TYROSINE PHOSPHATASE PROTEIN INHIBITORS AND THEIR METHODS OF USE

Abstract

Compounds, compositions, and methods useful for inhibiting protein tyrosine phosphatase, for example, type 2 non-receptor protein tyrosine phosphatase (PTPN2) and / or type 1 non-receptor protein tyrosine phosphatase (PTPN1), are provided herein, and for treating diseases, disorders, and related conditions that respond favorably to treatment with PTPN1 or PTPN2 inhibitors, for example, cancer or metabolic disease.

Description

[0001] PROTEIN TYROSINE PHOSPHATASE INHIBITORS AND METHODS OF USE

[0002] THEREOF

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority to U.S. Provisional Application No. 62 / 688,226, filed on June 21, 2018, which is incorporated herein by reference in its entirety.

[0005] BACKGROUND

[0006] Cancer immunotherapy regimens targeting immune evasion mechanisms including checkpoint blockade (e.g. PD-1 / PD-L1 and CTLA-4 blocking antibodies) have been shown to be effective in treating in a variety of cancers, dramatically improving outcomes in some populations refractory to conventional therapies. However, incomplete clinical responses and the development of intrinsic or acquired resistance will continue to limit the patient populations who could benefit from checkpoint blockade.

[0007] Protein tyrosine phosphatase non-receptor type 2 (PTPN2), also known as T cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of the class 1 subfamily of phospho- tyrosine specific phosphatases that control multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, but expression is highest in hematopoietic and placental cells (Mosinger, B. Jr. et al., Proc Natl Acad Sci USA 89:499-503; 1992). In humans, PTPN2 expression is controlled post-transcriptionally by the existence of two splice variants: a 45 kDa form that contains a nuclear localization signal at the C-terminus upstream of the splice junction, and a 48 kDa canonical form which has a C-terminal ER retention motif (Tillmann U. et al., Mol Cell Biol 14:3030-3040; 1994). The 45 kDa isoform can passively transfuse into the cytosol under certain cellular stress conditions. Both isoforms share an N-terminal phospho-tyrosine phosphatase catalytic domain. PTPN2 negatively regulates 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 critical negative regulator of the JAK-STAT pathway, PTPN2 functions to directly regulate signaling through cytokine receptors, including IFNy. The PTPN2 catalytic domain shares 74% sequence homology with PTPN1 (also called PTP1B), and shares similar enzymatic kinetics (Romsicki Y. et al., Arch Biochem Biophys 414:40-50; 2003). Data from a loss of function in vivo genetic screen using CRISPR / Cas9 genome editing in a mouse B16F10 transplantable tumor model show that deletion of Ptpn2 gene in tumor cells improved response to the immunotherapy regimen of a GM-CSF secreting vaccine (GVAX) plus PD-l checkpoint blockade (Manguso R. T. et al., Nature 547:413-418; 2017). Loss of Ptpn2 sensitized tumors to immunotherapy by enhancing IFNy-mediated effects on antigen

[0008] presentation and growth suppression. The same screen also revealed that genes known to be involved in immune evasion, including PD-L1 and CD47, were also depleted under

[0009] immunotherapy selective pressure, while genes involved in the IFNy signaling pathway, including IFNGR, JAK1, and STAT1, were enriched. These observations point to a putative role for therapeutic strategies that enhance IFNy sensing and signaling in enhancing the efficacy of cancer immunotherapy regimens.

[0010] Protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase- 1B (PTP1B), has been shown to play a key role in insulin and leptin signaling and is a primary mechanism for down-regulating both the insulin and leptin receptor signaling pathways (Kenner K. A. et al., J Biol Chem 271: 19810-19816, 1996). Animals deficient in PTP1B have improved glucose regulation and lipid profiles and are resistant to weight gain when treated with a high fat diet (Elchebly M. et al., Science 283: 1544-1548, 1999). Thus, PTP1B inhibitors are expected to be useful for the treatment of type 2 diabetes, obesity, and metabolic syndrome.

[0011] SUMMARY

[0012] The present disclosure is directed, at least in part, to compounds, compositions, and methods for the inhibition of protein tyrosine phosphatase, e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) and / or protein tyrosine phosphatase non-receptor type 1 ((PTPN1), also known as protein tyrosine phosphatase- 1B (PTP1B)). In some embodiments, disclosed herein is an inhibitor of protein tyrosine phosphatase, e.g., PTPN2 and / or PTP1B, comprising a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III). In other embodiments, disclosed herein are methods of treating a disease or disorder, e.g., cancer, type-2 diabetes, obesity, a metabolic disease, or any other disease, disorder or ailment favorably responsive to PTPN2 or PTP1B inhibitor treatment, comprising administering an effective amount of a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III). For example, disclosed herein is a compound represented by Formula (I):

[0013]

[0014] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, / V-oxide, stereoisomer or isotopically enriched variant thereof, wherein:

[0015] R1is selected from the group consisting of hydrogen, halogen, Ci-6alkyl, C3-6cycloalkyl, -

[0016] 0-Ci_6alkyl, -N(Ra)-Ci_6alkyl and -Ci_6alkylene-5-6 membered heterocyclyl;

[0017] wherein Ci_6alkyl, C3_6cycloalkyl, -0-Ci_6alkyl, -N(Ra)-Ci_6alkyl and -Ci_6alkylene-5-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci_6alkylene-5-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh;

[0018] R2is selected from the group consisting of hydrogen, hydroxyl, -CF1F2, -Cl¾OF[, - CH2CN, -CH2-0-Ci_6alkyl, -CH2-N(Ra)-Ci-6alkyl, C2-6alkyl, C2-6alkenyl, -0-C1-6alkyl, -N(Ra)- Ci_6alkyl, -S(0)w-Ci_6alkyl, -C(0)-N(Ra)-Ci_6alkyl, -N(Ra)-C(0)-Ci_6alkyl, -0-C(0)-N(Ra)-Ci_6alkyl, -N(Ra)-C(0)-0-Ci_6alkyl, -C3_6cycloalkyl, -0-C3-6cycloalkyl, Ci_6alkylene-C3_6cycloalkyl, -Ci_6alkenylene-C3_6cycloalkyl, -0-Ci_6alkylene-C3-6cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -0-Ci_6alkylene-5-6 membered heteroaryl, -0-4-6 membered heterocyclyl, -N(Ra)-4-6 membered heterocyclyl, -Ci_6alkylene-4-6 membered heterocyclyl and - 0-Ci_6alkylene-4-6 membered heterocyclyl;

[0019] wherein -Cl¾-0-Ci_6alkyl, -CFl2-N(Ra)-Ci_6alkyl, C2-6alkyl, C2-6alkenyl, -0-Ci_

[0020] 6alkyl, -N(Ra)-Ci_6alkyl, -S(0)w-Ci_6alkyl, -C(0)-N(Ra)-Ci_6alkyl, -N(Ra)-C(0)-Ci_6alkyl, -O- C(0)-N(Ra)-Ci_6alkyl, -N(Ra)-C(0)-0-Ci_6alkyl, -C3-6cycloalkyl, -0-C3-6cycloalkyl, -C, 6alkylene-C3_6cycloalkyl, -Ci_6alkenylene-C3_6cycloalkyl, -0-Ci_6alkylene-C3-6cycloalkyl, 5-6 membered heteroaryl, -0-Ci_6alkylene-5-6 membered heteroaryl, 4-6 membered heterocyclyl, - 0-4-6 membered heterocyclyl, -N(Ra)-4-6 membered heterocyclyl, -Ci_6alkylene-4-6 membered heterocyclyl and -0-Ci_6alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(Ra)- 4-6 membered heterocyclyl, -Cj-ealkylene-d-h membered heterocyclyl or -O-C i _fial kylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh;

[0021] or R 1 and R 2 taken together with the atoms to which they are attached form a 5-6 membered aryl or heteroaryl; wherein aryl or heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, Ci_6al yl and Ci_6alkoxy; wherein Ci_6alkyl and Ci_6alkoxy may optionally be substituted by one, two three or more substituents each independently selected from Rp;

[0022] R3is selected from the group consisting of hydrogen, -Ci_6alkyl, -0-Ci_6alkyl, -N(Ra)-Ci_ ealkyl, -S(0)w-Ci_6alkyl, -C(0)-N(Ra)-Ci_6alkyl, -N(Ra)-C(0)-Ci_6alkyl and -Ci_6alkylene-4-6 membered heterocyclyl;

[0023] wherein -Ci_6alkyl, -0-Ci_6alkyl, -N(Ra)-Ci_6alkyl, -S(0)w-Ci_6alkyl, -C(0)-N(Ra)- Ci_6alkyl, -N(Ra)-C(0)-Ci_6alkyl and -Ci_6alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci_6alkylene_4_6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh;

[0024] R4is selected from the group consisting of hydrogen, halogen, Ci_6alkyl, C3_6cycloalkyl and -Ci_6alkylene-4-6 membered heterocyclyl; wherein Ci_6alkyl, C3_6cycloalkyl and -Ci_6alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -CYf,alkylcnc-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh;

[0025] wherein at least one of R 1 , R2 , R 3 and R 4 is not hydrogen;

[0026] R5is selected from the group consisting of hydrogen, halogen, Ci_6alkyl, C3_6cycloalkyl and -Ci_6alkylene-4-6 membered heterocyclyl; wherein Ci_6alkyl, C3_6cycloalkyl and -Ci_6alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci_6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh;

[0027] R6is hydrogen;

[0028] R7is hydrogen; Rgis independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, oxo, -C(0)0H, RaRbN-, RaRbN-C(0)-, RaRbN-SOw-, RaRbN- C(0)-N(Ra)-, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3_6cycloalkyl, phenyl, Ci_6alkylene-C3_6cycloalkyl, -0-Ci-6alkylene-C3-6cycloalkyl, -(CO)-(NRa)-Ci-6alkylene-C3-6cycloalkyl, Ci-6alkoxy, C3_6alkenyloxy, C3_6alkynyloxy, C3_6cycloalkoxy, Ci_6alkyl-C(0)-, Ci_6alkyl-0-C(0)-, Ci_6alkyl-C(0)-0-, Ci_6alkyl-S(0)w-, Ci_6alkyl-N(Ra)-, Ci_6alkyl-N(Ra)-C(0)-, Ci_6alkyl-C(0)- N(Ra), Ci_6alkyl-N(Ra)-C(0)-N(Ra)-, Ci_6alkyl-N(Ra)-SOw-, C3-6cycloalkyl-N(Ra)-SOw-, C ,6alkyl-SOw-N(Ra)-, C3_6cycloalkyl-SOw-N(Ra)-, 4-6 membered heterocyclyl-SOw-N(Ra)-, Ci_6alkoxy-C(0)-N(Ra)-, Ci_6alkyl-C(0)-N(Ra)-Ci_6alkyl-, Ci_6alkyl-N(Ra)-C(0)-Ci_6alkyl-, - P(0)(Ci_3alkyl)2and Ci_6alkoxy-Ci_6alkyl-; wherein Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3_6cycloalkyl, phenyl, C1_6alkylene-C3_6cycloalkyl, -0-C1-6alkylene-C3-6cycloalkyl, -(CO)-(NRa)-

[0029] C3-6cycloalkyl-N(Ra)-SOw-, Ci_6alkyl-SOw-N(Ra)-, C3_6cycloalkyl-SOw-N(Ra)-, 4-6 membered heterocyclyl-SOw-N(Ra)-, Ci_6alkoxy-C(0)-N(Ra)-, Ci_6alkyl-C(0)-N(Ra)-Ci_6alkyl-, Ci_6alkyl- N(Ra)-C(0)-Ci_6alkyl-, -P(0)(Ci_3alkyl)2and Ci_6alkoxy-Ci_6alkyl- may optionally be substituted by one, two three or more substituents each independently selected from Rp;

[0030] Rhis independently selected for each occurrence from the group consisting of Ci_6alkyl, C3_6alkenyl, C3_6alkynyl, C3_6cycloalkyl, -Ci_6alkyl-C3_6cycloalkyl, Ci_6alkyl-S(0)2-, C3-6cycloalkyl-S(0)2-, 4-6 membered heterocyclyl-S(0)2-, 4-6 membered heterocyclyl-Ci_6alkyl- S(0)2-, 5-6 membered heteroaryl-S(0)2-, phenyl-S(0)2-, phenyl-Ci_6alkyl-S(0)2-, Ci_6alkyl- C(O)-, Ci_6cycloalkyl-C(0)-, Ci_6alkoxy-C(0)-, RaRbN-C(0)-, RaRbN-S02- and -P(0)(C _ 3alkyl)2; wherein Ci_6alkyl, C3_6alkenyl, C3_6alkynyl, C3_6cycloalkyl, -Ci_6alkyl-C3_6cycloalkyl, Ci_6alkyl-S(0)2-, C3-6cycloalkyl-S(0)2-, 4-6 membered heterocyclyl-S(0)2-, 4-6 membered heterocyclyl-Ci_6alkyl-S(0)2-, 5-6 membered heteroaryl-S(0)2-, phenyl-S(0)2-, phenyl-Ci_6alkyl- S(0)2-, Ci_6alkyl-C(0)-, Ci_6cyeloalkyl-C(0)-, Ci_6alkoxy-C(0)-, RaRbN-C(0)-, RaRbN-S02- and -P(0)(Ci_3alkyl)2may optionally be substituted by one, two three or more substituents each independently selected from Rp;

[0031] Rpis independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, Chalky I, C^alkoxy, C3_6cycloalkyl, 4-6 membered heterocyclyl, RaRbN-, RaRbN -carbonyl- , RaRbN-S02-, and RaRbN-carbonyl-N(Ra)-; Raand Rbare independently selected, for each occurrence, from the group consisting of hydrogen, Ci-6alkyl and C3-6cycloalkyl; wherein Ci-6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo, hydroxyl and Ci-6alkoxy (optionally substituted by one, two or three fluorine atoms); or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein the heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl; and w is 0, 1 or 2.

[0032] Also disclosed herein is a compound represented by Formula (II):

[0033]

[0034] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, / V-oxide or stereoisomer thereof, wherein:

[0035] X is selected from the group consisting of -O- and -N(Ra)-;

[0036] L is straight or branched Ci_6alkylene;

[0037] R2 nis selected from the group consisting of hydrogen, cyano, -NRaRb, Ci_2alkoxy, C3_

[0038] 6cycloalkyl-S02-N(Ra)-, Ci_6alkyl-S02-N(Ra)-, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and C3_6cycloalkyl; wherein phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and C3_6cycloalkyl may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, Ci_2alkyl (optionally substituted by one, two or three halogens) and Ci_2alkoxy (optionally substituted by one, two or three halogens); and wherein if 5-6 membered heteroaryl or 4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Ci_3alkyl;

[0039] R5is selected from the group consisting of hydrogen, deuterium and halogen;

[0040] R6is selected from the group consisting of hydrogen and deuterium;

[0041] R7is selected from the group consisting of hydrogen and deuterium; and Raand Rbare each independently selected for each occurrence from the group consisting of hydrogen and Ci-3alkyl.

[0042] Also disclosed herein is a compound represented by Formula (III):

[0043]

[0044] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, / V-oxide or stereoisomer thereof, wherein:

[0045] Xmis selected from the group consisting of a bond, -C]¾-, -NRa-, -0-, -0-CH2- and - OCH2-CH2- m is 1, 2, or 3;

[0046] n is 1, 2, or 3;

[0047] R1_niis selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -

[0048] NR a R b , Ci-2alkyl (optionally substituted by one, two or three halogens) and Ci-2alkoxy

[0049] (optionally substituted by one, two or three halogens);

[0050] R2 niis selected from the group consisting of hydrogen, Ci_4alkyl, -C(0)-Ci_4alkyl, - C(0)-0-Ci_4alkyl, -C(0)-N(Ra)-Ci_4alkyl, -S(0)2-Ci_4alkyl and -S(0)2-C3-6cycloalkyl; wherein Ci_4alkyl, -C(0)-Ci alkyl, -C(0)-0-Ci_4alkyl, -C(0)-N(Ra)-Ci_4alkyl, -S(0)2-Ci_4alkyl and - S(0)2-C3-6cycloalkyl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, -NRaRb, Ci_2alkyl (optionally substituted by one, two or three halogens) and Ci_2alkoxy (optionally substituted by one, two or three halogens);

[0051] R5is selected from the group consisting of hydrogen, deuterium and halogen;

[0052] R6is selected from the group consisting of hydrogen and deuterium;

[0053] R7is selected from the group consisting of hydrogen and deuterium; and

[0054] Raand Rbare each independently selected for each occurrence from the group consisting of hydrogen and Ci_3alkyl. Further disclosed herein is a compound selected from the group consisting of:

[0055] 5-{ l-fluoro-3-hydroxy-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;

[0056] 5 - { 7-[ 1 -(cyclopropanesulfonyl)pyrrolidin-3-yl]- l-fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0057] 5- [1 -fluoro-3-hydroxy-7-(pyrrolidin-3-yl)naphthalen-2-yl] - l76,2,5-thiadiazolidine- 1 , 1 ,3-trione; 8-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl)naphthalcn-2-yl propan-2- ylcarbamate;

[0058] 5-(9-fluoro-7-hydroxynaphtho| 2, 1 - / ? ]fu ran- 8-yl )- 1 / \2, 5-th iadiazolidinc- 1 , 1 ,3-trione;

[0059] 5- { 7-[2-(azetidin- 1 -yl)ethoxy]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - l76,2,5-thiadiazolidine- l,l,3-trione;

[0060] 5-| 1 -fluoio-3-hydi oxy-7-methoxy(4-2H)naphthalen-2-yl ](4,4-2fF)- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0061] 5-| 1 -fluoio-3-hydroxy-7-(mcthylamino)naphthalcn-2-yl ]- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione; 5- { l-fluoro-3-hydroxy-7-[2-(piperidin-4-yl)ethoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l,l,3- trione;

[0062] 5-(l-fluoro-7-{ [3-fluoro-l-(propan-2-yl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0063] 5 - { 1 -fluoro-7 - [(3 -fluoropyrrolidin- 3 -yl)methoxy ] -3 -hydroxynaphthalen-2-yl } - 1 l6,2, 5- thiadiazolidine- 1 , 1 ,3-trione ;

[0064] 5- { 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalen-2- yl] oxy } pentanenitrile ;

[0065] 5- { 1 -fluoro-3-hydroxy-7 - [2-(piperidin- 1 -yl)ethoxy] naphthalen-2-yl } - 176,2,5-thiadiazolidine- l,l,3-trione;

[0066] 5- { 7-[ 1 -(cyclopropanesulf onyl)-2, 5-dihydro- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2- yl } - 176,2,5-thiadiazolidine- 1 , 1 ,3-trione ;

[0067] 5-{ l-fluoro-3-hydroxy-7-[(piperidin-4-yl)methoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;

[0068] 5- { 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalen-2-yl ]oxy }-3,3- dimethylpentanenitrile ;

[0069] 5 - { 7 - 1 (3,3-dimcthylbutyl )amino] - 1 -fluoro-3-hydroxynaphthalen-2-yl }- 1 / ’,2, 5-th iadi azolid inc- l,l,3-trione;

[0070] 5-( 1 ,4-difluoio-3-hydroxy-7-mcthoxynaphthalcn-2-yl )- 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0071] 5- { l-fluoro-3-hydroxy-7-[(2H3)methyloxy]naphthalen-2-yl } - 1 / / \2,5-thiadiazolidine- 1 , 1 ,3-trione; 5- [1 -fluoro-3-hydroxy-7-(2-methoxyethoxy)naphthalen-2-yl] - 1 / / \2,5-thiadiazolidinc- 1,1,3- trione;

[0072] 4-{ [8-fluoro-6-hydroxy-7-(l,l,4-trioxo-l76,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-2,2- dimethylbutanenitrile ;

[0073] 5- { 7-[2-(3-aminobicyclo[ 1.1.1 ] pen tan- 1 -yl)ethoxy]- 1 -fluoro-3-hydroxynaphthalen-2-yl} -

[0074] I / / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc;

[0075] 5-(7- { [2-(dimethylamino)ethyl] amino } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0076] 5-( 1 -fluoiO-3-hydiOxy-7-mcthoxynaphthalcn-2-yl)(4,4- H )- 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trionc; 5-( 1 -fluoio-3-hydroxy-7-mcthoxynaphthalcn-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc;

[0077] N-(2- { 18-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl] amino } ethyl)cyclopropanesulfonamide ;

[0078] 5-(l -fluoro- 3 -hydroxy-7- { [ 1 -(methanesulfonyl)pyrrolidin-3-yl] amino }naphthalen-2-yl)- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0079] N-(2- { 18-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl]oxy}ethyl)cyclopropanesulfonamide5-(l-fluoro-3-hydroxy-7-{ [l-(methanesulfonyl)azetidin-

[0080] 3-yl ]amino }naphthalcn-2-yl )- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc;

[0081] 4- ( 18-fiuoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl] oxy } butanenitrile ;

[0082] I I -( { 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalen-2- yl] oxy } methyl)cyclopropyl] acetonitrile ;

[0083] 5- { 7-[2-(dimethylamino)ethoxy] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - l76,2,5-thiadiazolidine- l,l,3-trione;

[0084] 5- { 7-[ 1 -(cyclopropylmethyl)- l / / -pyrazol-4-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0085] 5-{ l-fluoro-3-hydroxy-7-[(l / / -pyrazol-4-yl)methoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;

[0086] 5- [1 -fluoro-3-hydroxy-7-(2-methylpropoxy)naphthalen-2-yl] - 1 / / ’,2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0087] 5-| 1 -fluoio-3-hydi oxy-7-(2-hydioxypi opoxy)naphthalen-2-yl ]- 1 / / ’,2,5-thiadiazolidinc- 1 , 1 ,3- trionc;

[0088] / V-(cyclopropylmethyl)-8-fluoro-6-hydroxy-7-(l,l,4-trioxo-l76,2,5-thiadiazolidin-2- yl)naphthalene-2-carboxamide ; 5- [1 -fluoro-3 -hydroxy-7- (2- { [2-(trifluoromethoxy)ethyl] amino }ethoxy)naphthalen-2-yl]- 1l6, 2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0089] 5-(l-fluoro-3-hydroxy-7-{2-[(2-methoxyethyl)amino]ethoxy}naphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0090] 5 - { 1 -fluoro-3 -hydroxy-7 - [3 -(methylamino)propyl] naphthalen-2-yl } - 1 l6,2,5 -thiadiazolidine- l,l,3-trione;

[0091] 5- { 7-[3-(ethylamino)propyl]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0092] 5-{7-[5-(dimethylphosphoryl)thiophen-2-yl]-l-fluoro-3-hydroxynaphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0093] 5- { 7-[2-(cyclopropylamino)ethoxy] - l-fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0094] 5-{ l-fhioro-3-hydroxy-7-[2-(methylamino)ethoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;

[0095] 5- { 7-[2-(ethylamino)ethoxy]- 1 -fluoro-3-hydroxynaphthalcn-2-yl }- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0096] 5-(l-fluoro-3-hydroxy-7-{2-[(propan-2-yl)amino]ethoxy}naphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0097] 5-{7-[3-(diethylphosphoryl)propoxy]-l-fluoro-3-hydroxynaphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0098] 5- { 1 -fluoro-3 -hydroxy-7 - [(35)-3-hydroxybutoxy] naphthalen-2-yl } - 176,2,5-thiadiazolidine- 1 , 1 ,3- trione;

[0099] 5-{ l,4-difluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazolidme- l,l,3-trione;

[0100] 5-{ l-fluoro-3-hydroxy-7-[(3T?)-3-hydroxybutoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidme-l,l,3- trione;

[0101] 5-[7-(2-cyclopropyl-2-hydroxyethoxy)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0102] 5- { l-fluoro-3-hydroxy-7-[(47?)-4-hydroxypentyl]naphthalen-2-yl } - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0103] 5- { l-fluoro-3-hydroxy-7-[(47?)-4-hydroxypentyl]naphthalen-2-yl } - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0104] 5 - { 1 -fluoro-3 -hydroxy-7 - [(45)-4-hydroxypentyl] naphthalen-2-yl } - 1 l6,2,5 -thiadiazolidine- 1 , 1 ,3- trione ; 5-[l-fluoro-3-hydroxy-7-(4-hydroxy-4-methylpentyl)naphthalen-2-yl]-l76,2,5-thiadiazolidine- l,l,3-trione;

[0105] 5- { l-fluoro-3-hydroxy-7-[(3-oxopentyl)oxy]naphthalen-2-yl}- l76,2,5-thiadiazolidine-l , 1 ,3- trione;

[0106] 5- [1 -fluoro-3-hydroxy-7-(3-hydroxybutoxy)naphthalen-2-yl] - l76,2,5-thiadiazolidine- 1 , 1 ,3- trione;

[0107] N-\ 8-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2-yl ]-3- methylbutanamide ;

[0108] 5- [1 -fluoro-3-hydroxy-7-(4,4,4-trifluorobutoxy)naphthalen-2-yl] - l76,2,5-thiadiazolidine- 1 , 1 ,3- trione;

[0109] 1 -(2- { [8-fluoro-6-hydroxy-7-(l , 1 ,4-trioxo- 176,2,5-thiadiazolidin-2-yl)naphthalen-2- yl] oxy } ethyl)cyclopropane- 1 -carbonitrile ;

[0110] 5-(l-fluoro-3-hydroxy-7-{2-[l-(methoxymethyl)cyclopropyl]ethoxy}naphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0111] 5-(7- { [(cyclopropylmethyl)amino]methyl } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0112] 5- { 7-[(2,2-difluoropropyl)amino]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - l76,2,5-thiadiazolidine- l,l,3-trione;

[0113] 5- { 7-[3,3-dimethyl-4-(methylamino)butoxy] - 1 -fluoro-3-hydroxynaphthalen-2-yl }- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0114] 5-{ l-fluoro-3-hydroxy-7-[(2-phenylethyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l,l,3- trione;

[0115] 5-[7-(3-amino-3-methylbutoxy)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5-thiadiazolidine- l,l,3-trione;

[0116] 5-{ l-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;

[0117] 5- [7-(difluoromethyl)- 1 -fluoro-3-hydroxynaphthalcn-2-yl ]- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0118] 5- { 7-[ 1 -(dimethylphosphoryl)-2, 5-dihydro- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0119] 5-{ l-fluoro-3-hydroxy-7-[(3,3,3-trifluoropropyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;

[0120] 5 - [ 1 -fluoro-3 -hydroxy-7 - (3 -methoxy-3 -methylbutoxy)naphthalen-2-yl] - 1 l6,2, 5-thiadiazolidine- l,l,3-trione; 5-[7-(2-cyclopropylpropoxy)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5-thiadiazolidine-l,l,3- trione;

[0121] 5-[l-fluoro-3-hydroxy-7-({2-[(propan-2-yl)oxy]ethyl}amino)naphthalen-2-yl]-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0122] 5 - ( 1 -fluoro- 3 -hydroxy-7 - { [ 1 -(methanesulfonyl)pyrrolidin-3 -yl] methoxy } naphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0123] 4- ( 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl] amino } butanenitrile ;

[0124] 5- [1 -fluoro-3-hydroxy-7-(2-hydroxyethyl)naphthalen-2-yl]- l76,2,5-thiadiazolidine- 1 , 1 ,3-trione; 5-[7-(4-amino-3,3-dimethylbutoxy)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5-thiadiazolidine- l,l,3-trione;

[0125] 5-(7- { [2-(azetidin- 1 -yl)ethyl] amino } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0126] 5-(7- { [1 -(cyclopropanesulfonyl)azetidin-3-yl]oxy } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0127] 5-{ l-fluoro-3-hydroxy-7-[(2-methoxyethyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;

[0128] 5-[l-fluoro-3-hydroxy-7-(3,3,3-trifluoropropoxy)naphthalen-2-yl]-l76,2,5-thiadiazolidine-l,l,3- trione;

[0129] 1 -( { 18-fluoi o-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl] amino } methyl)cyclopropane- 1 -carbon it rile ;

[0130] 5-[l-fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-l76,2,5-thiadiazolidine- l,l,3-trione;

[0131] 5-{ l-fluoro-3-hydroxy-7-[3-(l / / -pyrazol-l-yl)propoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;

[0132] 5-(7-{ 1 -| (4-aminophcnyl )mcthancsulfonyl ]-2,5-dihydro- 1 / / -pyrrol-3-yl }- 1 -fluoro-3- hydroxynaphthalcn-2-yl )- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0133] 5- [1 -fluoro-3-hydroxy-7-(hydroxymethyl)naphthalen-2-yl]- l76,2,5-thiadiazolidine- 1 , 1 ,3-trione; 5- { 7-[ 1 -(cyclopropanesulfonyl)piperidin-3-yl]- l-fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0134] 5- { 7-[ 1 -(cyclopropanecarbonyl)pyrrolidin-2-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl} - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0135] 5-{ l-fluoro-3-hydroxy-7-[2-(l / / -pyrazol-l-yl)ethoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione; 5 - { 7- [ 1 -(cyclopropanesulfonyl)pyrrolidin-2-yl] - 1 -fluoro-3 -hydroxynaphthalen-2-yl } - 1 l6,2, 5 - thiadiazolidine- 1 , 1 ,3-trione ;

[0136] 5 - { 7- [ 1 -(cyclopropanesulfonyl)pyrrolidin-2-yl] - 1 -fluoro-3 -hydroxynaphthalen-2-yl } - 1 l6,2, 5 - thiadiazolidine- 1 , 1 ,3-trione ;

[0137] 5-| 1 -fluoio-3-hydi oxy-7-(pipcridin-3-yl)naphthalcn-2-yl ]- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc; 5-{7-[2-(2,2-difluorocyclopropyl)ethoxy]-l-fluoro-3-hydroxynaphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0138] 5 - { 1 -fluoro-3 -hydroxy-7 - [2-( 1 -methylcyclopropyl)ethoxy] naphthalen-2-yl } - 1 l6,2, 5 - thiadiazolidine- 1 , 1 ,3-trione ;

[0139] 5-(7-{ l-[(3-aminophenyl)methanesulfonyl]-2,5-dihydro-l / / -pyrrol-3-yl}-l -fluoro-3- hydroxynaphthalcn-2-yl )- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc;

[0140] 5-(7-{ 1 -| (2-aminophcnyl )mcthancsulfonyl ]-2, 5-dihydro- 1 / / -pyrrol-3-yl }- 1 -fluoro-3- hydroxynaphthalcn-2-yl )- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc;

[0141] 5- [7-(2, 2-diflu oroethyl)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - l76,2,5-thiadiazolidine- 1 , 1 ,3- trione;

[0142] 5- [1 -fluoro-3-hydroxy-7-(2,2,2-trifluoroethoxy)naphthalen-2-yl] - l76,2,5-thiadiazolidine- 1 , 1 ,3- trione;

[0143] 5- [1 -fluoro-7-(2-fhioroethoxy)-3-hydroxynaphthalen-2-yl] - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0144] 1 -( { 18-fluoi o-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yljoxy } methyl)cyclopropane- 1 -carbonitrile ;

[0145] 5-{ l-fhioro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l ,l,3- trione;

[0146] 5 - { 1 -fluoro-3 -hydroxy-7 - [(2-methylpropyl) amino] naphthalen-2-yl } - 1 l6,2,5 -thiadiazolidine- l,l,3-trione;

[0147] 5- { 7-[(cyclopropylmethyl)amino] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - l76,2,5-thiadiazolidine- l,l,3-trione;

[0148] { 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl] oxy } acetonitrile ;

[0149] 5 - [ 1 -fluoro-3 -hydroxy-7 - (3 -methylbutoxy)naphthalen-2-yl] - 1 l6,2, 5 -thiadiazolidine- 1 , 1 ,3-trione ; 5-( 1 ,8-difluoio-3-hydroxy-7-mcthoxynaphthalcn-2-yl )- 1 / / \2,5-thiadiazolidine- 1 , 1 ,3-trionc;

[0150] 5- { 7-[ 1 -(cyclopropanesulfonyl)azetidin-3-yl] - l-fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0151] 5- { 7-[ 1 -(cyclopropanecarbonyl)azetidin-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ; (2£T)-3-[8-fluoro-6-hydroxy-7-(l,l,4-trioxo-l76,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]prop-2- enenitrile;

[0152] 5- [7-(2-cyclopropylethyl)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1 / \2,5-thiadiazolidinc- 1,1,3- trione;

[0153] 5- { 7-[(2,2-difluorocyclopropyl)methoxy]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0154] 5- [7-(2-cyclopropylethoxy)- 1 -fluoro-3-hydroxynaphthalen-2-yl]- l76,2,5-thiadiazolidine- 1 , 1 ,3- trione;

[0155] 5- { 7-[2-(cyclopropylmethoxy)ethoxy]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0156] 5-{ l-fluoro-3-hydroxy-7-[2-(oxolan-2-yl)ethoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l,l,3- trione;

[0157] 5- { 7-[2-(cyclobutyloxy)ethoxy]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - l76,2,5-thiadiazolidine-

[0158] 1,1,3-trione;

[0159] 5-(l-fluoro-3-hydroxy-7-{2-[(propan-2-yl)oxy]ethoxy}naphthalen-2-yl)-l76,2,5-thiadiazolidine-

[0160] 1,1,3-trione;

[0161] 5- [7-(3-ethoxypropoxy)- 1 -fluoro-3-hydroxynaphthalcn-2-yl ]- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0162] 5- [7-(2-ter / -butoxyethoxy)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0163] 5-(7-{ [rac-(l7?,27?)-2-ethylcyclopropyl]methoxy}-l-fluoro-3-hydroxynaphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0164] 5-[l-fluoro-3-hydroxy-7-(4-methylpentyl)naphthalen-2-yl]-l76,2,5-thiadiazolidine-l,l,3-trione; 5- { 7-[3-(2,2-dimethylpropyl)pyrrolidin- 1 -yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl} - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0165] 5- [7-(l -chloro-3-hydroxypropan-2-yl)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0166] 5- { 7-[ 1 -(cyclopropylmethyl)pyrrolidin-3-yl]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0167] 5-|7-(cyclopropyloxy)- 1 -fluoro-3-hydroxynaphthalcn-2-yl ]- 1 / / \2,5-thiadiazol idinc- 1 , 1 ,3-trione; 5-{7-[(2-cyclopropylethyl)amino]-l-fluoro-3-hydroxynaphthalen-2-yl}-l76,2,5-thiadiazolidine-

[0168] 1,1,3-trione;

[0169] 5 - [ 1 -fluoro-3 -hydroxy-7 - (4-methyl- 17 / -imidazol-2-yl)naphthalen-2-yl] - 1 l6,2,5 - thiadiazolidine -

[0170] 1,1,3-trione; 5- [7-(azetidin-3-yl)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0171] 5 - [ 1 -fluoro-3 -hydroxy-7 - (5 -methoxythiophen-2-yl)naphthalen-2-yl] - 1 l6,2,5 -thiadiazolidine- l,l,3-trione;

[0172] [8-fluoro-6-hydroxy-7-(l , 1 ,4-trioxo- 1l6, 2, 5-thiadiazolidin-2-yl)naphthalen-2-yl] acetonitrile;

[0173] 5-| 1 -fluoio-3-hydi oxy-7-(methoxymethyl )naphthalen-2-yl ]- 1 / \2,5-thiadiazol idinc- 1 , 1 ,3-trione; 5-{ l-fluoro-3-hydroxy-7-[(3-methyloxetan-3-yl)methoxy]naphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0174] 5-{4-bromo-7-[l-(cyclopropanesulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]-l-fluoro-3- hydroxynaphthalen-2-yl}- l76,2,5-thiadiazolidine-l , 1 ,3-trione;

[0175] 5- { 4-bromo-7-[ l-(cyclopropanesulfonyl)- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc;

[0176] 5-{ l-fluoro-3-hydroxy-7-[(35)-pyrrolidin-3-yl]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l,l,3- trione;

[0177] 5- { l-fluoro-3-hydroxy-7-[(3 ?)-pyrrolidin-3-yl]naphthalen-2-yl } - l76,2,5-thiadiazolidine- 1 , 1 ,3- trione;

[0178] 5-(8-chloro-l-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-l76,2,5-thiadiazolidine-l,l,3-trione; 5- { 7-[(3,3-difluorocyclobutyl)methoxy] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0179] 5-(7-cyclopropyl- 1 -fluoro-3-hydroxynaphthalcn-2-yl )- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc;

[0180] 5- { 7-[ 1 -(cyclopropanecarbonyl)-2, 5-dihydro- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2- yl } - 176,2,5-thiadiazolidine- 1 , 1 ,3-trionc ;

[0181] 5-(4-chloro- 1 -fluoio-3-hydroxy-7-mcthoxynaphthalcn-2-yl)- 1 / / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trionc; 5- { 7-[(£T)-2-cyclopropylethenyl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - l76,2,5-thiadiazolidine- l,l,3-trione;

[0182] 5- { 1 -fluoro-3 -hydroxy-7 - [( l£T)-4-methylpent- 1 -en- 1 -yl] naphthalen-2-yl } - 1 l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0183] 5-{ l-fluoro-3-hydroxy-7-[l-(pentamethylphenyl)ethenyl]naphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0184] 5- { 7-| 1 -(cyclopropylmethyl )-2, 5-dihydro- 1 / / -pyrrol-3-yl ]- 1 -fluoro-3-hydroxynaphthalen-2-yl }- 1 / / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0185] 5-(4-bromo- 1 -fluoro-3-hydroxy-7-mcthoxynaphthalcn-2-yl)- 1 / / ’,2,5-thiadiazol idinc- 1 , 1 ,3-trione; 5- { 7-[ 1 -(2-cyclopropylethyl )-2, 5-dihydro- 1 / / -pyrrol-3-yl ]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1 / / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trione; 5-{ l-fluoro-3-hydroxy-7-[(l£T)-3-methoxyprop-l-en-l-yl]naphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0186] 5-|7-(2-cthoxycthoxy)- 1 -fluoiO-3-hydroxynaphthalen-2-yl ]- 1 / \2,5-thiadiazol idinc- 1 , 1 ,3-trione; 5- [1 -fluoro-3-hydroxy-7-(3-methoxypropoxy)naphthalen-2-yl] - 1 / \2, 5-thiadiazolidinc- 1 , 1 ,3- trione;

[0187] 5- [7-( 1 , 1 -dioxo- 1 / ’-thian-4-yl )- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 176,2,5-thiadiazolidine- l,l,3-trione;

[0188] 5-[l-fluoro-3-hydroxy-7-(oxan-3-yl)naphthalen-2-yl]-l76,2,5-thiadiazolidine-l,l,3-trione;

[0189] 5- [7-(cyclopropylmethoxy)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1 lή,2, 5-thiadiazolidinc- 1 , 1 ,3- trione;

[0190] 5-(l-fluoro-3-hydroxy-7-{ [l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]methyl}naphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0191] 5-(l-fluoro-3-hydroxy-7-{ [l-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl}naphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0192] 5 - ( 1 -fluoro- 3 -hydroxy-7 - { 2- [methyl(2-methylpropyl)amino] ethoxy } naphthalen-2-yl)- 1 l6,2,5 - thiadiazolidine- 1 , 1 ,3-trione ;

[0193] 5-{ l-fluoro-3-hydroxy-7-[(oxolan-2-yl)methoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l ,l,3- trione;

[0194] 5-| 1 -fluoio-3-hydroxy-7-(oxolan-3-yl)naphthalcn-2-yl ]- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0195] 5-(7- { [1 -(cyclopropanesulfonyl)azetidin-3-yl]methyl } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0196] 5-(7- { [ 1 -(cyclopropanesulfonyl)piperidin-4-yl] methyl } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0197] 5- [1 -fluoro-3-hydroxy-7-(pyrrolidin-2-yl)naphthalen-2-yl] - 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione; 5-(7- { [1 -(cyclopropanesulfonyl)piperidin-3-yl]methyl } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione;

[0198] 5- [7-(difluoromethoxy)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione; 5-(7- { [1 -(cyclopropanesulfonyl)pyrrolidin-3-yl]methyl } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione;

[0199] 5 - { 1 -fluoro-3 -hydroxy-7 - [(pyrrolidin-3 -yl)methyl] naphthalen-2-yl } - 1 l6,2,5 -thiadiazolidine- l,l,3-trione;

[0200] 5-|7-(2,5-dihydrofuran-3-yl )- 1 -fluoro-3-hydroxynaphthalcn-2-yl ]- l / \2,5-thiadiazolidinc- 1 , 1 ,3- trione; 5-[7-(3,6-dihydro-2 / / -pyran-4-yl)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5-thiadiazolidine- l,l,3-trione;

[0201] 5-[7-(2,5-dihydro-l / / -pyrrol-3-yl)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5-thiadiazolidine- l,l,3-trione;

[0202] 5 - [ 1 -fluoro-3 -hydroxy-7 - (pyridin-3 -yl)naphthalen-2-yl] - 1 l6,2, 5 -thiadiazolidine- 1,1,3 -trione ;

[0203] 5- { 7-[(azetidin-3-yl)methyl]- 1 -fluoro-3-hydroxynaphthalcn-2-yl }- 1 / \2,5-thiadiazolidinc- 1,1,3- trione;

[0204] / V-(2-cyclopropylethyl)-2-{ [8-fluoro-6-hydroxy-7-(l,l,4-trioxo-l76,2,5-thiadiazolidin-2- yl)naphthalen-2-yl] amino } acetamide ;

[0205] 4- ( 18-fluoio-6-hydioxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2-yl ]oxy }- / V- methylbutanamide ;

[0206] / V-cthyl- / V’-(2- ( 18-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl)naphthalcn-2- yl] oxy } ethyl)urea ;

[0207] 5- { l-fluoro-3-hydroxy-7-[(oxan-3-yl)methoxy]naphthalen-2-yl } - 1 / / \2,5-thiadiazolidinc- 1,1,3- trione;

[0208] 5- { 7-[(l -chloro-3-hydroxypropan-2-yl)oxy]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0209] 5- { 1 -fluoro-3 -hydroxy-7 - [(oxan-4-yl)methoxy] naphthalen-2-yl } - 1 lή,2,5- thiadiazolidine- 1 , 1 ,3- trione;

[0210] 5-{ l-fluoro-3-hydroxy-7-[(oxetan-3-yl)oxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l,l,3- trione;

[0211] 5-{ l-fluoro-3-hydroxy-7-[l-(2,2,2-trifluoroethyl)-l,2,3,6-tetrahydropyridin-4-yl]naphthalen-2- yl } - 1 lή,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0212] 5 - ( 1 -fluoro- 3 ,7 -dihydroxynaphthalen-2-yl)- 1 l6,2,5 -thiadiazolidine- 1,1,3 -trione ;

[0213] 5 - [ 1 -fluoro-3 -hydroxy-7 - (2-hydroxyethoxy)naphthalen-2-yl] - 1 l6,2, 5 -thiadiazolidine- 1 , 1 ,3- trione ;

[0214] 5 - ( 1 -fluoro- 3 -hydroxy-7 -propoxynaphthalen-2-yl) - 1 l6,2, 5 -thiadiazolidine- 1 , 1 ,3-trione ;

[0215] 5- { l-fluoro-3-hydroxy-7-[(propan-2-yl)oxy]naphthalen-2-yl } - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0216] { [8-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1l6, 2, 5-thiadiazolidin-2-yl)naphthalen-2-yl] amino } acetic acid;

[0217] / V-(2-cyclopropylcthyl )-2- ( 18-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2- yl)naphthalen-2-yl] oxy } acetamide ; / V, / V-dicthyl-2- ( | 8-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl)naphthalcn-2- yl] oxy } acetamide ;

[0218] 5- { 1 -fluoro-3-hydroxy-7 - [2-oxo-2-(pyrrolidin- 1 -yl)ethoxy] naphthalen-2-yl } - 1 l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0219] 5-(l-fluoro-3-hydroxy-7-{ [l-(methanesulfonyl)piperidin-4-yl]oxy}naphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0220] 5-{ l-fluoro-3-hydroxy-7-[l-(oxolane-3-sulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]naphthalen-2-yl}- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0221] 5-{ l-fluoro-3-hydroxy-7-[l-(2-methoxyethanesulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]naphthalen- 2-yl } - 1 l6,2, 5-thiadiazolidine- 1 , 1 ,3-trione ;

[0222] 5- { l-fluoro-3-hydroxy-7-[l-(3, 3, 3-trifluoropropane-l-sulfonyl)-2, 5-dihydro- l / / -pyrrol-3- yl]naphthalen-2-yl } - 1l6, 2, 5 -thiadiazolidine- 1 , 1 ,3-trione;

[0223] 5- { l-fluoro-3-hydroxy-7-[l-(3, 3, 3-trifluoropropane-l-sulfonyl)-2, 5-dihydro- l / / -pyrrol-3- yl]naphthalen-2-yl } - 1l6, 2, 5 -thiadiazolidine- 1 , 1 ,3-trione;

[0224] 5-(l-fluoro-3-hydroxy-7-{ l-[(oxan-2-yl)methanesulfonyl]-2,5-dihydro-l / / -pyrrol-3- yl }naphthalcn-2-yl )- 1 / / \2, 5-thiadiazolidine- 1 , 1 ,3-trione;

[0225] 5- { 1 -fluoi o-3-hydroxy-7-| 1 -(4,4,4-trifluorobutanc- 1 -sulfonyl )-2, 5-dihydro- 1 / / -pyrrol -3- yl]naphthalen-2-yl } - 1l6, 2, 5 -thiadiazolidine- 1 , 1 ,3-trione;

[0226] 5- { 7-[ 1 -(butane- 1 -sulfonyl)-2, 5-dihydro- l / / -pyrrol-3-yl] - l-fluoro-3-hydroxynaphthalen-2-yl } - 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione;

[0227] 5-(7-{ l-[(l,4-dioxan-2-yl)methanesulfonyl]-2,5-dihydro-l / / -pyrrol-3-yl}-l-fluoro-3- hydroxynaphthalcn-2-yl )- 1 / / \2, 5-thiadiazolidine- 1 , 1 ,3-trione;

[0228] 5- { 3-| 8-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalcn-2-yl ]-2,5- dihydro- 1 / / -pyrrole- 1 -sulfonyl } pentanenitrile ;

[0229] 5-{ l-fluoro-3-hydroxy-7-[l-(pentane-2-sulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]naphthalen-2-yl}- 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione;

[0230] 5- { 7-[ 1 -(ethanesulfonyl)-2, 5-dihydro- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione;

[0231] 5-{ l-fluoro-3-hydroxy-7-[l-(propane-2-sulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]naphthalen-2-yl}- 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione;

[0232] 5- { 7-[ 1 -(cyclopropanesulfonyl)- 1 ,2,3,6-tetrahydropyridin-4-yl] - 1 -fluoro-3-hydroxynaphthalen- 2-yl } - 1 l6,2, 5-thiadiazolidine- 1 , 1 ,3-trione ;

[0233] / V-(2- ( 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl]oxy}ethyl)oxetane-3-sulfonamide; 5-| 1 -fluoiO-3-hycli oxy-7-(pipericlin-4-yl)naphthalen-2-yl ]- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0234] 5- { l-fluoro-3-hydroxy-7-[l -(2-methylpropane- 1 -sulfonyl)-2, 5-dihydro- l / / -pyrrol-3- yl]naphthalen-2-yl } - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0235] 5-(7-ethoxy- 1 -fluoro-3-hydroxynaphthalen-2-yl)- l76,2,5-thiadiazolidine- 1 , 1 ,3-trione;

[0236] 5- [7-(2, 2-diflu oroethoxy)- 1 -fluoro-3-hydroxynaphthalcn-2-yl ]- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0237] 5- { 7-[ 1 -(cyclopropanesulfonyl)- l / / -pyrazol-4-yl]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0238] 5-(l-fluoro-3-hydroxy-7-{ [(3 ?)-l-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0239] 5-(l-fluoro-3-hydroxy-7-{ [l-(methanesulfonyl)piperidin-4-yl]amino}naphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0240] 5-(7- { [1 -(cyclopropanesulfonyl)pyrrolidin-3-yl] amino } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0241] 5 - ( 1 -fluoro-7- { [3 -fluoro- 1 - (methanesulfonyl)pyrrolidin-3 -yl] methoxy } -3 -hydroxynaphthalen-2- yl)- 1 l6, 2, 5 -thiadiazolidine- 1 , 1 ,3-trione ;

[0242] 5-{ l-fluoro-3-hydroxy-7-[l-(propane-2-sulfonyl)pyrrolidin-3-yl]naphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0243] 5- [7-(2-aminoethoxy)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - l76,2,5-thiadiazolidine- 1 , 1 ,3-trione; 5- { 7-[ 1 -(1 ,3-dimethyl- l / / -pyrazole-4-sulf onyl)-2, 5-dihydro- l / / -pyrrol-3-yl]- 1 -fluoro-3- hydroxynaphthalen-2-yl}- l76,2,5-thiadiazolidine-l , 1 ,3-trione;

[0244] N-(2- { 18-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl] oxy } ethyl)ethanesulfonamide ;

[0245] 5-{ l-fluoro-7-[l-(furan-3-sulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]-3-hydroxynaphthalen-2-yl}- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0246] 5- { 1 -fluoi o-3-hydroxy-7-| 1 -(3-mcthylbutanc- 1 -sulfonyl )-2,5-dihydro- 1 / / -pyrrol-3- yl]naphthalen-2-yl } - 1l6, 2, 5 -thiadiazolidine- 1 , 1 ,3-trione;

[0247] 5-{ l-fluoro-3-hydroxy-7-[l-(thiophene-3-sulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]naphthalen-2- yl } - 1' / / \2, 5- thiadiazolidine- 1 , 1 ,3-trione ;

[0248] 5- { 7-[ 1 -(benzenesulfonyl)-2, 5-dihydro- l / / -pyrrol-3-yl]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - I / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0249] 5- { 7-[ 1 -(cyclobutanesulfonyl)-2, 5-dihydro- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2- yl } - 1' / / \2, 5- thiadiazolidine- 1 , 1 ,3-trione ; methyl (25)-2-amino-4-{ [8-fluoro-6-hydroxy-7-(l,l,4-trioxo-l76,2,5-thiadiazolidin-2- yl)naphthalen-2-yl] oxy } butanoate ;

[0250] 5- { 7-[(3, 5-dimethyl- l / / -pyrazol-4-yl)methoxy] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0251] 5- [7-(3, 5-dimethyl- l / / -pyrazol-4-yl)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1l6, 2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0252] 5- [7-(2-cyclohexylethoxy)- 1 -†luoro-3-hydroxynaphthalcn-2-yl ]- 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0253] 2-|8-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl)naphthalcn-2-yl ]- 1 H- imidazole-4-carbonitrile ;

[0254] and a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

[0255] In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III) is formulated as a pharmaceutically acceptable composition comprising a disclosed compound and a pharmaceutically acceptable carrier.

[0256] Also disclosed herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III) in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an

[0257] immunotherapeutic agent. For example, in some embodiments, the immunotherapeutic agent is selected from the group consisting of an anti- PD- 1 antibody, an anti-PD-Ll antibody and an anti-CTLA-4 antibody.

[0258] For example, disclosed herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III).

[0259] Further provided herein is a method of treating type-2 diabetes in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III).

[0260] Disclosed herein, for example, is a method of treating and / or controlling obesity in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III).

[0261] For example, disclosed herein is a method of inhibiting further weight gain in an overweight or obese patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III).

[0262] Further disclosed herein is a method of treating a metabolic disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III).

[0263] In some embodiments, the method comprises the treatment of cancer. In some embodiments, the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, melanoma, or a cancer of the secretory cells. In some embodiments, the method comprises the treatment of a metabolic disease. In some embodiments, the metabolic disease comprises non alcoholic steatohepatitis (NASF1), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, type-2 diabetes, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, metabolic syndrome or Kearns-Sayre disease.

[0264] Also disclosed herein is a composition for use in treating cancer in a patient in need thereof, wherein the composition comprises a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), in combination with an additional therapeutic agent.

[0265] In some embodiments, the additional therapeutic agent is an immunotherapeutic agent. For example, in some embodiments, the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-Ll antibody and an anti-CTLA-4 antibody.

[0266] For example, disclosed herein is a composition for use in treating cancer in a patient in need thereof, wherein the composition comprises a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III).

[0267] Further provided herein is a composition for use in treating type-2 diabetes in a patient in need thereof, wherein the composition comprises a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III).

[0268] Disclosed herein, for example, is a composition for use in treating and / or controlling obesity in a patient in need thereof, wherein the composition comprises a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III).

[0269] For example, disclosed herein is a composition for use in inhibiting further weight gain in an overweight or obese patient in need thereof, wherein the composition comprises a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III).

[0270] Further disclosed herein is a composition for use in treating a metabolic disease in a patient in need thereof, wherein the composition comprises a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III). In some embodiments, the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, melanoma, or a cancer of the secretory cells. In some embodiments, the metabolic disease comprises non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, type-2 diabetes, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, metabolic syndrome or Kearns-Sayre disease.

[0271] BRIEF DESCRIPTION OF THE SEQUENCE LISTING

[0272] Incorporated herein by reference in its entirety is a Sequence Listing entitled,“CLS- Ol4WO_SEQ_ID_List_ST25”, comprising SEQ ID NO: 1 through SEQ ID NO: 3, which includes the amino acid sequences disclosed herein. The Sequence listing has been submitted herewith in ASCII text format via EFS. The Sequence Listing was first created on June 13, 2019, and is 8 KB in size.

[0273] DETAILED DESCRIPTION

[0274] The present disclosure is directed, at least in part, to compounds, compositions, and methods for the inhibition of protein tyrosine phosphatase, e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) and / or protein tyrosine phosphatase non-receptor type 1 ((PTPN1), also known as protein tyrosine phosphatase- 1B (PTP1B)).

[0275] Definitions

[0276] Chemical Definitions

[0277] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, 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 Edition, Cambridge University Press, Cambridge, 1987. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0278] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al.,

[0279] Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al. , Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0280] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the“R” form of the compound and is, thus, in enantiomeric excess of the“R” form. The term“enantiomerically pure” or“pure enantiomer” denotes that the compound comprises 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 weights are based upon total weight of all enantiomers or

[0281] stereoisomers of the compound.

[0282] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R- compound in such compositions can, for example, comprise, at least about 95% by weight R- compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0283] “Isotopically enriched variant” as used herein refers to a disclosed compound having one or more isotopic substitutions, wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,180,170,31P,32P,35S,18F, and36Cl, respectively. For example, hydrogen (H) may be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium); carbon (C) may be in any isotopic form, including12C,13C, and14C; oxygen (O) may be in any isotopic form, including160 and180; and the like. For example, an isotopically enriched variant as disclosed herein may have one or more hydrogen atoms replaced with deuterium.

[0284] The articles“a” and“an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example“an analogue” means one analogue or more than one analogue.

[0285] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example“Ci-C6alkyl” is intended to encompass, , C\ C3, C4, C5, C6,

[0286] Ci-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-

[0287] C5, and C5-C6alkyl.

[0288] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present disclosure.

[0289] “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-C20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“Cj-C^ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-C8alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci-C6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“ -C5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-C4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-C3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-C2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-C6 alkyl”). Examples of Ci-C6alkyl groups include methyl ( ), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Each instance of an alkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a“substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain

[0290] embodiments, the alkyl group is unsubstituted Ci_io alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted Ci_6alkyl. Common alkyl abbreviations include Me (-CH3), Et (- CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (- CH2CH(CH3)2).

[0291] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, - CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present disclosure.

[0292] The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. An alkylene group may be described as, e.g., a Ci-C6- membered alkylene, wherein the term“membered” refers to the non-hydrogen atoms within the moiety.

[0293] “Alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds (“C2- C2o alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-Cio alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-C8alkenyl”).

[0294] In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-C6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-C3alkenyl”). In some

[0295] embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-C4alkenyl”). In some

[0296] embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-C3alkenyl”). In some

[0297] embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-C4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Each instance of an alkenyl group may be independently optionally substituted, e.g., unsubstituted (an“unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents, e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-io alkenyl. In certain embodiments, the alkenyl group is substituted C2-6alkenyl.

[0298] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-Ci4aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1- naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl). An aryl group may be described as, e.g., a CVCio-membered aryl, wherein the term“membered” refers to the non-hydrogen ring atoms within the moiety. Aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group may be independently optionally substituted, e.g., unsubstituted (an “unsubstituted aryl”) or substituted (a“substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C C14aryl. In certain embodiments, the aryl group is substituted CVC14aryl.

[0299] In certain embodiments, an aryl group is substituted with one or more of groups selected from halo, Ci-C8alkyl, halo-Ci-Cs alkyl, haloxy-Ci-Cs alkyl, cyano, hydroxy, alkoxy Ci-C8alkyl, and amino.

[0300] Examples of representative substituted aryls include the following

[0301] wherein one of R 56 and R 51 may be hydrogen and at least one of R 56 and R 51 is each independently selected from Ci-C8alkyl, halo-Ci-C8alkyl, 4-10 membered heterocyclyl, alkanoyl, alkoxy-Ci-C8alkyl, heteroaryloxy, alkylamino, arylamino, heteroarylamino,

[0302] NR58COR59, NR58S0R59NR58S02R59, C(0)0alkyl, C(0)0aryl, CONR58R59, CONR58OR59, NR58R59, S02NR58R59, S-alkyl, S(0)-alkyl, S(0)2-alkyl, S-aryl, S(0)-aryl, S(02)-aryl; or R56and R may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatomic groups selected from the group N, O, S, S(O) or S(0)2.

[0303] Other representative aryl groups having a fused heterocyclyl group include the following:

[0304] wherein each W’ is selected from C(R66)2, NR66, O, and S; and each Y’ is selected from carbonyl, NR66, O and S; and R66is independently hydrogen, Ci-C8alkyl, C3-C10cycloalkyl, 4- 10 membered heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl.

[0305] An "arylene" and a "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. Non-limiting examples of heteroaryl groups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthanyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinonyl, benzoisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl,

[0306] pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl, or quinolyl. The examples above may be substituted or unsubstituted and divalent radicals of each heteroaryl example above are non limiting examples of heteroarylene.

[0307] “Halo” or“halogen,” independently or as part of another substituent, mean, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. The term “halide” by itself or as part of another substituent, refers to a fluoride, chloride, bromide, or iodide atom. In certain embodiments, the halo group is either fluorine or chlorine.

[0308] Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo-CYQ, alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, and the like.

[0309] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Exemplary heteroalkyl groups include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2- N(CH3)-CH3, -CH2-S-CH2-CH3, -S(0)-CH3, -S(0)2-CH3-CH2-CH2-S(0)2-CH3, -CH=CH-O- CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -0-CH3, and -0-CH2-CH3. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3and -CH2- 0-Si(CH3)3. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -CH20-CH3, -NR R , or the like, it will be understood that the terms heteroalkyl and -CH20-CH3or -NRBRCare not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -CH20-CH3, -NR R , or the like.

[0310] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH20- and -CH2CH20-. A heteroalkylene group may be described as, e.g., a 2-7- membered heteroalkylene, wherein the term“membered” refers to the non-hydrogen atoms within the moiety. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(0)2R’- may represent both -C(0)2R’- and -R’C(0)2-.

[0311] “Heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 p electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.“Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). A heteroaryl group may be described as, e.g., a 6-10-membered heteroaryl, wherein the term“membered” refers to the non-hydrogen ring atoms within the moiety. In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein 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 has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.

[0312] In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heteroaryl group may be independently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.

[0313] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.

[0314] Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6- membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0315] Examples of representative heteroaryls include the following formulae:

[0316]

[0317] wherein each Y is selected from carbonyl, N, NR65, O, and S; and R65is independently hydrogen, Ci-C8alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10 membered heteroaryl.

[0318] “Cycloalkyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-C10cycloalkyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-

[0319] Cscycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-C10 cycloalkyl”). A cycloalkyl group may be described as, e.g., a C4-C7-membered cycloalkyl, wherein the term“membered” refers to the non-hydrogen ring atoms within the moiety.

[0320] Exemplary C3-C6cycloalkyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 cycloalkyl groups include, without limitation, the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[l.l.l]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. Exemplary C3-C10cycloalkyl groups include, without limitation, the aforementioned C3-C8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl ( o), cyclodecenyl (CJO), octahydro- 1 / / -indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated.“Cycloalkyl” also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group may be independently optionally substituted, e.g., unsubstituted (an“unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-C10cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-C10cycloalkyl.

[0321] In some embodiments,“cycloalkyl” is a monocyclic, saturated cycloalkyl group having from 3 to 10 ring carbon atoms (“C3-C10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-C8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-C6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-C10cycloalkyl”). Examples of C5-C6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-C6cycloalkyl groups include the aforementioned C5-C6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4).

[0322] Examples of C3-C8cycloalkyl groups include the aforementioned C3-C6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an“unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-C10cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3-C10cycloalkyl.

[0323] “Heterocyclyl” or“heterocyclic” refers to a radical of a 3- to lO-membered non aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatomic groups, wherein each heteroatomic group is independently selected from nitrogen, oxygen, sulfur and oxidized forms of sulfur (for example, S, S(O) and S(0)2), boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term“membered” refers to the non hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur and oxidized forms of sulfur (for eample, S, S(O) and S(0)2), boron, phosphorus, and silicon, within the moiety. Each instance of heterocyclyl may be independently optionally substituted, e.g., unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 4-6 membered heterocyclyl.

[0324] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur and oxidized forms of sulfur (for eample,

[0325] S, S(O) and S(0)2), boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur and oxidized forms of sulfur (for eample, S, S(O) and S(0)2) (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur and oxidized forms of sulfur (for eample, S, S(O) and S(0)2) (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, sulfur and oxidized forms of sulfur (for eample, S, S(O) and S(0)2). In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, sulfur and oxidized forms of sulfur (for eample, S, S(O) and S(0)2). In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, sulfur and oxidized forms of sulfur (for eample, S, S(O) and S(0)2).

[0326] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.

[0327] Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0328] Particular examples of heterocyclyl groups are shown in the following illustrative examples:

[0329]

[0330] wherein each W” is selected from CR67, C(R67)2, NR67, O, and S; and each Y” is selected from NR67, O, and S; and R67is independently hydrogen, Ci-C8alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10-membered heteroaryl. These heterocyclyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (e.g., amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S- aryl, -S(0)-alkyl, -S(0)-aryl, -S(0)2-alkyl, and -S(0)2-aryl. Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.

[0331] “Nitrogen-containing heterocyclyl” group means a 4- to 7- membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, 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 / V-alkyl piperazines such as / V-mcthyl piperazine. Particular examples include azetidine, piperidone and piperazone.

[0332] “Amino” refers to the radical -NR R , wherein R and R are each independently hydrogen, Ci-C8alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10- membered heteroaryl. In some embodiments, amino refers to NH2.

[0333] “Cyano” refers to the radical -CN.

[0334] “Hydroxy” or“hydroxyl” refers to the radical -OH.

[0335] In some embodiments one or more of the nitrogen atoms of a disclosed compound if present are oxidized to the corresponding / V-oxidc.

[0336] 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

[0337] “unsubstituted” cycloalkyl,“substituted” or“unsubstituted” heterocyclyl,“substituted” or “unsubstituted” aryl or“substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”, whether preceded by the term“optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a“substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term“substituted” is contemplated to include substitution with all permissible substituents of organic compounds, such as any of the substituents described herein that result in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocyclyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring forming substituents are attached to non-adjacent members of the base structure.

[0338] A“counterion” or“anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F~, CF, Br , G), NOf , Cl OF, OFT, FFPOf, HSOf, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

[0339] The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,

[0340] monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present disclosure. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms. In other cases, the preparation may be a lyophilized powder in a first buffer, e.g., in 1 mM-50 mM histidine, 0. l%-2% sucrose, 2%- 7% mannitol at a pH range of 4.5 to 5.5, that is combined with a second buffer prior to use.

[0341] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art.

[0342] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0343] In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0344] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0345] As used herein, the term "salt" refers to acid or base salts of the compounds used in the methods of the present disclosure. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.

[0346] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that may be defined, in terms of absolute

[0347] stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those which are known in art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0348] As used herein, the term "isomers" refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.

[0349] The term "tautomer," as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0350] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

[0351] “Treating” or“treatment” includes preventing or delaying the onset of the symptoms, complications, or biochemical indicia of a disease, alleviating or ameliorating the symptoms or arresting or inhibiting further development of the disease, condition, or disorder.“Treating” or “treatment” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like. For example certain methods herein treat cancer by decreasing or reducing or preventing the occurrence, growth, metastasis, or progression of cancer or decreasing a symptom of cancer. The term "treating" and conjugations thereof, include prevention of an injury, pathology, condition, or disease (e.g. preventing the development of one or more symptoms of a disease, disorder, or condition described herein).

[0352] An "effective amount" is an amount sufficient to accomplish a stated purpose (e.g.

[0353] achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, or reduce one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a

[0354] "therapeutically effective amount. " A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman,

[0355] 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).

[0356] A "reduction" of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).

[0357] "Control" or "control experiment" is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment.

[0358] In some instances, the control is used as a standard of comparison in evaluating experimental effects.

[0359] "Contacting" is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including

[0360] biomolecules, or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated, however, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture. The term "contacting" may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme, e.g., a protein tyrosine phosphatase, e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) or protein tyrosine phosphatase non-receptor type 1 (PTP1B). As defined herein, the term "inhibition", "inhibit", "inhibiting" and the like in reference to a protein-inhibitor (e.g., antagonist) interaction means negatively affecting (e.g., decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to reduction of a disease or symptoms of disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In some embodiments, inhibition refers to a decrease in the activity of a protein tyrosine phosphatase, e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) or protein tyrosine phosphatase non-receptor type 1 (PTP1B). Thus, inhibition may include, at least in part, partially or totally decreasing stimulation, decreasing or reducing activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein tyrosine phosphatase, e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) or protein tyrosine phosphatase non-receptor type 1 (PTP1B).

[0361] "Patient" or "subject” in need thereof refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a compound or pharmaceutical composition, as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human. In some embodiments, a patient is a domesticated animal. In some embodiments, a patient is a dog. In some embodiments, a patient is a parrot. In some embodiments, a patient is livestock animal. In some embodiments, a patient is a mammal. In some embodiments, a patient is a cat. In some embodiments, a patient is a horse. In some embodiments, a patient is bovine. In some embodiments, a patient is a canine. In some embodiments, a patient is a feline. In some embodiments, a patient is an ape. In some embodiments, a patient is a monkey. In some embodiments, a patient is a mouse. In some embodiments, a patient is an experimental animal. In some embodiments, a patient is a rat. In some embodiments, a patient is a hamster. In some embodiments, a patient is a test animal. In some embodiments, a patient is a newborn animal. In some embodiments, a patient is a newborn human. In some embodiments, a patient is a newborn mammal. In some embodiments, a patient is an elderly animal. In some embodiments, a patient is an elderly human. In some

[0362] embodiments, a patient is an elderly mammal. In some embodiments, a patient is a geriatric patient. "Disease",“disorder” or "condition" refers to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein. In some embodiments, the compounds and methods described herein comprise reduction or elimination of one or more symptoms of the disease, disorder, or condition, e.g., through administration of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0363] The term "signaling pathway" as used herein refers to a series of interactions between cellular and optionally extra-cellular components (e.g. proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propagated to other signaling pathway components.

[0364] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0365] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.

[0366] Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0367] As used herein, the term "administering" means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow- release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By "co-administer" it is meant that a compound or composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., anti-cancer agent, chemotherapeutic, or

[0368] immunotherapeutic agent). The compounds or compositions described herein can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compound or composition individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation).

[0369] The term“PTPN2” as used herein refers to protein tyrosine phosphatase non-receptor type 2. The term“PTPN1” refers to protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase- 1B (PTP1B),

[0370] Compounds

[0371] Disclosed herein, for example, is a compound of Formula (I):

[0372]

[0373] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, / V-oxide, stereoisomer or isotopically enriched variant thereof, wherein:

[0374] R1is selected from the group consisting of hydrogen, halogen, Ci_6alkyl, C3_6cycloalkyl, - 0-Ci_6alkyl, -N(Ra)-Ci_6alkyl and -Ci_6alkylene-5-6 membered heterocyclyl;

[0375] wherein Ci-6alkyl, C3-6cycloalkyl, -0-Ci-6alkyl, -N(Ra)-Ci-6alkyl and -Ci_6alkylene-5-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci_6alkylene-5-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh; 2

[0376] R is selected from the group consisting of hydrogen, hydroxyl, -CHF2, -CH2OH, - CH2CN, -CH2-O-C1-6 alkyl, -CH2-N(Ra)-Ci-6alkyl, C2-6alkyl, C2-6alkenyl, -0-Ci-6alkyl, -N(Ra)- Ci_6alkyl, -S(0)w-Ci_6alkyl, -C(0)-N(Ra)-Ci_6alkyl, -N(Ra)-C(0)-Ci_6alkyl, -0-C(0)-N(Ra)-Ci_6alkyl, -N(Ra)-C(0)-0-Ci-6alkyl, -C3-6cycloalkyl, -0-C3-6cycloalkyl, Ci-6alkylene-C3-6cycloalkyl, -Ci_6alkenylene-C3_6cycloalkyl, -0-Ci_6alkylene-C3-6cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -0-Ci_6alkylene-5-6 membered heteroaryl, -0-4-6 membered heterocyclyl, -N(Ra)-4-6 membered heterocyclyl, -Ci_6alkylene-4-6 membered heterocyclyl and - 0-Ci_6alkylene-4-6 membered heterocyclyl;

[0377] wherein -CH2-0-Ci-6alkyl, -CH2-N(Ra)-Ci-6alkyl, C2-6alkyl, C2-6alkenyl, -O-Ci-6alkyl, -N(Ra)-Ci_6alkyl, -S(0)w-Ci_6alkyl, -C(0)-N(Ra)-Ci_6alkyl, -N(Ra)-C(0)-Ci_6alkyl, -O- C(0)-N(Ra)-Ci-6alkyl, -N(Ra)-C(0)-0-Ci-6alkyl, -C3-6cycloalkyl, -0-C3-6cycloalkyl, -Ci_ 6alkylene-C3_6cycloalkyl, -Ci_6alkenylene-C3_6cycloalkyl, -0-Ci_6alkylene-C3-6cycloalkyl, 5-6 membered heteroaryl, -0-Ci_6alkylene-5-6 membered heteroaryl, 4-6 membered heterocyclyl, - 0-4-6 membered heterocyclyl, -N(Ra)-4-6 membered heterocyclyl, -Ci_6alkylene-4-6 membered heterocyclyl and -0-Ci_6alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(Ra)- 4-6 membered heterocyclyl, -Ci_6alkylene-4-6 membered heterocyclyl or -0-Ci_6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh;

[0378] or R 1 and R 2 taken together with the atoms to which they are attached form a 5-6 membered aryl or heteroaryl; wherein aryl or heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, Ci-6alkyl and Ci-6alkoxy; wherein Ci-6alkyl and Ci-6alkoxy may optionally be substituted p

[0379] by one, two three or more substituents each independently selected from R ;

[0380] R3is selected from the group consisting of hydrogen, -Ci_6alkyl, -0-Ci_6alkyl, -N(Ra)-Ci_ ealkyl, -S(0)w-Ci_6alkyl, -C(0)-N(Ra)-Ci_6alkyl, -N(Ra)-C(0)-Ci_6alkyl and -Ci_6alkylene-4-6 membered heterocyclyl;

[0381] wherein -Ci-6alkyl, -0-Ci-6alkyl, -N(Ra)-Ci-6alkyl, -S(0)w-Ci-6alkyl, -C(0)-N(Ra)- Ci_6alkyl, -N(Ra)-C(0)-Ci_6alkyl and -Ci_6alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci_6alkylene_4_6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh; R4is selected from the group consisting of hydrogen, halogen, Ci_6alkyl, C3_6cycloalkyl and -Ci-6alkylene-4-6 membered heterocyclyl; wherein Ci-6alkyl, C3-6cycloalkyl and -Ci_6alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci_6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh;

[0382] wherein at least one of R 1 , R2 , R 3 and R 4 is not hydrogen;

[0383] R5is selected from the group consisting of hydrogen, halogen, Ci_6alkyl, C3_6cycloalkyl and -Ci_6alkylene-4-6 membered heterocyclyl; wherein Ci_6alkyl, C3_6cycloalkyl and -Ci_6alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci_6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh;

[0384] R6is hydrogen;

[0385] R7is hydrogen;

[0386] Rgis independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, oxo, -C(0)0H, RaRbN-, RaRbN-C(0)-, RaRbN-SOw-, RaRbN- C(0)-N(Ra)-, Chalky I, C2-6alkenyl, C2-6alkynyl, C3_6cycloalkyl, phenyl, C1_6alkylene-C3_6cycloalkyl, -0-C1-6alkylene-C3-6cycloalkyl, -(CO)-(NRa)-C1_6alkylene-C3_6cycloalkyl, Cj_

[0387] 6alkyl-SOw-N(Ra)-, C3_6cycloalkyl-SOw-N(Ra)-, 4-6 membered heterocyclyl-SOw-N(Ra)-, .6alkoxy-C(0)-N(Ra)-, Ci_6alkyl-C(0)-N(Ra)-Ci_6alkyl-, Ci_6alkyl-N(Ra)-C(0)-Ci_6alkyl-, - P(0)(Ci_3alkyl)2and Ci_6alkoxy-Ci_6alkyl-; wherein Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3_6cycloalkyl, phenyl, Ci_6alkylene-C3_6cycloalkyl, -0-Ci_6alkylene-C3-6cycloalkyl, -(CO)-(NRa)- Ci_6alkylene-C3_6cycloalkyl, Ci_6alkoxy, C3_6alkenyloxy, C3_6alkynyloxy, C3_6cycloalkoxy, Ci_6alkyl-C(0)-, Ci_6alkyl-0-C(0)-, Ci_6alkyl-C(0)-0-, Ci_6alkyl-S(0)w-, Ci_6alkyl-N(Ra)-, C ,_6alkyl-N(Ra)-C(0)-, Ci_6alkyl-C(0)-N(Ra), Ci_6alkyl-N(Ra)-C(0)-N(Ra)-, Ci_6alkyl-N(Ra)-SOw-, C3-6cycloalkyl-N(Ra)-SOw-, Ci_6alkyl-SOw-N(Ra)-, C3_6cycloalkyl-SOw-N(Ra)-, 4-6 membered heterocyclyl-SOw-N(Ra)-, Ci_6alkoxy-C(0)-N(Ra)-, Ci_6alkyl-C(0)-N(Ra)-Ci_6alkyl-, Ci_6alkyl- N(Ra)-C(0)-Ci_6alkyl-, -P(0)(Ci_3alkyl)2and Ci_6alkoxy-Ci_6alkyl- may optionally be substituted by one, two three or more substituents each independently selected from Rp;

[0388] Rhis independently selected for each occurrence from the group consisting of Ci-6alkyl, C3_6alkenyl, C3_6alkynyl, C3_6cycloalkyl, -Ci_6alkyl-C3_6cycloalkyl, Ci_6alkyl-S(0)2-, C3-6cycloalkyl-S(0)2-, 4-6 membered heterocyclyl-S(0)2-, 4-6 membered heterocyclyl-Ci-6alkyl- S(0)2-, 5-6 membered heteroaryl-S(0)2-, phenyl-S(0)2-, phenyl-Ci_6alkyl-S(0)2-, Ci_6alkyl- C(O)-, Ci-6cycloalkyl-C(0)-, Ci-6alkoxy-C(0)-, RaRbN-C(0)-, RaRbN-S02- and -P(0)(Ci- 3alkyl)2; wherein Ci_6alkyl, C3_6alkenyl, C3_6alkynyl, C3_6cycloalkyl, -Ci_6alkyl-C3_6cycloalkyl, Ci-6alkyl-S(0)2-, C3-6cycloalkyl-S(0)2-, 4-6 membered heterocyclyl-S(0)2-, 4-6 membered heterocyclyl-Ci_6alkyl-S(0)2-, 5-6 membered heteroaryl-S(0)2-, phenyl-S(0)2-, phenyl-Ci_6alkyl- S(0)2-, Ci-6alkyl-C(0)-, Ci-6cyeloalkyl-C(0)-, Ci-6alkoxy-C(0)-, RaRbN-C(0)-, RaRbN-S02- and -P(0)(Ci_3alkyl)2may optionally be substituted by one, two three or more substituents each independently selected from Rp;

[0389] Rpis independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, Ci_6alkyl, Ci_6alkoxy, C3_6cycloalkyl, 4-6 membered heterocyclyl, RaRbN-, RaRbN -carbonyl- , RaRbN-S02-, and RaRbN-carbonyl-N(Ra)-;

[0390] Raand Rbare independently selected, for each occurrence, from the group consisting of hydrogen, Ci_6alkyl and C3_6cycloalkyl; wherein Ci_6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo, hydroxyl and Ci_6alkoxy (optionally substituted by one, two or three fluorine atoms);

[0391] or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein the heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl; and w is 0, 1 or 2.

[0392] In some embodiments, one, two, three or more hydrogen atoms of the compound may optionally be deuterium atoms; and wherein all other atoms of the compound are present at their naturally occurring isotopic abundance. For example, in some embodiments, one, two, three or more hydrogen atoms may optionally be deuterium atoms at one, two three or more groups each independently selected from R1, R2, R4, R5, R6, R7, and Rg.

[0393] In some embodiments, R1is selected from the group consisting of, e.g., hydrogen, deuterium, chlorine and fluorine. In some embodiments, R 2 is 4-6 membered heterocyclyl; wherein R 2 may optionally be substituted on one or more available carbons by one, two or three substituent each independently selected from Rg, wherein if 4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from Rh. For example, in some embodiments R is 4-6 membered heterocyclyl; wherein R may optionally be substituted on one or more available carbons by one, two or three substituents each

[0394] 2 independently selected from the group consisting of hydrogen and Ci_6alkyl; and wherein if R contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from the group consisting of hydrogen, Ci_6alkyl (optionally substituted by one, two or three fluorine atoms), -Ci_6alkyl-C3_6cycloalkyl, Ci_6cycloalkyl-C(0)-, Chalky I -S(O) - (optionally substituted by cyano, methoxy or one, two or three fluorine atoms), C3-6cycloalkyl-S(0)2-, 4-6 membered heterocyclyl-S(0)2-, 4-6 membered heterocyclyl-Ci_6alkyl- S(0)2-, 5-6 membered heteroaryl-S(0)2-, phenyl-S(0)2-, phenyl-C1-6alkyl-S(0)2-(optionally substituted by RaRbN-), and -P(0)(Ci_3alkyl)2- For example, in somebodiments R2is selected from the group consisting of, e.g.:

[0395]

[0396] In other embodiments, R 2 is 5-6 membered heteroaryl; wherein R 2 may optionally be substituted on one or more available carbons by one, two or three substituents each

[0397] independently selected from Rg, and wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from Rh. For example, in some embodiments R is 5-6 membered heteroaryl; wherein R may optionally be substituted on one or more available carbons by one, two or three substituents each

[0398] independently selected from the group consisting of hydrogen, cyano, Ci_6alkyl, Ci_6alkoxy and - P(0)(C]_ialkyl) ; and wherein if R contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from the group consisting of hydrogen, -Ci^alkyl-C vrcycloalkyl and C3-6cycloalkyl-S(0)2-. For example, in some embodiments R is selected from the group consisting of, e.g.:

[0399]

[0400] In further embodiments, R 2 is -0-Ci-6alkylene-4-6 membered heterocyclyl, wherein R 2 may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from Rg, and wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from Rh. For example, in some embodiments, R is -0-Ci_6alkylene-4-6 membered heterocyclyl, wherein R may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from the group consisting of hydrogen, halogen and Ci_6alkyl, and wherein if R contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from the group consisting of hydrogen, Ci_6alkyl and _6alkyl-S(0)2-. For example, in some embodiments R is selected from the group consisting of, e.g.:

[0401]

[0402] 2

[0403] In other embodiments, R is -0-Ci_6alkylene-5-6 membered heteroaryl. For example, in

[0404] 2

[0405] some embodiments R is selected from the group consisting of, e.g.:

[0406] 2

[0407] In further embodiments, R is selected from the group consisting of -C2-6alkyl, C2-6alkenyl, and C3_6cycloalkyl; wherein R may optionally be substituted by one, two, three or more substituents each independently selected from Rg. For example, in some embodiments R2is selected from the group consisting of -C2-6alkyl, C2-6alkenyl, C3_6cycloalkyl, -Ci_6alkylene-C3_6cycloalkyl and -Ci-6alkenylene-C3-6cycloalkyl; wherein R may optionally be substituted by one, two, three or more substituents each independently selected from the group consisting of cyano, chlorine, fluorine, hydroxyl, Ci_6alkoxy, phenyl, and RaRbN-. For example, in some embodiments R is selected from the group consisting of, e.g.:

[0408]

[0409] In other embodiments, R is -0-Ci_6alkyl; wherein R may optionally be substituted by one, two, three or more substituents each independently selected from Rg. For example, in some embodiments R is -O-C^ealkyl; wherein R may optionally be substituted by one, two, three or more substituents each independently selected from the group consisting of cyano, deuterium, chlorine, fluorine, hydroxyl, oxo, Ci_6alkoxy, C3_6cycloalkoxy, -0-Ci_6alkylene-C3-6cycloalkyl, - (CO)-(NRa)-Ci-6alkylene-C3-6cycloalkyl, Ci-6alkyl-0-C(0)-, RaRbN- (wherein Rbis optionally substituted by -OCH3or -OCF3), Ci_6alkyl-N(Ra)-, RaRbN-C(0)-, -P(0)(Ci_3alkyl)2, Ci_6alkyl- N(Ra)-C(0)-, Ci-6alkyl-N(Ra)-C(0)-N(Ra)-, Ci-6alkyl-S02-N(Ra)-, C3-6cycloalkyl-SC>2-N(Ra)- and 4-6 memberedheterocyclyl-S02-N(Ra)-. For example, in some embodiments R2is selected from the group consisting of, e.g.:

[0410] 2

[0411] In other embodiments, R is -0-C3-6cycloalkyl or -0-4-6 membered heterocyclyl; wherein if R contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from Rh. For example, in some embodiments R2is -0-C3_6cycloalkyl or -0-4-6 membered heterocyclyl; wherein if R contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from the group consisting of Ci_6alkyl-S02-N(Ra)- and C3-6cycloalkyl-S02-N(Ra)-. For example,

[0412] 2

[0413] in some embodiments R is selected from the group consisting of, e.g.:

[0414] In still further embodiments, R2is -N(Ra)-Ci-6alkyl, wherein R2may optionally be substituted by one, two or three substituents each independently selected from Rg. For example, in some embodiments R2is -N(Ra)-Ci-6alkyl, wherein R2may optionally be substituted by one, two or three substituents each independently selected from the group consisting of fluoro, - C(0)0Fl, cyano, oxo, RaRbN-, Ci-6alkoxy, phenyl, -C3-6cycloalkyl, C3-6cycloalkyl-S02-N(Ra)-, and -(CO)-(NRa)-Ci_6alkylene-C3_6cycloalkyl. For example, in some embodiments R2is selected from the group consisting of, e.g.:

[0415]

[0416] ay optionally be substituted by one, two or three substituents each independently selected from Rg. For example, in some embodiments R is -0-Ci_6alkylene-C3-6cycloalkyl, wherein R may optionally be substituted by one, two or three substituents each independently selected from the group consisting of fluoro, hydroxyl, RaRbN-, cyano, and Ci_3alkyl; wherein Ci_3alkyl may be optionally substituted by a substituient selected from the group consisting of cyano and Ci_ 3alkoxy. For example, in some embodiments R is selected from the group consisting of, e.g.:

[0417] In some embodiments, R 2 is -0-C(0)-N(R a )-Ci_6alkyl. For example, in some embodiments

[0418] R2is represented by,

[0419] In further embodiments, R2is -N(Ra)-4-6 membered heterocyclyl, wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from Rh. For example, in some embodiments R2is -N(Ra)-4-6 membered heterocyclyl, wherein if R contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from the group consisting of Ci_6alkyl- S(¾-N(Ra)- and C3-6cycloalkyl-S02-N(Ra)-. For example, in some embodiments R2is selected from the group consisting of, e.g.:

[0420]

[0421] In other embodiments, R 2 is -Ci_6alkylene-4-6 membered heterocyclyl, wherein if R 2 contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from Rh. For example, in some embodiments R2is -Ci_6alkylene-4-6 membered heterocyclyl, wherein if R contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from the group consisting of Ci_6alkyl, Ci_6alkyl-S02-N(Ra)- and C3-6cycloalkyl-S02-N(Ra)-, wherein Ci_6alkyl may optionally be substituted by one, two or three fluorine atoms. For example, in some embodiments R is selected from the group consisting of, e.g.:

[0422]

[0423] In some embodiments, R is selected from the group consisting of, for example,

[0424] In some embodiments, R 1 and R 2 taken together with the atoms to which they are attached form a 5 membered heteroaryl. For example, in some embodiments R and R taken together with the atoms to which they are attached form, e.g., furanyl. For example, in some embodiments the compound of Formula (I) is represented by:

[0425] In some embodiments, R3is hydrogen. In other embodiments, R4is hydrogen. In further embodiments, R5is selected from the group consisting of hydrogen, deuterium, bromine, chlorine, and fluorine. In other embodiments, R6is selected from the group consisting of hydrogen and deuterium. In futher embodiments, R7is selected from the group consisting of hydrogen and deuterium. In some embodiments, all atoms of the compound of Formula (I) are present at their naturally occurring isotopic abundance.

[0426] Also disclosed herein is compound represented by Formula (II):

[0427]

[0428] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, / V-oxide or stereoisomer thereof, wherein: X is selected from the group consisting of -O- and -N(Ra)-;

[0429] L is straight or branched Ci_6alkylene;

[0430] R2 nis selected from the group consisting of hydrogen, cyano, -NRaRb, Ci_2alkoxy, CV6cycloalkyl-S02-N(Ra)-, Ci_6alkyl-S02-N(Ra)-, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and C3_6cycloalkyl; wherein phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and C3_6cycloalkyl may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, Ci_2alkyl (optionally substituted by one, two or three halogens) and Ci_2alkoxy (optionally substituted by one, two or three halogens); and wherein if 5-6 membered heteroaryl or 4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Ci_3alkyl;

[0431] R5is selected from the group consisting of hydrogen, deuterium and halogen;

[0432] R6is selected from the group consisting of hydrogen and deuterium;

[0433] h

[0434] R is selected from the group consisting of hydrogen and deuterium; and

[0435] R a and R b are each independently selected for each occurrence from the group consisting of hydrogen and Ci-3alkyl.

[0436] In some embodiments, X is selected from the group consisting of -0-, -N(H)-, and -N(Cl¾)-

[0437] In other embodiments, L is selected from the group consisting of

[0438] wherein * and # represent the covalent points of attachment to R 2-II and X, respectively. In further embodiments, R 2 -II is selected from the group consisting of: hydrogen, cyano,

[0439]

[0440] In some embodiments, Rsis selected from the group consisting of hydrogen, deuterium, and fluorine.

[0441] Also disclosed herein is a compound represented by Formula (III):

[0442]

[0443] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, / V-oxide or stereoisomer thereof, wherein:

[0444] Xmis selected from the group consisting of a bond, -CH2-, -NRa-, -0-, -0-CH2- and -

[0445] OCH2-CH2- m is 1, 2, or 3;

[0446] n is 1, 2, or 3;

[0447] R1_niis selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, - NRaRb, Ci-2alkyl (optionally substituted by one, two or three halogens) and Ci-2alkoxy

[0448] (optionally substituted by one, two or three halogens);

[0449] R2 niis selected from the group consisting of hydrogen, Ci_4alkyl, -C(0)-Ci_4alkyl, - C(0)-0-Ci-4alkyl, -C(0)-N(Ra)-Ci-4alkyl, -S(0)2-Ci-4alkyl and -S(0)2-C3-6cycloalkyl; wherein Ci_4alkyl, -C(0)-Ci alkyl, -C(0)-0-Ci_4alkyl, -C(0)-N(Ra)-Ci_4alkyl, -S(0)2-Ci_4alkyl and - S(0)2-C3-6cycloalkyl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, -NRaRb, Ci_2alkyl (optionally substituted by one, two or three halogens) and Ci-2alkoxy (optionally substituted by one, two or three halogens); R5is selected from the group consisting of hydrogen, deuterium and halogen;

[0450] R6is selected from the group consisting of hydrogen and deuterium;

[0451] R7is selected from the group consisting of hydrogen and deuterium; and

[0452] Raand Rbare each independently selected for each occurrence from the group consisting of hydrogen and Ci_3alkyl.

[0453] In some embodiments, Xmis selected from the group consisting of a bond, -Cl¾, -0-, -NH- and -O-CH2-.

[0454] In other embodiments, R2 111is selected from the group consisting of hydrogen, isopropyl, - CH2CF3, -S(0)2-CH3and -S(0)2-cyclopropyl.

[0455] In further embodiments, R5is selected from the group consisting of hydrogen, deuterium, and fluorine.

[0456] Further disclosed herein is a compound selected from the group consisting of:

[0457] 5-{ l-fluoro-3-hydroxy-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;

[0458] 5 - { 7-[ 1 -(cyclopropanesulfonyl)pyrrolidin-3-yl]- l-fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0459] 5- [1 -fluoro-3-hydroxy-7-(pyrrolidin-3-yl)naphthalen-2-yl] - l76,2,5-thiadiazolidine- 1 , 1 ,3-trione; 8-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl)naphthalcn-2-yl propan-2- ylcarbamate;

[0460] 5-(9-fluoio-7-hydroxynaphtho| 2, 1 - / ? ]fu ran- 8-yl )- 1 / \2, 5-th iadiazolidinc- 1 , 1 ,3-trione; 5-{7-[2- (azetidin- 1 -yl)ethoxy] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione; 5-[l-fluoro-3-hydroxy-7-methoxy(4-2F[)naphthalen-2-yl](4,4-2F[2)-l76,2,5-thiadiazolidine-l,l,3- trione;

[0461] 5-| 1 -fluoio-3-hydi oxy-7-(methylamino)naphthalen-2-yl ]- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0462] 5-{ l-fluoro-3-hydroxy-7-[2-(piperidin-4-yl)ethoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;

[0463] 5-(l-fluoro-7-{ [3-fluoro-l-(propan-2-yl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0464] 5 - { 1 -fluoro-7 - [(3 -fluoropyrrolidin- 3 -yl)methoxy ] -3 -hydroxynaphthalen-2-yl } - 1 l6,2, 5- thiadiazolidine- 1 , 1 ,3-trione ;

[0465] 5- { 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl] oxy } pentanenitrile ; 5- { 1 -fluoro-3-hydroxy-7 - [2-(piperidin- 1 -yl)ethoxy] naphthalen-2-yl } - 1 / \2,5-thiadiazolidinc- l,l,3-trione;

[0466] 5- { 7-[ 1 -(cyclopropanesulf onyl)-2, 5-dihydro- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2- yl } - 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione ;

[0467] 5-{ l-fluoro-3-hydroxy-7-[(piperidin-4-yl)methoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;

[0468] 5- { 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2-yl ]oxy }-3,3- dimethylpentanenitrile ;

[0469] 5 - { 7 - 1 (3,3-dimcthylbutyl )amino| - 1 -fluoro-3-hydroxynaphthalcn-2-yl }- 1 / ’,2, 5-th iadi azolid inc- l,l,3-trione;

[0470] 5-( 1 ,4-difluoio-3-hydroxy-7-mcthoxynaphthalcn-2-yl )- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc;

[0471] 5- { l-fluoro-3-hydroxy-7-[(2H3)methyloxy]naphthalen-2-yl } - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione; 5- [1 -fluoro-3-hydroxy-7-(2-methoxyethoxy)naphthalen-2-yl] - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0472] 4- ( 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalcn-2-yl ]oxy }-2,2- dimethylbutanenitrile ;

[0473] 5- { 7-[2-(3-aminobicyclo[ 1.1.1 ] pen tan- 1 -yl)ethoxy]- 1 -fluoro-3-hydroxynaphthalen-2-yl} -

[0474] I / / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc;

[0475] 5-(7- { [2-(dimethylamino)ethyl] amino } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0476] 5-( 1 -†luoio-3-hydroxy-7-mcthoxynaphthalcn-2-yl)(4,4-2H2 )- 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trionc; 5-( 1 -†luoro-3-hydroxy-7-mcthoxynaphthalcn-2-yl)- 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trionc;

[0477] / V-(2- ( 18-†luoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalen-2- yl] amino } ethyl)cyclopropanesulfonamide ;

[0478] 5-(l -fluoro- 3 -hydroxy-7- { [ 1 -(methanesulfonyl)pyrrolidin-3-yl] amino }naphthalen-2-yl)- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0479] / V-(2- ( 18-†luoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalen-2- yl]oxy}ethyl)cyclopropanesulfonamide5-(l-fluoro-3-hydroxy-7-{ [l-(methanesulfonyl)azetidin-

[0480] 3-yl ]amino }naphthalcn-2-yl )- 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trionc;

[0481] 4- ( 18-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalen-2- yl] oxy } butanenitrile ;

[0482] I I -( { 18-†luoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalen-2- yl] oxy } methyl)cyclopropyl] acetonitrile ; 5- { 7-[2-(dimethylamino)ethoxy] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - l76,2,5-thiadiazolidine- l,l,3-trione;

[0483] 5- { 7-[ 1 -(cyclopropylmethyl)- l / / -pyrazol-4-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0484] 5-{ l-fluoro-3-hydroxy-7-[(l / / -pyrazol-4-yl)methoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidme- l,l,3-trione;

[0485] 5- [1 -fluoro-3-hydroxy-7-(2-methylpropoxy)naphthalen-2-yl] - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0486] 5-| 1 -fluoiO-3-hydiOxy-7-(2-hydiOxypiOpoxy)naphthalen-2-yl ]- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0487] / V-(cyclopropylmethyl)-8-fluoro-6-hydroxy-7-(l,l,4-trioxo-l76,2,5-thiadiazolidin-2- yl)naphthalene-2-carboxamide ;

[0488] 5- [1 -fluoro-3 -hydroxy-7- (2- { [2-(trifluoromethoxy)ethyl] amino }ethoxy)naphthalen-2-yl]- 1l6, 2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0489] 5-(l-fluoro-3-hydroxy-7-{2-[(2-methoxyethyl)amino]ethoxy}naphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0490] 5 - { 1 -fluoro-3 -hydroxy-7 - [3 -(methylamino)propyl] naphthalen-2-yl } - 1 l6,2,5 -thiadiazolidine- l,l,3-trione;

[0491] 5- { 7-[3-(ethylamino)propyl]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1 / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0492] 5-{7-[5-(dimethylphosphoryl)thiophen-2-yl]-l-fluoro-3-hydroxynaphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0493] 5- { 7-[2-(cyclopropylamino)ethoxy] - l-fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0494] 5-{ l-fluoro-3-hydroxy-7-[2-(methylamino)ethoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;

[0495] 5- { 7-[2-(ethylamino)ethoxy]- 1 -fluoro-3-hydroxynaphthalcn-2-yl }- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0496] 5-(l-fluoro-3-hydroxy-7-{2-[(propan-2-yl)amino]ethoxy}naphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0497] 5-{7-[3-(diethylphosphoryl)propoxy]-l-fluoro-3-hydroxynaphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0498] 5- { 1 -fluoro-3 -hydroxy-7 - [(35)-3-hydroxybutoxy] naphthalen-2-yl } - 1 lή,2, 5- thiadiazolidine- 1 , 1 ,3- trione; 5-{ l,4-difluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;

[0499] 5-{ l-fluoro-3-hydroxy-7-[(37?)-3-hydroxybutoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l,l,3- trione;

[0500] 5-[7-(2-cyclopropyl-2-hydroxyethoxy)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0501] 5- { l-fluoro-3-hydroxy-7-[(47?)-4-hydroxypentyl]naphthalen-2-yl } - 1 / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0502] 5- { l-fluoro-3-hydroxy-7-[(47?)-4-hydroxypentyl]naphthalen-2-yl } - 1 / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0503] 5 - { 1 -fluoro-3 -hydroxy-7 - [(45)-4-hydroxypentyl] naphthalen-2-yl } - 1 l6,2,5 -thiadiazolidine- 1 , 1 ,3- trione ;

[0504] 5-| 1 -fluoro-3-hydroxy-7-(4-hydroxy-4-mcthylpcntyl )naphthalcn-2-yl ]- 1 / / \2,5-thiadiazolidinc- l,l,3-trione;

[0505] 5- { l-fluoro-3-hydroxy-7-[(3-oxopentyl)oxy]naphthalen-2-yl}- l76,2,5-thiadiazolidine-l , 1 ,3- trione;

[0506] 5- [1 -fluoro-3-hydroxy-7-(3-hydroxybutoxy)naphthalen-2-yl] - l76,2,5-thiadiazolidine- 1 , 1 ,3- trione;

[0507] N-\ 8-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalcn-2-yl ]-3- methylbutanamide ;

[0508] 5- [1 -fluoro-3-hydroxy-7-(4, 4, 4-trifluorobutoxy)naphthalen-2-yl] - l76,2,5-thiadiazolidine- 1 , 1 ,3- trione;

[0509] 1 -(2- { [8-fluoro-6-hydroxy-7-(l , 1 ,4-trioxo- 176,2,5-thiadiazolidin-2-yl)naphthalen-2- yl] oxy } ethyl)cyclopropane- 1 -carbonitrile ;

[0510] 5-(l-fluoro-3-hydroxy-7-{2-[l-(methoxymethyl)cyclopropyl]ethoxy}naphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0511] 5-(7- { [(cyclopropylmethyl)amino]methyl } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0512] 5- { 7-[(2,2-difluoropropyl)amino]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - l76,2,5-thiadiazolidine- l,l,3-trione;

[0513] 5- { 7-[3,3-dimethyl-4-(methylamino)butoxy] - 1 -fluoro-3-hydroxynaphthalen-2-yl }- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0514] 5-{ l-fluoro-3-hydroxy-7-[(2-phenylethyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l,l,3- trione; 5-[7-(3-amino-3-methylbutoxy)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5-thiadiazolidine- l,l,3-trione;

[0515] 5-{ l-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;

[0516] 5- [7-(difluoromethyl)- 1 -fluoro-3-hydroxynaphthalen-2-yl]- l76,2,5-thiadiazolidine- 1 , 1 ,3-trione;

[0517] 5- { 7-[ 1 -(dimethylphosphoryl)-2, 5-dihydro- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0518] 5-{ l-fluoro-3-hydroxy-7-[(3,3,3-trifluoropropyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;

[0519] 5 - [ 1 -fluoro-3 -hydroxy-7 - (3 -methoxy-3 -methylbutoxy)naphthalen-2-yl] - 1 l6,2, 5-thiadiazolidine- l,l,3-trione;

[0520] 5 - [7-(2-cyclopropylpropoxy) - 1 -fluoro-3 -hydroxynaphthalen-2-yl] - 1 l6,2,5 -thiadiazolidine- 1 , 1 ,3- trione ;

[0521] 5-[l-fluoro-3-hydroxy-7-({2-[(propan-2-yl)oxy]ethyl}amino)naphthalen-2-yl]-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0522] 5 - ( 1 -fluoro- 3 -hydroxy-7 - { [ 1 -(methanesulfonyl)pyrrolidin-3 -yl] methoxy } naphthalen-2-yl)- 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0523] 4- ( 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl] amino } butanenitrile ;

[0524] 5- [1 -fluoro-3-hydroxy-7-(2-hydroxyethyl)naphthalen-2-yl]- l76,2,5-thiadiazolidine- 1 , 1 ,3-trione; 5-[7-(4-amino-3,3-dimethylbutoxy)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5-thiadiazolidine- l,l,3-trione;

[0525] 5-(7- { [2-(azetidin- 1 -yl)ethyl] amino } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0526] 5-(7- { [1 -(cyclopropanesulfonyl)azetidin-3-yl]oxy } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0527] 5-{ l-fluoro-3-hydroxy-7-[(2-methoxyethyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;

[0528] 5-| 1 -fluoio-3-hydi oxy-7-(3,3,3-ti ifluoiopropoxy)naphthalcn-2-yl ]- 1 / / ’,2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0529] 1 -( { 18-fluoi o-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl] amino } methyl)cyclopropane- 1 -carbonitrile ;

[0530] 5-| 1 -fluoro-3-hydroxy-7-(3-hydroxy-3-mcthylbutoxy)naphthalcn-2-yl ]- 1 / ’,2,5-thiadiazol idinc- l,l,3-trione; 5-{ l-fluoro-3-hydroxy-7-[3-(l / / -pyrazol-l-yl)propoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidme- l,l,3-trione;

[0531] 5-(7-{ l-[(4-aminophenyl)methanesulfonyl]-2,5-dihydro-l / / -pyrrol-3-yl}-l -fluoro-3- hydroxynaphthalcn-2-yl )- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc;

[0532] 5-[l-fluoro-3-hydroxy-7-(hydroxymethyl)naphthalen-2-yl]-l76,2,5-thiadiazohdine-l,l,3-trione; 5- { 7-[ 1 -(cyclopropanesulfonyl)piperidin-3-yl]- l-fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0533] 5- { 7-[ 1 -(cyclopropanecarbonyl)pyrrolidin-2-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl} - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0534] 5-{ l-fluoro-3-hydroxy-7-[2-(l / / -pyrazol-l-yl)ethoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidme- l,l,3-trione;

[0535] 5 - { 7- [ 1 -(cyclopropanesulfonyl)pyrrolidin-2-yl] - 1 -fluoro-3 -hydroxynaphthalen-2-yl } - 1 l6,2, 5 - thiadiazolidine- 1 , 1 ,3-trione ;

[0536] 5 - { 7- [ 1 -(cyclopropanesulfonyl)pyrrolidin-2-yl] - 1 -fluoro-3 -hydroxynaphthalen-2-yl } - 1 l6,2, 5 - thiadiazolidine- 1 , 1 ,3-trione ;

[0537] 5-| 1 -fluoio-3-hydi oxy-7-(pipcridin-3-yl)naphthalcn-2-yl ]- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc; 5-{7-[2-(2,2-difluorocyclopropyl)ethoxy]-l-fluoro-3-hydroxynaphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0538] 5 - { 1 -fluoro-3 -hydroxy-7 - [2-( 1 -methylcyclopropyl)ethoxy] naphthalen-2-yl } - 1 l6,2, 5 - thiadiazolidine- 1 , 1 ,3-trione ;

[0539] 5-(7-{ l-[(3-aminophenyl)methanesulfonyl]-2,5-dihydro-l / / -pyrrol-3-yl}-l -fluoro-3- hydroxynaphthalcn-2-yl )- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc;

[0540] 5-(7-{ 1 -| (2-aminophcnyl )mcthancsulfonyl ]-2, 5-dihydro- 1 / / -pyrrol-3-yl }- 1 -fluoro-3- hydroxynaphthalcn-2-yl )- 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trionc;

[0541] 5- [7-(2, 2-diflu oroethyl)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - l76,2,5-thiadiazolidine- 1 , 1 ,3- trione;

[0542] 5- [1 -fluoro-3-hydroxy-7-(2,2,2-trifluoroethoxy)naphthalen-2-yl] - l76,2,5-thiadiazolidine- 1 , 1 ,3- trione;

[0543] 5- [1 -fluoro-7-(2-fhioroethoxy)-3-hydroxynaphthalen-2-yl] - 1 / / \2,5-thiadiazolidine- 1 , 1 ,3-trione;

[0544] 1 -( { 18-fluoi o-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalen-2- yljoxy } methyl)cyclopropane- 1 -carbonitrile ;

[0545] 5-{ l-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazohdine-l ,l,3- trione; 5 - { 1 -fluoro-3 -hydroxy-7 - [(2-methylpropyl) amino] naphthalen-2-yl } - 1 l6,2,5 -thiadiazolidine- l,l,3-trione;

[0546] 5- { 7-[(cyclopropylmethyl)amino] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - l76,2,5-thiadiazolidine- l,l,3-trione;

[0547] { 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl] oxy } acetonitrile ;

[0548] 5 - [ 1 -fluoro-3 -hydroxy-7 - (3 -methylbutoxy)naphthalen-2-yl] - 1 l6,2, 5 -thiadiazolidine- 1 , 1 ,3 -trione ; 5-(l,8-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-l76,2,5-thiadiazolidine-l,l,3-trione;

[0549] 5- { 7-[ 1 -(cyclopropanesulfonyl)azetidin-3-yl] - l-fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0550] 5- { 7-[ 1 -(cyclopropanecarbonyl)azetidin-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0551] (2£)-3-| 8-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2-yl ]prop-2- enenitrile;

[0552] 5- [7-(2-cyclopropylethyl)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1 / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0553] 5- { 7-[(2,2-difluorocyclopropyl)methoxy]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0554] 5- [7-(2-cyclopropylethoxy)- 1 -fluoro-3-hydroxynaphthalcn-2-yl ]- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0555] 5- { 7-[2-(cyclopropylmethoxy)ethoxy]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0556] 5-{ l-fluoro-3-hydroxy-7-[2-(oxolan-2-yl)ethoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l,l,3- trione;

[0557] 5- { 7-[2-(cyclobutyloxy)ethoxy]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - l76,2,5-thiadiazolidine- l,l,3-trione;

[0558] 5-(l-fluoro-3-hydroxy-7-{2-[(propan-2-yl)oxy]ethoxy}naphthalen-2-yl)-l76,2,5-thiadiazolidine- l,l,3-trione;

[0559] 5- [7-(3-ethoxypropoxy)- 1 -fluoro-3-hydroxynaphthalen-2-yl ]- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0560] 5- [7-(2-ter / -butoxyethoxy)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0561] 5-(7-{ [rac-(l7?,27?)-2-ethylcyclopropyl]methoxy}-l-fluoro-3-hydroxynaphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ; 5-[l-fluoro-3-hydroxy-7-(4-methylpentyl)naphthalen-2-yl]-l76,2,5-thiadiazolidine-l,l,3-trione; 5- { 7-[3-(2,2-dimethylpropyl)pyrrolidin- 1 -yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl} - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0562] 5- [7-(l -chloro-3-hydroxypropan-2-yl)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0563] 5- { 7-[ 1 -(cyclopropylmethyl)pyrrolidin-3-yl]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0564] 5-|7-(cyclopropyloxy)- 1 -fluoro-3-hydroxynaphthalcn-2-yl ]- 1 / \2,5-thiadiazol idinc- 1 , 1 ,3-trione; 5-{7-[(2-cyclopropylethyl)amino]-l-fluoro-3-hydroxynaphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;

[0565] 5 - [ 1 -fluoro-3 -hydroxy-7 - (4-methyl- 17 / -imidazol-2-yl)naphthalen-2-yl] - 1 l6,2,5 -thiadiazolidine- l,l,3-trione;

[0566] 5- [7-(azetidin-3-yl)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0567] 5 - [ 1 -fluoro-3 -hydroxy-7 - (5 -methoxythiophen-2-yl)naphthalen-2-yl] - 1 l6,2,5 -thiadiazolidine- l,l,3-trione;

[0568] 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalcn-2-yl ]acctonitrilc;

[0569] 5-| 1 -fluoio-3-hydroxy-7-(mcthoxymcthyl )naphthalcn-2-yl ]- 1 / \2,5-thiadiazol idinc- 1 , 1 ,3-trione; 5-{ l-fluoro-3-hydroxy-7-[(3-methyloxetan-3-yl)methoxy]naphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0570] 5- { 4-bromo-7-| 1 -(cyclopropancsulfonyl )-2, 5-dihydro- 1 / / -pyrrol-3-yl ]- 1 -fluoro-3- hydroxynaphthalen-2-yl}- l76,2,5-thiadiazolidine-l , 1 ,3-trione;

[0571] 5- { 4-bromo-7-[ l-(cyclopropanesulfonyl)- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0572] 5-{ l-fluoro-3-hydroxy-7-[(35)-pyrrolidin-3-yl]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l,l,3- trione;

[0573] 5- { l-fluoro-3-hydroxy-7-[(3T?)-pyrrolidin-3-yl]naphthalen-2-yl } - l76,2,5-thiadiazolidine- 1 , 1 ,3- trione;

[0574] 5-(8-chloro- 1 -fluoio-3-hydroxy-7-mcthoxynaphthalcn-2-yl)- 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trione; 5- { 7-[(3,3-difluorocyclobutyl)methoxy] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0575] 5-(7-cyclopropyl- 1 -fluoro-3-hydroxynaphthalcn-2-yl )- 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0576] 5- { 7-[ 1 -(cyclopropanecarbonyl)-2, 5-dihydro- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2- yl } - 176,2,5-thiadiazolidine- 1 , 1 ,3-trione ;

[0577] 5-(4-chloro- 1 -fluoio-3-hydroxy-7-mcthoxynaphthalcn-2-yl)- 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trione; 5- { 7-[(£T)-2-cyclopropylethenyl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - l76,2,5-thiadiazolidine- l,l,3-trione;

[0578] 5- { 1 -fluoro-3-hydroxy-7 - |( l £)-4-mcthylpcnt- 1 -en- 1 -yl] naphthalen-2-yl } - 1 l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0579] 5-{ l-fluoro-3-hydroxy-7-[l-(pentamethylphenyl)ethenyl]naphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0580] 5-{7-[l-(cyclopropylmethyl)-2,5-dihydro-l / / -pyrrol-3-yl]-l-fluoro-3-hydroxynaphthalen-2-yl}- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0581] 5-(4-bromo- 1 -fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)- l76,2,5-thiadiazolidine- 1 , 1 ,3-trione; 5- { 7-[ 1 -(2-cyclopropylethyl)-2,5-dihydro- l / / -pyrrol-3-yl]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0582] 5-{ l-fluoro-3-hydroxy-7-[(l£T)-3-methoxyprop-l-en-l-yl]naphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0583] 5-|7-(2-cthoxycthoxy)- 1 -fluoro-3-hydroxynaphthalcn-2-yl ]- 1 / \2,5-thiadiazol idinc- 1 , 1 ,3-trione; 5- [1 -fluoro-3-hydroxy-7-(3-methoxypropoxy)naphthalen-2-yl] - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0584] 5- [7-( 1 , 1 -dioxo- 1 / ’-thian-4-yl )- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 176,2,5-thiadiazolidine- l,l,3-trione;

[0585] 5-| 1 -fluoro-3-hydroxy-7-(oxan-3-yl )naphthalcn-2-yl ]- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0586] 5- [7-(cyclopropylmethoxy)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0587] 5-(l-fluoro-3-hydroxy-7-{ [l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]methyl}naphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0588] 5-(l-fluoro-3-hydroxy-7-{ [l-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl}naphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0589] 5 - ( 1 -fluoro- 3 -hydroxy-7 - { 2- [methyl(2-methylpropyl)amino] ethoxy } naphthalen-2-yl)- 1 l6,2,5 - thiadiazolidine- 1 , 1 ,3-trione ;

[0590] 5-{ l-fluoro-3-hydroxy-7-[(oxolan-2-yl)methoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l ,l,3- trione;

[0591] 5-| 1 -fluoio-3-hydroxy-7-(oxolan-3-yl)naphthalcn-2-yl ]- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0592] 5-(7- { [1 -(cyclopropanesulfonyl)azetidin-3-yl]methyl } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0593] 5-(7- { [ 1 -(cyclopropanesulfonyl)piperidin-4-yl] methyl } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione; 5- [1 -fluoro-3-hydroxy-7-(pyrrolidin-2-yl)naphthalen-2-yl] - l6,2,5-thiadiazolidine- 1 , 1 ,3-trione; 5-(7- { [1 -(cyclopropanesulfonyl)piperidin-3-yl]methyl } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0594] 5- [7-(difluoromethoxy)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione; 5-(7- { [1 -(cyclopropanesulfonyl)pyrrolidin-3-yl]methyl } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0595] 5 - { 1 -fluoro-3 -hydroxy-7 - [(pyrrolidin-3 -yl)methyl] naphthalen-2-yl } - 1 l6,2,5 -thiadiazolidine- l,l,3-trione;

[0596] 5-[7-(2,5-dihydrofuran-3-yl)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5-thiadiazolidine-l,l,3- trione;

[0597] 5-[7-(3,6-dihydro-2 / / -pyran-4-yl)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5-thiadiazolidine- l,l,3-trione;

[0598] 5-[7-(2,5-dihydro-l / / -pyrrol-3-yl)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5-thiadiazolidme- l,l,3-trione;

[0599] 5 - [ 1 -fluoro-3 -hydroxy-7 - (pyridin-3 -yl)naphthalen-2-yl] - 1 l6,2, 5 -thiadiazolidine- 1,1,3 -trione ;

[0600] 5- { 7-[(azetidin-3-yl)methyl]- 1 -fluoro-3-hydroxynaphthalcn-2-yl }- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0601] / V-(2-cyclopropylcthyl )-2- ( 18-fluoiO-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2- yl)naphthalen-2-yl] amino } acetamide ;

[0602] 4- ( 18-fluoio-6-hydioxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2-yl ]oxy }- / V- methylbutanamide ;

[0603] / V-cthyl- / V’-(2- ( 18-fluoiO-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl)naphthalcn-2- yl] oxy } ethyl)urea ;

[0604] 5- { l-fluoro-3-hydroxy-7-[(oxan-3-yl)methoxy]naphthalen-2-yl } - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0605] 5- { 7-[(l -chloro-3-hydroxypropan-2-yl)oxy]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0606] 5- { 1 -fluoro-3 -hydroxy-7 - [(oxan-4-yl)methoxy] naphthalen-2-yl } - 1 lή,2, 5- thiadiazolidine- 1 , 1 ,3- trione;

[0607] 5-{ l-fluoro-3-hydroxy-7-[(oxetan-3-yl)oxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l,l,3- trione;

[0608] 5-{ l-fluoro-3-hydroxy-7-[l-(2,2,2-trifluoroethyl)-l,2,3,6-tetrahydropyridin-4-yl]naphthalen-2- yl } - 1' / / \2, 5- thiadiazolidine- 1 , 1 ,3-trione ;

[0609] 5 - ( 1 -fluoro- 3 ,7 -dihydroxynaphthalen-2-yl)- 1 l6,2,5 -thiadiazolidine- 1,1,3 -trione ; 5 - [ 1 -fluoro-3 -hydroxy-7 - (2-hydroxyethoxy)naphthalen-2-yl] - 1 l6,2, 5 -thiadiazolidine- 1 ,1,3- trione;

[0610] 5 - ( 1 -fluoro- 3 -hydroxy-7 -propoxynaphthalen-2-yl) - 1 l6,2, 5 -thiadiazolidine- 1 , 1 ,3 - trione ;

[0611] 5- { l-fluoro-3-hydroxy-7-[(propan-2-yl)oxy]naphthalen-2-yl } - 1 / / \2,5-thiadiazolidinc- 1,1 ,3- trione;

[0612] { [8-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2-yl ] amino } acetic acid;

[0613] / V-(2-cyclopropylcthyl )-2- ( 18-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2- yl)naphthalen-2-yl] oxy } acetamide ;

[0614] / V, / V-dicthyl-2- ( 18-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl)naphthalcn-2- yl] oxy } acetamide ;

[0615] 5- { 1 -fluoro-3 -hydroxy-7 - [2-oxo-2-(pyrrolidin- 1 -yl)ethoxy] naphthalen-2-yl } - 1 l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0616] 5-(l-fluoro-3-hydroxy-7-{ [l-(methanesulfonyl)piperidin-4-yl]oxy}naphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0617] 5-{ l-fluoro-3-hydroxy-7-[l-(oxolane-3-sulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]naphthalen-2-yl}- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0618] 5-{ l-fluoro-3-hydroxy-7-[l-(2-methoxyethanesulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]naphthalen- 2-yl } - 1 l6,2, 5-thiadiazolidine- 1 , 1 ,3-trione ;

[0619] 5- { l-fluoro-3-hydroxy-7-[l-(3, 3, 3-trifluoropropane-l-sulfonyl)-2, 5-dihydro- l / / -pyrrol-3- yl]naphthalen-2-yl } - 1l6, 2, 5 -thiadiazolidine- 1 , 1 ,3-trione;

[0620] 5- { l-fluoro-3-hydroxy-7-[l-(3, 3, 3-trifluoropropane-l-sulfonyl)-2, 5-dihydro- l / / -pyrrol-3- yl]naphthalen-2-yl } - 1l6, 2, 5 -thiadiazolidine- 1 , 1 ,3-trione;

[0621] 5-(l-fluoro-3-hydroxy-7-{ l-[(oxan-2-yl)methanesulfonyl]-2,5-dihydro-l / / -pyrrol-3- yl }naphthalcn-2-yl )- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0622] 5- { 1 -fluoi o-3-hydroxy-7-| 1 -(4,4,4-tnfluorobutane- 1 -sulfonyl )-2,5-dihydro- 1 / / -pyrrol -3- yl]naphthalen-2-yl } - 1l6, 2, 5 -thiadiazolidine- 1 , 1 ,3-trione;

[0623] 5- { 7-[ 1 -(butane- 1 -sulfonyl)-2, 5-dihydro- l / / -pyrrol-3-yl] - l-fluoro-3-hydroxynaphthalen-2-yl } - 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione;

[0624] 5-(7-{ l-[(l,4-dioxan-2-yl)methanesulfonyl]-2,5-dihydro-l / / -pyrrol-3-yl}-l -fluoro-3- hydroxynaphthalcn-2-yl )- 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0625] 5- { 3-| 8-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalen-2-yl ]-2,5- dihydro- 1 / / -pyrrole- 1 -sulfonyl } pentanenitrile ; 5-{ l-fluoro-3-hydroxy-7-[l-(pentane-2-sulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]naphthalen-2-yl}- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0626] 5- { 7-[ 1 -(ethanesulfonyl)-2, 5-dihydro- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0627] 5-{ l-fluoro-3-hydroxy-7-[l-(propane-2-sulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]naphthalen-2-yl}- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0628] 5- { 7-[ 1 -(cyclopropanesulfonyl)- 1 ,2,3,6-tetrahydropyridin-4-yl] - 1 -fluoro-3-hydroxynaphthalen- 2-yl } - 1 l6,2, 5-thiadiazolidine- 1 , 1 ,3-trione ;

[0629] N-(2- { 18-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl]oxy}ethyl)oxetane-3-sulfonamide;

[0630] 5-| 1 -fluoio-3-hydi oxy-7-(pipcridin-4-yl)naphthalcn-2-yl ]- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0631] 5- { l-fluoro-3-hydroxy-7-[l -(2-methylpropane- 1 -sulfonyl )-2, 5-dihydro- 1 / / -pyrrol-3- yl]naphthalen-2-yl } - 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione;

[0632] 5-(7-ethoxy- 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione;

[0633] 5- [7-(2, 2-diflu oroethoxy)- 1 -fluoro-3-hydroxynaphthalen-2-yl]- 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3- trione;

[0634] 5- { 7-[ 1 -(cyclopropanesulfonyl)- l / / -pyrazol-4-yl]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0635] 5-(l-fluoro-3-hydroxy-7-{ [(3f?)-l-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)- 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione;

[0636] 5-(l-fluoro-3-hydroxy-7-{ [l-(methanesulfonyl)piperidin-4-yl]amino}naphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0637] 5-(7- { [1 -(cyclopropanesulfonyl)pyrrolidin-3-yl] amino } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione;

[0638] 5 - ( 1 -fluoro-7- { [3 -fluoro- 1 - (methanesulfonyl)pyrrolidin-3 -yl] methoxy } -3 -hydroxynaphthalen-2- yl)- 1 l6, 2, 5 -thiadiazolidine- 1 , 1 ,3-trione ;

[0639] 5-{ l-fluoro-3-hydroxy-7-[l-(propane-2-sulfonyl)pyrrolidin-3-yl]naphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0640] 5- [7-(2-aminoethoxy)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione; 5- { 7-[ 1 -(1 ,3-dimethyl- l / / -pyrazole-4-sulf onyl)-2, 5-dihydro- l / / -pyrrol-3-yl]- 1 -fluoro-3- hydroxynaphthalen-2-yl}- l76,2,5-thiadiazolidine-l , 1 ,3-trione;

[0641] / V-(2- ( 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalen-2- yl] oxy } ethyl)ethanesulfonamide ; 5-{ l-fluoro-7-[l-(furan-3-sulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]-3-hydroxynaphthalen-2-yl}- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0642] 5-{ l-fluoro-3-hydroxy-7-[l-(3-methylbutane-l-sulfonyl)-2,5-dihydro-l / / -pyrrol-3- yl]naphthalen-2-yl } - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0643] 5-{ l-fluoro-3-hydroxy-7-[l-(thiophene-3-sulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]naphthalen-2- yl } - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione ;

[0644] 5- { 7-[ 1 -(benzenesulfonyl)-2, 5-dihydro- l / / -pyrrol-3-yl]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;

[0645] 5- { 7-[ 1 -(cyclobutanesulfonyl)-2, 5-dihydro- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2- yl } - 1' / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trione ;

[0646] methyl (25)-2-amino-4-{ 18-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2- yl)naphthalen-2-yl] oxy } butanoate ;

[0647] 5- { 7-[(3, 5-dimethyl- l / / -pyrazol-4-yl)methoxy] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0648] 5-[7-(3, 5-dimethyl- l / / -pyrazol-4-yl)-l-fluoro-3-hydroxynaphthalen-2-yl]-176,2,5- thiadiazolidine- 1 , 1 ,3-trione ;

[0649] 5- [7-(2-cyclohexylethoxy)- 1 -fluoro-3-hydroxynaphthalcn-2-yl ]- 1 / / ’,2,5-thiadiazolidinc- 1 , 1 ,3- trione;

[0650] 2-|8-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl)naphthalen-2-yl ]- 1 H- imidazole-4-carbonitrile;

[0651] and a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

[0652] In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), is formulated as a pharmaceutically acceptable composition comprising a disclosed compound and a pharmaceutically acceptable carrier.

[0653] In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), is selected from a compound set forth in Table 1. Table 1: Exemplary compounds of the disclosure.

[0654] -69-

[0655]

[0656]

[0657] Methods of Making Exemplary Compounds

[0658] The compounds of the present disclosure may be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds can be prepared. The compounds of the present disclosure can be prepared by a variety of synthetic procedures. Representative synthetic procedures are shown in, but not limited to, Schemes 1-7. The variables R , R , R , R , R , R , and R are defined as detailed herein, i.e., in the Summary. Scheme 1: Representative scheme for synthesis of exemplary compounds of the disclosure.

[0659]

[0660] Ar=optionally substituted aryl

[0661]

[0662]

[0663] cro

[0664]

[0665] As shown in Scheme 1, compounds of formula (1-9), formula (1-10), formula (1-11), and formula (1-12) can be prepared from compounds of formula (1-1). Compounds of formula (1-1) can be alkylated with an optionally substituted benzyl bromide (e.g., benzyl bromide, 4- methoxybenzyl bromide, or 3,4-dimethoxybenzyl bromide) in the presence of a base such as cesium carbonate in a solvent such as / V, / V-dimcthylformamidc. The carboxylic acid group also reacts under these conditions producing a benzyl ester. The benzyl ester can be hydrolyzed with a base such as lithium hydroxide or sodium hydroxide in methanol or a mixture of methanol and water to give compounds of formula (1-2). Compounds of formula (1-2) can be reacted under Curtius reaction conditions (diphenyl phosphor azidate, teri-butanol, triethylamine in heated toluene) to give compounds of formula (1-3). The tert- butoxycarbonyl moiety can be removed from compounds of formula (1-3) by treatment with heated diethylenetriamine to give compounds of formula (1-4). Compounds of formula (1-4) can be reacted with 2-bromoacetates of formula (1-5) in the presence of a base such as potassium carbonate in warmed solvent such as but not limited to a mixture of / V. / V- d i m c t h y I fo r m a m i dc and water to give compounds of formula (1-6). Compounds of formula (1-6) can then be fluorinated with a reagent such as N- fluorobenzenesulfonimide (NFSI) in a solvent such as tetrahydrofuran or Selectfluor® in optionally warmed / V, / V-dimethylformamide to give compounds of formula (1-7). Compounds of formula (1-7) can be reacted with chlorosulfonyl isocyanate and tot-butanol in the presence of a tertiary amine base such as triethylamine in a solvent such as cooled dichloromethane.

[0666] Subsequent treatment under acid conditions such as trifluoroacetic acid in dichloromethane to remove the tert- butoxycarbonyl group delivers compounds of formula (1-8). Compounds of formula (1-8) can be reacted with an alkoxide base, e.g., sodium methoxide in optionally warmed methanol or a mixture methanol and water or potassium teri-butoxide in tetrahydrofuran and then quenched with an acid such as 1 M hydrochloric acid to give compounds of formula (1- 9) or formula (1-10). Compounds of formula (1-9) can be converted to compounds of formula (1-11) with water under cross-coupling reaction conditions such as water in the presence of a precatalyst, RockPhos Pd G3, a base, cesium carbonate, and a warmed solvent, NN- dimethylformamide. The optionally substituted benzyl ether of compounds of formula (1-10) can be removed using conditions known to one of skill in the art and dependent on the particular benzyl ether. For example, an unsubstituted benzyl ether can be removed by treatment with trichloroborane in the presence of l,2,3,4,5-pentamethylbenzene in dichloromethane at -60 to - 80 °C to give compounds of formula (1-12). Compounds of formula (1-12) are representative of compounds of formula (I).

[0667] Scheme 2: Representative scheme for synthesis of exemplary compounds of the disclosure.

[0668]

[0669] 2) deprotection

[0670]

[0671]

[0672] As shown in Scheme 2, compounds of formula (2-2), formula (2-4), formula (2-6), and formula (2-8) can be prepared from compounds of formula (1-9). Compounds of formula (1-9) can be reacted under C-cross-coupling reaction conditions. For example, Suzuki reaction conditions can be used to couple compounds of formula (1-9) with compounds of formula (2-1), wherein A represents an alkene moiety, cyclopropyl or aromatic or partially unsaturated ring. Reaction conditions to couple compounds of formula (1-9) with compounds of formula (2-1) may include a catalyst, (tetrakis(triphenylphosphine)palladium(O), 1,1- bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, or [ 1,1'- bis(di-ter / -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 one of skill in the art and dependent on the particular benzyl ether. For example, an unsubstituted benzyl ether can be removed by treatment with trichloroborane in the presence of l,2,3,4,5-pentamethylbenzene in

[0673] dichloromethane at -60 to -80 °C to give compounds of formula (2-2). Additionally, an unsubstituted benzyl ether can be removed by treatment with hydrogen and a palladium catalyst in a solvent such as dioxane or tetrahydrofuran. Compounds of formula (2-2) or the protected precursor can be further modified as known to one of skill in the art and illustrated in the Examples.

[0674] Compounds of formula (1-9) can be reacted under N-cross-coupling reaction conditions. For example, Buchwald-Flartwig reaction conditions can be used to couple compounds of formula (1-9) with compounds of formula (2-3). For example, compounds of formula (1-9) and compounds of formula (2-3) can be coupled in the presence of a precatalyst (BrettPhos Pd G3 or RuPhos Pd G3) or catalyst (palladium(II) acetate), a ligand (BrettPhos, RuPhos, or Xantphos), and a base (sodium teri-butoxide or cesium carbonate), in a heated solvent such as dioxane or tert- amyl alcohol. Subsequently, the optionally substituted benzyl ether protecting group can be removed as previously described above to give compounds of formula (2-4), wherein NR R represents a cyclic or acyclic moiety of R2. Compounds of formula (2-4) or the protected precursor can be further modified as known to one of skill in the art and illustrated in the Examples.

[0675] Compounds of formula (1-9) can be reacted under O-cross-coupling reaction conditions. For example, cross-coupling reaction conditions can be used to couple compounds of formula (1-9) with compounds of formula (2-5). For example, compounds of formula (1-9) and compounds of formula (2-5) can be coupled in the presence of a precatalyst, RockPhos Pd G3, and a base, cesium carbonate, in a heated solvent such as / V, / V-di methyl form amide.

[0676] Subsequently, the optionally substituted benzyl ether protecting group can be removed as previously described above to give compounds of formula (2-6), wherein OR represents an ether moiety of R . Compounds of formula (2-6) or the protected precursor can be further modified as known to one of skill in the art and illustrated in the Examples.

[0677] Compounds of formula (1-9) can be reacted under C-cross-coupling reaction conditions. For example, compounds of formula (1-9) can be coupled with allyl compounds of formula (2-7), wherein R represents the remainder of R beyond the allyl moiety. Reaction conditions to couple compounds of formula (1-9) with compounds of formula (2-7) may include a catalyst, such as palladium(II) acetate, a phosphine ligand, such as 2-(di-m / -butylphosphino)bi phenyl , 2-dicyclohexylphosphino-2 (6 '-dimethoxybiphenyl, or 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene, and a base, such as a tertiary amine base, e.g., triethylamine, or cesium carbonate, in a heated solvent, such as / V. / V- d i m c th y I f o r m a m i dc or dioxane. Subsequently, the optionally substituted benzyl ether protecting group can be removed as previously described above to give compounds of formula to give compounds of formula (2-8). Compounds of formula (2-8) or the protected precursor can be further modified as known to one of skill in the art and illustrated in the Examples.

[0678] Compounds of formula (2-2), formula (2-4), formula (2-6), or formula (2-8) are representative of compounds of formula (I) or are precursors to compounds of formula (I). Scheme 3: Representative scheme for synthesis of exemplary compounds of the disclosure.

[0679]

[0680]

[0681]

[0682]

[0683]

[0684] As shown in Scheme 3, compounds of formula (3-1) and formula (3-2) can be prepared from compounds of formula (1-11). Compounds of formula (1-11) can be alkylated with compounds of formula R3 1-LG1, wherein LG1is a leaving group such as chloro, bromo, iodo or sulfonate and R is an optionally substituted alkyl, optionally substituted heterocyclyl or optionally substituted cycloalkyl. The alkylation conditions can include treatment with a base, such as but not limited to cesium carbonate or sodium hydride, in an optionally heated solvent, such as / V, / V-di methyl form amide. Subsequently, the optionally substituted benzyl ether protecting group can be removed using conditions known to one of skill in the art and dependent on the particular benzyl ether. For example, an unsubstituted benzyl ether can be removed by treatment with trichloroborane in the presence of 1,2,3,4,5-pentamethylbenzene in

[0685] dichloromethane at -60 to -80 °C to give compounds of formula (3-1). Compounds of formula (3-1) or the corresponding protected precursors can be further modified as known to one of skill in the art and illustrated in the Examples. The group OR 3-1 represents an ether moiety of R 2.

[0686] An alternative preparation of compounds of formula (3-1) involves reacting compounds of formula (1-11) with compounds of formula R 3-1 -OH, wherein R 3-1 is an optionally substituted alkyl or optionally substituted cycloalkyl, under Mitsunobu reaction conditions. Accordingly, compounds of formula (1-11) and compounds of formula R 3-1 -OH can be treated with (£)- diazene-l,2-diylbis(piperidin-l-ylmethanone) and tri -«-butyl phosphine in a solvent such as warmed tetrahydrofuran. Subsequent removal of the benzyl protecting group as described above gives compounds of formula (3-1). Compounds of formula (3-1) or the corresponding protected precursors can be further modified as known to one of skill in the art and illustrated in the Examples.

[0687] Compounds of formula (1-11) can also be transformed to compounds of formula (3-2).

[0688] Compounds of formula (1-11) can be reacted with compounds of formula of R 3-2 -NCO, wherein R is an optionally substituted Ci-6alkyl, in the presence of 4-dimethylaminopyridine in a solvent such as / V, / V- d i m c t h y I f r m a m i dc to give the corresponding carbamate. Subsequent removal of the benzyl protecting group as described above gives compounds of formula (3-2). The group -0C(0)NHR represents a carbamate moiety of R . Compounds of formula (3-2) or the corresponding protected precursors can be further modified as known to one of skill in the art and illustrated in the Examples. Compounds of formula (3-1) and formula (3-2) are representative of compounds of formula (I) or are precursors to compounds of formula (I).

[0689] Scheme 4: Representative scheme for synthesis of exemplary compounds of the disclosure.

[0690]

[0691]

[0692] C-cross-coupling

[0693] reaction conditions

[0694] 2) deprotection

[0695]

[0696] As shown in Scheme 4, compounds of formula (4-4) can be prepared from compounds of formula (1-9). Compounds of formula (1-9) can be reacted under cross-coupling reaction conditions with a boron reagent of formula (4-1), such as bis(pinacolato)diboron, wherein one RBis connected to another RB, to give compounds of formula (4-2). Reaction conditions to couple compounds of formula (1-9) with compounds of formula (4-1) may include a catalyst ([l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane) and base (potassium acetate or potassium carbonate) in heated dioxane. Compounds of formula (4-2) can be subsequently coupled with compounds of formula (4-3), wherein R represents an aromatic or partially unsaturated ring, an alkyl group, or an alkylene group, and LG is a leaving group such as iodine, bromine or chlorine. Reaction conditions to couple compounds of formula (4-4) with compounds of formula (4-3) may include a catalyst

[0697] (tetrakis(triphenylphosphine)palladium(O), XPhos Pd G2, or meCgpPh Pd G3) and a base (sodium carbonate, potassium phosphate or potassium carbonate) in a heated mixture of toluene and ethanol, or dioxane and water, or / V-mcthyl -2- pyrrol idi none. Subsequently, the optionally substituted benzyl ether protecting group can be removed using conditions known to one of skill in the art and dependent on the particular benzyl ether. For example, an unsubstituted benzyl ether can be removed by treatment with trichloroborane in the presence of 1, 2, 3,4,5- pentamethylbenzene in dichloromethane at -60 to -80 °C to give compounds of formula (4-4). Compounds of formula (4-4) or the corresponding protected precursors can be further modified as known to one of skill in the art and illustrated in the Examples.

[0698] Compounds of formula (4-4) are representative of compounds of formula (I) or are precursors to compounds of formula (I).

[0699] Scheme 5: Representative scheme for synthesis of exemplary compounds of the disclosure.

[0700]

[0701] 2) deprotection

[0702] As shown in Scheme 5, compounds of formula (5-3) can be prepared from compounds of formula (1-9). Compounds of formula (1-9) can be coupled with compounds of formula (5-1), wherein RPRis a potassium trifluoroborate or carboxylic acid moiety and wherein B represents an optionally substituted heterocyclyl or optionally substituted alkyl under photoredox conditions. The conditions to couple compounds of formula (1-9) and compounds of formula (5-1) are treatment with NK¾ dimethoxyethane adduct, a ligand (4,4'-di- tot-butyl -2, 2'- dipyridyl), a base (cesium carbonate), and bis[3,5-difluoro-2-[5-(trifluoromethyl)-2- pyridyl] phenyl] iridium(l+); 2-(2-pyridyl)pyridine; hexafluorophosphate in solvents such as dioxane with optional / V, / V-di methyl acetamide in a 450 nm LED photoreactor. Subsequently, the optionally substituted benzyl ether protecting group can be removed using conditions known to one of skill in the art and dependent on the particular benzyl ether. For example, an

[0703] unsubstituted benzyl ether can be removed by hydrogenation in the presence of a palladium on carbon catalyst in tetrahydrofuran to give compounds of formula (5-3).

[0704] Alternatively, the reaction conditions described above also couple compounds of formula

[0705] (5-1) with compounds of formula (5-2), wherein PG is (2-methoxyethoxy)methyl. Deprotection of one or both protecting groups can be achieved by treatment with hydrochloric acid in dioxane to give compounds of formula (5-3).

[0706] Compounds of formula (5-3) or the corresponding protected precursors can be further modified as known to one of skill in the art and illustrated in the Examples. Compounds of formula (5-3) are representative of compounds of formula (I) or are precursors to compounds of formula (I).

[0707] Scheme 6: Representative scheme for synthesis of exemplary compounds of the disclosure.

[0708]

[0709] 2) optional deprotection

[0710] As shown in Scheme 6, compounds of formula (6-3) can be prepared from compounds of formula (6-1). Compounds of formula (6-1), wherein PG1is a protecting group such as (2- methoxyethoxy)methyl and PG is an optionally substituted benzyl group or (2- methoxyethoxy)methyl can be coupled with compounds of formula (6-2), wherein R6 1is an optionally substituted alkyl group, optionally substituted cycloalkyl group or optionally substituted heterocyclyl group. The conditions to couple compounds of formula (6-1) with compounds of formula (6-2) are treatment with a catalyst (Pd SPhos G4) in heated NN- dimethylacetamide. When present, the optionally substituted benzyl ether protecting group can be removed using conditions known to one of skill in the art and dependent on the particular benzyl ether. For example, an unsubstituted benzyl ether (PG2) can be removed by

[0711] hydrogenation in the presence of a palladium on carbon catalyst or upon treatment with trichloroborane in dichloromethane to give compounds of formula (6-3). When either PG1or PG is a (2-methoxyethoxy)methyl group, either or both can be removed by treatment with an acid such as hydrochloric acid in dioxane to give compounds of formula (6-3). Compounds of formula (6-3) or the corresponding protected precursors can be further modified as known to one of skill in the art and illustrated in the Examples.

[0712] Compounds of formula (6-3) are representative of compounds of formula (I) or are precursors to compounds of formula (I). Scheme 7 : Representative scheme for synthesis of exemplary compounds of the disclosure.

[0713]

[0714] As shown in Scheme 7, compounds of formula (2-2) can be prepared from compounds of formula (1-9) in a reverse synthetic sequence to that described in Scheme 2. In the first step, the optionally substituted benzyl moiety can be removed using conditions known to one of skill in the art and dependent on the particular benzyl ether. For example, an unsubstituted benzyl ether can be removed by treatment with trichloroborane in the presence of 1, 2, 3,4,5- pentamethylbenzene in dichloromethane at -60 to -80 °C to give compounds of formula (7-1). Compounds of formula (7-1) can be reacted under C-cross-coupling reaction conditions. For example, Suzuki reaction conditions can be used to couple compounds of formula (7-1) with compounds of formula (2-1), wherein A represents an alkene moiety, a cyclopropyl, or an aromatic or a partially unsaturated ring. The corresponding boronic acids of compounds of formula (2-1) are also suitable for the cross-coupling reaction. Reaction conditions to couple compounds of formula (7-1) with compounds of formula (2-1) may include a catalyst (l,F- bis(di-teri-butylphosphino)ferrocene palladium dichloride), and a base (sodium carbonate or potassium carbonate) in heated dioxane or a mixture of dioxane and water. Compounds of formula (2-2) or the corresponding protected precursors can be further modified as known to one of skill in the art and illustrated in the Examples.

[0715] Compounds of formula (2-2) are representative of compounds of formula (I) or are precursors to compounds of formula (I). Pharmaceutical Compositions

[0716] The present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III). In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), is provided in an effective amount in the pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0717] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing a disclosed compound (the“active ingredient”) into association with a carrier and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into a desired single- or multi-dose unit. Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. As used herein, a“unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage such as, for example, one -half or one-third of such a dosage.

[0718] Relative amounts of a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition of the disclosure will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w / w) of a compound disclosed herein.

[0719] The term“pharmaceutically acceptable excipient” refers to a non-toxic carrier, adjuvant, diluent, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable excipients useful in the manufacture of the pharmaceutical compositions of the disclosure are any of those that are well known in the art of pharmaceutical formulation and include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Pharmaceutically acceptable excipients useful in the manufacture of the pharmaceutical compositions of the disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0720] Compositions of the present disclosure may be administered orally, parenterally

[0721] (including subcutaneous, intramuscular, intravenous and intradermal), by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some embodiments, provided compounds or compositions are administrable intravenously and / or orally.

[0722] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intraperitoneal intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in l,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0723] Pharmaceutically acceptable compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. In some embodiments, a provided oral formulation is formulated for immediate release or sustained / delayed release. In some embodiments, the composition is suitable for buccal or sublingual administration, including tablets, lozenges and pastilles. A compound disclosed herein may also be in micro-encapsulated form. The compositions of the present disclosure can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. The compositions of the present disclosure may additionally include components to provide sustained release and / or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates.

[0724] These components are discussed in greater detail in U.S. Patent Nos. 4,911,920; 5,403,841; 5,212, 162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present disclosure can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res.12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, the formulations of the compositions of the present disclosure can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, e.g., by employing receptor ligands attached to the liposome that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present disclosure into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, J. Hosp. Pharm. 46: 1576-1587, 1989). The compositions of the present disclosure can also be delivered as nanoparticles.

[0725] Alternatively, pharmaceutically acceptable compositions of the present disclosure may be administered in the form of suppositories for rectal administration. Pharmaceutically acceptable compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. In some embodiments, in order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0726] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of ah sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0727] Compounds provided herein, e.g., a compound of Formula (I), Formula (II) or Formula (III) are typically formulated in dosage unit form, e.g., single unit dosage form, for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0728] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0729] It will be also appreciated that a compound or composition disclosed herein can be administered in combination with one or more additional pharmaceutical agents. The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their bioavailability, reduce and / or modify their metabolism, inhibit their excretion, and / or modify their distribution within the body. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects.

[0730] The compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents.

[0731] Pharmaceutical agents also include prophylactically active agents. Each additional

[0732] pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional pharmaceutical agents and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0733] Exemplary additional pharmaceutical agents include, but are not limited to, anti proliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressant agents, and pain-relieving agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. Pharmaceutical compositions provided by the present disclosure include compositions wherein the active ingredient (e.g., compounds described herein, including embodiments or examples) is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. When administered in methods to treat a disease, such compositions will contain an amount of active ingredient effective to achieve the desired result, e.g., inhibiting the activity of a target molecule (e.g. PTPN2 and / or PTPN1), and / or reducing, eliminating, or slowing the progression of disease symptoms. Determination of a therapeutically effective amount of a compound disclosed herein is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein.

[0734] The dosage and frequency (single or multiple doses) administered to a mammal can vary depending upon a variety of factors, for example, whether the mammal suffers from another disease, and its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated, kind of concurrent treatment, complications from the disease being treated or other health-related problems. Other therapeutic regimens or agents can be used in conjunction with the methods, compounds and compositions disclosed herein. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the ability of those skilled in the art.

[0735] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.

[0736] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

[0737] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present disclosure should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

[0738] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.

[0739] Also encompassed by the present are kits (e.g., pharmaceutical packs). The kits provided herein may be useful for preventing and / or treating a disease (e.g., cancer, type-2 diabetes, obesity, a metabolic disease, or other disease or condition described herein).

[0740] The kits provided may comprise an inventive pharmaceutical composition or compound and a container (e.g., a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or compound. In some embodiments, the inventive pharmaceutical composition or compound provided in the container and the second container are combined to form one unit dosage form.

[0741] Thus, in one aspect, provided are kits including a first container comprising a compound disclosed herein. In certain embodiments, the kits are useful in preventing and / or treating a proliferative disease in a subject. In certain embodiments, the kits further include instructions for administering a disclosed compound to a subject to prevent and / or treat a disease described herein.

[0742] Methods of Treatment

[0743] The present disclosure features compounds, compositions, and methods comprising a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III). In some embodiments, the compounds, compositions, and methods disclosed herein are used in the prevention or treatment of a disease, disorder, or condition. Exemplary diseases, disorders, or conditions include, but are not limited to cancer, type-2 diabetes, metabolic syndrome, obesity, or a metabolic disease.

[0744] Cancer

[0745] In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III) is used to treat cancer. As used herein, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas (e.g., papillary adenocarcinomas), lymphomas, leukemias, melanomas, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, liver cancer, including hepatocarcinoma, lymphoma, including 13- acute lymphoblastic lymphoma, non-Flodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas), Flodgkin's lymphoma, leukemia (including AML, ALL, and CML), and / or multiple myeloma. In some further instances, "cancer" refers to lung cancer, breast cancer, ovarian cancer, epithelial ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, biliary tract cancer, adrenal gland cancer, salivary gland cancer, bronchus cancer, oral cancer, cancer of the oral cavity or pharynx, laryngeal cancer, renal cancer, gynecologic cancers, brain cancer, central nervous system cancer, peripheral nervous system cancer, cancer of the hematological tissues, small bowel or appendix cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, or carcinoma.

[0746] As used herein, the term "cancer" refers to all types of cancer, neoplasm or malignant tumors found in mammals, including leukemia, lymphoma, carcinomas and sarcomas.

[0747] Exemplary cancers that may be treated with a compound, pharmaceutical composition, or method provided herein include lymphoma, B-cell lymphoma, heavy chain disease, alpha chain disease, gamma chain disease, mu chain disease, Waldenstrom’s macroglobulinemia, benign monoclonal gammopathy, sarcoma, bladder cancer, bone cancer, brain 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, F1ER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, acoustic neuroma, retinoblastoma, astrocytoma, craniopharyngioma, hemangioblastoma, pinealoma, ependymoma, oligodendroglioma, meningioma, glioma, or melanoma. Additional examples include, cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus or Medulloblastoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, immunocytic amyloidosis, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget' s Disease of the Nipple, Phyllodes Tumors, Lobular Carcinoma, Ductal Carcinoma, cancer of the pancreatic stellate cells, cancer of the hepatic stellate cells, or prostate cancer.

[0748] The term "leukemia" refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, chronic leukemia, acute nonlymphocytic leukemia, acute lymphocytic leukemia, B-ceii chronic lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, erythroleukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblasts leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, polycythemia vera, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0749] The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound, pharmaceutical composition, or method provided herein include a chondrosarcoma,

[0750] fibrosarcoma, leiomyosarcoma, lymphosarcoma, lymphangiosarcoma,

[0751] lymphangioendotheliosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, endotheliosarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, osteogenic sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0752] The term "melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding- Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.

[0753] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bile duct carcinoma, bladder carcinoma, breast carcinoma, Brenner carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchiogenic carcinoma, cerebriform carcinoma, cervical carcinoma, cholangiocellular carcinoma, chordoma, chorionic carcinoma, clear cell carcinoma, colloid carcinoma, colon carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, cystadenocarcinoma, duct carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, endometrioid carcinoma, epiermoid carcinoma, epithelial carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lung carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, nonpapillary renal cell carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, ovarian carcinoma, pancreatic ductal carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, sebaceous gland carcinoma, seminoma, serous carcinoma, signet ring cell carcinoma, carcinoma simplex, small -cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, sweat gland carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, tuberous carcinoma, undifferentiated carcinoma, verrucous carcinoma, or carcinoma villosum.

[0754] In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), is used to treat pancreatic cancer, breast cancer, multiple myeloma, cancers of secretory cells. For example certain methods herein treat cancer by decreasing or reducing or preventing the occurrence, growth, metastasis, or progression of cancer. In some embodiments, the methods described herein may be used to treat cancer by decreasing or eliminating a symptom of cancer. In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), may be used as a single agent in a composition or in combination with another agent in a composition to treat a cancer described herein (e.g., pancreatic cancer, breast cancer, multiple myeloma, cancers of secretory cells). In some embodiments, the compounds (compounds described herein, e.g., a compound of Formula (I), Formula (II) or Formula (III)) and compositions (e.g., compositions comprising a compound described herein, e.g., a compound of Formula (I), Formula (II) or Formula (III)) are used with a cancer immunotherapy (e.g., a checkpoint blocking antibody) to treat a subject (e.g., a human subject), e.g., suffering from a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)). The methods described herein comprise administering a compound described herein, e.g., a compound of Formula (I), Formula (II) or Formula (III) and an immunotherapy to a subject having abnormal cell growth such as cancer. Exemplary immunotherapies include, but are not limited to the following.

[0755] In some embodiments, the immunotherapeutic agent is a compound (e.g., a ligand, an antibody) that inhibits the immune checkpoint blockade pathway. In some embodiments, the immunotherapeutic agent is a compound that inhibits the indoleamine 2,3-dioxygenase (IDO) pathway. In some embodiments, the immunotherapeutic agent is a compound that agonizes the STING pathway. Cancer immunotherapy refers to the use of the immune system to treat cancer. Three groups of immunotherapy used to treat cancer include cell-based, antibody-based, and cytokine therapies. All groups exploit cancer cells’ display of subtly different structures (e.g., molecular structure; antigens, proteins, molecules, carbohydrates) on their surface that can be detected by the immune system. Cancer immunotherapy (e.g., anti-tumor immunotherapy or anti-tumor immunotherapeutics) includes but is not limited to, immune checkpoint antibodies (e.g., PD-l antibodies, PD-L1 antibodies, PD-L2 antibodies, CTLA-4 antibodies, TIM3 antibodies, LAG3 antibodies, TIGIT antibodies); and cancer vaccines (e.g., anti-tumor vaccines or vaccines based on neoantigens such as a peptide or RNA vaccine).

[0756] Cell-based therapies (e.g., cancer vaccines), usually involve the removal of immune cells from a subject suffering from cancer, either from the blood or from a tumor. Immune cells specific for the tumor will be activated, grown, and returned to a subject suffering from cancer where the immune cells provide an immune response against the cancer. Cell types that can be used in this way are e.g., natural killer cells, lymphokine-activated killer cells, cytotoxic T-cells, dendritic cells, CAR-T therapies (e.g., chimeric antigen receptor T-cells which are T-cells engineered to target specific antigens), TIL therapy (e.g., administration of tumor-infilrating lymphocytes), TCR gene therapy, protein vaccines, and nucleic acid vaccines. An exemplary cell-based therapy is Provenge. In some embodiments, the cell-based therapy is a CAR-T therapy.

[0757] Interleukin-2 and interferon-alpha are examples of cytokines, proteins that regulate and coordinate the behavior of the immune system. Cancer Vaccines with Neoantigens

[0758] Neoantigens are antigens encoded by tumor-specific mutated genes. Technological innovations have made it possible to dissect the immune response to patient-specific neoantigens that arise as a consequence of tumor-specific mutations, and emerging data suggest that recognition of such neoantigens is a major factor in the activity of clinical immunotherapies. These observations indicate that neoantigen load may form a biomarker in cancer

[0759] immunotherapy. Many novel therapeutic approaches are being developed that selectively enhance T cell reactivity against this class of antigens. One approach to target neoantigens is via cancer vaccine. These vaccines can be developed using peptides or RNA, e.g., synthetic peptides or synthetic RNA.

[0760] Antibody therapies are antibody proteins produced by the immune system and that bind to a target antigen on the surface of a cell. Antibodies are typically encoded by an

[0761] immunoglobulin gene or genes, or fragments thereof. In normal physiology antibodies are used by the immune system to fight pathogens. Each antibody is specific to one or a few proteins, and those that bind to cancer antigens are used, e.g., for the treatment of cancer. Antibodies are capable of specifically binding an antigen or epitope (Fundamental Immunology, 3 Edition, Paul, W.E, ed., Raven Press, N.Y. (1993). Specific binding occurs to the corresponding antigen or epitope even in the presence of a heterogeneous population of proteins and other biologies. Specific binding of an antibody indicates that it binds to its target antigen or epitope with an affinity that is substantially greater than binding to irrelevant antigens. The relative difference in affinity is often at least 25% greater, more often at least 50% greater, most often at least 100% greater. The relative difference can be at least 2-fold, at least 5-fold, at least lO-fold, at least 25- fold, at least 50-fold, at least lOO-fold, or at least 1000-fold, for example.

[0762] Exemplary types of antibodies include without limitation human, humanized, chimeric, monoclonal, polyclonal, single chain, antibody binding fragments, and diabodies. Once bound to a cancer antigen, antibodies can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, prevent a receptor interacting with its ligand or deliver a payload of chemotherapy or radiation, all of which can lead to cell death. Exemplary antibodies for the treatment of cancer include but are not limited to, Alemtuzumab, Bevacizumab, Bretuximab vedotin, Cetuximab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Ipilimumab, Ofatumumab, Panitumumab, Rituximab, Tositumomab, Trastuzumab, Nivolumab,

[0763] Pembrolizumab, Avelumab, durvalumab and pidilizumab. Checkpoint Blocking Antibodies

[0764] The methods described herein comprise, in some embodiments, treating a human subject suffering from a disease or disorder described herein, the method comprising administering a composition comprising a cancer immunotherapy (e.g., an immunotherapeutic agent). In some embodiments, the immunotherapeutic agent is a compound (e.g., an inhibitor or antibody) that inhibits the immune checkpoint blockade pathway. Immune checkpoint proteins, under normal physiological conditions, maintain self-tolerance (e.g., prevent autoimmunity) and protect tissues from damage when the immune system is responding to e.g., pathogenic infection. Immune checkpoint proteins can be dysregulated by tumors as an important immune resistance mechanism (Pardoll, Nature Rev. Cancer, 2012, 12, 252-264). Agonists of co-stimulatory receptors or antagonists of inhibitory signals (e.g., immune checkpoint proteins), provide an amplification of antigen-specific T-cell responses. Antibodies that block immune checkpoints do not target tumor cells directly but typically target lymphocyte receptors or their ligands to enhance endogenous antitumor activity.

[0765] Exemplary checkpoint blocking antibodies include but are not limited to, anti-CTLA-4, anti-PD-l, anti-LAG3 (e.g., antibodies against lymphocyte activation gene 3), and anti-TIM3 (e.g., antibodies against T-cell membrane protein 3). Exemplary anti-CTLA-4 antibodies include but are not limited to, ipilimumab and tremelimumab. Exemplary anti-PD-l ligands include but are not limited to, PD-L1 (e.g., B7-H1 and CD274) and PD-L2 (e.g., B7-DC and CD273). Exemplary anti-PD-l antibodies include but are not limited to, nivolumab (e.g., MDX- 1106, BMS-936558, or ONO-4538)), CT-011, AMP-224, pembrolizumab (trade name

[0766] Keytruda), and MK-3475. Exemplary PD-L1 -specific antibodies include but are not limited to, BMS936559 (e.g., MDX-1105), MEDI4736 and MPDL-3280A. Exemplary checkpoint blocking antibodies also include but are not limited to, IMP321 and MGA271.

[0767] T-regulatory cells (e.g., CD4+, CD25+, or T-reg) are also involved in policing the distinction between self and non-self (e.g., foreign) antigens, and may represent an important mechanism in suppression of immune response in many cancers. T-reg cells can either emerge from the thymus (e.g.,“natural T-reg”) or can differentiate from mature T-cells under circumstances of peripheral tolerance induction (e.g.,“induced T-reg”). Strategies that minimize the action of T-reg cells would therefore be expected to facilitate the immune response to tumors. IDO pathway inhibitors

[0768] The IDO pathway regulates immune response by suppressing T cell function and enabling local tumor immune escape. IDO expression by antigen-presenting cells (APCs) can lead to tryptophan depletion, and resulting antigen- specific T cell energy and regulatory T cell recruitment. Some tumors even express IDO to shield themselves from the immune system. A compound that inhibits IDO or the IDO pathway activates the immune system to attack the cancer (e.g., tumor in a subject). Exemplary IDO pathway inhibitors include indoximod, epacadostat and EOS200271.

[0769] STING pathway agonists

[0770] Stimulator of interferon genes (STING) is an adaptor protein that plays an important role in the activation of type I interferons in response to cytosolic nucleic acid ligands. Evidence indicates involvement of the STING pathway in the induction of antitumor immune response. For example, activation of the STING-dependent pathway in cancer cells can result in tumor infiltration with immune cells and modulation of the anticancer immune response. STING agonists are being developed as a class of cancer therapeutics. Exemplary STING agonists include MK-1454 and ADU-S100.

[0771] Co-stimulatory antibodies

[0772] The methods described herein comprise, in some embodiments, treating a human subject suffering from a disease or disorder described herein, the method comprising administering a composition comprising a cancer immunotherapy (e.g., an immunotherapeutic agent). In some embodiments, the immunotherapeutic agent is a co-stimulatory inhibitor or antibody. In some embodiments, the methods described herein comprise depleting or activating anti-4-lBB, anti- 0X40, anti-GITR, anti-CD27 and anti-CD40, and variants thereof.

[0773] Methods of the present disclosure contemplate single as well as multiple administrations of a therapeutically effective amount of a compound as described herein. Compounds, e.g., a compound as described herein, can be administered at regular intervals, depending on the nature, severity and extent of the subject’s condition. In some embodiments, a compound described herein is administered in a single dose. In some embodiments, a compound described herein is administered in multiple doses. Metabolic Diseases

[0774] In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), is used to treat a metabolic disease. As used herein, the term "metabolic disease" refers to a disease or condition affecting a metabolic process in a subject. Exemplary metabolic diseases that may be treated with a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), include non-alcoholic steatohepatitis (NASF1), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., Type I diabetes, Type II diabetes, or gestational diabetes), metabolic syndrome, phenylketonuria, proliferative retinopathy, or Kearns- Sayre disease.

[0775] In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), is used to treat a metabolic disease (e.g., a metabolic disease described herein) by decreasing or eliminating a symptom of the disease. In some embodiments, the method of treatment comprises decreasing or eliminating a symptom comprising elevated blood pressure, elevated blood sugar level, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and the like. In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), may be used as a single agent in a composition or in combination with another agent in a composition to treat a metabolic disease.

[0776] Infectious Diseases

[0777] In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), is used to treat an infectious disease. Exemplary infectious diseases that may be treated with a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), include bacterial infections, viral infections (e.g., herpes, shingles, influenza, the common cold, encephalitis), and parasitic infections.

[0778] In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), is used to treat an infectious disease (e.g., an infectious disease described herein) by decreasing or eliminating a symptom of the disease. In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), may be used as a single agent in a composition or in combination with another agent in a composition to treat an infectious disease. Parasitic Infections

[0779] In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), is used to treat a parasitic infection.

[0780] In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), is used to treat a parasitic infection by decreasing or eliminating a symptom of the disease. In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), may be used as a single agent in a composition or in combination with another agent in a composition to treat a parasitic infection.

[0781] Immunosuppressive Diseases

[0782] In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), is used to treat an immunosuppressive disease.

[0783] In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), is used to treat an immunosuppressive disease by decreasing or eliminating a symptom of the disease. In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), may be used as a single agent in a composition or in combination with another agent in a composition to treat a immunosuppressive disease.

[0784] In some embodiments, the compounds disclosed herein are provided as pharmaceutical compositions including a disclosed compound, e.g., of Formula (I), Formula (II) or Formula (III) and a pharmaceutically acceptable excipient. In embodiments of the method, a disclosed compound, e.g., of Formula (I), Formula (II) or Formula (III) is co- administered with a second agent (e.g. therapeutic agent). In other embodiments of the method, a disclosed compound, e.g., of Formula (I), Formula (II) or Formula (III) is co-administered with a second agent (e.g.

[0785] therapeutic agent), which is administered in a therapeutically effective amount.

[0786] Combination Therapy

[0787] The present disclosure provides a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula (I), Formula (II) or Formula (III), as well as a second agent (e.g. a second therapeutic agent). In some embodiments, the pharmaceutical composition includes a second agent (e.g. a second therapeutic agent) in a therapeutically effective amount. In some embodiments, the second agent is an agent for treating cancer, a metabolic disease (e.g., type-2 diabetes or obesity) or a disease or disorder favorably responsive to PTPN2 or PTP1B inhibitor treatment.

[0788] The compounds described herein can be used in combination with one another, with other active agents known to be useful in treating cancer, a metabolic disease (e.g., type-2 diabetes or obesity) or a disease or disorder favorably responsive to PTPN2 or PTP1B inhibitor treatment, or with adjunctive agents that may not be effective alone but may contribute to the efficacy of the active agent.

[0789] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co- administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and / or adjunctive agents may be linked or conjugated to one another. In some embodiments, the compounds described herein may be combined with treatments for a cancer, a metabolic disease (e.g., type-2 diabetes or obesity) or a disease or disorder favorably responsive to PTPN2 or PTP1B inhibitor treatment. In embodiments, the second agent is an anti-cancer agent. In embodiments, the second agent is a chemotherapeutic. In embodiments, the second agent is an agent for treating a metabolic disease. In embodiments, the second agent is an anti-diabetic agent. In some embodiments, the second agent is an anti-obesity agent.

[0790] Anti-cancer agents

[0791] "Anti-cancer agent" is used in accordance with its plain ordinary meaning and refers to a composition (e.g. compound, drug, antagonist, inhibitor, modulator) having antineoplastic properties or the ability to inhibit the growth or proliferation of cells. In some embodiments, an anti-cancer agent is a chemotherapeutic. In some embodiments, an anti-cancer agent is an agent identified herein having utility in methods of treating cancer. In some embodiments, an anticancer agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating cancer. Examples of anti-cancer agents include, but are not limited to, MEK (e.g. MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g. XL518, Cl- 1040, PD035901, selumetinib / AZD6244, GSK1120212 / trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin), triazenes (decarbazine), anti-metabolites (e.g., 5- azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine,

[0792] Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP 16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g. cisplatin, oxaloplatin, carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide),

[0793] epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g. U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43- 9006, wortmannin, or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituxan), gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec.RTM.), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,

[0794] LY294002, bortezomib, trastuzumab, BAY 1 1-7082, PKC412, PD184352, 20-epi-l, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;

[0795] adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;

[0796] angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;

[0797] apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-ale thine; betaclamycin B; betulinic acid; bFGF inhibitor;

[0798] bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis- porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B;

[0799] combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol;

[0800] cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine;

[0801] dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol;

[0802] duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists;

[0803] etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin

[0804] hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors;

[0805] hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons;

[0806] interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin;

[0807] loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol;

[0808] mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin;

[0809] monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone;

[0810] oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer;

[0811] ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol;

[0812] phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum- triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins;

[0813] pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists;

[0814] raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid;

[0815] spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;

[0816] tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide;

[0817] tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin;

[0818] ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium;

[0819] bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin;

[0820] carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;

[0821] cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;

[0822] enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;

[0823] estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II (including recombinant interleukin II, or rlL.sub.2), interferon alfa-2a; interferon alfa-2b;

[0824] interferon alfa-nl; interferon alfa-n3; interferon beta-la; interferon gamma-lb; iprop latin;

[0825] irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole

[0826] hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol;

[0827] maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate;

[0828] melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;

[0829] meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin;

[0830] mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate;

[0831] perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;

[0832] puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride;

[0833] spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone;

[0834] thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;

[0835] zinostatin; zorubicin hydrochloride, agents that arrest cells in the G2-M phases and / or modulate the formation or stability of microtubules, (e.g. Taxol, i.e. paclitaxel), Taxotere, compounds comprising the taxane skeleton, Erbulozole (i.e. R-55104), Dolastatin 10 (i.e. DLS-10 and NSC- 376128), Mivobulin isethionate (i.e. as CI-980), Vincristine, NSC-639829, Discodermolide (i.e. as NVP-XX-A-296), ABT-751 (Abbott, i.e. E-7010), Altorhyrtins (e.g. Altorhyrtin A and Altorhyrtin C), Spongistatins (e.g. Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (i.e. LU-103793 and SC-D-669356), Epothilones (e.g. Epothilone A, Epothilone B, Epothilone C (i.e. desoxyepothilone A or dEpoA), Epothilone D (i.e. KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21 -aminoepothilone B (i.e. BMS-310705), 21-hydroxyepothilone D (i.e. Desoxyepothilone F and dEpoF), 26-fluoroepothilone, Auristatin PE (i.e. NSC-654663), Soblidotin (i.e. TZT-1027), LS-4559-P (Pharmacia, i.e. LS-4577), LS-4578 (Pharmacia, i.e. LS- 477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-1 12378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e. WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, i.e. ILX-651 and LU- 223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM- 97 (Armad / Kyowa Hakko), AM- 132 (Armad), AM- 138 (Armad / Kyowa Hakko), IDN-5005 (Indena),

[0836] Cryptophycin 52 (i.e. LY-355703), AC-7739 (Ajinomoto, i.e. AVE-8063A and CS-39.HC1), AC-7700 (Ajinomoto, i.e. AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (i.e. NSC-106969), T-138067 (Tularik, i.e. T-67, TL-138067 and TI- 138067), COBRA-1 (Parker Hughes Institute, i.e. DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A 1 (i.e. BTO-956 and DIME), DDE- 313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, i.e. SPIKET-P), 3-IAABU

[0837] (Cytoskeleton / Mt. Sinai School of Medicine, i.e. MF-569), Narcosine (also known as NSC- 5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, i.e. MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (i.e. NSC-698666), 3- IAABE (Cytoskeleton / Mt. Sinai School of Medicine), A- 204197 (Abbott), T-607 (Tularik, i.e. T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, lsoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (A vends), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (i.e. NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, i.e. D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e. SPA- 110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC- 12983 (NCI), 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., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette- Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., anti- CD20 monoclonal antibody conjugated tou' in,90Y, or131I, etc. ), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxy adenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5- nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapy or therapeutic (e.g. gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP- 724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OSI-420 / desmethyl erlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, or the like.

[0838] "Chemotherapeutic" or "chemotherapeutic agent" is used in accordance with its plain ordinary meaning and refers to a chemical composition or compound having antineoplastic properties or the ability to inhibit the growth or proliferation of cells.

[0839] Additionally, the compounds described herein can be co-administered with conventional immunotherapeutic agents including, but not limited to, immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha- interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti- CD22 monoclonal antibody -pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated tomIn,90Y, or131I, etc.).

[0840] In a further embodiment, the compounds described herein can be co-administered with conventional radiotherapeutic agents including, but not limited to, radionuclides such as47Sc,

[0841] 64^ Cu, 67^ Cu, 89 Scr, 86vY, 87vY, 90vY, 105pRh, , m A. g, mTIn, 117m Scn, 149pPm, 153 Scm, 166tHto, 177TLu, 186pRe, 188pRe,211At, and212Bi, optionally conjugated to antibodies directed against tumor antigens.

[0842] EXAMPLES

[0843] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

[0844] Synthetic Protocols

[0845] The compounds provided herein can be prepared from readily available starting materials using modifications to the specific synthesis protocols set forth below that would be well known to those of skill in the art. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures. General scheme relating to methods of making exemplary compounds of the invention are additionally described in the section entitled Methods of Making Exemplary Compounds.

[0846] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in Greene et al, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. Abbreviations

[0847] APCI for atmospheric pressure chemical ionization; DCI for desorption chemical ionization; DMSO for dimethyl sulfoxide; ESI for electrospray ionization; HPLC for high performance liquid chromatography; LC / MS for liquid chromatography / mass spectrometry;

[0848] LED for light-emitting diode; MS for mass spectrum; NMR for nuclear magnetic resonance; psi for pounds per square inch; and TLC for thin-layer chromatography.

[0849] Example 1: 5-{l-fluoro-3-hydroxy-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-l>’,2,5- thiadiazolidine-l,l,3-trione (Compound 100)

[0850] Example 1A: benzyl 3-(benzyloxy)-7-bromonaphthalene-2-carboxylate

[0851] A mixture of 7-bromo-3-hydroxy-2-naphthoic acid (100 g, 374 mmol) and cesium carbonate (366 g, 1123 mmol) in / V, / V- d i m c t h y I fo r m a m i dc (749 mL) was rapidly stirred for 5 minutes at 23 °C. Thereafter, benzyl bromide (89.0 mL, 749 mmol) was added, and the internal temperature rose to 49 °C. After 90 minutes, the light yellow mixture was poured into H O (1.5 L), and the resulting white precipitate was collected via filtration. The collected precipitate was washed sequentially with H O (3 x 1 L) and teri-butyl methyl ether / heptanes (1:2, 2 x 300 mL) and then dried in vacuo (15 mbar) at 45 °C to constant weight to afford the title compound (160.3 g, 358 mmol, 96% yield) as an off-white solid. MS (APCI+) m / z 449 [M+H]+.

[0852] Example IB: 3-(benzyloxy)-7-bromonaphthalene-2-carboxylic acid

[0853] To a mixture of the product of Example 1A (150.1 g, 336 mmol), water (746 mL), and methanol (1.49 L) was added lithium hydroxide monohydrate (28.2 g, 671 mmol). The thick slurry was agitated via overhead mechanical stirring and heated to an internal temperature of 70 °C. After 3 hours, the mixture was cooled to room temperature in an ice bath and 6 M HC1 (168 mL) was added over 5 minutes, causing an off-white solid to precipitate. The solid was collected via filtration and washed with H O (2 x 1 L), triturated with teri-butyl methyl ether (2 x 300 mL), and dried to constant weight in vacuo at 65 °C to afford the title compound (101.5 g, 284 mmol, 85% yield) as a white solid. MS (APCI+) m / z 358 [M+H]+.

[0854] Example 1C: 3-(benzyloxy)-7-bromonaphthalen-2-amine

[0855] To a suspension of the product of Example 1B (101 g, 283 mmol) in toluene (794 mL) and teri-butanol (794 mL) was added triethylamine (41.8 mL, 300 mmol). The hazy light yellow solution was heated to an internal temperature of 80 °C under nitrogen, and diphenyl phosphorazidate (64.4 mL, 300 mmol) was added dropwise over 90 minutes with the entire reaction behind a blast shield. After 5 hours, the reaction mixture was cooled to room temperature, diluted with H O (1.5 L), and extracted with ethyl acetate (2 x 400 mL). The combined organic layers were washed with brine (2 x 150 mL), dried over sodium sulfate, filtered and concentrated to give a white solid. The solid was carried forward to hydrolysis without further purification.

[0856] To the crude intermediate was added diethylenetriamine (253 mL, 2.34 mol). The heterogeneous suspension was heated to an internal temperature of 130 °C under nitrogen, at which time a homogeneous dark orange solution formed. After 13 hours, the mixture was cooled to room temperature in an ice bath, and 1¾0 (800 mL) was added slowly over 3 minutes, resulting in precipitation of a yellow solid and a concomitant exotherm to an internal temperature of 53 °C. Once the heterogeneous suspension had cooled to room temperature, the crude solid was dissolved in CH CI (1.5 L), and the layers were separated. The aqueous layer was back- extracted with CH CI (3 x 150 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over sodium sulfate, filtered, and the volatiles were removed in vacuo to afford an orange solid. The solid was combined with isopropanol (250 mL) to form a slurry that then was filtered. The resulting solid was again combined with isopropanol (2 x 100 mL), and solids were isolated via filtration. The solid was dried in vacuo (13 mbar) at 35 °C to afford the title compound (68.48 g, 209 mmol, 74% yield over two steps) as a white solid. MS (APCI+) m / z 329 [M+H]+.

[0857] Example ID: methyl { [3-(benzyloxy)-7-bromonaphthalen-2-yl]amino}acetate

[0858] To a mixture of the product of Example 1C (67.8 g, 207 mmol) and potassium carbonate (57.1 g, 413 mmol) in / V, / V- d i m c th y I f rm a m i dc (354 mL) and H O (1.861 mL, 103 mmol) was added methyl 2-bromoacetate (29.3 mL, 310 mmol). The suspension was vigorously stirred at room temperature for 5 minutes then heated to an internal temperature of 60 °C. After 4 hours, the suspension was cooled to room temperature and partitioned between H O (400 mL) and ethyl acetate (400 mL). The aqueous layer was extracted with ethyl acetate (2 x 100 mL), and the combined organic layers were washed with saturated aqueous ammonium chloride (3 x 60 mL), dried over sodium sulfate, filtered, and concentrated to afford a pale beige solid. The solid was triturated with heptanes (100 mL), and the resulting beige solid was isolated via filtration, washed with additional heptanes (2 x 30 mL) and dried to constant weight in vacuo (15 mbar) at 35 °C to afford the title compound (68.52 g, 171 mmol, 83% yield) as an off-white solid. MS (APCI+) m / z 401 [M+H]+.

[0859] Example IE: methyl {[3-(benzyloxy)-7-bromo-l -fluoronaphthalen-2-yl]amino}acetate

[0860] To a solution of the product of Example 1D (15 g, 37.5 mmol) in NN- dimethylformamide (300 mL) at 2 °C was added a solution of l-chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (15.93 g, 45.0 mmol) in NN- dimethylformamide (100 mL) over 5 minutes. The resulting solution was stirred for 15 minutes, and then quenched with a 0.33 M solution of sodium thiosulfate (300 mL, exothermic). The mixture was diluted with ethyl acetate (150 mL) and saturated aqueous ammonium chloride (75 mL) and stirred for 15 minutes at room temperature. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 75 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (4 x 75 mL) and brine (75 mL), then dried over sodium sulfate, filtered and concentrated in vacuo to give an orange solid. Ethyl acetate (30 mL) was added to the crude solid, and the mixture was sonicated for 30 seconds. Then heptanes (150 mL) were slowly added via an addition funnel over 15 minutes. The resulting yellow solid was collected via filtration and washed with 33% v / v ethyl acetate in heptanes (3 x 60 mL). The solid was discarded, and the filtrate was concentrated in vacuo to give a yellow / orange solid, which was triturated with anhydrous ethanol (45 mL) heated to an internal temperature of 55 °C and stirred for 30 minutes, then slowly cooled to room temperature. The resulting yellow solid was collected by filtration, then washed with anhydrous ethanol (30 mL), and dried in vacuo (15 mbar) at 50 °C to constant weight to give the title compound (10.1 g, 24.25 mmol, 64.7% yield) as a pale yellow solid.JH NMR (DMSO-de) d ppm 7.79 (d, J = 2.1 Hz, 1H), 7.65 (dd, J = 8.7,

[0861] 1.7 Hz, 1H), 7.56 - 7.51 (m, 2H), 7.46 - 7.35 (m, 3H), 7.38 - 7.31 (m, 2H), 7.28 (s, 1H), 5.64 (td, J = 6.7, 2.5 Hz, 1H), 5.28 (s, 2H), 4.21 (dd, J = 6.8, 4.0 Hz, 2H), 3.61 (s, 3H); MS (ESI+) m / z 418, 420 [M+H]+.

[0862] Example IF: methyl {[3-(benzyloxy)-7-bromo-l -fluoronaphthalen-2- yl]( sulfamoyl )amino }acetate

[0863] To a solution of chlorosulfonyl isocyanate (2.26 mL, 26.0 mmol) in dichloromethane (43.5 mL) at 0 °C was added tot-butanol (2.5 mL, 26.0 mmol) slowly so that the internal temperature remained below 10 °C. After stirring for 30 minutes at 0 °C, a preformed solution of the product of Example 1E (7.25 g, 17.34 mmol) and triethylamine (4.83 mL, 34.7 mmol) in dichloromethane (29.0 mL) was slowly added via addition funnel so that the internal temperature remained below 10 °C. Upon complete addition, the addition funnel was rinsed with dichloromethane (12.5 mL). The resulting solution was stirred for 30 minutes at 0 °C and then was allowed to warm to room temperature. After 1 hour, the reaction mixture was quenched with H20 (73 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 x 36 mL). The combined organic layers were washed with 1 M sodium bisulfate (2 x 73 mL). The aqueous washes were back extracted with dichloromethane (DCM) (36 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give an orange foam, which was used without purification. MS (APCI+) m / z 541, 543 [M-ter / -butyl+H]+.

[0864] To a solution of the crude intermediate in dichlorome thane (41 mL) was added trifluoroacetic acid (20 mL, 260 mmol), and the resulting dark solution was stirred at room temperature. After 30 minutes, the reaction was quenched by slow addition of saturated aqueous sodium bicarbonate (230 mL) via an addition funnel. The layers were separated, and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic layers were concentrated to give an orange foam, which was suspended in dichloromethane (20 mL), and stirred for 5 minutes giving a slurry, which was diluted by dropwise addition of heptanes (40 mL) via an addition funnel. The resulting yellow solid was collected by filtration, washed with 25% v / v dichloromethane in heptanes (2 x 20 mL) and dried in vacuo (15 mbar) at 50 °C to constant weight to give the title compound (7.5 g, 15.05 mmol, 87% yield).JH NMR (DMSO- de) d ppm 8.11 (d, J = 2.0 Hz, 1H), 7.84 - 7.80 (m, 1H), 7.67 (dd, J = 8.8, 2.0 Hz, 1H), 7.58 - 7.53 (m, 2H), 7.44 - 7.36 (m, 3H), 7.36 - 7.30 (m, 1H), 7.07 (s, 2H), 5.26 (s, 2H), 4.47 (d, J = 17.9 Hz, 1H), 4.31 (d, J = 17.8 Hz, 1H), 3.54 (s, 3H); MS (ESI+) m / z 497, 499 [M+H]+.

[0865]

[0866] trione

[0867] To a solution of the product of Example 1F (24.14 g, 48.5 mmol) in tetrahydrofuran (THF) (241 mL) at room temperature was added a solution of sodium methoxide (16.65 mL,

[0868] 72.8 mmol) (25 weight% in methanol) via syringe, and the resulting solution was stirred at room temperature. After 20 minutes, the reaction was quenched with 1 M hydrochloric acid (240 mL) and diluted with ethyl acetate (120 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 120 mL). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (120 mL), then dried over sodium sulfate, filtered and concentrated to 40 mL total volume to give a dark red solution, which was diluted with dichloromethane (75 mL) and concentrated to 40 mL of total volume. The resulting yellow suspension was diluted with dichloromethane (72 mL), then slowly diluted with heptanes (72 mL). The suspension was sonicated for 30 seconds and stirred for 5 minutes at room temperature. The resulting white solid was collected via filtration, then washed with 25% v / v dichloromethane in heptanes (72 mL) and dried in vacuo (15 mbar) at 50 °C to constant weight to give the title compound (16.4 g, 35.2 mmol, 72.5% yield).1H NMR (D SO-cL) d ppm 8.16 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 8.9, 1.4 Hz, 1H), 7.74 (dd, J = 8.8, 2.0 Hz, 1H), 7.54 - 7.48 (m, 3H), 7.47 - 7.29 (m, 3H), 5.28 (s, 2H), 4.54 (s, 2H); MS (EST) m / z 463, 465 [M-H]-. Example 1H: 5-[3-(benzyloxy)-l-fluoro-7-hydroxynaphthalen-2-yl]-l6,2,5-thiadiazolidine- JJ3-trione, ammonium salt

[0869] In a 500 mL round bottom flask were combined the product of Example 1G (9 g, 19.34 mmol), RockPhos Pd G3 precatalyst (0.324 g, 0.387 mmol), and cesium carbonate (18.9 g, 58.0 mmol). The solids were placed under vacuum and stirred for 5 minutes, then the flask was filled with nitrogen and a preformed mixture of / V, / V- d i m c t h y I f r m a m i dc (90 mL) and ¾0 (1.045 mL, 58.0 mmol) was added. The resulting suspension was degassed by five vacuum / nitrogen backfills, and then heated to an internal temperature of 80 °C. After 3 hours, the reaction mixture was cooled to room temperature, quenched by slow addition of 1 M hydrochloric acid (100 mL), and diluted with ethyl acetate (100 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (4 x 50 mL). The combined aqueous washes were back extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with a 4: 1 mixture of brine and 1 M hydrochloric acid (50 mL), then dried over sodium sulfate, filtered, and concentrated to give a viscous, dark oil. The crude oil was dissolved in acetonitrile (9 mL), then teri-butyl methyl ether (180 mL) was added via addition funnel over 5 minutes with vigorous stirring. The resulting black solid was removed via filtration and washed with 50% v / v it' / -butyl methyl ether in ethyl acetate (2 x 45 mL). The solid was discarded, and the filtrate was concentrated in vacuo. The resulting dark oil was diluted with methanol (9 mL), and then a solution of ammonia in methanol (2.76 mL, 7 M, 19.34 mmol) was added. The resulting solution was diluted by slow addition of 50% v / v ethyl acetate in heptanes (135 mL) via an addition funnel. The resulting solid was collected via filtration, then washed with the cold filtrate, followed by 50% v / v ethyl acetate in heptanes (45 mL), and dried in vacuo (15 mbar) at 50 °C to constant weight to give the title compound as an ammonium salt (6.33 g, 15.10 mmol, 78% yield).JH NMR (DMSO-<¾) d ppm 9.81 (s, 1H), 7.68 (dd, J = 8.9, 1.4 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.39 - 7.31 (m, 2H), 7.33 - 7.26 (m, 1H), 7.23 (s, 1H), 7.14 (d, J = 2.5 Hz, 1H), 7.10 (dd, J = 8.8, 2.5 Hz, 1H), 5.19 (s, 2H), 4.08 (s, 2H); MS (ESI-) m / z 401

[0870] Example II: 5-j3-( benzyloxy)- 1 -fiuoro-7-l 2-(morpholin-4-yl jethoxy j n

[0871] thiadiaz.olidine- 1 , 1 ,3-trione

[0872] A mixture of 2-morpholinoethanol (1.69 g, 12.9 mmol), triethylamine (2.70 mL, 19.35 mmol), and anhydrous dichloromethane (71.7 mL) was cooled to 0 °C. Thereafter,

[0873] methanesulfonyl chloride (1.206 mL, 15.48 mmol) was added dropwise over 5 minutes, and after 10 minutes, the reaction was warmed to room temperature and stirred for an additional 30 minutes. The majority of the dichloromethane was removed in vacuo, and the resulting residue was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (2 x 30 mL), dried over sodium sulfate, filtered, and the volatiles were removed in vacuo at 29 °C to afford 2-morpholinoethyl methanesulfonate (1.71 g, 8.17 mmol, 63.3% yield) as an amorphous yellow residue which was used immediately in the subsequent reaction.

[0874] To a solution of the product of Example 1H (120 mg, 0.286 mmol) in N,N- dimethylformamide (954 pL) was added cesium carbonate (186 mg, 0.572 mmol). The suspension was stirred at room temperature for 5 minutes, followed by addition of 2- morpholinoethyl methanesulfonate (114 mg, 0.544 mmol). The reaction was heated to 40 °C. After 80 minutes, the mixture was cooled to room temperature. The residual cesium carbonate was collected via filtration, and the cesium carbonate was washed with dimethyl sulfoxide (l x 500 pL) to afford a dark yellow filtrate containing the crude product, which was purified via HPLC (Phenomenex® Luna® 10 pM Cl 8(2) 100A, AXIA™ (00G-4253-U0-AX) column, 250 x 300 mm, flow rate 50 mL / minute, 5-95% gradient of acetonitrile in buffer (0.025 M aqueous ammonium acetate) to give the title compound (75.5 mg, 0.146 mmol, 51% yield). MS (APCI+) m / z 516 [

[0875] Example

[0876] thiadiaz.olidine- 1 , 1 ,3 -trione hydrochloride

[0877] A mixture of the product of Example II (68.2 mg, 0.132 mmol), and pentamethylbenzene (58.8 mg, 0.397 mmol) in dichloromethane (661 pL) was cooled to an internal temperature of -76 °C under an atmosphere of dry nitrogen. Subsequently, a 1 M solution of boron trichloride (1.59 mL, 1.59 mmol) in CH2CI2 was added dropwise over 15 minutes, so as not to raise the internal temperature past -72 °C. The reaction was warmed to 0 °C and stirred 20 minutes. Thereafter, the mixture was re-cooled to -76 °C and rapidly quenched with anhydrous methanol (2.67 mL, 66.1 mmol). The resulting colorless, homogeneous solution was warmed to room temperature over 20 minutes under nitrogen. The volatiles were removed in vacuo to afford an off-white solid that was purified via HPLC (Phenomenex® Luna® 10 pM Cl 8(2) 100 A, AXIA™ (00G-4253-U0-AX) column, 250 x 300 mm, flow rate 50 mL / minute, 5-95% gradient of acetonitrile in buffer (0.025 M aqueous ammonium acetate) to give the title compound as the ammonium salt. This was suspended in methanol / ethyl acetate (1:1, 2 mL) and treated with a freshly-prepared 1 M solution of anhydrous hydrochloric acid in ethyl acetate (66 pL, 0.066 mmol). After stirring 5 minutes at room temperature, the volatiles were removed in vacuo (15 mbar), and the resulting white solid was dried at 35 °C to afford the title compound (22.6 mg, 0.053 mmol, 40% yield).JH NMR (DMSO-de) d ppm 9.89 (br s, 1H), 9.57 (s, 1H), 7.73 (dd, J = 9.1, 1.1 Hz, 1H), 7.30 (d, J = 2.5 Hz, 1 H), 7.21 (dd, J = 9.1, 2.5 Hz, 1H), 7.06 (s, 1H), 4.47 (t, J = 4.8 Hz, 2H), 4.11 (s, 2 H), 3.84 (m, 4H), 3.59 (s, 2H), 3.34 (m, 2H); MS (APCI+) m / z 426 [M+H]+.

[0878] Example 2: 5-{7-[l-(cyclopropanesulfonyl)pyrrolidin-3-yl]-l-fluoro-3-hydroxynaphthalen- 2-yl }- 1 >’,2,5-thiadiazolidine- 1 , 1 ,3-trione (Compound 101)

[0879] Example 2A: tert-butyl 3-[6-(benzyloxy)-8-fluoro-7-(l J ,4-trioxo-l / 6,2,5-thiadiazolidin-2- yl )naphthalen-2-yl ]pyrrolidine-l -carboxylate

[0880] The product of Example 14A (340 mg, 0.614 mmol) and tetrahydrofuran (THF) (1 mL) were added to 5% Pt / C wet, (100 mg, 0.211 mmol) in a 20 mL Barnstead Hastelloy C reactor and stirred for 0.55 h under 50 psi hydrogen at 25 °C. The reaction mixture was filtered, the volatiles were removed under reduced pressure, and the crude residue was subjected to column chromatography (Si(¾, dry load with diatomaceous earth, 5% methanol in dichloromethane) to give the title compound (164 mg, 0.295 mmol, 48% yield) as a white solid.1H NMR (501 MHz, DMSO-de) d ppm 7.82 - 7.69 (m, 2H), 7.59 - 7.52 (m, 2H), 7.54 - 7.47 (m, 1H), 7.40 - 7.33 (m, 2H), 7.36 - 7.27 (m, 2H), 5.25 (s, 2H), 4.08 (s, 2H), 3.76 (dd, J = 10.4, 7.5 Hz, 1H), 3.59 - 3.45 (m, 2H), 3.33-3.23 (m, 2H), 3.17 (s, 1H), 2.26 (s, 1H), 2.04 (q, J = 9.9 Hz, 1H), 1.43 (d, J = 5.9 Hz, 9H); MS (APCT) m / z 554 | M-H ]\

[0881] Example 2B: 5-[ 3-(benzyloxy)-l-fluoro-7-(pyrrolidin-3-yl)naphthalen-2-yl]-l6,2,5- thiadiaz.olidine- / , 1 ,3-trione

[0882] A solution of the product of Example 2A (164 mg, 0.295 mmol) and trifluoroacetic acid (1 mL, 12.98 mmol) in dichloromethane (2 mL) was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure. Dichloromethane (5 mL) was added, and the volatiles were again removed under reduced pressure. The residue was purified by preparative HPLC [Phenomenex® Luna® Cl 8(2) 5 pm IOqA AXIA™ column (250 mm x 25 mm); 30- 100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes, at a flow rate of 25 mL / minute] to afford the title compound (77 mg, 0.169 mmol, 57% yield) as a white solid. (501 MHz, DMSO-<¾) d ppm 8.77 (s, 2H), 7.87 - 7.79 (m, 2H), 7.57 - 7.43 (m, 3H), 7.42 - 7.25 (m, 5H), 5.24 (s, 2H), 4.07 (s, 2H), 3.70 - 3.57 (m, 2H), 3.18 (dd, J = 10.9, 9.3 Hz, 1H), 2.41 (dtd, J = 13.0, 7.1, 3.5 Hz, 1H), 2.02 (dq, J = 12.6, 9.5 Hz, 1H); MS (APCI-) m / z 454 [M-H]-.

[0883] Example 2C: 5-{3-(benzyloxy)-7-[l-(cyclopropanesulfonyl)pyrrolidin-3-yl]-l-fluoronaphthalen- 2-yl}-l6,2, 5-thiadiazolidine-l ,i ,3-trione

[0884] To a solution of product of Example 2B (77 mg, 0.169 mmol) in dichloromethane (5 mL) was added cyclopropanesulfonyl chloride (0.041 mL, 0.338 mmol) at room temperature followed by / V-ethyl- / V-isopropylpropan-2-amine (0.089 mL, 0.507 mmol). The reaction stirred overnight at room temperature. Additional A-ethyl-A-isopropylpropan-2-amine (0.089 mL, 0.507 mmol) was added which resulted in a clear solution. After 3 hours stirring at room temperature, the volatiles were removed under reduced pressure, and the crude was subjected to column chromatography (Si(¾, dry load with diatomaceous earth, 8% CH3OH in CH2CI2) to afford the title compound (80 mg, 0.143 mmol, 85% yield). MS (APCI-) m / z 558 [M-H] .

[0885] Example 2D: 5-{7-[ l-(cyclopropanesulfonyl)pyrrolidin-3-yl]-l-fluoro-3-hydroxynaphthalen-2- ylj-ΐl6, 2,5-thiadiazolidine-J i, 3-trione

[0886] The product of Example 2C (80 mg, 0.143 mmol) and l,2,3,4,5-pentamethylbenzene (63.6 mg, 0.429 mmol) in a 50 mL round bottom flask was flushed with nitrogen for 5 minutes. Dichloromethane (5 mL) was then added, and the heterogeneous suspension was cooled to -78 °C and equilibrated for 5 minutes. Subsequently, a 1 M solution of trichloroborane (0.429 mL, 0.429 mmol) in dichloromethane was added dropwise over 5 minutes. After 20 minutes, the reaction was quenched at -78 °C with dichloromethane: ethanol = 9:1 (1 mL) and then slowly warmed to room temperature. The volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® Cl 8(2) 5 pm 100A AXIA™ column (250 mm x 25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes, at a flow rate of 25 mL / minute] to afford the title compound (36 mg, 0.077 mmol, 54% yield).JH NMR (501 MHz, DMSO-<¾) d ppm 9.74 (s, 1H), 7.70 (t, J =

[0887] 1.2 Hz, 1H), 7.66 (dd, J = 8.8, 1.5 Hz, 1H), 7.41 (dd, J = 8.7, 1.8 Hz, 1H), 6.99 (s, 1H), 4.05 (s, 2H), 3.74 (dd, J = 9.7, 7.6 Hz, 1H), 3.60- 3.46 (m, 2H), 3.42- 3.36 (m, 1H), 3.30 -3.26 (m, 1H), 3.27- 3.17 (m, 1H), 2.77 - 2.68 (m, 1H), 2.03 (dq, J = 12.0, 9.0 Hz, 1H), 0.98 - 0.85 (m, 4H); MS (APCI-) m / z 467 [M-H]-.

[0888] Example 3: 5-[l-fluoro-3-hydroxy-7-(pyrrolidin-3-yl)naphthalen-2-yl]-l>’,2,5- thiadiazolidine-1,1, 3-trione (Compound 102)

[0889] Example 3 A: tert-butyl 3-[8-fluoro-6-hydroxy-7-(lJ,4-trioxo-l6,2,5-thiadiazolidin-2- yl )naphthalen-2-yl ]pyrrolidine-l -carboxylate

[0890] The product of Example 14A (300 mg, 0.560 mmol) in tetrahydrofuran (THF) (5 mL) was added to 5% wet Pd / C (500 mg, 2.189 mmol) in a 20 mL Barnstead Hastelloy C reactor, and the mixture was stirred for 6 hours under 50 psi hydrogen at 25 °C. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was used in the next step without further purification. MS (APCI-) m / z 446 [M-H] . Example 3B: 5-[ l-fluoro-3-hydroxy-7-(pyrrolidin-3-yl)naphthalen-2-yl ]-l6,2,5-thiadiazolidine- JJ3-trione

[0891] To a solution of product of Example 3A (20 mg, 0.043 mmol) and in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL, 12.98 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure, and the residue was purified by preparative HPLC [Phenomenex® Luna® Cl 8(2) 5 pm 100A AXIA™ column (250 mm x 25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 mL / minute] to afford the title compound (7 mg, 0.019 mmol, 27% yield) as a white solid.JH NMR (501 MHz, DMSO-c4) d ppm 7.73 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.42 - 7.36 (m, 1H), 7.00 (s, 1H), 4.03 (s, 2H), 3.62 - 3.51 (m, 2H), 3.23 - 3.13 (m, 2H), 3.13 - 3.05 (m, 1H), 2.34 (ddd, J = 12.7, 6.7, 3.5 Hz, 1H), 1.95 (dq, J = 12.7, 9.4 Hz, 1H); MS (APCI-) m / z 363 [M-H]-.

[0892] Example 4: 8-fluoro-6-hydroxy-7-(l,l,4-trioxo-l>’,2,5-thiadiazolidin-2-yl)naphthalen-2-yl propan-2-ylcarbamate (Compound 103)

[0893] Example 4 A: 6-(benzyloxy)-8-fiuoro-7-( / , 1 ,4-trioxo- 1 / f 2,5-thiadiaz.olidin-2-yl )naphthalen-2-yl propan-2-ylcarbamate

[0894] To a solution of the product of Example 1H (80 mg, 0.199 mmol) in N,N- dimethylformamide (1 mL) was added 4-dimethylaminopyridine (4.86 mg, 0.040 mmol) and isopropyl isocyanate (22.00 mg, 0.258 mmol). The mixture was stirred at ambient temperature for 14 hours. The reaction mixture was then filtered, purified by preparative HPLC on a Phenomenex® Luna® 10 pm C18 column (30 mm x 250 mm) eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) 0.1% with trifluoroacetic acid at a flow rate of 50 mL / minute (0-1 minute 10% A, 1-20 minutes linear gradient 10-100%) to give the title compound (48 mg, 0.098 mmol, 49.5% yield).1H NMR (501 MHz, DMSO-cC) d ppm 7.93 (d, J = 8.9 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.68 (s, 1H), 7.56 - 7.50 (m, 2H), 7.44 - 7.30 (m, 5H), 5.27 (s, 2H), 4.42 (s, 2H), 3.73 - 3.66 (m, 1H), 1.16 (d, J = 6.6 Hz, 6H); MS (APCL) m / z 486 [M-H

[0895] Example 4B: 8-fi uo ro-6-hyd roxy-7 -(

[0896] propan-2-ylcarbamate

[0897] To a mixture of the product of Example 4A (42 mg, 0.086 mmol) and

[0898] pentamethylbenzene (63.9 mg, 0.431 mmol) in dichloromethane (2 mL) cooled to -78 °C was added a solution of boron trichloride (1 M, 0.517 mL, 0.517 mmol) in dichloromethane dropwise over 5 minutes. After 30 minutes, the reaction was quenched with 2 N HC1 (0.5 mL). The reaction mixture was extracted with ethyl acetate. The organic phase washed with brine, dried over anhydrous Na SCL and concentrated under reduced pressure. The residue was purified by preparative HPLC using a Phenomenex® Luna® 10 pm C18 column (30 mm x 250 mm) eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) 0.1% with trifluoroacetic acid at a flow rate of 50 mL / minute (0-1 minute 10% A, 1-20 minutes linear gradient 10-70%) to give the title compound (28 mg, 0.070 mmol, 82% yield).JH NMR (400 MHz, DMSO-i¾) d ppm 10.59 (s, 1H), 7.78 (dd, J = 11.2, 8.3 Hz, 2H), 7.55 (d, J = 2.3 Hz, 1H), 7.29 (dd, J = 8.9, 2.3 Hz, 1H), 7.14 (s, 1H), 4.48 (s, 2H), 3.73 - 3.65 (m, 1H), 1.15 (d, J = 6.6 Hz, 6H); MS (APCL) m / z 396 [M-H]+.

[0899] Example 5: 5-(9-fluoro-7-hydroxynaphtho[2,l-¾]furan-8-yl)-17ft,2,5-thiadiazolidine-l,l,3- trione (Compound 104)

[0900] Example 5A: 5-[ 3-(benzyloxy)-7-(2,2-dimethoxyethoxy)- 1 -fiuomnaphthalen-2-yl / - / / 2,5- thiadiaz.olidine- / , 1 ,3-trione

[0901] To a solution of the product of Example 1H (500 mg, 1.243 mmol) and cesium carbonate (891 mg, 2.73 mmol) in / V, / V-di methyl form amide (5 mL) was added 2-bromo-l,l- dimethoxyethane (420 mg, 2.485 mmol). The reaction stirred at 75 °C for 5 hours. After cooling down to room temperature, the volatiles were removed under reduced pressure, and the residue was subjected to column chromatography (Si(¾, dry load with diatomaceous earth, 15% CH3OH in CH2CI2) to afford the title compound (475 mg, 0.968 mmol, 78% yield) as a beige solid. NMR (501 MHz, DMSO-d6) d ppm 7.76 (dd, J = 9.1, 1.4 Hz, 1H), 7.56 (dt, J = 6.6, 1.4 Hz, 2H), 7.40 - 7.32 (m, 2H), 7.34 - 7.26 (m, 3H), 7.22 (dd, J = 9.0, 2.6 Hz, 1H), 5.22 (s, 2H), 4.75 (t, J = 5.1 Hz, 1H), 4.11 (d, J = 5.1 Hz, 2H), 4.09 (s, 2H), 3.38 (s, 6H); MS (APCI-) m / z 489 [M-H] .

[0902] Example 5B: 5-[ 7-( 2,2-dimethoxyethoxy )-l -fluoro-3-hydroxynaphthalen-2-yl] -1l6, 2,5- thiadiaz.olidine- 1 , 1 ,3-trione

[0903] The product of Example 5A (475 mg, 0.968 mmol) in tetrahydrofuran (THF) (10 mL) was added to wet 5% Pd / C (475 mg, 2.080 mmol) in a 20 mL Barnstead Hastelloy C reactor and stirred for 15 minutes under 50 psi of hydrogen at 25 °C. The mixture was filtered, and the crude material was subjected to column chromatography (Si(¾ dry load with diatomaceous earth, 15% CH3OH in CH2CI2) to afford the title compound (182 mg, 0.455 mmol, 47% yield).

[0904] NMR (500 MHz, DMSO-<¾) d ppm 9.50 (s, 1H), 7.68 (dd, J = 9.1, 1.4 Hz, 1H), 7.21 (d, J = 2.6 Hz, 1H), 7.16 (dd, J = 9.0, 2.6 Hz, 1H), 7.03 (s, 1H), 4.74 (t, J = 5.1 Hz, 1H), 4.09 (d, J = 4.9 Hz, 4H), 3.37 (s, 6H); MS (APCL) m / z 398 [M-H] . Example 5C: 5-( 9-fluoro-7 -hydroxy naphtha / 2, 1 -b jfuran-8-yl )- 1 / !' ,2J-thiadiaz.olidine- 1 , 1,3- trione

[0905] A solution of the product of Example 5B (30 mg, 0.075 mmol) and trifluoroacetic acid (1 mL, 12.98 mmol) in dichlorome thane (2 mL) was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC [Phenomenex® Luna® Cl 8(2) 5 pm IOqA AXIA™ column (250 mm x 25 mm); 30- 100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 mL / minute] to afford the title compound (12 mg, 0.036 mmol, 48% yield) as a beige solid.JH NMR (501 MHz, DMSO-<¾) d ppm 8.13 (d, J = 2.0 Hz, 1H), 7.96 (s, 3H), 7.77 (d, J = 8.9 Hz, 1H), 7.66 (dd, J = 9.0, 1.7 Hz, 1H), 7.33 (dd, J = 3.8, 2.0 Hz, 1H), 7.23 (d, J = 1.3 Hz, 1H), 4.13 (s, 2H); MS (APCI-) m / z 334 [M-H]-.

[0906] Example 6: 5-{7-[2-(azetidin-l-yl)ethoxy]-l-fluoro-3-hydroxynaphthalen-2-yl}-17ft,2,5- thiadiazolidine-l,l,3-trione (Compound 105)

[0907] Example 6 A: 5-j 7-[2-( az.etidin- / -yl )ethoxy / -3-( benzyloxyj- / -fliioronaphthalen-2-ylj- 1 / 2, 5- thiadiaz.olidine- 1 , 1 ,3-trione

[0908] A mixture of the product of Example 1H (121 mg, 0.3 mmol), l-(2-chloroethyl)azetidine, hydrochloric acid (94 mg, 0.600 mmol), cesium carbonate (391 mg, 1.20 mmol) and

[0909] triethylamine (100 mg, 0.990 mmol) in dimethylformamide (0.8 mL) was stirred at 70 °C for 1.5 hours. The solution was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with dichloromethane, then dichloromethane / methanol (7:1) to give the title compound (35 mg, 0.072 mmol, 24% yield) as a solid. NMR (400 MHz, DMSO-d6) d ppm 7.80 (d, J = 8 Hz, 1H), 7.56 (d, J = 8 Hz, 2H), 7.37 (t, J = 8 Hz, 2H), 7.31 (m, 3H), 7.23 (dd, J = 8, 2 Hz, 1H), 5.23 (s, 2H), 4.28 (t, J = 8 Hz, 2H), 4.09 (s, 2H), 4.01 (t, J = 8 Hz, 4H), 2.31 (m, 2H); MS (EST) m / z 484 [M-H]-.

[0910] Example 6B: 5-{7-[2-(azetidin-l-yl)ethoxy]-l-fluoro-3-hydroxynaphthalen-2-yl}-l6,2,5- thiadiaz.olidine- 1 , 1 ,3-trione

[0911] To the product of Example 6A (0.034 g, 0.07 mmol) and l,2,3,4,5-pentamethylbenzene (0.031 g, 0.210 mmol) in dichloromethane (2 mL) at -78 °C was added trichloroborane (0.700 mL, 0.700 mmol, 1.0 M in dichloromethane). The mixture was stirred at -78 °C for 40 minutes. Methanol (3 mL) was added at -78 °C. The mixture was stirred for 5 minutes at room temperature and then was concentrated under reduced pressure. The resulting solids were washed with heptane (5 mL x 4), then dissolved in methanol (0.5 mL) and N,N- dimethylformamide (3 mL). This material was purified by preparative HPLC [YMC TriArt™ C18 Hybrid 20 pm column, 25 x 150 mm, flow rate 80 mL / minute, 5-100% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (20 mg, 0.051 mmol, 72% yield).1H NMR (400 MHz, DMSO-de) d ppm 9.54 (s, 1H), 7.71 (d, J = 8 Hz, 1H), 7.25 (d, J = 2 Hz, 1H), 7.17 (dd, J = 8, 2 Hz, 1H), 7.05 (br s, 1H), 4.28 (t, J = 8 Hz, 2H), 4.09 (s, 2H), 4.08 (t, J = 8 Hz, 4H), 2.33 (m, 2H); MS (ESI ) m / z 394 [M-H]-.

[0912] Example 7: 5-[l-fluoro-3-hydroxy-7-methoxy(4-2H)naphthalen-2-yl](4,4-2H2)-lk6,2,5- thiadiazolidine-l,l,3-trione (Compound 106)

[0913] To a stirred suspension of the product of Example 25G (0.10 g, 0.306 mmol) in deuterated methanol (methanol-^, 99.5%-D) (3.06 mL) was added sodium hydride (0.061 g, 1.532 mmol, 60% in mineral oil). All of solids went into solution, and then the mixture was heated to 60 °C. After 72 hours, deuterium enrichment was complete as judged by1H NMR.

[0914] The volatiles were removed, and the solution was treated with DC1 in D20 (1.839 mL, 1.839 mmol, 1 N solution) and ethyl acetate (3 mL). The layers were shaken in a vial and separated, and the organic layer was concentrated under reduced pressure. The resulting organic residue was partitioned between a dimethyl sulfoxide methanol layer (2 mL 1 :1) and a heptane layer (1 mL) to remove any residual mineral oil before purification. Separation of the layers and purification of the dimethyl sulfoxide methanol layer by reverse phase HPLC [Phenomenex® Luna® Cl 8(2) 5 pm IOqA AXIA™ column (150 mm x 30 mm); 3-100% gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) over 17 minutes at a flow rate of 50 mL / minute] yielded a white solid which was dissolved in D20:CH¾CN (2 mL, 1 :1). The solution was frozen with dry-ice and lyophilized to yield the title compound as a fluffy white powder (19.9 mg,

[0915] 0.060 19.7% yield). ' H NMR (400 MHz, DMSO-<¾) d ppm 7.67 (d, J = 9.0 Hz, 1H), 7.18 (d, / = 2.3 Hz, 1H), 7.13 (dd, / = 8.7, 2.7 Hz, 2H), 3.85 (s, 3H); MS (APCT) m / z 328 [M-H]-.

[0916] Example 8: 5-[l-fluoro-3-hydroxy-7-(methylamino)naphthalen-2-yl]-lkft,2,5- thiadiazolidine-l,l,3-trione (Compound 107)

[0917] In a 4 mL vial with a septum screw cap, the product of Example 1G (0.1 g, 0.215 mmol), sodium teri-butoxide (0.062 g, 0.645 mmol), BrettPhos Pd G3 precatalyst (5.84 mg, 6.45 pmol), and BrettPhos (3.46 mg, 6.45 pmol) were combined. The solids were placed under vacuum for 5 minutes with stirring, then the vial was filled with nitrogen, followed by 1 ,4-dioxane (2 mL) and a solution of methylamine in tetrahydrofuran (0.215 mL, 2 M, 0.430 mmol). The resulting suspension was degassed by five vacuum / nitrogen backfills, was stirred for 10 minutes at room temperature, and then was heated to 100 °C. After 30 minutes at 100 °C, the reaction mixture was cooled to room temperature, then was quenched with 1 M hydrochloric acid (1 mL), and diluted with ethyl acetate (2 mL). The aqueous layer was extracted with ethyl acetate (2 x 1 mL). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (1 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give, 5-[3-(benzyloxy)-l-fluoro-7-(methylamino)naphthalen-2-yl]- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione, a viscous orange oil, which was used for the next reaction without purification. MS (APCT) m / z 414 [M-H]~.

[0918] To a suspension of the crude intermediate, 5-[3-(benzyloxy)-l-fluoro-7- (mcthylamino)naphthalcn-2-yl ]- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione, in dichloromethane (2 mL) at -78 °C was added a solution of boron trichloride in dichloromethane (1.29 mL, 1 M, 1.29 mmol) slowly along the side of the flask so that the internal temperature remained below -70 °C. The resulting solution was stirred for 5 minutes at -78 °C, then the cooling bath was removed, and the reaction mixture was allowed to warm to an internal temperature of 10 °C before cooling back to -78 °C. The reaction was quenched by addition of ethyl acetate (1 mL), followed by anhydrous ethanol (0.5 mL). The mixture was warmed to room temperature and then was concentrated under reduced pressure. The crude residue was dissolved in a dimethyl sulfoxide / methanol mixture and was filtered through a glass microfiber frit. The resulting solution was directly purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 pm 100A AXIA column (30 mm x 75 mm) with gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) at a flow rate of 50 mL / minute (0-1.0 minute 5% A, 1.0-8.5 minutes linear gradient 5-100% A, 8.5-11.5 minutes 100% A, 11.5-12.0 minutes linear gradient 95-5% A) to give the title compound (0.0136 g, 0.040 mmol, 18.6% yield).JH NMR (400 MHz, DMSO-r / r ) d ppm 7.45 (d, J = 8.8 Hz, 1H), 6.93 (dd, J = 8.9, 2.3 Hz, 1H), 6.89 (s, 1H), 6.56 (d, J = 2.3 Hz, 1H), 5.93 - 5.80 (m, 1H), 4.07 (s, 2H), 2.76 - 2.72 (m, 3H); MS (EST) m / z 324 [M-H]-.

[0919] Example 9: 5-{ l-fluoro-3-hydroxy-7-[2-(piperidin-4-yl)ethoxy]naphthalen-2-yl}-lZ / ’,2,5- thiadiazolidine-l,l,3-trione (Compound 108)

[0920] To a solution of the product of Example 1H (0.1 g, 0.249 mmol) and teri-butyl 4-(2- bromoethyl)piperidine-l-carboxylate (0.145 g, 0.497 mmol) in dimethylformamide (1 mL) was added cesium carbonate (0.243 g, 0.0.746 mmol) as a solid, and the resulting suspension was heated to 60 °C. After 1 hour, the reaction mixture was cooled to room temperature, quenched with 2 M hydrochloric acid (1 mL), and diluted with ethyl acetate (2 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 1 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (3 x 1 mL). The combined aqueous washes were back extracted with ethyl acetate (1 mL), and the combined organic layers were washed with a 4: 1 mixture of brine and 1 M hydrochloric acid, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert- butyl 4-(2- ( 16-(bcnzyloxy)-8-fluoro-7-( 1 , 1 ,4-trioxo- 1 / ’,2,5-thiadiazol idin-2-yl)naphthalcn-2- yl]oxy}ethyl)piperidine-l-carboxylate, a dark gel, which was used for the next reaction without purification. MS (APCT) m / z 612 [M-H] .

[0921] To a suspension of the crude intermediate, teri-butyl 4-(2-{ [6-(benzyloxy)-8-fluoro-7- (1 ,1 ,4-trioxo- 1 k6,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy } ethyl)piperidine- 1 -carboxylate, in dichloromethane (2 mL) at -78 °C was added a solution of boron trichloride in dichloromethane (2.49 mL, 1 M, 2.49 mmol) slowly along the side of the vial so that the internal temperature remained below -70 °C. The resulting solution was stirred for 5 minutes at -78 °C, then the cooling bath was removed, and the reaction mixture was allowed to warm to an internal temperature of 10 °C before cooling back to -78 °C. The reaction was quenched by the addition of ethyl acetate (1 mL), followed by anhydrous ethanol (0.5 mL), warmed to room temperature and concentrated under reduced pressure to give a tan solid. The crude solid was dissolved in a dimethyl sulfoxide / methanol mixture and was filtered through a glass microfiber frit. The resulting solution was directly purified by preparative HPLC [Phenomenex® Luna® 10 pm Cl 8(2) 250 x 30 mm column, flow rate 100 mL / minute, a gradient of 5-95% acetonitrile in buffer (0.010 M aqueous ammonium acetate)]. The HPLC purified product was further purified by trituration with a 50% v / v mixture of dichloromethane and acetonitrile (3 mL) to give the title compound (0.066 g, 0.155 mmol, 64.9% yield).1H NMR (400 MHz, DMSO-cL) d ppm 7.66 (d, J = 9.0 Hz, 1H), 7.19 (d, J = 2.5 Hz, 1H), 7.11 (dd, J = 9.0, 2.5 Hz, 1H), 7.03 (s, 1H), 4.13 (t, J = 6.1 Hz, 2H), 4.09 (s, 2H), 2.89 - 2.76 (m, 1H), 1.90 (s, 3H), 1.86 (s, 2H), 1.82 - 1.69 (m, 3H), 1.34 (td, J = 12.9, 12.1, 8.7 Hz, 2H); MS (EST) m / z 422 [M-H]-.

[0922] Example 10: 5-(l-fluoro-7-{[3-fluoro-l-(propan-2-yl)pyrrolidin-3-yl]methoxy}-3- hydroxynaphthalen-2-yl)-lkft,2,5-thiadiazolidine-l,l,3-trione (Compound 109)

[0923] To a solution of the product of Example 1H (100 mg, 0.249 mmol) and (3-fluoro-l- isopropylpyrrolidin-3-yl)methanol (120 mg, 0.746 mmol) in tetrahydrofuran (THF) (5 mL) at 0 °C was added (£)-diazcnc- 1 ,2-diylbi sf pi pci idi n- 1 -ylmcthanonc) (219 mg, 0.870 mmol). The reaction was flushed with N at 0 °C for 5 minutes followed by addition of tri -«-butyl phosphine (0.215 mL, 0.870 mmol). The reaction was stirred at 45 °C for 14 hours. The volatiles were removed under reduced pressure, and the residue was subjected to column chromatography (Si02, dry load with diatomaceous earth, 10% methanol in dichloromethane) to afford the title compound (24 mg, 0.044 mmol, 18% yield) as a beige solid.JH NMR (400 MHz, DMSO-cC) d ppm 7.68 (d, J = 9.1 Hz, 1H), 7.25 (d, J = 2.6 Hz, 1H), 7.17 (dd, J = 9.0, 2.5 Hz, 1H), 7.04 (s, 1H), 4.30 (broad, 1H), 4.24 (broad, 1H), 4.09 (s, 2H), 3.06 - 2.77 (m, 4H), 2.23 - 1.98 (m, 2H), 1.46 - 1.37 (broad, 1H), 1.05 (d, J = 6.2 Hz, 6H); MS (APCI-) m / z 454.13 [M-CH2C6H5-H]·, 544 [M-H]-.

[0924] Example 10B: 5-(l-fluoro-7-{[3-fluoro-l-(propan-2-yl)pyrrolidin-3-yl]methoxy}-3- hydroxynaphthalen-2-yl )-1l6, 2,5-thiadiaz.ohdine- 1 , i, 3-trione

[0925] The product of Example 10A (22 mg, 0.040 mmol) and l,2,3,4,5-pentamethylbenzene (17.93 mg, 0.121 mmol) in a 50 mL round bottom flask was flushed with nitrogen for 5 minutes. Dichloromethane (5 mL) was then added, and the heterogeneous suspension was cooled to -78 °C and equilibrated for 5 minutes. Subsequently, a 1 M solution of trichloroborane (0.121 mL, 0.121 mmol) in dichloromethane was added dropwise over 5 minutes. After 30 minutes, the reaction was quenched at -77 °C with dichloromethane: me thanol= 9: 1 (0.5 mL), and then the mixture was slowly warmed to room temperature. The volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® Cl 8(2) 5 pm 100 A AXIA™ column (250 mm x 25 mm).;30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes, at a flow rate of 25 mL / minute] to afford the title compound (7 mg, 0.015 mmol, 38% yield).1H NMR (400 MHz, D SO-cC) d ppm 7.68 (d, J = 9.1 Hz, 1H), 7.25 (d, J = 2.6 Hz, 1H), 7.17 (dd, J = 9.0, 2.5 Hz, 1H), 7.04 (s, 1H), 4.30 (broad, 1H), 4.24 (broad, 1H), 4.09 (s, 2H), 3.06 - 2.77 (m, 4H), 2.23 - 1.98 (m, 2H), 1.46 - 1.37 (broad, 1H), 1.05 (d, J = 6.2 Hz, 6H); MS (APCI-) m / z 454.13 [M-H]-.

[0926] Example 11: 5-{l-fluoro-7-[(3-fluoropyrrolidin-3-yl)methoxy]-3-hydroxynaphthalen-2-yl}- 1l6, 2, 5-thiadiazolidine-l,l, 3-trione (Compound 110)

[0927] Example 11 A: tert-butyl 3-({ [ 6-( benzyloxy )-8-fl uom-7-( / , 1,4-trioxo- / / L 2, 5-thiadiaz.olidin-2- yl )naphthalen-2-yl ]oxy }methyl )-3-fluoropyrrolidine-l-carboxylate

[0928] To a solution of the product of Example 1H (100 mg, 0.249 mmol) and teri-butyl 3- fluoro-3-(hydroxymethyl)pyrrolidine-l-carboxylate (163 mg, 0.746 mmol) in tetrahydrofuran (THE) (5 mL) at 0 °C was added (£)-diazcnc- 1 ,2-di ylb isfpi pci idi n- 1 -ylmcthanonc) (219 mg, 0.870 mmol). The reaction was flushed with N2at 0 °C for 5 minutes followed by addition of tri -«-butyl phosphine (0.215 mL, 0.870 mmol). The reaction was stirred at 45 °C for 14 hours. The volatiles were removed under reduced pressure, and the residue was subjected to column chromatography (Si(¾, dry load with diatomaceous earth, 10% methanol in dichloromethane) to afford the title compound (48 mg, 0.080 mmol, 32% yield). MS (APCI-) m / z 602 [M-H] .

[0929] Example l IB: 5-{ l-fluoro-7-[(3-fluoropyrrolidin-3-yl)methoxy]-3-hydroxynaphthalen-2-yl}- l6,2,5-thiadiazolidine-l ,1 ,3-trione

[0930] The product of Example 11A (45 mg, 0.075 mmol) and l,2,3,4,5-pentamethylbenzene (33.2 mg, 0.224 mmol) in a 50 mL round bottom flask was flushed with nitrogen for 5 minutes. Dichloromethane (5 mL) was then added, and the heterogeneous suspension was cooled to -78 °C and equilibrated for 5 minutes. Subsequently, a 1 M solution of trichloroborane (0.224 mL, 0.224 mmol) in dichloromethane was added dropwise over 5 minutes. After 30 minutes, the reaction was quenched at -77 °C with dichloromethane: me thanol= 9: 1 (0.5 mL) and then slowly warmed to room temperature. The volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® Cl 8(2) 5 pm 100A AXIA™ column (250 mm x 25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes, at a flow rate of 25 mL / minute] to afford the title compound (9 mg, 0.022 mmol, 29% yield).JH NMR (501 MHz, DMSO-<¾) d ppm 9.63 (d, J = 69.3 Hz, 1H), 7.72 (d, J = 9.1 Hz, 1H), 7.28 (d, J = 2.6 Hz, 1H), 7.19 (dd, J = 9.0, 2.6 Hz, 1H), 7.06 (s, 1H), 4.57 - 4.41 (s, 2H), 4.10 (s, 2H), 3.73 - 3.48 (m, 4H), 2.43 - 2.20 (m, 2H); MS (APCI-) m / z 411.89 [M-H]-.

[0931] Example 12: 5-{[8-fluoro-6-hydroxy-7-(l,l,4-trioxo-lkft,2,5-thiadiazolidin-2-yl)naphthalen- 2-yl]oxy}pentanenitrile (Compound 111)

[0932] Example 12 A: 5-{[6-(benzyloxy)-8-fluoro-7-(lJ,4-trioxo-l6,2,5-thiadiazolidin-2- yl)naphthalen-2-yl]oxy}pentanenitrile

[0933] A mixture of the product of Example 1H (100 mg, 0.249 mmol), cesium carbonate (162 mg, 0.497 mmol) in / V, / V-di mcthy Iformam idc (2 mL) was stirred at room temperature for 14 hours. The reaction mixture was filtered and purified by preparative HPLC [Phenomenex® Luna® 10 pm C18 column (30 mm x 250 mm) eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) 0.1% with trifluoroacetic acid at a flow rate of 50 mL / minute (0-1 minute 10% A, 1-20 minutes linear gradient 10-100%) to give the title compound (80 mg, 0.165 mmol, 67% yield).JH NMR (501 MHz, DMSO-de) d ppm 7.86 - 7.78 (m, 1H), 7.57 - 7.48 (m, 2H), 7.42 (s, 1H), 7.41 - 7.36 (m, 2H), 7.36 - 7.31 (m, 1H), 7.31 - 7.25 (m, 2H), 5.24 (s, 2H), 4.50 (s, 2H), 4.15 (t, J = 6.2 Hz, 2H), 2.61 (t, J = 7.1 Hz, 2H), 1.87 (m, 2H), 1.82 - 1.70 (m, 2H); MS (APCL) m / z 482 [M-H]+. Example 12B: 5-f [ 8-fiuoro-6-hydroxy-7-( / , 1 ,4-trioxo- 1 / .6,2J-thiadiaz.olidin-2-yl )naphthalen-2- yl ]oxy}pentanenitrile

[0934] To a mixture of the product of Example 12A (75 mg, 0.155 mmol) and

[0935] pentamethylbenzene (115 mg, 0.776 mmol) in dichloromethane (2 mL) cooled to -78 °C was added a solution of boron trichloride (1 M, 0.931 mL, 0.931 mmol) in dichloromethane dropwise over 5 minutes. After 30 minutes, the reaction mixture was quenched with 2 N HC1 (0.5 mL). The mixture was then extracted with ethyl acetate, washed with brine, dried over Na SCp and concentrated under reduced pressure. The residue was purified by preparative HPLC on a Phenomenex® Luna® 10 pm C18 column (30 mm x 250 mm) eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) 0.1% with trifluoroacetic acid at a flow rate of 50 mL / minute (0-1 minute 10% A, 1-20 minutes linear gradient 10-100%) to give the title compound (40 mg, 0.102 mmol, 65.6% yield).JH NMR (501 MHz, DMSO-c / f,) d ppml0.27 (s, 1H), 7.71 (dd, J = 9.1, 1.4 Hz, 1H), 7.25 - 7.16 (m, 2H), 7.07 (s, 1H), 4.44 (s, 2H), 4.12 (t, J = 6.2 Hz, 2H), 2.60 (t, J = 7.1 Hz, 2H), 1.87 (dq, J = 8.5, 6.4 Hz, 2H), 1.76 (dq, J = 9.9, 7.1 Hz, 2H); MS (APCL) m / z 392 [M-H]+.

[0936] Example 13: 5-{l-fluoro-3-hydroxy-7-[2-(piperidin-l-yl)ethoxy]naphthalen-2-yl}-17ft,2,5- thiadiazolidine-l,l,3-trione (Compound 112)

[0937] Example 13 A: 5-{3-( benzyloxy )- / -fluoro-7-[ 2-( pipe rid in- / -yl jethoxy j naphthalen-2-yl j - 1 / !' ,2, 5- thiadiaz.olidine- 1 , 1 ,3-trione

[0938] A mixture of the product of Example 1H (84 mg, 0.2 mmol), l-(2-chloroethyl)piperidine (94 mg, 0.640 mmol), and cesium carbonate (235 mg, 0.720 mmol) in dimethylformamide (1 mL) was stirred at 75 °C for 2 hours. The solution was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with dichloromethane, then dichloromethane / methanol (10:1) to give the title compound (65 mg, 0.127 mmol, 63% yield) as a solid. MS (ESI+) m / z 514 [M+H]+.

[0939] Example 13B: 5-{ l-fluoro-3-hydroxy-7-[2-(piperidin-l-yl)ethoxy]naphthalen-2-yl}-l / 6,2,5- thiadiaz.olidine- 1 , 1 ,3-trione

[0940] To the product of Example 13A (60 mg, 0.117 mmol) and 1,2, 3, 4, 5 -pentamethylbenzene (55.4 mg, 0.374 mmol) in dichloromethane (2 mL) at -78 °C was added trichloroborane (1168 pL, 1.168 mmol, 1.0 M in dichloromethane). The mixture was stirred at -78 °C for 40 minutes. Methanol (3 mL) was added at -78 °C . The mixture was stirred for 5 minutes at room temperature, then concentrated under reduced pressure. The solid was washed with heptane (4 x 5 mL), then dissolved in methanol (0.5 mL) and / V, / V- d i m c th y I fo r m a m i dc (3 mL). The crude material was purified by preparative HPLC [YMC TriArt™ Cl 8 Hybrid 20 pm column, 25 x 150 mm, flow rate 80 mL / minute, 5-100% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (30 mg, 0.071 mmol, 61% yield).1H NMR (400 MHz, D SO-uV,) d ppm 9.52 (br s, 1H), 7.71 (d, J = 8 Hz, 1H), 7.28 (d, J = 2 Hz, 1H), 7.19 (dd, J = 8, 2 Hz, 1H), 7.05 (br s, 1H), 4.42 (m, 2H), 4.09 (s, 2H), 3.46 (m, 4H), 3.00 (m, 2H), 1.72 (m, 4H), 1.47 (m, 2H); MS (ESI ) m / z 422 [M-H]-.

[0941] Example 14: 5-{7-[l -(cyclopropanesulfonyl)-2, 5-dihydro- l / 7-pyrrol-3-yl]-l-fluoro-3- hydroxynaphthalen-2-yl }- 1 >’,2,5-thiadiazolidine- 1 ,1 ,3-trione (Compound 113)

[0942] Example 14A: tert-butyl 3-j 6-(benzyloxy)-8-fluoro-7-( / , 1 ,4-trioxo- 1 / . 2J-thiadiaz.oIidin-2- yl )naphthalen-2-yl ] -2, 5-dihydro- 1 H-pyrrole-1 -carboxylate

[0943] To the product of Example 1G in dioxane (5 mL) was added tert- butyl 3-(4,4,5,5- tetramethyl-l, 3, 2-dioxaborolan-2-yl)-2, 5-dihydro- l / / -pyrrole-l -carboxylate (381 mg, 1.290 mmol) and sodium carbonate (1.290 mL, 2.58 mmol). Tetrakis(triphenylphosphine)palladium(0) (99 mg, 0.086 mmol) was added, and the reaction mixture was sparged with N for 5 minutes. The mixture was heated at 100 °C overnight. The reaction was cooled down to room

[0944] temperature, and the volatiles were removed under reduced pressure. The residue was subjected to column chromatography (dry loading with diatomaceous earth, 5% CH3OH in CH2CI2) to afford the title compound (346 mg, 0.625 mmol, 73% yield) as a yellow solid.1H (500 MHz, DMSO-de) d ppm 7.87 - 7.80 (m, 2H), 7.75 (d, J = 12.7 Hz, 1H), 7.60 - 7.52 (m, 2H), 7.41 - 7.35 (m, 3H), 7.35 - 7.28 (m, 1H), 6.59 - 6.52 (m, 1H), 5.27 (s, 2H), 4.53 (d, J = 7.7 Hz, 2H), 4.26 (d,

[0945] J = 12.0 Hz, 2H), 4.09 (s, 2H), 1.47 (d, J = 10.6 Hz, 9H); MS (APCI-) m / z 551 [M-H]-.

[0946] To a solution of the product of Example 14A (100 mg, 0.181 mmol) in dichloromethane (2 mL) was added 2,2,2-trifluoroacetic acid (1 mL, 3.61 mmol). The mixture was stirred at room temperature for 30 minutes. The volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® Cl 8(2) 5 pm 100A AXIA™ column (250 mm x 25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 mL / minute] to afford the title compound (60 mg, 0.132 73% yield).JH NMR (400 MHz, DMSO-d6) d ppm 7.86 (d, J = 3.7 Hz, 2H), 7.60 - 7.48 (m, 2H), 7.46 - 7.27 (m, 5H), 6.60 (t, J = 2.2 Hz, 1H), 5.28 (s, 2H), 4.50 (q, J = 2.3 Hz, 2H), 4.19 (dt, J = 5.0, 2.5 Hz, 2H), 4.10 (s, 2H); MS (APCI-) m / z 452 [M-H] .

[0947] To a solution of the product of Example 14B (88 mg, 0.194 mmol) in dichloromethane (5 mL) was added cyclopropanesulfonyl chloride (0.071 mL, 0.582 mmol) at room temperature followed by / V, / V-di isopropyl ethyl amine (0.102 mL, 0.582 mmol). The reaction mixture was stirred overnight at room temperature. The volatiles were removed under reduced pressure, and the residue was subjected to column chromatography (Si(¾,dry load with diatomaceous earth, 5% CH3OH in CH2CI2) to afford the title compound (77 mg, 0.138 mmol, 71% yield) as a beige solid. MS (APCI-) m / z 555 [M-H]-.

[0948] A solution of product of Example 14C (66 mg, 0.118 mmol) and 1, 2, 3,4,5- pentamethylbenzene (52.6 mg, 0.355 mmol) in dichloromethane (5 mL) was flushed with nitrogen gas for 5 minutes. The solution was cooled to -78 °C and equilibrated for 5 minutes. Subsequently, a 1 M solution of trichloroborane (0.355 mL, 0.355 mmol) in dichloromethane was added dropwise over 5 minutes. After 30 minutes, the reaction was quenched at -77 °C with dichloromethane :methanol= 2:1 (0.5 mL) and then slowly warmed to room temperature. The volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® Cl 8(2) 5 pm IOqA AXIA™ column (250 mm x 25 mm); 30- 100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 mL / minute] to afford the title compound (25 mg, 0.053 mmol, 45% yield) as a beige solid.JH NMR (400 MHz, DMSO-<¾) d ppm 9.87 (s, 1H), 7.14 (s, 1H), 7.03 - 6.99 (m, 2H), 6.89 (s, 1H), 6.46 (t, J = 2.1 Hz, 1H), 4.62 - 4.55 (m, 2H), 4.29 (dt, J = 6.9, 3.0 Hz, 2H),

[0949] 4.03 (s, 2H), 2.82 - 2.71 (m, 1H), 0.97 (dt, J = 5.4, 2.8 Hz, 2H), 0.96 - 0.86 (m, 2H); MS (APCI-) m / z 465 [M-H]-.

[0950] Example 15: 5-{l-fluoro-3-hydroxy-7-[(piperidin-4-yl)methoxy]naphthalen-2-yl}-l>’,2,5- thiadiazolidine-1, 1,3-trione (Compound 114)

[0951] To a solution of the product of Example 1H (0.1 g, 0.238 mmol) and teri-butyl 4-(2- bromomethyl)piperidine-l-carboxylate (0.133 g, 0.477 mmol) in dimethylformamide (1 mL) was added cesium carbonate (0.311 g, 0.954 mmol) as a solid, and the resulting suspension was heated to 60 °C. After 3.5 hours, the reaction was cooled to room temperature, quenched with 2 M hydrochloric acid (1 mL), and diluted with ethyl acetate (2 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 1 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (3 x 1 mL). The combined aqueous washes were back extracted with ethyl acetate (1 mL), and the combined organic layers were washed with a 4: 1 mixture of brine and 1 M hydrochloric acid, then dried over sodium sulfate, filtered and concentrated under reduced pressure to give teri-butyl 4-({ [6-(benzyloxy)-8-fluoro- 7-( 1 , 1 ,4-trioxo- l / \2,5-thiadiazolidin-2-yl)naphthalcn-2-yl ]oxy [ methyl )pipcridinc- 1 -carboxyl ate which was used for the next reaction without purification. MS (APCT) m / z 598 [M-H] .

[0952] To a suspension of teri-butyl 4-( ( |6-(bcnzyloxy)-8-fluoro-7-( 1 , 1 ,4-trioxo- 1 lή,2,5- thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)piperidine-l-carboxylate in dichloromethane (2 mL) at -78 °C was added a solution of boron trichloride in dichloromethane (2.38 mL, 1 M, 2.38 mmol) slowly along the side of the flask so that the internal temperature remained below -70 °C. The resulting solution was stirred for 5 minutes at -78 °C, then the cooling bath was removed and the reaction mixture was allowed to warm to an internal temperature of 10 °C before cooling back to -78 °C. The reaction was quenched by addition of ethyl acetate (1 mL) followed by anhydrous ethanol (0.5 mL), was warmed to room temperature, and concentrated under reduced pressure to give a tan solid. The crude solid was suspended in ethyl acetate (5 mL) and sonicated for 30 seconds giving a suspension. The solid was collected via filtration and washed with ethyl acetate (2 mL). The solid was dissolved in a dimethyl sulfoxide / methanol mixture and was filtered through a glass microfiber frit. The resulting solution was directly purified by preparative HPLC [Waters XBridge™ C18 5 pm OBD column, 30 x 100 mm, flow rate 40 mL / minute, a gradient of 3-30% methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (0.066 g, 0.155 mmol, 65% yield).JH NMR (400 MHz, DMSO-<¾) d ppm 7.65 (dd, J = 9.1, 1.5 Hz, 1H), 7.19 (d, J = 2.5 Hz, 1H), 7.13 (dd, J = 9.0, 2.5 Hz, 1H), 7.02 (s, 1H), 4.11 (s, 2H), 3.96 (s, 2H), 3.27 (s, 2H), 2.90 (td, J = 12.8, 3.0 Hz, 2H), 2.08 (d, J = 11.0 Hz, 1H), 1.95 (dd, J = 14.6, 3.5 Hz, 2H), 1.58 - 1.37 (m, 2H); MS (EST) m / z 408 [M-H]-.

[0953] Example 16: 5-{[8-fluoro-6-hydroxy-7-(l,l,4-trioxo-lkft,2,5-thiadiazolidin-2-yl)naphthalen- 2-yl]oxy}-3,3-dimethylpentanenitrile (Compound 115)

[0954] Example 16 A: 5-bromo-3,3-dimethylpentanenitrile

[0955] To a solution of 5-bromo-3,3-dimethylpentanoic acid (0.5 g, 2.391 mmol), in

[0956] dichloromethane (10 mL) was added chlorosulfonyl isocyanate (0.208 mL, 2.391 mmol) dropwise. The resulting solution was stirred for 15 minutes at room temperature, and then heated to an internal temperature of 40 °C. After 2 hours, gas evolution had ceased, and the reaction mixture was cooled to 0 °C. / V. / V-Diisopi opylcthylaminc was added slowly via syringe so that the internal temperature remained below 7 °C. The resulting solution was then warmed to room temperature and stirred for 1 hour. The reaction was quenched with 1 M sodium bisulfate (5 mL), and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 5 mL), and the combined organic layers were dried over anhydrous sod...

Claims

CLAIMS1. A compound represented by Formula (I) :or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, / V-oxidc, stereoisomer or isotopically enriched variant thereof, wherein:R1is selected from the group consisting of hydrogen, halogen, Chalky I, C3_6cycloalkyl, - 0-Ci_6alkyl, -N(Ra)-Ci_6alkyl and -Ci_6alkylene-5-6 membered heterocyclyl;wherein Ci_6alkyl, C3_6cycloalkyl, -0-Ci_6alkyl, -N(Ra)-Ci_6alkyl and -Ci_6alkylene-5-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci_6alkylene-5-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh;2R is selected from the group consisting of hydrogen, hydroxyl, -CHF2, -Cl¾OF[, - CH2CN, -CH2-0-Ci_6alkyl, -CH2-N(Ra)-Ci_6alkyl, C2-6alkyl, C2-6alkenyl, -0-Ci_6alkyl, -N(Ra)- Ci-ealkyl, -S(0)w-Ci-6alkyl, -C(0)-N(Ra)-Ci-6alkyl, -N(Ra)-C(0)-Ci-6alkyl, -0-C(0)-N(Ra)-Ci_6alkyl, -N(Ra)-C(0)-0-Ci_6alkyl, -C3_6cycloalkyl, -0-C3-6cycloalkyl, Ci_6alkylene-C3_6cycloalkyl, -Ci-6alkenylene-C3-6cycloalkyl, -0-Ci-6alkylene-C3-6cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -0-Ci_6alkylene-5-6 membered heteroaryl, -0-4-6 membered heterocyclyl, -N(Ra)-4-6 membered heterocyclyl, -Ci-6alkylene-4-6 membered heterocyclyl and - 0-Ci_6alkylene-4-6 membered heterocyclyl;wherein -Cl¾-0-Ci_6alkyl, -CFl2-N(Ra)-Ci_6alkyl, C2-6alkyl, C2-6alkenyl, -0-Ci_6alkyl, -N(Ra)-Ci_6alkyl, -S(0)w-Ci_6alkyl, -C(0)-N(Ra)-Ci_6alkyl, -N(Ra)-C(0)-Ci_6alkyl, -O- C(0)-N(Ra)-Ci_6alkyl, -N(Ra)-C(0)-0-Ci_6alkyl, -C3-6cycloalkyl, -0-C3-6cycloalkyl, -C ,6alkylene-C3_6cycloalkyl, -C1_6alkenylene-C3_6cycloalkyl, -O-C 1 _fial kylcnc-Cv^cyc loal kyl , 5-6 membered heteroaryl, -0-Ci_6alkylene-5-6 membered heteroaryl, 4-6 membered heterocyclyl, - 0-4-6 membered heterocyclyl, -N(Ra)-4-6 membered heterocyclyl, -Ci_6alkylene-4-6 membered heterocyclyl and -0-Ci_6alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independentlyselected from Rg; and wherein if 5-6 membered heteroaryl, 4-6 membered heterocyclyl, -N(Ra)- 4-6 membered heterocyclyl, -Ci-6alkylene-4-6 membered heterocyclyl or -0-Ci-6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh;or R 1 and R 2 taken together with the atoms to which they are attached form a 5-6 membered aryl or heteroaryl; wherein aryl or heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, Ci_6alkyl and Ci_6alkoxy; wherein Ci_6alkyl and Ci_6alkoxy may optionally be substituted pby one, two three or more substituents each independently selected from R ;R3is selected from the group consisting of hydrogen, -Ci_6alkyl, -0-Ci_6alkyl, -N(Ra)-Ci_ ealkyl, -S(0)w-Ci_6alkyl, -C(0)-N(Ra)-Ci_6alkyl, -N(Ra)-C(0)-Ci_6alkyl and -Ci_6alkylene-4-6 membered heterocyclyl;wherein -Ci_6alkyl, -0-Ci_6alkyl, -N(Ra)-Ci_6alkyl, -S(0)w-Ci_6alkyl, -C(0)-N(Ra)- Ci_6alkyl, -N(Ra)-C(0)-Ci_6alkyl and -Ci_6alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci_6alkylene_4_6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh;R4is selected from the group consisting of hydrogen, halogen, Chalky I, C3_6cycloalkyl and -Ci_6alkylene-4-6 membered heterocyclyl; wherein Ci_6alkyl, C3_6cycloalkyl and -Ci_6alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci_6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh;wherein at least one of R 1 , R2 , R 3 and R 4 is not hydrogen;R5is selected from the group consisting of hydrogen, halogen, Ci_6alkyl, C3_6cycloalkyl and -Ci_6alkylene-4-6 membered heterocyclyl; wherein Ci_6alkyl, C3_6cycloalkyl and -Ci_6alkylene-4-6 membered heterocyclyl may optionally be substituted on one or more available carbons by one, two, three or more substituents each independently selected from Rg; and wherein if -Ci_6alkylene-4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Rh;R6is hydrogen;R7is hydrogen;Rgis independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, oxo, -C(0)0H, RaRbN-, RaRbN-C(0)-, RaRbN-SOw-, RaRbN- C(0)-N(Ra)-, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3_6cycloalkyl, phenyl, Ci_6alkylene-C3_6cycloalkyl, -0-Ci-6alkylene-C3-6cycloalkyl, -(CO)-(NRa)-Ci-6alkylene-C3-6cycloalkyl, Ci-6alkoxy, C3_6alkenyloxy, C3_6alkynyloxy, C3_6cycloalkoxy, Ci_6alkyl-C(0)-, Ci_6alkyl-0-C(0)-, Ci-6alkyl-C(0)-0-, Ci-6alkyl-S(0)w-, Ci-6alkyl-N(Ra)-, Ci-6alkyl-N(Ra)-C(0)-, Ci-6alkyl-C(0)- N(Ra), Ci_6alkyl-N(Ra)-C(0)-N(Ra)-, Ci_6alkyl-N(Ra)-SOw-, C3-6cycloalkyl-N(Ra)-SOw-, C ,6alkyl-SOw-N(Ra)-, C3-6cycloalkyl-SOw-N(Ra)-, 4-6 membered heterocyclyl-SOw-N(Ra)-, Ci-6alkoxy-C(0)-N(Ra)-, Ci_6alkyl-C(0)-N(Ra)-Ci_6alkyl-, Ci_6alkyl-N(Ra)-C(0)-Ci_6alkyl-, - P(0)(Ci-3alkyl)2and Ci-6alkoxy-Ci-6alkyl-; wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, phenyl, Ci_6alkylene-C3_6cycloalkyl, -0-Ci_6alkylene-C3-6cycloalkyl, -(CO)-(NRa)- Ci_6alkylene-C3_6cycloalkyl, Ci_6alkoxy, C3_6alkenyloxy, C3_6alkynyloxy, C3_6cycloalkoxy, Ci_6alkyl-C(0)-, Ci_6alkyl-0-C(0)-, Ci_6alkyl-C(0)-0-, Ci_6alkyl-S(0)w-, Ci_6alkyl-N(Ra)-, C ,6alkyl-N(Ra)-C(0)-, Ci_6alkyl-C(0)-N(Ra), Ci_6alkyl-N(Ra)-C(0)-N(Ra)-, Ci_6alkyl-N(Ra)-SOw-, C3-6cycloalkyl-N(Ra)-SOw-, Ci_6alkyl-SOw-N(Ra)-, C3_6cycloalkyl-SOw-N(Ra)-, 4-6 membered heterocyclyl-SOw-N(Ra)-, Ci_6alkoxy-C(0)-N(Ra)-, Ci_6alkyl-C(0)-N(Ra)-Ci_6alkyl-, Ci_6alkyl- N(Ra)-C(0)-Ci_6alkyl-, -P(0)(Ci_3alkyl)2and Ci_6alkoxy-Ci_6alkyl- may optionally be substituted by one, two three or more substituents each independently selected from Rp;Rhis independently selected for each occurrence from the group consisting of Ci-6alkyl, C3_6alkenyl, C3_6alkynyl, C3_6cycloalkyl, -Ci_6alkyl-C3_6cycloalkyl, Ci_6alkyl-S(0)2-, C3-6cycloalkyl-S(0)2-, 4-6 membered heterocyclyl-S(0)2-, 4-6 membered heterocyclyl-Ci-6alkyl- S(0)2-, 5-6 membered heteroaryl-S(0)2-, phenyl-S(0)2-, phenyl-Ci_6alkyl-S(0)2-, Ci_6alkyl- C(O)-, Ci-6cycloalkyl-C(0)-, Ci-6alkoxy-C(0)-, RaRbN-C(0)-, RaRbN-S02- and -P(0)(Ci_ 3alkyl)2; wherein Ci_6alkyl, C3_6alkenyl, C3_6alkynyl, C3_6cycloalkyl, -Ci_6alkyl-C3_6cycloalkyl, Ci-6alkyl-S(0)2-, C3-6cycloalkyl-S(0)2-, 4-6 membered heterocyclyl-S(0)2-, 4-6 membered heterocyclyl-Ci_6alkyl-S(0)2-, 5-6 membered heteroaryl-S(0)2-, phenyl-S(0)2-, phenyl-Ci_6alkyl- S(0)2-, Ci-6alkyl-C(0)-, Ci-6cyeloalkyl-C(0)-, Ci-6alkoxy-C(0)-, RaRbN-C(0)-, RaRbN-S02- and -P(0)(Ci_3alkyl)2may optionally be substituted by one, two three or more substituents each independently selected from Rp;Rpis independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, Ci_6alkyl, Ci_6alkoxy, C3_6cycloalkyl, 4-6 membered heterocyclyl, RaRbN-, RaRbN -carbonyl- , RaRbN-S02-, and RaRbN-carbonyl-N(Ra)-;Raand Rbare independently selected, for each occurrence, from the group consisting of hydrogen, Ci-6alkyl and C3-6cycloalkyl; wherein Ci-6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo, hydroxyl and Ci-6alkoxy (optionally substituted by one, two or three fluorine atoms);or Raand Rbtogether with the nitrogen to which they are attached form a 4-6 membered heterocyclyl, wherein the heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, oxo and hydroxyl; and w is 0, 1 or 2.

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

3. The compound of claim 1 or 2, wherein one, two, three or more hydrogen atoms may optionally be deuterium atoms at one, two three or more groups each independently selected from R1, R2, R4, R5, R6, R7, and Rg.

4. The compound of any one of claims 1-3, wherein R1is selected from the group consisting of hydrogen, deuterium, chlorine and fluorine.

5. The compound of any one of claims 1-4, wherein R is 4-6 membered heterocyclyl; wherein R may optionally be substituted on one or more available carbons by one, two or three substituent each independently selected from Rg, wherein if 4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from Rh.

6. The compound of any one of claims 1-5, wherein R2is 4-6 membered heterocyclyl; wherein R may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from the group consisting of hydrogen and Ci_6alkyl; and wherein if R contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from the group consisting of hydrogen, Ci_6alkyl (optionally substituted by one, two or three fluorine atoms), -Ci_6alkyl-C3_6cycloalkyl, Ci_6cycloalkyl-C(0)-, Ci_6alkyl-S(0)2- (optionally substituted by cyano, methoxy or one, two or three fluorine atoms), C3-6cycloalkyl-S(0)2-, 4-6 membered heterocyclyl-S(0)2-, 4-6 membered heterocyclyl-Ci_6alkyl-S(0)2-, 5-6 membered heteroaryl-S(0)2-, phenyl-S(0)2-, phenyl-Ci_6alkyl- S(0)2-(optionally substituted by RaRbN-), and -P(0)(C1-3alkyl)2.

7. The compound of any one of claims 1-6, wherein R is selected from the group consisting of:

8. The compound of any one of claims 1-4, wherein R 2 is 5-6 membered heteroaryl; wherein R 2 may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from Rg, and wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from Rh.

9. The compound of claim 8, wherein R is 5-6 membered heteroaryl; wherein R may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from the group consisting of hydrogen, cyano, Ci_6alkyl, Ci_6alkoxy and - P(0)(Ci-3alkyl)2; and wherein if R contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from the group consisting of hydrogen, -Ci_6alkyl-C3_6cycloalkyl and C3-6cycloalkyl-S(0)2-.

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

211. The compound of any one of claims 1-4, wherein R is -0-Ci-6alkylene-4-6 membered heterocyclyl, wherein R may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from Rg, and wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from Rh.

212. The compound of claim 11, wherein R is -0-Ci_6alkylene-4-6 membered heterocyclyl, wherein R may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from the group consisting of hydrogen, halogen and _6alkyl, and wherein if R contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from the group consisting of hydrogen, Ci_6alkyl and Ci_6alkyl-S(0)2-.

213. The compound of claim 11 or 12, wherein R is selected from the group consisting of:

214. The compound of any one of claims 1-4, wherein R is -0-Ci_6alkylene-5-6 membered heteroaryl.

215. The compound of claim 14, wherein R is selected from the group consisting of:

216. The compound of any one of claims 1-4, wherein R is selected from the group consisting of -C2-6alkyl, C2-6alkenyl, and C3-6cycloalkyl; wherein R may optionally be substituted by one, two, three or more substituents each independently selected from Rg.

17. The compound of claim 16, wherein R is selected from the group consisting of -C2-6alkyl, C2-6alkenyl, C3_6cycloalkyl, -Ci_6alkylene-C3_6cycloalkyl and -Ci_6alkenylene-C3_6cycloalkyl; wherein R may optionally be substituted by one, two, three or more substituents each independently selected from the group consisting of cyano, chlorine, fluorine, hydroxyl, Ci_6alkoxy, phenyl, and RaRbN-.

18. The compound of claim 16 or 17, wherein R is selected from the group consisting of:

19. The compound of any one of claims 1-4, wherein R 2 is -0-Ci_6alkyl; wherein R 2 may optionally be substituted by one, two, three or more substituents each independently selected from Rg.

20. The compound of claim 19, wherein R is -0-Ci_6alkyl; wherein R may optionally be substituted by one, two, three or more substituents each independently selected from the group consisting of cyano, deuterium, chlorine, fluorine, hydroxyl, oxo, Ci_6alkoxy, C3_6cycloalkoxy, 0-Ci_6alkylene-C3-6cycloalkyl, -(CO)-(NRa)-Ci_6alkylene-C3_6cycloalkyl, Ci_6alkyl-0-C(0)-, RaRbN- (wherein Rbis optionally substituted by -OCH3 or -OCF3), Ci_6alkyl-N(Ra)-, RaRbN- C(O)-, -P(0)(Ci_3alkyl)2, Ci_6alkyl-N(Ra)-C(0)-, Ci_6alkyl-N(Ra)-C(0)-N(Ra)-, Ci_6alkyl-S02- N(Ra)-, C3-6cycloalkyl-S02-N(Ra)- and 4-6 membered heterocyelyl-S02-N(Ra)-.

21. The compound of claim 19 or 20, wherein R is selected from the group consisting of:

222. The compound of any one of claims 1-4, wherein R is -0-C3-6cycloalkyl or -0-4-6 membered heterocyclyl; wherein if R contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from Rh.

23. The compound of claim 22, wherein R is -0-C3-6cycloalkyl or -0-4-6 membered heterocyclyl; wherein if R contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from the group consisting of Ci_6alkyl- S02-N(Ra)- and C3-6cycloalkyl-S02-N(Ra)-.

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

25. The compound of any one of claims 1-4, wherein R 2 is -N(R a )-Ci_6alkyl, wherein R 2 may optionally be substituted by one, two or three substituents each independently selected from Rg.

26. The compound of claim 25, wherein R is -N(R )-Ci_6alkyl, wherein R may optionally be substituted by one, two or three substituents each independently selected from the groupconsisting of fluoro, -C(0)0H, cyano, oxo, RaRbN-, Ci_6alkoxy, phenyl, -C3_6cycloalkyl, C3_6cycloalkyl-S02-N(Ra)-, and -(CO)-(NRa)-Ci-6alkylene-C3-6cycloalkyl.

227. The compound of claim 25 or 26, wherein R is selected from the group consisting of:

228. The compound of any one of claims 1-4, wherein R is -0-Ci_6alkylene-C3-6cycloalkyl, wherein R may optionally be substituted by one, two or three substituents each independently selected from Rg.

29. The compound of claim 28, wherein wherein R is -0-C1-6alkylene-C3-6cycloalkyl, wherein R may optionally be substituted by one, two or three substituents each independently selected from the group consisting of fluoro, hydroxyl, RaRbN-, cyano, and Ci_3alkyl; wherein Ci_3alkyl may be optionally substituted by a substituient selected from the group consisting of cyano and Ci-3alkoxy.

230. The compound of claim 28 or 29, wherein R is selected from the group consisting of:

31. The compound of any one of claims 1-4, wherein R2is -0-C(0)-N(Ra)-Ci_6alkyl.O0I.A,32. The compound of claim 31 , wherein R is represented by H33. The compound of any one of claims 1-4, wherein R2is -N(Ra)-4-6 membered heterocyclyl, wherein if R contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from Rh.

34. The compound of claim 33, wherein R2is -N(Ra)-4-6 membered heterocyclyl, wherein if R2contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from the group consisting of Ci_6alkyl-S02-N(Ra)- and C3_6cycloalkyl- S02-N(Ra)-.

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

236. The compound of any one of claims 1-4, wherein R is -Ci_6alkylene-4-6 membered heterocyclyl, wherein if R contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from Rh.

37. The compound of claim 36, R is -Ci_6alkylene-4-6 membered heterocyclyl, wherein if R contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by a substitutent selected from the group consisting of Chalky!, C i^alkyl-SO -N / R3)- and C3_6cycloalkyl-S02-N(Ra)-, wherein Chalky I may optionally be substituted by one, two or three fluorine atoms.

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

39. The compound of any one of claims 1-4, wherein R2is selected from the group consisting of:

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

41. The compound of claim 40, wherein R and R taken together with the atoms to which they are attached form furanyl.

42. The compound of claim 40 or 41, wherein the compound is represented by:

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

44. The compound of any one of claims 1-43, wherein R4is hydrogen.

45. The compound of any one of claims 1-44, wherein R5is selected from the group consisting of hydrogen, deuterium, bromine, chlorine, and fluorine.

46. The compound of any one of claims 1-45, wherein R6is selected from the group consisting of hydrogen and deuterium.

47. The compound of any one of claims 1-46, wherein R7is selected from the group consisting of hydrogen and deuterium.

48. The compound of any one of claims 1-47, wherein all atoms of the compound are present at their naturally occurring isotopic abundance.

49. A compound represented by Formula (II):or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, / V-oxide or stereoisomer thereof, wherein:X is selected from the group consisting of -O- and -N(Ra)-;L is straight or branched Ci_6alkylene;R2 nis selected from the group consisting of hydrogen, cyano, -NRaRb, Ci_2alkoxy, CV6cycloalkyl-S02-N(Ra)-, Ci_6alkyl-S02-N(Ra)-, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl and C3_6cycloalkyl; wherein phenyl, 5-6 membered heteroaryl, 4-6 memberedheterocyclyl and C3_6cycloalkyl may optionally be substituted on one or more available carbons by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, Ci_2alkyl (optionally substituted by one, two or three halogens) and Ci-2alkoxy (optionally substituted by one, two or three halogens); and wherein if 5-6 membered heteroaryl or 4-6 membered heterocyclyl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Ci_3alkyl;R5is selected from the group consisting of hydrogen, deuterium and halogen;R6is selected from the group consisting of hydrogen and deuterium;R7is selected from the group consisting of hydrogen and deuterium; andRaand Rbare each independently selected for each occurrence from the group consisting of hydrogen and Ci_3alkyl.

50. The compound of claim 49, wherein X is selected from the group consisting of -0-, -N(H)-, and -N(C]¾)-.

51. The compound of claim 49 or 50, wherein L is selected from the group consisting of; wherein * and # represent the covalent points of attachment to R 2 -II and X, respectively.

52. The compound of any one of claims 49-51 , wherein R 2 -II is selected from the group consisting of hydrogen, cyano, -N1¾, -N(0¾)2, -OCH3,53. The compound of any one of claims 49-52, wherein R5is selected from the group consisting of hydrogen, deuterium, and fluorine.

54. A compound represented by Formula (III):or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, / V-oxide or stereoisomer thereof, wherein:X III is selected from the group consisting of a bond, -CH -, -NR a2 -, -0-, -O-CH2- and - OCH2-CH2- m is 1, 2, or 3;n is 1, 2, or 3;R1_niis selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, - NRaRb, Ci_2alkyl (optionally substituted by one, two or three halogens) and Ci_2alkoxy(optionally substituted by one, two or three halogens);R2_mis selected from the group consisting of hydrogen, Ci_4alkyl, -C(0)-Ci_4alkyl, - C(0)-0-C| -4alkyl, -C(0)-N( Ra)-C 1 _4al kyl , -S(0)2-C|-4alkyl and -S(0)2-C3_6cycloalkyl; wherein Ci_4alkyl, -C(0)-C alkyl, -C(0)-0-Ci_4alkyl, -C(0)-N(Ra)-Ci_4alkyl, -S(0)2-Ci_4alkyl and - S(0)2-C3_6cycloalkyl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, -NRaRb, Ci-2alkyl (optionally substituted by one, two or three halogens) and Ci_2alkoxy (optionally substituted by one, two or three halogens);R5is selected from the group consisting of hydrogen, deuterium and halogen;R6is selected from the group consisting of hydrogen and deuterium;R7is selected from the group consisting of hydrogen and deuterium; andRaand Rbare each independently selected for each occurrence from the group consisting of hydrogen and Ci_3alkyl.

55. The compound of claim 54, wherein Xmis selected from the group consisting of a bond, - CH2, -0-, -NH- and -0-CH2-.

56. The compound of claim 54 or 55, wherein R2 111is selected from the group consisting of hydrogen, isopropyl, -CH2CF3, -S(0)2-CH3 and -S(0)2-cyclopropyl.

57. The compound of any one of claims 54-56, wherein R5is selected from the group consisting of hydrogen, deuterium, and fluorine.

58. A compound selected from the group consisting of:5-{ l-fluoro-3-hydroxy-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;5- { 7-[ 1 -(cyclopropanesulfonyl)pyrrolidin-3-yl]- l-fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5- [1 -fluoro-3-hydroxy-7-(pyrrolidin-3-yl)naphthalen-2-yl] - l76,2,5-thiadiazolidine- 1 , 1 ,3-trione; 8-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl)naphthalcn-2-yl propan-2- ylcarbamate;5-(9-fluoio-7-hydroxynaphtho| 2, 1 - / ? ]fu ran- 8-yl )- 1 / \2, 5-th iadiazolidinc- 1 , 1 ,3-trione;5- { 7-[2-(azetidin- 1 -yl)ethoxy]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - l76,2,5-thiadiazolidine- l,l,3-trione;5-| 1 -fluoio-3-hydroxy-7-mcthoxy(4-2H)naphthalcn-2-yl ](4,4-2HI)- 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3- trione;5-| 1 -fluoro-3-hydroxy-7-(mcthylamino)naphthalcn-2-yl ]- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione; 5- { 1 -fluoio-3-hydroxy-7-| 2-(pipcndin-4-yl)cthoxy]naphthalcn-2-yl }- 1 / / ’,2,5-thiadiazolidinc- 1 , 1 ,3- trione;5-(l-fluoro-7-{ [3-fluoro-l-(propan-2-yl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)- 1 / / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trione;5 - { 1 -fluoro-7 - [(3 -fluoropyrrolidin- 3 -yl)methoxy ] -3 -hydroxynaphthalen-2-yl } - 1 l6,2, 5- thiadiazolidine- 1 , 1 ,3-trione ;5- { 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl] oxy } pentanenitrile ;5- { 1 -fluoro-3-hydroxy-7 - [2-(piperidin- 1 -yl)ethoxy] naphthalen-2-yl } - 1' / ’,2,5-thiadiazolidinc- l,l,3-trione;5- { 7-[ 1 -(cyclopropanesulf onyl)-2, 5-dihydro- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2- yl } - 176,2,5-thiadiazolidine- 1 , 1 ,3-trione ;5-{ l-fluoro-3-hydroxy-7-[(piperidin-4-yl)methoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;5- { 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalen-2-yl ]oxy }-3,3- dimethylpentanenitrile ;5 - { 7 - 1 (3,3-dimcthylbutyl )amino] - 1 -fluoro-3-hydroxynaphthalcn-2-yl }- 1 / ’, 2, 5-th iadi azolid inc- l,l,3-trione;5-(l,4-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-l76,2,5-thiadiazolidine-l,l,3-trione;5- { l-fluoro-3-hydroxy-7-[(2H3)methyloxy]naphthalen-2-yl } - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione; 5- [1 -fluoro-3-hydroxy-7-(2-methoxyethoxy)naphthalen-2-yl] - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;4- ( 18-fluoio-6-hydioxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2-yl ]oxy }-2,2- dimethylbutanenitrile ;5- { 7-[2-(3-aminobicyclo[ 1.1.1 ] pen tan- 1 -yl)ethoxy]- 1 -fluoro-3-hydroxynaphthalen-2-yl} -I / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;5-(7- { [2-(dimethylamino)ethyl] amino } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-(l-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)(4,4-2H2)-l76,2,5-thiadiazolidine-l,l,3-trione;5-(l-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-l76,2,5-thiadiazolidine-l,l,3-trione;N-(2- { 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl] amino } ethyl)cyclopropanesulfonamide ;5-(l -fluoro- 3 -hydroxy-7- { [ 1 -(methanesulfonyl)pyrrolidin-3-yl] amino }naphthalen-2-yl)- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;N-(2- { 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl]oxy}ethyl)cyclopropanesulfonamide5-(l-fluoro-3-hydroxy-7-{ [l-(methanesulfonyl)azetidin-3-yl]amino}naphthalen-2-yl)-l76,2,5-thiadiazolidine-l,l,3-trione;4- ( 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl] oxy } butanenitrile ;I I -( { 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl] oxy } methyl)cyclopropyl] acetonitrile ;5- { 7-[2-(dimethylamino)ethoxy] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - l76,2,5-thiadiazolidine- l,l,3-trione;5- { 7-[ 1 -(cyclopropylmethyl)- l / / -pyrazol-4-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-{ l-fluoro-3-hydroxy-7-[(l / / -pyrazol-4-yl)methoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;5- [1 -fluoro-3-hydroxy-7-(2-methylpropoxy)naphthalen-2-yl] - 1 / / ’,2,5-thiadiazolidinc- 1 , 1 ,3- trione;5-| 1 -fluoio-3-hydi oxy-7-(2-hydioxypropoxy)naphthalcn-2-yl ]- 1 / / ’,2,5-thiadiazolidinc- 1 , 1 ,3- trione; / V-(cyclopropylmethyl)-8-fluoro-6-hydroxy-7-(l,l,4-trioxo-l76,2,5-thiadiazolidin-2- yl)naphthalene-2-carboxamide ;5- [1 -fluoro-3 -hydroxy-7- (2- { [2-(trifluoromethoxy)ethyl] amino }ethoxy)naphthalen-2-yl]- 1l6, 2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-(l-fluoro-3-hydroxy-7-{2-[(2-methoxyethyl)amino]ethoxy}naphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5 - { 1 -fluoro-3 -hydroxy-7 - [3 -(methylamino)propyl] naphthalen-2-yl } - 1 l6,2,5 -thiadiazolidine- l,l,3-trione;5- { 7-[3-(ethylamino)propyl]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3- trione;5-{7-[5-(dimethylphosphoryl)thiophen-2-yl]-l-fluoro-3-hydroxynaphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5- { 7-[2-(cyclopropylamino)ethoxy] - l-fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-{ l-fluoro-3-hydroxy-7-[2-(methylamino)ethoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;5- { 7-[2-(ethylamino)ethoxy]- 1 -fluoro-3-hydroxynaphthalcn-2-yl }- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;5-(l-fluoro-3-hydroxy-7-{2-[(propan-2-yl)amino]ethoxy}naphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-{7-[3-(diethylphosphoryl)propoxy]-l-fluoro-3-hydroxynaphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5- { 1 -fluoro-3 -hydroxy-7 - [(35)-3-hydroxybutoxy] naphthalen-2-yl } - 1 lή,2, 5- thiadiazolidine- 1 , 1 ,3- trione;5-{ l,4-difhioro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;5-{ l-fluoro-3-hydroxy-7-[(3f?)-3-hydroxybutoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidme-l,l,3- trione;5-[7-(2-cyclopropyl-2-hydroxyethoxy)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5- { l-fluoro-3-hydroxy-7-[(47?)-4-hydroxypentyl]naphthalen-2-yl } - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;5- { l-fluoro-3-hydroxy-7-[(47?)-4-hydroxypentyl]naphthalen-2-yl } - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;5 - { 1 -fluoro-3 -hydroxy-7 - [(45)-4-hydroxypentyl] naphthalen-2-yl } - 1 l6,2,5 -thiadiazolidine- 1,1,3- trione;5-| 1 -fluoro-3-hydroxy-7-(4-hydroxy-4-mcthylpcntyl )naphthalcn-2-yl ]- 1 / / \2,5-thiadiazolidinc- l,l,3-trione;5- { l-fluoro-3-hydroxy-7-[(3-oxopentyl)oxy]naphthalen-2-yl}- l76,2,5-thiadiazolidine-l , 1 ,3- trione;5- [1 -fluoro-3-hydroxy-7-(3-hydroxybutoxy)naphthalen-2-yl] - l76,2,5-thiadiazolidine- 1 , 1 ,3- trione; / V-| 8-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2-yl ]-3- methylbutanamide ;5- [1 -fluoro-3-hydroxy-7-(4,4,4-trifluorobutoxy)naphthalen-2-yl] - l76,2,5-thiadiazolidine- 1 , 1 ,3- trione;1 -(2- { [8-fluoro-6-hydroxy-7-(l , 1 ,4-trioxo- 176,2,5-thiadiazolidin-2-yl)naphthalen-2- yl] oxy } ethyl)cyclopropane- 1 -carbonitrile ;5-(l-fluoro-3-hydroxy-7-{2-[l-(methoxymethyl)cyclopropyl]ethoxy}naphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-(7- { [(cyclopropylmethyl)amino]methyl } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5- { 7-[(2,2-difluoropropyl)amino]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - l76,2,5-thiadiazolidine- l,l,3-trione;5- { 7-[3,3-dimethyl-4-(methylamino)butoxy] - 1 -fluoro-3-hydroxynaphthalen-2-yl }- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-{ l-fluoro-3-hydroxy-7-[(2-phenylethyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l,l,3- trione;5-[7-(3-amino-3-methylbutoxy)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5-thiadiazolidine- l,l,3-trione;5-{ l-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;5- [7-(difluoromethyl)- 1 -fluoro-3-hydroxynaphthalcn-2-yl ]- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;5- { 7-[ 1 -(dimethylphosphoryl)-2, 5-dihydro- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3-trione;5-{ l-fluoro-3-hydroxy-7-[(3,3,3-trifluoropropyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;5 - [ 1 -fluoro-3 -hydroxy-7 - (3 -methoxy-3 -methylbutoxy)naphthalen-2-yl] - 1 l6,2, 5-thiadiazolidine- l,l,3-trione;5 - [7-(2-cyclopropylpropoxy) - 1 -fluoro-3 -hydroxynaphthalen-2-yl] - 1 l6,2,5 -thiadiazolidine- 1,1,3- trione;5-[l-fluoro-3-hydroxy-7-({2-[(propan-2-yl)oxy]ethyl}amino)naphthalen-2-yl]-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5 - ( 1 -fluoro- 3 -hydroxy-7 - { [ 1 -(methanesulfonyl)pyrrolidin-3 -yl] methoxy } naphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;4- ( 18-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl] amino } butanenitrile ;5- [1 -fluoro-3-hydroxy-7-(2-hydroxyethyl)naphthalen-2-yl]- l76,2,5-thiadiazolidine- 1 , 1 ,3-trione; 5-[7-(4-amino-3,3-dimethylbutoxy)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5-thiadiazolidine- l,l,3-trione;5-(7- { [2-(azetidin- 1 -yl)ethyl] amino } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-(7- { [1 -(cyclopropanesulfonyl)azetidin-3-yl]oxy } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-{ l-fluoro-3-hydroxy-7-[(2-methoxyethyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;5-[l-fluoro-3-hydroxy-7-(3,3,3-trifluoropropoxy)naphthalen-2-yl]-l76,2,5-thiadiazolidine-l,l,3- trione;1 -( { 18-fluoi o-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl] amino } methyl)cyclopropane- 1 -carbonitrile ;5-[l-fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-l76,2,5-thiadiazolidine- l,l,3-trione;5-{ l-fluoro-3-hydroxy-7-[3-(l / / -pyrazol-l-yl)propoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;5-(7-{ l-[(4-aminophenyl)methanesulfonyl]-2,5-dihydro-l / / -pyrrol-3-yl}-l -fluoro-3- hydroxynaphthalcn-2-yl )- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;5- [1 -fluoro-3-hydroxy-7-(hydroxymethyl)naphthalen-2-yl]- l76,2,5-thiadiazolidine- 1 , 1 ,3-trione; 5- { 7-[ 1 -(cyclopropanesulfonyl)piperidin-3-yl]- l-fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5- { 7-[ 1 -(cyclopropanecarbonyl)pyrrolidin-2-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl} - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-{ l-fluoro-3-hydroxy-7-[2-(l / / -pyrazol-l-yl)ethoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidme- l,l,3-trione;5 - { 7- [ 1 -(cyclopropanesulfonyl)pyrrolidin-2-yl] - 1 -fluoro-3 -hydroxynaphthalen-2-yl } - 1 l6,2, 5 - thiadiazolidine- 1 , 1 ,3-trione ;5 - { 7- [ 1 -(cyclopropanesulfonyl)pyrrolidin-2-yl] - 1 -fluoro-3 -hydroxynaphthalen-2-yl } - 1 l6,2, 5 - thiadiazolidine- 1 , 1 ,3-trione ;5-| 1 -fluoio-3-hydi oxy-7-(pipcridin-3-yl)naphthalcn-2-yl ]- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc; 5-{7-[2-(2,2-difluorocyclopropyl)ethoxy]-l-fluoro-3-hydroxynaphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5 - { 1 -fluoro-3 -hydroxy-7 - [2-( 1 -methylcyclopropyl)ethoxy] naphthalen-2-yl } - 1 l6,2, 5 - thiadiazolidine- 1 , 1 ,3-trione ;5-(7-{ l-[(3-aminophenyl)methanesulfonyl]-2,5-dihydro-l / / -pyrrol-3-yl}-l -fluoro-3- hydroxynaphthalcn-2-yl )- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc;5-(7-{ 1 -| (2-aminophcnyl )mcthancsulfonyl ]-2, 5-dihydro- 1 / / -pyrrol-3-yl }- 1 -fluoro-3- hydroxynaphthalcn-2-yl )- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc;5- [7-(2, 2-diflu oroethyl)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1 / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;5- [1 -fluoro-3-hydroxy-7-(2,2,2-trifluoroethoxy)naphthalen-2-yl] - l76,2,5-thiadiazolidine- 1 , 1 ,3- trione;5- [1 -fluoro-7-(2-fhioroethoxy)-3-hydroxynaphthalen-2-yl] - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;1 -( { 18-fluoi o-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yljoxy } methyl)cyclopropane- 1 -carbonitrile ;5-{ l-fhioro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l ,l,3- trione;5 - { 1 -fluoro-3 -hydroxy-7 - [(2-methylpropyl) amino] naphthalen-2-yl } - 1 l6,2,5 -thiadiazolidine- l,l,3-trione;5- { 7-[(cyclopropylmethyl)amino] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - l76,2,5-thiadiazolidine- l,l,3-trione;{ 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalen-2- yl] oxy } acetonitrile ;5 - [ 1 -fluoro-3 -hydroxy-7 - (3 -methylbutoxy)naphthalen-2-yl] - 1 l6,2, 5 -thiadiazolidine- 1 , 1 ,3-trione ; 5-(l,8-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-l76,2,5-thiadiazolidine-l,l,3-trione;5- { 7-[ 1 -(cyclopropanesulfonyl)azetidin-3-yl] - l-fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5- { 7-[ 1 -(cyclopropanecarbonyl)azetidin-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;(2£T)-3-[8-fluoro-6-hydroxy-7-(l,l,4-trioxo-l76,2,5-thiadiazolidm-2-yl)naphthalen-2-yl]prop-2- enenitrile;5- [7-(2-cyclopropylethyl)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1 / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;5- { 7-[(2,2-difluorocyclopropyl)methoxy]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5- [7-(2-cyclopropylethoxy)- 1 -fluoro-3-hydroxynaphthalcn-2-yl ]- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;5- { 7-[2-(cyclopropylmethoxy)ethoxy]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-{ l-fluoro-3-hydroxy-7-[2-(oxolan-2-yl)ethoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l,l,3- trione;5- { 7-[2-(cyclobutyloxy)ethoxy]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - l76,2,5-thiadiazolidine- l,l,3-trione;5-( 1 -fluoio-3-hydroxy-7- ( 2- | (propan-2-yl)oxy] ethoxy }naphthalcn-2-yl)- 1 / / \2,5-thiadiazolidinc- l,l,3-trione;5- [7-(3-ethoxypropoxy)- 1 -fluoro-3-hydroxynaphthalcn-2-yl ]- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;5- [7-(2-ter / -butoxyethoxy)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;5-(7-{ [rac-(l ?,2 ?)-2-ethylcyclopropyl]methoxy}-l-fluoro-3-hydroxynaphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-[l-fluoro-3-hydroxy-7-(4-methylpentyl)naphthalen-2-yl]-l76,2,5-thiadiazolidine-l,l,3-trione; 5- { 7-[3-(2,2-dimethylpropyl)pyrrolidin- 1 -yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl} - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5- [7-(l -chloro-3-hydroxypropan-2-yl)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5- { 7-[ 1 -(cyclopropylmethyl)pyrrolidin-3-yl]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-|7-(cyclopropyloxy)- 1 -fluoro-3-hydroxynaphthalcn-2-yl ]- 1 / / \2,5-thiadiazol idinc- 1 , 1 ,3-trione; 5-{7-[(2-cyclopropylethyl)amino]-l-fluoro-3-hydroxynaphthalen-2-yl}-l76,2,5-thiadiazolidine- l,l,3-trione;5 - [ 1 -fluoro-3 -hydroxy-7 - (4-methyl- 17 / -imidazol-2-yl)naphthalen-2-yl] - 1 l6,2,5 -thiadiazolidine- l,l,3-trione;5- [7-(azetidin-3-yl)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;5 - [ 1 -fluoro-3 -hydroxy-7 - (5 -methoxythiophen-2-yl)naphthalen-2-yl] - 1 l6,2,5 -thiadiazolidine- l,l,3-trione;[8-fluoro-6-hydroxy-7-(l , 1 ,4-trioxo- 1l6, 2, 5-thiadiazolidin-2-yl)naphthalen-2-yl] acetonitrile;5-| 1 -fluoio-3-hydroxy-7-(mcthoxymcthyl )naphthalcn-2-yl ]- 1 / ’,2,5-thiadiazol idinc- 1 , 1 ,3-trione; 5-{ l-fluoro-3-hydroxy-7-[(3-methyloxetan-3-yl)methoxy]naphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5- { 4-bromo-7-| 1 -(cyclopropancsulfonyl )-2, 5-dihydro- 1 / / -pyrrol-3-yl ]- 1 -fluoro-3- hydroxynaphthalen-2-yl}- l76,2,5-thiadiazolidine-l , 1 ,3-trione;5- { 4-bromo-7-[ l-(cyclopropanesulfonyl)- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;5-{ l-fluoro-3-hydroxy-7-[(35)-pyrrolidin-3-yl]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l,l,3- trione;5- { l-fluoro-3-hydroxy-7-[(3f?)-pyrrolidin-3-yl]naphthalen-2-yl } - l76,2,5-thiadiazolidine- 1 , 1 ,3- trione;5-(8-chloro-l-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-l76,2,5-thiadiazolidine-l,l,3-trione; 5- { 7-[(3,3-difluorocyclobutyl)methoxy] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-(7-cyclopropyl- 1 -fluoro-3-hydroxynaphthalcn-2-yl )- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc;5- { 7-[ 1 -(cyclopropanecarbonyl)-2, 5-dihydro- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2- yl } - 176,2,5-thiadiazolidine- 1 , 1 ,3-trione ;5-(4-chloro- 1 -fluoio-3-hydroxy-7-methoxynaphthalen-2-yl)- 1 / ’,2,5-thiadiazolidine- 1 , 1 ,3-trione; 5- { 7-[(£T)-2-cyclopropylethenyl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - l76,2,5-thiadiazolidine- l,l,3-trione;5- { 1 -fluoro-3 -hydroxy-7 - [( l£T)-4-methylpent- 1 -en- 1 -yl] naphthalen-2-yl } - 1 l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-{ l-fluoro-3-hydroxy-7-[l-(pentamethylphenyl)ethenyl]naphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-{7-[l-(cyclopropylmethyl)-2,5-dihydro-l / / -pyrrol-3-yl]-l-fluoro-3-hydroxynaphthalen-2-yl}- 1 / / \2,5-thiadiazolidine- 1 , 1 ,3-trione;5-(4-bromo- 1 -fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)- l76,2,5-thiadiazolidine- 1 , 1 ,3-trione;5- { 7-[ 1 -(2-cyclopropylethyl)-2,5-dihydro- l / / -pyrrol-3-yl]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;5-{ l-fluoro-3-hydroxy-7-[(l£T)-3-methoxyprop-l-en-l-yl]naphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-|7-(2-cthoxycthoxy)- 1 -fluoro-3-hydroxynaphthalcn-2-yl ]- 1 / \2,5-thiadiazol idinc- 1 , 1 ,3-trionc; 5- [1 -fluoro-3-hydroxy-7-(3-methoxypropoxy)naphthalen-2-yl] - 1' / \2, 5-thiadiazolidinc- 1 , 1 ,3- trione;5- [7-( 1 , 1 -dioxo- 1 / ’-thian-4-yl )- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 176,2,5-thiadiazolidine- l,l,3-trione;5-| 1 -fluoro-3-hydroxy-7-(oxan-3-yl )naphthalcn-2-yl ]- 1 lή,2, 5-thiadiazolidinc- 1 , 1 ,3-trionc;5- [7-(cyclopropylmethoxy)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1 lή,2, 5-thiadiazolidinc- 1 , 1 ,3- trione;5-(l-fluoro-3-hydroxy-7-{ [l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]methyl}naphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;5-(l-fluoro-3-hydroxy-7-{ [l-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl}naphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;5 - ( 1 -fluoro- 3 -hydroxy-7 - { 2- [methyl(2-methylpropyl)amino] ethoxy } naphthalen-2-yl)- 1 l6,2,5 - thiadiazolidine- 1 , 1 ,3-trione ;5-{ l-fluoro-3-hydroxy-7-[(oxolan-2-yl)methoxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l ,l,3- trione;5-| 1 -fluoio-3-hydi oxy-7-(oxolan-3-yl)naphthalcn-2-yl ]- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trionc;5-(7- { [1 -(cyclopropanesulfonyl)azetidin-3-yl]methyl } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;5-(7- { [ 1 -(cyclopropanesulfonyl)piperidin-4-yl] methyl } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;5- [1 -fluoro-3-hydroxy-7-(pyrrolidin-2-yl)naphthalen-2-yl] - 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione; 5-(7- { [1 -(cyclopropanesulfonyl)piperidin-3-yl]methyl } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione;5- [7-(difluoromethoxy)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione; 5-(7- { [1 -(cyclopropanesulfonyl)pyrrolidin-3-yl]methyl } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione;5 - { 1 -fluoro-3 -hydroxy-7 - [(pyrrolidin-3 -yl)methyl] naphthalen-2-yl } - 1 l6,2,5 -thiadiazolidine- l,l,3-trione;5-[7-(2,5-dihydrofuran-3-yl)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5-thiadiazolidine-l,l,3- trione;5-[7-(3,6-dihydro-2 / / -pyran-4-yl)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5-thiadiazolidine- l,l,3-trione;5-[7-(2,5-dihydro-l / / -pyrrol-3-yl)-l-fluoro-3-hydroxynaphthalen-2-yl]-l76,2,5-thiadiazolidme- l,l,3-trione;5 - [ 1 -fluoro-3 -hydroxy-7 - (pyridin-3 -yl)naphthalen-2-yl] - 1 l6,2, 5 -thiadiazolidine- 1,1,3 -trione ;5- { 7-[(azetidin-3-yl)methyl]- 1 -fluoro-3-hydroxynaphthalcn-2-yl }- 1 / \2,5-thiadiazolidinc- 1,1,3- trione; / V-(2-cyclopropylcthyl )-2- ( 18-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2- yl)naphthalen-2-yl] amino } acetamide ;4- ( 18-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl )naphthalcn-2-yl ]oxy }- / V- methylbutanamide ; / V-cthyl- / V’-(2- ( 18-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2-yl)naphthalcn-2- yl] oxy } ethyl)urea ;5- { l-fluoro-3-hydroxy-7-[(oxan-3-yl)methoxy]naphthalen-2-yl } - 1 / / \2,5-thiadiazolidinc- 1,1,3- trione;5- { 7-[(l -chloro-3-hydroxypropan-2-yl)oxy]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5- { 1 -fluoro-3 -hydroxy-7 - [(oxan-4-yl)methoxy] naphthalen-2-yl } - 1 lή,2,5- thiadiazolidine- 1 , 1 ,3- trione;5-{ l-fluoro-3-hydroxy-7-[(oxetan-3-yl)oxy]naphthalen-2-yl}-l76,2,5-thiadiazolidine-l,l,3- trione;5-{ l-fluoro-3-hydroxy-7-[l-(2,2,2-trifluoroethyl)-l,2,3,6-tetrahydropyridin-4-yl]naphthalen-2- yl } - 1 lή,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5 - ( 1 -fluoro- 3 ,7 -dihydroxynaphthalen-2-yl)- 1 l6,2,5 -thiadiazolidine- 1,1,3 -trione ;5 - [ 1 -fluoro-3 -hydroxy-7 - (2-hydroxyethoxy)naphthalen-2-yl] - 1 l6,2, 5 -thiadiazolidine- 1 , 1 ,3- trione ;5 - ( 1 -fluoro- 3 -hydroxy-7 -propoxynaphthalen-2-yl) - 1 l6,2, 5 -thiadiazolidine- 1 , 1 ,3-trione ;5- { l-fluoro-3-hydroxy-7-[(propan-2-yl)oxy]naphthalen-2-yl } - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;{ [8-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1l6, 2, 5-thiadiazolidin-2-yl)naphthalen-2-yl] amino } acetic acid; / V-(2-cyclopropylethyl)-2-{ [8-fluoro-6-hydroxy-7-(l,l,4-trioxo-l76,2,5-thiadiazolidin-2- yl)naphthalen-2-yl] oxy } acetamide ; / V, / V-diethyl-2- ( 18-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl)naphthalcn-2- yl] oxy } acetamide ;5- { 1 -fluoro-3-hydroxy-7 - [2-oxo-2-(pyrrolidin- 1 -yl)ethoxy] naphthalen-2-yl } - 1 l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-(l-fluoro-3-hydroxy-7-{ [l-(methanesulfonyl)piperidin-4-yl]oxy}naphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-{ l-fluoro-3-hydroxy-7-[l-(oxolane-3-sulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]naphthalen-2-yl}- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;5-{ l-fluoro-3-hydroxy-7-[l-(2-methoxyethanesulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]naphthalen- 2-yl } - 1 l6,2, 5-thiadiazolidine- 1 , 1 ,3-trione ;5- { l-fluoro-3-hydroxy-7-[l-(3, 3, 3-trifluoropropane-l-sulfonyl)-2, 5-dihydro- l / / -pyrrol-3- yl]naphthalen-2-yl } - 1l6, 2, 5 -thiadiazolidine- 1 , 1 ,3-trione;5- { l-fluoro-3-hydroxy-7-[l-(3, 3, 3-trifluoropropane-l-sulfonyl)-2, 5-dihydro- l / / -pyrrol-3- yl]naphthalen-2-yl } - 1l6, 2, 5 -thiadiazolidine- 1 , 1 ,3-trione;5-(l-fluoro-3-hydroxy-7-{ l-[(oxan-2-yl)methanesulfonyl]-2,5-dihydro-l / / -pyrrol-3- yl }naphthalcn-2-yl )- 1 lή,2, 5-thiadiazolidinc- 1 , 1 ,3-trione;5- { l-fluoro-3-hydroxy-7-[l-(4,4,4-trifluorobutane- l-sulfonyl)-2, 5-dihydro- l / / -pyrrol-3- yl]naphthalen-2-yl } - 1l6, 2, 5 -thiadiazolidine- 1 , 1 ,3-trione;5- { 7-[ 1 -(butane- 1 -sulfonyl)-2, 5-dihydro- l / / -pyrrol-3-yl] - l-fluoro-3-hydroxynaphthalen-2-yl } - 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione;5-(7-{ l-[(l,4-dioxan-2-yl)methanesulfonyl]-2,5-dihydro-l / / -pyrrol-3-yl}-l-fluoro-3- hydroxynaphthalcn-2-yl )- 1 lή,2, 5-thiadiazolidinc- 1 , 1 ,3-trione;5- { 3-| 8-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalcn-2-yl ]-2,5- dihydro- 1 / / -pyrrole- 1 -sulfonyl } pentanenitrile ;5-{ l-fluoro-3-hydroxy-7-[l-(pentane-2-sulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]naphthalen-2-yl}- 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione;5- { 7-[ 1 -(ethanesulfonyl)-2, 5-dihydro- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione;5-{ l-fluoro-3-hydroxy-7-[l-(propane-2-sulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]naphthalen-2-yl}- 1l6, 2, 5-thiadiazolidine- 1 , 1 ,3-trione;5- { 7-[ 1 -(cyclopropanesulfonyl)- 1 ,2,3,6-tetrahydropyridin-4-yl] - 1 -fluoro-3-hydroxynaphthalen- 2-yl } - 1 l6,2, 5-thiadiazolidine- 1 , 1 ,3-trione ;N-(2- { 18-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl]oxy}ethyl)oxetane-3-sulfonamide;5-| 1 -flu i -3-hydi oxy-7-(pipci idin-4-yl)naphthalcn-2-yl ]- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;5- { l-fluoro-3-hydroxy-7-[l -(2-methylpropane- 1 -sulfonyl )-2, 5-dihydro- 1 / / -pyrrol-3- yl]naphthalen-2-yl } - 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;5-(7-ethoxy- 1 -fluoro-3-hydroxynaphthalen-2-yl)- l76,2,5-thiadiazolidine- 1 , 1 ,3-trione;5- [7-(2,2-difluoroethoxy)- 1 -fluoro-3-hydroxynaphthalcn-2-yl ]- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3- trione;5- { 7-[ 1 -(cyclopropanesulfonyl)- l / / -pyrazol-4-yl]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-(l-fluoro-3-hydroxy-7-{ [(3 ?)-l-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;5-(l-fluoro-3-hydroxy-7-{ [l-(methanesulfonyl)piperidin-4-yl]amino}naphthalen-2-yl)-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5-(7- { [1 -(cyclopropanesulfonyl)pyrrolidin-3-yl] amino } - 1 -fluoro-3-hydroxynaphthalen-2-yl)- 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;5 - ( 1 -fluoro-7- { [3 -fluoro- 1 - (methanesulfonyl)pyrrolidin-3 -yl] methoxy } -3 -hydroxynaphthalen-2- yl)- 1 l6, 2, 5 -thiadiazolidine- 1 , 1 ,3-trione ;5-{ l-fluoro-3-hydroxy-7-[l-(propane-2-sulfonyl)pyrrolidin-3-yl]naphthalen-2-yl}-l76,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5- [7-(2-aminoethoxy)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - l76,2,5-thiadiazolidine- 1 , 1 ,3-trione; 5- { 7-[ 1 -(1 ,3-dimethyl- l / / -pyrazole-4-sulf onyl)-2, 5-dihydro- l / / -pyrrol-3-yl]- 1 -fluoro-3- hydroxynaphthalen-2-yl}- l76,2,5-thiadiazolidine-l , 1 ,3-trione; / V-(2- ( 18-fluoio-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl )naphthalcn-2- yl] oxy } ethyl)ethanesulfonamide ;5-{ l-fluoro-7-[l-(furan-3-sulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]-3-hydroxynaphthalen-2-yl}- 1 / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;5- { 1 -fluoi o-3-hydroxy-7-| 1 -(3-mcthylbutanc- 1 -sulfonyl )-2,5-dihydro- 1 / / -pyrrol-3- yl]naphthalen-2-yl } - 1l6, 2, 5 -thiadiazolidine- 1 , 1 ,3-trione;5-{ l-fluoro-3-hydroxy-7-[l-(thiophene-3-sulfonyl)-2,5-dihydro-l / / -pyrrol-3-yl]naphthalen-2- yl } - 1' / / \2, 5- thiadiazolidine- 1 , 1 ,3-trione ;5- { 7-[ 1 -(benzenesulfonyl)-2, 5-dihydro- l / / -pyrrol-3-yl]- 1 -fluoro-3-hydroxynaphthalen-2-yl } - I / / \2,5-thiadiazolidinc- 1 , 1 ,3-trione;5- { 7-[ 1 -(cyclobutanesulfonyl)-2, 5-dihydro- l / / -pyrrol-3-yl] - 1 -fluoro-3-hydroxynaphthalen-2- yl } - 1 / \2,5-thiadiazolidinc- 1 , 1 ,3-trione ;methyl (25)-2-amino-4-{ 18-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / \2,5-thiadiazolidin-2- yl)naphthalen-2-yl] oxy } butanoate ;5- { 7-[(3, 5-dimethyl- l / / -pyrazol-4-yl)methoxy] - 1 -fluoro-3-hydroxynaphthalen-2-yl } - 1l6,2,5- thiadiazolidine- 1 , 1 ,3-trione ;5- [7-(3, 5-dimethyl- l / -pyrazol-4-yl)- 1 -fluoro-3-hydroxynaphthalen-2-yl] - 1l6, 2,5- thiadiazolidine- 1 , 1 ,3-trione ;5- [7-(2-cyclohexylethoxy)- 1 -†luoro-3-hydroxynaphthalcn-2-yl ]- 1 / ’,2,5-thiadiazolidinc- 1 , 1 ,3- trione;2-|8-fluoro-6-hydroxy-7-( 1 , 1 ,4-trioxo- 1 / / \2,5-thiadiazolidin-2-yl)naphthalcn-2-yl ]- 1 H- imidazole-4-carbonitrile ;and a pharmaceutically acceptable salt, solvate, hydrate, tautomer, ester, N-oxide or stereoisomer thereof.

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

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

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

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

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

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

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

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

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

68. A method of treating and / or controlling obesity in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-58 or the composition of claim 59 or 60.

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

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