydroxybenzoyl)-1H-indole-2-sulfonohydrazide)

[0651]

[0652] Step 1) Synthesis of A66

[0653] In tetrahydrofuran (20 mL) A65n-BuLi (4.0 mL, 2.5 M in hexanes, 10.0 mmol, 1.1 eq) was added to a stirred solution of (tert-butyl 1H-indole-1-carboxylate, 2.00 g, 9.2 mmol, 1.0 eq) -70 o Dropped at C. After 1 hour, SO2 (gas, 1 L) was -70 o It was added slowly at C. The reaction mixture was heated to 10°C over 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (DCM, 20 mL). N-chlorosuccinimide (NCS, 1.84 g, 13.8 mmol, 1.5 eq) was added. The mixture was stirred at room temperature for 10 hours. The mixture was washed with water (2 x 20 mL) and brine (2 x 20 mL). The organic layer was dried and concentrated. The residue was purified by column chromatography (PE / EA=30 / 1-5 / 1) A66 (tert-butyl 2-(chlorosulfonyl)-1H-indole-1-carboxylate, 1.0 g, yield 34.4%) was obtained as a brown oil.

[0654] 1HNMR (CDCl3, 400 MHz): δ 8.23-8.25 (m, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.56-7.60 (m, 1H), 7.35-7.39 (m, 1H), 1.75(s, 9H).

[0655] Step 2) Synthesis of A67

[0656] In a stirred solution of 4-hydroxybenzohydrazide (481 mg, 3.17 mmol, 1.0 eq) in pyridine (10 mL), a solution of A66 (tert-butyl 2-(chlorosulfonyl)-1H-indole-1-carboxylate, 1.0 g, 3.17 mmol, 1.0 eq) in pyridine (5 mL) was added. o It was added dropwise at C. The mixture was stirred at room temperature for 5 hours. The mixture was filtered. The filtrate was concentrated and purified by column chromatography. A67(tert-butyl 2-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)-1H-indole-1-carboxylate, 500 mg, yield 36.5%) was obtained as a white solid.

[0657] Step 3) Synthesis of Compound 33

[0658] 4N HCl(g) / MeOH (2 mL) to a stirred solution of A67 (500 mg, 1.16 mmol, 1.0 eq) in methanol (MeOH, 5 mL) 0 o It was added at C. The mixture was stirred at room temperature for 4 hours. The mixture was concentrated, purified by prep-HPLC, and freeze-dried. Compound 33 (N'-(4-hydroxybenzoyl)-1H-indole-2-sulfonohydrazide, 50 mg, yield 13%) was obtained as a grayish-white solid.

[0659] 1HNMR (DMSO-d6, 400 MHz): δ 11.94 (s, 1H), 10.42 (d, J = 1.6 Hz, 1H), 10.09 (s, 1H), 9.86 (d, J = 2.8 Hz, 1H), 7.61-7.64 (m, 3H), 7.45-7.47 (m, 1H), 7.24-7.28 (m, 1H), 7.07-7.11 (m, 1H), 6.99 (d, J = 1.2 Hz, 1H), 6.77 (d, J = 8.8 Hz, 2H).

[0660] LCMS ; Mass Calcd.:341; MS Found: 342 [MS+1].

[0661] Experimental Example 1-34. Preparation of Compound 34 (4-amino-N'-(2-phenylacetyl)benzenesulfonohydrazide)

[0662]

[0663] Step 1) Synthesis of A69

[0664] In pyridine (5 mL) A684-nitrobenzene-1-sulfonyl chloride (738 mg, 3.33 mmol, 1.0 eq) in pyridine (5 mL) was added dropwise to a mixture of (2-phenylacetohydrazide, 500 mg, 3.33 mmol, 1.0 eq). Subsequently, the mixture 10 o It was stirred at C for 2 hours. The solution was poured into water (30 mL) and extracted with ethyl acetate (EA, 30 mL x 3). The combined organic layer was washed with brine, dried and concentrated with Na2SO4 to obtain a crude product, and stirred in DCM (30 mL) for 30 minutes. The mixture was filtered and the filter cake was dried. A69 (4-nitro-N'-(2-phenylacetyl)benzenesulfonohydrazide, 1 g, yield 89.6%) was obtained as a yellow solid.

[0665] 1HNMR (DMSO-d6, 400 MHz): δ 10.50 (s, 1H), 10.37 (s, 1H), 8.22 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.21-7.29 (m, 3H), 7.10-7.12 (m, 2H), 3.30 (s, 2H).

[0666] Step 1) Synthesis of Compound 34

[0667] In MeOH (10 mL) A69 Pd / C (50 mg) was added to a mixture of (200 mg, 0.60 mmol, 1.0 eq). Subsequently, the mixture 10 o It was stirred under an H2 balloon at C for 2 hours. The solution was filtered and the filtrate was concentrated. The crude product was crystallized three times in MeOH (10 mL) and Compound 34 (4-amino-N'-(2-phenylacetyl)benzenesulfonohydrazide, 20 mg, yield 10.9%) was obtained as a gray solid. (TLC: DCM / MeOH =10 / 1, Rf=0.3)

[0668] 1HNMR (DMSO-d6, 400 MHz): δ 9.87 (s, 1H), 8.77 (s, 1H), 7.40 (d, J = 6.8 Hz, 2H), 7.18-7.29 (m, 3H), 7.13 (d, J = 6.8 Hz, 2H), 5.74 (s, 2H), 3.37 (s, 2H).

[0669] LCMS ; Mass Calcd.:305; MS Found: 306.1 [MS+1].

[0670] Experimental Example 1-35. Preparation of Compound 35 (N'-(4-hydroxybenzoyl)-1H-indazole-3-sulfonohydrazide)

[0671]

[0672] Step 1) Synthesis of A70

[0673] NaNO2 (0.62 g, 9.0 mmol, 1.2 eq) was added to a stirred solution of 1H-indazole-3-amine (1.00 g, 7.5 mmol, 1.0 eq) in acetic acid (16 mL), conjugated hydrochloric acid (1.6 mL) and formic acid (1.6 mL). o It was added at C. The mixture was stirred for 1 hour. SO2 (gas, 1 L) and CuCl2 (0.38 g, 2.3 mmol, 0.3 eq) were 0 o It was added slowly at C. The reaction mixture was heated to 10°C. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA=30:1-1:1) A70 (1H-indazole-3-sulfonyl chloride, 0.5 g, yield 30.8%) was obtained as a brown solid.

[0674] 1HNMR (DMSO-d6, 400 MHz): δ 14.13 (s, 2H), 7.94-7.92 (m, 1H), 7.46-7.38 (m, 2H), 7.14 (s, 1H).

[0675] Step 2) Synthesis of Compound 35 (N'-(4-hydroxybenzoyl)-1H-indazole-3-sulfonohydrazide)

[0676] In a stirred solution of 4-hydroxybenzohydrazide (225 mg, 1.48 mmol, 0.8 eq) in pyridine (5 mL) in pyridine (5 mL) A70 A solution of (1H-indazole-3-sulfonyl chloride, 0.40 g, 1.85 mmol, 1.0 eq) is 0 o It was added dropwise at C. The mixture was stirred at room temperature for 5 hours. The mixture was concentrated. The residue was purified by prep-HPLC and freeze-dried. Compound 35 (N'-(4-hydroxybenzoyl)-1H-indazole-3-sulfonohydrazide, 60 mg, yield 9.77%) was obtained as a white solid.

[0677] 1HNMR (DMSO-d6, 400 MHz): δ 13.90 (s, 1H), 10.43 (s, 1H), 10.05-9.99 (m, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 7.0 Hz, 1H), 7.22 (t, J = 7.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 2H).

[0678] LCMS; Mass Calcd.:332; MS Found: 333 [MS+1].

[0679] Experimental Example 1-36. Preparation of Compound 36 (4-amino-N'-(indolin-6-carbonyl)benzenesulfonohydrazide)

[0680]

[0681] Step 1) Synthesis of A72

[0682] A71 A mixture of (methyl 1H-indole-6-carboxylate, 500 mg, 2.86 mmol, 1.0 eq) and hydrazine monohydrate (10 mL) 100 o It was stirred at C for 3 hours. Subsequently, the mixture was 0 o It was cooled to C and filtered. The filter cake was washed with ice water and dried in a vacuum. A72(1H-indole-6-carbohydrazide, 300 mg, yield 60.0%) was obtained as a white solid.

[0683] LCMS; Mass Calcd.:175.18; MS Found: 176.0 [MS+1].

[0684] Step 2) Synthesis of A73

[0685] In pyridine (5 mL) A72 4-nitrobenzenesulfonyl chloride (380 mg, 1.71 mmol, 1.0 eq) in a mixture of (300 mg, 1.71 mmol, 1.0 eq) 0 o It was added at C. Subsequently, the mixture was 10 o It was stirred at C for 3 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL x 3). The combined organic layer was washed with 1N HCl (30 mL x 2) and brine, dried with Na2SO4, and concentrated to obtain the crude product, which was purified by flash column (DCM / MeOH=50 / 1~30 / 1) A73 (N'-(1H-indole-6-carbonyl)-4-nitrobenzenesulfonohydrazide, 500 mg, yield 81.0%) was obtained as a yellow solid.

[0686] LCMS; Mass Calcd.:360.34; MS Found: 361.1 [MS+1].

[0687] Step 3) Synthesis of A74

[0688] In DCM (15 mL) and TFA (5 mL) A73 NaBH3CN (209 mg, 3.33 mmol, 3.0 eq) in a mixture of (400 mg, 1.11 mmol, 1.0 eq) 0 o It was added at C. Subsequently, the mixture was 15 oIt was stirred at C for 1 hour. The solution was poured into ice water (30 mL) and adjusted to pH=7–8 with sat. aq. NaHCO3. The solution was filtered, and the filter cake was washed with PE and dried. A74 (N'-(indolin-6-carbonyl)-4-nitrobenzenesulfonohydrazide, 200 mg crude) was obtained as a yellow solid.

[0689] LCMS; Mass Calcd.:362.36; MS Found: 363.1 [MS+1].

[0690] Step 3) Synthesis of Compound 36

[0691] In H2O (10 mL) and EtOH (20 mL) A74 A mixture of (200 mg, 0.55 mmol, 1.0 eq), NH4Cl (146 mg, 2.75 mmol, 5.0 eq), and Fe (154 mg, 2.75 mmol, 5.0 eq) was 85 o It was stirred at C for 2 hours. The mixture was filtered, and the filtrate was extracted with EA (20 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated. The crude product was recrystallized with methanol, and the solid was freeze-dried. Compound 36 (4-amino-N'-(indolin-6-carbonyl)benzenesulfonohydrazide, 60 mg, 32.7%) was obtained as a white solid.

[0692] 1HNMR (DMSO-d6, 400 MHz): δ 10.32 (s, 1H), 9.14 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 6.75 (s, 1H), 6.49 (d, J = 8.4 Hz, 2H), 5.95 (s, 2H), 5.67 (s, 1H), 3.41 (t, J = 8.2 Hz, 2H), 2.91 (t, J = 8.6 Hz, 2H).

[0693] LCMS; Mass Calcd.:332; MS Found: 333 [M+1].

[0694] Experimental Example 1-37. Preparation of Compound 37 (4-amino-N'-(indolin-3-carbonyl)benzenesulfonohydrazide)

[0695]

[0696] Step 1) Synthesis of A76

[0697] In DCM (10 mL) A75 Boc2O (1.37 g, 6.28 mmol, 1.1 eq) was added to a mixture of (methyl 1H-indole-3-carboxylate, 1.00 g, 5.71 mmol, 1.0 eq) and triethylamine (TEA, 1.16 g, 11.4 mmol, 2.0 eq) at a concentration of 20 o It was added dropwise at C. Subsequently, the mixture was 20 o It was stirred at C for 12 hours. The solution was poured into water (60 mL) and extracted with DCM (60 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated. A76 (1-(tert-butyl)3-methyl 1H-indole-1,3-dicarboxylate, 1.20 g, crude) was obtained as a yellow solid.

[0698] Step 2) Synthesis of A77

[0699] In ethyl acetate (EA, 30 mL) A76 Pd / C (0.65 g) was added to a mixture of (1.20 g, 4.36 mmol, 1.0 eq) and degassed. Subsequently, the mixture was 60 o It was stirred at C for 12 hours under H2 (50 psi). The solution was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified with silica gel (PE / EA=30:1~15:1) A77 (1-(tert-butyl)3-methyl indoline-1,3-dicarboxylate, 0.80 g, yield 66.2%) was obtained as a white solid.

[0700] Step 3) Synthesis of A78

[0701] In MeOH (20 mL) A77 N2H4·H2O (1.6 mL) was added to a mixture of (800 mg, 2.89 mmol, 1.0 eq). Subsequently, the mixture was 80 o It was stirred at C for 4 hours. The reaction mixture was concentrated and A78 (tert-butyl 3-(hydrazine carbonyl)indoline-1-carboxylate 700 mg, yield 87.5%) was obtained as a white solid.

[0702] Step 3) Synthesis of A79

[0703] In pyridine (5 mL) A78 4-nitrobenzene-1-sulfonyl chloride (0.24 g, 1.08 mmol, 1.0 eq) was partially added to a mixture of (tert-butyl 3-(hydrazine carbonyl)indoline-1-carboxylate, 300 mg, 1.08 mmol, 1.0 eq). Subsequently, the mixture 10 o It was stirred at C for 4 hours. The solution was poured into water (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated. A79 (tert-butyl 3-(2-((4-nitrophenyl)sulfonyl)hydrazine-1-carbonyl)indoline-1-carboxylate, 200 mg, yield 39.7%) was obtained as a yellow solid.

[0704] Step 4) Synthesis of A80

[0705] In EA (10 mL) A79 Pd / C (50 mg) was added to a mixture of (200 mg, 0.43 mmol, 1.0 eq). Subsequently, the mixture 10 o It was stirred under an H2 balloon at C for 12 hours. The solution was filtered, and the filtrate was concentrated. A80(tert-butyl 3-(2-((4-aminophenyl)sulfonyl)hydrazine-1-carbonyl)indoline-1-carboxylate, 200 mg, yield: 100%) was obtained as a yellow solid.

[0706] Step 5) Synthesis of Compound 37 (4-amino-N'-(indolin-3-carbonyl)benzenesulfonohydrazide)

[0707] In DCM (5 mL) A80 Trifluoroacetic acid (TFA, 1 mL) was added to a mixture of (200 mg, 0.463 mmol, 1.0 eq). Subsequently, the mixture 10 o It was stirred at C for 2 hours. The solution was concentrated, H2O (5 mL) was added to the residue, and the pH was adjusted to 9-10 with aq. K2CO3. The solution was extracted with EA (20 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to obtain the crude product. The crude product was purified by Prep-HPLC and freeze-dried Compound 37 (4-amino-N'-(indolin-3-carbonyl)benzenesulfonohydrazide, 30.0 mg, yield 19.6%) was obtained as a grayish-white solid.

[0708] 1HNMR (DMSO_d6, 400 MHz): δ 7.45 (d, J = 8.4 Hz, 2H), 6.91-6.95 (m, 2H), 6.48-6.59 (m, 4H), 5.72 (s, 2H), 5.23 (s, 1H), 3.93 (br s, 1H), 3.49 (d, J = 9.2 Hz, 2H).

[0709] LCMS; MS Found: 333.1 [MS+1].

[0710] Experimental Example 1-38. Preparation of Compound 38 (N'-(4-hydroxybenzoyl)piperidine-4-sulfonohydrazide)

[0711]

[0712] Step 1) Synthesis of A82

[0713] In a mixture of 4-hydroxybenzohydrazide (A2, 268 mg, 1.77 mmol, 1.0 eq) in pyridine (2 mL) in pyridine (1 mL) A81 A solution of (tert-butyl 4-(chlorosulfonyl)piperidine-1-carboxylate, 500 mg, 1.77 mmol, 1.0 eq) is 0 o It was added dropwise at C. The mixture was stirred at room temperature for 5 hours. The solution was filtered. The filtrate was concentrated and purified by column chromatography (DCM / MeOH=100:1-10:1) A82 (tert-butyl 4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)piperidine-1-carboxylate, 300 mg, yield 42%) was obtained as a yellow solid.

[0714] 1HNMR (CDCl3, 400 MHz): δ 8.47 (br s, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.30 (br s, 1H), 6.87 (d, J = 8.4 Hz, 2H), 3.15-3.18 (m, 1H), 2.67-2.71 (m, 2H), 2.25 (d, J = 10.8 Hz, 2H), 1.72-1.78 (m, 2H), 1.61-1.63 (m, 2H), 1.45 (s, 9H).

[0715] Step 2) Synthesis of Compound 38 (N'-(4-hydroxybenzoyl)piperidine-4-sulfonohydrazide)

[0716] In DCM (5 mL) A82 TFA (1.5 mL) in a mixture of (300 mg, 0.75 mmol, 1.0 eq) 0 o It was added at C. The mixture was stirred at room temperature for 4 hours. The solution was concentrated, purified by prep-HPLC, and freeze-dried. Compound 38 (N'-(4-hydroxybenzoyl)piperidine-4-sulfonohydrazide, 50 mg, yield 22%) was obtained as a yellow solid.

[0717] 1HNMR (DMSO-d6, 400 MHz): δ 10.40 (br s, 1H), 8.34 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 3.17-3.24 (m, 3H), 2.69 (t, J = 12.0 Hz, 2H), 2.28 (d, J = 12.0 Hz, 2H), 1.64-1.74 (m, 2H).

[0718] LCMS; Mass Calcd.:299; MS Found: 300 [Ms+1].

[0719] Experimental Example 1-39. Preparation of Compound 39 (4-amino-N'-(indolin-6-carbonyl)-3-morpholinobenzenesulfonohydrazide)

[0720]

[0721] Step 1) Synthesis of A83

[0722] In pyridine (5 mL) A72 3-fluoro-4-nitrobenzene-1-sulfonyl chloride (686 mg, 2.86 mmol, 1.0 eq) in pyridine (2 mL) in a mixture of (1H-indole-6-carbohydrazide, 500 mg, 2.86 mmol, 1.0 eq) o It was added dropwise at C. Subsequently, the mixture was 10 o It was stirred at C for 3 hours. The solution was concentrated to obtain a crude product, which was purified by a column (DCM:MeOH=50:1---20:1) A83 (3-fluoro-N'-(1H-indole-6-carbonyl)-4-nitrobenzenesulfonohydrazide, 700 mg, yield: 64.8%) was obtained as a yellow solid.

[0723] LCMS; Mass Calcd.:378.3; MS Found: 379.1 [Ms+1].

[0724] Step 2) Synthesis of A84

[0725] In DMF (7 mL) A83Morpholine (193 mg, 2.22 mmol, 1.2 eq) was added to a mixture of (700 mg, 1.85 mmol, 1.0 eq) and K2CO3 (640 mg, 4.64 mmol, 2.5 eq). o It was added at C. Subsequently, the mixture was 25 o It was stirred at C for 16 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated. A84 (N'-(1H-indole-6-carbonyl)-3-morpholino-4-nitrobenzenesulfonohydrazide, 600 mg, yield: 72.8%) was obtained as a yellow solid.

[0726] LCMS; Mass Calcd.:445.4; MS Found: 446.1 [Ms+1].

[0727] Step 3) Synthesis of A85

[0728] In DCM (5 mL) A84 TFA (1 mL) and NaBH3CN (251 mg, 4.04 mmol, 3.0 eq) were added to a mixture of (600 mg, 1.35 mmol, 1.0 eq). o It was added at C. Subsequently, the mixture was 25 o It was stirred at C for 4 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated. A85 (N'-(indolin-6-carbonyl)-3-morpholino-4-nitrobenzenesulfonohydrazide, 450 mg, crude) was obtained as a yellow solid.

[0729] LCMS; Mass Calcd.:447.4; MS Found: 448.2 [Ms+1].

[0730] Step 4) Synthesis of Compound 39 (4-amino-N'-(indolin-6-carbonyl)-3-morpholinobenzenesulfonohydrazide)

[0731] In EtOH (5 mL) A85 Fe (282 mg, 5.05 mmol, 5.0 eq) and sat. aq. NH4Cl (1 mL) were added to a mixture of (450 mg, 1.01 mmol, 1.0 eq). Subsequently, the mixture was 85 o It was stirred at C for 3 hours. The solution was concentrated, then DMSO (5 mL) was added and filtered. The filtrate was purified by prep-HPLC and freeze-dried. Compound 39 (4-amino-N'-(indolin-6-carbonyl)-3-morpholinobenzenesulfonohydrazide, 30 mg, yield 7.0%) was obtained as a grayish-white solid.

[0732] 1HNMR (DMSO-d6, 400 MHz): δ10.36 (d, J = 4.4 Hz, 1H), 9.21 (d, J = 4.4 Hz, 1H), 7.23-7.27 (m, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.67 (s, 1H), 6.65 (d, J = 8.4 Hz, 1H), 5.63 (br s, 2H), 3.69 (t, J = 4.2 Hz, 4H), 3.42 (t, J = 8.6 Hz, 2H), 2.91 (t, J = 8.6 Hz, 2H),2.63 (t, J = 4.2 Hz, 4H).

[0733] LCMS; Mass Calcd.:417.1; MS Found: 418.1 [MS+1].

[0734] Experimental Example 1-40. Preparation of Compound 40 (4-amino-N'-(piperazine-1-carbonyl)benzenesulfonohydrazide)

[0735]

[0736] Step 1) Synthesis of A87

[0737] In pyridine (10 mL) A864-nitrobenzene-1-sulfonyl chloride (906 mg, 4.09 mmol, 1.0 eq) in pyridine (5 mL) in a mixture of (tert-butyl 4-(hydrazine carbonyl)piperazine-1-carboxylate, 1.00 g, 4.09 mmol, 1.0 eq) o It was added dropwise at C. Subsequently, the mixture was 10 o It was stirred at C for 3 hours. The solution was poured into water (50 mL) and extracted with EA (50 mL x 3). The combined organic layer was washed with 1N HCl (50 mL x 2) and brine, dried with Na2SO4, and concentrated to obtain a crude product. The crude product was washed with EA (5 mL), filtered, and the solid was dried under vacuum. A87 (tert-butyl 4-(2-((4-nitrophenyl)sulfonyl)hydrazine-1-carbonyl)piperazine-1-carboxylate, 800 mg, yield 45.5%) was obtained as a yellow solid.

[0738] 1HNMR (DMSO-d6, 400 MHz): δ 9.74 (s, 1H), 9.08 (s, 1H), 8.38 (d, J = 8.0 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 3.17 (br s, 8H), 1.40 (s, 9H).

[0739] Step 2) Synthesis of A88

[0740] In THF (10 mL) A87 Pd / C (40 mg) was added to a mixture of (400 mg, 0.93 mmol, 1.0 eq). Subsequently, the mixture was 10 o It was stirred under an H2 balloon at C for 16 hours. The solution was filtered, and the filtrate was concentrated. A88 (tert-butyl 4-(2-((4-aminophenyl)sulfonyl)hydrazine-1-carbonyl)piperazine-1-carboxylate, 350 mg, yield 94%) was obtained as a yellow solid.

[0741] Step 3) Synthesis of Compound 40 (4-amino-N'-(piperazine-1-carbonyl)benzenesulfonohydrazide)

[0742] In DCM (5 mL) A88 TFA (1 mL) was added to a mixture of (150 mg, 0.37 mmol, 1.0 eq). Subsequently, the mixture 25 o It was stirred at C for 3 hours. The solution was concentrated to obtain a crude product. MeOH (5 mL) and K2CO3 (62 mg, 0.45 mmol) were added to the crude product, and it was stirred at room temperature for 1 hour. The solution was filtered, purified by prep-HPLC, and freeze-dried. Compound 40 (4-amino-N'-(piperazine-1-carbonyl)benzenesulfonohydrazide, 50 mg, yield 38.7%) was obtained as a white solid.

[0743] 1HNMR (DMSO-d6, 400 MHz): δ 8.80 (d, J = 2.8 Hz, 1H), 8.28-8.32 (m, 3H), 7.38 (d, J = 8.8 Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H), 5.98 (s, 2H), 3.22 (s, 4H), 2.69 (s, 4H).

[0744] LCMS; Mass Calcd.:299; MS Found: 300 [MS+1].

[0745] Experimental Example 1-41. Preparation of Compound 41 (4-amino-3-morpholino-N'-(piperazine-1-carbonyl)benzenesulfonohydrazide)

[0746]

[0747] Step 1) Synthesis of A89

[0748] In pyridine (10 mL) A86 3-fluoro-4-nitrobenzene-1-sulfonyl chloride (1.46 g, 6.14 mmol, 1.0 eq) in pyridine (5 mL) was added dropwise to a mixture of (1.50 g, 6.14 mmol, 1.0 eq). Subsequently, the mixture 10 oIt was stirred at C for 3 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL x 3). The combined organic layer was washed with 1N HCl (30 mL x 2) and brine, dried with Na2SO4, and concentrated. A89 (tert-butyl 4-(2-((3-fluoro-4-nitrophenyl)sulfonyl)hydrazine-1-carbonyl)piperazine-1-carboxylate, 1.5 g, crude) was obtained as a yellow solid.

[0749] Step 2) Synthesis of A90

[0750] In DMF (15 mL) A89 Morpholine (350 mg, 4.02 mmol, 1.2 eq) was added to a mixture of (1.50 g, 3.35 mmol, 1.0 eq) and K2CO3 (1.16 g, 8.37 mmol, 2.5 eq). o It was added at C. Subsequently, the mixture was 25 o It was stirred at C for 16 hours. The solution was poured into water (50 mL) and extracted with EA (30 mL x 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to obtain the crude product, which was purified by column (DCM / MeOH = 50 / 1–10 / 1) A90 (tert-butyl 4-(2-((3-morpholino-4-nitrophenyl)sulfonyl)hydrazine-1-carbonyl)piperazine-1-carboxylate, 700 mg, yield: 40.6%) was obtained as a yellow solid.

[0751] LCMS; Mass Calcd.:514.55; MS Found: 516.2[MS+2].

[0752] Step 3) Synthesis of A91

[0753] In THF (10 mL) A90Pd / C (200 mg) was added to a mixture of (700 mg, 1.36 mmol, 1.0 eq). The mixture was then stirred under H2 (50 psi) for 15 minutes at room temperature. The solution was filtered, and the filtrate was concentrated. A91 (tert-butyl 4-(2-((4-amino-3-morpholinophenyl)sulfonyl)hydrazine-1-carbonyl)piperazine-1-carboxylate, 300 mg, crude) was obtained as a yellow solid.

[0754] Step 4) Synthesis of Compound 41 (4-amino-3-morpholino-N'-(piperazine-1-carbonyl)benzenesulfonohydrazide)

[0755] In DCM (10 mL) A91 TFA (2 mL) was added to a mixture of (200 mg, 0.41 mmol, 1.0 eq). The mixture was then stirred at room temperature for 3 hours. The mixture was concentrated, purified by prep-HPLC, and lyophilized. Compound 41 (4-amino-3-morpholino-N'-(piperazine-1-carbonyl)benzenesulfonohydrazide, 20.0 mg, yield 12.6%) was obtained as a pink solid.

[0756] 1HNMR (DMSO-d6, 400 MHz): δ 8.92 (d, J = 5.2 Hz, 1H), 8.69-8.75 (m, 2H), 7.23 (d, J = 5.6 Hz, 2H), 6.70 (t, J = 8.6 Hz, 1H), 5.68 (s, 2H), 3.78 (s, 4H), 3.39 (s, 4H), 2.98 (s, 4H), 2.76 (s, 4H).

[0757] LCMS; Mass Calcd.:384; MS Found: 384.9 [MS+1].

[0758] Experimental Example 1-42. Preparation of Compound 42 (N'-(4-hydroxybenzoyl)-2-methylthiazole-4-sulfonohydrazide)

[0759]

[0760] Step 1) Synthesis of A92

[0761] A stirred mixture of 2,2,2-trichloroacetaldehyde (20 g, 0.13 mmol), acetamide (7 g, 0.118 mmol), and concentrated sulfuric acid (1.2 g) 100 o It was heated at C for 1 hour. The reaction mixture was cooled and crystallized. The mixture was ground with deionized water, filtered, washed with a large amount of water, and recrystallized with ethanol. A92 (N-(2,2,2-trichloro-1-hydroxyethyl)acetamide, 15 g) was obtained as a white solid.

[0762] 1HNMR (DMSO_d6, 400 MHz): 8.72 (d, 1H), 7.64 (d, 1H), 5.74-5.70 (m, 1H), 1.92 (s, 3H).

[0763] Step 2) Synthesis of A93

[0764] Zinc powder (5 g, 78 mmol) in glacial acetic acid (50 mL) A92 It was slowly added over 3 hours to a stirred suspension of (8 g, 39 mmol). During zinc addition, the temperature of the reaction mixture was 40 o It was maintained below C. The reaction mixture was stirred at room temperature for 24 hours. Subsequently, the precipitated zinc salt was filtered and washed with glacial acetic acid. Acetic acid was removed under reduced pressure. The solid residue was ground with deionized water and recrystallized A93 (N-(2,2-dichlorovinyl)acetamide, 3 g) was obtained as a white solid.

[0765] 1HNMR (DMSO_d6, 400 MHz): 9.87 (d, 1H), 7.21 (d, 1H), 2.03 (s, 3H).

[0766] Step 3) Synthesis of A94

[0767] Benzylthiol (4 g, 32 mmol) and triethylamine (3.29 g, 32.6 mmol) in 2-propanol (25 mL) A93It was added to a stirred solution of (2 g, 13 mmol). The reaction mixture was stirred at room temperature for 48 hours. Subsequently, the solvent was removed under reduced pressure, and the residue was ground with water to produce a crystalline solid. The crude product was purified by recrystallization from 2-propanol or ethanol and A94 (N-(1-(benzylthio)-2,2-dichloroethyl)acetamide, 2.5 g) was obtained as a white solid.

[0768] 1HNMR (DMSO_d6, 400 MHz): 8.72 (d, 1H), 7.23-7.25 (m, 5H), 6.42 (d, 1H), 5.40 (dd, 1H), 3.87 (q, 2H), 1.93 (S, 3H).

[0769] Step 4) Synthesis of A95

[0770] Lawesson reagent (7.6 g, 18.8 mmol) in toluene (30 mL) A94 It was added to a stirred solution of (5 mmol). The reaction mixture was refluxed for 8 hours, and the solvent was removed under reduced pressure. The residue was ground with 10% aqueous NaOH and adjusted to pH 9. The raw product was filtered, dried, and recrystallized from 2-propanol. The liquid product was extracted with dichloromethane and A95 (4-(benzylthio)-2-methylthiazole, crude, 2.5 g) was obtained as a yellow oil.

[0771] 1HNMR (DMSO_d6, 400 MHz): 7.44 (s, 1H), 7.30-7.20 (m, 5H), 4.04 (s, 2H), 2.59 (S, 3H).

[0772] Step 5) Synthesis of A96

[0773] Acetic acid (10 ml) A95 NCS (3 g) and water (2 mL) in a solution of (crude, 1 g) 0 oIt was added at C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was ground with 10% aqueous NaHCO3 adjusted to pH = 8 and extracted with DCM (30 mL * 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to obtain the crude product. The residue was purified by passing through silica gel. A96 (2-methylthiazole-4-sulfonyl chloride, 100 mg) was obtained as a yellow solid.

[0774] 1HNMR (CDCl3, 400 MHz): 8.33 (s, 1H), 2.86 (S, 3H).

[0775] Step 6) Synthesis of Compound 42 (N'-(4-hydroxybenzoyl)-2-methylthiazole-4-sulfonohydrazide)

[0776] In pyridine (20 mL) A96 A mixture of (100 mg, 0.5 mmol) and A2 (4-hydroxybenzohydrazide, 80 mg, 0.5 mmol) is 80 o It was stirred overnight at C. The solution was poured into water (30 mL) and extracted with EA (30 mL * 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to obtain the crude product. The residue was purified by prep-HPLC. Compound 42 (N'-(4-hydroxybenzoyl)-2-methylthiazole-4-sulfonohydrazide, 30 mg) was obtained as a grayish-white solid.

[0777] 1HNMR (DMSO-d6, 400 MHz): 10.53 (s, 1H), 10.27 (s, 1H), 10.13 (s, 1H), 8.02 (s, 1H), 7.63 (d, 2H), 6.80 (d, 2H), 2.70 (s, 3H).

[0778] LCMS; Mass Calcd.:313.3; MS Found: 314.0 [MS+1].

[0779] Experimental Example 1-43. Preparation of Compound 43 ((1S,4S)-4-amino-N'-(4-hydroxybenzoyl)cyclohexane-1-sulfonohydrazide).

[0780]

[0781] Step 1) Synthesis of A98

[0782] In pyridine (100mL) A97 4-methylbenzenesulfonyl chloride (28.6 g, 151 mmol, 1.2 eq) was partially added to a mixture of (tert-butyl ((1r,4r)-4-hydroxycyclohexyl)carbamate, 27 g, 126 mmol, 1.0 eq), and the mixture was stirred overnight at room temperature. Pyridine was removed under vacuum, and the residue was purified by silica gel column chromatography. A98 ((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate, 40 g, 86.4%) was obtained as a white solid.

[0783] Step 2) Synthesis of A99

[0784] In DMF (100mL) A98 A solution of (10.0 g, 27.1 mmol, 1.0 eq) is treated with potassium thioacetate (9.3 g, 81.3 mmol, 3.0 eq) and the reaction mixture is 60 o It was stirred under nitrogen at C for 4 hours. The reaction mixture was quenched with brine (200 mL) and extracted with EtOAc (100 mL * 2). The combined organic matter was dried and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography. A99 (S-((1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl)ethanethioate, 3.0 g, 40.5%) was obtained as a white solid.

[0785] Step 3) Synthesis of A100

[0786] In DCM (30 mL) and water (30 mL) A99 0 in a solution of (2.50 g, 9.16 mmol, 1.0 eq). oChlorine gas was bubbled at C for 30 minutes. The two layers were separated, the DCM layer was washed with aq. sodium thiosulfate and brine, dried with sodium sulfate, filtered, and concentrated to crude A100 (tert-butyl ((1s,4s)-4-(chlorosulfonyl)cyclohexyl)carbamate) was obtained as a brown solid.

[0787] Step 4) Synthesis of A101

[0788] In a solution of 4-hydroxybenzohydrazide (A2, 2.76 g, 18.2 mmol, 2.0 eq) in pyridine (10 mL) in DCM (5 mL) A100 A solution of (crude) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum, and the crude product was purified by silica gel column chromatography. A101 (tert-butyl ((1s,4s)-4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)cyclohexyl)carbamate, 0.2 g, 5.3% for 2 steps) was obtained as a white solid.

[0789] Step 5) Synthesis of Compound 43 ((1s,4s)-4-amino-N'-(4-hydroxybenzoyl)cyclohexane-1-sulfonohydrazide)

[0790] A101 (200 mg, 4.2 mmol, 1.0 eq) was dissolved in a mixture of TFA (1 mL) and DCM (5 mL) and stirred for 2 hours. The mixture was concentrated under vacuum and dissolved in MeOH, NH3 / MeOH was added to pH=9, the solvent was concentrated under vacuum, the residue was dissolved in MeOH, purified by prep-HPLC, and freeze-dried. Compound 43 ((1s,4s)-4-amino-N'-(4-hydroxybenzoyl)cyclohexane-1-sulfonohydrazide, 20 mg, 13.2%) was obtained as a yellow solid.

[0791] 1HNMR (CD3OD, 400 MHz): δ 7.749 (d, J=8.8Hz, 2H), 6.862 (d, J=8.4Hz, 2H), 3.286-3.331 (m, 2H), 2.315-2.350 (m, 2H), 1.995-2.153 (m, 4H), 1.855-1.918 (m, 2H).

[0792] LCMS; MS Calcd.:313.11; MS Found: 313.9 ([M+1]+).

[0793] Experimental Example 1-44. Preparation of Compound 44 ((1R,4R)-4-amino-N'-(4-hydroxybenzoyl)cyclohexane-1-sulfonohydrazide).

[0794] Compound 44 was synthesized as a white solid (26.7% yield) using tert-butyl ((1s,4s)-4-hydroxycyclohexyl)carbamate as a starting material instead of A97 in the same manner as in Experimental Example 1-45.

[0795] 1HNMR (CD3OD, 400 MHz): δ 7.750 (d, J=8.8Hz, 2H), 6.868 (d, J=8.4Ha, 2H), 3.042-3.174 (m, 2H), 2.567 (d, J=12.4Hz, 2H), 2.180 (d, J=12.4Hz, 2H), 1.680-1.784 (m, 2H), 1.410-1.514 (m, 2H).

[0796] LCMS; MS Calcd.:313.11; MS Found: 313.9 ([M+1]+).

[0797] Experimental Example 1-45. Preparation of Compound 45 (4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)-5-methylfuran-2-carboxylic acid).

[0798]

[0799] Step 1) Synthesis of A102

[0800] A stirred mixture of 5-methylfuran-2-carboxylic acid (10 g, 80 mmol) and chlorosulfonic acid (30 mL) is 50 before being quenched in ice water oIt was stirred at C for 3 hours. The aqueous layer was extracted with DCM, the combined organic extract was washed with brine, dried with anhydrous sodium sulfate, and concentrated under vacuum to form the compound. A102 (14 g) was obtained as a yellow solid.

[0801] 1HNMR (DMSO_d6, 400 MHz): 13.95 (s, 1H), 6.97 (s, 1H), 2.50 (s, 3H).

[0802] Step 2) Synthesis of Compound 45 (4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)-5-methylfuran-2-carboxylic acid).

[0803] Compound in pyridine (50 mL) A102 A mixture of (5 g, 22.3 mmol) and compound A2 (3.4 g, 22.3 mmol) 60 o It was stirred overnight at C. The solution was poured into water (30 mL) and extracted with EA (30 mL * 3). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to obtain the crude product. The residue was purified by prep-HPLC. Compound 45 (4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)-5-methylfuran-2-carboxylic acid, 1.3 g) was obtained as a yellow solid.

[0804] 1HNMR (DMSO-d6, 400 MHz): 13.5 (brs, 1H), 10.47 (s, 1H), 10.14 (s, 1H), 10.03 (s, 1H), 7.63 (d, 2H), 7.18 (s, 1H), 6.79 (s, 2H), 3.17 (s, 3H)

[0805] Experimental Example 1-46. Preparation of Compound 46 (N'-(4-hydroxybenzoyl)pyrrolidine-3-sulfonohydrazide)

[0806]

[0807] Step 1) Synthesis of A104

[0808] In DCM (50 mL) A103In a stirred solution of (5.00 g, 26.7 mmol, 1.0 eq) and TEA (5.40 g, 53.4 mmol, 2.0 eq), methanesulfonyl chloride (4.59 g, 40.1 mmol, 1.5 eq) was 0 o Dropwise at C. The mixture was stirred at room temperature for 2 hours. The mixture was quenched with H2O (100 mL) and extracted with DCM (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried, and concentrated. The residue was purified by column chromatography (PE / EA=100:1-10:1) A104 (5.0 g, yield 70.6%) was obtained as a yellow oil. (PE / EA = 10:1, Rf = 0.6)

[0809] Step 2) Synthesis of A105

[0810] In DMF (50 mL) A104 A mixture of potassium thioacetate (5.00 g, 18.9 mmol, 1.0 eq) and potassium thioacetate (4.30 g, 37.7 mmol, 2.0 eq) was 70 o The mixture was stirred at C for 16 hours. The mixture was treated with H2O (200 mL) and extracted with EA (200 mL x 2). The combined organic layers were washed with H2O (100 mL x 3) and brine (100 mL), dried, and concentrated. The residue was purified by column chromatography (PE / EA=50:1-5:1) A105 (2.0 g, yield 43.4%) was obtained as a brown solid.

[0811] Step 3) Synthesis of A106

[0812] In acetic acid (AcOH 30 mL) and H2O (30 mL) A105N-chlorosuccinimide (5.45 g, 40.8 mmol, 5.0 eq) was added to a stirred solution of (2.00 g, 8.16 mmol, 1.0 eq). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated and purified by column chromatography (PE / EA=50:1-1:1) A106 (1.0 g, yield 45.6%) was obtained as a yellow oil. (PE / EA = 3:1, Rf = 0.5)

[0813] 1HNMR (CDCl3, 400 MHz): δ 4.28-4.31 (m, 1H), 4.00-4.02 (m, 1H), 3.85-3.95 (m, 1H), 3.66-3.75 (m, 1H), 3.52-3.58 (m, 1H), 2.63 (br s, 1H), 2.44-2.54 (m, 1H), 1.49 (s, 9H).

[0814] Step 4) Synthesis of A107

[0815] In a stirred solution of 4-hydroxybenzohydrazide (0.56 g, 3.71 mmol, 1.0 eq) in pyridinium (30 mL) in pyridinium (10 mL) A106 A solution of (1.00 g, 3.71 mmol, 1.0 eq) is 0 o It was added dropwise at C. The mixture was stirred at room temperature for 6 hours. The mixture was concentrated and purified by column chromatography (DCM / MeOH=100:1-10:1) A107 (0.50 g, yield 34.9%) was obtained as a yellow oil. (DCM / MeOH = 10:1, Rf = 0.4)

[0816] Step 5) Synthesis of Compound 46 (N'-(4-hydroxybenzoyl)pyrrolidine-3-sulfonohydrazide)

[0817] In DCM (10 mL) A107 TFA (4 mL) in a mixture of (500 mg, 1.30 mmol, 1.0 eq) 0 oIt was added at C. The mixture was stirred at room temperature for 4 hours. The solution was concentrated, purified by prep-HPLC, and freeze-dried. Compound 46 (N'-(4-hydroxybenzoyl)pyrrolidine-3-sulfonohydrazide, 30 mg, yield 7.0%) was obtained as a pale yellow solid. (TLC: N / A)

[0818] 1HNMR (DMSO-d6, 400 MHz): δ 10.47 (br s, 2H), 8.25 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 3.67-3.72 (m, 1H), 3.19-3.21 (m, 2H), 2.89-2.91 (m, 1H), 2.83-2.85 (m, 1H), 2.07-2.10 (m, 2H).

[0819] Experimental Example 1-47. Preparation of Compound 47 (N'-(4-hydroxybenzoyl)-1H-pyrrolo[2,3-b]pyridine-2-sulfonohydrazide).

[0820]

[0821] Step 1) Synthesis of A109

[0822] 1H-pyrrolo[2,3-b]pyridine in THF (60 mL) A108 In a mixture of , 6.00 g, 50.8 mmol, 1.0 eq), NaH (2.44 g (60% w / w), 60.9 mmol, 1.2 eq) was added 0 o Added at C and 0 for 1 hour o It was stirred at C. Subsequently, TsCl (9.65 g, 50.8 mmol, 1.0 eq) in THF (20 mL) was added dropwise to the solution. The solution was stirred for 16 hours. The solution was poured into water (200 mL) and extracted with EA (100 mL x 3). The combined organic layer was dried and concentrated with Na2SO4 to obtain the crude product, washed with PE (30 mL) for one hour, filtered, and the solid was collected. The solid was dried under vacuum and A109 (11.0 g, yield 79.5%) was obtained as a white solid. (TLC: N / A)

[0823] *LCMS; Mass Calcd.:272.32; MS Found: 273.1 [MS+1].

[0824] Step 2) Synthesis of A110

[0825] In THF (20 mL) A109 n-BuLi (3.24 mL, 8.08 mmol, 1.1 eq) was added to a mixture of -76 (2.00 g, 7.35 mmol, 1.0 eq). o It was added dropwise at C. The mixture was -76 o The mixture was stirred at C for 1 hour. Subsequently, the mixture was -76 o C to 10 o The solution was stirred under a SO2 balloon at C for 1 hour and concentrated. NCS (1.58 g, 11.7 mmol, 1.6 eq) was added to the residue in DCM (30 mL) at a concentration of 20 o It was added at C, and then the mixture was 20 o It was stirred at C for one hour. The solution was poured into water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layer was dried with Na2SO4 and concentrated. A110 (1.30 g, yield 47.8%) was obtained as a yellow solid.

[0826] LCMS; Mass Calcd.:370.82; MS Found: 371.0 [MS+1].

[0827] Step 3) Synthesis of A111

[0828] In pyridine (10 mL) A110 4-hydroxybenzohydrazide (A2, 587 mg, 3.86 mmol, 1.1 eq) in pyridine (5 mL) in a mixture of (1.30 g, 3.51 mmol, 1.0 eq) 10 o It was added dropwise at C. Subsequently, the mixture was 10 oThe mixture was stirred at C for 3 hours. The solution was poured into water (50 mL) and extracted with EA (50 mL x 3). The combined organic layer was washed with 1N HCl (50 mL x 2) and brine (50 mL), dried with Na2SO4, and concentrated to obtain a crude product. The crude product was washed with EA (5 mL), filtered, and dried to a solid under vacuum. A111 (600 mg, yield 35.3%) was obtained as a yellow solid. (TLC: N / A)

[0829] LCMS; Mass Calcd.:486.51; MS Found: 487.1 [MS+1].

[0830] Step 4) Synthesis of Compound 47 (N'-(4-hydroxybenzoyl)-1H-pyrrolo[2,3-b]pyridine-2-sulfonohydrazide)

[0831] In MeOH (6 mL) A111 Con. HCl (2 mL) was added to a mixture of (350 mg, 0.71 mmol, 1.0 eq). Subsequently, the mixture was 60 o It was stirred at C for 3 hours. The solution was concentrated, the crude product was purified by prep-HPLC and freeze-dried, Compound 47 (N'-(4-hydroxybenzoyl)-1H-pyrrolo[2,3-b]pyridine-2-sulfonohydrazide, 20 mg, yield 8.36%) was obtained as a white solid. (TLC: N / A)

[0832] 1HNMR (DMSO-d6, 400 MHz): δ 12.61 (s, 1H), 10.45 (s, 1H), 10.11 (br s, 1H), 9.90 (d, J=2 Hz, 1H), 8.40-8.42 (m, 1H), 8.08-8.10 (m, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.16-7.19 (m, 1H), 7.13 (s, 1H), 6.77 (d, J=8.8 Hz, 2H).

[0833] LCMS; Mass Calcd.:332; MS Found: 333 [MS+1].

[0834] Experimental Example 1-48. Compound 48 (4-hydroxy- N Preparation of '-(4-methoxybenzyl)benzohydrazide'

[0835]

[0836] Using the same preparation method as in Experimental Example 1-19, using 1-(bromomethyl)-4-methoxybenzene instead of 1-(bromomethyl)-4-nitrobenzene Compound 48 This is obtained.

[0837] Experimental Example 1-49. Compound 49 ( N -(4-aminobenzyl)-2,3-dehydro-1 H Preparation of -Indene-2-Carbohydrazide)

[0838]

[0839] A60 instead of A2 (2,3-dehydro-1 H Using -indene-2-carbohydrazide) as a starting material, by the same manufacturing method as in Experimental Example 1-19 Compound 49 is obtained.

[0840] Experimental Example 1-50. Compound 50 (4-amino- N Preparation of (2-(4-hydroxyphenyl)-2-oxoethyl)-3-morpholinobenzenesulfonamide)

[0841]

[0842] 4-nitrobenzene-1-sulfonyl chloride in step 3 of Experimental Example 1-12 Instead, using 3-fluoro-4-nitrobenzenesulfonyl chloride, by a preparation method similar to Experimental Examples 1-12 Compound 50 This is obtained.

[0843] Experimental Example 1-51. Compound 51 (3,5-diamino- N Preparation of (2-(4-hydroxyphenyl)-2-oxoethyl)benzenesulfonamide)

[0844]

[0845] 4-nitrobenzene-1-sulfonyl chloride in step 3 of Experimental Example 1-12 Instead, using 3,5-dinitrobenzenesulfonyl chloride (A20) by a preparation method similar to Experimental Example 1-12 Compound 51 This is obtained.

[0846] Experimental Example 1-52. Compound 52 (2-((4-aminophenyl)sulfonyl)- N Preparation of (3-hydroxyphenyl)hydrazine-1-carboxamide)

[0847]

[0848] In Step 3 of Experimental Example 1-27, using 3-isocyanatophenol instead of isocyanatobenzene, by the same preparation method as in Experimental Example 1-27 Compound 52 is obtained.

[0849] Experimental Example 1-53. Compound 53 (2-((4-amino-3-morpholinophenyl)sulfonyl)- N Preparation of -phenylhydrazine-1-carboxamide)

[0850]

[0851] A method of preparation similar to Experimental Example 1-27 using 3-fluoro-4-nitrobenzenesulfonyl chloride instead of 4-nitrobenzenesulfonyl chloride as the starting material Compound 53 This is obtained.

[0852] Experimental Example 1-54. Compound 54 (4-hydroxy- N - (((4-methoxyphenyl)sulfonyl)methyl)benzamide) preparation

[0853]

[0854] Using the same manufacturing method as in Experimental Examples 1-16, but using 4-methoxybenzenethiol instead of 4-nitrobenzenethiol in synthesis step 3 Compound 54 is obtained.

[0855] Experimental Example 1-55. Compound 55 ( N Preparation of -(((4-aminophenyl)sulfonyl)methyl)-[1,1'-biphenyl]-4-carboxamide)

[0856]

[0857] A method of preparation similar to Experimental Example 1-16 using [1,1'-biphenyl]-4-carboxamide as a starting material instead of A28, the intermediate of Experimental Example 1-16 Compound 55 is obtained.

[0858] Example 2. Binding assay experiment

[0859] Example 2-1 Determination of whether muscle actin is an Arg / N-degron pathway substrate

[0860] L6 cell lines, derived from rat muscle, were cultured in DMEM medium containing 10% FBS and 1% streptomycin / penicillin in an incubator maintained at 5% carbon dioxide, and then seeded into 12-well plates. An additional 24 hours of incubation were performed to allow the cells to fully adhere to the surface of the plate. To determine whether MG132 increases UBR1 binding, cells were aggregated after treatment with MG132 (10 µM) alone for 24 hours. To extract proteins from the aggregated cells, 50 µL of lysis buffer (20 mM Tris, pH 7.4, 150 mM NaCl, 1% triton-X-100, 2 mM NaF, 2 mM EDTA, 2 mM β-glycerophosphate, 5 mM sodium orthovanadate, 1 mM PMSF, leupeptin, aprotenin) was injected into each sample, and the cells were lysed. Based on the measured total protein concentration, sample buffer was added to each sample and reacted at 100°C for 5 minutes. After the reaction was complete, 5 μL was taken from each sample and dispensed into each well of the acrylamide gel, and immunoblotting was performed. The results of the experiment are shown in [Figure 1]. The immunoblotting method was represented from at least three independent experiments.

[0861] Referring to Figure 1, it was confirmed that the levels of ACTA1, ACTC1, and ACTG2 increased more with MG132 than with the control. Additionally, it was confirmed that the levels of ACTA1 and ACTG2 increased when UBR protein was knocked down. In other words, it was confirmed that muscle actin is a substrate of the Arg / N-degron pathway.

[0862] Example 2-2 Confirmation of R-nsP4 degradation inhibition via in vitro transcriptional translation method

[0863] The TnT® Quick Coupled Transcription / Translation System kit was used to confirm the R-nsP4 expression of the compounds. A pre-mix was prepared using Transcend Biotin-Lysyl-tRNA, Methionine, Bestatin, TnT quick Master mix, and DHFR-Ub-R-nsP4 Plasmid, and then mixed with the compounds (1 μM). Each sample was incubated at 30°C for 40 minutes, after which 5X SDS loading dye was added. After incubating at 95°C for 2 minutes, 5 μL was taken and dispensed into each well of an acrylamide gel, followed by immunoblotting. The experimental results are shown in [Figure 2]. The in vitro transcription and translation method was represented from at least three independent experiments.

[0864] Referring to Figure 2, it can be seen that the levels of R-nsP4 are further increased by compounds 2, 3, 7, 12, 14, and 16 compared to the control group. In other words, it was confirmed that the levels of R-nsP4 increase by binding to UBR1 when treated with the compounds according to the present invention.

[0865] Examples 2-3 Evaluation of Inhibition of Intracellular RGS4 Degradation via Transfection

[0866] L6 cell lines derived from rat muscle were cultured in DMEM medium containing 10% FBS and 1% streptomycin / penicillin in an incubator maintained at 5% carbon dioxide. To measure UBR1 binding affinity following treatment with a selected representative compound among the compounds, each cell was seeded into a 6-well plate. An additional 24 hours of culture were performed to allow the cells to fully adhere to the surface of the plate. Opti-MEM, Lipofectamin, and RGS4 plasmid were reacted for transfection. After the reaction was complete, the cells were treated to allow DNA to be expressed within the cells. After 24 hours, to determine whether the compound increased UBR1 binding, the cells were aggregated after treating with the compound (5 uM) alone for 24 hours. To extract proteins from the aggregated cells, 50 µL of lysis buffer (20 mM Tris, pH 7.4, 150 mM NaCl, 1% triton-X-100, 2 mM NaF, 2 mM EDTA, 2 mM β-glycerophosphate, 5 mM sodium orthovanadate, 1 mM PMSF, leupeptin, aprotenin) was injected into each sample, and the cells were lysed. Based on the measured total protein concentration, sample buffer was added to each sample and reacted at 100°C for 5 minutes. After the reaction, 5 µL of the sample was taken and dispensed into each well of the acrylamide gel, and immunoblotting was performed. The results of the experiment are shown in [Figure 3]. The immunoblotting method was represented from at least three independent experiments.

[0867] Referring to Figure 3, it was confirmed that the level of RGS4 increased further with compounds 2 and 3 compared to the control group. That is, it was confirmed that the level of RGS4 increased further by binding to UBR1 when treated with the compounds according to the present invention.

[0868] Examples 2-4 Evaluation of Muscle Cell Actin Degradation Inhibition via Immunoblotting

[0869] To evaluate the degradation of actin in muscle cells by the compounds, L6 cell lines derived from rat muscle were cultured in DMEM medium containing 10% FBS and 1% streptomycin / penicillin in an incubator maintained at 5% carbon dioxide. To measure UBR1 binding affinity following treatment with a selected representative compound among the compounds, each cell was seeded into a 12-well plate. An additional 24 hours of culture were performed to allow the cells to fully adhere to the surface of the plate. To determine whether the compound increased UBR1 binding, cells were aggregated after treatment with the compound (5 uM) alone for 24 hours. To extract proteins from the aggregated cells, 50 µL of lysis buffer (20 mM Tris, pH 7.4, 150 mM NaCl, 1% triton-X-100, 2 mM NaF, 2 mM EDTA, 2 mM β-glycerophosphate, 5 mM sodium orthovanadate, 1 mM PMSF, leupeptin, aprotenin) was injected into each sample, and the cells were lysed. Based on the measured total protein concentration, sample buffer was added to each sample and reacted at 100°C for 5 minutes. After the reaction, 5 µL of the sample was taken and dispensed into each well of the acrylamide gel, and immunoblotting was performed. The results of the experiment are shown in [Fig. 4], [Fig. 5], [Fig. 6], [Fig. 7], [Fig. 8], and [Fig. 9]. Representative immunoblotting results from at least three independent experiments were plotted.

[0870] Referring to Figures 4 and 5, it can be seen that the levels of ACTA1 are further increased by Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 16, Compound 35, Compound 36, Compound 37, Compound 38, Compound 39, Compound 43, Compound 44, Compound 45, Compound 46, and Compound 47 compared to the control group. In other words, it was confirmed that when treated with the compounds according to the present invention, the degradation of ACTA1, a muscle protein, is inhibited by binding to UBR1.

[0871] Referring to Figures 6 and 7, it can be seen that the levels of ACTA2 increased further with compounds 8, 9, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 32, 33, and 34 compared to the control group. In other words, it was confirmed that when treated with the compounds according to the present invention, the degradation of ACTA2, a muscle protein, was inhibited by binding to UBR1.

[0872] Referring to Fig. 8, it can be seen that the levels of ACTC1 increased further with compounds 41 and 42 compared to the control group. In other words, it was confirmed that when treated with the compounds according to the present invention, the degradation of ACTC1, a muscle protein, was inhibited by binding to UBR1.

[0873] Referring to Fig. 9, it was confirmed that the levels of ACTG2 increased further with compounds 12, 13, 14, 15, 17, 29, 30, and 31 compared to the control group. In other words, it was confirmed that when treated with the compounds according to the present invention, the degradation of ACTG2, a muscle protein, was inhibited by binding to UBR1.

[0874] Examples 2-5 Evaluation of UBR box domain binding affinity via immunoprecipitation analysis

[0875] To evaluate the binding affinity of compounds to UBR1, UBR2, UBR3, and UBR5 through the UBR box domains, L6 cell lines derived from rat muscle were cultured in DMEM medium containing 10% FBS and 1% streptomycin / penicillin in an incubator maintained at 5% carbon dioxide. To measure the binding affinity to UBR1 following treatment with a selected representative compound among the compounds, each cell was seeded into a 100 pi dish. An additional 24 hours of incubation were performed to allow the cells to fully adhere to the surface of the plate. To determine whether the compound increased UBR1 binding, cells were aggregated after treatment with compound (5 µM), the proteasome inhibitor MG132 (10 µM), or a positive control (5 µM) alone for 24 hours. To extract proteins from aggregated cells, 50 µL of lysis buffer (20 mM Tris, pH 7.4, 150 mM NaCl, 1% triton-X-100, 2 mM NaF, 2 mM EDTA, 2 mM β-glycerophosphate, 5 mM sodium orthovanadate, 1 mM PMSF, leupeptin, aprotenin) was injected into each sample, and the cells were lysed. Based on the measured total protein concentration, UBR1 antibodies were incubated in each sample for 16 hours, followed by incubation with Protein A / G beads for 3 hours. Sample buffer was added to the incubated samples, and the mixture was incubated at 100°C for 5 minutes. 20 µL of the incubated samples were taken and dispensed into each well of an acrylamide gel, after which immunoblotting was performed. The results of the experiment are shown in [Fig. 10] and [Fig. 11]. The immunoblotting method was represented from at least three independent experiments.

[0876] Referring to Figures 10 and 11, when treated with MG132, a proteasome inhibitor used as a DMSO control and negative control, the binding affinity between UBR1 and its substrate ACTA1 is maintained. However, when treated with the compound, the binding affinities between ACTA1, UBR2 and ACTA1, UBR3 and ACTA1, and UBR5 and ACTA1 decrease, similar to the positive control, thereby confirming that Compound 2 binds to the UBR box domains of the actual UBR proteins. In other words, when treated with the compound according to the present invention, it was confirmed that the degradation of ACTG2, a muscle protein, is inhibited by binding to UBR1, UBR2, UBR3, or UBR5.

[0877] Examples 2-6 Evaluation of UBR box domain binding strength via MST

[0878] 1) Preparation of UBR1 protein

[0879] The Gln97-Pro168 region corresponding to the UBR box of Human UBR1 (UniProt ID: Q8IWV7) was cloned into a modified expression vector and expressed in E. coli. After affinity chromatography, the tag was removed with protease, and Gly-His-Met was added to the N-terminus. After performing ion chromatography, the final UBR1 UBR box protein was purified using gel filtration chromatography in a buffer composition of 10 mM NaCl, 20 mM Tris-HCl, 2 mM beta-mercaptoethanol, and pH 7.5.

[0880] 2) UBR1 UBR box protein labeling

[0881] The dye of the Monolith protein labeling Kit RED-NHS 2nd generation (Cat# MO-L011) has an NHS-ester group that forms covalent bonds with primary amines (lysine residues). This dye is optimized for Monolith-series instruments equipped with a RED detector. Using this kit, purified UBR1 UBR box proteins were labeled according to the presented protocol.

[0882] 3) Measure UBR1 and ligand binding using MST

[0883] Thermophoresis refers to the phenomenon in which particles move due to a temperature gradient. Particles in a high-temperature region possess greater kinetic energy than those in a low-temperature region, causing them to collide more frequently with surrounding particles at higher energies. As a result, particles move from the high-temperature region to the low-temperature region.

[0884] Thermophoresis of proteins is typically different from that of protein-ligand complexes. This is because the size, charge, and solvation energy change upon ligand binding. Even if ligand binding does not significantly alter the size or charge of the protein, MST can detect changes in the solvation entropy of the protein molecule caused by ligand binding. Therefore, the binding of the UBR1 UBR box protein to the ligand compound was measured using MST, and it was confirmed that the proposed ligand binds to the UBR1 UBR box (see Figures 12 to 19).

Claims

Claim 1 In a composition for UBR box domain binding, the composition comprises a compound having the structure of Formula 1-1 or a salt thereof, [Formula 1-1] , where X1 has any one structure selected from the group consisting of the following: , , , , , , , , , , , , , , , , , , , , , , , , , , , and ;X4 has any one structure selected from the group consisting of the following: , , , , , , , , , , , , , and ;A1 is CH 2　 A composition for UBR box domain bonding, wherein NH or I is an integer of 0 or 1. Claim 2 delete Claim 3 delete Claim 4 delete Claim 5 delete Claim 6 delete Claim 7 delete Claim 8 delete Claim 9 A composition for UBR box domain binding according to claim 1, wherein the compound is any one of the following compounds selected: N -(4-hydroxybenzoyl)-4-methylbenzenesulfonohydrazide; 4-amino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide;4-amino- N -(4-hydroxybenzoyl)-3-morpholinobenzenesulfonohydrazide; N -(4-hydroxybenzoyl)-2-oxoindoline-5-sulfonohydrazide; N -(4-hydroxybenzoyl)indolin-5-sulfonohydrazide; N '-([1,1'-biphenyl]-4-carbonyl)-4-aminobenzenesulfonohydrazide; N '-([1,1'-biphenyl]-3-carbonyl)-4-aminobenzenesulfonohydrazide;3-amino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide; 4-(1-aminoethyl)- N -(4-hydroxybenzoyl)benzenesulfonohydrazide;3,5-diamino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide; N -(4-hydroxybenzoyl)-4-((2-hydroxyethyl)amino)benzenesulfonohydrazide; N -(4-hydroxybenzoyl)-4-methoxybenzenesulfonohydrazide;4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)benzimidamide;4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)benzamide;6-amino- N -(4-hydroxybenzoyl)-[1,1'-biphenyl]-3-sulfonohydrazide; 4-(2-((4-aminophenyl)sulfonyl)hydrazine-1-carbonyl)benzamide; 4-amino- N '-(1 H -Indole-3-carbonyl)benzenesulfonohydrazide;4-amino- N -(4-hydroxybenzoyl)-3-(pyrrolidine-1-yl)benzenesulfonohydrazide; N -(4-hydroxybenzoyl)-4-nitro-3-(pyrrolidine-1-yl)benzenesulfonohydrazide;4-amino- N -(4-hydroxybenzoyl)-3-(piperidine-1-yl)benzenesulfonohydrazide; N -(4-hydroxybenzoyl)-1 H -Pyrazole-4-sulfonohydrazide; N -(4-hydroxybenzoyl)indolin-4-sulfonohydrazide; N -(4-hydroxybenzoyl)-1 H -Indole-4-sulfonohydrazide;2-((4-aminophenyl)sulfonyl)- N -phenylhydrazine-1-carboxamide; 4-amino- N '-(1 H -Indole-4-carbonyl)-3-morpholinobenzenesulfonohydrazide;4-amino- N -(Indolin-4-carbonyl)benzenesulfonohydrazide;4-amino- N -(4-hydroxybenzoyl)-3-(peparazine-1-yl)benzenesulfonohydrazide;4-amino- N -(2,3-dehydro-1 H -Indene-2-carbonyl)benzenesulfonohydrazide; 4-amino- N -(isoindolin-2-carbonyl)benzenesulfonohydrazide; N -(4-hydroxybenzoyl)-1 H -Indole-2-sulfonohydrazide;4-amino- N -(2-phenylacetyl)benzenesulfonohydrazide; N -(4-hydroxybenzoyl)-1 H -Indazole-3-sulfonohydrazide;4-amino- N -(Indolin-6-carbonyl)benzenesulfonohydrazide;4-amino- N -(Indolin-3-carbonyl)benzenesulfonohydrazide; N -(4-hydroxybenzoyl)piperidine-4-sulfonohydrazide;4-amino- N -(Indolin-6-carbonyl)-3-morpholinobenzenesulfonohydrazide;4-amino- N -(piperazine-1-carbonyl)benzenesulfonohydrazide;4-amino-3-morpholino- N '-(piperazine-1-carbonyl)benzenesulfonohydrazide;N'-(4-hydroxybenzoyl)-2-methylthiazole-4-sulfonohydrazide;(1 S ,4 S )-4-amino- N '-(4-hydroxybenzoyl)cyclohexane-1-sulfonohydrazide;(1 R ,4 R )-4-amino- N -(4-hydroxybenzoyl)cyclohexane-1-sulfonohydrazide; 4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)-5-methylfuran-2-carboxylic acid; N -(4-hydroxybenzoyl)pyrrolidine-3-sulfonohydrazide; N' -(4-hydroxybenzoyl)-1 H -pyrrolo[2,3- b ]pyridine-2-sulfonohydrazide; 2-((4-aminophenyl)sulfonyl)-N-(3-hydroxyphenyl)hydrazine-1-carboxamide; and 2-((4-amino-3-morpholinophenyl)sulfonyl)-N-phenylhydrazine-1-carboxamide. Claim 10 In claim 1, the composition for UBR box domain binding, wherein the compound is any one of the following compounds: 4-amino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide;2-((4-aminophenyl)sulfonyl)- N -phenylhydrazine-1-carboxamide; 4-amino- N -(4-hydroxybenzoyl)-3-morpholinobenzenesulfonohydrazide; and 4-amino- N '-(1 H -Indole-4-carbonyl)-3-morpholinobenzenesulfonohydrazide. Claim 11 A pharmaceutical composition for treating UBR-related diseases, wherein the pharmaceutical composition comprises any one of the compounds described in claims 1, 9 and 10 and a pharmaceutically acceptable carrier, and wherein the UBR-related disease is sarcopenia, muscular dystrophy, cystic fibrosis, Johanson-Blizzard syndrome, urethral obstruction sequence, autoimmune pancreatitis, or Usher syndrome. Claim 12 Any one of the following compounds or salts thereof selected from: 4-amino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide;4-amino- N -(4-hydroxybenzoyl)-3-morpholinobenzenesulfonohydrazide; N -(4-hydroxybenzoyl)-2-oxoindoline-5-sulfonohydrazide; N -(4-hydroxybenzoyl)indolin-5-sulfonohydrazide; N '-([1,1'-biphenyl]-4-carbonyl)-4-aminobenzenesulfonohydrazide; N '-([1,1'-biphenyl]-3-carbonyl)-4-aminobenzenesulfonohydrazide;3-amino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide; 4-(1-aminoethyl)- N -(4-hydroxybenzoyl)benzenesulfonohydrazide;3,5-diamino- N -(4-hydroxybenzoyl)benzenesulfonohydrazide; N -(4-hydroxybenzoyl)-4-((2-hydroxyethyl)amino)benzenesulfonohydrazide; N -(4-hydroxybenzoyl)-4-methoxybenzenesulfonohydrazide;4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)benzimidamide;4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)benzamide;6-amino- N -(4-hydroxybenzoyl)-[1,1'-biphenyl]-3-sulfonohydrazide; 4-(2-((4-aminophenyl)sulfonyl)hydrazine-1-carbonyl)benzamide; 4-amino- N '-(1 H -Indole-3-carbonyl)benzenesulfonohydrazide;4-amino- N -(4-hydroxybenzoyl)-3-(pyrrolidine-1-yl)benzenesulfonohydrazide; N -(4-hydroxybenzoyl)-4-nitro-3-(pyrrolidine-1-yl)benzenesulfonohydrazide;4-amino- N -(4-hydroxybenzoyl)-3-(piperidine-1-yl)benzenesulfonohydrazide; N -(4-hydroxybenzoyl)-1 H -Pyrazole-4-sulfonohydrazide; N -(4-hydroxybenzoyl)indolin-4-sulfonohydrazide; N -(4-hydroxybenzoyl)-1 H -Indole-4-sulfonohydrazide;4-amino- N '-(1 H -Indole-4-carbonyl)-3-morpholinobenzenesulfonohydrazide;4-amino- N -(Indolin-4-carbonyl)benzenesulfonohydrazide;4-amino- N -(4-hydroxybenzoyl)-3-(peparazine-1-yl)benzenesulfonohydrazide;4-amino- N -(2,3-dehydro-1 H -Indene-2-carbonyl)benzenesulfonohydrazide; 4-amino- N -(isoindolin-2-carbonyl)benzenesulfonohydrazide; N -(4-hydroxybenzoyl)-1 H -Indole-2-sulfonohydrazide;4-amino- N -(2-phenylacetyl)benzenesulfonohydrazide; N -(4-hydroxybenzoyl)-1 H -Indazole-3-sulfonohydrazide;4-amino- N -(Indolin-6-carbonyl)benzenesulfonohydrazide;4-amino- N -(Indolin-3-carbonyl)benzenesulfonohydrazide; N -(4-hydroxybenzoyl)piperidine-4-sulfonohydrazide;4-amino- N -(Indolin-6-carbonyl)-3-morpholinobenzenesulfonohydrazide;4-amino- N -(piperazine-1-carbonyl)benzenesulfonohydrazide;4-amino-3-morpholino- N '-(piperazine-1-carbonyl)benzenesulfonohydrazide;N'-(4-hydroxybenzoyl)-2-methylthiazole-4-sulfonohydrazide;(1 S ,4 S )-4-amino- N '-(4-hydroxybenzoyl)cyclohexane-1-sulfonohydrazide;(1 R ,4 R )-4-amino- N -(4-hydroxybenzoyl)cyclohexane-1-sulfonohydrazide; 4-((2-(4-hydroxybenzoyl)hydrazinyl)sulfonyl)-5-methylfuran-2-carboxylic acid; N -(4-hydroxybenzoyl)pyrrolidine-3-sulfonohydrazide; N' -(4-hydroxybenzoyl)-1 H -pyrrolo[2,3- b ]pyridine-2-sulfonohydrazide; and 2-((4-amino-3-morpholinophenyl)sulfonyl)-N-phenylhydrazine-1-carboxamide. Claim 13 A pharmaceutical composition for treating UBR-related diseases, wherein the pharmaceutical composition comprises any one of the compounds described in claim 12 and a pharmaceutically acceptable carrier, and wherein the UBR-related disease is sarcopenia, muscular dystrophy, cystic fibrosis, Johanson-Blizzard syndrome, urethral obstruction sequence, autoimmune pancreatitis, or Usher syndrome. Claim 14 delete Claim 15 delete Claim 16 delete Claim 17 delete Claim 18 delete Claim 19 delete Claim 20 delete

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