Protein tyrosine phosphatase inhibitors and methods of using them

Abstract

Provided are compounds, compositions, and methods useful 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), and for treating related diseases, disorders, and conditions, such as cancer or metabolic diseases, that respond favorably to treatment with a PTPN1 or PTPN2 inhibitor. The present 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: TIFF2023055771000437.tif28128

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of priority of U.S. Provisional Application No. 62 / 688,226, filed on June 21, 2018, which is hereby incorporated by reference in its entirety.

Background Art

[0002] Background Cancer immunotherapy regimens targeting immune evasion mechanisms, including checkpoint blockade agents (e.g., PD - 1 / PD - L1 and CTLA - 4 blocking antibodies), have been shown to be effective in the treatment of various cancers and to dramatically improve outcomes in populations resistant to conventional therapies. However, due to incomplete clinical responses and the development of intrinsic or acquired resistance, the patient population that may benefit from checkpoint blockade agents remains limited.

[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 phosphorylation tyrosine-specific phosphatases that controls multiple cell regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, with the highest expression in hematopoietic cells and placental cells (Mosinger, B. Jr. et al., Proc Natl Acad Sci USA 89:499-503; 1992 (Non-Patent Document 1)). In humans, the expression of PTPN2 is post-transcriptionally regulated by the presence of two splice variants, namely, a 45 kDa form containing a nuclear localization signal at the C-terminus upstream of the splice junction, and a standard 48 kDa form with a C-terminal ER retention motif (Tillmann U. et al., Mol Cell Biol 14:3030-3040; 1994 (Non-Patent Document 2)). The 45 kDa isoform can passively penetrate into the cytosol under specific cell stress conditions. Both isoforms share an N-terminal phosphorylation tyrosine phosphatase catalytic domain. PTPN2 negatively regulates the signal transduction of non-receptor type tyrosine kinases (e.g., JAK1, JAK3), receptor type tyrosine kinases (e.g., INSR, EGFR, CSF1R, PDGFR), transcription factors (e.g., STAT1, STAT3, STAT5a / b), and Src family kinases (e.g., Fyn, Lck). As an important 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 homology with PTPN1 (also called PTP1B) and shares similar enzyme kinetics (Romsicki Y. et al., Arch Biochem Biophys 414:40-50; 2003 (Non-Patent Document 3)).

[0004] Data from loss-of-function in vivo gene screening using CRISPR / Cas9 genome editing in a mouse B16F10 transplantable tumor model indicate that deletion of the Ptpn2 gene in tumor cells improved the response to an immunotherapy regimen that added a PD-1 checkpoint blocker to a GM-CSF-secreting vaccine (GVAX) (Manguso R. T. et al., Nature 547:413-418; 2017 (Non-Patent Document 4)). Loss of Ptpn2 sensitized tumors to immunotherapy by enhancing the effects on antigen presentation and growth inhibition via IFNγ. By the same screening as above, it was also revealed that 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 under the selective pressure of immunotherapy. These observations indicate 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 the signaling of insulin and leptin, and is a major mechanism for downregulating the receptor signaling pathways of both insulin and leptin (Kenner K. A. et al., J Biol Chem 271: 19810-19816, 1996 (Non-Patent Document)). Animals deficient in 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 (Non-Patent Document 6)). Therefore, PTP1B inhibitors are expected to be useful for the treatment of type 2 diabetes, obesity, and metabolic syndrome.

Prior Art Documents

Non-Patent Documents

[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 271: 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, 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)). In some embodiments, disclosed herein are inhibitors of protein tyrosine phosphatases, such as PTPN2 and / or PTP1B, including the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III). In other embodiments, disclosed herein are methods of treating a disease or disorder, such as cancer, type 2 diabetes, obesity, a metabolic disorder, or any other disease, disorder, or condition that would benefit advantageously from treatment with a PTPN2 or PTP1B inhibitor, comprising administering an effective amount of a compound disclosed herein, for example, a compound of formula (I), formula (II), or formula (III).

[0008] For example, disclosed herein is a compound represented by formula (I) TIFF0007704787000001.tif27128, wherein R 1 is selected from the group consisting of 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, provided that 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 are each independently optionally substituted on one or more available carbons with one, two, three, or more substituents selected from R g , and -C 1~6When the alkylene-5- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, the ring nitrogen atom may optionally be substituted by R h and may be substituted by R 2 is hydrogen, hydroxyl, -CHF2, -CH2OH, -CH2CN, -CH2-O-C 1~6 alkyl, -CH2-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)-O-C 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, and is selected from the group consisting of, provided that -CH2-O-C 1~6 alkyl, -CH2-N(R a )-C 1~6 alkyl, C 2~6 alkyl, C 2~6 alkenyl, -O-C1~6 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)-O-C 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 Alkylene-4- to 6-membered heterocyclyl is optionally, on one or more available carbons, each independently substituted by one, two, three, or more substituents selected from R g and, when 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 Alkylene-4- to 6-membered heterocyclyl contains a ring nitrogen atom that is substitutable, that ring nitrogen atom is optionally substituted by R h , or or, R 1 and R 2forms a 5- to 6-membered aryl or heteroaryl together with the atoms to which they are attached, provided that the aryl or heteroaryl is optionally and independently substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1~6 alkyl, and C 1~6 alkoxy, provided that C 1~6 alkyl and C 1~6 alkoxy are optionally and independently substituted by one, two, three, or more substituents selected from R p , 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, provided 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 alkylene-4- to 6-membered heterocyclyl are optionally substituted by one, two, three, or more substituents selected from R g on one or more available carbons, and when -C 1~6 alkylene-4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, the ring nitrogen atom is optionally substituted by R h , R 4is hydrogen, halogen, C 1~6 alkyl, C 3~6 cycloalkyl, and -C 1~6 alkylene-4- to 6-membered heterocyclyl selected from the group consisting of, provided that C 1~6 alkyl, C 3~6 cycloalkyl, and -C 1~6 alkylene-4- to 6-membered heterocyclyl may each independently be substituted on one or more available carbons with 1, 2, 3, or more substituents selected from R g , and when -C 1~6 alkylene-4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, that ring nitrogen atom may optionally be substituted by R h , provided that at least one of R 1 , R 2 , R 3 , and R 4 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 selected from the group consisting of, provided that C 1~6 alkyl, C 3~6 cycloalkyl, and -C 1~6 alkylene-4- to 6-membered heterocyclyl may each independently be substituted on one or more available carbons with 1, 2, 3, or more substituents selected from R g , and when -C 1~6 alkylene-4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, that ring nitrogen atom may optionally be substituted by R h , R 6 is hydrogen, R 7 is hydrogen, R g is, for each occurrence independently, hydrogen, halogen, hydroxyl, cyano, nitro, oxo, -C(O)OH, R a R bN-, R a R b N-C(O)-, R a R b N-SO w -, R a R b N-C(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- selected from the group consisting of, provided that 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 3~6Cycloalkyl-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- may optionally be substituted by one, two, three or more substituents each independently selected from R p and R h is, independently for each occurrence, 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-, 4-6 membered heterocyclyl-S(O)2-, 4-6 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 N-C(O)-, R a R bN-SO2-, and -P(O)(C 1~3 alkyl)2 selected from the group consisting of, 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-, 4-6 membered heterocyclyl-S(O)2-, 4-6 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 N-C(O)-, R a R b N-SO2-, and -P(O)(C 1~3 alkyl)2 are each optionally and independently substituted by 1, 2, 3 or more substituents selected from R p and may be, R p is, for each occurrence independently, 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 )- selected from the group consisting of, R a and R b is, for each occurrence independently, hydrogen, C 1~6 alkyl, and C 3~6Selected from the group consisting of cycloalkyl, provided that C 1~6 alkyl is optionally and independently selected from one or more substituents selected from the group consisting of halogen, cyano, oxo, hydroxyl, and C 1~6 alkoxy (which may be optionally substituted by one, two, or three fluorine atoms), and or, R a and R b together with the nitrogen to which they are attached form a 4- to 6-membered heterocyclyl, provided that the heterocyclyl is optionally and independently selected from one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl, and w is 0, 1, or 2, The above compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer, or isotopically enriched variant thereof is disclosed.

[0009] In the present specification, a compound represented by formula (II) TIFF0007704787000002.tif27128, wherein In the formula, X is selected from the group consisting of -O- and -N(R a )-, L is a linear or branched C 1~6 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, provided that phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, and C 3~6Cycloalkyl may optionally be substituted on one or more available carbons independently with one, two, or three substituents selected from the group consisting of halogen, hydroxyl, -NR a R b 、 C 1~2 alkyl (optionally substituted with one, two, or three halogens), and C 1~2 alkoxy (optionally substituted with one, two, or three halogens), and when 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclyl contains a ring nitrogen atom that may be substituted, the ring nitrogen atom may optionally be substituted with C 1~3 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 each independently selected from the group consisting of hydrogen and C 1~3 alkyl for each instance of their presence, Also disclosed are the above compounds, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof.

[0010] In this specification, a compound represented by formula (III) TIFF0007704787000003.tif27128, wherein in the formula X III is selected from the group consisting of a bond, -CH2-, -NR a -, -O-, -O-CH2-, and -OCH2-CH2-, 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 by 1, 2, or 3 halogens), and C 1~2 alkoxy (optionally substituted by 1, 2, or 3 halogens), selected from the group consisting of: 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, selected from the group consisting of: provided that 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 is optionally, each independently, substituted by 1, 2, or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, -NR a R b , C 1~2 alkyl (optionally substituted by 1, 2, or 3 halogens), and C 1~2 alkoxy (optionally substituted by 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 each independently selected from the group consisting of hydrogen and C 1~3 alkyl for each instance of their presence; The above-mentioned compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is also disclosed.

[0011] As used herein, 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-methylpenta-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 -thia-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-thiazolidin-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-thiazolidin-2-yl)naphthalen-2-yl]oxy}acetamide, N,N-diethyl-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiazolidin-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-thiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidin-4-yl]oxy}naphthalen-2-yl)-1λ 6 ,2,5-thiazolidine-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-thiazolidine-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-thiazolidine-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-thiazolidine-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-(propan-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-methylpropan-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-(propan-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, 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 Compounds selected from the group consisting of, and pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof are further disclosed.

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

[0013] Also disclosed herein is a method of treating cancer in a patient in need thereof, the method 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 a further therapeutic agent. In some embodiments, the further therapeutic agent is an immunotherapy agent. For example, in some embodiments, the immunotherapy agent is selected from the group consisting of anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-CTLA-4 antibodies.

[0014] For example, also disclosed herein is a method of treating cancer in a patient in need thereof, the method 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] Also provided herein is a method of treating type 2 diabetes in a patient in need thereof, the method 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, as described herein, there is provided a method for treating and / or managing obesity in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound disclosed herein, such as a compound of formula (I), formula (II), or formula (III).

[0017] For example, as described herein, there is provided 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 a compound disclosed herein, such as a compound of formula (I), formula (II), or formula (III).

[0018] As described herein, there is further provided a method for treating a metabolic disease in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound disclosed herein, such as a compound of formula (I), formula (II), or formula (III).

[0019] In some embodiments, the method includes the treatment of cancer. In some embodiments, the cancer includes pancreatic cancer, breast cancer, multiple myeloma, melanoma, or cancer of secretory cells. In some embodiments, the method includes the treatment of a metabolic disease. In some embodiments, the metabolic disease includes 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] As described herein, there is also provided a composition for use in treating cancer in a patient in need thereof, the composition comprising a compound disclosed herein, such as a compound of formula (I), formula (II), or formula (III), in combination with a further therapeutic agent. In some embodiments, the further therapeutic agent is an immunotherapeutic agent. For example, in some embodiments, the immunotherapeutic agent is selected from the group consisting of anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-CTLA-4 antibodies.

[0021] For example, in the present specification, a composition for treating cancer of a patient in need of a composition for treating cancer, which comprises a compound disclosed herein, for example, a compound of formula (I), formula (II), or formula (III), is disclosed.

[0022] In the present specification, a composition for treating type 2 diabetes of a patient in need of a composition for treating type 2 diabetes, which comprises a compound disclosed herein, for example, a compound of formula (I), formula (II), or formula (III), is further provided.

[0023] For example, in the present specification, a composition for treating and / or managing obesity of a patient in need of a composition for treating and / or managing obesity, which comprises a compound disclosed herein, for example, a compound of formula (I), formula (II), or formula (III), is disclosed.

[0024] For example, in the present specification, a composition for suppressing further weight gain of an overweight or obese patient in need of a composition for suppressing further weight gain, which comprises a compound disclosed herein, for example, a compound of formula (I), formula (II), or formula (III), is disclosed.

[0025] In the present specification, a composition for treating a metabolic disorder of a patient in need of a composition for treating a metabolic disorder, which comprises a compound disclosed herein, for example, a compound of formula (I), formula (II), or formula (III), is further disclosed.

[0026] In some embodiments, the cancer includes pancreatic cancer, breast cancer, multiple myeloma, melanoma, or cancer of secretory cells. In some embodiments, the metabolic disorder includes 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.

[0027] Brief Description of the Sequence Listing The entire sequence listing entitled "CLS-014WO_SEQ_ID_List_ST25" containing SEQ ID NOs. 1 to SEQ ID NOs. 3 including the amino acid sequences disclosed in this specification is incorporated herein by reference. The above sequence listing has been filed as an ASCII text file attached hereto via EFS. The sequence listing was first created on June 13, 2019 and is 8 KB in size. [Invention 1001] Formula (I) A compound represented by TIFF0007704787000004.tif28128, wherein R 1 is selected from the group consisting of 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, provided that 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 are each independently optionally substituted on one or more available carbons by one, two, three or more substituents selected from R g , and when -C 1~6 alkylene-5- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, the ring nitrogen atom is optionally substituted by R h , R 2 is hydrogen, hydroxyl, -CHF2, -CH2OH, -CH2CN, -CH2-O-C 1~6 alkyl, -CH2-N(R a )-C 1~6 alkyl, C 2~6 alkyl, C 2~6 alkenyl, -O-C 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, -O-C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-O-C 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, selected from the group consisting of, provided that -CH2-O-C 1~6 Alkyl, -CH2-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)-O-C 1~6Alkyl, -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 Alkylene-4- to 6-membered heterocyclyl may, optionally, be independently substituted on one or more available carbons with one, two, three, or more substituents selected from R g , and 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 If alkylene-4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, the ring nitrogen atom may, optionally, be substituted by R h , or or, R 1 and R 2 together with the atom to which they are attached form a 5- to 6-membered aryl or heteroaryl, provided that the aryl or heteroaryl may, optionally, be independently substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1~6 alkyl, and C 1~6 alkoxy, provided that C 1~6 alkyl and C 1~6 alkoxy may, optionally, be independently substituted with one, two, three, or more substituents selected from R p , R 3 is hydrogen, -C 1~6Alkyl, -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 Selected from the group consisting of alkylene-4- to 6-membered heterocyclyl, provided 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 Alkylene-4- to 6-membered heterocyclyl may each independently be substituted, optionally on one or more available carbons, by one, two, three, or more substituents selected from R g , and, when alkylene-4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, that ring nitrogen atom may optionally be substituted by R 1~6 h h , R 4 Is selected from the group consisting of 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 Alkylene-4- to 6-membered heterocyclyl may each independently be substituted, optionally on one or more available carbons, by one, two, three, or more substituents selected from R g , 1~6When the alkylene-4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, the ring nitrogen atom may optionally be substituted by R h and may be substituted by provided that at least one of R 1 R 2 R 3 and R 4 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 alkylene-4- to 6-membered heterocyclyl may each independently be substituted by one, two, three, or more substituents selected from R g ; when the -C 1~6 alkylene-4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, the ring nitrogen atom may optionally be substituted by R h and may be substituted by R 6 is hydrogen, R 7 is hydrogen, R g is, for each occurrence independently, 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 N-C(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-C1~6 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 )-、4-6 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 1~6selected from the group consisting of alkyl, provided that 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 )-、4~6 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 and independently substituted by one, two, three, or more substituents selected from R p respectively, and may be substituted; R h is, independently for each occurrence, 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-SO2-, and -P(O)(C 1~3 Alkyl)2 and is selected from the group consisting of, 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- 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-SO2-, and -P(O)(C 1~3 alkyl)2 may optionally be independently substituted by one, two, three, or more substituents selected from R p and may be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, C 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-SO2-, and R a R b N-carbonyl-N(R a )-, and 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, provided that C 1~6 alkyl may optionally be independently substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, hydroxyl, and C 1~6 alkoxy (optionally substituted by one, two, or three fluorine atoms), and may be substituted by one or more substituents or, R a and R bforms a 4- to 6-membered heterocyclyl together with the nitrogen to which they are attached, provided that said heterocyclyl may optionally and independently be substituted by one or more substituents 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. [Invention 1002] 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 abundances, a compound of Invention 1001. [Invention 1003] one, two, three, or more hydrogen atoms may optionally and independently be deuterium atoms in one, two, three, or more groups selected from R 1 R 2 R 4 R 5 R 6 R 7 and R g respectively, a compound of Invention 1001 or 1002. [Invention 1004] R 1 is selected from the group consisting of hydrogen, deuterium, chlorine, and fluorine, a compound of any one of Inventions 1001 to 1003. [Invention 1005] R 2 is a 4- to 6-membered heterocyclyl, provided that R 2 may optionally be substituted on one or more available carbons by one, two, or three substituents independently selected from R g respectively, and when the 4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, said ring nitrogen atom may optionally be substituted by a substituent selected from R h respectively, a compound of any one of Inventions 1001 to 1004. [Invention 1006] R2 is a 4- to 6-membered heterocyclyl, provided that R 2 is, optionally, on one or more available carbons, each independently hydrogen and C 1~6 alkyl may be substituted by 1, 2, or 3 substituents selected from the group consisting of, and R 2 when containing a ring nitrogen atom that can be substituted, the ring nitrogen atom is, optionally, hydrogen, C 1~6 alkyl (which may optionally be substituted by 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- (which may optionally be 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- (which may optionally be substituted by R a R b N-), and -P(O)(C 1~3 alkyl)2 may be substituted by a substituent selected from the group consisting of, and any compound of the present invention from 1001 to 1005. [The present invention 1007] R 2 is TIFF0007704787000005.tif198148TIFF0007704787000006.tif55139 and is selected from the group consisting of, and any compound of the present invention from 1001 to 1006. [The present invention 1008] R 2 is 5- to 6-membered heteroaryl, provided that R 2 is, optionally, on one or more available carbons, each independently R g selected from may be substituted by 1, 2, or 3 substituents, and R 2When it contains a ring nitrogen atom that can be substituted, the ring nitrogen atom is optionally substituted by a substituent selected from R h and is any one of the compounds of the present invention 1001 to 1004, which may be substituted by a substituent selected from [The present invention 1009] R 2 is a 5- to 6-membered heteroaryl, provided that R 2 is optionally, on one or more available carbons, independently hydrogen, cyano, C 1~6 alkyl, C 1~6 alkoxy, and -P(O)(C 1~3 alkyl)2, and may be substituted by one, two, or three substituents selected from the group consisting of. When R 2 contains a ring nitrogen atom that can be substituted, the ring nitrogen atom is optionally substituted by a substituent selected from hydrogen, -C 1~6 alkyl-C 3~6 cycloalkyl, and C 3~6 cycloalkyl-S(O)2-, and is any one of the compounds of the present invention 1008, which may be substituted by a substituent selected from the group consisting of [The present invention 1010] R 2 is TIFF0007704787000007.tif47145, and is any one of the compounds of the present invention 1008 or 1009, which is selected from the group consisting of [The present invention 1011] R 2 is -O-C 1~6 alkylene-4- to 6-membered heterocyclyl, provided that R 2 is optionally, on one or more available carbons, independently R g and may be substituted by one, two, or three substituents selected from the group consisting of. When R 2 contains a ring nitrogen atom that can be substituted, the ring nitrogen atom is optionally substituted by a substituent selected from R h and is any one of the compounds of the present invention 1001 to 1004, which may be substituted by a substituent selected from the group consisting of [The present invention 1012] R 2 is -O-C 1~6 alkylene-4- to 6-membered heterocyclyl, provided that R 2is optionally substituted on one or more available carbons, independently of each other, by one, two, or three substituents selected from the group consisting of hydrogen, halogen, and C 1~6 alkyl, and when R 2 contains a ring nitrogen atom that can be substituted, the ring nitrogen atom is optionally substituted by a substituent selected from the group consisting of hydrogen, C 1~6 alkyl, and C 1~6 alkyl-S(O)2-, a compound of the present invention 1011. [The present invention 1013] R 2 is selected from the group consisting of TIFF0007704787000008.tif71132, a compound of the present invention 1011 or 1012. [The present invention 1014] R 2 is -O-C 1~6 alkylene-5- to 6-membered heteroaryl, a compound of any one of the present inventions 1001 to 1004. [The present invention 1015] R 2 is selected from the group consisting of TIFF0007704787000009.tif19128, a compound of the present invention 1014. [The present invention 1016] R 2 is -C 2~6 alkyl, C 2~6 alkenyl, and C 3~6 cycloalkyl, provided that R 2 is optionally, independently of each other, substituted by one, two, three, or more substituents selected from R g , a compound of any one of the present inventions 1001 to 1004. [The present invention 1017] R 2 is -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 selected from the group consisting of cycloalkyl, provided that R 2 is, optionally, each independently cyano, chlorine, fluorine, hydroxyl, C 1~6 alkoxy, phenyl, and R a R b N - and may be substituted by one, two, three, or more substituents selected from the group consisting of, the compound of the present invention 1016. [The present invention 1018] R 2 is -CH2CHF2, selected from the group consisting of TIFF0007704787000010.tif60147, the compound of the present invention 1016 or 1017. [The present invention 1019] R 2 is -O-C 1~6 alkyl, provided that R 2 is, optionally, each independently R g selected from and may be substituted by one, two, three, or more substituents, any of the compounds of the present invention 1001 to 1004. [The present invention 1020] R 2 is -O-C 1~6 alkyl, provided that R 2 is, optionally, each independently 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 - (provided that R b may be optionally substituted by -OCH3 or -OCF3), C 1~6 alkyl-N(R a )-, R a R bN-C(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 by one, two, three, or more substituents selected from the group consisting of: the compounds of the present invention 1019. [The present invention 1021] R 2 is -OCH3, -OCD3, -OCF3, -OCHF2, -OCH2CH3, TIFF0007704787000011.tif73150TIFF0007704787000012.tif116145, the compounds of the present invention 1019 or 1020. [The present invention 1022] R 2 is -O-C 3~6 cycloalkyl or -O-4- to 6-membered heterocyclyl, provided that when R 2 contains a ring nitrogen atom that can be substituted, the ring nitrogen atom can optionally be substituted by a substituent selected from R h , any of the compounds of the present invention 1001 to 1004. [The present invention 1023] R 2 is -O-C 3~6 cycloalkyl or -O-4- to 6-membered heterocyclyl, provided that when R 2 contains a ring nitrogen atom that can be substituted, the ring nitrogen atom can optionally be substituted by a substituent selected from the group consisting of C 1~6 alkyl-SO2-N(R a )- and C 3~6 cycloalkyl-SO2-N(R a )-, the compounds of the present invention 1022. [The present invention 1024] R 2 is a compound of the present invention 1022 or 1023 selected from the group consisting of TIFF0007704787000013.tif19128. [The present invention 1025] R 2 is -N(R a )-C 1~6 alkyl, provided that R 2 is optionally and independently substituted by 1, 2, or 3 substituents selected from R g any compound of the present invention 1001 - 1004. [The present invention 1026] R 2 is -N(R a )-C 1~6 alkyl, provided that R 2 is optionally and independently 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 and may be substituted by 1, 2, or 3 substituents selected from the group consisting of, a compound of the present invention 1025. [The present invention 1027] R 2 is -N(H)CH3, a compound of the present invention 1025 or 1026 selected from the group consisting of TIFF0007704787000014.tif66134. [The present invention 1028] R 2 is -O - C 1~6 alkylene - C 3~6 cycloalkyl, provided that R 2 is optionally and independently R gA compound of any one of Compounds 1001 to 1004 of the present invention, which may be substituted by 1, 2, or 3 substituents selected from . [Compound 1029 of the present invention] R 2 is -O-C 1~6 alkylene-C 3~6 cycloalkyl, provided that R 2 is optionally and each independently fluoro, hydroxyl, R a R b N-, cyano, and C 1~3 alkyl, and may be substituted by 1, 2, or 3 substituents selected from the group consisting of, provided that C 1~3 alkyl is optionally substituted by a substituent selected from the group consisting of cyano and C 1~3 alkoxy, a compound of Compound 1028 of the present invention. [Compound 1030 of the present invention] R 2 is TIFF0007704787000015.tif53140, a compound of Compound 1028 or 1029 of the present invention. [Compound 1031 of the present invention] R 2 is -O-C(O)-N(R a )-C 1~6 alkyl, a compound of any one of Compounds 1001 to 1004 of the present invention. [Compound 1032 of the present invention] R 2 is TIFF0007704787000016.tif13128, a compound of Compound 1031 of the present invention. [Compound 1033 of the present invention] R 2 is -N(R a )-4- to 6-membered heterocyclyl, provided that when R 2 contains a ring nitrogen atom that can be substituted, the ring nitrogen atom is optionally substituted by a substituent selected from R h , a compound of any one of Compounds 1001 to 1004 of the present invention. [Compound 1034 of the present invention] R 2 is -N(Ra ) - A 4- to 6-membered heterocyclyl, provided that when R 2 contains a ring nitrogen atom that can be substituted, the ring nitrogen atom is optionally substituted by a substituent selected from the group consisting of C 1~6 alkyl-SO2-N(R a )- and C 3~6 cycloalkyl-SO2-N(R a )-, of the compound of the present invention 1033. [The present invention 1035] R 2 is selected from the group consisting of TIFF0007704787000017.tif28128, of the compound of the present invention 1033 or 1034. [The present invention 1036] R 2 is -C 1~6 alkylene-4- to 6-membered heterocyclyl, provided that when R 2 contains a ring nitrogen atom that can be substituted, the ring nitrogen atom is optionally substituted by a substituent selected from R h , of any one of the compounds of the present invention 1001 to 1004. [The present invention 1037] R 2 is -C 1~6 alkylene-4- to 6-membered heterocyclyl, provided that when R 2 contains a ring nitrogen atom that can be substituted, the ring nitrogen atom is optionally substituted by a substituent selected from the group consisting of C 1~6 alkyl, C 1~6 alkyl-SO2-N(R a )-, and C 3~6 cycloalkyl-SO2-N(R a )-, and provided that C 1~6 alkyl is optionally substituted by 1, 2, or 3 fluorine atoms, of the compound of the present invention 1036. [The present invention 1038] R 2 is selected from the group consisting of TIFF0007704787000018.tif48128, of the compound of the present invention 1036 or 1037. [Invention 1039] R 2 is -CHF2, -CH2OH, -CH2OCH3, -CH2CN, -OH, a compound of any one of Inventions 1001 - 1004 selected from the group consisting of TIFF0007704787000019.tif14128. [Invention 1040] R 1 and R 2 forms a 5 - membered heteroaryl together with the atom to which they are attached, a compound of Invention 1001. [Invention 1041] R 1 and R 2 forms furanyl together with the atom to which they are attached, a compound of Invention 1040. [Invention 1042] represented by TIFF0007704787000020.tif27128, a compound of Invention 1040 or 1041. [Invention 1043] R 3 is hydrogen, a compound of any one of Inventions 1001 - 1042. [Invention 1044] R 4 is hydrogen, a compound of any one of Inventions 1001 - 1043. [Invention 1045] R 5 is selected from the group consisting of hydrogen, deuterium, bromine, chlorine, and fluorine, a compound of any one of Inventions 1001 - 1044. [Invention 1046] R 6 is selected from the group consisting of hydrogen and deuterium, a compound of any one of Inventions 1001 - 1045. [Invention 1047] R 7 is selected from the group consisting of hydrogen and deuterium, a compound of any one of Inventions 1001 - 1046. [Invention 1048] A compound according to any one of the compounds of the present invention 1001 to 1047, wherein all atoms of the compound are present in their naturally occurring isotope abundances. [The present invention 1049] Formula (II) A compound represented by TIFF0007704787000021.tif28128, wherein X is selected from the group consisting of -O- and -N(R a ), L is a linear or branched C 1~6 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, provided that phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, and C 3~6 cycloalkyl are each independently optionally substituted on one or more available carbons with one, two, or three substituents selected from the group consisting of halogen, hydroxyl, -NR a R b , C 1~2 alkyl (optionally substituted with one, two, or three halogens), and C 1~2 alkoxy (optionally substituted with one, two, or three halogens), and when 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, the ring nitrogen atom is optionally substituted with C 1~3 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 each independently selected from the group consisting of hydrogen and C 1~3 alkyl, said compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. [Invention 1050] A compound of Invention 1049, wherein X is selected from the group consisting of -O-, -N(H)-, and -N(CH3)-. [Invention 1051] L is selected from the group consisting of TIFF0007704787000022.tif25133, provided that * and # each represent a covalent bond point to R 2-II and X, a compound of Invention 1049 or 1050. [Invention 1052] R 2-II is selected from the group consisting of hydrogen, cyano, -NH2, -N(CH3)2, -OCH3, TIFF0007704787000023.tif54150, a compound of any one of Inventions 1049 to 1051. [Invention 1053] R 5 is selected from the group consisting of hydrogen, deuterium, and fluorine, a compound of any one of Inventions 1049 to 1052. [Invention 1054] Formula (III) A compound represented by TIFF0007704787000024.tif28128, wherein X III is selected from the group consisting of a bond, -CH2-, -NR a -, -O-, -O-CH2-, and -OCH2-CH2-, m is 1, 2, or 3, n is 1, 2, or 3, R 1-IIIis selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR a R b , C 1~2 alkyl (optionally substituted by 1, 2, or 3 halogens), and C 1~2 alkoxy (optionally substituted by 1, 2, or 3 halogens), and is R 2-III is selected from the group consisting of 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, provided that 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 may optionally be substituted by 1, 2, or 3 substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, -NR a R b , C 1~2 alkyl (optionally substituted by 1, 2, or 3 halogens), and C 1~2 alkoxy (optionally substituted by 1, 2, or 3 halogens), and 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 each independently, for their respective presence, 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. [Inventive Item 1055] X III is a bond, -CH2, -O-, -NH-, or -O-CH2-, and is the compound of Inventive Item 1054. [Inventive Item 1056] R 2-III is hydrogen, isopropyl, -CH2CF3, -S(O)2-CH3, or -S(O)2-cyclopropyl, and is the compound of Inventive Item 1054 or 1055. [Inventive Item 1057] R 5 is hydrogen, deuterium, or fluorine, and is the compound of any one of Inventive Items 1054 to 1056. [Inventive Item 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-thiadiazolidine-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-(Cyclopropylsulfonyl)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-(propan-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-(propan-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, 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 A compound selected from the group consisting of, and a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. [Inventive item 1059] A pharmaceutically acceptable composition comprising a compound according to any one of Inventive items 1001 to 1058 and a pharmaceutically acceptable carrier. [Inventive item 1060] The composition of Inventive item 1059, formulated for oral administration. [Inventive item 1061] A method for treating cancer in a patient in need of a method for treating cancer, comprising administering to the patient an effective amount of a compound according to any one of Inventive items 1001 to 1058 in combination with an additional therapeutic agent. [Inventive item 1062] A method for treating cancer in a patient in need of a method for treating cancer, comprising administering to the patient an effective amount of a pharmaceutically acceptable composition of Inventive item 1059 or 1060 in combination with an additional therapeutic agent. [Inventive item 1063] The method of Inventive item 1061 or 1062, wherein the additional therapeutic agent is an immunotherapeutic agent. [Inventive item 1064] The method of Inventive item 1063, 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. [Inventive item 1065] A method for treating cancer in a patient in need of a cancer treatment method, the method comprising administering to the patient an effective amount of any one of Compounds 1001 to 1058 of the present invention. [Inventive Concept 1066] A method for treating cancer in a patient in need of a cancer treatment method, the method comprising administering to the patient an effective amount of a pharmaceutically acceptable composition of the present invention 1059 or 1060. [Inventive Concept 1067] A method for treating type 2 diabetes in a patient in need of a method for treating type 2 diabetes, the method comprising administering to the patient an effective amount of any one of Compounds 1001 to 1058 of the present invention or a composition of the present invention 1059 or 1060. [Inventive Concept 1068] A method for treating and / or managing obesity in a patient in need of a method for treating and / or managing obesity, the method comprising administering to the patient an effective amount of any one of Compounds 1001 to 1058 of the present invention or a composition of the present invention 1059 or 1060. [Inventive Concept 1069] A method for suppressing further weight gain in an overweight or obese patient in need of a method for suppressing further weight gain, the method comprising administering to the patient an effective amount of any one of Compounds 1001 to 1058 of the present invention or a composition of the present invention 1059 or 1060. [Inventive Concept 1070] A method for treating a metabolic disorder in a patient in need of a method for treating a metabolic disorder, the method comprising administering to the patient an effective amount of any one of Compounds 1001 to 1058 of the present invention or a composition of the present invention 1059 or 1060. [Mode for Carrying Out the Invention]

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

[0029] Definitions of Terms Definitions of Chemical Terms The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are specified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., and specific functional groups are defined generally as described in the above compendium. 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] The abbreviations used herein have their conventional meanings within the scope of the technical fields of chemistry and biology. The chemical structures and chemical formulas described herein are constructed in accordance with the standard rules of chemical valency known in the technical field of chemistry.

[0031] The compounds described herein may contain one or more chiral centers and, accordingly, may exist in various isomers, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from the mixture by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or the 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 (E.L. Eliel, Ed., Univ. 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 enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomerically pure). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is thus enantiomerically pure with respect to the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean 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% of the enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

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

[0034] As used herein, "isotope-enriched variant" refers to a disclosed compound having one or more isotope substitutions, where one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number normally found in nature. Examples of isotopes that can be introduced into the compounds of the present disclosure include, respectively2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, etc., include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. For example, hydrogen (H) may be in any isotopic form including 1 H, 2 H (D, i.e., deuterium), and 3 H (T, i.e., tritium), and carbon (C) may be in any isotopic form including 12 C, 13 C, and 14 C, and oxygen (O) may be in any isotopic form including 16 O and 18 O, and so on. For example, in the isotope-enriched variants disclosed herein, one or more hydrogen atoms may be replaced by deuterium.

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

[0036] When a numerical range is recited, the range is intended to include each numerical value and sub-range 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 set forth below with the terms and are useful for understanding the description and intended scope of the present disclosure.

[0038] "Alkyl" refers to a radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C1-C 20 alkyl"). In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C1-C 12 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C1-C4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C1-C3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C1-C2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the 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 example of the alkyl group may independently be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, that is, it may be unsubstituted ("unsubstituted alkyl") or substituted with the above substituents ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C1- 10It is alkyl (for example, -CH3). In certain embodiments, the alkyl group is substituted C1-C6 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, unless otherwise specified, means a divalent radical derived from alkyl, exemplified by but not limited to -CH2CH2CH2CH2-. Generally, an alkyl (or alkylene) group has 1 to 24 carbon atoms, and in the present disclosure, an alkyl (or alkylene) group having 10 or fewer carbon atoms is preferred. The term "alkenylene", by itself or as part of another substituent, unless otherwise specified, means a divalent radical derived from alkene. The alkylene group may be described, for example, as C1-C6 alkylene, where the term "member" refers to non-hydrogen atoms within the moiety.

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

[0041] "Aryl" means a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array), having 6 to 14 ring carbon atoms provided in the aromatic ring system and no heteroatoms, a radical of the aromatic ring system ("C6-C 14refers to "aryl". In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl"; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10 aryl"; for example, 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 may be described, for example, as C6-C 10 member aryl, provided that the term "member" refers to non-hydrogen ring atoms within that moiety. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each example of an aryl group may independently be optionally substituted with one or more substituents, for example, unsubstituted ("unsubstituted aryl") or may be substituted with the above substituents ("substituted aryl"). In certain embodiments, the above aryl group is unsubstituted C6-C 14 aryl. In certain embodiments, the above aryl group is substituted C6-C 14 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] Examples of representative substituted aryls include the following TIFF0007704787000025.tif17128, wherein R 56 and R 57 one of which may be hydrogen, and R 56 and R 57 at least one of which is each independently C1-C8 alkyl, halo-C1-C8 alkyl, 4-10 membered heterocyclyl, alkanoyl, alkoxy-C1-C8 alkyl, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR59 , NR 58 SOR 59 , NR 58 SO2R 59 , C(O)O alkyl, C(O)O aryl, CONR 58 R 59 , CONR 58 OR 59 , NR 58 R 59 , SO2NR 58 R 59 , selected from S-alkyl, S(O)-alkyl, S(O)2-alkyl, S-aryl, S(O)-aryl, S(O2)-aryl, or R 56 and R 57 may combine to form a cyclic ring (saturated or unsaturated) consisting of 5 to 8 atoms, optionally containing one or more heteroatom groups selected from the group consisting of N, O, S, S(O), or S(O)2.

[0044] Other representative aryl groups having a fused heterocyclyl group include the following TIFF0007704787000026.tif12128, wherein each W’ is selected from C(R 66 )2, NR 66 , O, and S, each Y’ is selected from carbonyl, NR 66 , O, and S, and R 66 is independently hydrogen, C1-C8 alkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl.

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

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

[0047] Furthermore, 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", whether by itself or in combination with another term, unless otherwise specified, means an acyclic stable straight or branched chain, or combinations thereof, having at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein said nitrogen and sulfur atoms may optionally be oxidized and said nitrogen heteroatoms may optionally be quaternized. Said heteroatom(s) O, N, P, S, and Si may be located at any internal position of said heteroalkyl group or at the position where said 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)2-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. For example, up to two or three heteroatoms may be consecutive, such as in -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. When a specific heteroalkyl group such as -CH2O-CH3, -NR B R C is described, it will be understood that the terms heteroalkyl and -CH2O-CH3 or -NR B R C are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is described for clarity. Thus, in this specification, the term "heteroalkyl" should not be construed to exclude specific heteroalkyl groups such as -CH2O-CH3, -NR B R C and the like.

[0049] Similarly, the term "heteroalkylene", by itself or as part of another substituent, unless otherwise specified, means a divalent radical derived from heteroalkyl, exemplified by, but not limited to, -CH2O- and -CH2CH2O-. The heteroalkylene group may be described, for example, as a 2- to 7-membered heteroalkylene, where the term "member" refers to non-hydrogen atoms within the moiety. For the heteroalkylene group, the heteroatom may occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Moreover, for the linking group of alkylene and heteroalkylene, the directionality of the linking group is not indicated by the direction in which the formula of the linking group is described. For example, the formula -C(O)2R'- can represent both -C(O)2R'- and -R'C(O)2-.

[0050] "Heteroaryl" refers to 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 given to the above aromatic ring system, and each heteroatom is independently a radical of the above aromatic ring system selected from nitrogen, oxygen, and sulfur ( "5- to 10-membered heteroaryl"). In a heteroaryl group containing one or more nitrogen atoms, the bonding point may be a carbon or nitrogen atom as long as the valence permits. The heteroaryl bicyclic ring system may contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes a ring system in which the heteroaryl ring defined above is condensed with one or more aryl groups and the bonding point is on either the aryl ring or the heteroaryl ring. In such a case, the ring member number indicates the ring member number of the condensed (aryl / heteroaryl) ring system. In a bicyclic heteroaryl group in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the bonding point may be on either ring, i.e., on the ring having a heteroatom (e.g., 2-indolyl) or on the ring not containing a heteroatom (e.g., 5-indolyl). The heteroaryl group may be described, for example, as 6- to 10-membered heteroaryl, provided that the term "member" refers to non-hydrogen ring atoms within that portion.

[0051] In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently being selected from nitrogen, oxygen, and sulfur, the aromatic ring system (a "5- to 10-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently being selected from nitrogen, oxygen, and sulfur, the aromatic ring system (a "5- to 8-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently being selected from nitrogen, oxygen, and sulfur, the aromatic ring system (a "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 example of the heteroaryl group may independently be optionally substituted with one or more substituents, i.e., it may be unsubstituted (a "non-substituted heteroaryl") or may be substituted with the above substituents (a "substituted heteroaryl"). 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-fused bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-fused bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0053] Examples of representative heteroaryls include the following formula TIFF0007704787000027.tif64128, where each Y is selected from carbonyl, N, NR 65 , O, and S, and R 65is independently hydrogen, C1-C8 alkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl.

[0054] "Cycloalkyl" means a non-aromatic cyclic hydrocarbon group having 3-10 ring carbon atoms ( "C3-C 10 cycloalkyl"), and a radical of the hydrocarbon group having no hetero atom in the non-aromatic ring system. In some embodiments, the cycloalkyl group has 3-8 ring carbon atoms ( "C3-C8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3-6 ring carbon atoms ( "C3-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 3-6 ring carbon atoms ( "C3-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5-10 ring carbon atoms ( "C5-C 10 cycloalkyl"). The cycloalkyl group may be described, for example, as a C4-C7 membered cycloalkyl, provided that the term "membered" refers to non-hydrogen ring atoms within 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), etc. Exemplary C3-C8 cycloalkyl groups include, but are not limited to, the above-described C3-C6 cycloalkyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrieneyl (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), etc. Exemplary C3-C 10Examples of the cycloalkyl group include, but are not limited to, the above-mentioned C3-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]decan-1-yl (C 10 ), and the like. As shown in the above examples, in certain embodiments, the cycloalkyl group is either monocyclic ("monocyclic cycloalkyl") or includes a fused, bridged, or spiro ring system such as a bicyclic system ("bicyclic cycloalkyl"), and may be saturated or partially unsaturated. "Cycloalkyl" also includes a ring system in which the cycloalkyl ring defined above is fused to one or more aryl groups and the bonding point is on the cycloalkyl ring, and in such a case, the number of carbon atoms continues to indicate the number of carbon atoms in the cycloalkyl ring system. Each example of the cycloalkyl group may independently be optionally substituted with one or more substituents, for example, it may be unsubstituted ("unsubstituted cycloalkyl") or may be substituted with the above substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is unsubstituted C3-C 10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3-C 10 cycloalkyl.

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

[0056] "Heterocyclyl" or "heterocyclic" refers to a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatom groups, where each heteroatom group is independently selected from nitrogen, oxygen, sulfur and oxidized forms of sulfur (e.g., S, S(O), and S(O)2), boron, phosphorus, and silicon, and is a radical of the above non-aromatic ring system ("3- to 10-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valence allows. The heterocyclyl group may be monocyclic ("monocyclic heterocyclyl") or any of a fused, bridged, or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. The bicyclic heterocyclic ring system may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which the heterocyclyl ring 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 a ring system in which the heterocyclyl ring 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 ring member count continues to indicate the ring member count of the heterocyclyl ring system. The heterocyclyl group may be described, for example, as 3- to 7-membered heterocyclyl, provided that the term "member" refers to non-hydrogen ring atoms within the moiety, i.e., carbon, nitrogen, oxygen, sulfur and oxidized forms of sulfur (e.g., S, S(O), and S(O)2), boron, phosphorus, and silicon. Each example of heterocyclyl may independently be optionally substituted with one or more substituents, e.g., unsubstituted ("unsubstituted heterocyclyl") or substituted with the above substituents ("substituted heterocyclyl"). 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, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatom groups, wherein each heteroatom group is independently selected from nitrogen, oxygen, sulfur and oxidized forms of sulfur (e.g., S, S(O), and S(O)2), boron, phosphorus, and silicon, and the non-aromatic ring system (a "5- to 10-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur and oxidized forms of sulfur (e.g., S, S(O), and S(O)2), and the non-aromatic ring system (a "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 1 to 4 ring heteroatom groups, wherein each heteroatom group is independently selected from nitrogen, oxygen, sulfur and oxidized forms of sulfur (e.g., S, S(O), and S(O)2), and the non-aromatic ring system (a "5- to 6-membered heterocyclyl"). In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 3 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 1 to 2 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 1 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, aziridinyl, oxiranyl, and thiirenyl. 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 pyrrol-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 fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0059] Specific examples of heterocyclic groups are given in the following exemplary examples TIFF0007704787000028.tif43128, wherein each W” is CR 67 , C(R 67 )2, NR 67 , O, and S, each Y is selected from NR 67 , O, and S, and R 67 is independently hydrogen, C1-C8 alkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl. These heterocyclic rings are 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., amide), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azide, 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. Examples of substituents include carbonyl or thiocarbonyl that give lactam and urea derivatives.

[0060] The term “nitrogen-containing heterocyclyl” group means a 4-7 membered non-aromatic cyclic group containing at least one nitrogen atom, such as, 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, in the formula, R70 and R 71 is each independently hydrogen, C1-C8 alkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and the above radicals which are 5-10 membered heteroaryl. 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] The 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). Generally, the term “substituted,” whether or not preceded by the term “optionally,” means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, i.e., a substituent that produces a compound that does not spontaneously change, such as by rearrangement, cyclization, elimination, or other reactions, during substitution, to form a stable compound. Unless otherwise specified, a “substituted” group has substituents at one or more substitutable positions of the group, and if more than one position of any given structure is substituted, the substituents may be the same or different at each position. The term “substituted” is intended to encompass substitution by any of the acceptable substituents of an organic compound, such as any of the substituents described herein that lead to the formation of a stable compound. The present disclosure contemplates any and all such combinations for reaching a stable compound. For the purposes of the present disclosure, a heteroatom such as nitrogen may have the hydrogen substituents and / or optional and appropriate substituents described herein that satisfy the valence of the heteroatom and lead to the formation of a stable moiety.

[0066] Two or more substituents may optionally be joined to form an aryl, heteroaryl, cycloalkyl, or heterocyclyl group. Such so-called ring-forming substituents, although not necessarily, generally exist attached to a cyclic base structure. In one embodiment, the ring-forming substituent is attached to adjacent constituent atoms of the base structure. For example, a fused ring structure is formed by two ring-forming substituents attached to adjacent constituent atoms of a cyclic base structure. In another embodiment, the ring-forming substituent is attached to a single constituent atom of the base structure. For example, a spiro ring structure is formed by two ring-forming substituents attached to a single constituent atom of a cyclic base structure. In yet another embodiment, the ring-forming substituent is attached to non-adjacent constituent 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 - , OH - , 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, ethanate ion, propionate ion, benzoate ion, glycerate ion, lactate ion, tartrate ion, glycolate ion, etc.).

[0068] The term "pharmaceutically acceptable salt" means salts of the active compounds prepared with relatively non-toxic acids or bases depending on certain substituents present on the compounds described herein. When the compounds of the present disclosure contain relatively acidic functional groups, the base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base either neat or in a suitable 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 the compounds of the present disclosure contain relatively basic functional groups, the acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid either neat or in a suitable 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, bicarbonic acid, phosphoric acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, monohydrogen sulfuric acid, hydroiodic acid, or phosphorous acid, and 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-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Salts of amino acids such as alginates, and salts of organic acids such as glucuronic acid or galacturonic acid are also included (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 that enable the conversion of the compound into either a base addition salt or an acid addition salt. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for the present disclosure. The salts tend to be more soluble in aqueous or other protic solvents in the form of the corresponding free base. In other cases, the above formulation may be a lyophilized powder in a first buffer, for example, 1 mM to 50 mM histidine, 0.1% to 2% sucrose, 2% to 7% mannitol, in a pH range of 4.5 to 5.5, which is mixed with a second buffer before use.

[0069] Accordingly, 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 mixtures thereof including racemic mixtures), 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 form of the compound is preferably regenerated by contacting the salt with a base or an acid and isolating the parent compound by conventional methods. The parent form of the compound differs from the various salt forms in certain physical properties such as solubility in polar solvents.

[0071] In addition to the salt forms, the present disclosure also provides compounds in prodrug form. A prodrug of a compound described herein is a compound that undergoes an easy chemical change under physiological conditions to give the compound of the present disclosure. Further, the prodrug can be converted to the compound of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to the compound of the present disclosure when placed in a transdermal patch reservoir together with a suitable enzyme or chemical reagent.

[0072] Certain compounds of the present disclosure may exist not only in non-solvated forms but also in solvated forms including hydrated forms. Generally, the above solvated forms are equivalent to the non-solvated 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 intended to be 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 methods of the present disclosure. Exemplary examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts.

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

[0075] As used herein, the term "isomer" refers to compounds having the same number and type of atoms and thus the same molecular weight, but differing 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 convertible from one isomer to another.

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

[0078] "Treating" or "treatment" includes preventing or delaying the onset of symptoms, complications, or biochemical signs of a disease, alleviating or improving such symptoms, or arresting or inhibiting further development of a disease, illness, or disorder. "Treating" or "treatment" includes any effect leading to improvement of a disease, illness, disorder, etc., such as attenuation, reduction, regulation, or elimination. For example, a particular method herein treats cancer by reducing or alleviating or preventing the occurrence, growth, metastasis, or progression of cancer, or by reducing the symptoms of cancer. The terms "treat" and its conjugations include prevention of an injury, condition, disease, or disorder (e.g., preventing the onset of one or more symptoms of a disease, disorder, or illness described herein).

[0079] "Effective amount" means an amount sufficient to achieve the 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). Examples of "effective amount" are amounts sufficient to contribute to the treatment, prevention, or alleviation of one or more symptoms of a disease, which amounts are also referred to as "therapeutically effective amounts." The "prophylactically effective amount" of a drug is an amount of the drug that, when administered to a subject, will, for example, prevent or delay the onset (or recurrence) of an injury, disease, condition, or disorder, or reduce the likelihood of the onset (or recurrence) of an injury, disease, condition, or disorder, or one or more symptoms thereof. A complete prophylactic effect does not necessarily occur with a single administration and may occur only after a series of administrations. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amount depends on the particular treatment objective and can be ascertained by techniques known to those of ordinary skill in the art (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" of one or more symptoms (and grammatical equivalents of this phrase) means reducing the severity or frequency of the symptom(s) or eliminating the symptom(s).

[0081] "Control" or "control experiment" is used in accordance with its plain and ordinary meaning and refers to an experiment in which the subject or reagent of the experiment is treated as in a parallel experiment, except for the omission of the experimental procedure, reagent, or variable. In some cases, the above control is used as a reference for comparison when evaluating the effect of the experiment.

[0082] "Contact" is used in accordance with its plain and ordinary meaning and refers to the process of bringing at least two different species (e.g., compounds including biomolecules or cells) into close proximity sufficient to react, interact, or physically contact each other. However, it should be understood that the resulting reaction product may be generated from intermediates derived from one or more of the added reactants, which may be generated directly from the reaction between the added reactants or in the reaction mixture. The term "contact" may include reacting, interacting, or physically contacting two species, provided that the two species may be the compounds and proteins or enzymes described herein, such as protein tyrosine phosphatases, such as non-receptor type 2 protein tyrosine phosphatase (PTPN2) or non-receptor type 1 protein tyrosine phosphatase (PTP1B).

[0083] As defined herein, terms such as "inhibition", "inhibit", "inhibiting" related to protein-inhibitor (e.g., antagonist) interactions mean to have a negative effect (e.g., decrease) on the activity or function of a protein as 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 symptoms of a disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or a signaling pathway. Thus, inhibition includes, at least in part, partially, or completely, blocking a stimulus, reducing or preventing activation, or delaying, or inactivating, desensitizing, or downregulating signal transduction or enzyme activity or the amount of a protein. In some embodiments, inhibition refers to reducing the activity of a protein tyrosine phosphatase, such as non-receptor type 2 protein tyrosine phosphatase (PTPN2) or non-receptor type 1 protein tyrosine phosphatase (PTP1B). Thus, inhibition may include, at least in part, partially, or completely, reducing a stimulus, reducing or decreasing activation, or inactivating, desensitizing, or downregulating signal transduction or enzyme activity or the amount of a protein tyrosine phosphatase, such as non-receptor type 2 protein tyrosine phosphatase (PTPN2) or non-receptor type 1 protein tyrosine phosphatase (PTP1B).

[0084] As used herein, a "patient" or "subject" in need thereof refers to an organism that has or is susceptible to a disease or disorder that can be treated by administration of the compounds or pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient is a human. In some embodiments, the patient is a pet animal. In some embodiments, the patient is a dog. In some embodiments, the patient is a bird. In some embodiments, the patient is a farm 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. In some embodiments, the patient is a canine. In some embodiments, the patient is a feline. 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 newborn. 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 "illness" refers to a condition or state of health 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, for example, the reduction or elimination of one or more symptoms of the above diseases, disorders, or illnesses by administration of a pharmaceutical composition comprising a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0086] As used herein, the term "signaling pathway" refers to a series of interactions between cellular components 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 may in turn transmit the change to additional components, which may optionally be propagated to components of other signaling pathways.

[0087] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that assist in the administration of an active agent to a subject and its absorption by the subject and can be included in the compositions of the present disclosure without causing significant toxicological adverse effects to the subject. 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, flavoring agents, salt solutions (such as Ringer's solution), alcohol, oils, gelatin, lactose, amylose, or carbohydrates such as starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such formulations may be sterilized and, if necessary, may be mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifying agents, salts for affecting osmotic pressure, buffering agents, coloring agents, and / or aromatic substances that do not react detrimentally with the compounds of the present disclosure. Those skilled in the art will recognize that other pharmaceutical excipients are also useful in the present disclosure.

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

[0089] As used herein, the term "administration" means 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 can be 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, intracerebroventricular, and intracranial administration. Other delivery modes include, but are not limited to, the use of liposomal formulations, intravenous infusions, transdermal patches, etc. "Co-administering" means that the compounds or compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapeutic agents (e.g., an anti-cancer agent, a chemotherapeutic agent, or an immunotherapeutic agent). The compounds or compositions described herein can be administered to a patient alone or co-administered. Co-administration is intended to include simultaneous or sequential administration of the present compound or composition individually or in combination (multiple compounds or agents). Thus, the above formulations can also be combined, if desired, with other active substances (e.g., for reducing metabolic degradation).

[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 In this specification, for example, a compound represented by formula (I) TIFF0007704787000029.tif27128, wherein in the formula R 1 is selected from the group consisting of 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, provided that 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 may each independently be substituted on one or more available carbons by one, two, three, or more substituents selected from R g , and when -C 1~6 alkylene-5- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, that ring nitrogen atom may optionally be substituted by R h , R 2 is hydrogen, hydroxyl, -CHF2, -CH2OH, -CH2CN, -CH2-O-C 1~6 alkyl, -CH2-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(Ra )-C(O)-O-C 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, selected from the group consisting of, provided that -CH2-O-C 1~6 alkyl, -CH2-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)-O-C 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 1~6Alkylene-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 Alkylene-4- to 6-membered heterocyclyl is optionally, on one or more available carbons, independently of each other, substituted by one, two, three, or more substituents selected from R g If 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 Alkylene-4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, the ring nitrogen atom is optionally substituted by R h , or, R 1 and R 2 together with the atom to which they are attached form a 5- to 6-membered aryl or heteroaryl, provided that the aryl or heteroaryl is optionally, independently of each other, halogen, hydroxyl, cyano, C 1~6 alkyl, and C 1~6 alkoxy, and is optionally substituted by one or more substituents selected from the group consisting of, provided that C 1~6 alkyl and C 1~6 alkoxy are optionally, independently of each other, substituted by one, two, three, or more substituents selected from R p , 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 1~6Selected from the group consisting of alkylene-4- to 6-membered heterocyclyl, provided 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 be independently substituted on one or more available carbons by one, two, three, or more substituents selected from R g , and when the alkylene-4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, the ring nitrogen atom may optionally be substituted by R 1~6 , h R 4 is hydrogen, halogen, C 1~6 alkyl, C 3~6 cycloalkyl, and -C 1~6 Selected from the group consisting of 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 substituted on one or more available carbons by one, two, three, or more substituents selected from R g , and when the alkylene-4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, the ring nitrogen atom may optionally be substituted by R 1~6 , h Provided that at least one of R 1 , R 2 , R 3 , and R 4 is not hydrogen, R 5 is hydrogen, halogen, C 1~6 alkyl, C 3~6Cycloalkyl, and -C 1~6 selected from the group consisting of alkylene-4- to 6-membered heterocyclyl, provided that C 1~6 alkyl, C 3~6 cycloalkyl, and -C 1~6 alkylene-4- to 6-membered heterocyclyl may optionally be substituted, each independently, on one or more available carbons, by one, two, three, or more substituents selected from R g ; when alkylene-4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, the ring nitrogen atom may optionally be substituted by R 1~6 ; h R is hydrogen, 6 R is hydrogen, 7 R is, for each occurrence independently, hydrogen, halogen, hydroxyl, cyano, nitro, oxo, -C(O)OH, R g R a R b N-, R a R b N-C(O)-, R a R b N-SO w -, R a R b N-C(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 1~6Alkyl-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 ), 4-6 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- selected from the group consisting of, provided that 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-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-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- is optionally and each independently substituted by 1, 2, 3, or more substituents selected from R p and may be substituted, Rh is, independently for each occurrence, 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-SO2-, and -P(O)(C 1~3 alkyl)2 selected from the group consisting of, 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- 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-SO2-, and -P(O)(C 1~3(Alkyl)2 is optionally and independently substituted by one, two, three or more substituents selected from R p and may be substituted by one or more substituents selected from the group consisting of 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-SO2-, and R a R b N-carbonyl-N(R a )- and 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 and is selected from the group consisting of, provided that C 1~6 alkyl is optionally and independently substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, hydroxyl, and C 1~6 alkoxy (optionally substituted by one, two or three fluorine atoms), and may be substituted by one or more substituents selected from the group consisting of or R a and R b together with the nitrogen to which they are attached form a 4- to 6-membered heterocyclyl, provided that the heterocyclyl is optionally and independently substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl, w is 0, 1 or 2, The above compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer or isotopically enriched variant thereof is disclosed.

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

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

[0094] In some embodiments, R 2 is a 4- to 6-membered heterocyclyl, provided that R 2 is optionally substituted on one or more available carbons with one, two, or three substituents each independently selected from R g respectively, and when the 4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, that ring nitrogen atom is optionally substituted with a substituent selected from R h respectively. For example, in some embodiments, R 2 is a 4- to 6-membered heterocyclyl, provided that R 2 is optionally substituted on one or more available carbons with one, two, or three substituents each independently selected from the group consisting of hydrogen and C 1~6 alkyl respectively, and when R 2 contains a ring nitrogen atom that can be substituted, that ring nitrogen atom is optionally hydrogen, C 1~6 alkyl (optionally substituted with one, two, or three 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 one, two, or three 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 optionally substituted by N-), and -P(O)(C 1~3 alkyl)2 and may be substituted by a substituent selected from the group consisting of. For example, in some embodiments, R 2 is, for example, selected from the group consisting of TIFF0007704787000030.tif105146TIFF0007704787000031.tif149146.

[0095] In other embodiments, R 2 is 5- to 6-membered heteroaryl, provided that R 2 is optionally, on one or more available carbons, each independently R g substituted by one, two, or three substituents selected from, and when R 2 contains a ring nitrogen atom that can be substituted, the ring nitrogen atom is optionally R h substituted by a substituent selected from. For example, in some embodiments, R 2 is 5- to 6-membered heteroaryl, provided that R 2 is 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 alkyl)2 substituted by one, two, or three substituents selected from the group consisting of, and when R 2 contains a ring nitrogen atom that can be substituted, the ring nitrogen atom is optionally hydrogen, -C 1~6 alkyl-C 3~6Cycloalkyl, and C 3~6 It may be substituted by a substituent selected from the group consisting of cycloalkyl-S(O)2-. For example, in some embodiments, R 2 is, for example, Selected from the group consisting of TIFF0007704787000032.tif48141.

[0096] In a further embodiment, R 2 is -O-C 1~6 Alkylene-4- to 6-membered heterocyclyl, provided that R 2 is optionally, on one or more available carbons, independently of each other, R g It may be substituted by 1, 2, or 3 substituents selected from, and if R 2 contains a ring nitrogen atom that can be substituted, that ring nitrogen atom is optionally substituted by a substituent selected from R h . For example, in some embodiments, R 2 is -O-C 1~6 Alkylene-4- to 6-membered heterocyclyl, provided that R 2 is optionally, on one or more available carbons, independently of each other, hydrogen, halogen, and C 1~6 It may be substituted by 1, 2, or 3 substituents selected from the group consisting of alkyl, and if R 2 contains a ring nitrogen atom that can be substituted, that ring nitrogen atom is optionally hydrogen, C 1~6 Alkyl, and C 1~6 It may be substituted by a substituent selected from the group consisting of alkyl-S(O)2-. For example, in some embodiments, R 2 is, for example, Selected from the group consisting of TIFF0007704787000033.tif70131.

[0097] In other embodiments, R 2 is -O-C 1~6 Alkylene-5- to 6-membered heteroaryl. For example, in some embodiments, R 2 is, for example, is selected from the group consisting of TIFF0007704787000034.tif19128.

[0098] In a further embodiment, R 2 is -C 2~6 alkyl, C 2~6 alkenyl, and C 3~6 cycloalkyl, provided that R 2 is optionally and independently substituted by 1, 2, 3, or more substituents selected from R g . For example, in some embodiments, R 2 is -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, provided that R 2 is optionally and independently substituted by 1, 2, 3, or more substituents selected from cyano, chlorine, fluorine, hydroxyl, C 1~6 alkoxy, phenyl, and R a R b N-. For example, in some embodiments, R 2 is, for example, -CH2CHF2, is selected from the group consisting of TIFF0007704787000035.tif62146.

[0099] In another embodiment, R 2 is -O-C 1~6 alkyl, provided that R 2 is optionally and independently substituted by 1, 2, 3, or more substituents selected from R g . For example, in some embodiments, R 2 is -O-C 1~6 alkyl, provided that R 2is, optionally, each independently 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- (provided that R b is optionally substituted by -OCH3 or -OCF3), C 1~6 alkyl-N(R a )-, R a R b N-C(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 )- and may be substituted by one, two, three, or more substituents selected from the group consisting of. For example, in some embodiments, R 2 is, for example, -OCH3, -OCD3, -OCF3, -OCHF2, -OCH2CH3, TIFF0007704787000036.tif192149 selected from the group consisting of.

[0100] In other embodiments, R 2 is -O-C 3~6 cycloalkyl or -O-4- to 6-membered heterocyclyl, provided that when R 2 contains a ring nitrogen atom that can be substituted, the ring nitrogen atom is optionally R hmay be substituted by a substituent selected from. For example, in some embodiments, R 2 is -O-C 3~6 cycloalkyl or -O-4- to 6-membered heterocyclyl, provided that when R 2 contains a ring nitrogen atom that can be substituted, the ring nitrogen atom is optionally C 1~6 alkyl-SO2-N(R a )- and C 3~6 cycloalkyl-SO2-N(R a )- may be substituted by a substituent selected from the group consisting of. For example, in some embodiments, R 2 is, for example, selected from the group consisting of TIFF0007704787000037.tif18128.

[0101] In still further embodiments, R 2 is -N(R a )-C 1~6 alkyl, provided that R 2 is optionally substituted by 1, 2, or 3 substituents each independently selected from R g . For example, in some embodiments, R 2 is -N(R a )-C 1~6 alkyl, provided that R 2 is optionally, each independently, 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 may be substituted by 1, 2, or 3 substituents selected from the group consisting of. For example, in some embodiments, R 2 is, for example, -N(H)CH3, selected from the group consisting of TIFF0007704787000038.tif66132.

[0102] In other embodiments, R 2 is -O-C 1~6 alkylene-C 3~6 cycloalkyl, provided that R 2 is optionally and each independently substituted by 1, 2, or 3 substituents selected from R g . For example, in some embodiments, R 2 is -O-C 1~6 alkylene-C 3~6 cycloalkyl, provided that R 2 is optionally and each independently substituted by 1, 2, or 3 substituents selected from fluoro, hydroxyl, R a R b N-, cyano, and C 1~3 alkyl, provided that C 1~3 alkyl is optionally substituted by a substituent selected from the group consisting of cyano and C 1~3 alkoxy. For example, in some embodiments, R 2 is, for example, selected from the group consisting of TIFF0007704787000039.tif14141TIFF0007704787000040.tif35130.

[0103] In some embodiments, R 2 is -O-C(O)-N(R a )-C 1~6 alkyl. For example, in some embodiments, R 2 is, for example, represented by TIFF0007704787000041.tif13128.

[0104] In a further embodiment, R 2 is -N(R a )-4- to 6-membered heterocyclyl, provided that R 2When it contains a ring nitrogen atom that can be substituted, the ring nitrogen atom may optionally be substituted by a substituent selected from R h . For example, in some embodiments, R 2 is -N(R a )-4- to 6-membered heterocyclyl, provided that when R 2 contains a ring nitrogen atom that can be substituted, the ring nitrogen atom may optionally be substituted by a substituent selected from the group consisting of C 1~6 alkyl-SO2-N(R a )- and C 3~6 cycloalkyl-SO2-N(R a )-. For example, in some embodiments, R 2 is selected from the group consisting of, for example, TIFF0007704787000042.tif27128.

[0105] In other embodiments, R 2 is -C 1~6 alkylene-4- to 6-membered heterocyclyl, provided that when R 2 contains a ring nitrogen atom that can be substituted, the ring nitrogen atom may optionally be substituted by a substituent selected from R h . For example, in some embodiments, R 2 is -C 1~6 alkylene-4- to 6-membered heterocyclyl, provided that when R 2 contains a ring nitrogen atom that can be substituted, the ring nitrogen atom may optionally be substituted by a substituent selected from the group consisting of C 1~6 alkyl, C 1~6 alkyl-SO2-N(R a )-, and C 3~6 cycloalkyl-SO2-N(R a )-, provided that C 1~6 alkyl may optionally be substituted by 1, 2, or 3 fluorine atoms. For example, in some embodiments, R 2 is selected from the group consisting of, for example, TIFF0007704787000043.tif47128.

[0106] In some embodiments, R 2 is, for example, -CHF2, -CH2OH, -CH2OCH3, -CH2CN, -OH, is selected from the group consisting of TIFF0007704787000044.tif14128.

[0107] In some embodiments, R 1 and R 2 together with the atoms to which they are attached form a 5-membered heteroaryl. For example, in some embodiments, R 1 and R 2 together with the atoms to which they are attached form, for example, furanyl. For example, in some embodiments, the compound of formula (I) is represented by TIFF0007704787000045.tif26128.

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

[0109] As used herein, a compound represented by formula (II) TIFF0007704787000046.tif27128, wherein wherein X is selected from the group consisting of -O- and -N(R a )-, L is a linear or branched C 1~6 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, provided that phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, and C 3~6 cycloalkyl may optionally be substituted by one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, -NR a R b , C 1~2 alkyl (optionally substituted by one, two, or three halogens), and C 1~2 alkoxy (optionally substituted by one, two, or three halogens), and when 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, the ring nitrogen atom may optionally be substituted by C 1~3 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 each independently selected from the group consisting of hydrogen and C 1~3 alkyl for each instance of their presence, 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(CH3)-.

[0111] In other embodiments, L is selected from the group consisting of TIFF0007704787000047.tif24132, provided that * and # each represent a covalent bond point to R 2-II and X.

[0112] In further embodiments, R 2-II is selected from the group consisting of hydrogen, cyano, -NH2, -N(CH3)2, -OCH3, TIFF0007704787000048.tif41128.

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

[0114] As used herein, a compound represented by formula (III) TIFF0007704787000049.tif27128, wherein wherein X III is selected from the group consisting of a bond, -CH2-, -NR a -, -O-, -O-CH2-, and -OCH2-CH2-, m is 1, 2, or 3, n is 1, 2, or 3, R 1-III is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NR a R b C 1~2 alkyl (optionally substituted by 1, 2, or 3 halogens), and C 1~2 alkoxy (optionally substituted by 1, 2, or 3 halogens), R 2-III is hydrogen, C 1~4 alkyl, -C(O)-C 1~4Alkyl, -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 Selected from the group consisting of cycloalkyl, provided that 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 is optionally and independently selected from one, two, or three substituents selected from the group consisting of halogen, hydroxyl, cyano, -NR a R b , C 1~2 Alkyl (optionally substituted by one, two, or three halogens), and C 1~2 Alkoxy (optionally substituted by one, two, or three halogens), and may be substituted by one, two, or three substituents selected from the group consisting of 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 each independently selected from the group consisting of hydrogen and C 1~3 Alkyl, The above compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof is also disclosed.

[0115] In some embodiments, X III Is selected from the group consisting of a bond, -CH2, -O-, -NH-, and -O-CH2-.

[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] As used herein, 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-(Cyclopropylsulfonyl)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-thiadiazolidine-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-methylpenta-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 -thia-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 - Thiazolidin - 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 - Thiazolidin - 2 - yl)naphthalen - 2 - yl]oxy}acetamide, N,N - Diethyl - 2-{[8 - fluoro - 6 - hydroxy - 7-(1,1,4 - trioxo - 1λ 6 ,2,5 - Thiazolidin - 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 - Thiazolidine - 1,1,3 - trione, 5-(1 - fluoro - 3 - hydroxy - 7-{[1 - (methanesulfonyl)piperidin - 4 - yl]oxy}naphthalen - 2 - yl)-1λ 6 ,2,5 - Thiazolidine - 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 - Thiazolidine - 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 - Thiazolidine - 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 - Thiazolidine - 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-(propan-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-methylpropan-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-(propan-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-Thiadiazolidine-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, 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-Thiazolidin-2-yl)naphthalen-2-yl]-1H-imidazole-4-carbonitrile Compounds selected from the group consisting of, and pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof are further disclosed.

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

[0120] In some embodiments, the compounds disclosed herein, e.g., of formula (I), formula (II), or formula (III), are selected from the compounds listed in Table 1.

[0121] (Table 1) Exemplary Compounds of the Present Disclosure TIFF0007704787000050.tif204155TIFF0007704787000051.tif209155TIFF0007704787000052.tif213155TIFF0007704787000053.tif210155TIFF0007704787000054.tif212155TIFF0007704787000055.tif209155TIFF0007704787000056.tif219155TIFF0007704787000057.tif215155TIFF0007704787000058.tif211155TIFF0007704787000059.tif218155TIFF0007704787000060.tif205155TIFF0007704787000061.tif225155TIFF0007704787000062.tif220156TIFF0007704787000063.tif225156TIFF0007704787000064.tif204156TIFF0007704787000065.tif219156TIFF0007704787000066.tif73156

[0122] Method for producing exemplary compounds The compounds of the present disclosure may be more deeply understood in the context of the following synthetic schemes and methods of synthesis that illustrate the means by which the above compounds can be prepared. The compounds of the present disclosure can be prepared by a variety of synthetic procedures. Representative synthetic procedures are shown in Schemes 1-7, but are not limited thereto. The variables R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、and R 7 are defined as detailed herein, namely in the "Summary of the Invention".

[0123] Scheme 1: Representative scheme for the synthesis of exemplary compounds of the present disclosure TIFF0007704787000067.tif70166TIFF0007704787000068.tif120150As shown in Scheme 1, the compounds of formula (1-9), formula (1-10), formula (1-11), and formula (1-12) can be prepared from the compound of formula (1-1). The compound 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 obtain the compound of formula (1-2). The compound of formula (1-2) can be reacted under Curtius reaction conditions (diphenylphosphoric acid azide, tert-butanol, triethylamine in heated toluene) to obtain the compound of formula (1-3). Treatment with heated diethylenetriamine removes the tert-butoxycarbonyl moiety from the compound of formula (1-3) to obtain the compound of formula (1-4). The compound of formula (1-4) can be reacted with a 2-bromoacetate of formula (1-5) in a heated solvent such as, but not limited to, a mixture of N,N-dimethylformamide and water in the presence of a base such as potassium carbonate to obtain the compound of formula (1-6). Subsequently, the compound of formula (1-6) can be fluorinated with a reagent such as N-fluorobenzenesulfonimide (NFSI) in a solvent such as tetrahydrofuran or Selectfluor® in optionally heated N,N-dimethylformamide to obtain the compound of formula (1-7). The compound of formula (1-7) can be reacted with chlorosulfonyl isocyanate and tert-butanol in a solvent such as cooled dichloromethane in the presence of a tertiary amine base such as triethylamine. Subsequently, treatment under acidic conditions such as trifluoroacetic acid in dichloromethane to remove the tert-butoxycarbonyl group gives the compound of formula (1-8).The compound of formula (1-8) is reacted with an alkoxide base, for example, sodium methoxide in optionally heated methanol or a mixture of methanol and water, or potassium tert-butoxide in tetrahydrofuran, and then quenched with an acid such as 1M hydrochloric acid to obtain a compound of formula (1-9) or formula (1-10). The compound of formula (1-9) can be converted to the compound of formula (1-11) using water under cross-coupling reaction conditions such as water in the presence of RockPhos Pd G3 as a precatalyst, cesium carbonate as a base, and N,N-dimethylformamide as a heated solvent. The optionally substituted benzyl ether of the compound of formula (1-10) is known to those skilled in the art and can be removed using conditions according to the specific benzyl ether. For example, an unsubstituted benzyl ether can be removed by treating it with boron trichloride at -60 to -80 °C in the presence of 1,2,3,4,5-pentamethylbenzene in dichloromethane to obtain a compound of formula (1-12). The compound of formula (1-12) represents the compound of formula (I).

[0124] Scheme 2: Representative scheme for the synthesis of exemplary compounds of the present disclosure TIFF0007704787000069.tifAs shown in Scheme 2, the compounds of formula (2-2), formula (2-4), formula (2-6), and formula (2-8) can be prepared from the compound of formula (1-9). The compound of formula (1-9) can be reacted under C-cross-coupling reaction conditions. For example, using Suzuki reaction conditions, the compound of formula (1-9) can be coupled with a compound of formula (2-1) (wherein A represents an alkene moiety, cyclopropyl, or an aromatic or partially unsaturated ring). The reaction conditions for coupling the compound of formula (1-9) with the 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. Subsequently, an optionally substituted benzyl ether protecting group can be removed using conditions known to those skilled in the art and appropriate for the specific benzyl ether. For example, an unsubstituted benzyl ether can be removed by treatment with boron trichloride at -60 to -80 °C in the presence of 1,2,3,4,5-pentamethylbenzene in dichloromethane to obtain the compound of formula (2-2). Also, an unsubstituted benzyl ether can be removed by treatment with hydrogen and a palladium catalyst in a solvent such as dioxane or tetrahydrofuran. The compound of formula (2-2) or the protected precursor may be further modified using methods known to those skilled in the art and as shown in the examples.

[0125] The compound of formula (1-9) can be reacted under N-cross-coupling reaction conditions. For example, using Buchwald-Hartwig reaction conditions, the compound of formula (1-9) can be coupled with the compound of formula (2-3). For example, the compound of formula (1-9) and the compound 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 a catalyst (palladium(II) acetate), a ligand (BrettPhos, RuPhos, or Xantphos), and a base (sodium tert-butoxide or cesium carbonate). Subsequently, an optionally substituted benzyl ether protecting group can be removed as described above to obtain a compound of formula (2-4) (wherein NR 2-1 R 2-2 represents the cyclic or acyclic moiety of R 2 ). The compound of formula (2-4) or the protected precursor may be further modified as known to those skilled in the art and as shown in the examples.

[0126] The compound of formula (1-9) can be reacted under O-cross-coupling reaction conditions. For example, using cross-coupling reaction conditions, the compound of formula (1-9) can be coupled with the compound of formula (2-5). For example, the compound of formula (1-9) and the compound of formula (2-5) can be coupled in a solvent such as heated N,N-dimethylformamide in the presence of a precatalyst RockPhos Pd G3 and a base cesium carbonate. Subsequently, an optionally substituted benzyl ether protecting group can be removed as described above to obtain a compound of formula (2-6) (wherein OR 2-3 represents the ether moiety of R 2 ). The compound of formula (2-6) or the protected precursor may be further modified as known to those skilled in the art and as shown in the examples.

[0127] The compound of formula (1-9) can be reacted under C-cross-coupling reaction conditions. For example, the compound of formula (1-9) with formula (2-7) (wherein R 2-4is R beyond the scope of the allyl moiety 2 The remaining portion of (representing) can be coupled with an allyl compound. The reaction conditions for coupling the compound of formula (1-9) with the compound of formula (2-7) are in a solvent such as heated N,N-dimethylformamide or dioxane, 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 may contain a tertiary amine base such as triethylamine or a base such as cesium carbonate. Subsequently, an optionally substituted benzyl ether protecting group can be removed as described above to obtain the compound of formula (2-8). The compound of formula (2-8) or the protected precursor may be further modified as known to those skilled in the art and as shown in the examples.

[0128] The compound of formula (2-2), formula (2-4), formula (2-6), or formula (2-8) represents the compound of formula (I) or is a precursor of the compound of formula (I).

[0129] Scheme 3: A representative scheme for the synthesis of exemplary compounds of the present disclosure As shown in Scheme 3 of TIFF0007704787000070.tif105135, the compounds of formula (3-1) and formula (3-2) can be prepared from the compound of formula (1-11). The compound of formula (1-11) is converted to R 3-1 -LG 1 (wherein LG 1 is a leaving group such as chloro, bromo, iodo, or sulfonate, and R 3-1It can be alkylated with a compound that is (optionally substituted alkyl, optionally substituted heterocyclyl, or optionally substituted cycloalkyl). The alkylation conditions may include treatment with a base such as cesium carbonate or sodium hydride, but not limited to these, in a solvent such as optionally heated N,N-dimethylformamide. Subsequently, the optionally substituted benzyl ether protecting group is known to those skilled in the art and can be removed using conditions corresponding to the specific benzyl ether. For example, an unsubstituted benzyl ether can be removed by treating it with boron trichloride at -60 to -80 °C in the presence of 1,2,3,4,5-pentamethylbenzene in dichloromethane to obtain the 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 moiety of.

[0130] An alternative preparation of the compound of formula (3-1) involves reacting the compound of formula (1-11) with a compound of the formula R 3-1 -OH (wherein R 3-1 is optionally substituted alkyl or optionally substituted cycloalkyl) under Mitsunobu reaction conditions. Thus, the compound of formula (1-11) and the compound of formula R 3-1 -OH may be treated with (E)-diazene-1,2-diylbis(piperidine-1-ylmethanone) and tri-n-butylphosphine in a solvent such as warmed tetrahydrofuran. Subsequently, removing the benzyl protecting group as described above gives the 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.

[0131] The compound of formula (1-11) can also be converted to the compound of formula (3-2). The compound of formula (1-11) is reacted with R 3-2 -NCO of the formula (wherein R3-2 is optionally substituted C 1~6 alkyl) to obtain the corresponding carbamate. Subsequently, removing the benzyl protecting group as described above gives the compound of formula (3-2). The group -OC(O)NHR 3-2 represents the carbamate moiety of 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) represent the compounds of formula (I) or are precursors of the compounds of formula (I).

[0133] Scheme 4: Representative scheme for the synthesis of exemplary compounds of the present disclosure TIFF0007704787000071.tif93134 As shown in Scheme 4, the compound of formula (4-4) can be prepared from the compound of formula (1-9). The compound of formula (1-9) is reacted with a boron reagent of formula (4-1) such as bis(pinacolato)diboron in which one R B is bonded to another R B under cross-coupling reaction conditions to obtain the compound of formula (4-2). The reaction conditions for coupling the compound of formula (1-9) with the compound of formula (4-1) may 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) is reacted with a compound of formula (4-3) (wherein R 2-C represents an aromatic ring or a partially unsaturated ring, an alkyl group, or an alkylene group, and LG 2It can be coupled with a compound having a leaving group such as iodine, bromine, or chlorine). The reaction conditions for coupling the compound of formula (4-4) with the compound of formula (4-3) are in heated toluene and ethanol, or a mixture of dioxane and water, or N-methyl-2-pyrrolidinone, in the presence of a catalyst (tetrakis(triphenylphosphine)palladium(0), XPhos Pd G2, or meCgpPh Pd G3), and a base (sodium carbonate, potassium phosphate, or potassium carbonate). Subsequently, an optionally substituted benzyl ether protecting group is known to those skilled in the art and can be removed using conditions corresponding to the specific benzyl ether. For example, an unsubstituted benzyl ether can be removed by treating it with boron trichloride at -60 to -80 °C in the presence of 1,2,3,4,5-pentamethylbenzene in dichloromethane to obtain the compound of formula (4-4). The compound of formula (4-4) or the corresponding protected precursor may be further modified as known to those skilled in the art and as shown in the examples.

[0134] The compound of formula (4-4) represents the compound of formula (I) or is a precursor of the compound of formula (I).

[0135] Scheme 5: Representative scheme for the synthesis of exemplary compounds of the present disclosure As shown in Scheme 5 of TIFF0007704787000072.tif84128, the compound of formula (5-3) can be prepared from the compound of formula (1-9). The compound of formula (1-9) is reacted with 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) can be coupled with a compound. The conditions for coupling the compound of formula (1-9) with the compound of formula (5-1) are in a solvent such as dioxane containing an optional N,N-dimethylacetamide in a 450 nm LED photoreactor, NiCl2-dimethoxyethane adduct, ligand (4,4'-di-tert-butyl-2,2'-dipyridyl), base (cesium carbonate), and treatment with bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+); 2-(2-pyridyl)pyridine; hexafluorophosphate. Subsequently, the optionally substituted benzyl ether protecting group is known to those skilled in the art and can be removed using conditions according to the specific benzyl ether. For example, an unsubstituted benzyl ether can be removed by hydrogenation in tetrahydrofuran in the presence of a carbon-supported palladium catalyst to obtain the compound of formula (5-3).

[0136] Alternatively, under the above reaction conditions, the compound of formula (5-1) can also be coupled with a compound of formula (5-2) (wherein PG 3 is (2-methoxyethoxy)methyl). Treatment with a dioxane solution of hydrochloric acid can deprotect one or both protecting groups to obtain the compound of formula (5-3).

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

[0138] The compound of formula (5-3) represents or is a precursor of the compound of formula (I).

[0139] Scheme 6: A representative scheme for the synthesis of exemplary compounds of the present disclosure TIFF0007704787000073.tif37128 As shown in Scheme 6, the compound of formula (6-3) can be prepared from the compound of formula (6-1). The compound of formula (6-1) (wherein PG 1 is a protecting group such as (2-methoxyethoxy)methyl, and PG 2 is an optionally substituted benzyl group or (2-methoxyethoxy)methyl) can be coupled with a compound of formula (6-2) (wherein R 6-1 is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted heterocyclyl group). The conditions for coupling the compound of formula (6-1) with the 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, are known to those skilled in the art and can be removed using conditions appropriate to the particular benzyl ether. For example, an 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 obtain the compound of formula (6-3). If either PG 1 or PG 2 is a (2-methoxyethoxy)methyl group, either or both can be removed by treatment with an acid such as a dioxane solution of hydrochloric acid to obtain the compound of formula (6-3). The compound of formula (6-3) or the corresponding protected precursor may be further modified as known to those skilled in the art and as shown in the examples.

[0140] The compound of formula (6-3) represents or is a precursor of the compound of formula (I).

[0141] Scheme 7: Representative scheme for the synthesis of exemplary compounds of the present disclosure TIFF0007704787000074.tif71144 As shown in Scheme 7, the compound of formula (2-2) can be prepared from the compound of formula (1-9) in the reverse synthetic order as 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 depending on the particular benzyl ether. For example, an unsubstituted benzyl ether can be removed by treating with boron trichloride at -60 to -80 °C in the presence of 1,2,3,4,5-pentamethylbenzene in dichloromethane to obtain the compound of formula (7-1). The compound of formula (7-1) can be reacted under C-cross-coupling reaction conditions. For example, using Suzuki reaction conditions, the compound of formula (7-1) can be coupled with a compound of formula (2-1) (wherein A represents an alkene moiety, cyclopropyl, or an aromatic or partially unsaturated ring). The corresponding boronic acid of the compound of formula (2-1) is also suitable for the above cross-coupling reaction. The 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] The compound of formula (2-2) represents or is a precursor of the compound of formula (I).

[0143] Pharmaceutical composition The present disclosure provides a pharmaceutical composition comprising a compound disclosed herein, for example, 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, for example, a compound of formula (I), formula (II) or formula (III), is provided in an effective amount in the pharmaceutical composition. 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 composition described herein can be prepared by any method known in the art of pharmacology. Generally, such a preparation method includes the step of co-existing the disclosed compound ("active ingredient") with a carrier and / or one or more other accessory components, and then, if necessary and / or desirable, shaping and / or packaging the product into a desired single-dose unit or multiple-dose units. The pharmaceutical composition may be formulated, packaged, and / or sold in bulk, as a single unit dose, and / or as multiple unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition containing 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 convenient fraction of such dosage, for example, half or one-third of such dosage.

[0145] The relative amounts of the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III), pharmaceutically acceptable excipients, and / or any additional components in the pharmaceutical compositions of the present disclosure will vary depending on the identity, body size, and / or condition of the subject being treated, and further depending on the route by which the composition is to be administered. By way of example, the composition may contain from 0.1% to 100% (w / w) of the compounds 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 the manufacture of the pharmaceutical compositions of the present disclosure are any pharmaceutically acceptable excipients well-known in the field of pharmaceutical formulations and include inert diluents, dispersing agents and / or granulating agents, surfactants and / or emulsifying agents, disintegrants, binders, preservatives, buffering agents, lubricants, and / or oils. Pharmaceutically acceptable excipients useful in the manufacture of the 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; buffering substances such as phosphoric acid, glycine, sorbic acid, potassium sorbate; 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; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulosic substances; polyethylene glycol; sodium carboxymethylcellulose; polyacrylic esters; waxes; polyethylene-polyoxypropylene block polymers; polyethylene glycol; and lanolin.

[0147] The compositions of the present disclosure can be administered by oral administration, parenteral administration (including subcutaneous, intramuscular, intravenous, and intradermal administration), administration by inhalation spray, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration, or via an implant reservoir. In some embodiments, the compounds or compositions provided are capable of intravenous and / or oral administration.

[0148] As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intrasynovial, intrasternal, intramedullary, intrahepatic, intraperitoneal, intralesional, and intracranial injection or infusion techniques. The composition is preferably administered orally, subcutaneously, intraperitoneally, or intravenously. The sterile injectable form of the compositions of the present disclosure may be an aqueous or oily suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable formulations may also be sterile injection solutions or suspensions in a non-toxic diluent or solvent acceptable for parenteral administration, for example, an injection solution as a 1,3-butanediol solution. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils have conventionally been used as a solvent or suspending medium.

[0149] The pharmaceutically acceptable compositions of the present disclosure may be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. A lubricant, such as magnesium stearate, is also typically added. In the case of oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is mixed with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may also be added. In some embodiments, the oral formulations provided are formulated for immediate release or sustained / delayed release. In some embodiments, the composition is suitable for buccal or sublingual administration including tablets, lozenges, and troches. 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, coatings, powders, and aerosols and delivered by topical route for transdermal administration. Oral formulations include tablets, pills, powders, dragees, capsules, solutions, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by a patient. Solid formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid formulations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. The compositions of the present disclosure may further include components for providing sustained release and / or comfort. Such components include high molecular weight anionic mucoadhesive polymers, gelling polysaccharides, and micronized 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 these patents 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, the microspheres may be drug-containing microspheres and administered via intradermal injection of the microspheres that slowly 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 microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, the above formulations of the compositions of the present disclosure are liposomes, and may be delivered, for example, by using receptor ligands bound to the liposomes that bind to cell surface membrane protein receptors and thus lead to endocytosis, so as to fuse with the cell membrane or be endocytosed.By using liposomes, particularly liposomes having on their surface a receptor ligand specific for the target cell or otherwise preferentially targeting a particular organ in other forms, the delivery of the compositions of the present disclosure can be concentrated on the target cells 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 may 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, particularly when the target of treatment includes regions or organs that are readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations for each of these regions or organs can be readily prepared.

[0152] In some embodiments, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection in order to prolong the effect of the drug. This can be achieved by using a suspension of a poorly water-soluble crystalline or amorphous substance. In that case, the absorption rate of the drug depends on its dissolution rate, which in turn may depend on the crystal size and crystal form. Alternatively, the delay in absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oily vehicle.

[0153] The description of the pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, but one of ordinary skill in the art will understand that such compositions are generally suitable for administration to all species of animals. Modifications to make pharmaceutical compositions suitable for administration to humans into compositions suitable for administration to various animals are well understood, and an ordinary 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 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 dosage level for any particular subject or organism will depend on a variety of factors including the severity of the disease and disorder being treated; the activity of the specific active ingredient being used; the specific composition being 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 being used; the duration of the treatment; drugs used in combination with or coincidentally used concomitantly with the specific active ingredient being used; and like factors well known in the medical arts.

[0155] The exact amount of the compound necessary to achieve an effective amount will vary from subject to subject depending, for example, on the species, age, and general condition of the subject, the severity of side effects or disorders, the identity of the specific compound(s), the mode of administration, etc. Desirable dosages may be delivered three times a day, twice a day, once a day, every other day, once every three days, once a week, once every two weeks, once every three weeks, or once every four weeks. In certain embodiments, desirable dosages 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 one of ordinary skill 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 modify their metabolism, inhibit their excretion, and / or modify their distribution in the body. It will also be understood that the therapies used can achieve the desired effect for the same disorder and / or that the therapies used may achieve different effects.

[0158] The compounds or compositions may be administered simultaneously with, before, or after one or more additional agents, which may be useful, for example, as combination therapy agents. Agents include therapeutically active agents. Agents also include prophylactically active agents. Each additional agent may be administered at the dosage and / or time schedule determined for the particular medicament. The additional agents may also be administered together with each other and / or with the compounds or compositions described herein either in a single administration or in separate administrations at different times. The particular combinations used in a regimen will take into account the compatibility of the compounds of the invention with the additional agents and / or the desired therapeutic and / or prophylactic effect to be achieved. Generally, the additional agents used in combination are required to be used at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in combination will be lower than the levels used individually.

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

[0160] The pharmaceutical compositions provided by the present disclosure include compositions in which an active ingredient (e.g., a compound described herein including embodiments or examples) is included in a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. The actual amount effective for a particular use depends, inter alia, on the disease being treated. Such compositions, when administered in a method of treating a disease, include an amount of the active ingredient effective to achieve a desired result, e.g., inhibition of the activity of a target molecule (e.g., PTPN2 and / or PTPN1), and / or reduction, elimination, or delay in the progression of the symptoms of the disease. Determination of the therapeutically effective amount of the compounds disclosed herein is well within the ability of one of ordinary skill in the art, particularly in light of the detailed disclosure herein.

[0161] The dosage and frequency (single or multiple administrations) administered to a mammal may vary depending on various factors, e.g., whether the mammal is suffering from another disease and its route of administration; the size, age, sex, health status, weight, body mass index, and diet of the recipient; the nature and extent of the symptoms of the disease being treated, the type of combination therapy, complications due to the disease being treated, or other health-related problems. Other treatment 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 ability of one of ordinary skill in the art.

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

[0163] As is well known in the art, a therapeutically effective amount for use in humans can also be determined from animal models. For example, the dosage for humans can be formulated to achieve a concentration known to be effective in animals. The dosage in humans can, as described above, be adjusted by monitoring the effectiveness of the compound and adjusting the dosage up or down. Adjusting the dosage to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

[0164] The dosage can be varied depending on the requirements of the patient and the compound to be used. In the context of the present disclosure, the dosage administered to a patient should be sufficient to affect a beneficial therapeutic response in the patient over time. The magnitude of the dosage 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 the physician. In general, treatment is initiated at a smaller dosage, lower than the optimum dosage of the compound. Thereafter, the dosage is increased in small increments until the optimum effect under the circumstances is reached. The dosage and interval can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This results in a therapeutic regimen that is commensurate with the severity of the patient's condition.

[0165] Using the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and is effective in treating the clinical symptoms exhibited by a particular patient. In this planning, it is necessary to carefully select the active compound by considering factors such as the potency of the compound, relative bioavailability, patient weight, presence and severity of adverse side effects, 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 diseases (e.g., cancer, type 2 diabetes, obesity, metabolic diseases, or other diseases or disorders described herein).

[0167] The kits provided may comprise the pharmaceutical composition or compound of the present invention and a container (e.g., vial, ampoule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, the kits provided may optionally further comprise a second container containing a pharmaceutical excipient for dilution or suspension of the pharmaceutical composition or compound of the present invention. In some embodiments, the pharmaceutical composition or compound of the present invention provided in the above container and the second container are mixed to form one unit dosage form.

[0168] Accordingly, in one aspect, a kit is provided that comprises a first container containing the 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 for preventing and / or treating the diseases described herein.

[0169] Method of treatment The present disclosure features compounds, compositions, and methods that include the compounds disclosed herein, such as compounds of Formula (I), Formula (II), or Formula (III). In some embodiments, the compounds, compositions, and methods disclosed herein are used for the prevention or treatment of a disease, disorder, or illness. Exemplary diseases, disorders, or illnesses include, but are not limited to, cancer, type 2 diabetes, metabolic syndrome, obesity, or metabolic diseases.

[0170] Cancer In some embodiments, the compounds disclosed herein, such as compounds of Formula (I), Formula (II), or Formula (III), are used for treating cancer. As used herein, “cancer” refers to human cancers and carcinomas, sarcomas, adenocarcinomas (such as papillary adenocarcinoma), lymphomas, leukemias, melanomas, etc., including solid cancers and lymphocyte 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 lymphoma (such as Burkitt lymphoma, small cell lymphoma, and large cell lymphoma), Hodgkin lymphoma, leukemias (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, cholangiocarcinoma, adrenal cancer, salivary gland cancer, bronchial cancer, oral cancer, cancer of the mouth or pharynx, laryngeal cancer, kidney cancer, gynecological cancer, brain cancer, central nervous system cancer, peripheral nervous system cancer, blood tissue cancer, small intestine cancer or appendiceal cancer, cervical cancer, colon cancer, esophageal cancer, stomach 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, neoplasm, or malignant tumor 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, Waldenström macroglobulinemia, benign monoclonal gammopathy, sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate 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 cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid, sarcoma), glioblastoma multiforme, acoustic neuroma, retinoblastoma, astrocytoma, craniopharyngioma, hemangioblastoma, pineal tumor, epithelioma, oligodendroglioma, meningioma, glioma, or melanoma. Further examples include cancer of the thyroid, endocrine system, brain, breast, neck, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, immunocytic amyloidosis, ovarian cancer, rhabdomyosarcoma, idiopathic thrombocytopenia, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical cancer, endocrine or exocrine pancreatic neoplasm, medullary thyroid cancer, medullary thyroid cancer, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's disease of the nipple, tumor that is philo, lobular carcinoma, ductal carcinoma, cancer of pancreatic stellate cells, cancer of hepatic stellate cells, or prostate cancer.

[0172] The term "leukemia" broadly refers to a progressive, malignant disease of the hematopoietic organs, and generally is characterized by the distorted proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia is generally clinically classified based on (1) the duration and characteristics of the disease, i.e., acute or chronic; (2) the type of cells involved, i.e., myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) whether the number of abnormal cells in the blood increases or not, i.e., leukemic or aleukemic (subleukemic). Exemplary leukemias that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, chronic leukemia, acute non-lymphocytic 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, blast cell leukemia, bovine leukemia, acute myeloblastic leukemia, chronic myeloblastic leukemia, cutaneous leukemia, embryonal cell leukemia, eosinophilic leukemia, erythroleukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micro myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasmacytic leukemia, multiple myeloma, plasmacytic leukemia, polycythemia vera, promyelocytic leukemia, leader cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0173] The term "sarcoma" generally refers to a tumor composed of cells densely packed and made up of substances such as embryonic connective tissue, 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, lymphoma, lymphangiosarcoma, lymphangioendotheliosarcoma, melanoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, lipomatous sarcoma, alveolar soft part sarcoma, ameloblastic epitheliosarcoma, botryoid sarcoma, chloroma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, endotheliosarcoma, stromal sarcoma, Ewing's sarcoma, fasciitis sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer stellate cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma, osteosarcoma, juxtacortical osteosarcoma, reticuloendotheliosarcoma, Rous sarcoma, serous cystadenosarcoma, synovial sarcoma, or peripheral angiectatic sarcoma.

[0174] The term "melanoma" is interpreted to mean a tumor arising from the melanocyte cell line 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, malignant lentigo melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0175] The term "cancer" refers to a malignant neoplasm composed of epithelial cells that tend to invade surrounding tissues and cause metastasis. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided in this specification include, for example, medullary thyroid cancer, familial medullary thyroid cancer, lobular carcinoma, alveolar carcinoma, cystadenocarcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortical carcinoma, alveolar cell carcinoma, alveolar carcinoma, basal cell carcinoma, basal cell carcinoma, basaloid carcinoma, basal spiny cell carcinoma, cholangiocarcinoma, bladder cancer, breast cancer, Brenner tumor, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchiogenic carcinoma, cerebriform carcinoma, cervical cancer, cholangiocarcinoma, chordoma, choriocarcinoma, clear cell carcinoma, mucinous carcinoma, colon cancer, acneiform carcinoma, corpus carcinoma, cribriform carcinoma, scirrhous carcinoma, skin cancer, cylindrical carcinoma, cylindrical cell carcinoma, cystadenocarcinoma, duct carcinoma, ductal carcinoma, carcinoma durum, fetal carcinoma, medullary carcinoma, endometroid carcinoma, epidermoid carcinoma, epithelial carcinoma, epithelial adenoid carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrous carcinoma, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, trichoblastoma, hematoid carcinoma, hepatoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelialcarcinoma), Krompecher carcinoma, Kulchitsky cell carcinoma, large cell carcinoma, lenticular carcinoma, lipomatous carcinoma, lobular carcinoma, lung cancer, lymphoepithelial carcinoma, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, non-papillary renal cell carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, ovarian carcinoma, pancreatic duct carcinoma, papillary carcinoma, periportal carcinoma, pre-invasive carcinoma, spinous cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schnyder carcinoma, scirrhous carcinoma, scrotal carcinoma, sebaceous adenocarcinoma, seminoma, serous carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma, ellipsoidal cell carcinoma of rotation, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, sweat gland carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, tuberousExamples include carcinoma, undifferentiated carcinoma, basal cell carcinoma, or carcinoma villosum.

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

[0177] In some embodiments, the present compounds (compounds described herein, e.g., compounds of formula (I), formula (II), or formula (III)) and compositions (e.g., compositions containing the compounds described herein, e.g., compounds of formula (I), formula (II), or formula (III)) are used in combination with a cancer immunotherapeutic agent (e.g., a checkpoint blockade antibody) 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., the cancers 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 having 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., ligand, 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. The three groups of immunotherapies used to treat cancer include cell-based therapies, antibody-based therapies, and cytokine therapies. All groups utilize the display of subtly different structures (e.g., molecular structures; antigens, proteins, molecules, carbohydrates) on the surface of cancer cells that can be detected by the immune system. Cancer immunotherapeutic agents (e.g., anti-tumor immunotherapy or anti-tumor immunotherapeutics) include 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), but are not limited thereto.

[0179] Cell-based therapies (e.g., cancer vaccines) typically involve removing immune cells from either the blood or a tumor of a subject suffering from cancer. The immune cells specific to the tumor are activated and proliferated and then returned to the subject suffering from cancer, where the immune cells will mount an immune response against the tumor. Examples of cell types that can be used in this way include, for example, natural killer cells, lymphokine-activated killer cells, cytotoxic T cells, dendritic cells, CAR-T therapeutics (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 therapeutic agent is Provenge. In some embodiments, the cell-based therapy is CAR-T therapy.

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

[0181] Cancer vaccines using neoantigens Neoantigens are antigens encoded by tumor-specific mutant genes. Technological innovations have made it possible to examine the immune response to patient-specific neoantigens resulting from tumor-specific mutations, and the data obtained suggest that the recognition of such neoantigens is a major factor in the activity of clinical immunotherapeutic agents. These observations indicate that neoantigen load may form a biomarker in cancer immunotherapy. Many novel therapeutic approaches have been developed to selectively enhance the reactivity of T cells against this type of antigen. One approach targeting neoantigens is by cancer vaccines. These vaccines can be developed using peptides or RNA, such as synthetic peptides or synthetic RNA.

[0182] Antibody therapeutic agents are antibody proteins produced by the immune system that bind to target antigens on the cell surface. Antibodies are generally encoded by immunoglobulin genes or multiple 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, in the treatment of cancer. Antibodies can specifically bind to antigens or epitopes (Fundamental Immunology, 3 rdEdition, Paul, W.E, ed., Raven Press, N.Y. (1993). Even when there is a heterogeneous population of proteins and other biologic agents, specific binding to the corresponding antigen or epitope occurs. Specific binding of an antibody indicates that the antibody binds to its target antigen or epitope with a substantially greater affinity than binding to irrelevant antigens. The relative difference in the above affinities is often at least 25% greater, more often at least 50% greater, and most often at least 100% greater. The above relative differences 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 types of antibodies include, but are not limited to, human, humanized, chimeric, monoclonal, polyclonal, single-chain, antibody binding fragments, and diabodies. When an antibody binds to a cancer antigen, it can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, prevent a receptor from interacting with its ligand, or deliver a payload of a chemotherapeutic agent 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 afflicted with a disease or disorder described herein, the method including 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 an antibody) that inhibits an immune checkpoint pathway. Immune checkpoint proteins normally maintain self - immune tolerance (e.g., prevent autoimmunity) and protect tissues from damage when the immune system is reacting, for example, to an infection by a pathogen under normal physiological conditions. Immune checkpoint proteins can be dysregulated by tumors as an important immune escape mechanism (Pardoll, Nature Rev. Cancer, 2012, 12, 252 - 264). Agonists of co - stimulatory receptors or antagonists of inhibitory signals (e.g., immune checkpoint proteins) amplify antigen - specific T - cell responses. Antibodies that block immune checkpoints do not directly target tumor cells but generally target lymphocyte receptors or their ligands to enhance endogenous anti - tumor 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-antigens and non-self (e.g., foreign) antigens and may be an important mechanism in the suppression of immune responses in many cancers. T-reg cells may arise from the thymus (e.g., "intrinsic T-reg") or may result from the differentiation of T cells that have matured in an environment that induces peripheral immune tolerance (e.g., "induced T-reg"). Therefore, a strategy to minimize the action of T-reg cells is expected to promote the immune response against tumors.

[0187] IDO pathway inhibitor The IDO pathway regulates the immune response by suppressing T cell function and enabling local tumor immune escape. Expression of IDO by antigen-presenting cells (APCs) depletes tryptophan, resulting in antigen-specific T cells becoming anergic and regulatory T cells potentially being recruited. 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., the subject's tumor). Exemplary IDO pathway inhibitors include indoximod, epacadostat, and EOS200271.

[0188] STING pathway agonist Stimulator of interferon genes (STING) is an adaptor protein that plays an important role in the activation of type I interferons in response to cytosolic nucleic acid ligands. There is evidence indicating the involvement of the STING pathway in the induction of anti-tumor immune responses. For example, by activating the STING-dependent pathway in cancer cells, immune cells may invade the tumor and the anti-cancer immune response may be regulated. STING agonists are being developed as a group of cancer therapeutics. Exemplary STING agonists include MK-1454 and ADU-S100.

[0189] Co-stimulatory antibody In some embodiments, the methods described herein include treating a human subject afflicted with a disease or disorder described herein, the method including administering a composition comprising a cancer immunotherapy (e.g., an immunotherapeutic agent). In some embodiments, the immunotherapeutic agent is a co-stimulation inhibitor or antibody. In some embodiments, the methods described herein include 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 a therapeutically effective amount of the compounds described herein. The compounds, such as the compounds described herein, can be administered at regular intervals depending on the nature, severity, and extent of the disease of the subject. In some embodiments, the compounds described herein are administered as a single dose. In some embodiments, the compounds described herein are administered in multiple doses.

[0191] Metabolic disease In some embodiments, the compounds disclosed herein, such as compounds of formula (I), formula (II), or formula (III), are used to treat metabolic diseases. As used herein, the term "metabolic disease" refers to a disease or disorder that affects the metabolic processes of a subject. Exemplary metabolic diseases that can be treated by the compounds disclosed herein, such as compounds of formula (I), formula (II), or formula (III), include non-alcoholic steatohepatitis (NASH), non-alcoholic 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, the compounds disclosed herein, such as compounds of formula (I), formula (II), or formula (III), are used to treat a metabolic disease (e.g., a metabolic disease described herein) by reducing or eliminating the symptoms of the disease. In some embodiments, the treatment method includes reducing or eliminating symptoms including hypertension, hyperglycemia, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and the like. In some embodiments, the compounds disclosed herein, such as 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, such as the compounds of formula (I), formula (II), or formula (III), are used for treating infectious diseases. Exemplary infectious diseases that can be treated by the compounds disclosed herein, such as the compounds of formula (I), formula (II), or formula (III), include bacterial infections, viral infections (e.g., herpes, shingles, influenza, common cold, encephalitis), and parasitic infections.

[0194] In some embodiments, the compounds disclosed herein, such as the compounds of formula (I), formula (II), or formula (III), are used for treating an infectious disease (e.g., an infectious disease described herein) by reducing or eliminating the symptoms of the disease. In some embodiments, the compounds disclosed herein, such as the 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 an infectious disease.

[0195] Parasitic infection In some embodiments, the compounds disclosed herein, such as the compounds of formula (I), formula (II), or formula (III), are used for treating parasitic infections.

[0196] In some embodiments, the compounds disclosed herein, such as the compounds of formula (I), formula (II), or formula (III), are used for treating parasitic infections by reducing or eliminating the symptoms of the disease. In some embodiments, the compounds disclosed herein, such as the 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 parasitic infections.

[0197] Immunosuppressive disease In some embodiments, the compounds disclosed herein, such as the compounds of formula (I), formula (II), or formula (III), are used for treating immunosuppressive diseases.

[0198] In some embodiments, the compounds disclosed herein, such as the compounds of formula (I), formula (II), or formula (III), are used to treat immunosuppressive diseases by reducing or eliminating the symptoms of the diseases. In some embodiments, the compounds disclosed herein, such as the compounds of formula (I), formula (II), or formula (III), are 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 a pharmaceutical composition comprising a disclosed compound of formula (I), formula (II), or formula (III), and a pharmaceutically acceptable excipient. In embodiments of the method, for example, a disclosed compound 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 method, for example, a disclosed compound 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 a pharmaceutical composition comprising a compound disclosed herein, such as 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 the second agent (e.g., a second therapeutic agent) in a therapeutically effective amount. 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 useful in the treatment of cancer, metabolic diseases (such as type 2 diabetes or obesity), or diseases or disorders that respond favorably to treatment with PTPN2 or PTP1B inhibitors, in combination with another active agent, with a plurality of other such active agents, or with an adjuvant that alone may not be effective but can contribute to the efficacy of the active agent.

[0202] In some embodiments, co - administration comprises administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co - administration includes administering the two active agents simultaneously, substantially simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co - administration may be effected by co - formulation, i.e., by preparing a single pharmaceutical composition containing both active agents. In other embodiments, the active agents may be formulated separately. In another embodiment, the active agent and / or adjuvant may be conjugated or coupled to each other. In some embodiments, the compounds described herein may be used in combination with a therapeutic agent for the treatment of cancer, metabolic diseases (such as type 2 diabetes or obesity), or diseases or disorders that respond favorably to treatment with PTPN2 or PTP1B inhibitors. In an embodiment, the second agent is an anti - cancer agent. In an embodiment, the second agent is a chemotherapeutic agent. In an embodiment, the second agent is a drug for treating metabolic diseases. In an embodiment, the second agent is an anti - diabetic agent. In some embodiments, the second agent is an anti - obesity agent.

[0203] Anti - cancer agent (Resverastatin phosphate sodium), BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi), steroids (such as dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids (such as prednisone), progestins (such as hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (such as diethylstilbestrol, ethinyl estradiol), anti-estrogens (such as tamoxifen), androgens (such as testosterone propionate, fluoxymesterone), anti-androgens (such as flutamide), immunostimulants (such as Bacillus Calmette-Guerin (BCG), levamisole, interleukin 2, α-interferon, etc.), monoclonal antibodies (such as anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (such as anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy agents (such as m In, 90 Y, or 131Anti-CD20 monoclonal antibody conjugated to I etc., tripteridol, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitor, therapeutic agent or therapeutic targeting epidermal growth factor receptor (EGFR) (e.g., gefitinib (Iressa (trademark)), erlotinib (Tarceva (trademark)), cetuximab (Erbitux (trademark)), lapatinib (Tykerb (trademark)), panitumumab (Vectibix (trademark)), vandetanib (Caprelsa (trademark)), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OSI-420 / desmethyl erlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, etc., but are not limited thereto.

[0204] "Chemotherapeutic agent" or "chemotherapeutic agent" is used according to its plain ordinary meaning and refers to a chemical composition or compound having anti-cancer properties or the ability to inhibit cell growth or proliferation.

[0205] In addition, the compounds described herein may be co-administered with conventional immunotherapeutic agents, including but not limited to 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.), and radioimmunotherapeutic agents (e.g., m In, 90 Y, or 131 I conjugated anti-CD20 monoclonal antibody).

[0206] In a further embodiment, the compounds described herein are optionally complexed with an antibody against a tumor antigen and are 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 Bi and other radionuclides, including but not limited to, may be co-administered with conventional radiotherapy agents.

Examples

[0207] The following examples are provided to more fully understand the invention described herein. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and should not be construed as limiting their scope in any way.

[0208] Synthesis protocol The compounds provided in this specification can be prepared from readily available starting materials using modifications to the specific synthesis protocols described below, which will be well known to those skilled in the art. Given general or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), it will be understood that other process conditions can be used unless otherwise specified. The optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art using conventional optimization procedures. A general scheme for the preparation of exemplary compounds of the present invention is further described in the section entitled "Methods for Preparing Exemplary Compounds".

[0209] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be required to prevent certain functional groups from undergoing unwanted reactions. The selection of suitable protecting groups for specific functional groups, as well as the conditions suitable for protection and deprotection, are well known in the art. For example, numerous protecting groups, as well as 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] Abbreviations 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: Pound 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 stirred at 23 °C for 5 minutes at high speed. Then benzyl bromide (89.0 mL, 749 mmol) was added and the internal temperature was raised to 49 °C. After 90 minutes, the pale yellow mixture was poured into H2O (1.5 L) and the resulting white precipitate was collected by filtration. The filtered precipitate was washed successively with H2O (3 × 1 L) and tert-butyl methyl ether / heptane (1:2, 2 × 300 mL), and then dried at 45 °C under vacuum (15 mbar) until constant weight to obtain 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 of 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 by mechanical stirring with a stirring blade inserted from above and heated to an internal temperature of 70 °C. After 3 hours, the mixture was cooled to room temperature in an ice bath and 6M HCl (168 mL) was added over 5 minutes, whereupon an off-white solid precipitated. The solid was collected by filtration, washed with H2O (2 × 1 L), triturated with tert-butyl methyl ether (2 × 300 mL), and dried at 65 °C under vacuum until constant weight to obtain 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-bromonaphthalene-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 the whole reaction system was placed behind an explosion-proof wall. Diphenylphosphoric azide (64.4 mL, 300 mmol) was added dropwise over 90 minutes. After 5 hours, the reaction mixture was cooled to room temperature, diluted with H2O (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 above crude intermediate was added diethylenetriamine (253 mL, 2.34 mol). When this heterogeneous suspension was heated to an internal temperature of 130 °C under nitrogen, a homogeneous dark orange solution was formed at that point. After 13 hours, the mixture was cooled to room temperature in an ice bath, and H2O (800 mL) was slowly added over 3 minutes. A yellow solid precipitated, and at the same time, exotherm occurred and the internal temperature reached 53 °C. When this heterogeneous suspension was cooled to room temperature, the crude solid was dissolved in CH2Cl2 (1.5 L), and the layers were separated. The aqueous layer was back-extracted with CH2Cl2 (3 × 150 mL). The combined organic layers were washed with saturated brine (3 × 100 mL), dried over sodium sulfate, filtered, and the volatiles were removed in vacuo to give an orange solid. This solid was mixed with isopropanol (250 mL) to form a slurry, and then the slurry was filtered. The resulting solid was mixed again with isopropanol (2 × 100 mL), and the solid was isolated by filtration. This 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 2 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 of Example 1C (67.8 g, 207 mmol) and potassium carbonate (57.1 g, 413 mmol) in N,N-dimethylformamide (354 mL) and H2O (1.861 mL, 103 mmol), methyl 2-bromoacetate (29.3 mL, 310 mmol) was added. 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 H2O (400 mL) and ethyl acetate (400 mL). The aqueous layer was extracted with ethyl acetate (2 × 100 mL), 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), the resulting beige solid was isolated by filtration, washed with additional heptane (2 × 30 mL), and dried at 35 °C in vacuo (15 mbar) to constant weight to afford 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]aminoacetate 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 dropwise over 5 minutes 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). 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 solution (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 solution (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 this crude solid and the mixture was sonicated for 30 seconds. Next, heptane (150 mL) was slowly added dropwise from a dropping funnel over 15 minutes. The resulting yellow solid was collected by filtration and washed with a 33% v / v heptane solution of ethyl acetate (3 × 60 mL). This solid was discarded and the filtrate was concentrated in vacuo to give a yellow / orange solid which was triturated with anhydrous 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, then washed with anhydrous ethanol (30 mL) and dried at 50 °C in vacuo (15 mbar) to constant weight to give the title compound as a pale yellow solid (10.1 g, 24.25 mmol, 64.7% yield). TIFF0007704787000075.tif25146

[0217] Example 1F: Methyl [3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl](sulfamoyl)amino}acetate 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 slowly added while maintaining the internal temperature below 10 °C. After stirring at 0 °C for 30 minutes, 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 slowly added via a dropping funnel while maintaining the internal temperature below 10 °C. When the addition was complete, the dropping funnel was rinsed with dichloromethane (12.5 mL). The resulting solution was stirred at 0 °C for 30 minutes and then warmed to room temperature. After 1 hour, the reaction mixture was quenched with H2O (73 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 × 36 mL). The combined organic layers were washed with 1 M sodium bisulfate solution (2 × 73 mL). This aqueous wash was back-extracted with dichloromethane (DCM) (36 mL), the combined organic layers were dried over sodium sulfate, filtered, 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 above crude intermediate in dichloromethane (41 mL) was added trifluoroacetic acid (20 mL, 260 mmol), and the resulting dark solution was stirred at room temperature. After 30 minutes, the reaction mixture was quenched by slowly adding saturated aqueous sodium bicarbonate solution (230 mL) via a dropping 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), stirred for 5 minutes to give a slurry, and diluted by dropwise addition of heptane (40 mL) via a dropping funnel. The resulting yellow solid was collected by filtration, washed with 25% v / v dichloromethane / heptane (2 × 20 mL), and dried at 50 °C in vacuo (15 mbar) to constant weight to give the title compound (7.5 g, 15.05 mmol, 87% yield). TIFF0007704787000076.tif25146

[0219] Example 1G: 5-[3-(Benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione To a solution of the product of Example 1F (24.14 g, 48.5 mmol) in tetrahydrofuran (THF) (241 mL) at room temperature was added dropwise via syringe a solution of sodium methoxide (25 wt% in methanol, 16.65 mL, 72.8 mmol). 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, then washed with 25% v / v dichloromethane / heptane (72 mL) and dried at 50 °C under vacuum (15 mbar) to constant weight to give the title compound (16.4 g, 35.2 mmol, 72.5% yield). TIFF0007704787000077.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 of 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 mixed. These solids were placed un...

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein, w is 0, 1, or 2, R １ is selected from the group consisting of 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, where 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 may each independently be substituted on one or more available carbons by one, two, three, or more substituents selected from R ｇ , and when -C １～６ alkylene-5- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, the ring nitrogen atom may be substituted by R ｈ . R ２ is selected from the group consisting of hydroxyl, -O-C １～６ alkyl, -O-C(O)-N(R ａ )-C １～６ alkyl, -O-C ３～６ cycloalkyl, -O-C １～６ alkylene-C ３～６ cycloalkyl, -O-C １～６ alkylene-5- to 6-membered heteroaryl, -O-4- to 6-membered heterocyclyl, and -O-C １～６ alkylene-4- to 6-membered heterocyclyl, wherein -O-C １～６ alkyl, -O-C(O)-N(R ａ )-C １～６ alkyl, -O-C ３～６ cycloalkyl, -O-C １～６ alkylene-C ３～６ cycloalkyl, -O-C １～６ alkylene-5- to 6-membered heteroaryl, -O-4- to 6-membered heterocyclyl, and -O-C １～６ alkylene-4- to 6-membered heterocyclyl may each independently be substituted on one or more available carbons by one, two, three, or more substituents selected from R ｇ , and when 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 alkylene-4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, the ring nitrogen atom may be substituted by R ｈ . Or, R １ and R ２ together with the atoms to which they are attached form a 5- or 6-membered aryl or heteroaryl, where the aryl or heteroaryl is independently halogen, hydroxyl, cyano, C １～６ alkyl, and C １～６ alkoxy may each be substituted by one or more substituents selected from the group consisting of, where C １～６ alkyl and C １～６ alkoxy may each be independently substituted by 1, 2, 3, or more substituents selected from R ｐ and may be substituted, R ３ is selected from the group consisting of 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, wherein -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 may each independently be substituted on one or more available carbons by one, two, three, or more substituents selected from R ｇ , and when -C １～６ alkylene-4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, that ring nitrogen atom may be substituted by R ｈ . R ４ is selected from the group consisting of hydrogen, halogen, C １～６ alkyl, C ３～６ cycloalkyl, and -C １～６ alkylene-4- to 6-membered heterocyclyl, wherein C １～６ alkyl, C ３～６ cycloalkyl, and -C １～６ alkylene-4- to 6-membered heterocyclyl may each independently be substituted on one or more available carbons by one, two, three, or more substituents selected from R ｇ , and when -C １～６ alkylene-4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, the ring nitrogen atom may be substituted by R ｈ . R ５ is selected from the group consisting of hydrogen, halogen, C １～６ alkyl, C ３～６ cycloalkyl, and -C １～６ alkylene-4- to 6-membered heterocyclyl, where C １～６ alkyl, C ３～６ cycloalkyl, and -C １～６ alkylene-4- to 6-membered heterocyclyl may each independently be substituted on one or more available carbons by one, two, three, or more substituents selected from R ｇ , and when the -C １～６ alkylene-4- to 6-membered heterocyclyl contains a ring nitrogen atom that can be substituted, that ring nitrogen atom may be substituted by R ｈ . 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 N-C(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 )-, 4-6 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- selected from the group consisting of, 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 alkyl- may each independently be substituted by one, two, three, or more substituents selected from R ｐ and may be substituted, R ｈ is, independently for each occurrence, 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 selected from the group consisting of, where 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 - 1. 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 each independently optionally substituted by 1, 2, 3 or more substituents selected from R ｐ and may be substituted by 1, 2, 3 or more substituents selected from R 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 )-selected from the group consisting of, R ａ and R ｂ are each independently selected from the group consisting of hydrogen, C １～６ alkyl, and C ３～６ cycloalkyl, where C １～６ alkyl may each independently be substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, hydroxyl, and C １～６ alkoxy (which may be substituted by 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, where the heterocyclyl may each independently be substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, and hydroxyl; and the compound is not .

2. R １ The compound according to claim 1, wherein R is selected from the group consisting of hydrogen, chlorine, and fluorine.

3. R ２ is -O-C １～６ alkylene - a 4- to 6-membered heterocyclyl, where R ２ is, on one or more available carbons, independently of each other, R ｇ optionally substituted by one, two, or three substituents selected from R ２ When R contains a ring nitrogen atom that can be substituted, the ring nitrogen atom may be substituted by a substituent selected from R ｈ The compound according to any one of claims 1 to 2, which may be substituted by a substituent selected from

4. R ２ is -O-C １～６ alkylene - 4 - to 6 - membered heterocyclyl, where R ２ is, on one or more available carbons, independently of one another, hydrogen, halogen, and C １～６ alkyl, and may be substituted by one, two, or three substituents selected from the group consisting of R ２ If it contains a ring nitrogen atom that can be substituted, the ring nitrogen atom is C １～６ alkyl, and C １～６ alkyl - S(O) ２ - and may be substituted by a substituent selected from the group consisting of: The compound according to claim 3.

5. R ２ is The compound according to claim 3 or 4, selected from the group consisting of

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

7. R ２ is The compound according to claim 6, selected from the group consisting of

8. R ２ is -O-C １～６ alkyl, wherein R ２ is each independently substituted by one, two, three, or more substituents selected from R ｇ and the compound according to any one of claims 1 to 2 may be substituted.

9. R ２ is -O-C １～６ alkyl, where R ２ is independently cyano, 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-(where R ｂ is optionally substituted by -OCH ３ or -OCF ３ ), C １～６ alkyl-N(R ａ ), R ａ R ｂ N-C(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 ), and is optionally substituted by one, two, three, or more substituents selected from the group consisting of: the compound according to claim 8.

10. R ２ is -OCH ３ 、-OCD ３ 、-OCF ３ 、-OCHF ２ 、-OCH ２ CH ３ 、 The compound according to claim 8 or 9, selected from the group consisting of

11. R ２ is -O-C ３～６ cycloalkyl or -O-4- to 6-membered heterocyclyl, where, when R ２ contains a ring nitrogen atom that is substitutable, the ring nitrogen atom may be substituted by a substituent selected from R ｈ The compound according to any one of claims 1 to 2, which may be substituted by a substituent selected from

12. R ２ is -O-C ３～６ cycloalkyl or -O-4- to 6-membered heterocyclyl, where R ２ when containing a ring nitrogen atom that can be substituted, the ring nitrogen atom is C １～６ alkyl-SO ２ -N(R ａ )- and C ３～６ cycloalkyl-SO ２ -N(R ａ )- and may be substituted by a substituent selected from the group consisting of, the compound according to claim 11.

13. R ２ is The compound according to claim 11 or 12, selected from the group consisting of

14. R ２ is - O - C １～６ alkylene - C ３～６ cycloalkyl, wherein R ２ is each independently optionally substituted by one, two, or three substituents selected from R ｇ The compound according to any one of claims 1 to 2, which may be substituted by

15. R ２ is -O-C １～６ alkylene-C ３～６ cycloalkyl, where R ２ is each independently fluoro, hydroxyl, R ａ R ｂ N-, cyano, and C １～３ alkyl may be substituted by 1, 2, or 3 substituents selected from the group consisting of, where C １～３ alkyl may be substituted by a substituent selected from the group consisting of cyano and C １～３ alkoxy, the compound according to claim 14.

16. R ２ is The compound according to claim 14 or 15, selected from the group consisting of

17. R ２ is -O-C(O)-N(R ａ )-C １～６ is alkyl, the compound according to any one of claims 1 to 2.

18. R ２ is The compound according to claim 17, represented by

19. R ３ The compound according to any one of claims 1 to 18, wherein R is hydrogen.

20. R ４ The compound according to any one of claims 1 to 19, wherein R is hydrogen.

21. R ５ The compound according to any one of claims 1 to 20, wherein R is selected from the group consisting of hydrogen, bromine, chlorine, and fluorine.

22. R ６ The compound according to any one of claims 1 to 21, wherein R is hydrogen.

23. R ７ The compound according to any one of claims 1 to 22, wherein R is hydrogen.

24. The compound according to any one of claims 1 to 23, wherein all atoms of the compound are present in their natural abundance ratios of isotopes.

25. The following: A compound selected from the group consisting of

26. A pharmaceutically acceptable composition comprising the compound according to any one of claims 1 to 25 and a pharmaceutically acceptable carrier.

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