Protein tyrosine phosphatase inhibitors and methods of use thereof

Abstract

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

Description

[Technical Field]

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

[0002] background Immunotherapy regimens targeting immune evasion mechanisms, including checkpoint blockers (e.g., PD-1 / PD-L1 and CTLA-4 blocking antibodies), have proven effective in treating a variety of cancers and have dramatically improved outcomes in populations resistant to conventional therapies. However, incomplete clinical responses and the development of endogenous or acquired resistance continue to limit the patient population that may benefit from checkpoint blockers.

[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 phosphorylated tyrosine-specific phosphatases that regulate multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, but its expression is highest in hematopoietic cells and placental cells (Mosinger, B. Jr. et al., Proc Natl Acad Sci USA 89:499-503;1992 (Non-patent Literature 1)). In humans, PTPN2 expression is post-transcriptionally regulated by the presence of two splice variants: 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-retaining motif (Tillmann U. et al., Mol Cell Biol 14:3030-3040; 1994 (Non-Patent Literature 2)). The 45 kDa isoform can passively penetrate the cytosol under certain cellular stress conditions. Both isoforms share an N-terminal phosphorylated tyrosine phosphatase catalytic domain. PTPN2 negatively modulates signaling of non-receptor tyrosine kinases (e.g., JAK1, JAK3), receptor 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 a key negative regulator of the JAK-STAT pathway, PTPN2 functions to directly regulate signal transduction mediated by cytokine receptors, including IFNγ. The PTPN2 catalytic domain shares 74% sequence homology with PTPN1 (also known as PTP1B) and shares similar enzyme dynamics (Romsicki Y. et al., Arch Biochem Biophys 414:40-50;2003 (Non-Patent Literature 3)).

[0004] Data from loss-of-function in vivo gene screening using CRISPR / Cas9 genome editing in the mouse B16F10 transplantable tumor model showed that deletion of the Ptpn2 gene in tumor cells improved the response to an immunotherapy regimen of GM-CSF secretion vaccine (GVAX) plus a PD-1 checkpoint blocker (Manguso RT et al., Nature 547:413-418;2017 (Non-Patent Literature 4)). Loss of Ptpn2 led to increased tumor sensitization to immunotherapy by enhancing the effects of IFNγ-mediated antigen presentation and proliferation inhibition. The same screening revealed that under the selective pressure of immunotherapy, genes known to be involved in immune evasion, including PD-L1 and CD47, were depleted, while genes involved in the IFNγ signaling pathway, including IFNGR, JAK1, and STAT1, were enriched. These observations suggest a putative role for therapeutic strategies that enhance IFNγ sensing and signaling in improving the effectiveness 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 a crucial role in insulin and leptin signaling, and is a major mechanism for downregulating both insulin and leptin receptor signaling pathways (Kenner KA et al., J Biol Chem 271: 19810-19816, 1996 (Non-Patent Literature)). Animals lacking PTP1B exhibit improved glucose regulation and lipid profiles, and are tolerant to weight gain on a high-fat diet (Elchebly M. et al., Science 283: 1544-1548, 1999 (Non-Patent Literature 6)). Therefore, PTP1B inhibitors are expected to be useful in the treatment of type 2 diabetes, obesity, and metabolic syndromes. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Mosinger, B. Jr. et al., Proc Natl Acad Sci USA 89:499-503;1992 [Non-Patent Document 2] Tillmann U. et al., Mol Cell Biol 14:3030-3040;1994 [Non-Patent Document 3] Romsicki Y. et al., Arch Biochem Biophys 414:40-50;2003 [Non-Patent Document 4] Manguso R. T. et al., Nature 547:413-418;2017 [Non-Patent Document 5] Kenner K. A. et al., J Biol Chem 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, inhibitors of protein tyrosine phosphatases, such as PTPN2 and / or PTP1B, are disclosed herein, including compounds disclosed herein, such as compounds of formula (I), formula (II), or formula (III). In other embodiments, 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, are disclosed herein, including administering an effective amount of a compound disclosed herein, such as a compound of formula (I), formula (II), or formula (III).

[0008] For example, disclosed herein is a compound represented by formula (I) TIFF0007881804000001.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 may each independently be substituted, optionally, on one or more available carbons, with one, two, three, or more substituents selected from R g , and -C 1~6If an alkylene-5 to 6-membered heterocycline contains a replaceable ring nitrogen atom, that ring nitrogen atom is optionally R h It may also be replaced by, R 2 These are hydrogen, hydroxyl, -CHF2, -CH2OH, -CH2CN, and -CH2-OC 1~6 Alkyl, -CH2-N(R a )-C 1~6 Alkyl, C 2~6 Alkyl, C 2~6 Alkenyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, -OC(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-OC 1~6 Alkyl, -C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkenylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, 5-6 member heteroaryl, 4-6 member heterocyclyl, -OC 1~6 Alkilen-5~6 member heteroaryl, -O-4~6 member heterocyclyl, -N(R) a )-4~6 member heterocyclyl, -C 1~6 Alkylene-4 to 6-membered heterocyclyls, and -OC 1~6 Selected from the group consisting of alkylene-4-6 member heterocyclyl, except for -CH2-OC 1~6 Alkyl, -CH2-N(R a )-C 1~6 Alkyl, C 2~6 Alkyl, C 2~6 Alkenyl, -OC1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, -OC(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-OC 1~6 Alkyl, -C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, -C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkenylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, 5-6 member heteroaryl, -OC 1~6 Alkylene-5-6 member heteroaryl, 4-6 member heterocyclyl, -O-4-6 member heterocyclyl, -N(R a )-4~6 member heterocyclyl, -C 1~6 Alkylene-4 to 6-membered heterocyclyls, and -OC 1~6 Alkylene-4 to 6-membered heterocyclines can be optionally configured with R on one or more available carbon atoms, each independently. g They may be substituted with one, two, three or more substituents selected from, and include 5-6 member heteroaryls, 4-6 member heterocyclines, and -N(R a )-4~6 member heterocyclyl, -C 1~6 Alkilen-4 to 6-membered heterocyclyl, or -OC 1~6 If an alkylene-4 to 6-membered heterocycline contains a replaceable ring nitrogen atom, that ring nitrogen atom is optionally R h It may also be replaced by, Or, R 1 and R 2forms, together with the atoms to which they are attached, a 5- to 6-membered aryl or heteroaryl, 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 and independently 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 is optionally substituted by R h , R 4is hydrogen, halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 Selected from the group consisting of alkylene-4-6 member heterocyclyl, however, C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 Alkylene-4 to 6-membered heterocyclines can be optionally configured with R on one or more available carbon atoms, each independently. g It may be substituted with one, two, three, or more substituents selected from -C 1~6 If an alkylene-4 to 6-membered heterocycline contains a replaceable ring nitrogen atom, that ring nitrogen atom is optionally R h It may also be replaced by, However, R 1 , R 2 , R 3 , and R 4 At least one of them is not hydrogen, R 5 is hydrogen, halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 Selected from the group consisting of alkylene-4-6 member heterocyclyl, however, C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 Alkylene-4 to 6-membered heterocyclines can be optionally configured with R on one or more available carbon atoms, each independently. g It may be substituted with one, two, three, or more substituents selected from -C 1~6 If an alkylene-4 to 6-membered heterocycline contains a replaceable ring nitrogen atom, that ring nitrogen atom is optionally R h It may also be replaced by, R 6 It is hydrogen, R 7 It is hydrogen, R g Independently of each entity, hydrogen, halogen, hydroxyl, cyano, nitro, oxo, -C(O)OH, R a R bN-, R a R b NC(O)-, R a R b N-SO w -, R a R b NC(O)-N(R a )-, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, phenyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, -(CO)-(NR a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 3~6 Alkenyloxy, C 3~6 Alkynyloxy, C 3~6 Cycloalkoxy, C 1~6 Alkyl-C(O)-, C 1~6 Alkyl-OC(O)-, C 1~6 Alkyl-C(O)-O-, C 1~6 Alkyl-S(O) w -, C 1~6 alkyl-N(R a )-, C 1~6 alkyl-N(R a )-C(O)-, C 1~6 alkyl-C(O)-N(R a ), C 1~6 alkyl-N(R a )-C(O)-N(R a )-, C 1~6 alkyl-N(R a )-SO w -, C 3~6 Cycloalkyl-N(R a )-SO w -, C 1~6 Alkyl-SO w -N(R a )-, C 3~6 Cycloalkyl-SO w -N(R a)-, 4-6 member 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 Selected from the group consisting of alkyl-, however, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, phenyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, -(CO)-(NR a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 3~6 Alkenyloxy, C 3~6 Alkynyloxy, C 3~6 Cycloalkoxy, C 1~6 Alkyl-C(O)-, C 1~6 Alkyl-OC(O)-, C 1~6 Alkyl-C(O)-O-, C 1~6 Alkyl-S(O) w -, C 1~6 alkyl-N(R a )-, C 1~6 alkyl-N(R a )-C(O)-, C 1~6 alkyl-C(O)-N(R a ), C 1~6 alkyl-N(R a )-C(O)-N(R a )-, C 1~6 alkyl-N(R a )-SO w -, C 3~6Cycloalkyl-N(R a )-SO w -, C 1~6 Alkyl-SO w -N(R a )-, C 3~6 Cycloalkyl-SO w -N(R a )-, 4-6 member 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 optional, and each is independently R p It may be substituted with one, two, three, or more substituents selected from the following: R h Independently of each existence, C 1~6 Alkyl, C 3~6 Alkenil, C 3~6 Alkinyl, 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 member heterocyclyl-S(O)2-, 4-6 member heterocyclyl-C 1~6 Alkyl-S(O)2-, 5-6 member heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-C 1~6 Alkyl-S(O)2-, C 1~6 Alkyl-C(O)-, C 1~6 Cycloalkyl-C(O)-, C 1~6 Alkoxy-C(O)-, R a R b NC(O)-, R a R bN-SO2- and -P(O)(C 1~3 Selected from the group consisting of alkyl)2, however, C 1~6 Alkyl, C 3~6 Alkenil, C 3~6 Alkinyl, 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 member heterocyclyl-S(O)2-, 4-6 member heterocyclyl-C 1~6 Alkyl-S(O)2-, 5-6 member heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-C 1~6 Alkyl-S(O)2-, C 1~6 Alkyl-C(O)-, C 1~6 Cycloalkyl-C(O)-, C 1~6 Alkoxy-C(O)-, R a R b NC(O)-, R a R b N-SO2- and -P(O)(C 1~3 Alkyl)2 is optional, and each is independently R p It may be substituted with one, two, three, or more substituents selected from the following: R p These are, independently of each other, halogen, hydroxyl, cyano, and C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, 4-6 member 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 Independently of each entity, hydrogen and C 1~6 Alkyl and C 3~6Selected from the group consisting of cycloalkyl, however, C 1~6 Alkyls can be optionally and independently halogenated, cyano, oxo, hydroxyl, and C. 1~6 It may be substituted with one or more substituents selected from the group consisting of alkoxys (which may optionally be substituted with one, two, or three fluorine atoms), Or, R a and R b However, together with the nitrogen to which they are bound, they form a 4-6 membered heterocycline, wherein the heterocycline may optionally be substituted with one or more substituents independently selected from the group consisting of halogens, cyanos, oxos, and hydroxyls. w is 0, 1, or 2. The above-mentioned compounds, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, stereoisomers, or isotopic enriched variants thereof, are disclosed.

[0009] In this specification, formula (II) A compound represented by TIFF0007881804000002.tif27128, During the ceremony, X is -O- and -N(R a Selected from the group consisting of )-, L is a linear or branched C 1~6 It is alkylene, R 2-II is hydrogen, cyano, -NR a R b , C 1~2 Alkoxy, C 3~6 Cycloalkyl-SO2-N(R a )-, C 1~6 Alkyl-SO2-N(R a )-, phenyl, 5-6 member heteroaryl, 4-6 member heterocyclyl, and C 3~6 Selected from the group consisting of cycloalkyls, provided that phenyl, 5-6 membered heteroaryls, 4-6 membered heterocyclyls, and C 3~6Cycloalkyls can optionally have one or more available carbon atoms independently of a halogen, hydroxyl, or -NR. a R b , C 1~2 Alkyl (which may be optionally substituted with 1, 2, or 3 halogens), and C 1~2 It may be substituted with one, two, or three substituents selected from the group consisting of alkoxys (which may optionally be substituted with one, two, or three halogens), and if it contains a ring nitrogen atom that can be substituted with a 5-6 membered heteroaryl or 4-6 membered heterocyclyl, the ring nitrogen atom may optionally be C 1~3 It may also be substituted with alkyl groups. R 5 It is selected from the group consisting of hydrogen, deuterium, and halogens. R 6 It is selected from the group consisting of hydrogen and deuterium, R 7 It is selected from the group consisting of hydrogen and deuterium, R a and R b For each of their respective existences, hydrogen and C 1~3 Selected from the group consisting of alkyl groups, The above compounds, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof, are also disclosed.

[0010] In this specification, formula (III) A compound represented by TIFF0007881804000003.tif27128, During the ceremony, X III The bonded, -CH2-, -NR a Selected from the group consisting of -, -O-, -O-CH2-, and -OCH2-CH2-, m is 1, 2, or 3. n is 1, 2, or 3. R 1-III These are hydrogen, halogen, hydroxyl, cyano, -NR a R b, C 1~2 Alkyl (which may be optionally substituted with 1, 2, or 3 halogens), and C 1~2 Selected from the group consisting of alkoxys (which may be optionally substituted with 1, 2, or 3 halogens), R 2-III is hydrogen, C 1~4 Alkyl, -C(O)-C 1~4 Alkyl, -C(O)-OC 1~4 Alkyl, -C(O)-N(R a )-C 1~4 Alkyl, -S(O)2-C 1~4 Alkyl and -S(O)2-C 3~6 Selected from the group consisting of cycloalkyl, however, C 1~4 Alkyl, -C(O)-C 1~4 Alkyl, -C(O)-OC 1~4 Alkyl, -C(O)-N(R a )-C 1~4 Alkyl, -S(O)2-C 1~4 Alkyl and -S(O)2-C 3~6 Cycloalkyl groups can be optionally and independently selected from halogen, hydroxyl, cyano, and -NR. a R b , C 1~2 Alkyl (which may be optionally substituted with 1, 2, or 3 halogens), and C 1~2 It may be substituted with one, two, or three substituents selected from the group consisting of alkoxys (which may be optionally substituted with one, two, or three halogens), R 5 It is selected from the group consisting of hydrogen, deuterium, and halogens. R 6 It is selected from the group consisting of hydrogen and deuterium, R 7 It is selected from the group consisting of hydrogen and deuterium, R a and R b For each of their respective existences, hydrogen and C 1~3 Selected from the group consisting of alkyl groups, The above compounds, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof, are also disclosed.

[0011] In this specification, 5-{1-fluoro-3-hydroxy-7-[2-(morpholine-4-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidine-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(pyrrolidine-3-yl)naphthalene-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)naphthalene-2-ylpropane-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-(azetidine-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-methoxy(4- 2 H) Naphthalene-2-yl (4,4- 2 H2)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(methylamino)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[2-(piperidine-4-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-7-{[3-fluoro-1-(propan-2-yl)pyrrolidine-3-yl]methoxy}-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-7-[(3-Fluoropyrrolidine-3-yl)methoxy]-3-hydroxynaphthalene-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)naphthalene-2-yl]oxy}pentanenitrile, 5-{1-fluoro-3-hydroxy-7-[2-(piperidine-1-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(Piperidine-4-yl)methoxy]naphthalene-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)naphthalene-2-yl]oxy}-3,3-dimethylpentanenitrile, 5-{7-[(3,3-dimethylbutyl)amino]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1,4-difluoro-3-hydroxy-7-methoxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[( 2 H3)methyloxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(2-methoxyethoxy)naphthalene-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)naphthalene-2-yl]oxy}-2,2-dimethylbutanenitrile, 5-{7-[2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[2-(dimethylamino)ethyl]amino}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-methoxynaphthalene-2-yl)(4,4- 2 H2)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-methoxynaphthalene-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]aminoethyl)cyclopropanesulfonamide, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidine-3-yl]amino}naphthalene-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]oxyethyl)cyclopropanesulfonamide 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)azetidine-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)naphthalene-2-yl]oxy}butanenitrile, [1-({[8-Fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidined-2-yl)naphthalen-2-yl]oxymethyl)cyclopropyl]acetonitrile, 5-{7-[2-(dimethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)-1H-pyrazole-4-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(1H-pyrazole-4-yl)methoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-methylpropoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(2-hydroxypropoxy)naphthalene-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-thiadiazolidine-2-yl)naphthalene-2-carboxamide, 5-[1-Fluoro-3-hydroxy-7-(2-{[2-(trifluoromethoxy)ethyl]amino}ethoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(2-methoxyethyl)amino]ethoxy}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[3-(methylamino)propyl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(ethylamino)propyl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[5-(dimethylphosphoryl)thiophen-2-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclopropylamino)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(methylamino)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(ethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)amino]ethoxy}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(diethylphosphoryl)propoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3S)-3-hydroxybutoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1,4-difluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3R)-3-hydroxybutoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropyl-2-hydroxyethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(4S)-4-hydroxypentyl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(4-hydroxy-4-methylpentyl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(3-oxopentyl)oxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(3-hydroxybutoxy)naphthalene-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)naphthalene-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)naphthalene-2-yl]oxyethyl)cyclopropane-1-carbonitrile, 5-(1-fluoro-3-hydroxy-7-{2-[1-(methoxymethyl)cyclopropyl]ethoxy}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[(cyclopropylmethyl)amino]methyl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2,2-difluoropropyl)amino]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3,3-dimethyl-4-(methylamino)butoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-phenylethyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3-amino-3-methylbutoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(difluoromethyl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(dimethylphosphoryl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3,3,3-trifluoropropyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(3-methoxy-3-methylbutoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropylpropoxy)-1-fluoro-3-hydroxynaphthalene-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)pyrrolidine-3-yl]methoxy}naphthalene-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)naphthalene-2-yl]amino}butanenitrile, 5-[1-Fluoro-3-hydroxy-7-(2-hydroxyethyl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(4-amino-3,3-dimethylbutoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[2-(azetidine-1-yl)ethyl]amino}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)azetidine-3-yl]oxy}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(2-methoxyethyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3,3,3-trifluoropropoxy)naphthalene-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)naphthalene-2-yl]aminomethyl)cyclopropane-1-carbonitrile, 5-[1-Fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[3-(1H-pyrazole-1-yl)propoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(4-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrole-3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(hydroxymethyl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)piperidine-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)pyrrolidine-2-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[2-(1H-pyrazole-1-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidine-2-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidine-2-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(piperidine-3-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(2,2-difluorocyclopropyl)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(1-methylcyclopropyl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(3-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrole-3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(2-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrole-3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,2-difluoroethyl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2,2,2-trifluoroethoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-7-(2-fluoroethoxy)-3-hydroxynaphthalene-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)naphthalene-2-yl]oxymethyl)cyclopropane-1-carbonitrile, 5-{1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-methylpropyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxynaphthalene-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)naphthalene-2-yl]oxy}acetonitrile, 5-[1-fluoro-3-hydroxy-7-(3-methylbutoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1,8-difluoro-3-hydroxy-7-methoxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)azetidine-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)azetidine-3-yl]-1-fluoro-3-hydroxynaphthalene-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)naphthalene-2-yl]propa-2-ennitrile, 5-[7-(2-cyclopropylethyl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2,2-difluorocyclopropyl)methoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropylethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclopropylmethoxy)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[2-(oxolan-2-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclobutyloxy)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)oxy]ethoxy}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3-ethoxypropoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-tert-butoxyethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[rac-(1R,2R)-2-ethylcyclopropyl]methoxy}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(4-methylpentyl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(2,2-dimethylpropyl)pyrrolidine-1-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(1-chloro-3-hydroxypropan-2-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)pyrrolidine-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(cyclopropyloxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(4-methyl-1H-imidazole-2-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(azetidine-3-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(5-methoxythiophen-2-yl)naphthalene-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)naphthalene-2-yl]acetonitrile, 5-[1-Fluoro-3-hydroxy-7-(methoxymethyl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(3-methyloxetan-3-yl)methoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{4-bromo-7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{4-bromo-7-[1-(cyclopropanesulfonyl)-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(3S)-pyrrolidine-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(3R)-pyrrolidine-3-yl]naphthalene-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-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-cyclopropyl-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-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-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1E)-4-methylpenta-1-en-1-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(pentamethylphenyl)ethenyl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(4-bromo-1-fluoro-3-hydroxy-7-methoxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(2-cyclopropylethyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1E)-3-methoxypropane-1-en-1-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-ethoxyethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(3-methoxypropoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(1,1-dioxo-1λ 6 [-thian-4-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(oxan-3-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(cyclopropylmethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(2,2,2-trifluoroethyl)pyrrolidine-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)piperidine-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}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(oxolan-2-yl)methoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(oxolan-3-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)azetidine-3-yl]methyl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)piperidine-4-yl]methyl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(pyrrolidine-2-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)piperidine-3-yl]methyl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(difluoromethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)pyrrolidine-3-yl]methyl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(pyrrolidine-3-yl)methyl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,5-dihydrofuran-3-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3,6-dihydro-2H-pyran-4-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,5-dihydro-1H-pyrrole-3-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(pyridine-3-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(azetidine-3-yl)methyl]-1-fluoro-3-hydroxynaphthalene-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-thiadiazolidine-2-yl)naphthalene-2-yl]aminoacetamide, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl]oxy}-N-methylbutanamide, N-ethyl-N'-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidined-2-yl)naphthalene-2-yl]oxyethyl)urea, 5-{1-fluoro-3-hydroxy-7-[(oxan-3-yl)methoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(1-chloro-3-hydroxypropane-2-yl)oxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(oxan-4-yl)methoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(oxetane-3-yl)oxy]naphthalene-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-tetrahydropyridine-4-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3,7-dihydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(2-hydroxyethoxy)naphthalene-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]naphthalene-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)naphthalene-2-yl]aminoacetic acid, N-(2-cyclopropylethyl)-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidine-2-yl)naphthalene-2-yl]oxy}acetamide, N,N-diethyl-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidine-2-yl)naphthalene-2-yl]oxy}acetamide, 5-{1-fluoro-3-hydroxy-7-[2-oxo-2-(pyrrolidine-1-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidine-4-yl]oxy}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[1-(oxolan-3-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(2-methoxyethanesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-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-pyrrole-3-yl]naphthalene-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-pyrrole-3-yl]naphthalene-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-pyrrole-3-yl}naphthalene-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-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(butane-1-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(1,4-dioxan-2-yl)methanesulfonyl]-2,5-dihydro-1H-pyrrole-3-yl}-1-fluoro-3-hydroxynaphthalene-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-thiadiazolidined-2-yl)naphthalene-2-yl]-2,5-dihydro-1H-pyrrole-1-sulfonyl}pentanenitrile, 5-{1-fluoro-3-hydroxy-7-[1-(pentan-2-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(ethanesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(propane-2-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-1,2,3,6-tetrahydropyridine-4-yl]-1-fluoro-3-hydroxynaphthalene-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)naphthalene-2-yl]oxyethyl)oxetane-3-sulfonamide, 5-[1-Fluoro-3-hydroxy-7-(piperidine-4-yl)naphthalene-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-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-ethoxy-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,2-difluoroethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-1H-pyrazole-4-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[(3R)-1-(methanesulfonyl)pyrrolidine-3-yl]amino}naphthalene-2-yl)-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidine-4-yl]amino}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)pyrrolidine-3-yl]amino}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-7-{[3-fluoro-1-(methanesulfonyl)pyrrolidine-3-yl]methoxy}3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[1-(propan-2-sulfonyl)pyrrolidine-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxynaphthalene-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-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-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]oxyethyl)ethanesulfonamide, 5-{1-fluoro-7-[1-(furan-3-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(3-methylbutan-1-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(thiophen-3-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(benzenesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclobutanesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-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-thiadiazolidined-2-yl)naphthalen-2-yl]oxy}butanoate methyl, 5-{7-[(3,5-dimethyl-1H-pyrazole-4-yl)methoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3,5-dimethyl-1H-pyrazole-4-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclohexylethoxy)-1-fluoro-3-hydroxynaphthalene-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-thiadiazolidine-2-yl)naphthalene-2-yl]-1H-imidazole-4-carbonitrile Compounds selected from the group consisting of the above, as well as pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof, are further disclosed.

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

[0013] This specification also discloses a method for treating cancer in a patient requiring a method for treating cancer, comprising administering to the patient an effective amount of a compound disclosed herein, for example, 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, this specification discloses a method for treating cancer in a patient requiring a method for treating cancer, the method comprising administering an effective amount of a compound disclosed herein, for example, a compound of formula (I), formula (II), or formula (III), to the patient.

[0015] This specification further provides a method for treating type 2 diabetes in a patient requiring a method for treating type 2 diabetes, comprising administering an effective amount of a compound disclosed herein, for example, a compound of formula (I), formula (II), or formula (III), to the patient.

[0016] For example, this specification discloses a method for treating and / or managing obesity in a patient requiring such treatment and / or management, the method comprising administering to the patient an effective amount of a compound disclosed herein, for example, a compound of formula (I), formula (II), or formula (III).

[0017] For example, this specification discloses a method for controlling further weight gain in an overweight or obese patient who requires a method for controlling further weight gain, the method comprising administering an effective amount of a compound disclosed herein, for example, a compound of formula (I), formula (II), or formula (III), to the patient.

[0018] This specification further discloses a method for treating a metabolic disorder in a patient requiring a treatment method for a metabolic disorder, the method comprising administering an effective amount of one of the compounds disclosed herein, for example, a compound of formula (I), formula (II), or formula (III), to the patient.

[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 secretory cell carcinoma. In some embodiments, the method includes the treatment of metabolic diseases. In some embodiments, the metabolic diseases include non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hepatic fibrosis, obesity, type 2 diabetes, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, metabolic syndrome, or Kearns-Thayer disease.

[0020] This specification also discloses compositions for use in the treatment of cancer in patients who require a composition for use in the treatment of cancer, comprising a compound disclosed herein, for example, 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.

[0021] For example, this specification discloses compositions for use in the treatment of cancer in patients who require a composition for use in the treatment of cancer, comprising the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III).

[0022] This specification further provides compositions for use in the treatment of type 2 diabetes in patients who require a composition for use in the treatment of type 2 diabetes, comprising the compounds disclosed herein, for example, the compound of formula (I), formula (II), or formula (III).

[0023] For example, this specification discloses compositions for use in the treatment and / or management of obesity in patients requiring a composition for use in the treatment and / or management of obesity, comprising a compound disclosed herein, for example, a compound of formula (I), formula (II), or formula (III).

[0024] For example, this specification discloses compositions for use in suppressing further weight gain in overweight or obese patients who require a composition for use in suppressing further weight gain, comprising the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III).

[0025] This specification further discloses compositions for use in the treatment of metabolic diseases in patients requiring compositions for use in the treatment of metabolic diseases, comprising the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III).

[0026] In some embodiments, the cancers include pancreatic cancer, breast cancer, multiple myeloma, melanoma, or carcinoma of secretory cells. In some embodiments, the metabolic diseases include non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hepatic fibrosis, obesity, type 2 diabetes, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, metabolic syndromes, or Kearns-Thayer disease.

[0027] A brief explanation of sequence listings The entire sequence listing, titled "CLS-014WO_SEQ_ID_List_ST25," including SEQ ID NOs. 1 to 3, which contain the amino acid sequences disclosed herein, is incorporated herein by reference. The above sequence listing is submitted attached herein via EFS in ASCII text format. The sequence listing was first created on June 13, 2019, and its size is 8KB. [Invention 1001] Equation (I) A compound represented by TIFF0007881804000004.tif28128, During the ceremony, R 1 is hydrogen, halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl and -C 1~6 Selected from the group consisting of alkylene-5-6 member heterocyclines, however, C 1~6 Alkyl, C 3~6 Cycloalkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl and -C 1~6 Alkylene-5 to 6-membered heterocyclines can be optionally configured with R on one or more available carbon atoms, each independently. g It may be substituted with one, two, three, or more substituents selected from -C 1~6 If an alkylene-5 to 6-membered heterocycline contains a replaceable ring nitrogen atom, that ring nitrogen atom is optionally R h It may also be replaced by, R 2 These are hydrogen, hydroxyl, -CHF2, -CH2OH, -CH2CN, and -CH2-OC 1~6 Alkyl, -CH2-N(R a )-C 1~6 Alkyl, C 2~6 Alkyl, C 2~6 Alkenyl, -OC 1~6Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, -OC(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-OC 1~6 Alkyl, -C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkenylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, 5-6 member heteroaryl, 4-6 member heterocyclyl, -OC 1~6 Alkilen-5~6 member heteroaryl, -O-4~6 member heterocyclyl, -N(R) a )-4~6 member heterocyclyl, -C 1~6 Alkylene-4 to 6-membered heterocyclyls, and -OC 1~6 Selected from the group consisting of alkylene-4-6 member heterocyclyl, except for -CH2-OC 1~6 Alkyl, -CH2-N(R a )-C 1~6 Alkyl, C 2~6 Alkyl, C 2~6 Alkenyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, -OC(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-OC 1~6Alkyl, -C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, -C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkenylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, 5-6 member heteroaryl, -OC 1~6 Alkylene-5-6 member heteroaryl, 4-6 member heterocyclyl, -O-4-6 member heterocyclyl, -N(R a )-4~6 member heterocyclyl, -C 1~6 Alkylene-4 to 6-membered heterocyclyls, and -OC 1~6 Alkylene-4 to 6-membered heterocyclines can be optionally configured with R on one or more available carbon atoms, each independently. g They may be substituted with one, two, three or more substituents selected from, and include 5-6 member heteroaryls, 4-6 member heterocyclines, and -N(R a )-4~6 member heterocyclyl, -C 1~6 Alkilen-4 to 6-membered heterocyclyl, or -OC 1~6 If an alkylene-4 to 6-membered heterocycline contains a replaceable ring nitrogen atom, that ring nitrogen atom is optionally R h It may also be replaced by, Or, R 1 and R 2 However, together with the atoms they bond to, they form 5-6 membered aryl or heteroaryl compounds, where the aryl or heteroaryl is optional and can be independently a halogen, hydroxyl, cyano, or C13. 1~6 Alkyl and C 1~6 It may be substituted with one or more substituents selected from the group consisting of alkoxys, provided that C 1~6 Alkyl and C 1~6 The alkoxys are optional and each is independently R p It may be substituted with one, two, three, or more substituents selected from the following: R 3 is hydrogen, -C 1~6Alkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl and -C 1~6 Selected from the group consisting of alkylene-4 to 6-membered heterocyclines, provided that -C 1~6 Alkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl and -C 1~6 Alkylene-4 to 6-membered heterocyclines can be optionally configured with R on one or more available carbon atoms, each independently. g It may be substituted with one, two, three, or more substituents selected from -C 1~6 If an alkylene-4 to 6-membered heterocycline contains a replaceable ring nitrogen atom, that ring nitrogen atom is optionally R h It may also be replaced by, R 4 is hydrogen, halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 Selected from the group consisting of alkylene-4-6 member heterocyclyl, however, C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 Alkylene-4 to 6-membered heterocyclines can be optionally configured with R on one or more available carbon atoms, each independently. g It may be substituted with one, two, three, or more substituents selected from -C 1~6If an alkylene-4 to 6-membered heterocycline contains a replaceable ring nitrogen atom, that ring nitrogen atom is optionally R h It may also be replaced by, However, R 1 , R 2 , R 3 , and R 4 At least one of them is not hydrogen, R 5 is hydrogen, halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 Selected from the group consisting of alkylene-4-6 member heterocyclyl, however, C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 Alkylene-4 to 6-membered heterocyclines can be optionally configured with R on one or more available carbon atoms, each independently. g It may be substituted with one, two, three, or more substituents selected from -C 1~6 If an alkylene-4 to 6-membered heterocycline contains a replaceable ring nitrogen atom, that ring nitrogen atom is optionally R h It may also be replaced by, R 6 It is hydrogen, R 7 It is hydrogen, R g Independently of each entity, hydrogen, halogen, hydroxyl, cyano, nitro, oxo, -C(O)OH, R a R b N-, R a R b NC(O)-, R a R b N-SO w -, R a R b NC(O)-N(R a )-, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, phenyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -OC1~6 Alkylene-C 3~6 Cycloalkyl, -(CO)-(NR a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 3~6 Alkenyloxy, C 3~6 Alkynyloxy, C 3~6 Cycloalkoxy, C 1~6 Alkyl-C(O)-, C 1~6 Alkyl-OC(O)-, C 1~6 Alkyl-C(O)-O-, C 1~6 Alkyl-S(O) w -, C 1~6 alkyl-N(R a )-, C 1~6 alkyl-N(R a )-C(O)-, C 1~6 alkyl-C(O)-N(R a ), C 1~6 alkyl-N(R a )-C(O)-N(R a )-, C 1~6 alkyl-N(R a )-SO w -, C 3~6 Cycloalkyl-N(R a )-SO w -, C 1~6 Alkyl-SO w -N(R a )-, C 3~6 Cycloalkyl-SO w -N(R a )-, 4-6 member 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-, however, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, phenyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, -(CO)-(NR a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 3~6 Alkenyloxy, C 3~6 Alkynyloxy, C 3~6 Cycloalkoxy, C 1~6 Alkyl-C(O)-, C 1~6 Alkyl-OC(O)-, C 1~6 Alkyl-C(O)-O-, C 1~6 Alkyl-S(O) w -, C 1~6 alkyl-N(R a )-, C 1~6 alkyl-N(R a )-C(O)-, C 1~6 alkyl-C(O)-N(R a ), C 1~6 alkyl-N(R a )-C(O)-N(R a )-, C 1~6 alkyl-N(R a )-SO w -, C 3~6 Cycloalkyl-N(R a )-SO w -, C 1~6 Alkyl-SO w -N(R a )-, C 3~6 Cycloalkyl-SO w -N(R a )-, 4-6 member 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 optional, and each is independently R p It may be substituted with one, two, three, or more substituents selected from the following: R h Independently of each existence, C 1~6 Alkyl, C 3~6 Alkenil, C 3~6 Alkinyl, 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 member heterocyclyl-S(O)2-, 4-6 member heterocyclyl-C 1~6 Alkyl-S(O)2-, 5-6 member heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-C 1~6 Alkyl-S(O)2-, C 1~6 Alkyl-C(O)-, C 1~6 Cycloalkyl-C(O)-, C 1~6 Alkoxy-C(O)-, R a R b NC(O)-, R a R b N-SO2- and -P(O)(C 1~3 Selected from the group consisting of alkyl)2, however, C 1~6 Alkyl, C 3~6 Alkenil, C 3~6 Alkinyl, 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 member heterocyclyl-S(O)2-, 4-6 member heterocyclyl-C 1~6Alkyl-S(O)2-, 5- to 6-member 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, each independently, substituted by one, two, three, or more substituents selected from R p and may be substituted by one, two, three, or more substituents selected from R R p is, for each occurrence independently, halogen, hydroxyl, cyano, C 1~6 alkyl, C 1~6 alkoxy, C 3~6 cycloalkyl, 4- to 6-member 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, for each occurrence independently, 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, each independently, substituted by one or more substituents selected from 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 bHowever, together with the nitrogen to which they are bound, they form a 4-6 membered heterocycline, wherein the heterocycline may optionally be substituted with one or more substituents independently selected from the group consisting of halogens, cyano, oxo, and hydroxyl. w is 0, 1, or 2. The aforementioned compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, stereoisomer, or isotopic enriched variant thereof. [Invention 1002] The compound of the present invention 1001, wherein one, two, three, or more hydrogen atoms of the compound may be optionally deuterium atoms, and all other atoms of the compound are present in their naturally occurring isotopic abundances. [Invention 1003] One, two, three, or more hydrogen atoms are arbitrarily selected and each independently R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R g The compounds of the present invention 1001 or 1002, which may be deuterium atoms in one, two, three or more groups selected from the above. [Invention 1004] R 1 However, any of the compounds 1001 to 1003 of the present invention, selected from the group consisting of hydrogen, deuterium, chlorine, and fluorine. [Invention 1005] R 2 It is a 4-6 member heterocycline, however, R 2 This is optional, and R is independently applied to one or more available carbon atoms. g It may be substituted by one, two, or three substituents selected from, and if the 4- to 6-membered heterocyclyl contains a substituted ring nitrogen atom, the ring nitrogen atom may optionally be R h A compound of any of the present invention 1001 to 1004, which may be substituted with a substituent selected from the above. [Invention 1006] R2 It is a 4-6 member heterocycline, however, R 2 This is optional, with one or more available carbon atoms, each independently containing hydrogen and C 1~6 R may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups, 2 If it contains a substituted ring nitrogen atom, that ring nitrogen atom may optionally be hydrogen, C 1~6 Alkyl (which may optionally be substituted with 1, 2, or 3 fluorine atoms), -C 1~6 Alkyl-C 3~6 Cycloalkyl, C 1~6 Cycloalkyl-C(O)-, C 1~6 Alkyl-S(O)2- (which may optionally be substituted with cyano, methoxy, or 1, 2, or 3 fluorine atoms), C 3~6 Cycloalkyl-S(O)2-, 4-6 member heterocyclyl-S(O)2-, 4-6 member heterocyclyl-C 1~6 Alkyl-S(O)2-, 5-6 member heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-C 1~6 Alkyl-S(O)2-(Optional R a R b (may be substituted by N-), and -P(O)(C 1~3 A compound according to any one of the present invention 1001 to 1005, which may be substituted with a substituent selected from the group consisting of alkyl)2. [Invention 1007] R 2 but, A compound selected from the group consisting of TIFF0007881804000005.tif198148TIFF0007881804000006.tif55139, which is any of the compounds 1001 to 1006 of the present invention. [Invention 1008] R 2 It is a 5-6 member heteroaryl, however, R 2 This is optional, and R is independently applied to one or more available carbon atoms. g R may be substituted with one, two, or three substituents selected from 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 a compound of any one of the compounds 1001 to 1004 of the present invention, 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 1, 2, or 3 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 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 a compound 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 TIFF0007881804000007.tif47145, and is a compound 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 1, 2, or 3 substituents selected from, 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 R h and is a compound of any one of the compounds 1001 to 1004 of the present invention, which may be substituted by a substituent selected from [The present invention 1012] R 2 is -O-C 1~6 alkylene-4- to 6-membered heterocyclyl, provided that R 2However, at will, on one or more available carbon atoms, hydrogen, halogen, and C can be independently selected. 1~6 R may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups, 2 If it contains a substituted ring nitrogen atom, that ring nitrogen atom may optionally be hydrogen, C 1~6 Alkyl and C 1~6 The compound of the present invention 1011, which may be substituted with a substituent selected from the group consisting of alkyl-S(O)2-. [Invention 1013] R 2 but, A compound of the present invention 1011 or 1012, selected from the group consisting of TIFF0007881804000008.tif71132. [Invention 1014] R 2 ga-OC 1~6 A compound of any of the present invention 1001 to 1004, which is an alkylene-5 to 6-membered heteroaryl. [Invention 1015] R 2 but, A compound of the present invention 1014, selected from the group consisting of TIFF0007881804000009.tif19128. [Invention 1016] R 2 However, -C 2~6 Alkyl, C 2~6 Alkenyl and C 3~6 Selected from the group consisting of cycloalkyl, however, R 2 These are optional choices, and each is independently R g A compound of any of the present invention 1001 to 1004, which may be substituted with one, two, three or more substituents selected from the above. [Invention 1017] R 2 However, -C 2~6 Alkyl, C 2~6 Alkenil, 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, however, R 2 These are optional and can be independently selected as cyano, chlorine, fluorine, hydroxyl, and C. 1~6 Alkoxy, phenyl, and R a R b The compound of the present invention 1016, which may be substituted with one, two, three or more substituents selected from the group consisting of N-. [Invention 1018] R 2 but, -CH2CHF2, A compound of the present invention 1016 or 1017, selected from the group consisting of TIFF0007881804000010.tif60147. [Invention 1019] R 2 ga-OC 1~6 It is alkyl, however, R 2 These are optional choices, and each is independently R g A compound of any of the present invention 1001 to 1004, which may be substituted with one, two, three or more substituents selected from the above. [Invention 1020] R 2 ga-OC 1~6 It is alkyl, however, R 2 These are optional and can be independently selected as cyano, deuterium, chlorine, fluorine, hydroxyl, oxo, and C. 1~6 Alkoxy, C 3~6 Cycloalkoxy, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, -(CO)-(NR a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Alkyl-OC(O)-, R a R b N-(however, R b (This may be optionally replaced by -OCH3 or -OCF3), C 1~6 alkyl-N(R a )-, R a R bNC(O)-, -P(O)(C 1~3 Alkyl)2, C 1~6 alkyl-N(R a )-C(O)-, C 1~6 alkyl-N(R a )-C(O)-N(R a )-, C 1~6 Alkyl-SO2-N(R a )-, C 3~6 Cycloalkyl-SO2-N(R a )-, and 4-6 member heterocyclyl-SO2-N(R a A compound of the present invention 1019, which may be substituted with one, two, three or more substituents selected from the group consisting of )-. [Invention 1021] R 2 but, -OCH3, -OCD3, -OCF3, -OCHF2, -OCH2CH3, A compound of the present invention 1019 or 1020, selected from the group consisting of TIFF0007881804000011.tif73150 and TIFF0007881804000012.tif116145. [Invention 1022] R 2 ga-OC 3~6 It is a cycloalkyl or -O-4~6 member heterocycline, however, R 2 If it contains a replaceable ring nitrogen atom, that ring nitrogen atom may optionally be R h A compound of any of the present invention 1001 to 1004, which may be substituted with a substituent selected from the above. [Invention 1023] R 2 ga-OC 3~6 It is a cycloalkyl or -O-4~6 member heterocycline, however, R 2 If it contains a replaceable ring nitrogen atom, that ring nitrogen atom may optionally be C 1~6 Alkyl-SO2-N(R a )- and C 3~6 Cycloalkyl-SO2-N(R a The compound of the present invention 1022, which may be substituted with a substituent selected from the group consisting of )-. [Invention 1024] R 2 but, A compound of the present invention 1022 or 1023, selected from the group consisting of TIFF0007881804000013.tif19128. [Invention 1025] R 2 ga-N(R a )-C 1~6 It is alkyl, however, R 2 These are optional choices, and each is independently R g A compound of any of the present invention 1001 to 1004, which may be substituted with one, two, or three substituents selected from the above. [Invention 1026] R 2 ga-N(R a )-C 1~6 It is alkyl, however, R 2 These are optional and can be independently selected as fluoro, -C(O)OH, cyano, oxo, and 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 A compound of the present invention 1025, which may be substituted with one, two, or three substituents selected from the group consisting of cycloalkyl groups. [Invention 1027] R 2 but, -N(H)CH3, A compound of the present invention 1025 or 1026, selected from the group consisting of TIFF0007881804000014.tif66134. [Invention 1028] R 2 ga-OC 1~6 Alkylene-C 3~6 It is a cycloalkyl group, however, R 2 These are optional choices, and each is independently R gA compound of any of the present invention 1001 to 1004, which may be substituted with one, two, or three substituents selected from the above. [Invention 1029] R 2 ga-OC 1~6 Alkylene-C 3~6 It is a cycloalkyl group, however, R 2 These are optional and can be independently selected as fluoro, hydroxyl, and R. a R b N-, cyano, and C 1~3 It may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups, provided that C 1~3 Alkyl groups can be optionally cyano and C. 1~3 The compound of the present invention 1028, which may be substituted with a substituent selected from the group consisting of alkoxys. [Invention 1030] R 2 but, A compound of the present invention 1028 or 1029, selected from the group consisting of TIFF0007881804000015.tif53140. [Invention 1031] R 2 -OC(O)-N(R a )-C 1~6 A compound according to any of the present invention 1001 to 1004, which is alkyl. [Invention 1032] R 2 but The compound of the present invention 1031, represented by TIFF0007881804000016.tif13128. [Invention 1033] R 2 ga-N(R a )-4~6 member heterocyclyl, however, R 2 If it contains a replaceable ring nitrogen atom, that ring nitrogen atom may optionally be R h A compound of any of the present invention 1001 to 1004, which may be substituted with a substituent selected from the above. [Invention 1034] R 2 ga-N(Ra )-4~6 member heterocyclyl, however, R 2 If it contains a replaceable ring nitrogen atom, that ring nitrogen atom may optionally be C 1~6 Alkyl-SO2-N(R a )- and C 3~6 Cycloalkyl-SO2-N(R a The compound of the present invention 1033, which may be substituted with a substituent selected from the group consisting of )-. [Invention 1035] R 2 but, A compound of the present invention 1033 or 1034, selected from the group consisting of TIFF0007881804000017.tif28128. [Invention 1036] R 2 ga-C 1~6 It is an alkylene-4 to 6-membered heterocycline, however, R 2 If it contains a replaceable ring nitrogen atom, that ring nitrogen atom may optionally be R h A compound of any of the present invention 1001 to 1004, which may be substituted with a substituent selected from the above. [Invention 1037] R 2 ga-C 1~6 It is an alkylene-4 to 6-membered heterocycline, however, R 2 If it contains a replaceable ring nitrogen atom, that ring nitrogen atom may optionally be C 1~6 Alkyl, C 1~6 Alkyl-SO2-N(R a )-, and C 3~6 Cycloalkyl-SO2-N(R a )- may be substituted with substituents selected from the group consisting of, however C 1~6 The alkyl group of the compound 1036 of the present invention may optionally be substituted with one, two, or three fluorine atoms. [Invention 1038] R 2 but, A compound of the present invention 1036 or 1037, selected from the group consisting of TIFF0007881804000018.tif48128. [Invention 1039] R 2 but, -CHF2, -CH2OH, -CH2OCH3, -CH2CN, -OH, A compound selected from the group consisting of TIFF0007881804000019.tif14128, any of the compounds 1001 to 1004 of the present invention. [Invention 1040] R 1 and R 2 However, the compound of the present invention 1001 forms a five-membered heteroaryl compound with the atoms to which they bond. [Invention 1041] R 1 and R 2 However, the compound of the present invention 1040 forms furanyl with the atoms to which they bond. [Invention 1042] Compound 1040 or 1041 of the present invention, represented by TIFF0007881804000020.tif27128. [Invention 1043] R 3 A compound according to any of the invention 1001 to 1042, wherein the compound is hydrogen. [Invention 1044] R 4 A compound according to any of the inventions 1001 to 1043, wherein the compound is hydrogen. [Invention 1045] R 5 However, any of the compounds 1001 to 1044 of the present invention, selected from the group consisting of hydrogen, deuterium, bromine, chlorine, and fluorine. [Invention 1046] R 6 However, any compound selected from the group consisting of hydrogen and deuterium, according to invention 1001 to 1045. [Invention 1047] R 7 However, any compound selected from the group consisting of hydrogen and deuterium, according to any of the invention items 1001 to 1046. [Invention 1048] A compound according to any of the present invention 1001 to 1047, wherein all atoms of the aforementioned compound are present in their naturally occurring isotopic abundances. [Invention 1049] Formula (II) A compound represented by TIFF0007881804000021.tif28128, During the ceremony, X is -O- and -N(R a Selected from the group consisting of )-, L is a linear or branched C 1~6 It is alkylene, R 2-II is hydrogen, cyano, -NR a R b , C 1~2 Alkoxy, C 3~6 Cycloalkyl-SO2-N(R a )-, C 1~6 Alkyl-SO2-N(R a )-, phenyl, 5-6 member heteroaryl, 4-6 member heterocyclyl, and C 3~6 Selected from the group consisting of cycloalkyls, provided that phenyl, 5-6 membered heteroaryls, 4-6 membered heterocyclyls, and C 3~6 Cycloalkyls can optionally have one or more available carbon atoms independently of a halogen, hydroxyl, or -NR. a R b , C 1~2 Alkyl (which may be optionally substituted with 1, 2, or 3 halogens), and C 1~2 It may be substituted with one, two, or three substituents selected from the group consisting of alkoxys (which may optionally be substituted with one, two, or three halogens), and if it contains a ring nitrogen atom that can be substituted with a 5-6 membered heteroaryl or 4-6 membered heterocyclyl, the ring nitrogen atom may optionally be C 1~3 It may also be substituted with alkyl groups. R 5 It is selected from the group consisting of hydrogen, deuterium, and halogens. R 6 It is selected from the group consisting of hydrogen and deuterium, R7 It is selected from the group consisting of hydrogen and deuterium, R a and R b For each of their respective existences, hydrogen and C 1~3 Selected from the group consisting of alkyl groups, The aforementioned compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. [Invention 1050] A compound of the present invention 1049, wherein X is selected from the group consisting of -O-, -N(H)-, and -N(CH3)-. [Invention 1051] L, Selected from the group consisting of TIFF0007881804000022.tif25133, where * and # are R respectively. 2-II A compound of the present invention 1049 or 1050, representing a covalent bond site with respect to X. [Invention 1052] R 2-II However, hydrogen, cyano, -NH2, -N(CH3)2, -OCH3, A compound selected from the group consisting of TIFF0007881804000023.tif54150, any of the compounds 1049 to 1051 of the present invention. [Invention 1053] R 5 However, any of the compounds 1049 to 1052 of the present invention, selected from the group consisting of hydrogen, deuterium, and fluorine. [Invention 1054] Formula (III) A compound represented by TIFF0007881804000024.tif28128, During the ceremony, X III The bonded, -CH2-, -NR a Selected from the group consisting of -, -O-, -O-CH2-, and -OCH2-CH2-, m is 1, 2, or 3. n is 1, 2, or 3. R 1-IIIThese are hydrogen, halogen, hydroxyl, cyano, -NR a R b , C 1~2 Alkyl (which may be optionally substituted with 1, 2, or 3 halogens), and C 1~2 Selected from the group consisting of alkoxys (which may be optionally substituted with 1, 2, or 3 halogens), R 2-III is hydrogen, C 1~4 Alkyl, -C(O)-C 1~4 Alkyl, -C(O)-OC 1~4 Alkyl, -C(O)-N(R a )-C 1~4 Alkyl, -S(O)2-C 1~4 Alkyl and -S(O)2-C 3~6 Selected from the group consisting of cycloalkyl, however, C 1~4 Alkyl, -C(O)-C 1~4 Alkyl, -C(O)-OC 1~4 Alkyl, -C(O)-N(R a )-C 1~4 Alkyl, -S(O)2-C 1~4 Alkyl and -S(O)2-C 3~6 Cycloalkyl groups can be optionally and independently selected from halogen, hydroxyl, cyano, and -NR. a R b , C 1~2 Alkyl (which may be optionally substituted with 1, 2, or 3 halogens), and C 1~2 It may be substituted with one, two, or three substituents selected from the group consisting of alkoxys (which may be optionally substituted with one, two, or three halogens), R 5 It is selected from the group consisting of hydrogen, deuterium, and halogens. R 6 It is selected from the group consisting of hydrogen and deuterium, R 7 It is selected from the group consisting of hydrogen and deuterium, R a and R b For each of their respective existences, hydrogen and C1~3 Selected from the group consisting of alkyl groups, The aforementioned compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide, or stereoisomer thereof. [Invention 1055] X III The compound of the present invention 1054, selected from the group consisting of a bond, -CH2, -O-, -NH-, and -O-CH2-. [Invention 1056] R 2-III The compound of the present invention 1054 or 1055, selected from the group consisting of hydrogen, isopropyl, -CH2CF3, -S(O)2-CH3, and -S(O)2-cyclopropyl. [Invention 1057] R 5 However, any of the compounds 1054 to 1056 of the present invention, selected from the group consisting of hydrogen, deuterium, and fluorine. [Invention 1058] 5-{1-fluoro-3-hydroxy-7-[2-(morpholine-4-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidine-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(pyrrolidine-3-yl)naphthalene-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)naphthalene-2-ylpropane-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-(azetidine-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-methoxy(4- 2 H) Naphthalene-2-yl (4,4- 2 H2)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(methylamino)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[2-(piperidine-4-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-7-{[3-fluoro-1-(propan-2-yl)pyrrolidine-3-yl]methoxy}-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-7-[(3-Fluoropyrrolidine-3-yl)methoxy]-3-hydroxynaphthalene-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)naphthalene-2-yl]oxy}pentanenitrile, 5-{1-fluoro-3-hydroxy-7-[2-(piperidine-1-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(Piperidine-4-yl)methoxy]naphthalene-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)naphthalene-2-yl]oxy}-3,3-dimethylpentanenitrile, 5-{7-[(3,3-dimethylbutyl)amino]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1,4-difluoro-3-hydroxy-7-methoxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[( 2 H3)methyloxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(2-methoxyethoxy)naphthalene-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)naphthalene-2-yl]oxy}-2,2-dimethylbutanenitrile, 5-{7-[2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[2-(dimethylamino)ethyl]amino}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-methoxynaphthalene-2-yl)(4,4-2 H2)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-methoxynaphthalene-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]aminoethyl)cyclopropanesulfonamide, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidine-3-yl]amino}naphthalene-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]oxyethyl)cyclopropanesulfonamide 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)azetidine-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)naphthalene-2-yl]oxy}butanenitrile, [1-({[8-Fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidined-2-yl)naphthalen-2-yl]oxymethyl)cyclopropyl]acetonitrile, 5-{7-[2-(dimethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)-1H-pyrazole-4-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(1H-pyrazole-4-yl)methoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-methylpropoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(2-hydroxypropoxy)naphthalene-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-thiadiazolidine-2-yl)naphthalene-2-carboxamide, 5-[1-Fluoro-3-hydroxy-7-(2-{[2-(trifluoromethoxy)ethyl]amino}ethoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(2-methoxyethyl)amino]ethoxy}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[3-(methylamino)propyl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(ethylamino)propyl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[5-(dimethylphosphoryl)thiophen-2-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclopropylamino)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(methylamino)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(ethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)amino]ethoxy}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(diethylphosphoryl)propoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3S)-3-hydroxybutoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1,4-difluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3R)-3-hydroxybutoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropyl-2-hydroxyethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalene-2-yl}-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(4S)-4-hydroxypentyl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(4-hydroxy-4-methylpentyl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(3-oxopentyl)oxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(3-hydroxybutoxy)naphthalene-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)naphthalene-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)naphthalene-2-yl]oxyethyl)cyclopropane-1-carbonitrile, 5-(1-fluoro-3-hydroxy-7-{2-[1-(methoxymethyl)cyclopropyl]ethoxy}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[(cyclopropylmethyl)amino]methyl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2,2-difluoropropyl)amino]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3,3-dimethyl-4-(methylamino)butoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-phenylethyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3-amino-3-methylbutoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(difluoromethyl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(dimethylphosphoryl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3,3,3-trifluoropropyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(3-methoxy-3-methylbutoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropylpropoxy)-1-fluoro-3-hydroxynaphthalene-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)pyrrolidine-3-yl]methoxy}naphthalene-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)naphthalene-2-yl]amino}butanenitrile, 5-[1-Fluoro-3-hydroxy-7-(2-hydroxyethyl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(4-amino-3,3-dimethylbutoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[2-(azetidine-1-yl)ethyl]amino}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)azetidine-3-yl]oxy}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(2-methoxyethyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3,3,3-trifluoropropoxy)naphthalene-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)naphthalene-2-yl]aminomethyl)cyclopropane-1-carbonitrile, 5-[1-Fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[3-(1H-pyrazole-1-yl)propoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(4-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrole-3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(hydroxymethyl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)piperidine-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)pyrrolidine-2-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[2-(1H-pyrazole-1-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidine-2-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidine-2-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(piperidine-3-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(2,2-difluorocyclopropyl)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(1-methylcyclopropyl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(3-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrole-3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(2-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrole-3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,2-difluoroethyl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2,2,2-trifluoroethoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-7-(2-fluoroethoxy)-3-hydroxynaphthalene-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)naphthalene-2-yl]oxymethyl)cyclopropane-1-carbonitrile, 5-{1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-methylpropyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxynaphthalene-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)naphthalene-2-yl]oxy}acetonitrile, 5-[1-fluoro-3-hydroxy-7-(3-methylbutoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1,8-difluoro-3-hydroxy-7-methoxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)azetidine-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)azetidine-3-yl]-1-fluoro-3-hydroxynaphthalene-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)naphthalene-2-yl]propa-2-ennitrile, 5-[7-(2-cyclopropylethyl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2,2-difluorocyclopropyl)methoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropylethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclopropylmethoxy)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[2-(oxolan-2-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclobutyloxy)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)oxy]ethoxy}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3-ethoxypropoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-tert-butoxyethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[rac-(1R,2R)-2-ethylcyclopropyl]methoxy}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(4-methylpentyl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(2,2-dimethylpropyl)pyrrolidine-1-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(1-chloro-3-hydroxypropan-2-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)pyrrolidine-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(cyclopropyloxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(4-methyl-1H-imidazole-2-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(azetidine-3-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(5-methoxythiophen-2-yl)naphthalene-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)naphthalene-2-yl]acetonitrile, 5-[1-Fluoro-3-hydroxy-7-(methoxymethyl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(3-methyloxetan-3-yl)methoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{4-bromo-7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{4-bromo-7-[1-(cyclopropanesulfonyl)-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(3S)-pyrrolidine-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(3R)-pyrrolidine-3-yl]naphthalene-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-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-cyclopropyl-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-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-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1E)-4-methylpenta-1-en-1-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(pentamethylphenyl)ethenyl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(4-bromo-1-fluoro-3-hydroxy-7-methoxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(2-cyclopropylethyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1E)-3-methoxypropane-1-en-1-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-ethoxyethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(3-methoxypropoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(1,1-dioxo-1λ 6 [-thian-4-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(oxan-3-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(cyclopropylmethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(2,2,2-trifluoroethyl)pyrrolidine-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)piperidine-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}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(oxolan-2-yl)methoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(oxolan-3-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)azetidine-3-yl]methyl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)piperidine-4-yl]methyl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(pyrrolidine-2-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)piperidine-3-yl]methyl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(difluoromethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)pyrrolidine-3-yl]methyl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(pyrrolidine-3-yl)methyl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,5-dihydrofuran-3-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3,6-dihydro-2H-pyran-4-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,5-dihydro-1H-pyrrole-3-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(pyridine-3-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(azetidine-3-yl)methyl]-1-fluoro-3-hydroxynaphthalene-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-thiadiazolidine-2-yl)naphthalene-2-yl]aminoacetamide, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ6 ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl]oxy}-N-methylbutanamide, N-ethyl-N'-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidined-2-yl)naphthalene-2-yl]oxyethyl)urea, 5-{1-fluoro-3-hydroxy-7-[(oxan-3-yl)methoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(1-chloro-3-hydroxypropane-2-yl)oxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(oxan-4-yl)methoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(oxetane-3-yl)oxy]naphthalene-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-tetrahydropyridine-4-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3,7-dihydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(2-hydroxyethoxy)naphthalene-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]naphthalene-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)naphthalene-2-yl]aminoacetic acid, N-(2-cyclopropylethyl)-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidine-2-yl)naphthalene-2-yl]oxy}acetamide, N,N-diethyl-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidine-2-yl)naphthalene-2-yl]oxy}acetamide, 5-{1-fluoro-3-hydroxy-7-[2-oxo-2-(pyrrolidine-1-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidine-4-yl]oxy}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[1-(oxolan-3-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(2-methoxyethanesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-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-pyrrole-3-yl]naphthalene-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-pyrrole-3-yl]naphthalene-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-pyrrole-3-yl}naphthalene-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-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(butane-1-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(1,4-dioxan-2-yl)methanesulfonyl]-2,5-dihydro-1H-pyrrole-3-yl}-1-fluoro-3-hydroxynaphthalene-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-thiadiazolidined-2-yl)naphthalene-2-yl]-2,5-dihydro-1H-pyrrole-1-sulfonyl}pentanenitrile, 5-{1-fluoro-3-hydroxy-7-[1-(pentan-2-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(ethanesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(propane-2-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-1,2,3,6-tetrahydropyridine-4-yl]-1-fluoro-3-hydroxynaphthalene-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)naphthalene-2-yl]oxyethyl)oxetane-3-sulfonamide, 5-[1-Fluoro-3-hydroxy-7-(piperidine-4-yl)naphthalene-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-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-ethoxy-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,2-difluoroethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-1H-pyrazole-4-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[(3R)-1-(methanesulfonyl)pyrrolidine-3-yl]amino}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidine-4-yl]amino}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)pyrrolidine-3-yl]amino}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-7-{[3-fluoro-1-(methanesulfonyl)pyrrolidine-3-yl]methoxy}3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[1-(propan-2-sulfonyl)pyrrolidine-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxynaphthalene-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-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-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]oxyethyl)ethanesulfonamide, 5-{1-fluoro-7-[1-(furan-3-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(3-methylbutan-1-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(thiophen-3-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(benzenesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclobutanesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-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-thiadiazolidined-2-yl)naphthalen-2-yl]oxy}butanoate methyl, 5-{7-[(3,5-dimethyl-1H-pyrazole-4-yl)methoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3,5-dimethyl-1H-pyrazole-4-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclohexylethoxy)-1-fluoro-3-hydroxynaphthalene-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-thiadiazolidine-2-yl)naphthalene-2-yl]-1H-imidazole-4-carbonitrile Compounds selected from the group consisting of the above, as well as pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof. [Invention 1059] A pharmaceutically acceptable composition comprising any compound according to invention 1001 to 1058 and a pharmaceutically acceptable carrier. [Invention 1060] A composition of the present invention 1059, formulated for oral administration. [Invention 1061] A method for treating cancer in a patient requiring a cancer treatment method, comprising administering an effective amount of any compound 1001 to 1058 of the present invention to the patient in combination with a further therapeutic agent. [Invention 1062] A method for treating cancer in a patient requiring a method for treating cancer, comprising administering to the patient an effective amount of a pharmaceutically acceptable composition of the present invention 1059 or 1060 in combination with a further therapeutic agent. [Invention 1063] The method of the present invention 1061 or 1062, wherein the further therapeutic agent is an immunotherapy agent. [Invention 1064] The method of the present invention 1063, wherein the immunotherapy agent is selected from the group consisting of anti-PD-1 antibody, anti-PD-L1 antibody, and anti-CTLA-4 antibody. [Invention 1065] A method for treating cancer in a patient requiring a cancer treatment method, comprising administering an effective amount of any compound 1001 to 1058 of the present invention to the patient. [Invention 1066] A method for treating cancer in a patient requiring a method for treating cancer, comprising administering to the patient an effective amount of a pharmaceutically acceptable composition of the present invention 1059 or 1060. [Invention 1067] A method for treating type 2 diabetes in a patient requiring a treatment method for type 2 diabetes, comprising administering to the patient an effective amount of any compound from Invention 1001 to 1058 or a composition of Invention 1059 or 1060. [Invention 1068] A method for treating and / or managing obesity in a patient requiring a method for treating and / or managing obesity, comprising administering to the patient an effective amount of any compound from Invention 1001 to 1058 or a composition of Invention 1059 or 1060. [Invention 1069] A method for suppressing further weight gain in an overweight or obese patient who requires a method for suppressing further weight gain, comprising administering to the patient an effective amount of any compound from Invention 1001 to 1058 or a composition from Invention 1059 or 1060. [Invention 1070] A method for treating a metabolic disorder in a patient requiring treatment for a metabolic disorder, comprising administering to the patient an effective amount of any compound from Invention 1001 to 1058 or a composition from Invention 1059 or 1060. [Modes for carrying out the invention]

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

[0029] Definition of Terms Definitions of chemical terms The definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are based on the periodic table of elements, the CAS edition, and Handbook of Chemistry and Physics, 75. th Ed., specified according to the endpapers, and specific functional groups are defined as generally described in the above handbook. Furthermore, general principles of organic chemistry, as well as specific functional parts and reactivity, are as follows: 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 This is described in Edition, Cambridge University Press, Cambridge, 1987.

[0030] The abbreviations used herein have their conventional meanings within the scope of the arts of chemistry and biology. The chemical structures and chemical formulas described herein are constructed in accordance with the standard rules of chemical valence known in the art of chemistry.

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

[0032] In this specification, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomer-rich). In other words, the "S" isomer of the compound is substantially free of the "R" isomer and is therefore enantiomer-rich of the "R" isomer. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight of the enantiomer. In certain embodiments, the above weights are based on the total weight of all enantiomers or stereoisomers of the compound.

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

[0034] In this specification, “isotope-enriched variant” means a compound of the disclosure having one or more isotopic substitutions, in which one or more atoms are substituted with atoms having atomic weights or mass numbers different from those normally present in nature. Examples of isotopes that can be introduced into the compounds of this disclosure are,2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as Cl. For example, hydrogen (H) is 1 H, 2 H (D, i.e., deuterium), and 3 It may be any isotopic form containing H (T, i.e., tritium), and carbon (C) is 12 C, 13 C, and 14 It may be any isotopic form containing C, and oxygen (O) is 16 O and 18 This may be any isotopic form containing O, and so on. For example, in the isotopic 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 in question. For example, "an analogue" means one or more analogues.

[0036] When a numerical range is specified, that range is intended to encompass each number within that range and its subranges. For example, "C1~C6 alkyl" is intended to encompass 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 together with these terms and will be helpful in understanding the description and intended scope of this disclosure.

[0038] "Alkyl" refers to a radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C1-C20"). 20 "Alkyl" refers to a group having 1 to 12 carbon atoms. In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1-C12"). 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) and n-octyl (C8). Each example of an 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, i.e., it may be unsubstituted ("unsubstituted alkyl") or substituted with the above substituents ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C1- 10The alkyl group is an alkyl group (e.g., -CH3). In certain embodiments, the alkyl group is a substituted C1-6 alkyl group. Common abbreviations for alkyl groups include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0039] The term "alkylene" means, unless otherwise specified, a divalent radical derived from an alkyl group, such as -CH2CH2CH2CH2-, either by itself or as part of another substituent. Generally, alkyl (or alkylene) groups have 1 to 24 carbon atoms, and in this disclosure, alkyl (or alkylene) groups having 10 or fewer carbon atoms are preferred. The term "alkenylene" means, unless otherwise specified, a divalent radical derived from an alkene, either by itself or as part of another substituent. An alkylene group may also be described, for example, as a C1-C6 member alkylene, where "member" refers to a non-hydrogen atom within that part.

[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, but no triple bonds ("C2- 20 An alkenyl group is defined as having 2 to 10 carbon atoms ("C2-C10"). In some embodiments, the alkenyl group has 2 to 10 carbon atoms. 10In 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 (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), and butadienyl (C4). Examples of C2-C6 alkenyl groups include the aforementioned C 2~4 Examples of alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyls include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Each example of an 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, being unsubstituted ("unsubstituted alkenyl") or substituted with the above substituents ("substituted alkenyl"). In certain embodiments, the above alkenyl group is unsubstituted C 2~10 It is an alkenyl. In certain embodiments, the alkenyl group is a substituted C 2~6 It is Alkenil.

[0041] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6 to 14 ring carbon atoms assigned to the aromatic ring system and lacking heteroatoms, which is a radical of the aromatic ring system ("C6~C"). 14This refers to an aryl group. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl groups such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14 "Aryl" (e.g., anthracyl). Aryl groups are, for example, C6~C 10 It may also be described as a member aryl, where the term "member" refers to the non-hydrogen ring atom within that part. 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 substituted with the above substituents ("substituted aryl"). In certain embodiments, the above aryl group is unsubstituted C6-C6 14 It is aryl. In certain embodiments, the above aryl group is substituted C6-C 14 It is Ariel.

[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] Typical examples of substitution aryls are as follows: TIFF0007881804000025.tif17128 is given as an example, and in the formula, R 56 and R 57 One of them may be hydrogen, R 56 and R 57 At least one of them is independently C1-C8 alkyl, halo-C1-C8 alkyl, 4-10 member heterocyclyl, alkanoyl, alkoxy-C1-C8 alkyl, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR59 , NR 58 SOR 59 , NR 58 SO2R 59 C(O)Oalkyl, C(O)Oaryl, CONR 58 R 59 CONR 58 Ure 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 These atoms may bond to form a cyclic ring (saturated or unsaturated) consisting of 5 to 8 atoms, which optionally contains one or more heteroatom groups selected from the groups N, O, S, S(O), or S(O)2.

[0044] Other representative aryl groups having a condensed heterocyclyl group include the following: TIFF0007881804000026.tif12128 is given, and in the formula, each W' is C(R 66 )2, NR 66 Selected from , O, and S, each Y' is a carbonyl, NR 66 Selected from O and S, R 66 These are independently hydrogen, C1-C8 alkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 They are aryl and 5- to 10-membered heteroaryl groups.

[0045] "Arylene" and "heteroarylene" refer to divalent radicals derived from aryl and heteroaryl groups, respectively, either alone or as part of another substituent. Non-exclusive examples of heteroaryl groups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthalyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyradinyl, quinazolinonyl, benzoisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, and pyro Examples include lyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, prinyl, benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl, pyroropyrimidinyl, benzotriazolyl, benzoxazolyl, or quinolyl. The above examples may be substituted or unsubstituted, and the divalent radicals of each of the above heteroaryl examples are non-limiting examples of heteroarylenes.

[0046] Unless otherwise specified, "halo" or "halogen" means a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom, either by itself or as part of another substituent. The term "halide" means 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" encompass both monohaloalkyl and polyhaloalkyl compounds. For example, the term "halo-C1~C6 alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl.

[0048] The term "heteroalkyl" means, by itself or in combination with other terms, unless otherwise specified, an acyclic, stable linear or branched chain, or a combination thereof, containing a heteroatom selected from the group consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) O, N, P, S, and Si may be located at any internal position of the heteroalkyl group or at a position where the alkyl group is bonded to the remainder of the molecule. Examples of 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, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3 may have up to two or three heteroatoms in a row. They are described as "heteroalkyl" followed by -CH2O-CH3, -NR B R C When specific heteroalkyl groups are described, the terms heteroalkyl and -CH2O-CH3 or -NR are used. B R C It will be understood that these are not redundant or mutually exclusive. Rather, specific heteroalkyl groups are listed for clarity. Thus, in this specification, the term "heteroalkyl" means -CH2O-CH3, -NR B R C This should not be interpreted as excluding specific heteroalkyl groups such as those mentioned above.

[0049] Similarly, the term "heteroalkylene" means, unless otherwise specified, a divalent radical derived from a heteroalkyl group, such as, but not limited to, -CH2O- and -CH2CH2O-, either by itself or as part of another substituent. A heteroalkylene group may also be described, for example, as a 2- to 7-membered heteroalkylene, where "member" refers to a non-hydrogen atom within that part. For heteroalkylene groups, the heteroatoms may occupy either or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for linking groups of alkylenes and heteroalkylenes, the orientation of the linking group is not indicated by the direction in which the formula of the linking group is written. 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 (for example, having 6 or 10 π electrons shared in a cyclic array) having a ring carbon atom and 1 to 4 heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur, and is a radical of the aromatic ring system ("5- to 10-membered heteroaryl"). In a heteroaryl group containing one or more nitrogen atoms, the bond site may be a carbon or nitrogen atom, as long as the valence allows. A heteroaryl bicyclic ring system may contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which the heteroaryl ring defined above is fused with one or more aryl groups, and the bond site is on either the aryl ring or the heteroaryl ring, in which case the number of ring members indicates the number of ring members of the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl), the bond site may be on either ring, i.e., on the ring containing a heteroatom (e.g., 2-indolyl) or on the ring not containing a heteroatom (e.g., 5-indolyl). The heteroaryl group may also be described, for example, as a 6- to 10-membered heteroaryl, where the term "member" refers to the non-hydrogen ring atom within that part.

[0051] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one or two ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one 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., unsubstituted ("unsubstituted heteroaryl") or substituted with the substituents described above ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0052] Examples of five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Examples of six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Examples of seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolidinyl, and prinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolinyl, isoquinolinyl, sinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0053] A typical example of a heteroaryl is shown below. TIFF0007881804000027.tif64128 is an example, where Y is carbonyl, N, NR 65 Selected from O and S, R 65These are independently hydrogen, C1-C8 alkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 They are aryl and 5- to 10-membered heteroaryl groups.

[0054] "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C3-C 10 This refers to a radical of the hydrocarbon group that is a "cycloalkyl" group and does not have a heteroatom in the non-aromatic ring system. 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 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C 10 Cycloalkyl groups are defined as C4-C7 member cycloalkyl groups, where "member" refers to the non-hydrogen ring atom within that group. Examples of 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), and cyclohexadienyl (C6). Examples of C3-C8 cycloalkyl groups include, but are not limited to, the C3-C6 cycloalkyl groups mentioned above, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), and bicyclo[3.1.1]heptanyl (C7). 10The cycloalkyl groups are not limited to the above-mentioned C3-C8 cycloalkyl groups, as well as cyclononyl (C9), cyclononenyl (C9), and cyclodecyl (C9). 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C 10 Examples include the above. As the above examples show, in certain embodiments, the cycloalkyl group is either monocyclic ("monocyclic cycloalkyl") or includes condensed, crosslinked, or spirocyclic systems such as bicyclic systems ("bicyclic cycloalkyl"), and may be saturated or partially unsaturated. "Cycloalkyl" also includes ring systems in which the cycloalkyl ring defined above is condensed with one or more aryl groups and the bond site is on the cycloalkyl ring, in which case the carbon number still indicates the carbon number of the cycloalkyl ring system. Each example of a cycloalkyl group may independently be optionally substituted with one or more substituents, for example, unsubstituted ("unsubstituted cycloalkyl") or substituted with the above substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is unsubstituted C3-C 10 It is a cycloalkyl group. In certain embodiments, the cycloalkyl group is a substituted C3-C3 group. 10 It is a cycloalkyl group.

[0055] In some embodiments, "cycloalkyl" refers to a monocyclic saturated cycloalkyl group having 3 to 10 ring carbon atoms ("C3-C3"). 10 A cycloalkyl group is a "C3-C8 cycloalkyl group". In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl group"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl group"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C5-C6 cycloalkyl group"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C6 cycloalkyl group"). 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 either unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the above cycloalkyl group is unsubstituted C3-C 10 It is a cycloalkyl group. In certain embodiments, the cycloalkyl group is a substituted C3-C3 group. 10 It is a cycloalkyl group.

[0056] A "heterocyclyl" or "heterocyclic" is a 3-10 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatom groups, where each heteroatom group is independently selected from nitrogen, oxygen, sulfur and its oxidation forms (e.g., S, S(O), and S(O)2), boron, phosphorus, and silicon, and is a radical of the above non-aromatic ring system ("3-10 membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the bond site may be a carbon or nitrogen atom, as long as the valence allows. A heterocyclyl group may be monocyclic ("monocyclic heterocyclyl") or a bicyclic system ("bicyclic heterocyclyl"), which may be condensed, bridged, or spirocyclic, and may be saturated or partially unsaturated. A heterocyclyl bicyclic 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 with one or more cycloalkyl groups and the bond site is located on either the cycloalkyl ring or the heterocyclyl ring, or a ring system in which the heterocyclyl ring defined above is fused with one or more aryl or heteroaryl groups and the bond site is located on the heterocyclyl ring, in which case the number of ring members still indicates the number of ring members of the heterocyclyl ring system. A heterocyclyl group may also be described, for example, as a 3- to 7-membered heterocyclyl, where the term "member" means the non-hydrogen ring atoms within the part, 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 a heterocyclyl may independently be optionally substituted with one or more substituents, for example, being unsubstituted ("unsubstituted heterocyclyl") or substituted with the substituents described above ("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 5-10 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, and oxidation forms of sulfur (e.g., S, S(O), and S(O)2), boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, and oxidation forms of sulfur (e.g., S, S(O), and S(O)2) ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatom groups, wherein each heteroatom group is independently selected from nitrogen, oxygen, sulfur, and oxidation forms of sulfur (e.g., S, S(O), and S(O)2), forming the above non-aromatic ring system ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, sulfur, and oxidation forms of sulfur (e.g., S, S(O), and S(O)2). In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, sulfur, and oxidation forms of sulfur (e.g., S, S(O), and S(O)2). In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, sulfur, and oxidation forms of sulfur (e.g., S, S(O), and S(O)2).

[0058] Examples of three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azildinyl, oxylanyl, and thiorenyl. Examples of four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Examples of five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinil, dithianil, and dioxanil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinyl. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanil, oxepanil, and thiepanil. Examples of eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanil, oxecanil, and thiokanil. Examples of five-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinonyl. Examples of six-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0059] Specific examples of heterocyclyl groups are shown below. As shown in TIFF0007881804000028.tif43128, in the formula, each W'' is CR 67 , C(R 67 )2, NR 67 Selected from , O, and S, each Y is NR 67 Selected from O and S, R 67 These are independently hydrogen, C1-C8 alkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 These are aryl and 5-10 membered heteroaryl groups. These heterocyclyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (e.g., 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 groups that give lactam and urea derivatives.

[0060] The term "nitrogen-containing heterocyclyl" refers to a 4- to 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-alkylpiperazine such as N-methylpiperazine. Specific examples include azetidine, piperidone, and piperazone.

[0061] "Amino" refers to radical-NR 70 R 71 And in the formula, R70 and R 71 These are, independently, hydrogen, C1-C8 alkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 The above radicals are aryl and 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 compound are oxidized to the corresponding N-oxide, if present.

[0065] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups as defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" cycloalkyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means, whether or not the term "optionally" precedes it, that at least one hydrogen atom on the group (e.g., a carbon or nitrogen atom) is substituted with an acceptable substituent, e.g., a substituent that, upon substitution, produces a stable compound, e.g., a compound that does not spontaneously change by rearrangement, cyclization, elimination, or other reactions. Unless otherwise expressly stated, a “substituted” group has substituents at one or more substituted positions on the group, and if multiple positions on any given structure are substituted, the substituents are either identical or different at each position. The term “substituted” is intended to encompass substitution by all acceptable substituents on an organic compound, including any substituents described herein that lead to the formation of a stable compound. This disclosure intends all such combinations to reach a stable compound. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any 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 be optionally bonded to form an aryl, heteroaryl, cycloalkyl, or heterocyclyl group. Such so-called ring-forming substituents are generally, though not necessarily, bonded to a cyclic base structure. In one embodiment, the ring-forming substituents are bonded to adjacent constituent atoms of the base structure. For example, two ring-forming substituents bonded to adjacent constituent atoms of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are bonded to a single constituent atom of the base structure. For example, two ring-forming substituents bonded to a single constituent atom of a cyclic base structure create a spiro-ring structure. In yet another embodiment, the ring-forming substituents are bonded to non-adjacent constituent atoms of the base structure.

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

[0068] The term “pharmaceutically acceptable salt” means a salt of the active compound prepared using a relatively non-toxic acid or base, depending on the specific substituents present on the compound described herein. If the compound of the disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound 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. If the compound of the disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monocarbonate, phosphoric acid, monohydrogen-phosphoric acid, dihydrogen-phosphoric acid, sulfuric acid, monohydrogen-sulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. 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 this 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 this disclosure. Salts tend to be more soluble in aqueous or other protic solvents, which are in the form of the corresponding free base. In other cases, the formulation may be a lyophilized powder in a first buffer, for example, in 1 mM to 50 mM histidine, 0.1% to 2% sucrose, 2% to 7% mannitol, and a pH range of 4.5 to 5.5, which is mixed with a second buffer before use.

[0069] Accordingly, the compounds of this disclosure may exist as salts, such as salts with pharmaceutically acceptable acids. This disclosure includes such salts. Examples of such salts include salts with hydrochlorides, hydrobroms, sulfates, methanesulfons, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and 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 this compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound by conventional methods. The parent form of this compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

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

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

[0073] In this specification, the term “salt” means an acid acid or base salt of a compound used in the methods of this disclosure. Exemplary examples of acceptable salts are mineral acid salts (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid), organic acid salts (e.g., acetic acid, propionic acid, glutamic acid, citrate), and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide).

[0074] Certain compounds in this disclosure have an asymmetric carbon atom (optical or chiral center) or a double bond, and stereoisomers that can be defined in terms of absolute stereochemistry as (R)- or (S)-, or in the case of amino acids as (D)- or (L)-, and individual isomers are included within the scope of this disclosure. The compounds in this disclosure do not include compounds known in the art to be excessively unstable and unable to be synthesized and / or isolated. This disclosure is intended to include racemic and optically pure forms of compounds. Optically active (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral starting materials or chiral reagents, or can be divided using conventional techniques. Where a compound described herein contains an olefin bond or other geometrically asymmetric center, unless otherwise specified, such compound is intended to include both E and Z geometric isomers.

[0075] In this specification, the term "isomer" means a compound having the same number and type of atoms, and therefore the same molecular weight, but differing in terms of the structural arrangement or stereochemistry of its atoms.

[0076] In this specification, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and can be readily converted from one isomer to another.

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

[0078] "Treatment" includes preventing or delaying the onset of symptoms, complications, or biochemical signs of a disease, alleviating or improving such symptoms, or preventing or suppressing the further development of a disease, disorder, or disability. "Treatment" includes any effect that leads to improvement of a disease, disorder, or disability, such as attenuation, reduction, regulation, or elimination. For example, certain methods described herein treat cancer by reducing, mitigating, or preventing the development, growth, metastasis, or progression of cancer, or by reducing the symptoms of cancer. The term "treatment" and its inflections include the prevention of injury, condition, disease, or disorder (for example, preventing the onset of one or more symptoms of a disease, disorder, or disorder described herein).

[0079] An "effective dose" is the amount sufficient to achieve the stated purpose (for example, to achieve the effect for which it is intended, to treat a disease, to reduce enzyme activity, to increase enzyme activity, or to alleviate one or more symptoms of a disease or illness). An example of an "effective dose" is an amount sufficient to contribute to the treatment, prevention, or alleviation of one or more symptoms of a disease, and this amount is also called a "therapeutic effective dose." The "preventive effective dose" of a drug is the amount of drug administered to a subject that would produce the intended preventive effect, such as preventing or delaying the onset (or recurrence) of injury, disease, condition, or illness, or reducing the likelihood of the onset (or recurrence) of injury, disease, condition, or illness, or their symptoms. Complete preventive effect does not necessarily occur with a single dose, but may only occur after a series of doses. Therefore, a preventive effective dose may be administered in one or more doses. The exact amount depends on the purpose of the treatment and can be determined by a person skilled in the art using known techniques (see, for example, 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] "Reduction" (and its grammatical equivalent) of one or more symptoms means reducing the severity or frequency of a symptom(s), or eliminating the symptom(s)(s).

[0081] The terms "control" or "controlled experiment" are used according to their obvious and ordinary meaning, referring to an experiment in which the subject or reagents of the experiment are treated as in a parallel experiment, except for the omission of experimental procedures, reagents, or variables. In some cases, the control is used as a standard of comparison when evaluating the effect of an experiment.

[0082] "Contact" is used in its obvious and ordinary sense to mean a process of bringing at least two different species (e.g., compounds including biomolecules or cells) close enough to react, interact, or physically come into contact. However, it should be understood that the reaction products obtained may be produced directly from the reaction between the added reagents, or from intermediates derived from one or more added reagents, which may be produced in the reaction mixture. The above term "contact" may also encompass the reaction, interaction, or physical contact of two species, wherein the two species may be the compounds and proteins or enzymes described herein, e.g., protein tyrosine phosphatases, e.g., non-receptor type 2 protein tyrosine phosphatase (PTPN2) or non-receptor type 1 protein tyrosine phosphatase (PTP1B).

[0083] Where defined herein, terms such as “inhibition,” “inhibit,” and “inhibiting” in relation to protein-inhibitor (e.g., antagonist) interactions mean a negative effect on the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor (e.g., a reduction). In some embodiments, inhibition means the alleviation of a disease or the symptoms of a disease. In some embodiments, inhibition means the reduction of the activity of a signal transduction or signaling pathway. Thus, inhibition includes, at least partially, partially, or completely, blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signaling or enzyme activity or the amount of a protein. In some embodiments, inhibition means the reduction of the activity of a protein tyrosine phosphatase, e.g., non-receptor type 2 protein tyrosine phosphatase (PTPN2) or non-receptor type 1 protein tyrosine phosphatase (PTP1B). Therefore, inhibition may include, at least partially, partially, or completely, reducing stimulation, reducing or decreasing activation, or inactivating, desensitizing, or downregulating signaling or enzyme activity or the amount of protein tyrosine phosphatases, such as non-receptor type 2 protein tyrosine phosphatase (PTPN2) or non-receptor type 1 protein tyrosine phosphatase (PTP1B).

[0084] The “patient” or “subject” requiring this means an organism that is suffering from or susceptible to a disease or illness that can be treated by administration of the compounds or pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, Bovidae, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammals. In some embodiments, the patient is a human. In some embodiments, the patient is a domesticated animal. In some embodiments, the patient is a dog. In some embodiments, the patient is a parrot. In some embodiments, the patient is livestock. 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 Bovidae. In some embodiments, the patient is a canid. 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 neonatal animal. In some embodiments, the patient is a human neonatal. 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 patient with geriatric disease.

[0085] "Disease," "disorder," or "illness" means a physical condition or health condition 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 alleviation or elimination of one or more symptoms of the above-mentioned disease, disorder, or illness by administration of a pharmaceutical composition comprising, for example, one of the compounds disclosed herein, a pharmaceutically acceptable salt thereof, or one of the pharmaceutical compositions comprising one of the compounds disclosed herein, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0086] In this specification, 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 changes in one component to one or more other components, which may then successively transmit changes to further components, which may optionally propagate to components of other signaling pathways.

[0087] "Pharmacologically acceptable excipients" and "pharmaceutically acceptable carriers" mean substances that can be included in the compositions of the Disclosure without causing serious toxicological adverse effects to the patient, and which assist in the administration and absorption of the active agent to the subject. Non-limiting examples of pharmacochemically acceptable excipients include water, NaCl, ordinary saline, Ringer's lactate solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, lactose, amylose, or carbohydrates such as starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and colorants. Such formulations may be sterilized and, if necessary, may be mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure, buffers, colorants, and / or aromatics, which do not react adversely with the compounds of the Disclosure. Those skilled in the art will recognize that other pharmaceutical excipients are also useful in this disclosure.

[0088] The term "formulation" is intended to encompass formulations of active compounds having an encapsulating material as a carrier, which provides a capsule, in which the active ingredient is surrounded by a carrier, and thus the carrier is integrated with the active ingredient, with or without the presence of other carriers. 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] In this specification, the term “administration” means oral administration, suppository administration, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intrafocal administration, intrathecal administration, intracranial administration, intranasal administration, or subcutaneous administration, or implantation of a sustained-release device to the subject, such as a mini osmotic pump. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palate, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administrations include, for example, intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, and transdermal patches. “Concurrent administration” means that the compound or composition described herein is administered simultaneously with, immediately before, or immediately after the administration of one or more further therapeutic agents (e.g., anticancer agents, chemotherapeutic agents, or immunotherapeutic agents). The compounds or compositions described herein may be administered to a patient alone or concurrently. Concurrent administration is intended to include the simultaneous or sequential administration of the compounds or compositions individually or in combination (multiple compounds or drugs). Accordingly, the formulations may also be combined with other active substances (e.g., to reduce metabolic degradation) if desired.

[0090] In this specification, 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, formula (I) A compound represented by TIFF0007881804000029.tif27128, During the ceremony, R 1 is hydrogen, halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl and -C 1~6 Selected from the group consisting of alkylene-5-6 member heterocyclines, however, C 1~6 Alkyl, C 3~6 Cycloalkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl and -C 1~6 Alkylene-5 to 6-membered heterocyclines can be optionally configured with R on one or more available carbon atoms, each independently. g It may be substituted with one, two, three, or more substituents selected from -C 1~6 If an alkylene-5 to 6-membered heterocycline contains a replaceable ring nitrogen atom, that ring nitrogen atom is optionally R h It may also be replaced by, R 2 These are hydrogen, hydroxyl, -CHF2, -CH2OH, -CH2CN, and -CH2-OC 1~6 Alkyl, -CH2-N(R a )-C 1~6 Alkyl, C 2~6 Alkyl, C 2~6 Alkenyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, -OC(O)-N(R a )-C 1~6 Alkyl, -N(Ra )-C(O)-OC 1~6 Alkyl, -C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkenylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, 5-6 member heteroaryl, 4-6 member heterocyclyl, -OC 1~6 Alkilen-5~6 member heteroaryl, -O-4~6 member heterocyclyl, -N(R) a )-4~6 member heterocyclyl, -C 1~6 Alkylene-4 to 6-membered heterocyclyls, and -OC 1~6 Selected from the group consisting of alkylene-4-6 member heterocyclyl, except for -CH2-OC 1~6 Alkyl, -CH2-N(R a )-C 1~6 Alkyl, C 2~6 Alkyl, C 2~6 Alkenyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl, -OC(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-OC 1~6 Alkyl, -C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, -C 1~6 Alkylene-C 3~6 Cycloalkyl, -C 1~6 Alkenylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, 5-6 member heteroaryl, -OC 1~6Alkylene-5-6 member heteroaryl, 4-6 member heterocyclyl, -O-4-6 member heterocyclyl, -N(R a )-4~6 member heterocyclyl, -C 1~6 Alkylene-4 to 6-membered heterocyclyls, and -OC 1~6 Alkylene-4 to 6-membered heterocyclines can be optionally configured with R on one or more available carbon atoms, each independently. g They may be substituted with one, two, three or more substituents selected from, and include 5-6 member heteroaryls, 4-6 member heterocyclines, and -N(R a )-4~6 member heterocyclyl, -C 1~6 Alkilen-4 to 6-membered heterocyclyl, or -OC 1~6 If an alkylene-4 to 6-membered heterocycline contains a replaceable ring nitrogen atom, that ring nitrogen atom is optionally R h It may also be replaced by, Or, R 1 and R 2 However, together with the atoms they bond to, they form 5-6 membered aryl or heteroaryl compounds, where the aryl or heteroaryl is optional and can be independently a halogen, hydroxyl, cyano, or C13. 1~6 Alkyl and C 1~6 It may be substituted with one or more substituents selected from the group consisting of alkoxys, provided that C 1~6 Alkyl and C 1~6 The alkoxys are optional and each is independently R p It may be substituted with one, two, three, or more substituents selected from the following: R 3 is hydrogen, -C 1~6 Alkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl and -C 1~6Selected from the group consisting of alkylene-4 to 6-membered heterocyclines, provided that -C 1~6 Alkyl, -OC 1~6 Alkyl, -N(R a )-C 1~6 Alkyl, -S(O) w -C 1~6 Alkyl, -C(O)-N(R a )-C 1~6 Alkyl, -N(R a )-C(O)-C 1~6 Alkyl and -C 1~6 Alkylene-4 to 6-membered heterocyclines can be optionally configured with R on one or more available carbon atoms, each independently. g It may be substituted with one, two, three, or more substituents selected from -C 1~6 If an alkylene-4 to 6-membered heterocycline contains a replaceable ring nitrogen atom, that ring nitrogen atom is optionally R h It may also be replaced by, R 4 is hydrogen, halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 Selected from the group consisting of alkylene-4-6 member heterocyclyl, however, C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 Alkylene-4 to 6-membered heterocyclines can be optionally configured with R on one or more available carbon atoms, each independently. g It may be substituted with one, two, three, or more substituents selected from -C 1~6 If an alkylene-4 to 6-membered heterocycline contains a replaceable ring nitrogen atom, that ring nitrogen atom is optionally R h It may also be replaced by, However, R 1 , R 2 , R 3 , and R 4 At least one of them is not hydrogen, R 5 is hydrogen, halogen, C 1~6 Alkyl, C 3~6Cycloalkyl, and -C 1~6 Selected from the group consisting of alkylene-4-6 member heterocyclyl, however, C 1~6 Alkyl, C 3~6 Cycloalkyl, and -C 1~6 Alkylene-4 to 6-membered heterocyclines can be optionally configured with R on one or more available carbon atoms, each independently. g It may be substituted with one, two, three, or more substituents selected from -C 1~6 If an alkylene-4 to 6-membered heterocycline contains a replaceable ring nitrogen atom, that ring nitrogen atom is optionally R h It may also be replaced by, R 6 It is hydrogen, R 7 It is hydrogen, R g Independently of each entity, hydrogen, halogen, hydroxyl, cyano, nitro, oxo, -C(O)OH, R a R b N-, R a R b NC(O)-, R a R b N-SO w -, R a R b NC(O)-N(R a )-, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, phenyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, -(CO)-(NR a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Alkoxy, C 3~6 Alkenyloxy, C 3~6 Alkynyloxy, C 3~6 Cycloalkoxy, C 1~6 Alkyl-C(O)-, C 1~6Alkyl-OC(O)-, C 1~6 Alkyl-C(O)-O-, C 1~6 Alkyl-S(O) w -, C 1~6 alkyl-N(R a )-, C 1~6 alkyl-N(R a )-C(O)-, C 1~6 alkyl-C(O)-N(R a ), C 1~6 alkyl-N(R a )-C(O)-N(R a )-, C 1~6 alkyl-N(R a )-SO w -, C 3~6 Cycloalkyl-N(R a )-SO w -, C 1~6 Alkyl-SO w -N(R a )-, C 3~6 Cycloalkyl-SO w -N(R a )-, 4-6 member 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 Selected from the group consisting of alkyl-, however, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 Cycloalkyl, phenyl, C 1~6 Alkylene-C 3~6 Cycloalkyl, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, -(CO)-(NR a )-C 1~6 Alkylene-C3~6 Cycloalkyl, C 1~6 Alkoxy, C 3~6 Alkenyloxy, C 3~6 Alkynyloxy, C 3~6 Cycloalkoxy, C 1~6 Alkyl-C(O)-, C 1~6 Alkyl-OC(O)-, C 1~6 Alkyl-C(O)-O-, C 1~6 Alkyl-S(O) w -, C 1~6 alkyl-N(R a )-, C 1~6 alkyl-N(R a )-C(O)-, C 1~6 alkyl-C(O)-N(R a ), C 1~6 alkyl-N(R a )-C(O)-N(R a )-, C 1~6 alkyl-N(R a )-SO w -, C 3~6 Cycloalkyl-N(R a )-SO w -, C 1~6 Alkyl-SO w -N(R a )-, C 3~6 Cycloalkyl-SO w -N(R a )-, 4-6 member 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 optional, and each is independently R p It may be substituted with one, two, three, or more substituents selected from the following: Rh Independently of each existence, C 1~6 Alkyl, C 3~6 Alkenil, C 3~6 Alkinyl, 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 member heterocyclyl-S(O)2-, 4-6 member heterocyclyl-C 1~6 Alkyl-S(O)2-, 5-6 member heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-C 1~6 Alkyl-S(O)2-, C 1~6 Alkyl-C(O)-, C 1~6 Cycloalkyl-C(O)-, C 1~6 Alkoxy-C(O)-, R a R b NC(O)-, R a R b N-SO2- and -P(O)(C 1~3 Selected from the group consisting of alkyl)2, however, C 1~6 Alkyl, C 3~6 Alkenil, C 3~6 Alkinyl, 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 member heterocyclyl-S(O)2-, 4-6 member heterocyclyl-C 1~6 Alkyl-S(O)2-, 5-6 member heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-C 1~6 Alkyl-S(O)2-, C 1~6 Alkyl-C(O)-, C 1~6 Cycloalkyl-C(O)-, C 1~6 Alkoxy-C(O)-, R a R b NC(O)-, R a R b N-SO2- and -P(O)(C 1~3Alkyl)2 is optional, and each is independently R p It may be substituted with one, two, three, or more substituents selected from the following: R p These are, independently of each other, halogen, hydroxyl, cyano, and C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, 4-6 member 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 Independently of each entity, hydrogen and C 1~6 Alkyl and C 3~6 Selected from the group consisting of cycloalkyl, however, C 1~6 Alkyls can be optionally and independently halogenated, cyano, oxo, hydroxyl, and C. 1~6 It may be substituted with one or more substituents selected from the group consisting of alkoxys (which may optionally be substituted with one, two, or three fluorine atoms), Or, R a and R b However, together with the nitrogen to which they are bound, they form a 4-6 membered heterocycline, wherein the heterocycline may optionally be substituted with one or more substituents independently selected from the group consisting of halogens, cyanos, oxos, and hydroxyls. w is 0, 1, or 2. The above-mentioned compounds, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, stereoisomers, or isotopic enriched variants thereof, are disclosed.

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

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

[0094] In some embodiments, R 2 It is a 4-6 member heterocycline, however, R 2 This is optional, and R is independently applied to one or more available carbon atoms. g It may be substituted by one, two, or three substituents selected from, and if the 4- to 6-membered heterocyclyl contains a substituted ring nitrogen atom, the ring nitrogen atom may optionally be R h It may be substituted by a substituent selected from. For example, in some embodiments, R 2 It is a 4-6 member heterocycline, however, R 2 This is optional, with one or more available carbon atoms, each independently containing hydrogen and C 1~6 R may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups, 2 If it contains a substituted ring nitrogen atom, that ring nitrogen atom may optionally be hydrogen, C 1~6 Alkyl (which may optionally be substituted with 1, 2, or 3 fluorine atoms), -C 1~6 Alkyl-C 3~6 Cycloalkyl, C 1~6 Cycloalkyl-C(O)-, C 1~6Alkyl-S(O)2- (which may optionally be substituted with cyano, methoxy, or 1, 2, or 3 fluorine atoms), C 3~6 Cycloalkyl-S(O)2-, 4-6 member heterocyclyl-S(O)2-, 4-6 member heterocyclyl-C 1~6 Alkyl-S(O)2-, 5-6 member heteroaryl-S(O)2-, phenyl-S(O)2-, phenyl-C 1~6 Alkyl-S(O)2-(Optional R a R b (may be substituted by N-), and -P(O)(C 1~3 It may be substituted with substituents selected from the group consisting of alkyl)2. For example, in some embodiments, R 2 For example, The data is selected from the group consisting of TIFF0007881804000030.tif105146 and TIFF0007881804000031.tif149146.

[0095] In other embodiments, R 2 It is a 5-6 member heteroaryl, however, R 2 This is optional, and R is independently applied to one or more available carbon atoms. g R may be substituted with one, two, or three substituents selected from 2 If it contains a replaceable ring nitrogen atom, that ring nitrogen atom may optionally be R h It may be substituted by a substituent selected from. For example, in some embodiments, R 2 It is a 5-6 member heteroaryl, however, R 2 This is optional, with one or more available carbon atoms, each independently containing hydrogen, cyano, and C 1~6 Alkyl, C 1~6 Alkoxy, and -P(O)(C 1~3 R may be substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl)2, 2 If it contains a substituted ring nitrogen atom, that ring nitrogen atom may optionally be hydrogen, -C 1~6 Alkyl-C 3~6Cycloalkyl, and C 3~6 It may be substituted with substituents selected from the group consisting of cycloalkyl-S(O)2-. For example, in some embodiments, R 2 For example, Selected from the group consisting of TIFF0007881804000032.tif48141.

[0096] In a further embodiment, R 2 ha-OC 1~6 It is an alkylene-4 to 6-membered heterocycline, however, R 2 This is optional, and R is independently applied to one or more available carbon atoms. g R may be substituted with one, two, or three substituents selected from 2 If it contains a replaceable ring nitrogen atom, that ring nitrogen atom may optionally be R h It may be substituted by a substituent selected from. For example, in some embodiments, R 2 ha-OC 1~6 It is an alkylene-4 to 6-membered heterocycline, however, R 2 This is optional, with one or more available carbon atoms, each independently containing hydrogen, halogen, and C 1~6 R may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups, 2 If it contains a substituted ring nitrogen atom, that ring nitrogen atom may optionally be hydrogen, C 1~6 Alkyl and C 1~6 It may be substituted with substituents selected from the group consisting of alkyl-S(O)2-. For example, in some embodiments, R 2 For example, Selected from the group consisting of TIFF0007881804000033.tif70131.

[0097] In other embodiments, R 2 ha-OC 1~6 It is an alkylene-5-6 member heteroaryl. For example, in some embodiments, R 2 For example, Selected from the group consisting of TIFF0007881804000034.tif19128.

[0098] In a further embodiment, R 2 is -C 2~6 Alkyl, C 2~6 Alkenyl and C 3~6 Selected from the group consisting of cycloalkyl, however, R 2 These are optional choices, and each is independently R g It may be substituted with one, two, three, or more substituents selected from. For example, in some embodiments, R 2 is -C 2~6 Alkyl, C 2~6 Alkenil, C 3~6 Cycloalkyl, -C 1~6 Alkylene-C 3~6 Cycloalkyl, and -C 1~6 Alkenylene-C 3~6 Selected from the group consisting of cycloalkyl, however, R 2 These are optional and can be independently selected as cyano, chlorine, fluorine, hydroxyl, and C. 1~6 Alkoxy, phenyl, and R a R b It may be substituted with one, two, three, or more substituents selected from the group consisting of N-. For example, in some embodiments, R 2 For example, -CH2CHF2, Selected from the group consisting of TIFF0007881804000035.tif62146.

[0099] In other embodiments, R 2 ha-OC 1~6 It is alkyl, however, R 2 These are optional choices, and each is independently R g It may be substituted with one, two, three, or more substituents selected from. For example, in some embodiments, R 2 is, -OC 1~6 It is alkyl, however, R 2These are optional and can be independently selected as cyano, deuterium, chlorine, fluorine, hydroxyl, oxo, and C. 1~6 Alkoxy, C 3~6 Cycloalkoxy, -OC 1~6 Alkylene-C 3~6 Cycloalkyl, -(CO)-(NR a )-C 1~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Alkyl-OC(O)-, R a R b N-(however, R b (This is optionally replaced by -OCH3 or -OCF3), C 1~6 alkyl-N(R a )-, R a R b NC(O)-, -P(O)(C 1~3 Alkyl)2, C 1~6 alkyl-N(R a )-C(O)-, C 1~6 alkyl-N(R a )-C(O)-N(R a )-, C 1~6 Alkyl-SO2-N(R a )-, C 3~6 Cycloalkyl-SO2-N(R a )-, and 4-6 member heterocyclyl-SO2-N(R a )- may be substituted with one, two, three, or more substituents selected from the group consisting of ). For example, in some embodiments, R 2 For example, -OCH3, -OCD3, -OCF3, -OCHF2, -OCH2CH3, Selected from the group consisting of TIFF0007881804000036.tif192149.

[0100] In other embodiments, R 2 ha-OC 3~6 It is a cycloalkyl or -O-4~6 member heterocycline, however, R 2 If it contains a replaceable ring nitrogen atom, that ring nitrogen atom may optionally be R hIt may be substituted by a substituent selected from. For example, in some embodiments, R 2 ha-OC 3~6 It is a cycloalkyl or -O-4~6 member heterocycline, however, R 2 If it contains a replaceable ring nitrogen atom, that ring nitrogen atom may optionally be C 1~6 Alkyl-SO2-N(R a )- and C 3~6 Cycloalkyl-SO2-N(R a )- may be substituted by substituents selected from the group consisting of ). For example, in some embodiments, R 2 For example, Selected from the group consisting of TIFF0007881804000037.tif18128.

[0101] In further embodiments, R 2 is -N(R a )-C 1~6 It is alkyl, however, R 2 These are optional choices, and each is independently R g It may be substituted with one, two, or three substituents selected from. For example, in some embodiments, R 2 is -N(R a )-C 1~6 It is alkyl, however, R 2 These are optional and can be independently selected as fluoro, -C(O)OH, cyano, oxo, and 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 It may be substituted with one, two, or three substituents selected from the group consisting of cycloalkyl groups. For example, in some embodiments, R 2 For example, -N(H)CH3, Selected from the group consisting of TIFF0007881804000038.tif66132.

[0102] In other embodiments, R 2 ha-OC 1~6 Alkylene-C 3~6 It is a cycloalkyl group, however, R 2 These are optional choices, and each is independently R g It may be substituted with one, two, or three substituents selected from. For example, in some embodiments, R 2 ha-OC 1~6 Alkylene-C 3~6 It is a cycloalkyl group, however, R 2 These are optional and can be independently selected as fluoro, hydroxyl, and R. a R b N-, cyano, and C 1~3 It may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups, provided that C 1~3 Alkyl groups can be optionally cyano and C. 1~3 It may be substituted with substituents selected from the group consisting of alkoxys. For example, in some embodiments, R 2 For example, Selected from the group consisting of TIFF0007881804000039.tif14141TIFF0007881804000040.tif35130.

[0103] In some embodiments, R 2 -OC(O)-N(R a )-C 1~6 It is alkyl. For example, in some embodiments, R 2 For example, Represented by TIFF0007881804000041.tif13128.

[0104] In a further embodiment, R 2 is -N(R a )-4~6 member heterocyclyl, however, R 2If it contains a replaceable ring nitrogen atom, that ring nitrogen atom may optionally be R h It may be substituted by a substituent selected from. For example, in some embodiments, R 2 is -N(R a )-4~6 member heterocyclyl, however, R 2 If it contains a replaceable ring nitrogen atom, that ring nitrogen atom may optionally be C 1~6 Alkyl-SO2-N(R a )- and C 3~6 Cycloalkyl-SO2-N(R a )- may be substituted by substituents selected from the group consisting of ). For example, in some embodiments, R 2 For example, Selected from the group consisting of TIFF0007881804000042.tif27128.

[0105] In other embodiments, R 2 is -C 1~6 It is an alkylene-4 to 6-membered heterocycline, however, R 2 If it contains a replaceable ring nitrogen atom, that ring nitrogen atom may optionally be R h It may be substituted by a substituent selected from. For example, in some embodiments, R 2 is -C 1~6 It is an alkylene-4 to 6-membered heterocycline, however, R 2 If it contains a replaceable ring nitrogen atom, that ring nitrogen atom may optionally be C 1~6 Alkyl, C 1~6 Alkyl-SO2-N(R a )-, and C 3~6 Cycloalkyl-SO2-N(R a )- may be substituted with substituents selected from the group consisting of, however C 1~6 The alkyl group may optionally be substituted with one, two, or three fluorine atoms. For example, in some embodiments, R 2 For example, Selected from the group consisting of TIFF0007881804000043.tif47128.

[0106] In some embodiments, R 2 For example, -CHF2, -CH2OH, -CH2OCH3, -CH2CN, -OH, Selected from the group consisting of TIFF0007881804000044.tif14128.

[0107] In some embodiments, R 1 and R 2 These, together with the atoms to which they bond, form a five-membered heteroaryl. For example, in some embodiments, R 1 and R 2 These, together with the atoms to which they bond, form, for example, furanyl. For example, in some embodiments, compounds of formula (I) Represented by TIFF0007881804000045.tif26128.

[0108] In some embodiments, R 3 is hydrogen. In other embodiments, R 4 is hydrogen. In a further embodiment, R 5 R is selected from the group consisting of hydrogen, deuterium, bromine, chlorine, and fluorine. In other embodiments, R 6 R is selected from the group consisting of hydrogen and deuterium. In a further embodiment, R 7 The atoms are 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] In this specification, formula (II) A compound represented by TIFF0007881804000046.tif27128, During the ceremony, X is -O- and -N(R a Selected from the group consisting of )-, L is a linear or branched C 1~6 It is alkylene, R2-II is hydrogen, cyano, -NR a R b , C 1~2 Alkoxy, C 3~6 Cycloalkyl-SO2-N(R a )-, C 1~6 Alkyl-SO2-N(R a )-, phenyl, 5-6 member heteroaryl, 4-6 member heterocyclyl, and C 3~6 Selected from the group consisting of cycloalkyls, provided that phenyl, 5-6 membered heteroaryls, 4-6 membered heterocyclyls, and C 3~6 Cycloalkyls can optionally have one or more available carbon atoms independently of a halogen, hydroxyl, or -NR. a R b , C 1~2 Alkyl (which may be optionally substituted with 1, 2, or 3 halogens), and C 1~2 It may be substituted with one, two, or three substituents selected from the group consisting of alkoxys (which may optionally be substituted with one, two, or three halogens), and if it contains a ring nitrogen atom that can be substituted with a 5-6 membered heteroaryl or 4-6 membered heterocyclyl, the ring nitrogen atom may optionally be C 1~3 It may also be substituted with alkyl groups. R 5 It is selected from the group consisting of hydrogen, deuterium, and halogens. R 6 It is selected from the group consisting of hydrogen and deuterium, R 7 It is selected from the group consisting of hydrogen and deuterium, R a and R b For each of their respective existences, hydrogen and C 1~3 Selected from the group consisting of alkyl groups, The above compounds, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof, are also disclosed.

[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 TIFF0007881804000047.tif24132, where * and # are R respectively. 2-II This represents a covalent bond point with respect to X.

[0112] In a further embodiment, R 2-II These are hydrogen, cyano, -NH2, -N(CH3)2, -OCH3, Selected from the group consisting of TIFF0007881804000048.tif41128.

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

[0114] In this specification, formula (III) A compound represented by TIFF0007881804000049.tif27128, During the ceremony, X III The bonded, -CH2-, -NR a Selected from the group consisting of -, -O-, -O-CH2-, and -OCH2-CH2-, m is 1, 2, or 3. n is 1, 2, or 3. R 1-III These are hydrogen, halogen, hydroxyl, cyano, -NR a R b , C 1~2 Alkyl (which may be optionally substituted with 1, 2, or 3 halogens), and C 1~2 Selected from the group consisting of alkoxys (which may be optionally substituted with 1, 2, or 3 halogens), R 2-III is hydrogen, C 1~4 Alkyl, -C(O)-C 1~4Alkyl, -C(O)-OC 1~4 Alkyl, -C(O)-N(R a )-C 1~4 Alkyl, -S(O)2-C 1~4 Alkyl and -S(O)2-C 3~6 Selected from the group consisting of cycloalkyl, however, C 1~4 Alkyl, -C(O)-C 1~4 Alkyl, -C(O)-OC 1~4 Alkyl, -C(O)-N(R a )-C 1~4 Alkyl, -S(O)2-C 1~4 Alkyl and -S(O)2-C 3~6 Cycloalkyl groups can be optionally and independently selected from halogen, hydroxyl, cyano, and -NR. a R b , C 1~2 Alkyl (which may be optionally substituted with 1, 2, or 3 halogens), and C 1~2 It may be substituted with one, two, or three substituents selected from the group consisting of alkoxys (which may be optionally substituted with one, two, or three halogens), R 5 It is selected from the group consisting of hydrogen, deuterium, and halogens. R 6 It is selected from the group consisting of hydrogen and deuterium, R 7 It is selected from the group consisting of hydrogen and deuterium, R a and R b For each of their respective existences, hydrogen and C 1~3 Selected from the group consisting of alkyl groups, The above compounds, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof, are also disclosed.

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

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

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

[0118] In this specification, 5-{1-fluoro-3-hydroxy-7-[2-(morpholine-4-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidine-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(pyrrolidine-3-yl)naphthalene-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)naphthalene-2-ylpropane-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-(azetidine-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-methoxy(4- 2 H) Naphthalene-2-yl (4,4- 2 H2)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(methylamino)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[2-(piperidine-4-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-7-{[3-fluoro-1-(propan-2-yl)pyrrolidine-3-yl]methoxy}-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-7-[(3-Fluoropyrrolidine-3-yl)methoxy]-3-hydroxynaphthalene-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)naphthalene-2-yl]oxy}pentanenitrile, 5-{1-fluoro-3-hydroxy-7-[2-(piperidine-1-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(Piperidine-4-yl)methoxy]naphthalene-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)naphthalene-2-yl]oxy}-3,3-dimethylpentanenitrile, 5-{7-[(3,3-dimethylbutyl)amino]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1,4-difluoro-3-hydroxy-7-methoxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[( 2 H3)methyloxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(2-methoxyethoxy)naphthalene-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)naphthalene-2-yl]oxy}-2,2-dimethylbutanenitrile, 5-{7-[2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[2-(dimethylamino)ethyl]amino}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-methoxynaphthalene-2-yl)(4,4- 2 H2)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-methoxynaphthalene-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]aminoethyl)cyclopropanesulfonamide, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidine-3-yl]amino}naphthalene-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]oxyethyl)cyclopropanesulfonamide 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)azetidine-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)naphthalene-2-yl]oxy}butanenitrile, [1-({[8-Fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidined-2-yl)naphthalen-2-yl]oxymethyl)cyclopropyl]acetonitrile, 5-{7-[2-(dimethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)-1H-pyrazole-4-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(1H-pyrazole-4-yl)methoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2-methylpropoxy)naphthalene-2-yl]-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(2-hydroxypropoxy)naphthalene-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-thiadiazolidine-2-yl)naphthalene-2-carboxamide, 5-[1-Fluoro-3-hydroxy-7-(2-{[2-(trifluoromethoxy)ethyl]amino}ethoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(2-methoxyethyl)amino]ethoxy}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[3-(methylamino)propyl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(ethylamino)propyl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[5-(dimethylphosphoryl)thiophen-2-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclopropylamino)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(methylamino)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(ethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)amino]ethoxy}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(diethylphosphoryl)propoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3S)-3-hydroxybutoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1,4-difluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3R)-3-hydroxybutoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropyl-2-hydroxyethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(4S)-4-hydroxypentyl]naphthalene-2-yl}-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(4-hydroxy-4-methylpentyl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(3-oxopentyl)oxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(3-hydroxybutoxy)naphthalene-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)naphthalene-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)naphthalene-2-yl]oxyethyl)cyclopropane-1-carbonitrile, 5-(1-fluoro-3-hydroxy-7-{2-[1-(methoxymethyl)cyclopropyl]ethoxy}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[(cyclopropylmethyl)amino]methyl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2,2-difluoropropyl)amino]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3,3-dimethyl-4-(methylamino)butoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-phenylethyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3-amino-3-methylbutoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(difluoromethyl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(dimethylphosphoryl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(3,3,3-trifluoropropyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(3-methoxy-3-methylbutoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropylpropoxy)-1-fluoro-3-hydroxynaphthalene-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)pyrrolidine-3-yl]methoxy}naphthalene-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)naphthalene-2-yl]amino}butanenitrile, 5-[1-Fluoro-3-hydroxy-7-(2-hydroxyethyl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(4-amino-3,3-dimethylbutoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[2-(azetidine-1-yl)ethyl]amino}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)azetidine-3-yl]oxy}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(2-methoxyethyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(3,3,3-trifluoropropoxy)naphthalene-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)naphthalene-2-yl]aminomethyl)cyclopropane-1-carbonitrile, 5-[1-Fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[3-(1H-pyrazole-1-yl)propoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(4-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrole-3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(hydroxymethyl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)piperidine-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)pyrrolidine-2-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[2-(1H-pyrazole-1-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidine-2-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)pyrrolidine-2-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(piperidine-3-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(2,2-difluorocyclopropyl)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[2-(1-methylcyclopropyl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(3-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrole-3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(2-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrole-3-yl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,2-difluoroethyl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(2,2,2-trifluoroethoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-7-(2-fluoroethoxy)-3-hydroxynaphthalene-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)naphthalene-2-yl]oxymethyl)cyclopropane-1-carbonitrile, 5-{1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(2-methylpropyl)amino]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(cyclopropylmethyl)amino]-1-fluoro-3-hydroxynaphthalene-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)naphthalene-2-yl]oxy}acetonitrile, 5-[1-fluoro-3-hydroxy-7-(3-methylbutoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1,8-difluoro-3-hydroxy-7-methoxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)azetidine-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)azetidine-3-yl]-1-fluoro-3-hydroxynaphthalene-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)naphthalene-2-yl]propa-2-ennitrile, 5-[7-(2-cyclopropylethyl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2,2-difluorocyclopropyl)methoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclopropylethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclopropylmethoxy)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[2-(oxolan-2-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[2-(cyclobutyloxy)ethoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)oxy]ethoxy}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3-ethoxypropoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-tert-butoxyethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[rac-(1R,2R)-2-ethylcyclopropyl]methoxy}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(4-methylpentyl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[3-(2,2-dimethylpropyl)pyrrolidine-1-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(1-chloro-3-hydroxypropan-2-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)pyrrolidine-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(cyclopropyloxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(2-cyclopropylethyl)amino]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(4-methyl-1H-imidazole-2-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(azetidine-3-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(5-methoxythiophen-2-yl)naphthalene-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)naphthalene-2-yl]acetonitrile, 5-[1-Fluoro-3-hydroxy-7-(methoxymethyl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(3-methyloxetan-3-yl)methoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{4-bromo-7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{4-bromo-7-[1-(cyclopropanesulfonyl)-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(3S)-pyrrolidine-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(3R)-pyrrolidine-3-yl]naphthalene-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-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-cyclopropyl-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanecarbonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-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-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1E)-4-methylpenta-1-en-1-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(pentamethylphenyl)ethenyl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropylmethyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(4-bromo-1-fluoro-3-hydroxy-7-methoxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(2-cyclopropylethyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(1E)-3-methoxypropane-1-en-1-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-ethoxyethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(3-methoxypropoxy)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(1,1-dioxo-1λ 6 [-thian-4-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-fluoro-3-hydroxy-7-(oxan-3-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(cyclopropylmethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(2,2,2-trifluoroethyl)pyrrolidine-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)piperidine-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}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(oxolan-2-yl)methoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(oxolan-3-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)azetidine-3-yl]methyl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)piperidine-4-yl]methyl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(pyrrolidine-2-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)piperidine-3-yl]methyl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(difluoromethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)pyrrolidine-3-yl]methyl}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(pyrrolidine-3-yl)methyl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,5-dihydrofuran-3-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3,6-dihydro-2H-pyran-4-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,5-dihydro-1H-pyrrole-3-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(pyridine-3-yl)naphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(azetidine-3-yl)methyl]-1-fluoro-3-hydroxynaphthalene-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-thiadiazolidine-2-yl)naphthalene-2-yl]aminoacetamide, 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalene-2-yl]oxy}-N-methylbutanamide, N-ethyl-N'-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidined-2-yl)naphthalene-2-yl]oxyethyl)urea, 5-{1-fluoro-3-hydroxy-7-[(oxan-3-yl)methoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[(1-chloro-3-hydroxypropane-2-yl)oxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[(oxan-4-yl)methoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[(oxetane-3-yl)oxy]naphthalene-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-tetrahydropyridine-4-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3,7-dihydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[1-Fluoro-3-hydroxy-7-(2-hydroxyethoxy)naphthalene-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]naphthalene-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)naphthalene-2-yl]aminoacetic acid, N-(2-cyclopropylethyl)-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidine-2-yl)naphthalene-2-yl]oxy}acetamide, N,N-diethyl-2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidine-2-yl)naphthalene-2-yl]oxy}acetamide, 5-{1-fluoro-3-hydroxy-7-[2-oxo-2-(pyrrolidine-1-yl)ethoxy]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidine-4-yl]oxy}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[1-(oxolan-3-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(2-methoxyethanesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-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-pyrrole-3-yl]naphthalene-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-pyrrole-3-yl]naphthalene-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-pyrrole-3-yl}naphthalene-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-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(butane-1-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{1-[(1,4-dioxan-2-yl)methanesulfonyl]-2,5-dihydro-1H-pyrrole-3-yl}-1-fluoro-3-hydroxynaphthalene-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-thiadiazolidined-2-yl)naphthalene-2-yl]-2,5-dihydro-1H-pyrrole-1-sulfonyl}pentanenitrile, 5-{1-fluoro-3-hydroxy-7-[1-(pentan-2-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(ethanesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(propane-2-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-1,2,3,6-tetrahydropyridine-4-yl]-1-fluoro-3-hydroxynaphthalene-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)naphthalene-2-yl]oxyethyl)oxetane-3-sulfonamide, 5-[1-Fluoro-3-hydroxy-7-(piperidine-4-yl)naphthalene-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-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-ethoxy-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2,2-difluoroethoxy)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclopropanesulfonyl)-1H-pyrazole-4-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[(3R)-1-(methanesulfonyl)pyrrolidine-3-yl]amino}naphthalene-2-yl)-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)piperidine-4-yl]amino}naphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(7-{[1-(cyclopropanesulfonyl)pyrrolidine-3-yl]amino}-1-fluoro-3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(1-fluoro-7-{[3-fluoro-1-(methanesulfonyl)pyrrolidine-3-yl]methoxy}3-hydroxynaphthalene-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-Fluoro-3-hydroxy-7-[1-(propan-2-sulfonyl)pyrrolidine-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-aminoethoxy)-1-fluoro-3-hydroxynaphthalene-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-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-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]oxyethyl)ethanesulfonamide, 5-{1-fluoro-7-[1-(furan-3-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(3-methylbutan-1-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{1-fluoro-3-hydroxy-7-[1-(thiophen-3-sulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]naphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(benzenesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{7-[1-(cyclobutanesulfonyl)-2,5-dihydro-1H-pyrrole-3-yl]-1-fluoro-3-hydroxynaphthalene-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-thiadiazolidined-2-yl)naphthalen-2-yl]oxy}butanoate methyl, 5-{7-[(3,5-dimethyl-1H-pyrazole-4-yl)methoxy]-1-fluoro-3-hydroxynaphthalene-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(3,5-dimethyl-1H-pyrazole-4-yl)-1-fluoro-3-hydroxynaphthalene-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[7-(2-cyclohexylethoxy)-1-fluoro-3-hydroxynaphthalene-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-thiadiazolidine-2-yl)naphthalene-2-yl]-1H-imidazole-4-carbonitrile Compounds selected from the group consisting of the above, as well as pharmaceutically acceptable salts, solvates, hydrates, tautomers, esters, N-oxides, or stereoisomers thereof, are further disclosed.

[0119] In some embodiments, the compounds disclosed herein, for example, formula (I), formula (II), or formula (III), are formulated as pharmaceutically acceptable compositions comprising the disclosed compounds and a pharmaceutically acceptable carrier.

[0120] In some embodiments, the compounds disclosed herein, for example, 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 TIFF0007881804000050.tif204155TIFF0007881804000051.tif209155TIFF0007881804000052.tif213155TIFF0007881804000053.tif210155TIFF000 7881804000054.tif212155TIFF0007881804000055.tif209155TIFF0007881804000056.tif219155TIFF0007881804000057.tif215155TIFF0007881804 000058.tif211155TIFF0007881804000059.tif218155TIFF0007881804000060.tif205155TIFF0007881804000061.tif225155TIFF0007881804000062. tif220156TIFF0007881804000063.tif225156TIFF0007881804000064.tif204156TIFF0007881804000065.tif219156TIFF0007881804000066.tif73156

[0122] Method for producing an exemplary compound The compounds of this disclosure can be better understood in relation to the following synthetic schemes and methods that describe the means by which the above compounds can be prepared. The compounds of this disclosure can be prepared by various synthetic procedures. Representative synthetic procedures are shown in schemes 1 to 7, but are not limited to these. Variable R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 This is defined as described in detail in this specification, i.e., in the “Summary of the Invention.”

[0123] Scheme 1: A representative scheme for the synthesis of exemplary compounds of this disclosure. As shown in Scheme 1, the compounds of formulas (1-9), (1-10), (1-11), and (1-12) can be prepared from the compound of formula (1-1). The compound of formula (1-1) can be alkylated with 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 produce 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). Compound (1-2) can be reacted under Curtius reaction conditions (diphenyl phosphate azide, tert-butanol, and triethylamine in heated toluene) to obtain compound (1-3). By treating with heated diethylenetriamine, the tert-butoxycarbonyl moiety can be removed from compound (1-3) to obtain compound (1-4). Compound (1-4) can be reacted with 2-bromoacetic acid 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 compound (1-6). Compound (1-6) can then be fluorinated with a reagent such as N-fluorobenzenesulfonimide (NFSI) in a solvent such as tetrahydrofuran, or optionally Selectfluor® in heated N,N-dimethylformamide, to obtain compound (1-7). The compounds of formula (1-7) can be reacted with chlorosulfonyl isocyanate and tert-butanol in a cooled solvent such as dichloromethane in the presence of a tertiary amine base such as triethylamine. Subsequently, the tert-butoxycarbonyl group is removed by treatment in dichloromethane under acidic conditions such as trifluoroacetic acid to obtain the compound of formula (1-8).Compounds of formula (1-8) can be reacted with an alkoxide base, for example, optionally heated methanol or a mixture of methanol and water containing sodium methoxide, or potassium tert-butoxide in tetrahydrofuran, and then quenched with an acid such as 1M hydrochloric acid to obtain compounds of formula (1-9) or (1-10). Compound (1-9) can be converted to compound (1-11) using water under cross-coupling reaction conditions such as the presence of RockPhos Pd G3 as a pre-catalyst, cesium carbonate as a base, and water as a heated solvent, N,N-dimethylformamide. Optionally substituted benzyl ethers in compounds of formula (1-10) are known to those skilled in the art and can be removed using conditions appropriate to the specific benzyl ether. For example, unsubstituted benzyl ether can be removed by treatment with boron trichloride in dichloromethane in the presence of 1,2,3,4,5-pentamethylbenzene at -60 to -80°C to obtain compounds of formula (1-12). Compounds of formula (1-12) are representative of compounds of formula (I).

[0124] Scheme 2: A representative scheme for the synthesis of exemplary compounds of this disclosure. As shown in Scheme 2 of TIFF0007881804000069.tif158128, the compounds of formulas (2-2), (2-4), (2-6), and (2-8) can be prepared from the compounds of formula (1-9). The compounds of formula (1-9) can be reacted under C-cross-coupling reaction conditions. For example, using Suzuki reaction conditions, the compounds of formula (1-9) can be coupled with the compounds of formula (2-1) (wherein A represents an alkene moiety, a cyclopropyl group, an aromatic ring, or a partially unsaturated ring). The reaction conditions for coupling the compounds of formula (1-9) with the compounds 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, the optionally substituted benzyl ether protecting group can be removed using conditions known to those skilled in the art and applicable to a specific benzyl ether. For example, the unsubstituted benzyl ether can be removed by treatment with boron trichloride in dichloromethane in the presence of 1,2,3,4,5-pentamethylbenzene at -60 to -80°C to obtain the compound of formula (2-2). Furthermore, the unsubstituted benzyl ether can also be removed by treatment with a hydrogen and palladium catalyst in a solvent such as dioxane or tetrahydrofuran. The compound of formula (2-2) or the protected precursor may be further modified in ways known to those skilled in the art and as shown in the examples.

[0125] The compounds of formula (1-9) can be reacted under N-cross-coupling conditions. For example, the compounds of formula (1-9) can be coupled with the compounds of formula (2-3) using Buchwald-Hartwig reaction conditions. For example, the compounds of formula (1-9) and formula (2-3) can be coupled in a solvent such as heated dioxane or tert-amyl alcohol in the presence of a pre-catalyst (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, the optionally substituted benzyl ether protecting group can be removed as described above to obtain the compound of formula (2-4) (wherein NR 2-1 R 2-2 is R 2 Compounds of formula (2-4) (representing the cyclic or acyclic portion of ) can be obtained. The compounds of formula (2-4) or protected precursors may be further modified in ways known to those skilled in the art and as shown in the examples.

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

[0127] The compounds of formula (1-9) can be reacted under C-cross-coupling conditions. For example, the compounds of formula (1-9) can be reacted with the compounds of formula (2-7) (wherein R 2-4R exceeds the range of the allele portion. 2 It can be coupled with an allyl compound (representing the residual portion of ). The reaction conditions for coupling the compounds of formula (1-9) with the compounds of formula (2-7) may include a catalyst such as palladium(II) acetate, a phosphine ligand such as 2-(di-tert-butylphosphino)biphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and a tertiary amine base, such as triethylamine, or a base such as cesium carbonate, in a heated solvent such as N,N-dimethylformamide or dioxane. Subsequently, the 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 is known to those skilled in the art and as shown in the examples.

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

[0129] Scheme 3: A representative scheme for the synthesis of exemplary compounds of this disclosure. As shown in scheme 3 of TIFF0007881804000070.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 formula R 3-1 -LG 1 (In the formula, LG 1 R is a leaving group such as chloro, bromo, iodine, or sulfonate, 3-1The compounds can be alkylated with a compound of (optionally substituted alkyl, optionally substituted heterocyclyl, or optionally substituted cycloalkyl). The alkylation conditions may optionally include treatment with a base such as, but not limited to, cesium carbonate or sodium hydride in a solvent such as N,N-dimethylformamide heated. Subsequently, the optionally substituted benzyl ether protecting group can be removed using conditions known to those skilled in the art and applicable to a specific benzyl ether. For example, the unsubstituted benzyl ether can be removed by treatment with boron trichloride in dichloromethane in the presence of 1,2,3,4,5-pentamethylbenzene at -60 to -80°C to obtain the compound of formula (3-1). The compound of formula (3-1) or the corresponding protected precursor may be further modified using methods known to those skilled in the art and as shown in the examples. 3-1 is R 2 It represents the ether portion.

[0130] An alternative preparation of the compound of formula (3-1) is to use the compound of formula (1-11) under Mitsunobu reaction conditions, R 3-1 -OH(in the formula, R 3-1 This involves reacting compounds of formula (1-11) and formula R 3-1 The -OH compound may be treated with (E)-diazene-1,2-diylbis(piperidine-1-ylmethanone) and tri-n-butylphosphine in a solvent such as heated tetrahydrofuran. Subsequently, the benzyl protecting group is removed as described above to obtain the compound of formula (3-1). The compound of formula (3-1) or the corresponding protected precursor may be further modified in ways known to those skilled in the art and as shown in the examples.

[0131] The compounds of formula (1-11) can also be converted to the compounds of formula (3-2). The compounds of formula (1-11) are converted in a solvent such as N,N-dimethylformamide in the presence of 4-dimethylaminopyridine, R 3-2 -NCO formula (where R3-2 C is replaced by an optional substitution. 1~6 By reacting it with an alkyl compound, the corresponding carbamic acid ester can be obtained. Subsequently, by removing the benzyl protecting group as described above, the compound of formula (3-2) is obtained. Group -OC(O)NHR 3-2 is R 2 This represents the carbamic acid ester portion. The compound of formula (3-2) or the corresponding protected precursor may be further modified in ways known to those skilled in the art and as shown in the examples.

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

[0133] Scheme 4: A representative scheme for the synthesis of exemplary compounds of this disclosure. As shown in scheme 4 of TIFF0007881804000071.tif93134, the compound of formula (4-4) can be prepared from the compound of formula (1-9). The compound of formula (1-9) is subjected to a cross-coupling reaction under conditions of one R B But another R B The compound of formula (4-2) can be obtained by reacting it with a boron reagent of formula (4-1), such as bis(pinacolate)diborone, which is bonded to it. 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 the compound of formula (4-3) (wherein R 2-C LG represents an aromatic ring or a partially unsaturated ring, alkyl group, or alkylene group. 2The compound can be coupled with a compound of formula (4-4), which is 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) may include a catalyst (tetrakis(triphenylphosphine)palladium(0), XPhosPd G2, or meCgpPhPd G3) and a base (sodium carbonate, potassium phosphate, or potassium carbonate) in heated toluene and ethanol, or a mixture of dioxane and water, or N-methyl-2-pyrrolidinone. Subsequently, the optionally substituted benzyl ether protecting group is known to those skilled in the art and can be removed using conditions appropriate to the specific benzyl ether. For example, the compound of formula (4-4) can be obtained by removing the unsubstituted benzyl ether with boron trichloride in dichloromethane in the presence of 1,2,3,4,5-pentamethylbenzene at -60 to -80°C. The compound of formula (4-4) or the corresponding protected precursor may be further modified as is known to those skilled in the art and as shown in the examples.

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

[0135] Scheme 5: A representative scheme for the synthesis of the exemplary compounds of this disclosure. As shown in Scheme 5 of TIFF0007881804000072.tif84128, the compound of formula (5-3) can be prepared from the compound of formula (1-9). The compound of formula (1-9) can be prepared under photo-redox conditions using formula (5-1) (wherein R PRThe compounds can be coupled with compounds of formula (1-9) (where is potassium trifluoroborate or a carboxylic acid moiety, and B represents an optionally substituted heterocyclyl or optionally substituted alkyl). The conditions for coupling the compounds of formula (1-9) with the compounds of formula (5-1) are treatment with NiCl2-dimethoxyethane adduct, ligand (4,4'-di-tert-butyl-2,2'-dipyridyl), base (cesium carbonate), and bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+);2-(2-pyridyl)pyridine;hexafluorophosphate in a solvent such as dioxane containing an optionally selected N,N-dimethylacetamide in a 450 nm LED photoreactor. Subsequently, the optionally substituted benzyl ether protecting group is known to those skilled in the art and can be removed using conditions appropriate 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 reaction conditions described above, the compound of formula (5-1) is converted to formula (5-2) (wherein PG). 3 It also couples with compounds of (2-methoxyethoxy)methyl. By treating with a hydrochloric acid solution of dioxane, one or both protecting groups can be deprotected to obtain the compound of formula (5-3).

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

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

[0139] Scheme 6: A representative scheme for the synthesis of exemplary compounds of this disclosure. As shown in scheme 6 of TIFF0007881804000073.tif37128, 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 (2-methoxyethoxy)methyl is a protecting group, and PG 2 (wherein R is a benzyl group or (2-methoxyethoxy)methyl which is optionally substituted) is given formula (6-2) (wherein R 6-1 The compound can be coupled with a compound of formula (6-1) (which 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. The optionally substituted benzyl ether protecting group, if present, is known to those skilled in the art and can be removed using conditions appropriate to the specific benzyl ether. For example, unsubstituted benzyl ether (PG 2 The compound of formula (6-3) can be obtained by hydrogenating the compound in the presence of a carbon-supported palladium catalyst, or by treating it with boron trichloride in dichloromethane. 1 or PG 2 If either of the groups is a (2-methoxyethoxy)methyl group, one or both can be removed by treatment with an acid such as a hydrochloric acid solution of dioxane to obtain the compound of formula (6-3). The compound of formula (6-3) or the corresponding protected precursor may be further modified in ways known to those skilled in the art and as shown in the examples.

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

[0141] Scheme 7: A representative scheme for the synthesis of exemplary compounds of the present disclosure. As shown in Scheme 7, the compound of formula (2-2) can be prepared from the compounds of formula (1-9) in the reverse order of synthesis from that described in Scheme 2. In the first step, the optionally substituted benzyl moiety is known to those skilled in the art and can be removed using conditions appropriate to a particular benzyl ether. For example, the unsubstituted benzyl ether can be removed by treatment with boron trichloride in dichloromethane in the presence of 1,2,3,4,5-pentamethylbenzene at -60 to -80°C to obtain the compound of formula (7-1). The compound of formula (7-1) can be reacted under C-cross-coupling reaction conditions. For example, the compound of formula (7-1) can be coupled with the compound of formula (2-1) (wherein A represents an alkene moiety, cyclopropyl, or an aromatic ring or a partially unsaturated ring) using Suzuki reaction conditions. 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-butylphosphin)ferrocenepalladium 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 is known to those skilled in the art and as shown in the examples.

[0142] The compound of formula (2-2) is either representative of the compound of formula (I) or a precursor of the compound of formula (I).

[0143] Pharmaceutical composition This disclosure provides pharmaceutical compositions comprising the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III). In some embodiments, the pharmaceutical compositions further comprise pharmaceutically acceptable excipients. In some embodiments, the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III), are provided in the pharmaceutical composition in an effective amount. In some embodiments, the effective amount is a therapeutic effective amount. In certain embodiments, the effective amount is a prophylactic effective amount.

[0144] The pharmaceutical compositions described herein can be prepared by any method known in the field of pharmacology. Generally, such preparation methods include the steps of co-locating the compound disclosed ("active ingredient") with a carrier and / or one or more other minor components, and then, if necessary and / or desirable, molding and / or packaging the product into desired single-dose units or multi-dose units. The pharmaceutical compositions may be formulated, packaged and / or sold in bulk as single-dose units and / or as multiple single-dose units. In this specification, "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 dose of the active ingredient to be administered to a subject and / or a manageable fraction of such dose, for example, half or one-third of such dose.

[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 further components in the pharmaceutical compositions disclosed herein will vary depending on the identity, body size, and / or condition of the person being treated, and further on the route by which the composition is administered. For example, the composition may contain 0.1% to 100% (w / w) of the compounds disclosed herein.

[0146] The term "pharmaceutically acceptable excipient" means a non-toxic carrier, adjuvant, diluent, or vehicle that does not impair the pharmacological activity of the compound being formulated. pharmaceutically acceptable excipients useful for the manufacture of the pharmaceutical compositions of this disclosure are any pharmaceutically acceptable excipients well known in the field of pharmaceutical formulation, and include inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, and / or oils. Pharmaceutically acceptable excipients useful for the manufacture of the pharmaceutical compositions of this 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, and 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, and zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulosic substances; polyethylene glycol; sodium carboxymethylcellulose; polyacrylic acid esters; waxes; polyethylene-polyoxypropylene block polymers; polyethylene glycol; and lanolin tallow.

[0147] The compositions of this disclosure may be administered orally, parenterally (including subcutaneous, intramuscular, intravenous, and intradermal), by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. In some embodiments, the compounds or compositions provided may be administered intravenously and / or orally.

[0148] In this specification, the term “parenteral” includes subcutaneous, intravenous, intramuscular, intraocular, intravitreous, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intraperitoneal, intralesional, and intracranial injection or infusion techniques. The composition is preferably administered orally, subcutaneously, intraperitoneally, or intravenously. The sterile injection form of the composition disclosed herein may be aqueous or oily suspension. These suspensions can be formulated according to techniques known in the art using appropriate dispersants or wetting agents and suspending agents. The sterile injection formulation may also be a sterile injection solution or suspension 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. Furthermore, sterile non-volatile oils have conventionally been used as solvents or suspension media.

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

[0150] The compositions of this disclosure may be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, topical applications, powders, and aerosols and delivered transdermally via topical routes. Oral formulations include tablets, pills, powders, sugar-coated tablets, capsules, liquids, lozenges, cachets, gels, syrups, slurries, and suspensions suitable for patient ingestion. Solid formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid formulations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. The compositions of this disclosure may further contain components to provide sustained release and / or comfort. Such components include high molecular weight anionic mucosal mimic polymers, gelling polysaccharides, and micronized drug carrier substrates. These components are discussed in more detail in U.S. Patents 4,911,920, 5,403,841, 5,212,162, and 4,861,760. The entirety of these patents is incorporated herein by reference for all purposes. The compositions of this disclosure may also be delivered as microspheres for sustained release in the body. For example, the microspheres may be drug-containing microspheres administered by intradermal injection of the microspheres to sustainably release the drug subcutaneously (see, for example, Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995); as a biodegradable and injectable gel formulation (see, for example, Gao Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (see, for example, Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, the formulation of the composition of the present disclosure may be delivered by using liposomes that fuse with the cell membrane or are endocytosed, for example, by using a receptor ligand bound to the liposome that binds to a cell surface membrane protein receptor, thereby leading to endocytosis.By using liposomes, particularly liposomes whose surface has a target cell-specific receptor ligand or, in other forms, liposomes that preferentially direct to a specific organ, the delivery of the compositions of the present disclosure can be concentrated on 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 this disclosure may be administered in the form of suppositories for rectal administration. The pharmaceutically acceptable compositions of this disclosure may also be administered topically, particularly when the therapeutic target includes areas or organs that are easily accessible by topical application, including diseases of the eyes, skin, or lower intestines. Suitable topical formulations for each of these areas or organs can be easily prepared.

[0152] In some embodiments, it is often desirable to slow down the absorption of a drug from subcutaneous or intramuscular injection in order to prolong its effects. This can be achieved by using a suspension of a crystalline or amorphous substance with low water solubility. In this case, the absorption rate of the drug depends on its dissolution rate, which in turn may depend on the size and morphology of the crystals. Alternatively, the slowing of absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oily vehicle.

[0153] The descriptions of pharmaceutical compositions provided herein primarily concern pharmaceutical compositions suitable for administration to humans; however, those skilled in the art will understand that such compositions are generally suitable for administration to all species of animals. Modifications of pharmaceutical compositions suitable for administration to humans to compositions suitable for administration to various animals are well understood, and such modifications can be designed and / or carried out in routine experiments by a typical skilled veterinary pharmacologist.

[0154] The compounds provided herein, for example, those of formula (I), formula (II), or formula (III), are generally formulated into unit dosage forms, e.g., single-dose unit dosage forms, for ease of administration and uniformity of dosage. However, it will be understood that the total daily dose of the compositions disclosed herein is to be determined by the attending physician within the bounds of sound medical judgment. A specific therapeutically effective dose 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 used; the specific composition used; the subject's age, weight, overall health, sex, and diet; the time of administration, route of administration, and excretion rate of the specific active ingredient used; the duration of treatment; drugs used in combination with or incidentally with the specific active ingredient used; and similar factors well known in the medical field.

[0155] The exact amount of compound required to achieve an effective dose will vary from subject to subject, depending on factors such as the species, age, and overall condition of the subject, the severity of side effects or disorders, the identity of the specific compound(s), and the mode of administration. The desired dosage may be delivered three times daily, twice daily, once daily, every other day, every three days, once a week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered using multiple doses (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more doses).

[0156] It will be understood that the dose ranges described herein are intended to provide guidelines for administering the provided pharmaceutical compositions to adults. For example, the amount administered to children or adolescents may be determined by a physician or a person skilled in the art and may be less than or equal to the amount administered to adults.

[0157] It will also be understood that the compounds or compositions disclosed herein may be administered in combination with one or more further agents. These compounds or compositions may be administered in combination with further agents that improve their bioavailability, reduce and / or modify their metabolism, inhibit their excretion, and / or alter their distribution in the body. It will also be understood that different treatments may achieve the desired effect on the same disorder, and / or different treatments may achieve different effects.

[0158] The compound or composition may be administered simultaneously with, before, or after, one or more further agents, which may, for example, be useful as combination therapy agents. Examples of agents include therapeutically active agents. Examples of agents include prophylactically active agents. Each further agent may be administered in a dose and / or time schedule determined for the pharmacopoeia. These further agents may also be administered together with each other and / or together with the compound or composition described herein in a single dose, or separately in different doses. The specific combination used in a regimen will take into account the compatibility of the compound of the present invention with the further agents, and / or the desired therapeutic and / or prophylactic effects to be achieved. Generally, further agents used in combination are required to be used at levels not exceeding those used individually. In some embodiments, the level of combined use will be lower than that of individual use.

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

[0160] The pharmaceutical compositions provided herein include compositions containing an active ingredient (e.g., a compound described herein, including embodiments or examples) in a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. The actual amount effective for a particular use depends, among other things, on the disease being treated. When administered in a method of treating a disease, such compositions contain an amount of the active ingredient effective to achieve the desired result, e.g., inhibition of the activity of a target molecule (e.g., PTPN2 and / or PTPN1), and / or reduction, elimination, or delay of the progression of the disease symptoms. Determining the therapeutically effective amount of the compounds disclosed herein is well within the capabilities of those skilled in the art, particularly in light of the detailed disclosure herein.

[0161] The dosage and frequency (single or multiple doses) administered to mammals may vary depending on various factors, such as whether the mammal has another disease and the route of administration; the size, age, sex, health status, weight, body mass index, and diet of the recipient; the nature and severity of the symptoms of the disease being treated, the type of concomitant therapy, complications from the disease being treated, or other health-related issues. Other treatment regimens or agents may be used in combination with the methods, compounds, and compositions disclosed herein. Adjustments and manipulations of established dosages (e.g., frequency and duration) are well within the capabilities of those skilled in the art.

[0162] For any compound described herein, the therapeutically effective dose can initially be determined by a cell culture assay. The target concentration is the concentration of the active compound(s) capable of achieving the method described herein, as measured using the methods described herein or methods known in the art.

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

[0164] The dosage can be varied depending on the patient's requirements and the compound used. In the context of this disclosure, the dose administered to the patient must be sufficient to influence the patient's beneficial therapeutic response over time. The size of the dose will also be determined by the presence, nature, and severity of any adverse side effects. Determining the appropriate dosage for a particular situation is within the scope of the physician's skill. Generally, treatment is initiated with a smaller dose than the optimal dose of the compound. The dosage is then increased in small increments until the optimal effect for the situation is achieved. The dosage and interval may be individually adjusted to a level of the compound that is effective for the specific clinical indication being treated. This will provide a treatment regimen that is appropriate to the severity of the individual's condition.

[0165] Using the teachings provided herein, effective prophylactic or therapeutic regimens can be planned that do not cause substantial toxicity and are effective in treating the clinical symptoms exhibited by specific patients. This planning requires careful selection of active compounds, taking into account 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 drug.

[0166] This disclosure also includes kits (e.g., drug packs). The kits provided herein may be useful for the prevention and / or treatment of diseases (e.g., cancer, type 2 diabetes, obesity, metabolic disorders, or other diseases or illnesses described herein).

[0167] The provided kit may comprise the pharmaceutical composition or compound of the present invention and a container (e.g., a vial, ampoule, bottle, syringe, and / or dispenser package, or other appropriate container). In some embodiments, the provided kit may further optionally comprise a second container for holding 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 a unit dosage form.

[0168] Accordingly, in one embodiment, a kit is provided comprising a first container for containing the compounds disclosed herein. In a particular embodiment, the kit is useful for preventing and / or treating proliferative disorders in a subject. In a particular embodiment, the kit further comprises instructions for administering the compounds disclosed to a subject for preventing and / or treating the diseases described herein.

[0169] Treatment method This disclosure features compounds, compositions, and methods comprising the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III). In some embodiments, the compounds, compositions, and methods disclosed herein are used to prevent or treat diseases, disorders, or illnesses. Exemplary diseases, disorders, or illnesses include, but are not limited to, cancer, type 2 diabetes, metabolic syndromes, obesity, or metabolic disorders.

[0170] cancer In some embodiments, the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III), are used to treat cancer. Herein, “cancer” means human cancers and carcinomas, sarcomas, adenocarcinomas (e.g., papillary adenocarcinoma), lymphomas, leukemias, melanomas, etc., and includes solid tumors and lymphocyte cancers, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, liver cancer including hepatocellular carcinoma, lymphomas including acute lymphoblastic lymphoma, non-Hodgkin lymphomas (e.g., 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” means lung cancer, breast cancer, ovarian cancer, epithelial ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, bile duct cancer, adrenal cancer, salivary gland cancer, bronchial cancer, oral cancer, oral or pharyngeal cancer, laryngeal cancer, kidney cancer, gynecological cancer, brain cancer, central nervous system cancer, peripheral nervous system cancer, hematological cancer, small intestine 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] In this specification, the term “cancer” means all types of cancer, neoplasms, or malignant tumors found in mammals, including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include lymphoma, B-cell lymphoma, heavy chain disease, alpha-chain disease, gamma-chain disease, μ-chain disease, Waldenström macroglobulinemia, benign monoclonal hypergammaglobulinemia, 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, breast cancer (e.g., ER-positive, ER-negative, chemotherapy-resistant), Examples include 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 pleomorphic, acoustic neuroma, retinoblastoma, astrocytoma, craniopharyngioma, hemangioblastoma, pineal tumor, ependymoma, oligodendroglioma, meningioma, glioma, or melanoma. Further examples include cancers of the thyroid, endocrine system, brain, breast, neck, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovarian, sarcoma, stomach, and uterine cancer, or medulloblastoma, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, immunocellular amyloidosis, ovarian cancer, rhabdomyosarcoma, primary thrombocytopenia, primary macroglobulinemia, primary brain tumors, cancer, and malignant pancreatic cancer. These include linoma, malignant carcinoid, bladder cancer, precancerous skin disorders, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, neoplasms of the endocrine or exocrine pancreas, medullary thyroid carcinoma, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, Paget's disease of the papillary thyroid, phyllocarcinoma, lobular carcinoma, ductal carcinoma, astrocellular carcinoma of the pancreas, astrocellular carcinoma of the liver, or prostate cancer.

[0172] The term "leukemia" broadly refers to a progressive, malignant disease of the hematopoietic organs, generally characterized by the abnormal 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., whether it is acute or chronic; (2) the type of cells involved, i.e., myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) whether there is an increase or absence of abnormal cells in the blood, i.e., whether it is 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 lymphoblastic leukemia, B-cell chronic lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocythemic leukemia, basophilic leukemia, myeloid leukemia, bovine leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, cutaneous leukemia, embryocellular leukemia, eosinophilic leukemia, erythroleukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia. Leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia Leukemia includes lymphosarcoma, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli's leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, polycythemia vera, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemia, or anaplastic cell leukemia.

[0173] The term "sarcoma" generally refers to a tumor composed of densely packed cells embedded in a fibrous or homogeneous material, and composed of a substance such as embryonic connective tissue. Sarcomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include chondrosarcoma, fibrosarcoma, leiomyosarcoma, lymphosarcoma, lymphangiosarcoma, intralymphatic sarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft tissue sarcoma, epiamelosarcoma, botrioid sarcoma, chloroplastoma, choriocarcinoma, embryonic sarcoma, Wilms tumor sarcoma, endometrial sarcoma, endosarcoma, and stromal sarcoma. Examples include sarcomas, Ewing's sarcoma, myofascial 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's astrocytic sarcoma, angiosarcoma, leukemosarcoma, malignant mesenchymal sarcoma, osteosarcoma, paraosteal osteosarcoma, reticular sarcoma, Roussarcoma, serous cystic sarcoma, synovial sarcoma, or peripheral telangiectatic sarcoma.

[0174] The term "melanoma" is interpreted to mean a tumor arising from the melanin-producing cell system of the skin and other organs. Examples of melanomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include acral lentiginous melanoma, achromatic melanoma, benign juvenile melanoma, Crowdmann melanoma, S91 melanoma, Harding-Passé melanoma, juvenile melanoma, lentiginous melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0175] The term "carcinoma" refers to a malignant neoplasm composed of epithelial cells that tends to invade surrounding tissues and cause metastasis. Examples of carcinomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, lobular carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma (carcinoma adenomatosum), adrenal cortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma (carcinoma basocellulare), basal cell carcinoma, basal squamous cell carcinoma, cholangiocarcinoma, bladder carcinoma, breast cancer, Brenner's carcinoma, bronchoalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cervical carcinoma, cholangiocarcinoma, chordoma, chorionic carcinoma, clear cell carcinoma, mucinous carcinoma, colon carcinoma, comedone carcinoma, corpus carcinoma, cribriform carcinoma, armory carcinoma, skin carcinoma, cylindrical carcinoma cylindrical cell carcinoma, cystadenocarcinoma, ductal carcinoma, ductal carcinoma, carcinoma durum, fetal stage carcinoma, medullary carcinoma, endometrioid carcinoma, epidermoid carcinoma, epithelial carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, ulcer carcinoma, fibrous carcinoma, gelatiniforni gelatinous carcinoma, giant cell carcinoma, carcinoma giantocellulare, adenocarcinoma, granulosa cell carcinoma, hematoid carcinoma, hepatoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, hypermephroid infantile embryonal carcinoma, carcinoma in situ, intraepithelial carcinoma,Carcinoma, Krompecher's carcinoma, Kulchitsky cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma, lipomatous carcinoma, lobular carcinoma, lung cancer, lipoplasty carcinoma, medullare carcinoma, medullary carcinoma, melanotic carcinoma, molle carcinoma, mucinous carcinoma, muciparum carcinoma, mucocellular carcinoma, mucoepidermoid carcinoma, mucosum carcinoma, mucous carcinoma, mucinous carcinoma Myxomatodes, pharyngeal carcinoma, non-papillary renal cell carcinoma, oat cell carcinoma, ossificans carcinoma, osteoid carcinoma, ovarian carcinoma, ductal carcinoma, papillary carcinoma, periportal carcinoma, anterior invasive carcinoma, prickle cell carcinoma, pulpaceous carcinoma, renal cell carcinoma of the kidney, pre-existing cell carcinoma, sarcomatodes carcinoma, scirrhous carcinoma, scrotal carcinoma, serous carcinoma, signet ring cell carcinoma, monocarcinoma, small cell carcinoma, potato carcinoma. Carcinoma, spindle cell carcinoma, spongiosum carcinoma, squamous carcinoma, squamous cell carcinoma, string carcinoma, sweat gland carcinoma, telangiectatic carcinoma, telangiectodes carcinoma, transitional cell carcinoma, tuberous carcinoma, tubular carcinoma, tuberous carcinomaExamples include carcinoma, undifferentiated carcinoma, wart-like carcinoma, or choriocarcinoma (carcinoma villosum).

[0176] In some embodiments, the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III), are used to treat pancreatic cancer, breast cancer, multiple myeloma, and secretory cell carcinoma. For example, certain methods disclosed herein treat cancer by reducing, mitigating, or preventing the development, growth, metastasis, or progression of cancer. In some embodiments, the methods disclosed herein can be used to treat cancer by reducing or eliminating the symptoms of cancer. In some embodiments, the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III), can be used as a monotherapy 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, secretory cell carcinoma).

[0177] In some embodiments, the compound (the compound described herein, e.g., the compound of formula (I), formula (II), or formula (III)) and the composition (e.g., a composition comprising the compound described herein, e.g., formula (I), formula (II), or formula (III)) are used together with a cancer immunotherapy agent (e.g., a checkpoint-blocking antibody) to treat, for example, 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., cancer described herein)). The methods described herein involve administering the compound described herein, e.g., the compound of formula (I), formula (II), or formula (III) and the immunotherapy agent to a subject having abnormal cell proliferation such as cancer. Examples of immunotherapy agents include, but are not limited to, the following.

[0178] In some embodiments, the immunotherapy agent is a compound (e.g., ligand, antibody) that inhibits an immune checkpoint pathway. In some embodiments, the immunotherapy agent is a compound that inhibits the indoleamine 2,3-dioxygenase (IDO) pathway. In some embodiments, the immunotherapy agent is a compound that stimulates the STING pathway. Cancer immunotherapy refers to the use of the immune system to treat cancer. Three groups of immunotherapies used to treat cancer include cell-based therapies, antibody-based therapies, and cytokine therapies. All groups utilize the representation of cancer cells by the immune system of subtly different structures on the surface of the cancer cells (e.g., molecular structures; antigens, proteins, molecules, carbohydrates). Cancer immunotherapy agents (e.g., anti-tumor immunotherapy agents or anti-tumor immunotherapeutics, such as 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 neogenic antigens such as peptides or RNA vaccines) are examples of cancer immunotherapy agents (e.g., anti-tumor vaccines or vaccines based on neogenic antigens such as peptides or RNA vaccines), but are not limited to these.

[0179] Cell-based therapies (e.g., cancer vaccines) typically involve extracting immune cells from either the blood or tumor of a patient affected by cancer. These tumor-specific immune cells are then activated, proliferated, and returned to the patient, where they initiate an immune response against the cancer. Types of cells that can be used in this way include, for example, natural killer cells, lymphokine-activated killer cells, cytotoxic T cells, dendritic cells, CAR-T therapy agents (e.g., chimeric antigen receptor T cells, which are T cells engineered to target specific antigens), TIL therapy (e.g., administration of tumor-infiltrating lymphocytes), TCR gene therapy, protein vaccines, and nucleic acid vaccines. An exemplary cell-based therapy agent is Provenge. In some embodiments, the cell-based therapy is a CAR-T therapy.

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

[0181] Cancer vaccine using new antigens Emerging antigens are antigens encoded by tumor-specific mutant genes. Technological advancements have made it possible to examine immune responses to patient-specific nascent antigens resulting from tumor-specific mutations, and the data obtained suggest that recognition of such nascent antigens is a major factor in the activity of clinical immunotherapies. These observations indicate that nascent antigen loading may form a biomarker in cancer immunotherapy. Many novel therapeutic approaches have been developed to selectively enhance the responsiveness of T cells to this type of antigen. One approach targeting nascent antigens is through cancer vaccines. These vaccines can be developed using peptides or RNA, for example, synthetic peptides or synthetic RNA.

[0182] Antibody therapies are antibody proteins produced by the immune system that bind to target antigens on the cell surface. Antibodies are generally encoded by immunoglobulin genes, multiple genes, or fragments thereof. In normal physiology, antibodies are used by the immune system to fight pathogens. Each antibody is specific to one or more 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, WE, ed., Raven Press, NY (1993). Specific binding to the corresponding antigen or epitope occurs even in the presence of heterogeneous populations of proteins and other biologics. Specific binding of an antibody indicates that the antibody binds to its target antigen or epitope with substantially greater affinity than it would to an unrelated antigen. The relative difference in affinity is often at least 25% greater, more often at least 50% greater, and most often at least 100% greater. The relative difference may be, for example, at least 2 times, at least 5 times, at least 10 times, at least 25 times, at least 50 times, at least 100 times, or at least 1000 times.

[0183] Examples of antibody types include, but are not limited to, human, humanized, chimeric, monoclonal, polyclonal, single-stranded, antibody-binding fragments, and diabodies. When antibodies bind to cancer antigens, they can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, prevent receptors from interacting with their ligands, or deliver the payload of chemotherapeutic agents or radiation, all of which can lead to cell death. Examples of antibodies for cancer treatment include, but are not limited to, alemtuzumab, bevacizumab, brentuximab vedotin, cetuximab, gemtuzumab ozogamicin, ibritumomab tiuxetan, ipilimumab, ofatumumab, panitumumab, rituximab, tocitumomab, trastuzumab, nivolumab, pembrolizumab, avelumab, durvalumab, and pizilizumab.

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

[0185] Examples of checkpoint-blocking antibodies include, but are not limited to, anti-CTLA-4, anti-PD-1, anti-LAG3 antibodies (e.g., antibodies against lymphocyte-activating gene 3), and anti-TIM3 antibodies (e.g., antibodies against T cell membrane protein 3). Examples of anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab. Examples of 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). Examples of 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. Examples of PD-L1-specific antibodies include, but are not limited to, BMS936559 (e.g., MDX-1105), MEDI4736, and MPDL-3280A. Examples of checkpoint-blocking antibodies include, but are not limited to, IMP321 and MGA271.

[0186] Regulatory T cells (e.g., CD4+, CD25+, or T-regs) are also involved in monitoring the distinction between self-antigens and non-self (e.g., exogenous) antigens, and may play a crucial role in suppressing the immune response in many cancers. T-reg cells can either originate from the thymus (e.g., "endogenous T-regs") or arise from the differentiation of mature T cells in an environment of peripheral immune tolerance induction (e.g., "inducible T-regs"). Therefore, strategies to minimize the action of T-reg cells are expected to promote the immune response against tumors.

[0187] IDO pathway inhibitors The IDO pathway modulates the immune response by suppressing T cell function and enabling localized immune evasion by tumors. IDO expression by antigen-presenting cells (APCs) depletes tryptophan, potentially leading to anergy in antigen-specific T cells and recruitment of regulatory T cells. Some tumors even express IDO to protect themselves from the immune system. Compounds that inhibit IDO or the IDO pathway activate the immune system to attack cancer (e.g., the target tumor). Exemplary IDO pathway inhibitors include indoximod, epacadostat, and EOS200271.

[0188] STING pathway agonist Interferon gene stimulants (STINGs) are adapter proteins that play a crucial role in the activation of type I interferons in response to cytosolic nucleic acid ligands. There is evidence that the STING pathway is involved in inducing anti-tumor immune responses. For example, activating the STING-dependent pathway in cancer cells may allow immune cells to invade the tumor and modulate the anti-cancer immune response. STING agonists are being developed as a class of cancer therapeutics. Exemplary STING agonists include MK-1454 and ADU-S100.

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

[0190] The methods described herein are intended for single and multiple doses of therapeutically effective amounts of the compounds described herein. The compounds, for example, those described herein, may be administered at regular intervals depending on the nature, severity, and extent of the disease being treated. In some embodiments, the compounds described herein are administered as a single dose. In some embodiments, the compounds described herein are administered as multiple doses.

[0191] metabolic disease In some embodiments, the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III), are used to treat metabolic disorders. Hereinafter, the term “metabolic disorder” means a disease or illness affecting a metabolic process of interest. Exemplary metabolic disorders that can be treated with the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III), include non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hepatic fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes mellitus (e.g., type 1 diabetes, type 2 diabetes, or gestational diabetes), metabolic syndromes, phenylketonuria, proliferative retinopathy, or Kearns-Thayer disease.

[0192] In some embodiments, the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III), are used to treat metabolic disorders (e.g., metabolic disorders as described herein) by reducing or eliminating the symptoms of said disorders. In some embodiments, the therapeutic method includes reducing or eliminating symptoms including hypertension, hyperglycemia, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, and jaundice. In some embodiments, the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III), can be used in a composition as a monotherapy agent or in combination with other agents in a composition to treat metabolic disorders.

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

[0194] In some embodiments, the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III), are used to treat an infection (e.g., the infections described herein) by reducing or eliminating the symptoms of the disease. In some embodiments, the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III), can be used in a composition as a monotherapy agent or in combination with other agents in a composition to treat an infection.

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

[0196] In some embodiments, the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III), are used to treat parasitic infections by reducing or eliminating the symptoms of the disease. In some embodiments, the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III), can be used in a composition as a monotherapy agent or in combination with other agents in a composition to treat parasitic infections.

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

[0198] In some embodiments, the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III), are used to treat immunosuppressive diseases by reducing or eliminating the symptoms of said disease. In some embodiments, the compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III), can be used in a composition as a monotherapy agent or in combination with other agents in a composition to treat immunosuppressive diseases.

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

[0200] Combination therapy This disclosure provides pharmaceutical compositions comprising compounds disclosed herein, for example, compounds of formula (I), formula (II), or formula (III), and a second agent (for example, a second therapeutic agent). In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the second agent (for example, a second therapeutic agent). In some embodiments, the second agent is an agent for treating cancer, metabolic diseases (for example, type 2 diabetes or obesity), or diseases or disorders that respond favorably to treatment with PTPN2 or PTP1B inhibitors.

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

[0202] In some embodiments, co-administration involves administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the second active agent. Co-administration involves administering two active agents simultaneously, substantially simultaneously (e.g., within approximately 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration may be carried out 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 agents and / or adjuvants may be combined or conjugated with each other. In some embodiments, the compounds described herein may be used in combination with therapeutic agents for cancer, metabolic diseases (e.g., type 2 diabetes or obesity), or diseases or disorders that respond favorably to treatment with PTPN2 or PTP1B inhibitors. In embodiments, the second agent is an anticancer agent. In embodiments, the second agent is a chemotherapeutic agent. In some embodiments, the second agent is a drug for treating metabolic diseases. In some embodiments, the second agent is an antidiabetic agent. In some embodiments, the second agent is an antiobesity agent.

[0203] anticancer drugs (Resverastatin phosphate sodium), BPR-OY-007 (National Health Research Institutes), and SSR-25041 1 (Sanofi), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinylestradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, α-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy agents (e.g., m In, 90 Y, or 131Anti-CD20 monoclonal antibodies conjugated to I, etc.), triptolide, homohalintonin, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, therapies or therapies targeting the epidermal growth factor receptor (EGFR) (e.g., gefitinib (Iressa®), erlotinib (Tarceva®), cetuximab (Erbitux®), lapatinib (Tyke) rb(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 / PF299 Examples include, but are not limited to, 804, OSI-420 / desmethylerlotinib, AZD8931, AEE788, peritinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, and dasatinib.

[0204] "Chemotherapy agent" or "chemotherapeutic agent" is used in its obvious and ordinary sense to mean a chemical composition or compound having anti-tumor properties or the ability to inhibit cell growth or proliferation.

[0205] Furthermore, the compounds described herein include 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 radioimmunotherapy agents (e.g., m In, 90 Y, or 131 It may be administered concurrently with conventional immunotherapy agents, including, but not limited to, anti-CD20 monoclonal antibodies conjugated to I, etc.

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

[0207] To allow for a more complete understanding of the inventions described herein, the following examples are provided. The synthetic and biological examples described herein 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 herein 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. Where general or preferred process conditions (i.e., reaction temperature, time, molar ratio of reagents, solvent, pressure, etc.) are given, it will be understood that other process conditions may also be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reagents or solvents used, but such conditions can be determined by conventional optimization procedures for those skilled in the art. A general scheme relating to the method for producing exemplary compounds of the present invention is further described in the section titled “Method for Producing Exemplary Compounds.”

[0209] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. The selection of suitable protecting groups for specific functional groups, as well as the conditions favorable 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 above.

[0210] Abbreviation APCI: Atmospheric pressure chemical ionization, DCI: Desorption chemical ionization, DMSO: Dimethyl sulfoxide, ESI: Electrospray ionization, HPLC: High-performance liquid chromatography, LC / MS: Liquid chromatography / mass spectrometry, LED: Light-emitting diode, MS: Mass spectrometry, NMR: Nuclear magnetic resonance, psi: Pounds per square inch, TLC: Thin-layer chromatography.

[0211] Example 1: 5-{1-fluoro-3-hydroxy-7-[2-(morpholine-4-yl)ethoxy]naphthalene-2-yl}-1λ 6,2,5-thiadiazolidine-1,1,3-trione (compound 100) Example 1A: 3-(benzyloxy)-7-bromonaphthalene-2-carboxylate benzyl 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 high speed at 23°C for 5 minutes. 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 filtered off. This filtered precipitate was successively washed 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 was obtained, yielding the marked compound as a grayish-white solid (160.3 g, 358 mmol, yield 96%). MS (APCI) + ) m / z 449 [M+H] + .

[0212] Example 1B: 3-(benzyloxy)-7-bromonaphthalene-2-carboxylic acid A mixture of the product from Example 1A (150.1 g, 336 mmol), water (746 mL), and methanol (1.49 L) was mixed with lithium hydroxide monohydrate (28.2 g, 671 mmol). This concentrated 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, resulting in the precipitation of a grayish-white solid. This solid was filtered, washed with H2O (2 × 1 L), powdered with tert-butyl methyl ether (2 × 300 mL), and dried at 65°C under vacuum until constant weight was obtained, yielding the marked compound as a white solid (101.5 g, 284 mmol, yield 85%). MS (APCI+) m / z 358 [M+H] + .

[0213] Example 1C: 3-(benzyloxy)-7-bromonaphthalene-2-amine Triethylamine (41.8 mL, 300 mmol) was added to a suspension of the product of Example 1B (101 g, 283 mmol) in toluene (794 mL) and tert-butanol (794 mL). This turbid, pale yellow solution was heated to an internal temperature of 80°C under nitrogen, and the entire reaction system was placed behind an explosion-proof wall. Diphenyl phosphate 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 layer was washed with saturated brine (2 × 150 mL), dehydrated over sodium sulfate, filtered, and concentrated to obtain a white solid. This solid was subjected to hydrolysis without further purification.

[0214] Diethylenetriamine (253 mL, 2.34 mol) was added to the crude intermediate described above. 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, this mixture was cooled to room temperature in an ice bath, and H2O (800 mL) was slowly added over 3 minutes, causing a yellow solid to precipitate and simultaneously generating heat, raising the internal temperature to 53°C. Once this heterogeneous suspension had 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), dehydrated on sodium sulfate, filtered, and volatile components were removed under vacuum to obtain an orange solid. This solid was mixed with isopropanol (250 mL) to form a slurry, which was then filtered. The obtained 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 obtain the labeled compound as a white solid (68.48 g, 209 mmol, 74% yield in 2 steps). MS (APCI+) m / z 329 [M+H] + .

[0215] Example 1D: {[3-(benzyloxy)-7-bromonaphthalene-2-yl]aminoacetate methyl} 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) was mixed with methyl 2-bromoacetate (29.3 mL, 310 mmol). This suspension was vigorously stirred 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), and the combined organic layer was washed with saturated ammonium chloride aqueous solution (3 × 60 mL), dehydrated over sodium sulfate, filtered, and concentrated to obtain a pale beige solid. This solid was powdered with heptane (100 mL), the resulting beige solid was isolated by filtration, washed with further heptane (2 × 30 mL), and dried at 35°C under vacuum (15 mbar) until constant weight was obtained, yielding the marked compound as a grayish-white solid (68.52 g, 171 mmol, yield 83%). MS (APCI) + ) m / z 401[M+H] + .

[0216] Example 1E: {[3-(benzyloxy)-7-bromo-1-fluoronaphthalene-2-yl]aminomethyl acetate} To a solution of the product of Example 1D (15 g, 37.5 mmol) in N,N-dimethylformamide (300 mL) at 2°C, a solution of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate) (15.93 g, 45.0 mmol) in N,N-dimethylformamide (100 mL) was added over 5 minutes. The resulting solution was stirred for 15 minutes and then quenched with a 0.33 M solution of sodium thiosulfate (300 mL) (exothermic). The mixture was diluted with ethyl acetate (150 mL) and saturated ammonium chloride aqueous 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 ammonium chloride aqueous solution (4 × 75 mL) and saturated brine (75 mL), then dehydrated over sodium sulfate, filtered, and concentrated under vacuum to obtain an orange solid. Ethyl acetate (30 mL) was added to the crude solid, and the mixture was sonicated for 30 seconds. Next, heptane (150 mL) was slowly added from a dropping funnel over 15 minutes. The resulting yellow solid was filtered and washed with a 33% v / v ethyl acetate heptane solution (3 × 60 mL). This solid was discarded, and the filtrate was concentrated under vacuum to obtain a yellow / orange solid, which was powdered 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 filtered, washed with anhydrous ethanol (30 mL), and dried at 50°C under vacuum (15 mbar) until constant weight was obtained, yielding the marked compound as a pale yellow solid (10.1 g, 24.25 mmol, yield 64.7%). TIFF0007881804000075.tif25146

[0217] Example 1F: {[3-(benzyloxy)-7-bromo-1-fluoronaphthalene-2-yl](sulfamoyl)amino}methyl acetate To a 43.5 mL solution of chlorosulfonyl isocyanate (2.26 mL, 26.0 mmol) in dichloromethane (4°C) 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, the previously prepare...

Claims

1. Equation (I): A pharmaceutical composition for treating cancer in a patient in need, comprising an effective amount of the compound represented by, or a pharmaceutically acceptable salt thereof: During the ceremony, 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, wherein 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 be independently 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 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 heteroaryls, -O-4 to 6-membered heterocyclines, and -O-C １～６ Selected from the group consisting of alkylene-4 to 6-membered heterocyclines, where -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 heteroaryls, -O-4 to 6-membered heterocyclines, and -O-C １～６ Alkylene-4 to 6-membered heterocyclines have one or more available carbon atoms, each independently of R ｇ They may be substituted with one, two, three or more substituents selected from, a 5-6 member heteroaryl, a 4-6 member heterocyclyl, -N(R ａ ) -4-6 member heterocyclyl, -C １～６ Alkylene-4 to 6-membered heterocyclyl, or -O-C １～６ When an alkylene-4 to 6-membered heterocycline contains a replaceable ring nitrogen atom, that ring nitrogen atom is R ｈ It may also be replaced by, Or, R １ and R ２ However, together with the atoms they bond to, they form a 5-6 membered aryl or heteroaryl group, where the aryl or heteroaryl group is independently a halogen, hydroxyl, cyano, or C13. １～６ Alkyl and C １～６ It may be substituted with one or more substituents selected from the group consisting of alkoxys, where C １～６ Alkyl and C １～６ Each alkoxy independently ｐ It may be substituted with one, two, three, or more substituents selected from the following: 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 Selected from the group consisting of alkylene-4 to 6-membered heterocyclines, where -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 heterocyclines have one or more available carbon atoms, each independently of R ｇ It may be substituted with one, two, three or more substituents selected from -C １～６ When an alkylene-4 to 6-membered heterocycline contains a replaceable ring nitrogen atom, that ring nitrogen atom is R ｈ It may also be replaced by, 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 heterocyclines, where C １～６ Alkyl, C ３～６ Cycloalkyl and -C １～６ Alkylene-4 to 6-membered heterocyclines have one or more available carbon atoms, each independently of R ｇ It may be substituted with one, two, three or more substituents selected from -C １～６ When an alkylene-4 to 6-membered heterocycline contains a replaceable ring nitrogen atom, that ring nitrogen atom is R ｈ It may also be replaced by, 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, 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 ; 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 ６ It is hydrogen, R ７ It is hydrogen, R ｇ is, independently for each existence, 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<​​​​​​​​​​​​​​​​​​​​​​​​ ｗ -N(R) ａ ) -, C ３～６ Cycloalkyl-SO ｗ -N(R) ａ )-, 4-6 member 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 Selected from the group consisting of alkyl groups, where C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, 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 member 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 Each alkyl group is independently R ｐ It may be substituted with one, two, three, or more substituents selected from the following: R ｈ Independently of each existence, C １～６ Alkyl, C ３～６ Alkenil, C ３～６ Alkinyl, 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 member heterocyclyl-S(O) ２ -, 4-6 member heterocyclyl-C １～６ Alkyl-S(O) ２ -, 5-6 member 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 A group consisting of C is selected, where C １～６ Alkyl, C ３～６ Alkenil, C ３～６ Alkinyl, 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 member heterocyclyl-S(O) ２ -, 4-6 member heterocyclyl-C １～６ Alkyl-S(O) ２ -, 5-6 member 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 Each of these independently controls R ｐ It may be substituted with one, two, three, or more substituents selected from the following: R ｐ These are, independently of each other, halogen, hydroxyl, cyano, and C. １～６ Alkyl, C １～６ Alkoxy, C ３～６ Cycloalkyl, 4-6 member 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 Independently of each entity, hydrogen and C １～６ Alkyl and C ３～６ Selected from the group consisting of cycloalkyl groups, where C １～６ Alkyls are, independently, halogen, cyano, oxo, hydroxyl, and C. １～６ It may be substituted with one or more substituents selected from the group consisting of alkoxys (which may be substituted with one, two, or three fluorine atoms), Or, R ａ and R ｂ However, together with the nitrogen to which they are bound, they form a 4-6 membered heterocycline, where each of the heterocyclines may be independently substituted with one or more substituents selected from the group consisting of halogens, cyanos, oxos, and hydroxyls. w is 0, 1, or 2.

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

3. R ２ ga-O-C １～６ Alkilen-4 to 6-membered heterocyclyl, where R ２ R is formed on one or more available carbon atoms, each independently. ｇ R may be substituted with one, two, or three substituents selected from the above, ２ If it contains a replaceable ring nitrogen atom, that ring nitrogen atom is R ｈ The pharmaceutical composition according to any one of claims 1 to 2, which may be substituted with substituents selected from the above.

4. R ２ ga-O-C １～６ Alkilen-4 to 6-membered heterocyclyl, where R ２ However, on one or more available carbon atoms, hydrogen, halogen, and C can be independently produced. １～６ R may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups, ２ If it contains a replaceable ring nitrogen atom, that ring nitrogen atom is C １～６ Alkyl and C １～６ Alkyl-S(O) ２ The pharmaceutical composition according to claim 3, which may be substituted with substituents selected from the group consisting of -.

5. R ２ but, A pharmaceutical composition according to claim 3 or 4, selected from the group consisting of the following.

6. R ２ ga-O-C １～６ A pharmaceutical composition according to any one of claims 1 to 2, wherein the alkylene is a 5-6 member heteroaryl.

7. R ２ but, A pharmaceutical composition according to claim 6, selected from the group consisting of the following.

8. R ２ ga-O-C １～６ It is alkyl, and here, R ２ Each of these independently controls R ｇ The pharmaceutical composition according to any one of claims 1 to 2, which may be substituted with one, two, three or more substituents selected from the above.

9. R ２ ga-O-C １～６ It is alkyl, and here, R ２ These are independently cyano, chlorine, fluorine, hydroxyl, oxo, and 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, -OCH ３ or -OCF ３ (may be replaced by C) １～６ Alkyl-N(R) ａ ) -, R ａ R ｂ NC(O)-, -P(O)(C １～３ Alkyl) ２ , C １～６ Alkyl-N(R) ａ )-C(O)-, C １～６ Alkyl-N(R) ａ )-C(O)-N(R ａ ) -, C １～６ Alkyl-SO ２ -N(R) ａ ) -, C ３～６ Cycloalkyl-SO ２ -N(R) ａ )-, and 4-6 member heterocyclyl-SO ２ -N(R) ａ The pharmaceutical composition according to claim 8, which may be substituted with one, two, three or more substituents selected from the group consisting of ) -

10. R ２ but, -OCH ３ ,-O4 ３ 、-OCF ３ 、-OCHF ２ ,-OCH ２ CH ３ 、 A pharmaceutical composition according to claim 8 or 9, selected from the group consisting of the following.

11. R ２ ga-O-C ３～６ It is a cycloalkyl or -O-4 to 6-membered heterocycline, where R ２ If it contains a replaceable ring nitrogen atom, that ring nitrogen atom is R ｈ The pharmaceutical composition according to any one of claims 1 to 2, which may be substituted with substituents selected from the above.

12. R ２ ga-O-C ３～６ It is a cycloalkyl or -O-4 to 6-membered heterocycline, where R ２ If it contains a replaceable ring nitrogen atom, that ring nitrogen atom is C １～６ Alkyl-SO ２ -N(R) ａ ) - and C ３～６ Cycloalkyl-SO ２ -N(R) ａ The pharmaceutical composition according to claim 11, which may be substituted with substituents selected from the group consisting of ) -

13. R ２ but, A pharmaceutical composition according to claim 11 or 12, selected from the group consisting of the following.

14. R ２ ga-O-C １～６ Alkylene-C ３～６ It is a cycloalkyl, where R ２ Each of these independently controls R ｇ The pharmaceutical composition according to any one of claims 1 to 2, which may be substituted with one, two, or three substituents selected from the above.

15. R ２ ga-O-C １～６ Alkylene-C ３～６ It is a cycloalkyl, where R ２ These are independently fluoro, hydroxyl, and R. ａ R ｂ N-, cyano, and C １～３ It may be substituted with one, two, or three substituents selected from the group consisting of alkyl groups, where C １～３ Alkyl is cyano and C １～３ The pharmaceutical composition according to claim 14, which may be substituted with substituents selected from the group consisting of alkoxys.

16. R ２ but, A pharmaceutical composition according to claim 14 or 15, selected from the group consisting of the following.

17. R ２ ga-O-C(O)-N(R ａ )-C １～６ A pharmaceutical composition according to any one of claims 1 to 2, wherein the alkyl group is alkyl.

18. R ２ but The pharmaceutical composition according to claim 17, as represented by [the specified formula].

19. R ３ A pharmaceutical composition according to any one of claims 1 to 18, wherein is hydrogen.

20. R ４ A pharmaceutical composition according to any one of claims 1 to 19, wherein is hydrogen.

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

22. R ６ The pharmaceutical composition according to any one of claims 1 to 21, wherein the most abundant element is hydrogen.

23. R ７ The pharmaceutical composition according to any one of claims 1 to 22, wherein the most abundant element is hydrogen.

24. The pharmaceutical composition according to any one of claims 1 to 23, wherein all atoms of the compound are present in their naturally occurring isotopic abundances.

25. below: A pharmaceutical composition for treating cancer in a patient in need, comprising an effective amount of a compound selected from the group consisting of , and pharmaceutically acceptable salts thereof.

26. The pharmaceutical composition according to any one of claims 1 to 25, wherein the cancer is selected from the group consisting of solid tumors and lymphocyte cancers, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, liver cancer including hepatocellular carcinoma, lymphoma including acute lymphoblastic lymphoma B, non-Hodgkin lymphoma (e.g., Burkitt lymphoma, small cell lymphoma, and large cell lymphoma), Hodgkin lymphoma, leukemia (including AML, ALL, and CML), and multiple myeloma.

27. ​​The pharmaceutical composition according to any one of claims 1 to 25, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, ovarian cancer, epithelial ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, bile duct cancer, adrenal cancer, salivary gland cancer, bronchial cancer, oral cancer, oral or pharyngeal cancer, laryngeal cancer, kidney cancer, gynecological cancer, brain cancer, central nervous system cancer, peripheral nervous system cancer, hematological tissue cancer, small intestine cancer or appendiceal cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, and carcinoma.

28. The pharmaceutical composition according to any one of claims 1 to 25, wherein the cancer is selected from the group consisting of leukemia, lymphoma, carcinoma, and sarcoma.

29. Cancer is lymphoma, B-cell lymphoma, heavy chain disease, alpha chain disease, gamma chain disease, μ-chain disease, Waldenström macroglobulinemia, benign monoclonal hypergammaglobulinemia, 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, breast cancer (e.g., ER-positive, ER-negative, chemotherapy-resistant, Herceptin-resistant, HER2-positive, doxorubicin-resistant, tamoxifen-positive herceptin-resistant, HER2-positive, doxorubicin-resistant, tamoxifen-positive, mercury-resistant, mercury-resistant, mercury-positive, mercury-negative, mercury-resistant, tamoxifen-positive, mercury-negative, mercury-resistant, mercury-resistant, mercury-positive, mercury-negative, mercury-resistant, mercury-positive, mercury-negative, mercury-resistant, mercury-positive, mercury-negative, mercury-resistant, mercury-positive, mercury-negative, mercury-resistant, mercury-positive, mercury-negative, mercury-positive, mercury-negative, mercury-positive, mercury-negative, mercury-positive, mercury-negative, mercury-positive, mercury-negative, mercur Fen-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 pleomorphoni, acoustic neuroma, retinoblastoma, astrocytoma, craniopharyngioma, hemangioblastoma, pineal tumor, ependymoma, oligodendroglioma, meningioma, glioma, melanoma, thyroid, endocrine system, brain, breast, neck, colon, head and neck, liver Cancers of the organs, kidneys, lungs, non-small cell lung, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach, uterine cancer, or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, immunocellular amyloidosis, ovarian cancer, rhabdomyosarcoma, primary thrombocytopenia, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, precancerous skin disorders, testicular cancer, lymphocyte A pharmaceutical composition according to any one of claims 1 to 25, selected from the group consisting of tumors, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, neoplasms of the endocrine or exocrine pancreas, medullary thyroid carcinoma, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, Paget's disease of the papillary thyroid, phylloblastoma, lobular carcinoma, ductal carcinoma, astrocytic carcinoma of the pancreas, astrocytic carcinoma of the liver, and prostate cancer.

30. The pharmaceutical composition according to any one of claims 1 to 25, wherein the cancer is a solid tumor.

31. The pharmaceutical composition according to any one of claims 1 to 25, wherein the cancer is leukemia.

32. The leukemia is 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, aleukocytic leukemia, a leukocythemic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, cutaneous leukemia, embryonic cell leukemia, eosinophilic leukemia, erythroleukemia, gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia Leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia A pharmaceutical composition according to claim 31, selected from the group consisting of leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli's leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, polycythemia vera, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemia, and anaplastic cell leukemia.

33. The pharmaceutical composition according to any one of claims 1 to 25, wherein the cancer is a sarcoma.

34. The sarcoma is chondrosarcoma, fibrosarcoma, leiomyosarcoma, lymphosarcoma, lymphangiosarcoma, intralymphatic sarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, supraamelosarcoma, botrioid sarcoma, green sarcoma, choriocarcinoma, embryonic sarcoma, Wilms tumor sarcoma, endometrial sarcoma, endosarcoma, stromal sarcoma A pharmaceutical composition according to claim 33, selected from the group consisting of sarcoma, Ewing's sarcoma, myofascial 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's astrocytic sarcoma, angiosarcoma, leukemosarcoma, malignant mesenchymal sarcoma, osteosarcoma, paraosteal osteosarcoma, reticular erythrocyte sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and peripheral telangiectatic sarcoma.

35. The pharmaceutical composition according to any one of claims 1 to 25, wherein the cancer is melanoma.

36. The pharmaceutical composition according to claim 35, wherein the melanoma is selected from the group consisting of acral lentiginous melanoma, achromatic melanoma, benign juvenile melanoma, Crowdmann melanoma, S91 melanoma, Harding-Passé melanoma, juvenile melanoma, lentigo malignant melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

37. The pharmaceutical composition according to any one of claims 1 to 25, wherein the cancer is a carcinoma. 【Request Item 38】 Cancer, thyroid cancer, familial thyroid cancer, adenocarcinoma, lobular carcinoma, adenoid carcinoma, adenomatosum carcinoma, adrenal cortex carcinoma, lung cell carcinoma, basal cell carcinoma, basal cell carcinoma, basal cell carcinoma, basal cell carcinoma-like carcinoma, basal spiculated cell carcinoma, cholangiocarcinoma, bladder cancer, breast cancer, bronchial carcinoma, vascular branch lung cell epithelial carcinoma, vascular branch carcinoma, vascular mycoplasma carcinoma, cerebriform carcinoma, cervical cancer, cholangiocarcinoma, chordoma, chorionic carcinoma, leukocyte carcinoma, mucinous carcinoma, colon cancer, acne carcinoma, corpus uterine cancer Carcinoma, cribriform carcinoma, armored carcinoma, skin cancer, cylindrical carcinoma, cylindrical cell carcinoma, adenocarcinoma, duct carcinoma, ductal carcinoma, carcinoma durum, fetal carcinoma, marrow carcinoma, endometrial carcinoma, epidermal carcinoma, epithelial carcinoma, epithelial carcinoma, epithelial adenocarcinoma, exophytic carcinoma, ulcerative carcinoma, fibrous carcinoma, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, giantocellular carcinoma, adenocarcinoma, granular cell carcinoma, pilomatricoma, hematoid carcinoma, hepatoma, hepatocellular carcinoma carcinoma, hyaline carcinoma, hypomephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepithelial carcinoma, intraepithelial carcinoma, Krompecher carcinoma, Kulchitsky cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinomalobular 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 ductal carcinoma, papillary carcinoma, periportal carcinoma carcinoma), preinvasive carcinoma, squamous cell carcinoma, medullary carcinoma (pultaceous carcinoma), preinvasive carcinoma, squamous cell carcinoma, Carcinoma, renal cell carcinoma of kidney, pre-cell carcinoma, sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, sebaceous carcinoma, seminomas, serous carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma, ellipsoidal cell carcinoma, spindle cell carcinoma, spongiosum carcinoma, squamous carcinoma, squamous cell carcinoma, string carcinoma, sweat gland carcinoma, telangiectaticum carcinoma, telangiectodes carcinoma, transitional cell carcinoma, tuberosum carcinoma, tubular carcinoma, tubeous carcinoma, undifferentiated carcinoma, wart-like carcinoma, and choriocarcinoma A pharmaceutical composition according to claim 37, selected from the group consisting of villosum.

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