INHIBITORS OF PROTEIN TYROSINE PHOSPHATASE, COMPOSITIONS, AND METHODS OF USE CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Serial No. 63/383,005 filed November 9, 2022 which is incorporated herein in its entirety. FIELD OF THE INVENTION Disclosed are compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and combinations thereof, and methods of using the same as inhibitors of protein tyrosine phosphatases. BACKGROUND Immune checkpoint blockade (ICB) is an innovative approach to immunotherapy that targets immune evasion mechanisms to improve clinical responses in cancer patients. For example, checkpoint blockade antibodies target cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and its ligands, such as programmed cell death ligand 1 (PD-L1), in the treatment of multiple types of cancer to significantly improve the treatment and survival outcomes of patients affected by these malignancies. A majority of patients who undergo ICB, however, are either refractory to treatment or eventually acquire resistance. In particular, mutation or loss of interferon-gamma (IFNγ) signaling pathway represents a significant mechanism of clinical ICB resistance ( Zaretsky, N. Engl. J. Med.375, 819– 829). IFNγ is a T-cell-derived cytokine that signals through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT) to restrict tumor growth directly. Furthermore, IFNγ indirectly restricts tumor growth by promoting upregulation of major histocompatibility complex class I (MHC-I), thereby enabling antigen (Ag) presentation to T-cells. In vivo CRISPR screening using syngeneic mouse models has revealed enrichment of the IFNγ pathway in tumors resistant to anti-PD-1. These studies identified the aforementioned IFNγ pathway members (JAK1/2 and STAT1) and Interferon Gamma Receptor (IFNGR1/IFNGR2) as resistance hits, in addition to newly identified negative regulators - such as PTPN2 and Apelin Receptor (APLNR) - which represent novel therapeutic targets (Charles Sinclair et al. Emerg Top Life Sci. (2021) 5 (5): 675–680). Data pooled from in vivo genetic screening using CRISPR–Cas9 genome editing to identify genes that cause resistance to checkpoint blockade identified that deletion of the protein tyrosine phosphatase (PTPN2) gene in tumor cells increased the efficacy of immunotherapy. The PTPN2 gene encodes a protein tyrosine phosphatase that regulates a range of intracellular processes. Loss of PTPN2 in tumor cells promotes amplified IFNγ signaling, antigen presentation to T cells and growth arrest in response to cytokines; these data suggest that PTPN2 therapeutic inhibition may potentiate the effect of immunotherapies that invoke an IFNγ response (Manguso, Robert T et al. Nature vol.547, 7664 (2017): 413- 418). Protein tyrosine phosphatase non-receptor type 2 (PTPN2), also known as T cell protein tyrosine phosphatase (TCPTP), is an intracellular member of the class 1 subfamily 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 (1992) 89:499-503). 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 (1994) 14:3030-3040). 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, and as a critical negative regulator of the JAK-STAT pathway, PTPN2 directly regulates signaling through cytokine receptors. 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 (2003) 414:40-50). T cell protein tyrosine phosphatase PTPN2 has been further identified as a key negative regulator of TCR signaling, underscoring an association between PTPN2 Single nucleotide polymorphisms (SNPs) and autoimmune disease (Wiede F et al., J Clin Invest. (2011);121(12):4758-4774). PTPN2 dephosphorylates and inactivates Src family kinases to regulate T cell responses. PTPN2 deficiency has been demonstrated to lower the in vivo threshold for TCR-dependent CD8 ⁺ T cell proliferation. Consistent with these findings, T cell-specific PTPN2-deficient mice have been shown to develop widespread inflammation and autoimmunity. This autoimmunity is associated with increased serum levels of proinflammatory cytokines, anti-nuclear antibodies, T cell infiltrates in non-lymphoid tissues, and liver disease. These data further indicate that PTPN2 is a critical negative regulator of TCR signaling that sets the threshold for TCR-induced naive T cell responses to prevent autoimmune and inflammatory disorders. In addition to PTPN2 encoding T cell PTP (TCPTP) as a susceptibility locus for autoimmune diseases, SNPs in PTPN2 have been linked to the development of type 1 diabetes, rheumatoid arthritis, and Crohn’s disease. Moreover, a type 1 diabetes–linked PTPN2 variant rs1893217(C) has also been associated with decreased PTPN2 expression in T cells (Florian Wiede J Clin Invest.2011;121(12):4758-4774). The above findings suggest that inhibition of PTPN2 is a potential therapeutic strategy to improve the efficacy of cancer therapy regimens associated with ICB resistance. SUMMARY The present disclosure is directed to compounds pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, are effective inhibitors of protein tyrosine phosphatases, 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)). The invention further provides methods of treating, preventing, or ameliorating cancers comprising administering to a subject in need thereof an effective amount of PTPN2/PTPN1 inhibitors disclosed herein. In a preferred embodiment, the compounds have a mono-cyclic core structure compared to literature- reported compounds, where compounds contain fused bicyclic cores. 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). 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). These and other features of the invention will be set forth in expanded form in this disclosure. The first aspect of the present invention provides at least one compound of Formula (I) of the following structure: O wherein, independently for each occurrence: R ¹ is selected from the group consisting of: 6-oxo-1,6-dihydropyridin-2-yl, ; R ² is selected from the group consisting of: −H, cycloalkyl, alkyl, and substituted alkyl; R ³ is selected from the group consisting of: −H, alkyl, halogen, −CN, −OCH ₃ , cycloalkyl, −CF ₃ , −C(CH ₃ ) ₂ R ⁷ , aryl, substituted alkyl, alkoxyl, -CH(CH3)2, - C(CH3)3, -OCF3, -OH and benzyloxy; R ⁴ is selected from the group consisting of: −H, alkyl, substituted alkyl, amines, secondary amines, tertiary amines, −CHF ₂ , halogen, −CN, −OCH ₃ , −N(CH ₃ ) ₂ , −OCHF ₂ , alkoxyl, -NHCH3, -OH, -CH2CH3, and morpholin-4-yl; R ⁵ is selected from the group consisting of: −H, alkyl, substituted alkyl, alkoxyl, amines, secondary amines, tertiary amines, halogen, −CH ₂ CH ₃ , −CN, −OCH ₃ , - N(CH3)2, -NHCH3, cyclopropyl, cyclopropoxy, cyclohexyl, −CF ₃ , -OH, -Ph, - ; ; R ⁶ is selected from the group consisting of: −H, alkyl, −CH ₂ CH ₃ , −OCH ₃ , -OH, and −CF ₃ ; R ⁷ is selected from the group consisting of: −H and −CH ₃ ; R ⁸ is selected from the group consisting of: −O− and −CH ₂ O−. Further disclosed is a compound selected from a group consisting of: 5-(4-(((4-cyclopropylpyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((4-(trifluoromethyl)pyridin-2-yl)a mino)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((3-(trifluoromethyl)pyridin-2-yl)a mino)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((5-(tert-butyl)pyridin-2-yl)amino)methyl)-2-fluoro-6- hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((4,6-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hy droxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((4-cyclopropoxypyridin-2-yl)amino)methyl)-2-fluoro-6- hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((4-methylpyridin-2-yl)amino)methyl )phenyl)-1,2,5-thiadiazolidin-3- one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-phenylpyridin-2-yl)amino)methyl )phenyl)-1,2,5-thiadiazolidin-3- one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((4-methoxy-5-methylpyridin-2-yl)am ino)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((5-cyclopropylpyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 2-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro -5- hydroxybenzyl)amino)isonicotinonitrile; 5-(2-fluoro-6-hydroxy-4-(((4-methoxypyridin-2-yl)amino)methy l)phenyl)-1,2,5-thiadiazolidin- 3-one 1,1-dioxide; 5-(4-(((4-ethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxy phenyl)-1,2,5-thiadiazolidin-3- one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-methylpyridin-2-yl)amino)methyl )phenyl)-1,2,5-thiadiazolidin-3- one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((3-methylpyridin-2-yl)amino)methyl )phenyl)-1,2,5-thiadiazolidin-3- one 1,1-dioxide; 5-(2-fluoro-4-(((4-fluoropyridin-2-yl)amino)methyl)-6-hydrox yphenyl)-1,2,5-thiadiazolidin-3- one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methylpyridin-2-yl)amino)methyl )phenyl)-1,2,5-thiadiazolidin-3- one 1,1-dioxide; 5-(4-(((4,6-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((5,6-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hy droxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((3,6-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hy droxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-[4-[[(3,6-dimethoxy-2-pyridyl)amino]methyl]-2-fluoro-6-hyd roxy-phenyl]-1,1-dioxo-1,2,5- thiadiazolidin-3-one 5-(2-fluoro-6-hydroxy-4-(((3-methoxy-6-methylpyridin-2-yl)am ino)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((3-ethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxy phenyl)-1,2,5-thiadiazolidin-3- one 1,1-dioxide; 5-(4-(((3,5-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hy droxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((3,4-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hy droxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((4,5-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((3,4-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((4,5-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hy droxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methoxy-3-methylpyridin-2-yl)am ino)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((3,5-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-4-(((5-fluoro-4-methylpyridin-2-yl)amino)methyl) -6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 6-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro -5-hydroxybenzyl)amino)-4- methylnicotinonitrile; 5-(2-fluoro-4-(((4-fluoro-5-methylpyridin-2-yl)amino)methyl) -6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((3-methoxypyridin-2-yl)amino)methy l)phenyl)-1,2,5-thiadiazolidin- 3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methoxypyridin-2-yl)amino)methy l)phenyl)-1,2,5-thiadiazolidin- 3-one 1,1-dioxide; 5-(4-(((5,6-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((pyridin-2-ylamino)methyl)phenyl)-1 ,2,5-thiadiazolidin-3-one 1,1- dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-methoxypyridin-2-yl)amino)methy l)phenyl)-1,2,5-thiadiazolidin- 3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methoxy-4-methylpyridin-2-yl)am ino)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 6-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro -5- hydroxybenzyl)amino)picolinonitrile; 5-(2-fluoro-6-hydroxy-4-(((4-methoxy-6-methylpyridin-2-yl)am ino)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((6-(difluoromethyl)pyridin-2-yl)amino)methyl)-2-fluor o-6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((6-(difluoromethoxy)pyridin-2-yl)amino)methyl)-2-fluo ro-6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((6-(dimethylamino)pyridin-2-yl)amino)methyl)-2-fluoro -6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-isopropylpyridin-2-yl)amino)met hyl)phenyl)-1,2,5-thiadiazolidin- 3-one 1,1-dioxide; 5-(4-(((4-(benzyloxy)pyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((5-(benzyloxy)pyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((6-bromo-4-methylpyridin-2-yl)amino)methyl)-2-fluoro- 6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((4-methyl-6-morpholinopyridin-2-yl )amino)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-((cyclopropyl(5-(trifluoromethyl)pyridin-2-yl)amino)met hyl)-2-fluoro-6-hydroxyphenyl)- 1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-oxo-1,6-dihydropyridin-2-yl)ami no)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methyl-4-phenoxypyridin-2-yl)am ino)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; or pharmaceutically acceptable salts thereof. In some embodiments, the compound of Formula (I) is formulated as a pharmaceutically acceptable composition comprising the compound of Formula (I) and a pharmaceutically acceptable carrier. Also disclosed herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of the compound of formula (I) disclosed herein in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an immunotherapeutic agent. For example, in some embodiments, the immunotherapeutic agent is an antibody. 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). 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). 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. 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) in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an immunotherapeutic agent. For example, in some embodiments, the immunotherapeutic agent is selected from the group consisting of an anti- PD-1 antibody, and an anti-PD-L1 antibody. 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). DETAILED DESCRIPTION The present disclosure is directed to compounds pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, are effective inhibitors of protein tyrosine phosphatases, 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)). The invention further provides methods of treating, preventing, or ameliorating cancers comprising administering to a subject in need thereof an effective amount of PTPN2/PTPN1 inhibitors disclosed herein. In a preferred embodiment, the compounds have a mono-cyclic core structure compared to literature- reported compounds, where compounds contain fused bicyclic cores. Definitions Chemical Definitions 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, 75 ^th Ed., 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, 5 ^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 ^rd Edition, Cambridge University Press, Cambridge, 1987. 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. 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, geometric isomer, or a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. 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. The features and advantages of the invention as described in this disclosure may be more readily understood by those of ordinary skill in the art in view of the following definitions. Certain features of the invention described within the context of separate embodiments may also be combined to form a single or extrapolated to include multiple embodiments. Embodiments identified herein as exemplary or preferred are illustrative and not limiting. Unless expressly stated otherwise herein, references made in the singular may also include the plural. For example, “a” and “an” may refer to either one or one or more. As used herein, the phrase “compounds” refers to at least one compound. For example, a compound of Formula (I) includes a compound of Formula (I) and two or more compounds of Formula (I). Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences. The definitions set forth herein take precedence over definitions set forth in any patent, patent application, and/or patent application publication incorporated herein by reference. Listed below are definitions of various terms used to describe the present invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group. Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds. In accordance with a convention in the art, is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure. The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, and I. The term “cyano” refers to the group −CN. The term “amino” refers to the group −NH ₂ . The term "oxo" refers to the group =O. The term “alkyl” as used herein, refers to both branched and straight-chain saturated aliphatic hydrocarbon groups containing, for example, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl (e.g., n-butyl, i- butyl, sec-butyl, and t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2- methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When numbers appear in a subscript after the symbol “C”, the subscript defines with more specificity the number of carbon atoms that a particular group may contain. For example, “C ₁₋₆ alkyl” denotes straight and branched chain alkyl groups with one to six carbon atoms. The term "fluoroalkyl" as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C ₁₋₄ fluoroalkyl" is intended to include C ₁ , C ₂ , C ₃ , and C ₄ alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, −CF ₃ and −CH ₂ CF ₃ . The term "cyanoalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more cyano groups. For example, "cyanoalkyl" includes −CH ₂ CN, −CH ₂ CH ₂ CN, and C ₁ − ₄ cyanoalkyl. The term "aminoalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more amine groups. For example, "aminoalkyl" includes −CH ₂ NH ₂ , −CH ₂ CH ₂ NH ₂ , and C ₁ − ₄ aminoalkyl. The term "hydroxyalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes −CH ₂ OH, −CH ₂ CH ₂ OH, and C ₁₋₄ hydroxyalkyl. The term "hydroxy-fluoroalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups and one or more fluorine atoms. For example, "hydroxy-fluoroalkyl" includes −CHFCH ₂ OH, −CH ₂ CHFC(CH ₃ ) ₂ OH, and C ₁₋₄ hydroxy-fluoroalkyl. The term “cycloalkyl,” “carbocyclic” “carbocyclyl” as used herein, refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by removal of one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When numbers appear in a subscript after the symbol “C”, the subscript defines with more specificity the number of carbon atoms that a particular cycloalkyl group may contain. For example, “C ₃ −C ₆ cycloalkyl” denotes cycloalkyl groups with three to six carbon atoms. The term “heterocyclic” as used herein, refers to organic compounds with cyclic structures of both carbon atoms and non-carbon atoms such as oxygen, nitrogen. The term “alkoxy,” as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom, for example, methoxy group (−OCH ₃ ). For example, “C ₁ − ₃ alkoxy” denotes alkoxy groups with one to three carbon atoms. The term “alkoxyalkyl,” as used herein, refers to an alkoxy group attached through its oxygen atom to an alkyl group, which is attached to the parent molecular moiety, for example, methoxymethyl group (−CH ₂ OCH ₃ ). For example, “C ₂₋₄ alkoxyalkyl” denotes alkoxyalkyl groups with two to four carbon atoms, such as −CH ₂ OCH ₃ , −CH ₂ CH ₂ OCH ₃ , −CH ₂ OCH ₂ CH ₃ , and −CH ₂ CH ₂ OCH ₂ CH ₃ . The term “amine” or “amines” as used herein refers to compounds in which a nitrogen atom is directly bonded to several carbon atoms. Embodiments are comprised of derivatives of ammonia (-NH ₃ ) resulting from a progressive substitution of the three hydrogen atoms by hydrocarbon groups. Amines are classified as primary, secondary, or tertiary by the number of carbons bonded to the nitrogen atom. For example, a primary amine has one carbon bonded to the nitrogen (R−NH ₂ ), a secondary amine has two carbons bonded to the nitrogen, amine (R2−NH), and a tertiary amine has three carbons bonded to the nitrogen (R3−N) wherein R is an alkyl group. The term “heteroaryl” as used herein, refers to an aromatic heterocycle ring of 5 to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The compounds of Formula (I) can be provided as amorphous solids or crystalline solids. Lyophilization can be employed to provide the compounds of Formula (I) as amorphous solids. It should further be understood that solvates (e.g., hydrates) of the compounds of Formula (I) are also within the scope of the present invention. The term “solvate” means a physical association of a compound of Formula (I) with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art. Various forms of prodrugs are well known in the art and are described in: a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996); b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, P. Krogsgaard–Larson and H. Bundgaard, eds. Ch 5, pgs 113 – 191 (Harwood Academic Publishers, 1991); and d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer, (Wiley-VCH, 2003). In addition, compounds of Formula (I), subsequent to their preparation, can be isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% of a compound of Formula (I) (“substantially pure”), which is then used or formulated as described herein. Such “substantially pure” compounds of Formula (I) are also contemplated herein as part of the present invention. “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present invention is intended to embody stable compounds. A person of ordinary skill in the art would also understand that the compounds described and claimed herein as embodiments of the invention also exist in their “tautomeric forms.” As used herein, Tautomers that exist in tautomeric form pertain to compounds that are structural isomers that can readily interconvert in rapid equilibrium. As used herein the process of interconversion is called “tautomerization.” For example, the following an embodiment a pyridone tautomer may be represented by the following: The disclosed structures readily interconvert between left-handed and right-handed structural representations. “Therapeutically effective amount” is intended to include an amount of a compound of the present invention alone or an amount of the combination of compounds claimed or an amount of a compound of the present invention in combination with other active ingredients effective to act as an inhibitor or effective to treat or ameliorate cancer. As used herein, “treating” or “treatment” cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state. The compounds of the present invention are intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include ¹³ C and ¹⁴ C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. For example, methyl (-CH ₃ ) also includes deuterated methyl groups such as -CD ₃ . The term "pharmaceutically acceptable salts" is meant to include salts of 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, magnesium salt, or a similar salt. 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 a 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). "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 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. 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. "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. 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. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration. 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 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). 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. Methods of Treatment The present disclosure features compounds, compositions, and methods comprising a compound disclosed herein, e.g., a compound of Formula (I). 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. Cancer In some embodiments, a compound disclosed herein, e.g., a compound of Formula (I), 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 B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas), Hodgkin'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. 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, HER2 positive, doxorubicin-resistant, tamoxifen-resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, acoustic neuroma, retinoblastoma, astrocytoma, craniopharyngioma, hemangioblastoma, 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 insulinoma, 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, and hepatocellular carcinoma. The first aspect of the present invention provides at least one compound of Formula (I) of the following structure: O wherein, independently for each occurrence: R ¹ is selected from the group consisting of: 6-oxo-1,6-dihydropyridin-2-yl, ; R ² is selected from the group consisting of: −H, cycloalkyl, alkyl, and substituted alkyl; R ³ is selected from the group consisting of: −H, alkyl, halogen, −CN, −OCH ₃ , cycloalkyl, −CF ₃ , −C(CH ₃ ) ₂ R ⁷ , aryl, substituted alkyl, alkoxyl, -CH(CH3)2, - C(CH3)3, -OCF3, -OH and benzyloxy; R ⁴ is selected from the group consisting of: −H, alkyl, substituted alkyl, amines, secondary amines, tertiary amines, −CHF ₂ , halogen, −CN, −OCH ₃ , −N(CH ₃ ) ₂ , −OCHF ₂ , alkoxyl, -NHCH3, -OH, -CH2CH3, and morpholin-4-yl; R ⁵ is selected from the group consisting of: −H, alkyl, substituted alkyl, alkoxyl, amines, secondary amines, tertiary amines, halogen, −CH ₂ CH ₃ , −CN, −OCH ₃ , - N(CH3)2, -NHCH3, cyclopropyl, cyclopropoxy, cyclohexyl, −CF ₃ , -OH, -Ph, - ; ; R ⁶ is selected from the group consisting of: −H, alkyl, −CH ₂ CH ₃ , −OCH ₃ , -OH, and −CF ₃ ; R ⁷ is selected from the group consisting of: −H and −CH ₃ ; R ⁸ is selected from the group consisting of: −O− and −CH ₂ O−. In one embodiment of the compound of formula (I): R ¹ is ; R ² is selected from the group consisting of: −H and cyclopropyl; R ³ is selected from the group consisting of: −H, −CH ₃ , cyclopropyl, phenyl, and benzyloxy; R ⁴ is selected from the group consisting of: −H, −CH ₃ , and −Br R ⁵ is selected from the group consisting of: −CH ₃ and −F; R ⁶ is selected from the group consisting of: −H, −CH ₃ , and −OCH ₃ . In another embodiment of the compound of formula (I): R ³ is −H; R ⁴ is selected from the group consisting of: −H, alkyl, halogen, and −CN; R ⁵ is selected from the group consisting of: −H and . In one embodiment of the compound of formula (I): R ² is −H; R ³ is selected from the group consisting of: cyclyl, −CF ₃ , −C(CH ₃ ) ₂ R ⁷ , aryl, and benzyloxy; R ⁵ is −H; R ⁶ is −H. In another embodiment of the compound of formula (I): R ² is −H; R ⁴ is selected from the group consisting of: −H, −N(CH ₃ ) ₂ , −OCHF ₂ , and morpholin- 4-yl; R ⁵ is selected from the group consisting of: halogen, −CH ₂ CH ₃ , −CF ₃ , and ; R ⁶ is selected from the group consisting of: −H and −CH ₂ CH ₃ . In one embodiment of the compound of formula (I) R ³ is −H; R ⁵ is selected from the group consisting of: −H, −CH ₂ CH ₃ , −CN, and −CF ₃ . In another embodiment of the compound of formula (I) R ³ is selected from the group consisting of: −H, alkyl, and −F; R ⁴ is selected from the group consisting of: −H, −CHF ₂ , halogen, −CN, −OCH ₃ , −N(CH ₃ ) ₂ , −OCHF ₂ , and morpholin-4-yl. In one embodiment of the compound of formula (I) R ¹ is ; R ³ is selected from the group consisting of: alkyl, −CN, −OCH ₃ , and −CF ₃ ; R ⁴ is selected from the group consisting of: −H, alkyl, and −OCH ₃ ; R ⁵ is selected from the group consisting of: −H, alkyl, and −OCH ₃ ; R ⁶ is selected from the group consisting of: −H and −OCH ₃ . In another embodiment the compounds are selected from the following group: 5-(4-(((4-cyclopropylpyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((4-(trifluoromethyl)pyridin-2-yl)a mino)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((3-(trifluoromethyl)pyridin-2-yl)a mino)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((5-(tert-butyl)pyridin-2-yl)amino)methyl)-2-fluoro-6- hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((4,6-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hy droxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((4-cyclopropoxypyridin-2-yl)amino)methyl)-2-fluoro-6- hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((4-methylpyridin-2-yl)amino)methyl )phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-phenylpyridin-2-yl)amino)methyl )phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((4-methoxy-5-methylpyridin-2-yl)am ino)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((5-cyclopropylpyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 2-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro -5- hydroxybenzyl)amino)isonicotinonitrile; 5-(2-fluoro-6-hydroxy-4-(((4-methoxypyridin-2-yl)amino)methy l)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((4-ethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxy phenyl)-1,2,5-thiadiazolidin- 3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-methylpyridin-2-yl)amino)methyl )phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((3-methylpyridin-2-yl)amino)methyl )phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-4-(((4-fluoropyridin-2-yl)amino)methyl)-6-hydrox yphenyl)-1,2,5-thiadiazolidin- 3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methylpyridin-2-yl)amino)methyl )phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((4,6-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((5,6-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hy droxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((3,6-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hy droxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-[4-[[(3,6-dimethoxy-2-pyridyl)amino]methyl]-2-fluoro-6-hyd roxy-phenyl]-1,1-dioxo- 1,2,5-thiadiazolidin-3-one 5-(2-fluoro-6-hydroxy-4-(((3-methoxy-6-methylpyridin-2-yl)am ino)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((3-ethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxy phenyl)-1,2,5-thiadiazolidin- 3-one 1,1-dioxide; 5-(4-(((3,5-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hy droxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((3,4-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hy droxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((4,5-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((3,4-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((4,5-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hy droxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methoxy-3-methylpyridin-2-yl)am ino)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((3,5-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-4-(((5-fluoro-4-methylpyridin-2-yl)amino)methyl) -6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 6-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro -5-hydroxybenzyl)amino)-4- methylnicotinonitrile; 5-(2-fluoro-4-(((4-fluoro-5-methylpyridin-2-yl)amino)methyl) -6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((3-methoxypyridin-2-yl)amino)methy l)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methoxypyridin-2-yl)amino)methy l)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((5,6-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((pyridin-2-ylamino)methyl)phenyl)-1 ,2,5-thiadiazolidin-3-one 1,1- dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-methoxypyridin-2-yl)amino)methy l)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methoxy-4-methylpyridin-2-yl)am ino)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 6-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro -5- hydroxybenzyl)amino)picolinonitrile; 5-(2-fluoro-6-hydroxy-4-(((4-methoxy-6-methylpyridin-2-yl)am ino)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((6-(difluoromethyl)pyridin-2-yl)amino)methyl)-2-fluor o-6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((6-(difluoromethoxy)pyridin-2-yl)amino)methyl)-2-fluo ro-6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((6-(dimethylamino)pyridin-2-yl)amino)methyl)-2-fluoro -6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-isopropylpyridin-2-yl)amino)met hyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((4-(benzyloxy)pyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((5-(benzyloxy)pyridin-2-yl)amino)methyl)-2-fluoro-6-h ydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((6-bromo-4-methylpyridin-2-yl)amino)methyl)-2-fluoro- 6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((4-methyl-6-morpholinopyridin-2-yl )amino)methyl)phenyl)- 1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-((cyclopropyl(5-(trifluoromethyl)pyridin-2-yl)amino)met hyl)-2-fluoro-6- hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-oxo-1,6-dihydropyridin-2-yl)ami no)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methyl-4-phenoxypyridin-2-yl)am ino)methyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide; or pharmaceutically acceptable salts thereof. In one embodiment, the invention comprises a pharmaceutical composition comprising a compound of Formula (I), a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In another embodiment, the invention comprises a method for treating cancer comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein the cancer/disease is selected from: human cancers, carcinomas, sarcomas, adenocarcinomas, papillary adenocarcinomas, lymphomas, leukemias, melanomas, solid lymphoid cancers, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine, testicular, glioma, esophagus, liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas, Burkitt's lymphoma, Small lymphomas, Hodgkin's lymphoma, leukemia, and multiple myeloma. In another embodiment, the invention comprises a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound of formula I in combination with an additional therapeutic agent. In one embodiment, the additional therapeutic agent is an immunotherapeutic agent. In another embodiment, the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody. In one embodiment, the method of treating cancer in a patient in need thereof, comprises administering to the patient an effective amount of a pharmaceutically acceptable composition of the compound of formula I. In another embodiment, the method of treating cancer is selected from radiation, surgery, chemotherapy, or administration of a biologic drug. In one embodiment, the method of treating cancer is the administration of a biologic drug and the biologic drug is a drug that stimulates the immune system. In another embodiment, the method of treating cancer comprises administering to the subject an inhibitor of DGKα and/or DGKζ, an antagonist of the PD1/PD-L1 axis and an antagonist of CTLA4. These embodiments are not intended to limit the scope of the invention. SYNTHETIC METHODS The compounds of the invention may be prepared by the methods and examples presented below and by methods known to those of ordinary skill in the art. In each of the examples below, the R groups are as defined above for each formula unless noted. Optimum reaction conditions and reaction times may vary according to the reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. The intermediates used in the syntheses below are either commercially available or easily prepared by methods known to those skilled in the art. Reaction progress may be monitored by conventional methods such as thin-layer chromatography (TLC) or high- pressure liquid chromatography-mass spec (HPLC-MS). Intermediates and products may be purified by methods known in the art, including column chromatography, HPLC, preparative TLC or Preparatory HPLC. Preparation of relevant synthetic key intermediates (Int-2) Preparation of 5-(4-bromo-2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (Int-2) as shown in Scheme 1. Scheme 1: Int-1 1-6 Int-2 Step 1: Synthesis of 5-bromo-1-fluoro-3-((4-methoxybenzyl)oxy)-2-nitrobenzene (1-2) To a stirred solution of 5-bromo-1,3-difluoro-2-nitro-benzene (10 g, 42.02 mmol) and (4- methoxyphenyl)methanol (6.1 g, 44.12 mmol) in DMF (100 mL) was added K ₂ CO ₃ (17.4 g, 126.06 mmol) in portions at room temperature. The resulting mixture was stirred over night at 70 °C under a nitrogen atmosphere. TLC showed the reaction was completed. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (3*300 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (ethyl acetate/petroleum ether = 1/20) to afford the desired product 5-bromo-1-fluoro-3-[(4-methoxyphenyl)methoxy]-2-nitro-benzen e (10 g, 66.8% yield) as a light yellow solid. Step 2: Synthesis of 4-bromo-2-fluoro-6-((4-methoxybenzyl)oxy)aniline (1-3) To a stirred solution of 5-bromo-1-fluoro-3-[(4-methoxyphenyl)methoxy]-2-nitro-benzen e (10 g, 28.08 mmol) in ethanol (200 mL) and water (20 mL) were added NH ₄ Cl (15.16 g, 280.79 mmol), and Fe (15.68 g, 280.79 mmol) at room temperature. The resulting mixture was stirred at 80 ^o C overnight under a nitrogen atmosphere. LCMS showed the reaction was completed. The reaction mixture was filtrated. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on a silica gel (PE/EA = 9/1) to afford the desired product 4-bromo-2-fluoro-6-[(4- methoxyphenyl)methoxy]aniline (6 g, 65.50% yield) as a light yellow solid. MS: m/z: Calc’d for C ₁₄ H ₁₃ BrFNO ₂ [M+H] ⁺ 326, found 326. Step 3: Synthesis of tert-butyl (4-bromo-2-fluoro-6-((4- methoxybenzyl)oxy)phenyl)glycinate (1-4) To a stirred solution of 4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]aniline (5.9 g, 18.09 mmol) and tert-butyl 2-bromoacetate (10.58 g, 54.27 mmol) in DMF (90 mL) was added K ₂ CO ₃ (7.49 g, 54.27 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 48 h. LCMS showed the starting material was consumed completely. The reaction mixture was filtrated and the filtrate was washed with brine 3 times. The organic phase was dried over sodium sulfate, filtrated, and concentrated. The residue was subjected to silica gel column chromatography to obtain the product as a mixture. The mixture was further purified by reversed-phase flash chromatography (0.05% NH ₄ HCO ₃ in H ₂ O/ACN) to afford tert-butyl 2-[4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]anilino]acet ate (5 g, 62.70% yield) as a white solid. MS: m/z: Calc’d for C ₂₀ H ₂₃ BrFNO ₄ [M+H] ⁺ 440, found 440. Step 4: Synthesis of tert-butyl N-(4-bromo-2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)- N-sulfamoylglycinate (1-5) To a stirred solution of tert-butyl 2-[4-bromo-2-fluoro-6-[(4- methoxyphenyl)methoxy]anilino]acetate (3.3 g, 7.49 mmol) in DMA (80 mL) was added a solution of sulfamoyl chloride (2.6 g, 22.48 mmol) in DMA (4 mL) at 0 °C. The reaction mixture was stirred at room temperature overnight. LCMS showed the starting material was consumed completely. The mixture was diluted with ethyl acetate (300 mL) and washed with brine 6 times until the DMA was washed out completely. The organic phase was dried over anhydrous sodium sulfate, filtrated, and concentrated to obtain tert-butyl 2-[4-bromo-2- fluoro-6-[(4-methoxyphenyl)methoxy]-N-sulfamoyl-anilino]acet ate (4 g, 7.70 mmol, 102.70% yield) as a brown oil. MS: m/z: Calc’d for C ₂₀ H ₂₄ BrFN ₂ O ₆ S [M-H]- 517, found 517. Step 5: Synthesis of 5-(4-bromo-2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (Int-1) To a stirred solution of tert-butyl 2-[4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]-N- sulfamoyl-anilino]acetate (4 g, 7.70 mmol) in Methanol (20 mL) was added 30% NaOMe in MeOH (8.32 g, 46.30 mmol) at 0 °C. The mixture was stirred at room temperature overnight. LCMS showed the starting material was consumed completely. The mixture was concentrated. The resulting suspension was dissolved in water (200 mL), and extracted with ethyl acetate. The organic phase was separated and discarded. The aqueous layer was diluted with ethyl acetate, acidified by 1N HCl solution to pH = 3. and extracted with ethyl acetate 3 times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in a vacuum. The resulting residue was further purified by reversed-phase column (0.05% NH ₄ CO ₃ in H ₂ O and MeCN) to afford 5-[4-bromo-2-fluoro- 6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiaz olidin-3-one (2.50 g, 5.61 mmol, 72.90% yield) as an off-white solid. MS: m/z: Calc’d for C ₁₆ H ₁₄ BrFN ₂ O ₅ S [M-H]- 443, found 443. Step 6: Synthesis of 5-(2-fluoro-6-((4-methoxybenzyl)oxy)-4-vinylphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (1-6) To a solution of 5-[4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1- dioxo- 1,2,5-thiadiazolidin-3-one (2 g, 4.49 mmol) and tributyl(vinyl)stannane (2.85 g, 8.98 mmol) in DMA (20 mL) were added P(t-Bu) ₃ HBF ₄ (0.43 g, 0.90 mmol) and Pd ₂ (dba) ₃ (0.41 g, 0.45 mmol). The resulting mixture was purged with nitrogen for 5 minutes. Then, the mixture was stirred at 80 °C for 12 h. LCMS showed the starting material was consumed completely. The reaction mixture was filtrated, and the filtrate was directly purified by a reversed-phase column to obtain 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-vinyl-phenyl]-1,1 -dioxo- 1,2,5-thiadiazolidin-3-one (1.2 g, 3.05 mmol, 68.08% yield) as a light yellow semi-solid. MS: m/z: Calc’d for C ₁₈ H ₁₈ FN ₂ O ₅ S [M-H]- 391, found 391. Step 7: Synthesis of 4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-( (4- methoxybenzyl)oxy)benzaldehyde (Int-2) To a stirred solution of 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-vinyl-phenyl]-1,1 - dioxo-1,2,5-thiadiazolidin-3-one (970 mg, 2.47 mmol), Citric acid (1.04 g, 4.94 mmol) and NMO (579.18 mg, 4.94 mmol) in tert-butanol (6 mL) and Water (6 mL) was added K ₂ OsO ₄ (91.07 mg, 0.25 mmol). The resulting mixture was stirred at room temperature for 1 h. LCMS showed the starting material was converted to the intermediate completely. Then, NaIO ₄ (1.07 mL, 7.42 mmol) was added to the mixture at 0 °C. The resulting mixture was stirred at room temperature for 2 h. LCMS showed the reaction was completed. The reaction mixture was diluted with water and extracted with ethyl acetate for 4 times. The organic phase was dried over sodium sulfate, filtrated, and concentrated. The resulting residue was purified by reversed-phase column (0.05% NH ₄ CO ₃ , H ₂ O/ACN) to obtain 3-fluoro-5-[(4- methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin- 2-yl)benzaldehyde (500 mg, 1.26 mmol, 51.20% yield) as a brown solid. MS: m/z: Calc’d for C ₁₇ H ₁₅ FN ₂ O ₆ S [M-H]- 393, found 393. Preparation of Examples EXAMPLE 1: 5-[4-[[(4-cyclopropyl-2-pyridyl)amino]methyl]-2-fluoro-6-hyd roxy-phenyl]- 1,1-dioxo-1,2,5-thiadiazolidin-3-one Key Int.2 2-1 Step 1: To a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo- 1,2,5-thiadiazolidin-2-yl)benzaldehyde (Int-2, 100 mg, 0.25 mmol) and 4- cyclopropylpyridin-2-amine (51.04 mg, 0.38 mmol) in DMF (3 mL) was added TMSCl (0.08 mL, 0.63 mmol) dropwise at 0 °C. After stirring at 80 °C for 30 mins, the mixture was cooled to 0 °C and a solution of BH ₃ in THF (1 M, 0.5 mL, 0.48 mmol) was added slowly with a syringe. After the addition, the reaction mixture was stirred at 80 °C for 1 h. LCMS showed the reaction was completed. The mixture was quenched by ice water (0.4 ml) and directly purified by a reversed-phase column chromatography (0.05% NH ₄ HCO ₃ in H ₂ O and MeCN) to obtain 5-[4-[[(4-cyclopropyl-2-pyridyl)amino]methyl]-2-fluoro-6-[(4 - methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin -3-one (50 mg, 0.09 mmol, 38.47% yield) as a light brown solid. MS: m/z: Calc’d for C ₂₅ H ₂₄ FN ₄ O ₅ S [M+H] ⁺ 513, found 513 Step 2: TFA (3 mL) was added to 5-[4-[[(4-cyclopropyl-2-pyridyl)amino]methyl]-2-fluoro-6- [(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazol idin-3-one (45 mg, 0.09 mmol) in DCM (3 mL). The mixture was stirred at room temperature for 2 h. After completion of the reaction monitored by LCMS, the mixture was concentrated. The resulting residue was purified by a reversed-phase column chromatography (0.05% NH ₄ HCO ₃ in H ₂ O and MeCN) firstly and further purified by Prep-HPLC to obtain 5-[4-[[(4-cyclopropyl-2- pyridyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1 ,2,5-thiadiazolidin-3-one (11.8 mg, 0.02 mmol, 33.22% yield) as a white solid. MS: m/z: Calc’d for C ₁₇ H ₁₇ N ₄ O ₄ S [M+H] ⁺ 393, Found 393. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.77 (d, J = 5.8 Hz, 1H), 6.68 – 6.57 (m, 2H), 6.43 (s, 1H), 6.30 (d, J = 5.8 Hz, 1H), 4.39 (s, 2H), 3.94 (s, 2H), 1.84 (d, J = 9.4 Hz, 1H), 1.09 – 0.96 (m, 2H), 0.82-0.65 (m, 2H). Prep-HPLC purification conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ +0.1%NH ₃ ^. H ₂ O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 26% B to 36% B in 7 min, 36% B; Wave Length: 254/220 nm. EXAMPLE 2: 5-[2-fluoro-6-hydroxy-4-[[[4-(trifluoromethyl)-2- pyridyl]amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin- 3-one F F F _F ^HN N O O S HN N HO O The title compound was prepared in 17.47% overall yield as a white solid according to the preparation of EXAMPLE 1 using 4-(trifluoromethyl)pyridin-2-amine in STEP 1. The reductive amination was performed at room temperature instead of 80 °C. MS: m/z: Calc’d for C ₁₅ H ₁₂ F ₄ N ₄ O ₄ S, [M+H] ⁺ 421; Found 421. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.38 (s, 1H), 8.19 (d, J = 5.4 Hz, 1H), 7.81 (s, 1H), 6.91 – 6.76 (m, 2H), 6.74 – 6.66 (m, 2H), 4.48 (s, 2H), 4.37 (s, 2H). Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 23% B to 53% B in 10 min, 53% B; Wave Length: 254 nm. EXAMPLE 3: 5-[2-fluoro-6-hydroxy-4-[[[3-(trifluoromethyl)-2- pyridyl]amino]methyl]phenyl]- 3-one O The title compound was prepared in 9.45% overall yield as a white solid according to the preparation of EXAMPLE 1 using 3-(trifluoromethyl)pyridin-2-amine in STEP 1. The reductive amination was performed at room temperature instead of 80 °C. MS: m/z: Calc’d for C ₁₅ H ₁₂ F ₄ N ₄ O ₄ S, [M+H] ⁺ 421; Found 421. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.10 (s, 1H), 8.22 (s, 1H), 7.80 (t, J = 5.7 Hz, 1H), 7.17 (d, J = 5.6 Hz, 1H), 6.68 (d, J = 10.9 Hz, 3H), 4.55 (d, J = 5.3 Hz, 2H), 4.26 (s, 2H). Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 50% B in 10 min, 50% B; Wave Length: 254 nm. EXAMPLE 4: 5-[4-[[(5-tert-butyl-2-pyridyl)amino]methyl]-2-fluoro-6-hydr oxy-phenyl]-1,1- Key Int.2 3-1 Step 1: To a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo- 1,2,5-thiadiazolidin-2-yl)benzaldehyde (80 mg, 0.20 mmol) and 5-tert-butylpyridin-2-amine (45.71 mg, 0.30 mmol) in DCM (5 mL) was added Trimethylsilyl trifluoromethanesulfonate (0.07 mL, 0.41 mmol) at 0 ^o C. The mixture was stirred at room temperature for 1 h. To the mixture was added NaBH(AcO) ₃ (86.01 mg, 0.41 mmol), and the resulting mixture was stirred at room temperature for an additional 2 h. LCMS showed the starting material was consumed completely (product 3-1 and de-PMB protected product 006-03 were formed with a 5/4 ratio). The resulting solution was diluted with 30 mL of DCM and directly concentrated in vacuo to obtain the crude, which was used for the next step without further purification. MS: m/z: Calc’d for C ₂₄ H ₂₅ FN ₄ O ₅ S [M+H] ⁺ 529, found 529. (Note: Depending on the substrate, PMB protecting group may be totally or partially cleaved during the reductive amination reaction. If it is not completely cleaved, an appropriate amount of TFA can be added directly to the above mixture to drive the PMB deprotection to completion). The resulting solution was concentrated at a low temperature (bath temperature: 25 ^o C). Step 2: TFA (3 mL) was added to 5-[4-[[(5-tert-butyl-2-pyridyl)amino]methyl]-2-fluoro-6- [(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazol idin-3-one (80 mg crude, purity: 40%) in DCM (3 mL). The mixture was stirred at room temperature for 2 h. After completion of the reaction monitored by LCMS, the reaction mixture was diluted with DCM (20 mL) and concentrated. The resulting residue was purified by a reversed-phase column chromatography (0.05% NH ₄ HCO ₃ in H ₂ O and ACN) and further purified by Prep-HPLC to obtain 5-[4-[[(5-tert-butyl-2-pyridyl)amino]methyl]-2-fluoro-6-hydr oxy-phenyl]-1,1-dioxo- 1,2,5-thiadiazolidin-3-one (22.4 mg, 0.05 mmol, 35.87% yield) as a white solid. MS: m/z: Calc’d for C ₁₈ H ₂₁ FN ₄ O ₄ S [M+H] ⁺ 409; Found 409. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.02 – 7.65 (m, 2H), 6.81 (d, J = 9.1 Hz, 1H), 6.70 – 6.62 (m, 2H), 4.43 (s, 2H), 3.95 (s, 2H), 1.23 (s, 9H). Prep-HPLC conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ +0.1%NH ₃ ^. H ₂ O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 30% B in 8 min, 30% B; Wave Length: 254/220 nm. EXAMPLE 5: 5-[4-[[(4,6-dimethyl-2-pyridyl)amino]methyl]-2-fluoro-6-hydr oxy-phenyl]- 1,1-dioxo-1,2,5-thiadiazolidin- O The title compound was prepared with 9.46% overall yield as a white solid according to the preparation of EXAMPLE 4 using 4,6-dimethylpyridin-2-amine in STEP 1. Step 1: To a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo- 1,2,5-thiadiazolidin-2-yl)benzaldehyde (400 mg, 1.01 mmol) in DCM (10 mL) were added 4,6-dimethylpyridin-2-amine (161.09 mg, 1.32 mmol) and Trimethylsilyl trifluoromethanesulfonate (0.37 mL, 2.03 mmol) at 0 ^o C, the mixture was stirred at room temperature for 1 h. To the mixture was added NaBH(AcO) ₃ (430.05 mg, 2.03 mmol), and the reaction was stirred at room temperature for an additional 2 h. LCMS showed the starting material was consumed completely (product 2 and de-PMB protected product 013-01 were formed with a 5/3 ratio). The resulting solution was diluted with 50 mL of DCM and directly concentrated in vacuo to obtain the crude, which was used for the following step without further purification. MS: m/z: Calc’d for C ₂₄ H ₂₅ FN ₄ O ₅ S [M+H] ⁺ 501, found 501. Step 2: To a solution of the mixture 5-[4-[[(4,6-dimethyl-2-pyridyl)amino]methyl]-2-fluoro- 6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiaz olidin-3-one and 5-(4-(((4,6- dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl) -1,2,5-thiadiazolidin-3-one 1,1-dioxide (600 mg crude, 1.2 mmol) in DCM (5 mL) was added TFA (10 mL) at 0 °C, the mixture was stirred at room temperature for 2 h. LCMS showed the starting material was consumed completely. The mixture was concentrated, and the resulting residue was purified by reversed-phase column chromatography (0.05% TFA in water and MeCN) and further purified by Prep-HPLC to obtain 5-[4-[[(4,6-dimethyl-2-pyridyl)amino]methyl]-2-fluoro-6- hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (329.3 mg, 0.83 mmol, 69.69% yield) as a white solid. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₄ S [M+H] ⁺ 381, found 381. ¹ H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 9.80 (s, 1H), 8.38 (s, 1H), 7.30 – 6.26 (m, 4H), 4.53 (d, J = 5.9 Hz, 2H), 4.04 (s, 2H), 2.42 (s, 3H), 2.30 (s, 3H). Prep-HPLC conditions: Column: SunFire Prep C18 OBD Column, 30*50 mm, 5μm; Mobile Phase A: Water (0.05%TFA) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 3% B to 30% B in 8 min, 30% B; Wave Length: 254/210 nm. EXAMPLE 6: 5-[4-[[[4-(cyclopropoxy)-2-pyridyl]amino]methyl]-2-fluoro-6- hydroxy- phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one O The title compound was prepared in 8.36% overall yield as a white solid according to the preparation of EXAMPLE 4 using 4-(cyclopropoxy)pyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₇ H ₁₇ FN ₄ O ₅ S, [M+H] ⁺ 381; Found 381. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 9.79 (s, 1H), 8.79 (s, 1H), 7.88 (d, J = 7.2 Hz, 1H), 6.88-6.40 (m, 4H), 4.48 (d, J = 5.7 Hz, 2H), 4.07 (dq, J = 6.3, 3.0 Hz, 1H), 4.01 (s, 2H), 0.84 (t, J = 6.1 Hz, 2H), 0.75 (s, 2H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 50% B to 70% B in 5.3 min, 70% B; Wave Length: 210/254 nm. EXAMPLE 7: 5-[2-fluoro-6-hydroxy-4-[[(4-methyl-2-pyridyl)amino]methyl]p henyl]-1,1- dioxo-1,2,5-thiadiazolidin-3-one _F ^HN O O _N S HN N HO O The title compound was prepared in 4.44% overall yield as a white solid according to the preparation of EXAMPLE 4 using 4-methylpyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₅ H ₁₅ FN ₄ O ₄ S [M+H] ⁺ 367, found 367. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.74 (s, 1H), 8.80 (s, 1H), 7.85 (d, J = 6.5 Hz, 1H), 6.89 (s, 1H), 6.78 (dd, J = 6.6, 1.5 Hz, 1H), 6.74 – 6.66 (m, 2H), 4.49 (d, J = 5.8 Hz, 2H), 2.35 (s, 3H). Purification condition: Column: SunFire Prep C18 OBD Column, 30*50 mm, 5μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 3% B to 30% B in 8 min, 30% B; Wave Length: 254/210 nm. EXAMPLE 8: 5-[2-fluoro-6-hydroxy-4-[[(5-phenyl-2-pyridyl)amino]methyl]p henyl]-1,1- dioxo-1,2,5-thiadiazolidin-3-one O The title compound was prepared in 22.55% overall yield as a white solid according to the preparation of EXAMPLE 4 using 5-phenylpyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₂₀ H ₁₇ FN ₄ O ₄ S, [M+H] ⁺ 429; Found 429. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.02 (s, 1H), 8.62 (s, 1H), 8.25 (d, J = 2.4 Hz, 1H), 8.22 – 8.14 (m, 1H), 7.66 (dd, J = 7.4, 1.7 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.42 – 7.34 (m, 1H), 7.04 (d, J = 9.2 Hz, 1H), 6.75 – 6.73 (s, 2H), 4.57 – 4.52 (m, 2H).4.16 (s, 2H). Prep-HPLC purification conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 7% B to 37% B in 10 min, 37% B; Wave Length: 254 nm. EXAMPLE 9: 5-[2-fluoro-6-hydroxy-4-[[(4-methoxy-5-methyl-2- pyridyl)amino]methyl]phenyl]- 3-one O The title compound was prepared in 30.22% overall yield as a white solid according to the preparation of EXAMPLE 4 using 4-methoxy-5-methyl-pyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₅ S, [M+H] ⁺ 397; Found 397. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.60 (s, 1H), 9.61 (s, 1H), 8.55 (s, 1H), 7.70 (d, J = 1.2 Hz, 1H), 6.68 (d, J = 8.9 Hz, 2H), 6.43 (s, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.93 (d, J = 9.2 Hz, 5H), 2.11 – 1.88 (m, 3H). Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 4% B to 34% B in 10 min, 34% B; Wave Length: 254 nm. EXAMPLE 10: 5-[4-[[(5-cyclopropyl-2-pyridyl)amino]methyl]-2-fluoro-6-hyd roxy-phenyl]- 1,1-dioxo-1,2,5-thiadiazolidin-3-one O The title compound was prepared in 20.22% overall yield as a white solid according to the preparation of EXAMPLE 4 using 5-cyclopropylpyridin-2-amine in STEP 1. MS: m/z: Calc’d for C17H17FN4O4S, [M+H] ⁺ 393; Found 393. ¹ H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.68 (s, 1H), 7.33 (d, J = 8.9 Hz, 1H), 6.70 – 6.59 (m, 3H), 4.39 (d, J = 4.8 Hz, 2H), 3.94 (s, 2H), 1.87 – 1.76 (m, 1H), 0.90 – 0.79 (m, 2H), 0.63 – 0.55 (m, 2H). Prep-HPLC purification conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ +0.1%NH ₃ .H ₂ O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 30% B in 8 min, 30% B; Wave Length: 254/220 nm. EXAMPLE 11: 2-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin- 2- yl)phenyl]methylamino] 4- O The title compound was prepared in 30.09% overall yield as a white solid according to the preparation of EXAMPLE 4 using 2-aminopyridine-4-carbonitrile in STEP 1. MS: m/z: Calc’d for C ₁₅ H ₁₂ FN ₅ O ₄ S, [M+H] ⁺ 378; Found 378. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.30 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.73 (s, 1H), 6.95-6.78 (m, 2H), 6.71 – 6.64 (m, 2H), 4.34 (d, J = 10.2 Hz, 2H), 4.43 (s, 2H). Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 4% B to 34% B in 10 min, 34% B; Wave Length: 254 nm. EXAMPLE 12: 5-[2-fluoro-6-hydroxy-4-[[(4-methoxy-2-pyridyl)amino]methyl] phenyl]-1,1- dioxo-1,2,5-thiadiazolidin-3- O The title compound was prepared in 21.91% overall yield as a white solid according to the preparation of EXAMPLE 1 using 4-methoxypyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₅ H ₁₅ FN ₄ O ₅ S, [M+H] ⁺ 383; Found 383. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.75 (s, 1H), 8.69 (s, 1H), 7.87 (d, J = 7.2 Hz, 1H), 6.73 - 6.69 (m, 2H), 6.58 (dd, J = 7.2, 2.4 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 4.50 (d, J = 5.8 Hz, 2H), 4.00 (s, 2H), 3.91 (s, 3H). Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 25% B in 10 min, 25% B; Wave Length: 254 nm. EXAMPLE 13: 5-[4-[[(4-ethyl-2-pyridyl)amino]methyl]-2-fluoro-6-hydroxy-p henyl]-1,1- dioxo-1,2,5-thiadiazolidin-3- O The title compound was prepared in 32.57% overall yield as a white solid according to the preparation of EXAMPLE 4 using 4-ethylpyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₄ S, [M+H] ⁺ 381; Found 381. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.08 (s, 1H), 9.55 (d, J = 6.7 Hz, 1H), 8.24 (s, 1H), 7.86 (d, J = 6.2 Hz, 1H), 7.27 – 6.93 (m, 1H), 6.80 – 6.54 (m, 4H), 4.46 (d, J = 5.8 Hz, 2H), 3.95 (d, J = 1.9 Hz, 2H), 2.59 (q, J = 7.6 Hz, 2H), 1.16 (t, J = 7.5 Hz, 3H). Prep-HPLC purification conditions: Column: XBridge C18 OBD Prep Column, 100Å 5 μm, 19 mm X 250 mm; Mobile Phase A: Water (10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 25% B to 55% B in 6 min, 55% B; Wave Length: 254 nm. EXAMPLE 14: 5-[2-fluoro-6-hydroxy-4-[[(5-methyl-2-pyridyl)amino]methyl]p henyl]-1,1- dioxo-1,2,5-thiadiazolidin-3-one O The title compound was prepared in 24.22% overall yield as a white solid according to the preparation of EXAMPLE 4 using 5-methylpyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₅ H ₁₅ FN ₄ O ₄ S, [M+H] ⁺ 367; Found 367. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 (d, J = 4.3 Hz, 1H), 8.02 (s, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.27 – 6.91 (m, 1H), 6.79 (d, J = 8.7 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H), 6.65 (d, J = 8.4 Hz, 2H), 4.42 (d, J = 5.1 Hz, 2H), 3.95 (s, 2H), 2.15 (s, 3H). Prep-HPLC purification conditions: Column: XBridge C18 OBD Prep Column, 100Å 5 μm, 19 mm X 250 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 25% B to 55% B in 6 min, 55% B; Wave Length: 254 nm. EXAMPLE 15: 5-[2-fluoro-6-hydroxy-4-[[(3-methyl-2-pyridyl)amino]methyl]p henyl]-1,1- dioxo-1,2,5-thiadiazolidin-3- O The title compound was prepared in 5.38% overall yield as a white solid according to the preparation of EXAMPLE 4 using 3-methylpyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₅ H ₁₅ FN ₄ O ₄ S, [M+H] ⁺ 367; Found 367. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.70 (s, 1H), 8.23 (s, 1H), 7.79 (t, J = 9.7 Hz, 1H), 7.73 (d, J = 11.2 Hz, 1H), 6.80 (s, 1H), 6.65 (s, 2H), 4.61 – 4.55 (s, 2H), 4.00 (s, J = 9.4 Hz, 2H), 2.28 – 2.15 (m, 3H) Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 60% B in 5.3 min, 60% B; Wave Length: 210/254 nm. EXAMPLE 16: 5-[2-fluoro-4-[[(4-fluoro-2-pyridyl)amino]methyl]-6-hydroxy- phenyl]-1,1- dioxo-1,2,5-thiadiazolidin-3-one O The title compound was prepared in 5.21% overall yield as a white solid according to the preparation of EXAMPLE 4 using 4-fluoropyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₄ H ₁₂ F ₂ N ₄ O ₄ S, [M+H] ⁺ 371; Found 371. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.02 (t, J = 7.0 Hz, 1H), 6.83 – 6.67 (m, 4H), 4.46 (s, 2H), 4.11 (d, J = 4.7 Hz, 2H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 35% B to 50% B in 5.3 min, 50% B; Wave Length: 210/254 nm. EXAMPLE 17: 5-[2-fluoro-6-hydroxy-4-[[(6-methyl-2-pyridyl) amino] methyl] phenyl]-1,1- dioxo-1,2,5-thiadiazolidin-3- O The title compound was prepared in 29.15% overall yield as a white solid according to the preparation of EXAMPLE 4 using 6-methylpyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₅ H ₁₅ FN ₄ O ₄ S, [M+H] ⁺ 367; Found 367. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 9.56 (s, 1H), 7.95 (d, J = 41.3 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.26 – 6.93 (m, 1H), 6.72 – 6.58 (m, 4H), 4.47 (d, J = 5.2 Hz, 2H), 3.97 (s, 2H), 2.38 (s, 3H). Prep-HPLC purification conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 60% B in 6 min, 60% B; Wave Length: 254/210 nm. EXAMPLE 18: 5-[4-[[(4,6-dimethoxy-2-pyridyl)amino]methyl]-2-fluoro-6-hyd roxy- - 4-1 4-2 4-3 Step 1: To a mixture of 4,6-dichloropyridin-2-amine (2.0 g, 12.27 mmol) in sodium methoxide (30％ in MeOH, 20 mL) was stirred at 140 °C for 12 h in a sealed tube. LCMS showed the starting material was consumed completely. The resulting solution was purified by reversed-phase column chromatography (0.05% NH ₄ HCO ₃ in H ₂ O and MeCN) to obtain 4,6-dimethoxypyridin-2-amine (193 mg, 1.25 mmol, 10.20% yield) as an off-white solid. MS: m/z: Calc’d for C ₇ H ₁₀ N ₂ O ₂ , [M+H] ⁺ 155; Found 155. Step 2: The compound 4-3 was prepared in 37.02% yield as a light yellow solid according to the preparation of EXAMPLE 1 using 4,6-dimethoxypyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₂₄ H ₂₅ FN ₄ O ₇ S, [M+H] ⁺ 533; Found 533. Step 3: The title compound was prepared in 33.03% yield as a white solid according to the preparation of EXAMPLE 1 using 4-3 in STEP 2. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₆ S, [M+H] ⁺ 413; Found 413. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.10 (s, 1H), 7.04 (d, J = 51.1 Hz, 1H), 6.72 – 6.63 (m, 2H), 5.60 (d, J = 17.8 Hz, 2H), 4.34 (s, 2H), 4.24 (s, 2H), 3.75-3.65 (m, 6H). Prep-HPLC purification conditions: Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 40% B in 7 min, 40% B; Wave Length: 210/254 nm. EXAMPLE 19: 5-[4-[[(5,6-dimethyl-2-pyridyl) amino] methyl]-2-fluoro-6-hydroxy-phenyl]- 1,1-dioxo-1,2,5- O The title compound was prepared in 2.24% overall yield as a white solid according to the preparation of EXAMPLE 4 using 5,6-dimethylpyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₄ S, [M+H] ⁺ 381; Found 381. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.31 (s, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.65 (d, J = 5.8 Hz, 2H), 6.61 (d, J = 1.9 Hz, 1H), 6.60 – 6.53 (m, 1H), 6.20 (d, J = 8.2 Hz, 1H), 4.32 (d, J = 6.2 Hz, 2H), 3.92 (s, 2H), 2.22 (s, 3H), 2.05 (s, 3H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 70% B in 5.5 min, 70% B; Wave Length: 210/254 nm. EXAMPLE 20: 5-[4-[[(3,6-dimethyl-2-pyridyl)amino]methyl]-2-fluoro-6-hydr oxy-phenyl]- 1,1-dioxo-1,2,5-thiadiazolidin- O The title compound was prepared in 20.52% overall yield as a white solid according to the preparation of EXAMPLE 4 using 3,6-dimethylpyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₄ S, [M+H] ⁺ 381; Found 381. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.48 (s, 1H), 9.96 (s, 1H), 8.29 (s, 1H), 7.71 (d, J = 7.3 Hz, 1H), 6.75 – 6.66 (m, 3H), 4.71 (d, J = 5.3 Hz, 2H), 4.13 (d, J = 3.1 Hz, 2H), 2.43 (s, 3H), 2.22 (s, 3H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 40% B to 60% B in 5.5 min, 60% B; Wave Length: 210/254 nm. EXAMPLE 21: 5-[4-[[(3,6-dimethoxy-2-pyridyl)amino]methyl]-2-fluoro-6-hyd roxy- - 3-one O Scheme 5: O Cl C ^Cl Cl l 5-4 _Cl O ^{Pd ,t-BuBrettp} MeI,K CO N _(dba) ^hos N N N Z _n,NH ^Cl pyridine,DMAP K PO O N DMF,rt,o/n O N THF/H O=3/1,rt H N DCM,0 C-rt,o/n N ^{dioxane/MeOH,80} _C,o/n Step 1 Step 2 Step 3 H Step 4 HO O O O 5-1 5-2 5-3 5-5 O F O _S ^NH N O O O O O ^N O F _S ^{H O} Key Int.2 O N O _N N TMSCl, DMF, 0 C-rt ^O _H TFA/DCM N _F ^HN H N ^NaBH _CN,0 C-rt,2h O Step 6 O O S O Ste N O p 5 HN N O O O HO 5-6 5-7 Step 1: To a stirred solution of 6-chloro-2-nitro-pyridin-3-ol (2 g, 11.46 mmol) and MeI (4.88 g, 34.38 mmol) in DMF (20 mL) was added K ₂ CO ₃ (4.74 g, 34.38 mmol). The reaction was stirred at room temperature for 14 h. After completion of the reaction monitored by LCMS, the mixture was diluted with ethyl acetate and washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtrated, and concentrated. The resulting residue was purified by a silica column chromatography (10%~30% ethyl acetate in petroleum ether) to obtain 6-chloro-3-methoxy-2-nitro-pyridine (1.5 g, 7.95 mmol, 69.42% yield) as an off- white solid. MS: m/z: Calc’d for C ₆ H ₅ ClN ₂ O ₃ [M-H]- 187; Found 187. Step 2: To a stirred solution of 6-chloro-3-methoxy-2-nitro-pyridine (1.5 g, 7.95 mmol) and NH ₄ Cl (6.81 g, 127.27 mmol) in a mixed solvent of THF (30 mL) and water (10 mL) was added zinc powder (3.12 g, 47.73 mmol) at 0 ^o C. The mixture was stirred at room temperature for 12 h. After completion of the reaction monitored by LCMS, the mixture was filtrated. The filtrate was diluted with water, and the solution was extracted with ethyl acetate 3 times. The combined organic phase was dried over anhydrous sodium sulfate, filtrated, and concentrated. The residue was purified by a silica column chromatography (20%~40% ethyl acetate in petroleum ether) to obtain 6-chloro-3-methoxy-pyridin-2-amine (800 mg, 5.04 mmol, 63.41% yield) as a light-yellow solid. MS: m/z: Calc’d for C ₆ H ₇ ClN ₂ O [M+H] ⁺ 159; Found 159. Step 3: To a stirred solution of 6-chloro-3-methoxy-pyridin-2-amine (800 mg, 5.04 mmol) and pyridine (1.195 g, 15.13 mmol) in DCM (10 mL) was added 2,2-dimethylpropanoyl chloride (729.91 mg, 6.05 mmol) at 0 ^o C. The mixture was stirred at room temperature for 12 h. After completion of the reaction monitored by LCMS, the mixture was quenched with water. The solution was extracted with DCM, 3 times. The combined organic phase was dried over anhydrous sodium sulfate, filtrated, and concentrated. The residue was purified by a silica column chromatography (0~40% ethyl acetate in petroleum ether) to obtain N-(6- chloro-3-methoxy-2-pyridyl)-2,2-dimethyl-propanamide (700 mg, 2.88 mmol, 57.17% yield) as a white solid. MS: m/z: Calc’d for C ₁₁ H ₁₅ ClN ₂ O ₂ [M+H] ⁺ 243; Found 243. Step 4: To a stirred solution of N-(6-chloro-3-methoxy-2-pyridyl)-2,2-dimethyl-propanamide (400 mg, 1.65 mmol) and K ₃ PO ₄ (698.81 mg, 3.3 mmol) in 1,4-dioxane (12 mL) and methanol (2 mL) were added Pd ₂ (dba) ₃ (150.92 mg, 0.16 mmol) and t-BuBrettphos (190.52 mg, 0.33 mmol) under nitrogen. The mixture was stirred at 80 °C for 12 h under nitrogen. After completion of the reaction monitored by LCMS, the mixture was diluted with ethyl acetate and washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtrated, and concentrated. The residue was purified by a silica column chromatography (10%~40% ethyl acetate in petroleum ether) to obtain N-(3,6-dimethoxy-2-pyridyl)-2,2- dimethyl-propanamide (140 mg, 0.58 mmol, 35.64% yield) as a light-yellow solid. MS: m/z: Calc’d for C ₇ H ₁₀ N ₂ O ₂ [M+H] ⁺ 155; Found 155. Step 5: To a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo- 1,2,5-thiadiazolidin-2-yl)benzaldehyde (90 mg, 0.23 mmol) and 3,6-dimethoxypyridin-2- amine (45.73 mg, 0.29 mmol) in DMF (9 mL) was added TMSCl (42.7 μL, 0.34 mmol) dropwise at 0 °C. After the mixture was stirred at room temperature for 1 h, NaBH ₃ CN (35.8 mg, 0.57 mmol) was added to the above mixture. The suspension was stirred at room temperature for another 2 h. LCMS showed the reaction was completed. The resulting solution was directly purified by a reversed-phase column chromatography (0.05% NH ₄ HCO ₃ in H ₂ O and MeCN) to obtain 5-[4-[[(3,6-dimethoxy-2-pyridyl)amino]methyl]-2- fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-t hiadiazolidin-3-one (100 mg, 0.18 mmol, 82.28% yield) as a light yellow oil. MS: m/z: Calc’d for C ₂₄ H ₂₅ FN ₄ O ₇ S [M+H] ⁺ 533; Found 533. Step 6: To a stirred solution of 5-[4-[[(3,6-dimethoxy-2-pyridyl)amino]methyl]-2-fluoro-6- [(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazol idin-3-one (40 mg, 0.08 mmol) in DCM (2 mL) was added TFA (4 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. After completion of the reaction monitored by LCMS, the mixture was concentrated. The resulting residue was purified by a reversed-phase column chromatography (0.05% NH ₄ HCO ₃ in H ₂ O and MeCN) and further purified by Prep-HPLC to obtain 5-[4- [[(3,6-dimethoxy-2-pyridyl)amino]methyl]-2-fluoro-6-hydroxy- phenyl]-1,1-dioxo-1,2,5- thiadiazolidin-3-one (7.6 mg, 0.017 mmol, 23.38% yield) as a grey solid. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₆ S [M+H] ⁺ 413, Found 413. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.21 (s, 3H), 7.03 (s, 1H), 6.46 (d, J = 8.4 Hz, 2H), 5.50 (s, 2H), 3.91 (s, 2H), 3.72 (d, J = 14.2 Hz, 6H), 3.62 (s, 2H). Prep-HPLC conditions: Column: XBridge Prep Phenyl OBD Column, 19*100 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 45% B to 65% B in 8 min, 65% B; Wave Length: 254/210 nm. EXAMPLE 22: 5-[2-fluoro-6-hydroxy-4-[[(3-methoxy-6-methyl-2- pyridyl)amino]methyl]phenyl]- 3-one O The title compound was prepared in 9.32% overall yield as a white solid according to the preparation of EXAMPLE 4 using 3-methoxy-6-methyl-pyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₅ S, [M+H] ⁺ 397; Found 397. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.88 (s, 1H), 7.30 (s, 1H), 6.66 (d, J = 13.0 Hz, 3H), 4.63 (s, 2H), 4.09 (s, 2H), 3.90 (s, 3H), 2.34 (s, 3H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 50% B in 5.3 min, 50% B; Wave Length: 210/254 nm. EXAMPLE 23: 5-[4-[[(3-ethyl-2-pyridyl) amino] methyl]-2-fluoro-6-hydroxy-phenyl]-1,1- dioxo-1,2,5-thiadiazolidin-3-one _F ^HN O O _N S HN N HO O The title compound was prepared in 4.45% overall yield as a white solid according to the preparation of EXAMPLE 4 using 3-ethylpyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₄ S, [M+H] ⁺ 381; Found 381. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 9.85 (s, 1H), 8.44 (s, 1H), 7.79 (s, 2H), 6.92 – 6.82 (m, 1H), 6.68 (d, J = 16.6 Hz, 2H), 4.71 – 4.45 (m, 2H), 4.16 – 3.94 (m, 2H), 2.63 – 2.62 (m, 2H), 1.23 – 1.19 (m, 3H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 30% B to 55% B in 6.5 min, 55% B; Wave Length: 254 nm. EXAMPLE 24: 5-[4-[[(3,5-dimethyl-2-pyridyl)amino]methyl]-2-fluoro-6-hydr oxy-phenyl]- 1,1-dioxo-1,2,5-thiadiazolidin-3-one O The title compound was prepared in 17.83% overall yield as an off-white solid according to the preparation of EXAMPLE 4 using 3,5-dimethylpyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₄ S, [M+H] ⁺ 381; Found 381. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.93 (s, 1H), 9.64 (s, 1H), 8.27 (s, 1H), 7.68 (d, J = 11.8 Hz, 1H), 7.62 (s, 1H), 6.65 (dd, J = 13.4, 2.6 Hz, 2H), 4.56 (d, J = 5.8 Hz, 2H), 3.98 (s, 2H), 2.32 – 2.12 (m, 6H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(0.1%TFA ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 8% B to 40% B in 7 min, 40% B; Wave Length: 210/254 nm. EXAMPLE 25: 5-[4-[[(3,4-dimethyl-2-pyridyl)amino]methyl]-2-fluoro-6-hydr oxy-phenyl]- 1,1-dioxo-1,2,5-thiadiazolidin-3-one _F ^HN O O _N S HN N HO O The title compound was prepared in 12.02% overall yield as an off-white solid according to the preparation of EXAMPLE 4 using 3,4-dimethylpyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₄ S, [M+H] ⁺ 381; Found 381. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.90 (s, 1H), 9.64 (s, 1H), 8.28 (s, 1H), 7.72 (d, J = 6.3 Hz, 1H), 6.81 (d, J = 6.7 Hz, 1H), 6.65 (d, J = 11.6 Hz, 2H), 4.58 (d, J = 6.0 Hz, 2H), 3.97 (s, 2H), 2.34 (d, J = 8.1 Hz, 3H), 2.18 (s, 3H), 2.09 (d, J = 7.1 Hz, 1H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 25% B in 6 min, 25% B; Wave Length: 210/254 nm. EXAMPLE 26: 5-[4-[[(4,5-dimethoxy-2-pyridyl)amino]methyl]-2-fluoro-6-hyd roxy- phenyl]-1,1-dioxo-1,2,5- O The title compound was prepared in 21.72% overall yield as a white solid according to the preparation of EXAMPLE 4 using 4,5-dimethoxypyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₆ S, [M+H] ⁺ 413; Found 413. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.57 (s, 1H), 9.82 (s, 1H), 8.52 (s, 1H), 7.43 (d, J = 1.8 Hz, 1H), 6.71 (d, J = 10.1 Hz, 2H), 6.53 (s, 1H), 4.49 (d, J = 5.4 Hz, 2H), 4.05 (d, J = 4.1 Hz, 2H), 3.93 (s, 3H), 3.77 (s, 3H). Prep-HPLC purification conditions: Column: Sun Fire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 30% B to 50% B in 5 min, 50% B, in 0.3 min; Wave Length: 254/210 nm. EXAMPLE 27: 5-[4-[[(3,4-dimethoxy-2-pyridyl)amino]methyl]-2-fluoro-6-hyd roxy- phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one O O F ^HN O O _N S HN N HO O Scheme 6： O NH O O O O ^,B O O ^{C Cl} O _Pd(OAc) ^INAP K CO O HN N _TFA Step 1 Step 3 N ^Cl _{To N} S _l, t ₁ ^C e ₃ p ₀ 2 ^{H N} _N O 6-1 6-2 6-3 6-4 O F O _S ^NH N ^O O O O O F O _S ^NH O Int-2 O _N ^O TMSCl,DMF,60 C,2h H TFA, DCM ^HN t N N O O O _{F N} B ^H _,r Step 5 Step 4 S HN N O O O O HO 6 ^-5 Step 1：To a stirred mixture of 3,4-dimethoxypyridine (2.00 g, 14.37 mmol) in THF (100.0 mL) was added a solution of n-butyllithium (17 mL, 43.08 mmol) in Hexane at -70 °C under nitrogen atmosphere. The resulting mixture was stirred at -70 °C for 1 h under a nitrogen atmosphere. A solution of C ₂ Cl ₆ (3.41 g, 14.40 mmol) in THF (20 mL) was added to the above mixture at -70 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 12 h. After completion of the reaction monitored by LCMS, the reaction was quenched with NH ₄ Cl at room temperature. The solution was extracted with ethyl acetate 3 times. The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtrated, and concentrated. The residue was purified by silica column chromatography(eluting with ethyl acetate) to afford 2-chloro-3,4-dimethoxy- pyridine (800 mg, 4.61 mmol, 32.06% yield) as a white solid. MS: m/z: Calc’d for C ₇ H ₈ ClNO ₂ , [M+H] ⁺ 174; Found 174. Step 2: To a stirred mixture of (4-methoxyphenyl)methanamine (813 mg, 5.93 mmol), 2- chloro-3,4-dimethoxy-pyridine (872 mg, 5.02 mmol) and K ₂ CO ₃ (2.095 g, 15.18 mmol) in toluene (20 mL) were added Pd(OAc) ₂ (112.77 mg, 0.50 mmol) and BINAP (938.31 mg, 1.51 mmol) at room temperature. The resulting mixture was stirred at 130 °C for 12 h under nitrogen atmosphere. LCMS showed the starting material was consumed completely. The reaction mixture was concentrated and purified by reversed-phase column chromatography to afford 3,4-dimethoxy-N-[(4-methoxyphenyl)methyl]pyridin-2-amine (770 mg, 2.81 mmol, 55.88% yield) as a yellow solid. MS: m/z: Calc’d for C ₁₅ H ₁₈ N ₂ O ₃ , [M+H] ⁺ 275; Found 275. Step 3: To a stirred mixture of 3,4-dimethoxy-N-[(4-methoxyphenyl)methyl]pyridin-2-amine (770 mg, 2.81 mmol) in DCM (20 mL) was added TFA (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 14 h. After completion of the reaction monitored by LCMS, the mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase column chromatography (0.05% NH ₄ HCO ₃ in H ₂ O and MeCN) to afford 3,4-dimethoxypyridin-2-amine (300 mg, 1.95 mmol, 69.40% yield) as a white solid. MS: m/z: Calc’d for C ₇ H ₁₀ N ₂ O ₂ , [M+H] ⁺ 155; Found 155. Step 4: The compound 6-5 was prepared in 29.62% yield as a white solid according to the preparation of EXAMPLE 1 using 3,4-dimethoxypyridin-2-amine in STEP 1. After adding TMSCl, the reaction mixture was stirred at 60 ^o C. MS: m/z: Calc’d for C ₂₄ H ₂₅ FN ₄ O ₇ S, [M+H] ⁺ 533; Found 533. Step 5: The title compound was prepared in 20.50% yield as a white solid according to the preparation of EXAMPLE 4 using 6-5 in STEP 2. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₆ S, [M+H] ⁺ 413; Found 413. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.92 (s, 1H), 8.47 (s, 1H), 7.79 (d, J = 7.1 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 6.68 (d, J = 9.4 Hz, 2H), 4.56 (d, J = 5.5 Hz, 2H), 4.12 (s, 2H), 4.03 (s, 3H), 3.84 (s, 3H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 6.8 min, 50% B; Wave Length: 254/210 nm. EXAMPLE 28: 5-[4-[[(4,5-dimethyl-2-pyridyl)amino]methyl]-2-fluoro-6-hydr oxy-phenyl]- 1,1-dioxo-1,2,5-thiadiazolidin-3-one _F ^HN O O _N S HN N HO O The title compound was prepared in 11.79% overall yield as a white solid according to the preparation of EXAMPLE 4 using 4,5-dimethylpyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₄ S, [M+H] ⁺ 381; Found 381. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.68 (s, 1H), 6.87 (s, 1H), 6.67 (d, J = 9.8 Hz, 2H), 4.45 (s, 2H), 3.95 (s, 2H), 2.27 (s, 3H), 2.10 (s, 3H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 50% B to 65% B in 5.3 min, 65% B; Wave Length: 210/254 nm. EXAMPLE 29: 5-[2-fluoro-6-hydroxy-4-[[(6-methoxy-3-methyl-2- pyridyl)amino]methyl]phenyl]- 3-one O Scheme 7:

O O NH O ₂ O N _Pd(dppf)Cl2 ^{, Zn(CH} ₃₎₂ N _Pd(OAc)2 ^{, BINAP, K} ₂ ^CO ₃ N Cl Tol/dioxane, 90 ^o C Cl ^{toluene, 130 o} _{C, N2} ^{, 3 h} N Step 3 Step 1 Step 2 O Br H 7-1 7-2 7-3 O F O _S ^NH N O O O O O F O _S ^NH O Int-2 O O N N N ^TiCl(i-PrO) _{3, DCE, RT,O/N} H TFA/DCM ^HN N O O _F H ₂ N NaBH ₃ CN, rt O Step 5 Step 4 S N HN N O O HO O 7-4 7-5 Step 1: To a stirred mixture of 2-methoxy-5-bromo-6-chloro-pyridine (1 g, 7.19 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf) ₂ Cl ₂ (155.66 mg, 0.22 mmol) and a solution of Zn(CH ₃ ) ₂ (1.37 g, 14.37 mmol) in toluene (8.5 mL) at room temperature. The resulting mixture was stirred at 90 °C overnight under nitrogen atmosphere. After completion of the reaction monitored by LCMS, the mixture was quenched with ice water (20 mL). The solution was extracted with ethyl acetate, 3 times. The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtrated, and concentrated. The residue was purified by silica gel column chromatography (eluting with petroleum ether) to afford 2-chloro-6-methoxy-3-methyl-pyridine (280.00 mg, 1.77 mmol, 24.7% yield) as a white solid. MS: m/z: Calc’d for C ₇ H ₈ ClNO, [M+H] ⁺ 158; Found 158. Step 2: To a stirred mixture of 2-chloro-6-methoxy-3-methyl-pyridine (500 mg, 3.17 mmol), (4-methoxyphenyl)methanamine (500 mg, 3.64 mmol) and K ₂ CO ₃ (1313.45 mg, 9.52 mmol) in toluene (10 mL) were added Pd(OAc) ₂ (71.23 mg, 0.32 mmol) and BINAP (592.64 mg, 0.95 mmol) under nitrogen. The resulting mixture was stirred at 130 °C for 5 h under nitrogen atmosphere. After completion of the reaction monitored by LCMS, the mixture was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (10%~30% ethyl acetate in petroleum ether) to afford 6-methoxy-N- [(4-methoxyphenyl)methyl]-3-methyl-pyridin-2-amine (300 mg, 1.1614 mmol, 36.60% yield) as a yellow oil. MS: m/z: Calc’d for MS: m/z: Calc’d for C ₁₅ H ₁₈ N ₂ O ₂ , [M+H] ⁺ 259; Found 259. Step 3: To a stirred mixture of 6-methoxy-N-[(4-methoxyphenyl)methyl]-3-methyl-pyridin- 2-amine (300 mg, 1.16 mmol) in DCM (10 mL) was added TFA (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 12 h. After completion of the reaction monitored by LCMS, the resulting mixture was concentrated under reduced pressure to afford 6-methoxy-3-methyl-pyridin-2-amine (500 mg, TFA salt). MS: m/z: Calc’d for MS: m/z: Calc’d for C ₇ H ₁₀ N ₂ O, [M+H] ⁺ 139; Found 139. Step 4: To a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo- 1,2,5-thiadiazolidin-2-yl)benzaldehyde (80 mg, 0.20 mmol) in 1,2-dichloroethane (4 mL) were added 6-methoxy-3-methyl-pyridin-2-amine (56.06 mg, 0.41 mmol) and Chlorotitanium triisopropoxide (105.48 mg, 0.41 mmol) at 0 ^o C. The reaction mixture was stirred at room temperature for 16 h. NaBH ₃ CN (0.05 mL, 0.61 mmol) was added to the mixture, and the reaction was stirred at room temperature for an additional 2 h. LCMS showed the starting material was consumed completely. The resulting solution was diluted with dichloromethane (10 mL) and directly concentrated in vacuo. The resulting residue was directly purified by a reversed-phase column chromatography (0.05% NH ₄ HCO ₃ in H ₂ O and MeCN) to obtain 5- [2-fluoro-4-[[(6-methoxy-3-methyl-2-pyridyl)amino]methyl]-6- [(4- methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin -3-one (50 mg, 0.09 mmol, 47.71% yield) as a light yellow solid. MS: m/z: Calc’d for C ₂₄ H ₂₅ FN ₄ O ₆ S, [M+H] ⁺ 517; Found 517. Step 5: To a stirred solution of 5-[2-fluoro-4-[[(6-methoxy-3-methyl-2- pyridyl)amino]methyl]-6-[(4-methoxyphenyl)methoxy]phenyl]-1, 1-dioxo-1,2,5- thiadiazolidin-3-one (7-5, 93 mg, 0.18 mmol) in DCM (3 mL) was added TFA (3 mL), and the mixture was stirred at room temperature for 2 h. Upon completion, the reaction mixture was concentrated. The resulting residue was purified by reversed-flash (0.05% NH ₄ HCO ₃ in H ₂ O and ACN) and further purified by Prep-HPLC to obtain 5-[2-fluoro-6-hydroxy-4-[[(6- methoxy-3-methyl-2-pyridyl)amino]methyl]phenyl]-1,1-dioxo-1, 2,5-thiadiazolidin-3-one (8 mg, 12.67 % yield) as a white solid. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₅ S, [M+H] ⁺ 397; Found 397. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.20 (s, 1H), 7.17 (d, J = 7.7 Hz, 1H), 6.88 – 6.37 (m, 3H), 5.84 (d, J = 7.7 Hz, 1H), 4.46 (s, 2H), 4.33 (d, J = 4.6 Hz, 2H), 3.64 (s, 3H), 2.03 (s, 3H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 45% B in 6.8 min, 45% B; Wave Length: 254/210 nm. EXAMPLE 30: 5-[4-[[(3,5-dimethoxy-2-pyridyl)amino]methyl]-2-fluoro-6-hyd roxy- phenyl]-1,1-dioxo-1,2,5- O The title compound was prepared in 22.59% overall yield as a white solid according to the preparation of EXAMPLE 4 using 3,5-dimethoxypyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₆ S, [M+H] ⁺ 413; Found 413. ¹ H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.09 (s, 1H), 7.46 – 7.02 (m, 2H), 6.70 – 6.61 (m, 2H), 4.51 (s, 2H), 4.18 (d, J = 5.7 Hz, 2H), 3.95 (d, J = 2.2 Hz, 3H), 3.76 (s, 3H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 45% B in 5.3 min, 45% B; Wave Length: 210/254 nm. EXAMPLE 31: 5-[2-fluoro-4-[[(5-fluoro-4-methyl-2-pyridyl)amino]methyl]-6 -hydroxy- phenyl]-1,1-dioxo-1,2,5- O The title compound was prepared in 12.31% overall yield as an off-white solid according to the preparation of EXAMPLE 4 using 5-fluoro-4-methyl-pyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₅ H ₁₄ F ₂ N ₄ O ₄ S, [M+H] ⁺ 385; Found 385. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.89 (d, J = 2.6 Hz, 1H), 6.73 – 6.61 (m, 3H), 4.38 (s, 2H), 4.08 (s, 2H), 2.21 (s, 3H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 30*50 mm, 5μm; Mobile Phase A: Water (0.05%TFA) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 30% B in 8 min, 30% B; Wave Length: 254/210 nm. EXAMPLE 32: 6-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin- 2- yl)phenyl]methylamino]-4- O The title compound was prepared in 10.68% overall yield as a white solid according to the preparation of EXAMPLE 1 using 6-amino-4-methyl-pyridine-3-carbonitrile in STEP 1. MS: m/z: Calc’d for C ₁₆ H ₁₄ FN ₅ O ₄ S, [M+H] ⁺ 392; Found 392. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (s, 1H), 7.99 (t, J = 6.1 Hz, 1H), 7.57 (s, 1H), 6.63 – 6.54 (m, 2H), 6.49 (s, 1H), 4.44 (d, J = 6.1 Hz, 2H), 3.93 (s, 2H), 2.28 (s, 3H). Prep-HPLC purification conditions: Column: XBridge Shield RP18 OBD Column, 19*250 mm, 10μm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 25% B to 35% B in 6 min, 35% B; Wave Length: 254/210 nm. EXAMPLE 33: 5-[2-fluoro-4-[[(4-fluoro-5-methyl-2-pyridyl)amino]methyl]-6 -hydroxy- phenyl]-1,1-dioxo-1,2,5- O The title compound was prepared in 5.33% overall yield as a white solid according to the preparation of EXAMPLE 4 using 4-fluoro-5-methyl-pyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₅ H ₁₄ F ₂ N ₄ O ₄ S, [M+H] ⁺ 385; Found 385. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.92 (s, 1H), 8.14 (s, 1H), 7.94 (d, J = 9.4 Hz, 1H), 6.72 – 6.61 (m, 3H), 4.43 (s, 2H), 4.13 (s, 2H), 2.08 (s, 3H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 25% B to 50% B in 5.3 min, 50% B; Wave Length: 210/254 nm. EXAMPLE 34: 5-[2-fluoro-6-hydroxy-4-[[(3-methoxy-2-pyridyl)amino]methyl] phenyl]-1,1- dioxo-1,2,5-thiadiazolidin-3- O The title compound was prepared in 11.08% overall yield as a brown solid according to the preparation of EXAMPLE 4 using 3-methoxypyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₅ H ₁₅ FN ₄ O ₄ S, [M+H] ⁺ 383; Found 383. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.44 (d, J = 6.2 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.64 (d, J = 10.3 Hz, 2H), 4.54 (s, 2H), 4.39 (s, 0H), 4.00 (s, 2H), 3.94 (s, 3H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 30*50 mm, 5μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 4% B to 35% B in 9 min, 35% B; Wave Length: 254/210 nm. EXAMPLE 35: 5-[2-fluoro-6-hydroxy-4-[[(6-methoxy-2-pyridyl)amino]methyl] phenyl]-1,1- dioxo-1,2,5-thiadiazolidin-3- O The title compound was prepared in 6.83% overall yield as a white solid according to the preparation of EXAMPLE 4 using 6-methoxypyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₅ H ₁₅ FN ₄ O ₅ S, [M+H] ⁺ 383; Found 383. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (s, 1H), 7.39-7.29 (m, 1H), 7.18 – 6.91 (m, 1H), 6.80 – 6.61 (m, 2H), 6.03 (dd, J = 7.8, 1.8 Hz, 1H), 5.90 (dd, J = 7.7, 1.7 Hz, 1H), 4.36 (d, J = 2.5 Hz, 4H), 3.71 (d, J = 1.1 Hz, 3H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 30*50 mm, 5μm; Mobile Phase A: Water (0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 35% B in 8 min, 35% B; Wave Length: 254/210 nm. EXAMPLE 36: 5-[4-[[(5,6-dimethoxy-2-pyridyl) amino] methyl]-2-fluoro-6-hydroxy- phenyl]-1,1-dioxo-1,2,5- O The title compound was prepared in 22.83% overall yield as an off-white solid according to the preparation of EXAMPLE 4 using 4,5-dimethoxypyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₆ S, [M+H] ⁺ 413; Found 413. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.48 (s, 2H), 7.09 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 1.9 Hz, 1H), 6.65 – 6.58 (m, 2H), 5.91 (d, J = 8.3 Hz, 1H), 4.27 (d, J = 6.2 Hz, 2H), 3.92 (s, 2H), 3.75 (s, 3H), 3.61 (s, 3H). Prep-HPLC purification conditions: Column: XBridge BEH C18 OBD Prep Column, 19*250 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 27% B to 27% B in 6 min, 27% B; Wave Length: 254 nm. EXAMPLE 37: 5-[2-fluoro-6-hydroxy-4-[(2-pyridylamino) methyl] phenyl]-1,1-dioxo- 1,2,5-thiadiazolidin-3-one O The title compound was prepared in 6.01% overall yield as a white solid according to the preparation of EXAMPLE 4 using pyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₄ H ₁₃ FN ₄ O ₄ S, [M+H] ⁺ 353; Found 353. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.54 (s, 1H), 7.95 (d, J = 5.8 Hz, 2H), 7.64 (dd, J = 11.7, 4.6 Hz, 1H), 7.34 – 6.94 (m, 1H), 6.89 – 6.55 (m, 4H), 4.43 (d, J = 5.6 Hz, 2H), 3.96 (s, 2H). Prep-HPLC purification conditions: Column: XBridge BEH C18 OBD Prep Column, 19*250 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 13% B to 38% B in 6 min, 38% B; Wave Length: 254 nm. EXAMPLE 38: 5-[2-fluoro-6-hydroxy-4-[[(5-methoxy-2-pyridyl)amino]methyl] phenyl]-1,1- dioxo-1,2,5-thiadiazolidin-3-one ^N _{O F} ^{HN O} _O S HN N HO O The title compound was prepared in 15.72% overall yield as a white solid according to the preparation of EXAMPLE 4 using 5-methoxypyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₅ H ₁₅ FN ₄ O ₅ S, [M+H] ⁺ 383; Found 383. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.79 (s, 1H), 8.19 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 2.9 Hz, 1H), 6.92 (d, J = 9.5 Hz, 1H), 6.69 (m, J = 9.2, 1.9 Hz, 2H), 4.44 (s, 2H), 4.06 (m, J = 4.3 Hz, 2H), 3.76 (s, 3H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 55% B in 5.3 min, 55% B; Wave Length: 210/254 nm. EXAMPLE 39: 5-(2-fluoro-6-hydroxy-4-(((6-methoxy-4-methylpyridin-2- yl)amino)methyl)phenyl)- O Scheme 8:

O F O _S ^NH N O O O B B O Br O O B O 8-2 Key Int.2 K ₂ ^CO _{3,Pd(dppf)Cl2} ^{H Ti(i-PrO)} _{4, NaBH3} ^{CN H2N} _{N O} ^{dioxane, 115o} C _,o/n ^2N _{N O} DCE,rt,o/n S _{tep 1} ^{Step 2} 8-1 8-3 O F O _S ^NH N O F O O H TFA,DCM O S N ^{N N} _N O Step 3 HN N _H O HO O O 8-4 Step 1: To a stirred solution of 4-bromo-6-methoxy-pyridin-2-amine (300 mg, 1.48 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (370.95 mg, 2.96 mmol) and K ₂ CO ₃ (611.7 mg, 4.43 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl ₂ (60.33 mg, 0.07 mmol). The reaction mixture was placed under vacuum, sonicated, and backfilled with nitrogen. The resulting mixture was stirred at 115 °C for 20 h. After completion of the reaction monitored by LCMS, the mixture was filtered and the filtrate was concentrated. The residue was purified by silica column chromatography to afford 6-methoxy-4-methyl-pyridin-2-amine (150 mg, 1.08 mmol, 73.47% yield) as a yellow solid. MS: m/z: Calc’d for C ₇ H ₁₀ N ₂ O [M+H] ⁺ 139; Found 139. Step 2: To a solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5- thiadiazolidin-2-yl)benzaldehyde (100 mg, 0.25 mmol) and 6-methoxy-4-methyl-pyridin-2- amine (52.55 mg, 0.38 mmol) in DCE (10 mL) was added a solution of Ti(i-PrO) ₄ (143.01 mg, 0.51 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. NaBH3CN (32.02, 0.51 mmol) was added to the mixture at 0 ^o C. The resulting mixture was stirred at room temperature for additional 30 mins. Upon completion, the reaction mixture was concentrated. The resulting residue was dissolved with DMSO and purified by a reversed-phase column chromatography (0.05% NH ₄ HCO ₃ in H ₂ O and MeCN) to obtain 5- [2-fluoro-4-[[(6-methoxy-4-methyl-2-pyridyl)amino]methyl]-6- [(4- methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin -3-one (100 mg, 0.12 mmol, 47.56% yield) as a yellow oil. MS: m/z: Calc’d for C ₂₄ H ₂₅ FN ₄ O ₆ S, [M+H]+ 517; Found, 517. Step 3: To a solution of 5-[2-fluoro-4-[[(6-methoxy-4-methyl-2-pyridyl)amino]methyl]- 6- [(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazol idin-3-one (100 mg, 0.19 mmol) in DCM (10 mL) was added TFA (5 mL), and the mixture was stirred at room temperature for 2 h. Upon completion, the reaction mixture was concentrated. The resulting residue was purified by a reversed-phase column chromatography (0.05% NH ₄ HCO ₃ in H ₂ O and MeCN) and further purified by Prep-HPLC to obtain 5-[2-fluoro-6-hydroxy-4-[[(6- methoxy-4-methyl-2-pyridyl)amino]methyl]phenyl]-1,1-dioxo-1, 2,5-thiadiazolidin-3-one (10.8 mg, 0.02 mmol, 13.58% yield) as a white solid. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₅ S, [M+H] ⁺ 397; Found 397. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.35 (s, 1H), 7.27 – 7.02 (m, 1H), 6.83 – 6.60 (m, 2H), 5.93 – 5.79 (m, 2H), 4.37 (s, 4H), 3.71 (s, 3H), 2.11 (s, 3H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 10% B to 30% B in 6 min, 30% B; Wave Length: 210/254 nm. EXAMPLE 40: 6-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin- 2- yl)phenyl]methylamino] 2- O The title compound was prepared in 8.88% overall yield as a white solid according to the preparation of EXAMPLE 1 using 6-aminopyridine-2-carbonitrile in STEP 1. After adding TMSCl, the reaction mixture was stirred at 60 ^o C instead of room temperature. MS: m/z: Calc’d for C ₁₅ H ₁₂ FN ₅ O ₄ S, [M+H] ⁺ 378; Found 378. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.52 (dd, J = 8.7, 7.1 Hz, 1H), 7.01 (dd, J = 7.1, 0.8 Hz, 1H), 6.81 – 6.74 (m, 2H), 6.70 (dd, J = 10.6, 1.9 Hz, 1H), 4.50 (s, 2H), 4.41 (s, 2H). Prep-HPLC purification conditions: Column: SunFire C18 OBD Prep Column, 19*250 mm, 5μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 20% B to 55% B in 7 min, 55% B; Wave Length: 254/210 nm. EXAMPLE 41: 5-[2-fluoro-6-hydroxy-4-[[(4-methoxy-6-methyl-2-pyridyl) amino] methyl] phenyl]-1,1-dioxo-1,2,5- The title compound was prepared in 3.97% overall yield as an off-white solid according to the preparation of EXAMPLE 4 using 4-methoxy-6-methyl-pyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₆ H ₁₇ FN ₄ O ₅ S, [M+H] ⁺ 397; Found 397. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.66 (d, J = 10.8 Hz, 2H), 6.28 (s, 1H), 6.00 (s, 1H), 4.39 (s, 2H), 3.76 (s, 3H), 2.28 (s, 3H). Prep-HPLC purification conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 53% B to 60% B in 8 min, 60% B; Wave Length: 254/210 nm. EXAMPLE 42: 5-[4-[[[6-(difluoromethyl)-2-pyridyl] amino] methyl]-2-fluoro-6-hydroxy- phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one O The title compound was prepared in 16.46% overall yield as a white solid according to the preparation of EXAMPLE 1 using 6-(difluoromethyl) pyridin-2-amine in STEP 1. The reductive amination was performed at 60 °C instead of room temperature. MS: m/z: Calc’d for C ₁₅ H ₁₃ F ₃ N ₄ O ₄ S, [M+H] ⁺ 403; Found 403. ¹ H NMR (400 MHz, DMSO-d ₆ +D ₂ O) δ 7.58 – 7.50 (m, 1H), 6.82 – 6.48 (m, 5H), 4.38 (s, 2H), 3.94 (s, 2H). Prep-HPLC purification conditions: Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 28% B to 48% B in 6 min, 48% B; Wave Length: 254/210 nm. EXAMPLE 43: 5-[4-[[[6-(difluoromethoxy)-2-pyridyl] amino] methyl]-2-fluoro-6-hydroxy- phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one F O O S ^N HN N _{H N} O HO O ^{F F} The title compound was prepared in 27.09% overall yield as an off-white solid according to the preparation of EXAMPLE 4 using 6-(difluoromethoxy)pyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₁₅ H ₁₃ F ₃ N ₄ O ₅ S, [M+H] ⁺ 419; Found 419. ¹ H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 73.8 Hz, 1H), 7.48 – 7.38 (m, 2H), 7.18 (s, 2H), 6.67 – 6.62 (m, 1H), 6.29 (d, J = 8.1 Hz, 1H), 6.06 (d, J = 7.5 Hz, 1H), 4.33 (d, J = 6.1 Hz, 2H), 3.93 (s, 2H). Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 24% B to 34% B in 7 min, 34% B to 49% B in 8.5 min, 49% B; Wave Length: 254 nm. EXAMPLE 44: 5-(4-(((6-(dimethylamino)pyridin-2-yl)amino)methyl)-2-fluoro -6- hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide Int-2 9-2 Step 1：To a stirred solution of 3-fluoro-5-[(4-methoxyphenyl) methoxy]-4-(1,1,4-trioxo- 1,2,5-thiadiazolidin-2-yl) benzaldehyde (100 mg, 0.25 mmol) and N, N-dimethylpyridine- 2,6-diamine (52.18 mg, 0.38 mmol) in dry DMF (5 mL) was added TMSCl (0.07 mL, 0.63 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C, and a solution of NaBH ₃ CN (32.02 mg, 0.51 mmol) in DMF (2 mL) was added. After the addition, the reaction mixture was stirred at room temperature for 12 h. LCMS showed the reaction was completed. The resulting solution was quenched by ice water (0.5 ml) and directly purified by a reversed-phase column chromatography (0.05% FA in H ₂ O and MeCN) to obtain 5-[4-[[[6-(dimethylamino)-2- pyridyl] amino] methyl]-2-fluoro-6-[(4-methoxyphenyl) methoxy] phenyl]-1,1-dioxo-1,2,5- thiadiazolidin-3-one (50 mg, 0.09 mmol, 38.24% yield) as a light yellow oil. MS: m/z: Calc’d for C ₂₄ H ₂₂ FN ₅ O ₅ S [M+H] ⁺ 516; Found 516 Step 2：To a stirred mixture of 5-[4-[[[6-(dimethylamino)-2-pyridyl] amino] methyl]-2- fluoro-6-[(4-methoxyphenyl) methoxy] phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (50 mg, 0.09 mmol) in DCM (2 mL) was added TFA (2 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. After completion of the reaction monitored by LCMS, the mixture was concentrated. The residue was purified by a reversed- phase column chromatography (0.05% NH ₄ HCO ₃ in H ₂ O and MeCN) and further purified by Prep-HPLC to afford 5-[4-[[[6-(dimethylamino)-2-pyridyl] amino] methyl]-2-fluoro-6- hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2.7 mg, 0.006 mmol, 6.75% yield) as a light green solid. MS: m/z: Calc’d for: C ₁₆ H ₁₈ FN ₅ O ₄ S [M+H] ⁺ 396, Found 396. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 7.13 (t, J = 7.9 Hz, 1H), 6.69 – 6.56 (m, 3H), 5.71 (t, J = 8.3 Hz, 2H), 4.32 (d, J = 6.2 Hz, 2H), 3.93 (s, 2H), 2.90 (d, J = 1.2 Hz, 6H). Prep-HPLC-conditions: Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH ₄ HCO ₃ +0.1%NH ₃ ^. H ₂ O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 45% B in 7.5 min, 45% B; Wave Length: 254/210 nm. EXAMPLE 45: 5-[2-fluoro-6-hydroxy-4-[[(5-isopropyl-2-pyridyl)amino]methy l]phenyl]- 1,1-dioxo-1,2,5- O The title compound was prepared in 11.50% overall yield as a white solid according to the preparation of EXAMPLE 1 using 5-isopropylpyridin-2-amin in STEP 1. After adding TMSCl, the reaction mixture was stirred at 60 ^o C instead of 80 ^o C. MS: m/z: Calc’d for C ₁₇ H ₁₉ FN ₄ O ₄ S, [M+H] ⁺ 395; Found 395. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.81 (s, 1H), 8.84 (s, 1H), 7.96 (d, J = 9.3 Hz, 1H), 7.73 (s, 1H), 7.05 (d, J = 9.3 Hz, 1H), 6.76 – 6.66 (m, 2H), 4.49 (d, J = 5.6 Hz, 2H), 4.03 (s, 2H), 2.88 (m, J = 6.9 Hz, 1H), 1.17 (d, J = 6.9 Hz, 6H). Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 3% B to 33% B in 10 min, 33% B; Wave Length: 254 nm. EXAMPLE 46: 5-[4-[[(4-benzyloxy-2-pyridyl)amino]methyl]-2-fluoro-6-hydro xy-phenyl]- 1,1-dioxo-1,2,5- O The title compound was prepared in 9.27% overall yield as a white solid according to the preparation of EXAMPLE 1 using 4-benzyloxypyridin-2-amine in STEP 1. After adding TMSCl, the reaction mixture was stirred at 60 ^o C. MS: m/z: Calc’d for C ₂₁ H ₁₉ FN ₄ O ₅ S, [M+H] ⁺ 459; Found 459. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.81 (d, J = 6.2 Hz, 1H), 7.48 – 7.30 (m, 5H), 6.68 – 6.57 (m, 2H), 6.34 (d, J = 6.3 Hz, 1H), 6.21 (s, 1H), 5.12 (s, 2H), 4.38 (s, 2H), 3.93 (s, 2H). Prep-HPLC purification conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ +0.1%NH ₃ .H ₂ O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 23% B to 33% B in 9 min, 33% B; Wave Length: 254/220 nm EXAMPLE 47: 5-[4-[[(5-benzyloxy-2-pyridyl)amino]methyl]-2-fluoro-6-hydro xy-phenyl]- 1,1-dioxo-1,2,5-thiadiazolidin-3-one ^N _{O F} ^HN O O S HN N O HO The title compound was prepared in 10.23% overall yield as a white solid according to the preparation of EXAMPLE 81 using 5-benzyloxypyridin-2-amine in STEP 1. MS: m/z: Calc’d for C ₂₁ H ₁₉ FN ₄ O ₅ S, [M+H] ⁺ 459; Found 459. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.90 (s, 1H), 7.71 (s, 1H), 7.63 (s, 1H), 7.48 – 7.36 (m, 4H), 7.40 – 7.31 (m, 1H), 6.95 (s, 1H), 6.70 (d, J = 11.0 Hz, 2H), 5.08 (s, 2H), 4.44 (s, 2H), 4.10 (s, 2H). Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 40% B in 10 min, 40% B; Wave Length: 254 nm. EXAMPLE 48: 5-(4-(((6-bromo-4-methylpyridin-2-yl)amino)methyl)-2-fluoro- 6- hydroxyphenyl)-1,2,5- To a solution of 4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-( (4- methoxybenzyl)oxy)benzaldehyde (Int-2, 100 mg, 0.254 mmol) and 6-bromo-4- methylpyridin-2-amine (95 mg, 0.507 mmol) in DCM (10 mL) was added trimethylsilyl trifluoromethanesulfonate (0.092 mL, 0.507 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. To the reaction mixture was added NaBH(AcO) ₃ (107 mg, 0.507 mmol) at 0 ^o C. The mixture was stirred at room temperature for an additional 8 h. LCMS showed the starting material was consumed completely (50% of desired product was observed together with 5% of PMB-protected intermediate). The reaction mixture was concentrated, and the resulting residue was added 1:1 TFA/DCM solution and stirred at RT for 2h. The resulting solution was concentrated at a low temperature (bath temperature: 25 ^o C). The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 μm particles; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation to give 33.6 mg (29.7% yield) of 5-(4-(((6-bromo-4-methylpyridin-2-yl)amino)methyl)-2- fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide as white solid. MS: m/z: Calc’d for C ₁₅ H ₁₄ BrFN ₄ O ₄ S [M+H] ⁺ 445, found 445. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 6.76 - 6.62 (m, 2H), 6.56 (s, 1H), 6.30 (s, 1H), 4.42 - 4.24 (m, 4H), 2.13 (s, 3H) EXAMPLE 49: 5-(2-fluoro-6-hydroxy-4-(((4-methyl-6-morpholinopyridin-2- - 1 ^0-1 Step 1: To a 250-mL pressure tube were added 6-bromo-4-methylpyridin-2-amine (1478 mg, 7.9 mmol), morpholine (895 mg, 10.27 mmol), and diisopropylethyl amine (4146 µl, 23.8 mmol). The mixture was heated at 150 °C for 18 h. The reaction mixture was quenched with water (10 ml) and extracted with EtOAc (2 x 25 ml). The organic phase was dried over sodium sulfate, filtered, and concentrated to give 740 mg of 4-methyl-6-morpholinopyridin- 2-amine (49% yield) as a brown solid and used as is in the next step. MS: m/z: Calc’d for C ₁₅ H ₁₄ BrFN ₄ O ₄ S [M+H] ⁺ 194, found 194. Step 2: To a solution of 4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-( (4- methoxybenzyl)oxy)benzaldehyde (Int-2, 100 mg, 0.254 mmol) and 4-methyl-6- morpholinopyridin-2-amine (98 mg, 0.507 mmol) in DCM (10 mL) was added trimethylsilyl trifluoromethanesulfonate (0.092 mL, 0.507 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. To the reaction mixture was added NaBH(AcO) ₃ (107 mg, 0.507 mmol) at 0 ^o C. The mixture was stirred at room temperature for an additional 8 h. LCMS showed the starting material was consumed completely (50% of desired product was observed together with 5% of PMB-protected intermediate). The reaction mixture was concentrated, and the resulting residue was added 1:1 TFA/DCM solution and stirred at RT for 2h. The resulting solution was concentrated at a low temperature (bath temperature: 25 ^o C). The crude material was purified via preparative Reverse Phase chromatography with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 μm particles; Flow Rate: 20 mL/min; Column Temperature: 25 °C.Fraction collection was triggered by MS (ESI +). Fractions containing the desired product were combined and dried via centrifugal evaporation. MS: m/z: Calc’d for C ₁₉ H ₂₂ FN ₅ O ₅ S [M+H] ⁺ 452, found 452. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 6.76 - 6.61 (m, 2H), 6.00 - 5.88 (m, 1H), 5.88 - 5.77 (m, 1H), 4.44 - 4.30 (m, 2H), 4.21 - 4.05 (m, 2H), 3.77 - 3.60 (m, 3H), 3.57 - 3.41 (m, 3H), 3.40 - 3.28 (m, 2H), 2.13 (s, 3H) EXAMPLE 50: 5-(4-((cyclopropyl(5-(trifluoromethyl)pyridin-2-yl)amino)met hyl)-2-fluoro- - 3-one 1,1-dioxide O Scheme 11: O O F _S ^NH N O O O F F H ₂ N HN Int-2 O F F F N _{1)TMSOTf,NaBH(OAc)3} ^,DCM OH N N F DMSO,130 ^o C, 2h 2)TFA,DCM,rt,2h N F Step 1 Step 2 ^N _O F F F O ^S _NH F O 11-1 Step 1: To the stirred mixture of 2-fluoro-5-(trifluoromethyl)pyridine (500 mg, 3.03 mmol) in DMSO (8 mL) was added cyclopropanamine (1.729 g, 30.29 mmol) at room temperature. The resulting mixture was stirred at 130 ^o C for 2 h. LCMS showed the starting material was consumed completely. The reaction mixture was directly purified by reversed-phase column chromatography to obtain N-cyclopropyl-5-(trifluoromethyl)pyridin-2-amine (400 mg, 1.97 mmol, 65.32% yield) as a white solid. MS: m/z: Calc’d for C ₉ H ₉ F ₃ N ₂ [M+H] ⁺ 203, found 203. Step 2: To a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo- 1,2,5-thiadiazolidin-2-yl)benzaldehyde (Int-2120 mg, 0.30 mmol) and N-cyclopropyl-5- (trifluoromethyl)pyridin-2-amine (92.28 mg, 0.46 mmol) in DCM (8 mL) was added TMSOTf (101.33 mg, 0.46 mmol) at 0 ^o C. The reaction mixture was stirred at 50 °C for 2 h. The mixture was cooled to 0 ^o C, and NaBH(AcO) ₃ (129.02 mg, 0.61 mmol) was added to the above mixture. The resulting mixture was stirred at room temperature for an additional 1 h. LCMS showed the starting material was consumed completely (50% of desired product, was observed together with 8% of PMB-protected intermediate). Then, TFA (8 mL) was added to the reaction system at 0 ^o C, and the mixture was stirred at room temperature for another 3 h. After completion of the reaction monitored by LCMS, the mixture was concentrated. The resulting residue was purified by a reversed-phase column chromatography to obtain 5-[4- [[cyclopropyl-[5-(trifluoromethyl)-2-pyridyl]amino]methyl]-2 -fluoro-6-hydroxy-phenyl]-1,1- dioxo-1,2,5-thiadiazolidin-3-one (14.9 mg, 0.031 mmol, 10.63% yield) as a white solid. MS: m/z: Calc’d for C ₁₈ H ₁₆ F ₄ N ₄ O ₄ S [M+H] ⁺ 461, found 461. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 6.46 (d, J = 7.8 Hz, 2H), 4.81 (s, 2H), 3.96 (s, 2H), 2.68 (s, 1H), 0.94 (d, J = 6.6 Hz, 2H), 0.68 (s, 2H). Prep-HPLC purification conditions: Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 40% B to 55% B in 5.8 min, 55% B; Wave Length: 254/210 nm. EXAMPLE 51: 5-(2-fluoro-6-hydroxy-4-(((6-oxo-1,6-dihydropyridin-2- yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide Int-2 Step 1：To a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo- 1,2,5-thiadiazolidin-2-yl)benzaldehyde (80 mg, 0.20 mmol) and 6-aminopyridin-2-ol (33.5 mg, 0.30 mmol) was added TMSOTf (135.1 mg, 0.61 mmol) dropwise at 0 °C. Then, NaBH(AcO) ₃ (86.01 mg, 0.41 mmol) was added slowly. The resulting mixture was stirred at room temperature for 30 mins. LCMS showed the starting material was consumed completely (approximately 50% of desired product, was observed together with 10% of PMB-protected intermediate). The resulting solution was concentrated at a low temperature (water bath temperature: 25 ^o C). The residue was purified by a reversed-phase column chromatography (0.05% NH ₄ HCO ₃ in H ₂ O and MeCN) and further purified by Prep-HPLC to obtain 5-[2- fluoro-6-hydroxy-4-[[(6-oxo-1H-pyridin-2-yl)amino]methyl]phe nyl]-1,1-dioxo-1,2,5- thiadiazolidin-3-one (10.1 mg, 0.03 mmol, 13.24% yield) as an off-white solid. MS: m/z: Calc’d for C ₁₄ H ₁₃ FN ₄ O ₅ S, [M+H] ⁺ 369 found 369. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.19 (s, 1H), 7.37 (t, J = 8.2 Hz, 1H), 7.01 (s, 1H), 6.68 (t, J = 5.0 Hz, 2H), 5.71 (dd, J = 14.7, 8.1 Hz, 2H), 4.33 (s, 2H), 4.23 (s, 2H). Prep-HPLC condition: Column: Welch Utimate HS-C18, 21.2*250 mm, 7μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 17% B to 32% B in 8 min, 32% B; Wave Length: 254/210 nm. EXAMPLE 52: 5-(2-fluoro-6-hydroxy-4-(((6-methyl-4-phenoxypyridin-2- yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide 13-1 13-3 Step 1：To a solution of [N,N'-bis(2,5-dimethylpyrrol-1-yl)oxamide] (L ₁ , 44 mg, 0.16 mmol) in DMSO (5 mL) were added CuBr (11.47 mg, 0.08 mmol) and K ₃ PO ₄ (510.05 mg, 2.41 mmol). The mixture was stirred at room temperature for 30 mins.4-bromo-6-methyl- pyridin-2-amine (300 mg, 1.6 mmol) and phenol (226.42 mg, 2.41 mmol) were added to the aforementioned mixture. The resulting mixture was heated to 120 °C for 16 h. LCMS showed that 80% of the product was formed. The reaction mixture was directly purified by reversed- phase column chromatography (0.05% NH ₄ HCO ₃ in H ₂ O and MeCN) to afford 6-methyl-4- phenoxy-pyridin-2-amine (160 mg, 0.79 mmol, 49.81% yield) as a brown oil. MS: m/z: Calc’d for C ₁₂ H ₁₂ N ₂ O [M+H] ⁺ 201, found 201. Step 2：To a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo- 1,2,5-thiadiazolidin-2-yl)benzaldehyde (60 mg, 0.15 mmol) and 6-methyl-4-phenoxy-pyridin- 2-amine (39.6 mg, 0.20 mmol) in DCM (5 mL) was added TMSOTf (0.08 mL, 0.46 mmol) dropwise at 0 ^o C, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was then cooled to 0 °C and NaBH(AcO) ₃ (43.82 mg, 0.46 mmol) was added slowly. After the addition, the reaction mixture was stirred at room temperature for an additional 1 h. LCMS showed the starting material was consumed completely (approximately 50% of de-PMB protected product was formed). The resulting solution was concentrated at a low temperature (bath temperature: 25 ^o C). The residue was purified by a reversed-phase column chromatography (0.05% NH ₄ HCO ₃ in H ₂ O and MeCN) and further purified by Prep- HPLC to obtain 5-[2-fluoro-6-hydroxy-4-[[(6-methyl-4-phenoxy-2- pyridyl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin- 3-one (19.7 mg, 0.04 mmol, 39.44% yield) as a white solid. MS: m/z: Calc’d for C ₂₁ H ₁₉ FN ₄ O ₅ S [M+H] ⁺ 459, found 459. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 9.87 (s, 1H), 8.37 (s, 1H), 7.53 (t, J = 7.9 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 6.61 (d, J = 9.4 Hz, 2H), 6.49 (s, 1H), 6.03 (d, J = 2.3 Hz, 1H), 4.43 (d, J = 5.6 Hz, 2H), 4.09 (d, J = 3.3 Hz, 2H), 2.42 (s, 3H). Prep-HPLC purification conditions: Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 55% B in 7.8 min, 55% B; Wave Length: 254/210 nm

Compound Examples Prepared by the Procedures above are listed in Table 1. 5 Examples of Prepared Compounds Table 1 ,

BIOLOGICAL ASSAYS The pharmacological properties of the compounds of this invention may be confirmed by many biological assays known in the art. The exemplified biological assays which follow, have been carried out with compounds of the invention. PhosphoSens Assays A PhosphoSens® kinase assay was performed as described by the vendor (AssayQuant Technologies, Marlborough, MA). Briefly, 1000X solutions of compounds were prepared in DMSO via serial dilution of the 10 mM DMSO stocks using 3-fold intervals in a 384-well reagent plate.50 nL of the compound dilution series was then added to the corresponding wells of a 384-well assay plate. 40 mL of 1.25X substrate (AQT0264) in 1X assay buffer (50 mM HEPES pH 7.5, 500 µM EGTA, 10 nM MgCl2, 0.01% Brij-35, 1% Glycerol, 1 mM DTT, and 0.2 mg/mL BSA) was transferred to each well of the assay plate to achieve a final substrate concentration of 20 µM. Finally, 10 mL of 5X PTPN2 enzyme stock was added to each well of the assay plate for a final enzyme concentration of 150 pM. Reaction progress curves were collected by sampling fluorescence intensity at the excitation wavelength 360 nm (λex360) and emission wavelength 480 nm (λem480) every 71 seconds for one hour using a Synergy H4 plate reader (BioTek Instruments/Agilent Technologies, Winooski, VT) at room temperature. Phosphotase activity assay using DIFMUP as substrate: The PTPN2 biochemical assay was performed as follows, a 5X stock solution of human PTPN2 (SRP5075, MilliporeSigma, Burlington, MA) and a 1.25X stock solution of DiFMUP (D6567, ThermoFisher Scientific, Waltham, MA), were prepared in 1X reaction buffer consisting of 50 mM HEPES, pH 7.4, 1 mM EDTA, 150 mM NaCl, 0.2 mg/mL BSA, 100 U/mL catalase and 10 mM DTT.40 mL of the DiFMUP substrate solution, for a final concentration of 25 mM DiFMUP substrate, was added to a Corning 3574384-well, white, non-binding surface microtiter plate containing 0.05 mL of serially diluted test compounds prepared in DMSO. The reactions were started with the addition of 10 mL of the enzyme solution, for a final PTPN2 concentration of 0.15 nM, and monitored every 105 seconds for 60 minutes at λ _EX 360/λ _EM 460 in a BioTek Synergy HTX plate reader (Agilent Technologies, Santa Clara, CA) at room temperature. The initial linear portions of the progress curves were fit according to a linear equation to yield the slopes and converted to % inhibition based on a value of 100% activity for the no inhibitor treated control. IC ₅₀ values of each compound were obtained by fitting the % inhibition-compound concentration curves using Dotmatics software (Dotmatics, Bishops Stortford, Hertfordshire, England). Cell proliferation assay protocol B16-F10 cells (ATCC, Manassas, VA, #CRL-6475) were cultured in DMEM growth medium (ThermoFisher Scientific, Waltham, MA, #11995-040) supplemented with 10% heat-inactivated FBS (ThermoFisher Scientific, #16140-071) and 1% pen/strep (ThermoFisher Scientific, #15140-122). The cells were seeded into two white opaque 384- well tissue culture-treated microplates (PerkinElmer, Waltham, MA, #6007688) at a density of 100 cells/well in 20uL total volume and incubated overnight at 37C and 5% CO2.30nL of compounds dissolved in DMSO were then transferred from a source plate into target wells with the Echo650 acoustic liquid handler (Beckman Coulter, Indianapolis, IN). Negative control wells received 30nL of DMSO only (0.15% final concentration). Plates were returned to the incubator for 1 hour and then cells were treated with either 5uL of growth medium or 5uL of growth medium containing 50 ng/mL of recombinant mouse IFN-gamma protein (R&D Systems, Minneapolis, MN, #485-MI/CF, 10 ng/mL final concentration) using the Assist automated pipetting platform (INTEGRA Biosciences, Hudson, NH). Plates were incubated at 37C for 4 days and cell proliferation was assayed with the CellTiter-Glo reagent (Promega, Madison, WI, #G7573, 25uL per well). Luminescence signal intensity was collected with the EnVision 2105 plate reader (PerkinElmer) 15 minutes after CellTiter-Glo reagent addition and analyzed with the Dotmatics software platform to calculate compound IC50 values. Off-target compound-mediated cytotoxicity was identified by checking for growth inhibition in the absence of IFNg. Phospho-STAT1 assay protocol B16-F10 cells (ATCC, Manassas, VA, #CRL-6475) were cultured in DMEM growth medium (ThermoFisher Scientific, Waltham, MA, #11995-040) supplemented with 10% heat-inactivated FBS (ThermoFisher Scientific, #16140-071) and 1% pen/strep (ThermoFisher Scientific, #15140-122). The cells were seeded into a white opaque 384-well tissue culture treated microplate (PerkinElmer, Waltham, MA, #6007688) at a density of 10,000 cells/well in 20uL total volume and incubated overnight at 37C and 5% CO2.30nL of compounds dissolved in DMSO were then transferred from a source plate into target wells with the Echo650 acoustic liquid handler (Beckman Coulter, Indianapolis, IN). Negative control wells received 30nL of DMSO only (0.15% final concentration). Plates were returned to the incubator for 1 hour and then cells were treated with either 5uL of growth medium or 5uL of growth medium containing 500 ng/mL of recombinant mouse IFN-gamma protein (R&D Systems, Minneapolis, MN, #485-MI/CF, 100 ng/mL final concentration) using the Assist automated pipetting platform (INTEGRA Biosciences, Hudson, NH). Plates were incubated at 37C for 1 hour and assayed for phosphorylated STAT1 protein levels with the phospho-STAT1 (Tyr701) HTRF kit (Cisbio, Bedford, MA, #63ADK026PEH) according to the manufacturer’s instructions. HTRF signal intensity was collected with the EnVision 2105 plate reader (PerkinElmer) 24 hours later and analyzed with the Dotmatics software platform to calculate compound IC50 values. Biological Assay Data Table 2 is a summary of Biological Assay data for Examples/Embodiments Prepared. For IC50 data, High DDT concentration and/or DiFMUP substrate assays were used; a skilled artisan may use either assay. A row or column with a double asterisk indicates that one IC50 value or embodiment has been provided. Table 2