Protein tyrosine phosphatase inhibitors and methods of use thereof

Abstract

To provide compounds, compositions and methods useful for inhibiting protein tyrosine phosphatase, e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) and / or protein tyrosine phosphatase non-receptor type 1 (PTPN1), and for treating related diseases, disorders and conditions favorably responsive to PTPN1 or PTPN2 inhibitor treatment, e.g., a cancer or a metabolic disease.SOLUTION: The invention provides a compound represented by formula (1) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer or isotopically enriched variant thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 688,226, filed June 21, 2018, which is incorporated herein by reference in its entirety. [Background technology]

[0002] background Cancer immunotherapy regimens that target immune evasion mechanisms, including checkpoint blockade (e.g., PD-1 / PD-L1 and CTLA-4 blocking antibodies), have been shown to be effective in treating a variety of cancers and dramatically improve outcomes in populations resistant to conventional therapies. However, incomplete clinical responses and the development of intrinsic or acquired resistance continue to limit the patient population that could potentially benefit from checkpoint blockade.

[0003] Non-receptor type 2 protein tyrosine phosphatase (PTPN2), also known as T-cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of the class 1 subfamily of phosphotyrosine-specific phosphatases that controls multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, but expression is highest in hematopoietic and placental cells (Mosinger, B. Jr. et al., Proc Natl Acad Sci USA 89:499-503; 1992). In humans, PTPN2 expression is posttranscriptionally regulated by the existence of two splice variants: a 45-kDa form containing a nuclear localization signal at the C-terminus upstream of the splice junction, and a 48-kDa canonical form with a C-terminal ER retention motif (Tillmann U. et al., Mol Cell Biol 14:3030-3040; 1994). The 45-kDa isoform can passively penetrate the cytosol under certain conditions of cellular stress. Both isoforms share an N-terminal phosphorylation tyrosine phosphatase catalytic domain. PTPN2 negatively regulates signal transduction of nonreceptor tyrosine kinases (e.g., JAK1 and JAK3), receptor tyrosine kinases (e.g., INSR, EGFR, CSF1R, and PDGFR), transcription factors (e.g., STAT1, STAT3, and STAT5a / b), and Src family kinases (e.g., Fyn and Lck). As a key negative regulator of the JAK-STAT pathway, PTPN2 functions to directly regulate signal transduction through cytokine receptors, including IFNγ. The PTPN2 catalytic domain shares 74% sequence identity with PTPN1 (also called PTP1B) and shares similar enzyme kinetics (Romsicki Y. et al., Arch Biochem Biophys 414:40-50; 2003).

[0004] Data from a loss-of-function in vivo genetic screen using CRISPR / Cas9 genome editing in a mouse B16F10 transplantable tumor model showed that deletion of the Ptpn2 gene in tumor cells improved response to an immunotherapy regimen consisting of a GM-CSF-secreting vaccine (GVAX) plus a PD-1 checkpoint blockade (Manguso RT et al., Nature 547:413-418; 2017). Loss of Ptpn2 sensitized tumors to immunotherapy by enhancing IFNγ-mediated antigen presentation and growth suppression. The same screen also revealed that under the selective pressure of immunotherapy, genes known to be involved in immune evasion, including PD-L1 and CD47, were depleted, while genes involved in the IFNγ signaling pathway, including IFNGR, JAK1, and STAT1, were enriched. These observations suggest a putative role for therapeutic strategies that enhance IFNγ sensing and signaling in enhancing the efficacy of cancer immunotherapy regimens.

[0005] Non-receptor type 1 protein tyrosine phosphatase (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B), has been shown to play an important role in insulin and leptin signal transduction and is a major mechanism for downregulating both insulin and leptin receptor signaling pathways (Kenner KA et al., J Biol Chem 271: 19810-19816, 1996). Animals lacking PTP1B have improved glucose regulation and lipid profiles and are resistant to weight gain when fed a high-fat diet (Elchebly M. et al., Science 283: 1544-1548, 1999). Therefore, PTP1B inhibitors are expected to be useful for the treatment of type 2 diabetes, obesity, and metabolic syndrome. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Mosinger, B. Jr. et al., Proc Natl Acad Sci USA 89:499-503;1992 [Non-Patent Document 2] Tillmann U. et al., Mol Cell Biol 14:3030-3040;1994 [Non-Patent Document 3] Romsicki Y. et al., Arch Biochem Biophys 414:40-50;2003 [Non-Patent Document 4] Manguso R. T. et al., Nature 547:413-418;2017 [Non-Patent Document 5] Kenner K. A. et al., J Biol Chem 27: 19810-19816, 1996 [Non-Patent Document 6] Elchebly M. et al., Science 283: 1544-1548, 1999 [Summary of the Invention]

[0007] Summary The present disclosure relates, at least in part, to compounds, compositions, and methods for inhibiting protein tyrosine phosphatases, e.g., non-receptor type 2 protein tyrosine phosphatase (PTPN2) and / or non-receptor type 1 protein tyrosine phosphatase (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B). In some embodiments, disclosed herein are inhibitors of protein tyrosine phosphatases, e.g., PTPN2 and / or PTP1B, comprising a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III). In other embodiments, disclosed herein are methods for treating a disease or disorder, e.g., cancer, type 2 diabetes, obesity, a metabolic disorder, or any other disease, disorder, or condition that responds favorably to treatment with a PTPN2 or PTP1B inhibitor, comprising administering an effective amount of a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III).

[0008] For example, as used herein, the compound of formula (I) A compound represented by TIFF2025143330000001.tif27128, During the ceremony, R 1 is hydrogen, halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, and -C 1~6 alkylene-5-6 membered heterocyclyl, provided that C 1~6 Alkyl, C 3~6 Cycloalkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, and -C 1~6 The alkylene-5- to 6-membered heterocyclyl may optionally be substituted with R on one or more available carbons. g and optionally substituted by one, two, three or more substituents selected from -C 1~6When the alkylene-5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R h and optionally substituted by R 2 is hydrogen, hydroxyl, -CHF2, -CH2OH, -CH2CN, -CH2-OC 1~6 Alkyl, -CH2-N(R a )-C 1~6 Alkyl, C 2~6 Alkyl, C 2~6 Alkenyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, -OC(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-OC 1~6 Alkyl, -C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkenylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -OC 1~6 alkylene-5-6 membered heteroaryl, -O-4-6 membered heterocyclyl, -N(R a )-4 to 6-membered heterocyclyl, -C 1~6 Alkylene-4 to 6-membered heterocyclyl, and -OC 1~6 alkylene-4 to 6-membered heterocyclyl, provided that: -CH2-OC 1~6 Alkyl, -CH2-N(R a )-C 1~6 Alkyl, C 2~6 Alkyl, C 2~6 Alkenyl, -OC1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, -OC(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-OC 1~6 Alkyl, -C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, -C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkenylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, 5-6 membered heteroaryl, -OC 1~6 alkylene-5-6 membered heteroaryl, 4-6 membered heterocyclyl, -O-4-6 membered heterocyclyl, -N(R a )-4 to 6-membered heterocyclyl, -C 1~6 Alkylene-4 to 6-membered heterocyclyl, and -OC 1~6 The alkylene-4- to 6-membered heterocyclyl may optionally be independently R on one or more available carbons. g and may be substituted by one, two, three or more substituents selected from 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, -N(R a )-4 to 6-membered heterocyclyl, -C 1~6 Alkylene-4 to 6-membered heterocyclyl, or -OC 1~6 When alkylene-4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R h and optionally substituted by Or, R 1 and R 2together with the atom to which they are attached form a 5-6 membered aryl or heteroaryl, provided that the aryl or heteroaryl are optionally each independently selected from halogen, hydroxyl, cyano, C 1~6 Alkyl, and C 1~6 and optionally substituted by one or more substituents selected from the group consisting of alkoxy, with the proviso that C 1~6 Alkyl and C 1~6 The alkoxy is optionally independently selected from R p and optionally substituted by one, two, three or more substituents selected from R 3 is hydrogen, -C 1~6 Alkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, and -C 1~6 alkylene-4 to 6 membered heterocyclyl, provided that -C 1~6 Alkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, and -C 1~6 The alkylene-4- to 6-membered heterocyclyl may optionally be independently R on one or more available carbons. g and optionally substituted by one, two, three or more substituents selected from -C 1~6 When alkylene-4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R h and optionally substituted by R 4is hydrogen, halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 alkylene-4 to 6 membered heterocyclyl, provided that C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 The alkylene-4- to 6-membered heterocyclyl may optionally be independently R on one or more available carbons. g and optionally substituted by one, two, three or more substituents selected from -C 1~6 When alkylene-4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R h and optionally substituted by However, R 1 , R 2 , R 3 , and R 4 At least one of them is not hydrogen, R 5 is hydrogen, halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 alkylene-4 to 6 membered heterocyclyl, provided that C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 The alkylene-4- to 6-membered heterocyclyl may optionally be independently R on one or more available carbons. g and optionally substituted by one, two, three or more substituents selected from -C 1~6 When alkylene-4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R h and optionally substituted by R 6 is hydrogen, R 7 is hydrogen, R g is, independently for each occurrence, hydrogen, halogen, hydroxyl, cyano, nitro, oxo, -C(O)OH, R a R bN-, R a R b NC(O)-, R a R b N-SO w -, R a R b NC(O)-N(R a )-, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, phenyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, -(CO)-(NR a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 3~6 Alkenyloxy, C 3~6 Alkynyloxy, C 3~6 Cycloalkoxy, C 1~6 Alkyl-C(O)-, C 1~6 Alkyl-OC(O)-, C 1~6 Alkyl-C(O)-O-, C 1~6 Alkyl-S(O) w -, C 1~6 Alkyl-N(R a )-, C 1~6 Alkyl-N(R a )-C(O)-, C 1~6 Alkyl-C(O)-N(R a ), C 1~6 Alkyl-N(R a )-C(O)-N(R a )-, C 1~6 Alkyl-N(R a )-SO w -, C 3~6 Cycloalkyl-N(R a )-SO w -, C 1~6 Alkyl-SO w -N(R a )-, C 3~6 Cycloalkyl-SO w -N(R a)-, 4-6 membered heterocyclyl-SO w -N(R a )-, C 1~6 Alkoxy-C(O)-N(R a )-, C 1~6 Alkyl-C(O)-N(R a )-C 1~6 Alkyl-, C 1~6 Alkyl-N(R a )-C(O)-C 1~6 Alkyl-, -P(O)(C 1~3 alkyl)2, and C 1~6 Alkoxy-C 1~6 alkyl-, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, phenyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, -(CO)-(NR a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 3~6 Alkenyloxy, C 3~6 Alkynyloxy, C 3~6 Cycloalkoxy, C 1~6 Alkyl-C(O)-, C 1~6 Alkyl-OC(O)-, C 1~6 Alkyl-C(O)-O-, C 1~6 Alkyl-S(O) w -, C 1~6 Alkyl-N(R a )-, C 1~6 Alkyl-N(R a )-C(O)-, C 1~6 Alkyl-C(O)-N(R a ), C 1~6 Alkyl-N(R a )-C(O)-N(R a )-, C 1~6 Alkyl-N(R a )-SO w -, C 3~6Cycloalkyl-N(R a )-SO w -, C 1~6 Alkyl-SO w -N(R a )-, C 3~6 Cycloalkyl-SO w -N(R a )-, 4-6 membered heterocyclyl-SO w -N(R a )-, C 1~6 Alkoxy-C(O)-N(R a )-, C 1~6 Alkyl-C(O)-N(R a )-C 1~6 Alkyl-, C 1~6 Alkyl-N(R a )-C(O)-C 1~6 Alkyl-, -P(O)(C 1~3 alkyl)2, and C 1~6 Alkoxy-C 1~6 alkyl- is optionally independently R p and optionally substituted by one, two, three or more substituents selected from R h is independently for each occurrence of C 1~6 Alkyl, C 3~6 Alkenyl, C 3~6 Alkynyl, C 3~6 Cycloalkyl, -C 1~6 Alkyl-C 3~6 Cycloalkyl, C 1~6 Alkyl-S(O)2-, C 3~6 Cycloalkyl-S(O)2-, 4- to 6-membered heterocyclyl-S(O)2-, 4- to 6-membered heterocyclyl-C 1~6 Alkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-C 1~6 Alkyl-S(O)2-, C 1~6 Alkyl-C(O)-, C 1~6 Cycloalkyl-C(O)-, C 1~6 Alkoxy-C(O)-, R a R b NC(O)-, R a R bN-SO2- and -P(O)(C 1~3 alkyl)2, provided that C 1~6 Alkyl, C 3~6 Alkenyl, C 3~6 Alkynyl, C 3~6 Cycloalkyl, -C 1~6 Alkyl-C 3~6 Cycloalkyl, C 1~6 Alkyl-S(O)2-, C 3~6 Cycloalkyl-S(O)2-, 4- to 6-membered heterocyclyl-S(O)2-, 4- to 6-membered heterocyclyl-C 1~6 Alkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-C 1~6 Alkyl-S(O)2-, C 1~6 Alkyl-C(O)-, C 1~6 Cycloalkyl-C(O)-, C 1~6 Alkoxy-C(O)-, R a R b NC(O)-, R a R b N-SO2- and -P(O)(C 1~3 alkyl)2 optionally each independently represent R p and optionally substituted by one, two, three or more substituents selected from R p is, independently for each occurrence, halogen, hydroxyl, cyano, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, R a R b N-, R a R b N-carbonyl-, R a R b N-SO2- and R a R b N-carbonyl-N(R a )-, R a and R b are independently for each occurrence hydrogen, C 1~6 Alkyl, and C 3~6cycloalkyl, wherein C 1~6 Alkyl is optionally, independently, halogen, cyano, oxo, hydroxyl, and C 1~6 alkoxy (optionally substituted with 1, 2, or 3 fluorine atoms); Or, R a and R b together with the nitrogen to which they are attached form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo, and hydroxyl; w is 0, 1, or 2, Disclosed are the above compounds or pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, stereoisomers, or isotopically enriched variants thereof.

[0009] As used herein, the formula (II) A compound represented by TIFF2025143330000002.tif27128, During the ceremony, X is -O- and -N(R a )-, L is a linear or branched C 1~6 is alkylene, R 2-II is hydrogen, cyano, -NR a R b , C 1~2 Alkoxy, C 3~6 Cycloalkyl-SO2-N(R a )-, C 1~6 Alkyl-SO2-N(R a )-, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, and C 3~6 cycloalkyl, with the proviso that phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, and C 3~6Cycloalkyl optionally includes, on one or more available carbons, each independently, a halogen, a hydroxyl, or an -NR a R b , C 1~2 alkyl (optionally substituted with 1, 2, or 3 halogens), and C 1~2 and alkoxy (optionally substituted by 1, 2, or 3 halogens), and when the 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted by C 1~3 optionally substituted by alkyl, R 5 is selected from the group consisting of hydrogen, deuterium, and halogen; R 6 is selected from the group consisting of hydrogen and deuterium; R 7 is selected from the group consisting of hydrogen and deuterium; R a and R b are, independently for each occurrence, hydrogen and C 1~3 selected from the group consisting of alkyl, Also disclosed are the above compounds, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof.

[0010] As used herein, the formula (III) A compound represented by TIFF2025143330000003.tif27128, During the ceremony, X III is a bond, -CH2-, -NR a selected from the group consisting of -, -O-, -O-CH2-, and -OCH2-CH2-; m is 1, 2, or 3; n is 1, 2, or 3; R 1-III represents hydrogen, halogen, hydroxyl, cyano, -NR a R b, C 1~2 alkyl (optionally substituted with 1, 2, or 3 halogens), and C 1~2 alkoxy (optionally substituted with 1, 2, or 3 halogens); R 2-III is hydrogen, C 1~4 Alkyl, -C(O)-C 1~4 Alkyl, -C(O)-OC 1~4 Alkyl, -C(O)-N(R a )-C 1~4 Alkyl, -S(O)2-C 1~4 Alkyl, and -S(O)2-C 3~6 cycloalkyl, wherein C 1~4 Alkyl, -C(O)-C 1~4 Alkyl, -C(O)-OC 1~4 Alkyl, -C(O)-N(R a )-C 1~4 Alkyl, -S(O)2-C 1~4 Alkyl, and -S(O)2-C 3~6 Cycloalkyl optionally includes, independently, halogen, hydroxyl, cyano, -NR a R b , C 1~2 alkyl (optionally substituted with 1, 2, or 3 halogens), and C 1~2 alkoxy (optionally substituted with 1, 2, or 3 halogens); R 5 is selected from the group consisting of hydrogen, deuterium, and halogen; R 6 is selected from the group consisting of hydrogen and deuterium; R 7 is selected from the group consisting of hydrogen and deuterium; R a and R b are, independently for each occurrence, hydrogen and C 1~3 selected from the group consisting of alkyl, Also disclosed are the above compounds, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof.

[0011] In this specification, 5-{1-fluoro-3-hydroxy-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(pyrrolidin-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 8-Fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ) 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-ylpropan-2-ylcarbamate, 5-(9-fluoro-7-hydroxynaphtho[2,1-b]furan-8-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(azetidin-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-methoxy(4- 2 H) naphthalen-2-yl](4,4- 2 H2)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(methylamino)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(piperidin-4-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-7-{[3-fluoro-1-(propan-2-yl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-7-[(3-fluoropyrrolidin-3-yl)methoxy]-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}pentanenitrile, 5-{1-fluoro-3-hydroxy-7-[2-(piperidin-1-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(piperidin-4-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-3,3-dimethylpentanenitrile, 5-{7-[(3,3-dimethylbutyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1,4-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[( 2 H3) methyloxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-methoxyethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-2,2-dimethylbutanenitrile, 5-{7-[2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[2-(dimethylamino)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)(4,4- 2 H2)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}ethyl)cyclopropanesulfonamide, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-Thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)cyclopropanesulfonamide 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)azetidin-3-yl]amino}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanenitrile, [1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropyl]acetonitrile, 5-{7-[2-(dimethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1H-pyrazol-4-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-methylpropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-hydroxypropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(cyclopropylmethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ) 6 ,2,5-thiadiazolidin-2-yl)naphthalene-2-carboxamide, 5-[1-fluoro-3-hydroxy-7-(2-{[2-(trifluoromethoxy)ethyl]amino}ethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(2-methoxyethyl)amino]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[3-(methylamino)propyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(ethylamino)propyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[5-(dimethylphosphoryl)thiophen-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclopropylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(methylamino)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(ethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)amino]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(diethylphosphoryl)propoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3S)-3-hydroxybutoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1,4-difluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3R)-3-hydroxybutoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropyl-2-hydroxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(4S)-4-hydroxypentyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(4-hydroxy-4-methylpentyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3-oxopentyl)oxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3-hydroxybutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-3-methylbutanamide, 5-[1-fluoro-3-hydroxy-7-(4,4,4-trifluorobutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 1-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)cyclopropane-1-carbonitrile, 5-(1-fluoro-3-hydroxy-7-{2-[1-(methoxymethyl)cyclopropyl]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[(cyclopropylmethyl)amino]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2,2-difluoropropyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3,3-dimethyl-4-(methylamino)butoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-phenylethyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3-amino-3-methylbutoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(difluoromethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(dimethylphosphoryl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3,3,3-trifluoropropyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3-methoxy-3-methylbutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropylpropoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-({2-[(propan-2-yl)oxy]ethyl}amino)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}butanenitrile, 5-[1-fluoro-3-hydroxy-7-(2-hydroxyethyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(4-amino-3,3-dimethylbutoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[2-(azetidin-1-yl)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]oxy}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-methoxyethyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3,3,3-trifluoropropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}methyl)cyclopropane-1-carbonitrile, 5-[1-fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[3-(1H-pyrazol-1-yl)propoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(4-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(hydroxymethyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)piperidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(1H-pyrazol-1-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(piperidin-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(2,2-difluorocyclopropyl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(1-methylcyclopropyl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(3-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(2-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,2-difluoroethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2,2,2-trifluoroethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-7-(2-fluoroethoxy)-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropane-1-carbonitrile, 5-{1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-methylpropyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, {[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetonitrile, 5-[1-fluoro-3-hydroxy-7-(3-methylbutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1,8-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)azetidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)azetidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, (2E)-3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]prop-2-enenitrile, 5-[7-(2-cyclopropylethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2,2-difluorocyclopropyl)methoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclopropylmethoxy)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(oxolan-2-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclobutyloxy)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)oxy]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3-ethoxypropoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-tert-butoxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[rac-(1R,2R)-2-ethylcyclopropyl]methoxy}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(4-methylpentyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(2,2-dimethylpropyl)pyrrolidin-1-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(1-chloro-3-hydroxypropan-2-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(cyclopropyloxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(4-methyl-1H-imidazol-2-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(azetidin-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(5-methoxythiophen-2-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, [8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]acetonitrile, 5-[1-fluoro-3-hydroxy-7-(methoxymethyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3-methyloxetan-3-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{4-bromo-7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{4-bromo-7-[1-(cyclopropanesulfonyl)-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3S)-pyrrolidin-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3R)-pyrrolidin-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(8-chloro-1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(3,3-difluorocyclobutyl)methoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-cyclopropyl-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(4-chloro-1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(E)-2-cyclopropylethenyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1E)-4-methylpent-1-en-1-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(pentamethylphenyl)ethenyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(4-bromo-1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(2-cyclopropylethyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1E)-3-methoxyprop-1-en-1-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-ethoxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3-methoxypropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(1,1-dioxo-1λ 6 -thian-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(oxan-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(cyclopropylmethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]methyl}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[methyl(2-methylpropyl)amino]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(oxolan-2-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(oxolan-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)piperidin-4-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(pyrrolidin-2-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)piperidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(difluoromethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(pyrrolidin-3-yl)methyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,5-dihydrofuran-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3,6-dihydro-2H-pyran-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,5-dihydro-1H-pyrrol-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(pyridin-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(azetidin-3-yl)methyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(2-cyclopropylethyl)-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ] 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}acetamide, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-N-methylbutanamide, N-ethyl-N'-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)urea, 5-{1-fluoro-3-hydroxy-7-[(oxan-3-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(1-chloro-3-hydroxypropan-2-yl)oxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(oxan-4-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(oxetan-3-yl)oxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3,7-dihydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-hydroxyethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-propoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(propan-2-yl)oxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, {[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}acetic acid, N-(2-cyclopropylethyl)-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ] 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetamide, N,N-diethyl-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetamide, 5-{1-fluoro-3-hydroxy-7-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidin-4-yl]oxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(oxolane-3-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(2-methoxyethanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(3,3,3-trifluoropropane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(3,3,3-trifluoropropane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-(1-Fluoro-3-hydroxy-7-{1-[(oxan-2-yl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(4,4,4-trifluorobutane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(butane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(1,4-dioxan-2-yl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-2,5-dihydro-1H-pyrrole-1-sulfonyl}pentanenitrile, 5-{1-fluoro-3-hydroxy-7-[1-(pentane-2-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(ethanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(propane-2-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)oxetane-3-sulfonamide, 5-[1-fluoro-3-hydroxy-7-(piperidin-4-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(2-methylpropane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-ethoxy-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,2-difluoroethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-1H-pyrazol-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[(3R)-1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidin-4-yl]amino}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-7-{[3-fluoro-1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(propane-2-sulfonyl)pyrrolidin-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(1,3-dimethyl-1H-pyrazole-4-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)ethanesulfonamide, 5-{1-fluoro-7-[1-(furan-3-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(3-methylbutane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(thiophene-3-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(benzenesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclobutanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, (2S)-2-amino-4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanoic acid methyl ester, 5-{7-[(3,5-dimethyl-1H-pyrazol-4-yl)methoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3,5-dimethyl-1H-pyrazol-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclohexylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 2-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6,2,5-Thiadiazolidin-2-yl)naphthalen-2-yl]-1H-imidazole-4-carbonitrile Further disclosed is a compound selected from the group consisting of: and pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof.

[0012] In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III), is formulated as a pharmaceutically acceptable composition comprising a disclosed compound and a pharmaceutically acceptable carrier.

[0013] Also disclosed herein are methods for treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III), in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an immunotherapeutic agent. For example, in some embodiments, the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody.

[0014] For example, disclosed herein is a method for treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III).

[0015] Further provided herein is a method for treating type 2 diabetes in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III).

[0016] For example, disclosed herein is a method for treating and / or managing obesity in a patient in need thereof, comprising administering to said patient an effective amount of a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III).

[0017] For example, disclosed herein is a method for inhibiting further weight gain in an overweight or obese patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III).

[0018] Further disclosed herein is a method for treating a metabolic disease in a patient in need thereof, comprising administering to said patient an effective amount of a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III).

[0019] In some embodiments, the method comprises treating cancer. In some embodiments, the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, melanoma, or cancer of secretory cells. In some embodiments, the method comprises treating a metabolic disease. In some embodiments, the metabolic disease comprises non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, type 2 diabetes, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, metabolic syndrome, or Kearns-Sayre disease.

[0020] Also disclosed herein are compositions for use in treating cancer in a patient in need thereof, comprising a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III), in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an immunotherapeutic agent. For example, in some embodiments, the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody.

[0021] For example, disclosed herein are compositions for use in treating cancer in a patient in need thereof, comprising a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III).

[0022] Further provided herein are compositions for use in treating type 2 diabetes in a patient in need thereof, comprising a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III).

[0023] For example, disclosed herein are compositions for use in the treatment and / or management of obesity in a patient in need thereof, comprising a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III).

[0024] For example, disclosed herein are compositions for use in inhibiting further weight gain in an overweight or obese patient in need thereof, comprising a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III).

[0025] Further disclosed herein are compositions for use in treating metabolic disorders in a patient in need thereof, comprising a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III).

[0026] In some embodiments, the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, melanoma, or cancer of secretory cells. In some embodiments, the metabolic disease comprises nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, type 2 diabetes, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, metabolic syndrome, or Kearns-Sayre disease.

[0027] Brief description of the sequence listing The sequence listing entitled "CLS-014WO_SEQ_ID_List_ST25," including SEQ ID NOs: 1-3, which contain the amino acid sequences disclosed herein, is incorporated herein by reference in its entirety. The sequence listing has been submitted herewith via EFS in ASCII text format. The sequence listing was first created on June 13, 2019, and is 8 KB in size. [The present invention 1001] Formula (I) A compound represented by TIFF2025143330000004.tif28128, During the ceremony, R 1 is hydrogen, halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, and -C 1~6 alkylene-5-6 membered heterocyclyl, provided that C 1~6 Alkyl, C 3~6 Cycloalkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, and -C 1~6 The alkylene-5- to 6-membered heterocyclyl may optionally be substituted with R on one or more available carbons. g and optionally substituted by one, two, three or more substituents selected from -C 1~6 When the alkylene-5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R h and optionally substituted by R 2 is hydrogen, hydroxyl, -CHF2, -CH2OH, -CH2CN, -CH2-OC 1~6 Alkyl, -CH2-N(R a )-C 1~6 Alkyl, C 2~6 Alkyl, C 2~6 Alkenyl, -OC 1~6Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, -OC(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-OC 1~6 Alkyl, -C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkenylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -OC 1~6 alkylene-5-6 membered heteroaryl, -O-4-6 membered heterocyclyl, -N(R a )-4 to 6-membered heterocyclyl, -C 1~6 Alkylene-4 to 6-membered heterocyclyl, and -OC 1~6 alkylene-4 to 6-membered heterocyclyl, provided that: -CH2-OC 1~6 Alkyl, -CH2-N(R a )-C 1~6 Alkyl, C 2~6 Alkyl, C 2~6 Alkenyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, -OC(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-OC 1~6Alkyl, -C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, -C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkenylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, 5-6 membered heteroaryl, -OC 1~6 alkylene-5-6 membered heteroaryl, 4-6 membered heterocyclyl, -O-4-6 membered heterocyclyl, -N(R a )-4 to 6-membered heterocyclyl, -C 1~6 Alkylene-4 to 6-membered heterocyclyl, and -OC 1~6 The alkylene-4- to 6-membered heterocyclyl may optionally be independently R on one or more available carbons. g and may be substituted by one, two, three or more substituents selected from 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, -N(R a )-4 to 6-membered heterocyclyl, -C 1~6 Alkylene-4 to 6-membered heterocyclyl, or -OC 1~6 When alkylene-4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R h and optionally substituted by Or, R 1 and R 2 together with the atom to which they are attached form a 5-6 membered aryl or heteroaryl, provided that the aryl or heteroaryl are optionally each independently selected from halogen, hydroxyl, cyano, C 1~6 Alkyl, and C 1~6 and optionally substituted by one or more substituents selected from the group consisting of alkoxy, with the proviso that C 1~6 Alkyl and C 1~6 The alkoxy is optionally independently selected from R p and optionally substituted by one, two, three or more substituents selected from R 3 is hydrogen, -C 1~6Alkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, and -C 1~6 alkylene-4 to 6 membered heterocyclyl, provided that -C 1~6 Alkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, and -C 1~6 The alkylene-4- to 6-membered heterocyclyl may optionally be independently R on one or more available carbons. g and optionally substituted by one, two, three or more substituents selected from -C 1~6 When alkylene-4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R h and optionally substituted by R 4 is hydrogen, halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 alkylene-4 to 6 membered heterocyclyl, provided that C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 The alkylene-4- to 6-membered heterocyclyl may optionally be independently R on one or more available carbons. g and optionally substituted by one, two, three or more substituents selected from -C 1~6When alkylene-4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R h and optionally substituted by However, R 1 , R 2 , R 3 , and R 4 At least one of them is not hydrogen, R 5 is hydrogen, halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 alkylene-4 to 6 membered heterocyclyl, provided that C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 The alkylene-4- to 6-membered heterocyclyl may optionally be independently R on one or more available carbons. g and optionally substituted by one, two, three or more substituents selected from -C 1~6 When alkylene-4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R h and optionally substituted by R 6 is hydrogen, R 7 is hydrogen, R g is, independently for each occurrence, hydrogen, halogen, hydroxyl, cyano, nitro, oxo, -C(O)OH, R a R b N-, R a R b NC(O)-, R a R b N-SO w -, R a R b NC(O)-N(R a )-, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, phenyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -OC1~6 Alkylene-C 3~6 Cycloalkyl, -(CO)-(NR a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 3~6 Alkenyloxy, C 3~6 Alkynyloxy, C 3~6 Cycloalkoxy, C 1~6 Alkyl-C(O)-, C 1~6 Alkyl-OC(O)-, C 1~6 Alkyl-C(O)-O-, C 1~6 Alkyl-S(O) w -, C 1~6 Alkyl-N(R a )-, C 1~6 Alkyl-N(R a )-C(O)-, C 1~6 Alkyl-C(O)-N(R a ), C 1~6 Alkyl-N(R a )-C(O)-N(R a )-, C 1~6 Alkyl-N(R a )-SO w -, C 3~6 Cycloalkyl-N(R a )-SO w -, C 1~6 Alkyl-SO w -N(R a )-, C 3~6 Cycloalkyl-SO w -N(R a )-, 4-6 membered heterocyclyl-SO w -N(R a )-, C 1~6 Alkoxy-C(O)-N(R a )-, C 1~6 Alkyl-C(O)-N(R a )-C 1~6 Alkyl-, C 1~6 Alkyl-N(R a )-C(O)-C 1~6 Alkyl-, -P(O)(C 1~3 alkyl)2, and C 1~6 Alkoxy-C 1~6alkyl-, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, phenyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, -(CO)-(NR a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 3~6 Alkenyloxy, C 3~6 Alkynyloxy, C 3~6 Cycloalkoxy, C 1~6 Alkyl-C(O)-, C 1~6 Alkyl-OC(O)-, C 1~6 Alkyl-C(O)-O-, C 1~6 Alkyl-S(O) w -, C 1~6 Alkyl-N(R a )-, C 1~6 Alkyl-N(R a )-C(O)-, C 1~6 Alkyl-C(O)-N(R a ), C 1~6 Alkyl-N(R a )-C(O)-N(R a )-, C 1~6 Alkyl-N(R a )-SO w -, C 3~6 Cycloalkyl-N(R a )-SO w -, C 1~6 Alkyl-SO w -N(R a )-, C 3~6 Cycloalkyl-SO w -N(R a )-, 4-6 membered heterocyclyl-SO w -N(R a )-, C 1~6 Alkoxy-C(O)-N(R a )-, C 1~6 Alkyl-C(O)-N(R a)-C 1~6 Alkyl-, C 1~6 Alkyl-N(R a )-C(O)-C 1~6 Alkyl-, -P(O)(C 1~3 alkyl)2, and C 1~6 Alkoxy-C 1~6 alkyl- is optionally independently R p and optionally substituted by one, two, three or more substituents selected from R h is independently for each occurrence of C 1~6 Alkyl, C 3~6 Alkenyl, C 3~6 Alkynyl, C 3~6 Cycloalkyl, -C 1~6 Alkyl-C 3~6 Cycloalkyl, C 1~6 Alkyl-S(O)2-, C 3~6 Cycloalkyl-S(O)2-, 4- to 6-membered heterocyclyl-S(O)2-, 4- to 6-membered heterocyclyl-C 1~6 Alkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-C 1~6 Alkyl-S(O)2-, C 1~6 Alkyl-C(O)-, C 1~6 Cycloalkyl-C(O)-, C 1~6 Alkoxy-C(O)-, R a R b NC(O)-, R a R b N-SO2- and -P(O)(C 1~3 alkyl)2, provided that C 1~6 Alkyl, C 3~6 Alkenyl, C 3~6 Alkynyl, C 3~6 Cycloalkyl, -C 1~6 Alkyl-C 3~6 Cycloalkyl, C 1~6 Alkyl-S(O)2-, C 3~6 Cycloalkyl-S(O)2-, 4- to 6-membered heterocyclyl-S(O)2-, 4- to 6-membered heterocyclyl-C 1~6Alkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-C 1~6 Alkyl-S(O)2-, C 1~6 Alkyl-C(O)-, C 1~6 Cycloalkyl-C(O)-, C 1~6 Alkoxy-C(O)-, R a R b NC(O)-, R a R b N-SO2- and -P(O)(C 1~3 alkyl)2 optionally each independently represent R p and optionally substituted by one, two, three or more substituents selected from R p is, independently for each occurrence, halogen, hydroxyl, cyano, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, R a R b N-, R a R b N-carbonyl-, R a R b N-SO2- and R a R b N-carbonyl-N(R a )-, R a and R b are independently for each occurrence hydrogen, C 1~6 Alkyl, and C 3~6 cycloalkyl, wherein C 1~6 Alkyl is optionally, independently, halogen, cyano, oxo, hydroxyl, and C 1~6 alkoxy (optionally substituted with 1, 2, or 3 fluorine atoms); Or, R a and R btogether with the nitrogen to which they are attached form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo, and hydroxyl; w is 0, 1, or 2, The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer, or isotopically enriched variant thereof. [The present invention 1002] 1001. A compound of the present invention, wherein one, two, three, or more hydrogen atoms of said compound may optionally be deuterium atoms, and all other atoms of said compound are present in their naturally occurring isotopic abundance ratios. [The present invention 1003] 1, 2, 3, or more hydrogen atoms are optionally each independently R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R g The compound of claim 1001 or 1002, wherein the compound may be a deuterium atom in one, two, three or more groups selected from: [The present invention 1004] R 1 The compound of any one of claims 1001 to 1003, wherein is selected from the group consisting of hydrogen, deuterium, chlorine, and fluorine. [The present invention 1005] R 2 is a 4- to 6-membered heterocyclyl, provided that R 2 optionally, on one or more available carbons, each independently R g and when the 4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted by one, two, or three substituents selected from R h The compound of any one of 1001 to 1004 of the present invention, which may be substituted with a substituent selected from the following: [The present invention 1006] R2 is a 4- to 6-membered heterocyclyl, provided that R 2 optionally, on one or more available carbons, each independently, hydrogen and C 1~6 alkyl; R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally selected from hydrogen, C 1~6 alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), —C 1~6 Alkyl-C 3~6 Cycloalkyl, C 1~6 Cycloalkyl-C(O)-, C 1~6 alkyl-S(O)2- (optionally substituted by cyano, methoxy, or 1, 2, or 3 fluorine atoms), C 3~6 Cycloalkyl-S(O)2-, 4- to 6-membered heterocyclyl-S(O)2-, 4- to 6-membered heterocyclyl-C 1~6 Alkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-C 1~6 Alkyl-S(O)2- (optionally R a R b -N-), and -P(O)(C 1~3 The compound of any one of 1001 to 1005 of the present invention, which may be substituted with a substituent selected from the group consisting of alkyl). [The present invention 1007] R 2 but, Any of compounds 1001 to 1006 of the present invention selected from the group consisting of TIFF2025143330000005.tif198148TIFF2025143330000006.tif55139. [The present invention 1008] R 2 is a 5- to 6-membered heteroaryl, provided that R 2 optionally, on one or more available carbons, each independently R g and R 2When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be replaced by R h The compound of any one of 1001 to 1004 of the present invention, which may be substituted with a substituent selected from the following: [The present invention 1009] R 2 is a 5- to 6-membered heteroaryl, provided that R 2 optionally, on one or more available carbons, each independently, hydrogen, cyano, C 1~6 Alkyl, C 1~6 Alkoxy, and -P(O)(C 1~3 and R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be hydrogen, -C 1~6 Alkyl-C 3~6 Cycloalkyl, and C 3~6 The compound of the present invention 1008, optionally substituted with a substituent selected from the group consisting of cycloalkyl-S(O)2-. [The present invention 1010] R 2 but, The compound of the present invention 1008 or 1009 selected from the group consisting of TIFF2025143330000007.tif47145. [The present invention 1011] R 2 Ga-OC 1~6 alkylene-4 to 6-membered heterocyclyl, provided that R 2 optionally, on one or more available carbons, each independently R g and R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be replaced by R h The compound of any one of 1001 to 1004 of the present invention, which may be substituted with a substituent selected from the following: [The present invention 1012] R 2 Ga-OC 1~6 alkylene-4 to 6-membered heterocyclyl, provided that R 2optionally, on one or more available carbons, each independently, hydrogen, halogen, and C 1~6 alkyl; R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally selected from hydrogen, C 1~6 Alkyl, and C 1~6 The compound of the present invention 1011, optionally substituted with a substituent selected from the group consisting of alkyl-S(O)2-. [The present invention 1013] R 2 but, The compound of the present invention 1011 or 1012 selected from the group consisting of TIFF2025143330000008.tif71132. [The present invention 1014] R 2 Ga-OC 1~6 The compound of any one of 1001 to 1004 of the present invention, which is alkylene-5- to 6-membered heteroaryl. [The present invention 1015] R 2 but, The compound of the present invention 1014 selected from the group consisting of TIFF2025143330000009.tif19128. [The present invention 1016] R 2 But -C 2~6 Alkyl, C 2~6 Alkenyl, and C 3~6 cycloalkyl, wherein R 2 are optionally each independently R g The compound of any one of 1001 to 1004 of the present invention, which may be substituted with one, two, three or more substituents selected from: [The present invention 1017] R 2 But -C 2~6 Alkyl, C 2~6 Alkenyl, C 3~6 Cycloalkyl, -C 1~6 Alkylene-C 3~6 Cycloalkyl, and -C 1~6Alkenylene-C 3~6 cycloalkyl, wherein R 2 are optionally each independently selected from cyano, chlorine, fluorine, hydroxyl, C 1~6 Alkoxy, phenyl, and R a R b The compound of the present invention 1016, optionally substituted with one, two, three or more substituents selected from the group consisting of N-. [The present invention 1018] R 2 but, -CH2CHF2, The compound of the present invention 1016 or 1017 selected from the group consisting of TIFF2025143330000010.tif60147. [The present invention 1019] R 2 Ga-OC 1~6 alkyl, provided that R 2 are optionally each independently R g The compound of any one of 1001 to 1004 of the present invention, which may be substituted with one, two, three or more substituents selected from: [The present invention 1020] R 2 Ga-OC 1~6 alkyl, provided that R 2 are optionally each independently selected from cyano, deuterium, chlorine, fluorine, hydroxyl, oxo, C 1~6 Alkoxy, C 3~6 Cycloalkoxy, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, -(CO)-(NR a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Alkyl-OC(O)-, R a R b N-(However, R b is optionally substituted by -OCH3 or -OCF3), C 1~6 Alkyl-N(R a )-, R a R bNC(O)-, -P(O)(C 1~3 Alkyl)2, C 1~6 Alkyl-N(R a )-C(O)-, C 1~6 Alkyl-N(R a )-C(O)-N(R a )-, C 1~6 Alkyl-SO2-N(R a )-, C 3~6 Cycloalkyl-SO2-N(R a )-, and 4- to 6-membered heterocyclyl-SO2-N(R a )-, optionally substituted with one, two, three or more substituents selected from the group consisting of: [The present invention 1021] R 2 but, -OCH3, -OCD3, -OCF3, -OCHF2, -OCH2CH3, The compound of the present invention 1019 or 1020 selected from the group consisting of TIFF2025143330000011.tif73150TIFF2025143330000012.tif116145. [The present invention 1022] R 2 Ga-OC 3~6 cycloalkyl or -O-4 to 6-membered heterocyclyl, provided that R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be replaced by R h The compound of any one of 1001 to 1004 of the present invention, which may be substituted with a substituent selected from the following: [The present invention 1023] R 2 Ga-OC 3~6 cycloalkyl or -O-4 to 6-membered heterocyclyl, provided that R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be C 1~6 Alkyl-SO2-N(R a )- and C 3~6 Cycloalkyl-SO2-N(R a )-, optionally substituted with a substituent selected from the group consisting of: [The present invention 1024] R 2 but, The compound of the present invention 1022 or 1023 selected from the group consisting of TIFF2025143330000013.tif19128. [The present invention 1025] R 2 -N(R a )-C 1~6 alkyl, provided that R 2 are optionally each independently R g The compound of any one of 1001 to 1004 of the present invention, which may be substituted with 1, 2, or 3 substituents selected from: [The present invention 1026] R 2 -N(R a )-C 1~6 alkyl, provided that R 2 are optionally each independently selected from fluoro, —C(O)OH, cyano, oxo, R a R b N-, C 1~6 Alkoxy, phenyl, -C 3~6 Cycloalkyl, C 3~6 Cycloalkyl-SO2-N(R a )-, and -(CO)-(NR a )-C 1~6 Alkylene-C 3~6 The compound of the present invention 1025 optionally substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl. [The present invention 1027] R 2 but, -N(H)CH3, The compound of the present invention 1025 or 1026 selected from the group consisting of TIFF2025143330000014.tif66134. [The present invention 1028] R 2 Ga-OC 1~6 Alkylene-C 3~6 cycloalkyl, provided that R 2 are optionally each independently R gThe compound of any one of 1001 to 1004 of the present invention, which may be substituted with 1, 2, or 3 substituents selected from: [The present invention 1029] R 2 Ga-OC 1~6 Alkylene-C 3~6 cycloalkyl, provided that R 2 are optionally each independently selected from fluoro, hydroxyl, R a R b N-, cyano, and C 1~3 alkyl, with the proviso that C 1~3 The alkyl is optionally substituted with cyano and C 1~3 The compound of the present invention 1028, optionally substituted with a substituent selected from the group consisting of alkoxy. [The present invention 1030] R 2 but, The compound of the present invention 1028 or 1029 selected from the group consisting of TIFF2025143330000015.tif53140. [The present invention 1031] R 2 -OC(O)-N(R a )-C 1~6 The compound of any one of 1001 to 1004 of the present invention, which is alkyl. [The present invention 1032] R 2 but The compound of the present invention 1031 is represented by TIFF2025143330000016.tif13128. [The present invention 1033] R 2 -N(R a )-4 to 6-membered heterocyclyl, provided that R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be replaced by R h The compound of any one of 1001 to 1004 of the present invention, which may be substituted with a substituent selected from the following: [The present invention 1034] R 2 -N(Ra )-4 to 6-membered heterocyclyl, provided that R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be C 1~6 Alkyl-SO2-N(R a )- and C 3~6 Cycloalkyl-SO2-N(R a )-, optionally substituted with a substituent selected from the group consisting of: [This invention 1035] R 2 but, The compound of the present invention 1033 or 1034 selected from the group consisting of TIFF2025143330000017.tif28128. [The present invention 1036] R 2 Ga-C 1~6 alkylene-4 to 6-membered heterocyclyl, provided that R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be replaced by R h The compound of any one of 1001 to 1004 of the present invention, which may be substituted with a substituent selected from the following: [This invention 1037] R 2 Ga-C 1~6 alkylene-4 to 6-membered heterocyclyl, provided that R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be C 1~6 Alkyl, C 1~6 Alkyl-SO2-N(R a )-, and C 3~6 Cycloalkyl-SO2-N(R a )-, with the proviso that C 1~6 1036. A compound of the present invention wherein the alkyl is optionally substituted with 1, 2, or 3 fluorine atoms. [The present invention 1038] R 2 but, The compound of the present invention 1036 or 1037 selected from the group consisting of TIFF2025143330000018.tif48128. [This invention 1039] R 2 but, -CHF2, -CH2OH, -CH2OCH3, -CH2CN, -OH, Any of the compounds of the present invention 1001 to 1004 selected from the group consisting of TIFF2025143330000019.tif14128. [The present invention 1040] R 1 and R 2 together with the atom to which they are attached form a 5-membered heteroaryl. [The present invention 1041] R 1 and R 2 together with the atom to which they are attached form a furanyl. [The present invention 1042] Compound 1040 or 1041 of the present invention, represented by TIFF2025143330000020.tif27128. [This invention 1043] R 3 The compound of any one of claims 1001 to 1042, wherein is hydrogen. [This invention 1044] R 4 The compound of any one of claims 1001 to 1043, wherein is hydrogen. [This invention 1045] R 5 is selected from the group consisting of hydrogen, deuterium, bromine, chlorine, and fluorine. [The present invention 1046] R 6 is selected from the group consisting of hydrogen and deuterium. [This invention 1047] R 7 is selected from the group consisting of hydrogen and deuterium. [This invention 1048] Compounds of any of claims 1001 to 1047, wherein all atoms of said compound are present in their naturally occurring isotopic abundance ratios. [This invention 1049] Formula (II) A compound represented by TIFF2025143330000021.tif28128, During the ceremony, X is -O- and -N(R a )-, L is a linear or branched C 1~6 is alkylene, R 2-II is hydrogen, cyano, -NR a R b , C 1~2 Alkoxy, C 3~6 Cycloalkyl-SO2-N(R a )-, C 1~6 Alkyl-SO2-N(R a )-, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, and C 3~6 cycloalkyl, with the proviso that phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, and C 3~6 Cycloalkyl optionally includes, on one or more available carbons, each independently, a halogen, a hydroxyl, or an -NR a R b , C 1~2 alkyl (optionally substituted with 1, 2, or 3 halogens), and C 1~2 and alkoxy (optionally substituted by 1, 2, or 3 halogens), and when the 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted by C 1~3 optionally substituted by alkyl, R 5 is selected from the group consisting of hydrogen, deuterium, and halogen; R 6 is selected from the group consisting of hydrogen and deuterium; R7 is selected from the group consisting of hydrogen and deuterium; R a and R b are, independently for each occurrence, hydrogen and C 1~3 selected from the group consisting of alkyl, The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. [The present invention 1050] 1049. The compound of claim 10, wherein X is selected from the group consisting of -O-, -N(H)-, and -N(CH3)-. [This invention 1051] L, TIFF2025143330000022.tif25133, where * and # are each R 2-II and a point of covalent attachment to X. [This invention 1052] R 2-II However, hydrogen, cyano, -NH2, -N(CH3)2, -OCH3, Any of the compounds of the present invention 1049 to 1051 selected from the group consisting of TIFF2025143330000023.tif54150. [This invention 1053] R 5 The compound of any one of claims 1049 to 1052, wherein is selected from the group consisting of hydrogen, deuterium, and fluorine. [This invention 1054] Formula (III) A compound represented by TIFF2025143330000024.tif28128, During the ceremony, X III is a bond, -CH2-, -NR a selected from the group consisting of -, -O-, -O-CH2-, and -OCH2-CH2-; m is 1, 2, or 3; n is 1, 2, or 3; R 1-IIIrepresents hydrogen, halogen, hydroxyl, cyano, -NR a R b , C 1~2 alkyl (optionally substituted with 1, 2, or 3 halogens), and C 1~2 alkoxy (optionally substituted with 1, 2, or 3 halogens); R 2-III is hydrogen, C 1~4 Alkyl, -C(O)-C 1~4 Alkyl, -C(O)-OC 1~4 Alkyl, -C(O)-N(R a )-C 1~4 Alkyl, -S(O)2-C 1~4 Alkyl, and -S(O)2-C 3~6 cycloalkyl, wherein C 1~4 Alkyl, -C(O)-C 1~4 Alkyl, -C(O)-OC 1~4 Alkyl, -C(O)-N(R a )-C 1~4 Alkyl, -S(O)2-C 1~4 Alkyl, and -S(O)2-C 3~6 Cycloalkyl optionally includes, independently, halogen, hydroxyl, cyano, -NR a R b , C 1~2 alkyl (optionally substituted with 1, 2, or 3 halogens), and C 1~2 alkoxy (optionally substituted with 1, 2, or 3 halogens); R 5 is selected from the group consisting of hydrogen, deuterium, and halogen; R 6 is selected from the group consisting of hydrogen and deuterium; R 7 is selected from the group consisting of hydrogen and deuterium; R a and R b are, independently for each occurrence, hydrogen and C1~3 selected from the group consisting of alkyl, The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. [This invention 1055] X III is selected from the group consisting of a bond, —CH2, —O—, —NH—, and —O—CH2—. [The present invention 1056] R 2-III The compound of any one of claims 1054 to 1055, wherein is selected from the group consisting of hydrogen, isopropyl, -CH2CF3, -S(O)2-CH3, and -S(O)2-cyclopropyl. [This invention 1057] R 5 The compound of any one of claims 1054 to 1056, wherein is selected from the group consisting of hydrogen, deuterium, and fluorine. [This invention 1058] 5-{1-fluoro-3-hydroxy-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(pyrrolidin-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 8-Fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ) 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-ylpropan-2-ylcarbamate, 5-(9-fluoro-7-hydroxynaphtho[2,1-b]furan-8-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(azetidin-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-methoxy(4- 2 H) naphthalen-2-yl](4,4- 2 H2)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(methylamino)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(piperidin-4-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-7-{[3-fluoro-1-(propan-2-yl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-7-[(3-fluoropyrrolidin-3-yl)methoxy]-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}pentanenitrile, 5-{1-fluoro-3-hydroxy-7-[2-(piperidin-1-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(piperidin-4-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-3,3-dimethylpentanenitrile, 5-{7-[(3,3-dimethylbutyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1,4-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[( 2 H3) methyloxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-methoxyethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-2,2-dimethylbutanenitrile, 5-{7-[2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[2-(dimethylamino)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)(4,4-2 H2)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}ethyl)cyclopropanesulfonamide, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-Thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)cyclopropanesulfonamide 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)azetidin-3-yl]amino}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanenitrile, [1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropyl]acetonitrile, 5-{7-[2-(dimethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1H-pyrazol-4-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-methylpropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-hydroxypropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(cyclopropylmethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ) 6 ,2,5-thiadiazolidin-2-yl)naphthalene-2-carboxamide, 5-[1-fluoro-3-hydroxy-7-(2-{[2-(trifluoromethoxy)ethyl]amino}ethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(2-methoxyethyl)amino]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[3-(methylamino)propyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(ethylamino)propyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[5-(dimethylphosphoryl)thiophen-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclopropylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(methylamino)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(ethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)amino]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(diethylphosphoryl)propoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3S)-3-hydroxybutoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1,4-difluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3R)-3-hydroxybutoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropyl-2-hydroxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalen-2-yl}-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(4S)-4-hydroxypentyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(4-hydroxy-4-methylpentyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3-oxopentyl)oxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3-hydroxybutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-3-methylbutanamide, 5-[1-fluoro-3-hydroxy-7-(4,4,4-trifluorobutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 1-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)cyclopropane-1-carbonitrile, 5-(1-fluoro-3-hydroxy-7-{2-[1-(methoxymethyl)cyclopropyl]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[(cyclopropylmethyl)amino]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2,2-difluoropropyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3,3-dimethyl-4-(methylamino)butoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-phenylethyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3-amino-3-methylbutoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(difluoromethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(dimethylphosphoryl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3,3,3-trifluoropropyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3-methoxy-3-methylbutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropylpropoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-({2-[(propan-2-yl)oxy]ethyl}amino)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}butanenitrile, 5-[1-fluoro-3-hydroxy-7-(2-hydroxyethyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(4-amino-3,3-dimethylbutoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[2-(azetidin-1-yl)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]oxy}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-methoxyethyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3,3,3-trifluoropropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}methyl)cyclopropane-1-carbonitrile, 5-[1-fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[3-(1H-pyrazol-1-yl)propoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(4-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(hydroxymethyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)piperidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(1H-pyrazol-1-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(piperidin-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(2,2-difluorocyclopropyl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(1-methylcyclopropyl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(3-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(2-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,2-difluoroethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2,2,2-trifluoroethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-7-(2-fluoroethoxy)-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropane-1-carbonitrile, 5-{1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-methylpropyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, {[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetonitrile, 5-[1-fluoro-3-hydroxy-7-(3-methylbutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1,8-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)azetidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)azetidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, (2E)-3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]prop-2-enenitrile, 5-[7-(2-cyclopropylethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2,2-difluorocyclopropyl)methoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclopropylmethoxy)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(oxolan-2-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclobutyloxy)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)oxy]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3-ethoxypropoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-tert-butoxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[rac-(1R,2R)-2-ethylcyclopropyl]methoxy}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(4-methylpentyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(2,2-dimethylpropyl)pyrrolidin-1-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(1-chloro-3-hydroxypropan-2-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(cyclopropyloxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(4-methyl-1H-imidazol-2-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(azetidin-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(5-methoxythiophen-2-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, [8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]acetonitrile, 5-[1-fluoro-3-hydroxy-7-(methoxymethyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3-methyloxetan-3-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{4-bromo-7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{4-bromo-7-[1-(cyclopropanesulfonyl)-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3S)-pyrrolidin-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3R)-pyrrolidin-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(8-chloro-1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(3,3-difluorocyclobutyl)methoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-cyclopropyl-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(4-chloro-1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(E)-2-cyclopropylethenyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1E)-4-methylpent-1-en-1-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(pentamethylphenyl)ethenyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(4-bromo-1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(2-cyclopropylethyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1E)-3-methoxyprop-1-en-1-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-ethoxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3-methoxypropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(1,1-dioxo-1λ 6 -thian-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(oxan-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(cyclopropylmethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]methyl}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[methyl(2-methylpropyl)amino]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(oxolan-2-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(oxolan-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)piperidin-4-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(pyrrolidin-2-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)piperidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(difluoromethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(pyrrolidin-3-yl)methyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,5-dihydrofuran-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3,6-dihydro-2H-pyran-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,5-dihydro-1H-pyrrol-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(pyridin-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(azetidin-3-yl)methyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(2-cyclopropylethyl)-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ] 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}acetamide, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-N-methylbutanamide, N-ethyl-N'-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)urea, 5-{1-fluoro-3-hydroxy-7-[(oxan-3-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(1-chloro-3-hydroxypropan-2-yl)oxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(oxan-4-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(oxetan-3-yl)oxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3,7-dihydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-hydroxyethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-propoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(propan-2-yl)oxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, {[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}acetic acid, N-(2-cyclopropylethyl)-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ] 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetamide, N,N-diethyl-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetamide, 5-{1-fluoro-3-hydroxy-7-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidin-4-yl]oxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(oxolane-3-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(2-methoxyethanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(3,3,3-trifluoropropane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(3,3,3-trifluoropropane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-Fluoro-3-hydroxy-7-{1-[(oxan-2-yl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(4,4,4-trifluorobutane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(butane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(1,4-dioxan-2-yl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-2,5-dihydro-1H-pyrrole-1-sulfonyl}pentanenitrile, 5-{1-fluoro-3-hydroxy-7-[1-(pentane-2-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(ethanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(propane-2-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)oxetane-3-sulfonamide, 5-[1-fluoro-3-hydroxy-7-(piperidin-4-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(2-methylpropane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-ethoxy-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,2-difluoroethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-1H-pyrazol-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[(3R)-1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidin-4-yl]amino}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-7-{[3-fluoro-1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(propane-2-sulfonyl)pyrrolidin-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(1,3-dimethyl-1H-pyrazole-4-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)ethanesulfonamide, 5-{1-fluoro-7-[1-(furan-3-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(3-methylbutane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(thiophene-3-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(benzenesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclobutanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, (2S)-2-amino-4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanoic acid methyl ester, 5-{7-[(3,5-dimethyl-1H-pyrazol-4-yl)methoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3,5-dimethyl-1H-pyrazol-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclohexylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 2-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-Thiadiazolidin-2-yl)naphthalen-2-yl]-1H-imidazole-4-carbonitrile and pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof. [This invention 1059] A pharmaceutically acceptable composition comprising any one of the compounds of the present invention 1001 to 1058 and a pharmaceutically acceptable carrier. [The present invention 1060] A composition of the present invention 1059 formulated for oral administration. [This invention 1061] A method for treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of any of the compounds of the present inventions 1001 to 1058 in combination with an additional therapeutic agent. [This invention 1062] A method for treating cancer in a patient in need thereof, comprising administering to said patient an effective amount of a pharmaceutically acceptable composition of invention 1059 or 1060 in combination with an additional therapeutic agent. [This invention 1063] 1063. The method of any one of claims 1061 to 1062, wherein said further therapeutic agent is an immunotherapeutic agent. [This invention 1064] 1063. The method of claim 1063, wherein said immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody. [This invention 1065] A method for treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of any of the compounds of the present inventions 1001 to 1058. [The present invention 1066] A method for treating cancer in a patient in need thereof, comprising administering to said patient an effective amount of a pharmaceutically acceptable composition of invention 1059 or 1060. [This invention 1067] A method for treating type 2 diabetes in a patient in need thereof, comprising administering to the patient an effective amount of any of the compounds of the present inventions 1001 to 1058 or the composition of the present invention 1059 or 1060. [The present invention 1068] A method for treating and / or managing obesity in a patient in need thereof, comprising administering to said patient an effective amount of any of the compounds of the present inventions 1001 to 1058 or the composition of the present invention 1059 or 1060. [The present invention 1069] A method for suppressing further weight gain in an overweight or obese patient in need thereof, the method comprising administering to the patient an effective amount of any of the compounds of the present inventions 1001 to 1058 or the composition of the present invention 1059 or 1060. [The present invention 1070] A method for treating a metabolic disease in a patient in need thereof, comprising administering to the patient an effective amount of any of the compounds of the present inventions 1001 to 1058 or the composition of the present invention 1059 or 1060. DETAILED DESCRIPTION OF THE INVENTION

[0028] Detailed Description The present disclosure relates, at least in part, to compounds, compositions, and methods for inhibiting protein tyrosine phosphatases, such as non-receptor type 2 protein tyrosine phosphatase (PTPN2) and / or non-receptor type 1 protein tyrosine phosphatase (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B)).

[0029] Definition of Terms Chemical term definitions Definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75 th Ed., endpapers, and specific functional groups are generally defined as described in the above handbook. Further, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0030] Abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0031] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0032] As used herein, a pure enantiomer of a compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, more than 99.5%, or more than 99.9% by weight of the enantiomer. In certain embodiments, the weights are based on the total weight of all enantiomers or stereoisomers of the compound.

[0033] In the compositions provided herein, the enantiomerically pure compound may be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R compound may contain, for example, about 90% excipients and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may contain, for example, at least about 95% by weight of the R compound and up to about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S compound may contain, for example, about 90% excipients and about 10% of the enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may contain, for example, at least about 95% by weight of the S compound and up to about 5% by weight of the R compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipients or carriers.

[0034] As used herein, "isotopically enriched variants" refer to disclosed compounds having one or more isotopic substitutions, in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include:2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 These include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as Cl. For example, hydrogen (H) is: 1 H, 2 H (D or deuterium), and 3 H (T or tritium) and carbon (C) can be in any isotopic form. 12 C. 13 C, and 14 C may be in any isotopic form, including oxygen (O) 16 O and 18 It may be in any isotopic form, including O, etc. For example, in the isotopically enriched variants disclosed herein, one or more hydrogen atoms may be replaced with deuterium.

[0035] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or more than one analogue.

[0036] When a range of numerical values ​​is recited, it is intended that the range encompass each numerical value and subrange within the range. For example, "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0037] The following terms are intended to have the meanings indicated below and are helpful in understanding the description and intended scope of the present disclosure.

[0038] "Alkyl" means a radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C1-C 20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1-C 12 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-C4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-C3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-C2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Each alkyl group can be independently optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, i.e., unsubstituted ("unsubstituted alkyl") or substituted with the above-described substituents ("substituted alkyl"). In certain embodiments, the alkyl group can be an unsubstituted C1- 10Alkyl (e.g., -CH). In certain embodiments, the alkyl group is a substituted C1-6 alkyl. Common abbreviations for alkyl include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0039] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkyl, for example, but not limited to, -CHCHCHCH-. Generally, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with alkyl (or alkylene) groups having 10 or fewer carbon atoms being preferred in this disclosure. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. An alkylene group may be described, for example, as a C1-C6 membered alkylene, where the term "membered" refers to a non-hydrogen atom in the moiety.

[0040] "Alkenyl" means a radical of a straight-chain or branched-chain hydrocarbon group having 2 to 20 carbon atoms and one or more carbon-carbon double bonds and no triple bonds ("C2-C 20 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C-C 10In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-C6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-C5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-C4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-C3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), and butadienyl (C4). Examples of C2-C6 alkenyl groups include the aforementioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Each instance of an alkenyl group independently may be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, e.g., unsubstituted ("unsubstituted alkenyl") or substituted with the above-mentioned substituents ("substituted alkenyl"). In certain embodiments, the alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~6 It is alkenyl.

[0041] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6 to 14 ring carbon atoms associated with said aromatic ring system and no heteroatoms ("C6-C 14In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 Aryl"; for example, anthracyl). The aryl group is, for example, C6-C 10 aryl, where the term "membered" refers to a non-hydrogen ring atom in the moiety. Aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group may independently be optionally substituted with one or more substituents, e.g., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with the substituents described above. In certain embodiments, the aryl group is an unsubstituted C6-C 14 In certain embodiments, the aryl group is a substituted C-C 14 It is aryl.

[0042] In certain embodiments, the aryl group is substituted with one or more groups selected from halo, C1-C8 alkyl, halo-C1-C8 alkyl, halooxy-C1-C8 alkyl, cyano, hydroxy, alkoxy-C1-C8 alkyl, and amino.

[0043] Representative examples of substituted aryl are as follows: TIFF2025143330000025.tif17128, in which R 56 and R 57 may be hydrogen, and R 56 and R 57 At least one of the groups independently represents C1-C8 alkyl, halo-C1-C8 alkyl, 4- to 10-membered heterocyclyl, alkanoyl, alkoxy-C1-C8 alkyl, heteroaryloxy, alkylamino, arylamino, heteroarylamino, or NR 58 COR59 , N.R. 58 SOR 59 , N.R. 58 SO2R 59 , C(O)O alkyl, C(O)O aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , SO2NR 58 R 59 , S-alkyl, S(O)-alkyl, S(O)2-alkyl, S-aryl, S(O)-aryl, S(O2)-aryl, or R 56 and R 57 may be linked to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatom groups selected from the groups N, O, S, S(O), or S(O)2.

[0044] Other representative aryl groups having a fused heterocyclyl group include the following: TIFF2025143330000026.tif12128, wherein each W' is C(R 66 )2, NR 66 , O, and S; each Y' is selected from carbonyl, NR 66 , O, and S; R 66 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0045] The terms "arylene" and "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. Non-limiting examples of heteroaryl groups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthalenyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinonyl, benzisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, and pyrrolopyridinyl. Examples of heteroaryl include aryl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl, and quinolyl. The above examples may be substituted or unsubstituted, and the divalent radical of each of the above heteroaryl examples is a non-limiting example of heteroarylene.

[0046] "Halo" or "halogen," independently or as part of another substituent, means, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. The term "halide," by itself or as part of another substituent, refers to a fluoride, chloride, bromide, or iodide atom. In certain embodiments, the halo group is either fluorine or chlorine.

[0047] Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo-C1-C6 alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0048] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, an acyclic, stable, straight or branched chain, or combination thereof, containing at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Exemplary heteroalkyl groups include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S(O)-CH3, -S(O)-CH3, -CH2-CH2-S(O)-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. Up to two or three heteroatoms may be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The term "heteroalkyl" followed by -CHO-CH3, -NR B R C When specific heteroalkyl groups such as -CH2O-CH3 or -NR B R C It will be understood that the terms "heteroalkyl" and "heteroalkyl-" are not redundant or mutually exclusive. Rather, specific heteroalkyl groups are recited for clarity. Thus, as used herein, the term "heteroalkyl" refers to any group including, but not limited to, -CH2O-CH3, -NR B R C The term should not be construed as excluding specific heteroalkyl groups such as:

[0049] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, for example, but not limited to, -CHO- and -CHCHO-. A heteroalkylene group may be described, for example, as a 2- to 7-membered heteroalkylene, where the term "member" refers to a non-hydrogen atom within the moiety. For heteroalkylene groups, heteroatoms can occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, no directionality of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- can represent both -C(O)R'- and -R'C(O)-.

[0050] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1 to 4 heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" also encompasses ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring containing the heteroatom (e.g., 2-indolyl) or on the ring without the heteroatom (e.g., 5-indolyl). Heteroaryl groups may be described, for example, as 6- to 10-membered heteroaryl, where the term "member" refers to the non-hydrogen ring atoms in the moiety.

[0051] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having the given ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having the given ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having the given ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heteroaryl group independently may be optionally substituted with one or more substituents, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with the substituents described above. In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0052] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0053] Representative examples of heteroaryls include those of the formula: TIFF2025143330000027.tif64128, wherein each Y is a carbonyl, N, NR 65 , O, and S; R 65are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0054] "Cycloalkyl" means a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C3-C 10 "Cycloalkyl" refers to a radical of any of the above hydrocarbon groups that has no heteroatoms in the non-aromatic ring system. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C 10 Cycloalkyl groups may be described, for example, as C4-C7 membered cycloalkyl, where the term "membered" refers to a non-hydrogen ring atom in the moiety. Exemplary C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 cycloalkyl groups include, but are not limited to, the C3-C6 cycloalkyl groups described above, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. 10The cycloalkyl group includes, but is not limited to, the above-mentioned C3 to C8 cycloalkyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 As the examples above illustrate, in certain embodiments, the cycloalkyl group is either monocyclic ("monocyclic cycloalkyl") or includes fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic cycloalkyl"), and may be saturated or partially unsaturated. "Cycloalkyl" also encompasses ring systems in which a cycloalkyl ring, as defined above, is fused to one or more aryl groups and the point of attachment is on the cycloalkyl ring; in such cases, the carbon number continues to refer to the carbon number of the cycloalkyl ring system. Each instance of a cycloalkyl group may independently be optionally substituted with one or more substituents, e.g., unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with the substituents described above. In certain embodiments, the cycloalkyl group is an unsubstituted C3-C6 10 In certain embodiments, the cycloalkyl group is a substituted C3-C 10 It is cycloalkyl.

[0055] In some embodiments, "cycloalkyl" refers to a monocyclic saturated cycloalkyl group having 3 to 10 ring carbon atoms ("C 10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C 10Examples of C5-C6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C6). Examples of C3-C6 cycloalkyl groups include the C5-C6 cycloalkyl groups mentioned above as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-C8 cycloalkyl groups include the C3-C6 cycloalkyl groups mentioned above as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted with one or more substituents (a "substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is an unsubstituted C3-C 10 In certain embodiments, the cycloalkyl group is a substituted C3-C 10 It is cycloalkyl.

[0056] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatom groups, each heteroatom group independently selected from nitrogen, oxygen, sulfur and oxidized forms of sulfur (e.g., S, S(O), and S(O)), boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also encompasses ring systems in which a heterocyclyl ring, as defined above, is fused to one or more cycloalkyl groups and the point of attachment is on either the cycloalkyl ring or the heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups and the point of attachment is on the heterocyclyl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Heterocyclyl groups may be described, for example, as 3- to 7-membered heterocyclyls, where the term "members" refers to the non-hydrogen ring atoms in the moiety, i.e., carbon, nitrogen, oxygen, sulfur and oxidized forms of sulfur (e.g., S, S(O), and S(O)), boron, phosphorus, and silicon. Each instance of heterocyclyl may independently be optionally substituted with one or more substituents, e.g., unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") with the substituents described above. In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 4- to 6-membered heterocyclyl.

[0057] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, and oxidized forms of sulfur (e.g., S, S(O), and S(O)2), boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, and oxidized forms of sulfur (e.g., S, S(O), and S(O)2) ("5- to 8-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and one to four ring heteroatom groups, each heteroatom group independently selected from nitrogen, oxygen, sulfur, and oxidized forms of sulfur (e.g., S, S(O), and S(O)2) ("5- to 6-membered heterocyclyl"). In some embodiments, the 5- to 6-membered heterocyclyl has one to three ring heteroatoms selected from nitrogen, oxygen, sulfur, and oxidized forms of sulfur (e.g., S, S(O), and S(O)2). In some embodiments, the 5- to 6-membered heterocyclyl has one to two ring heteroatoms selected from nitrogen, oxygen, sulfur, and oxidized forms of sulfur (e.g., S, S(O), and S(O)2). In some embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, sulfur, and oxidized forms of sulfur (e.g., S, S(O), and S(O)2).

[0058] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0059] Specific examples of heterocyclyl groups are shown in the illustrative examples below. TIFF2025143330000028.tif43128, where each W" is the CR 67 , C(R 67 )2, NR 67 , O, and S, and each Y is selected from NR 67 , O, and S; R 67 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 and aryl and 5- to 10-membered heteroaryl. These heterocyclyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (e.g., amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl, -S(O)-aryl, -S(O)2-alkyl, and -S(O)2-aryl. Substituents include, for example, carbonyl or thiocarbonyl, which give lactam and urea derivatives.

[0060] A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, including, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methylpiperazine. Specific examples include azetidine, piperidone, and piperazone.

[0061] "Amino" means the radical -NR 70 R 71 wherein R70 and R 71 are each independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 In some embodiments, amino refers to NH2.

[0062] "Cyano" refers to the radical --CN.

[0063] "Hydroxy" or "hydroxyl" refers to the radical --OH.

[0064] In some embodiments, one or more nitrogen atoms of the disclosed compounds, if present, are oxidized to the corresponding N-oxide.

[0065] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" cycloalkyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen present on the group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously change, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when multiple positions in any given structure are substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, including any substituents described herein, that result in the formation of stable compounds. The present disclosure contemplates any and all such combinations in order to arrive at stable compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any and all suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0066] Two or more substituents may optionally be bonded to form an aryl, heteroaryl, cycloalkyl, or heterocyclyl group. Such so-called ring-forming substituents are typically, but not necessarily, attached to a cyclic base structure. In one embodiment, the ring-forming substituents are bonded to adjacent atoms of the base structure. For example, two ring-forming substituents attached to adjacent atoms of a cyclic base structure form a fused ring structure. In another embodiment, the ring-forming substituents are bonded to a single atom of the base structure. For example, two ring-forming substituents attached to a single atom of a cyclic base structure form a spiro ring structure. In yet another embodiment, the ring-forming substituents are bonded to non-adjacent atoms of the base structure.

[0067] A "counterion" or "anionic counterion" is a negatively charged group attached to a cationic quaternary amino group to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , sulfonate ions (e.g., methanesulfonate ion, trifluoromethanesulfonate ion, p-toluenesulfonate ion, benzenesulfonate ion, 10-camphorsulfonate ion, naphthalene-2-sulfonate ion, naphthalene-1-sulfonic acid-5-sulfonate ion, ethane-1-sulfonic acid-2-sulfonate ion, etc.), and carboxylate ions (e.g., acetate ion, ethanoate ion, propanoate ion, benzoate ion, glycerate ion, lactate ion, tartrate ion, glycolate ion, etc.).

[0068] The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents present on the compounds described herein.When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in an appropriate inert solvent.Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts, or similar salts.When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in an appropriate inert solvent. Examples of pharmaceutically acceptable acid addition salts include acid addition salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as alginate, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain compounds of the present disclosure contain both basic and acidic functional groups, which allow the compounds to be converted into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for this disclosure. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms. In other cases, the formulation may be a lyophilized powder in a first buffer solution, e.g., 1 mM to 50 mM histidine, 0.1% to 2% sucrose, 2% to 7% mannitol, pH range 4.5 to 5.5, which is mixed with a second buffer solution prior to use.

[0069] Therefore, the compounds of the present disclosure may exist as salts, such as salts with pharmaceutically acceptable acids. The present disclosure includes such salts. Examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof, including a racemic mixture), succinate, benzoate, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

[0070] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent forms of the compounds differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0071] In addition to salt forms, the present disclosure also provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that easily undergo chemical changes under physiological conditions to yield the compounds of the present disclosure. Furthermore, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with an appropriate enzyme or chemical reactant.

[0072] Certain compounds of the present disclosure may exist in solvated forms, including hydrated forms, as well as unsolvated forms. Generally, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0073] As used herein, the term "salt" refers to an acid or base salt of a compound used in the method of the present disclosure. Illustrative examples of acceptable salts include mineral acid salts (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acid salts (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium salts (such as methyl iodide, ethyl iodide, etc.).

[0074] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers that can be specified in terms of absolute stereochemistry as (R)- or (S)-, or, for amino acids, as (D)- or (L)-, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include compounds known in the art to be excessively unstable and therefore unable to be synthesized and / or isolated. The present disclosure is intended to encompass compounds in racemic and optically pure form. Optically active (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral starting materials or chiral reactants, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to encompass both E and Z geometric isomers.

[0075] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and hence the same molecular weight, but differ with respect to the structural arrangement or configuration of the atoms.

[0076] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0077] It will be apparent to one skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present disclosure.

[0078] "Treating" or "treatment" includes preventing or delaying the onset of symptoms, complications, or biochemical manifestations of a disease, alleviating or ameliorating such symptoms, or preventing or inhibiting further development of a disease, condition, or disorder. "Treating" or "treatment" includes any effect that leads to the improvement of a disease, condition, disorder, or the like, e.g., attenuating, alleviating, modulating, or elimination. For example, certain methods herein treat cancer by reducing, alleviating, or preventing the onset, growth, metastasis, or progression of cancer, or by reducing the symptoms of cancer. The term "treatment" and its conjugations include prevention of an injury, condition, condition, or disease (e.g., preventing the onset of one or more symptoms of a disease, disorder, or condition described herein).

[0079] An "effective amount" is an amount sufficient to achieve a stated purpose (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, or alleviate one or more symptoms of a disease or disorder). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or alleviation of one or more symptoms of a disease, and this amount is also referred to as a "therapeutically effective amount." A "prophylactically effective amount" of a drug is an amount of drug that, when administered to a subject, will exhibit the intended prophylactic effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, condition, or illness, or reducing the likelihood of the onset (or recurrence) of an injury, disease, condition, or illness, or a symptom thereof. A complete prophylactic effect does not necessarily occur with a single administration, but may occur only after a series of administrations. Thus, a prophylactically effective amount may be administered in one or more administrations. The precise amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0080] "Alleviation" (and grammatical equivalents of this phrase) of one or more symptoms means a decrease in the severity or frequency of the symptom(s) or the elimination of said symptom(s).

[0081] "Control" or "control experiment" is used according to its plain and ordinary meaning to refer to an experiment in which the experimental subjects or agents are treated as in a parallel experiment, except for the omission of an experimental procedure, agent, or variable. In some cases, the control is used as a standard of comparison in evaluating the effectiveness of the experiment.

[0082] "Contacting" is used according to its plain and ordinary meaning to refer to the process of bringing at least two different species (e.g., compounds, including biomolecules or cells) into sufficient proximity to react, interact, or come into physical contact. However, it should be understood that the resulting reaction product may be generated directly from the reaction between the added reactants or from an intermediate derived from one or more added reactants that may be generated in the reaction mixture. The term "contacting" may encompass reacting, interacting, or physically contacting two species, where the two species may be a compound described herein and a protein or enzyme, e.g., a protein tyrosine phosphatase, e.g., non-receptor type 2 protein tyrosine phosphatase (PTPN2) or non-receptor type 1 protein tyrosine phosphatase (PTP1B).

[0083] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like, in reference to protein-inhibitor (e.g., antagonist) interaction, refer to negatively affecting (e.g., decreasing) the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to the alleviation of a disease or disease symptom. In some embodiments, inhibition refers to the reduction of the activity of a signal transduction pathway or signaling pathway. Thus, inhibition includes at least partially, partially, or completely blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signal transduction or enzymatic activity or the amount of a protein. In some embodiments, inhibition refers to the reduction of the activity of a protein tyrosine phosphatase, e.g., non-receptor type 2 protein tyrosine phosphatase (PTPN2) or non-receptor type 1 protein tyrosine phosphatase (PTP1B). Thus, inhibiting may include at least partially, partially, or completely reducing stimulation, reducing or decreasing activation, or inactivating, desensitizing, or downregulating signaling or enzymatic activity or the amount of a protein tyrosine phosphatase, e.g., non-receptor type 2 protein tyrosine phosphatase (PTPN2) or non-receptor type 1 protein tyrosine phosphatase (PTP1B).

[0084] A "patient" or "subject" in need thereof refers to an organism suffering from or susceptible to a disease or disorder that can be treated by administration of a compound or pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, bovine animals, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammals. In some embodiments, the patient is a human. In some embodiments, the patient is a domestic animal. In some embodiments, the patient is a dog. In some embodiments, the patient is a parrot. In some embodiments, the patient is a livestock animal. In some embodiments, the patient is a mammal. In some embodiments, the patient is a cat. In some embodiments, the patient is a horse. In some embodiments, the patient is a bovine animal. In some embodiments, the patient is a canine animal. In some embodiments, the patient is a feline animal. In some embodiments, the patient is an ape. In some embodiments, the patient is a monkey. In some embodiments, the patient is a mouse. In some embodiments, the patient is a laboratory animal. In some embodiments, the patient is a rat. In some embodiments, the patient is a hamster. In some embodiments, the patient is a test animal. In some embodiments, the patient is a newborn animal. In some embodiments, the patient is a human neonate. In some embodiments, the patient is a newborn mammal. In some embodiments, the patient is an elderly animal. In some embodiments, the patient is an elderly human. In some embodiments, the patient is an elderly mammal. In some embodiments, the patient is a geriatric patient.

[0085] "Disease," "disorder," or "condition" refers to a physical or physical state of a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein. In some embodiments, the compounds and methods described herein include the reduction or elimination of one or more symptoms of the disease, disorder, or condition, e.g., by administration of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0086] As used herein, the term "signal transduction pathway" refers to a series of interactions between cellular and optionally extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that transmit a change in one component to one or more other components, which in turn may transmit the change to additional components, which are optionally propagated to components of other signal transduction pathways.

[0087] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the administration and absorption of an active agent by a subject and can be included in the compositions of the present disclosure without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such formulations may be sterilized and, if necessary, mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring agents that do not adversely react with the compounds of the present disclosure. Those of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0088] The term "formulation" is intended to encompass formulations of active compounds with an encapsulating material as a carrier, providing a capsule, in which the active ingredient is surrounded by a carrier, with or without other carriers, thus uniting the carrier with the active ingredient. Cachets and lozenges are also encompassed. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0089] As used herein, the term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, or subcutaneous administration, or implantation of a sustained-release device, such as a mini-osmotic pump, into a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. "Co-administering" means that a compound or composition described herein is administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapeutic agents (e.g., anti-cancer, chemotherapeutic, or immunotherapeutic agents). The compounds or compositions described herein can be administered to patients alone or simultaneously. Simultaneous administration is intended to include simultaneous or sequential administration of the compounds or compositions individually or in combination (multiple compounds or drugs). Thus, the above formulations can also be combined with other active substances (e.g., to reduce metabolic degradation) if desired.

[0090] As used herein, the term "PTPN2" refers to non-receptor type 2 protein tyrosine phosphatase. The term "PTPN1" refers to non-receptor type 1 protein tyrosine phosphatase (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B).

[0091] compound As used herein, for example, the compound of formula (I) A compound represented by TIFF2025143330000029.tif27128, During the ceremony, R 1 is hydrogen, halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, and -C 1~6 alkylene-5-6 membered heterocyclyl, provided that C 1~6 Alkyl, C 3~6 Cycloalkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, and -C 1~6 The alkylene-5- to 6-membered heterocyclyl may optionally be substituted with R on one or more available carbons. g and optionally substituted by one, two, three or more substituents selected from -C 1~6 When alkylene-5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R h and optionally substituted by R 2 is hydrogen, hydroxyl, -CHF2, -CH2OH, -CH2CN, -CH2-OC 1~6 Alkyl, -CH2-N(R a )-C 1~6 Alkyl, C 2~6 Alkyl, C 2~6 Alkenyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, -OC(O)-N(R a )-C 1~6 Alkyl, -N(Ra )-C(O)-OC 1~6 Alkyl, -C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkenylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -OC 1~6 alkylene-5-6 membered heteroaryl, -O-4-6 membered heterocyclyl, -N(R a )-4 to 6-membered heterocyclyl, -C 1~6 Alkylene-4 to 6-membered heterocyclyl, and -OC 1~6 alkylene-4 to 6-membered heterocyclyl, provided that: -CH2-OC 1~6 Alkyl, -CH2-N(R a )-C 1~6 Alkyl, C 2~6 Alkyl, C 2~6 Alkenyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, -OC(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-OC 1~6 Alkyl, -C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, -C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkenylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, 5-6 membered heteroaryl, -OC 1~6alkylene-5-6 membered heteroaryl, 4-6 membered heterocyclyl, -O-4-6 membered heterocyclyl, -N(R a )-4 to 6-membered heterocyclyl, -C 1~6 Alkylene-4 to 6-membered heterocyclyl, and -OC 1~6 The alkylene-4- to 6-membered heterocyclyl may optionally be independently R on one or more available carbons. g and may be substituted by one, two, three or more substituents selected from 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, -N(R a )-4 to 6-membered heterocyclyl, -C 1~6 Alkylene-4 to 6-membered heterocyclyl, or -OC 1~6 When alkylene-4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R h and optionally substituted by Or, R 1 and R 2 together with the atom to which they are attached form a 5-6 membered aryl or heteroaryl, provided that the aryl or heteroaryl are optionally each independently selected from halogen, hydroxyl, cyano, C 1~6 Alkyl, and C 1~6 and optionally substituted by one or more substituents selected from the group consisting of alkoxy, with the proviso that C 1~6 Alkyl and C 1~6 The alkoxy is optionally independently selected from R p and optionally substituted by one, two, three or more substituents selected from R 3 is hydrogen, -C 1~6 Alkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, and -C 1~6alkylene-4 to 6 membered heterocyclyl, provided that -C 1~6 Alkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, and -C 1~6 The alkylene-4- to 6-membered heterocyclyl may optionally be independently R on one or more available carbons. g and optionally substituted by one, two, three or more substituents selected from -C 1~6 When alkylene-4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R h and optionally substituted by R 4 is hydrogen, halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 alkylene-4 to 6 membered heterocyclyl, provided that C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 The alkylene-4- to 6-membered heterocyclyl may optionally be independently R on one or more available carbons. g and optionally substituted by one, two, three or more substituents selected from -C 1~6 When alkylene-4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R h and optionally substituted by However, R 1 , R 2 , R 3 , and R 4 At least one of them is not hydrogen, R 5 is hydrogen, halogen, C 1~6 Alkyl, C 3~6Cycloalkyl, and -C 1~6 alkylene-4 to 6 membered heterocyclyl, provided that C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 The alkylene-4- to 6-membered heterocyclyl may optionally be independently R on one or more available carbons. g and optionally substituted by one, two, three or more substituents selected from -C 1~6 When alkylene-4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R h and optionally substituted by R 6 is hydrogen, R 7 is hydrogen, R g is, independently for each occurrence, hydrogen, halogen, hydroxyl, cyano, nitro, oxo, -C(O)OH, R a R b N-, R a R b NC(O)-, R a R b N-SO w -, R a R b NC(O)-N(R a )-, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, phenyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, -(CO)-(NR a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 3~6 Alkenyloxy, C 3~6 Alkynyloxy, C 3~6 Cycloalkoxy, C 1~6 Alkyl-C(O)-, C 1~6Alkyl-OC(O)-, C 1~6 Alkyl-C(O)-O-, C 1~6 Alkyl-S(O) w -, C 1~6 Alkyl-N(R a )-, C 1~6 Alkyl-N(R a )-C(O)-, C 1~6 Alkyl-C(O)-N(R a ), C 1~6 Alkyl-N(R a )-C(O)-N(R a )-, C 1~6 Alkyl-N(R a )-SO w -, C 3~6 Cycloalkyl-N(R a )-SO w -, C 1~6 Alkyl-SO w -N(R a )-, C 3~6 Cycloalkyl-SO w -N(R a )-, 4-6 membered heterocyclyl-SO w -N(R a )-, C 1~6 Alkoxy-C(O)-N(R a )-, C 1~6 Alkyl-C(O)-N(R a )-C 1~6 Alkyl-, C 1~6 Alkyl-N(R a )-C(O)-C 1~6 Alkyl-, -P(O)(C 1~3 alkyl)2, and C 1~6 Alkoxy-C 1~6 alkyl-, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, phenyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, -(CO)-(NR a )-C 1~6 Alkylene-C3~6 Cycloalkyl, C 1~6 Alkoxy, C 3~6 Alkenyloxy, C 3~6 Alkynyloxy, C 3~6 Cycloalkoxy, C 1~6 Alkyl-C(O)-, C 1~6 Alkyl-OC(O)-, C 1~6 Alkyl-C(O)-O-, C 1~6 Alkyl-S(O) w -, C 1~6 Alkyl-N(R a )-, C 1~6 Alkyl-N(R a )-C(O)-, C 1~6 Alkyl-C(O)-N(R a ), C 1~6 Alkyl-N(R a )-C(O)-N(R a )-, C 1~6 Alkyl-N(R a )-SO w -, C 3~6 Cycloalkyl-N(R a )-SO w -, C 1~6 Alkyl-SO w -N(R a )-, C 3~6 Cycloalkyl-SO w -N(R a )-, 4-6 membered heterocyclyl-SO w -N(R a )-, C 1~6 Alkoxy-C(O)-N(R a )-, C 1~6 Alkyl-C(O)-N(R a )-C 1~6 Alkyl-, C 1~6 Alkyl-N(R a )-C(O)-C 1~6 Alkyl-, -P(O)(C 1~3 alkyl)2, and C 1~6 Alkoxy-C 1~6 alkyl- is optionally independently R p and optionally substituted by one, two, three or more substituents selected from Rh is independently for each occurrence of C 1~6 Alkyl, C 3~6 Alkenyl, C 3~6 Alkynyl, C 3~6 Cycloalkyl, -C 1~6 Alkyl-C 3~6 Cycloalkyl, C 1~6 Alkyl-S(O)2-, C 3~6 Cycloalkyl-S(O)2-, 4- to 6-membered heterocyclyl-S(O)2-, 4- to 6-membered heterocyclyl-C 1~6 Alkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-C 1~6 Alkyl-S(O)2-, C 1~6 Alkyl-C(O)-, C 1~6 Cycloalkyl-C(O)-, C 1~6 Alkoxy-C(O)-, R a R b NC(O)-, R a R b N-SO2- and -P(O)(C 1~3 alkyl)2, provided that C 1~6 Alkyl, C 3~6 Alkenyl, C 3~6 Alkynyl, C 3~6 Cycloalkyl, -C 1~6 Alkyl-C 3~6 Cycloalkyl, C 1~6 Alkyl-S(O)2-, C 3~6 Cycloalkyl-S(O)2-, 4- to 6-membered heterocyclyl-S(O)2-, 4- to 6-membered heterocyclyl-C 1~6 Alkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-C 1~6 Alkyl-S(O)2-, C 1~6 Alkyl-C(O)-, C 1~6 Cycloalkyl-C(O)-, C 1~6 Alkoxy-C(O)-, R a R b NC(O)-, R a R b N-SO2- and -P(O)(C 1~3alkyl)2 optionally each independently represent R p and optionally substituted by one, two, three or more substituents selected from R p is, independently for each occurrence, halogen, hydroxyl, cyano, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, R a R b N-, R a R b N-carbonyl-, R a R b N-SO2- and R a R b N-carbonyl-N(R a )-, R a and R b are independently for each occurrence hydrogen, C 1~6 Alkyl, and C 3~6 cycloalkyl, wherein C 1~6 Alkyl is optionally, independently, halogen, cyano, oxo, hydroxyl, and C 1~6 alkoxy (optionally substituted with 1, 2, or 3 fluorine atoms); Or, R a and R b together with the nitrogen to which they are attached form a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo, and hydroxyl; w is 0, 1, or 2, Disclosed are the above compounds or pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, stereoisomers, or isotopically enriched variants thereof.

[0092] In some embodiments, one, two, three, or more hydrogen atoms of the compound may optionally be deuterium atoms, and all other atoms of the compound are present in their naturally occurring isotopic abundance. For example, in some embodiments, one, two, three, or more hydrogen atoms are optionally each independently selected from R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R g may be deuterium atoms in one, two, three or more groups selected from:

[0093] In some embodiments, R 1 is, for example, selected from the group consisting of hydrogen, deuterium, chlorine, and fluorine.

[0094] In some embodiments, R 2 is a 4- to 6-membered heterocyclyl, provided that R 2 optionally, on one or more available carbons, each independently R g and when the 4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted by one, two, or three substituents selected from R h For example, in some embodiments, R 2 is a 4- to 6-membered heterocyclyl, provided that R 2 optionally, on one or more available carbons, each independently, hydrogen and C 1~6 alkyl; R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally selected from hydrogen, C 1~6 alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), —C 1~6 Alkyl-C 3~6 Cycloalkyl, C 1~6 Cycloalkyl-C(O)-, C 1~6alkyl-S(O)2- (optionally substituted by cyano, methoxy, or 1, 2, or 3 fluorine atoms), C 3~6 Cycloalkyl-S(O)2-, 4- to 6-membered heterocyclyl-S(O)2-, 4- to 6-membered heterocyclyl-C 1~6 Alkyl-S(O)2-, 5-6 membered heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-C 1~6 Alkyl-S(O)2- (optionally R a R b -N-), and -P(O)(C 1~3 For example, in some embodiments, R 2 For example, TIFF2025143330000030.tif105146TIFF2025143330000031.tif149146.

[0095] In other embodiments, R 2 is a 5- to 6-membered heteroaryl, provided that R 2 optionally, on one or more available carbons, each independently R g and R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be replaced by R h For example, in some embodiments, R 2 is a 5- to 6-membered heteroaryl, provided that R 2 optionally, on one or more available carbons, each independently, hydrogen, cyano, C 1~6 Alkyl, C 1~6 Alkoxy, and -P(O)(C 1~3 and R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be hydrogen, -C 1~6 Alkyl-C 3~6Cycloalkyl, and C 3~6 cycloalkyl-S(O)-. For example, in some embodiments, R 2 For example, TIFF2025143330000032.tif48141.

[0096] In a further embodiment, R 2 Ha-OC 1~6 alkylene-4 to 6-membered heterocyclyl, provided that R 2 optionally, on one or more available carbons, each independently R g and R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be replaced by R h For example, in some embodiments, R 2 Ha-OC 1~6 alkylene-4 to 6-membered heterocyclyl, provided that R 2 optionally, on one or more available carbons, each independently, hydrogen, halogen, and C 1~6 alkyl; R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally selected from hydrogen, C 1~6 Alkyl, and C 1~6 For example, in some embodiments, R 2 For example, TIFF2025143330000033.tif70131.

[0097] In other embodiments, R 2 Ha-OC 1~6 alkylene-5-6 membered heteroaryl. For example, in some embodiments, R 2 For example, TIFF2025143330000034.tif19128.

[0098] In a further embodiment, R 2 Ha-C 2~6 Alkyl, C 2~6 Alkenyl, and C 3~6 cycloalkyl, wherein R 2 are optionally each independently R g For example, in some embodiments, R 2 -C 2~6 Alkyl, C 2~6 Alkenyl, C 3~6 Cycloalkyl, -C 1~6 Alkylene-C 3~6 Cycloalkyl, and -C 1~6 Alkenylene-C 3~6 cycloalkyl, wherein R 2 are optionally each independently selected from cyano, chlorine, fluorine, hydroxyl, C 1~6 Alkoxy, phenyl, and R a R b N-. For example, in some embodiments, R 2 For example, -CH2CHF2, TIFF2025143330000035.tif62146.

[0099] In other embodiments, R 2 Ha-OC 1~6 alkyl, provided that R 2 are optionally each independently R g For example, in some embodiments, R 2 -OC 1~6 alkyl, provided that R 2are optionally each independently selected from cyano, deuterium, chlorine, fluorine, hydroxyl, oxo, C 1~6 Alkoxy, C 3~6 Cycloalkoxy, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, -(CO)-(NR a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Alkyl-OC(O)-, R a R b N-(However, R b is optionally substituted by -OCH3 or -OCF3), C 1~6 Alkyl-N(R a )-, R a R b NC(O)-, -P(O)(C 1~3 Alkyl)2, C 1~6 Alkyl-N(R a )-C(O)-, C 1~6 Alkyl-N(R a )-C(O)-N(R a )-, C 1~6 Alkyl-SO2-N(R a )-, C 3~6 Cycloalkyl-SO2-N(R a )-, and 4- to 6-membered heterocyclyl-SO2-N(R a )-. For example, in some embodiments, R 2 For example, -OCH3, -OCD3, -OCF3, -OCHF2, -OCH2CH3, TIFF2025143330000036.tif192149.

[0100] In other embodiments, R 2 Ha-OC 3~6 cycloalkyl or -O-4 to 6-membered heterocyclyl, provided that R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be replaced by R hFor example, in some embodiments, R 2 Ha-OC 3~6 cycloalkyl or -O-4 to 6-membered heterocyclyl, provided that R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be C 1~6 Alkyl-SO2-N(R a )- and C 3~6 Cycloalkyl-SO2-N(R a For example, in some embodiments, R 2 For example, TIFF2025143330000037.tif18128.

[0101] In still further embodiments, R 2 -N(R a )-C 1~6 alkyl, provided that R 2 are optionally each independently R g For example, in some embodiments, R 2 -N(R a )-C 1~6 alkyl, provided that R 2 are optionally each independently selected from fluoro, —C(O)OH, cyano, oxo, R a R b N-, C 1~6 Alkoxy, phenyl, -C 3~6 Cycloalkyl, C 3~6 Cycloalkyl-SO2-N(R a )-, and -(CO)-(NR a )-C 1~6 Alkylene-C 3~6 cycloalkyl. For example, in some embodiments, R 2 For example, -N(H)CH3, TIFF2025143330000038.tif66132.

[0102] In other embodiments, R 2 Ha-OC 1~6 Alkylene-C 3~6 cycloalkyl, provided that R 2 are optionally each independently R g For example, in some embodiments, R 2 Ha-OC 1~6 Alkylene-C 3~6 cycloalkyl, provided that R 2 are optionally each independently selected from fluoro, hydroxyl, R a R b N-, cyano, and C 1~3 alkyl, with the proviso that C 1~3 The alkyl is optionally substituted with cyano and C 1~3 For example, in some embodiments, R 2 For example, TIFF2025143330000039.tif14141TIFF2025143330000040.tif35130.

[0103] In some embodiments, R 2 is -OC(O)-N(R a )-C 1~6 For example, in some embodiments, R 2 For example, Represented by TIFF2025143330000041.tif13128.

[0104] In a further embodiment, R 2 -N(R a )-4 to 6-membered heterocyclyl, provided that R 2When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be replaced by R h For example, in some embodiments, R 2 -N(R a )-4 to 6-membered heterocyclyl, provided that R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be C 1~6 Alkyl-SO2-N(R a )- and C 3~6 Cycloalkyl-SO2-N(R a For example, in some embodiments, R 2 For example, TIFF2025143330000042.tif27128.

[0105] In other embodiments, R 2 Ha-C 1~6 alkylene-4 to 6-membered heterocyclyl, provided that R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be replaced by R h For example, in some embodiments, R 2 Ha-C 1~6 alkylene-4 to 6-membered heterocyclyl, provided that R 2 When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be C 1~6 Alkyl, C 1~6 Alkyl-SO2-N(R a )-, and C 3~6 Cycloalkyl-SO2-N(R a )-, with the proviso that C 1~6 The alkyl may be optionally substituted with 1, 2, or 3 fluorine atoms. For example, in some embodiments, R 2 For example, TIFF2025143330000043.tif47128.

[0106] In some embodiments, R 2 For example, -CHF2, -CH2OH, -CH2OCH3, -CH2CN, -OH, TIFF2025143330000044.tif14128.

[0107] In some embodiments, R 1 and R 2 together with the atom to which they are attached form a 5-membered heteroaryl. For example, in some embodiments, R 1 and R 2 together with the atom to which they are attached form, for example, furanyl. For example, in some embodiments, the compound of formula (I) is Represented by TIFF2025143330000045.tif26128.

[0108] In some embodiments, R 3 is hydrogen. In other embodiments, R 4 is hydrogen. In a further embodiment, R 5 is selected from the group consisting of hydrogen, deuterium, bromine, chlorine, and fluorine. 6 is selected from the group consisting of hydrogen and deuterium. 7 is selected from the group consisting of hydrogen and deuterium. In some embodiments, all atoms of the compounds of Formula (I) are present in their naturally occurring isotopic abundance.

[0109] As used herein, the formula (II) A compound represented by TIFF2025143330000046.tif27128, During the ceremony, X is -O- and -N(R a )-, L is a linear or branched C 1~6 is alkylene, R2-II is hydrogen, cyano, -NR a R b , C 1~2 Alkoxy, C 3~6 Cycloalkyl-SO2-N(R a )-, C 1~6 Alkyl-SO2-N(R a )-, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, and C 3~6 cycloalkyl, with the proviso that phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, and C 3~6 Cycloalkyl optionally includes, on one or more available carbons, each independently, a halogen, a hydroxyl, or an -NR a R b , C 1~2 alkyl (optionally substituted with 1, 2, or 3 halogens), and C 1~2 and alkoxy (optionally substituted by 1, 2, or 3 halogens), and when the 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted by C 1~3 optionally substituted by alkyl, R 5 is selected from the group consisting of hydrogen, deuterium, and halogen; R 6 is selected from the group consisting of hydrogen and deuterium; R 7 is selected from the group consisting of hydrogen and deuterium; R a and R b are, independently for each occurrence, hydrogen and C 1~3 selected from the group consisting of alkyl, Also disclosed are the above compounds, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof.

[0110] In some embodiments, X is selected from the group consisting of —O—, —N(H)—, and —N(CH 3 )—.

[0111] In other embodiments, L is TIFF2025143330000047.tif24132, where * and # are each R 2-II and represents the point of covalent attachment to X.

[0112] In a further embodiment, R 2-II is hydrogen, cyano, -NH2, -N(CH3)2, -OCH3, TIFF2025143330000048.tif41128.

[0113] In some embodiments, R 5 is selected from the group consisting of hydrogen, deuterium, and fluorine.

[0114] As used herein, the formula (III) A compound represented by TIFF2025143330000049.tif27128, During the ceremony, X III is a bond, -CH2-, -NR a selected from the group consisting of -, -O-, -O-CH2-, and -OCH2-CH2-; m is 1, 2, or 3; n is 1, 2, or 3; R 1-III represents hydrogen, halogen, hydroxyl, cyano, -NR a R b , C 1~2 alkyl (optionally substituted with 1, 2, or 3 halogens), and C 1~2 alkoxy (optionally substituted with 1, 2, or 3 halogens); R 2-III is hydrogen, C 1~4 Alkyl, -C(O)-C 1~4Alkyl, -C(O)-OC 1~4 Alkyl, -C(O)-N(R a )-C 1~4 Alkyl, -S(O)2-C 1~4 Alkyl, and -S(O)2-C 3~6 cycloalkyl, wherein C 1~4 Alkyl, -C(O)-C 1~4 Alkyl, -C(O)-OC 1~4 Alkyl, -C(O)-N(R a )-C 1~4 Alkyl, -S(O)2-C 1~4 Alkyl, and -S(O)2-C 3~6 Cycloalkyl optionally includes, independently, halogen, hydroxyl, cyano, -NR a R b , C 1~2 alkyl (optionally substituted with 1, 2, or 3 halogens), and C 1~2 alkoxy (optionally substituted with 1, 2, or 3 halogens); R 5 is selected from the group consisting of hydrogen, deuterium, and halogen; R 6 is selected from the group consisting of hydrogen and deuterium; R 7 is selected from the group consisting of hydrogen and deuterium; R a and R b are, independently for each occurrence, hydrogen and C 1~3 selected from the group consisting of alkyl, Also disclosed are the above compounds, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof.

[0115] In some embodiments, X III is selected from the group consisting of a bond, —CH 2 , —O—, —NH—, and —O—CH 2 —.

[0116] In other embodiments, R 2-III is selected from the group consisting of hydrogen, isopropyl, —CH2CF3, —S(O)2—CH3, and —S(O)2-cyclopropyl.

[0117] In a further embodiment, R 5 is selected from the group consisting of hydrogen, deuterium, and fluorine.

[0118] In this specification, 5-{1-fluoro-3-hydroxy-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(pyrrolidin-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 8-Fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ) 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-ylpropan-2-ylcarbamate, 5-(9-fluoro-7-hydroxynaphtho[2,1-b]furan-8-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(azetidin-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-methoxy(4- 2 H) naphthalen-2-yl](4,4- 2 H2)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(methylamino)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(piperidin-4-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-7-{[3-fluoro-1-(propan-2-yl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-7-[(3-fluoropyrrolidin-3-yl)methoxy]-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}pentanenitrile, 5-{1-fluoro-3-hydroxy-7-[2-(piperidin-1-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(piperidin-4-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-3,3-dimethylpentanenitrile, 5-{7-[(3,3-dimethylbutyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1,4-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[( 2 H3) methyloxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-methoxyethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-2,2-dimethylbutanenitrile, 5-{7-[2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[2-(dimethylamino)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)(4,4- 2 H2)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}ethyl)cyclopropanesulfonamide, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-Thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)cyclopropanesulfonamide 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)azetidin-3-yl]amino}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanenitrile, [1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropyl]acetonitrile, 5-{7-[2-(dimethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1H-pyrazol-4-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-methylpropoxy)naphthalen-2-yl]-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-hydroxypropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(cyclopropylmethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ) 6 ,2,5-thiadiazolidin-2-yl)naphthalene-2-carboxamide, 5-[1-fluoro-3-hydroxy-7-(2-{[2-(trifluoromethoxy)ethyl]amino}ethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(2-methoxyethyl)amino]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[3-(methylamino)propyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(ethylamino)propyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[5-(dimethylphosphoryl)thiophen-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclopropylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(methylamino)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(ethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)amino]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(diethylphosphoryl)propoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3S)-3-hydroxybutoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1,4-difluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3R)-3-hydroxybutoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropyl-2-hydroxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(4S)-4-hydroxypentyl]naphthalen-2-yl}-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(4-hydroxy-4-methylpentyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3-oxopentyl)oxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3-hydroxybutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-3-methylbutanamide, 5-[1-fluoro-3-hydroxy-7-(4,4,4-trifluorobutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 1-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)cyclopropane-1-carbonitrile, 5-(1-fluoro-3-hydroxy-7-{2-[1-(methoxymethyl)cyclopropyl]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[(cyclopropylmethyl)amino]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2,2-difluoropropyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3,3-dimethyl-4-(methylamino)butoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-phenylethyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3-amino-3-methylbutoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(difluoromethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(dimethylphosphoryl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3,3,3-trifluoropropyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3-methoxy-3-methylbutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropylpropoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-({2-[(propan-2-yl)oxy]ethyl}amino)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}butanenitrile, 5-[1-fluoro-3-hydroxy-7-(2-hydroxyethyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(4-amino-3,3-dimethylbutoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[2-(azetidin-1-yl)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]oxy}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-methoxyethyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3,3,3-trifluoropropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}methyl)cyclopropane-1-carbonitrile, 5-[1-fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[3-(1H-pyrazol-1-yl)propoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(4-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(hydroxymethyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)piperidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(1H-pyrazol-1-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(piperidin-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(2,2-difluorocyclopropyl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(1-methylcyclopropyl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(3-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(2-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,2-difluoroethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2,2,2-trifluoroethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-7-(2-fluoroethoxy)-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropane-1-carbonitrile, 5-{1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-methylpropyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, {[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetonitrile, 5-[1-fluoro-3-hydroxy-7-(3-methylbutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1,8-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)azetidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)azetidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, (2E)-3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]prop-2-enenitrile, 5-[7-(2-cyclopropylethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2,2-difluorocyclopropyl)methoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclopropylmethoxy)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(oxolan-2-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclobutyloxy)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)oxy]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3-ethoxypropoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-tert-butoxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[rac-(1R,2R)-2-ethylcyclopropyl]methoxy}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(4-methylpentyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(2,2-dimethylpropyl)pyrrolidin-1-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(1-chloro-3-hydroxypropan-2-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(cyclopropyloxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(4-methyl-1H-imidazol-2-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(azetidin-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(5-methoxythiophen-2-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, [8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]acetonitrile, 5-[1-fluoro-3-hydroxy-7-(methoxymethyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3-methyloxetan-3-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{4-bromo-7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{4-bromo-7-[1-(cyclopropanesulfonyl)-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3S)-pyrrolidin-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3R)-pyrrolidin-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(8-chloro-1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(3,3-difluorocyclobutyl)methoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-cyclopropyl-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(4-chloro-1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(E)-2-cyclopropylethenyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1E)-4-methylpent-1-en-1-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(pentamethylphenyl)ethenyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(4-bromo-1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(2-cyclopropylethyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1E)-3-methoxyprop-1-en-1-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-ethoxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3-methoxypropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(1,1-dioxo-1λ 6 -thian-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(oxan-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(cyclopropylmethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]methyl}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[methyl(2-methylpropyl)amino]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(oxolan-2-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(oxolan-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)piperidin-4-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(pyrrolidin-2-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)piperidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(difluoromethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(pyrrolidin-3-yl)methyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,5-dihydrofuran-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3,6-dihydro-2H-pyran-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,5-dihydro-1H-pyrrol-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(pyridin-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(azetidin-3-yl)methyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(2-cyclopropylethyl)-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ] 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}acetamide, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-N-methylbutanamide, N-ethyl-N'-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)urea, 5-{1-fluoro-3-hydroxy-7-[(oxan-3-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(1-chloro-3-hydroxypropan-2-yl)oxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(oxan-4-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(oxetan-3-yl)oxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3,7-dihydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-hydroxyethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-propoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(propan-2-yl)oxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, {[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}acetic acid, N-(2-cyclopropylethyl)-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ] 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetamide, N,N-diethyl-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetamide, 5-{1-fluoro-3-hydroxy-7-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidin-4-yl]oxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(oxolane-3-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(2-methoxyethanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(3,3,3-trifluoropropane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(3,3,3-trifluoropropane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-(1-Fluoro-3-hydroxy-7-{1-[(oxan-2-yl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(4,4,4-trifluorobutane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(butane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(1,4-dioxan-2-yl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-2,5-dihydro-1H-pyrrole-1-sulfonyl}pentanenitrile, 5-{1-fluoro-3-hydroxy-7-[1-(pentane-2-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(ethanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(propane-2-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)oxetane-3-sulfonamide, 5-[1-fluoro-3-hydroxy-7-(piperidin-4-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(2-methylpropane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-ethoxy-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,2-difluoroethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-1H-pyrazol-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[(3R)-1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidin-4-yl]amino}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-7-{[3-fluoro-1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(propane-2-sulfonyl)pyrrolidin-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(1,3-dimethyl-1H-pyrazole-4-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)ethanesulfonamide, 5-{1-fluoro-7-[1-(furan-3-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(3-methylbutane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(thiophene-3-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(benzenesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclobutanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, (2S)-2-amino-4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanoic acid methyl ester, 5-{7-[(3,5-dimethyl-1H-pyrazol-4-yl)methoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3,5-dimethyl-1H-pyrazol-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclohexylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 2-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6,2,5-Thiadiazolidin-2-yl)naphthalen-2-yl]-1H-imidazole-4-carbonitrile Further disclosed is a compound selected from the group consisting of: and pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof.

[0119] In some embodiments, a compound disclosed herein, e.g., Formula (I), Formula (II), or Formula (III), is formulated as a pharmaceutically acceptable composition comprising a disclosed compound and a pharmaceutically acceptable carrier.

[0120] In some embodiments, a compound disclosed herein, eg, Formula (I), Formula (II), or Formula (III), is selected from the compounds set forth in Table 1.

[0121] Table 1: Exemplary compounds of the present disclosure TIFF2025143330000050.tif204155TIFF2025143330000051.tif209155TIFF2025143330000052.tif213155TIFF2025143330000053.tif210155TIFF202 5143330000054.tif212155TIFF2025143330000055.tif209155TIFF2025143330000056.tif219155TIFF2025143330000057.tif215155TIFF2025143330 000058.tif211155TIFF2025143330000059.tif218155TIFF2025143330000060.tif205155TIFF2025143330000061.tif225155TIFF2025143330000062. tif220156TIFF2025143330000063.tif225156TIFF2025143330000064.tif204156TIFF2025143330000065.tif219156TIFF2025143330000066.tif73156

[0122] Exemplary Compound Preparation Methods The compounds of the present disclosure may be better understood in connection with the following synthetic schemes and methods, which illustrate the means by which such compounds may be prepared. The compounds of the present disclosure may be prepared by a variety of synthetic procedures. Representative synthetic procedures are shown in Schemes 1-7, but are not limited thereto. The variable R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is defined as detailed herein, i.e., in the Summary of the Invention.

[0123] Scheme 1: Representative scheme for the synthesis of exemplary compounds of the present disclosure As shown in Scheme 1, compounds of Formula (1-9), Formula (1-10), Formula (1-11), and Formula (1-12) can be prepared from compounds of Formula (1-1). Compounds of Formula (1-1) can be alkylated with an optionally substituted benzyl bromide (e.g., benzyl bromide, 4-methoxybenzyl bromide, or 3,4-dimethoxybenzyl bromide) in a solvent such as N,N-dimethylformamide in the presence of a base such as cesium carbonate. Under these conditions, the carboxylic acid group also reacts to form a benzyl ester. This benzyl ester can be hydrolyzed with a base such as lithium hydroxide or sodium hydroxide in methanol or a mixture of methanol and water to give compounds of Formula (1-2). Compounds of formula (1-2) can be reacted under Curtius reaction conditions (diphenylphosphoryl azide, tert-butanol, triethylamine in heated toluene) to give compounds of formula (1-3). The tert-butoxycarbonyl moiety can be removed from compounds of formula (1-3) by treatment with heated diethylenetriamine to give compounds of formula (1-4). Compounds of formula (1-4) can be reacted with 2-bromoacetic acid esters of formula (1-5) in the presence of a base such as potassium carbonate in a warm solvent, such as, but not limited to, a mixture of N,N-dimethylformamide and water, to give compounds of formula (1-6). Compounds of formula (1-6) can then be fluorinated with a reagent such as N-fluorobenzenesulfonimide (NFSI) in a solvent such as tetrahydrofuran or Selectfluor® in optionally warmed N,N-dimethylformamide to give compounds of formula (1-7). Compounds of formula (1-7) can be reacted with chlorosulfonyl isocyanate and tert-butanol in the presence of a tertiary amine base such as triethylamine in a cold solvent such as dichloromethane, followed by treatment under acidic conditions such as trifluoroacetic acid in dichloromethane to remove the tert-butoxycarbonyl group to give compounds of formula (1-8).Compounds of formula (1-8) can be reacted with an alkoxide base, such as sodium methoxide in optionally warmed methanol or a mixture of methanol and water, or potassium tert-butoxide in tetrahydrofuran, followed by quenching with an acid such as 1 M hydrochloric acid, to give compounds of formula (1-9) or (1-10). Compounds of formula (1-9) can be converted to compounds of formula (1-11) using water under cross-coupling reaction conditions, such as water in the presence of a precatalyst, RockPhos Pd G3, a base, cesium carbonate, and a warm solvent, N,N-dimethylformamide. The optionally substituted benzyl ether of compounds of formula (1-10) can be removed using conditions known to those skilled in the art and dependent on the particular benzyl ether. For example, the unsubstituted benzyl ether can be removed by treatment with boron trichloride in the presence of 1,2,3,4,5-pentamethylbenzene in dichloromethane at −60 to −80° C. to give compounds of formula (1-12), which are representative of compounds of formula (I).

[0124] Scheme 2: Representative scheme for the synthesis of exemplary compounds of the present disclosure As shown in Scheme 2 of TIFF2025143330000069.tif158128, compounds of formula (2-2), formula (2-4), formula (2-6), and formula (2-8) can be prepared from compounds of formula (1-9). Compounds of formula (1-9) can be reacted under C-cross-coupling reaction conditions. For example, using Suzuki reaction conditions, compounds of formula (1-9) can be coupled with compounds of formula (2-1), where A represents an alkene moiety, a cyclopropyl, or an aromatic or partially unsaturated ring. Reaction conditions for coupling a compound of formula (1-9) with a compound of formula (2-1) may include a catalyst (tetrakis(triphenylphosphine)palladium(0), 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, or [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride) and a base (sodium carbonate, potassium carbonate, or cesium carbonate) in heated dioxane, a mixture of dioxane and water, or a mixture of tetrahydrofuran and water. The optionally substituted benzyl ether protecting group can then be removed using conditions known to those skilled in the art and dependent on the particular benzyl ether. For example, the unsubstituted benzyl ether can be removed by treatment with boron trichloride in dichloromethane in the presence of 1,2,3,4,5-pentamethylbenzene at −60 to −80° C. to afford a compound of formula (2-2). Alternatively, unsubstituted benzyl ethers can be removed by treatment with hydrogen and a palladium catalyst in a solvent such as dioxane or tetrahydrofuran. Compounds of formula (2-2) or protected precursors may be further modified as known to those skilled in the art and as illustrated in the examples.

[0125] Compounds of formula (1-9) can be reacted under N-cross-coupling reaction conditions. For example, compounds of formula (1-9) can be coupled with compounds of formula (2-3) using Buchwald-Hartwig reaction conditions. For example, compounds of formula (1-9) and compounds of formula (2-3) can be coupled in a solvent such as heated dioxane or tert-amyl alcohol in the presence of a precatalyst (BrettPhos Pd G3 or RuPhos Pd G3) or catalyst (palladium(II) acetate), ligand (BrettPhos, RuPhos, or Xantphos), and base (sodium tert-butoxide or cesium carbonate). Subsequently, the optionally substituted benzyl ether protecting group can be removed as described above to give compounds of formula (2-4) (wherein NR 2-1 R 2-2 is R 2 Compounds of formula (2-4) or protected precursors may be further modified as known to those skilled in the art and as illustrated in the examples.

[0126] Compounds of formula (1-9) can be reacted under O-cross-coupling reaction conditions. For example, compounds of formula (1-9) can be coupled with compounds of formula (2-5) using cross-coupling reaction conditions. For example, compounds of formula (1-9) and (2-5) can be coupled in a solvent such as heated N,N-dimethylformamide in the presence of a pre-catalyst, RockPhos Pd G3, and a base, cesium carbonate. The optionally substituted benzyl ether protecting group can then be removed as described above to give compounds of formula (2-6), where OR 2-3 is R 2 Compounds of formula (2-6) or protected precursors may be further modified as known to those skilled in the art and as illustrated in the examples.

[0127] Compounds of formula (1-9) can be reacted under C-cross-coupling reaction conditions. For example, compounds of formula (1-9) can be reacted with compounds of formula (2-7) (wherein R 2-4is R beyond the allylic portion. 2 (representing the remaining moiety of the formula). Reaction conditions for coupling a compound of formula (1-9) with a compound of formula (2-7) may include a catalyst such as palladium(II) acetate, a phosphine ligand such as 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and a base such as a tertiary amine base, e.g., triethylamine, or cesium carbonate, in a solvent such as heated N,N-dimethylformamide or dioxane. The optionally substituted benzyl ether protecting group can then be removed as described above to provide a compound of formula (2-8). The compound of formula (2-8) or its protected precursor may be further modified as known to those skilled in the art and as illustrated in the examples.

[0128] Compounds of formula (2-2), formula (2-4), formula (2-6), or formula (2-8) are representative of compounds of formula (I) or are precursors of compounds of formula (I).

[0129] Scheme 3: Representative scheme for the synthesis of exemplary compounds of the present disclosure As shown in Scheme 3, compounds of formula (3-1) and formula (3-2) can be prepared from compounds of formula (1-11). 3-1 -LG 1 (In the formula, LG 1 is a leaving group such as chloro, bromo, iodo, or sulfonate, and R 3-1is an optionally substituted alkyl, an optionally substituted heterocyclyl, or an optionally substituted cycloalkyl. Alkylation conditions may include treatment with a base such as, but not limited to, cesium carbonate or sodium hydride in a solvent such as N,N-dimethylformamide, optionally heated. The optionally substituted benzyl ether protecting group can then be removed using conditions known to those skilled in the art and dependent on the particular benzyl ether. For example, the unsubstituted benzyl ether can be removed by treatment with boron trichloride in dichloromethane in the presence of 1,2,3,4,5-pentamethylbenzene at -60 to -80°C to give a compound of formula (3-1). The compound of formula (3-1) or the corresponding protected precursor may be further modified as known to those skilled in the art and as shown in the Examples. The group OR 3-1 is R 2 represents the ether portion of

[0130] An alternative preparation of compounds of formula (3-1) is to react compounds of formula (1-11) with compounds of formula R under Mitsunobu reaction conditions. 3-1 -OH(in the formula, R 3-1 is optionally substituted alkyl or optionally substituted cycloalkyl. Thus, a compound of formula (1-11) and a compound of formula R 3-1 Compounds of formula (3-1) can be treated with (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) and tri-n-butylphosphine in a solvent such as warm tetrahydrofuran. Subsequent removal of the benzyl protecting group as described above provides compounds of formula (3-1). Compounds of formula (3-1) or the corresponding protected precursors can be further modified as known to those skilled in the art and as shown in the examples.

[0131] Compounds of formula (1-11) can also be converted to compounds of formula (3-2). Compounds of formula (1-11) can be converted to compounds of formula (3-2) by addition of R 3-2 -NCO (wherein R3-2 is optionally replaced by C 1~6 The benzyl protecting group can then be removed as described above to give compounds of formula (3-2). 3-2 is R 2 The compound of formula (3-2) or the corresponding protected precursor may be further modified as known to those skilled in the art and as shown in the examples.

[0132] The compounds of formula (3-1) and formula (3-2) are representative of compounds of formula (I) or are precursors of compounds of formula (I).

[0133] Scheme 4: Representative scheme for the synthesis of exemplary compounds of the present disclosure As shown in Scheme 4, a compound of formula (4-4) can be prepared from a compound of formula (1-9). Compound (1-9) can be prepared by coupling one R B is another R B The compound of formula (1-9) can be reacted with a boron reagent of formula (4-1), such as bis(pinacolato)diboron, which is bonded to the boron group, to give a compound of formula (4-2). Reaction conditions for coupling a compound of formula (1-9) with a compound of formula (4-1) can include a catalyst ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex) and a base (potassium acetate or potassium carbonate) in heated dioxane. Subsequently, the compound of formula (4-2) can be converted to a compound of formula (4-3), where R 2-C represents an aromatic ring or a partially unsaturated ring, an alkyl group, or an alkylene group; LG 2is a leaving group such as iodine, bromine, or chlorine. Reaction conditions for coupling a compound of formula (4-4) with a compound of formula (4-3) may include a catalyst (tetrakis(triphenylphosphine)palladium(0), XPhos Pd G2, or meCgpPh Pd G3) and a base (sodium carbonate, potassium phosphate, or potassium carbonate) in a heated mixture of toluene and ethanol, or dioxane and water, or N-methyl-2-pyrrolidinone. The optionally substituted benzyl ether protecting group can then be removed using conditions known to those skilled in the art and dependent on the particular benzyl ether. For example, the unsubstituted benzyl ether can be removed by treatment with boron trichloride in dichloromethane in the presence of 1,2,3,4,5-pentamethylbenzene at −60 to −80° C. to provide a compound of formula (4-4). Compounds of formula (4-4) or the corresponding protected precursors may be further modified as known to those skilled in the art and as shown in the examples.

[0134] Compounds of formula (4-4) are representative of compounds of formula (I) or are precursors of compounds of formula (I).

[0135] Scheme 5: Representative scheme for the synthesis of exemplary compounds of the present disclosure As shown in Scheme 5, a compound of formula (5-3) can be prepared from a compound of formula (1-9). Compound (1-9) can be converted to a compound of formula (5-1) (wherein R PRis potassium trifluoroborate or a carboxylic acid moiety, and B represents an optionally substituted heterocyclyl or an optionally substituted alkyl. Conditions for coupling compounds of formula (1-9) with compounds of formula (5-1) include treatment with NiCl-dimethoxyethane adduct, a ligand (4,4'-di-tert-butyl-2,2'-dipyridyl), a base (cesium carbonate), and bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+); 2-(2-pyridyl)pyridine; and hexafluorophosphate in a solvent such as dioxane, optionally containing N,N-dimethylacetamide, in a 450 nm LED photoreactor. The optionally substituted benzyl ether protecting group can then be removed using conditions known to those skilled in the art and dependent on the particular benzyl ether. For example, the unsubstituted benzyl ether can be removed by hydrogenation in the presence of a palladium on carbon catalyst in tetrahydrofuran to give compounds of formula (5-3).

[0136] Alternatively, the compound of formula (5-1) can be converted to the compound of formula (5-2) (wherein PG 3 is (2-methoxyethoxy)methyl). One or both protecting groups can be deprotected by treatment with hydrochloric acid in dioxane to give compounds of formula (5-3).

[0137] Compounds of formula (5-3) or the corresponding protected precursors may be further modified as known to those skilled in the art and as shown in the examples.

[0138] Compounds of formula (5-3) are representative of compounds of formula (I) or are precursors to compounds of formula (I).

[0139] Scheme 6: Representative scheme for the synthesis of exemplary compounds of the present disclosure As shown in Scheme 6, a compound of formula (6-3) can be prepared from a compound of formula (6-1). 1 is a protecting group such as (2-methoxyethoxy)methyl, and PG 2 is an optionally substituted benzyl group or (2-methoxyethoxy)methyl) in a compound of formula (6-2) 6-1 is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocyclyl group. Conditions for coupling a compound of formula (6-1) with a compound of formula (6-2) are treatment with a catalyst (Pd SPhos G4) in heated N,N-dimethylacetamide. Optionally substituted benzyl ether protecting groups, if present, can be removed using conditions known to those skilled in the art and dependent on the particular benzyl ether. For example, the unsubstituted benzyl ether (PG 2 ) can be removed by hydrogenation in the presence of a palladium on carbon catalyst or by treatment with boron trichloride in dichloromethane to give compounds of formula (6-3). PG 1 or PG 2 When either of is a (2-methoxyethoxy)methyl group, either or both can be removed by treatment with an acid such as hydrochloric acid in dioxane to give compounds of formula (6-3). Compounds of formula (6-3) or the corresponding protected precursors may be further modified as known to those skilled in the art and as shown in the examples.

[0140] Compounds of formula (6-3) are representative of compounds of formula (I) or are precursors to compounds of formula (I).

[0141] Scheme 7: Representative scheme for the synthesis of exemplary compounds of the present disclosure As shown in Scheme 7, compounds of formula (2-2) can be prepared from compounds of formula (1-9) by the reverse synthetic sequence described in Scheme 2. In the first step, the optionally substituted benzyl moiety can be removed using conditions known to those skilled in the art and dependent on the particular benzyl ether. For example, unsubstituted benzyl ethers can be removed by treatment with boron trichloride in the presence of 1,2,3,4,5-pentamethylbenzene in dichloromethane at −60 to −80°C to give compounds of formula (7-1). Compounds of formula (7-1) can be reacted under C-cross-coupling reaction conditions. For example, Suzuki reaction conditions can be used to couple compounds of formula (7-1) with compounds of formula (2-1), where A represents an alkene moiety, a cyclopropyl group, or an aromatic or partially unsaturated ring. The corresponding boronic acid of the compound of formula (2-1) is also suitable for the cross-coupling reaction. Reaction conditions for coupling the compound of formula (7-1) with the compound of formula (2-1) may include a catalyst (1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride) and a base (sodium carbonate or potassium carbonate) in heated dioxane or a mixture of dioxane and water. The compound of formula (2-2) or the corresponding protected precursor may be further modified as known to those skilled in the art and as shown in the examples.

[0142] Compounds of formula (2-2) are representative of compounds of formula (I) or are precursors of compounds of formula (I).

[0143] Pharmaceutical Composition The present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III). In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In some embodiments, the compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III), is provided in the pharmaceutical composition in an effective amount. In some embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0144] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. Generally, such preparation methods include the step of bringing the disclosed compound ("active ingredient") into association with a carrier and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into a desired single- or multi-dosage unit. Pharmaceutical compositions may be formulated, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single-unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient to be administered to a subject, and / or a manageable fraction of such a dosage, e.g., one-half or one-third of such a dosage.

[0145] The relative amounts of a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III), pharmaceutically acceptable excipient, and / or any additional components in a pharmaceutical composition of the present disclosure will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. By way of example, the composition may contain from 0.1% to 100% (w / w) of a compound disclosed herein.

[0146] The term "pharmaceutically acceptable excipient" refers to a non-toxic carrier, adjuvant, diluent, or vehicle that does not impair the pharmacological activity of the compound being formulated. Pharmaceutically acceptable excipients useful in preparing the pharmaceutical compositions of the present disclosure are any pharmaceutically acceptable excipients well known in the art of pharmaceutical formulation, including inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Pharmaceutically acceptable excipients useful in preparing pharmaceutical compositions of the present disclosure include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffer substances such as phosphoric acid, glycine, sorbic acid, potassium sorbate, and the like; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, and the like; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulosic substances; polyethylene glycol; sodium carboxymethylcellulose; polyacrylic acid esters; waxes; polyethylene-polyoxypropylene block polymers; polyethylene glycol; and wool fat.

[0147] Compositions of the present disclosure can be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously, and intradermally), by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. In some embodiments, provided compounds or compositions can be administered intravenously and / or orally.

[0148] As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intraperitoneal, intralesional, and intracranial injection or infusion techniques. The compositions are preferably administered orally, subcutaneously, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present disclosure may be aqueous or oily suspensions. These suspensions can be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media.

[0149] The pharmaceutically acceptable compositions of the present disclosure may be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. For tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants, such as magnesium stearate, are also commonly added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When an aqueous suspension is required for oral use, the active ingredient is mixed with emulsifying and suspending agents. If desired, certain sweeteners, flavorings, or coloring agents may also be added. In some embodiments, the provided oral formulations are formulated for immediate release or sustained / delayed release. In some embodiments, the compositions are suitable for buccal or sublingual administration, including tablets, lozenges, and pastilles. The compounds disclosed herein may also be in microencapsulated form.

[0150] The compositions of the present disclosure may be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols for topical delivery via transdermal administration. Oral formulations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by the patient. Solid formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid formulations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. The compositions of the present disclosure may further contain components for sustained release and / or comfort. Such components include high molecular weight anionic mucomimetic polymers, gelling polysaccharides, and finely divided drug carrier matrices. These components are discussed in more detail in U.S. Patent Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760, the entire contents of which are incorporated herein by reference for all purposes. The compositions of the present disclosure may also be delivered as microspheres for sustained release in the body. For example, microspheres may be administered via intradermal injection of drug-containing microspheres that release the drug subcutaneously (see, e.g., Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995); as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or as oral microspheres (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, the formulations of the compositions of the present disclosure may be delivered using liposomes that fuse with or are endocytosed by, for example, using a receptor ligand bound to the liposome that binds to a cell's surface membrane protein receptor, resulting in endocytosis.Liposomes, particularly those that have target cell-specific receptor ligands on their surface or that otherwise preferentially target specific organs, can be used to target the delivery of the compositions of the present disclosure in vivo (see, for example, Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, J. Hosp. Pharm. 46: 1576-1587, 1989). The compositions of the present disclosure can also be delivered as nanoparticles.

[0151] Alternatively, the pharmaceutically acceptable compositions of the present disclosure may be administered in the form of suppositories for rectal administration.The pharmaceutically acceptable compositions of the present disclosure may also be administered topically, especially when the target of treatment includes areas or organs that are easily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract.Suitable topical formulations for each of these areas or organs are easily prepared.

[0152] In some embodiments, to prolong the effect of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a suspension of crystalline or amorphous material with poor water solubility. In this case, the absorption rate of the drug depends on its dissolution rate, which in turn may depend on the size and crystalline form of the crystals. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0153] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, one skilled in the art will understand that such compositions are generally suitable for administration to animals of all species. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and an ordinarily skilled veterinary pharmacologist can design and / or perform such modifications with routine experimentation.

[0154] The compounds provided herein, for example, compounds of Formula (I), Formula (II), or Formula (III), are generally formulated into unit dosage forms, for example, single unit dosage forms, for ease of administration and uniformity of dosage. However, it will be understood that the total daily usage amount of the compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any specific subject or organism will depend on various factors, including the severity of the disease and disorder being treated; the activity of the specific active ingredient used; the specific composition used; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and excretion rate of the specific active ingredient used; the duration of treatment; drugs used in combination with or incidentally used simultaneously with the specific active ingredient used; and similar factors well known in the medical field.

[0155] The exact amount of compound required to achieve an effective dose will vary from subject to subject, depending, for example, on the subject's species, age, and general condition, the severity of any side effects or disorders, the identity of the particular compound(s), the mode of administration, etc. A desirable dosage may be delivered three times daily, twice daily, once daily, every other day, once every three days, once weekly, once every two weeks, once every three weeks, or once every four weeks. In certain embodiments, a desirable dosage may be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more administrations).

[0156] It will be understood that the dosage ranges described herein provide guidance for administering the provided pharmaceutical compositions to adults. For example, the amount administered to a child or adolescent can be determined by a physician or person skilled in the art and may be less than or the same as the amount administered to an adult.

[0157] It will also be understood that the compounds or compositions disclosed herein may be administered in combination with one or more additional agents. The compounds or compositions may be administered in combination with additional agents that improve their bioavailability, reduce and / or alter their metabolism, inhibit their excretion, and / or alter their biodistribution. It will also be understood that the treatments used may achieve the desired effect for the same disorder and / or the treatments used may achieve different effects.

[0158] The compound or composition may be administered simultaneously with, prior to, or subsequent to one or more additional agents, which may be useful, for example, as a combination therapy. The agents include therapeutically active agents. The agents also include prophylactically active agents. Each additional agent may be administered at a dosage and / or time schedule determined for that agent. The additional agents may also be administered together with each other and / or with the compounds or compositions described herein in a single administration, or separately in different doses. The particular combination employed in the regimen will take into consideration the compatibility of the compound of the present invention with the additional agents and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, additional agents utilized in combination should be utilized at levels that do not exceed the levels utilized individually. In some embodiments, the levels utilized in combination will be lower than the levels utilized individually.

[0159] Exemplary additional agents include, but are not limited to, antiproliferative agents, anticancer agents, antidiabetic agents, anti-inflammatory agents, immunosuppressants, and pain relievers. Agents include small organic molecules such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration listed in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules bound to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0160] Pharmaceutical compositions provided by the present disclosure include compositions in which the active ingredient (e.g., a compound described herein, including any embodiment or example) is contained in a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the disease being treated. Such compositions, when administered in a method of treating a disease, contain an amount of active ingredient effective to achieve the desired result, e.g., inhibiting the activity of a target molecule (e.g., PTPN2 and / or PTPN1) and / or reducing, eliminating, or slowing the progression of symptoms of the disease. Determination of a therapeutically effective amount of a compound disclosed herein is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein.

[0161] The dosage and frequency (single or multiple administrations) administered to a mammal may vary depending on a variety of factors, such as whether the mammal is suffering from another disease and the route of administration; the recipient's body size, age, sex, health, weight, body mass index, and diet; the nature and extent of symptoms of the disease being treated, the type of concurrent therapy, complications from the disease being treated, or other health-related issues. Other therapeutic regimens or agents may be used in combination with the methods, compounds, and compositions disclosed herein. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the capabilities of one of ordinary skill in the art.

[0162] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. The target concentration will be the concentration of active compound(s) that can achieve the methods described herein, as measured using methods described herein or known in the art.

[0163] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring the effectiveness of the compound and adjusting the dosage upward or downward, as described above. Adjusting the dosage to achieve maximum efficacy in humans based on the above and other methods is well within the capabilities of a person of ordinary skill in the art.

[0164] Dosage can vary depending on the patient's requirements and the compound used. In the context of the present disclosure, the dose administered to a patient should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the presence, nature, and extent of any adverse side effects. Determining the dosage appropriate for a particular situation is within the skill of a physician. Generally, treatment is initiated with smaller doses that are lower than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. Dosage amount and interval may be individually adjusted to provide a level of the administered compound that is effective for the particular clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the individual's condition.

[0165] The teachings provided herein can be used to design effective prophylactic or therapeutic treatment regimens that do not cause substantial toxicity yet are effective in treating the clinical symptoms exhibited by a particular patient. This design requires careful selection of active compounds by considering factors such as the potency of the compound, relative bioavailability, the patient's weight, the presence and severity of adverse side effects, the preferred mode of administration, and the toxicity profile of the selected agent.

[0166] The present disclosure also includes kits (e.g., pharmaceutical packs). The kits provided herein may be useful for the prevention and / or treatment of a disease (e.g., cancer, type 2 diabetes, obesity, a metabolic disease, or any other disease or condition described herein).

[0167] The provided kit may include a pharmaceutical composition or compound of the invention and a container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispenser package, or other suitable container). In some embodiments, the provided kit may optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound of the invention. In some embodiments, the pharmaceutical composition or compound of the invention provided in the container and the second container are mixed to form a single unit dosage form.

[0168] Thus, in one aspect, a kit is provided comprising a first container containing a compound disclosed herein. In certain embodiments, the kit is useful for preventing and / or treating a proliferative disease in a subject. In certain embodiments, the kit further comprises instructions for administering the disclosed compound to a subject to prevent and / or treat a disease described herein.

[0169] Treatment method The disclosure features compounds, compositions, and methods that include the compounds disclosed herein, e.g., compounds of Formula (I), Formula (II), or Formula (III). In some embodiments, the compounds, compositions, and methods disclosed herein are used to prevent or treat a disease, disorder, or condition. Exemplary diseases, disorders, or conditions include, but are not limited to, cancer, type 2 diabetes, metabolic syndrome, obesity, or metabolic disease.

[0170] cancer In some embodiments, the compounds disclosed herein, such as compounds of Formula (I), Formula (II), or Formula (III), are used to treat cancer. As used herein, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas (e.g., papillary adenocarcinoma), lymphomas, leukemias, melanomas, etc., including solid and lymphoid cancers, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, liver cancer, including hepatocellular carcinoma, lymphomas, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's lymphoma, small cell lymphoma, and large cell lymphoma), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), and / or multiple myeloma. In some further examples, "cancer" refers to lung cancer, breast cancer, ovarian cancer, epithelial ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, bile duct cancer, adrenal cancer, salivary gland cancer, bronchial cancer, oral cancer, cancer of the oral cavity or pharynx, laryngeal cancer, renal cancer, gynecological cancer, brain cancer, central nervous system cancer, peripheral nervous system cancer, blood tissue cancer, small intestine or appendix cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, or carcinoma.

[0171] As used herein, the term "cancer" refers to all types of cancer, neoplasms, or malignant tumors found in mammals, including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include lymphoma, B-cell lymphoma, heavy chain disease, alpha chain disease, gamma chain disease, mu chain disease, Waldenstrom's macroglobulinemia, benign monoclonal gammopathy, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., ER-positive, ER-negative, chemotherapy-resistant, Herceptin-resistant, HER2-positive, doxorubicin-resistant, tamoxifen-resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, acoustic neuroma, retinoblastoma, astrocytoma, craniopharyngioma, hemangioblastoma, pineal tumor, ependymoma, oligodendroglioma, meningioma, glioma, or melanoma. Further examples include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterine, or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, immune cell amyloidosis, ovarian cancer, rhabdomyosarcoma, primary thrombocytopenia, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, These include lymphoma, malignant carcinoid, bladder cancer, precancerous skin disorders, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, neoplasms of the endocrine or exocrine pancreas, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, Paget's disease of the nipple, filoblastoma, lobular carcinoma, ductal carcinoma, carcinoma of pancreatic stellate cells, carcinoma of hepatic stellate cells, or prostate cancer.

[0172] The term "leukemia" refers broadly to progressive, malignant diseases of the blood-forming organs, generally characterized by distorted proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemias are generally classified clinically based on (1) the duration and nature of the disease, i.e., acute or chronic; (2) the type of cell involved, i.e., myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) whether the number of abnormal cells in the blood is increased or not, i.e., leukemic or non-leukemic (subleukemic). Exemplary leukemias that can be treated with a compound, pharmaceutical composition, or method provided herein include, for example, chronic leukemia, acute nonlymphocytic leukemia, acute lymphocytic leukemia, B-cell chronic lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, leukemia cutis, embryonic cell leukemia, eosinophilic leukemia, erythroleukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia leukemia), lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloblastic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, polycythemia vera, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, or anaplastic cell leukemia.

[0173] The term "sarcoma" generally refers to a tumor composed of closely packed cells composed of a substance like embryonic connective tissue and embedded in a fibrous or homogeneous substance. Sarcomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include chondrosarcoma, fibrosarcoma, leiomyosarcoma, lymphosarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, endothelial sarcoma, stromal sarcoma, and sarcoma. sarcoma), Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer's astrocytic sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, osteosarcoma, parosteal osteosarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0174] The term "melanoma" is intended to mean a tumor arising from the melanocyte system of the skin and other organs. Melanomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0175] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, lobular carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatous carcinoma, adrenal cortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bile duct carcinoma, bladder carcinoma, breast cancer, Brenner's carcinoma, bronchoalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cervical carcinoma, cholangiocarcinoma, chordoma, choriocarcinoma, clear cell carcinoma, mucinous carcinoma, colon carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, armor carcinoma, skin carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, cystadenocarcinoma, ductal carcinoma, ductal carcinoma, carcinoma durum, fetal stage carcinoma, medullary carcinoma, endometrioid carcinoma, epidermoid carcinoma, epithelial carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, ulcer carcinoma, fibrous carcinoma, gelatiniforni gelatinous carcinoma, giant cell carcinoma, carcinoma giantocellulare, adenocarcinoma, granulosa cell carcinoma, hematoid carcinoma, hepatoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, hypermephroid infantile embryonal carcinoma, carcinoma in situ, intraepithelial carcinoma,carcinoma), Krompecher's carcinoma, Kulchitsky cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lung carcinoma, linpericarcinoma, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, muciparum carcinoma, mucocellular carcinoma, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes), upper pharyngeal carcinoma, non-papillary renal cell carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, ovarian carcinoma, pancreatic duct carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthocyte carcinoma, pultaceous carcinoma, renal cell carcinoma of the kidney, pre-cell carcinoma, carcinoma sarcomatodes, shinaida carcinoma, scirrhous carcinoma, penile carcinoma, sebaceous gland carcinoma, epithelioma, serous carcinoma, ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma carcinoma), elliptical cell carcinoma, spindle cell carcinoma, spongiosum carcinoma, squamous carcinoma, squamous cell carcinoma, string carcinoma, sweat gland carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional carcinoma, carcinoma tuberosum, tubular carcinoma, tuberous carcinomacarcinoma, undifferentiated carcinoma, verrucous carcinoma, or choriocarcinoma (carcinoma villosum).

[0176] In some embodiments, compounds disclosed herein, e.g., compounds of Formula (I), Formula (II), or Formula (III), are used to treat pancreatic cancer, breast cancer, multiple myeloma, and secretory cell cancer. For example, certain methods herein treat cancer by reducing, reducing, or preventing the onset, growth, metastasis, or progression of cancer. In some embodiments, methods described herein can be used to treat cancer by reducing or eliminating the symptoms of cancer. In some embodiments, compounds disclosed herein, e.g., compounds of Formula (I), Formula (II), or Formula (III), can be used as a single agent in a composition or in combination with another agent in a composition to treat cancers described herein (e.g., pancreatic cancer, breast cancer, multiple myeloma, and secretory cell cancer).

[0177] In some embodiments, the compounds (compounds described herein, e.g., a compound of Formula (I), Formula (II), or Formula (III)) and compositions (e.g., a composition comprising a compound described herein, e.g., Formula (I), Formula (II), or Formula (III)) are used in conjunction with a cancer immunotherapeutic agent (e.g., a checkpoint blockade antibody), e.g., to treat a subject (e.g., a human subject) suffering from a disease or disorder described herein (e.g., abnormal cell proliferation, e.g., cancer (e.g., a cancer described herein)). The methods described herein include administering a compound described herein, e.g., a compound of Formula (I), Formula (II), or Formula (III), and an immunotherapeutic agent to a subject with abnormal cell proliferation, such as cancer. Exemplary immunotherapeutic agents include, but are not limited to, the following:

[0178] In some embodiments, the immunotherapeutic agent is a compound (e.g., a ligand, an antibody) that inhibits an immune checkpoint pathway. In some embodiments, the immunotherapeutic agent is a compound that inhibits the indoleamine 2,3-dioxygenase (IDO) pathway. In some embodiments, the immunotherapeutic agent is a compound that stimulates the STING pathway. Cancer immunotherapy refers to the use of the immune system to treat cancer. Three groups of immunotherapies used to treat cancer include cell-based therapy, antibody-based therapy, and cytokine therapy. All groups utilize cancer cells to display subtly different structures (e.g., molecular structures; antigens, proteins, molecules, carbohydrates) on their surface that can be detected by the immune system. Cancer immunotherapeutics (e.g., anti-tumor immunotherapy or anti-tumor immunotherapeutics) include, but are not limited to, immune checkpoint antibodies (e.g., PD-1 antibody, PD-L1 antibody, PD-L2 antibody, CTLA-4 antibody, TIM3 antibody, LAG3 antibody, TIGIT antibody); and cancer vaccines (e.g., anti-tumor vaccines or vaccines based on neoantigens such as peptides or RNA vaccines).

[0179] Cell-based therapies (e.g., cancer vaccines) typically involve the removal of immune cells from a cancer-affected subject, either from the blood or tumor. Tumor-specific immune cells are activated, expanded, and then infused back into the cancer-affected subject, where they mount an immune response against the cancer. Cell types that can be used in this manner include, for example, natural killer cells, lymphokine-activated killer cells, cytotoxic T cells, dendritic cells, CAR-T therapy (e.g., chimeric antigen receptor T cells, which are T cells engineered to target specific antigens), TIL therapy (e.g., administration of tumor-infiltrating lymphocytes), TCR gene therapy, protein vaccines, and nucleic acid vaccines. An exemplary cell-based therapy is Provenge. In some embodiments, the cell-based therapy is CAR-T therapy.

[0180] Interleukin 2 and interferon alpha are examples of cytokines, which are proteins that regulate and modulate the behavior of the immune system.

[0181] Neoantigen-based cancer vaccines Neoantigens are antigens encoded by tumor-specific mutated genes. Technological advances have made it possible to probe immune responses to patient-specific neoantigens that arise as a result of tumor-specific mutations, and emerging data suggest that recognition of such neoantigens is a key factor in the activity of clinical immunotherapeutic agents. These observations suggest that neoantigen load may form a biomarker in cancer immunotherapy. Many novel therapeutic approaches have been developed to selectively enhance T cell reactivity against these antigens. One approach to targeting neoantigens is through cancer vaccines. These vaccines can be developed using peptides or RNA, e.g., synthetic peptides or synthetic RNA.

[0182] Antibody therapeutics are antibody proteins produced by the immune system that bind to target antigens on cell surfaces. Antibodies are generally encoded by an immunoglobulin gene or genes, or fragments thereof. In normal physiology, antibodies are used by the immune system to fight pathogens. Each antibody is specific for one or several proteins, and antibodies that bind to cancer antigens are used, for example, to treat cancer. Antibodies can specifically bind to antigens or epitopes (Fundamental Immunology, 3 rdEdition, Paul, WE, ed., Raven Press, NY (1993). Specific binding to a corresponding antigen or epitope occurs even in the presence of a heterogeneous population of proteins and other biologics. Specific binding of an antibody indicates that the antibody binds to its target antigen or epitope with substantially greater affinity than it would to an unrelated antigen. The relative difference in affinity is often at least 25% greater, more often at least 50% greater, and in most cases at least 100% greater. The relative difference can be, for example, at least 2-fold, at least 5-fold, at least 10-fold, at least 25-fold, at least 50-fold, at least 100-fold, or at least 1000-fold.

[0183] Exemplary antibody types include, but are not limited to, human, humanized, chimeric, monoclonal, polyclonal, single-chain, antibody-binding fragments, and diabodies. Upon binding to a cancer antigen, an antibody may induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, prevent a receptor from interacting with its ligand, or deliver a payload of chemotherapeutic agents or radiation, all of which can lead to cell death. Exemplary antibodies for the treatment of cancer include, but are not limited to, alemtuzumab, bevacizumab, brentuximab vedotin, cetuximab, gemtuzumab ozogamicin, ibritumomab tiuxetan, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, nivolumab, pembrolizumab, avelumab, durvalumab, and pidilizumab.

[0184] Checkpoint blockade antibodies The methods described herein, in some embodiments, include treating a human subject suffering from a disease or disorder described herein, the method comprising administering a composition comprising a cancer immunotherapy (e.g., an immunotherapeutic agent). In some embodiments, the immunotherapeutic agent is a compound (e.g., an inhibitor or antibody) that inhibits an immune checkpoint pathway. Under normal physiological conditions, immune checkpoint proteins maintain self-tolerance (e.g., prevent autoimmunity) and protect tissues from damage when the immune system is responding, for example, to infection by pathogens. Immune checkpoint proteins can be dysregulated by tumors as an important immune resistance mechanism (Pardoll, Nature Rev. Cancer, 2012, 12, 252-264). Agonists of costimulatory receptors or antagonists of inhibitory signals (e.g., immune checkpoint proteins) amplify antigen-specific T cell responses. Antibodies that block immune checkpoints do not target tumor cells directly, but generally target lymphocyte receptors or their ligands to enhance endogenous antitumor activity.

[0185] Exemplary checkpoint blockade antibodies include, but are not limited to, anti-CTLA-4, anti-PD-1, anti-LAG3 antibodies (e.g., antibodies against lymphocyte activation gene 3), and anti-TIM3 antibodies (e.g., antibodies against T-cell membrane protein 3). Exemplary anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab. Exemplary anti-PD-1 ligands include, but are not limited to, PD-L1 (e.g., B7-H1 and CD274) and PD-L2 (e.g., B7-DC and CD273). Exemplary anti-PD-1 antibodies include, but are not limited to, nivolumab (e.g., MDX-1106, BMS-936558, or ONO-4538), CT-011, AMP-224, pembrolizumab (trade name Keytruda), and MK-3475. Exemplary PD-L1-specific antibodies include, but are not limited to, BMS936559 (e.g., MDX-1105), MEDI4736, and MPDL-3280A. Exemplary checkpoint blockade antibodies also include, but are not limited to, IMP321 and MGA271.

[0186] Regulatory T cells (e.g., CD4+, CD25+, or T-reg) are also involved in monitoring the distinction between self and non-self (e.g., foreign) antigens and may be an important mechanism in suppressing immune responses in many cancers. T-reg cells can either arise from the thymus (e.g., "endogenous T-reg") or arise by differentiation of mature T cells in the setting of peripheral immune tolerance induction (e.g., "inducible T-reg"). Therefore, strategies that minimize the effects of T-reg cells would be expected to enhance immune responses against tumors.

[0187] IDO pathway inhibitors The IDO pathway regulates immune responses by suppressing T cell function and enabling local tumor immune escape. Expression of IDO by antigen-presenting cells (APCs) can deplete tryptophan, resulting in anergy of antigen-specific T cells and the recruitment of regulatory T cells. Some tumors even express IDO to protect themselves from the immune system. Compounds that inhibit IDO or the IDO pathway activate the immune system to attack cancer (e.g., a target tumor). Exemplary IDO pathway inhibitors include indoximod, epacadostat, and EOS200271.

[0188] STING pathway agonists Stimulator of interferon genes (STING) is an adaptor protein that plays a key role in activating type I interferons in response to cytosolic nucleic acid ligands. Evidence suggests that the STING pathway is involved in inducing antitumor immune responses. For example, activating the STING-dependent pathway in cancer cells may allow immune cells to infiltrate tumors and modulate anticancer immune responses. STING agonists are being developed as a class of cancer therapeutics. Exemplary STING agonists include MK-1454 and ADU-S100.

[0189] costimulatory antibody The methods described herein, in some embodiments, include treating a human subject suffering from a disease or disorder described herein, the method comprising administering a composition comprising a cancer immunotherapy (e.g., an immunotherapeutic agent). In some embodiments, the immunotherapeutic agent is a costimulatory inhibitor or antibody. In some embodiments, the methods described herein comprise depleting or activating anti-4-1BB, anti-OX40, anti-GITR, anti-CD27, and anti-CD40, and variants thereof.

[0190] The methods of the present disclosure contemplate single and multiple administrations of therapeutically effective amounts of the compounds described herein. Compounds, e.g., compounds described herein, can be administered at regular intervals depending on the nature, severity, and extent of the subject's disease. In some embodiments, the compounds described herein are administered in a single dose. In some embodiments, the compounds described herein are administered in multiple doses.

[0191] metabolic disease In some embodiments, compounds disclosed herein, e.g., compounds of Formula (I), Formula (II), or Formula (III), are used to treat metabolic disorders. As used herein, the term "metabolic disorder" refers to a disease or illness that affects a subject's metabolic processes. Exemplary metabolic disorders that can be treated by compounds disclosed herein, e.g., compounds of Formula (I), Formula (II), or Formula (III), include nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., type I diabetes, type II diabetes, or gestational diabetes), metabolic syndrome, phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease.

[0192] In some embodiments, compounds disclosed herein, e.g., compounds of Formula (I), Formula (II), or Formula (III), are used to treat metabolic diseases (e.g., metabolic diseases described herein) by reducing or eliminating symptoms of the disease. In some embodiments, the methods of treatment include reducing or eliminating symptoms including high blood pressure, high blood sugar levels, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, etc. In some embodiments, compounds disclosed herein, e.g., compounds of Formula (I), Formula (II), or Formula (III), can be used as a single agent in a composition or in combination with another agent in a composition to treat a metabolic disease.

[0193] infectious disease In some embodiments, the compounds disclosed herein, e.g., compounds of Formula (I), Formula (II), or Formula (III), are used to treat infectious diseases. Exemplary infectious diseases that can be treated by the compounds disclosed herein, e.g., compounds of Formula (I), Formula (II), or Formula (III), include bacterial infections, viral infections (e.g., herpes, shingles, influenza, the common cold, encephalitis), and parasitic infections.

[0194] In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III), is used to treat an infectious disease (e.g., an infectious disease described herein) by reducing or eliminating the symptoms of the disease. In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III), can be used as a single agent in a composition or in combination with another agent in a composition to treat an infectious disease.

[0195] Parasitic infections In some embodiments, the compounds disclosed herein, eg, compounds of Formula (I), Formula (II), or Formula (III), are used to treat parasitic infections.

[0196] In some embodiments, the compounds disclosed herein, e.g., compounds of Formula (I), Formula (II), or Formula (III), are used to treat parasitic infections by reducing or eliminating the symptoms of the disease. In some embodiments, the compounds disclosed herein, e.g., compounds of Formula (I), Formula (II), or Formula (III), can be used as a single agent in a composition or in combination with another agent in a composition to treat a parasitic infection.

[0197] immunosuppressive disease In some embodiments, the compounds disclosed herein, eg, compounds of Formula (I), Formula (II), or Formula (III), are used to treat immunosuppressive diseases.

[0198] In some embodiments, the compounds disclosed herein, e.g., compounds of Formula (I), Formula (II), or Formula (III), are used to treat immunosuppressive diseases by reducing or eliminating the symptoms of the disease. In some embodiments, the compounds disclosed herein, e.g., compounds of Formula (I), Formula (II), or Formula (III), can be used as a single agent in a composition or in combination with another agent in a composition to treat immunosuppressive diseases.

[0199] In some embodiments, the compounds disclosed herein are provided as pharmaceutical compositions comprising a disclosed compound, e.g., of Formula (I), Formula (II), or Formula (III), and a pharmaceutically acceptable excipient. In embodiments of the methods, a disclosed compound, e.g., of Formula (I), Formula (II), or Formula (III), is co-administered with a second agent (e.g., a therapeutic agent). In other embodiments of the methods, a disclosed compound, e.g., of Formula (I), Formula (II), or Formula (III), is co-administered with a second agent (e.g., a therapeutic agent), and the second agent is administered in a therapeutically effective amount.

[0200] Combination therapy The present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, e.g., a compound of Formula (I), Formula (II), or Formula (III), and a second agent (e.g., a second therapeutic agent). In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a second agent (e.g., a second therapeutic agent). In some embodiments, the second agent is an agent for treating cancer, a metabolic disease (e.g., type 2 diabetes or obesity), or a disease or disorder that responds favorably to treatment with a PTPN2 or PTP1B inhibitor.

[0201] The compounds described herein may be used in combination with another active agent known to be useful in the treatment of cancer, metabolic diseases (e.g., type 2 diabetes or obesity), or diseases or disorders that respond favorably to treatment with a PTPN2 or PTP1B inhibitor, with other such active agents, or with adjuvants that may not be effective alone but may contribute to the efficacy of the active agent.

[0202] In some embodiments, simultaneous administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the second active agent. Simultaneous administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, simultaneous administration may be achieved by co-formulation, i.e., preparing a single pharmaceutical composition containing both active agents. In other embodiments, the active agents may be formulated separately. In another embodiment, the active agents and / or adjunct agents may be combined or conjugated to each other. In some embodiments, the compounds described herein may be used in combination with an agent for treating cancer, a metabolic disease (e.g., type 2 diabetes or obesity), or a disease or disorder that responds favorably to treatment with a PTPN2 or PTP1B inhibitor. In embodiments, the second agent is an anti-cancer agent. In embodiments, the second agent is a chemotherapeutic agent. In embodiments, the second agent is an agent for treating a metabolic disease. In embodiments, the second agent is an antidiabetic agent. In some embodiments, the second agent is an anti-obesity agent.

[0203] anticancer drugs (Resverastatin phosphate sodium), BPR-OY-007 (National Health Research Institutes), and SSR-25041 1 (Sanofi), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin 2, α-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapeutic agents (e.g., m In, 90 Y, or 131anti-CD20 monoclonal antibodies conjugated to IFN-γ, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR) targeted therapies or therapeutics (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tyke rb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299 804, OSI-420 / desmethylerlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, and dasatinib.

[0204] "Chemotherapeutic" or "chemotherapeutic agent" is used according to its plain and ordinary meaning to refer to a chemical composition or compound having antineoplastic properties or the ability to inhibit the growth or proliferation of cells.

[0205] The compounds described herein may also be used in combination with immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin 2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), and radioimmunotherapeutic agents (e.g., m In, 90 Y, or 131 The antibody may also be co-administered with conventional immunotherapeutic agents, including, but not limited to, anti-CD20 monoclonal antibodies conjugated to I or the like.

[0206] In a further embodiment, the compounds described herein are optionally conjugated to an antibody against a tumor antigen: 47 Sc, 64 Cu, 67 Cu, 89 Sr, 86 Y, 87 Y, 90 Y, 105 Rh, m Ag, m In, 117m Sn, 149 Pm, 153 Sm, 166 Ho, 177 Lu, 186 Re, 188 Re, 211 At, and 212 It may also be co-administered with conventional radiotherapeutic agents, including but not limited to nuclides such as Bi. [Example]

[0207] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed as limiting the scope thereof in any way.

[0208] Synthesis protocol The compounds provided herein can be prepared from readily available starting materials using modifications to the specific synthetic protocols described below that would be known to one of ordinary skill in the art. Where general or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one of ordinary skill in the art by routine optimization procedures. General schemes for the preparation of exemplary compounds of the present invention are further described in the section entitled "Methods for Making Exemplary Compounds."

[0209] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups and their introduction and removal are described in Greene et al., Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and the references cited therein.

[0210] Abbreviation APCI: atmospheric pressure chemical ionization, DCI: desorption chemical ionization, DMSO: dimethyl sulfoxide, ESI: electrospray ionization, HPLC: high performance liquid chromatography, LC / MS: liquid chromatography / mass spectrometry, LED: light-emitting diode, MS: mass spectrometry, NMR: nuclear magnetic resonance, psi: pounds per square inch, TLC: thin layer chromatography.

[0211] Example 1: 5-{1-fluoro-3-hydroxy-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-1λ 6,2,5-Thiadiazolidine-1,1,3-trione (Compound 100) Example 1A: Benzyl 3-(benzyloxy)-7-bromonaphthalene-2-carboxylate A mixture of 7-bromo-3-hydroxy-2-naphthoic acid (100 g, 374 mmol) and cesium carbonate (366 g, 1123 mmol) in N,N-dimethylformamide (749 mL) was rapidly stirred at 23 °C for 5 min. Benzyl bromide (89.0 mL, 749 mmol) was then added, and the internal temperature was raised to 49 °C. After 90 min, the pale yellow mixture was poured into HO (1.5 L), and the resulting white precipitate was collected by filtration. The collected precipitate was washed successively with HO (3 × 1 L) and tert-butyl methyl ether / heptane (1:2, 2 × 300 mL), then dried to constant weight in vacuo (15 mbar) at 45 °C to give the title compound as an off-white solid (160.3 g, 358 mmol, 96% yield). MS (APCI + ) m / z 449 [M+H] + .

[0212] Example 1B: 3-(benzyloxy)-7-bromonaphthalene-2-carboxylic acid To a mixture of the product from Example 1A (150.1 g, 336 mmol), water (746 mL), and methanol (1.49 L) was added lithium hydroxide monohydrate (28.2 g, 671 mmol). The thick slurry was stirred with overhead mechanical stirring using an impeller and heated to an internal temperature of 70 °C. After 3 h, the mixture was cooled to room temperature in an ice bath, and 6 M HCl (168 mL) was added over 5 min, precipitating an off-white solid. The solid was collected by filtration, washed with HO (2 × 1 L), triturated with tert-butyl methyl ether (2 × 300 mL), and dried to constant weight in vacuo at 65 °C to give the title compound as a white solid (101.5 g, 284 mmol, 85% yield). MS (APCI+) m / z 358 [M+H] + .

[0213] Example 1C: 3-(benzyloxy)-7-bromonaphthalen-2-amine To a suspension of the product of Example 1B (101 g, 283 mmol) in toluene (794 mL) and tert-butanol (794 mL) was added triethylamine (41.8 mL, 300 mmol). The cloudy, pale yellow solution was heated to an internal temperature of 80 °C under nitrogen, and diphenylphosphoryl azide (64.4 mL, 300 mmol) was added dropwise over 90 min with the entire reaction system placed behind an explosion-proof wall. After 5 h, the reaction mixture was cooled to room temperature, diluted with HO (1.5 L), and extracted with ethyl acetate (2 × 400 mL). The combined organic layers were washed with saturated brine (2 × 150 mL), dried over sodium sulfate, filtered, and concentrated to give a white solid. This solid was subjected to hydrolysis without further purification.

[0214] To the crude intermediate was added diethylenetriamine (253 mL, 2.34 mol). The heterogeneous suspension was heated under nitrogen to an internal temperature of 130 °C, at which point a homogeneous dark orange solution formed. After 13 h, the mixture was cooled to room temperature in an ice bath, and HO (800 mL) was added slowly over 3 min, resulting in the precipitation of a yellow solid and a concomitant exotherm that caused the internal temperature to reach 53 °C. Once the heterogeneous suspension had cooled to room temperature, the crude solid was dissolved in CHCl (1.5 L) and the layers were separated. The aqueous layer was back-extracted with CHCl (3 × 150 mL). The combined organic layers were washed with saturated brine (3 × 100 mL), dried over sodium sulfate, filtered, and the volatiles removed in vacuo to give an orange solid. This solid was mixed with isopropanol (250 mL) to form a slurry, which was then filtered. The resulting solid was mixed again with isopropanol (2 x 100 mL) and isolated by filtration. The solid was dried at 35 °C under vacuum (13 mbar) to give the title compound as a white solid (68.48 g, 209 mmol, 74% yield over two steps). MS (APCI+) m / z 329 [M+H] + .

[0215] Example 1D: Methyl {[3-(benzyloxy)-7-bromonaphthalen-2-yl]amino}acetate To a mixture of the product from Example 1C (67.8 g, 207 mmol) and potassium carbonate (57.1 g, 413 mmol) in N,N-dimethylformamide (354 mL) and HO (1.861 mL, 103 mmol) was added 2-bromomethyl acetate (29.3 mL, 310 mmol). The suspension was stirred vigorously at room temperature for 5 minutes and then heated to an internal temperature of 60 °C. After 4 hours, the suspension was cooled to room temperature and partitioned between HO (400 mL) and ethyl acetate (400 mL). The aqueous layer was extracted with ethyl acetate (2 × 100 mL), and the combined organic layers were washed with saturated aqueous ammonium chloride (3 × 60 mL), dried over sodium sulfate, filtered, and concentrated to give a pale beige solid. This solid was triturated with heptane (100 mL) and the resulting beige solid was isolated by filtration, washed with more heptane (2 x 30 mL) and dried to constant weight in vacuo (15 mbar) at 35°C to give the title compound as an off-white solid (68.52 g, 171 mmol, 83% yield). MS (APCI + ) m / z 401[M+H] + .

[0216] Example 1E: Methyl {[3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]amino}acetate To a solution of the product of Example 1D (15 g, 37.5 mmol) in N,N-dimethylformamide (300 mL) at 2° C. was added a solution of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (15.93 g, 45.0 mmol) in N,N-dimethylformamide (100 mL) over 5 minutes. The resulting solution was stirred for 15 minutes and then quenched with a 0.33 M solution of sodium thiosulfate (300 mL) (exothermic). The mixture was diluted with ethyl acetate (150 mL) and saturated aqueous ammonium chloride (75 mL) and stirred at room temperature for 15 minutes. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 75 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (4 × 75 mL) and saturated brine (75 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo to give an orange solid. Ethyl acetate (30 mL) was added to the crude solid, and the mixture was sonicated for 30 seconds. Heptane (150 mL) was then added slowly via addition funnel over 15 minutes. The resulting yellow solid was collected by filtration and washed with 33% v / v ethyl acetate in heptane (3 × 60 mL). The solid was discarded, and the filtrate was concentrated in vacuo to give a yellow / orange solid, which was triturated with absolute ethanol (45 mL) heated to an internal temperature of 55 °C, stirred for 30 minutes, and then slowly cooled to room temperature. The resulting yellow solid was collected by filtration, washed with absolute ethanol (30 mL), and dried to constant weight in vacuo (15 mbar) at 50 °C to give the title compound (10.1 g, 24.25 mmol, 64.7% yield) as a pale yellow solid. TIFF2025143330000075.tif25146

[0217] Example 1F: {[3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl](sulfamoyl)amino}acetate methyl To a solution of chlorosulfonyl isocyanate (2.26 mL, 26.0 mmol) in dichloromethane (43.5 mL) at 0°C, tert-butanol (2.5 mL, 26.0 mmol) was added slowly so that the internal temperature remained below 10°C. After stirring for 30 minutes at 0°C, a previously prepared solution of the product of Example 1E (7.25 g, 17.34 mmol) and triethylamine (4.83 mL, 34.7 mmol) in dichloromethane (29.0 mL) was added slowly via addition funnel so that the internal temperature remained below 10°C. Upon completion of the addition, the addition funnel was rinsed with dichloromethane (12.5 mL). The resulting solution was stirred at 0°C for 30 minutes and then allowed to warm to room temperature. After 1 hour, the reaction mixture was quenched with HO (73 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 36 mL). The combined organic layers were washed with 1 M sodium hydrogen sulfate solution (2 x 73 mL). The aqueous washes were back-extracted with dichloromethane (DCM) (36 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give an orange foam which was used without purification. MS (APCI + ) m / z 541, 543 [M-tert-butyl + H] + .

[0218] To a solution of the crude intermediate above in dichloromethane (41 mL) was added trifluoroacetic acid (20 mL, 260 mmol), and the resulting dark solution was stirred at room temperature. After 30 min, the reaction mixture was quenched by the slow addition of saturated aqueous sodium bicarbonate (230 mL) via an addition funnel. The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 50 mL). The combined organic layers were concentrated to give an orange foam, which was suspended in dichloromethane (20 mL) and stirred for 5 min to give a slurry, which was then diluted with heptane (40 mL) added dropwise via an addition funnel. The resulting yellow solid was collected by filtration, washed with 25% v / v dichloromethane / heptane (2 × 20 mL), and dried to constant weight in vacuo (15 mbar) at 50 °C to give the title compound (7.5 g, 15.05 mmol, 87% yield). TIFF2025143330000076.tif25146

[0219] Example 1G: 5-[3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a room temperature solution of the product from Example 1F (24.14 g, 48.5 mmol) in tetrahydrofuran (THF) (241 mL), a solution of sodium methoxide (25 wt % in methanol, 16.65 mL, 72.8 mmol) was added via syringe, and the resulting solution was stirred at room temperature. After 20 minutes, the reaction mixture was quenched with 1 M hydrochloric acid (240 mL) and diluted with ethyl acetate (120 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 120 mL). The combined organic layers were washed with a 4:1 mixture of saturated brine and 1 M hydrochloric acid (120 mL), then dried over sodium sulfate, filtered, and concentrated to a total volume of 40 mL to give a dark red solution, which was diluted with dichloromethane (75 mL) and then concentrated to a total volume of 40 mL. The resulting yellow suspension was diluted with dichloromethane (72 mL) and then slowly diluted with heptane (72 mL). The suspension was sonicated for 30 seconds and stirred at room temperature for 5 minutes. The resulting white solid was collected by filtration, washed with 25% v / v dichloromethane / heptane (72 mL), and dried to constant weight at 50°C in vacuo (15 mbar) to give the title compound (16.4 g, 35.2 mmol, 72.5% yield). TIFF2025143330000077.tif18150

[0220] Example 1H: 5-[3-(benzyloxy)-1-fluoro-7-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione ammonium salt In a 500 mL round-bottom flask, the product from Example 1G (9 g, 19.34 mmol), RockPhos Pd G3 precatalyst (0.324 g, 0.387 mmol), and cesium carbonate (18.9 g, 58.0 mmol) were combined. The solids were placed under vacuum and stirred for 5 minutes. The flask was then filled with nitrogen and a previously prepared mixture of N,N-dimethylformamide (90 mL) and HO (1.045 mL, 58.0 mmol) was added. The resulting suspension was degassed by five vacuum / nitrogen refill cycles and then heated to an internal temperature of 80 °C. After 3 hours, the reaction mixture was cooled to room temperature and quenched by the slow addition of 1 M hydrochloric acid (100 mL) and diluted with ethyl acetate (100 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (4 × 50 mL). The combined aqueous washes were back-extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with a 4:1 mixture of saturated brine and 1 M hydrochloric acid (50 mL), then dried over sodium sulfate, filtered, and concentrated to give a viscous, dark oil. This crude oil was dissolved in acetonitrile (9 mL), and then tert-butyl methyl ether (180 mL) was added via a dropping funnel over 5 minutes with vigorous stirring. The resulting black solid was filtered off and washed with a 50% v / v tert-butyl methyl ether in ethyl acetate solution (2 × 45 mL). This solid was discarded, and the filtrate was concentrated in vacuo. The resulting dark oil was diluted with methanol (9 mL), followed by the addition of a 7 M ammonia in methanol solution (2.76 mL, 19.34 mmol). The resulting solution was diluted by slow addition of 50% v / v ethyl acetate / heptane (135 mL) via an addition funnel. The resulting solid was collected by filtration, washed with the cooled filtrate followed by 50% v / v ethyl acetate / heptane (45 mL), and dried to constant weight in vacuo (15 mbar) at 50 °C to give the title compound as the ammonium salt (6.33 g, 15.10 mmol, 78% yield). TIFF2025143330000078.tif18146

[0221] Example 1I: 5-{3-(benzyloxy)-1-fluoro-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione A mixture of 2-morpholinoethanol (1.69 g, 12.9 mmol), triethylamine (2.70 mL, 19.35 mmol), and anhydrous dichloromethane (71.7 mL) was cooled to 0 °C. Methanesulfonyl chloride (1.206 mL, 15.48 mmol) was then added dropwise over 5 min. After 10 min, the reaction mixture was warmed to room temperature and stirred for an additional 30 min. Most of the dichloromethane was removed in vacuo, and the resulting residue was diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate (2 × 30 mL), dried over sodium sulfate, filtered, and the volatiles were removed in vacuo at 29 °C to give 2-morpholinoethyl methanesulfonate (1.71 g, 8.17 mmol, 63.3% yield) as an amorphous yellow residue, which was used immediately in the subsequent reaction.

[0222] To a solution of the product from Example 1H (120 mg, 0.286 mmol) in N,N-dimethylformamide (954 μL) was added cesium carbonate (186 mg, 0.572 mmol). The suspension was stirred at room temperature for 5 minutes, followed by the addition of 2-morpholinoethyl methanesulfonate (114 mg, 0.544 mmol). The reaction mixture was heated to 40° C. After 80 minutes, the mixture was cooled to room temperature. The remaining cesium carbonate was filtered off and washed with dimethyl sulfoxide (1 × 500 μL) to give a dark yellow filtrate containing the crude product, which was purified by HPLC (Phenomenex® Luna® 10 μm C18(2) 100 Å, AXIA™ (00G-4253-U0-AX) column, 250 × 300 mm, flow rate 50 mL / min, 5-95% gradient of acetonitrile / buffer (0.025 M aqueous ammonium acetate)) to give the title compound (75.5 mg, 0.146 mmol, 51% yield). MS (APCI + ) m / z 516 [M+H] + .

[0223] Example 1J: 5-{1-fluoro-3-hydroxy-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione hydrochloride A mixture of the product of Example 1I (68.2 mg, 0.132 mmol) and pentamethylbenzene (58.8 mg, 0.397 mmol) in dichloromethane (661 μL) was cooled to an internal temperature of −76° C. under a dry nitrogen atmosphere. Subsequently, a 1 M solution of boron trichloride in CHCl (1.59 mL, 1.59 mmol) was added dropwise over 15 minutes, ensuring that the internal temperature did not exceed −72° C. The reaction mixture was warmed to 0° C. and stirred for 20 minutes. The mixture was then recooled to −76° C. and rapidly quenched with anhydrous methanol (2.67 mL, 66.1 mmol). The resulting colorless, homogeneous solution was allowed to warm to room temperature under nitrogen over 20 minutes. The volatiles were removed in vacuo to give an off-white solid, which was purified by HPLC (Phenomenex® Luna® 10 μm C18(2) 100 Å, AXIA™ (00G-4253-U0-AX) column, 250 × 300 mm, flow rate 50 mL / min, 5–95% gradient of acetonitrile / buffer (0.025 M aqueous ammonium acetate)) to give the title compound as the ammonium salt. This was suspended in methanol / ethyl acetate (1:1, 2 mL) and treated with a freshly prepared 1 M solution of anhydrous hydrogen chloride in ethyl acetate (66 μL, 0.066 mmol). After stirring at room temperature for 5 min, the volatiles were removed in vacuo (15 mbar), and the resulting white solid was dried at 35 °C to give the title compound (22.6 mg, 0.053 mmol, 40% yield). TIFF2025143330000079.tif25147

[0224] Example 2: 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 101) Example 2A: 3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ] 6 ,2,5-Thiadiazolidin-2-yl)naphthalen-2-yl]pyrrolidine-1-carboxylate tert-butyl ester The product of Example 14A (340 mg, 0.614 mmol) and tetrahydrofuran (THF) (1 mL) were added to wet 5% Pt / C (100 mg, 0.211 mmol) in a 20 mL Barnstead Hastelloy C reactor and stirred under 50 psi of hydrogen at 25° C. for 0.55 h. The reaction mixture was filtered, volatiles removed under reduced pressure, and the crude residue was subjected to column chromatography (SiO, dry-loaded with diatomaceous earth, 5% methanol / dichloromethane) to give the title compound as a white solid (164 mg, 0.295 mmol, 48% yield). TIFF2025143330000080.tif31148

[0225] Example 2B: 5-[3-(benzyloxy)-1-fluoro-7-(pyrrolidin-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione A solution of the product from Example 2A (164 mg, 0.295 mmol) and trifluoroacetic acid (1 mL, 12.98 mmol) in dichloromethane (2 mL) was stirred at room temperature for 1 hour. Volatiles were removed under reduced pressure. Dichloromethane (5 mL) was added, and the volatiles were again removed under reduced pressure. The residue was purified by preparative HPLC (Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm × 25 mm); a 30 to 100% gradient of acetonitrile (A) and 0.1% aqueous ammonium acetate (B) over 15 minutes at a flow rate of 25 mL / min) to give the title compound (77 mg, 0.169 mmol, 57% yield) as a white solid. TIFF2025143330000081.tif25148

[0226] Example 2C: 5-{3-(benzyloxy)-7-[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a solution of the product of Example 2B (77 mg, 0.169 mmol) in dichloromethane (5 mL) was added cyclopropanesulfonyl chloride (0.041 mL, 0.338 mmol) at room temperature, followed by N-ethyl-N-isopropylpropan-2-amine (0.089 mL, 0.507 mmol). The reaction mixture was stirred at room temperature overnight. Additional N-ethyl-N-isopropylpropan-2-amine (0.089 mL, 0.507 mmol) was added, resulting in a clear solution. After stirring at room temperature for 3 hours, the volatiles were removed under reduced pressure, and the crude product was subjected to column chromatography (SiO, dry-loaded with diatomaceous earth, 8% CHOH / CHCl) to give the title compound (80 mg, 0.143 mmol, 85% yield). MS (APCI-) m / z 558 [M−H] - .

[0227] Example 2D: 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione The product of Example 2C (80 mg, 0.143 mmol) and 1,2,3,4,5-pentamethylbenzene (63.6 mg, 0.429 mmol) were placed in a 50 mL round-bottom flask and flushed with nitrogen for 5 minutes. Dichloromethane (5 mL) was then added, and the heterogeneous suspension was cooled to −78° C. and equilibrated for 5 minutes. Subsequently, a 1 M solution of boron trichloride in dichloromethane (0.429 mL, 0.429 mmol) was added dropwise over 5 minutes. After 20 minutes, the reaction mixture was quenched with 9:1 dichloromethane:ethanol (1 mL) at −78° C. and then...

Claims

1. Formula (I) A compound represented by During the ceremony, R １ is hydrogen, halogen, C １～６ Alkyl, C ３～６ Cycloalkyl, —O—C １～６ Alkyl, —N(R ａ )-C １～６ Alkyl, and -C １～６ alkylene-5- to 6-membered heterocyclyl, １～６ Alkyl, C ３～６ Cycloalkyl, —O—C １～６ Alkyl, —N(R ａ )-C １～６ Alkyl, and -C １～６ The alkylene-5- to 6-membered heterocyclyl may optionally have, independently on one or more available carbons, R ｇ and optionally substituted by one, two, three or more substituents selected from -C １～６ When the alkylene-5- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R ｈ and optionally substituted by R ２ is hydrogen, hydroxyl, -CHF ２ , -CH ２ OH, -CH ２ CN, -CH ２ -O-C １～６ Alkyl, —CH ２ -N(R ａ )-C １～６ Alkyl, C ２～６ Alkyl, C ２～６ Alkenyl, —O—C １～６ Alkyl, —N(R ａ )-C １～６ Alkyl, —S(O) ｗ -C １～６ Alkyl, —C(O)—N(R ａ )-C １～６ Alkyl, —N(R ａ )-C(O)-C １～６ Alkyl, —O—C(O)—N(R ａ )-C １～６ Alkyl, —N(R ａ )-C(O)-OC １～６ Alkyl, -C ３～６ Cycloalkyl, —O—C ３～６ Cycloalkyl, C １～６ Alkylene-C ３～６ Cycloalkyl, —C １～６ Alkenylene-C ３～６ Cycloalkyl, —O—C １～６ Alkylene-C ３～６ cycloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, —O—C １～６ alkylene-5 to 6-membered heteroaryl, —O-4 to 6-membered heterocyclyl, —N(R ａ )-4 to 6-membered heterocyclyl, —C １～６ alkylene-4 to 6-membered heterocyclyl, and —O—C １～６ alkylene-4 to 6 membered heterocyclyl, provided that: ２ -O-C １～６ Alkyl, —CH ２ -N(R ａ )-C １～６ Alkyl, C ２～６ Alkyl, C ２～６ Alkenyl, —O—C １～６ Alkyl, —N(R ａ )-C １～６ Alkyl, —S(O) ｗ -C １～６ Alkyl, —C(O)—N(R ａ )-C １～６ Alkyl, —N(R ａ )-C(O)-C １～６ Alkyl, —O—C(O)—N(R ａ )-C １～６ Alkyl, —N(R ａ )-C(O)-OC １～６ Alkyl, -C ３～６ Cycloalkyl, —O—C ３～６ Cycloalkyl, —C １～６ Alkylene-C ３～６ Cycloalkyl, —C １～６ Alkenylene-C ３～６ Cycloalkyl, —O—C １～６ Alkylene-C ３～６ cycloalkyl, 5- to 6-membered heteroaryl, —O—C １～６ alkylene-5 to 6-membered heteroaryl, 4 to 6-membered heterocyclyl, —O-4 to 6-membered heterocyclyl, —N(R ａ )-4 to 6-membered heterocyclyl, —C １～６ alkylene-4 to 6-membered heterocyclyl, and —O—C １～６ The alkylene-4 to 6-membered heterocyclyl may optionally have, independently on one or more available carbons, R ｇ and optionally substituted by one, two, three or more substituents selected from 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, —N(R ａ )-4 to 6-membered heterocyclyl, —C １～６ alkylene-4 to 6-membered heterocyclyl, or —O—C １～６ When the alkylene-4 to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R ｈ and optionally substituted by Or, R １ and R ２ together with the atom to which they are attached form a 5-6 membered aryl or heteroaryl, provided that the aryl or heteroaryl are optionally each independently selected from halogen, hydroxyl, cyano, C １～６ Alkyl, and C １～６ and optionally substituted by one or more substituents selected from the group consisting of alkoxy, with the proviso that C １～６ Alkyl and C １～６ The alkoxy is optionally independently selected from R ｐ and optionally substituted by one, two, three or more substituents selected from R ３ is hydrogen, -C １～６ Alkyl, —O—C １～６ Alkyl, —N(R ａ )-C １～６ Alkyl, —S(O) ｗ -C １～６ Alkyl, —C(O)—N(R ａ )-C １～６ Alkyl, —N(R ａ )-C(O)-C １～６ Alkyl, and -C １～６ alkylene-4 to 6 membered heterocyclyl, with the proviso that -C １～６ Alkyl, —O—C １～６ Alkyl, —N(R ａ )-C １～６ Alkyl, —S(O) ｗ -C １～６ Alkyl, —C(O)—N(R ａ )-C １～６ Alkyl, —N(R ａ )-C(O)-C １～６ Alkyl, and -C １～６ The alkylene-4 to 6-membered heterocyclyl may optionally have, independently on one or more available carbons, R ｇ and optionally substituted by one, two, three or more substituents selected from -C １～６ When the alkylene-4 to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R ｈ and optionally substituted by R ４ is hydrogen, halogen, C １～６ Alkyl, C ３～６ cycloalkyl, and —C １～６ alkylene-4 to 6 membered heterocyclyl, １～６ Alkyl, C ３～６ cycloalkyl, and —C １～６ The alkylene-4 to 6-membered heterocyclyl may optionally have, independently on one or more available carbons, R ｇ and optionally substituted by one, two, three or more substituents selected from -C １～６ When the alkylene-4 to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R ｈ and optionally substituted by However, R １ , R ２ , R ３ , and R ４ At least one of them is not hydrogen, R ５ is hydrogen, halogen, C １～６ Alkyl, C ３～６ cycloalkyl, and —C １～６ alkylene-4 to 6 membered heterocyclyl, １～６ Alkyl, C ３～６ cycloalkyl, and —C １～６ The alkylene-4 to 6-membered heterocyclyl may optionally have, independently on one or more available carbons, R ｇ and optionally substituted by one, two, three or more substituents selected from -C １～６ When the alkylene-4 to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R ｈ and optionally substituted by R ６ is hydrogen, R ７ is hydrogen, R ｇ is independently for each occurrence hydrogen, halogen, hydroxyl, cyano, nitro, oxo, —C(O)OH, R ａ R ｂ N-, R ａ R ｂ N—C(O)—, R ａ R ｂ N-SO ｗ -, R ａ R ｂ NC(O)-N(R ａ ) -, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ Cycloalkyl, phenyl, C １～６ Alkylene-C ３～６ Cycloalkyl, —O—C １～６ Alkylene-C ３～６ cycloalkyl, —(CO)—(NR ａ )-C １～６ Alkylene-C ３～６ Cycloalkyl, C １～６ Alkoxy, C ３～６ Alkenyloxy, C ３～６ Alkynyloxy, C ３～６ Cycloalkoxy, C １～６ Alkyl-C(O)-, C １～６ Alkyl-O—C(O)—, C １～６ Alkyl-C(O)—O—, C １～６ Alkyl-S(O) ｗ -, C １～６ Alkyl-N(R ａ ) -, C １～６ Alkyl-N(R ａ )-C(O)-, C １～６ Alkyl-C(O)—N(R ａ ), C １～６ Alkyl-N(R ａ )-C(O)-N(R ａ ) -, C １～６ Alkyl-N(R ａ )-SO ｗ -, C ３～６ Cycloalkyl-N(R ａ )-SO ｗ -, C １～６ Alkyl-SO ｗ -N(R ａ ) -, C ３～６ Cycloalkyl-SO ｗ -N(R ａ )-, 4- to 6-membered heterocyclyl-SO ｗ -N(R ａ ) -, C １～６ Alkoxy-C(O)-N(R ａ ) -, C １～６ Alkyl-C(O)—N(R ａ )-C １～６ Alkyl-, C １～６ Alkyl-N(R ａ )-C(O)-C １～６ Alkyl-, -P(O)(C １～３ alkyl) ２ , and C １～６ Alkoxy-C １～６ alkyl-, wherein C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ Cycloalkyl, phenyl, C １～６ Alkylene-C ３～６ Cycloalkyl, —O—C １～６ Alkylene-C ３～６ cycloalkyl, —(CO)—(NR ａ )-C １～６ Alkylene-C ３～６ Cycloalkyl, C １～６ Alkoxy, C ３～６ Alkenyloxy, C ３～６ Alkynyloxy, C ３～６ Cycloalkoxy, C １～６ Alkyl-C(O)-, C １～６ Alkyl-O—C(O)—, C １～６ Alkyl-C(O)—O—, C １～６ Alkyl-S(O) ｗ -, C １～６ Alkyl-N(R ａ ) -, C １～６ Alkyl-N(R ａ )-C(O)-, C １～６ Alkyl-C(O)—N(R ａ ), C １～６ Alkyl-N(R ａ )-C(O)-N(R ａ ) -, C １～６ Alkyl-N(R ａ )-SO ｗ -, C ３～６ Cycloalkyl-N(R ａ )-SO ｗ -, C １～６ Alkyl-SO ｗ -N(R ａ ) -, C ３～６ Cycloalkyl-SO ｗ -N(R ａ )-, 4- to 6-membered heterocyclyl-SO ｗ -N(R ａ ) -, C １～６ Alkoxy-C(O)-N(R ａ ) -, C １～６ Alkyl-C(O)—N(R ａ )-C １～６ Alkyl-, C １～６ Alkyl-N(R ａ )-C(O)-C １～６ Alkyl-, -P(O)(C １～３ alkyl) ２ , and C １～６ Alkoxy-C １～６ The alkyl- is optionally independently selected from R ｐ and optionally substituted by one, two, three or more substituents selected from R ｈ is independently for each occurrence of C １～６ Alkyl, C ３～６ Alkenyl, C ３～６ Alkynyl, C ３～６ Cycloalkyl, —C １～６ Alkyl-C ３～６ Cycloalkyl, C １～６ Alkyl-S(O) ２ -, C ３～６ Cycloalkyl-S(O) ２ -, 4- to 6-membered heterocyclyl-S(O) ２ -, 4- to 6-membered heterocyclyl-C １～６ Alkyl-S(O) ２ -, 5- to 6-membered heteroaryl-S(O) ２ -, phenyl-S(O) ２ -, phenyl-C １～６ Alkyl-S(O) ２ -, C １～６ Alkyl-C(O)-, C １～６ Cycloalkyl-C(O)-, C １～６ Alkoxy-C(O)-, R ａ R ｂ N—C(O)—, R ａ R ｂ N-SO ２ -, and -P(O)(C １～３ alkyl) ２ and wherein C is selected from the group consisting of １～６ Alkyl, C ３～６ Alkenyl, C ３～６ Alkynyl, C ３～６ Cycloalkyl, —C １～６ Alkyl-C ３～６ Cycloalkyl, C １～６ Alkyl-S(O) ２ -, C ３～６ Cycloalkyl-S(O) ２ -, 4- to 6-membered heterocyclyl-S(O) ２ -, 4- to 6-membered heterocyclyl-C １～６ Alkyl-S(O) ２ -, 5- to 6-membered heteroaryl-S(O) ２ -, phenyl-S(O) ２ -, phenyl-C １～６ Alkyl-S(O) ２ -, C １～６ Alkyl-C(O)-, C １～６ Cycloalkyl-C(O)-, C １～６ Alkoxy-C(O)-, R ａ R ｂ N—C(O)—, R ａ R ｂ N-SO ２ -, and -P(O)(C １～３ alkyl) ２ are optionally each independently R ｐ and optionally substituted by one, two, three or more substituents selected from R ｐ is independently for each occurrence halogen, hydroxyl, cyano, C １～６ Alkyl, C １～６ Alkoxy, C ３～６ cycloalkyl, 4- to 6-membered heterocyclyl, R ａ R ｂ N-, R ａ R ｂ N-carbonyl-, R ａ R ｂ N-SO ２ - and R ａ R ｂ N-carbonyl-N(R ａ )- is selected from the group consisting of R ａ and R ｂ is, independently for each occurrence, hydrogen, C １～６ Alkyl, and C ３～６ cycloalkyl, wherein C １～６ Alkyl is optionally, independently, halogen, cyano, oxo, hydroxyl, and C １～６ alkoxy (optionally substituted with 1, 2, or 3 fluorine atoms); Or, R ａ and R ｂ together with the nitrogen to which they are attached form a 4- to 6-membered heterocyclyl, wherein said heterocyclyl is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo, and hydroxyl; w is 0, 1, or 2; The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer, or isotopically enriched variant thereof.

2. 10. The compound of claim 1, wherein one, two, three, or more hydrogen atoms of said compound may optionally be deuterium atoms, and all other atoms of said compound are present in their naturally occurring isotopic abundance ratios.

3. One, two, three, or more hydrogen atoms are optionally each independently R １ , R ２ , R ４ , R ５ , R ６ , R ７ , and R ｇ 3. The compound of claim 1 or 2, wherein the deuterium atoms are in one, two, three or more groups selected from:

4. R １ The compound according to any one of claims 1 to 3, wherein is selected from the group consisting of hydrogen, deuterium, chlorine, and fluorine.

5. R ２ is a 4- to 6-membered heterocyclyl, provided that R ２ optionally, on one or more available carbons, each independently R ｇ and when a 4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be substituted by 1, 2, or 3 substituents selected from R ｈ The compound according to any one of claims 1 to 4, which is optionally substituted by a substituent selected from the group consisting of:

6. R ２ is a 4- to 6-membered heterocyclyl, provided that R ２ optionally, on one or more available carbons, each independently hydrogen and C １～６ alkyl, and R ２ When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be hydrogen, C １～６ alkyl (optionally substituted with 1, 2, or 3 fluorine atoms), —C １～６ Alkyl-C ３～６ Cycloalkyl, C １～６ Cycloalkyl-C(O)-, C １～６ Alkyl-S(O) ２ -(optionally substituted by cyano, methoxy, or 1, 2, or 3 fluorine atoms), C ３～６ Cycloalkyl-S(O) ２ -, 4- to 6-membered heterocyclyl-S(O) ２ -, 4- to 6-membered heterocyclyl-C １～６ Alkyl-S(O) ２ -, 5- to 6-membered heteroaryl-S(O) ２ -, phenyl-S(O) ２ -, phenyl-C １～６ Alkyl-S(O) ２ - (Optionally R ａ R ｂ -N-), and -P(O)(C １～３ alkyl) ２ The compound according to any one of claims 1 to 5, which is optionally substituted with a substituent selected from the group consisting of:

7. R ２ but, The compound according to any one of claims 1 to 6, selected from the group consisting of:

8. R ２ is a 5- to 6-membered heteroaryl, with the proviso that R ２ optionally, on one or more available carbons, each independently R ｇ and R ２ When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be ｈ The compound according to any one of claims 1 to 4, which is optionally substituted by a substituent selected from the group consisting of:

9. R ２ is a 5- to 6-membered heteroaryl, with the proviso that R ２ are optionally each independently hydrogen, cyano, C on one or more available carbons; １～６ Alkyl, C １～６ Alkoxy, and —P(O)(C １～３ alkyl) ２ and R ２ When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be hydrogen, —C １～６ Alkyl-C ３～６ Cycloalkyl, and C ３～６ Cycloalkyl-S(O) ２ 9. The compound of claim 8, wherein the compound is optionally substituted with a substituent selected from the group consisting of:

10. R ２ but, 10. The compound of claim 8 or 9, selected from the group consisting of:

11. R ２ Ga-O-C １～６ alkylene-4 to 6-membered heterocyclyl, provided that R ２ optionally, on one or more available carbons, each independently R ｇ and R ２ When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be ｈ The compound according to any one of claims 1 to 4, which is optionally substituted by a substituent selected from the group consisting of:

12. R ２ Ga-O-C １～６ alkylene-4 to 6-membered heterocyclyl, provided that R ２ optionally, on one or more available carbons, each independently, hydrogen, halogen, and C １～６ alkyl, and R ２ When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be hydrogen, C １～６ Alkyl, and C １～６ Alkyl-S(O) ２ 12. The compound of claim 11, optionally substituted with a substituent selected from the group consisting of:

13. R ２ but, 13. The compound of claim 11 or 12, selected from the group consisting of:

14. R ２ Ga-O-C １～６ The compound according to any one of claims 1 to 4, which is alkylene-5 to 6-membered heteroaryl.

15. R ２ but, 15. The compound of claim 14 selected from the group consisting of:

16. R ２ But, -C ２～６ Alkyl, C ２～６ Alkenyl, and C ３～６ cycloalkyl, wherein R ２ are optionally each independently R ｇ The compound according to any one of claims 1 to 4, optionally substituted by one, two, three or more substituents selected from:

17. R ２ But, -C ２～６ Alkyl, C ２～６ Alkenyl, C ３～６ cycloalkyl, —C １～６ Alkylene-C ３～６ cycloalkyl, and —C １～６ Alkenylene-C ３～６ cycloalkyl, wherein R ２ are optionally each independently selected from cyano, chlorine, fluorine, hydroxyl, C １～６ Alkoxy, phenyl, and R ａ R ｂ 17. The compound of claim 16, optionally substituted with one, two, three, or more substituents selected from the group consisting of N-.

18. R ２ but, -CH ２ CHF ２ 、 18. The compound of claim 16 or 17, selected from the group consisting of:

19. R ２ Ga-O-C １～６ alkyl, provided that R ２ are optionally each independently R ｇ The compound according to any one of claims 1 to 4, optionally substituted by one, two, three or more substituents selected from:

20. R ２ Ga-O-C １～６ alkyl, provided that R ２ are optionally each independently selected from cyano, deuterium, chlorine, fluorine, hydroxyl, oxo, C １～６ Alkoxy, C ３～６ Cycloalkoxy, —O—C １～６ Alkylene-C ３～６ cycloalkyl, —(CO)—(NR ａ )-C １～６ Alkylene-C ３～６ Cycloalkyl, C １～６ Alkyl-O—C(O)—, R ａ R ｂ N- (However, R ｂ is optionally -OCH ３ or -OCF ３ and C １～６ Alkyl-N(R ａ ) -, R ａ R ｂ NC(O)-, -P(O)(C １～３ alkyl) ２ , C １～６ Alkyl-N(R ａ )-C(O)-, C １～６ Alkyl-N(R ａ )-C(O)-N(R ａ ) -, C １～６ Alkyl-SO ２ -N(R ａ ) -, C ３～６ Cycloalkyl-SO ２ -N(R ａ )-, and 4- to 6-membered heterocyclyl-SO ２ -N(R ａ 20. The compound of claim 19, optionally substituted with one, two, three, or more substituents selected from the group consisting of:

21. R ２ but, -OCH ３ ,-O4 ３ 、-OCF ３ 、-OCHF ２ ,-OCH ２ CH ３ 、 21. The compound of claim 19 or 20, selected from the group consisting of:

22. R ２ Ga-O-C ３～６ cycloalkyl or —O-4 to 6-membered heterocyclyl, provided that R ２ When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be ｈ The compound according to any one of claims 1 to 4, which is optionally substituted by a substituent selected from the group consisting of:

23. R ２ Ga-O-C ３～６ cycloalkyl or —O-4 to 6-membered heterocyclyl, provided that R ２ When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be １～６ Alkyl-SO ２ -N(R ａ )- and C ３～６ Cycloalkyl-SO ２ -N(R ａ 23. The compound of claim 22, optionally substituted with a substituent selected from the group consisting of:

24. R ２ but, 24. The compound of claim 22 or 23, selected from the group consisting of:

25. R ２ -N (R ａ )-C １～６ alkyl, provided that R ２ are optionally each independently R ｇ The compound according to any one of claims 1 to 4, optionally substituted by 1, 2 or 3 substituents selected from:

26. R ２ -N (R ａ )-C １～６ alkyl, provided that R ２ are optionally each independently selected from fluoro, —C(O)OH, cyano, oxo, R ａ R ｂ N-, C １～６ Alkoxy, phenyl, -C ３～６ Cycloalkyl, C ３～６ Cycloalkyl-SO ２ -N(R ａ )-, and -(CO)-(NR ａ )-C １～６ Alkylene-C ３～６ 26. The compound of claim 25, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of cycloalkyl.

27. R ２ but, -N(H)CH ３ 、 27. The compound of claim 25 or 26, selected from the group consisting of:

28. R ２ Ga-O-C １～６ Alkylene-C ３～６ cycloalkyl, provided that R ２ are optionally each independently R ｇ The compound according to any one of claims 1 to 4, optionally substituted by 1, 2 or 3 substituents selected from:

29. R ２ Ga-O-C １～６ Alkylene-C ３～６ cycloalkyl, provided that R ２ are optionally each independently selected from fluoro, hydroxyl, R ａ R ｂ N-, cyano, and C １～３ and optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, with the proviso that C １～３ Alkyl is optionally substituted with cyano and C １～３ 29. The compound of claim 28, optionally substituted with a substituent selected from the group consisting of alkoxy.

30. R ２ but, 30. The compound of claim 28 or 29, selected from the group consisting of:

31. R ２ is -O-C(O)-N(R ａ )-C １～６ The compound according to any one of claims 1 to 4, which is alkyl.

32. R ２ but 32. The compound of claim 31 , represented by:

33. R ２ -N (R ａ )-4 to 6-membered heterocyclyl, provided that R ２ When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be ｈ The compound according to any one of claims 1 to 4, which is optionally substituted by a substituent selected from the group consisting of:

34. R ２ -N (R ａ )-4 to 6-membered heterocyclyl, provided that R ２ When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be １～６ Alkyl-SO ２ -N(R ａ )- and C ３～６ Cycloalkyl-SO ２ -N(R ａ 34. The compound of claim 33, optionally substituted with a substituent selected from the group consisting of:

35. R ２ but, 35. The compound of claim 33 or 34, selected from the group consisting of:

36. R ２ Ga-C １～６ alkylene-4 to 6-membered heterocyclyl, provided that R ２ When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be ｈ The compound according to any one of claims 1 to 4, which is optionally substituted by a substituent selected from the group consisting of:

37. R ２ Ga-C １～６ alkylene-4 to 6-membered heterocyclyl, provided that R ２ When contains a substitutable ring nitrogen atom, the ring nitrogen atom may optionally be １～６ Alkyl, C １～６ Alkyl-SO ２ -N(R ａ ) - and C ３～６ Cycloalkyl-SO ２ -N(R ａ )-, with the proviso that C １～６ 37. The compound of claim 36, wherein the alkyl is optionally substituted with 1, 2, or 3 fluorine atoms.

38. R ２ but, 38. The compound of claim 36 or 37, selected from the group consisting of:

39. R ２ but, -CHF ２ 、-CH ２ OH、-H ２ OCH ３ 、-CH ２ CN、-OH、 The compound according to any one of claims 1 to 4, selected from the group consisting of:

40. R １ and R ２ 10. The compound of claim 1, wherein together with the atoms to which they are attached form a 5-membered heteroaryl.

41. R １ and R ２ together with the atoms to which they are attached form a furanyl.

42. A compound described in claim 40 or 41, represented by:

43. R ３ The compound of any one of claims 1 to 42, wherein is hydrogen.

44. R ４ The compound of any one of claims 1 to 43, wherein is hydrogen.

45. R ５ The compound of any one of claims 1 to 44, wherein is selected from the group consisting of hydrogen, deuterium, bromine, chlorine, and fluorine.

46. R ６ The compound of any one of claims 1 to 45, wherein is selected from the group consisting of hydrogen and deuterium.

47. R ７ The compound of any one of claims 1 to 46, wherein is selected from the group consisting of hydrogen and deuterium.

48. 48. The compound of any one of claims 1 to 47, wherein all atoms of said compound are present in their naturally occurring isotopic abundance ratios.

49. Formula (II) A compound represented by During the ceremony, X is —O— and —N(R ａ )- is selected from the group consisting of L is a linear or branched chain C １～６ is alkylene, R ２－ＩＩ is hydrogen, cyano, -NR ａ R ｂ , C １～２ Alkoxy, C ３～６ Cycloalkyl-SO ２ -N(R ａ ) -, C １～６ Alkyl-SO ２ -N(R ａ )-, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, and C ３～６ cycloalkyl, with the proviso that phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, and C ３～６ Cycloalkyl optionally has, on one or more available carbons, each independently, a halogen, a hydroxyl, or a —NR ａ R ｂ , C １～２ alkyl (optionally substituted with 1, 2, or 3 halogens), and C １～２ and alkoxy (optionally substituted by 1, 2, or 3 halogens), and when the 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted by C １～３ optionally substituted by alkyl, R ５ is selected from the group consisting of hydrogen, deuterium, and halogen; R ６ is selected from the group consisting of hydrogen and deuterium; R ７ is selected from the group consisting of hydrogen and deuterium; R ａ and R ｂ is, independently for each occurrence, hydrogen and C １～３ selected from the group consisting of alkyl, The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof.

50. X is —O—, —N(H)—, or —N(CH ３ 50. The compound of claim 49, wherein the compound is selected from the group consisting of:

51. L, wherein * and # are each selected from the group consisting of R ２－ＩＩ and represents a point of covalent attachment to X.

52. R ２－ＩＩ is hydrogen, cyano, -NH ２ , -N(CH ３ ) ２ , -OCH ３ , 52. The compound of any one of claims 49 to 51, selected from the group consisting of:

53. R ５ 53. The compound of any one of claims 49 to 52, wherein is selected from the group consisting of hydrogen, deuterium, and fluorine.

54. Formula (III) A compound represented by During the ceremony, X ＩＩＩ is a bond, -CH ２ -, -NR ａ -, -O-, -O-CH ２ - and -OCH ２ -CH ２ - selected from the group consisting of m is 1, 2, or 3; n is 1, 2, or 3; R １－ＩＩＩ is hydrogen, halogen, hydroxyl, cyano, -NR ａ R ｂ , C １～２ alkyl (optionally substituted with 1, 2, or 3 halogens), and C １～２ alkoxy (optionally substituted with 1, 2, or 3 halogens); R ２－ＩＩＩ is hydrogen, C １～４ Alkyl, —C(O)—C １～４ Alkyl, —C(O)—O—C １～４ Alkyl, —C(O)—N(R ａ )-C １～４ Alkyl, —S(O) ２ -C １～４ Alkyl, and —S(O) ２ -C ３～６ cycloalkyl, wherein C １～４ Alkyl, —C(O)—C １～４ Alkyl, —C(O)—O—C １～４ Alkyl, —C(O)—N(R ａ )-C １～４ Alkyl, —S(O) ２ -C １～４ Alkyl, and —S(O) ２ -C ３～６ Cycloalkyl optionally includes, independently at each occurrence, halogen, hydroxyl, cyano, -NR ａ R ｂ , C １～２ alkyl (optionally substituted with 1, 2, or 3 halogens), and C １～２ alkoxy (optionally substituted with 1, 2, or 3 halogens); R ５ is selected from the group consisting of hydrogen, deuterium, and halogen; R ６ is selected from the group consisting of hydrogen and deuterium; R ７ is selected from the group consisting of hydrogen and deuterium; R ａ and R ｂ is, independently for each occurrence, hydrogen and C １～３ selected from the group consisting of alkyl, The compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof.

55. X ＩＩＩ is a bond, -CH ２ , —O—, —NH—, and —O—CH ２ 55. The compound of claim 54, selected from the group consisting of:

56. R ２－ＩＩＩ is hydrogen, isopropyl, -CH ２ CF ３ , -S(O) ２ -CH ３ , and -S(O) ２ -cyclopropyl.

57. R ５ 57. The compound of any one of claims 54 to 56, wherein is selected from the group consisting of hydrogen, deuterium, and fluorine.

58. 5-{1-fluoro-3-hydroxy-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(pyrrolidin-3-yl)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-ylpropan-2-ylcarbamate, 5-(9-fluoro-7-hydroxynaphtho[2,1-b]furan-8-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(azetidin-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-methoxy(4- ２ H) naphthalen-2-yl](4,4- ２ H ２ ) -1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(methylamino)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(piperidin-4-yl)ethoxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-7-{[3-fluoro-1-(propan-2-yl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-7-[(3-fluoropyrrolidin-3-yl)methoxy]-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}pentanenitrile, 5-{1-fluoro-3-hydroxy-7-[2-(piperidin-1-yl)ethoxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(piperidin-4-yl)methoxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-3,3-dimethylpentanenitrile, 5-{7-[(3,3-dimethylbutyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1,4-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[( ２ H ３ ) methyloxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-methoxyethoxy)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-2,2-dimethylbutanenitrile, 5-{7-[2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[2-(dimethylamino)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)(4,4- ２ H ２ ) -1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}ethyl)cyclopropanesulfonamide, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)cyclopropanesulfonamide 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)azetidin-3-yl]amino}naphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanenitrile, [1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropyl]acetonitrile, 5-{7-[2-(dimethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1H-pyrazol-4-yl)methoxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-methylpropoxy)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-hydroxypropoxy)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, N-(cyclopropylmethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalene-2-carboxamide, 5-[1-fluoro-3-hydroxy-7-(2-{[2-(trifluoromethoxy)ethyl]amino}ethoxy)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(2-methoxyethyl)amino]ethoxy}naphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[3-(methylamino)propyl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(ethylamino)propyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[5-(dimethylphosphoryl)thiophen-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclopropylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(methylamino)ethoxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(ethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)amino]ethoxy}naphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(diethylphosphoryl)propoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3S)-3-hydroxybutoxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1,4-difluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3R)-3-hydroxybutoxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropyl-2-hydroxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(4S)-4-hydroxypentyl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(4-hydroxy-4-methylpentyl)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3-oxopentyl)oxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3-hydroxybutoxy)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, N-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-3-methylbutanamide, 5-[1-fluoro-3-hydroxy-7-(4,4,4-trifluorobutoxy)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 1-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)cyclopropane-1-carbonitrile, 5-(1-fluoro-3-hydroxy-7-{2-[1-(methoxymethyl)cyclopropyl]ethoxy}naphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[(cyclopropylmethyl)amino]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2,2-difluoropropyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3,3-dimethyl-4-(methylamino)butoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-phenylethyl)amino]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3-amino-3-methylbutoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(difluoromethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(dimethylphosphoryl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3,3,3-trifluoropropyl)amino]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3-methoxy-3-methylbutoxy)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropylpropoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-({2-[(propan-2-yl)oxy]ethyl}amino)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}naphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}butanenitrile, 5-[1-fluoro-3-hydroxy-7-(2-hydroxyethyl)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(4-amino-3,3-dimethylbutoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[2-(azetidin-1-yl)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]oxy}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-methoxyethyl)amino]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3,3,3-trifluoropropoxy)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}methyl)cyclopropane-1-carbonitrile, 5-[1-fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[3-(1H-pyrazol-1-yl)propoxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(4-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(hydroxymethyl)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)piperidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(1H-pyrazol-1-yl)ethoxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(piperidin-3-yl)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(2,2-difluorocyclopropyl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(1-methylcyclopropyl)ethoxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(3-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(2-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,2-difluoroethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2,2,2-trifluoroethoxy)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-7-(2-fluoroethoxy)-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropane-1-carbonitrile, 5-{1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-methylpropyl)amino]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, {[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetonitrile, 5-[1-fluoro-3-hydroxy-7-(3-methylbutoxy)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1,8-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)azetidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)azetidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, (2E)-3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]prop-2-enenitrile, 5-[7-(2-cyclopropylethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2,2-difluorocyclopropyl)methoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclopropylmethoxy)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(oxolan-2-yl)ethoxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclobutyloxy)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)oxy]ethoxy}naphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3-ethoxypropoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-tert-butoxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[rac-(1R,2R)-2-ethylcyclopropyl]methoxy}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(4-methylpentyl)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(2,2-dimethylpropyl)pyrrolidin-1-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(1-chloro-3-hydroxypropan-2-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(cyclopropyloxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(4-methyl-1H-imidazol-2-yl)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(azetidin-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(5-methoxythiophen-2-yl)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, [8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]acetonitrile, 5-[1-fluoro-3-hydroxy-7-(methoxymethyl)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3-methyloxetan-3-yl)methoxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{4-bromo-7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{4-bromo-7-[1-(cyclopropanesulfonyl)-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3S)-pyrrolidin-3-yl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3R)-pyrrolidin-3-yl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(8-chloro-1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(3,3-difluorocyclobutyl)methoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(7-cyclopropyl-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(4-chloro-1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(E)-2-cyclopropylethenyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1E)-4-methylpent-1-en-1-yl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(pentamethylphenyl)ethenyl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(4-bromo-1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(2-cyclopropylethyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1E)-3-methoxyprop-1-en-1-yl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-ethoxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3-methoxypropoxy)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(1,1-dioxo-1λ ６ -thian-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(oxan-3-yl)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(cyclopropylmethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]methyl}naphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl}naphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[methyl(2-methylpropyl)amino]ethoxy}naphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(oxolan-2-yl)methoxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(oxolan-3-yl)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)piperidin-4-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(pyrrolidin-2-yl)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)piperidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(difluoromethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(pyrrolidin-3-yl)methyl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,5-dihydrofuran-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3,6-dihydro-2H-pyran-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,5-dihydro-1H-pyrrol-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(pyridin-3-yl)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(azetidin-3-yl)methyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, N-(2-cyclopropylethyl)-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}acetamide, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-N-methylbutanamide, N-ethyl-N'-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)urea, 5-{1-fluoro-3-hydroxy-7-[(oxan-3-yl)methoxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(1-chloro-3-hydroxypropan-2-yl)oxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(oxan-4-yl)methoxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(oxetan-3-yl)oxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3,7-dihydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-hydroxyethoxy)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-propoxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(propan-2-yl)oxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, {[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}acetic acid, N-(2-cyclopropylethyl)-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetamide, N,N-diethyl-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetamide, 5-{1-fluoro-3-hydroxy-7-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidin-4-yl]oxy}naphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(oxolane-3-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(2-methoxyethanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(3,3,3-trifluoropropane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(3,3,3-trifluoropropane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{1-[(oxan-2-yl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}naphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(4,4,4-trifluorobutane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(butane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(1,4-dioxan-2-yl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-2,5-dihydro-1H-pyrrole-1-sulfonyl}pentanenitrile, 5-{1-fluoro-3-hydroxy-7-[1-(pentane-2-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(ethanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(propane-2-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)oxetane-3-sulfonamide, 5-[1-fluoro-3-hydroxy-7-(piperidin-4-yl)naphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(2-methylpropane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(7-ethoxy-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,2-difluoroethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-1H-pyrazol-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[(3R)-1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidin-4-yl]amino}naphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-7-{[3-fluoro-1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(propane-2-sulfonyl)pyrrolidin-3-yl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(1,3-dimethyl-1H-pyrazole-4-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)ethanesulfonamide, 5-{1-fluoro-7-[1-(furan-3-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(3-methylbutane-1-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(thiophene-3-sulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]naphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(benzenesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclobutanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, (2S)-2-amino-4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanoic acid methyl ester, 5-{7-[(3,5-dimethyl-1H-pyrazol-4-yl)methoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3,5-dimethyl-1H-pyrazol-4-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclohexylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 2-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-1H-imidazole-4-carbonitrile and pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof.

59. 59. A pharmaceutically acceptable composition comprising a compound of any one of claims 1 to 58 and a pharmaceutically acceptable carrier.

60. 60. The composition of claim 59, formulated for oral administration.

61. 100. A method of treating cancer in a patient in need thereof, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 58 in combination with an additional therapeutic agent.

62. 61. A method of treating cancer in a patient in need thereof, comprising administering to said patient an effective amount of the pharmaceutically acceptable composition of claim 59 or 60 in combination with an additional therapeutic agent.

63. 63. The method of claim 61 or 62, wherein the additional therapeutic agent is an immunotherapeutic agent.

64. 64. The method of claim 63, wherein the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody.

65. 100. A method of treating cancer in a patient in need thereof, comprising administering to said patient an effective amount of a compound of any one of claims 1-58.

66. 61. A method of treating cancer in a patient in need thereof, comprising administering to said patient an effective amount of the pharmaceutically acceptable composition of claim 59 or 60.

67. 61. A method for treating type 2 diabetes in a patient in need thereof, said method comprising administering to said patient an effective amount of a compound of any one of claims 1 to 58 or a composition of claim 59 or 60.

68. 61. A method for the treatment and / or management of obesity in a patient in need thereof, said method comprising administering to said patient an effective amount of a compound according to any one of claims 1 to 58 or a composition according to claim 59 or 60.

69. 61. A method for inhibiting further weight gain in an overweight or obese patient in need thereof, said method comprising administering to said patient an effective amount of a compound of any one of claims 1 to 58 or a composition of claim 59 or 60.

70. 61. A method of treating a metabolic disease in a patient in need thereof, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 58 or a composition of claim 59 or 60.

Images