Novel low-molecular compounds inhibiting irp2

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating cancer, comprising a benzenesulfonamide-substituted heterobicyclic derivative as an IRP2 interfering substance as an effective ingredient, which can provide a benzenesulfonamide-substituted heterobicyclic derivative compound that kills solid cancer cells, particularly colorectal cancer cells, by hindering the binding of IRP2 to IRE, thereby inducing the reprogramming of iron metabolism in cancer cells.

Description

Technical Field

[0001] This invention relates to a benzenesulfonamide-substituted heterobicyclic derivative as an IRP2 interfering substance, its preparation method, and its pharmaceutical uses.

[0002] This invention relates to a pharmaceutical composition for cancer prevention or treatment of a benzenesulfonamide-substituted heterobicyclic derivative that is an IRP2 interfering substance.

[0003] This invention relates to a pharmaceutical composition for the prevention or treatment of colorectal cancer, which is a benzenesulfonamide-substituted heterobicyclic derivative that acts as an IRP2 interfering substance. Background Technology

[0004] Iron is an essential biological component for DNA synthesis, mitochondrial respiration, and cell proliferation. Iron homeostasis is involved in redox activity, mitochondrial function, cell growth, and cell death (Miyazawa et al., 2019; Zhang et al., 2020). In particular, cancer cells have a relatively higher iron requirement to maintain cell growth compared to normal cells, and therefore, disorders in iron metabolism are frequently observed.

[0005] In all mammals, iron regulatory proteins 1 and 2 (IRP1 and 2) control intracellular iron homeostasis by binding iron-responsive elements (IREs) in the 5' or 3' untranslated regions (UTRs) of selected mRNAs (Jiao et al., 2019; Wang et al., 2020). Typically, in the 5' UTR of mRNA, IRP binding to IREs inhibits the translation of proteins including ferritin H (FTH) and ferroportin (FPN) (Li et al., 2019; Martelli et al., 2015), while IREs in the 3' UTR of mRNA activate the stability of transferrin receptor 1 (TfR1) and proteins containing divalent metallotransferrin 1 (DMT1) (Bellelli et al., 2016; Wallander et al., 2008).

[0006] IRP1 and IRP2 share high nucleotide sequence homology and are differentially expressed based on cellular iron availability, playing a crucial role in iron metabolism reprogramming (Miyazawa et al., 2019). For reference, IRP1 is a universally expressed protein with a 4Fe-4S cluster that prevents IRP1 from binding to IREs, while IRP2 is a selectively expressed protein lacking an iron-sulfur cluster and reported as the dominant IRE-binding protein (Moroishi et al., 2011). When there is iron overload in the cell, IRP1 activates binding to 4Fe-4S, while IRP2 is degraded by F-box and Leucine Rich Repeat Protein 5 (FBXL5) and E3 ubiquitin ligase (Muto et al., 2017; Zumbrennen-Bullough et al., 2014).

[0007] Colorectal cancer is the second leading cause of cancer death worldwide, after lung cancer. Compared to other cancer types, colorectal cancer has a low response rate to standard therapies and exhibits resistance to targeted therapies. For example, epidermal growth factor receptor (EGFR) inhibitors have shown effective responses in patients with KRAS wild-type tumors (Missiaglia et al., 2014). Furthermore, while promising new immunotherapies are available, they are only suitable for less than 5% of all patients with highly microsatellite instability (MSI-H) metastatic colorectal cancer, which is the ultimate limit to treatment development (Andre et al., 2020). Therefore, despite the increasing incidence of colorectal cancer, progress in the development of anticancer agents for colorectal cancer has stalled, with a 5-year survival rate of only 15% for stage IV colorectal cancer patients (Siegel et al., 2019). Although previous studies support the importance of excess iron and its direct consequences in colorectal cancer, therapies that reprogram iron metabolism in cancer cells, other than iron chelators, are currently unavailable. Therefore, the inventors hypothesize that by utilizing the difference in iron metabolism between cancer cells and normal cells, and targeting IRP2, cancer cell proliferation can be specifically inhibited, thereby inducing the development of effective cancer therapeutics.

[0008] In this study, the inventors identified a novel small-molecule inhibitor for blocking the binding of IRP2 to IRE through comprehensive quantum analysis, pharmacophore modeling, and molecular docking. They also discovered that inhibition of IRP2 by genetic or pharmacological methods disrupts cellular iron homeostasis and inhibits the growth of colorectal cancer cells in various model systems, including patient-derived cell lines, organoids, and tumor xenografts. Furthermore, the inventors elucidated the mechanism by which the therapeutic efficacy of the first IRP2 inhibitor compound 1, highlighting its association with colorectal cancer targeting IRP2, is demonstrated. Summary of the Invention

[0009] The problem the invention aims to solve The purpose of this invention is to provide a pharmaceutical composition for the prevention or treatment of colorectal cancer, comprising a benzenesulfonamide-substituted heterobicyclic derivative as an active ingredient, which kills colorectal cancer cells by inducing reprogramming of iron metabolism in cancer cells through hindering the binding of IRP2 to IRE.

[0010] means for solving problems This invention relates to a pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein the active ingredient comprises a compound represented by the following chemical formula 1, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof.

[0011] [Chemical Formula 1]

[0012] In the above chemical formula 1, R1 is selected from hydrogen, halogen, hydroxyl, amino, amide, cyano, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 Alkoxy, acetyl, acetamido, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkylamide, C5-C 10 Aryl, C5-C 10 heteroaryl, C4-C 10 cycloalkyl and C4-C 10 One or more substituents are used in the group consisting of heterocyclic alkyl groups; R2 is selected from hydrogen, halogen, hydroxyl, amide, CN, NO2, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C 10 The alkoxy group is substituted with one or more substituents from the group consisting of alkoxy, acetyl, C1-C6 alkylamino, di(C1-C6)alkylamino, di(C1-C6)alkylamino (C1-C6)alkyl, phenyl, and SEM (=2-(trimethylsilyl)ethoxymethyl). R3 can be hydrogen, halogen, or C1-C independently. 10 Alkoxy; R4 is selected freely substituted or unsubstituted (C5-C) 10 ) aryl-amino, substituted or unsubstituted (C5-C 10 Heteroaryl-amino, substituted or unsubstituted C5-C 10 Heteroaryl and substituted or unsubstituted C4-C 10 One or more substituents in the group consisting of heterocyclic alkyl groups are substituted. The substituted (C5-C) 10 ) aryl-amino, (C5-C 10Heteroaryl-amino, C5-C 10 heteroaryl or C4-C 10 In heterocyclic alkyl groups, one or more hydrogen atoms within the substituents are independently selected from hydrogen, halogen, hydroxyl, amide, halogenated C1-C6 alkyl, cyano, NO2, C1-C6 alkyl, acetyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl groups. 10 Alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C4-C 10 One or more substituents in the group consisting of heterocyclic alkyl groups are substituted. The substituted C1-C 10 Alkoxy, C3-C 10 cycloalkyl or C4-C 10 Heterocyclic alkyl groups are selected from hydrogen, halogen, hydroxyl, amide, halogenated C1-C6 alkyl, cyano, NO2, C1-C6 alkyl, and C1-C 10 One or more substituents are substituted in the group consisting of alkoxy groups; A can be CR1, CH, or N independently; It can be a single bond or a double bond; n is an integer from 0 to 3.

[0013] This invention relates to a pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein the active ingredient comprises a compound represented by the above-described chemical formula 1, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof.

[0014] In the above chemical formula 1, R1 is selected from hydrogen, halogen, hydroxyl, amino, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The substance is substituted with one or more substituents from the group consisting of alkoxy, acetyl, acetamido, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkylamide, phenyl, thiophene, and morpholino. R2 is selected from hydrogen, halogen, hydroxyl, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The alkoxy group is substituted with one or more substituents from the group consisting of alkoxy, acetyl, C1-C6 alkylamino, di(C1-C6)alkylamino, di(C1-C6)alkylamino (C1-C6)alkyl, phenyl, and SEM (=2-(trimethylsilyl)ethoxymethyl). R3 can be hydrogen, halogen, or C1-C independently. 10 Alkoxy; R4 can be freely replaced or not replaced. Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced and replaced or not replaced One or more substituents in the group constitute the group. The replacement , , , , or One or more hydrogen atoms in the substituent are independently selected from hydrogen, halogen, hydroxyl, amide, halogenated C1-C6 alkyl, CN, NO2, C1-C6 alkyl, acetyl, carbamoyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C4-C 10 Cycloalkyl and substituted or unsubstituted C4-C 10 One or more substituents from the group consisting of heterocyclic alkyl groups are used for substitution. The substituted C1-C 10 Alkoxy, C3-C 10 cycloalkyl or C4-C 10 Heterocyclic alkyl groups are selected from hydrogen, halogens, hydroxyl groups, amides, halogenated C1-C6 alkyl groups, CN, NO2, C1-C6 alkyl groups, and C1-C6 alkyl groups. 10 One or more substituents are substituted in the group consisting of alkoxy groups; A can be CR1, CH, or N independently; It can be a single bond or a double bond; n is an integer from 0 to 3.

[0015] This invention relates to a pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein the active ingredient comprises a compound represented by the following chemical formula 2, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof.

[0016] [Chemical Formula 2]

[0017] In the above chemical formula 2, R1 is selected from hydrogen, halogen, hydroxyl, amino, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The substance is substituted with one or more substituents from the group consisting of alkoxy, acetyl, acetamido, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkylamide, phenyl, thiophene, and morpholino. R2 is selected from hydrogen, halogen, hydroxyl, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The alkoxy group is substituted with one or more substituents from the group consisting of alkoxy, acetyl, C1-C6 alkylamino, di(C1-C6)alkylamino, di(C1-C6)alkylamino (C1-C6)alkyl, phenyl, and SEM (=2-(trimethylsilyl)ethoxymethyl). R3 can be hydrogen, halogen, or C1-C independently. 10 Alkoxy; R4 can be freely replaced or not replaced. Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced One or more substituents in the group constitute the group. The replacement , , , , or One or more hydrogen atoms in the substituent are independently selected from hydrogen, halogen, hydroxyl, amide, halogenated C1-C6 alkyl, CN, NO2, C1-C6 alkyl, acetyl, carbamoyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C4-C 10 One or more substituents from the group consisting of heterocyclic alkyl groups are used for substitution. The substituted C1-C 10 Alkoxy, C3-C 10 cycloalkyl or C4-C 10 Heterocyclic alkyl groups are selected from hydrogen, halogens, hydroxyl groups, amides, halogenated C1-C6 alkyl groups, CN, NO2, C1-C6 alkyl groups, and C1-C6 alkyl groups. 10 One or more substituents are substituted in the group consisting of alkoxy groups; n is an integer from 0 to 3.

[0018] This invention relates to a pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein the active ingredient comprises a compound represented by the above-described chemical formula 2, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof.

[0019] In the above chemical formula 2, R1 is substituted with one or more substituents selected from the group consisting of hydrogen, amino, amide, halogenated C1-C6 alkyl, C1-C6 alkyl, acetyl, acetamido, phenyl, thiophene, and morpholino. R2 is substituted by one or more substituents selected from the group consisting of hydrogen, halo-C1-C6 alkyl, C1-C6 alkyl and acetyl; R3 can be hydrogen, halogen, or C1-C6 alkoxy independently; R4 can be freely replaced or not replaced. and replaced or not taken One or more substituents in the group constitute the group. The replacement or One or more hydrogen atoms in a substituent are independently substituted by one or more substituents selected from the group consisting of hydrogen, halogen, halogenated C1-C6 alkyl, CN and C1-C6 alkyl and acetyl; n is an integer from 0 to 3.

[0020] This invention relates to a pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein the active ingredient comprises a compound represented by the following chemical formula 3, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof.

[0021] [Chemical Formula 3]

[0022] In the above chemical formula 3, R1 is selected from hydrogen, halogen, hydroxyl, amino, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The substance is substituted with one or more substituents from the group consisting of alkoxy, acetyl, acetamido, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkylamide, phenyl, thiophene, and morpholino. R2 is selected from hydrogen, halogen, hydroxyl, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The alkoxy group is substituted with one or more substituents from the group consisting of alkoxy, acetyl, C1-C6 alkylamino, di(C1-C6)alkylamino, di(C1-C6)alkylamino (C1-C6)alkyl, phenyl, and SEM (=2-(trimethylsilyl)ethoxymethyl). R3 can be hydrogen, halogen, or C1-C independently. 10 Alkoxy; R4 can be freely replaced or not replaced. Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced One or more substituents in the group constitute the group. The replacement , , , , or One or more hydrogen atoms in the substituent are independently selected from hydrogen, halogen, hydroxyl, amide, halogenated C1-C6 alkyl, CN, NO2, C1-C6 alkyl, acetyl, carbamoyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C4-C 10 One or more substituents from the group consisting of heterocyclic alkyl groups are used for substitution. The substituted C1-C 10 Alkoxy, C3-C 10 cycloalkyl or C4-C 10 Heterocyclic alkyl groups are selected from hydrogen, halogens, hydroxyl groups, amides, halogenated C1-C6 alkyl groups, CN, NO2, C1-C6 alkyl groups, and C1-C6 alkyl groups. 10 One or more substituents are substituted in the group consisting of alkoxy groups; n is an integer from 0 to 3.

[0023] This invention relates to a pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein the active ingredient comprises a compound represented by the above-described chemical formula 3, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof.

[0024] In the above chemical formula 3, R1 is substituted with one or more substituents selected from the group consisting of hydrogen, amino, amide, halogenated C1-C6 alkyl, C1-C6 alkyl, acetyl, acetamido, phenyl, thiophene, and morpholino. R2 is substituted by one or more substituents selected from the group consisting of hydrogen, halo-C1-C6 alkyl, C1-C6 alkyl and acetyl; R3 can be hydrogen, halogen, or C1-C6 alkoxy independently; R4 can be freely replaced or not replaced. and replaced or not taken One or more substituents in the group constitute the group. The replacement or One or more hydrogen atoms in a substituent are independently substituted by one or more substituents selected from the group consisting of hydrogen, halogen, halogenated C1-C6 alkyl, CN, C1-C6 alkyl and acetyl; n is an integer from 0 to 3.

[0025] This invention relates to a pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein the active ingredient comprises a compound represented by the following chemical formula 4, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof.

[0026] [Chemical Formula 4]

[0027] In the above chemical formula 4, R1 is selected from hydrogen, halogen, hydroxyl, amino, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The substance is substituted with one or more substituents from the group consisting of alkoxy, acetyl, acetamido, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkylamide, phenyl, thiophene, and morpholino. R2 is selected from hydrogen, halogen, hydroxyl, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The alkoxy group is substituted with one or more substituents from the group consisting of alkoxy, acetyl, C1-C6 alkylamino, di(C1-C6)alkylamino, di(C1-C6)alkylamino (C1-C6)alkyl, phenyl, and SEM (=2-(trimethylsilyl)ethoxymethyl). R3 can be hydrogen, halogen, or C1-C independently. 10 Alkoxy; R4 can be freely replaced or not replaced. Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced and replaced or not replaced One or more substituents in the group constitute the group. The replacement , , , , or One or more hydrogen atoms in the substituent are independently selected from hydrogen, halogen, hydroxyl, amide, halogenated C1-C6 alkyl, CN, NO2, C1-C6 alkyl, acetyl, carbamoyl, substituted or unsubstituted C1-C 10Alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C4-C 10 One or more substituents from the group consisting of heterocyclic alkyl groups are used for substitution. The substituted C1-C 10 Alkoxy, C3-C 10 cycloalkyl or C4-C 10 Heterocyclic alkyl groups are selected from hydrogen, halogens, hydroxyl groups, amides, halogenated C1-C6 alkyl groups, CN, and NO. 2、 C1-C6 alkyl and C1-C 10 One or more substituents are substituted in the group consisting of alkoxy groups; n is an integer from 0 to 3.

[0028] This invention relates to a pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein the active ingredient comprises a compound represented by the above chemical formula 4, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof.

[0029] In the above chemical formula 4, R1 is substituted with one or more substituents selected from the group consisting of hydrogen, amino, amide, halogenated C1-C6 alkyl, C1-C6 alkyl, acetyl, acetamido, phenyl, thiophene, and morpholino. R2 is substituted by one or more substituents selected from the group consisting of hydrogen, halo-C1-C6 alkyl, C1-C6 alkyl and acetyl; R3 can be hydrogen, halogen, or C1-C6 alkoxy independently; R4 can be freely replaced or not replaced. and replaced or not taken One or more substituents in the group constitute the group. The replacement or One or more hydrogen atoms in a substituent are independently substituted by one or more substituents selected from the group consisting of hydrogen, halogen, halogenated C1-C6 alkyl, CN, C1-C6 alkyl and acetyl; n is an integer from 0 to 3.

[0030] This invention relates to a pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein the active ingredient comprises a compound represented by the following chemical formula 5, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof.

[0031] [Chemical Formula 5]

[0032] In the above chemical formula 5, R1 is selected from hydrogen, halogen, hydroxyl, amino, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The substance is substituted with one or more substituents from the group consisting of alkoxy, acetyl, acetamido, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkylamide, phenyl, thiophene, and morpholino. R2 is selected from hydrogen, halogen, hydroxyl, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The alkoxy group is substituted with one or more substituents from the group consisting of alkoxy, acetyl, C1-C6 alkylamino, di(C1-C6)alkylamino, di(C1-C6)alkylamino (C1-C6)alkyl, phenyl, and SEM (=2-(trimethylsilyl)ethoxymethyl). R3 can be hydrogen, halogen, or C1-C6 alkoxy independently; R4 can be freely replaced or not replaced. Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced One or more substituents in the group constitute the group. The replacement , , , , or One or more hydrogen atoms in the substituent are independently selected from hydrogen, halogen, hydroxyl, amide, halogenated C1-C6 alkyl, CN, NO2, C1-C6 alkyl, acetyl, carbamoyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C4-C 10 One or more substituents from the group consisting of heterocyclic alkyl groups are used for substitution. The substituted C1-C 10 Alkoxy, C3-C 10 cycloalkyl or C4-C 10 Heterocyclic alkyl groups are selected from hydrogen, halogens, hydroxyl groups, amides, halogenated C1-C6 alkyl groups, CN, NO2, C1-C6 alkyl groups, and C1-C6 alkyl groups. 10 One or more substituents are substituted in the group consisting of alkoxy groups; n is an integer from 0 to 3.

[0033] This invention relates to a pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein the active ingredient comprises a compound represented by the above chemical formula 5, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof.

[0034] In the above chemical formula 5, R1 is substituted with one or more substituents selected from the group consisting of hydrogen, amino, amide, halogenated C1-C6 alkyl, C1-C6 alkyl, acetyl, acetamido, phenyl, thiophene, and morpholino. R2 is substituted by one or more substituents selected from the group consisting of hydrogen, halo-C1-C6 alkyl, C1-C6 alkyl and acetyl; R3 can be hydrogen, halogen, or C1-C6 alkoxy independently; R4 can be freely replaced or not replaced. and replaced or not taken One or more substituents in the group constitute the group. The replacement or One or more hydrogen atoms in a substituent are independently substituted by one or more substituents selected from the group consisting of hydrogen, halogen, halogenated C1-C6 alkyl, CN, C1-C6 alkyl and acetyl; n is an integer from 0 to 3.

[0035] This invention relates to a pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein the active ingredient comprises a compound represented by the following chemical formula 6, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof.

[0036] [Chemical Formula 6]

[0037] In the above chemical formula 6, R1 is selected from hydrogen, halogen, hydroxyl, amino, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The substance is substituted with one or more substituents from the group consisting of alkoxy, acetyl, acetamido, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkylamide, phenyl, thiophene, and morpholino. R2 is selected from hydrogen, halogen, hydroxyl, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The alkoxy group is substituted with one or more substituents from the group consisting of alkoxy, acetyl, C1-C6 alkylamino, di(C1-C6)alkylamino, di(C1-C6)alkylamino (C1-C6)alkyl, phenyl, and SEM (=2-(trimethylsilyl)ethoxymethyl). R3 can be hydrogen, halogen, or C1-C6 alkoxy independently; R4 can be freely replaced or not replaced. Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced and replacement or non-replacement One or more substituents in the group constitute the group. The replacement , , , , or One or more hydrogen atoms in the substituent are independently selected from hydrogen, halogen, hydroxyl, amide, halogenated C1-C6 alkyl, CN, NO2, C1-C6 alkyl, acetyl, carbamoyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C4-C 10 One or more substituents from the group consisting of heterocyclic alkyl groups are used for substitution. The substituted C1-C 10 Alkoxy, C3-C 10 cycloalkyl or C4-C 10 Heterocyclic alkyl groups are selected from hydrogen, halogens, hydroxyl groups, amides, halogenated C1-C6 alkyl groups, CN, NO2, C1-C6 alkyl groups, and C1-C6 alkyl groups. 10 One or more substituents are substituted in the group consisting of alkoxy groups; n is an integer from 0 to 3.

[0038] This invention relates to a pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein the active ingredient comprises a compound represented by the above-described chemical formula 6, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof.

[0039] In the above chemical formula 6, R1 is substituted with one or more substituents selected from the group consisting of hydrogen, amino, amide, halogenated C1-C6 alkyl, C1-C6 alkyl, acetyl, acetamido, phenyl, thiophene, and morpholino. R2 is substituted by one or more substituents selected from the group consisting of hydrogen, halo-C1-C6 alkyl, C1-C6 alkyl and acetyl; R3 can be hydrogen, halogen, or C1-C6 alkoxy independently; R4 can be freely replaced or not replaced. and replaced or unreplaced One or more substituents in the group constitute the group. The replacement or One or more hydrogen atoms in a substituent are independently substituted by one or more substituents selected from the group consisting of hydrogen, halogen, halogenated C1-C6 alkyl, CN, C1-C6 alkyl and acetyl; n is an integer from 0 to 3.

[0040] More specifically, the compounds of the present invention are selected from compounds consisting of: 4-Methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 1); 4-Methoxy-N-phenyl-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 2); 4-Methoxy-N-(3-Methoxyphenyl)-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 3); 3-((4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)sulfonamido)benzamide (compound 4); 4-Methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(3-(trifluoromethyl)phenyl)benzenesulfonamide (compound 5); N-(3-cyanophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 6); N-(3-fluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 7); N-(4-fluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 8); N-(2-fluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 9); N-(3-chlorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 10); N-(4-chlorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 11); N-(2-chlorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 12); N-(2-Cyclopropylphenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 13); N-(4-hydroxyphenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 14); N-(3-(2-hydroxyethoxy)phenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 15); N-(4-(2-hydroxyethoxy)phenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 16); N-(2-(2-hydroxyethoxy)phenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 17); 4-Methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 18); 4-Methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(pyridin-3-yl)benzenesulfonamide (compound 19); N-(3-fluorophenyl)-3-(4-oxo-1,4-dihydroquinoline-6-yl)benzenesulfonamide (compound 20); 5-(5-((1H-pyrazol-1-yl)sulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridine (compound 21); 5-(2-methoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (compound 22); 4-((4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)sulfonyl)morpholine (compound 23); N-(3,5-difluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 24); N-(3-chloro-5-fluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 25); 4-Methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzamide (compound 26); N-(3-fluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (compound 27); N-Phenyl-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 28); 3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 29); N-(3-fluorophenyl)-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 30); N-(3-chlorophenyl)-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 31); 3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(o-tolyl)benzenesulfonamide (compound 32); 4-Methoxy-3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 33); 4-Methoxy-3-(1-Phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 34); N-(5-(2-methoxy-5-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 35); N-(5-(4-fluoro-3-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 36); N-(5-(2-fluoro-5-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 37); N-(5-(3-fluoro-5-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 38); N-(5-(2,4-difluoro-5-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 39); N-(5-(2-fluoro-3-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 40); N-(5-(2-methoxy-5-(N-(p-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 41); N-(5-(2-methoxy-5-(N-(o-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 42); N-(5-(2-methoxy-5-(N-phenylaminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 43); N-(5-(5-(N-(3-fluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 44); N-(5-(4-fluoro-3-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 45); N-(5-(2-fluoro-5-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 46); N-(5-(3-fluoro-5-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 47); N-(5-(2,4-difluoro-5-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 48); N-(5-(2-fluoro-3-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 49); N-(5-(5-(N-(4-fluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 50); N-(5-(5-(N-(2-fluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 51); N-(5-(5-(N-(3-chlorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 52); N-(5-(5-(N-(4-chlorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 53); N-(5-(5-(N-(2-chlorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 54); N-(5-(5-(N-(3-hydroxyphenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 55); N-(5-(5-(N-(4-hydroxyphenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 56); N-(5-(2-methoxy-5-(N-(pyridin-3-yl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 57); N-(5-(2-methoxy-5-(N-(pyridin-2-yl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 58); N-(5-(2-methoxy-5-(morpholinosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 59); N-(5-(5-(N-(3,5-difluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 60); N-(5-(5-(N-(3-chloro-5-fluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 61); N-(3-fluorophenyl)-4-methoxy-3-(3-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 62); N-(3-fluorophenyl)-4-methoxy-3-(3-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 63); 4-Methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 64); 4-Methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(p-tolyl)benzenesulfonamide (compound 65); 4-Methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(o-tolyl)benzenesulfonamide (compound 66); 4-Methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-phenylbenzenesulfonamide (compound 67); N-(3-fluorophenyl)-4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 68); N-(2-fluorophenyl)-4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 69); N-(2-chlorophenyl)-4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 70); N-(3-hydroxyphenyl)-4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 71); 4-((4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)sulfonyl)morpholine (compound 72); 4-Methoxy-3-(1-Phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 73); 3-(1-(2-(dimethylamino)ethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methoxy-N-(m-tolyl)benzenesulfonamide (compound 74); 4-Methoxy-3-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 75); 3-(1-acetyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methoxy-N-(m-tolyl)benzenesulfonamide (compound 76); N-((3-(1-acetyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methoxyphenyl)sulfonyl)-N-(m-tolyl)acetamide (compound 77); 4-((3-(1H-indazol-5-yl)-4-methoxyphenyl)sulfonyl)morpholine (compound 78); 3-(1H-indazol-5-yl)-4-methoxy-N-(m-tolyl)benzenesulfonamide (compound 79); N-(3-fluorophenyl)-3-(1H-indazol-5-yl)-4-methoxybenzenesulfonamide (compound 80); 2,4-Difluoro-N-(3-fluorophenyl)-5-(1H-indazol-5-yl)benzenesulfonamide (compound 81); N-(5-(5-(N-(3-fluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-indazol-3-yl)acetamide (compound 82); N-(5-(2,4-difluoro-5-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-indazol-3-yl)acetamide (compound 83); 3-(1-acetyl-3-amino-1H-indazol-5-yl)-N-(3-fluorophenyl)-4-methoxybenzenesulfonamide (compound 84); 5-(1-acetyl-3-amino-1H-indazol-5-yl)-2,4-difluoro-N-(3-fluorophenyl)benzenesulfonamide (compound 85); 4-((4-methoxy-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)sulfonyl)morpholine (compound 86); 4-Methoxy-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 87); N-(3-fluorophenyl)-4-methoxy-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzenesulfonamide (compound 88); 4-Methoxy-3-(3-morpholino-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 90); 4-Methoxy-3-(3-morpholino-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(o-tolyl)benzenesulfonamide (compound 91); 4-Methoxy-3-(3-morpholino-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-phenylbenzenesulfonamide (compound 92); N-(2-fluorophenyl)-4-methoxy-3-(3-morpholino-1H-pyrrolo[2,3-b]pyridin-5-yl)benzenesulfonamide (compound 93); N-(2-chlorophenyl)-4-methoxy-3-(3-morpholino-1H-pyrrolo[2,3-b]pyridin-5-yl)benzenesulfonamide (compound 94); N-(5-(2-methoxy-5-(N-phenylaminosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (compound 95); N-(5-(2,4-difluoro-5-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (compound 96); 3-(1H-indol-5-yl)-4-methoxy-N-(m-tolyl)benzenesulfonamide (compound 97); N-(3-fluorophenyl)-3-(1H-indol-5-yl)-4-methoxybenzenesulfonamide (compound 98); 4-Methoxy-N-(m-Tolyl)-3-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)benzenesulfonamide (compound 99); 3-(3H-imidazo[4,5-b]pyridin-6-yl)-4-methoxy-N-(m-tolyl)benzenesulfonamide (compound 100); N-(3-fluorophenyl)-4-methoxy-3-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)benzenesulfonamide (compound 101); N-(3-fluorophenyl)-3-(3H-imidazo[4,5-b]pyridin-6-yl)-4-methoxybenzenesulfonamide (compound 102); 4-Methoxy-3-(4-oxo-1,4-dihydroquinolin-6-yl)-N-(m-tolyl)benzenesulfonamide (compound 103); N-(3-fluorophenyl)-4-methoxy-3-(4-oxo-1,4-dihydroquinoline-6-yl)benzenesulfonamide (compound 104); and 3-(4-oxo-1,4-dihydroquinolin-6-yl)-N-(m-tolyl)benzenesulfonamide (compound 105).

[0041] This invention relates to a pharmaceutical composition for treating, preventing, inhibiting or eliminating IRP2-dependent diseases or disorders, comprising a compound represented by the above-described chemical formula 1, its stereoisomer, its solvate, its prodrug or a pharmaceutically acceptable salt thereof as an active ingredient.

[0042] This invention relates to a pharmaceutical composition for the prevention or treatment of solid cancer as an IKZF2-dependent disease, comprising a compound represented by the above-described chemical formula 1, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0043] The solid cancer may be selected from the group consisting of non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite stable colorectal cancer (mss CRC), thymoma, carcinoid tumor, gastrointestinal stromal tumor (GIST), prostate cancer, breast cancer, lymphoma, leukemia, bladder cancer, colon cancer, skin melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid cancer, tongue cancer, pancreatic cancer, esophageal cancer, bile duct cancer, gastric cancer, soft tissue sarcoma, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, hepatoid carcinoma, and Ewing sarcoma, preferably colorectal cancer.

[0044] The compounds represented by Formula 1, their stereoisomers, their solvates, their prodrugs, or their pharmaceutically acceptable salts of the present invention can enhance the efficacy of cancer treatment through co-administration with anticancer agents for the treatment of solid cancer. The anticancer agents that can be used as said co-administration therapy can be selected from taxane antitumor drugs, alkylating antitumor drugs, antimetabolite antitumor drugs, antitumor antibiotics, plant-derived antitumor drugs, platinum-based antitumor complexes, antitumor camptothecin derivatives, antitumor kinase inhibitors, antitumor antibodies, hormonal antitumor drugs, antitumor viral agents, and angiogenesis inhibitors.

[0045] The taxane-based antitumor drugs may be paclitaxel, docetaxel, cabazitaxel, larotaxel, BMS-184476, BMS-188797, BMS275183, miratataxel, olatataxel, TL-310, docosahexaenoic acid-paclitaxel (DHA-paclitaxel), albumin-bound paclitaxel (nab-paclitaxel), EndoTAG+paclitaxel, XRP9881, polymeric micelle paclitaxel, or RPR-109881A; the alkylated antitumor drugs may be nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, dioxin, etc. Bromomannitol, carboquinone, thiotepa, lanimustine, nimustine, temozolomide, or carmustine; the antimetabolite antitumor drugs may be methotrexate, 6-mercaptopurine nucleoside, mercaptopurine, 5-fluorouracil, tegafur, doxefluorouridine, carmoflu, cytarabine, cytarabine phosphate, enoxabin, S-1, gemcitabine, fludarabine, or pemetrexed disodium; the antitumor antibiotics may be actinomycin D, doxorubicin, daunorubicin, neo-carcinomacin, bleomycin, pepromycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, ganostatin, stamalalin, enoxabin, etc. Dabecin, sirolimus, or vararubicin; the plant-derived antitumor drug may be vincristine, vinblastine, vindesine, etoposide, sobuzosen, docetaxel, paclitaxel, or vinorelbine; the platinum-based antitumor complex may be cisplatin, carboplatin, nedaplatin, or oxaliplatin; the antitumor camptothecin derivative may be irinotecan, topotecan, or camptothecin; the antitumor kinase inhibitor may be gefitinib, imatinib, or erlotinib; the antitumor antibody may be cetuximab, bevacizumab, rituximab, alemtuzumab, or trastuzumab; the hormonal antitumor drug may be goserelin (g The anti-tumor viral agent may be iodine, leuprolide, or tamoxifen; the angiogenesis inhibitor may be imlygic; the angiogenesis inhibitor may be avastin, bevacizumab, ramucirumab, aflibercept, cetuximab, panitumumab, regorafenib, sunitinib, sorafenib, pazopanib, vandetanib, axitinib, sildenafil, vataranib, motishanib, rucatinib, nintedanib, cemakshanib, apatinib, lenvatinib, cabozantinib, or combinations thereof, but is not limited thereto.

[0046] In addition, unless otherwise indicated, the following terms in this invention have the following meanings. Any undefined terms have the meaning as understood in the art.

[0047] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). The term "alkyl" in the above context refers to a single-chain, straight-chain or branched hydrocarbon group. Examples include methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, 1-methylpropyl, etc.

[0048] The term "amino" in the above context refers to -NH2.

[0049] The term "alkoxy" refers to an oxygen group bonded to a single-chain, straight-chain or branched saturated hydrocarbon. Examples include methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, and 1-methylpropoxy.

[0050] The term "cycloalkyl" as used above refers to a cyclic, single-bonded saturated hydrocarbon group. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0051] The term "aryl" as used above refers to an aromatic substituent having at least one ring with a conjugated π-electron system, such as, but not limited to, phenyl, benzyl, etc.

[0052] The term "heterocyclic alkyl" refers to a cyclic single-bonded saturated hydrocarbon group containing one or more heteroatoms such as N, O, or S. Depending on the number, type, and number of carbon atoms in the ring, it includes, but is not limited to, azirropropyl, pyrrolidinyl, piperidinyl, piperazine, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, etc.

[0053] The term "heteroaryl" refers to an aromatic ring compound containing one or more heteroatoms such as N, O, or S. Depending on the number, type, and number of carbon atoms in the ring, it may include pyrroleyl, furanyl, pyridyl, pyrimidinyl, pyranyl, pyrazolyl, thienyl (or Thienyl), etc., but is not limited to these.

[0054] The term "halogenated alkyl" as used above refers to an alkyl group substituted with a halogen, wherein the halogen and the alkyl group are as described above.

[0055] The term "alkylamino" as used above refers to an amino group substituted with an alkyl group, wherein the alkyl group and the amino group are as described above.

[0056] The term "dialkylamino" as used above refers to an amino group substituted with two alkyl groups, wherein the alkyl groups and the amino group are as described above.

[0057] The term "dialkylaminoalkyl" as used above refers to an alkyl group substituted with a dialkylamino group, wherein the dialkylamino group and the alkyl group are as described above.

[0058] The term "arylamino" refers to an amino group substituted with an aryl group, wherein the aryl group and the amino group are as described above.

[0059] In this invention, the colorectal cancer may be collectively referred to as rectal cancer, colon cancer, and anal cancer, but is not particularly limited thereto.

[0060] In this invention, the pharmaceutically acceptable salt refers to a salt or complex of chemical formula 1 having preferred biological activity. Examples of such salts are not limited to these, and include acid addition salts formed from inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), as well as salts formed from organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, papoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, and polygalacturonic acid. The compounds can also be formulated into pharmaceutically acceptable quaternary ammonium salts known to those skilled in the art, particularly including chlorides, bromides, iodides, -O-alkyl groups, p-toluenesulfonates, methanesulfonates, sulfonates, phosphates, or carboxylates (e.g., benzoates, succinates, acetates, glycolate, maleates, malates, fumarates, citrates, tartrates, ascorbic acid salts, cinnamates, mandelates, and diphenylacetates). The compounds of Formula 1 of the present invention can include not only pharmaceutically acceptable salts but also all salts, hydrates, solvates, and prodrugs that can be prepared using conventional methods in the art.

[0061] The acid addition salt according to the present invention can be prepared by conventional methods, for example, by dissolving the derivative of chemical formula 1 in organic solvents such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., adding organic or inorganic acid, filtering out the precipitate and drying it; or, by distilling the solvent and excess acid under reduced pressure, drying it and crystallizing it in an organic solvent.

[0062] In addition, pharmaceutically acceptable metal salts can be prepared using alkalis. Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the insoluble salt, and then evaporating and drying the filtrate. From a pharmaceutical perspective, preparing sodium, potassium, or calcium salts is more suitable in this case. Furthermore, the corresponding salts can also be obtained by reacting the alkali metal salt or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0063] Furthermore, the compounds of the present invention may contain more than one asymmetric carbon atom and may exist in racemic and optically active forms. All such compounds and diastereomers are included within the scope of the present invention.

[0064] The pharmaceutical compositions according to the invention can be formulated into suitable forms with commonly used pharmaceutically acceptable carriers. "Pharmaceutically acceptable" means a composition that is physiologically acceptable and generally does not cause gastrointestinal discomfort, dizziness, or other allergic reactions or similar reactions when administered to the human body. Furthermore, the compositions can be prepared into dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, oral dosage forms, topical preparations, suppositories, and sterile injections according to conventional methods in the art.

[0065] The carrier, excipients, and diluents that may be included in the composition may include lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil, but are not limited thereto. For formulation, commonly used fillers, stabilizers, binders, disintegrants, surfactants, and other diluents or excipients in the art can be used. Solid dosage forms for oral administration include tablets, pills, powders, granules, and capsules. Such solid dosage forms are typically prepared by adding at least one excipient to the compound of the present invention, such as starch, microcrystalline cellulose, sucrose, or lactose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. In addition to common excipients, lubricants such as magnesium stearate and talc can also be used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups. Besides commonly used simple diluents (such as water and liquid paraffin), they may also contain various excipients, such as wetting agents, sweeteners, flavorings, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may use propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may use Wipedol, Macrogol, Tween 61, cocoa butter, lauryl acetate, glycerin, and gelatin. To prepare a dosage form for parenteral administration, the benzenesulfonamide-substituted heterobicyclic derivative compound of the above chemical formula 1 or its pharmaceutically acceptable salt is mixed with sterile and / or excipients containing preservatives, stabilizers, wetting agents or emulsifying agents, salts for adjusting osmotic pressure and / or buffers, and other substances with therapeutic uses in water to prepare a solution or suspension, which can be prepared into ampoules or vials for unit doses.

[0066] The pharmaceutical composition provides a pharmaceutical composition comprising a benzenesulfonamide-substituted heterobicyclic derivative compound of the above-described chemical formula 1 and an excipient. The compound is preferably added in an amount of 0.001% to 50% by weight, more preferably 0.001% to 40% by weight, and most preferably 0.001% to 30% by weight relative to the total weight of the composition.

[0067] Pharmaceutical compositions comprising a compound of Formula 1 disclosed in this invention as an active ingredient can be administered to mammals such as mice, livestock, and humans via various routes. All routes of administration are contemplated, for example, oral, rectal or intravenous, intramuscular, subcutaneous, intradural, or intracerebral injection. The dosage will vary depending on factors such as the age, sex, weight of the recipient, the specific disease or pathological condition being treated, the severity of the disease or pathological condition, the timing of administration, the route of administration, the rate of absorption, distribution, and excretion of the drug, the types of other drugs used, and the prescribing physician's judgment. Determining the dosage based on the above factors is within the scope of skill of those skilled in the art, and the typical dosage range is from 0.01 mg / kg / day to approximately 2000 mg / kg / day. More preferred dosages are from 1 mg / kg / day to 500 mg / kg / day. Administration can be once daily or divided into several doses. The above dosages do not limit the scope of this invention in any way.

[0068] Invention Effects This invention relates to pharmaceutical compositions for the prevention or treatment of colorectal cancer containing a benzyl sulfonamide-substituted heterobicyclic derivative as an IRP2 interfering substance as an active ingredient. These compositions can provide benzyl sulfonamide-substituted heterobicyclic derivative compounds that kill colorectal cancer cells by inducing iron metabolism reprogramming in cancer cells through interference with IRP2 binding to IRE. Attached Figure Description

[0069] Figure 1 IRP2 is an important factor in regulating cell growth and is a result indicating treatment relevance in colorectal cancer. Figure 2 This is the result of identifying small molecule inhibitors with strong selectivity for IRP2.

[0070] Figure 3 To demonstrate the results of the cancer cell toxicity induced by compounds 1 and 44 and the changes in iron metabolism-related factors blocked by IRP2.

[0071] Figure 4 The results show the effects of IRP2 ubiquitination and subsequent reductions in LIP, ROS, and mitochondrial OCR by IRP2 inhibitors.

[0072] Figure 5 The results, obtained through gene expression profiling and GSEA analysis, showed that compound 1 induced a decrease in mitochondrial OCR genes and an increase in autophagy genes.

[0073] Figure 6 The result is the induction of autophagic cancer cell death through the activation of the AMPK-ULK1-Beclin1-LC3B pathway of compounds 1 and 44.

[0074] Figure 7 This is the result of inhibiting tumor growth in organoids and in vivo animal models of compounds 1 and 44.

[0075] Figure 8 This study used FAC and DFO to alter intracellular iron levels to identify iron metabolism-related factors.

[0076] Figure 9 It is the result of confirming the mRNA and protein expression levels of IRP1 and IRP2 in the patient's normal and cancerous tissues.

[0077] Figure 10 This shows the results of compound hits in the database (DB)-based pharmacophore screening.

[0078] Figure 11 This is a synthetic route plan for compounds 1 (A) and 44 (B). Figure 12 Effects of treatment with compounds 1 and 44 on transcriptional activity and cell cycle.

[0079] Figure 13 This is a result of compound 1-induced mitochondrial dysfunction and autophagy-dependent cancer cell death. Detailed Implementation

[0080] Preferred embodiments of the present invention are described in detail below. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, it is provided to ensure thoroughness and completeness of the description herein and to fully convey the spirit of the invention to those skilled in the art.

[0081] <Example 1. Synthesis and physicochemical property confirmation of benzenesulfonamide-substituted heterobicyclic derivative compounds> Compounds 1 to 105 of the present invention were used to synthesize a variety of benzenesulfonamide-substituted heterobicyclic derivatives, the physicochemical properties of which are as follows.

[0082] Compound 1,4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide

[0083] Synthesis of 1-1,3-bromo-4-methoxybenzenesulfonyl chloride (compound 1-1) After adding 2-bromoanisole (12.4 mL, 100.0 mmol) and DCM (200 mL), the mixture was stirred at 0 °C, followed by slow addition of chlorosulfonic acid (20 mL, 300.0 mmol) (3.0 eq.), and stirring was continued at room temperature for 12 hours. After the reaction was complete, the reactants were slowly added to ice water, extracted with DCM, and the organic layer was dried over MgSO4 and concentrated under reduced pressure to obtain compound 1-1 in 99% (28.3 g) yield.

[0084] Synthesis of 1-2,3-bromo-4-methoxy-N-(m-tolyl)benzenesulfonamide (compounds 1-2) Compound 1-1 (3-bromo-4-methoxybenzenesulfonyl chloride; 14.4 g, 50.0 mmol), THF (150 mL), and pyridine (4.0 mL, 50.0 mmol) (1.0 eq.) were added and stirred at 0 °C. Then, m-toluidine (6.4 mL, 60.0 mmol) (1.5 eq.) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was extracted with H₂O and EtOAc. The organic layer was then dried over MgSO₄ and concentrated under reduced pressure. Compound 1-2 was then separated by silica gel column chromatography in 90% (16 g) yield.

[0085] Synthesis of 1-3,4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide) (Compound 1) Add 5-bromo-1H-pyrazolo[3,4-b]pyridine (990 mg, 5 mmol), bis(pinacolato)diboron (1.52 g, 6 mmol) (1.2 eq.), [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (408 mg, 0.5 mmol) (10 mol%), potassium acetate (1.47 g, 15 mmol) (3.0 eq.), and 1,4-dioxane (10 mL), and react in a microwave reactor at 120 °C for 1 hour. After cooling to room temperature, compounds 1-2 (3-bromo-4-methoxy-N-(m-tolyl)benzenesulfonamide; 1.78 g, 5 mmol) (1.0 eq.) and an aqueous solution of sodium carbonate (2 M, 5 mL) (2.0 eq.) were added, and the mixture was reacted at 120 °C for 1 hour. After the reaction was complete, the solvent was removed by diatomite filtration, and the mixture was extracted with water and EtOAc. The organic layer was dried over MgSO4 and concentrated under reduced pressure. Then, compound 1 was obtained by silica gel column chromatography in a yield of 25% (495 mg).

[0086] 1 H NMR (300 MHz, DMSO-d6) δ 13.8 (s, 1H), 10.1 (s, 1H), 8.51 (d, J =2.1 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 1.1 Hz, 1H), 7.77 (dd, J = 8.7, 2.4 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 7.00 - 6.90 (m, 2H), 6.91-6.82 (m, 1H), 3.84 (s, 3H), 2.21 (s, 3H) Compound 2,4-methoxy-N-phenyl-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0087] Compound 2 was synthesized using the same method as compound 1 described above (yield 45%).

[0088] 1 H NMR (300 MHz, DMSO-d6) δ 13.76 (brs, 1H), 10.12 (brs, 1H), 8.51 (d,J = 2.1 Hz, 1H), 8.25 - 8.17 (m, 2H), 7.79 - 7.68 (m, 2H), 7.32 - 7.21 (m, 3H), 7.16 - 7.10 (m, 2H), 7.04 (t, J = 7.2 Hz, 1H), 3.83 (s, 3H).

[0089] Compound 3,4-methoxy-N-(3-methoxyphenyl)-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0090] Compound 3 was synthesized using the same method as compound 1 described above (yield 52%).

[0091] 1 H NMR (300 MHz, DMSO-d6) δ 13.77 (brs, 1H), 10.16 (brs, 1H), 8.52 (d,J = 2.0 Hz, 1H), 8.26 - 8.18 (m, 2H), 7.78 (dd,J = 8.7, 2.4 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.15 (t, J = 8.4 Hz, 1H), 6.75- 6.69 (m, 2H), 6.66 - 6.59 (m, 1H), 3.84 (s, 3H), 3.66 (s, 3H).

[0092] Compound 4,3-((4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)sulfonamido)benzamide

[0093] Compound 4 was synthesized using the same method as compound 1 described above (yield 20%).

[0094] 1 H NMR (300 MHz, DMSO-d6) δ 13.76 (brs, 1H), 10.28 (brs, 1H), 8.55 (d,J = 2.1 Hz, 1H), 8.21 (d,J = 2.1 Hz, 2H), 7.96 (brs, 1H), 7.77 (dd, J = 8.6, 2.5 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.54 (d, J =7.3 Hz, 1H), 7.41 (brs, 1H), 7.36 - 7.24 (m, 3H), 3.83 (s, 3H).

[0095] Compound 5,4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(3-(trifluoromethyl)phenyl)benzenesulfonamide

[0096] Compound 5 was synthesized using the same method as compound 1 described above (63% yield).

[0097] 1 H NMR (300 MHz, DMSO-d6) δ 13.77 (brs, 1H), 10.60 (brs, 1H), 8.51 (s,1H), 8.26 - 8.16 (m, 2H), 7.85 - 7.70 (m, 2H), 7.55 - 7.37 (m, 4H), 7.31 (d,J = 8.9 Hz, 1H), 3.84 (s, 3H).

[0098] Compound 6.N-(3-cyanophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0099] Compound 6 was synthesized using the same method as compound 1 described above (yield 34%).

[0100] 1H NMR (300 MHz, DMSO-d6) δ 13.77 (brs, 1H), 10.65 (brs, 1H), 8.55 (d,J = 2.1 Hz, 1H), 8.26 (d,J = 2.1 Hz, 1H), 8.20 (d,J = 1.4 Hz, 1H), 7.85 -7.75 (m, 2H), 7.56 - 7.42 (m, 4H), 7.30 (d, J = 8.8 Hz, 1H), 3.84 (s, 3H).

[0101] Compound 7.N-(3-fluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0102] Compound 7 was synthesized using the same method as compound 1 described above (yield 58%).

[0103] 1 H NMR (300 MHz, DMSO-d6) δ 13.77 (brs, 1H), 10.47 (brs, 1H), 8.54 (d,J = 2.1 Hz, 1H), 8.24 (dd, J = 15.3, 1.7 Hz, 2H), 7.90 - 7.69 (m, 2H), 7.39 -7.20 (m, 2H), 7.06 - 6.80 (m, 3H), 3.85 (s, 3H).

[0104] Compound 8.N-(4-fluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0105] Compound 8 was synthesized using the same method as compound 1 described above (yield 34%).

[0106] 1H NMR (300 MHz, DMSO-d6) δ 13.76 (brs, 1H), 10.09 (brs, 1H), 8.53 (d,J = 2.1 Hz, 1H), 8.25 (d,J = 2.2 Hz, 1H), 8.20 (d,J = 1.3 Hz, 1H), 7.70 (d,J = 7.4 Hz, 2H), 7.31 - 7.24 (m, 1H), 7.16 - 7.07 (m, 4H), 3.84 (s, 3H).

[0107] Compound 9.N-(2-fluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0108] Compound 9 was synthesized using the same method as compound 1 described above (yield 47%).

[0109] 1 H NMR (300 MHz, DMSO-d6) δ 13.74 (brs, 1H), 10.05 (brs, 1H), 8.53 (d,J = 2.1 Hz, 1H), 8.24 (d,J = 2.1 Hz, 1H), 8.20 (d,J = 1.2 Hz, 1H), 7.77 -7.67 (m, 2H), 7.34 - 7.24 (m, 2H), 7.20 - 7.06 (m, 3H), 3.85 (s, 3H).

[0110] Compound 10.N-(3-chlorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0111] Compound 10 was synthesized using the same method as that used for compound 1 described above (68% yield).

[0112] 1H NMR (300 MHz, DMSO-d6) δ 13.77 (brs, 1H), 10.45 (brs, 1H), 8.54 (s,1H), 8.28 - 8.17 (m, 2H), 7.85 - 7.69 (m, 2H), 7.29 (t, J = 9.3 Hz, 2H), 7.20-7.04 (m, 3H), 3.84 (s, 3H).

[0113] Compound 11. N-(4-chlorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0114] Compound 11 was synthesized using the same method as compound 1 (yield 34%).

[0115] 1 H NMR (300 MHz, DMSO-d6) δ 13.76 (brs, 1H), 10.09 (brs, 1H), 8.53 (d,J = 2.1 Hz, 1H), 8.25 (d,J = 2.2 Hz, 1H), 8.20 (d,J = 1.3 Hz, 1H), 7.70 (d,J = 7.4 Hz, 2H), 7.31 - 7.24 (m, 1H), 7.16 - 7.07 (m, 4H), 3.84 (s, 3H).

[0116] Compound 12,N-(2-chlorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0117] Compound 12 was synthesized using the same method as compound 1 described above (yield 47%).

[0118] 1H NMR (300 MHz, DMSO-d6) δ 13.74 (brs, 1H), 10.05 (brs, 1H), 8.53 (d,J = 2.1 Hz, 1H), 8.24 (d,J = 2.1 Hz, 1H), 8.20 (d,J = 1.2 Hz, 1H), 7.77 -7.67 (m, 2H), 7.34 - 7.24 (m, 2H), 7.20 - 7.06 (m, 3H), 3.85 (s, 3H).

[0119] Compound 13.N-(2-cyclopropylphenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide Synthesis of 13-1,2-cyclopropylaniline (2-cyclopropylaniline) (compound 13-1)

[0120] 2-bromoaniline (1.72 g, 10.0 mmol), cyclopropylboronic acid (1.12 g, 13.0 mmol) (1.3 eq.), palladium(II) acetate (220 mg, 1.0 mmol) (0.1 eq.), triphenylphosphine (260 mg, 1.0 mmol) (0.1 eq.), potassium carbonate (4.84 g, 35.0 mmol) (3.5 eq.), and toluene / H₂O (50 / 5 mL) were added, and the mixture was stirred at 110 °C for 24 hours. After the reaction was complete, the solvent was removed by diatomite filtration, and the mixture was extracted with water and EtOAc. The organic layer was dried over MgSO₄ and concentrated under reduced pressure. Then, the mixture was separated by silica gel column chromatography to obtain compound 13-1 in 30% (405 mg) yield.

[0121] Synthesis of 13-2. N-(2-cyclopropylphenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 13)

[0122] Compound 13 was synthesized using the same methods as those used in the synthesis of compound 1 in methods 1-2 and 1-3 above (yield 3%).

[0123] 1 H NMR (400 MHz, Acetone-d6) δ 12.81 (s, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.26 (s, 1H), 8.20 (d, J = 2.1 Hz, 1H), 8.16 (s, 1H), 7.79 (dd, J = 8.7, 2.4 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.43 (dd, J = 7.6, 1.8 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.22 - 7.12 (m, 2H), 6.95 (dd, J = 7.4, 1.9 Hz, 1H), 3.95 (s, 3H), 1.97 - 1.89 (m, 2H), 0.85 - 0.78 (m, 2H), 0.48 - 0.41 (m, 2H).

[0124] Compound 14.N-(4-hydroxyphenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0125] Compound 14 was synthesized using the same method as that used for compound 1 described above (yield 10%).

[0126] 1 H NMR (300 MHz, DMSO-d6) δ 13.76 (s, 1H), 9.59 (s, 1H), 9.35 (s, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 2.2 Hz, 2H), 7.66 (dd, J = 8.7, 2.4Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H), 6.946.86 (m, 2H), 6.65 (d, J = 8.7 Hz, 2H), 3.85 (s, 3H).

[0127] Compound 15.N-(3-(2-hydroxyethoxy)phenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide Synthesis of 15-1,2-(3-aminophenoxy)ethan-1-ol (compound 15-1)

[0128] Add m-nitrophenol (1.39 g, 10.0 mmol), sodium hydroxide (8 g, 200 mmol) (20.0 eq.), 2-chloroethanol (13.4 mL, 200 mmol) (20.0 eq.), and water (50 mL), and stir at 80 °C for 3 hours. After the reaction is complete, extract with water and EtOAc, then dry the organic layer with MgSO4 and concentrate under reduced pressure. Add MeOH (20 mL) and Palladium on carbon (360 mg, 20 wt%), attach a hydrogen balloon, and stir at room temperature for 4 hours. After the reaction is complete, filter through a celite filter, concentrate the filtrate under reduced pressure, and give compound 15-1 in 68% (1.05 g, 2 steps) yield.

[0129] Synthesis of 15-2. N-(3-(2-hydroxyethoxy)phenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 15)

[0130] Compound 15 was synthesized using the same methods as those used in the synthesis of compound 1 in methods 1-2 and 1-3 above (yield 3%).

[0131] 1H NMR (300 MHz, Acetone-d6) δ 12.83 (s, 1H), 8.98 - 8.93 (m, 1H), 8.60 (s, 1H), 8.26 (d, J = 1.7 Hz, 1H), 8.19 (s, 1H), 7.86 (dd, J = 8.7, 2.4Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.19 (t, J = 8.2Hz, 1H), 6.93 (t, J = 2.2 Hz, 1H), 6.85 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H), 6.70 (ddd, J = 8.3, 2.5, 0.9 Hz, 1H), 3.93 (d, J = 0.9 Hz, 3H), 3.85 (q, J = 5.0Hz, 2H), 2.88 (d, J = 10.1 Hz, 2H).

[0132] Compound 16.N-(4-(2-hydroxyethoxy)phenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0133] Following the same process as in synthesis method 15-1 of compound 15 described above, compound 16 was synthesized by the same methods as in synthesis methods 1-2 and 1-3 of compound 1 described above (yield 5%).

[0134] 1 H NMR (300 MHz, Acetone-d6) δ 12.84 (s, 1H), 8.61 (s, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 8.18 (s, 1H), 7.75 (dd, J = 8.7, 2.4Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.20 - 7.11 (m, 2H), 6.93 - 6.86 (m, 2H), 4.11 - 4.05 (m, 2H), 3.93 (s, 3H), 3.90 - 3.82 (m, 2H).

[0135] Compound 17.N-(2-(2-hydroxyethoxy)phenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0136] Following the same process as in the synthesis method 15-1 of compound 15 described above, compound 17 was synthesized by the same method as in the synthesis methods 1-2 and 1-3 of compound 1 described above (yield 1%).

[0137] 1 H NMR (300 MHz, Acetone-d6) δ 12.79 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.35 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.17 (s, 1H), 7.79 (dd, J = 8.7, 2.4 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.63 - 7.57 (m, 1H), 7.25 (d, J = 8.7Hz, 1H), 7.18 - 7.09 (m, 1H), 6.98 (td, J = 7.8, 1.1 Hz, 2H), 3.92 (s, 3H), 3.91 - 3.87 (m, 2H), 3.70 (q, J = 5.2 Hz, 2H).

[0138] Compound 18,4-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0139] Compound 18 was synthesized using the same method as compound 1 described above (yield 12%).

[0140] 1H NMR (300 MHz, DMSO-d6) δ 13.77 (brs, 1H), 9.64 (brs, 1H), 8.50 (d,J = 2.0 Hz, 1H), 8.23 ​​- 8.15 (m, 2H), 7.68 (dd,J = 8.7, 2.4 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.93 (d, J = 9.1 Hz, 2H), 6.82 (d, J = 9.2 Hz, 2H), 3.84 (s, 3H), 3.03 (m, 4H), 2.39 (m, 4H), 2.19 (s, 3H).

[0141] Compound 19,4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(pyridin-3-yl)benzenesulfonamide

[0142] Compound 19 was synthesized using the same method as compound 1 described above (yield 38%).

[0143] 1 H NMR (300 MHz, DMSO-d6) δ 13.77 (brs, 1H), 10.43 (brs, 1H), 8.54 (d,J = 2.1 Hz, 1H), 8.31 (d,J = 2.0 Hz, 1H), 8.27 (dd,J = 4.9, 1.7 Hz, 2H), 8.21 (d, J = 1.4 Hz, 1H), 7.80 - 7.72 (m, 2H), 7.56 (ddd, J = 8.3, 2.8, 1.6Hz, 1H), 7.36 - 7.26 (m, 2H), 3.84 (s, 3H).

[0144] Compound 20.N-(3-fluorophenyl)-3-(4-oxo-1,4-dihydroquinoline-6-yl)benzenesulfonamide

[0145] Compound 20 was synthesized by the same method as in step B of the synthesis of compound 26 described below (yield 17%).

[0146] 1 H NMR (400 MHz, DMSO- d6) δ 11.93 (s, 1H), 10.56 (s, 1H), 8.36 (d, J =2.3 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 8.00-7.91 (m, 3H), 7.75 (dd, J = 7.8,1.7 Hz, 1H), 7.71-7.62 (m, 2H), 7.29-7.21 (m, 1H), 6.98-6.89 (m, 2H), 6.81 (td, J = 8.6, 2.6 Hz, 1H), 6.10 (d, J = 7.4 Hz, 1H).

[0147] Compound 21,5-(5-((1H-pyrazol-1-yl)sulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridine

[0148] Compound 21 was synthesized using the same method as compound 1 described above (yield 12%).

[0149] 1 H NMR (300 MHz, DMSO-d6) δ 13.77 (brs, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.20 (s, 1H), 8.03 (dd, J = 8.8, 2.5 Hz, 1H), 7.92 (d, J = 2.5 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.41 (d, J = 9.0 Hz, 1H), 6.59 (dd, J = 2.8, 1.6 Hz, 1H), 3.89 (s, 3H).

[0150] Compound 22,5-(2-methoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridine

[0151] Compound 22 was synthesized using the same method as compound 1 described above (yield 23%).

[0152] 1H NMR (300 MHz, DMSO-d6) δ 13.75 (brs, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 2.1 Hz, 1H), 8.20 (s, 1H), 7.77 (dd, J = 8.7, 2.4 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 3.90 (s, 3H), 2.92 (m, 4H), 2.38 (m, 4H), 2.14 (s, 3H).

[0153] Compound 23,4-((4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)sulfonyl)morpholine

[0154] Compound 23 was synthesized using the same method as compound 1 described above (yield 21%).

[0155] 1 H NMR (300 MHz, DMSO-d6) δ 13.76 (brs, 1H), 8.66 (d, J = 2.1 Hz, 1H), 8.37 (d, J = 2.1 Hz, 1H), 8.20 (s, 1H), 7.78 (dd, J = 8.7, 2.4 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 3.91 (s, 3H), 3.70 - 3.59 (m, 4H), 2.90 (m, 4H).

[0156] Compound 24.N-(3,5-difluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0157] 5-Bromo-1H-pyrazolo[3,4-b]pyridine (198 mg, 1.0 mmol), bis(pinacolato)diboron (305 mg, 1.2 mmol), [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (82 mg, 0.1 mmol) (10 mol%), potassium acetate (294 mg, 3.0 mmol), and 1,4-dioxane (5 mL) were added. After degassing under nitrogen (N2) for 10 minutes, the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the solvent was removed by celite filtration. Then, 3-bromo-N-(3,5-difluorophenyl)-4-methoxybenzenesulfonamide (378 mg, 1.0 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (73 mg, 0.1 mmol), sodium carbonate aqueous solution (2.0 M, 1 mL), and 1,4-dioxane (5 mL) were added, and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete, the solvent was removed by celite filtration. The mixture was then extracted with water and EtOAc. The organic layer was dried over MgSO4 and concentrated under reduced pressure. Finally, the mixture was separated by silica gel column chromatography, yielding compound 24 in 48% (200 mg) yield.

[0158] 1 H NMR (300 MHz, DMSO- d 6) δ 13.77 (s, 1H), 10.77 (s, 1H), 8.56 (d, J =2.1 Hz, 1H), 8.28 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 7.86 (dd, J=8.7, 2.5 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.94-6.86 (m, 1H), 6.85-6.75 (m, 2H), 3.86 (s, 3H).

[0159] Compound 25,N-(3-chloro-5-fluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0160] Compound 25 was synthesized using the same method as compound 24 described above (yield 42%).

[0161] 1 H NMR (300 MHz, DMSO- d 6) δ 13.77 (s, 1H), 10.76 (s, 1H), 8.56 (d, J =2.1 Hz, 1H), 8.28 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 7.85 (dd, J =8.7, 2.5 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.12-7.08 (m, 1H), 7.01-6.99 (m, 1H), 6.97-6.92 (m, 1H), 3.86 (s, 3H).

[0162] Compound 26,4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzamide Step A) Preparation of 3-bromo-4-methoxy-N-(m-tolyl)benzamide

[0163] 3-Bromo-4-methoxybenzoic acid (500 mg, 2.16 mmol), m-toluidine (280 μL, 2.59 mmol), HATU (1.23 g, 3.25 mmol), triethylamine (280 μL, 4.33 mmol), and DMF (10 mL) were stirred at 30 °C for 16 hours. After the reaction was complete, the mixture was extracted with water and DCM, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The compound was then separated by silica gel column chromatography in 75% (520 mg) yield.

[0164] Step B) Preparation of 4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzamide (compound 26)

[0165] 5-Bromo-1H-pyrazolo[3,4-b]pyridine (99 mg, 0.5 mmol), bis(pinacolato)diboron (152 mg, 0.6 mmol), [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (41 mg, 0.05 mmol), potassium acetate (147 mg, 1.5 mmol), and 1,4-dioxane (5 mL) were added. After degassing under nitrogen (N2) for 10 minutes, the mixture was stirred at 105 °C for 12 hours. After cooling to room temperature, 160 mg (0.5 mmol) of 3-bromo-4-methoxy-N-(m-tolyl)benzamide and 0.5 mL of sodium carbonate aqueous solution (2.0 M) were added, and the mixture was stirred at 105 °C for 12 hours. After the reaction was complete, the solvent was removed by diatomite filtration, followed by extraction with water and EtOAc. The organic layer was dried over MgSO4 and concentrated under reduced pressure. Compound 26 was then separated by silica gel column chromatography in 52% (94 mg) yield.

[0166] 1 H NMR (300 MHz, DMSO- d 6) δ 13.73 (s, 1H), 10.07 (s, 1H), 8.71 (d, J =2.1 Hz, 1H), 8.38 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 8.10-8.00 (m, 2H), 7.62-7.52 (m, 2H), 7.30 (d, J = 8.5 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 3.89 (s, 3H), 2.31 (s, 3H).

[0167] Compound 27.N-(3-fluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide

[0168] Compound 27 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 40%).

[0169] 1 H NMR (300 MHz, DMSO- d 6) δ 13.73 (s, 1H), 10.32 (s, 1H), 8.70 (d, J =2.0 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.21 (s, 1H), 8.05 (d, J = 7.5 Hz, 2H), 7.76 (dt, J = 12.0, 2.2 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.44-7.27 (m, 2H), 6.92 (dt, J = 9.6, 4.7 Hz, 1H), 3.89 (s, 3H).

[0170] Compound 28. N-phenyl-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0171] Compound 28 was synthesized using the same method as compound 1 described above (yield 44%).

[0172] 1 H NMR (300 MHz, DMSO-d6) δ 13.82 (brs, 1H), 10.31 (brs, 1H), 8.77 (d,J = 2.2 Hz, 1H), 8.47 (d,J = 2.3 Hz, 1H), 8.25 (s, 1Hz), 8.07 (t, J = 1.9Hz, 1H), 8.00 (dt, J = 7.6, 1.6 Hz, 1H), 7.84 - 7.57 (m, 3H), 7.25 (dd, J =8.5, 7.2 Hz, 2H), 7.17 - 7.09 (m, 2H), 7.04 (t, J = 7.3 Hz, 1H).

[0173] Compound 29.3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide

[0174] Compound 29 was synthesized using the same method as compound 1 described above (yield 41%).

[0175] 1 H NMR (300 MHz, DMSO-d6) δ 13.82 (s, 1H), 10.23 (s, 1H), 8.76 (d, J =2.2 Hz, 1H), 8.46 (d, J = 2.2 Hz, 1H), 8.24 (d, J = 1.0 Hz, 1H), 8.06 (t, J =1.8 Hz, 1H), 8.00 (dt, J = 7.6, 1.5 Hz, 1H), 7.76 (dt, J = 7.9, 1.5 Hz, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.17 - 7.06 (m, 1H), 6.95 (d, J = 7.8 Hz, 2H), 6.86 (d, J = 7.5 Hz, 1H), 2.20 (s, 3H).

[0176] Compound 30.N-(3-fluorophenyl)-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0177] Compound 30 was synthesized using the same method as compound 1 described above (yield 38%).

[0178] 1 H NMR (300 MHz, DMSO-d6) δ 13.81 (s, 1H), 10.60 (s, 1H), 8.79 (d, J =2.2 Hz, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.24 (d, J = 1.3 Hz, 1H), 8.12 (d, J =1.9 Hz, 1H), 8.03 (dt, J = 7.9, 1.4 Hz, 1H), 7.79 (dt, J = 7.9, 1.4 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.29 (td, J = 8.4, 6.7 Hz, 1H), 7.02 - 6.90 (m,2H), 6.86 (td, J = 8.4, 2.6 Hz, 1H).

[0179] Compound 31. N-(3-chlorophenyl)-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0180] Compound 31 was synthesized using the same method as compound 1 described above (yield 46%).

[0181] 1 H NMR (300 MHz, DMSO-d6) δ 13.81 (s, 1H), 10.59 (s, 1H), 8.79 (d, J =2.2 Hz, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.24 (d, J = 1.3 Hz, 1H), 8.10 (t, J =1.8 Hz, 1H), 8.03 (dt, J = 7.7, 1.5 Hz, 1H), 7.78 (dt, J = 7.9, 1.4 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.17 (t, J = 2.0 Hz, 1H), 7.11 (dddd, J = 8.9, 7.9, 2.1, 1.0 Hz, 2H).

[0182] Compound 32,3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(o-tolyl)benzenesulfonamide

[0183] Compound 32 was synthesized using the same method as compound 1 described above (yield 12%).

[0184] 1 H NMR (300 MHz, DMSO-d6) δ 13.80 (s, 1H), 9.61 (s, 1H), 8.73 (d, J =2.2 Hz, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.26 - 8.22 (m, 1H), 8.04 (dt, J =5.5, 2.2 Hz, 1H), 7.93 - 7.90 (m, 1H), 7.70 - 7.65 (m, 2H), 7.13 (tt, J =9.3, 3.7 Hz, 3H), 7.03 - 6.98 (m, 1H), 2.01 (s, 3H).

[0185] Compound 33,4-methoxy-3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide

[0186] Compound 33 was synthesized using the same method as compound 24 described above (yield 58%).

[0187] 1 H NMR (300 MHz, DMSO- d 6) δ 13.31 (s, 1H), 10.04 (s, 1H), 8.48 (d, J =2.1 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 8.7, 2.4 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 6.98-6.91 (m, 2H), 6.87 (d, J= 7.5 Hz, 1H), 3.84 (s, 3H), 2.52 (s, 3H), 2.22 (s, 3H).

[0188] Compound 34,4-methoxy-3-(1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide

[0189] Compound 33 (123 mg, 0.3 mmol), phenylboronic acid (55 mg, 0.45 mmol), Cu(OAc)₂ (16 mg, 0.09 mmol), pyridine (70 μL, 0.9 mmol), and DMF (3 mL) were added, and the mixture was stirred at 90 °C for 12 hours. After the reaction was complete, compound 34 was obtained by silica gel column chromatography in 58% yield.

[0190] 1 H NMR (300 MHz, Chloroform- d ) δ 8.65 (d, J = 2.1 Hz, 1H), 8.25-8.22 (m, 2H), 7.94 (d, J = 2.1 Hz, 1H), 7.81 (dd, J = 8.7, 2.4 Hz, 1H), 7.73 (d, J = 2.4Hz, 1H), 7.70 (s, 1H), 7.50 (t, J = 7.9 Hz, 2H), 7.30-7.26 (m, 1H), 7.13 (t, J =7.7 Hz, 1H), 7.01-6.99 (m, 2H), 6.94 (t, J = 6.8 Hz, 2H), 3.85 (s, 3H), 2.65 (s, 3H), 2.28 (s, 3H) 。

[0191] Compound 35.N-(5-(2-methoxy-5-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide Synthesis of 35-1,5-bromo-1H-pyrazolo[3,4-b]pyridine-3-amine (compound 35-1)

[0192] 5-Bromo-2-chloropyridine-3-carbonitrile (10 g, 46.0 mmol), EtOH (150 mL), and hydrazine hydrate (5.6 mL, 115 mmol) (2.5 eq.) were added, and the mixture was stirred at 85 °C for 12 hours. After the reaction was complete, the solvent was removed, and the solid was filtered off with water to give compound 35-1 in 95% (9.3 g) yield.

[0193] Synthesis of 35-2.N-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 35-2)

[0194] Compound 35-1 (5-bromo-1H-pyrazolo[3,4-b]pyridin-3-amine; 1.2 g, 5.63 mmol) and pyridine (10 mL) were stirred at 0 °C, followed by the slow addition of acetyl chloride (440 μL, 6.19 mmol) (1.1 eq.), and then stirred at room temperature for 12 hours. After the reaction was complete, the mixture was extracted with water and EtOAc, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. Compound 35-2 was then obtained by silica gel column chromatography in 99% (1.43 g) yield.

[0195] Synthesis of 35-3.N-(5-(2-methoxy-5-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 35)

[0196] Compound 35 was synthesized using the same method as compound 1 described above (yield 32%).

[0197] 1H NMR (300 MHz, DMSO-d6) δ 13.32 (s, 1H), 10.75 (s, 1H), 10.11 (s, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.35 (d, J = 2.2 Hz, 1H), 7.76 (dd, J = 8.7,2.4 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.12 (t, J =7.7 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 7.5 Hz, 1H), 3.83 (s, 3H), 2.21 (s, 3H), 2.11 (d, J = 13.5 Hz, 3H).

[0198] Compound 36.N-(5-(4-fluoro-3-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0199] Compound 36 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 6%).

[0200] 1 H NMR (300 MHz, DMSO- d 6) δ 13.36 (s, 1H), 10.77 (s, 1H), 10.64 (s, 1H), 8.73 (d, J = 2.2 Hz, 1H), 8.55 (d, J = 2.3 Hz, 1H), 8.01 (d, J = 5.9 Hz, 2H), 7.55 (t, J = 9.4 Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H), 7.01-6.92 (m, 2H), 6.84 (d, J = 7.6 Hz, 1H), 2.20 (s, 3H), 2.14 (s, 3H).

[0201] Compound 37.N-(5-(2-fluoro-5-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0202] Compound 37 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 1%).

[0203] 1 H NMR (300 MHz, DMSO- d 6) δ 13.43 (s, 1H), 10.81 (s, 1H), 10.26 (s, 1H), 8.57 (s, 1H), 8.52 (s, 1H), 7.92 (d, J = 6.8 Hz, 1H), 7.84-7.74 (m, 1H), 7.56 (t, J = 9.4 Hz, 1H), 7.14 (t, J = 7.7 Hz, 1H), 6.99-6.86 (m, 3H), 2.22 (s, 3H), 2.14 (s, 3H).

[0204] Compound 38.N-(5-(3-fluoro-5-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0205] Compound 38 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 3%).

[0206] 1 H NMR (300 MHz, DMSO- d 6) δ 13.41 (s, 1H), 10.79 (s, 1H), 10.37 (s, 1H), 8.77 (d, J = 2.3 Hz, 1H), 8.61 (d, J = 2.3 Hz, 1H), 7.91 (d, J = 11.1 Hz, 1H), 7.86 (s, 1H), 7.52 (dd, J = 8.0, 2.3 Hz, 1H), 7.14 (t, J = 7.7 Hz, 1H), 6.99 - 6.92 (m, 2H), 6.88 (d, J = 7.6 Hz, 1H), 2.21 (s, 3H), 2.15 (s, 3H).

[0207] Compound 39. N-(5-(2,4-difluoro-5-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0208] Compound 39 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 17%).

[0209] 1 H NMR (300 MHz, DMSO- d 6) δ 13.42 (s, 1H), 10.80 (s, 1H), 10.67 (s, 1H), 8.58 (d, J = 2.1 Hz, 1H), 8.50 (s, 1H), 7.96 (t, J = 8.1 Hz, 1H), 7.71 (t, J = 10.2 Hz, 1H), 7.14 (t, J = 7.7 Hz, 1H), 7.01-6.92 (m, 2H), 6.87 (d, J = 7.5Hz, 1H), 2.22 (s, 3H), 2.13 (s, 3H) 。

[0210] Compound 40.N-(5-(2-fluoro-3-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0211] Compound 40 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 11%).

[0212] 1 H NMR (300 MHz, DMSO- d 6) δ 13.43 (s, 1H), 10.79 (s, 1H), 10.58 (s, 1H), 8.57 (d, J = 1.8 Hz, 1H), 8.52 (s, 1H), 7.90 - 7.79 (m, 2H), 7.46 (t, J =7.8 Hz, 1H), 7.11 (dd, J = 9.0, 7.4 Hz, 1H), 6.97 - 6.90 (m, 2H), 6.85 (d,J =7.5 Hz, 1H), 2.19 (s, 3H), 2.12 (s, 3H).

[0213] Compound 41. N-(5-(2-methoxy-5-(N-(p-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0214] Compound 41 was synthesized using the same method as compound 1 described above (yield 13%).

[0215] 1 H NMR (300 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.48-8.45 (m, 1H), 8.37-8.35 (m, 1H), 7.74-7.69 (m, 2H), 7.64 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 8.8Hz, 1H), 7.08-6.96 (m, 4H), 3.82 (s, 3H), 2.13 (s, 3H), 2.08 (s, 3H).

[0216] Compound 42.N-(5-(2-methoxy-5-(N-(o-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0217] Compound 42 was synthesized using the same method as compound 1 described above (yield 12%).

[0218] 1 H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.47 (s, 1H), 8.48 (d, J =2.1 Hz, 1H), 8.33 (d, J = 2.1 Hz, 1H), 7.67 (dd, J = 8.7, 2.4 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.20 - 7.07 (m, 4H), 7.04 -6.99 (m, 1H), 3.87 (s, 3H), 2.14 (s, 3H), 2.06 (s, 3H).

[0219] Compound 43. N-(5-(2-methoxy-5-(N-phenylaminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0220] Compound 43 was synthesized using the same method as compound 1 described above (yield 21%).

[0221] 1 H NMR (300 MHz, DMSO-d6) δ 10.73 (s, 1H), 10.16 (s, 1H), 8.51 (d, J =2.1 Hz, 1H), 8.36 (d, J = 2.1 Hz, 1H), 7.76 (dd, J = 8.7, 2.4 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.27 (t, J = 8.5 Hz, 3H), 7.16 (d, J = 1.4 Hz, 1H), 7.13 (s, 1H), 7.05 (t, J = 7.3 Hz, 1H), 3.84 (s, 3H), 2.15 (s, 3H).

[0222] Compound 44. N-(5-(5-(N-(3-fluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0223] Compound 44 was synthesized using the same method as compound 1 described above (yield 38%).

[0224] 1 H NMR (300 MHz, DMSO-d6) δ 13.32 (s, 1H), 10.74 (s, 1H), 10.49 (s,1H), 8.52 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 2.1 Hz, 1H), 7.80 (dd, J = 8.7, 2.4 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.29 (td, J = 8.4, 6.3 Hz, 2H), 7.01 -6.90 (m, 2H), 6.86 (ddd, J = 10.5, 8.3, 2.5 Hz, 1H), 3.84 (s, 3H), 2.13 (s, 3H).

[0225] Compound 45.N-(5-(4-fluoro-3-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0226] Compound 45 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 9%).

[0227] 1 H NMR (300 MHz, DMSO- d 6) δ 13.36 (s, 1H), 11.01 (s, 1H), 10.76 (s, 1H), 8.76 (d, J = 2.2 Hz, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.13-7.97 (m, 2H), 7.62-7.52 (m, 1H), 7.30 (q, J = 7.8 Hz, 1H), 7.05-6.93 (m, 2H), 6.91-6.83 (m, 1H), 2.14 (s, 3H).

[0228] Compound 46.N-(5-(2-fluoro-5-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0229] Compound 46 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 8%).

[0230] 1 H NMR (300 MHz, DMSO- d 6) δ 13.43 (s, 1H), 10.81 (s, 1H), 10.65 (s, 1H), 8.61 (t, J = 2.1 Hz, 1H), 8.54 (s, 1H), 7.97 (dd, J = 7.2, 2.4 Hz, 1H),7.84 (ddd, J = 7.3, 4.4, 2.4 Hz, 1H), 7.58 (dd, J = 10.2, 8.7 Hz, 1H), 7.31 (td, J= 8.3, 6.7 Hz, 1H), 7.05-6.83 (m, 3H), 2.14 (s, 3H).

[0231] Compound 47.N-(5-(3-fluoro-5-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0232] Compound 47 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 18%).

[0233] 1 H NMR (300 MHz, DMSO- d 6) δ 13.42 (s, 1H), 10.83-10.68 (m, 2H), 8.79 (d, J = 2.3 Hz, 1H), 8.62 (d, J = 2.3 Hz, 1H), 7.98-7.88 (m, 2H), 7.57 (dt, J =7.9, 2.0 Hz, 1H), 7.31 (td, J = 8.4, 6.7 Hz, 1H), 7.03-6.86 (m, 3H), 2.16 (s, 3H).

[0234] Compound 48. N-(5-(2,4-difluoro-5-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0235] Compound 48 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 20%).

[0236] 1 H NMR (300 MHz, DMSO- d 6) δ 13.42 (s, 1H), 11.04 (s, 1H), 10.79 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.52 (s, 1H), 8.02 (t, J = 8.1 Hz, 1H), 7.74 (t, J = 10.2 Hz, 1H), 7.32 (q, J= 7.7 Hz, 1H), 7.05-6.84 (m, 3H), 2.13 (s, 3H).

[0237] Compound 49. N-(5-(2-fluoro-3-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0238] Compound 49 was synthesized using the same method as in step B of the synthesis of compound 26 described above (yield 23%).

[0239] 1 H NMR (300 MHz, DMSO- d 6) δ 13.41 (s, 1H), 11.00 (s, 1H), 10.79 (s, 1H), 8.59 (s, 1H), 8.55 (s, 1H), 7.96-7.86 (m, 2H), 7.50 (t, J = 7.8 Hz, 1H), 7.29 (q, J = 8.0 Hz, 1H), 7.01-6.82 (m, 3H), 2.12 (s, 3H).

[0240] Compound 50.N-(5-(5-(N-(4-fluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0241] Compound 50 was synthesized using the same method as compound 1 described above (yield 8%).

[0242] 1 H NMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.41 (s, 1H), 7.73 (dd,J = 8.7, 2.3 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.16 - 7.10 (m, 2H), 7.00 (t, J = 8.7 Hz, 2H), 3.89 (s, 3H), 2.25 (s, 3H).

[0243] Compound 51.N-(5-(5-(N-(2-fluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0244] Compound 51 was synthesized using the same method as compound 1 described above (yield 15%).

[0245] 1 H NMR (300 MHz, DMSO-d6) δ 13.31 (s, 1H), 10.73 (s, 1H), 10.08 (s,1H), 8.51 (d, J = 2.0 Hz, 1H), 8.36 (s, 1H), 7.72 (dd, J = 8.7, 2.4 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.34 - 7.27 (m, 2H), 7.17 (t, J = 7.9 Hz, 3H), 3.86 (s, 3H), 2.14 (s, 3H).

[0246] Compound 52.N-(5-(5-(N-(3-chlorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0247] Compound 52 was synthesized using the same method as compound 1 described above (yield 41%).

[0248] 1 H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H), 10.47 (s, 1H), 8.52 (d, J =2.1 Hz, 1H), 8.37 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 8.7, 2.4 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.29 (t, J = 8.1 Hz, 2H), 7.19 - 7.05 (m, 3H), 3.84 (s, 3H), 2.12 (d, J = 5.9 Hz, 3H).

[0249] Compound 53.N-(5-(5-(N-(4-chlorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0250] Compound 53 was synthesized using the same method as compound 1 described above (yield 25%).

[0251] 1 H NMR (300 MHz, DMSO-d6) δ 10.74 (s, 1H), 10.34 (s, 1H), 8.52 (d, J =2.1 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 7.77 - 7.67 (m, 2H), 7.37 - 7.24 (m, 3H), 7.19 - 7.11 (m, 2H), 3.83 (s, 3H), 2.14 (s, 3H).

[0252] Compound 54.N-(5-(5-(N-(2-chlorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0253] Compound 54 was synthesized using the same method as compound 1 described above (yield 35%).

[0254] 1 H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1H), 9.90 (s, 1H), 8.51 (d, J =2.1 Hz, 1H), 8.36 (d, J = 2.2 Hz, 1H), 7.72 (dd, J = 8.7, 2.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.43 (dd, J = 7.8, 1.1 Hz, 1H), 7.34 - 7.26 (m, 3H), 7.20 (ddd, J = 7.9, 5.2, 3.8 Hz, 1H), 3.86 (s, 3H), 2.13 (s, 3H).

[0255] Compound 55.N-(5-(5-(N-(3-hydroxyphenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0256] Compound 55 was synthesized using the same method as compound 1 described above (yield 15%).

[0257] 1 H NMR (300 MHz, DMSO-d6) δ 13.31 (s, 1H), 10.73 (s, 1H), 10.05 (s, 1H), 9.49 - 9.36 (m, 1H), 8.50 (d, J = 9.3 Hz, 1H), 8.39 (d, J = 2.1 Hz, 1H),7.79 - 7.64 (m, 2H), 7.35 - 7.21 (m, 1H), 7.07 - 6.97 (m, 1H), 6.67 - 6.49 (m, 2H), 6.41 (d, J = 8.4 Hz, 1H), 3.90 - 3.80 (m, 3H), 2.18 - 2.09 (m, 3H).

[0258] Compound 56.N-(5-(5-(N-(4-hydroxyphenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0259] Compound 56 was synthesized using the same method as compound 1 described above (7% yield).

[0260] 1 H NMR (300 MHz, DMSO-d6) δ 13.31 (s, 1H), 10.74 (s, 1H), 9.64 (s, 1H), 9.32 (s, 1H), 8.51 (d, J = 2.1 Hz, 1H), 8.39 (d, J = 2.2 Hz, 1H), 7.66 -7.60 (m, 2H), 7.25 (d, J = 9.4 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.64 (d, J= 8.7 Hz, 2H), 3.84 (s, 3H), 2.14 (s, 3H).

[0261] Compound 57.N-(5-(2-methoxy-5-(N-(pyridin-3-yl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0262] Compound 57 was synthesized using the same method as compound 1 described above (yield 14%).

[0263] 1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 10.44 (s, 1H), 8.53 (d, J =1.9 Hz, 1H), 8.38 (s, 1H), 8.29 (d, J = 19.3 Hz, 2H), 7.77 (dd, J = 8.8, 2.4Hz, 1H), 7.71 (s, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 8.7 Hz, 2H), 3.86 (s, 3H), 2.15 (s, 3H).

[0264] Compound 58.N-(5-(2-methoxy-5-(N-(pyridin-2-yl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0265] Compound 58 was synthesized using the same method as compound 1 described above (yield 15%).

[0266] 1 H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.58 (d, J = 1.8 Hz, 1H), 8.41 (s, 1H), 8.07 (s, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.14 (s, 1H), 6.88 (s, 1H), 3.85 (s, 3H), 2.14 (d, J = 9.0 Hz, 3H).

[0267] Compound 59.N-(5-(2-methoxy-5-(morpholinosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0268] Compound 59 was synthesized using the same method as compound 1 described above (64% yield).

[0269] 1H NMR (300 MHz, Chloroform-d) δ 12.68 (s, 1H), 9.64 (s, 1H), 8.76 (d, J = 2.0 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 7.77 (dq, J = 4.3, 2.4 Hz, 2H), 7.11 (d, J = 9.3 Hz, 1H), 3.92 (s, 3H), 3.76 (dd, J = 5.7, 3.7 Hz, 4H), 3.12 - 2.98 (m, 4H), 2.32 (s, 3H).

[0270] Compound 60.N-(5-(5-(N-(3,5-difluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0271] Compound 60 was synthesized using the same method as compound 24 described above (yield 31%).

[0272] 1 H NMR (400 MHz, DMSO- d 6) δ 13.31 (s, 1H), 10.79 (s, 1H), 10.73 (s, 1H), 8.54 (d, J = 2.2 Hz, 1H), 8.37 (d, J = 2.1 Hz, 1H), 7.85 (dd, J = 8.8, 2.5Hz, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 6.94-6.84 (m, 1H), 6.84-6.76 (m, 2H), 3.85 (s, 3H), 2.12 (s, 3H).

[0273] Compound 61.N-(5-(5-(N-(3-chloro-5-fluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide

[0274] Compound 61 was synthesized using the same method as compound 24 (yield 36%).

[0275] 1 H NMR (400 MHz, DMSO- d 6) δ 13.31 (s, 1H), 10.79 (s, 1H), 10.73 (s, 1H), 8.53 (d, J = 2.2 Hz, 1H), 8.37 (d, J = 2.2 Hz, 1H), 7.84 (dd, J = 8.7, 2.5Hz, 1H), 7.74 (d, J = 2.5 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 8.6Hz, 1H), 7.02-6.90 (m, 2H), 3.85 (s, 3H), 2.12 (s, 3H).

[0276] Compound 62.N-(3-fluorophenyl)-4-methoxy-3-(3-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0277] Synthesis of 62-1,5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (compound 62-1) 3-bromo-1H-pyrazolo[3,4-b]pyridine (9.9 g, 50.0 mmol) and DMF (50 mL) were added at 0 °C, followed by the addition of potassium hydroxide (11.2 g, 200.0 mmol) (4.0 eq.) and stirring for 10 minutes. Iodine (14.0 g, 55.0 mmol) (1.2 eq.) was then added and the mixture was stirred at room temperature for 20 hours. After the reaction was complete, a saturated sodium thiosulfate solution and water were added, and the resulting solid was filtered to give compound 62-1 in 100% (16.2 g) yield.

[0278] Synthesis of 62-2,5-bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (5-bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine) (compound 62-2) Compound 62-1 (5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine; 16.2 g, 50.0 mmol) and DMF (200 mL) were added and stirred at 0 °C. Then, sodium hydride (4.0 mg, 100.0 mmol) (2.0 eq.) and 2-(trimethylsilyl)ethoxymethyl chloride (15 mL, 85.0 mmol) (1.7 eq.) were added, and the mixture was stirred at room temperature for 18 hours. After the reaction was complete, the mixture was quenched with water, extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure. Compound 62-2 was then obtained by silica gel column chromatography in 60% (13.6 g) yield.

[0279] Synthesis of 62-3,5-bromo-3-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (compound 62-3) Added compounds 62-2 (5-bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine (1.36 g, 3.0 mmol), phenylboronic acid (402 mg, 3.3 mmol) (1.1 eq.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (122 mg, 0.15 mmol) (0.05 eq.), potassium carbonate (1.36 g, 3.0 mmol), phenylboronic acid (402 mg, 3.3 mmol) (1.1 eq.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (122 mg, 0.15 mmol) (0.05 eq.), and potassium carbonate (1.36 g, 3.0 mmol). The reaction mixture was prepared by stirring 2 M, 4.5 mL of carbonate aqueous solution (3.0 eq.) and 10 mL of CH3CN at 85 °C for 6 hours. After the reaction was complete, the mixture was filtered through a celite pad, extracted with water and EtOAc, dried over MgSO4, and then concentrated under reduced pressure. Compound 62-3 was then obtained by silica gel column chromatography in 60% (728 mg) yield.

[0280] Synthesis of 5-bromo-3-phenyl-1H-pyrazolo[3,4-b]pyridine (compound 62-4) Compound 62-3 (5-bromo-3-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine; 728 mg, 1.8 mmol) and THF (10 mL) were stirred, and tetrabutylammonium fluoride (1 M in THF, 18 mL) (20.0 eq.) was added. The mixture was refluxed at 85 °C for 24 h. After the reaction was complete, the solvent was removed, and the mixture was extracted with water and EtOAc. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. Compound 62-4 was then separated by silica gel column chromatography in 83% (410 mg) yield.

[0281] Synthesis of 62-5. N-(3-fluorophenyl)-4-methoxy-3-(3-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 62) Compound 62 was synthesized using the same method as compound 1 described above (yield 40%).

[0282] 1 H NMR (300 MHz, DMSO-d6) δ 13.94 (s, 1H), 10.46 (s, 1H), 8.60 (d, J =2.0 Hz, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.08 - 7.99 (m, 2H), 7.84 (dd, J =6.6, 2.5 Hz, 2H), 7.61 - 7.51 (m, 2H), 7.51 - 7.39 (m, 1H), 7.37 - 7.22 (m, 2H), 7.03 - 6.91 (m, 2H), 6.91 - 6.79 (m, 1H), 3.85 (s, 3H).

[0283] Compound 63.N-(3-fluorophenyl)-4-methoxy-3-(3-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0284] Compound 63 was synthesized using the same methods as those used for the synthesis of compound 62 (62-1 to 62-4), and then compound 63 was synthesized using the same methods as those used for the synthesis of compound 1 (yield 12%).

[0285] 1 H NMR (300 MHz, DMSO-d6) δ 13.80 (s, 1H), 10.46 (s, 1H), 8.61 - 8.52 (m, 2H), 8.22 (dd, J = 2.7, 1.5 Hz, 1H), 7.83 (h, J = 2.5 Hz, 2H), 7.79 -7.68 (m, 2H), 7.37 - 7.22 (m, 2H), 7.02 - 6.92 (m, 2H), 6.90 - 6.82 (m, 1H), 3.85 (s, 3H).

[0286] Compound 64,4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide Synthesis of 64-1,4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)morpholine (4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)morpholine) (compound 44-1)

[0287] 5-Bromo-1H-pyrazolo[3,4-b]pyridin-3-amine (9.0 g, 42.25 mmol), 2-bromoethyl ether (9.0 mL, 71.83 mmol) (1.7 eq.), and N,N-diisopropylethylamine (15 mL, 86.61 mmol) (2.05 eq.) were placed in DMF (42 mL) and stirred at 110 °C for 2 hours. After the reaction was complete, the mixture was extracted with water and EtOAc, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The solution was then separated by silica gel column chromatography to give compound 64-1 in 35% (4.19 g) yield.

[0288] Synthesis of 64-2,4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 64)

[0289] Compound 64 was synthesized using the same method as compound 1 described above (yield 54%).

[0290] 1H NMR (300 MHz, Chloroform-d) δ 8.43 (d, J = 1.9 Hz, 1H), 8.05 (d, J = 1.9 Hz, 1H), 7.88 (s, 1H), 7.83 - 7.72 (m, 2H), 7.10 (t, J = 7.7 Hz, 1H), 6.93 (dd, J = 14.7, 8.3 Hz, 4H), 3.93 - 3.84 (m, 4H), 3.82 (s, 3H), 3.47 -3.37 (m, 4H), 2.25 (s, 3H).

[0291] Compound 65,4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(p-tolyl)benzenesulfonamide

[0292] Compound 65 was synthesized using the same method as compound 1 described above (yield 20%).

[0293] 1 H NMR (300 MHz, Chloroform-d) δ 8.49 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 1.9 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 8.6, 2.4 Hz, 1H), 7.70 (s, 1H), 7.12-7.06 (m, 4H), 6.98 (d, J = 8.6 Hz, 1H), 3.99 - 3.89 (m, 4H), 3.86 (s, 3H), 3.55 - 3.41 (m, 4H), 2.29 (s, 3H).

[0294] Compound 66,4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(o-tolyl)benzenesulfonamide

[0295] Compound 66 was synthesized using the same method as compound 1 described above (yield 12%).

[0296] 1H NMR (300 MHz, Chloroform-d) δ 8.53 (d, J = 4.0 Hz, 1H), 8.11 (d, J= 8.0 Hz, 1H), 7.77 (dd, J = 8.7, 2.3 Hz, 1H), 7.36 - 7.30 (m, 1H), 7.20 -7.13 (m, 4H), 7.10 (s, 1H), 7.03 - 6.98 (m, 1H), 3.98 - 3.90 (m, 4H), 3.88 (s, 3H), 3.53 - 3.43 (m, 4H), 2.11 (s, 3H).

[0297] Compound 67,4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-phenylbenzenesulfonamide

[0298] Compound 67 was synthesized using the same method as compound 1 described above (yield 24%).

[0299] 1 H NMR (300 MHz, Chloroform-d) δ 8.49 (s, 1H), 8.09 (s, 1H), 7.86 -7.74 (m, 2H), 7.69 (s, 1H), 7.26 (s, 1H), 7.22 - 7.11 (m, 3H), 7.00 (d, J =8.5 Hz, 1H), 3.94 (q, J = 5.0 Hz, 4H), 3.87 (s, 3H), 3.56 - 3.42 (m, 4H).

[0300] Compound 68.N-(3-fluorophenyl)-4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0301] Compound 68 was synthesized using the same method as compound 1 described above (yield 13%).

[0302] 1H NMR (300 MHz, DMSO-d6) δ 12.73 (brs, 1H), 10.44 (brs, 1H), 8.42 (s,1H), 8.24 (d, J = 2.5 Hz, 1H), 7.85 - 7.71 (m, 2H), 7.34 - 7.22 (m, 2H), 6.98- 6.80 (m, 3H), 3.89 - 3.73 (m, 7H), 3.37 (m, 4H).

[0303] Compound 69. N-(2-fluorophenyl)-4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0304] Compound 69 was synthesized using the same method as compound 1 described above (yield 21%).

[0305] 1 H NMR (300 MHz, DMSO-d6) δ 12.73 (s, 1H), 10.06 (s, 1H), 8.43 (d, J =2.0 Hz, 1H), 8.21 (s, 1H), 7.73 (dd, J = 8.8, 2.4 Hz, 1H), 7.66 (d, J = 2.3Hz, 1H), 7.36 - 7.22 (m, 2H), 7.22 - 7.01 (m, 3H), 3.84 (s, 3H), 3.83 - 3.74 (m, 4H), 3.48 - 3.38 (m, 4H).

[0306] Compound 70.N-(2-chlorophenyl)-4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0307] Compound 70 was synthesized using the same method as compound 1 described above (yield 54%).

[0308] 1H NMR (300 MHz, Chloroform-d) δ 10.64 (s, 1H), 8.47 (d, J = 1.9 Hz, 1H), 8.02 (d, J = 1.9 Hz, 1H), 7.80 (dd, J = 8.7, 2.5 Hz, 1H), 7.74 - 7.67 (m, 2H), 7.31 - 7.27 (m, 1H), 7.12 - 7.05 (m, 2H), 6.99 (d, J = 8.8 Hz, 1H), 3.97 - 3.90 (m, 4H), 3.86 (s, 3H), 3.47 (dd, J = 5.9, 3.7 Hz, 4H).

[0309] Compound 71. N-(3-hydroxyphenyl)-4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide

[0310] Compound 71 was synthesized using the same method as compound 1 described above (yield 23%).

[0311] 1 H NMR (300 MHz, DMSO-d6) δ 12.73 (s, 1H), 10.03 (s, 1H), 9.45 (s,1H), 8.43 (d, J = 2.0 Hz, 1H), 8.23 ​​(d, J = 2.0 Hz, 1H), 7.77 (dd, J = 8.7,2.4 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.00 (t, J =8.1 Hz, 1H), 6.63 (t, J = 2.2 Hz, 1H), 6.58 - 6.53 (m, 1H), 6.44 - 6.38 (m, 1H), 3.83 (s, 3H), 3.80 (t, J = 4.8 Hz, 4H), 3.42 (s, 4H).

[0312] Compound 72,4-((4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)sulfonyl)morpholine(4-((4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)sulfonyl)morpholine)

[0313] Compound 72 was synthesized using the same method as compound 1 described above (64% yield).

[0314] 1 H NMR (300 MHz, Chloroform-d) δ 12.68 (s, 1H), 9.64 (s, 1H), 8.76 (d, J = 2.0 Hz, 1H), 8.67 (d, J = 2.1 Hz, 1H), 7.77 (dq, J = 4.3, 2.4 Hz, 2H), 7.11 (d, J = 9.3 Hz, 1H), 3.92 (s, 3H), 3.76 (dd, J = 5.7, 3.7 Hz, 4H), 3.12 - 2.98 (m, 4H), 2.32 (s, 3H).

[0315] Compound 73,4-methoxy-3-(1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide

[0316] Add 4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (99 mg, 0.25 mmol), phenylboronic acid (46 mg, 0.375 mmol) (1.5 eq.), copper(II) acetate (14 mg, 0.075 mmol) (0.3 eq.), pyridine (60 μL, 0.75 mmol) (3.0 eq.), and DMF (3 mL), and stir at 90 °C for 12 hours. After the reaction is complete, filter using a celite pad, extract with water and EtOAc, dry the organic layer with MgSO4, and then concentrate under reduced pressure. Compound 73 was then separated by silica gel column chromatography and obtained in 61% (72 mg) yield.

[0317] 1 H NMR (300 MHz, Chloroform-d) δ 8.72 (d, J = 2.1 Hz, 1H), 8.29 -8.20 (m, 3H), 8.14 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 8.6, 2.4 Hz, 1H), 7.78 (d, J = 2.3 Hz, 1H), 7.61 - 7.50 (m, 2H), 7.39 - 7.31 (m, 1H), 7.15 (t, J =7.7 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 6.99 - 6.90 (m, 3H), 3.87 (s, 3H),2.29 (s, 3H).

[0318] Compound 74.3-(1-(2-(dimethylamino)ethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methoxy-N-(m-tolyl)benzenesulfonamide

[0319] Add 4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (99 mg, 0.25 mmol), 2-chloro-N,N-dimethylethylamine-hydrochloride (54 mg, 0.375 mmol) (1.5 eq.), Cs₂CO₃ (244 mg, 0.75 mmol) (3.0 eq.), and DMF (3 mL), and stir at 65 °C for 24 hours. After the reaction is complete, filter using a celite pad, extract with water and EtOAc, dry the organic layer with MgSO₄, and then concentrate under reduced pressure. Compound 74 was then separated by silica gel column chromatography in a yield of 30% (35 mg).

[0320] 1 H NMR 300 MHz, Chloroform-d)) δ 8.63 (d, J = 1.9 Hz, 1H), 8.13 (d, J = 2.1 Hz, 2H), 7.68 (dd, J = 8.7, 2.2 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 7.00 (s, 1H), 6.87 (d, J = 8.0 Hz, 1H), 3.92 (s, 3H), 3.75-3.63 (m, 2H), 2.52 -2.39 (m, 2H), 2.32 (s, 3H), 2.23 (s, 6H).

[0321] Compound 75,4-methoxy-3-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide

[0322] Synthesis of 5-bromo-1-methyl-1H-pyrazolo[3,4-b]pyridine (compound 75-1) 3-Bromo-1H-pyrazolo[3,4-b]pyridine (408 mg, 2.0 mmol), potassium carbonate (553 mg, 4.0 mmol) (2.0 eq.), and DMF (10 mL) were stirred, followed by the addition of iodomethane (150 μL, 2.4 mmol) (1.2 eq.), and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was extracted with water and EtOAc, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The solution was then separated by silica gel column chromatography to give compound 75-1 in 49% (206 mg) yield.

[0323] Synthesis of 75-2,5-(2-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (compound 75-2) Compound 75-1 (5-bromo-1-methyl-1H-pyrazolo[3,4-b]pyridine; 205 mg, 0.96 mmol), 2-methoxyphenylboronic acid (166 mg, 1.06 mmol) (1.1 eq.), [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (42 mg, 0.05 mmol) (0.05 eq.), potassium carbonate (2.0 M in H2O, 3 mL), and CH3CN (3 mL) were added, and the mixture was refluxed for 4 hours. After the reaction was complete, the solvent was removed by diatomite filtration, followed by extraction with water and EtOAc. The organic layer was dried with MgSO4 and concentrated under reduced pressure. Then, the mixture was separated by silica gel column chromatography to obtain compound 75-2 in 79% (181 mg) yield.

[0324] Synthesis of 75-3,4-methoxy-3-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonyl chloride (compound 75-3) Chlorosulfonic acid (1 mL) was slowly added to compound 75-2 (5-(2-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine; 181 mg, 0.76 mmol) at 0 °C, and the mixture was stirred for 2 hours. After the reaction was complete, ice water was slowly added, and the mixture was extracted with EtOAc. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. Compound 75-3 was then obtained by silica gel column chromatography in 86% (221 mg) yield.

[0325] Synthesis of 4-methoxy-3-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 75) Compound 75-3 (4-methoxy-3-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonyl chloride; 220 mg, 0.65 mmol), m-toluidine (110 μL, 0.98 mmol) (1.5 eq.), and pyridine (55 μL, 0.65 mmol) (1.0 eq.) were added to THF (2 mL) and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was extracted with water and EtOAc, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. Compound 75 was then separated by silica gel column chromatography in 99% (262 mg) yield.

[0326] 1H NMR 300 MHz, Chloroform-d) δ 8.56 (d, J = 2.0 Hz, 1H), 8.01 - 7.96 (m, 2H), 7.81 (dd, J = 8.7, 2.4 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.37 (s,1H), 7.17 - 7.08 (m, 1H), 7.00 - 6.90 (m, 4H), 4.16 (s, 3H), 3.83 (s, 3H), 2.27 (s, 3H).

[0327] Compound 76.3-(1-acetyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methoxy-N-(m-tolyl)benzenesulfonamide

[0328] Synthesis of 76-1.1-(5-bromo-1H-pyrazolo[3,4-b]pyridin-1-yl)ethan-1-one (1-(5-bromo-1H-pyrazolo[3,4-b]pyridin-1-yl)ethan-1-one) (compound 76-1) After adding 3-bromo-1H-pyrazolo[3,4-b]pyridine (1.98 g, 10.0 mmol), DMAP (611 mg, 5.0 mmol) (0.5 eq.), THF (300 mL), and Et3N (4.5 mL, 30.0 mmol) (3.0 eq.), the mixture was stirred at 0 °C. Then, acetic anhydride (1.9 mL, 20.0 mmol) (2.0 eq.) was added, and the mixture was stirred at 80 °C for 12 hours. After the reaction was complete, the mixture was extracted with water and DCM. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The solution was then filtered through MeOH to give compound 76-1 in 88% (2.13 g) yield.

[0329] Synthesis of 76-2,3-(1-acetyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methoxy-N-(m-tolyl)benzenesulfonamide (3-(1-acetyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methoxy-N-(m-tolyl)benzenesulfonamide) (compound 76) 3-bromo-4-methoxy-N-(m-tolyl)benzenesulfonamide (712 mg, 2.0 mmol), bis(pinacolato)diboron (609 mg, 2.4 mmol) (1.2 eq.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (163 mg, 0.2 mmol) (10 mol%), potassium acetate (589 mg, 6.0 mmol) (3.0 eq.), and 1,4-dioxane (10 mL) were added, and after degassing under nitrogen (N2) for 10 minutes, the mixture was stirred at 100 °C for 12 hours. After the reaction was completed, the solvent was removed by diatomite filtration, and then compound 76-1 (1-(5-bromo-1H-pyrazolo[3,4-b]pyridin-1-yl)ethan-1-one (480 mg, 2.0 mmol) (1.0 eq.), Bis(diphenylphosphino)ferrocene]dichloropalladium (146 mg, 0.2 mmol) (10 mol%), potassium carbonate aqueous solution (2.0 M, 2 mL) (2.0 eq.), and 1,4-dioxane (5 mL) were added. The mixture was stirred at room temperature for 12 hours. After the reaction was complete, the solvent was removed by diatomaceous earth filtration, followed by extraction with water and EtOAc. The organic layer was dried with MgSO4 and concentrated under reduced pressure. Then, compound 76 was obtained by silica gel column chromatography in a yield of 1% (10 mg).

[0330] 1H NMR (300 MHz, Chloroform-d) δ 8.78 (d, J = 1.8 Hz, 1H), 8.16 (s,1H), 8.06 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 8.6, 2.2 Hz, 1H), 7.77 (d, J =2.2 Hz, 1H), 7.33 (s, 1H), 7.12 (t, J = 7.7 Hz, 1H), 6.97 (dd, J = 16.1, 8.5Hz, 3H), 6.91 (s, 1H), 3.84 (s, 3H), 2.88 (s, 3H), 2.26 (s, 3H).

[0331] Compound 77.N-((3-(1-acetyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methoxyphenyl)sulfonyl)-N-(m-tolyl)acetamide

[0332] 3-bromo-4-methoxy-N-(m-tolyl)benzenesulfonamide (99 mg, 0.25 mmol), THF (3 mL), and triethylamine (100 μL, 0.75 mmol) were stirred at 0 °C, followed by the slow addition of acetic anhydride (120 μL, 1.25 mmol), and the mixture was stirred at 80 °C for 12 hours. After the reaction was complete, the mixture was extracted with water and EtOAc, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. Compound 77 was then separated by silica gel column chromatography in 76% (83 g) yield.

[0333] 1 H NMR (300 MHz, Chloroform-d) δ 8.95 (d, J = 2.0 Hz, 1H), 8.27 -8.19 (m, 2H), 8.11 (dd, J = 8.7, 2.4 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.32 (dd, J = 16.6, 7.6 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 7.7 Hz, 1H), 3.93 (s, 3H), 2.91 (s, 3H), 2.40 (s, 3H), 1.87 (s, 3H).

[0334] Compound 78.4-((3-(1H-indazol-5-yl)-4-methoxyphenyl)sulfonyl)morpholine(4-((3-(1H-indazol-5-yl)-4-methoxyphenyl)sulfonyl)morpholine)

[0335] Add 4-((3-bromo-4-methoxyphenyl)sulfonyl)morpholine (200 mg, 0.6 mmol), bis(pinacolato)diboron (183 mg, 0.72 mmol), [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (49 mg, 0.06 mmol) (10 mol%), potassium acetate (177 mg, 1.8 mmol), and 1,4-dioxane (2 mL), and react in a microwave reactor at 120 °C for 1 hour. After cooling at room temperature, 5-bromo-1H-indazole (118 mg, 0.6 mmol) and an aqueous solution of sodium carbonate (2 M, 0.5 mL) were added, and the mixture was reacted in a microwave reactor at 120 °C for 1 hour. After the reaction, the solvent was removed by diatomite filtration, followed by extraction with water and EtOAc. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The mixture was then separated by silica gel column chromatography to obtain compound 78 in 52% (117 mg) yield.

[0336] 1 H NMR (300 MHz, Chloroform-d) δ 10.36 (s, 1H), 8.14 (s, 1H), 7.89 (t, J = 1.2 Hz, 1H), 7.78 - 7.72 (m, 2H), 7.56 (d, J = 1.2 Hz, 2H), 7.14 -7.08 (m, 1H), 3.92 (s, 3H), 3.79 - 3.73 (m, 4H), 3.07 - 3.00 (m, 4H).

[0337] Compound 79.3-(1H-indazol-5-yl)-4-methoxy-N-(m-tolyl)benzenesulfonamide

[0338] Compound 79 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 59%).

[0339] 1 H NMR (300 MHz, DMSO- d 6) δ 13.14 (s, 1H), 10.05 (s, 1H), 8.12 (t, J =1.2 Hz, 1H), 7.75-7.70 (m, 2H), 7.65 (d, J = 2.4 Hz, 1H), 7.58 (dt, J = 8.7,1.0 Hz, 1H), 7.38 (dd, J = 8.7, 1.6 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 7.00-6.90 (m, 2H), 6.90-6.85 (m, 1H), 3.82 (s, 3H), 2.21 (s, 3H).

[0340] Compound 80.N-(3-fluorophenyl)-3-(1H-indazol-5-yl)-4-methoxybenzenesulfonamide

[0341] Compound 80 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 33%).

[0342] 1 H NMR (300 MHz, DMSO- d 6) δ 13.11 (s, 1H), 10.39 (s, 1H), 8.10 (t, J =1.2 Hz, 1H), 7.77-7.72 (m, 2H), 7.70 (d, J = 2.4 Hz, 1H), 7.57 (dt, J = 8.6,1.0 Hz, 1H), 7.39 (dd, J= 8.7, 1.6 Hz, 1H), 7.32-7.21 (m, 2H), 6.99-6.91 (m, 2H), 6.88-6.80 (m, 1H), 3.83 (s, 3H).

[0343] Compound 81,2,4-difluoro-N-(3-fluorophenyl)-5-(1H-indazol-5-yl)benzenesulfonamide

[0344] Compound 81 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 48%).

[0345] 1 H NMR (300 MHz, DMSO- d 6) δ 13.25 (s, 1H), 11.02 (s, 1H), 8.17 (d, J =1.5 Hz, 1H), 8.03-7.90 (m, 2H), 7.73-7.63 (m, 2H), 7.47 (dt, J = 8.8, 1.8 Hz,1H), 7.32 (q, J = 7.7 Hz, 1H), 7.04-6.84 (m, 3H).

[0346] Compound 82.N-(5-(5-(N-(3-fluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-indazol-3-yl)acetamide

[0347] Step A) Preparation of N-(5-bromo-1H-indazole-3-yl)acetamide 5-bromo-1H-indazole-3-amine (440 mg, 2.07 mmol) and pyridine (10 mL) were stirred at 0 °C, followed by the slow addition of acetyl chloride (160 μL, 2.28 mmol). The mixture was then stirred at room temperature for 12 hours. After the reaction was complete, the mixture was extracted with water and EtOAc, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. N-(5-bromo-1H-indazole-3-yl)acetamide was then obtained by silica gel column chromatography in 58% (308 mg) yield.

[0348] Step B) Preparation of N-(5-(5-(N-(3-fluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-indazol-3-yl)acetamide (compound 82) Compound 82 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 3%).

[0349] 1 H NMR (300 MHz, DMSO- d 6) δ 12.72 (s, 1H), 10.47 (s, 1H), 10.41 (s, 1H), 7.79-7.73 (m, 2H), 7.66 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.34-7.23 (m, 2H), 6.99-6.81 (m, 3H), 3.81 (s, 3H), 2.11 (s, 3H).

[0350] Compound 83.N-(5-(2,4-difluoro-5-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-indazole-3-yl)acetamide

[0351] Compound 83 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 18%).

[0352] 1 H NMR (400 MHz, DMSO- d 6) δ 12.83 (s, 1H), 11.02 (s, 1H), 10.48 (s, 1H), 7.96-7.88 (m, 2H), 7.67 (t, J = 10.2 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.34-7.27 (m, 1H), 7.01-6.92 (m, 2H), 6.88 (td, J =8.5, 2.5 Hz, 1H), 2.12 (s, 3H).

[0353] Compound 84.3-(1-acetyl-3-amino-1H-indazol-5-yl)-N-(3-fluorophenyl)-4-methoxybenzenesulfonamide

[0354] Step A) Preparation of 1-(3-amino-5-bromo-1H-indazol-1-yl)ethane-1-one 5-Bromo-1H-indazole-3-amine (1.06 g, 5.0 mmol), triethylamine (1.2 mL, 15 mmol), and THF (5 mL) were stirred at 0 °C, followed by the slow addition of acetyl chloride (430 μL, 6.0 mmol). The mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was extracted with water and EtOAc, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The solution was then separated by silica gel column chromatography to obtain 1-(3-amino-5-bromo-1H-indazole-1-yl)ethane-1-one in 69% (880 mg) yield.

[0355] Step B) Preparation of 3-(1-acetyl-3-amino-1H-indazol-5-yl)-N-(3-fluorophenyl)-4-methoxybenzenesulfonamide (compound 84) Compound 84 was synthesized using the same method as step B of the synthesis of compound 26 described above (7% yield).

[0356] 1 H NMR (300 MHz, DMSO- d 6) δ 10.49 (s, 1H), 8.23 ​​(d, J = 8.6 Hz, 1H), 8.04-7.98 (m, 1H), 7.79 (dd, J = 8.7, 2.5 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.57 (dd, J = 8.6, 1.7 Hz, 1H), 7.33-7.24 (m, 2H), 6.99-6.80 (m, 3H), 6.53 (s, 2H), 3.84 (s, 3H), 2.53 (s, 3H).

[0357] Compound 85.5-(1-acetyl-3-amino-1H-indazol-5-yl)-2,4-difluoro-N-(3-fluorophenyl)benzenesulfonamide

[0358] Compound 85 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 8%).

[0359] 1 H NMR (400 MHz, DMSO- d 6) δ 11.04 (s, 1H), 8.30 (d, J = 8.6 Hz, 1H), 8.13 (s, 1H), 8.02 (t, J = 8.1 Hz, 1H), 7.76-7.68 (m, 2H), 7.35-7.26 (m, 1H), 7.01-6.92 (m, 2H), 6.92-6.85 (m, 1H), 6.58 (s, 2H), 2.54 (s, 3H).

[0360] Compound 86,4-((4-methoxy-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)sulfonyl)morpholine

[0361] Add 4-((3-bromo-4-methoxyphenyl)sulfonyl)morpholine (200 mg, 0.6 mmol), bis(pinacolato)diboron (183 mg, 0.72 mmol), [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (49 mg, 0.06 mmol), potassium acetate (177 mg, 1.8 mmol), and 1,4-dioxane (2 mL), and react in a microwave reactor at 120 °C for 1 hour. After cooling to room temperature, 5-bromo-1H-pyrrolo[2,3-b]pyridine (118 mg, 0.6 mmol) and sodium carbonate aqueous solution (2 M, 0.5 mL) were added, and the reaction was carried out at 120 °C for 1 hour. After the reaction was completed, the solvent was removed by diatomite filtration, and the mixture was extracted with water and EtOAc. The organic layer was dried with MgSO4 and concentrated under reduced pressure. Then, the mixture was separated by silica gel column chromatography, and compound 86 was obtained in 67% (151 mg) yield.

[0362] 1 H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.33 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.74 (dd, J = 8.7, 2.4 Hz, 1H), 7.61 (d, J = 2.4Hz, 1H), 7.52 (dd, J = 3.4, 2.5 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 6.50 (dd,J = 3.4, 1.8 Hz, 1H), 3.90 (s, 3H), 3.64 (t, J = 4.6 Hz, 4H), 2.94 - 2.85 (m, 4H).

[0363] Compound 87,4-methoxy-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide

[0364] Synthesis of 87-1,5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (compound 87-1) 5-Bromo-1H-pyrrolo[2,3-b]pyridine (788 mg, 4.0 mmol) and THF (15 mL) were added, followed by sodium hydride (480 mg, 12.0 mmol) and benzyltriethylammonium chloride (18 mg, 0.08 mmol) at 0 °C, and the mixture was stirred for 30 minutes. Then, benzenesulfonyl chloride (615 μL, 4.8 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was quenched with water, extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure to obtain compound 87-1 in 99% (1.35 g) yield.

[0365] Synthesis of 87-2,5-(2-methoxyphenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (compound 87-2) Compound 87-1 (1.35 g, 4.0 mmol), 2-methoxyphenylboronicacid (669 mg, 4.4 mmol), tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol), potassium carbonate (3.54 g, 25.6 mmol), and toluene / EtOH (30 / 10 mL) were added, and the mixture was stirred at 110 °C for 5 hours. After the reaction was complete, the solvent was removed by diatomite filtration, and the mixture was extracted with water and EtOAc. The organic layer was dried over MgSO4 and concentrated under reduced pressure. Then, compound 87-2 was obtained by silica gel column chromatography in 82% (1.2 g) yield.

[0366] Synthesis of 87-3,5-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (compound 87-3) Compound 87-2 (1.09 mg, 3.0 mmol) and sodium tert-butoxide (576 mg, 6.0 mmol) were added to dioxane (10 mL), and the mixture was stirred at 80 °C for 4 hours. After the reaction was complete, the mixture was extracted with water and EtOAc, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The mixture was then filtered through EtOAc and Hex to obtain compound 87-3 in 80% (535 mg) yield.

[0367] 87-4. Synthesis of (5-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)methyl ketone (compound 87-4) Compound 87-3 (527 mg, 2.35 mmol), triethylamine (3.2 mL, 23.5 mmol), 4-dimethylaminopyridine (288 mg, 2.35 mmol), and THF (8 mL) were stirred, followed by the addition of benzoyl chloride (410 μL, 3.53 mmol), and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was extracted with water and EtOAc, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The solution was then filtered through EtOAc to give compound 87-4 in 49% (381 mg) yield.

[0368] Synthesis of 87-5,4-methoxy-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 87) Compound 87-4 (100 mg, 0.3 mmol) and DCM (1 mL) were stirred at 0 °C, followed by the slow addition of chlorosulfonic acid (30 μL, 0.45 mmol), and stirring for 1 hour. After the reaction was complete, ice water was slowly added, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. m-toluidine (50 μL, 0.45 mmol), pyridine (25 μL, 0.3 mmol), and THF (3 mL) were added to the mixture, and stirring was carried out at room temperature for 12 hours. After the reaction was complete, the mixture was extracted with water and EtOAc, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. Compound 87-4 was then separated by silica gel column chromatography in 24% (28 mg, 2 steps) yield.

[0369] 1H NMR 300 MHz, Chloroform-d)) δ 8.44 (s, 1H), 8.30 (s, 1H), 7.89 (s,1H), 7.83 (d, J = 8.1 Hz, 1H), 7.51 (s, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.00 (dd, J = 12.9, 8.3 Hz, 4H), 6.69 (s, 1H), 3.88 (s, 3H), 2.30 (s, 3H).

[0370] Compound 88. N-(3-fluorophenyl)-4-methoxy-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzenesulfonamide

[0371] Compound 88 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 67%).

[0372] 1 H NMR (300 MHz, DMSO- d 6) δ 11.75 (s, 1H), 10.43 (s, 1H), 8.21 (d, J =2.1 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 8.7, 2.5 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.58-7.44 (m, 1H), 7.35-7.23 (m, 2H), 7.00-6.92 (m, 2H), 6.92-6.82 (m, 1H), 6.50 (dd, J = 3.5, 1.8 Hz, 1H), 3.83 (s, 3H).

[0373] Compound 89,4-difluoro-N-(3-fluorophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzenesulfonamide

[0374] Compound 89 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 43%).

[0375] 1 H NMR (300 MHz, DMSO- d6) δ 11.89 (s, 1H), 11.03 (s, 1H), 8.32 (s, 1H), 8.13 (s, 1H), 8.01 (t, J = 8.1 Hz, 1H), 7.72 (t, J = 10.3 Hz, 1H), 7.58 (t, J = 3.0 Hz, 1H), 7.33 (q, J = 7.7 Hz, 1H), 7.09-6.82 (m, 3H), 6.62-6.49 (m, 1H) Compound 90.4-Methoxy-3-(3-morpholino-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide

[0376] Synthesis of 5-bromo-3-nitro-1H-pyrrolo[2,3-b]pyridine (compound 90-1) At 0 °C, nitric acid (72.5 mL) was slowly added to 5-bromo-1H-pyrrolo[2,3-b]pyridine (10 g, 50.75 mmol), and the mixture was stirred for 1 hour. After the reaction was complete, ice water was slowly added, and the resulting solid was filtered to give compound 90-1 in 82% (10.1 g) yield.

[0377] Synthesis of 5-bromo-1H-pyrrolo[2,3-b]pyridin-3-amine (compound 90-2) Compound 90-1 (5-bromo-3-nitro-1H-pyrrolo[2,3-b]pyridine; 10 g, 41.4 mmol), acetic acid (165 mL), tin(II) chloride (23.5 g, 124.2 mmol), and hydrochloric acid (21 mL) were added, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, ice water was slowly added to adjust the pH to 9, and the mixture was extracted with DCM. The organic layer was then dried over MgSO4 and concentrated under reduced pressure to obtain compound 90-2 in 46% (4.1 g) yield.

[0378] Synthesis of 90-3,4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)morpholine (4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)morpholine) (compound 90-3) Compound 90-2 (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-amine; 400 mg, 1.89 mmol), 2-bromoethyl ether (400 μL, 3.21 mmol), and N,N-diisopropylethylamine (670 μL, 3.87 mmol) were added to DMF (2 mL) and stirred at 110 °C for 2 hours. After the reaction was complete, the mixture was extracted with water and EtOAc, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. Compound 90-3 was then separated by silica gel column chromatography in 50% (266 mg) yield.

[0379] Synthesis of 4-methoxy-3-(3-morpholino-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 90) Add 3-bromo-4-methoxy-N-(m-tolyl)benzenesulfonamide (50 mg, 0.14 mmol), bis(pinacolato)diboron (43 mg, 0.17 mmol), [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 0.014 mmol), potassium acetate (41 mg, 0.42 mmol), and 1,4-dioxane (2 mL), and react in a microwave reactor at 120 °C for 1 hour. After cooling at room temperature, compound 90-3 (4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)morpholine (39 mg, 0.14 mmol) and an aqueous solution of sodium carbonate (2 M, 0.15 mL) were added, and the mixture was reacted at 120 °C for 1 hour. After the reaction was complete, the solvent was removed by diatomite filtration, and the mixture was extracted with water and EtOAc. The organic layer was dried with MgSO4 and concentrated under reduced pressure. Then, compound 90 was obtained by silica gel column chromatography in 11% (8 mg) yield.

[0380] 1H NMR (300 MHz, DMSO-d6) δ 11.29 - 11.22 (m, 1H), 10.08 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.74 (dd, J = 8.6, 2.4 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 6.95 (d, J = 6.9 Hz, 2H), 6.86 (d, J = 7.5 Hz, 1H), 3.82 (s, 3H), 3.78 (d, J = 4.8 Hz, 4H), 2.99 (t, J = 4.6 Hz, 4H), 2.21 (s, 3H).

[0381] Compound 91,4-methoxy-3-(3-morpholino-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(o-tolyl)benzenesulfonamide

[0382] Compound 91 was synthesized using the same method as that used for the synthesis of compound 90 described above (yield 37%).

[0383] 1 H NMR (300 MHz, DMSO-d6) δ 11.25 (s, 1H), 9.43 (s, 1H), 8.16 (d, J =2.1 Hz, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.66 (dd, J = 8.7, 2.4 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H), 7.14 (dt, J = 9.5, 3.7 Hz, 3H), 7.02 (dd, J = 10.7, 3.2 Hz, 2H), 3.85 (s, 3H), 3.80 (t, J = 4.6 Hz, 4H), 2.98 (t, J = 4.6 Hz, 4H), 2.05 (s, 3H).

[0384] Compound 92,4-methoxy-3-(3-morpholino-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-phenylbenzenesulfonamide

[0385] Compound 92 was synthesized using the same method as that used for the synthesis of compound 90 described above.

[0386] 1 H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.09 (s, 1H), 7.86-7.74 (m, 2H), 7.69 (s, 1H), 7.26 (s, 1H), 7.22-7.11 (m, 3H), 7.00 (d, J = 8.5 Hz, 1H), 3.94 (q, J = 5.0 Hz, 4H), 3.87 (s, 3H), 3.56-3.42 (m, 4H).

[0387] Compound 93. N-(2-fluorophenyl)-4-methoxy-3-(3-morpholino-1H-pyrrolo[2,3-b]pyridin-5-yl)benzenesulfonamide

[0388] Compound 93 was synthesized using the same method as that used for the synthesis of compound 90 (yield 36%).

[0389] 1 H NMR (300 MHz, DMSO-d6) δ 11.26 (s, 1H), 10.09 (s, 1H), 8.17 (d, J =2.0 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.69 (dd, J = 8.6, 2.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.16 - 7.09 (m, 4H), 7.00 (d,J = 2.5 Hz, 1H), 3.83 (s, 3H), 3.78 (d, J = 5.1 Hz, 4H), 2.99 (t, J = 4.7 Hz, 4H).

[0390] Compound 94. N-(2-chlorophenyl)-4-methoxy-3-(3-morpholino-1H-pyrrolo[2,3-b]pyridin-5-yl)benzenesulfonamide

[0391] Compound 94 was synthesized using the same method as compound 90 (yield 36%).

[0392] 1 H NMR (300 MHz, DMSO-d6) δ 11.25 (s, 1H), 9.88 (s, 1H), 8.19 (d, J =2.0 Hz, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.71 (dd, J = 8.7, 2.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.46 - 7.40 (m, 1H), 7.36 - 7.16 (m, 4H), 7.00 (d, J =2.5 Hz, 1H), 3.85 (s, 3H), 3.79 (d, J = 4.8 Hz, 4H), 2.98 (t, J = 4.7 Hz, 4H).

[0393] Compound 95.N-(5-(2-methoxy-5-(N-phenylaminosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide

[0394] Synthesis of 95-1. N-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (compound 95-1) 5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-amine (509 mg, 2.4 mmol) and THF (10 mL) were stirred at 0 °C, followed by the slow addition of trimethylamine (1 mL, 7.2 mmol) and acetic anhydride (450 μL, 4.8 mmol), and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the mixture was extracted with water and EtOAc, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. Compound 95-1 was then separated by silica gel column chromatography in 60% (365 mg) yield.

[0395] Synthesis of 95-2. N-(5-(2-methoxy-5-(N-phenylsulfamoyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (compound 95) 3-bromo-4-methoxy-N-phenylbenzenesulfonamide (89 mg, 0.26 mmol), bis(pinacolato)diboron (80 mg, 0.31 mmol), [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19 mg, 0.026 mmol), potassium acetate (76 mg, 0.78 mmol), and 1,4-dioxane (3 mL) were added, and the mixture was reacted in a microwave reactor at 120 °C for 1 hour. After cooling at room temperature, compound 95-1 (N-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (74 mg, 0.26 mmol) and an aqueous solution of sodium carbonate (2 M, 0.5 mL) were added, and the mixture was reacted at 120 °C for 1 hour. After the reaction was complete, the solvent was removed by diatomite filtration, and the mixture was extracted with water and EtOAc. The organic layer was dried over MgSO4 and concentrated under reduced pressure. Then, compound 95 was obtained by silica gel column chromatography in 11% (13 mg) yield.

[0396] 1 H NMR (300 MHz, Methanol-d4) δ 8.23 ​​(d, J = 2.0 Hz, 1H), 8.18 (d, J =2.1 Hz, 1H), 7.81 - 7.75 (m, 2H), 7.70 (d, J = 2.5 Hz, 1H), 7.31 - 7.06 (m,7H), 3.90 (s, 3H), 2.22 (s, 3H).

[0397] Compound 96.N-(5-(2,4-difluoro-5-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide

[0398] Step A) Synthesis of 5-bromo-3-nitro-1H-pyrrolo[2,3-b]pyridine (compound 96-1) At 0 °C, nitric acid (6 mL) was slowly added to 5-bromo-1H-pyrrolo[2,3-b]pyridine (2.0 g, 10.15 mmol), and the mixture was stirred for 1 hour. After the reaction was complete, the reactants were slowly added to ice water, and the resulting solid was filtered to give compound 96-1 in 84% (2.06 g) yield.

[0399] Step B) Synthesis of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-amine (compound 96-2) 5-Bromo-3-nitro-1H-pyrrolo[2,3-b]pyridine (750 mg, 3.1 mmol), tin(II) chloride (2.94 g, 15.5 mmol), conc. HCl (62 mL), and ethanol (180 mL) were stirred at 100 °C for 2 hours. After the reaction was complete, water was added, the pH was adjusted to 10 with 1N NaOH, and the mixture was extracted with DCM. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The next reaction was carried out without purification.

[0400] Step C) Synthesis of N-(5-(2,4-difluoro-5-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (compound 96) Compound 96-3 was synthesized using the same method as in step A of the synthesis of compound 82 described above. Then, compound 96 was synthesized using the same method as in step B of the synthesis of compound 26 described above (yield 7%).

[0401] 1 H NMR (400 MHz, DMSO- d 6) δ 11.58 (d, J= 2.6 Hz, 1H), 11.03 (s, 1H), 10.08 (s, 1H), 8.37 (s, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.02 (t, J = 8.1 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.73 (t, J = 10.2 Hz, 1H), 7.31 (td, J = 8.2, 6.7Hz, 1H), 7.03 - 6.93 (m, 2H), 6.89 (td, J = 8.5, 2.6 Hz, 1H), 2.10 (s, 3H).

[0402] Compound 97.3-(1H-indol-5-yl)-4-methoxy-N-(m-tolyl)benzenesulfonamide

[0403] Compound 97 was synthesized using the same method as in step B of the synthesis of compound 26 described above (yield 36%).

[0404] 1 H NMR (300 MHz, DMSO- d 6) δ 11.17 (s, 1H), 10.04 (s, 1H), 7.68 (dd, J =8.6, 2.5 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.53-7.50 (m, 1H), 7.45-7.35 (m, 2H), 7.20 (d, J = 8.7 Hz, 1H), 7.17-7.08 (m, 2H), 6.98-6.90 (m, 2H), 6.89-6.83 (m, 1H), 6.46 (ddd, J = 3.0, 1.9, 0.9 Hz, 1H), 3.81 (s, 3H), 2.22 (s, 3H).

[0405] Compound 98. N-(3-fluorophenyl)-3-(1H-indol-5-yl)-4-methoxybenzenesulfonamide

[0406] Compound 98 was synthesized using the same method as in step B of the synthesis of compound 26 described above (yield 37%).

[0407] 1 H NMR (300 MHz, DMSO- d 6) δ 11.18 (s, 1H), 10.42 (s, 1H), 7.72 (dd, J =8.6, 2.5 Hz, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.43 (dd, J = 8.4, 0.8 Hz, 1H), 7.38 (t, J = 2.7 Hz, 1H), 7.34-7.27 (m, 1H), 7.23 (d, J =8.7 Hz, 1H), 7.13 (dd, J = 8.4, 1.7 Hz, 1H), 6.99-6.91 (m, 2H), 6.87 (tdd, J =8.5, 2.5, 1.0 Hz, 1H), 6.47 (ddd, J = 3.0, 1.9, 0.9 Hz, 1H), 3.81 (s, 3H).

[0408] Compound 99.4-methoxy-N-(m-tolyl)-3-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)benzenesulfonamide

[0409] Step A) Synthesis of 6-bromo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine (compound 99-1) 6-Bromo-1H-imidazo[4,5-b]pyridine (693 mg, 3.5 mmol) and DMF (35 mL) were stirred at 0 °C, followed by the addition of NaH (235 mg, 7.0 mmol) and stirring for 10 minutes. Then, 2-(Trimethylsilyl)ethoxymethyl chloride (990 μL, 5.95 mmol) was added, and the mixture was stirred at room temperature for 6 hours. After the reaction was complete, the mixture was quenched with water, extracted with DCM, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The compound was then separated by silica gel column chromatography in 52% (597 mg) yield.

[0410] Step B) Synthesis of 4-methoxy-N-(m-tolyl)-3-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)benzenesulfonamide (compound 99) Compound 99 was synthesized using the same method as in step B of the synthesis of compound 26 described above (yield 36%).

[0411] 1 H NMR (300 MHz, DMSO- d 6) δ 10.06 (s, 1H), 8.67 (s, 1H), 8.37 (d, J =1.9 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 8.7, 2.4 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.99 -6.92 (m, 2H), 6.86 (d, J = 7.5 Hz, 1H), 5.68 (s, 2H), 3.84 (s, 3H), 3.69-3.56 (m, 2H), 2.21 (s, 3H), 0.86 (t, J = 8.0 Hz, 2H), -0.07 (s, 9H).

[0412] Compound 100.3-(3H-imidazo[4,5-b]pyridin-6-yl)-4-methoxy-N-(m-tolyl)benzenesulfonamide

[0413] 4-methoxy-N-(m-tolyl)-3-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)benzenesulfonamide (100 mg, 0.19 mmol) and THF (2 mL) were added to TBAF (500 mg, 1.91 mmol), and the mixture was refluxed for 24 hours. After the reaction was complete, the mixture was extracted with water and DCM, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. Compound 100 was then separated by silica gel column chromatography in 42% (32 mg) yield.

[0414] 1 H NMR (300 MHz, DMSO- d 6) δ 13.06 (s, 1H), 10.06 (s, 1H), 8.50 (s, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.76 (dd, J = 8.7, 2.5Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H), 7.13 (t, J = 7.7Hz, 1H), 6.98 - 6.91 (m, 2H), 6.86 (d, J = 7.6 Hz, 1H), 3.84 (s, 3H), 2.22 (s, 3H).

[0415] Compound 101.N-(3-fluorophenyl)-4-methoxy-3-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)benzenesulfonamide

[0416] Compound 101 was synthesized using the same method as compound 99 (yield 27%).

[0417] 1 H NMR (300 MHz, DMSO- d 6) δ 10.44 (s, 1H), 8.67 (s, 1H), 8.39 (d, J =1.9 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.7, 2.4 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.35-7.25 (m, 2H), 7.02-6.92 (m, 2H), 6.92-6.83 (m, 1H), 5.68 (s, 2H), 3.84 (s, 3H), 3.62 (t, J = 8.1 Hz, 2H), 0.86 (t, J = 8.0 Hz, 2H), -0.08 (s, 9H).

[0418] Compound 102.N-(3-fluorophenyl)-3-(3H-imidazo[4,5-b]pyridin-6-yl)-4-methoxybenzenesulfonamide

[0419] Compound 102 was synthesized using the same method as that used for compound 100 (yield 13%).

[0420] 1 H NMR (300 MHz, DMSO- d 6) δ 13.22 (s, 1H), 12.79 (s, 1H), 10.45 (s, 1H), 8.50 (s, 1H), 8.35 (s, 1H), 8.05 (s, 1H), 7.80 (dd, J = 8.5, 2.5 Hz, 1H),7.75 (d, J = 2.5 Hz, 1H), 7.30 (q, J = 7.5 Hz, 2H), 7.03-6.92 (m, 2H), 6.87 (t, J = 8.6 Hz, 1H), 3.84 (s, 3H).

[0421] Compound 103,4-methoxy-3-(4-oxo-1,4-dihydroquinolin-6-yl)-N-(m-tolyl)benzenesulfonamide

[0422] Compound 103 was synthesized using the same method as in step B of the synthesis of compound 26 described above (yield 11%).

[0423] 1 H NMR (300 MHz, DMSO- d 6) δ 11.85 (d, J = 5.7 Hz, 1H), 10.12 (s, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 7.4, 5.8 Hz, 1H), 7.75 - 7.69 (m, 3H), 7.58 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 9.4 Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H), 6.93 (d, J = 9.3 Hz, 2H), 6.85 (d, J = 7.5 Hz, 1H), 6.07 (d, J = 7.3 Hz, 1H), 3.83 (s, 3H), 2.21 (s, 3H).

[0424] Compound 104.N-(3-fluorophenyl)-4-methoxy-3-(4-oxo-1,4-dihydroquinoline-6-yl)benzenesulfonamide

[0425] Compound 104 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 10%).

[0426] 1 H NMR (300 MHz, DMSO- d 6) δ 11.86 (d, J = 5.7 Hz, 1H), 10.50 (s, 1H), 8.12 (d, J = 2.1 Hz, 1H), 7.93 (dd, J= 7.4, 5.7 Hz, 1H), 7.79-7.72 (m, 3H), 7.59 (d, J = 8.7 Hz, 1H), 7.34-7.24 (m, 2H), 6.99-6.81 (m, 3H), 6.07 (d, J =7.4 Hz, 1H), 3.84 (s, 3H).

[0427] Compound 105.3-(4-oxo-1,4-dihydroquinolin-6-yl)-N-(m-tolyl)benzenesulfonamide

[0428] Compound 105 was synthesized using the same method as step B of the synthesis of compound 26 described above (yield 20%).

[0429] 1 H NMR (400 MHz, DMSO- d 6) δ 11.91 (s, 1H), 10.31 (s, 1H), 8.38 - 8.32 (m, 1H), 8.11 (s, 1H), 8.00-7.91 (m, 3H), 7.72 (d, J = 7.8 Hz, 1H), 7.69-7.62 (m, 2H), 7.10 (t, J = 7.7 Hz, 1H), 6.98-6.87 (m, 2H), 6.84 (d, J = 7.6 Hz, 1H), 6.10 (d, J = 7.5 Hz, 1H), 2.19 (s, 3H).

[0430] <Experimental Example 1. Confirming the influence of IRP2 protein on cancer cell proliferation and iron homeostasis> It is known that cancer cells require a relatively higher iron content than normal cells for cell division, proliferation, and metastasis (Heath et al., 2013). To confirm the effect of iron on cancer cell growth, the inventors initially used ferric ammonium citrate (FAC, Fe) 3+ Treatment with (NH4)5[Fe(C6H4O7)2] replenished intracellular iron (Plath et al., 2015). Growth of colorectal cancer cell lines (DLD-1, HCT116, HCT15, LOVO, SW480, SW620) increased time-dependently by FAC treatment, while treatment with deferoxamine (DFO), which induces iron depletion, significantly inhibited cell growth. Figure 8A). Therefore, the amount of iron in cells was confirmed as a crucial factor determining the proliferation rate of cancer cells. Next, the inventors investigated whether FAC or DFO treatment induced changes in iron metabolism-related factors. Previous publications have highlighted the importance of iron regulatory proteins (IRPs) in maintaining iron homeostasis in cancer cells (Khiroya et al., 2017). Therefore, the expression results of IRP proteins were confirmed through FAC and DFO treatments. FAC reduced IRP2 expression, while DFO treatment increased IRP2 expression. Significant changes were observed in the expression of downstream proteins transferrin receptor 1 (TfR1) and ferritin H (FTH), while IRP1 expression remained unaffected. Figure 8 B). Since IRP2 is more specifically associated with iron metabolism disorders in colorectal cancer than IRP1, the effect of IRP2 on cancer cell growth was investigated. The results of IRP2-specific targeting deletion using small interfering RNA (siRNA) and clustered regularly spaced short palindromic repeats (CRISPR)-Cas9 showed that, compared with control cells, the survival rate of IRP2-deficient cells was significantly inhibited. Figure 1 A and Figure 1 B). Furthermore, the inventors evaluated the tumorigenicity of IRP2 knockout (KO) SW480 cells in vivo. They demonstrated that tumor formation in IRP2 KO cells showed a significantly delayed growth rate compared to tumor formation in WT cells. Figure 1 (C, 1D, and 1E). Overall, these results indicate that IRP2 plays a crucial role in determining cell proliferation by regulating iron homeostasis.

[0431] Furthermore, using the TCGA (Cancer Genome Atlas) database, the patterns of the top 100 genes with positive or negative correlations to IRP2 expression were compared and analyzed using heatmaps. Figure 1 F). Gene ontology analysis confirmed a positive correlation between IRP2 expression and ubiquitination-related signaling pathways and genes associated with cell differentiation. Figure 1 G). Furthermore, Kaplan-Meier curves, which allow for comparison of survival outcomes based on IRP2 expression, confirmed that patients with IRP2 overexpression had a poorer survival prognosis. Figure 1 This highlights the importance of IRP2 as a therapeutic target for colorectal cancer. The inventors also compared the expression of IRP1 / 2 mRNA and protein in paired normal and tumor tissues derived from colorectal cancer patients. Notably, IRP2 mRNA and protein expression were overexpressed by more than 1.5-fold in 5 out of 10 colon cancer patient tissues, but IRP1 expression did not differ significantly between normal and tumor tissues. Figure 9(A and 9B). Therefore, IRP2 was confirmed to be a more important factor than IRP1 for the growth of colorectal cancer cells. <Experimental Example 2. Identification of novel small molecules that interfere with IRP2 binding to IRE> Attempts to identify novel small molecules that interfere with the binding of IRP2 to IRE ( Figure 2 A). Homology modeling was performed to construct the three-dimensional structure of the IRP2-IRE complex based on the X-ray crystal structure of the IRP1 / IRE complex (PDB ID: 3SNP) and the Cryo-EM structure of IRP2 (PDB ID: 6VCD) (Selezneva et al., 2013; Wang et al., 2020). Furthermore, since the sequence identity between IRP1 and IRP2 is over 60%, mutational data of IRP1 can be used to identify the major target residues of IRP2 (Selezneva et al., 2013). The inventors discovered that S446 of IRP2 interacts with N7 of adenine (A15) via hydrogen bonding in the IRE, and with N7 of guanine (G16) via hydrogen bonding in both R454 and the IRE. Hydrophobic interactions are formed between A15 and G16 of the IRE and IRP2's I333, S444, V445, S446, P451, R454, and N610. Figure 2 B).

[0432] To construct the pharmacophore model, the inventors considered not only residues that directly interact with IRE via hydrogen bonding, but also residues that constitute the hydrophobic pocket of the IRE terminal loop. Figure 2 C). In the generated pharmacophore model, D334, S446, R454, and N610 were selected as major residues. Overall, the pharmacophore model based on the final structure consists of 7 pharmacophore functions, including 1 hydrogen bond donor (HBD), 3 hydrogen bond acceptors (HBA), 1 hydrophobic (Hy), and 2 cyclic aromatic (RA) functions. The 3 HBA functions originate from the hydroxyl group of S446, the guanidinyl group of Arg454, and the main chain of N610, respectively. Considering the purine base characteristics of IRE's A15 and G16, 2 additional RA functions were added. Figure 2 B and 2C). A hydrophobic function reflects the hydrophobic end loop binding pocket generated in D334 and an HBD function ( Figure 2 C).

[0433] Based on the pharmacophore model generated by the inventors, a virtual screening was performed using an internal database (DB) containing 8 million compounds. The first screening identified 5,782 compounds, which were then filtered based on a fitness score of 1.0 or higher, and further screened by visual inspection. Finally, 32 compounds were selected as virtual hits by the pharmacophore model. Figure 10 A), of these compounds, Hit02 exhibited potent cytotoxicity in colorectal cancer cell lines ( ). Figure 10 B). Subsequently, based on the X-ray crystal structure of HitO2, chemical modifications were performed, and compounds 1 and 44 exhibited excellent antitumor activity and improved solubility, and were further enhanced by utilizing K. D Surface plasmon resonance (SPR) analysis confirmed the binding of IRP2 ( Figure 2 D, 2E and Figure 11 In addition, RNA-protein pull-down analysis was performed to evaluate the binding affinity of IRP2 / IRE. As expected, compounds 1 and 44 altered the IRP / IRE system, a result also confirmed by RNA-immunoprecipitation, which showed a reduction in IRP2 binding to FTH mRNA. Figure 2 F and Figure 2 G).

[0434] To predict the binding modes of compounds 1 and 44, molecular docking studies were performed using Glide XP docking. Compound 1 was stabilized through hydrogen bonding interactions with Asp334, Ser444, Arg454, and Thr513, π-cation interactions with Arg454, and hydrophobic interactions with Ile333, Leu337, Ile441, Cys512, and Leu626. Figure 2 H). Compound 44 exhibits hydrogen-bonded interactions with Ser444, Arg454, and Asn514, π-cation interactions with Arg454, and hydrophobic interactions with Ile333 and Cys523. Figure 2 Therefore, compounds 1 and 44 are selective for the binding of IRP2 to IRE and are suitable as first-order inhibitors for reducing the IRP2 / IRE system in cells.

[0435] <Experimental Example 3. The toxic effects on cancer cells induced by iron metabolism reprogramming induced by compounds 1 and 44> The inventors measured the antitumor effects of compounds 1 and 44 by measuring cell viability in colorectal cancer cells. These compounds exhibited significant cytotoxicity in an IRP2-dependent manner, but had no effect on proliferation in IRP2-deficient cells. Figure 3A). Conversely, in various normal cell lines including CCD-18Co, VERO, HFL-1, L929, NIH 3T3, and CHO-K1, mild cytotoxicity was observed at high doses. Figure 3 A).

[0436] Because the spheroids of three-dimensional (3D) culture models more accurately reflect patient tumor tissue than 2D monolayer cell cultures (Song et al., 2018), the inhibitory effects of compounds 1 and 44 on cancer cell growth were evaluated in 3D rotating ellipsoid models of SW480 and LOVO cell lines. These compounds exhibited antiproliferative activity through increased intensity of ethidium homodimer-1 (EthD-1), which showed a reduction in spheroid area and an increase in the number of dead cells. Figure 3 B). Furthermore, the inventors performed cell cycle analysis to quantify the percentage of cells at different stages. Compounds 1 and 44 decreased in the G0 / G1 phase but showed significant cell accumulation in the G2 / M phase. Figure 12 A).

[0437] The inventors confirmed whether compounds 1 and 44 induce changes in iron metabolism by targeting IRP2 binding to IRE. As expected, these compounds reduced the expression of TfR1, which is responsible for iron uptake in cells, and increased the translational activity of FTH, an important component of iron storage, by decreasing IRP2. Figure 3 C), but it has no effect on the transcriptional activity of IRP2 ( Figure 12 B).

[0438] Next, the inventors observed the stability of IRP2 and its downstream proteins when treated with the protein translation inhibitor cycloheximide (CHX). When CHX and compound 1 were treated simultaneously, compound 1 did not affect the translational activity of proteins such as IRP1, IRP2, and TfR1; instead, it exhibited the structural characteristics of the FTH protein within 24 hours. Figure 12 C). These results indicate that compound 1 sensitively affects FTH translation activity and inhibits IRP2 protein expression, further regulating the translation of downstream proteins. Furthermore, by immunostaining, compounds 1 and 44 reduced cytoskeleton formation and IRP2 protein expression compared to solvent treatment. Figure 3 D). In summary, these results indicate that compounds 1 and 44 exhibit cytotoxic effects through reprogramming iron metabolism.

[0439] <Experiment 4. Confirming the effects of compounds 1 and 44 on intracellular iron deficiency and ROS reduction induced by IRP2 ubiquitin-dependent degradation> To elucidate the reason for the decreased IRP2 protein expression after treatment with compound 1, the ubiquitination of IRP2 protein was analyzed. Figure 4 As shown in Figure A, compound 1 induced IRP2 protein ubiquitination similar to that induced by treatment with the proteasome inhibitor MG-132, which was used as a positive control. Therefore, it was confirmed that compound 1 reduces IRP2 protein via a ubiquitin-dependent mechanism.

[0440] Since IRP2 inhibition-induced reduction of TfR1 affects intracellular iron uptake, the inventors hypothesized that IRP2 protein degradation induced by compounds 1 and 44 would lead to a reduction in intracellular free iron (LIP). The fluorescence of the LIP assay probe Calcein-AM decreased after iron chelation, and the degree of fluorescence reduction could be used to estimate iron content. Treatment with compounds 1 and 44, as well as with the iron chelating agent Di-2-puridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DPC), which forms a complex with iron to reduce free iron, increased the fluorescence intensity of Calcein-AM. Figure 4 B and 13D). Since the association between iron and reactive oxygen species (ROS) has been reported (Nakamura et al., 2019), intracellular ROS was measured using staining with the cellular ROS marker 2',7'-dichlorofluorescin diacetate (DCFDA). The results showed that compounds 1 and 44 significantly reduced ROS production by removing intracellular free iron. Figure 4 C). In summary, these results indicate that IRP2 ubiquitin-dependent degradation induced by compounds 1 and 44 disrupts the maintenance of iron homeostasis after LIP and ROS reduction.

[0441] Iron is used in various mitochondrial functions, such as ATP production, iron-sulfur cluster biogeneration, and respiration (Bauckman et al., 2015). Intracellular iron deficiency has been reported to impair mitochondrial activity due to a lack of iron-sulfur complexes (Cloonanet et al., 2016; Li et al., 2019). Therefore, it is predicted that IRP2 inhibitors, by inducing iron deficiency through altered iron metabolism, will also affect mitochondrial function. Compound 1 reduced oxygen consumption rate (OCR), basal respiration, and ATP production by inhibiting mitochondrial oxidative phosphorylation (OXPHOS). Figure 4 (D and 13A), while conversely, by activating glycolysis, an increase in basal and compensatory glycolysis was observed (D and 13A). Figure 4 D and 13B).

[0442] <Experimental Example 5. Gene Expression Profiling of Colorectal Cancer Cells Treated with IRP2 Inhibitor> To investigate the overall effect of IRP2 inhibitors in colorectal cancer cells, gene set enrichment analysis (GSEA) was further performed on RNA sequencing data. Compound 1 significantly inhibited genes involved in E2F target genes, G2M checkpoints, and mitosis, consistent with previous results showing proliferation inhibition through cell cycle arrest. Figure 5 A). Compound 1 increased the expression of genes involved in hypoxia, epithelial-mesenchymal transition, angiogenesis, and glycolysis, while inhibiting the expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS). Figure 5 A and 5B). Inhibition of IRP2 binding to the IRE in the 5'-UTR of mRNA upregulated the translation of hypoxia-inducible factor (HIF), which at the transcriptional level activates the expression of target genes associated with glucose metabolism, angiogenesis, invasion, and metastasis (Hong SS et al., 2004). Furthermore, since HIF-mediated hypoxia upregulation is associated with metabolic changes, compound 1 exhibited a metabolic reprogramming from OXPHOS to glycolysis. Figure 4 (D, 5A, and 5B). The enhancement of the HIF pathway by compound 1 suggests a compensatory mechanism for IRP2 inhibition in cancer cell survival. Specifically, compound 1 increases pathways associated with unfolded protein responses and autophagy, while decreasing mTORC1 signaling. Mitochondrial dysfunction leads to mitophagy, the selective degradation of mitochondria via autophagy (Youn DH et al., 2021), and stimulates AMP-activated protein kinase (AMPK), activating Unc-51-like autophagy-activated kinase-1 (ULK1) and the autophagy-promoting Beclin-1 (You L et al., 2015). This suggests that dysregulation of iron metabolism targeting IRP2 leads to autophagy activation through mitochondrial dysfunction.

[0443] <Experimental Example 6. Confirmation that the AMPK-ULK1-Beclin1-LC3B pathway induced by compounds 1 and 44 promotes autophagic cancer cell death> After confirming the activation of autophagy target genes by compound 1, the inventors confirmed whether compounds 1 and 44 actually induced autophagic cell death. In SW480 cells, genetic removal of IRP2 led to the formation of cellular multivesicles and autophagosomes, as observed by transmission electron microscopy (TEM). Figure 6 A), Compounds 1 and 44 also showed similar results in the pharmacological inhibition of IRP2 ( Figure 6B). Furthermore, compared to WT cells, IRP2-deficient SW480 cells showed significantly increased expression of AMPK, ULK1, Beclin-1, and LC3B proteins, while IRP2 supplementation inhibited the expression of these proteins. Figure 6 C). Pharmacological inhibition of IRP2 by compounds 1 and 44 increased AMPK phosphorylation, and the expression of ULK1 and Beclin-1 increased sequentially over time. Figure 6 D). Finally, the expression of LC3B, an important marker of autophagic death, was re-validated using immunostaining, and the results are as follows: Figure 6 As shown in E, compounds 1 and 44 significantly increased the expression of LC3B.

[0444] Next, to assess whether IRP2 inhibition is dependent on autophagic cell death, the inventors confirmed the expression of B-cell lymphoma 2 (Bcl2), cleaved caspase-3 (a regulator of cytotoxic pathways), and glutathione peroxidase-4 (GPX4) (an iron-dependent cell death regulator) in IRP2-deficient SW480 cells. The expression of these proteins did not change in SW480 cells due to the genetic removal of IRP2, indicating that IRP2 inhibition does not induce autophagy-dependent cell death through cytotoxic pathways or iron-dependent cell death. Figure 13 C). This indicates that the novel IRP2 inhibitor exhibits antitumor effects in colorectal cancer through an autophagic cell death mechanism activated via the AMPK-ULK1-Beclin1-LC3B pathway.

[0445] <Experimental Example 7. Confirmation of the various sensitivities of compounds 1 and 44 to colorectal cancer organoids and their in vivo tumor growth inhibition> Patient-derived organoids have recently been studied as platforms for applications ranging from drug discovery to cancer treatment (Kim et al., 2019). Therefore, the inventors treated nine established colorectal cancer organoids with compound 1 and used CellTiter-Glo to monitor morphological changes and cell viability. Organoids treated with compound 1 not only exhibited disruption of the intact organoid structure but also cell death, with IC50 values ​​ranging from 0.5 to 40 μM, showing varying sensitivities. Figure 7 A). To conduct further research, organoids were grouped according to their highest and lowest sensitivity to compound 1, and it was confirmed that IRP2 protein expression was significantly reduced in the most sensitive organoids. Figure 7(B and 7C) IRP2 protein expression was reduced in colorectal cancer organoids treated with compound 1. Specifically, IRP2 expression levels were correlated with organoid sensitivity to compound 1, while no correlation was observed with IRP1. Figure 7 D).

[0446] Finally, the in vivo antitumor activity of compounds 1 and 44 was evaluated using a xenograft mouse model established by subcutaneous injection of SW480 cell line. Intraperitoneal administration of compounds 1 and 44 (100 mpk) significantly reduced tumor volume. Figure 7 E and 7F), and effectively reduced the weight of the tumor ( Figure 7 G). To further validate the intracellular results, the expression of IRP2 in the tumor was confirmed. The results showed that IRP2 expression was decreased in the compound 1 and compound 44 administration groups compared with the solvent administration group. Figure 7 H). In summary, these results demonstrate that novel small molecule inhibitors targeting IRP2 exhibit effective tumor suppression responses in vivo.

[0447] <Experimental Example 8: Anticancer Activity> % or IC measured by using CCK 50 The values ​​were used to confirm the anticancer activity of the compounds of this invention.

[0448] 8-1. Cell Culture Human colorectal cancer cell lines were purchased from the Korea Cell Bank. The cell lines were maintained on appropriate complete growth media, primarily Dulbecco's Modified Eagled Medium (DMEM) and Roswell Park Memorial Institute-1640 (RPMI-1640), supplemented with 10% fetal bovine serum, 100 U / ml penicillin, and 100 μg / ml streptomycin. The cell lines were cultured at 37°C in a 5% CO2 incubator.

[0449] 8-2. Cell viability analysis Cell viability was determined using the Cell Counting Kit-8 (CCK-8). An appropriate amount of cells (2 × 10⁶) was used. 4 After being seeded in 96-well plates and cultured for 24 hours, cells were treated with different concentrations of compound 1 and compound 44 for 48 hours. After adding CCK-8 solution and culturing at 37°C for 3 hours, the absorbance was measured at 450 nm using a microplate reader. The experiment was repeated three times.

[0450] Table 1

[0451] Observing Table 1 above, it is confirmed that compounds 1 to 105 of the present invention have a cell-killing effect on cancer cells. In particular, in chemical formulas 2 to 5, which are benzenesulfonamide-substituted heterobicyclic derivatives, R1 is substituted with hydrogen, haloalkyl, alkyl, acetyl, acetamido, phenyl, thiophene, or morpholino; R2 is substituted with hydrogen, alkyl, or acetyl; R3 is substituted with hydrogen, halogen, or C1-C6 alkoxy; R4 is substituted with... or The substituted compounds exhibit excellent anticancer activity.

[0452] <Formulation Example 1. Preparation of Powders> 2g of compound 1 of the present invention and 1g of lactose were mixed and filled into an airtight bag to prepare a powder.

[0453] <Formulation Example 2. Preparation of Tablets> 100 mg of compound 1 of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose and 2 mg of magnesium stearate were mixed and then compressed into tablets according to conventional tablet preparation methods to prepare tablets.

[0454] <Formulation Example 3. Preparation of Capsules> 100 mg of compound 1 of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose and 2 mg of magnesium stearate were mixed and then filled into gelatin capsules according to conventional capsule preparation methods to prepare capsules.

[0455] <Formulation Example 4. Preparation of Pills> 90 mg of compound 1 of the present invention, 5 mg of glutinous rice starch, 5 mg of purified water, and a small amount of hygroscopic inhibitors, namely dextrin, maltodextrin, corn starch, and microcrystalline cellulose (MCC), were mixed and then a 100 mg pill was prepared by conventional methods.

[0456] <Formulation Example 5. Preparation of Injectables> After mixing 10 mg of compound 1 of the present invention, an appropriate amount of sterile distilled water for injection and an appropriate amount of pH adjuster, the mixture is prepared according to conventional injection preparation methods, with each ampoule (2 ml) containing the above-mentioned components.

Claims

1. A pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein, The active ingredient comprises a compound represented by the following chemical formula 1, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, R1 is selected from hydrogen, halogen, hydroxyl, amino, amide, cyano, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 Alkoxy, acetyl, acetamido, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkylamide, C5-C 10 Aryl, C5-C 10 heteroaryl, C4-C 10 cycloalkyl and C4-C 10 One or more substituents are used in the group consisting of heterocyclic alkyl groups; R2 is selected from hydrogen, halogen, hydroxyl, amide, CN, NO2, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C 10 The alkoxy group is substituted with one or more substituents from the group consisting of alkoxy, acetyl, C1-C6 alkylamino, di(C1-C6)alkylamino, di(C1-C6)alkylamino (C1-C6)alkyl, phenyl, and SEM (=2-(trimethylsilyl)ethoxymethyl). R3 can be hydrogen, halogen, or C1-C independently. 10 Alkoxy; R4 is selected freely substituted or unsubstituted (C5-C) 10 ) aryl-amino, substituted or unsubstituted (C5-C 10 Heteroaryl-amino, substituted or unsubstituted C5-C 10 Heteroaryl and substituted or unsubstituted C4-C 10 One or more substituents in the group consisting of heterocyclic alkyl groups are substituted. The substituted (C5-C) 10 ) aryl-amino, (C5-C 10 Heteroaryl-amino, C5-C 10 heteroaryl or C4-C 10 In heterocyclic alkyl groups, one or more hydrogen atoms within the substituents are independently selected from hydrogen, halogen, hydroxyl, amide, halogenated C1-C6 alkyl, cyano, NO2, C1-C6 alkyl, acetyl, carbamoyl, substituted or unsubstituted C1-C6 alkyl groups. 10 Alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C4-C 10 One or more substituents in the group consisting of heterocyclic alkyl groups are substituted. The substituted C1-C 10 Alkoxy, C3-C 10 cycloalkyl or C4-C 10 Heterocyclic alkyl groups are selected from hydrogen, halogen, hydroxyl, amide, halogenated C1-C6 alkyl, cyano, NO2, C1-C6 alkyl, and C1-C 10 One or more substituents are substituted in the group consisting of alkoxy groups; A can be CR1, CH, or N independently; It can be a single bond or a double bond; n is an integer from 0 to 3.

2. The pharmaceutical composition for the prevention or treatment of colorectal cancer according to claim 1, wherein, In the above chemical formula 1, R1 is selected from hydrogen, halogen, hydroxyl, amino, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The substance is substituted with one or more substituents from the group consisting of alkoxy, acetyl, acetamido, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkylamide, phenyl, thiophene, and morpholino. R2 is selected from hydrogen, halogen, hydroxyl, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The alkoxy group is substituted with one or more substituents from the group consisting of alkoxy, acetyl, C1-C6 alkylamino, di(C1-C6)alkylamino, di(C1-C6)alkylamino (C1-C6)alkyl, phenyl, and SEM (=2-(trimethylsilyl)ethoxymethyl). R3 can be hydrogen, halogen, or C1-C independently. 10 Alkoxy; R4 can be freely replaced or not replaced. Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced and replaced or not replaced One or more substituents in the group constitute the group. The replacement , , , , or One or more hydrogen atoms in the substituent are independently selected from hydrogen, halogen, hydroxyl, amide, halogenated C1-C6 alkyl, CN, NO2, C1-C6 alkyl, acetyl, carbamoyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C4-C 10 Cycloalkyl and substituted or unsubstituted C4-C 10 One or more substituents from the group consisting of heterocyclic alkyl groups are used for substitution. The substituted C1-C 10 Alkoxy, C3-C 10 cycloalkyl or C4-C 10 Heterocyclic alkyl groups are selected from hydrogen, halogens, hydroxyl groups, amides, halogenated C1-C6 alkyl groups, CN, NO2, C1-C6 alkyl groups, and C1-C6 alkyl groups. 10 One or more substituents are substituted in the group consisting of alkoxy groups; A can be CR1, CH, or N independently; It can be a single bond or a double bond; n is an integer from 0 to 3.

3. A pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein, The active ingredient comprises a compound represented by the following chemical formula 2, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof: [Chemical Formula 2] In the above chemical formula 2, R1 is selected from hydrogen, halogen, hydroxyl, amino, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The substance is substituted with one or more substituents from the group consisting of alkoxy, acetyl, acetamido, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkylamide, phenyl, thiophene, and morpholino. R2 is selected from hydrogen, halogen, hydroxyl, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The alkoxy group is substituted with one or more substituents from the group consisting of alkoxy, acetyl, C1-C6 alkylamino, di(C1-C6)alkylamino, di(C1-C6)alkylamino (C1-C6)alkyl, phenyl, and SEM (=2-(trimethylsilyl)ethoxymethyl). R3 can be hydrogen, halogen, or C1-C independently. 10 Alkoxy; R4 can be freely replaced or not replaced. Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced One or more substituents in the group constitute the group. The replacement , , , , or One or more hydrogen atoms in the substituent are independently selected from hydrogen, halogen, hydroxyl, amide, halogenated C1-C6 alkyl, CN, NO2, C1-C6 alkyl, acetyl, carbamoyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C4-C 10 One or more substituents from the group consisting of heterocyclic alkyl groups are used for substitution. The substituted C1-C 10 Alkoxy, C3-C 10 cycloalkyl or C4-C 10 Heterocyclic alkyl groups are selected from hydrogen, halogens, hydroxyl groups, amides, halogenated C1-C6 alkyl groups, CN, NO2, C1-C6 alkyl groups, and C1-C6 alkyl groups. 10 One or more substituents are substituted in the group consisting of alkoxy groups; n is an integer from 0 to 3.

4. The pharmaceutical composition for the prevention or treatment of colorectal cancer according to claim 3, wherein, In the above chemical formula 2, R1 is substituted with one or more substituents selected from the group consisting of hydrogen, amino, amide, halogenated C1-C6 alkyl, C1-C6 alkyl, acetyl, acetamido, phenyl, thiophene, and morpholino. R2 is substituted by one or more substituents selected from the group consisting of hydrogen, halo-C1-C6 alkyl, C1-C6 alkyl and acetyl; R3 can be hydrogen, halogen, or C1-C6 alkoxy independently; R4 can be freely replaced or not replaced. and replaced or not taken One or more substituents in the group constitute the group. The replacement or One or more hydrogen atoms in a substituent are independently substituted by one or more substituents selected from the group consisting of hydrogen, halogen, halogenated C1-C6 alkyl, CN and C1-C6 alkyl and acetyl; n is an integer from 0 to 3.

5. A pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein, The active ingredient comprises a compound represented by the following chemical formula 3, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof: [Chemical Formula 3] In the above chemical formula 3, R1 is selected from hydrogen, halogen, hydroxyl, amino, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The substance is substituted with one or more substituents from the group consisting of alkoxy, acetyl, acetamido, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkylamide, phenyl, thiophene, and morpholino. R2 is selected from hydrogen, halogen, hydroxyl, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The alkoxy group is substituted with one or more substituents from the group consisting of alkoxy, acetyl, C1-C6 alkylamino, di(C1-C6)alkylamino, di(C1-C6)alkylamino (C1-C6)alkyl, phenyl, and SEM (=2-(trimethylsilyl)ethoxymethyl). R3 can be hydrogen, halogen, or C1-C independently. 10 Alkoxy; R4 can be freely replaced or not replaced. Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced One or more substituents in the group constitute the group. The replacement , , , , or One or more hydrogen atoms in the substituent are independently selected from hydrogen, halogen, hydroxyl, amide, halogenated C1-C6 alkyl, CN, NO2, C1-C6 alkyl, acetyl, carbamoyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C4-C 10 One or more substituents from the group consisting of heterocyclic alkyl groups are used for substitution. The substituted C1-C 10 Alkoxy, C3-C 10 cycloalkyl or C4-C 10 Heterocyclic alkyl groups are selected from hydrogen, halogens, hydroxyl groups, amides, halogenated C1-C6 alkyl groups, CN, NO2, C1-C6 alkyl groups, and C1-C6 alkyl groups. 10 One or more substituents are substituted in the group consisting of alkoxy groups; n is an integer from 0 to 3.

6. The pharmaceutical composition for the prevention or treatment of colorectal cancer according to claim 5, wherein, In the above chemical formula 3, R1 is substituted with one or more substituents selected from the group consisting of hydrogen, amino, amide, halogenated C1-C6 alkyl, C1-C6 alkyl, acetyl, acetamido, phenyl, thiophene, and morpholino. R2 is substituted by one or more substituents selected from the group consisting of hydrogen, halo-C1-C6 alkyl, C1-C6 alkyl and acetyl; R3 can be hydrogen, halogen, or C1-C6 alkoxy independently; R4 can be freely replaced or not replaced. and replaced or not taken One or more substituents in the group constitute the group. The replacement or One or more hydrogen atoms in a substituent are independently substituted by one or more substituents selected from the group consisting of hydrogen, halogen, halogenated C1-C6 alkyl, CN, C1-C6 alkyl and acetyl; n is an integer from 0 to 3.

7. A pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein, The active ingredient comprises a compound represented by the following chemical formula 4, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof: [Chemical Formula 4] In the above chemical formula 4, R1 is selected from hydrogen, halogen, hydroxyl, amino, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The substance is substituted with one or more substituents from the group consisting of alkoxy, acetyl, acetamido, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkylamide, phenyl, thiophene, and morpholino. R2 is selected from hydrogen, halogen, hydroxyl, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The alkoxy group is substituted with one or more substituents from the group consisting of alkoxy, acetyl, C1-C6 alkylamino, di(C1-C6)alkylamino, di(C1-C6)alkylamino (C1-C6)alkyl, phenyl, and SEM (=2-(trimethylsilyl)ethoxymethyl). R3 can be hydrogen, halogen, or C1-C independently. 10 Alkoxy; R4 can be freely replaced or not replaced. Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced and replaced or not replaced One or more substituents in the group constitute the group. The replacement , , , , or One or more hydrogen atoms in the substituent are independently selected from hydrogen, halogen, hydroxyl, amide, halogenated C1-C6 alkyl, CN, NO2, C1-C6 alkyl, acetyl, carbamoyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C4-C 10 One or more substituents from the group consisting of heterocyclic alkyl groups are used for substitution. The substituted C1-C 10 Alkoxy, C3-C 10 cycloalkyl or C4-C 10 Heterocyclic alkyl groups are selected from hydrogen, halogens, hydroxyl groups, amides, halogenated C1-C6 alkyl groups, CN, and NO. 2、 C1-C6 alkyl and C1-C 10 One or more substituents are substituted in the group consisting of alkoxy groups; n is an integer from 0 to 3.

8. The pharmaceutical composition for the prevention or treatment of colorectal cancer according to claim 7, wherein, In the above chemical formula 4, R1 is substituted with one or more substituents selected from the group consisting of hydrogen, amino, amide, halogenated C1-C6 alkyl, C1-C6 alkyl, acetyl, acetamido, phenyl, thiophene, and morpholino. R2 is substituted by one or more substituents selected from the group consisting of hydrogen, halo-C1-C6 alkyl, C1-C6 alkyl and acetyl; R3 can be hydrogen, halogen, or C1-C6 alkoxy independently; R4 can be freely replaced or not replaced. and replaced or not taken One or more substituents in the group constitute the group. The replacement or One or more hydrogen atoms in a substituent are independently substituted by one or more substituents selected from the group consisting of hydrogen, halogen, halogenated C1-C6 alkyl, CN, C1-C6 alkyl and acetyl; n is an integer from 0 to 3.

9. A pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein, The active ingredient comprises a compound represented by the following chemical formula 5, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof: [Chemical Formula 5] In the above chemical formula 5, R1 is selected from hydrogen, halogen, hydroxyl, amino, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The substance is substituted with one or more substituents from the group consisting of alkoxy, acetyl, acetamido, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkylamide, phenyl, thiophene, and morpholino. R2 is selected from hydrogen, halogen, hydroxyl, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The alkoxy group is substituted with one or more substituents from the group consisting of alkoxy, acetyl, C1-C6 alkylamino, di(C1-C6)alkylamino, di(C1-C6)alkylamino (C1-C6)alkyl, phenyl, and SEM (=2-(trimethylsilyl)ethoxymethyl). R3 can be hydrogen, halogen, or C1-C6 alkoxy independently; R4 can be freely replaced or not replaced. Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced One or more substituents in the group constitute the group. The replacement , , , , or One or more hydrogen atoms in the substituent are independently selected from hydrogen, halogen, hydroxyl, amide, halogenated C1-C6 alkyl, CN, NO2, C1-C6 alkyl, acetyl, carbamoyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C4-C 10 One or more substituents from the group consisting of heterocyclic alkyl groups are used for substitution. The substituted C1-C 10 Alkoxy, C3-C 10 cycloalkyl or C4-C 10 Heterocyclic alkyl groups are selected from hydrogen, halogens, hydroxyl groups, amides, halogenated C1-C6 alkyl groups, CN, NO2, C1-C6 alkyl groups, and C1-C6 alkyl groups. 10 One or more substituents are substituted in the group consisting of alkoxy groups; n is an integer from 0 to 3.

10. The pharmaceutical composition for the prevention or treatment of colorectal cancer according to claim 9, wherein, In the above chemical formula 5, R1 is substituted with one or more substituents selected from the group consisting of hydrogen, amino, amide, halogenated C1-C6 alkyl, C1-C6 alkyl, acetyl, acetamido, phenyl, thiophene, and morpholino. R2 is substituted by one or more substituents selected from the group consisting of hydrogen, halo-C1-C6 alkyl, C1-C6 alkyl and acetyl; R3 can be hydrogen, halogen, or C1-C6 alkoxy independently; R4 can be freely replaced or not replaced. and replaced or not taken One or more substituents in the group constitute the group. The replacement or One or more hydrogen atoms in a substituent are independently substituted by one or more substituents selected from the group consisting of hydrogen, halogen, halogenated C1-C6 alkyl, CN, C1-C6 alkyl and acetyl; n is an integer from 0 to 3.

11. A pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein, The active ingredient comprises a compound represented by the following chemical formula 6, its stereoisomer, its solvate, its prodrug, or a pharmaceutically acceptable salt thereof: [Chemical Formula 6] In the above chemical formula 6, R1 is selected from hydrogen, halogen, hydroxyl, amino, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The substance is substituted with one or more substituents from the group consisting of alkoxy, acetyl, acetamido, C1-C6 alkylamino, di(C1-C6)alkylamino, C1-C6 alkylamide, phenyl, thiophene, and morpholino. R2 is selected from hydrogen, halogen, hydroxyl, amide, CN, halogenated C1-C6 alkyl, NO2, C1-C6 alkyl, C1-C 10 The alkoxy group is substituted with one or more substituents from the group consisting of alkoxy, acetyl, C1-C6 alkylamino, di(C1-C6)alkylamino, di(C1-C6)alkylamino (C1-C6)alkyl, phenyl, and SEM (=2-(trimethylsilyl)ethoxymethyl). R3 can be hydrogen, halogen, or C1-C6 alkoxy independently; R4 can be freely replaced or not replaced. Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced and replacement or non-replacement One or more substituents in the group constitute the group. The replacement , , , , or One or more hydrogen atoms in the substituent are independently selected from hydrogen, halogen, hydroxyl, amide, halogenated C1-C6 alkyl, CN, NO2, C1-C6 alkyl, acetyl, carbamoyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C3-C 10 Cycloalkyl and substituted or unsubstituted C4-C 10 One or more substituents from the group consisting of heterocyclic alkyl groups are used for substitution. The substituted C1-C 10 Alkoxy, C3-C 10 cycloalkyl or C4-C 10 Heterocyclic alkyl groups are selected from hydrogen, halogens, hydroxyl groups, amides, halogenated C1-C6 alkyl groups, CN, NO2, C1-C6 alkyl groups, and C1-C6 alkyl groups. 10 One or more substituents are substituted in the group consisting of alkoxy groups; n is an integer from 0 to 3.

12. The pharmaceutical composition for the prevention or treatment of colorectal cancer according to claim 11, wherein, In the above chemical formula 6, R1 is substituted with one or more substituents selected from the group consisting of hydrogen, amino, amide, halogenated C1-C6 alkyl, C1-C6 alkyl, acetyl, acetamido, phenyl, thiophene, and morpholino. R2 is substituted by one or more substituents selected from the group consisting of hydrogen, halo-C1-C6 alkyl, C1-C6 alkyl and acetyl; R3 can be hydrogen, halogen, or C1-C6 alkoxy independently; R4 can be freely replaced or not replaced. and replaced or unreplaced One or more substituents in the group constitute the group. The replacement or One or more hydrogen atoms in a substituent are independently substituted by one or more substituents selected from the group consisting of hydrogen, halogen, halogenated C1-C6 alkyl, CN, C1-C6 alkyl and acetyl; n is an integer from 0 to 3.

13. A pharmaceutical composition for the prevention or treatment of colorectal cancer, wherein, The active ingredient comprises compounds selected from the group consisting of, as well as their stereoisomers, solvates, prodrugs, or pharmaceutically acceptable salts thereof: 4-Methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 1); 4-Methoxy-N-phenyl-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 2); 4-Methoxy-N-(3-Methoxyphenyl)-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 3); 3-((4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)sulfonamido)benzamide (compound 4); 4-Methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(3-(trifluoromethyl)phenyl)benzenesulfonamide (compound 5); N-(3-cyanophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 6); N-(3-fluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 7); N-(4-fluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 8); N-(2-fluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 9); N-(3-chlorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 10); N-(4-chlorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 11); N-(2-chlorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 12); N-(2-Cyclopropylphenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 13); N-(4-hydroxyphenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 14); N-(3-(2-hydroxyethoxy)phenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 15); N-(4-(2-hydroxyethoxy)phenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 16); N-(2-(2-hydroxyethoxy)phenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 17); 4-Methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 18); 4-Methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(pyridin-3-yl)benzenesulfonamide (compound 19); N-(3-fluorophenyl)-3-(4-oxo-1,4-dihydroquinoline-6-yl)benzenesulfonamide (compound 20); 5-(5-((1H-pyrazol-1-yl)sulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridine (compound 21); 5-(2-methoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (compound 22); 4-((4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)sulfonyl)morpholine (compound 23); N-(3,5-difluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 24); N-(3-chloro-5-fluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 25); 4-Methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzamide (compound 26); N-(3-fluorophenyl)-4-methoxy-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (compound 27); N-Phenyl-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 28); 3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 29); N-(3-fluorophenyl)-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 30); N-(3-chlorophenyl)-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 31); 3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(o-tolyl)benzenesulfonamide (compound 32); 4-Methoxy-3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 33); 4-Methoxy-3-(1-Phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 34); N-(5-(2-methoxy-5-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 35); N-(5-(4-fluoro-3-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 36); N-(5-(2-fluoro-5-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 37); N-(5-(3-fluoro-5-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 38); N-(5-(2,4-difluoro-5-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 39); N-(5-(2-fluoro-3-(N-(m-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 40); N-(5-(2-methoxy-5-(N-(p-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 41); N-(5-(2-methoxy-5-(N-(o-tolyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 42); N-(5-(2-methoxy-5-(N-phenylaminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 43); N-(5-(5-(N-(3-fluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 44); N-(5-(4-fluoro-3-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 45); N-(5-(2-fluoro-5-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 46); N-(5-(3-fluoro-5-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 47); N-(5-(2,4-difluoro-5-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 48); N-(5-(2-fluoro-3-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 49); N-(5-(5-(N-(4-fluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 50); N-(5-(5-(N-(2-fluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 51); N-(5-(5-(N-(3-chlorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 52); N-(5-(5-(N-(4-chlorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 53); N-(5-(5-(N-(2-chlorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 54); N-(5-(5-(N-(3-hydroxyphenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 55); N-(5-(5-(N-(4-hydroxyphenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 56); N-(5-(2-methoxy-5-(N-(pyridin-3-yl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 57); N-(5-(2-methoxy-5-(N-(pyridin-2-yl)aminosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 58); N-(5-(2-methoxy-5-(morpholinosulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 59); N-(5-(5-(N-(3,5-difluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 60); N-(5-(5-(N-(3-chloro-5-fluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (compound 61); N-(3-fluorophenyl)-4-methoxy-3-(3-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 62); N-(3-fluorophenyl)-4-methoxy-3-(3-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 63); 4-Methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 64); 4-Methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(p-tolyl)benzenesulfonamide (compound 65); 4-Methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(o-tolyl)benzenesulfonamide (compound 66); 4-Methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-phenylbenzenesulfonamide (compound 67); N-(3-fluorophenyl)-4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 68); N-(2-fluorophenyl)-4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 69); N-(2-chlorophenyl)-4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 70); N-(3-hydroxyphenyl)-4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)benzenesulfonamide (compound 71); 4-((4-methoxy-3-(3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)sulfonyl)morpholine (compound 72); 4-Methoxy-3-(1-Phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 73); 3-(1-(2-(dimethylamino)ethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methoxy-N-(m-tolyl)benzenesulfonamide (compound 74); 4-Methoxy-3-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 75); 3-(1-acetyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methoxy-N-(m-tolyl)benzenesulfonamide (compound 76); N-((3-(1-acetyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methoxyphenyl)sulfonyl)-N-(m-tolyl)acetamide (compound 77); 4-((3-(1H-indazol-5-yl)-4-methoxyphenyl)sulfonyl)morpholine (compound 78); 3-(1H-indazol-5-yl)-4-methoxy-N-(m-tolyl)benzenesulfonamide (compound 79); N-(3-fluorophenyl)-3-(1H-indazol-5-yl)-4-methoxybenzenesulfonamide (compound 80); 2,4-Difluoro-N-(3-fluorophenyl)-5-(1H-indazol-5-yl)benzenesulfonamide (compound 81); N-(5-(5-(N-(3-fluorophenyl)aminosulfonyl)-2-methoxyphenyl)-1H-indazol-3-yl)acetamide (compound 82); N-(5-(2,4-difluoro-5-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-indazol-3-yl)acetamide (compound 83); 3-(1-acetyl-3-amino-1H-indazol-5-yl)-N-(3-fluorophenyl)-4-methoxybenzenesulfonamide (compound 84); 5-(1-acetyl-3-amino-1H-indazol-5-yl)-2,4-difluoro-N-(3-fluorophenyl)benzenesulfonamide (compound 85); 4-((4-methoxy-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)sulfonyl)morpholine (compound 86); 4-Methoxy-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 87); N-(3-fluorophenyl)-4-methoxy-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzenesulfonamide (compound 88); 4-Methoxy-3-(3-morpholino-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(m-tolyl)benzenesulfonamide (compound 90); 4-Methoxy-3-(3-morpholino-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(o-tolyl)benzenesulfonamide (compound 91); 4-Methoxy-3-(3-morpholino-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-phenylbenzenesulfonamide (compound 92); N-(2-fluorophenyl)-4-methoxy-3-(3-morpholino-1H-pyrrolo[2,3-b]pyridin-5-yl)benzenesulfonamide (compound 93); N-(2-chlorophenyl)-4-methoxy-3-(3-morpholino-1H-pyrrolo[2,3-b]pyridin-5-yl)benzenesulfonamide (compound 94); N-(5-(2-methoxy-5-(N-phenylaminosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (compound 95); N-(5-(2,4-difluoro-5-(N-(3-fluorophenyl)aminosulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (compound 96); 3-(1H-indol-5-yl)-4-methoxy-N-(m-tolyl)benzenesulfonamide (compound 97); N-(3-fluorophenyl)-3-(1H-indol-5-yl)-4-methoxybenzenesulfonamide (compound 98); 4-Methoxy-N-(m-Tolyl)-3-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)benzenesulfonamide (compound 99); 3-(3H-imidazo[4,5-b]pyridin-6-yl)-4-methoxy-N-(m-tolyl)benzenesulfonamide (compound 100); N-(3-fluorophenyl)-4-methoxy-3-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)benzenesulfonamide (compound 101); N-(3-fluorophenyl)-3-(3H-imidazo[4,5-b]pyridin-6-yl)-4-methoxybenzenesulfonamide (compound 102); 4-Methoxy-3-(4-oxo-1,4-dihydroquinolin-6-yl)-N-(m-tolyl)benzenesulfonamide (compound 103); N-(3-fluorophenyl)-4-methoxy-3-(4-oxo-1,4-dihydroquinoline-6-yl)benzenesulfonamide (compound 104); and 3-(4-oxo-1,4-dihydroquinolin-6-yl)-N-(m-tolyl)benzenesulfonamide (compound 105).

14. The pharmaceutical composition for the prevention or treatment of colorectal cancer according to any one of claims 1 to 13, characterized in that, The colorectal cancer mentioned includes rectal cancer, colon cancer, and anal cancer.

15. The pharmaceutical composition for the prevention or treatment of colorectal cancer according to claim 14, characterized in that, The pharmaceutical composition used for the prevention or treatment of colorectal cancer blocks the binding of IRP2 to IRE.

16. The pharmaceutical composition for the prevention or treatment of colorectal cancer according to any one of claims 1 to 13, characterized in that, It also includes pharmaceutically acceptable carriers, diluents, or excipients.

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