1,2,4-Thiadiazolidin-3-one 1,1-Dioxide Protein Tyrosine Phosphatase Inhibitors, Compositions, and Methods of Use

Abstract

Formula (I) as defined herein The compounds of TIFF2026503211000071.tif6464, their pharmaceutically acceptable salts, pharmaceutical compositions, and combinations thereof, and methods of using them as inhibitors of protein tyrosine phosphatase 2 (PTPN2), are disclosed. These compounds are useful for treating cancers and diseases susceptible to PTPN2 inhibition.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 476,520, filed December 21, 2022, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION This application discloses compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and combinations thereof, and methods of their use as protein tyrosine phosphatase inhibitors. [Background technology]

[0003] Immune checkpoint blockade (ICB) is an innovative approach in immunotherapy that targets immune evasion mechanisms to improve clinical responses in cancer patients. For example, checkpoint inhibitor antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and their ligands (e.g., programmed cell death ligand 1 (PD-L1)) have been used in the treatment of multiple cancer types, significantly improving treatment and survival outcomes for patients with these malignancies.

[0004] However, the majority of patients undergoing ICB develop a treatment-refractory state or ultimately acquire resistance. In particular, alterations or defects in the interferon-γ (IFNγ) signaling pathway represent an important mechanism for clinical ICB resistance (Zaretsky, N. Engl. J. Med. 375, 819-829). IFNγ is a T cell-derived cytokine that directly restricts tumor growth by signaling through the Janus kinase / signal transducer and activator of transcription (JAK / STAT) pathway. Furthermore, IFNγ indirectly restricts tumor growth by promoting the upregulation of major histocompatibility complex class I (MHC-I), thereby presenting antigen (Ag) to T cells. In vivo CRISPR screening using a syngeneic mouse model revealed improvements in the IFNγ pathway in anti-PD-1–resistant tumors. These studies have confirmed that the aforementioned members of the IFNγ pathway (JAK1 / 2 and STAT1) and interferon-γ receptors (IFNGR1 / IFNGR2) are effective in resistance, in addition to newly identified negative regulators (e.g., PTPN2 and apelin receptor (APLNR)), and these represent new therapeutic targets (Charles Sinclair et al. Emerg Top Life Sci. (2021) 5 (5): 675-680).

[0005] Data compiled from an in vivo genetic screen using CRISPR-Cas9 genome editing to identify genes that cause resistance to checkpoint inhibitors confirmed that deletion of the protein tyrosine phosphatase (PTPN2) gene in tumor cells enhances the efficacy of immunotherapy. The PTPN2 gene encodes a protein tyrosine phosphatase that regulates various intracellular processes. Loss of PTPN2 in tumor cells enhances IFNγ signaling and antigen presentation to T cells, leading to proliferation arrest in response to cytokines. These data suggest that therapeutic inhibition of PTPN2 may enhance the efficacy of immunotherapies that trigger IFNγ responses (Manguso, Robert T et al. Nature vol. 547, 7664 (2017): 413-418).

[0006] Protein tyrosine phosphatase non-receptor type 2 (PTPN2), also known as T-cell protein tyrosine phosphatase (TCPTP), is a cellular member of the class 1 subfamily of phosphotyrosine-specific phosphatases that mediates multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, but is most highly expressed in hematopoietic and placental cells (Mosinger, B. Jr. et al., Proc Natl Acad Sci USA (1992) 89:499-503). In humans, PTPN2 expression is posttranscriptionally regulated by the existence of two splice variants: a 45-kDa form containing a nuclear localization signal C-terminally upstream of the splice site, and a 48-kDa canonical form containing an ER retention motif C-terminally (Tillmann U. et al., Mol Cell Biol (1994) 14:3030-3040). The 45 kDa isoform can spontaneously translocate to the cytoplasm under certain cellular stress conditions. Both isoforms share an N-terminal phosphotyrosine phosphatase catalytic domain, and PTPN2 is a key negative regulator of the JAK-STAT pathway, directly controlling signal transduction through cytokine receptors. The PTPN2 catalytic domain shares 74% sequence identity with PTPN1 (also known as PTP1B) and has a similar enzymatic rate (Romsicki Y. et al., Arch Biochem Biophys (2003) 414:40-50).

[0007] Furthermore, T cell protein tyrosine phosphatase 2 (PTPN2) has been identified as an important negative regulator of T cell receptor (TCR) signaling, with a clear association between PTPN2 single nucleotide polymorphisms (SNPs) and autoimmune diseases (Wiede F et al., J Clin Invest. (2011);121(12):4758-4774). PTPN2 dephosphorylates and inactivates Src family kinases, regulating T cell responses. Deficiency of PTPN2 leads to TCR-dependent CD8 +PTPN2 has been shown to lower the in vivo threshold for T cell proliferation. Consistent with these findings, T cell-specific PTPN2-deficient mice have been shown to develop a variety of inflammatory and autoimmune diseases. Autoimmune diseases are associated with increased serum levels of proinflammatory cytokines and antinuclear antibodies, T cell infiltration into extralymphoid tissues, and liver disease. Furthermore, these data indicate that PTPN2 is a critical negative regulator of TCR signaling that sets the threshold for TCR-triggered naive T cell responses to prevent autoimmune and inflammatory diseases.

[0008] In addition to PTPN2, encoding the 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. Furthermore, the PTPN2 variant rs1893217(C), associated with type 1 diabetes, is also associated with decreased PTPN2 expression in T cells (Florian Wiede J Clin Invest. 2011;121(12):4758-4774).

[0009] These findings suggest that PTPN2 inhibition is a promising therapeutic strategy to enhance the efficacy of cancer treatment regimens with ICB resistance. Summary of the Invention

[0010] The present disclosure relates to compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, which 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 present invention further provides methods for treating, preventing, or ameliorating cancer, comprising administering to a subject in need thereof an effective amount of a PTPN2 / PTPN1 inhibitor of the present disclosure. In preferred embodiments, the compounds have a monocyclic core structure, compared to compounds described in the literature that contain a fused bicyclic core structure.

[0011] In some embodiments, the present application discloses inhibitors of protein tyrosine phosphatases (e.g., PTPN2 and / or PTP1B), comprising a compound of the present disclosure (e.g., a compound of Formula (I)). In other embodiments, the present application discloses a method of treating a disease or disorder (e.g., cancer, type 2 diabetes, obesity, metabolic disease, or any other disease, disorder, or condition that responds to PTPN2 or PTP1B inhibitory treatment), comprising administering an effective amount of a compound of the present disclosure (e.g., a compound of Formula (I)). These and other features of the present invention are broadly described in this disclosure.

[0012] A first aspect of the present invention is a compound having the structure of formula (I): [ka] wherein each independently represents: R 1 is -N= and -C(R 7 )= selected from the group consisting of; R 2 is -N= and -C(R 8 )= selected from the group consisting of; R 3 is -N= and -C(R 9 )= selected from the group consisting of; R 4 is -N= and -C(R 10 )= selected from the group consisting of; R 5 is -N= and -C(R 11 )= selected from the group consisting of; R 6 is selected from the group consisting of hydrogen, alkyl, and ethyl; R 7 is selected from the group consisting of hydrogen, alkyl, cyano, propan-2-yl, cyclopropyl, dimethylamino, phenyl, and 4-tert-butylphenoxy, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, phenyl, aryl, and substituted aryl; R8 is selected from the group consisting of hydrogen, alkyl, halogen, cyano, and trifluoromethyl, substituted alkyl, branched alkyl, alkoxy, amine, hydroxy, phenyl, aryl, and substituted aryl; R 9 is selected from the group consisting of hydrogen, alkyl, 4-(trifluoromethyl)phenyl, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, phenyl, aryl, and substituted aryl; R 10 is selected from the group consisting of hydrogen, alkyl, methoxy, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, phenyl, aryl, and substituted aryl; R 11 is hydrogen, alkyl, methoxy, propan-2-yl, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, phenyl, aryl, substituted aryl, and [ka] selected from the group consisting of: R 12 is selected from the group consisting of hydrogen and tert-butyl; R 13 is selected from the group consisting of hydrogen and cyano. The present invention provides at least one compound of the formula:

[0013] Additionally: 5-(4-(((6-(dimethylamino)pyridin-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((2,6-dimethylpyridin-4-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((2,4-dimethylpyridin-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-((4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)nicotinonitrile; 5-((4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)-2-methylnicotinonitrile; 5-(2-fluoro-6-hydroxy-4-(((6-phenylpyridin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-(trifluoromethyl)pyridin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((5-chloropyridin-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-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)pyrimidine-5-carbonitrile; 5-(4-(((6-cyclopropylpyridin-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-isopropylpyrimidin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-phenylpyridin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-isopropylpyridin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 2-(2-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)(ethyl)amino)-6-methylpyrimidin-4-yl)benzonitrile; 5-(4-(((2-(4-(tert-butyl)phenyl)-3-methylpyridin-4-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methylpyrazin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((2,6-dimethylpyrimidin-4-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((3,6-dimethylpyrazin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((5,6-dimethylpyrazin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((3-methoxy-6-methylpyrazin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methoxy-3-methylpyrazin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((2-methoxy-5-methylpyrimidin-4-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methoxypyrazin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((2-methylpyrimidin-4-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methoxy-5-methylpyrazin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methylpyrimidin-4-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((2,5-dimethylpyrimidin-4-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methylpyridazin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((4,6-dimethylpyrimidin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((4-(4-(trifluoromethyl)phenyl)pyridin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((6-(4-(tert-butyl)phenoxy)pyridin-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-((4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)pyrimidine-2-carbonitrile or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the compound of Formula (I) is formulated as a pharmaceutically acceptable composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.

[0015] Also disclosed herein is a method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) of the present disclosure in combination with another therapeutic agent. In some embodiments, the other therapeutic agent is an immunotherapeutic agent. For example, in some embodiments, the immunotherapeutic agent is an antibody.

[0016] Also disclosed herein is a method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of the present disclosure (e.g., a compound of Formula (I)).

[0017] Further disclosed herein is a method for treating a metabolic disorder, comprising administering to a patient in need thereof an effective amount of a compound of the present disclosure (e.g., a compound of Formula (I)).

[0018] In some embodiments, the methods include treating cancer, hi some embodiments, the cancer includes pancreatic cancer, breast cancer, multiple myeloma, melanoma, or cancer of secretory cells.

[0019] Also disclosed are compositions for use in treating cancer in a patient in need thereof, the compositions comprising a compound of the present disclosure (e.g., a compound of Formula (I)) in combination with another therapeutic agent. In some embodiments, the other 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.

[0020] Further disclosed herein are compositions for use in treating a metabolic disorder in a patient in need thereof, wherein the composition comprises a compound of the present disclosure (e.g., a compound of Formula (I)). DETAILED DESCRIPTION OF THE INVENTION

[0021] The present disclosure relates to compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof that are effective as 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 present invention further provides methods for treating, preventing, or ameliorating cancer, comprising administering to a subject in need thereof an effective amount of a PTPN2 / PTPN1 inhibitor of the present disclosure. Compared to compounds described in the literature that contain a fused bicyclic core structure, the present compounds possess a monocyclic core structure in preferred embodiments.

[0022] definition chemical definition Definitions of specific functional groups and chemical terms are detailed below. Chemical elements are listed in accordance with the CAS version of the Periodic Table of the Elements, Handbook of Chemistry and Physics, 75 thEd., and specific functional groups are generally defined as described therein. Further, general principles of organic chemistry and specific functional groups and reactivities are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th 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, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0023] 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 standard rules of atom valency known in the chemical arts.

[0024] The compounds described herein contain one or more asymmetric centers and may therefore exist in various isomers (e.g., enantiomers and / or diastereomers). For example, the compounds described herein may exist in the form of individual enantiomers, diastereomers, geometric isomers, or mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, such as chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). Additionally, the present disclosure encompasses compounds described herein as single isomers, substantially free of other isomers, or as mixtures of various isomers.

[0025] In the compositions described herein, the enantiomerically pure compound may be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R-compound may contain, for example, about 90% excipients and about 10% enantiomerically pure R-compound.

[0026] The features and utilities of the inventions described in this disclosure may be more readily understood by those skilled in the art in view of the following definitions. Features of the invention described in separate embodiments may be combined to form a single embodiment or may be incorporated to comprise multiple embodiments. Embodiments identified herein as examples or preferred embodiments are illustrative and not limiting.

[0027] Unless the context clearly indicates otherwise, words referred to in the singular may also include the plural. For example, "a" and "an" may refer to either "one" or "one or more."

[0028] As used herein, the term "compound" refers to at least one compound. For example, a compound of formula (I) includes one compound of formula (I) and two or more compounds of formula (I).

[0029] Unless otherwise specified, any heteroatom with unsatisfied valences is assumed to have enough hydrogen atoms to satisfy the valences.

[0030] The definitions set forth herein supersede definitions set forth in any patents, patent applications, and / or published patent applications incorporated herein by reference.

[0031] Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout the specification, either individually or as part of a larger group (unless otherwise limited in specific instances).

[0032] Throughout the specification, groups and substituents may be chosen by one skilled in the art to provide stable moieties and compounds.

[0033] According to the practice used in the art, [ka] is used in structural formulas herein to represent the bond that is the point of attachment of a moiety or substituent to the core or backbone structure.

[0034] As used herein, the terms "halo" and "halogen" refer to F, Cl, Br, and I.

[0035] The term "cyano" refers to the group --CN.

[0036] The term "amino" refers to the group -NH2.

[0037] The term "oxo" refers to the group =O.

[0038] The term "alkyl" as used herein refers to both branched and straight-chain saturated aliphatic hydrocarbon groups, for example, having 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 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 a number appears as a subscript after the symbol "C," the subscript more specifically qualifies the number of carbon atoms that a particular group may contain. For example, "C 1-6 "Alkyl" means straight and branched chain alkyl groups having from 1 to 6 carbon atoms.

[0039] As used herein, the term "fluoroalkyl" 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 The term "fluoroalkyl" is meant to include C, C, C, and C alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF and -CHCF.

[0040] The term "cyanoalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more cyano groups. For example, "cyanoalkyl" includes -CHCN, -CHCHCN, and -C 1-4 Examples include cyanoalkyl.

[0041] The term "aminoalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more amino groups. For example, "aminoalkyl" includes -CH2NH2, -CH2CH2NH2, and C 1-4 Aminoalkyl is an example.

[0042] The term "hydroxyalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CHOH, -CHCHOH, and C 1-4 Hydroxyalkyl is an example.

[0043] 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 -CHFCHOH, -CHCHFC(CH)OH, and -CHFCHOH. 1-4 Hydroxy-fluoroalkyl is an example.

[0044] As used herein, the terms "cycloalkyl," "carbocyclic," and "carbocyclyl" refer to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by removing a hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When a number appears as a subscript after the symbol "C," the subscript more specifically qualifies the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C3-C6 cycloalkyl" refers to a cycloalkyl group having from 3 to 6 carbon atoms.

[0045] The term "heterocycle" as used herein refers to an organic compound having a ring structure containing both carbon atoms and atoms other than carbon (eg, oxygen, nitrogen).

[0046] The term "alkoxy," as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom, for example, a methoxy group (-OCH). 1-3 "Alkoxy" means an alkoxy group having 1 to 3 carbon atoms.

[0047] The term "alkoxyalkyl," as used herein, refers to an alkoxy group (e.g., a methoxymethyl group (-CH2OCH3)) that is connected through an oxygen atom to an alkyl group that is bonded to the parent molecular moiety. For example, "C 2-4 "Alkoxyalkyl" refers to an alkoxyalkyl group having 2 to 4 carbon atoms, for example, -CH2OCH3, -CH2CH2OCH3, -CH2OCH2CH3, and -CH2CH2OCH2CH3.

[0048] As used herein, the term "amine" refers to a compound in which a nitrogen atom is directly bonded to several carbon atoms. Embodiments include derivatives of ammonia (-NH3), resulting from the stepwise replacement of three hydrogen atoms with hydrocarbon groups. Amines are classified as primary, secondary, or tertiary depending on the number of carbon atoms attached to the nitrogen atom. For example, primary amines have one carbon attached to the nitrogen (R-NH2), secondary amines have two carbons attached to the nitrogen and amine (R2-NH), and tertiary amines have three carbons attached to the nitrogen (R3-N), where R is an alkyl group.

[0049] As used herein, the term "heteroaryl" refers to a 5- to 10-membered aromatic heterocycle containing at least one carbon atom and at least one heteroatom selected from nitrogen, oxygen, and sulfur, and includes both monocyclic and bicyclic structures.

[0050] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, substances, compositions, and / or dosage forms that are, within the scope of ordinary medical judgment, suitable for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, and that are presenting a reasonable benefit / risk ratio.

[0051] The compound of formula (I) may be provided as an amorphous solid or a crystalline solid. The compound of formula (I) may be provided as an amorphous solid by lyophilization.

[0052] Additionally, solvates (e.g., hydrates) of compounds of formula (I) are also considered to be within the scope of the present invention. The term "solvate" refers to a physical association of a compound of formula (I) with one or more organic or inorganic solvent molecules. This physical association includes hydrogen bonding. In some cases, it is possible to isolate the solvate, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase and isolable solvates. Examples of solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0053] Various forms of prodrugs are well known in the art: 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) is described in.

[0054] Additionally, once prepared, the compounds of formula (I) may be isolated and purified to obtain compositions containing 99% or greater of the compound of formula (I) ("substantially pure"), which are then used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also considered herein to be part of the present invention.

[0055] By "stable compound" and "stable structure" is intended a compound that is sufficiently robust that it will not decompose upon isolation to a useful degree of purity from a reaction mixture, nor upon formulation into an efficacious therapeutic agent. The present invention is intended to embody stable compounds.

[0056] Those skilled in the art will also recognize that the compounds described and claimed herein as embodiments of the present invention may also exist in their "tautomeric forms." As used herein, tautomers refer to structural isomeric compounds that are readily interconvertible in rapid equilibrium. The process of interconversion is referred to herein as "tautomerization."

[0057] For example, an embodiment of a pyridone tautomer is shown below. [ka] The above structures readily interconvert between the structures shown on the left and right.

[0058] A "therapeutically effective amount" is intended to include an amount of a compound of the invention alone, or in combination with the claimed compounds, or in combination with other active ingredients, that is effective to act as an inhibitor or to treat or ameliorate cancer.

[0059] As used herein, the term "treating" or "treatment" includes the treatment of a condition in a mammal, particularly a human, and includes (a) preventing the mammal from acquiring a condition that arises in that mammal if the mammal is prone to the condition, but particularly if the mammal has not yet been diagnosed as suffering from the condition; (b) inhibiting the condition, i.e., arresting the progression of the condition; and / or (c) palliating the condition, i.e., reducing the condition.

[0060] The compounds of the present invention are intended to encompass all isotopes of atoms contained in the compounds. Isotopes include 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 methods analogous to those described herein, substituting the appropriate isotopically labeled reagent for the non-labeled reagent used elsewhere. For example, methyl (-CH3) also includes deuterated methyl groups (e.g., -CD3).

[0061] The term "pharmaceutically acceptable salts" refers to salts of active compounds prepared with relatively non-toxic acids or bases depending on the specific substituents in the compounds described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by reacting the compound in a neutral state with a sufficient amount of the desired base in either a pure solvent or a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amine salts, magnesium salts, or similar salts.

[0062] As defined herein, the terms "inhibition," "inhibiting," and the like, with respect to the interaction of a protein inhibitor (e.g., an antagonist), refer to negatively affecting (e.g., reducing) the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to the alleviation of a disease or disease symptom. In some embodiments, inhibition refers to the reduction of the activity of a signal transduction pathway or signal transduction pathway. Thus, at least in part, inhibition includes partial or complete inhibition of stimulation, reduction, suppression, or delay of activation, or inactivation, blunting, or downregulation of signal transduction or enzyme activity or protein amount. In some embodiments, inhibition refers to the reduction of 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, at least in part, inhibition can include partial or complete reduction in stimulation, decreased or diminished activation, or inactivation, blunting, or downregulation of signal transduction or enzymatic activity or amount of protein tyrosine phosphatase (e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) or protein tyrosine phosphatase non-receptor type 1 (PTP1B)).

[0063] "Patient" or "subject" refers to an organism suffering from or susceptible to a disease that can be treated by administration of a compound or pharmaceutical composition described herein. Examples include, but are not limited to, humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammalian animals. In some embodiments, the patient is a human. In some embodiments, the patient is a domestic animal. In some embodiments, the patient is a dog. In some embodiments, the patient is a parrot. In some embodiments, the patient is a livestock animal. In some embodiments, the patient is a mammal. In some embodiments, the patient is a cat. In some embodiments, the patient is a horse. In some embodiments, the patient is a cow. In some embodiments, the patient is a dog. In some embodiments, the patient is a cat. In some embodiments, the patient is an ape. In some embodiments, the patient is a monkey. In some embodiments, the patient is a mouse. In some embodiments, the patient is a laboratory animal. In some embodiments, the patient is a rat. In some embodiments, the patient is a hamster. In some embodiments, the patient is a test animal. In some embodiments, the patient is a newborn animal. In some embodiments, the patient is a newborn. In some embodiments, the patient is a newborn mammal. In some embodiments, the patient is an elderly animal. In some embodiments, the patient is an elderly person. In some embodiments, the patient is an elderly mammal. In some embodiments, the patient is an elderly patient.

[0064] A "disease," "disorder," or "condition" refers to a condition of a patient or subject that can be treated by a compound, pharmaceutical composition, or method described herein. In some embodiments, the compounds and methods described herein include reducing or eliminating one or more symptoms of a disease, disorder, or condition, for example, by administering a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0065] As used herein, the term "signal transduction pathway" refers to a series of interactions between cellular and any extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that transmit a change in one component to one or more other components, which in turn transmit the change to other components, and the change is transmitted to other signal transduction pathway components as appropriate.

[0066] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that can be included in the compositions of the present disclosure to facilitate administration and absorption of an active agent by a subject without causing significant toxic side effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, carbohydrates (e.g., lactose, amylose, or starch), fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations are sterilized and may contain, as needed, auxiliary substances (e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for adjusting osmotic pressure, buffers, coloring agents, and / or aromatic substances) that do not deleteriously react with the disclosed compounds. Those of skill in the art will recognize that other excipients are also useful in the present disclosure.

[0067] The term "formulation" is intended to include a formulation in which an encapsulating material as a carrier surrounds and combines with an active compound to form a capsule, which may or may not contain any other carriers other than the encapsulating material. Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid preparations suitable for oral administration.

[0068] As used herein, the term "administering" refers to oral administration, administration as a suppository, topical administration, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, or subcutaneous administration to a subject, or implantation of a delayed-release device (e.g., a mini-osmotic pump). Administration can be by any route, including parenteral administration and administration via mucosal membranes (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or dermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other delivery methods include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. By "in combination" is meant that a compound or composition described herein is administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapeutic agents (e.g., anti-cancer, chemotherapeutic, or immunotherapeutic agents). The compounds or compositions described herein can be administered to a patient alone or in combination. Combination is intended to include simultaneous or sequential administration of the compounds or compositions alone or in combination (with one or more other compounds or drugs). Thus, the formulations can also be combined with other active substances, if desired (e.g., to reduce metabolic degradation).

[0069] The pharmaceutical compositions described herein can be prepared by any method known in pharmacology. Generally, such preparation methods include the steps of bringing a disclosed compound (the "active ingredient") into association with the carrier and / or one or more other accessory ingredients, and then, as necessary and / or desired, shaping and / or packaging the product into the desired single unit dose or multiple unit doses. Pharmaceutical compositions may be prepared, packaged, and / or sold in bulk in single unit doses and / or multiple unit doses. As used herein, a "unit dose" is a respective amount of pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient will generally be equal to the dose of the active ingredient that would be administered to a subject and / or an appropriate fraction of that dose (e.g., one-half or one-third of that dose).

[0070] Treatment method The present disclosure features compounds, compositions, and methods that include compounds of the present disclosure (e.g., compounds of Formula (I)). In some embodiments, the compounds, compositions, and methods of the present disclosure are used to prevent or treat a disease, disorder, or condition. Examples of diseases, disorders, or conditions include, but are not limited to, cancer, type 2 diabetes, metabolic syndrome, obesity, or metabolic disease.

[0071] cancer In some embodiments, the compounds of the present disclosure (e.g., compounds of Formula (I)) are used to treat cancer. As used herein, "cancer" refers to human carcinoma and carcinomas of carcinomas, non-carcinomas, adenocarcinomas (e.g., papillary adenocarcinoma), lymphoma, leukemia, melanoma, etc. (including solid carcinomas and lymphatic cancers), kidney, breast, lung, bladder, colon, ovary, prostate, pancreas, stomach, brain, head and neck, skin, uterus, testis, glioma, esophagus, liver, including hepatocellular carcinoma, B-cell acute lymphoblastic lymphoma, non-Hodgkin's lymphoma (e.g., Burkitt's lymphoma, small cell lymphoma, and large cell lymphoma), lymphomas, including Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), and / or multiple myeloma. In yet another example, "cancer" refers to lung cancer, breast cancer, ovarian cancer, epithelial ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, non-epithelial carcinoma, bladder cancer, osteosarcoma, biliary tract cancer, adrenal cancer, salivary gland cancer, bronchial cancer, oral cancer, cancer of the oral cavity or pharynx, laryngeal cancer, kidney cancer, gynecological cancer, brain cancer, central nervous system cancer, peripheral nervous system cancer, cancer of the blood tissue, small intestine or appendix cancer, cervical cancer, colon cancer, esophageal cancer, stomach cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, or epithelial carcinoma.

[0072] Examples of cancers that may be treated with the compounds, pharmaceutical compositions, or methods described herein include lymphoma, B-cell lymphoma, heavy chain disease, alpha chain disease, gamma chain disease, mu chain disease, Waldenstrom's macroglobulinemia, benign monoclonal gammopathy, non-epithelial malignancies, bladder cancer, osteosarcoma, brain cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., ER-positive, ER-negative, chemotherapy-resistant, Herceptin-resistant, HER2-positive, HER2-negative ... The cancer may be HER2-positive, doxorubicin-resistant, tamoxifen-resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, non-epithelial malignant tumor), glioblastoma multiforme, acoustic neuroma, retinoblastoma, astrocytoma, craniopharyngioma, hemangioblastoma, pineal tumor, ependymoma, oligodendroglioma, meningioma, glioma, or melanoma. Further examples include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach, uterine cancer or medulloblastoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, immunocytic amyloidosis, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, cancer, malignant insulin-producing pancreatic insulinoma, malignant carcinoid, bladder cancer, precancerous lesions of the skin, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, neoplasms of the endocrine or exocrine system of the pancreas, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, and hepatocellular carcinoma.

[0073] A first aspect of the present invention is a compound having the structure of formula (I): [ka] wherein each independently represents: R 1 is -N= and -C(R 7 )= selected from the group consisting of; R 2is -N= and -C(R 8 )= selected from the group consisting of; R 3 is -N= and -C(R 9 )= selected from the group consisting of; R 4 is -N= and -C(R 10 )= selected from the group consisting of; R 5 is -N= and -C(R 11 )= selected from the group consisting of; R 6 is selected from the group consisting of hydrogen, alkyl, and ethyl; R 7 is selected from the group consisting of hydrogen, alkyl, cyano, propan-2-yl, cyclopropyl, dimethylamino, phenyl, and 4-tert-butylphenoxy, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, phenyl, aryl, and substituted aryl; R 8 is selected from the group consisting of hydrogen, alkyl, halogen, cyano, and trifluoromethyl, substituted alkyl, branched alkyl, alkoxy, amine, hydroxy, phenyl, aryl, and substituted aryl; R 9 is selected from the group consisting of hydrogen, alkyl, 4-(trifluoromethyl)phenyl, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, phenyl, aryl, and substituted aryl; R 10 is selected from the group consisting of hydrogen, alkyl, methoxy, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, phenyl, aryl, and substituted aryl; R 11 is hydrogen, alkyl, methoxy, propan-2-yl, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, phenyl, aryl, substituted aryl, and [ka] selected from the group consisting of: R 12 is selected from the group consisting of hydrogen and tert-butyl; R 13 is selected from the group consisting of hydrogen and cyano. The present invention provides at least one compound of the formula:

[0074] In another embodiment of the compounds of Formula (I), R 2 is -C(R 8 )=and; R 3 is -C(R 9 )=and; R 4 is -C(R 10 )=and; R 6 is hydrogen; R 7 is selected from the group consisting of hydrogen, methyl, dimethylamino, phenyl, and 4-tert-butylphenoxy; R 8 is selected from the group consisting of hydrogen, methyl, chloro, cyano, and trifluoromethyl; R 9 is selected from the group consisting of hydrogen, methyl, and 4-(trifluoromethyl)phenyl; R 10 is selected from the group consisting of hydrogen and methyl; R 11 is methyl.

[0075] In certain embodiments of compounds of Formula (I), R 1 is -C(R 7 )=and; R 6 is hydrogen; R 7 is selected from the group consisting of hydrogen, alkyl, cyano, and cyclopropyl; R 8 is selected from the group consisting of hydrogen and alkyl; R 9 is hydrogen; R 10 is hydrogen; R 11 is hydrogen and [ka] selected from the group consisting of: R 12 is hydrogen; R 13 is hydrogen.

[0076] In another embodiment of the compounds of Formula (I), R 2 is -C(R 8 )=and; R 7 is hydrogen; R 8 is selected from the group consisting of hydrogen and alkyl; R 9 is hydrogen; R 10 is selected from the group consisting of hydrogen and alkyl; R 11 is alkyl and [ka] is selected from the group consisting of:

[0077] In certain embodiments of compounds of Formula (I), R 6 is hydrogen; R 7 is selected from the group consisting of hydrogen and alkyl; R 8 is selected from the group consisting of hydrogen and alkyl; R 9 is selected from the group consisting of hydrogen and alkyl; R 10 is selected from the group consisting of hydrogen and methoxy; R 11 is selected from the group consisting of hydrogen, alkyl, and methoxy.

[0078] In another embodiment of the compounds of Formula (I), R 1 is -C(R 7 )=and; R 6 is hydrogen; R 7 is selected from the group consisting of hydrogen, alkyl, and cyano; R 8 is selected from the group consisting of hydrogen and alkyl; R 9 is hydrogen; R 10 is hydrogen; R 11 is alkyl.

[0079] In some embodiments, the compound is: 5-(4-(((6-(dimethylamino)pyridin-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((2,6-dimethylpyridin-4-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((2,4-dimethylpyridin-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-((4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)nicotinonitrile; 5-((4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)-2-methylnicotinonitrile; 5-(2-fluoro-6-hydroxy-4-(((6-phenylpyridin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-(trifluoromethyl)pyridin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((5-chloropyridin-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-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)pyrimidine-5-carbonitrile; 5-(4-(((6-cyclopropylpyridin-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-isopropylpyrimidin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-phenylpyridin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-isopropylpyridin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 2-(2-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)(ethyl)amino)-6-methylpyrimidin-4-yl)benzonitrile; 5-(4-(((2-(4-(tert-butyl)phenyl)-3-methylpyridin-4-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methylpyrazin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((2,6-dimethylpyrimidin-4-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((3,6-dimethylpyrazin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((5,6-dimethylpyrazin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((3-methoxy-6-methylpyrazin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methoxy-3-methylpyrazin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((2-methoxy-5-methylpyrimidin-4-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methoxypyrazin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((2-methylpyrimidin-4-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methoxy-5-methylpyrazin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methylpyrimidin-4-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((2,5-dimethylpyrimidin-4-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methylpyridazin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((4,6-dimethylpyrimidin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((4-(4-(trifluoromethyl)phenyl)pyridin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((6-(4-(tert-butyl)phenoxy)pyridin-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)pyrimidine-2-carbonitrile, or a pharmaceutically acceptable salt thereof.

[0080] In certain embodiments, the present invention encompasses a pharmaceutical composition comprising a compound of Formula (I), a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0081] In another embodiment, the present invention includes a method of treating cancer, comprising administering to a 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 carcinoma, carcinomas, sarcomas, adenocarcinomas, papillary adenocarcinomas, lymphomas, leukemias, melanomas, solid tumors, cancers of the lymphatic system, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, gliomas, esophageal cancer, liver cancer including hepatocellular carcinoma, B-cell acute lymphoblastic lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, small cell lymphoma, Hodgkin's lymphoma, leukemia, and multiple myeloma.

[0082] In another embodiment, the present invention comprises a method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) in combination with another therapeutic agent.

[0083] In certain embodiments, the additional therapeutic agent is an immunotherapeutic agent.

[0084] 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.

[0085] In certain embodiments, the method of treating cancer comprises administering to a patient in need of cancer treatment an effective amount of a pharmaceutically acceptable composition of a compound of Formula (I).

[0086] In another embodiment, the method of treating cancer is selected from radiation therapy, surgery, chemotherapy, or administration of a biopharmaceutical.

[0087] In some embodiments, a method of treating cancer is administering a biopharmaceutical, which is an agent that stimulates the immune system.

[0088] In another embodiment, a method of treating cancer comprises administering to a subject an inhibitor of DGKα and / or DGKζ, an antagonist of PD1 / PD-L1, and an antagonist of CTLA4.

[0089] These embodiments do not limit the scope of the invention.

[0090] Synthesis method The compounds of the present invention may be prepared from the methods and examples shown below, as well as from methods known to those skilled in the art. In each example below, the R group is defined as above in each formula unless otherwise specified. Optimum reaction conditions and reaction times may vary depending on the reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions can be readily selected by one skilled in the art.

[0091] The intermediates used in the following syntheses are either commercially available or readily 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 performance liquid chromatography-mass spectrometry (HPLC-MS). Intermediates and products may be purified by methods known in the art, such as column chromatography, HPLC, preparative TLC, or preparative HPLC.

[0092] Preparation of synthetic key intermediate (intermediate 2) Preparation of 5-(4-bromo-2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Intermediate 2) as shown in Scheme 1 [ka]

[0093] 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 K2CO3 (17.4 g, 126.06 mmol) portionwise at room temperature and stirred overnight at 70 °C under a nitrogen atmosphere, after which TLC showed the reaction was complete. 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, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 20) to give the desired product: 5-bromo-1-fluoro-3-[(4-methoxyphenyl)methoxy]-2-nitro-benzene (10 g, 66.8% yield) as a pale yellow solid.

[0094] 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-benzene (10 g, 28.08 mmol) in ethanol (200 mL) and water (20 mL) was added NH4Cl (15.16 g, 280.79 mmol) and Fe (15.68 g, 280.79 mmol) at room temperature. The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere, and LCMS showed that the reaction was complete. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, PE / EA = 9 / 1) to give the desired product: 4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]aniline (6 g, 65.50% yield) as a pale yellow solid. MS: m / z: C 14 H 13 BrFNO2[M+H] + Theoretical: 326, Observed: 326

[0095] 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 K2CO3 (7.49 g, 54.27 mmol) at room temperature and stirred at 100 °C for 48 h. LCMS showed complete consumption of the starting material. The reaction mixture was filtered, and the filtrate was washed three times with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was subjected to silica gel column chromatography to give the product as a mixture. This mixture was further purified by reverse-phase flash chromatography (H2O / ACN containing 0.05% NH4HCO3) to give tert-butyl 2-[4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]anilino]acetate (5 g, 62.70% yield) as a white solid. MS: m / z: C 20 H 23 BrFNO4[M+H] + Theoretical: 440, Observed: 440

[0096] 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 and stirred at room temperature overnight, after which LCMS showed complete consumption of the starting material. The mixture was diluted with ethyl acetate (300 mL) and washed six times with brine until complete removal of DMA. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 2-[4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]-N-sulfamoyl-anilino]acetate (4 g, 7.70 mmol, 102.70% yield) as a brown oil. MS: m / z: C 20 H 24 BrFN2O6S [MH] - Theoretical: 517, Observed: 517

[0097] Step 5: Synthesis of 5-(4-bromo-2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Intermediate 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 / MeOH (8.32 g, 46.30 mmol) at 0° C. and stirred at room temperature overnight. LCMS showed complete consumption of the starting material. The mixture was concentrated, and the resulting suspension was dissolved in water (200 mL) and extracted with ethyl acetate. The organic layer was separated and removed, and the aqueous layer was diluted with ethyl acetate, acidified to pH 3 with 1N HCl solution, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was further purified by reverse-phase column (0.05% NH4CO3 in H2O and MeCN) to give 5-[4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2.50 g, 5.61 mmol, 72.90% yield) as an off-white solid. MS: m / z: C 16 H 14 BrFN2O5S [MH] - Theoretical: 443, Observed: 443

[0098] 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) was added P(t-Bu)HBF (0.43 g, 0.90 mmol) and Pd(dba) (0.41 g, 0.45 mmol), and the mixture was purged with nitrogen for 5 minutes. The mixture was then stirred at 80 °C for 12 hours, at which point LCMS showed complete consumption of the starting material. The reaction mixture was filtered, and the filtrate was directly purified on a reverse-phase column to give 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 pale yellow semi-solid. MS: m / z: C 18 H 18 FN2O5S [MH] - Theoretical: 391, Observed: 391

[0099] Step 7: Synthesis of 4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-((4-methoxybenzyl)oxy)benzaldehyde (Intermediate 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 KOsO (91.07 mg, 0.25 mmol) and stirred at room temperature for 1 h, after which LCMS showed complete conversion of the starting material to the intermediate. NaIO (1.07 mL, 7.42 mmol) was then added to the mixture at 0 °C and stirred at room temperature for 2 h, after which LCMS showed the reaction was complete. The reaction mixture was diluted with water and extracted four times with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by reverse-phase column (0.05% NH4CO3, HO / ACN) to give 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: C 17 H 15 FN2O6S [MH] - Theoretical: 393, Observed: 393

[0100] Preparation of Examples Example 1: 5-[4-[[[6-(dimethylamino)-3-pyridyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] [ka]

[0101] Step 1: To a mixture of 3-fluoro-5-[(4-methoxyphenyl)ethoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (Intermediate 2, 100 mg, 0.25 mmol), N,N-dimethylpyridine-2,5-diamine trihydrochloride (62.52 mg, 0.25 mmol), and DIEA (0.12 mL, 1.52 mmol) in ethanol (8 mL), solutions of ZnCl / THF (0.7 M, 0.72 mL) and NaBHCN (64.91 mg, 1.01 mmol) in ethanol (2 mL) were added, respectively, and the mixture was stirred at 80° C. for 2 hours. After stirring was complete, the reaction mixture was concentrated. The resulting residue was dissolved in DMSO and purified on a reverse-phase column (0.05% NH4HCO3 in H2O and MeCN) to give 5-[4-[[[6-(dimethylamino)-3-pyridyl]amino]methyl]-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (100 mg, 76.49% yield) as a pale yellow oil. MS: m / z: C 24 H 26 FN5O5S [M+H] + Theoretical: 516; Observed: 516

[0102] Step 2: To a stirred solution of 5-[4-[[[6-(dimethylamino)-3-pyridyl]amino]methyl]-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2-1, 95 mg, 0.18 mmol) in DCM (3 mL) was added TFA (3 mL) and stirred at room temperature for 2 hours. After stirring was complete, the reaction mixture was concentrated, and the resulting residue was purified by reverse-phase flash column (0.05% NH4HCO3 in HO and ACN) and further purified by preparative HPLC to give 5-[4-[[[6-(dimethylamino)-3-pyridyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (40.3 mg, 52.98% yield) as a green solid. MS: m / z: Theoretical: C 16 H 18 FN5O4S [M+H]+ 396; Observations: 3969; 1 H NMR (300MHz, DMSO-d6) δ 7.36(d, J=9.3Hz, 1H), 7.09(s, 1H), 6.92(d, J=9.5Hz, 1H), 6.73-6.62(m, 2H), 4.17(s, 2H), 3.94(s, 2H), 2.99(s, 6H) Preparative HPLC purification conditions: Column: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3 + 0.1%NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 14%B~24%B in 8 minutes, followed by 24%B; Wavelength: 254 / 220nm

[0103] Example 2: 5-[4-[[(2,6-dimethyl-4-pyridyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] [ka]

[0104] 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 (Intermediate 2, 100 mg, 0.25 mmol) and 2,6-dimethylpyridin-4-amine (34.2 mg, 0.28 mmol) in dry DMF (6 mL) was added TMSCl (0.08 mL, 0.62 mmol) dropwise at 0° C. and stirred at room temperature for 30 minutes. The reaction mixture was then cooled to 60° C., and a solution of BH3 / THF (1 M, 0.45 mL, 0.46 mmol) was added slowly via syringe. After the addition, the reaction mixture was stirred at room temperature for 1 hour, at which time LCMS indicated the reaction was complete. The resulting solution was quenched with ice water (1 mL) and directly purified on a reverse-phase column (0.05% NH4HCO3 in HO and MeCN) to give 5-(4-(((2,6-dimethylpyridin-4-yl)amino)methyl)-2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (76 mg, 0.14 mmol, 56.40% yield) as a yellow solid. MS: m / z: C 24 H 20 ClFN4O5S [M+H] + Theoretical: 531; Observed: 531

[0105] Step 2: The title compound was prepared as a white solid (29.40% yield) using 3-1 in Step 2 according to the procedure in Example 1. MS: m / z: C 16 H 17 FN4O4S [M+H] + Theoretical: 381; Observed: 381; 1 H NMR (300MHz, DMSO-d6) δ 6.95-6.52(m, 4H), 4.41(s, 2H), 3.95(s, 2H), 2.38(s, 6H) Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3+0.1%NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 3%B~24%B elution for 8 minutes, then 24%B; Wavelength: 254 / 220nm

[0106] Example 3: 5-[4-[[(2,4-dimethyl-3-pyridyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as a white solid according to the procedure of Example 2 using 2,4-dimethylpyridin-3-amine in Step 1 (total yield: 34.21%). MS: m / z: C 16 H 17 FN4O4S [M+H] + Theoretical: 381; Observed: 381; 1 H NMR (400MHz, DMSO-d6) δ 9.38(s, 1H), 7.98(d, J=5.6Hz, 1H), 7.36(d, J=5.6Hz, 1H), 6.61(d, J=1.9Hz, 1H), 6.58(s, 1H), 5.46(s, 1H), 4.18(s, 2H), 3.86(s, 2H), 2.47(s, 3H), 2.32(s, 3H) Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3+0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 10%B~28%B elution for 8 minutes, then 28%B; Wavelength: 254 / 220nm

[0107] Example 4: 5-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]pyridine-3-carbonitrile [ka] The title compound was prepared as a white solid according to the procedure of Example 2 using 5-aminopyridine-3-carbonitrile in Step 1 (total yield: 22.10%). MS: m / z: C 15 H 12 FN5O4S [M+H] + Theoretical: 378; Observed: 378; 1 H NMR (300MHz, DMSO-d6) δ 6.95-6.52(m, 4H), 4.41(s, 2H), 3.95(s, 2H), 2.38(s, 6H) Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3 + 0.1%NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 3%B to 32%B over 8 min, followed by 32%B; Wavelength: 254 / 220nm

[0108] Example 5: 6-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]-4-methyl-pyridine-3-carbonitrile [ka] The title compound was prepared as a white solid according to the preparation of Example 2 using 6-amino-4-methyl-pyridine-3-carbonitrile in Step 1 (total yield: 10.68%). MS: m / z: C 16 H 14 FN5O4S [M+H] + Theoretical: 392; Observed: 392; 1H NMR (400MHz, DMSO-d6) δ 8.32(s, 1H), 7.99(t, J=6.1Hz, 1H), 7.57(s, 1H), 6.63-6.54(m, 2H), 6.49(s, 1H), 4.44(d, J=6.1Hz, 2H), 3.93(s, 2H), 2.28(s, 3H) Preparative HPLC purification conditions: Column: XBridge Shield RP18 OBD column, 19*250mm, 10μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 25%B to 35%B over 6 minutes, followed by 35%B; Wavelength: 254 / 210nm

[0109] Example 6: 5-[2-fluoro-6-hydroxy-4-[[(6-phenyl-3-pyridyl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as a white solid according to the preparation of Example 2 using 6-phenylpyridin-3-amine in Step 1 (total yield: 13.80%). MS: m / z: C 20 H 17 FN4O4S [M+H] + Theoretical: 429; Observed: 429; 1 H NMR (400MHz, DMSO-d6) δ 10.13(s, 1H), 8.01(d, J=2.8Hz, 1H), 7.96(d, J=8.9Hz, 1H), 7.90-7.82(m, 2H), 7.57-7.41(m, 4H), 6.80-6.72(m, 2H), 4.41(s, 2H), 4.21(s, 2H) Preparative HPLC purification conditions: Column: XSelect CSH Fluoro-Phenyl, 30*150mm, 5μm; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2% B to 25% B over 10 min, followed by 25% B; Wavelength: 254nm

[0110] Example 7: 5-[2-fluoro-6-hydroxy-4-[[[5-(trifluoromethyl)-3-pyridyl]amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] [ka] 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 5-(trifluoromethyl)pyridin-3-amine (61.66 mg, 0.38 mmol) in DCM (8 mL) was added TMSOTf (84.44 mg, 0.38 mmol) at 0 °C and stirred at room temperature for 2 h. The mixture was cooled to 0 °C, and NaBH(AcO) (107.51 mg, 0.51 mmol) was slowly added to the mixture. The mixture was stirred at room temperature for an additional 16 h. LCMS showed complete consumption of the starting material (approximately 50% of the desired product and 10% of the PMB-protected intermediate were observed simultaneously). TFA (10 mL) was added to the reaction mixture at 0 °C and stirred at room temperature for an additional 3 h. LCMS showed complete cleavage of the PMB protecting group, so the reaction mixture was concentrated. The resulting residue was purified by reverse-phase column chromatography (0.05% NH4HCO3 in HO and MeCN) and further purified by preparative HPLC to give 5-[2-fluoro-6-hydroxy-4-[[[5-(trifluoromethyl)-3-pyridyl]amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (22.6 mg, 0.05 mmol, 35.70% yield) as a white solid. MS: m / z: Theoretical: C 15 H 12 F4N4O4S, observed value: [M+H] + Observations: 421; 1 H NMR (400MHz, DMSO-d6) δ 10.46(s, 1H), 8.22(d, J=2.7Hz, 1H), 8.16-8.11(m, 1H), 7.25(t, J=2.3Hz, 1H), 7.18(s, 1H), 6.76(d, J=8.7Hz, 2H), 4.50-4.30(m, 4H) Preparative HPLC purification conditions: Column: Xselect CSH C18 OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 13% B to 43% B over 7 minutes, followed by 43% B; Wavelength: 254nm

[0111] Example 8: 5-[4-[[(5-chloro-3-pyridyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as a white solid using 5-chloropyridin-3-amine in Step 1 according to the preparation of Example 2 (total yield: 22.66%). MS: m / z: Calc.: C 14 H 12 ClFN4O4S [M+H] + Observations: 387; 1 H NMR (400MHz, DMSO-d6) δ 10.39(s, 1H), 7.95(d, J=3.1Hz, 1H), 7.84(s, 1H), 7.10(s, 1H), 6.77-6.70(m, 2H), 4.38-4.27(m, 4H) Preparative HPLC purification conditions: Column: XSelect CSH Fluoro-Phenyl, 30*150mm, 5μm; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2% B to 30% B over 10 min, followed by 30% B; Wavelength: 254nm

[0112] Example 9: 2-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]pyrimidine-5-carbonitrile [ka] [ka]

[0113] Step 1: To a stirred solution of 5-[4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (600 mg, 1.35 mmol), potassium (tert-butoxycarbonylamino)methyl-trifluoroboranide (638.92 mg, 2.7 mmol), and KCO (557.88 mg, 4.04 mmol) in 1,4-dioxane (8.0 mL) and water (0.8 mL) was added Pd(dba) (246.6 mg, 0.27 mmol) and RuPhos (251.52 mg, 0.54 mmol). The mixture was purged with N for 5 minutes and then stirred at 115 °C for 36 hours. The reaction was monitored for completion by LCMS, after which the mixture was concentrated. The resulting residue was dissolved in DMSO and purified by reverse phase column chromatography to give tert-butyl N-[[3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methyl]carbamate (300 mg, 0.60 mmol, 44.92% yield). MS: m / z: Theoretical value: C 22 H 26 FN3O7S [MH] - Observations: 494;

[0114] Step 2: To a stirred solution of tert-butyl N-[[3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methyl]carbamate (200 mg, 0.40 mmol) in DCM (4 mL) was added TFA (4 mL). After monitoring the reaction for completion by LCMS, the mixture was concentrated. The resulting crude material was azeotroped twice with toluene to give 5-[4-(aminomethyl)-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 2,2,2-trifluoroacetic acid (200 mg, 0.72 mmol), which was used in the next step. MS: m / z: Theoretical: CH 10 FN3O4S [MH] - Observations: 274;

[0115] Step 3: To a stirred solution of 5-[4-(aminomethyl)-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 2,2,2-trifluoroacetic acid (80 mg, 0.29 mmol) and 2-chloropyrimidine-5-carbonitrile (35.87 mg, 0.35 mmol) in DMSO (6 mL) was added DIEA (277 mg, 2.91 mmol) and stirred at 80° C. for 12 hours. After monitoring the reaction for completion by LCMS, the mixture was purified by reverse-phase column chromatography (0.05% NH4HCO3 in H2O and MeCN) and further purified by preparative HPLC to give 2-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]pyrimidine-5-carbonitrile (18 mg, 0.04 mmol, 16.02% yield) as a white solid. MS: m / z: C 14 H 11 FN6O4S [M+H] + Theoretical: 379; Observed: 379; 1H NMR (300MHz, DMSO-d6) δ 10.39(s, 1H), 8.85(t, J=6.4Hz, 1H), 8.72(d, J=1.1Hz, 2H), 6.71-6.61(m, 2H), 4.48(d, J=6.4Hz, 2H), 4.36(d, J=2.4Hz, 2H) Preparative HPLC purification conditions: Column: Xselect CSH C18 OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 19%B to 49%B over 10 minutes, followed by 49%B; Wavelength: 254nm

[0116] Example 10: 5-[4-[[(6-cyclopropyl-3-pyridyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as a white solid using 6-cyclopropylpyridin-3-amine in Step 1 according to the preparation of Example 2 (total yield: 23.01%). MS: m / z: C 17 H 17 FN4O4S, [M+H] + Theoretical: 393; Observed: 393; 1 H NMR (400MHz, DMSO-d6) δ 9.86(s, 1H), 7.74(d, J=2.7Hz, 1H), 7.61-7.50(m, 1H), 7.37(d, J=9.1Hz, 2H), 6.74-6.66(m, 2H), 4.33(m, 2H), 4.08(m, 2H), 2.20-2.05(m, 1H), 1.18-1.07(m, 2H), 1.00-0.90(m, 2H) Preparative HPLC purification conditions: Column: XSelect CSH Fluoro-Phenyl, 30*150mm, 5μm; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2% B to 25% B over 10 min, followed by 25% B; Wavelength: 254nm

[0117] Example 11: 5-[2-fluoro-6-hydroxy-4-[[(5-isopropylpyrimidin-2-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as a white solid using 5-isopropylpyrimidin-2-amine in Step 1 according to the preparation of Example 7 (total yield: 9.67%). MS: m / z: Calc.: C 16 H 13 FN4O5S, [M+H] + Observations: 393; 1 H NMR (400MHz, DMSO-d6) δ 8.19(s, 2H), 7.52(t, J=6.4Hz, 1H), 6.62-6.57(m, 2H), 4.36(d, J=6.4Hz, 2H), 3.93(s, 2H), 2.73(m, J=6.9Hz, 1H), 1.17(d, J=7.0Hz, 6H) Preparative HPLC purification conditions: Column: X Bridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3 + 0.1%NH3.H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 20%B to 30%B over 9 minutes, followed by 30%B; Wavelength: 254 / 220nm

[0118] Example 12: 5-[2-fluoro-6-hydroxy-4-[[(5-phenyl-3-pyridyl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as a white solid using 5-phenylpyridin-3-amine in step 1 according to the preparation of Example 2 (total yield: 25.77%). MS: m / z: Calc.: C 20 H 17 FN4O4S, [M+H] + Observations: 429; 1 H NMR (300MHz, DMSO-d6) δ 9.87(s, 1H), 8.35(d, J=1.6Hz, 1H), 8.03(d, J=2.5Hz, 1H), 7.81(d, J=2.0Hz, 1H), 7.79-7.65(m, 2H), 7.65-7.34(m, 4H), 6.86-6.66(m, 2H), 4.56(s, 2H), 4.10(s, 2H) Preparative HPLC purification conditions: Column: Xselect CSH C18 OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 4%B to 34%B over 10min, followed by 34%B; Wavelength: 254nm

[0119] Example 13: 5-[2-fluoro-6-hydroxy-4-[[(5-isopropyl-3-pyridyl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as a white solid using 5-isopropylpyridin-3-amine in step 1 according to the preparation of Example 2 (total yield: 23.60%). MS: m / z: Calc.: C 17 H 19 FN4O4S, [M+H] + Observations: 395; 1H NMR (400MHz, DMSO-d6) δ 9.82(s, 1H), 8.01(d, J=1.5Hz, 1H), 7.87(d, J=2.5Hz, 1H), 7.62-7.50(m, 2H), 6.76-6.68(m, 2H), 4.36(d, J=4.4Hz, 2H), 4.06(s, 2H), 3.10-2.90(m, 1H), 1.22(d, J=6.9Hz, 6H) Preparative HPLC purification conditions: Column: XSelect CSH Fluoro-Phenyl, 30*150mm, 5μm; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2% B to 27% B over 10 min, followed by 27% B; Wavelength: 254nm

[0120] Example 14: 2-[2-[ethyl-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methyl]amino]-6-methyl-pyrimidin-4-yl]benzonitrile [ka] [ka]

[0121] Step 1: To a stirred solution of 2,4-dichloro-6-methyl-pyrimidine (300 mg, 1.84 mmol), (2-cyanophenyl)boronic acid (270.44 mg, 1.84 mmol), and CsCO (1.794 g, 5.52 mmol) in a 20:1 mixture of 1,4-dioxane and water (v / v) was added Pd(dppf)Cl (150.3 mg, 0.18 mmol) under a nitrogen atmosphere and stirred at 100 °C for 4 h under a nitrogen atmosphere. After monitoring the reaction completion by LCMS, the mixture was diluted with water and the precipitate was filtered. The resulting filtrate was extracted three times with ethyl acetate, and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by reverse phase column (0.05% NH4HCO3 in H2O and MeCN) to give 2-(2-chloro-6-methyl-pyrimidin-4-yl)benzonitrile (200 mg, 0.87 mmol, 47.31% yield) as an off-white solid. MS: m / z: C 12 H8ClN3, [M+H] + Theoretical: 230; Observed: 230

[0122] Step 2: Compound 6-3 was prepared as a colorless solid using ethylamine in step 1 according to the preparation of Example 1 (yield 93.13%). MS: m / z: C 19 H 22 FN3O5S, [M+H] + Theoretical: 424; Observed: 424

[0123] Step 3: To a solution of 5-[4-(ethylaminomethyl)-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (35 mg, 0.08 mmol) and 2-(2-chloro-6-methyl-pyrimidin-4-yl)benzonitrile (18.98 mg, 0.08 mmol) in isopropyl alcohol (2 mL), DIEA (0.02 mL, 0.25 mmol) was added and the mixture was stirred at 120° C. for 4 hours. After stirring was complete, the mixture was concentrated and the resulting residue was purified by reverse phase column (0.05% NH4HCO3 in HO and ACN) to give 2-[2-[ethyl-[[3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methyl]amino]-6-methyl-pyrimidin-4-yl]benzonitrile (30 mg, 0.048 mmol, 58.86% yield) as an off-white solid. MS: m / z: C 31 H 29 FN6O5S, [M+H] + Theoretical: 617; Observed: 617

[0124] Step 4: The title compound was prepared as a white solid (28.60% yield) according to the procedure of Example 1 using 6-4 in step 2. MS: m / z: C 23 H 21 FN6O4S [M+H] + Theoretical: 497; Observed: 497; 1 H NMR (400MHz, DMSO-d6) δ 7.96(t, J=7.8Hz, 2H), 7.82(t, J=7.6Hz, 1H), 7.68(t, J=7.6Hz, 1H), 7.02(s, 1H), 6.62-6.53(m, 2H), 4.86(s, 2H), 3.93(s, 2H), 3.68(s, 2H), 2.39(s, 3H), 1.15(t, J=6.9Hz, 3H) Preparative HPLC purification conditions: Column: XBridge Shield RP18 OBD column, 19*250mm, 10μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 20mL / min; Gradient: 35%B~55%B over 6 min, followed by 55%B; Wavelength: 210 / 254nm

[0125] Example 15: 5-[4-[[[2-(4-tert-butylphenyl)-3-methyl-4-pyridyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] [ka]

[0126] Step 1: To a stirred solution of 2-bromo-3-methyl-pyridin-4-amine (500 mg, 2.67 mmol), (4-tert-butylphenyl)boronic acid (618 mg, 3.48 mmol), and NaCO (850 mg, 8.02 mmol) in a mixture of 1,4-dioxane (10 mL) and HO (2 mL) was added Pd(dppf)Cl (217.87 mg, 0.26 mmol) at room temperature under a nitrogen atmosphere and stirred at 80 °C for 2 h. LCMS showed complete consumption of the starting material. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified on a silica column (20% to 40% ethyl acetate / petroleum ether) to give 2-(4-tert-butylphenyl)-3-methyl-pyridin-4-amine (260 mg, 1.04 mmol, 38.8% yield) as a pale yellow solid. MS: m / z: Theoretical value: C 16 H 20 N2, [M+H] + Observations: 241;

[0127] 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 (Intermediate 2, 100 mg, 0.25 mmol) and 2-(4-tert-butylphenyl)-3-methyl-pyridin-4-amine (60.94 mg, 0.25 mmol) in DCM (5 mL) was added TMSOTf (0.15 mL, 1.01 mmol) dropwise at 0 °C and stirred at room temperature for 1 h. The reaction mixture was then cooled to 0 °C, and NaBH(AcO) (162 mg, 0.76 mmol) was added slowly. The mixture was stirred at room temperature for an additional 1 h. LCMS showed complete consumption of the starting material, yielding ~50% of the product. (Note: Depending on the substrate, the PMB protecting group may be fully or partially cleaved in the reductive amination reaction. If not completely cleaved, an appropriate amount of TFA may be added directly to the mixture to complete the deprotection of PMB.) The resulting solution was concentrated at low temperature (bath temperature: 25 °C). The resulting residue was purified by reverse-phase column (0.05% NH4HCO3 in H2O and MeCN) and further purified by preparative HPLC to give 5-[4-[[[2-(4-tert-butylphenyl)-3-methyl-4-pyridyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a white solid. MS: m / z: C 25 H 27 FN4O4S [M+H] + Theoretical: 499, Observed: 499; 1 H NMR (400MHz, DMSO-d6) δ 13.45(s, 1H), 9.69(s, 1H), 8.48(s, 1H), 8.16(s, 1H), 7.64(d, J=8.2Hz, 2H), 7.52(d, J=7.8Hz, 2H), 6.84(d, J=6.9Hz, 1H), 6.76(d, J=11.3Hz, 2H), 4.61(d, J=6.2Hz, 2H), 4.01(s, 2H), 2.13(s, 3H), 1.36(s, 9H) Preparative HPLC purification conditions: Column: SunFire Prep C18 OBD column, 19*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 20mL / min; Gradient: 20%B to 40%B over 5.5min, followed by 40%B; Wavelength: 210 / 254nm

[0128] Example 16: 5-[2-fluoro-6-hydroxy-4-[[(6-methylpyrazin-2-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared according to the preparation of Example 7 using 6-methylpyrazin-2-amine in Step 1 as a white solid (total yield: 7.38%). MS: m / z: C 14 H 14 FN5O4S [M+H] + Theoretical: 368; Observed: 368; 1 H NMR (400MHz, DMSO-d6) δ 10.16(s, 1H), 7.77(s, 1H), 7.60(s, 1H), 7.52(s, 1H), 6.68(m, 2H), 4.41(s, 2H), 4.27(s, 2H), 2.25(s, 3H) Preparative HPLC purification conditions: Column: SunFire Prep C18 OBD column, 19*150mm, 5μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 20mL / min; Gradient: 30%B~55%B over 5.3 min, followed by 55%B; Wavelength: 210 / 254nm

[0129] Example 17: 5-[4-[[(2,6-dimethylpyrimidin-4-yl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] [ka]

[0130] Step 1: To a stirred solution of 5-[4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (600 mg, 1.35 mmol), potassium (tert-butoxycarbonylamino)methyl-trifluoroboranide (638.92 mg, 2.7 mmol), and K2CO3 (557.88 mg, 4.04 mmol) in 1,4-dioxane (8.0 mL) and water (0.8 mL) was added Pd2(dba)3 (246.6 mg, 0.27 mmol) and RuPhos (251.52 mg, 0.54 mmol) and purged with N2 for 5 min. The mixture was then stirred at 115 °C for 36 h and monitored for completion by LCMS before being concentrated. The resulting residue was dissolved in DMSO and purified by reverse-phase column chromatography (0.05% NH4HCO3 in HO and ACN) to give tert-butyl N-[[3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methyl]carbamate (300 mg, 0.60 mmol, 44.92% yield). MS: m / z: C 22 H 26 FN3O7S [MH] - Theoretical: 494; Observed: 494

[0131] Step 2: To a stirred solution of tert-butyl N-[[3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methyl]carbamate (200 mg, 0.40 mmol) in DCM (4 mL) was added TFA (4 mL). After monitoring the reaction for completion by LCMS, the mixture was concentrated. The resulting crude material was azeotroped twice with toluene to give 5-[4-(aminomethyl)-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 2,2,2-trifluoroacetic acid (200 mg, 0.72 mmol), which was used in the next step. MS: m / z: CH 10 FN3O4S [MH] - Theoretical: 274; Observed: 274

[0132] Step 3: To a stirred solution of 5-[4-(aminomethyl)-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 2,2,2-trifluoroacetic acid (110 mg, 0.28 mmol) and 4-chloro-2,6-dimethyl-pyrimidine (80.58 mg, 0.57 mmol) in DMSO (6 mL) was added DIPEA (0.25 mL, 1.41 mmol) and stirred at 80° C. overnight. After monitoring the reaction for completion by LCMS, the mixture was purified by reverse-phase column chromatography followed by preparative HPLC to give 5-[4-[[(2,6-dimethylpyrimidin-4-yl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (17.4 mg, 0.04 mmol, 15.33% yield) as an off-white solid. MS: m / z: C 26 H 26 N4O3[M+H] + Theoretical: 382; Observed: 382; 1H NMR (400MHz, DMSO-d6) δ 13.69(s, 1H), 9.74(s, 1H), 9.61(t, J=6.0Hz, 1H), 6.71-6.61(m, 2H), 6.53(s, 1H), 4.59(d, J=5.8Hz, 2H), 4.02(d, J=4.5Hz, 2H), 2.52-2.43(m, 3H), 2.34(s, 3H) Preparative HPLC purification conditions: SunFire Prep C18 OBD column, 19*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 20mL / min; Gradient: 35%B to 55%B over 5.5min, followed by 55%B; Wavelength: 210 / 254nm

[0133] Example 18: 5-[4-[[(3,6-dimethylpyrazin-2-yl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as a white solid using 3,6-dimethylpyrazin-2-amine in Step 1 according to the preparation of Example 7 (total yield: 12.66%). MS: m / z: C 15 H 16 FN5O4S [M+H] + Theoretical: 382; Observed: 382; 1 H NMR (400MHz, DMSO-d6) δ 10.03(s, 1H), 7.53(s, 1H), 7.12(s, 1H), 6.69(d, J=10.6Hz, 2H), 4.50(s, 2H), 4.25(s, 2H), 2.33(s, 3H), 2.22(s, 3H) Preparative HPLC purification conditions: Column: SunFire Prep C18 OBD column, 19*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 20mL / min; Gradient: 30%B~50%B over 5.5min, followed by 50%B; Wavelength: 210 / 254nm

[0134] Example 19: 5-[4-[[(5,6-dimethylpyrazin-2-yl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as a white solid using 5,6-dimethylpyrazin-2-amine in Step 1 according to the preparation of Example 7 (total yield: 14.73%). MS: m / z: Calc.: C 15 H 16 FN5O4S, [M+H] + Observations: 382; 1 H NMR (400MHz, DMSO-d6) δ 10.32(s, 1H), 7.70(s, 1H), 7.42(s, 1H), 6.70(d, J=12.2Hz, 2H), 4.41(s, 2H), 4.34(s, 2H), 2.29(d, J=2.9Hz, 6H) Preparative HPLC purification conditions: Column: SunFire Prep C18 OBD column, 19*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 20mL / min; Gradient: 35%B~55%B over 5.5min, followed by 55%B; Wavelength: 210 / 254nm

[0135] Example 20: 5-[2-fluoro-6-hydroxy-4-[[(3-methoxy-6-methyl-pyrazin-2-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] [ka]

[0136] Step 1: To a mixture of 6-chloro-3-methoxy-pyrazin-2-amine (300 mg, 1.88 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (472.01 mg, 3.76 mmol) in 1,4-dioxane (5 mL) was added K2CO3 (778.34 mg, 5.64 mmol) and Pd(dppf)Cl2 (307.07 mg, 0.38 mmol) under a nitrogen atmosphere and stirred at 115 °C for 12 h under a nitrogen atmosphere. After monitoring the reaction for completion by LCMS, the mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by reverse-phase column chromatography (0.05% NH4HCO3 in H2O and MeCN) to give 3-methoxy-6-methyl-pyrazin-2-amine (200 mg, 1.43 mmol, 76.44% yield) as a brown solid. MS: m / z: Theoretical: C6H9N3O, [M+H] + 140; Observed: 140

[0137] Step 2: Compound 9-3 was prepared as a pale yellow solid (45.72% yield) using 3-methoxy-6-methyl-pyrazin-2-amine in step 1 according to the preparation of Example 2. MS: m / z: C 23 H 24 FN5O6S [M+H] + Theoretical: 518; Observed: 518

[0138] Step 3: The title compound was prepared as a white solid (25.16% yield) according to the procedure of Example 1 using 9-3 in Step 2. MS: m / z: C 15 H 16 FN5O5S [M+H] + Theoretical: 398; Observed: 398; 1H NMR (400MHz, DMSO-d6) δ 9.78 (br, 1H) 7.19(s, 1H), 7.09(s, 1H), 6.65(d, J=13.3Hz, 2H), 4.43(d, J=5.6Hz, 2H), 4.26(s, 1H), 4.13(s, 1H), 3.87(t, J=2.3Hz, 3H), 2.14(t, J=2.5Hz, 3H) Preparative HPLC purification conditions: Column: Sunfire prep C18 column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 10% B to 40% B over 7 min, followed by 40% B; Wavelength: 210nm

[0139] Example 21: 5-[2-fluoro-6-hydroxy-4-[[(6-methoxy-3-methyl-pyrazin-2-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] [ka]

[0140] Step 1: To a solution of 3,5-dichloro-2-methyl-pyrazine (400 mg, 2.45 mmol) in methanol (5 mL), sodium methoxide (30% in MeOH, 2.21 g, 12.27 mmol) was added and stirred at 60 °C overnight, after which LCMS showed complete consumption of the starting material. This solution was purified by reverse-phase column chromatography (0.05% NH4HCO3 in HO and MeCN) to give 3-chloro-5-methoxy-2-methyl-pyrazine (200 mg, 1.26 mmol, 51.39% yield) as a white solid. MS: m / z: C6H7ClNO [M+H] + Theoretical: 159; Observed: 159; 1H NMR (400 MHz, chloroform-d) δ 8.03 (s, 1H), 4.01 (d, J = 0.8 Hz, 3H), 2.46 (s, 3H)

[0141] Step 2: To a stirred mixture of 3-chloro-5-methoxy-2-methyl-pyrazine (200 mg, 1.26 mmol) and (4-methoxyphenyl)methanamine (519 mg, 3.78 mmol) in 1,4-dioxane (5 mL) was added NaOtBu (363.58 mg, 3.78 mmol), Pd(dba) (173.23 mg, 0.19 mmol), and Xantphos (218.68 mg, 0.38 mmol) at room temperature. The solution was then degassed by bubbling nitrogen through it for 5 minutes and stirred at 100 °C for 14 hours. After stirring was complete, the reaction mixture was concentrated, and the resulting residue was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by reverse-phase column chromatography (0.05% NH4HCO3 in H2O and MeCN) to give 6-methoxy-N-[(4-methoxyphenyl)methyl]-3-methyl-pyrazin-2-amine (300 mg, 1.15 mmol, 91.74% yield) as a pale yellow solid. MS: m / z: C 14 H 17 N3O2[M+H] + Theoretical: 260; Observed: 260

[0142] Step 3: To a solution of 6-methoxy-N-[(4-methoxyphenyl)methyl]-3-methyl-pyrazin-2-amine (300 mg, 1.16 mmol) in DCM (2 mL) was added TFA (4 mL) at room temperature and stirred at 60 °C for 2 h. After monitoring the completion of the reaction by LCMS, the mixture was concentrated. The resulting residue was purified by reverse-phase column chromatography (0.05% NHHCO in H2O and MeCN) to give 6-methoxy-3-methyl-pyrazin-2-amine (80 mg, 0.57 mmol, 49.68% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 7.44 (d, J = 1.4 Hz, 1H), 4.21 (s, 2H), 3.90 (d, J = 1.3 Hz, 3H), 2.33 (d, J = 1.4 Hz, 3H), 1.79 (s, 1H)

[0143] Step 4: The title compound was prepared as a white solid (3.95% yield) using 6-methoxy-3-methyl-pyrazin-2-amine in Step 1 according to the preparation of Example 7. MS: m / z: C 15 H 16 FN5O5S [M+H] + Theoretical: 398; Observed: 398; 1 H NMR (400MHz, DMSO-d6+D2O) δ 7.36(s, 1H), 6.71-6.61(m, 2H), 4.34(s, 2H), 3.99(s, 2H), 3.78(s, 3H), 2.16(s, 3H), 1.23(s, 1H), 0.85(s, 1H) Preparative HPLC purification conditions: Column: SunFire C18 OBD preparative column, 19*250mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 28%B~34%B over 6.5min, followed by 34%B; Wavelength: 254 / 210nm

[0144] Example 22: 5-[2-fluoro-6-hydroxy-4-[[(2-methoxy-5-methyl-pyrimidin-4-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] Following the preparation of Example 9, but using 4-chloro-2-methoxy-5-methyl-pyrimidine in Step 3 and running the reaction at 100° C. instead of 80° C., the title compound was prepared as a white solid (8.53% yield). MS: m / z: C 15 H 16 FN5O5S [M+H] +Theoretical: 398; Observed: 398; 1 H NMR (400MHz, DMSO-d6) δ 9.87-9.82(m, 1H), 9.19(t, J=5.9Hz, 1H), 7.92(s, 1H), 6.74(d, J=9.2Hz, 2H), 4.62(d, J=6.0Hz, 2H), 4.08(s, 2H), 4.00(s, 3H), 2.06(s, 3H) Preparative HPLC purification conditions: Column: SunFire C18 OBD preparative column, 19*250mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 13% B to 23% B over 6.5 min, followed by 23% B; Wavelength: 254 / 210nm

[0145] Example 23: 5-[2-fluoro-6-hydroxy-4-[[(6-methoxypyrazin-2-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as a white solid using 6-methoxypyrazin-2-amine in Step 1 according to the preparation of Example 7 (total yield: 29.31%). MS: m / z: C 14 H 14 FN5O5S [M+H] + Theoretical: 384; Observed: 384; 1 H NMR (400 MHz, methanol-d4) δ 7.43 (d, J = 6.7 Hz, 1H), 7.27 (s, 1H), 6.80-6.66 (m, 2H), 4.49 (s, 2H), 4.27 (s, 2H), 3.86 (s, 3H) Preparative HPLC purification conditions: Column: XBridge Shield RP18 OBD column, 19*250mm, 10μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 20%B to 27%B over 5 minutes, followed by 27%B; Wavelength: 254nm

[0146] Example 24: 5-[2-fluoro-6-hydroxy-4-[[(2-methylpyrimidin-4-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared according to the preparation of Example 9 using 4-chloro-2-methyl-pyrimidine in step 3 as a white solid (13.25% yield). MS: m / z: C 14 H 14 FN5O4S [M+H]+ Theoretical: 368; Observed: 368; 1 H NMR (400MHz, DMSO-d6) δ 13.81(s, 1H),9.70(m, 2H), 8.14(d, J=7.2Hz, 1H), 6.74-6.63(m, 2H), 4.61(d, J=5.9Hz, 2H), 3.98(s, 2H), 2.51(m, 3H) Preparative HPLC purification conditions: Column: SunFire Prep C18 OBD column, 19*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 25%B to 55%B over 5.5 min, followed by 55%B; Wavelength: 254 / 210nm

[0147] Example 25: 5-[2-fluoro-6-hydroxy-4-[[(6-methoxy-5-methyl-pyrazin-2-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] [ka]

[0148] Step 1: To a mixture of 5-bromo-6-methoxy-pyrazin-2-amine (400 mg, 1.96 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (492.23 mg, 3.92 mmol) in 1,4-dioxane (5 mL) was added KCO (541.12 mg, 3.92 mmol) and Pd(dppf)Cl (318.24 mg, 0.39 mmol) under a nitrogen atmosphere and stirred at 120 °C for 16 h under a nitrogen atmosphere. After monitoring the reaction for completion by LCMS, the solution was directly purified by reverse-phase column chromatography (0.05% NHHCO in HO and MeCN) to give 6-methoxy-5-methyl-pyrazin-2-amine (100 mg, 0.71 mmol, 36.65% yield) as a brown solid. MS: m / z: C6H9N3O [M+H] + Theoretical: 140; Observed: 140; 1 H NMR (400 MHz, chloroform-d) δ 7.43 (s, 1H), 4.19 (s, 2H), 3.88 (s, 3H), 2.32 (s, 3H)

[0149] Step 2: The title compound was prepared as a white solid (24.26% yield) using 6-methoxy-5-methyl-pyrazin-2-amine in Step 2 according to the preparation of Example 15. MS: m / z: C 15 H 16 FN5O5S [M+H] + Theoretical: 398; Observed: 398; 1 H NMR (400MHz, DMSO-d6) δ 10.34(s, 1H), 7.38(s, 2H), 6.76-6.67(m, 2H), 4.36(d, J=11.7Hz, 4H), 3.79(s, 3H), 2.18(s, 3H) Preparative HPLC purification conditions: Column: SunFire Prep C18 OBD column, 19*150mm, 5μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 50%B~70%B over 6.5min, followed by 70%B; Wavelength: 210 / 254nm

[0150] Example 26: 5-[2-fluoro-6-hydroxy-4-[[(6-methylpyrimidin-4-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as a white solid using 4-chloro-6-methyl-pyrimidine according to the preparation of Example 9 (10.79% yield). MS: m / z: C 14 H 14 FN5O4S [M+H] + Theoretical: 368; Observed: 368; 1 H NMR (400MHz, DMSO-d6) δ 9.80-9.45(m, 2H), 8.73(s, 1H), 6.64(s, 3H), 4.65-4.45(m, 2H), 3.95(s, 2H), 2.36(s, 3H) Preparative HPLC purification conditions: Column: SunFire Prep C18 OBD column, 19*150mm, 5μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 30%B~50%B over 5.31min, followed by 50%B; Wavelength: 254 / 210nm

[0151] Example 27: 5-[4-[[(2,5-dimethylpyrimidin-4-yl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as a white solid using 4-chloro-2,5-dimethyl-pyrimidine according to the preparation of Example 9 (14.57% yield). MS: m / z: C 15 H 16 FN5O4S [M+H] + Theoretical: 382; Observed: 382; 1H NMR (400MHz, DMSO-d6) δ 9.51(s, 1H), 8.88(s, 1H), 8.09(s, 1H), 6.66(d, J=10.9Hz, 2H), 4.63(d, J=6.0Hz, 2H), 3.93(s, 2H), 2.48(s, 3H), 2.11(s, 3H) Preparative HPLC purification conditions: Column: XBridge BEH C18 OBD preparative column, 19*250mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 11%B to 36%B over 6 minutes, followed by 36%B; Wavelength: 254nm

[0152] Example 28: 5-(2-fluoro-6-hydroxy-4-(((6-methylpyridazin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] [ka]

[0153] 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-methylpyridazin-3-amine (28.78 mg, 0.26 mmol) in dry DMF (3 mL) was added TMSCl (0.05 mL, 0.41 mmol) dropwise at 0° C. and stirred at room temperature for 1 hour. The reaction mixture was then cooled to 0° C., and a solution of BH3 / THF (1 M, 0.41 mL, 0.41 mmol) was added. After the addition, the reaction mixture was stirred at room temperature for an additional 2 hours. LCMS showed the reaction was complete. The resulting solution was quenched with ice water (1 mL) and directly purified by reverse-phase column chromatography (0.05% NH4HCO3 in water and MeCN) to give 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-[[(6-methylpyridazin-3-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (40 mg, 0.08 mmol, 40.44% yield) as a pale yellow solid. MS: m / z: C 22 H 22 FN5O5S [M+H] + Theoretical: 488; Observed: 488

[0154] Step 2: To a stirred solution of 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-[[(6-methylpyridazin-3-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (40 mg, 0.08 mmol) in DCM (2 mL) was added TFA (4 mL) at 0 °C and stirred at room temperature for 2 h. After monitoring the reaction for completion by LCMS, the mixture was concentrated. The resulting residue was purified by reverse-phase column chromatography (0.05% NH4HCO3 in water and MeCN) and further purified by preparative HPLC to give 5-[2-fluoro-6-hydroxy-4-[[(6-methylpyridazin-3-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (9 mg, 0.024 mmol, 29.70% yield) as a white solid. MS: m / z: C 14H 14 FN5O4S [M+H] + Theoretical: 368; Observed: 368; 1 H NMR (400MHz, DMSO-d6) δ 9.58(s, 1H), 8.82(s, 1H), 7.74(d, J=9.3Hz, 1H), 7.49(d, J=9.4Hz, 1H), 6.74-6.66(m, 2H), 4.46(d, J=5.8Hz, 2H), 3.97(s, 2H), 2.48(s, 3H) Preparative HPLC purification conditions: Column: SunFire Prep C18 OBD column, 19*150mm, 5μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 30%B~50%B over 5.3 min, followed by 55%B; Wavelength: 254 / 210nm

[0155] Example 29: 5-[4-[[(4,6-dimethylpyrimidin-2-yl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as an off-white solid using 2-chloro-4,6-dimethyl-pyrimidine according to the preparation of Example 9 (3.05% yield). MS: m / z: C 15 H 16 FN5O4S [M+H] + Theoretical: 382; Observed: 382; 1 H NMR (400MHz, DMSO-d6) δ 9.96(s, 1H), 7.80(s, 1H), 6.74-6.59(m, 2H), 6.52(s, 1H), 4.46(d, J=5.4Hz, 2H), 4.18(s, 2H), 2.26(s, 6H) Preparative HPLC purification conditions: Column: SunFire Prep C18 OBD column, 19*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 30%B~50%B over 6.8min, followed by 50%B; Wavelength: 254 / 210nm

[0156] Example 30: 5-[2-fluoro-6-hydroxy-4-[[[4-[4-(trifluoromethyl)phenyl]-3-pyridyl]amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] [ka]

[0157] Step 1: To a mixture of [4-(trifluoromethyl)phenyl]boronic acid (428.14 mg, 2.25 mmol) and 4-bromopyridin-3-amine (300 mg, 1.73 mmol) in toluene (4 mL), ethanol (2 mL), and water (1 mL) was added KCO (957.17 mg, 6.94 mmol) and Pd(PPh) (158.79 mg, 0.17 mmol). The mixture was degassed with nitrogen for 5 minutes and stirred at 100 °C under a nitrogen atmosphere for 16 hours. After monitoring the completion of the reaction by LCMS, it was mixed with saturated aqueous ammonium chloride and extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica column chromatography (30% ethyl acetate / petroleum ether) to give 4-[4-(trifluoromethyl)phenyl]pyridin-3-amine (350 mg, 1.47 mmol, 84.73% yield) as a pale yellow solid. MS: m / z: C 12 H9N3O2[M+H] + Theoretical: 239; Observed: 239

[0158] Step 2: The compound was prepared according to the preparation of Example 2 using 4-[4-(trifluoromethyl)phenyl]pyridin-3-amine in Step 1 as a white solid (31.89% yield). MS: m / z: C 29 H 24 F4N4O5S [M+H] + Theoretical: 617; Observed: 617

[0159] Step 3: The title compound was prepared as a white solid (66.6% yield) using 13-3 in Step 2 according to the procedure in Example 1. MS: m / z: C 21 H 16 F4N4O4S [M+H] + Theoretical: 497; Observed: 497; 1 H NMR (300MHz, DMSO-d6) δ 8.07-7.88(m, 3H), 7.85(s, 1H), 7.75(d, J=8.0Hz, 2H), 7.16(d, J=4.9Hz, 1H), 6.74-6.62(m, 2H), 4.28(s, 2H), 3.95(s, 2H) Preparative HPLC purification conditions: Column: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3 + 0.1% + NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 30%B~40%B over 8 minutes, followed by 40%B; Wavelength: 254 / 220nm

[0160] Example 31: 5-[4-[[[6-(4-tert-butylphenoxy)-3-pyridyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] [ka]

[0161] Step 1: To a stirred solution of 2-chloro-5-nitro-pyridine (1 g, 6.31 mmol) and 4-tert-butylphenol (1.23 g, 8.2 mmol), K2CO3 (1.31 g, 9.46 mmol) was added and stirred at room temperature for 16 hours. After the reaction was complete, the resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column (0.05% NH4HCO3 in H2O and MeCN) to give 2-(4-tert-butylphenoxy)-5-nitro-pyridine (1.3 g, 75.69% yield) as a white solid. MS: m / z: C 15 H 16 N2O3[M+H] + Theoretical: 617; Observed: 617

[0162] Step 2: To a mixture of 2-(4-tert-butylphenoxy)-5-nitro-pyridine (1.26 g, 4.63 mmol) in ethanol (7 mL) and water (7 mL), AcOH (2.8 mL) and Fe (1.29 g, 23.14 mmol) were added and stirred at 80 °C for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water, and the solution was adjusted to pH = 8 with saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to give 6-(4-tert-butylphenoxy)pyridin-3-amine (1 g, 89.18% yield) as a pale yellow solid without further purification.

[0163] Step 3: Compound 14-4 was prepared as a white solid (63.53% yield) using 6-(4-tert-butylphenoxy)pyridin-3-amine in step 1 according to the preparation of Example 2. MS: m / z: C 32 H 33 FN4O6S [M+H] + Theoretical: 612; Observed: 612

[0164] Step 4: The title compound was prepared as a white solid (24.56% yield) using 14-4 in Step 2 according to the procedure in Example 1. MS: m / z: C 24 H 25 FN4O5S [M+H] + Theoretical: 501; Observed: 501; 1 H NMR (300MHz, DMSO-d6) δ 7.50(d, J=3.0Hz, 1H), 7.39-7.28(m, 2H), 7.07(dd, J=8.8, 3.0Hz, 1H), 6.93-6.83(m, 2H), 6.78(dd, J=8.7, 0.6Hz, 1H), 6.73-6.61(m, 2H), 4.17(s, 2H), 3.94(s, 2H), 1.27(s, 9H) Preparative HPLC purification conditions: Column: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3 + 0.1%NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 33%B to 48%B over 8 minutes, followed by 48%B; Wavelength: 254 / 220nm

[0165] Example 32: 5-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)pyrimidine-2-carbonitrile [ka] The title compound was prepared as a white solid using 5-aminopyrimidine-2-carbonitrile in Step 1 according to the preparation of Example 2 (total yield: 25.9%). MS: m / z: C 14 H 11 FN6O4S [M+H] + Theoretical: 379; Observed: 379; 1 H NMR (300MHz, DMSO-d6) δ 8.20-8.17(m, 2H), 7.77-7.74(m, 1H), 6.69-6.68(m, 1H), 4.37-4.35(m, 2H), 3.94(s, 2H) Preparative HPLC purification conditions: Column: Xselect CSH C18 OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 3% B to 33% B over 10 minutes, followed by 33% B; Wavelength: 254nm

[0166] Example compounds prepared by the above procedures are listed in Table 1. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6]

[0167] Biological assays The pharmacological properties of the compounds of this invention may be confirmed by a number of biological assays known in the art. The following biological assays have been carried out with the compounds of this invention.

[0168] Assay The PhosphoSens® Kinase Assay was performed as described by the manufacturer (AssayQuant Technologies, Marlborough, MA). Briefly, 1000x DMSO solutions of compounds were prepared in a 384-well reagent plate by serially diluting 3x with a 10mM DMSO stock solution. 50nL of the serially diluted compound solution was then added to the corresponding wells of a 384-well assay plate. 40mL of a 1.25x diluted substrate (AQT0264) / 1x assay buffer (50mM HEPES pH 7.5, 500µM EGTA, 10nM MgCl2, 0.01% Brij-35, 1% glycerol, 1mM DTT, and 0.2mg / mL BSA) was added to each well of the assay plate, resulting in a final substrate concentration of 20µM. Finally, 10mL of a 5x diluted PTPN2 enzyme stock solution was added to each well of the assay plate, resulting in a final enzyme concentration of 150pM. 360nm(λ ex 360) excitation wavelength and 480 nm (λ em The fluorescence intensity at wavelength 480 was measured every 71 seconds at room temperature for 1 hour using a Synergy H4 plate reader (BioTek Instruments / Agilent Technologies, Winooski, VT), and a reaction progress curve was generated.

[0169] Phosphatase activity assay using DiFMUP as a 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 containing 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 DiFMUP substrate solution (25 mM final concentration) was added to a 384-well microtiter plate (Corning 3574, white, non-binding surface) containing 0.05 mL of serially diluted test compound in DMSO. The reaction was initiated by adding the enzyme solution (10 mL) to a final PTPN2 concentration of 0.15 nM, and the reaction was monitored at room temperature using a BioTek Synergy HTX plate reader (Agilent Technologies, Santa Clara, CA). ex 360 / λ em The activity was monitored at 460°C every 105 seconds for 60 minutes. The initial linear portion of the progress curve was fitted with a linear equation to determine the slope, and the value of the control treated with no inhibitor was defined as 100% activity, and the inhibition rate (%) was calculated. The IC value of each compound was calculated by fitting the inhibition rate (%)-compound concentration curve using Dotmatics software (Dotmatics, Bishops Stortford, Hertfordshire, England). 50 got the value.

[0170] Cell Proliferation Assay Protocol B16-F10 cells (ATCC, Manassas, VA, #CRL-6475) were cultured in DMEM basal medium (ThermoFisher Scientific, #11995-040) supplemented with 10% heat-inactivated FBS (ThermoFisher Scientific, Waltham, MA, #16140-071) and 1% penicillin / streptomycin (ThermoFisher Scientific, #15140-122). Cells were seeded into two opaque white 384-well tissue culture-treated microplates (PerkinElmer, Waltham, MA, #6007688) at a density of 100 cells / well in a total volume of 20 μL and incubated overnight at 37°C and 5% CO. The compound solution (30 nL) in DMSO was then transferred from the original plate to the desired wells using an Echo 650 acoustic liquid handler (Beckman Coulter, Indianapolis, IN). Negative control wells received DMSO alone (30 nL, final concentration 0.15%). The plates were returned to the incubator, and after 1 h, the cells were treated with either 5 μL of basal medium or 5 μL of basal medium containing 50 ng / mL of mouse IFN-γ recombinant protein (R&D Systems, Minneapolis, MN, #485-MI / CF, final concentration 10 ng / mL) using an ASSIST automated dispenser (INTEGRA Biosciences, Hudson, NH). The plates were incubated at 37°C for 4 days, and then cell proliferation assays were performed using CellTiter-Glo reagent (Promega, Madison, WI, #G7573, 25 μL / well). The luminescence signal intensity was measured 15 minutes after addition of the CellTiter-Glo reagent using an EnVision 2105 plate reader (PerkinElmer) and analyzed using the Dotmatics software platform to calculate the IC50 values ​​of the compounds. Cell Titer-Glo reagent inhibited growth in the absence of IFNγ, identifying off-target compounds that caused cytotoxicity.

[0171] Phospho-STAT1 Assay Protocol B16-F10 cells (ATCC, Manassas, VA, #CRL-6475) were cultured in DMEM basal medium (ThermoFisher Scientific, #11995-040) supplemented with 10% heat-inactivated FBS (ThermoFisher Scientific, Waltham, MA, #16140-071) and 1% penicillin / streptomycin (ThermoFisher Scientific, #15140-122). Cells were seeded into opaque white 384-well tissue culture-treated microplates (PerkinElmer, Waltham, MA, #6007688) at a density of 10,000 cells / well in a total volume of 20 μL and incubated overnight at 37°C and 5% CO. DMSO solutions (30 nL) of compounds were then transferred from the original plate to the appropriate wells using an Echo 650 acoustic liquid handler (Beckman Coulter, Indianapolis, IN). Negative control wells received DMSO alone (30 nL, final concentration 0.15%). The plates were returned to the incubator, and after 1 h, cells were treated with either 5 μL of basal medium or 5 μL of basal medium containing 500 ng / mL of mouse IFN-γ recombinant protein (R&D Systems, Minneapolis, MN, #485-MI / CF, final concentration 100 ng / mL) using an ASSIST automated dispenser (INTEGRA Biosciences, Hudson, NH). Plates were incubated at 37°C for 1 h, and phosphorylated STAT1 protein levels were assayed using the Phospho-STAT1 (Tyr701) HTRF kit (Cisbio, Bedford, MA, #63ADK026PEH) according to the manufacturer's instructions. After 24 h, HTRF signal intensity was measured with an EnVision 2105 plate reader (PerkinElmer) and analyzed using the Dotmatics software platform to determine the IC of compounds. 50 values ​​were calculated.

[0172] Biological Assay Data Table 2 summarizes the biological assay data for the examples / embodiments prepared. IC50 For data, a high concentration DDT assay and / or a DiFMUP substrate assay were used. Either assay may be utilized by those skilled in the art. Rows or columns marked with double asterisks represent the IC obtained. 50 Indicates that there is one value or aspect of. [Table 7] [Table 8] [Table 9] [Table 10] [Table 11]

Claims

1. The structure of Formula I: 【Chemistry 1】 wherein each independently represents R 1 is -N= and -C(R 7 )= selected from the group consisting of; R 2 is -N= and -C(R 8 )= selected from the group consisting of; R 3 is -N= and -C(R 9 )= selected from the group consisting of; R 4 is -N= and -C(R 10 )= selected from the group consisting of; R 5 is -N= and -C(R 11 )= selected from the group consisting of; R 6 is selected from the group consisting of hydrogen, alkyl, and ethyl; R 7 is selected from the group consisting of hydrogen, alkyl, cyano, propan-2-yl, cyclopropyl, dimethylamino, phenyl, and 4-tert-butylphenoxy, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, phenyl, aryl, and substituted aryl; R 8 is selected from the group consisting of hydrogen, alkyl, halogen, cyano, and trifluoromethyl, substituted alkyl, branched alkyl, alkoxy, amine, hydroxy, phenyl, aryl, and substituted aryl; R 9 is selected from the group consisting of hydrogen, alkyl, 4-(trifluoromethyl)phenyl, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, phenyl, aryl, and substituted aryl; R 10 is selected from the group consisting of hydrogen, alkyl, methoxy, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, phenyl, aryl, and substituted aryl; R 11 is hydrogen, alkyl, methoxy, propan-2-yl, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, phenyl, aryl, substituted aryl, and 【Chemistry 2】 selected from the group consisting of: R 12 is selected from the group consisting of hydrogen and tert-butyl; R 13 is selected from the group consisting of hydrogen and cyano. A compound having the formula:

2. During the ceremony, R 2 But -C(R 8 )=and; R 3 But -C(R 9 )=and; R 4 But -C(R 10 )=and; R 6 is hydrogen; R 7 is selected from the group consisting of hydrogen, methyl, dimethylamino, phenyl, and 4-tert-butylphenoxy; R 8 is selected from the group consisting of hydrogen, methyl, chloro, cyano, and trifluoromethyl; R 9 is selected from the group consisting of hydrogen, methyl, and 4-(trifluoromethyl)phenyl; R 10 is selected from the group consisting of hydrogen and methyl; R 11 is methyl, 2. The compound of claim 1.

3. During the ceremony, R 1 But -C(R 7 )=and; R 6 is hydrogen; R 7 is selected from the group consisting of hydrogen, alkyl, cyano, and cyclopropyl; R 8 is selected from the group consisting of hydrogen and alkyl; R 9 is hydrogen; R 10 is hydrogen; R 11 But hydrogen and 【Transformation 3】 selected from the group consisting of: R 12 is hydrogen; R 13 is hydrogen, 2. The compound of claim 1.

4. During the ceremony, R 2 But -C(R 8 )=and; R 7 is hydrogen; R 8 is selected from the group consisting of hydrogen and alkyl; R 9 is hydrogen; R 10 is selected from the group consisting of hydrogen and alkyl; R 11 However, alkyl and 【Chemistry 4】 selected from the group consisting of 2. The compound of claim 1.

5. During the ceremony, R 6 is hydrogen; R 7 is selected from the group consisting of hydrogen and alkyl; R 8 is selected from the group consisting of hydrogen and alkyl; R 9 is selected from the group consisting of hydrogen and alkyl; R 10 is selected from the group consisting of hydrogen and methoxy; R 11 is selected from the group consisting of hydrogen, alkyl, and methoxy; 2. The compound of claim 1.

6. During the ceremony, R 1 But -C(R 7 )=and; R 6 is hydrogen; R 7 is selected from the group consisting of hydrogen, alkyl, and cyano; R 8 is selected from the group consisting of hydrogen and alkyl; R 9 is hydrogen; R 10 is hydrogen; R 11 is alkyl, 2. The compound of claim 1.

7. below: 5-(4-(((6-(dimethylamino)pyridin-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((2,6-dimethylpyridin-4-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((2,4-dimethylpyridin-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-((4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)nicotinonitrile; 5-((4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)-2-methylnicotinonitrile; 5-(2-fluoro-6-hydroxy-4-(((6-phenylpyridin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-(trifluoromethyl)pyridin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((5-chloropyridin-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-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)pyrimidine-5-carbonitrile; 5-(4-(((6-cyclopropylpyridin-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-isopropylpyrimidin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-phenylpyridin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-isopropylpyridin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 2-(2-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)(ethyl)amino)-6-methylpyrimidin-4-yl)benzonitrile; 5-(4-(((2-(4-(tert-butyl)phenyl)-3-methylpyridin-4-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methylpyrazin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((2,6-dimethylpyrimidin-4-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((3,6-dimethylpyrazin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((5,6-dimethylpyrazin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((3-methoxy-6-methylpyrazin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methoxy-3-methylpyrazin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((2-methoxy-5-methylpyrimidin-4-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methoxypyrazin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((2-methylpyrimidin-4-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methoxy-5-methylpyrazin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methylpyrimidin-4-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((2,5-dimethylpyrimidin-4-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((6-methylpyridazin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((4,6-dimethylpyrimidin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((4-(4-(trifluoromethyl)phenyl)pyridin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((6-(4-(tert-butyl)phenoxy)pyridin-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-((4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)pyrimidine-2-carbonitrile 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

8. 10. A pharmaceutical composition comprising a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

9. 10. A method for treating cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the cancer / disease is selected from human carcinoma, epithelial carcinoma, non-epithelial carcinoma, adenocarcinoma, papillary adenocarcinoma, lymphoma, leukemia, melanoma, solid tumor, lymphatic system cancer, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, liver cancer including hepatocellular carcinoma, B-cell acute lymphoblastic lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, small cell lymphoma, Hodgkin's lymphoma, leukemia, and multiple myeloma.

10. 10. A method for treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 1 in combination with another therapeutic agent.

11. The method of claim 10, wherein the additional therapeutic agent is an immunotherapeutic agent.

12. 12. The method of claim 11, wherein the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody.

13. 10. A method for treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of the pharmaceutically acceptable composition of claim 1.

14. 10. The method of claim 1, wherein the method for treating cancer is selected from radiation therapy, surgery, chemotherapy, or administration of a biopharmaceutical.

15. The method of claim 14, wherein the method for treating cancer further comprises administering a biopharmaceutical that is an agent that stimulates the immune system.

16. The method of claim 14, further comprising administering to the subject an inhibitor of DGKα and / or DGKζ, an antagonist of PD1 / PD-L1, and an antagonist of CTLA4.

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