A compound and pharmaceutical composition for a ubr box domain ligand

Abstract

This specification relates to compounds acting as ligands for UBR box domains. This specification provides a small molecule compound that binds to a UBR box domain. Furthermore, this specification provides a composition for inhibiting matrix binding of UBR box domains, comprising a ligand compound binding to a UBR box domain, a pharmaceutical composition for treating UBR-related diseases, and its uses.

Description

Technical Field

[0001] This specification discloses compounds that function as ligands for UBR box domains. UBR box domains are domains typically found in ubiquitin protein ligase E3 fraction n-recognition proteins (UBRs) via the N-terminal regular pathway. In this case, the UBR box domain is referred to as the matrix-bound domain. The UBR box domain is essential for binding to N-terminal residues in the matrix to form polyubiquitin chains within the matrix, a process known to occur through matrix degradation.

[0002] This specification relates to compounds used as ligands that bind to UBR box domains. Prior Technology

[0003] Cells regulate the quantity and function of proteins within the body by degrading proteins. In this case, proteins in the body can be degraded based on their N-terminal residue sequences, and such degradation pathways are called N-terminal regularized pathways. That is, an N-terminal regularized pathway is a proteolytic system that uses the N-terminus of a specific protein as a degradation signal. An N-terminal regularized pathway may include the following proteolytic processes.

[0004] In eukaryotes, N-recognition proteins recognize N-terminal degradation signals of proteins, and these proteins degrade proteins by allowing ubiquitin to bind to the protein to be degraded. In this case, the N-terminal degradation signal can include N-terminal degradation signals with positively charged residues (Type 1: e.g., arginine, lysine, and histidine) or larger hydrophobic residues (Type 2: phenylalanine, leucine, tryptophan, isoleucine, and tyrosine). The inventors have first discovered or selected N-recognition proteins UBR1, UBR2, UBR3, and UBR5, and disclosed that these N-recognition proteins possess a UBR box domain that serves as a matrix recognition domain (Tasaki et al. 2005). In this case, the ubiquitinated matrix generated by the binding of the N-recognition protein to the N-terminal regular ligand is delivered to the proteasome and degraded into short peptides. In this process, specific N-terminal residues (Nt-Arg, Nt-His, Nt-Lys, Nt-Trp, Nt-Phe, Nt-Tyr, Nt-Leu, Nt-Leu) provide most of the hydrogen bonds required for N-recognition proteins to target the N-terminal regular matrix, and are therefore the determinants necessary for binding (Sriram and Kwon, 2010).

[0005] UBR is an abbreviation for ubiquitin protein ligase E3 component n-recognition protein, and UBR is an N-recognition protein that recognizes the N-terminal degradation signal of a protein. At least seven types of UBR 1 to UBR 7 are known to exist in mammals. Furthermore, the common UBR box domain is a zinc finger motif of approximately 70 residues, referred to as a highly conserved matrix-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].

[0006] That is, UBR is an N-recognition protein associated with the N-terminal regular pathway, which is a proteolytic pathway, and the UBR box domain in UBR is a matrix-binding domain. Specifically, among UBR 1 to UBR 7, UBR1, UBR2, UBR3, and UBR5 are known to act as ubiquitin-conjugating enzymes E3 and possess a RING or HECT domain. N-terminal regularized matrix bound to UBR is degraded via the ubiquitin-proteasome pathway. Specifically, the UBR box domain in UBR recognizes the N-terminal amino acid of the matrix and ubiquitinates the matrix via the RING or HECT domain, thereby degrading the matrix via the proteasome pathway. For example, when misfolded proteins are retained in the cell for an extended period, the proteins may aggregate to block the proteasome or impair other cellular functions, and thus be degraded via the ubiquitin-proteasome pathway (Ji and Kwon, 2017).

[0007] In other words, the UBR box domain plays an important role in intracellular proteolytic pathways by recognizing N-terminal degradation signals. Therefore, ligands that bind to the UBR box domain may influence intracellular proteolytic pathways.

[0008] As described above, this specification relates to a compound as a ligand that binds to a UBR box domain associated with an intra-sib protein hydrolysis pathway. Summary of the Invention

[0009] Technical issues

[0010] This specification provides a small molecule compound that binds to a UBR box domain. In this case, the UBR box domain comprises the UBR box domains from UBR 1 to UBR 7. The small molecule compound can act as a ligand suitable for binding to the UBR box domain.

[0011] In one embodiment, this specification provides a composition for inhibiting matrix binding of UBR box domains, comprising a ligand compound that binds to the UBR box domain.

[0012] In one particular embodiment, this specification provides a pharmaceutical composition for treating UBR-related diseases and its use therein, wherein the composition comprises a ligand compound that binds to a UBR box domain.

[0013] In a more specific embodiment, this specification provides a pharmaceutical composition for treating diseases including muscle loss caused by muscular dystrophy (Becker, congenital, Duchenne, distal, Emery-Dreifuss, face-shoulder-arm, limb-girdle, myotonia, ocuophargyngeal); muscular atrophy diseases mediated by muscle loss or degradation, including sarcopenia or cancer cachexia; diseases caused by excessive protein degradation, including liposarcoma, cystic fibrosis, Johanson-Blizzard syndrome, obstructive urinary tract disease (urethral obstruction sequence); autoimmune pancreatitis; or known diseases associated with the UBR box and UBR protein, including Usher syndrome, and uses thereof, wherein the composition includes a ligand compound that binds to the UBR box domain. Technical solutions

[0014] This specification provides a compound having the structure of Formula 1 or a salt thereof. [Formula 1] Wherein X1 is a selectively substituted or unsubstituted phenyl, cycloalkyl, or heterocyclic group with one or more R2 substitutions; 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 heterocyclic alkyl; X4 is a selectively substituted or unsubstituted phenyl, cycloalkyl, or heterocyclic group with one or more R3 substitutions; Each R3 is independently selected from alkyl, alkoxy, amino, halogen, hydroxy, alkylamino, dialkylamino, -NO2, -CONR'R'', -CO2 R', -NHCOR', phenyl, or heterocyclic alkyl; Each R' and R'' is independently -H or alkyl; X2 is SO2 or CRa Rb; Ra and Rb are each independently H or CH3; X3 is NH or CH2; B1 is CH2 or NH; A1 is CH2 or NH.

[0015] In this case, as an example, in Equation 1, -X2-B1-X3 is selected from the group consisting of: -SO2-NH-NH, -SO2-NH-CH2, -SO2-CH2-NH, and -CH2-NH-NH. X1 is a selectively substituted or unsubstituted phenyl, cycloalkyl, or heterocyclic group with one or more R2 substitutions; 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 heterocyclic alkyl; X4 is a selectively substituted or unsubstituted phenyl, cycloalkyl, or heterocyclic group with one or more R3 substitutions; Each R3 is independently selected from alkyl, alkoxy, amino, halogen, hydroxy, alkylamino, dialkylamino, -NO2, -CONR'R'', -CO2 R', -NHCOR', phenyl, or heterocyclic alkyl; wherein each R' and R'' is independently -H or alkyl; A1 is CH2 or NH. I is an integer that is either 0 or 1.

[0016] As a specific example, each X1 and X4 is independently a substituted or unsubstituted phenyl, cycloalkyl, or heterocyclic group; wherein each X1 and X4 may be independently selected from substituted or unsubstituted phenyl, cyclohexyl, cyclopentyl, furanyl, thiazolyl, 1H-pyrazolyl, pyrrolidyl, piperidinyl, piperazinyl, morpholinyl, indololinyl, 1H-indololinyl, 1H-inzolyl, isoindololinyl, indololin-2-one, 2,3-dihydro-1H-indenyl, and 1H-pyrrolopyridinyl.

[0017] In this case, as an example, each R2 can 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, pyrrolidyl, piperazine, piperidinyl, and morpholinyl.

[0018] In this case, as an example, each R3 is independently selected from hydroxyl, fluorine, chlorine, bromine, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, alkylamino, dialkylamino, -NO2, -C(=O)NH2, -CO2R', -NHCOR', -CONR'R'', and phenyl; Each R' and R'' is independently -H or alkyl.

[0019] As an example, this specification provides a compound or a salt thereof, wherein formula 1 is formula 1-1: [Equation 1-1] Where A1 is CH2 or NH, I is an integer that is either 0 or 1.

[0020] In this case, as an example, this specification provides a compound or a salt thereof, wherein formula 1 is equivalent to formula 1-2: [Equation 1-2] .

[0021] In this case, as an example, this specification provides a compound or a salt thereof, wherein formula 1 is equivalent to formulas 1-3: [Equation 1-3] .

[0022] In this case, as an example, this specification provides a compound or a salt thereof, wherein formula 1 is equivalent to formulas 1-4: [Equations 1-4] .

[0023] In this case, in equations 1-1, 1-2, 1-3, and 1-4, As an example, Wherein X1 is a selectively substituted or unsubstituted phenyl, cycloalkyl, or heterocyclic group with one or more R2s, wherein 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 heterocyclic alkyl; X4 is a selectively substituted or unsubstituted phenyl, cycloalkyl, or heterocyclic group with one or more R3s; wherein each R3 is independently selected from alkyl, alkoxy, amino, halogen, hydroxy, alkylamino, dialkylamino, -NO2, -CONR'R'', -CO2 R', -NHCOR', phenyl, or heterocyclic alkyl; and each R' and R'' is independently -H or alkyl.

[0024] As a specific example, each X1 and X4 is independently a substituted or unsubstituted phenyl, cycloalkyl, or heterocyclic group; wherein each X1 and X4 may be independently selected from substituted or unsubstituted phenyl, cyclohexyl, cyclopentyl, furanyl, thiazolyl, 1H-pyrazolyl, pyrrolidyl, piperidinyl, piperazinyl, morpholinyl, indololinyl, 1H-indololinyl, 1H-inzolyl, isoindololinyl, indololin-2-one, 2,3-dihydro-1H-indenyl, and 1H-pyrrolopyridinyl.

[0025] In this case, as an example, each R2 can 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, pyrrolidyl, piperazine, piperidinyl, and morpholinyl.

[0026] In this case, as a specific example, this specification provides a compound or a salt thereof, wherein R2 is an amino group.

[0027] In this case, as an example, this specification provides a compound or a salt thereof, wherein X1 is... or .

[0028] In this case, as an example, each R3 is independently selected from hydroxyl, fluorine, chlorine, bromine, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, alkylamino, dialkylamino, -NO2, -C(=O)NH2, -CO2R', -NHCOR', -CONR'R'', and phenyl; Each R' and R'' is independently -H or alkyl.

[0029] In this case, as an example, this specification provides a compound or a salt thereof, wherein X4 is... , or .

[0030] In this case, as an example, Compounds can be selected from: N'-(4-hydroxybenzoyl)-4-methylbenzenesulfonylhydrazine; 4-amino-N'-(4-hydroxybenzoyl)benzenesulfonamide; 4-amino-N'-(4-hydroxybenzoyl)-3-morpholinylbenzenesulfonhydrazide; N'-(4-hydroxybenzoyl)-2-sideoxyindoline-5-sulfadiazine; N'-(4-hydroxybenzoyl)indoline-5-sulfadiazine; N'-([1,1'-biphenyl]-4-carbonyl)-4-aminobenzenesulfonhydrazine; N'-([1,1'-biphenyl]-3-carbonyl)-4-aminobenzenesulfonhydrazine; 3-amino-N'-(4-hydroxybenzoyl)benzenesulfonamide; 4-(1-aminoethyl)-N'-(4-hydroxybenzoyl)benzenesulfonamide; 3,5-Diamino-N'-(4-hydroxybenzoyl)benzenesulfonamide; N'-(4-hydroxybenzoyl)-4-((2-hydroxyethyl)amino)benzenesulfonylhydrazine; N'-(4-hydroxybenzoyl)-4-methoxybenzenesulfonylhydrazine; 4-((2-(4-hydroxybenzoyl)hydrazino)sulfonyl)benzomidine; 4-((2-(4-hydroxybenzoyl)hydrazino)sulfonyl)benzoamide; 6-amino-N'-(4-hydroxybenzoyl)-[1,1'-biphenyl]-3-sulfadiazine; 4-(2-((4-aminophenyl)sulfonyl)hydrazine-1-carbonyl)benzamide; 4-amino-N'-(1H-indole-3-carbonyl)benzenesulfonylhydrazine; 4-amino-N'-(4-hydroxybenzoyl)-3-(pyrrolidin-1-yl)benzenesulfonhydrazine; N'-(4-hydroxybenzoyl)-4-nitro-3-(pyrrolidin-1-yl)benzenesulfonhydrazine; 4-amino-N'-(4-hydroxybenzoyl)-3-(piperidin-1-yl)benzenesulfonhydrazine; N'-(4-hydroxybenzoyl)-1H-pyrazole-4-sulfadiazine; N'-(4-hydroxybenzoyl)indoline-4-sulfadiazine; N'-(4-hydroxybenzoyl)-1H-indole-4-sulfadiazine; 2-((4-aminophenyl)sulfonyl)-N-phenylhydrazine-1-methylamine; 4-amino-N'-(1H-indole-4-carbonyl)-3-morpholinylbenzenesulfonhydrazine; 4-amino-N'-(indoline-4-carbonyl)benzenesulfonamide; 4-amino-N'-(4-hydroxybenzoyl)-3-(piperazin-1-yl)benzenesulfonhydrazine; 4-amino-N'-(2,3-dihydro-1H-indene-2-carbonyl)benzenesulfonamide; 4-amino-N'-(isoindoline-2-carbonyl)benzenesulfonamide; N'-(4-hydroxybenzoyl)-1H-indole-2-sulfadiazine; 4-amino-N'-(2-phenylacetyl)benzenesulfonamide; N'-(4-hydroxybenzoyl)-1H-indazole-3-sulfadiazine; 4-amino-N'-(indoline-6-carbonyl)benzenesulfonamide; 4-amino-N'-(indoline-3-carbonyl)benzenesulfonamide; N'-(4-hydroxybenzoyl)piperidine-4-sulfadiazine; 4-amino-N'-(indoline-6-carbonyl)-3-morpholinylbenzenesulfonhydrazine; 4-amino-N'-(piperazine-1-carbonyl)benzenesulfonamide; 4-amino-3-morpholino-N'-(piperazine-1-carbonyl)benzenesulfonhydrazine; N'-(4-hydroxybenzoyl)-2-methylthiazol-4-sulfadiazine; (1S,4S)-4-amino-N'-(4-hydroxybenzoyl)cyclohexane-1-sulfadiazine; (1R,4R)-4-amino-N'-(4-hydroxybenzoyl)cyclohexane-1-sulfadiazine; 4-((2-(4-hydroxybenzoyl)hydrazino)sulfonyl)-5-methylfuran-2-carboxylic acid; N'-(4-hydroxybenzoyl)pyrrolidine-3-sulfadiazine; N'-(4-hydroxybenzoyl)-1H-pyrrolo[2,3-b]pyridine-2-sulfadiazine; 2-((4-aminophenyl)sulfonyl)-N-(3-hydroxyphenyl)hydrazine-1-methylamine; 2-((4-amino-3-morpholinylphenyl)sulfonyl)-N-phenylhydrazine-1-methylamine; N'-(4-aminobenzyl)-4-hydroxybenzohydrazine; 4-Hydroxy-N'-(4-methoxybenzyl)benzylhydrazine; N'-(4-aminobenzyl)-2,3-dihydro-1H-indene-2-carbazine; 4-amino-N-(2-(4-hydroxyphenyl)-2-sideoxyethyl)benzenesulfonamide; 4-amino-N-(2-(4-hydroxyphenyl)-2-sideoxyethyl)-3-morpholinylbenzenesulfonamide; 3,5-Diamino-N-(2-(4-hydroxyphenyl)-2-sideoxyethyl)benzenesulfonamide; N-(((4-aminophenyl)sulfonyl)methyl)-4-hydroxybenzoamide; 4-Hydroxy-N-(((4-methoxyphenyl)sulfonyl))methyl)benzamide; N-(((4-aminophenyl)sulfonyl)methyl)-[1,1'-biphenyl]-4-methylamine.

[0031] In another embodiment, this specification provides a pharmaceutical composition for treating UBR-related diseases, comprising a compound or a pharmaceutically acceptable salt thereof; and a method of treating UBR-related diseases by using the compound.

[0032] In this context, as an example, UBR-related diseases may include muscle loss caused by various muscular dystrophys (Becker's, congenital, Duchenne's, distal, E. De's, face-shoulder-arm, limb-girdle, myotonic, oculopharyngeal); muscular atrophy diseases mediated by muscle loss or degradation, including sarcopenia or cancer cachexia; diseases caused by excessive protein degradation, including liposarcoma, cystic fibrosis, Johnson-Bliszer's syndrome, obstructive urinary tract disease (urethral obstruction sequence); autoimmune pancreatitis; or Ussell's syndrome. Beneficial effects

[0033] The invention disclosed herein provides a ligand compound with high binding strength relative to the UBR box domain.

[0034] UBR box domain ligand compounds can inhibit UBR box domain matrix binding and offer a variety of applications utilizing this feature. For example, UBR-related diseases (e.g., sarcopenia and similar conditions) can be treated with UBR box domain ligand compounds. Simple Explanation of the Diagram

[0035] Figure 1 shows the experimental results of using the immunoblotting method to confirm whether muscle actin is a matrix of the Arg / N-degradation determinant pathway. Figure 2 shows the experimental results of confirming whether the degradation of R-nsp4 was inhibited by in vitro transcription / translation, wherein R-nsp4 was degraded by allowing compounds (compound 2, compound 3, compound 7, compound 12, compound 14 and compound 16) to bind to UBR1. Figure 3 shows the experimental results of using an immunoblotting method to confirm whether the degradation of RGS4 was inhibited. RGS4 is the matrix of UBR protein in embryonic kidney cells and is degraded by allowing compounds (compounds 2 and 3) to bind to UBR1. Figure 4 shows the experimental results of using an immunoblotting assay to confirm whether compounds (compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, and compound 16) inhibit the degradation of actin, which is the matrix of UBR protein in muscle cells. Figure 5 shows the experimental results of using an immunospot assay to confirm whether compounds (compounds 35, 36, 37, 38, 39, 43, 44, 45, 46, and 47) inhibit the degradation of actin in muscle cells. Figure 6 shows the experimental results of using immunoblotting to confirm whether compounds (compound 8, compound 9, compound 18, compound 19, compound 20, compound 21, compound 22, compound 23, and compound 24) inhibit the degradation of actin in muscle cells. Figure 7 shows the experimental results of using an immunoblotting method to confirm whether compounds (compounds 25, 26, 27, 28, 32, 33, and 34) inhibit the degradation of actin in muscle cells. Figure 8 shows the experimental results of using the immunoblotting method to confirm whether compounds (compound 41 and compound 42) inhibit the degradation of actin in muscle cells. Figure 9 shows the experimental results of using an immunospot assay to confirm whether compounds (compound 12, compound 13, compound 14, compound 15, compound 17, compound 29, compound 30, and compound 31) inhibit the degradation of actin in muscle cells. Figures 10 and 11 show the experimental results of using immunoblotting to confirm the efficacy of compound 2 in binding to UBR 1, UBR 2, UBR 3 and UBR 5 in cells. Figures 12 to 19 show the results of microscale thermophoresis (MST) experiments confirming whether compounds (compound 1, compound 2, compound 5, compound 8, compound 9, compound 11, compound 12, and compound 13) bind to UBR1. Implementation

[0036] In the following description, the invention will be presented in more detail with reference to the accompanying drawings, through specific exemplary embodiments and examples. It should be noted that the accompanying drawings include some, but not all, exemplary embodiments of the invention. The invention disclosed herein can be practiced differently and is not limited to the specific exemplary embodiments described herein. Those skilled in the art to which the invention disclosed herein pertains will be able to conceive of many modifications and other exemplary embodiments of the invention disclosed herein. Therefore, it should be understood that the invention disclosed herein is not limited to the specific exemplary embodiments described herein, and that modifications and other exemplary embodiments thereof are also within the scope of the claims. [Definition of the term]

[0037] The following section provides definitions of the main terms used in this article. [Ubiquitin-protein ligase] [E3] [Components] [n-] [Recognition Protein()] [UBR] [)]

[0038] As used herein, the term UBR stands for the abbreviation for ubiquitin protein ligase E3 component n-recognition protein. UBR is an N-recognition protein that recognizes the N-terminal residues of proteins, and at least seven types of UBR 1 through UBR 7 are known to exist in mammals. UBR is an N-recognition protein and is associated with the N-terminal regular pathway, which is a proteolytic pathway in vivo. Specifically, UBR recognizes N-terminal degradation signals (N-degradation determinants) of proteins and participates in the degradation of matrix proteins via the ubiquitin-proteasome pathway. [UBR] [Box structure domain]

[0039] As used in this paper, the term UBR box domain refers to a domain present in UBR proteins and is a zinc finger motif. UBR proteins include UBR 1 through UBR 7. The UBR box domain is referred to as a matrix protein-binding domain. The compounds disclosed herein, acting as ligands for the UBR box domain, can inhibit matrix binding of the UBR box domain by binding to it. Furthermore, the compounds disclosed herein, acting as ligands for the UBR box domain, can influence intracellular proteolytic pathways. [RING] [Domain]

[0040] The term RING domain, as used in this paper, is known to exist in UBR1, UBR2, and UBR3 proteins. The RING domain is also interchangeable with the RING ubiquitination domain. The RING domain is a domain present in the protein and is a zinc finger motif. The RING domain plays a crucial role in the transfer of ubiquitin from E2 to the matrix protein, and it allows for the transfer of ubiquitin to the matrix protein in a single step. [HECT] [Domain]

[0041] The term HECT domain, as used herein, is known to exist in the UBR5 protein. The HECT domain is also interchangeable with the HECT ubiquitination domain. The HECT domain is a crucial domain in the transfer of ubiquitin from E2 to the matrix protein. Ubiquitin in E2 is delivered to the HECT domain and subsequently transferred to the matrix protein. In other words, the HECT domain allows for the transfer of ubiquitin to the matrix protein in two steps. [Zinc finger mold]

[0042] As used herein, the term zinc finger motif refers to a protein structural motif containing one or more zinc ions to stabilize the protein structure. The UBR box domain and RING domain in this specification are zinc finger motifs. [ligand]

[0043] As used herein, the term ligand refers to a substance that specifically binds to a protein. Proteins may contain enzymes or receptors, and when a protein is an enzyme, ligand may refer to the matrix or analogue that binds to the enzyme, and when a protein is a receptor, ligand may refer to a hormone or analogue that binds to the receptor.

[0044] The compounds used herein as ligands for UBR box domains refer to compounds that bind to UBR box domains. As an example, a compound refers to a compound that binds to the UBR box domain in a UBR protein. As a specific example, a compound refers to a compound that binds to the UBR box domain present in one or more proteins from UBR 1 to UBR 7. However, the compounds are not limited to these.

[0045] The compounds presented herein, acting as ligands for the UBR box domain, can competitively interact with the matrix of the UBR box domain. That is, the compounds can inhibit matrix binding of the UBR box domain. Furthermore, the compounds can inhibit matrix degradation by suppressing matrix binding. [Aminoalkyl]

[0046] As used herein, the term aminoalkyl refers to an alkyl moiety that has been substituted with an amino group. Aminoalkyl includes -CH(NH2)CH3 and -CH2(NH2). [Cycloalkyl and Heterocyclic Alkyl]

[0047] As used herein, the term cycloalkyl refers to a carbocyclic group containing one or more saturated ring structures and comprising a bicyclic group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0048] Heterocyclic alkyl refers to a ring structure that contains one or more heteroatoms selected from P, N, O and S, in addition to the cyclic carbon atom in the cycloalkyl group. [Heterocyclic group]

[0049] As used herein, the term heterocyclic group refers to an unsaturated, saturated, or partially unsaturated monocyclic, bicyclic, or tricyclic group having 12 to 14 ring carbon atoms, and containing one or more heteroatoms selected from P, N, O, and S in addition to the ring carbon atoms. Heterocyclic groups comprise heterocyclic alkyl groups. In various exemplary embodiments, the heterocyclic group is linked to another portion via a carbon or heteroatom, and is selectively substituted at the carbon or heteroatom. Examples of heterocyclic groups include acrylyl, benzimidazolyl, benzofuranyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carzolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, isoindolinyl, indolyl, indoleazinyl, indazole, isobenzofuranyl, isoindolyl, Isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, piperanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrroleyl, quinazolinyl, quinolinyl, tetrahydropiperanyl, tetrahydrothiopiperanyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazonopyridine Pyridyl, thiadiazolyl, thiazolyl, thiophene, triazolyl, 1,4-dioxane, hexahydroazepinyl, piperazinyl, piperidinyl, piperidin-2-one, pyrrolidyl, pyrrolopyridinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophene, dihydrobenzooxazolyl, dihydrofuranyl, dihydroimidazole The group includes dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrroleyl, dihydroquinolinyl, dihydrotetrazoleyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotriazolyl, dihydroacrylyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothiophenyl and similar groups.

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All disclosures, patents, and other references mentioned herein are incorporated herein by reference in their entirety.

[0051] The specific details of this invention will be disclosed below. [I.UBR] [Box structure domain] [1.] [Overview]

[0052] The compounds presented in this paper, acting as ligands for the UBR box domain, bind to the UBR box domain. The UBR box domain is referred to as the domain bound to the N-terminal residue sequence or N-terminal degradation signal. This domain is associated with the degradation of proteins via the N-terminal regular pathway. Therefore, the compounds can influence protein hydrolysis through the N-terminal regular pathway. [2.] [N] [Endpoint rule path]

[0053] Cells regulate the amount of protein through proteolysis. In this context, protein degradation is known to be performed by recognizing degradation determinants (which are the degradation signals of proteins). Specifically, proteolysis is regulated by the N-terminal residue sequence of a protein, and the proteolytic signals present at the N-terminus are collectively referred to as N-degradation determinants. N-degradation determinants include those with positively charged residues (e.g., arginine, lysine, and histidine) or larger hydrophobic residues (phenylalanine, leucine, tryptophan, isoleucine, and tyrosine) at the N-terminus. As described above, the term N-terminal rule has been used to describe the correlation between the protein's half-life and the amino acid residues present at the N-terminus of the protein. [3.] [UBR] [Box structure domain]

[0054] In the N-terminal regular pathway, N-degradation determinants are recognized by N-recognition proteins, and the ubiquitin-protein ligase E3 component n-recognition protein (UBR) has been identified as an N-recognition protein. It is known that UBR recognizes N-terminal residue sequences or N-terminal degradation signals via its UBR box domain. That is, UBR recognizes protein degradation signals via its UBR box domain and performs protein degradation by recognizing these signals.

[0055] Protein degradation processes mediated by UBR may include the following: The UBR box domain recognizes a matrix with an N-terminal degradation signal; ubiquitin binds to the matrix; and the ubiquitin-bound matrix can be degraded by the proteasome. That is, a matrix with an N-terminal degradation signal can be degraded by the ubiquitin proteasome system (UPS). [II.UBR] [Box domain ligands] [1.] [Overview] [1] [)] [The compounds described in this specification reflect...] [UBR] [Structure and relation of box-structured domains] [N] [Characteristics of matrix binding at the terminal pathway]

[0056] Considering the structure of the UBR box domain and the binding mode between the UBR box domain and the N-terminal pathway matrix, compounds were designed as ligands for the UBR box domain as disclosed in this paper.

[0057] Various amino acids residing in the UBR box domain interact with and bind to amino acids in the N-terminal pathway matrix via ionic interactions, hydrogen bonding, hydrophobic interactions, and the like. By analyzing these binding modes, small molecule compounds capable of forming suitable binding modes with the UBR box domain are synthesized and provided herein. Furthermore, compounds according to Formulas 1 to 55 are provided below. [2] [)] [The compounds in this specification have enhancing properties.] [UBR] [The core structure combining box-structured domains.]

[0058] In this specification, the binding mode of the UBR box domain and the amino acid of the N-terminal pathway matrix are analyzed as described above, and the core structure of the compound is deduced. The compounds provided herein may have the following structure [Equation 1] derived based on the core structure of the compound: [Equation 1] is as follows: [Formula 1] .

[0059] In this specification, various compounds are designed and provided based on [Equation 1]. In this case, candidates for X1, X2, X3, B1, A1, and X4 are derived considering the binding modes with the UBR box domain. More detailed descriptions of the various compounds based on [Equation 1] are given below. [2.] [Mode] [1] [[] [Mode] [1] 1) X2, B1, X3 and A1 X2

[0060] In Formula 1, X2 can be a structure that induces a kink structure in the compounds disclosed herein. The kink structure helps to smoothly maintain the charge-charge interaction, hydrogen bonding, or hydrophobic interaction between the compound X1 disclosed herein and the UBR box domain, and enhances the binding strength. Therefore, as an example, X2 can be one of various structures capable of inducing a kink structure. As a specific example, X2 can be SO2 or CRaRb. In this case, Ra and Rb can each be independently selected from H or CH2. Furthermore, X2 can be CH2, CH(CH3) or C(CH3)2. As another specific example, X2 can be SO2. B1, X3, and A1

[0061] In Equation 1, as an example, A1 can be CH2 or NH.

[0062] In Equation 1, as an example, B1 can be CH2 or NH.

[0063] In Equation 1, as an example, X3 can be CH2 or NH.

[0064] In this case, as an example, when B1 in Equation 1 is CH2, X3 may not be CH2.

[0065] However, the compounds are not limited to this. Instances of X2, B1, X3, and A1

[0066] Equation 1 may have a structure selected from the structures described below: [Equation 1-1] [Equation 1-2] , , [Equation 1-3] [Equation 1-4] , , [Equation 1-5] [Equation 1-6] , , [Equation 1-7] [Equation 1-8] , , [Equation 1-9] [Equation 1-10] , , [Equation 1-11] [Equation 1-12] , , [Equation 1-13] [Equation 1-14] , , [Equation 1-15] [Equation 1-16] , , [Equation 1-17] [Equation 1-18] , , [Equation 1-19] [Equation 1-20] , , [Equation 1-21] [Equation 1-22] , , [Equation 1-23] [Equation 1-24] , , [Equation 1-25] [Equation 1-26] , , [Equation 1-27] [Equation 1-28] , , [Equation 1-29] [Equation 1-30] , , [Equation 1-31] ​​[Equation 1-32] , , [Equation 1-33] [Equation 1-34] , , [Equation 1-35] [Equation 1-36] , , [Equation 1-37] [Equation 1-38] , , [Equation 1-39] [Equation 1-40] , , [Equation 1-41] [Equation 1-42] , , [Equation 1-43] [Equation 1-44] , , [Equation 1-45] .

[0067] As a specific instance, in Equation 1, -X2 -B1 -X3 are selected from the group consisting of: -SO2 -NH-NH, -SO2 -NH-CH2, -SO2 -CH2 -NH, and -CH2 -NH-NH. A1 is CH2 or NH, and I is an integer that is either 0 or 1.

[0068] As a specific instance, Equation 1 may have a structure selected from the structures described below: [Equation 1-1] , [Equation 1-2] , [Equation 1-3] , [Equations 1-4] . [2] [)] X1

[0069] As a result of structural analysis of the UBR boxes and N-degradation determinants of UBR1 and UBR2, and molecular docking studies of compounds having the core structure of Formula 1, in Formula 1, X1 corresponds to the side chain of the first residue (N1) of the N-degradation determinant, and X1 is expected to bind to the negatively charged region. Therefore, as an example, in Formula 1, X1 may have a charged ring structure or a portion containing hydrogen bonds. As a specific example, X1 may be a charged ring structure or a planar structure containing a portion forming hydrogen bonds. Furthermore, when the compound is used in combination with another substance, X1 in Formula 1 may contain a structure capable of binding to a linker.

[0070] As an example, X1 may be a selectively R2-substituted or unsubstituted phenyl, cycloalkyl, or heterocyclic group. As a specific example, X1 may be selected from selectively R2-substituted or unsubstituted phenyl, cyclohexyl, cyclopentyl, furanyl, thiazolyl, 1H-pyrazolyl, pyrrolidyl, piperidinyl, piperazinyl, morpholinyl, indololinyl, 1H-indololinyl, 1H-indolyl, 1H-inzolyl, isoindololinyl, indololin-2-one, 2,3-dihydro-1H-indenyl, and 1H-pyrrolopyridinyl. In this case, each R2 can be 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. As an example, each R2 can 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, pyrrolidyl, piperazinyl, piperidinyl, and morpholinyl. As a specific example, R2 can be amino.

[0071] As a more specific instance, X1 can be selected from the following structure: , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0072] As a specific instance, X1 can be selected from the following structure: , . [3] [)] X4

[0073] In Formula 1, X4 corresponds to the side chain of the second residue of the N-degradation determinant and may have a ring or chain structure to fill the binding gap when bound to the UBR box. In this case, as an example, the ring or chain structure may enhance the binding strength by introducing charged or hydrogen-bonding portions. Additionally, when the compounds in this specification are subsequently used in combination with another substance, X4 may contain a structure capable of binding to the linker.

[0074] As an example, X4 can be a selectively substituted or unsubstituted phenyl, cycloalkyl, or heterocyclic group with one or more R3 substituted groups. As a specific example, X4 can be selected from selectively substituted or unsubstituted phenyl, cyclohexyl, cyclopentyl, furanyl, thiazolyl, 1H-pyrazolyl, pyrrolidyl, piperidinyl, piperazinyl, morpholinyl, indololinyl, 1H-indolyl, 1H-indolayl, isoindololinyl, indololin-2-one, 2,3-dihydro-1H-indenyl, and 1H-pyrrolopyridinyl. In this case, each R3 can be independently selected from alkyl, alkoxy, amino, halogen, hydroxyl, alkylamino, dialkylamino, -NO2, -CONR'R'', -CO2 R', -NHCOR', phenyl, or heterocyclic alkyl groups. As an example, each R3 may be independently selected from hydroxyl, fluorine, chlorine, bromine, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, alkylamino, dialkylamino, -NO2, -C(=O)NH2, -CO2 R', -NHCOR', -CONR'R'', and phenyl. As a specific example, R3 may be hydroxyl. In this case, each R' and R'' may be independently -H or alkyl.

[0075] As a more specific instance, X4 can be selected from the following structure: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0076] As a more specific instance, X4 may be selected from those described below: , , .

[0077] The compounds disclosed herein may exist in their stereoisomers or salt forms, and such isomers or salt forms are included within the scope of this specification. [III.] [As] [UBR] [Specific examples of compounds with box-domain ligands] [1.] [Specific examples of compounds]

[0078] The following examples illustrate specific instances of the compounds disclosed herein. These specific examples are illustrative of the structures of the compounds disclosed herein for easy understanding, and the scope of the compounds disclosed herein is not limited to these examples.

[0079] As a specific example, the compounds disclosed herein may have the structure of [Formula 1-1]: [Equation 1-1] .

[0080] In this case, in the compound, A1 is CH2 or NH, and I is an integer of 0 or 1.

[0081] X1 and X4 are applied in the same manner as described in Content II. UBR Box Structure Domain Ligands 2)X1 and 3)X4.

[0082] As a particular example, the specific exemplary compounds of [Formula 1-1] may be selected from those compounds described below. [Table 1] Specific exemplary compounds of formula [1-1] Compound numbering compound 1 N'-(4-hydroxybenzoyl)-4-methylbenzenesulfonamide 2 4-amino-N'-(4-hydroxybenzoyl)benzenesulfonhydrazine 3 4-amino-N'-(4-hydroxybenzoyl)-3-morpholinylbenzenesulfonhydrazine 4 N'-(4-hydroxybenzoyl)-2-sideoxyindoline-5-sulfadiazine 5 N'-(4-hydroxybenzoyl)indoline-5-sulfadiazine 6 N'-([1,1'-biphenyl]-4-carbonyl)-4-aminobenzenesulfonhydrazine 7 N'-([1,1'-biphenyl]-3-carbonyl)-4-aminobenzenesulfonhydrazine 8 3-amino-N'-(4-hydroxybenzoyl)benzenesulfonhydrazine 9 4-(1-aminoethyl)-N'-(4-hydroxybenzoyl)benzenesulfonhydrazine 10 3,5-Diamino-N'-(4-hydroxybenzoyl)benzenesulfonhydrazine 11 N'-(4-hydroxybenzoyl)-4-((2-hydroxyethyl)amino)benzenesulfonylhydrazine 13 N'-(4-hydroxybenzoyl)-4-methoxybenzenesulfonylhydrazine 14 4-((2-(4-hydroxybenzoyl)hydrazino)sulfonyl)benzamidin 15 4-((2-(4-hydroxybenzoyl)hydrazino)sulfonyl)benzoamide 17 6-amino-N'-(4-hydroxybenzoyl)-[1,1'-biphenyl]-3-sulfadiazine 18 4-(2-((4-aminophenyl)sulfonyl)hydrazine-1-carbonyl)benzamide 20 4-amino-N'-(1H-indole-3-carbonyl)benzenesulfonhydrazine twenty one 4-amino-N'-(4-hydroxybenzoyl)-3-(pyrrolidin-1-yl)benzenesulfonhydrazine twenty two N'-(4-hydroxybenzoyl)-4-nitro-3-(pyrrolidin-1-yl)benzenesulfonamide twenty three 4-amino-N'-(4-hydroxybenzoyl)-3-(piperidin-1-yl)benzenesulfonhydrazine twenty four N'-(4-hydroxybenzoyl)-1H-pyrazole-4-sulfadiazine 25 N'-(4-hydroxybenzoyl)indoline-4-sulfadiazine 26 N'-(4-hydroxybenzoyl)-1H-indole-4-sulfadiazine 27 2-((4-aminophenyl)sulfonyl)-N-phenylhydrazine-1-methylamine 28 4-amino-N'-(1H-indole-4-carbonyl)-3-morpholinylbenzenesulfonhydrazine 29 4-amino-N'-(indoline-4-carbonyl)benzenesulfonamide 30 4-amino-N'-(4-hydroxybenzoyl)-3-(piperazin-1-yl)benzenesulfonhydrazine 31 4-amino-N'-(2,3-dihydro-1H-indene-2-carbonyl)benzenesulfonhydrazine 32 4-amino-N'-(isoindoline-2-carbonyl)benzenesulfonamide 33 N'-(4-hydroxybenzoyl)-1H-indole-2-sulfadiazine 34 4-amino-N'-(2-phenylacetyl)benzenesulfonhydrazine 35 N'-(4-hydroxybenzoyl)-1H-indazole-3-sulfadiazine 36 4-amino-N'-(indoline-6-carbonyl)benzenesulfonhydrazine 37 4-amino-N'-(indoline-3-carbonyl)benzenesulfonamide 38 N'-(4-hydroxybenzoyl)piperidine-4-sulfadiazine 39 4-amino-N'-(indoline-6-carbonyl)-3-morpholinylbenzenesulfonhydrazine 40 4-amino-N'-(piperazine-1-carbonyl)benzenesulfonhydrazine 41 4-amino-3-morpholino-N'-(piperazine-1-carbonyl)benzenesulfonhydrazine 42 N'-(4-hydroxybenzoyl)-2-methylthiazol-4-sulfadiazine 43 (1S,4S)-4-amino-N'-(4-hydroxybenzoyl)cyclohexane-1-sulfadiazine 44 (1R,4R)-4-amino-N'-(4-hydroxybenzoyl)cyclohexane-1-sulfadiazine 45 4-((2-(4-hydroxybenzoyl)hydrazino)sulfonyl)-5-methylfuran-2-carboxylic acid 46 N'-(4-hydroxybenzoyl)pyrrolidine-3-sulfadiazine 47 N'-(4-hydroxybenzoyl)-1H-pyrrolo[2,3-b]pyridine-2-sulfadiazine 52 2-((4-aminophenyl)sulfonyl)-N-(3-hydroxyphenyl)hydrazine-1-methylamine 53 2-((4-amino-3-morpholinylphenyl)sulfonyl)-N-phenylhydrazine-1-methylamine

[0083] In another specific instance, the compounds in this specification may have the structure of [Formula 1-2]: [Equation 1-2] .

[0084] In this case, compounds X1 and X4 are applied in the same manner as described in section II. UBR box domain ligands 2)X1 and 3)X4.

[0085] The specific exemplary compounds of [Formula 1-2] may be selected from the following: [Table 2] Specific exemplary compounds of formula [1-2] Compound numbering compound 19 N'-(4-aminobenzyl)-4-hydroxybenzohydrazine 48 4-Hydroxy-N'-(4-methoxybenzyl)benzylhydrazine 49 N'-(4-aminobenzyl)-2,3-dihydro-1H-indene-2-carbazide

[0086] In another specific instance, the compounds in this specification may have the structure of [Formula 1-3]: [Equation 1-3] .

[0087] In this case, compounds X1 and X4 are applied in the same manner as described in section II. UBR box domain ligands 2)X1 and 3)X4.

[0088] The specific exemplary compounds of [Formulas 1-3] may be selected from the following: [Table 3] Specific exemplary compounds of formulas [1-3] Compound numbering compound 12 4-amino-N-(2-(4-hydroxyphenyl)-2-sideoxyethyl)benzenesulfonamide 50 4-amino-N-(2-(4-hydroxyphenyl)-2-sideoxyethyl)-3-morpholinylbenzenesulfonamide 51 3,5-Diamino-N-(2-(4-hydroxyphenyl)-2-sideoxyethyl)benzenesulfonamide

[0089] In another specific instance, the compounds in this specification may have the structures of [Formulas 1-4]: [Equations 1-4] .

[0090] The specific exemplary compounds of [Formulas 1-4] may be selected from the following: [Table 4] Specific exemplary compounds of formulas [1-4] Compound numbering compound 16 N-(((4-aminophenyl)sulfonyl)methyl)-4-hydroxybenzoamide 54 4-Hydroxy-N-(((4-methyloxyphenyl)sulfonyl)methyl)benzamide 55 N-(((4-aminophenyl)sulfonyl)methyl)-[1,1'-biphenyl]-4-methylamine

[0091] In this case, its possible isomers or mixtures thereof can be considered as compounds. For example, all stereoisomers, including enantiomers and diastereomers, or mixtures thereof (e.g., racemic mixtures) can be considered. [2.] [Salts of compounds]

[0092] As the compounds disclosed herein, their salt forms may be considered. In this case, the salt contains a pharmaceutically acceptable salt. The salts disclosed herein include acid addition salts or base addition salts. Exemplary acids that form salts include hydrochloric acid, sulfuric acid, phosphoric acid, glycolic acid, lactic acid, pyruvic acid, citric acid, succinic acid, glutaric acid, and the like, and exemplary bases that form salts include lithium, sodium, potassium, calcium, magnesium, methylamine, trimethylamine, and the like. However, the acids and bases are not limited thereto and can be readily chosen by those skilled in the art. [IV.] [Uses of the compound] [1.UBR] [Inhibition of matrix binding to box domains] [Used to suppress] [UBR] [Components of the box-structured domain matrix]

[0093] The compounds disclosed herein can be used to prepare compositions for inhibiting matrix binding of UBR box domains. As an example, compositions containing the compounds disclosed herein can be used to inhibit matrix binding of UBR box domains by binding to them. As another example, compositions containing the compounds can be used to prevent degradation of matrix bound to and degraded by UBR box domains. As a specific example, compositions containing the compounds can be used to prevent degradation of matrix bound to UBR box domains by the ubiquitin-proteasome pathway.

[0094] As a specific example, compositions comprising the compounds disclosed herein can be used to inhibit the binding of a matrix having N-terminal residues that bind to a UBR box domain. As a specific example, compositions comprising the compounds disclosed herein can be used to inhibit the binding of a matrix having N-terminal residues such as arginine (Arg), lysine (Lys), histidine (His), tryptophan (Trp), phenylalanine (Phe), tyrosine (Tyr), leucine (Leu), and isoleucine (Ile). However, the use is not limited thereto; the compositions can be used to inhibit the binding of substances in the art that are known to be UBR box domains.

[0095] Referring to the examples, it can be confirmed that the compounds disclosed herein inhibit matrix degradation by binding to UBR (see Figures 1 to 19). [2.] [UBR] [Treatment of related diseases]

[0096] The compounds or their salts described herein possess the property of binding to the UBR box domain. That is, the compounds described herein act as ligands that bind to the UBR box domain. Therefore, these compounds can be used to inhibit the degradation of proteins that are degraded by binding to the UBR box domain in vivo, and this mechanism can be used to treat UBR-related diseases. [1] [Pharmaceutical components]

[0097] The compounds disclosed in this article can be used to prepare pharmaceutical compositions for the treatment of individuals in need.

[0098] In this context, treatment includes the ability to improve symptoms of a specific medical condition or slow the progression of a disease. In this context, "individual" includes both humans and non-human animals. In this context, the pharmaceutical composition may include pharmaceutically acceptable carriers, excipients, and / or additives, as well as the aforementioned compounds. Pharmaceutically acceptable carriers, excipients, and additives include, but are not limited to, water, saline, ethylene glycol, glycerol, animal and vegetable fats, oils, starches, and the like, and include all acceptable carriers, excipients, and / or additives known in the relevant pharmaceutical field. [2] [Treatment methods]

[0099] This specification provides a treatment method comprising administering to an individual in need the compound disclosed herein or a pharmaceutically acceptable salt thereof. In this case, administration of the compound or a pharmaceutically acceptable salt thereof may have the effect of alleviating symptoms of a specific medical condition or delaying disease progression compared to an individual who has not been administered the compound or its salt. In this case, the individual includes both humans and non-human animals. [-UBR] [Related Diseases]

[0100] As an example, this specification provides a treatment method comprising administering a compound or a pharmaceutically acceptable salt thereof to an individual suffering from a UBR-related disease. That is, the compounds disclosed herein or their pharmaceutically acceptable salts may be used to treat UBR-related diseases. As a specific example, the compounds or their pharmaceutically acceptable salts may be used to treat a specific disease by inhibiting the degradation of proteins that are degraded by binding to UBR box domains.

[0101] Specific diseases include muscle loss caused by muscular dystrophy (Becker's, congenital, Duchenne, distal, E. De's, face-shoulder-arm, limb-girdle, myotonic, oculopharyngeal); muscular atrophy diseases mediated by muscle loss or degradation, including sarcopenia or cancer cachexia; diseases caused by excessive protein degradation, including liposarcoma, cystic fibrosis, Johnson-Bliszer's syndrome, obstructive urinary tract disease (urethral obstruction sequence); autoimmune pancreatitis; or known diseases associated with the UBR box and UBR protein, including Ussell's syndrome. As an example, 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 conditions such as cancer, sepsis, and hyperthyroidism is associated with increased degradation of intramuscular proteins, known to be associated with activation of the ubiquitin-proteasome system. In this context, ubiquitin binding is known to increase, particularly through activation of the N-terminal regular pathway, leading to muscle loss [ALFRED L GOLDBERG et al. 1998, 1999]. Therefore, the compounds disclosed herein, or their pharmaceutically acceptable salts, can be used to treat diseases by preventing activation of the muscle loss pathway through binding to the UBR box domain. However, the invention is not limited thereto, and the specific disease encompasses all diseases known in the art to be related to UBR. [V.] [Example] [Example] [1.] [Compound Synthesis] [Table 5] List of compounds [serial number] [Name of the compound] 1 N'-(4-hydroxybenzoyl)-4-methylbenzenesulfonamide 2 4-amino-N'-(4-hydroxybenzoyl)benzenesulfonhydrazine 3 4-amino-N'-(4-hydroxybenzoyl)-3-morpholinylbenzenesulfonhydrazine 4 N'-(4-hydroxybenzoyl)-2-sideoxyindoline-5-sulfadiazine 5 N'-(4-hydroxybenzoyl)indoline-5-sulfadiazine 6 N'-([1,1'-biphenyl]-4-carbonyl)-4-aminobenzenesulfonhydrazine 7 N'-([1,1'-biphenyl]-3-carbonyl)-4-aminobenzenesulfonhydrazine 8 3-amino-N'-(4-hydroxybenzoyl)benzenesulfonhydrazine 9 4-(1-aminoethyl)-N'-(4-hydroxybenzoyl)benzenesulfonhydrazine 10 3,5-Diamino-N'-(4-hydroxybenzoyl)benzenesulfonhydrazine 11 N'-(4-hydroxybenzoyl)-4-((2-hydroxyethyl)amino)benzenesulfonylhydrazine 12 4-amino-N-(2-(4-hydroxyphenyl)-2-sideoxyethyl)benzenesulfonamide 13 N'-(4-hydroxybenzoyl)-4-methoxybenzenesulfonylhydrazine 14 4-((2-(4-hydroxybenzoyl)hydrazino)sulfonyl)benzamidin 15 4-((2-(4-hydroxybenzoyl)hydrazino)sulfonyl)benzoamide 16 N-(((4-aminophenyl)sulfonyl)methyl)-4-hydroxybenzoamide 17 6-amino-N'-(4-hydroxybenzoyl)-[1,1'-biphenyl]-3-sulfadiazine 18 4-(2-((4-aminophenyl)sulfonyl)hydrazine-1-carbonyl)benzamide 19 N'-(4-aminobenzyl)-4-hydroxybenzohydrazine 20 4-amino-N'-(1H-indole-3-carbonyl)benzenesulfonhydrazine twenty one 4-amino-N'-(4-hydroxybenzoyl)-3-(pyrrolidin-1-yl)benzenesulfonhydrazine twenty two N'-(4-hydroxybenzoyl)-4-nitro-3-(pyrrolidin-1-yl)benzenesulfonamide twenty three 4-amino-N'-(4-hydroxybenzoyl)-3-(piperidin-1-yl)benzenesulfonhydrazine twenty four N'-(4-hydroxybenzoyl)-1H-pyrazole-4-sulfadiazine 25 N'-(4-hydroxybenzoyl)indoline-4-sulfadiazine 26 N'-(4-hydroxybenzoyl)-1H-indole-4-sulfadiazine 27 2-((4-aminophenyl)sulfonyl)-N-phenylhydrazine-1-methylamine 28 4-amino-N'-(1H-indole-4-carbonyl)-3-morpholinylbenzenesulfonhydrazine 29 4-amino-N'-(indoline-4-carbonyl)benzenesulfonamide 30 4-amino-N'-(4-hydroxybenzoyl)-3-(piperazin-1-yl)benzenesulfonhydrazine 31 4-amino-N'-(2,3-dihydro-1H-indene-2-carbonyl)benzenesulfonhydrazine 32 4-amino-N'-(isoindoline-2-carbonyl)benzenesulfonamide 33 N'-(4-hydroxybenzoyl)-1H-indole-2-sulfadiazine 34 4-amino-N'-(2-phenylacetyl)benzenesulfonhydrazine 35 N'-(4-hydroxybenzoyl)-1H-indazole-3-sulfadiazine 36 4-amino-N'-(indoline-6-carbonyl)benzenesulfonhydrazine 37 4-amino-N'-(indoline-3-carbonyl)benzenesulfonamide 38 N'-(4-hydroxybenzoyl)piperidine-4-sulfadiazine 39 4-amino-N'-(indoline-6-carbonyl)-3-morpholinylbenzenesulfonhydrazine 40 4-amino-N'-(piperazine-1-carbonyl)benzenesulfonhydrazine 41 4-amino-3-morpholino-N'-(piperazine-1-carbonyl)benzenesulfonhydrazine 42 N'-(4-hydroxybenzoyl)-2-methylthiazol-4-sulfadiazine 43 (1S,4S)-4-amino-N'-(4-hydroxybenzoyl)cyclohexane-1-sulfadiazine 44 (1R,4R)-4-amino-N'-(4-hydroxybenzoyl)cyclohexane-1-sulfadiazine 45 4-((2-(4-hydroxybenzoyl)hydrazino)sulfonyl)-5-methylfuran-2-carboxylic acid 46 N'-(4-hydroxybenzoyl)pyrrolidine-3-sulfadiazine 47 N'-(4-hydroxybenzoyl)-1H-pyrrolo[2,3-b]pyridine-2-sulfadiazine 48 4-Hydroxy-N'-(4-methoxybenzyl)benzylhydrazine 49 N'-(4-aminobenzyl)-2,3-dihydro-1H-indene-2-carbazide 50 4-amino-N-(2-(4-hydroxyphenyl)-2-sideoxyethyl)-3-morpholinylbenzenesulfonamide 51 3,5-Diamino-N-(2-(4-hydroxyphenyl)-2-sideoxyethyl)benzenesulfonamide 52 2-((4-aminophenyl)sulfonyl)-N-(3-hydroxyphenyl)hydrazine-1-methylamine 53 2-((4-amino-3-morpholinylphenyl)sulfonyl)-N-phenylhydrazine-1-methylamine 54 4-Hydroxy-N-(((4-methyloxyphenyl)sulfonyl)methyl)benzamide 55 N-(((4-aminophenyl)sulfonyl)methyl)-[1,1'-biphenyl]-4-methylamine

[0102] ¹H NMR spectra were recorded on a Bruker Avance III 400 MHz and a Bruker Fourier 300 MHz spectrometer using TMS as an internal standard. LCMS was performed on an Agilent 1260 HPLC and a 6120 MSD quadrupole mass spectrometer (column: C18 (50 × 4.6 mm, 5 μm)) in ES (+) or (-) ionization mode; T = 30 °C; flow rate = 1.5 mL / min; detection wavelengths: 220 nm and 254 nm. [ , ] [Experimental Examples] [1-1.] [Preparation of Compounds] [1] [(] [ N' , ] [-(4-)] [Hydroxybenzoyl] [)-4-] [Methylbenzenesulfonamide] [)] Step 1) Synthesize A2

[0103] Will A mixture of [A1] (methyl 4-hydroxybenzoate, 2.00 g, 13 mmol, 1.0 equivalence) and hydrazine monohydrate (20 mL) was stirred at 100 °C for 16 h. The solvent was concentrated under reduced pressure to obtain a crude product, which was purified by rapid column chromatography (DCM / MeOH = 50 / 1 to 1 / 1) to give a white solid. [A2] (4-hydroxybenzohydrazine, 2.0 g, 60% yield). ¹H NMR (DMSO-d₆, 400 MHz): δ 9.49 (s, ¹H), 7.67–7.69 (m, 2H), 6.76–6.79 (m, 2H), 4.38 (br s, 2H). Step 2) Synthesize compound 1

[0104] Will A mixture of [A2] (4-hydroxybenzoylhydrazine, 0.3 g, 1.97 mmol, 1.0 equivalence) and 4-methylbenzenesulfonyl chloride (0.3 g, 1.57 mmol, 0.8 equivalence) in pyridine (5 mL) was stirred at 80 °C for 16 h. Then, 1 N HCl was added to the mixture until pH = 3, and extraction was performed using EA (20 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give a crude product (400 mg). Approximately 130 mg of the crude product was purified by preparative HPLC. The collected solvent was concentrated to remove most of the CH₃CN. The remaining solvent was freeze-dried to give a white solid. [Compound] [1] (N'-(4-hydroxybenzoyl)-4-methylbenzenesulfonamide, 50 mg, 24.8% yield). ¹H NMR (DMSO-d⁶, 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). LCMS; calculated mass value: 306.3; MS experimental value: 306.9. [Experimental Examples] [1-2.] [Preparation of Compounds] [2] [(] [4-] [Amine] [-, N' , -(4-] [Hydroxybenzoyl] [)] [Benzylsulfonylurea] [)] Step 1) Synthesize A3

[0105] Will A mixture of [A2] (4-hydroxybenzoylhydrazine, 0.3 g, 1.97 mmol, 1.0 equivalence) and 4-nitrobenzene-1-sulfonyl chloride (0.35 g, 1.57 mmol, 0.8 equivalence) in pyridine (5 mL) was stirred at 80 °C for 16 h. Then, 1 N HCl was added to the mixture until pH = 3, and extraction was performed using EA (20 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give a crude solid in yellow form. [A3] (N'-(4-hydroxybenzoyl)-4-nitrobenzenesulfonamide, 370 mg). LCMS; calculated value: 337.1; experimental values ​​on MS: 337.6 [MS], 359.6 [MS 22]. Step 2) Synthesize compound 2

[0106] Will A mixture of [A3](N'-(4-hydroxybenzoyl)-4-nitrobenzenesulfonamide, 150 mg, 0.45 mmol, 1.0 equivalent) and 5% Pd / C (200 mg, 50% in water) in EtOH (10 mL) was stirred with an H2 balloon at 10 °C for 4 hours. The mixture was then filtered and the filtrate concentrated to obtain a crude product, which was purified by preparative HPLC. The collected solvent was concentrated to remove most of the CH3CN. The remaining solvent was freeze-dried to obtain a white solid. [Compound] [2] (4-amino-N'-(4-hydroxybenzoyl)benzenesulfonazine, 50 mg, yield 36.6%). ¹H NMR (DMSO-d₆, 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). LCMS; calculated mass value: 307.3; MS experimental value: 307.9. [Experimental Examples] [1-3.] [Preparation of Compounds] [3] [(] [4-] [Amine] [-, N' , -(4-] [Hydroxybenzoyl] [)-3-] [morpholinobenzenesulfonamide] [)] Step 1) Synthesize A4

[0107] Towards [A2] A mixture of 4-hydroxybenzohydrazine, 500 mg, 3.29 mmol, 1.0 equivalence) and pyridine (5 mL) containing 3-fluoro-4-nitrobenzene-1-sulfonyl chloride (790 mg, 3.29 mmol, 1.0 equivalence) was added dropwise. The mixture was then stirred at 25 °C for 3 hours. The solution was poured into water (30 mL). The mixture was extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated to give a crude product, which was purified by rapid column chromatography (DCM / MeOH = 50 / 1 to 30 / 1) to give a white solid. [A4] (3-Fluoro-N'-(4-hydroxybenzoyl)-4-nitrobenzenesulfonazine, 500 mg, 42.8%). ¹H NMR (DMSO-d⁶, 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). Step 2) Synthesize A5

[0108] At 25℃, towards [A4] A mixture of (3-fluoro-N'-(4-hydroxybenzoyl)-4-nitrobenzenesulfonazine, 500 mg, 1.41 mmol, 1.0 equivalence) and morpholine (184 mg, 2.11 mmol, 1.5 equivalence) in DMF (10 mL) was supplemented with K2CO3 (486 mg, 3.52 mmol, 2.5 equivalence). The mixture was then stirred at 25 °C for 16 hours. The solution was poured into water (30 mL). The mixture was extracted with EA (30 mL × 3). The combined organic layers were washed with water (50 mL × 3) and brine, dried over Na2SO4 and concentrated to give a crude product, which was purified by rapid column chromatography (DCM / MeOH = 50 / 1 to 30 / 1) to give a white solid. [A5] (N'-(4-hydroxybenzoyl)-3-morpholino-4-nitrobenzenesulfonazine, 180 mg, 30.3%). ¹H NMR (DMSO-d⁶, 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). Step 3) Synthesize compound 3

[0109] At 25℃, towards [A5] Pd / C (200 mg) was added to a mixture of [N'-(4-hydroxybenzoyl)-3-morpholino-4-nitrobenzenesulfonamide, 180 mg, 0.427 mmol, 1.0 equivalence) in EtOH (10 mL). The mixture was then stirred at 25 °C under an H2 balloon for 4 hours. The solution was filtered, and the filtrate was concentrated and purified by preparative HPLC to obtain a white solid. [Compound] [3] (4-amino-N'-(4-hydroxybenzoyl)-3-morpholinylbenzenesulfonazine, 40 mg, 23.9%). (TLC: N / A)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). LCMS; calculated mass value: 392.4; MS experimental value: 393. [Experimental Examples] [1-4.] [Preparation of Compounds] [4] [(] [ N' , ] [-(4-)] [Hydroxybenzoyl] [)-2-] [Side-oxyindoline] [-5-] [Sulfohydrazine] [)] Step 1) Synthesize A7

[0110] Chlorosulfonic acid (0.88 g, 7.52 mmol, 1.0 equivalent) and A mixture of [A6] (indolin-2-one, 1.0 g, 7.52 mmol, 1.0 equivalent) was stirred at 25 °C for 1.5 h, followed by stirring at 68 °C for 1 h. The mixture was cooled and carefully poured into water. The precipitate formed was collected by filtration, washed with water, and dried under vacuum to obtain a pink solid. [A7] (2-Synephrine-5-sulfonyl chloride, 0.7 g, crude). ¹H NMR (DMSO-d₆, 400 MHz): δ 10.47 (br s, 1H), 7.44–7.46 (m, 2H), 6.75 (d, J = 8.8 Hz, 1H), 3.47 (s, 2H). Step 2) Synthesize compound 4

[0111] Will [A2] (4-hydroxybenzohydrazine, 0.20 g, 1.32 mmol, 1.0 equivalent) and [A7] A mixture of (2-side-oxyindoline-5-sulfonyl chloride, 0.30 g, 1.32 mmol, 1.0 equivalent) in pyridine (10 mL) was stirred at 30 °C for 5 hours. The mixture was poured into water. The precipitate formed was collected by filtration, washed with water, and dried under vacuum. The solid was stirred in DCM at 30 °C for 30 minutes. The mixture was filtered and the filter cake was dried to obtain a pink solid. [Compound] [4] (N'-(4-hydroxybenzoyl)-2-sideoxyindoline-5-sulfadiazine, 50 mg, 11%). ¹H NMR (DMSO-d₆, 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). LCMS; calculated mass value: 347.3; MS experimental value: 347.8. [Experimental Examples] [1-5.] [Preparation of Compounds] [5] [(] [ N', ] [-(4-)] [Hydroxybenzoyl] [)] [Indoline] [-5-] [Sulfohydrazine] [)] Step 1) Synthesize A8

[0112] Will [A2] (4-hydroxybenzohydrazine, 293 mg, 1.93 mmol, 1.0 equivalence) and 1-acetylindoline-5-sulfonylurea (500 mg, 1.93 mmol, 1.0 equivalence) in pyridine (10 mL) were stirred at 30 °C for 5 hours. After completion, the reaction mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated to give a yellow solid. [A8] (1-acetylated-N'-(4-hydroxybenzoyl)indoline-5-sulfadiazine, 500 mg, crude). Step 2) Synthesize compound 5

[0113] Will [A8] A mixture of (1-acetyl-N'-(4-hydroxybenzoyl)indoline-5-sulfadiazine, 200 mg, 0.53 mmol, 1.0 equivalence) and 2N HCl (6 mL) in THF (10 mL) was stirred at 50 °C for 5 hours. After completion, the reaction mixture was diluted with H₂O (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated. The crude product was purified by preparative HPLC and lyophilized to give compound 5 (N'-(4-hydroxybenzoyl)indoline-5-sulfadiazine, 50 mg, 28.2%) as a white solid. 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). LCMS; calculated mass value: 333.3; MS experimental value: 333.8. [Experimental Examples] [1-6.] [Preparation of Compounds] [6] [(] [ N' , ] [-([1,1'-] [Biphenyl] []-4-] [Carbonyl] [)-4-] [Aminobenzenesulfonamide] [)] Step 1) Synthesize A10

[0114] At room temperature, methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzoate was added to a solution of bromobenzene (400 mg, 2.5 mmol) in dioxane. [A9] , 801 mg, 3.0 mmol), K3 PO4 (541 mg, 7.5 mmol) and Pd(dppf)Cl2-CH2Cl2 (208 mg, 0.25 mmol). The mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the reaction mixture was cooled. The reaction mixture was filtered through diatomaceous earth and then extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography (Hex / EA = 3 / 1) to give a white solid. [A10] ([1,1'-biphenyl]-4-carboxylate, 160 mg, yield: 45%). 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); The LCMS calculated m / z for C14H12O2[M+H]+ was 213.25, and the experimental value was 213. Step 2) Synthesize A11

[0115] Will A solution of [A10] (methyl [1,1'-biphenyl]-4-carboxylate, 160 mg, 0.70 mmol) in hydrazine monohydrate (8 mL) was stirred at 100 °C for 16 h. After the reaction was complete, the reaction mixture was cooled and then concentrated under reduced pressure, followed by purification by rapid column chromatography (DCM / MeOH = 15 / 1) to give a crude product as a white solid. [A11] ([1,1'-biphenyl]-4-carbazine, 152 mg, theoretical yield: 100%). The LCMS calculated m / z of C13 H12 N2 O [M+H]+ is 213.25, and the experimental value is 213. Step 3) Synthesize A12

[0116] Towards [A11]([1,1'-biphenyl]-4-carbazine, 152 mg, 0.70 mmol) was added to a solution of pyridine (5 mL) with 4-nitrosulfonyl chloride (143 mg, 0.60 mmol). The mixture was refluxed for 12 hours. After the reaction was complete, the resulting mixture was cooled and evaporated to remove the pyridine, followed by purification by rapid column chromatography (DCM / MeOH = 15 / 1) to give a crude product as a yellow solid. [A12] (N'-([1,1'-biphenyl]-4-carbonyl)-4-nitrobenzenesulfonamide, 60 mg, yield: 21%). The LCMS calculated m / z of C19 H15 N3 O5 S [M+H]+ was 398.41, and the experimental value was 398. Step 4) Synthesize compound 6

[0117] Towards [A12](N'-([1,1'-biphenyl]-4-carbonyl)-4-nitrobenzenesulfonamide, 60 mg, 0.15 mmol) was added to a solution of Zn (99 mg, 1.5 mmol) and NH4Cl (81 mg, 1.5 mmol) in THF:MeOH = 3:1 (12 mL). The mixture was stirred at room temperature for 12 hours. After the reaction was complete, ethyl acetate was added. The mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (DCM / MeOH = 15 / 1) to give a white solid. [Compound] [6] (N'-([1,1'-biphenyl]-4-carbonyl)-4-aminobenzenesulfonazine, 10 mg, yield: 20%). 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); The LCMS calculated m / z value of C19H17N3O3S[M+H]+ is 368.42, and the experimental value is 368. [Experimental Examples] [1-7.] [Preparation of Compounds] [7] [(] [ N' , ] [-([1,1'-] [Biphenyl] []-3-] [Carbonyl] [)-4-] [Aminobenzenesulfonamide] [)] Step 1) Synthesize A14

[0118] At room temperature, methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzoate was added to 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). The mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the reaction mixture was cooled. The mixture was filtered through diatomaceous earth and then extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by rapid column chromatography (Hex / EA = 3 / 1) to give a white solid. [A14] ([1,1'-biphenyl]-3-carboxylic acid methyl ester, 160 mg, yield: 49%). 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); The LCMS calculated m / z value for C¹⁴H¹⁂O₂[M+H]⁺ is 213.25, and the experimental value is 213. Step 2) Synthesize A15

[0119] Will A solution of [A14] (methyl [1,1'-biphenyl]-3-carboxylate, 160 mg, 7.5 mmol) in hydrazine monohydrate (8 mL) was stirred at 100 °C for 16 h. After the reaction was complete, the reaction mixture was cooled and then concentrated under reduced pressure, followed by purification by rapid column chromatography (DCM / MeOH = 15 / 1) to give a crude product as a yellow solid. [A15] ([1,1'-biphenyl]-3-carbazine, 200 mg, yield: 100%). The LCMS calculated m / z of C13 H12 N2 O [M+H]+ is 213.25, and the experimental value is 213. Step 3) Synthesize A16

[0120] Towards [A15] ([1,1'-biphenyl]-3-carbazine, 200 mg, 0.90 mmol) was added to a solution of pyridine (7 mL) with 2.5 mL of 4-nitrosulfonyl chloride. The mixture was refluxed for 12 hours. After the reaction was complete, the resulting mixture was cooled and evaporated to remove the pyridine, followed by purification by rapid column chromatography (DCM / MeOH = 15 / 1) to give a crude product as a milky white solid. [A16] (N'-([1,1'-biphenyl]-3-carbonyl)-4-nitrobenzenesulfonhydrazine, 102 mg, yield: 53%). The LCMS calculated m / z of C19 H15 N3 O5 S [M+H]+ was 398.41, and the experimental value was 398. Step 4) Synthesis [Compound] [7]

[0121] Towards [A16](N'-([1,1'-biphenyl]-3-carbonyl)-4-nitrobenzenesulfonazine, 102 mg, 0.25 mmol) was added to a solution of THF:MeOH = 3:1 (10 mL) with Zn (168 mg, 2.5 mmol) and NH4Cl (137 mg, 2.5 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 diatomaceous earth. The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (DCM / MeOH = 15 / 1) to give a white solid. [Compound] [7] (N'-([1,1'-biphenyl]-3-carbonyl)-4-aminobenzenesulfonazine, 14 mg, yield: 14%, purity: 96.8%). 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), C19 H17 N3 O3 S [M+H]+ The calculated m / z value by ESI-MS is 368.42, while the experimental value is 368. [Experimental Examples] [1-8.] [Preparation of Compounds] [8] [(] [3-] [amine] [base] [-, N' , -(4-] [Hydroxybenzoyl] [)] [Benzylsulfonamide] Step 1) Synthesis [A17]

[0122] Towards [A2] 3-Nitrosulfonyl chloride (168 mg, 1.08 mmol) was added to a solution of pyridine (8 mL). The mixture was refluxed for 12 hours. After the reaction was complete, the resulting mixture was cooled and evaporated to remove pyridine, followed by purification by rapid column chromatography (DCM / MeOH = 15 / 1) to give a crude product as a milky white solid. [A17] (N'-(4-hydroxybenzoyl)-3-nitrobenzenesulfonazine, 129 mg, yield: 43%). The LCMS calculated m / z of C13 H11 N3 O6 S [M+H]+ was 338.31, and the experimental value was 338. Step 2) Synthesize compound 8

[0123] Towards [A17] (N'-(4-hydroxybenzoyl)-3-nitrobenzenesulfonamide, 129 mg, 0.38 mmol) was added to a solution of Zn (250 mg, 3.8 mmol) and NH4Cl (204 mg, 3.8 mmol) in THF:MeOH = 3:1 (10 mL). The mixture was stirred at room temperature for 12 hours. After the reaction was complete, ethyl acetate was added. The mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (DCM / MeOH = 15 / 1) to give a white solid. [UTL1013] (3-amino-N'-(4-hydroxybenzoyl)benzenesulfonamide, 25 mg, yield: 21%, purity: 98.0%). 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); The LCMS calculated m / z value of C13H13N3O4S[M+H]+ is 308.32, and the experimental value is 308. [Experimental Examples] [1-9.] [Preparation of Compounds] [9] [(] [4-(1-)] [Aminoethyl] [)-, N' , -(4-] [hydroxyl] [Benzomethyl] [)] [Benzylsulfonylurea] [)] Step 1) Synthesize A18

[0124] Will A mixture of [A2] (4-hydroxybenzohydrazine, 500 mg, 3.29 mmol, 1.0 equivalence) and 4-acetylenol-1-sulfonylurea (717 mg, 3.29 mmol, 1.0 equivalence) in pyridine (5 mL) was stirred at 25 °C for 3 hours. The mixture was cooled and carefully poured into water. The mixture was extracted with EA (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated to give a brown solid. [A18] (4-acetylated-N'-(4-hydroxybenzoyl)benzenesulfonamide, 0.5 g, crude). The LCMS calculated m / z of C15 H14 N2 O5 S [M+H]+ is 335.3, and the experimental value is 335. Step 2) Synthesize compound 9

[0125] Will [A18] A mixture of (4-acetylated-N'-(4-hydroxybenzoyl)benzenesulfonamide, 200 mg, 0.60 mmol, 1.0 equivalence), NH4OAc (461 mg, 5.98 mmol, 10 equivalence) and sodium cyanoborohydride (188 mg, 2.99 mmol, 5 equivalence) in MeOH (5 mL) was stirred at 60 °C for 16 hours. The mixture was concentrated, purified by preparative HPLC, and lyophilized to obtain a white solid. [Compound] [9] (4-(1-aminoethyl)-N'-(4-hydroxybenzoyl)benzenesulfonamide, 55 mg, 24%). ¹H NMR (DMSO-d₆, 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). LCMS; calculated mass: 335.3 (C15 H17 N3 O4 S); MS experimental value: 336. [Experimental Examples] [1-10.] [Preparation of Compounds]

[10] [(] [3,5-] [Diamino group] [-, N' , -(4-] [Hydroxybenzoyl] [)] [Benzylsulfonylurea] [)] Step 1) Synthesize A20

[0126] At 0°C, 3,5-dinitroaniline ( [A19] 500 mg, 2.73 mmol, 1.0 equivalence) was added to a mixture of concentrated HCl (10 mL) and H₂O (2 mL) containing NaNO₂ (226 mg, 3.28 mmol, 1.2 equivalence). The mixture was stirred at 0 °C for 0.5 h. SOCl₂ (1.30 g, 10.9 mmol, 4.0 equivalence) was added to a mixture of CuCl (27 mg, 0.27 mmol, 0.1 equivalence) and H₂O (10 mL) at 0 °C. Subsequently, a diazonium salt solution was added dropwise at 0 °C. The mixture was stirred at 0 °C for 3 h and then poured into water. The precipitate was collected by filtration and dried under vacuum to obtain a yellow solid. [A20] (3,5-dinitrobenzenesulfonyl chloride, 0.5 g, crude material). Step 2) Synthesize A21

[0127] Will [A20] (3,5-dinitrobenzenesulfonyl chloride, 175 mg, 0.66 mmol, 1.0 equivalent) and The mixture of [A2] (4-hydroxybenzohydrazine, 100 mg, 0.66 mmol, 1.0 equivalence) in pyridine (5 mL) was stirred at 60 °C for 16 hours. The mixture was cooled and carefully poured into water. The mixture was extracted with EA (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated to give a pink solid. [A21] (N'-(4-hydroxybenzoyl)-3,5-dinitrobenzenesulfonylhydrazine, 0.1 g, crude material). Step 3) Synthesize compound 10 (3,5-diamino-N'-(4-hydroxybenzoyl)benzenesulfonhydrazine)

[0128] Will A mixture of [A21] (N'-(4-hydroxybenzoyl)-3,5-dinitrobenzenesulfonamide, 0.1 g, 0.26 mmol, 1.0 equivalence) and 10% Pd / C (0.1 g) in EtOH (5 mL) was stirred for 3 hours at room temperature under an H2 balloon. The reaction mixture was filtered, and the filter cake was washed with EA (50 mL × 2). The combined filtrates were concentrated to give a crude product, which was stirred in MeOH (5 mL) for 10 minutes. The mixture was filtered, and the filter cake was dried under vacuum to give a yellow solid. [Compound]

[10] (3,5-Diamino-N'-(4-hydroxybenzoyl)benzenesulfonazine, 27 mg, 32%). ¹H NMR (DMSO-d₆, 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). LCMS; calculated mass: 322.3 (C13 H14 N4 O4 S); experimental MS value: 323 [MS+1]. [Experimental Examples] [1-11.] [Preparation of Compounds]

[11] [(] [ N' , ] [-(4-)] [Hydroxybenzoyl] [)-4-((2-] [hydroxyl] [Byethyl] [)] [Amine] [)] [Benzylsulfonylurea] [)]

[0129] Will [Compound] [2] A mixture of (4-amino-N'-(4-hydroxybenzoyl)benzenesulfonamide, 500 mg, 1.63 mmol, 1.0 equivalence) and ethylene oxide (72 mg, 1.63 mmol, 1.0 equivalence) in AcOH / H2O = 1:1 (4 mL) was stirred at 25 °C for 4 hours. NaHCO3 was then added to the mixture until pH = 8, and the mixture was extracted with EA (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by preparative TLC to obtain a white solid. [Compound]

[11] (N'-(4-hydroxybenzoyl)-4-((2-hydroxyethyl)amino)benzenesulfonazine, 50 mg, yield 8.8%). ¹H NMR (DMSO-d₆, 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). LCMS; calculated mass value: 351.3; experimental MS value: 351.8 [MS+1]. [Experimental Examples] [1-12.] [Preparation of Compounds]

[12] [(] [4-] [Amine] [-, N , -(2-(4-] [Hydroxyphenyl] [)-2-] [Side-oxyethyl] [)] [benzenesulfonamide] [)] Step 1) Synthesize A23

[0130] At 5℃ [A22] Br2 (2.83 g, 17.7 mmol, 1.0 equivalent) was added to a mixture of 1-(4-(benzyloxy)phenyl)ethyl-1-one, 4.0 g, 17.7 mmol, 1.0 equivalent) in EtOH (40 mL). The mixture was stirred at 30 °C for 30 minutes. The mixture was then poured into PE and stirred for 30 minutes. The mixture was filtered and the filter cake was dried to obtain a white solid. [A23] (1-(4-(benzyloxy)phenyl)-2-bromoethyl-1-one, 2.5 g, 46.3%). Step 2) Synthesize A24

[0131] Will A mixture of [A23] (1-(4-(benzyloxy)phenyl)-2-bromoethyl-1-one, 2.0 g, 6.55 mmol, 1.0 equivalent) and HMTA (1.38 g, 9.83 mmol, 1.5 equivalent) in DCM (20 mL) was stirred at 10 °C for 2 hours. The mixture was then filtered, and the filter cake was dissolved in EtOH (15 mL) and concentrated HCl (5 mL). The mixture was stirred at 85 °C for 2 hours. The mixture was filtered, and the filter cake was dried to obtain a white solid. [A24] (2-amino-1-(4-(benzyloxy)phenyl)ethyl-1-one hydrochloric acid, 2.0 g, crude material). 1 HNMR (CD3 OD, 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). Step 3) Synthesize A25

[0132] Will [A24] A mixture of (2-amino-1-(4-(benzyloxy)phenyl)ethyl-1-one hydrochloric acid, 2.00 g, 7.20 mmol, 1.0 equivalent), 4-nitrobenzene-1-sulfonyl chloride (1.60 g, 7.20 mmol, 1.0 equivalent), and TEA (2.19 g, 21.6 mmol, 3.0 equivalent) in DCM (20 mL) was stirred at 20 °C for 1 hour. The mixture was poured into water and extracted with DCM. The organic layer was washed with water and brine, dried over Na₂SO₄, and concentrated to obtain a crude product, which was stirred in PE for 30 minutes. The mixture was filtered and the filter cake was dried to obtain a white solid. [A25] (N-(2-(4-(benzyloxy)phenyl)-2-sideoxyethyl)-4-nitrobenzenesulfonamide, 1.0 g, 35.8% for 2 steps). 1 HNMR (CD3 Cl, 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). Step 4) Synthesize compound 12

[0133] Will [A25] A mixture of (N-(2-(4-(benzyloxy)phenyl)-2-t-oxyethyl)-4-nitrobenzenesulfonamide, 200 mg, 0.47 mmol, 1.0 equivalent) and Pd / C (150 mg, 50% in water) in EtOH (10 mL) was stirred at 25 °C under a H2 balloon for 4 hours. The mixture was then filtered, concentrated, purified by preparative HPLC, and lyophilized to give a white solid. [Compound]

[12] (4-amino-N-(2-(4-hydroxyphenyl)-2-sideoxyethyl)benzenesulfonamide, 69 mg, yield 48.0%). ¹H NMR (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). LCMS; calculated mass value: 306.3; experimental MS value: 307 [MS+1]. [Experimental Examples] [1-13.] [Preparation of Compounds]

[13] [(] [ N' , ] [-(4-)] [Hydroxybenzoyl] [)-4-] [Methoxybenzenesulfonamide]

[0134] Towards [A2] (4-hydroxybenzylhydrazine, 100 mg, 0.66 mmol) was added to a solution of triethylamine (0.11 mL, 0.76 mmol) and 4-methoxybenzenesulfonyl chloride (124 mg, 0.60 mmol) in DMF (6 mL). The mixture was allowed to stand 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 over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (DCM / MeOH = 5 / 1) to give a white solid. [Compound]

[13] (N'-(4-hydroxybenzoyl)-4-methoxybenzenesulfonylhydrazine, 25 mg, yield: 12%, purity: 96.9%). 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); The LCMS calculated m / z value of C14H14N2O5S[M+H]+ is 323.3, and the experimental value is 323. [Experimental Examples] [1-14.] [Preparation of Compounds]

[14] [(] [4-((2-(4-] [Hydroxybenzoyl] [)] [Hydrazine] [)] [sulfonyl] [)] [Benzomate] [)] Step 1) Synthesize A26

[0135] Towards [A2] A mixture of 4-hydroxybenzohydrazine, 1.00 g, 6.57 mmol, 1.0 equivalence) and pyridine (10 mL) was added dropwise to pyridine (3 mL). The mixture was then stirred at 25 °C for 3 hours. The solution was poured into water (50 mL). The mixture was extracted with EA (50 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give a crude product. The crude product was purified by rapid column chromatography (PE / EA = 1 / 1) to give a white solid. [A26] (4-Cyano-N'-(4-hydroxybenzoyl)benzenesulfonhydrazine; 1.40 g, 67.1%). ¹H NMR (DMSO-d₆, 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). Step 2) Synthesize compound 14

[0136] Will [A26] A mixture of (4-cyano-N'-(4-hydroxybenzoyl)benzenesulfonamide, 200 mg, 0.63 mmol, 1.0 equivalence) in HCl / EtOH (5 mL, 6 mmol / L) was stirred at 25 °C for 3 hours. The above 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 equivalence). The mixture was stirred at 25 °C for 16 hours. The mixture was concentrated and purified by preparative HPLC and lyophilized to give a white solid. [Compound]

[14] (4-(2-(4-hydroxybenzoyl)hydrazino)sulfonyl)benzomidine, 26 mg, 10.8%). ¹H NMR (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). LCMS; calculated mass value: 334; experimental MS value: 334.8 [MS+1]. [Experimental Examples] [1-15.] [Preparation of Compounds]

[15] [(] [4-((2-(4-] [Hydroxybenzoyl] [)] [Hydrazine] [)] [sulfonyl] [)] [Benzylamine] [)]

[0137] Towards [A26] (4-Cyano-N'-(4-hydroxybenzoyl)benzenesulfonamide, 210 mg, 0.66 mmol) was added to a cooled (0°C) solution of DMSO containing hydrogen peroxide, 35% w / w aqueous solution (0.42 mL, 4.8 mmol), and potassium carbonate (30 mg, 0.20 mmol). The reaction mixture 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 over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (DCM / MeOH = 5 / 1) to give a white solid. [Compound]

[15] (4-((2-(4-hydroxybenzoyl)hydrazino)sulfonyl)benzoylamine, 20 mg, yield: 10%, purity: 96.5%). 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); The LCMS calculated m / z value of C14H13N3O5S[M+H]+ is 336.33, and the experimental value is 336. [Experimental Examples] [1-16.] [Preparation of Compounds]

[16] [(] [ N , ] [-(((4-] [Aminophenyl] [)] [sulfonyl] [)] [methyl] [)-4-] Hydroxybenzonitramine [)] Step 1) Synthesize A28

[0138] Towards [A27] A mixture of 4-hydroxybenzoylamine (4.0 g, 29.2 mmol, 1.0 equivalence) in DMF (40 mL) was supplemented with K₂CO₃ (6.05 g, 43.8 mmol, 1.5 equivalence) and BnBr (4.99 g, 29.2 mmol, 1.0 equivalence). The mixture was stirred at 60 °C for 16 hours. The mixture was poured into water and extracted with EA. The organic layer was washed with water and brine, then dried over Na₂SO₄ and concentrated to give a white solid. [A28] (4-(benzyloxy)benzylamine, 6.0 g, 90.5%). Step 2) Synthesize A29

[0139] Will A mixture of [A28] (4-(benzyloxy)benzylamine, 4.0 g, 17.6 mmol, 1.0 equivalence), K₂CO₃ (0.24 g, 1.76 mmol, 0.1 equivalence), and HCOH (1.43 g, 17.6 mmol, 37% in water, 1.0 equivalence) in THF / H₂O (40 mL, v / v = 1 / 1) was stirred at 65 °C for 16 hours. The mixture was then concentrated and filtered. The filter cake was dried to obtain a white solid. [A29] (4-(benzoxy)-N-(hydroxymethyl)benzamide, 4.0 g, crude material). Step 3) Synthesize A30

[0140] Will [A29] A mixture of 4-(benzyloxy)-N-(hydroxymethyl)benzylamine, 4.00 g, 15.6 mmol, 1.0 equivalence) and 4-nitrobenzenethiol (2.41 g, 15.6 mmol, 1.0 equivalence) in TFA (20 mL) was stirred at 20 °C for 1 hour. The mixture was concentrated and added to water, and the pH was adjusted to 8 with NaHCO3 aqueous solution. The mixture was extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give a white solid. [A30] (4-(benzoxy)-N-(((4-nitrophenyl)thio)methyl)benzamide, 2.0 g, 32.6% for 2 steps). Step 4) Synthesize A31

[0141] Will [A30] A mixture of (4-(benzyloxy))-N-(((4-nitrophenyl)thio)methyl)benzylamine 500 mg, 1.27 mmol, 1.0 equivalence) and m-CPBA (656 g, 3.80 mmol, 3.0 equivalence) in DCM (20 mL) was stirred at 20 °C for 16 hours. The mixture was poured into an aqueous solution of Na₂O₃S₂ and extracted. The organic layer was washed with an aqueous solution of NaHCO₃ and brine, dried over Na₂SO₄ and concentrated to give a white solid. [A31] (4-(benzyloxy)-N-(((4-nitrophenyl)sulfonyl)methyl)benzylamine, 300 mg, crude). ¹H NMR (DMSO-d⁶, 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). Step 5) Synthesize compound 16

[0142] Will [A31] A mixture of (4-(benzoxy)-N-(((4-nitrophenyl)sulfonyl)methyl)benzamide, 300 mg, 0.47 mmol, 1.0 equivalent) and Pd / C (150 mg, 50% in water) in EtOH (10 mL) was stirred at 25 °C under an H2 balloon for 2 hours. The mixture was then filtered, concentrated, purified by preparative HPLC, and lyophilized to give a white solid. [Compound]

[16] (N-(((4-aminophenyl)sulfonyl)methyl)-4-hydroxybenzoamide, 35 mg, 9.0% yield for two steps). ¹H NMR (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). LCMS; calculated mass value: 306; experimental MS value: 307 [MS+1]. [Experimental Examples] [1-17.] [Preparation of Compounds]

[17] [(] [6-] [Amine] [-, N' , -(4-] [Hydroxybenzoyl] [)-[1,1'-] [Biphenyl] []-3-] [Sulfohydrazine] [)] Step 1) Synthesize A33

[0143] Will [A32] A mixture of [3-bromo-4-nitroaniline, 1 g, 4.61 mmol, 1.0 equivalence), phenylboronic acid (0.56 g, 4.61 mmol, 1.0 equivalence), Pd(dppf)Cl2 (337 mg, 0.09 mmol, 0.1 equivalence), and AcOK (1.14 g, 13.8 mmol, 3.0 equivalence) in toluene (10 mL) was stirred at 90 °C under N2 for 16 h. The mixture was poured into water (30 mL) and extracted with EA (30 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by rapid column chromatography (PE / EA = 30 / 1~10 / 1) to give a yellow solid. [A33] (6-nitro-[1,1'-biphenyl]-3-amine, 1 gram, crude substance). Step 2) Synthesize A34

[0144] At 0℃ [A33] (6-nitro-[1,1'-biphenyl]-3-amine, 500 mg, 2.33 mmol, 1.0 equivalence) was added dropwise to a mixture of AcOH (10 mL) and concentrated HCl (5 mL) with H₂O (2 mL) containing NaNO₂ (193 mg, 2.8 mmol, 1.2 equivalence). The mixture was stirred at 0 °C for 0.5 h. SOCl₂ (1.39 g, 11.6 mmol, 5.0 equivalence) was added dropwise to a mixture of CuCl (31.3 mg, 0.23 mmol, 0.1 equivalence) and H₂O (10 mL) at 0 °C. Subsequently, a diazonium salt solution was added dropwise at 0 °C. The mixture was stirred at 0 °C for 3 h and then poured into water. The precipitate was collected by filtration and dried under vacuum to obtain a yellow solid. [A34] (6-nitro-[1,1'-biphenyl]-3-sulfonyl chloride, 400 mg, 57.6%). ¹H NMR (DMSO-d⁶, 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). Step 3) Synthesize A35

[0145] Will A mixture of [A34] (6-nitro-[1,1'-biphenyl]-3-sulfonyl chloride, 200 mg, 0.67 mmol, 1.0 equivalence) and 4-hydroxybenzohydrazine (122 mg, 0.81 mmol, 1.2 equivalence) in pyridine (5 mL) was stirred at 30 °C for 0.5 h. The mixture was carefully poured into water. The mixture was extracted with EA (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated to give a brown solid. [A35] (N'-(4-hydroxybenzoyl)-6-nitro-[1,1'-biphenyl]-3-sulfadiazine, 200 mg, crude material). Step 4) Synthesize compound 17

[0146] Will [A35] (N'-(4-hydroxybenzoyl)-6-nitro-[1,1'-biphenyl]-3-sulfadiazine, 200 mg, 0.48 mmol, 1.0 equivalence) and 10% Pd / C (200 mg) in EtOH (10 mL) were stirred at 30 °C under a H2 balloon for 3 hours. The reaction mixture was filtered and the filter cake was washed with EA (50 mL × 2). The combined filtrates were concentrated to give a crude product, which was purified by preparative HPLC and lyophilized to give a white solid. [Compound]

[17] (6-amino-N'-(4-hydroxybenzoyl)-[1,1'-biphenyl]-3-sulfadiazine, 45 mg, 17.5% for 2 steps). ¹H NMR (DMSO-d₆, 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). LCMS; calculated mass value: 383; experimental MS value: 384 [MS+1]. [Experimental Examples] [1-18.] [Preparation of Compounds]

[18] [(] [4-(2-((4-)] [Aminophenyl] [)] [sulfonyl] [)] [Hydrazine] [-1-] [Carbonyl] [)] [Benzylamine] [)] Step 1) Synthesize A37

[0147] Ammonia solution (25% to 30%) (1.8 mL, 15 mmol) was added to a cooled (0°C) solution of methyl 4-(chlorocarbonyl)benzoate (A36, 1.5 g, 7.5 mmol) in DCM. The reaction mixture was heated to room temperature and stirred for 4 hours. After the reaction was complete, the reaction mixture was evaporated and water was subsequently added. The precipitate formed was collected by filtration. The filter cake was washed with water and dried to give a white solid. [A37] (methyl 4-aminomethylbenzoate, 1.0 g, 74%). The LCMS calculated m / z value of C9H9NO3[M+H]+ is 152.17, and the experimental value is 152. Step 2) Synthesize A38

[0148] Will A solution of [A37] (methyl 4-aminomethylbenzoate, 1 g, 6.6 mmol) and hydrazine monohydrate (10 mL) in MeOH (10 mL) was stirred at 80 °C for 16 h. The solvent was concentrated under reduced pressure to obtain a crude product, which was then purified by rapid column chromatography (DCM / MeOH = 10 / 1) to obtain a white solid. [A38] (4-(hydrazine carbonyl)benzylamine, 600 mg, yield: 60%). 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). Step 3) Synthesize A39

[0149] Towards [A38] (4-(hydrazine carbonyl)benzylamine, 600 mg, 3.3 mmol) was added to a solution of DMF (7 mL) with TEA (0.55 mL, 3.9 mmol) and 4-methoxybenzenesulfonyl chloride (676 mg, 3.0 mmol). The mixture was allowed to stand 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 over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (DCM / MeOH = 10 / 1) to give a white solid. [A39] (4-(2-(4-nitrophenyl)sulfonyl)hydrazine-1-carbonyl)benzylamine, 366 mg, yield: 30%). The LCMS calculated m / z of C14 H12 N4 O6 S [M+H]+ was 365.33, and the experimental value was 365. Step 4) Synthesize compound 18

[0150] At 60℃, towards [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)benzylamine, 366 mg, 1.0 mmol) in THF:MeOH = 3:1 (10 mL) for 5 hours. After the reaction was complete, the reaction mixture was cooled and then ethyl acetate was added. The mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (DCM / MeOH = 15 / 1) to give a white solid. [Compound]

[18] (4-(2-(4-aminophenyl)sulfonyl)hydrazine-1-carbonyl)benzamide, 10 mg, 4.51 mmol, yield: 3%, purity: 97.0%). 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); The LCMS calculated m / z value of C₁₄H₁₄N₄O₄S[M+H]⁺ is 335.35, and the experimental value is 335. [Experimental Examples] [1-19.] [Preparation of Compounds]

[19] [(] [ N' , ] [-(4-)] [aminobenzyl] [)-4-] [Hydroxybenzohydrazine] Step 1) Synthesize A40

[0151] Towards [A2] (500 mg, 3.2 mmol) of triethylamine (0.46 mL, 3.2 mmol) and 1-(bromomethyl)-4-nitrobenzene (545 mg, 2.5 mmol) were added to a solution in DMF (10 mL). The mixture was allowed to stand 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 over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (DCM / MeOH = 5 / 1) to give a yellow solid. [A40] (4-hydroxy-N'-(4-nitrophenylmethyl)benzylhydrazine, 410 mg, yield: 44%). The LCMS calculated m / z of C14H13N3O4[M+H]+ was 288.28, and the experimental value was 288. Step 2) Synthesize compound 19

[0152] Towards [A40] Zn (933 mg, 14 mmol) and NH₄Cl (764 mg, 14 mmol) were added to a solution of (4-hydroxy-N'-(4-nitrophenylmethyl)benzylhydrazine, 410 mg, 1.4 mmol) in THF:MeOH = 3:1 (12 mL). The mixture was stirred at room temperature for 12 hours. After the reaction was complete, ethyl acetate was added. The mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (DCM / MeOH = 15 / 1) to give a white solid. [Compound]

[19] (N'-(4-aminobenzyl)-4-hydroxybenzylhydrazine, 6 mg, yield: 16%, purity: 95.0%). 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); The LCMS calculated m / z of C14H15N3O2[M+H]+ is 258.29, and the experimental value is 258. [Experimental Examples] [1-20.] [Synthetic Compounds]

[20] [(] [4-] [Amine] [-, N' , -(1, H , -] [Indole] [-3-] [Carbonyl] [)] [Benzylsulfonylurea] [)] Step 1) Synthesize A42

[0153] Towards [A41] A mixture of 1H-indole-3-carbazine, 500 mg, 2.85 mmol, 1.0 equivalence) in pyridine (5 mL) was added dropwise to pyridine (5 mL). The mixture was then stirred at 10 °C for 2 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give a crude product. The crude product was purified by rapid column chromatography (DCM / MeOH = 50 / 1 to 30 / 1) to give a yellow solid. [A42] (N'-(1H-indole-3-carbonyl)-4-nitrobenzenesulfonamide, 0.9 g, 87.5% yield). (TLC: DCM / MeOH = 20 / 1, Rf = 0.5) Step 2) Synthesize compound 20

[0154] Towards [A42] Pd / C (100 mg) was added to a mixture of [N'-(1H-indole-3-carbonyl)-4-nitrobenzenesulfonamide, 300 mg, 0.83 mmol, 1.0 equivalence) in MeOH (10 mL). The mixture was then stirred at 10 °C under an H2 balloon for 2 hours. The solution was filtered, and the filtrate was purified by preparative HPLC and lyophilized to give a yellow solid. [Compound]

[20] (4-amino-N'-(1H-indole-3-carbonyl)benzenesulfonamide, 30 mg, 10.9% yield). ¹H NMR (DMSO-d₆, 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). LCMS; calculated mass value: 330; experimental MS value: 331.1 [MS+1]. [Experimental Examples] [1-21.] [and examples] [1-22.] [Preparation of Compounds] [twenty one] [(] [4-] [Amine] [-N'-(4-)] [Hydroxybenzoyl] [)-3-(] [Pyrrolidine] [-1-] [base] [)] [Benzylsulfonylurea] [)] [and compounds] [twenty two] [(] [ N' , ] [-(4-)] [Hydroxybenzoyl] [)-4-] [Nitro] [-3-(] [Pyrrolidine] [-1-] [base] [)] [Benzylsulfonylurea] [)] Step 1) Synthesize compound 22

[0155] At 10℃, towards [A4] A mixture of [3-fluoro-N'-(4-hydroxybenzoyl)-4-nitrobenzenesulfonazine, 400 mg, 1.13 mmol, 1.0 equivalence) and K₂CO₃ (389 mg, 2.81 mmol, 2.5 equivalence) in DMF (10 mL) was supplemented with pyrrolidone (96 mg, 1.35 mmol, 1.2 equivalence). The mixture was then stirred at 25 °C for 16 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated to give a crude product, which was purified by rapid column chromatography (DCM / MeOH = 50 / 1 to 30 / 1) to give a yellow solid. [Compound]

[22] (N'-(4-hydroxybenzoyl)-4-nitro-3-(pyrrolidin-1-yl)benzenesulfonazine, 176 mg, yield 38.5%). 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). Step 2) Synthesize compound 21

[0156] Towards [Compound]

[22] Pd / C (30 mg) was added to a mixture of (N'-(4-hydroxybenzoyl)-4-nitro-3-(pyrrolidin-1-yl)benzenesulfonamide, 100 mg, 0.54 mmol, 1.0 equivalence) in MeOH (5 mL). The mixture was then stirred at 10 °C under an H2 balloon for 16 hours. The solution was filtered and the filtrate was concentrated to obtain a 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 to obtain a grayish-white solid. [Compound]

[21] (4-amino-N'-(4-hydroxybenzoyl)-3-(pyrrolidone-1-yl)benzenesulfonazine, 30 mg, yield 32.4%). 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). LCMS; calculated mass value: 330; experimental MS value: 331.1 [MS+1]. [Experimental Examples] [1-23.] [Synthetic Compounds] [twenty three] [(] [4-] [Amine] [-, N' , -(4-] [Hydroxybenzoyl] [)-3-(] [piperidine] [-1-] [base] [)] [Benzylsulfonylurea] [)] Step 1) Synthesize A43

[0157] At 10℃, towards [A4] A mixture of [3-fluoro-N'-(4-hydroxybenzoyl)-4-nitrobenzenesulfonazine, 400 mg, 1.13 mmol, 1.0 equivalence) and K₂CO₃ (389 mg, 2.81 mmol, 2.5 equivalence) in DMF (10 mL) was supplemented with piperidine (115 mg, 1.35 mmol, 1.2 equivalence). The mixture was then stirred at 25 °C for 16 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated to give a crude product, which was purified by rapid column chromatography (DCM / MeOH = 50 / 1 to 30 / 1) to give a yellow solid. [A43] (N'-(4-hydroxybenzoyl)-4-nitro-3-(piperidin-1-yl)benzenesulfonazine, 240 mg, yield 50.7%). 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). Step 2) Synthesize compound 23

[0158] Towards [A43] A mixture of (N'-(4-hydroxybenzoyl)-4-nitro-3-(piperidin-1-yl)benzenesulfonamide, 100 mg, 0.24 mmol, 1.0 equivalence) in MeOH (5 mL) was supplemented with Pd / C (30 mg). The mixture was then stirred at 10 °C under an H2 balloon for 16 hours. The solution was filtered, and the filtrate was purified by preparative HPLC and lyophilized to give a yellow solid. [Compound]

[23] (4-amino-N'-(4-hydroxybenzoyl)-3-(piperidin-1-yl)benzenesulfonazine, 25 mg, yield 26.9%). 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). LCMS; calculated mass value: 390; experimental MS value: 390.8 [MS+1]. [Experimental Examples] [1-24.] [Synthetic Compounds] [twenty four] [(] [ N' , ] [-(4-)] [Hydroxybenzoyl] [)-1, H , -] [Pyrazole] [-4-] [Sulfohydrazine] [)] Step 1) Synthesize A44

[0159] A solution of 1H-pyrazole (1 g, 14.7 mmol, 1.0 equivalent) in chlorosulfonic acid (5 mL) was stirred overnight at 100 °C. The solution was then poured into water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to obtain a grayish-white solid. [A44] (1H-pyrazole-4-sulfonyl chloride, 340 mg, yield 14%). 1 HNMR (CDCl3, 400 MHz): 8.22 (s, 2H), 7.92 (s, 1H). Step 2) Synthesize compound 24

[0160] Will [A44] (1H-pyrazole-4-sulfadiazine chloride, 100 mg, 0.6 mmol, 1.0 equivalent) and A mixture of [A2] (4-hydroxybenzohydrazine, 109 mg, 0.72 mmol, 1.2 equivalences) in pyridine (20 mL) was stirred overnight at 80 °C. The solution was poured into water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give the crude product. The residue was purified by preparative TLC to give a grayish-white solid. [Compound]

[24] (N'-(4-hydroxybenzoyl)-1H-pyrazole-4-sulfadiazine, 60 mg). 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). [Experimental Examples] [1-25] [and experimental examples] [1-26.] [Preparation of Compounds]

[25] [(] [ N' , ] [-(4-)] [Hydroxybenzoyl] [)] [Indoline] [-4-] [Sulfohydrazine] [)] [and compounds]

[26] [(] [ N' , ] [-(4-)] [Hydroxybenzoyl] [)-1, H , -] [Indole] [-4-] [Sulfohydrazine] [)] Step 1) Synthesize A46

[0161] At 0℃ [A45] NaH (204 mg, 5.10 mmol, 60% in mineral oil, 1.0 equivalence) was added to a solution of (4-bromo-1H-indole, 1.0 g, 5.10 mmol, 1.0 equivalence) in THF (10 mL) and Et₂O (10 mL). After stirring for 15 minutes, the mixture was cooled to -78 °C, and t-BuLi (7.9 mL, 10.2 mmol, 1.3 M in THF, 2.0 equivalence) was slowly added. After 30 minutes, SO₂ (gas, 1 L) was slowly added at -78 °C. The mixture was then warmed to room temperature and stirred overnight. Acetic acid (307 mg, 5.10 mmol, 1.0 equivalence) was added to the mixture in Et₂O (15 mL) at 0 °C. The mixture was stirred at 0 °C for 30 minutes and then filtered. The filter cake was quickly washed with Et₂O. The solid was suspended in Et₂O (15 mL), cooled to 0 °C, and NCS (682 g, 5.10 mmol, 1.0 equivalence) was carefully added. The resulting suspension was rapidly stirred for 30 minutes and then filtered. The filter cake was washed with Et₂O. The combined filtrates were concentrated to obtain a brown solid. [A46] (1H-indole-4-sulfonyl chloride, 420 mg, crude). Step 2) Synthesize compound 26

[0162] Will [A46] (1H-indole-4-sulfonyl chloride, 420 mg, 1.95 mmol, 1.0 equivalent) and 4-hydroxybenzohydrazine ( A mixture of [A2] (297 mg, 1.95 mmol, 1.0 equivalence) in pyridine (30 mL) was stirred at 25 °C for 30 min. The solution was then poured into water (30 mL). The resulting solid was collected by filtration and the filter cake was washed with water. The crude product was purified by preparative HPLC and lyophilized to give a white solid. [Compound]

[26] (N'-(4-hydroxybenzoyl)-1H-indole-4-sulfadiazine, 200 mg, yield 31.0%). 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. LCMS; calculated mass value: 331.3; experimental MS value: 331.9 [MS+1]. Step 3) Synthesize compound 25

[0163] At 0℃ [Compound]

[26] NaBH3 CN (89 mg, 1.43 mmol, 3.0 equivalence) was added to a mixture of N'-(4-hydroxybenzoyl)-1H-indole-4-sulfadiazine, 150 mg, 0.48 mmol, 1.0 equivalence) in TFA (5 mL) and DCM (5 mL). The mixture was stirred at 10 °C for 30 min. The solution was poured into water (30 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give a crude product, which was purified by preparative HPLC and lyophilized to give a gray solid. [Compound]

[25] (N'-(4-hydroxybenzoyl)indoline-4-sulfadiazine, 30 mg, yield 20.0%). 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). LCMS; calculated mass value: 333; experimental MS value: 333.8 [MS+1]. [Experimental Examples] [1-27.] [Preparation of Compounds]

[27] [(] [2-((4-] [Aminophenyl] [)] [sulfonyl] [)-, N , -] [Phenylan] [-1-] [Methionine] [)] Step 1) Synthesize A47

[0164] To a mixture of 4-nitrobenzenesulfonyl chloride (3 g, 13.5 mmol, 1.0 equivalent) and pyridine (25 mL), pyridine (5 mL) containing tributyl hydrazide (1.8 g, 13.6 mmol, 1.0 equivalent) was added dropwise. The mixture was then stirred at 10 °C for 2 hours. The solution was then poured into water (100 mL) and stirred for 1 hour. The resulting solid was collected by filtration and dried to obtain a yellow solid. [A47] (2-((4-nitrophenyl)sulfonyl)hydrazine-1-carboxylic acid tributyl ester, 3.0 g, yield 69.7%). 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). Step 2) Synthesize A48

[0165] Towards [A47] A mixture of 3 g ((4-nitrophenyl)sulfonyl)hydrazide-1-carboxylic acid tributyl ester, 9.45 mmol, 1.0 equivalent) in MeOH (30 mL) was added to MeOH / HCl (30 mL, 6 mmol / L). The mixture was then stirred at 10 °C for 2 hours. The solution was concentrated to obtain a yellow solid. [A48] (4-Nitrobenzenesulfonylhydrazine hydrochloride, 2.0 g, yield 83.4%). 1 HNMR (DMSO-d 6 , 400 MHz): δ 8.45-8.48 (m, 2H), 8.15 (d,J = 8.8 Hz, 2H). Step 3) Synthesize A49

[0166] At 10℃ [A48] A mixture of 4-nitrobenzenesulfonazine hydrochloride, 500 mg, 1.97 mmol, 1.0 equivalence, and DIEA (764 mg, 5.91 mmol, 3.0 equivalence) and isocyanobenzoate (235 mg, 1.97 mmol, 1.0 equivalence) in THF (20 mL) was then added. The mixture was then stirred at 10 °C for 2 hours. The solution was poured into water (80 mL). The resulting solid was filtered, and the filter cake was stirred in EA (20 mL) for 30 minutes. The mixture was then filtered again, and the filter cake was dried to obtain a white solid. [A49] (2-((4-nitrophenyl)sulfonyl)-N-phenylhydrazine-1-methylamine, 340 mg, yield 51.3%). 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). Step 4) Synthesize compound 27

[0167] Will A mixture of [A49] (2-((4-nitrophenyl)sulfonyl)-N-phenylhydrazine-1-methylamine, 340 mg, 1.01 mmol, 1.0 equivalent) and Pd / C (200 mg) in MeOH (30 mL) was stirred at 10 °C under an H2 balloon for 15 hours. The solution was filtered and the filtrate was concentrated to obtain a crude product, which was stirred in MeOH (5 mL) for 30 minutes. The mixture was filtered and the filter cake was vacuum dried to obtain a white solid. [Compound]

[27] (2-((4-aminophenyl)sulfonyl)-N-phenylhydrazine-1-methylamine, 50 mg, yield 16.2%). 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). LCMS; calculated mass value: 306; MS experimental value: 306.9. [Experimental Examples] [1-28.] [Preparation of Compounds]

[28] [(] [4-] [Amine] [-, N' , -(1, H , -] [Indole] [-4-] [Carbonyl] [)-3-] [morpholinobenzenesulfonamide] [)] Step 1) Synthesize A51

[0168] Will A mixture of [A50] (methyl 1H-indole-4-carboxylate, 1.00 g, 5.71 mmol, 1.0 equivalence) in N2H4H2O (10 mL) was stirred at 100 °C for 1 hour. The solution was poured into water and extracted with EA (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give a yellow solid. [A51] (1H-indole-4-carbazine, 500 mg, crude). Step 2) Synthesize A52

[0169] Towards [A51] A mixture of pyridine (2 mL) containing 3-fluoro-4-nitrobenzene-1-sulfonyl chloride (175 mg, 0.57 mmol, 1.0 equivalence) was added dropwise to pyridine (2 mL). The mixture was then stirred at 10 °C for 3 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with 1N HCl (30 mL × 2) and brine, dried over Na₂SO₄ and concentrated to give a yellow solid. [A52] (3-Fluoro-N'-(1H-indole-4-carbonyl)-4-nitrobenzenesulfonylhydrazine, 200 mg, crude). Step 3) Synthesize A53

[0170] At 10℃, towards [A52] Morpholine (54 mg, 0.62 mmol, 1.2 equivalence) was added to a mixture of (3-fluoro-N'-(1H-indole-4-carbonyl)-4-nitrobenzenesulfonamide, 200 mg, 0.52 mmol, 1.0 equivalence) and K₂CO₃ (183 mg, 1.30 mmol, 2.5 equivalence) in DMF (5 mL). The mixture was then stirred at 25 °C for 16 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated to give a yellow solid. [A53] (N'-(1H-indole-4-carbonyl)-3-morpholino-4-nitrobenzenesulfonylhydrazine, 100 mg, crude material). Step 4) Synthesize compound 28

[0171] Towards [A53] A mixture of [N'-(1H-indole-4-carbonyl)-3-morpholino-4-nitrobenzenesulfonamide, 100 mg, 0.22 mmol, 1.0 equivalence) in EtOH (5 mL) was supplemented with Fe (61.6 mg, 1.10 mmol, 5.0 equivalence) and saturated NH4Cl aqueous solution (3 mL). The mixture was then stirred at 85 °C for 3 hours. The solution was filtered, and the filtrate was purified by preparative HPLC and lyophilized to give a white solid. [Compound]

[28] (4-amino-N'-(1H-indole-4-carbonyl)-3-morpholinylbenzenesulfonylhydrazine, 20 mg, yield 21.5%). 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). LCMS; calculated mass value: 415; experimental MS value: 415.9 [MS+1]. [Experimental Examples] [1-29.] [Preparation of Compounds]

[29] [(] [4-] [Amine] [-, N' , -(] [Indoline] [-4-] [Carbonyl] [)] [Benzylsulfonylurea] [)] Step 1) Synthesize A54

[0172] Towards [A51] A mixture of pyridine (5 mL) containing 4-nitrobenzene-1-sulfonyl chloride (505 mg, 2.29 mmol, 1.0 equivalence) was added dropwise to pyridine (5 mL). The mixture was then stirred at 10 °C for 3 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated to give a yellow solid. [A54] (N'-(1H-indole-4-carbonyl)-4-nitrobenzenesulfonylhydrazine, 300 mg, crude material). Step 2) Synthesize A55

[0173] At 10℃ [A54] A mixture of [N'-(1H-indole-4-carbonyl)-4-nitrobenzenesulfonamide, 300 mg, 0.83 mmol, 1.0 equivalence) in DCM (5 mL) was supplemented with TFA (1.5 mL) and NaBH3 CN (157 mg, 2.49 mmol, 3.0 equivalence). The mixture was then stirred at 10 °C for 45 min. The solution was poured into water (30 mL) and the pH was adjusted to 7 with a saturated NaHCO3 aqueous solution. The mixture was filtered, and the filter cake was washed with MTBE and vacuum dried to obtain a yellow solid. [A55] (N'-(indoline-4-carbonyl)-4-nitrobenzenesulfonylhydrazine, 150 mg, crude material). Step 3) Synthesize compound 29

[0174] Will A mixture of [A55] (N'-(indoline-4-carbonyl)-4-nitrobenzenesulfonamide, 150 mg, 0.41 mmol, 1.0 equivalence) and Pd / C (100 mg) in MeOH (5 mL) was stirred at 10 °C under an H2 balloon for 2 hours. The solution was filtered and the filtrate was concentrated to obtain a crude product, which was stirred in MeOH (10 mL) for 30 minutes. The mixture was filtered and the filter cake was dried under vacuum to obtain a white solid. [Compound]

[29] (4-amino-N'-(indoline-4-carbonyl)benzenesulfonamide, 40 mg, yield 29.1%). 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). LCMS; calculated mass value: 332; experimental MS value: 332.8 [MS+1]. [Experimental Examples] [1-30.] [Preparation of Compounds]

[30] [(] [4-] [Amine] [-N'-(4-)] [Hydroxybenzoyl] [)-3-(] [piperazine] [-1-] [base] [)] [Benzylsulfonylurea] [)] Step 1) Synthesize A56

[0175] At 10℃, towards [A4] A mixture of [3-fluoro-N'-(4-hydroxybenzoyl)-4-nitrobenzenesulfonamide, 500 mg, 1.41 mmol, 1.0 equivalence) and K₂CO₃ (290 mg, 2.10 mmol, 1.5 equivalence) in DMF (5 mL) was supplemented with tributyl piperazine-1-carboxylate (315 mg, 1.69 mmol, 1.2 equivalence). The mixture was then stirred at 10 °C for 16 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated to give a crude product, which was purified by rapid column chromatography (DCM / MeOH = 50 / 1 to 30 / 1) to give a yellow solid. [A56] (4-(5-((2-(4-hydroxybenzoyl)hydrazino)sulfonyl)-2-nitrophenyl)piperazine-1-carboxylic acid tributyl ester, 310 mg, crude material). Step 2) Synthesize A57

[0176] Towards [A56] A mixture of (4-(5-((2-(4-hydroxybenzoyl)hydrazino)sulfonyl)-2-nitrophenyl)piperazine-1-carboxylic acid tributyl ester, 250 mg, 0.48 mmol, 1.0 equivalence) in EtOH (3 mL) was mixed with saturated NH4Cl aqueous solution (3 mL) and Fe (135 mg, 2.41 mmol, 5.0 equivalence). The mixture was then stirred at 85 °C for 1 hour. The solution was filtered and the filtrate was poured into water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a yellow solid. [A57] (4-(2-amino-5-((2-(4-hydroxybenzoyl)hydrazyl)sulfonyl)phenyl)piperazine-1-carboxylic acid tributyl ester, 210 mg, crude material). Step 3) Synthesize compound 30

[0177] At 10℃, towards [A57] (4-(2-amino-5-((2-(4-hydroxybenzoyl)hydrazino)sulfonyl)phenyl)piperazine-1-carboxylic acid tributyl ester, 270 mg, 0.55 mmol, 1.0 equivalence) was added to a mixture of DCM (5 mL) and TFA (0.5 mL). The mixture was then stirred at 10 °C for 3 hours. The solution was concentrated to obtain a crude product, which was purified by preparative HPLC and lyophilized 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 to obtain a white solid. [Compound]

[30] (4-amino-N'-(4-hydroxybenzoyl)-3-(piperazin-1-yl)benzenesulfonazine, 20 mg, yield 9.30%). 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). LCMS; calculated mass value: 391; experimental MS value: 392.1 [MS+1]. [Experimental Examples] [1-31.] [Preparation of Compounds]

[31] [(] [4-] [Amine] [-, N' , -(2,3-] [Dihydrogen] [-1, H , -] [Indonesia] [-2-] [Carbonyl] [)] [Benzylsulfonylurea] [)] Step 1) Synthesize A59

[0178] Towards [A58] 5.0 g (30.8 mmol, 1.0 equivalence) of 2,3-dihydro-1H-indene-2-carboxylic acid was added dropwise to a mixture of 2,3-dihydro-1H-indene-2-carboxylic acid and 3,000 mmol of H₂SO₄ in 50 mL of MeOH. The mixture was then stirred at 70 °C for 12 hours. The solution was poured into water (60 mL) and extracted with EA (60 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give a yellow oil. [A59] (methyl 2,3-dihydro-1H-indene-2-carboxylate, 5.3 g, yield 97.5%). Step 2) Synthesize A60

[0179] Towards [A59] Methyl 2,3-dihydro-1H-indene-2-carboxylate, 3.0 g, 17.1 mmol, 1.0 equivalence) was added dropwise to a mixture of MeOH (30 mL) and N₂H₄·H₂O (8.56 g, 171 mmol, 10 equivalence). The mixture was then stirred at 80 °C for 12 hours. The solution was concentrated to obtain a yellow solid. [A60] (2,3-dihydro-1H-indene-2-carbazine, 2.0 g, 87.5% yield). 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). Step 3) Synthesize A61

[0180] Towards [A60] (2,3-dihydro-1H-indene-2-carbazine, 2 g, 11.4 mmol, 1.0 equivalence) was added fractionally to a mixture of pyridine (20 mL) and 4-nitrobenzene-1-sulfonyl chloride (2.52 g, 11.4 mmol, 1.0 equivalence). The mixture was then stirred at 10 °C for 2 hours. The solution was poured into water (100 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated to give a yellow solid. [A61] (N'-(2,3-dihydro-1H-indene-2-carbonyl)-4-nitrobenzenesulfonamide, 1.4 g, 34.1% yield). (TLC: DCM / MeOH = 10 / 1, Rf = 0.5) Step 4) Synthesize compound 31

[0181] Towards [A61] Pd / C (100 mg) was added to a mixture of [N'-(2,3-dihydro-1H-indene-2-carbonyl)-4-nitrobenzenesulfonamide, 200 mg, 0.83 mmol, 1.0 equivalence) in MeOH (10 mL). The mixture was then stirred at 10 °C under an H2 balloon for 12 hours. The solution was filtered, and the filtrate was purified by preparative HPLC and lyophilized to give a white solid. [Compound]

[31] (4-amino-N'-(2,3-dihydro-1H-indene-2-carbonyl)benzenesulfonamide, 80 mg, yield 43.6%). 1 HNMR (CD3 OD, 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). LCMS; calculated mass value: 331; experimental MS value: 331.8 [MS+1]. [Experimental Examples] [1-32.] [Preparation of Compounds]

[32] [(] [4-] [Amine] [-, N' , -(] [Isoindolin] [-2-] [Carbonyl] [)] [Benzylsulfonylurea] [)] Step 1) Synthesize A63

[0182] Triethylamine (2 mL) and 4-nitrobenzene chloroformate (1.68 g, 8.4 mmol) were added to a mixture of A62 (isoindoline, 1.00 g, 8.4 mmol) in dichloromethane (10 mL). The mixture was stirred at room temperature for 16 hours. The solution was poured into water (30 mL) and extracted with dichloromethane (30 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated. The product was added to tetrahydrofuran (10 mL) and N₂H₄H₂O (2 mL). The mixture was stirred at 60 °C for 16 hours. The solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulfate (Na₂SO₄) and concentrated to give a yellow solid. [A63] (Isoindolin-2-carbazine, 600 mg, crude). (TLC: DCM / MeOH = 10 / 1, Rf = 0.6) LC-MS; calculated mass: 177.2; experimental MS value: 178.2 [MS+1]. Step 2) Synthesize A64

[0183] Towards [A63] A mixture of pyridine (5 mL) containing 4-nitrobenzene-1-sulfonyl chloride (750 mg, 3.39 mmol, 1.0 equivalence) was added dropwise to pyridine (10 mL). The mixture was then stirred at 10 °C for 3 hours. The solution was poured into water (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with 1N HCl (50 mL × 2) and brine, dried over Na₂SO₄ and concentrated to give a yellow solid. [A64] (N'-(isoindoline-2-carbonyl)-4-nitrobenzenesulfonamide, 200 mg, crude). (TLC: DCM / MeOH = 20 / 1, Rf = 0.5) LCMS; calculated mass value: 362.3; experimental MS value: 363.1 [MS+1]. [step] [3] [)] [Synthetic Compounds]

[32] [(] [4-] [Amine] [-, N' , -(] [Isoindolin] [-2-] [Carbonyl] [)] [Benzylsulfonylurea] [)]

[0184] Towards [A64] Fe (154 mg, 2.75 mmol, 5.0 equivalence) and a saturated NH4Cl aqueous solution (6 mL) were added to a mixture of 200 mg, 0.55 mmol, and 1.0 equivalence in ethanol (10 mL). The mixture was then stirred at 85 °C for 3 hours. The solution was filtered and the filtrate was concentrated to obtain a crude product. The crude product was purified by preparative HPLC and lyophilized to obtain a white solid. [Compound]

[32] (4-amino-N'-(isoindoline-2-carbonyl)benzenesulfonazine, 20 mg, yield 11.0%). 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). LCMS; calculated mass value: 332; experimental MS value: 333 [MS+1]. [Experimental Examples] [1-33.] [Preparation of Compounds]

[33] [(] [ N' , ] [-(4-)] [Hydroxybenzoyl] [)-1, H , -] [Indole] [-2-] [Sulfohydrazine] [)] Step 1) Synthesize A66

[0185] At -70℃, towards [A65] n-BuLi (4.0 mL, 2.5 M in hexane, 10.0 mmol, 1.1 equivalence) was added dropwise to a stirred solution of [A65] (1H-indole-1-carboxylic acid tributyl ester, 2.00 g, 9.2 mmol, 1.0 equivalence) in tetrahydrofuran (20 mL). After 1 hour, SO2 (gas, 1 L) was slowly added at -70 °C. The reaction mixture was then heated to 10 °C over a 2-hour period. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane (DCM, 20 mL). N-chlorodiaminoimide (NCS, 1.84 g, 13.8 mmol, 1.5 equivalence) was added. The mixture was stirred at room temperature for 10 hours. The mixture was washed with water (2 × 20 mL) and brine (2 × 20 mL). The organic phase was dried and concentrated. The residue was purified by column chromatography (PE / EA = 30 / 1-5 / 1) to obtain a brown oily substance. [A66] (2-(chlorosulfonyl)-1H-indole-1-carboxylic acid tributyl ester, 1.0 g, yield 34.4%). 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). Step 2) Synthesize A67

[0186] Add dropwise to a stirred solution of 4-hydroxybenzohydrazine (481 mg, 3.17 mmol, 1.0 equivalence) in pyridine (10 mL) at 0 °C. [A66] A solution of (1.0 g, 3.17 mmol, 1.0 equivalent) in pyridine (5 mL). The mixture was stirred at room temperature for 5 hours. The mixture was filtered. The filtrate was concentrated and purified by column chromatography to give a white solid. [A67] (2-((2-(4-hydroxybenzoyl)hydrazino)sulfonyl)-1H-indole-1-carboxylic acid tributyl ester, 500 mg, yield 36.5%). Step 3) Synthesize compound 33

[0187] At 0℃ [A67] 4N HCl (g) / MeOH (2 mL) was added to a stirred solution of 500 mg, 1.16 mmol, 1.0 equivalence in methanol (MeOH, 5 mL). The mixture was stirred at room temperature for 4 hours. The mixture was concentrated, purified by preparative HPLC, and lyophilized to give a white solid. [Compound]

[33] (N'-(4-hydroxybenzoyl)-1H-indole-2-sulfadiazine, 50 mg, yield 13%). 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). LCMS; calculated mass value: 341; experimental MS value: 342 [MS+1]. [Experimental Examples] [1-34.] [Preparation of Compounds]

[34] [(] [4-] [Amine] [-, N' , -(2-] [Phenylacetyl] [)] [Benzylsulfonylurea] [)] Step 1) Synthesize A69

[0188] Towards [A68] A mixture of pyridine (5 mL) containing 4-nitrobenzene-1-sulfonyl chloride (738 mg, 3.33 mmol, 1.0 equivalence) was added dropwise to pyridine (5 mL). The mixture was then stirred at 10 °C for 2 hours. The solution was poured into water (30 mL) and extracted with ethyl acetate (EA, 30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated to give a crude product, which was stirred in DCM (30 mL) for 30 minutes. The mixture was filtered and the filter cake was dried to give a yellow solid. [A69] (4-nitro-N'-(2-phenylacetyl)benzenesulfonamide, 1 g, yield 89.6%). 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). Step 1) Synthesize compound 34

[0189] Towards [A69] Pd / C (50 mg) was added to a mixture of [200 mg, 0.60 mmol, 1.0 equivalence) in MeOH (10 mL). The mixture was then stirred at 10 °C under an H2 balloon for 2 hours, the solution was filtered, and the filtrate was concentrated. The crude product was crystallized three times from MeOH (10 mL) to give a gray solid. [Compound]

[34] (4-amino-N'-(2-phenylacetyl)benzenesulfonamide, 20 mg, yield 10.9%). (TLC: DCM / MeOH = 10 / 1, Rf = 0.3) 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). LCMS; calculated mass value: 305; experimental MS value: 306.1 [MS+1]. [Experimental Examples] [1-35.] [Preparation of Compounds]

[35] [(] [ N' , ] [-(4-)] [Hydroxybenzoyl] [)-1, H , -] [Indazole] [-3-] [Sulfohydrazine] [)] Step 1) Synthesize A70

[0190] NaNO₂ (0.62 g, 9.0 mmol, 1.2 equivalence) was added to a stirred solution of 1H-indazole-3-amine (1.00 g, 7.5 mmol, 1.0 equivalence) in acetic acid (16 mL), concentrated hydrochloric acid (1.6 mL), and formic acid (1.6 mL) at 0 °C. The mixture was stirred for 1 hour. SO₂ (gas, 1 L) and CuCl₂ (0.38 g, 2.3 mmol, 0.3 equivalence) were slowly added at 0 °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) to give a brown solid. [A70] (1H-indazole-3-sulfonyl chloride, 0.5 g, yield 30.8%). 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). Step 2) Synthesize compound 35(N'-(4-hydroxybenzoyl)-1H-indazole-3-sulfadiazine)

[0191] Add dropwise to a stirred solution of 4-hydroxybenzohydrazine (225 mg, 1.48 mmol, 0.8 equivalence) in pyridine (5 mL) at 0 °C. [A70] (1H-indazole-3-sulfonyl chloride, 0.40 g, 1.85 mmol, 1.0 equivalent) in pyridine (5 mL). The mixture was stirred at room temperature for 5 hours. The mixture was concentrated. The residue was purified by preparative HPLC and lyophilized to give a white solid. [Compound]

[35] (N'-(4-hydroxybenzoyl)-1H-indazole-3-sulfadiazine, 60 mg, yield 9.77%). 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). LCMS; calculated mass value: 332; experimental MS value: 333 [MS+1]. [Experimental Examples] [1-36.] [Preparation of Compounds]

[36] [(] [4-] [Amine] [-, N' , -(] [Indoline] [-6-] [Carbonyl] [)] [Benzylsulfonylurea] [)] Step 1) Synthesize A72

[0192] Will A mixture of [A71] (methyl 1H-indole-6-carboxylate, 500 mg, 2.86 mmol, 1.0 equivalent) and hydrazine monohydrate (10 mL) was stirred at 100 °C for 3 hours. The mixture was then cooled to 0 °C and filtered. The filter cake was washed with ice water and vacuum dried to obtain a white solid. [A72] (1H-indole-6-carbazine, 300 mg, yield 60.0%). LCMS; calculated mass: 175.18; experimental MS value: 176.0 [MS+1]. Step 2) Synthesize A73

[0193] At 0℃ [A72] 4-Nitrobenzenesulfonyl chloride (380 mg, 1.71 mmol, 1.0 equivalence) was added to a mixture of pyridine (5 mL). The mixture was then stirred at 10 °C for 3 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with 1N HCl (30 mL × 2) and brine, dried over Na₂SO₄ and concentrated to give a crude product. The crude product was purified by rapid column chromatography (DCM / MeOH = 50 / 1 to 30 / 1) to give a yellow solid. [A73] (N'-(1H-indole-6-carbonyl)-4-nitrobenzenesulfonylhydrazine, 500 mg, yield 81.0%). LCMS; calculated mass value: 360.34; experimental MS value: 361.1 [MS+1]. Step 3) Synthesize A74

[0194] At 0℃ [A73] NaBH3CN (209 mg, 3.33 mmol, 3.0 equivalence) was added to a mixture of DCM (15 mL) and TFA (5 mL). The mixture was then stirred at 15 °C for 1 hour. The solution was poured into water (30 mL) and the pH was adjusted to 7-8 with a saturated NaHCO3 aqueous solution. The solution was filtered, and the filter cake was washed with PE and dried to obtain a yellow solid. [A74] (N'-(indoline-6-carbonyl)-4-nitrobenzenesulfonylhydrazine, 200 mg, crude material). LCMS; calculated mass value: 362.36; experimental MS value: 363.1 [MS+1]. Step 3) Synthesize compound 36

[0195] Will A mixture of [A74] (200 mg, 0.55 mmol, 1.0 equivalence), NH4Cl (146 mg, 2.75 mmol, 5.0 equivalence), and Fe (154 mg, 2.75 mmol, 5.0 equivalence) in H2O (10 mL) and EtOH (20 mL) was stirred at 85 °C for 2 hours. The mixture was filtered, and the filtrate was extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude product was recrystallized from methanol and lyophilized to give a white solid. [Compound]

[36] (4-amino-N'-(indoline-6-carbonyl)benzenesulfonazine, 60 mg, 32.7%). 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). LCMS; calculated mass value: 332; MS experimental value: 333 [M+1]. [Experimental Examples] [1-37.] [Preparation of Compounds]

[37] [(] [4-] [Amine] [-, N' , -(] [Indoline] [-3-] [Carbonyl] [)] [Benzylsulfonylurea] [)] Step 1) Synthesize A76

[0196] At 20℃, towards [A75] Boc₂O (1.37 g, 6.28 mmol, 1.1 equivalence) was added dropwise to a mixture of [A75] (methyl 1H-indole-3-carboxylate, 1.00 g, 5.71 mmol, 1.0 equivalence) and triethylamine (TEA, 1.16 g, 11.4 mmol, 2.0 equivalence) in DCM (10 mL). The mixture was then stirred at 20 °C for 12 hours. The solution was poured into water (60 mL) and extracted with DCM (60 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give a yellow solid. [A76] (1.20 g of 1-(tert-butyl 3-methyl-1H-indole-1,3-dicarboxylic acid), crude material). Step 2) Synthesize A77

[0197] Towards [A76] A mixture of 1.20 g (4.36 mmol, 1.0 equivalence) in ethyl acetate (EA, 30 mL) was mixed with Pd / C (0.65 g) and degassed. The mixture was then stirred at 60 °C for 12 hours under H2 (50 psi). The solution was filtered and the filtrate was concentrated to give a crude product. The crude product was purified by silica gel (PE / EA = 30:1~15:1) to give a white solid. [A77] (3-Methylindoline-1,3-dicarboxylic acid 1-(tert-butyl ester), 0.80 g, yield 66.2%). Step 3) Synthesize A78

[0198] Towards [A77] (800 mg, 2.89 mmol, 1.0 equivalence) was added to a mixture in MeOH (20 mL) with N₂H₄·H₂O (1.6 mL). The mixture was then stirred at 80 °C for 4 hours. The reaction mixture was concentrated to give a white solid. [A78] (3-(hydrazine carbonyl)indoline-1-carboxylic acid tributyl ester, 700 mg, yield 87.5%). Step 3) Synthesize A79

[0199] Towards [A78] Tributyl 3-(hydrazine carbonyl)indoline-1-carboxylic acid, 300 mg, 1.08 mmol, 1.0 equivalence) was added fractionally to a mixture of pyridine (5 mL) with 4-nitrobenzene-1-sulfonyl chloride (0.24 g, 1.08 mmol, 1.0 equivalence). The mixture was then stirred at 10 °C for 4 hours. The solution was poured into water (100 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated to give a yellow solid. [A79] (3-(2-((4-nitrophenyl)sulfonyl)hydrazine-1-carbonyl)indoline-1-carboxylic acid tributyl ester, 200 mg, yield 39.7%). Step 4) Synthesize A80

[0200] Towards [A79] (200 mg, 0.43 mmol, 1.0 equivalence) was added to a mixture in EA (10 mL) with Pd / C (50 mg). The mixture was then stirred at 10 °C under an H2 balloon for 12 hours. The solution was filtered and the filtrate was concentrated to obtain a yellow solid. [A80] (3-(2-((4-aminophenyl)sulfonyl)hydrazine-1-carbonyl)indoline-1-carboxylic acid tributyl ester, 200 mg, yield: 100%). Step 5) Synthesize compound 37 (4-amino-N'-(indoline-3-carbonyl)benzenesulfonhydrazine)

[0201] Towards [A80] (200 mg, 0.463 mmol, 1.0 equivalence) was added to a mixture in DCM (5 mL) with trifluoroacetic acid (TFA, 1 mL). The mixture was then stirred at 10 °C for 2 hours. The solution was concentrated, and H₂O (5 mL) was added to the residue, and the pH was adjusted to 9-10 with K₂CO₃ aqueous solution. The solution was extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give a crude product. The crude product was purified by preparative HPLC and lyophilized to give a grayish-white solid. [Compound]

[37] (4-amino-N'-(indoline-3-carbonyl)benzenesulfonazine, 30.0 mg, 19.6% yield). ¹H NMR (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). LCMS; MS experimental value: 333.1 [MS+1]. [Experimental Examples] [1-38.] [Preparation of Compounds]

[38] [(] [ N' , ] [-(4-)] [Hydroxybenzoyl] [)] [piperidine] [-4-] [Sulfohydrazine] [)] Step 1) Synthesize A82

[0202] Add dropwise to a mixture of 4-hydroxybenzohydrazine (A2, 268 mg, 1.77 mmol, 1.0 equivalence) in pyridine (2 mL) at 0 °C. [A81] A solution of (4-(chlorosulfonylurea)piperidine-1-carboxylic acid tributyl ester, 500 mg, 1.77 mmol, 1.0 equivalent) in pyridine (1 mL). 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) to give a yellow solid. [A82] (4-((2-(4-hydroxybenzoyl)hydrazinoyl)sulfonylurea)piperidine-1-carboxylic acid tributyl ester, 300 mg, yield 42%). 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). Step 2) Synthesize compound 38 (N'-(4-hydroxybenzoyl)piperidine-4-sulfadiazine)

[0203] At 0℃ [A82] (300 mg, 0.75 mmol, 1.0 equivalence) was added to a mixture of DCM (5 mL) and TFA (1.5 mL). The mixture was stirred at room temperature for 4 hours. The above solution was concentrated and purified by preparative HPLC and lyophilized to obtain a yellow solid. [Compound]

[38] (N'-(4-hydroxybenzoyl)piperidine-4-sulfadiazine, 50 mg, yield 22%). 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). LCMS; calculated mass value: 299; MS experimental value: 300 [Ms+1]. [Experimental Examples] [1-39.] [Preparation of Compounds]

[39] [(] [4-] [Amine] [-, N' , -(] [Indoline] [-6-] [Carbonyl] [)-3-] [morpholinobenzenesulfonamide] [)] Step 1) Synthesize A83

[0204] At 0℃, towards [A72] A mixture of 1H-indole-6-carbazine, 500 mg, 2.86 mmol, 1.0 equivalent) in pyridine (5 mL) was added dropwise to a mixture of 3-fluoro-4-nitrobenzene-1-sulfonyl chloride (686 mg, 2.86 mmol, 1.0 equivalent) in pyridine (2 mL). The mixture was then stirred at 10 °C for 3 hours. The above solution was concentrated to obtain a crude product, which was purified by column chromatography (DCM:MeOH = 50:1-20:1) to obtain a yellow solid. [A83] (3-Fluoro-N'-(1H-indole-6-carbonyl)-4-nitrobenzenesulfonylhydrazine, 700 mg, yield: 64.8%). LCMS; calculated mass value: 378.3; MS experimental value: 379.1 [Ms+1]. Step 2) Synthesize A84

[0205] At 10℃ [A83] (700 mg, 1.85 mmol, 1.0 equivalence) and K₂CO₃ (640 mg, 4.64 mmol, 2.5 equivalence) were added to a mixture of DMF (7 mL) with morpholine (193 mg, 2.22 mmol, 1.2 equivalence). The mixture was then stirred at 25 °C for 16 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated to give a yellow solid. [A84] (N'-(1H-indole-6-carbonyl)-3-morpholino-4-nitrobenzenesulfonylhydrazine, 600 mg, yield: 72.8%). LCMS; calculated mass value: 445.4; MS experimental value: 446.1 [Ms+1]. Step 3) Synthesize A85

[0206] At 10℃ [A84] (600 mg, 1.35 mmol, 1.0 equivalence) was added to a mixture in DCM (5 mL) with TFA (1 mL) and NaBH3 CN (251 mg, 4.04 mmol, 3.0 equivalence). The mixture was then stirred at 25 °C for 4 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a yellow solid. [A85] (N'-(indoline-6-carbonyl)-3-morpholino-4-nitrobenzenesulfonylhydrazine, 450 mg, crude material). LCMS; calculated mass value: 447.4; MS experimental value: 448.2 [Ms+1]. Step 4) Synthesize compound 39 (4-amino-N'-(indoline-6-carbonyl)-3-morpholinylbenzenesulfonhydrazine)

[0207] Towards [A85] Fe (282 mg, 5.05 mmol, 5.0 equivalence) and a saturated aqueous solution of NH4Cl (1 mL) were added to a mixture of [A85] (450 mg, 1.01 mmol, 1.0 equivalence) and EtOH (5 mL). The mixture was then stirred at 85 °C for 3 hours. The solution was concentrated, followed by the addition of DMSO (5 mL) and filtration. The filtrate was purified by preparative HPLC and lyophilized to give a grayish-white solid. [Compound]

[39] (4-amino-N'-(indoline-6-carbonyl)-3-morpholinobenzenesulfonazine, 30 mg, yield 7.0%). 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). LCMS; calculated mass value: 417.1; experimental MS value: 418.1 [MS+1]. [Experimental Examples] [1-40.] [Preparation of Compounds]

[40] [(] [4-] [Amine] [-, N' , -(] [piperazine] [-1-] [Carbonyl] [)] [Benzylsulfonylurea] [)] Step 1) Synthesize A87

[0208] At 10℃, towards [A86] A mixture of 1.00 g (4.09 mmol, 1.0 equivalence) of tributyl 4-(hydrazine carbonyl)piperazine-1-carboxylic acid (10 mL) was added dropwise to pyridine (5 mL). The mixture was then stirred at 10 °C for 3 hours. The solution was poured into water (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with 1N HCl (50 mL × 2) and brine, dried over Na₂SO₄, and concentrated to give a crude product. The crude product was washed with EA (5 mL), filtered, and dried under vacuum to give a yellow solid. [A87] (4-(2-((4-nitrophenyl)sulfonyl)hydrazine-1-carbonyl)piperazine-1-carboxylic acid tributyl ester, 800 mg, yield 45.5%). 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). Step 2) Synthesize A88

[0209] Towards [A87] Pd / C (40 mg) was added to a mixture of [A87] (400 mg, 0.93 mmol, 1.0 equivalence) and [A87] (10 mL) of THF. The mixture was then stirred at 10 °C under an H2 balloon for 16 hours. The solution was filtered and the filtrate was concentrated to give a yellow solid. [A88] (4-(2-((4-aminophenyl)sulfonyl)hydrazine-1-carbonyl)piperazine-1-carboxylic acid tributyl ester, 350 mg, yield: 94%). Step 3) Synthesize compound 40 (4-amino-N'-(piperazine-1-carbonyl)benzenesulfonhydrazine)

[0210] Towards [A88] (150 mg, 0.37 mmol, 1.0 equivalence) was added to a mixture in DCM (5 mL) with TFA (1 mL). The mixture was then stirred at 25 °C for 3 hours. The solution was concentrated to obtain a crude product. MeOH (5 mL) was added to the crude product, followed by K₂CO₃ (62 mg, 0.45 mmol) and stirring at room temperature for 1 hour. The solution was filtered and purified by preparative HPLC and lyophilized to obtain a white solid. [Compound]

[40] (4-amino-N'-(piperazine-1-carbonyl)benzenesulfonazine, 50 mg, yield 38.7%). 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). LCMS; calculated mass value: 299; experimental MS value: 300 [MS+1]. [Experimental Examples] [1-41.] [Preparation of Compounds]

[41] [(] [4-] [Amine] [-3-] [morpholine] [base] [-, N' , -(] [piperazine] [-1-] [Carbonyl] [)] [Benzylsulfonylurea] [)] Step 1) Synthesize A89

[0211] Towards [A86] 5 mL of pyridine containing 1.46 g, 6.14 mmol, 1.0 equivalence (t / v) of 3-fluoro-4-nitrobenzene-1-sulfonyl chloride (t / v) was added dropwise to a mixture of pyridine (10 mL). The mixture was then stirred at 10 °C for 3 hours. The solution was poured into water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with 1 N HCl (30 mL × 2) and brine, dried over Na₂SO₄ and concentrated to give a yellow solid. [A89] (4-(2-((3-fluoro-4-nitrophenyl)sulfonyl)hydrazine-1-carbonyl)piperazine-1-carboxylic acid tributyl ester, 1.5 g, crude material). Step 2) Synthesize A90

[0212] At 10℃ [A89] Morpholine (350 mg, 4.02 mmol, 1.2 equivalence) was added to a mixture of [A89] (1.50 g, 3.35 mmol, 1.0 equivalence) and K2 CO3 (1.16 g, 8.37 mmol, 2.5 equivalence) in DMF (15 mL). The mixture was then stirred at 25 °C for 16 hours. The solution was poured into water (50 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na2 SO4, and concentrated to give a crude product. The crude product was purified by column chromatography (DCM / MeOH = 50 / 1-10 / 1) to give a yellow solid. [A90] (4-(2-((3-morpholino-4-nitrophenyl)sulfonyl)hydrazine-1-carbonyl)piperazine-1-carboxylic acid tributyl ester, 700 mg, yield: 40.6%). LCMS; calculated mass value: 514.55; experimental MS value: 516.2 [MS+2]. Step 3) Synthesize A91

[0213] Towards [A90] (700 mg, 1.36 mmol, 1.0 equivalence) was added to a mixture of THF (10 mL) and Pd / C (200 mg). The mixture was then stirred at room temperature for 15 minutes in H2 (50 psi). The solution was filtered and the filtrate was concentrated to give a yellow solid. [A91] (4-(2-((4-amino-3-morpholinylphenyl)sulfonyl)hydrazine-1-carbonyl)piperazine-1-carboxylic acid tributyl ester, 300 mg, crude material). Step 4) Synthesize compound 41 (4-amino-3-morpholino-N'-(piperazine-1-carbonyl)benzenesulfonhydrazine)

[0214] Towards [A91] (200 mg, 0.41 mmol, 1.0 equivalence) was added to a mixture of DCM (10 mL) and TFA (2 mL). The mixture was then stirred at room temperature for 3 hours. The mixture was concentrated and purified by preparative HPLC and lyophilized to give a pink solid. [Compound]

[41] (4-amino-3-morpholino-N'-(piperazine-1-carbonyl)benzenesulfonazine, 20.0 mg, yield 12.6%). 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 = 8.6Hz, 1H), 5.68 (s, 2H), 3.78 (s, 4H), 3.39 (s,4H), 2.98 (s, 4H), 2.76 (s, 4H). LCMS; calculated mass value: 384; experimental MS value: 384.9 [MS+1]. [Experimental Examples] [1-42.] [Preparation of Compounds]

[42] [(] [ N' , ] [-(4-)] [Hydroxybenzoyl] [)-2-] [Methylthiazole] [-4-] [Sulfohydrazine] [)] Step 1) Synthesize A92

[0215] 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) was heated at 100°C for 1 hour. After cooling, the reaction mixture was allowed to crystallize. The mixture was wet-milled with deionized water, filtered, washed with copious amounts of water, and recrystallized from ethanol to obtain a white solid. [A92] (N-(2,2,2-trichloro-1-hydroxyethyl)acetamide, 15 g). 1HNMR (DMSO_d6, 400 MHz): 8.72 (d, 1H), 7.64 (d, 1H), 5.74-5.70 (m, 1H), 1.92 (s, 3H). Step 2) Synthesize A93

[0216] Over a period of 3 hours, zinc powder (5 grams, 78 millimoles) was gradually added to... [A92] (8 g, 39 mmol) was added to a stirred suspension in glacial acetic acid (50 mL). The temperature of the reaction mixture was kept below 40 °C during zinc addition. The reaction mixture was then stirred at room temperature for 24 hours. The precipitated zinc salt was then filtered off and washed with glacial acetic acid. Acetic acid was removed under reduced pressure. The solid residue was wet-milled with deionized water and recrystallized to give a white solid. [A93] (N-(2,2-dichlorovinyl)acetamide, 3 g). 1HNMR (DMSO_d6, 400 MHz): 9.87 (d, 1H), 7.21 (d, 1H), 2.03 (s, 3H). Step 3) Synthesize A94

[0217] Benzyl mercaptan (4 g, 32 mmol) and triethylamine (3.29 g, 32.6 mmol) were added to... [A93] (2 g, 13 mmol) in a stirred solution of 2-propanol (25 mL). The reaction mixture was stirred at room temperature for 48 hours. The solvent was then removed under reduced pressure, and the residue was wet-milled with water to produce a crystalline solid. The crude product was purified by recrystallization from 2-propanol or ethanol to give a white solid. [A94] (N-(1-(benzylthio)-2,2-dichloroethyl)acetamide, 2.5 g). 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). Step 4) Synthesize A95

[0218] Lawson's reagent (7.6 g, 18.8 mmol) was added to... [A94] (5 mmol) in a stirred solution of toluene (30 mL). The reaction mixture was refluxed for 8 hours, followed by removal of the solvent under reduced pressure. The residue was wet-milled with 10% NaOH aqueous solution to adjust the pH to 9. The crude product was filtered, dried, and recrystallized from 2-propanol. The liquid product was extracted with dichloromethane to give a yellow oil. [A95] (4-(benzylthio)-2-methylthiazole, crude material, 2.5 g). 1HNMR (DMSO_d6, 400 MHz): 7.44 (s, 1H), 7.30-7.20 (m, 5H), 4.04 (s, 2H), 2.59 (S, 3H). Step 5) Synthesize compound A96

[0219] At 0℃ [A95] (Crude material, 1 g) was added to a solution of NCS (3 g) and water (2 mL) in acetic acid (10 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was wet-milled with a 10% NaHCO3 aqueous solution to adjust the pH to 8, and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product. The residue was purified by passing it through silicone to give a yellow oily substance. [A96] (2-methylthiazolyl-4-sulfochloro, 100 mg). 1HNMR (CDCl3, 400 MHz): 8.33 (s, 1H), 2.86 (S, 3H). Step 6) Synthesize compound 42(N'-(4-hydroxybenzoyl)-2-methylthiazol-4-sulfadiazine)

[0220] Will [A96] (100 mg, 0.5 mmol) and A mixture of [A2] (4-hydroxybenzoylhydrazine, 80 mg, 0.5 mmol) in pyridine (20 mL) was stirred overnight at 80 °C. The solution was poured into water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated to give the crude product. The residue was purified by preparative HPLC to give a grayish-white solid. [Compound]

[42] (N'-(4-hydroxybenzoyl)-2-methylthiazol-4-sulfadiazine, 30 mg). 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). LCMS; calculated mass value: 313.3; experimental MS value: 314.0 [MS+1]. [Experimental Examples] [1-43.] [Preparation of Compounds]

[43] [(] [(1S,4S)-4-] [Amine] [-, N' , -(4-] [Hydroxybenzoyl] [)] Cyclohexane [-1-] [Sulfohydrazine] [)] Step 1) Synthesize A98

[0221] Towards [A97] Tributyl 4-methylbenzenesulfonate (27 g, 126 mmol, 1.0 equivalence) was added fractionally to a mixture of pyridine (100 mL) and 4-methylbenzenesulfonyl chloride (28.6 g, 151 mmol, 1.2 equivalence). The mixture was stirred overnight at room temperature. The pyridine was removed under vacuum, and the residue was purified by silicone column chromatography to give a white solid. [A98] (4-Methylbenzenesulfonic acid (1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl ester, 40 g, 86.4%). Step 2) Synthesize A99

[0222] Treatment with potassium thioacetate (9.3 g, 81.3 mmol, 3.0 equivalents) [A98] (10.0 g, 27.1 mmol, 1.0 equivalence) was dissolved in DMF (100 mL), and the reaction mixture was stirred at 60 °C for 4 hours under nitrogen. 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 silicone column chromatography to give a white solid. [A99] (S-((1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl)thioacetate, 3.0 g, 40.5%). Step 3) Synthesize A100

[0223] At 0℃ [A99] (2.50 g, 9.16 mmol, 1.0 equivalence) was bubbled with chlorine gas in a solution of DCM (30 mL) and water (30 mL) for 30 minutes. The two layers were separated, and the DCM layer was washed with an aqueous solution of sodium thiosulfate and brine, dried over sodium sulfate, filtered, and concentrated to obtain a crude solid in brown form. [A100] (((1s,4s)-4-(chlorosulfonyl)cyclohexyl)aminoformate tributyl ester). Step 4) Synthesize A101

[0224] 4-hydroxybenzohydrazine ( [A2] , 2.76 g, 18.2 mmol, 2.0 equivalence) of a solution in pyridine (10 mL) was added dropwise to [A100] (crude substance) was added to a solution in DCM (5 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum, and the crude product was purified by silicone column chromatography to obtain a white solid. [A101] (((1s,4s)-4-((2-(4-hydroxybenzoyl)hydrazyl)sulfonyl)cyclohexyl)aminoformate tributyl ester, 0.2 g, 5.3% for 2 steps). Step 5) Synthesize compound 43((1s,4s)-4-amino-N'-(4-hydroxybenzoyl)cyclohexane-1-sulfadiazine)

[0225] Will [A101] (200 mg, 4.2 mmol, 1.0 equivalence) 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, and the solvent was concentrated under vacuum. The residue was dissolved in MeOH, purified by preparative HPLC, and freeze-dried to obtain a yellow solid. [Compound]

[43] ((1s,4s)-4-amino-N'-(4-hydroxybenzoyl)cyclohexane-1-sulfadiazine, 20 mg, 13.2%). 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). LCMS; MS calculated value: 313.11; MS experimental value: 313.9 ([M+1]+). [Experimental Examples] [1-44.] [Preparation of Compounds]

[44] [(] [(1, R , ,4, R , )-4-] [Amine] [-, N' , -(4-] [Hydroxybenzoyl] [)] Cyclohexane [-1-] [Sulfohydrazine] [)]

[0226] By using ((1s,4s)-4-hydroxycyclohexyl)aminoformate tributyl ester instead of A97 as the starting material, in order to... [Experimental Examples] [1-45] Synthesized in the same manner as in the present invention, the substance is a white solid. [Compound]

[44] (26.7% yield). 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). LCMS; MS calculated value: 313.11; MS experimental value: 313.9 ([M+1]+). [Experimental Examples] [1-45.] [Preparation of Compounds]

[45] [(] [4-((2-(4-] [Hydroxybenzoyl] [)] [Hydrazine] [)] [sulfonyl] [)-5-] [Methylfuran] [-2-] [Formic acid] Step 1) Synthesize A102

[0227] A mixture of 10 g (80 mmol) of 5-methylfuran-2-carboxylic acid and 30 mL of chlorosulfonic acid was stirred at 50 °C for 3 hours before quenching with ice water. The aqueous layer was extracted with DCM, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a compound as a yellow solid. [A102] (14 grams). 1HNMR (DMSO_d6, 400 MHz): 13.95 (s, 1H), 6.97 (s, 1H), 2.50 (s, 3H). Step 2) Synthesize compound 45(4-((2-(4-hydroxybenzoyl)hydrazino)sulfonyl)-5-methylfuran-2-carboxylic acid)

[0228] compound [A102] (5 g, 22.3 mmol) and compounds The mixture of [A2] (3.4 g, 22.3 mmol) in pyridine (50 mL) was stirred overnight at 60 °C. The solution was poured into water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give the crude product. The residue was purified by preparative HPLC to give a yellow solid. [Compound]

[45] (4-((2-(4-hydroxybenzoyl)hydrazyl)sulfonylurea)-5-methylfuran-2-carboxylic acid, 1.3 g) 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). [Experimental Examples] [1-46] [Preparation of Compounds]

[46] [(] [ N' , ] [-(4-)] [Hydroxybenzoyl] [)] [Pyrrolidine] [-3-] [Sulfohydrazine] [)] Step 1) Synthesize A104

[0229] At 0℃ [A103] (5.00 g, 26.7 mmol, 1.0 equivalence) and TEA (5.40 g, 53.4 mmol, 2.0 equivalence) were added dropwise to a stirred solution in DCM (50 mL) with methanesulfonyl chloride (4.59 g, 40.1 mmol, 1.5 equivalence). The mixture was stirred at room temperature for 2 hours. The mixture was quenched with H2O (100 mL) and extracted with DCM (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried, and concentrated. The residue was purified by column chromatography (PE / EA = 100:1–10:1) to give a yellow oil. [A104] (5.0 g, yield 70.6%). (PE / EA = 10:1, Rf = 0.6) Step 2) Synthesize A105

[0230] Will A mixture of [A104] (5.00 g, 18.9 mmol, 1.0 equivalence) and potassium thioacetate (4.30 g, 37.7 mmol, 2.0 equivalence) in DMF (50 mL) was stirred at 70 °C for 16 hours. The mixture was treated with H2O (200 mL) and extracted with EA (200 mL × 2). The combined organic layers were washed with H2O (100 mL × 3) and brine (100 mL), dried, and concentrated. The residue was purified by column chromatography (PE / EA = 50:1–5:1) to give a brown solid. [A105] (2.0 g, yield 43.4%). Step 3) Synthesize A106

[0231] Towards [A105] (2.00 g, 8.16 mmol, 1.0 equivalence) of N-chlorodiamide (5.45 g, 40.8 mmol, 5.0 equivalence) was added to a stirred solution of acetic acid (AcOH 30 mL) and H₂O (30 mL). 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) to give a yellow oil. [A106] (1.0 g, yield 45.6%). (PE / EA=3:1, Rf=0.5) 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). Step 4) Synthesize A107

[0232] Add dropwise 4-hydroxybenzohydrazine (0.56 g, 3.71 mmol, 1.0 equivalence) dropwise to a stirred solution of pyridinium (30 mL) at 0 °C. [A106] (1.00 g, 3.71 mmol, 1.0 equivalence) in a solution of pyridinium (10 mL). 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) to give a yellow oil. [A107] (0.50 g, yield 34.9%). (DCM / MeOH = 10:1, Rf = 0.4) Step 5) Synthesize compound 46(N'-(4-hydroxybenzoyl)pyrrolidine-3-sulfadiazine)

[0233] At 0℃, towards [A107] (500 mg, 1.30 mmol, 1.0 equivalence) was added to a mixture of DCM (10 mL) and TFA (4 mL). The mixture was stirred at room temperature for 4 hours. The solution was concentrated and purified by preparative HPLC and lyophilized to obtain a yellow solid. [Compound]

[46] (N'-(4-hydroxybenzoyl)pyrrolidine-3-sulfadiazine, 30 mg, yield 7.0%). (TLC:N / A) 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). [Experimental Examples] [1-47.] [Preparation of Compounds]

[47] [(] [ N' , ] [-(4-)] [Hydroxybenzoyl] [)-1, H , -] [pyrrolo] [[2,3-b]] [Pyridine] [-2-] [Sulfohydrazine] [)] Step 1) Synthesize A109

[0234] At 0°C, 1H-pyrrolo[2,3-b]pyridine ( [A108] , 6.00 g, 50.8 mmol, 1.0 equivalence) of NaH (2.44 g (60% w / w), 60.9 mmol, 1.2 equivalence) was added to a mixture of THF (60 mL) and stirred at 0 °C for 1 hour. Then, THF (20 mL) containing TsCl (9.65 g, 50.8 mmol, 1.0 equivalence) was added dropwise to the solution. The solution was stirred for 16 hours. The above solution was poured into water (200 mL) and extracted with EA (100 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to obtain a crude product. The crude product was washed with PE (30 mL) for 1 hour, filtered, and the solid was collected. The solid was dried under vacuum to obtain a white solid. [A109] (11.0 g, yield 79.5%). (TLC: N / A) *LCMS; Calculated mass: 272.32; MS experimental value: 273.1 [MS+1]. Step 2) Synthesize A110

[0235] At -76℃, towards [A109] n-BuLi (3.24 mL, 8.08 mmol, 1.1 equivalence) was added dropwise to a mixture of [A109] (2.00 g, 7.35 mmol, 1.0 equivalence) in THF (20 mL). The mixture was stirred at -76 °C for 1 hour. The mixture was then stirred at -76 °C to 10 °C under an SO2 balloon for 1 hour, and the solution was concentrated. DCM containing the residue (30 mL) was added to NCS (1.58 g, 11.7 mmol, 1.6 equivalence) at 20 °C, and the mixture was stirred at 20 °C for 1 hour. The solution was poured into water (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give a yellow solid. [A110] (1.30 g, yield 47.8%). LCMS; calculated mass: 370.82; experimental MS: 371.0 [MS+1]. Step 3) Synthesize A111

[0236] At 10℃, towards [A110] (1.30 g, 3.51 mmol, 1.0 equivalence) was added dropwise to a mixture containing 4-hydroxybenzohydrazine in pyridine (10 mL). [A2] , 587 mg, 3.86 mmol, 1.1 equivalence) of pyridine (5 mL). The mixture was then stirred at 10 °C for 3 hours. The above solution was poured into water (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with 1N HCl (50 mL × 2) and brine (50 mL), dried over Na2SO4 and concentrated to give a crude product. The crude product was washed with EA (5 mL), filtered, and dried under vacuum to give a yellow solid. [A111] (600 mg, yield 35.3%). (TLC: N / A) LCMS; calculated mass value: 486.51; experimental MS value: 487.1 [MS+1]. Step 4) Synthesize compound 47 (N'-(4-hydroxybenzoyl)-1H-pyrrolo[2,3-b]pyridine-2-sulfadiazine)

[0237] Towards [A111] (350 mg, 0.71 mmol, 1.0 equivalence) was added to a mixture of MeOH (6 mL) and concentrated HCl (2 mL) was added. The mixture was then stirred at 60 °C for 3 hours. The solution was concentrated, and the crude product was purified by preparative HPLC and lyophilized to give a white solid. [Compound]

[47] (N'-(4-hydroxybenzoyl)-1H-pyrrolo[2,3-b]pyridine-2-sulfadiazine, 20 mg, yield 8.36%). (TLC:N / A) 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). LCMS; calculated mass value: 332; experimental MS value: 333 [MS+1]. [Experimental Examples] [1-48.] [Preparation of Compounds]

[48] [(] [4-] [Hydroxy] [-, N' , -(4-] [Methoxybenzyl] [)] [Benzylhydrazine] [)]

[0238] Using the same preparation method as in Experimental Examples 1-19, 1-(bromomethyl)-4-methoxybenzene was used instead of 1-(bromomethyl)-4-nitrobenzene to obtain [Compound]

[48] [Experimental Examples] [1-49.] [Preparation of Compounds]

[49] [(] [ N' , ] [-(4-)] [Aminobenzyl] [)-2,3-] [Dihydrogen] [-1, H , -] [Indonesia] [-2-] [Carbazine] [)]

[0239] Using the same preparation method as in Experimental Examples 1-19, [A60] (2,3-dihydro-1H-indene-2-carbazine) instead [A2] is obtained as a starting material. [Compound]

[49] [Experimental Examples] [1-50.] [Preparation of Compounds]

[50] [(] [4-] [Amine] [-, N , -(2-(4-] [Hydroxyphenyl] [)-2-] [Side-oxyethyl] [)-3-] [Morphyrinylbenzenesulfonamide] [)]

[0240] By using a preparation method similar to that in Experimental Examples 1-12, 3-fluoro-4-nitrobenzenesulfonyl chloride was used instead of 4-nitrobenzene-1-sulfonyl chloride in step 3 of Experimental Examples 1-12 to obtain [Compound]

[50] [Experimental Examples] [1-51.] [Preparation of Compounds]

[51] [(] [3,5-] [Diamino group] [-, N , -(2-(4-] [Hydroxyphenyl] [)-2-] [Side-oxyethyl] [)] [benzenesulfonamide] [)]

[0241] By using a preparation method similar to that in Experimental Examples 1-12, 3,5-dinitrobenzenesulfonyl chloride (A20) was used instead of 4-nitrobenzene-1-sulfonyl chloride in step 3 of Experimental Examples 1-12 to obtain [Compound]

[51] [Experimental Examples] [1-52.] [Preparation of Compounds]

[52] [(] [2-((4-] [Aminophenyl] [)] [sulfonyl] [)-, N , -(3-] [Hydroxyphenyl] [)] [Hydrazine] [-1-] [Methionine] [)]

[0242] Using the same preparation method as in Experimental Examples 1-27, but replacing benzene isocyanate in step 3 of Experimental Examples 1-27 with 3-isocyanophenol, we obtained... [Compound]

[52] [Experimental Examples] [1-53.] [Preparation of Compounds]

[53] [(] [2-((4-] [Amine] [-3-] [morpholinophenyl] [)] [sulfonyl] [)-, N , -] [Phenylan] [-1-] [Methionine] [)]

[0243] By using a preparation method similar to that in Experimental Examples 1-27, 3-fluoro-4-nitrobenzenesulfonyl chloride was used instead of 4-nitrobenzenesulfonyl chloride as the starting material to obtain [Compound]

[53] [Experimental Examples] [1-54.] [Preparation of Compounds]

[54] [(] [4-] [Hydroxy] [-, N , -(((4-] [Methoxyphenyl] [)] [sulfonyl] [)] [methyl] [)] [Benzylamine] [)]

[0244] Using the same preparation method as in Experimental Examples 1-16, 4-methoxybenzylthiophenol was used instead of 4-nitrobenzylthiol to obtain [Compound]

[54] [Experimental Examples] [1-55.] [Preparation of Compounds]

[55] [(] [ N , ] [-(((4-] [Aminophenyl] [)] [sulfonyl] [)] [methyl] [)-[1,1'-] [Biphenyl] []-4-] [Methionine] [)]

[0245] Using a preparation method similar to that in Experimental Examples 1-16, [1,1'-biphenyl]-4-carboxymethylamine was used instead of intermediate A28 in Experimental Examples 1-16 as the starting material to obtain [Compound]

[55] [Example] [2.] [Combined analysis of experiments] [Example] [2-1] [Confirm if muscle actin is present] [Arg / N-] [Degradation Determinant Pathway Matrix]

[0246] L6 cell lines (rat myogenic cells) were cultured in DMEM medium containing 10% FBS and 1% streptomycin / penicillin in an incubator maintained at 5% CO2, and the cells were aliquoted into 12-well plates after culture. Cells were cultured for an additional 24 hours to allow complete attachment to the plate surface. To confirm whether MG132 increased UBR1 binding, cells were collected after treatment with MG132 (10 μmol) alone for 24 hours. For protein extraction from the collected 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, antifibrinolytic peptide, and aprotinin) was injected into each sample, and cells were lysed. Based on the measured total protein concentration, sample buffer was added to each sample, and the mixture was incubated at 100°C for 5 minutes. After taking 5 μL of the fully reacted sample and aliquoting it into each well of the acrylamide gel, an immunoblotting assay was performed, and the results are shown in [Figure 1].

[0247] For the immunoblotting method, a representative experiment is illustrated based on three or more independent experiments.

[0248] Referring to Figure 1, it has been confirmed that the levels of ACTA1, ACTC1, and ACTG2 increased by MG132 compared to the control. Furthermore, it has been confirmed that the levels of ACTA1 and ACTG2 increased when UBR protein gene expression was blocked. That is, muscle actin can be confirmed as the matrix of the Arg / N-degradation determinant pathway. [Example] [2-2] [Through in vitro transcription] [ / ] [Translation Method Confirmation] [R-nsP4] [Inhibition of Degradation]

[0249] The TnT® rapid coupling transcription / translation system kit was used to confirm the R-nsP4 expression of the compound. After preparing a premix using Transcend Biotin-Lysyl-tRNA, methionine, bestatin, TnTquick master mix, and DHFR-Ub-R-nsP4 plasmids, the premix was mixed with the compound (1 μmol). After incubating each sample at 30°C for 40 min, 5X SDS-loaded dye was added. After incubating the resulting mixture at 95°C for 2 min, 5 μL was aliquoted into each well of an acrylamide gel and subsequently subjected to immunoblotting. The results are shown in [Figure 2]. For in vitro transcription / translation, a representative experiment is schematically shown based on three or more independent experiments.

[0250] Referring to Figure 2, it can be confirmed that the content of R-nsP4 increases by compounds 2, 3, 7, 12, 14 and 16 compared to the control. That is, it can be confirmed that the content of R-nsP4 increases by binding with UBR1 when treated with the compounds according to the present invention. [Example] [2-3] [Assessing intracellular activity through transfection] [RGS4] [Inhibition of Degradation]

[0251] L6 cell lines (rat myogenic cells) were cultured in a DMEM medium containing 10% FBS and 1% streptomycin / penicillin in an incubator maintained at 5% CO2. To measure UBR1 binding strength based on treatment with a representative compound selected from the compounds of this invention, cells were aliquoted into 6-well plates. Cells were cultured for an additional 24 hours to allow complete attachment to the plate surface. Transfection was performed using Opti-MEM, lipoamine, and RGS4 plastids. After the reaction, cells were treated to induce intracellular DNA expression. Cells were collected after 24 hours of treatment with the compound alone (5 μmol) to confirm whether the compound increased UBR1 binding after 24 hours. To extract proteins from the collected 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, antifibrinolytic peptide, and aprotinin) 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 the mixture was incubated at 100°C for 5 minutes. After 5 μL of the fully reacted sample was aliquoted into each well of an acrylamide gel, an immunoblotting assay was performed, and the results are shown in [Figure 3]. For the immunoblotting assay, a representative experiment is schematically illustrated based on three or more independent experiments.

[0252] Referring to Figure 3, it can be confirmed that the content of RGS4 increases by compounds 2 and 3 compared to the control. That is, it can be confirmed that the content of RGS4 increases by binding with UBR1 when treated with the compounds according to the present invention. [Example] [2-4] [Assessment of Inhibition of Actin Degradation in Muscle Cells Using Immunomodulator Dots]

[0253] To assess the effect of the compounds on actin degradation in muscle cells, L6 cell lines (rat myogenic cells) were cultured in DMEM medium containing 10% FBS and 1% streptomycin / penicillin in an incubator maintained at 5% CO2. To measure UBR1 binding strength based on treatment with a representative compound selected from the compounds of this invention, cells were aliquoted into 12-well plates. Cells were cultured for an additional 24 hours to allow complete attachment to the plate surface. Cells were collected after treatment with the compound alone (5 μmol) for 24 hours to confirm whether the compound increased UBR1 binding. To extract proteins from the collected 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, antifibrinolytic peptide, and aprotinin) was injected into each sample, and cells were lysed. Based on the measured total protein concentration, sample buffer was added to each sample and the mixture was reacted at 100°C for 5 minutes. After aliquoting 5 μL of the fully reacted sample into each well of an acrylamide gel, an immunodiffusion assay was performed, and the results are shown in [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], and [Figure 9]. For the immunodiffusion assay, a representative experiment is schematically illustrated based on three or more independent experiments.

[0254] Referring to Figures 4 and 5, it can be confirmed that, compared to the control, the content of ACTA1 is further increased by compounds 1, 2, 3, 4, 5, 6, 7, 16, 35, 36, 37, 38, 39, 43, 44, 45, 46, and 47. That is, it can be confirmed that, when treated with the compounds according to the present invention, the degradation of the muscle protein ACTA1 is inhibited by binding to UBR1.

[0255] Referring to Figures 6 and 7, it can be confirmed that, compared to the control, the ACTA2 content is further increased by compounds 8, 9, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 32, 33, and 34. That is, it can be confirmed that, when treated with the compounds according to the present invention, the degradation of the muscle protein ACTA2 is inhibited by binding to UBR1.

[0256] Referring to Figure 8, it can be confirmed that the ACTC1 content is further increased by compounds 41 and 42 compared to the control. That is, it can be confirmed that when treated with the compounds according to the present invention, the degradation of the muscle protein ACTC1 is inhibited by binding to UBR1.

[0257] Referring to Figure 9, it can be confirmed that the ACTG2 content is further increased by compounds 12, 13, 14, 15, 17, 29, 30, and 31 compared to the control. That is, it can be confirmed that when treated with the compounds according to the present invention, the degradation of the muscle protein ACTG2 is inhibited by binding to UBR1. [Example] [2-5] [Assessment through immunoprecipitation analysis] [UBR] [Box-structure domain bonding strength]

[0258] To assess the binding strength of the compounds to UBR1, UBR2, UBR3, and UBR5 via the UBR box domain, L6 cell lines (rat myogenic cells) were cultured in DMEM medium containing 10% FBS and 1% streptomycin / penicillin in an incubator maintained at 5% CO2. To measure UBR1 binding strength based on treatment with a representative compound selected from the compounds of this invention, cells were aliquoted into 100 pi dishes. Cells were further cultured for 24 hours to allow complete attachment to the dish surface. To confirm whether the compounds increased UBR1 binding, cells were treated for 24 hours with either the compound alone (5 mmol), the proteasome inhibitor MG132 (10 mmol), or a positive control (5 mmol), and cells were subsequently harvested. To extract proteins from the collected 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, antifibrinolytic peptide, and aprotinin) was injected into each sample, and the cells were lysed. Based on the measured total protein concentration, each sample was reacted with UBR1 antibody for 16 hours, followed by reaction with protein A / G beads for 3 hours. Sample buffer was added to the fully reacted sample, and the resulting mixture was incubated at 100°C for 5 minutes. After 20 μL of the fully reacted sample was aliquoted into each well of an acrylamide gel, an immunodye assay was performed, and the results are shown in [Figure 10] and [Figure 11]. For the immunodye assay, a representative experiment is schematically shown based on three or more independent experiments.

[0259] Referring to Figures 10 and 11, similar to the positive control, the decrease in binding strength of ACTA1, UBR2 and ACTA1, UBR3 and ACTA1, and UBR5 and ACTA1 when cells were treated with the compound confirms that compound 2 (which is the compound according to the invention) actually binds to the UBR box domain of the UBR protein. The binding strength between UBR1 and matrix ACTA1 was maintained when cells were treated with the DMSO control group, and the proteasome inhibitor MG132 was used as a negative control.

[0260] That is, it can be confirmed that when treated with the compound according to the invention, the degradation of the muscle protein ACTG2 is inhibited by binding to UBR1, UBR2, UBR3 or UBR5. [Example] [2-6] [By] [MST] [Evaluate] [UBR] [Box-structure domain bonding strength] 1) Preparation of UBR1 protein

[0261] The Gln97-Pro168 moiety (UniProt ID: Q8IWV7) corresponding to the human UBR1 UBR1 cassette was selected and colonized into a modified expression vector, and subsequently expressed in *E. coli*. Following affinity chromatography, the label was removed by protease, and then Gly-His-Met was added to the N-terminus. After ion chromatography, the final UBR1 cassette protein was purified by gel filtration chromatography in a buffer solution of 10 mM NaCl, 20 mM Tris-HCl, 2 mM β-mercaptoethanol, and pH 7.5. 2) UBR1 UBR box protein labeling

[0262] The Monolith protein labeling kit RED-NHS Generation 2 dye (catalog number MO-L011) has an NHS-ester group that forms a covalent bond with a primary amine (lysine residue). This dye is optimized for Monolith series devices equipped with RED detectors. Use this kit to label purified UBR1 UBR box proteins according to the provided protocol. 3) Use MST to measure whether there is binding between UBR1 and the ligand.

[0263] Thermophoresis refers to the phenomenon of particles moving due to temperature gradients. Particles in high-temperature regions have greater kinetic energy than those in low-temperature regions and collide more frequently with surrounding particles that have even greater energy. Therefore, particles move from high-temperature regions to low-temperature regions.

[0264] Thermophoresis of proteins typically differs from that of protein-ligand complexes. This is because ligand binding alters their size, charge, and solubility. Furthermore, even if ligand binding does not significantly change the size and charge of the protein, MST can detect changes in the solventhalpy of the protein molecule caused by ligand binding. Therefore, MST was used to measure the binding of the UBR1 UBR box protein to the ligand compound and to confirm the binding of the provided ligand to the UBR1 UBR box (see Figures 12 to 19).

[0265] none

Claims

1. A compound having the structure of Formula 1: [Formula 1] or a salt thereof, wherein X1 is a selectively substituted or unsubstituted phenyl, cycloalkyl, or heterocyclic group substituted with one or more R2 groups; 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 heterocyclic alkyl; X4 is a selectively substituted or unsubstituted phenyl, cycloalkyl, or heterocyclic group substituted with one or more R3 groups; each R3 is independently selected from alkyl, alkoxy, amino, halogen, hydroxyl, alkylamino, dialkylamino, -NO2, -CONR'R'', -CO2 R', -NHCOR', phenyl, or heterocyclic alkyl; each R' and R'' is independently -H or alkyl; X2 is SO2 or CRa Rb; Ra and Rb are each independently H or CH3; X3 is NH or CH2; B1 is CH2 or NH; A1 is CH2 or NH.

2. The compound as claimed in claim 1, wherein the -X2 -B1 -X3 of formula 1 is selected from the group consisting of: SO2 -NH-NH, -SO2 -NH-CH2, -SO2 -CH2 -NH and -CH2 -NH-NH.

3. The compound as claimed in claim 1, wherein formula 1 is formula 1-1: [Formula 1-1].

4. The compound as claimed in claim 1, wherein formula 1 is formula 1-2: [formula 1-2].

5. The compound as claimed in claim 1, wherein formula 1 is formula 1-3: [Formula 1-3].

6. The compound as claimed in claim 1, wherein formula 1 is formula 1-4: [formula 1-4].

7. The compound of any one of claims 1 to 6, wherein each X1 and X4 is independently a substituted or unsubstituted phenyl, cycloalkyl, or heterocyclic group; wherein each X1 and X4 is independently selected from substituted or unsubstituted phenyl, cyclohexyl, cyclopentyl, furanyl, thiazolyl, 1H-pyrazolyl, pyrrolidyl, piperidinyl, piperazinyl, morpholinyl, indololinyl, 1H-indololinyl, 1H-inzolyl, isoindololinyl, indololin-2-one, 2,3-dihydro-1H-indenyl, and 1H-pyrrolopyridinyl.

8. The compound of any one of claims 1 to 6, wherein each of the R2 is independently selected from methyl, ethyl, amino, aminoalkyl, amino(hydroxyalkyl), methoxy, ethoxy, -C(=NH)NH2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)OH, phenyl, pyrrolidyl, piperazine, piperidinyl and morpholinyl.

9. The compound as claimed in claim 8, wherein R2 is an amino group.

10. The compound as claimed in any one of claims 1 to 6, wherein X1 is or.

11. The compound of any one of claims 1 to 6, wherein each R3 is independently selected from hydroxyl, fluorine, chlorine, bromine, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, alkylamino, dialkylamino, -NO2, -C(=O)NH2, -CO2R', -NHCOR', -CONR'R'', and phenyl; and each R' and R'' is independently -H or alkyl.

12. The compound as claimed in claim 11, wherein R3 is a hydroxyl group.

13. The compound of any one of claims 1 to 6, wherein X4 is, or.

14. The compound of claim 3, wherein the compound is selected from the following: N'-(4-hydroxybenzoyl)-4-methylbenzenesulfonhydrazine; 4-amino-N'-(4-hydroxybenzoyl)benzenesulfonhydrazine; 4-amino-N'-(4-hydroxybenzoyl)-3-morpholinylbenzenesulfonhydrazine; N'-(4-hydroxybenzoyl)-2-sideoxyindoline-5-sulfonhydrazine; N'-(4-hydroxybenzoyl)indoline-5-sulfonhydrazine; N'-([1,1'-biphenyl]-4-carbonyl)-4-aminobenzenesulfonhydrazine; N'-([1,1'-biphenyl]-3-carbonyl)-4-aminobenzenesulfonhydrazine; 3-Amino-N'-(4-hydroxybenzoyl)benzenesulfonhydrazide; 4-(1-aminoethyl)-N'-(4-hydroxybenzoyl)benzenesulfonhydrazide; 3,5-Diamino-N'-(4-hydroxybenzoyl)benzenesulfonhydrazide; N'-(4-hydroxybenzoyl)-4-((2-hydroxyethyl)amino)benzenesulfonhydrazide; N'-(4-hydroxybenzoyl)-4-methoxybenzenesulfonhydrazide; 4-((2-(4-hydroxybenzoyl)hydrazyl)sulfonyl)benzamidinium; 4-((2-(4-hydroxybenzoyl)hydrazyl)sulfonyl)benzamide; 6-Amino-N'-(4-hydroxybenzoyl)-[1,1'-biphenyl]-3-sulfonylhydrazine; 4-(2-((4-aminophenyl)sulfonyl)hydrazine-1-carbonyl)benzylamine; 4-Amino-N'-(1H-indole-3-carbonyl)benzylsulfonylhydrazine; 4-Amino-N'-(4-hydroxybenzoyl)-3-(pyrrolidin-1-yl)benzylsulfonylhydrazine; N'-(4-hydroxybenzoyl)-4-nitro-3-(pyrrolidin-1-yl)benzylsulfonylhydrazine; 4-Amino-N'-(4-hydroxybenzoyl)-3-(piperidin-1-yl)benzylsulfonylhydrazine; N'-(4-hydroxybenzoyl)-1H-pyrazole-4-sulfonylhydrazine; N'-(4-hydroxybenzoyl)indoline-4-sulfadiazine; N'-(4-hydroxybenzoyl)-1H-indoline-4-sulfadiazine; 2-((4-aminophenyl)sulfadiazine)-N-phenylhydrazine-1-methylamine; 4-amino-N'-(1H-indoline-4-carbonyl)-3-morpholinylbenzenesulfadiazine; 4-amino-N'-(indoline-4-carbonyl)benzenesulfadiazine; 4-amino-N'-(4-hydroxybenzoyl)-3-(piperazin-1-yl)benzenesulfadiazine; 4-amino-N'-(2,3-dihydro-1H-indene-2-carbonyl)benzenesulfadiazine; 4-amino-N' -(isoindoline-2-carbonyl)benzenesulfonhydrazide; N'-(4-hydroxybenzoyl)-1H-indole-2-sulfonhydrazide; 4-amino-N'-(2-phenylacetyl)benzenesulfonhydrazide; N'-(4-hydroxybenzoyl)-1H-indazole-3-sulfonhydrazide; 4-amino-N'-(indoline-6-carbonyl)benzenesulfonhydrazide;4-Amino-N'-(Indoline-3-carbonyl)benzenesulfonhydrazide; N'-(4-hydroxybenzoyl)piperidine-4-sulfonhydrazide; 4-Amino-N'-(Indoline-6-carbonyl)-3-morpholinylbenzenesulfonhydrazide; 4-Amino-N'-(piperazine-1-carbonyl)benzenesulfonhydrazide; 4-Amino-3-morpholinyl-N'-(piperazine-1-carbonyl)benzenesulfonhydrazide; N'-(4-hydroxybenzoyl)-2-methylthiazolyl-4-sulfonhydrazide; (1S,4S)-4-Amino-N'-(4-hydroxybenzoyl)cyclohexane-1-sulfonhydrazide; (1R,4R)-4-Amino-N'-(4-hydroxybenzoyl)cyclohexane-1-sulfonhydrazide; 4-((2-(4-hydroxybenzoyl)hydrazyl)sulfonyl)-5-methylfuran-2-carboxylic acid; N'-(4-hydroxybenzoyl)pyrrolidin-3-sulfadiazine; N'-(4-hydroxybenzoyl)-1H-pyrrolo[2,3-b]pyrrolidin-2-sulfadiazine; 2-((4-aminophenyl)sulfonyl)-N-(3-hydroxyphenyl)hydrazine-1-methylamine; 2-((4-aminophenyl)sulfonyl)-N-phenylhydrazine-1-methylamine; and 2-((4-amino-3-morpholinylphenyl)sulfonyl)-N-phenylhydrazine-1-methylamine.

15. The compound of claim 14, wherein the compound is selected from the following: 4-amino-N'-(4-hydroxybenzoyl)benzenesulfonhydrazide; 2-((4-aminophenyl)sulfonyl)-N-phenylhydrazine-1-methylamine; 4-amino-N'-(4-hydroxybenzoyl)-3-morpholinylbenzenesulfonhydrazide; and 4-amino-N'-(1H-indole-4-carbonyl)-3-benzenesulfonhydrazide.

16. The compound of claim 4, wherein the compound is selected from the following: N'-(4-aminobenzyl)-4-hydroxybenzylhydrazine; 4-hydroxy-N'-(4-methoxybenzyl)benzylhydrazine; and N'-(4-aminobenzyl)-2,3-dihydro-1H-indene-2-carbohydrazine.

17. The compound of claim 5, wherein the compound is selected from the following: 4-amino-N-(2-(4-hydroxyphenyl)-2-sideoxyethyl)benzenesulfonamide; 4-amino-N-(2-(4-hydroxyphenyl)-2-sideoxyethyl)-3-morpholinylbenzenesulfonamide; and 3,5-diamino-N-(2-(4-hydroxyphenyl)-2-sideoxyethyl)benzenesulfonamide.

18. The compound of claim 6, wherein the compound is selected from the following: N-(((4-aminophenyl)sulfonyl)methyl)-4-hydroxybenzamide; 4-hydroxy-N-(((4-methoxyphenyl)sulfonyl))methyl)benzamide; and N-(((4-aminophenyl)sulfonyl)methyl)-[1,1'-biphenyl]-4-methylamine.

19. A pharmaceutical composition for treating UBR-related diseases, wherein the composition comprises a compound as described in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition for treating UBR-related diseases as described in claim 19, wherein the UBR-related diseases include muscle loss caused by muscular dystrophy (Becker, congenital, Duchenne, distal, Emery-Dreifuss, face-shoulder-arm, limb-girdle, myotonic, ocuophargyngeal); muscular atrophy diseases mediated by muscle loss or degradation, including sarcopenia or cancer cachexia; diseases caused by excessive protein degradation, including liposarcoma, cystic fibrosis, Johanson-Blizzard syndrome, obstructive urinary tract diseases (urethral obstruction sequence); autoimmune pancreatitis; or known diseases associated with the UBR box and UBR protein, including Usher syndrome.