Inhibitors of protein tyrosine phosphatases, compositions and methods of use

Abstract

Disclosed are compounds of formula (I): The present invention relates to compounds of the formula (I) TIFF2026501267000047.tif57133, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, as well as methods of using them as inhibitors of protein tyrosine phosphatase 2 (PTPN2). These compounds are useful for treating cancer and diseases sensitive to PTPN2 inhibition.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 476,513, filed December 21, 2022, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION Disclosed are compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof as inhibitors of protein tyrosine phosphatases, and methods of using them. [Background technology]

[0003] Immune checkpoint blockade (ICB) is an innovative approach to immunotherapy that targets immune evasion mechanisms and improves clinical responses in cancer patients. For example, checkpoint blockade antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and its ligands, such as programmed cell death ligand 1 (PD-L1), in the treatment of multiple types of cancer, greatly improving the treatment and survival outcomes of patients affected by these malignancies.

[0004] However, the majority of patients receiving ICB are either resistant to treatment or ultimately develop resistance. In particular, mutations or loss of the interferon-gamma (IFNγ) signaling pathway represent an important mechanism for clinical ICB resistance (Zaretsky, N., Engl. J. Med. 375, 819-829). IFNγ is a T cell-inducible 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 1 (MHC-1), thereby enabling antigen (Ag) presentation to T cells. In vivo CRISPR screening using a syngeneic mouse model demonstrated activation of the IFNγ pathway in tumors resistant to anti-PD-1 therapy. These studies identified the IFNγ pathway members (JAK1 / 2 and STAT1) and interferon gamma receptors (IFNGR1 / IFNGR2) as resistance-related hit factors, in addition to newly identified negative regulators such as PTPN2 and apelin receptor (APLNR), which represent novel therapeutic targets (Charles Sinclair et al., Emerg Top Life Sci. (2021) 5(5):675-680).

[0005] Pooled data from an in vivo genetic screen using CRISPR-Cas9 genome editing to identify genes that cause resistance to checkpoint blockade revealed that deletion of the protein tyrosine phosphatase (PTPN2) gene in tumor cells increases the efficacy of immunotherapy. The PTPN2 gene encodes a protein tyrosine phosphatase that regulates a range of intracellular processes. Loss of PTPN2 in tumor cells promotes amplification of IFNγ signaling, antigen presentation to T cells, and proliferation arrest in response to cytokines; these data suggest that therapeutic inhibition of PTPN2 may enhance the efficacy of immunotherapies that induce 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 an intracellular member of the class 1 subfamily of phosphotyrosine-specific phosphatases that regulates multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, with the highest expression 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 with a nuclear localization signal at the C-terminus upstream of the splice junction, and a 48-kDa canonical form with a C-terminal ER retention motif (Tillmann U. et al., Mol Cell Biol (1994) 14:3030-3040). The 45 kDa isoform can passively translocate to the cytoplasm under certain conditions of cellular stress. Both isoforms share an N-terminal phosphotyrosine phosphatase catalytic domain, and as a key negative regulator of the JAK-STAT pathway, PTPN2 directly controls signal transduction through cytokine receptors. The PTPN2 catalytic domain shares 74% sequence identity with PTPN1 (also called PTP1B) and shares similar enzymatic kinetics (Romsicki Y. et al., Arch Biochem Biophys (2003) 414:40-50).

[0007] The T cell protein tyrosine phosphatase PTPN2 has further been identified as a key negative regulator of TCR signaling, highlighting the association between single nucleotide polymorphisms (SNPs) in PTPN2 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 were shown to develop widespread inflammation and autoimmunity. This autoimmunity is associated with increased serum levels of inflammatory cytokines, antinuclear antibodies, T cell infiltration into nonlymphoid tissues, and liver disease. These data further demonstrate that PTPN2 is a critical negative regulator of TCR signaling that sets the threshold for TCR-induced naive T cell responses and prevents autoimmune and inflammatory disorders.

[0008] In addition to PTPN2, encoding the T cell PTP (TCPTP), as a susceptibility locus for autoimmune diseases, SNPs in PTPN2 are associated with the development of type 1 diabetes, rheumatoid arthritis, and Crohn's disease. Furthermore, the type 1 diabetes-associated PTPN2 variant rs1893217(C) was also associated with decreased PTPN2 expression in T cells (Florian Wiede, J Clin Invest. 2011;121(12):4758-4774).

[0009] The above findings suggest that inhibition of PTPN2 is a potential therapeutic solution to improve the efficacy of cancer treatment regimens associated with ICB resistance. Summary of the Invention

[0010] The present disclosure is directed to compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, that are effective inhibitors of protein tyrosine phosphatases, such as 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 a method for treating, preventing, or ameliorating cancer, comprising administering to a subject in need thereof an effective amount of a PTPN2 / PTPN1 inhibitor disclosed herein. In preferred embodiments, the compounds have a monocyclic core structure, compared to compounds reported in the literature, which contain a fused bicyclic core.

[0011] In some embodiments, disclosed herein are inhibitors of protein tyrosine phosphatases, e.g., PTPN2 and / or PTP1B, including compounds disclosed herein, e.g., compounds of Formula (I). In other embodiments, disclosed herein are methods for treating a disease or disorder, e.g., cancer, type 2 diabetes, obesity, metabolic disease, or any other disease, disorder, or condition that responds well to treatment with a PTPN2 or PTP1B inhibitor, comprising administering an effective amount of a compound disclosed herein, e.g., a compound of Formula (I). These and other features of the present invention will be described in detail in this disclosure.

[0012] In a first aspect, the present invention provides a compound having the following structural formula: [ka] wherein, for each occurrence, independently: R 1 is 1H-1,2,4-triazol-3-yl, [ka] selected from the group consisting of: R 2is selected from the group consisting of —H, alkyl, and substituted alkyl; R 3 is selected from the group consisting of —H, alkyl, and substituted alkyl; R 4 is selected from the group consisting of -H, alkyl, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, aryl, and substituted aryl; R 5 is selected from the group consisting of -H, alkyl, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, aryl, and substituted aryl. At least one compound of formula (I) is provided,

[0013] Furthermore, 5-(4-(((4-(2,4-dimethylphenyl)thiazol-2-yl)(methyl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((1H-pyrazol-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((isoxazol-3-ylamino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-methylisoxazol-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((1H-1,2,4-triazol-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((1-methyl-1H-pyrazol-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((1,3,4-thiadiazol-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-methyl-1H-imidazol-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((thiazol-2-ylamino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((1H-imidazol-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((1-methyl-1H-imidazol-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-methyl-1,3,4-thiadiazol-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((4-methylthiazol-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((3-methylisothiazol-5-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((3-methyl-1H-pyrazol-5-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 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. Also disclosed herein are methods of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formula (I) disclosed herein in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an immunotherapeutic agent. For example, in some embodiments, the immunotherapeutic agent is an antibody.

[0015] Also disclosed herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula (I). Also disclosed herein is a method of treating a metabolic disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of formula (I). In some embodiments, the method comprises treating cancer, hi some embodiments, the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, melanoma, or cancer of secretory cells.

[0016] Also disclosed herein are compositions for use in treating cancer in a patient in need thereof, the compositions comprising a compound disclosed herein, e.g., a compound of Formula (I), in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an immunotherapeutic agent. For example, in some embodiments, the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody and an anti-PD-L1 antibody.

[0017] Also disclosed herein are compositions for use in treating metabolic disorders in a patient in need thereof, the compositions comprising a compound disclosed herein, e.g., a compound of Formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0018] The present disclosure is directed to compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, that are effective inhibitors of protein tyrosine phosphatases, such as 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 a method for treating, preventing, or ameliorating cancer, comprising administering to a subject in need thereof an effective amount of a PTPN2 / PTPN1 inhibitor disclosed herein. In preferred embodiments, the compounds have a monocyclic core structure, compared to compounds containing a fused bicyclic core reported in the literature.

[0019] definition chemical definition The definition of specific functional groups and chemical terms will be explained in more detail below.Chemical elements are identified according to the Periodic Table of Elements (CAS edition, Handbook of Chemistry and Physics, 75th edition), and specific functional groups are generally defined as described in this handbook.In addition, the general principles of organic chemistry, and specific functional moieties and reactivity are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 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.

[0020] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0021] The compounds described herein may contain one or more asymmetric centers and thus may exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be 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, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; alternatively, preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, ed., University of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers, or alternatively, as mixtures of various isomers.

[0022] In the compositions provided 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% of the enantiomerically pure R-compound.

[0023] The features and advantages of the present invention described in this disclosure can be more readily understood by those skilled in the art in view of the following definitions. Certain features of the present invention described within the context of separate embodiments may also be combined to form a single embodiment or extrapolated to include multiple embodiments. What is identified herein as exemplary or preferred embodiments is illustrative and not limiting.

[0024] Unless expressly stated otherwise herein, references made in the singular include the plural, for example, "a" and "an" may refer to either one or one or more. 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).

[0025] Unless otherwise specified, any heteroatom with unsatisfied valences is assumed to have enough hydrogen atoms to satisfy the valences. The definitions set forth herein supersede any definitions set forth in any patent, patent application, and / or patent application publication incorporated herein by reference. Listed below are definitions of various terms used to describe 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). Throughout the specification, groups and substituents may be chosen by one skilled in the art to provide stable moieties and compounds.

[0026] According to the practice used in the art, [ka] is used in structural formulas herein to indicate the bond, which is the point at which a moiety or substituent is attached to a core or backbone structure. The terms "halo" and "halogen" as used herein refer to F, Cl, Br and I. The term "cyano" refers to the group --CN. The term "amino" refers to the group --NH.sub.2. The term "oxo" refers to the group =O.

[0027] The term "alkyl" as used herein refers to both branched and straight-chain saturated aliphatic hydrocarbon groups, for example, containing 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 is added as a subscript after the symbol "C," the subscript more specifically defines the number of carbon atoms that a particular group may contain. For example, "C" 1-6 "Alkyl" means a straight or branched chain alkyl group having from 1 to 6 carbon atoms.

[0028] As used herein, the term "fluoroalkyl" is intended to encompass both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4 "Fluoroalkyl" is intended to encompass 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. 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 Cyanoalkyl is included.

[0029] The term "aminoalkyl" encompasses both branched and straight-chain saturated alkyl groups substituted with one or more amine groups. For example, "aminoalkyl" includes -CH2NH2, -CH2CH2NH2, and -C 1-4 Includes aminoalkyl. 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 Includes hydroxyalkyl. The term "hydroxyfluoroalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups and one or more fluorine atoms. For example, "hydroxyfluoroalkyl" includes -CHFCHOH, -CHCHFC(CH)OH, and -CHFCH(CH)OH. 1-4 Includes hydroxyfluoroalkyl.

[0030] 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 is added as a subscript after the symbol "C," the subscript more specifically defines 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.

[0031] The term "heterocyclic" as used herein refers to organic compounds with ring structures containing both carbon atoms and non-carbon atoms such as oxygen and nitrogen. The term "alkoxy" as used herein refers to an alkyl group attached to the parent molecule through an oxygen atom, such as a methoxy group (-OCH). 1-3 "Alkoxy" means an alkoxy group having 1 to 3 carbon atoms. The term "alkoxyalkyl," as used herein, refers to an alkoxy group attached to an alkyl group through an oxygen atom, where the alkyl group is attached to the parent molecular moiety, e.g., a methoxymethyl group (-CH2OCH3). For example, "C 2-4 "Alkoxyalkyl" refers to an alkoxyalkyl group having from 2 to 4 carbon atoms, such as -CH2OCH3, -CH2CH2OCH3, -CH2OCH2CH3, and -CH2CH2OCH2CH3.

[0032] As used herein, the term "amine" refers to a compound in which a nitrogen atom is directly bonded to several carbon atoms. An embodiment consists of derivatives of ammonia (-NH3) resulting from the progressive replacement of three hydrogen atoms with hydrocarbon groups. Amines are classified as primary, secondary, or tertiary depending on the number of carbon atoms bonded to the nitrogen atom. For example, primary amines have one carbon bonded to the nitrogen (R-NH2), secondary amines have two carbons bonded to the nitrogen (R2-NH), and tertiary amines have three carbons bonded to the nitrogen (R3-N), where R is an alkyl group. The term "heteroaryl" as used herein refers to a 5- to 10-membered aromatic heterocyclic ring having at least one heteroatom from nitrogen, oxygen, and sulfur and containing at least one carbon atom, including both monocyclic and bicyclic ring systems.

[0033] The term "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The compound of formula (I) may be provided as an amorphous solid or a crystalline solid. Lyophilization may be used to provide the compound of formula (I) as an amorphous solid.

[0034] It should further be understood that solvates (e.g., hydrates) of compounds of formula (I) are also 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 solvent molecules, either organic or inorganic. This physical association includes hydrogen bonding. In certain cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be capable of isolation. "Solvate" includes both solution-phase and isolatable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0035] Various forms of prodrugs are well known in the art and include the following: a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Chapter 31 (Academic Press, 1996); b) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by P. Krogsgaard-Larson and H. Bundgaard, Chapter 5, pp. 113-191 (Harwood Academic Publishers, 1991); and d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer (Wiley-VCH, 2003) It is described in.

[0036] Additionally, after its preparation, the compound of formula (I) can be isolated and purified to obtain a composition containing 99% by weight or more of the compound of formula (I) ("substantially pure"), which can then be used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also included herein as part of the present invention. "Stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present invention embodies stable compounds.

[0037] Those skilled in the art will also understand that the compounds described and claimed herein as embodiments of the present invention exist in their "tautomeric forms." As used herein, tautomers, which exist in tautomeric forms, refer to compounds that are structural isomers that are readily interconvertible in rapid equilibrium. As used herein, the process of interconversion is referred to as "tautomerization."

[0038] For example, in the following embodiment, the pyridone tautomers can be depicted as follows: [ka] The disclosed structures are easily interchangeable between left-handed and right-handed structural representations.

[0039] A "therapeutically effective amount" is intended to encompass an amount of a compound of the invention alone, or in combination with the claimed compounds, or in combination with other active ingredients that are effective to act as inhibitors or to treat or ameliorate cancer.

[0040] The terms "treating" or "treatment" as used herein include the treatment of a condition in a mammal, particularly a human, and encompass (a) preventing the onset of the condition in a mammal, particularly where the mammal is predisposed to the condition but has not yet been diagnosed with the condition; (b) inhibiting the condition, i.e., arresting its progression; and / or alleviating the condition, i.e., regression of the condition.

[0041] The compounds of the present invention are intended to include all isotopes of atoms present in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. Common examples, without limitation, include isotopes of hydrogen, such as deuterium (D) and tritium (T). Isotopes of carbon are 13 C and 14 C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described herein, substituting appropriately isotopically labeled reagents for the unlabeled reagents otherwise utilized. For example, methyl (-CH3) also encompasses deuterated methyl groups such as -CD3.

[0042] The term "pharmaceutically acceptable salts" is intended to encompass salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found 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 contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, magnesium salts, or similar salts.

[0043] As defined herein, terms such as "inhibition," "inhibit," "inhibiting," and the like, with respect to protein-inhibitor (e.g., antagonist) interactions, 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 alleviating a disease or disease symptom. In some embodiments, inhibition refers to reducing the activity of a signal transduction pathway or a pathway that transmits a signal. Thus, inhibition encompasses at least partially, partially, or fully blocking a stimulus; reducing, preventing, or delaying activation; or inactivating, desensitizing, or downregulating signal transduction or enzymatic activity; or reducing the amount of a protein. In some embodiments, inhibition refers to reducing 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, inhibiting refers to at least partially, partially, or wholly reducing stimulation, reducing or decreasing activation, or inactivating, desensitizing, or downregulating signaling or enzymatic activity, or decreasing the amount of a protein tyrosine phosphatase, e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) or protein tyrosine phosphatase non-receptor type 1 (PTP1B).

[0044] A "patient" or "subject" in need thereof refers to an organism suffering from or susceptible to a disease or condition that can be treated by administering a compound or pharmaceutical composition provided herein. Non-limiting examples include 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 domesticated 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 bovine. In some embodiments, the patient is a canine. In some embodiments, the patient is a feline. In some embodiments, the patient is an ape. In some embodiments, the patient is a monkey. In some embodiments, the patient is a mouse. In some embodiments, the patient is a laboratory animal. In some embodiments, the patient is a rat. In some embodiments, the patient is a hamster. In some embodiments, the patient is a test animal. In some embodiments, the patient is a neonatal animal. In some embodiments, the patient is a newborn human. In some embodiments, the patient is a newborn mammal. In some embodiments, the patient is an elderly animal. In some embodiments, the patient is an elderly human. In some embodiments, the patient is an elderly mammal. In some embodiments, the patient is a geriatric patient.

[0045] A "disease," "disorder," or "condition" refers to a state or condition of a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein. In some embodiments, the compounds and methods described herein involve alleviating or eliminating one or more symptoms of a disease, disorder, or condition, e.g., through administration of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0046] As used herein, the term "signal transduction pathway" refers to a series of interactions between cellular components 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 additional components, which may then be propagated to other signal transduction pathway components, if desired.

[0047] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the administration of an active agent to a subject and its absorption by the subject, and that can be incorporated into the compositions of the present disclosure without causing significant adverse toxic effects in the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline, lactated Ringer's solution, sucrose, glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, coloring agents, and the like. Such preparations can be sterilized and, if necessary, mixed with auxiliary substances that do not adversely react with the compounds of the present disclosure, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, coloring and / or aromatic substances, and the like. Those skilled in the art will appreciate that other pharmaceutical excipients are useful in the present disclosure.

[0048] The term "formulation" is intended to include formulations of the active compound with an encapsulating material as a carrier to provide a capsule in which the active ingredient is surrounded by, and therefore coexists with, a carrier, with or without other carriers. Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets and lozenges can be used as solid dosage forms suitable for oral administration.

[0049] As used herein, the term "administering" refers to oral administration, administration by suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal, or subcutaneous administration to a patient, or implantation of a sustained-release device, e.g., a mini-osmotic pump. Administration may be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, or transdermal). 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. "Coadministration" refers to administration of a compound or composition described herein simultaneously with, immediately before, or immediately after administration of one or more additional therapeutic agents (e.g., anticancer, chemotherapeutic, or immunotherapeutic agents). The compounds or compositions described herein can be administered to a patient alone or simultaneously. Simultaneous administration is intended to include simultaneous or sequential administration of the compounds or compositions individually or in combination (with multiple compounds or drugs). Thus, formulations can also be combined with other active agents, if necessary (e.g., to reduce metabolic degradation).

[0050] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. Generally, such preparations 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, if necessary and / or desired, shaping and / or packaging the product into a desired single or multiple dosage unit. Pharmaceutical compositions may be prepared, packaged, and / or sold in bulk, as a single unit dose and / or as a plurality of single unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient will generally be equal to the dosage of the active ingredient that would be administered to a subject and / or a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.

[0051] Treatment method The present disclosure features compounds, compositions, and methods that include the compounds disclosed herein, e.g., compounds of Formula (I). In some embodiments, the compounds, compositions, and methods disclosed herein are used to prevent or treat a disease, disorder, or condition. Exemplary diseases, disorders, or conditions include, but are not limited to, cancer, type 2 diabetes, metabolic syndrome, obesity, or metabolic disease.

[0052] cancer In some embodiments, the compounds disclosed herein, e.g., compounds of Formula (I), are used to treat cancer. As used herein, "cancer" refers to human cancers and carcinomas, including solid and lymphatic cancers, sarcomas, adenocarcinomas (e.g., papillary adenocarcinoma), lymphomas, leukemias, melanomas, and the like, including cancers of the kidney, breast, lung, bladder, colon, ovary, prostate, pancreas, stomach, brain, head and neck, skin, uterus, testis, glioma, esophagus, liver cancer (including hepatocellular carcinoma), lymphomas (B-acute lymphoblastic lymphoma, non-Hodgkin's lymphoma (e.g., Burkitt's, small cell, and large cell lymphoma), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), multiple myeloma, and the like. In some further examples, "cancer" refers to lung cancer, breast cancer, ovarian cancer, epithelial ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, 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, gastric cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, or carcinoma.

[0053] Exemplary cancers that may be treated with the compounds, pharmaceutical compositions, or methods provided herein include lymphoma, B-cell lymphoma, heavy chain disease, alpha chain disease, gamma chain disease, mu chain disease, Waldenstrom's macroglobulinemia, benign monoclonal gammopathy, sarcoma, bladder cancer, bone cancer, 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, etc.), and leukemia. The cancers include, but are not limited to, HER2-positive, doxorubicin-resistant, tamoxifen-resistant, ductal carcinoma, lobular carcinoma, primary, and metastatic carcinomas of the breast, ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung adenocarcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, and sarcoma), glioblastoma multiforme, acoustic neuroma, retinoblastoma, astrocytoma, craniopharyngioma, hemangioblastoma, pinealoma, ependymoma, oligodendroglioma, meningioma, glioma, and melanoma. Additional examples include cancer of the thyroid, endocrine system, brain, breast, uterus, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelial carcinoma, ovarian cancer, sarcoma, gastric cancer, uterine cancer or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, immune cell amyloidosis, ovarian cancer, rhabdomyosarcoma, primary thrombocytoma, primary macroglobulinemia, primary brain tumor, carcinoma, malignant pancreatic insulinoma, malignant carcinoid, urethral bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, pancreatic endocrine or exocrine neoplasms, medullary thyroid carcinoma, meningeal thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, and hepatocellular carcinoma.

[0054] A first aspect of the present invention is a compound of formula (I) having the following structure: [ka] wherein, for each occurrence, independently: R 1 is 1H-1,2,4-triazol-3-yl, [ka] selected from the group consisting of: R 2 is selected from the group consisting of —H, alkyl, and substituted alkyl; R 3 is selected from the group consisting of —H, alkyl, and substituted alkyl; R 4 is selected from the group consisting of -H, alkyl, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, aryl, and substituted aryl; R 5 is selected from the group consisting of -H, alkyl, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, aryl, and substituted aryl. The present invention provides at least one compound having the formula:

[0055] In one embodiment of the compounds of formula (I), R 1 teeth [ka] selected from the group consisting of: R 3 is selected from the group consisting of -H and -CH3; R 4 are -H and -CH3.

[0056] In another embodiment of the compounds of formula (I), R 1 teeth [ka] and; R 4 is selected from the group consisting of -H and -CH3.

[0057] In another embodiment of the compounds of formula (I), R 1 teeth [ka] and; R 4 is selected from the group consisting of -H, -CH3, and 2,4-dimethylphenyl; R 5 is selected from the group consisting of -H and -CH3.

[0058] In another embodiment of the compounds of formula (I), R 1 teeth [ka] selected from the group consisting of: R 4 is selected from the group consisting of -H and -CH3.

[0059] In another embodiment of the compounds of formula (I), R 1 teeth [ka] and; R 3 is selected from the group consisting of -H and -CH3; R 4 is -H or -CH3; R 5 is -H or -CH3.

[0060] In another embodiment, the compound is 5-(4-(((4-(2,4-dimethylphenyl)thiazol-2-yl)(methyl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((1H-pyrazol-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((isoxazol-3-ylamino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-methylisoxazol-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((1H-1,2,4-triazol-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((1-methyl-1H-pyrazol-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((1,3,4-thiadiazol-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-methyl-1H-imidazol-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((thiazol-2-ylamino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((1H-imidazol-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((1-methyl-1H-imidazol-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-methyl-1,3,4-thiadiazol-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((4-methylthiazol-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((3-methylisothiazol-5-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((3-methyl-1H-pyrazol-5-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0061] In one embodiment, the present invention comprises a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0062] In another embodiment, the present invention comprises a method of treating cancer comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the cancer / disease is selected from human cancer, carcinoma, sarcoma, adenocarcinoma, papillary adenocarcinoma, lymphoma, leukemia, melanoma, solid lymphoid 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), lymphoma (including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, small cell lymphoma, Hodgkin's lymphoma), leukemia, and multiple myeloma.

[0063] In another embodiment, the present invention comprises a method of treating cancer in a patient in need thereof, comprising administering to said patient an effective amount of a compound of formula I in combination with an additional therapeutic agent. In one embodiment, the additional therapeutic agent is an immunotherapeutic agent.

[0064] In another embodiment, the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody. In one embodiment, a method of treating cancer in a patient in need thereof comprises administering to said patient an effective amount of a pharmaceutically acceptable composition of a compound of Formula I. In another embodiment, the method of treating cancer is selected from radiation therapy, surgery, chemotherapy, or administration of a biologic drug.

[0065] In one embodiment, the method of treating cancer is to administer a biologic drug, which is a drug that stimulates the immune system. In another embodiment, a method for treating cancer comprises administering to a subject an inhibitor of DGKα and / or DGKζ, an antagonist of the PD1 / PD-L1 axis, and an antagonist of CTLA4. These embodiments are not intended to limit the scope of the invention.

[0066] Synthesis method The compounds of the present invention can be prepared by the methods and examples shown below, as well as by methods known to those skilled in the art. In each of the following examples, the R group is as defined above for each formula unless otherwise specified. Optimal reaction conditions and reaction times may vary depending on the reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions can be easily selected by those skilled in the art.

[0067] The intermediates used in the syntheses below are either commercially available or readily prepared by methods known to those skilled in the art. Reaction progress can be monitored by conventional methods such as thin layer chromatography (TLC) or high pressure liquid chromatography-mass spectrometry (HPLC-MS). Intermediates and products can be purified by methods known in the art, including column chromatography, HPLC, preparative TLC, or preparative HPLC.

[0068] Preparation of the key intermediate (Int-2) in the synthesis Preparation of 5-(4-bromo-2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Int-2) as shown in Scheme 1 Scheme 1: [ka]

[0069] 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-nitrobenzene (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. The resulting mixture was stirred overnight at 70 °C under a nitrogen atmosphere. TLC showed the reaction was complete. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 × 300 mL). The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. 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-nitrobenzene (10 g, 66.8% yield), as a light yellow solid.

[0070] 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-nitrobenzene (10 g, 28.08 mmol) in ethanol (200 mL) and water (20 mL), NH4Cl (15.16 g, 280.79 mmol) and Fe (15.68 g, 280.79 mmol) were added at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere overnight. LCMS showed the reaction was complete. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on 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 light yellow solid. MS: m / z: C 14 H 13 Calculated for BrFNO2: [M+H] + 326;Measurement: 326

[0071] 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. The resulting mixture was 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 phase was dried over sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography to give the product as a mixture. The mixture was further purified by reverse-phase flash chromatography (0.05% NH4HCO3 in H2O / ACN) 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 Calculated for BrFNO4: [M+H]+ 440;Measurement:440

[0072] Step 4: Synthesis of tert-butyl N-(4-bromo-2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-N-sulfamoylglycinate (1-5) To a stirred solution of tert-butyl 2-[4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]anilino]acetate (3.3 g, 7.49 mmol) in DMA (80 mL) was added a solution of sulfamoyl chloride (2.6 g, 22.48 mmol) in DMA (4 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. LCMS showed complete consumption of the starting material. The mixture was diluted with ethyl acetate (300 mL) and washed six times with brine until the DMA was completely washed out. The organic phase 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 Calculated for BrFN2O6S: [MH] - 517; Measurement: 517

[0073] Step 5: Synthesis of 5-(4-bromo-2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Int-1) To a stirred solution of tert-butyl 2-[4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]-N-sulfamoyl-anilino]acetate (4 g, 7.70 mmol) in methanol (20 mL) was added 30% NaOMe in MeOH (8.32 g, 46.30 mmol) at 0° C. The mixture was stirred at room temperature overnight. LCMS showed complete consumption of the starting material. The mixture was concentrated. The resulting suspension was dissolved in water (200 mL) and extracted with ethyl acetate. The organic phase was separated and discarded. The aqueous layer was diluted with ethyl acetate, acidified with 1N HCl solution to pH=3, and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. 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 Calculated for BrFN2O5S: [MH] - 443; Measurement: 443

[0074] 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). The resulting mixture was purged with nitrogen for 5 minutes. The mixture was then stirred at 80 °C for 12 hours. LCMS showed that the starting material had been completely consumed. The reaction mixture was filtered, and the filtrate was directly purified by reverse-phase column chromatography 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 light yellow semi-solid. MS: m / z: C 18 H 18 Calculated value for FN2O5S: [MH] - 391; Measurement: 391

[0075] Step 7: Synthesis of 4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-((4-methoxybenzyl)oxy)benzaldehyde (Int-2) To a stirred solution of 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-vinyl-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (970 mg, 2.47 mmol), citric acid (1.04 g, 4.94 mmol), and NMO (579.18 mg, 4.94 mmol) in tert-butanol (6 mL) and water (6 mL) was added KOsO (91.07 mg, 0.25 mmol). The resulting mixture was stirred at room temperature for 1 hour. LCMS showed that the starting material was completely converted to the intermediate. Next, NaIO (1.07 mL, 7.42 mmol) was added to the mixture at 0° C. The resulting mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The reaction mixture was diluted with water and extracted four times with ethyl acetate. The organic phase 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 Calculated value for FN2O6S: [MH] - 393;Measurement: 393

[0076] Preparation of Examples Example 1: 5-[4-[[[4-(2,4-dimethylphenyl)thiazol-2-yl]-methyl-amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka]

[0077] Scheme 1: [ka]

[0078] Step 1: To a stirred solution of methanamine (70.88 mg, 2.28 mmol) and 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (Int-2, 300 mg, 0.76 mmol) in methanol (10 mL) was added acetic acid (91.36 mg, 1.52 mmol). The mixture was stirred at room temperature for 1 hour. Then, NaBHCN (191.09 mg, 3.04 mmol) was added to the reaction mixture at 0° C. The resulting mixture was stirred at room temperature for an additional 1 hour. After the reaction was complete as monitored by LCMS, the mixture was concentrated. The resulting residue was purified by reverse phase column chromatography to give 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-(methylaminomethyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (210 mg, 0.51 mmol, 67.42% yield) as a white solid. MS: m / z: C 18 H 20 Calculated for FN3O5S: [M+H] + 410;Measurement:410

[0079] Step 2: To a stirred solution of 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-(methylaminomethyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (205 mg, 0.50 mmol) and 4-bromo-2-chloro-thiazole (198.75 mg, 1 mmol) in DMSO (4 mL) was added DIEA (0.02 mL, 1.5 mmol). The mixture was stirred at 80° C. for 16 hours. LCMS showed complete consumption of the starting material. The mixture was purified by reverse phase column chromatography to give 5-[4-[[(4-bromothiazol-2-yl)-methyl-amino]methyl]-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (120 mg, 0.21 mmol, 41.94% yield) as a brown solid. MS: m / z: C 21 H 20 Calculated for BrFN4O5S2: [M+H] +571; Measurement: 571

[0080] Step 3: To a stirred solution of 5-[4-[[(4-bromothiazol-2-yl)-methyl-amino]methyl]-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (90 mg, 0.16 mmol), (2,4-dimethylphenyl)boronic acid (35.43 mg, 0.24 mmol), and NaCO (50.08 mg, 0.47 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl (38.59 mg, 0.05 mmol) under nitrogen. The resulting mixture was stirred at 80 °C for 2 hours. After completion of the reaction as monitored by LCMS, the mixture was concentrated. The resulting residue was purified by reverse phase column chromatography to give 5-[4-[[[4-(2,4-dimethylphenyl)thiazol-2-yl]-methyl-amino]methyl]-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (60 mg, 0.10 mmol, 63.84% yield) as a yellow solid. MS: m / z: C 29 H 29 Calculated for FN4O5S2: [M+H] + 597;Measurement: 597

[0081] Step 4: To a stirred solution of 5-[4-[[[4-(2,4-dimethylphenyl)thiazol-2-yl]-methyl-amino]methyl]-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (60 mg, 0.10 mmol) in DCM (3 mL), TFA (3 mL) was added, and the mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was concentrated. The resulting residue was purified by reverse-phase flash chromatography (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 (3 mg, 5.69% yield) as a green solid. MS:m / z:C 21 H 21 Calculated for FN4O4S2: [M+H] + Measurement: 477; 1 H NMR (400MHz, DMSO-d6) δ 10.36(s,1H), 7.47(d,J=7.8Hz,1H), 7.06-6.95(m,2H), 6.79(s,1H), 6.72-6 .64(m,2H), 4.67(s,2H), 4.31(s,2H), 3.09(s,3H), 2.36(s,3H), 2.28(s,3H) Preparative HPLC purification conditions: Column: Welch Ultimate AQ C18, 50*250mm, 10μm; Mobile phase A: Water (0.1% TFA), Mobile phase B: ACN; Flow rate: 100mL / min; Gradient: 40%B to 65%B, 65%B in 20min; Wavelength: 254nm

[0082] Example 2: 5-[2-fluoro-6-hydroxy-4-[(1H-pyrazol-3-ylamino)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka]

[0083] The title compound was prepared according to the preparation of Example 4 using 1H-pyrazol-3-amine in step 1 in 8.78% overall yield as a white solid. MS: m / z: C 12 H 12 Calculated for FN5O4S: [M+H] + Measurement: 342; 1 H NMR (400MHz, DMSO-d6) δ 9.39(s,1H), 7.65(s,1H), 6.60-6.50(m,3H), 3.96(s,2H), 3.62(s,2H) 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: 60mL / min; Gradient: 20%B to 40%B, 40%B in 6.5min; Wavelength: 254 / 210nm

[0084] Example 3: 5-[2-fluoro-6-hydroxy-4-[(isoxazol-3-ylamino)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka]

[0085] The title compound was prepared according to the preparation of Example 4 using isoxazol-3-amine in step 1 in 4.75% overall yield as a white solid. MS: m / z: C 12 H 11 Calculated for FN4O5S: [M+H] + Measurement: 343; 1 H NMR (400MHz, DMSO-d6) δ 8.35(d,J=1.8Hz,1H), 6.71(d,J=1.9Hz,1H), 6.66(dd,J=10.7, 1.8Hz,1H), 6.00(d,J=1.8Hz,1H), 4.20(d,J=10.8Hz,4H) 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: 60mL / min; Gradient: 40%B to 60%B, 60%B in 6.5 min; Wavelength: 254 / 210nm

[0086] Example 4: 5-[2-fluoro-6-hydroxy-4-[[(5-methylisoxazol-3-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka]

[0087] Scheme 2: [ka]

[0088] 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-methylisoxazol-3-amine (61.66 mg, 0.38 mmol) in DCM (8 mL) was added TMSOTf (84.44 mg, 0.38 mmol) at 0 °C. The reaction mixture was 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 above mixture. After the addition, the resulting 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 was observed along with 10% of the PMB-protected intermediate). TFA (10 mL) was added to the reaction mixture at 0 °C. The resulting mixture was stirred at room temperature for an additional 3 hours. LCMS showed that the PMB protecting group was totally cleaved, and the reaction mixture was concentrated. The residue was purified by reverse-phase column chromatography (0.05% NHHCO in H2O and MeCN) and further purified by preparative HPLC to give 5-[2-fluoro-6-hydroxy-4-[[(5-methylisoxazol-3-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (9 mg, 8.02% yield) as a yellow solid. MS: m / z: C 13 H 13 Calculated for FN4O5S: [M+H] + Measurement: 357; 1 H NMR (400MHz, DMSO-d6) δ 7.60(s,2H), 6.65(s,1H), 6.64-6.52(m,2H), 5.66(s,1H), 4.13(d,J=6.2Hz,2H), 3.94(d,J=2.2Hz,2H), 2.21(s,3H) Preparative HPLC purification conditions: Column: XBridge Prep Phenyl OBD column, 19*100mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 50mL / min; Gradient: 35%B to 45%B, 45%B in 8 min; Wavelength: 254 / 210nm

[0089] Example 5: 5-[2-fluoro-6-hydroxy-4-[(1H-1,2,4-triazol-3-ylamino)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka]

[0090] Scheme 3: [ka]

[0091] Step 1: To a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (Int-2, 100 mg, 0.25 mmol) and 1H-1,2,4-triazol-3-amine (34.2 mg, 0.28 mmol) in dry DMF (6 mL), TMSCl (0.08 mL, 0.62 mmol) was added dropwise at 0° C., and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was then cooled to 60° C., and a solution of BH3 in 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. LCMS indicated the reaction was complete. The resulting solution was quenched with ice water (1 ml) and directly purified by reverse phase column (0.05% NH4HCO3 in H2O and MeCN) to give 5-[2-fluoro-6-hydroxy-4-[(1H-1,2,4-triazol-3-ylamino)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one 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 20Calculated for ClFN4O5S: [M+H] + 531; Measurement: 531

[0092] Step 2: The title compound was prepared according to the preparation of Example 1 using 3-1 in Step 2 as a white solid in 5.99% yield. MS:m / z:C 11 H 11 Calculated for FN6O4S: [M+H] + Measurement: 343; 1 H NMR (400MHz, DMSO-d6+D2O) δ 6.86-6.50(m,2H), 4.23(s,2H), 3.94(s,2H) Preparative HPLC purification conditions: Column: Xbridge BEH C18 OBD preparative column, 19*250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 8% B to 20% B, 20% B in 6 min; Wavelength: 254 nm

[0093] Example 6: 5-[2-fluoro-6-hydroxy-4-[[(1-methylpyrazol-3-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka]

[0094] The title compound was prepared according to the preparation of Example 4 using 1-methylpyrazol-3-amine in step 1 in 6.93% overall yield as a white solid. MS: m / z: C 13 H 14 Calculated for FN5O4S: [M+H] + Measurement: 356; 1 H NMR (400MHz, DMSO-d6+D2O) δ 7.52-7.51(m,1H), 6.72-6.59(m,2H), 4.17(s,2H), 4.09(s,2H), 3.62(d,J=1.6Hz,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: 15%B to 28%B, 28%B in 5.5 min; Wavelength: 210 / 254nm

[0095] Example 7: 5-[2-fluoro-6-hydroxy-4-[(1,3,4-thiadiazol-2-ylamino)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka]

[0096] The title compound was prepared according to the preparation of Example 5 using 1,3,4-thiadiazol-2-amine in step 1 in 8.99% overall yield as a white solid. MS: m / z: C 11 H 10 Calculated for FN5O4S2: [M+H] + 360;Measurement:360; 1 H NMR (400MHz, DMSO-d6) δ 8.64(s,1H), 8.27(t,J=5.8Hz,1H), 6.87-6.52(m,2H), 4.39(d,J=5.8Hz,2H), 3.93(s,2H) Preparative HPLC purification conditions: Column: Xbridge BEH C18 OBD column, 19*250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 10% B to 25% B, 25% B in 7 min; Wavelength: 254 nm

[0097] Example 8: 5-[2-fluoro-6-hydroxy-4-[[(5-methyl-1H-imidazol-2-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka]

[0098] The title compound was prepared as a white solid in 7.52% overall yield according to the procedure of Example 5, using 5-methyl-1H-imidazol-2-amine hydrochloride in Step 1. MS: m / z: C 13 H 14 Calculated for FN5O4S: [M+H] + Measurement: 356; 1 H NMR (400MHz, DMSO-d6) δ 11.75(s,1H), 9.45(s,1H), 7.20(s,2H), 6.56(d,J=9.5Hz,2H), 3.99(d,J=25.2Hz,2H), 3.70(s,2H), 2.11(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: 60mL / min; Gradient: 22%B to 40%B, 45%B in 7 min; Wavelength: 254 / 210nm

[0099] Example 9: 5-[2-fluoro-6-hydroxy-4-[(thiazol-2-ylamino)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka]

[0100] Scheme 4: [ka]

[0101] 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 (60 mg, 0.15 mmol) and thiazol-2-amine (36 mg, 0.36 mmol) in DCE (10 mL) was added Ti(i-PrO) (172.83 mg, 0.61 mmol) at 0 °C. The resulting mixture was stirred at 60 °C for 12 h. NaBHCN (19.47, 0.30 mmol) was added to the mixture at 0 °C. The resulting mixture was stirred at room temperature for an additional 2 h. After completion, the reaction mixture was concentrated. The resulting residue was dissolved in DMSO and purified directly by reverse-phase column (0.05% TFA in HO and MeCN) to give 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-[(thiazol-2-ylamino)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (70.0 mg, 0.14 mmol, 96.15% yield) as a white solid. MS: m / z: C 20 H 19 Calculated for FN4O5S2: [M+H] + 479;Measurement:479

[0102] Step 2: To a stirred solution of 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-[(thiazol-2-ylamino)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (70 mg, 0.15 mmol) in DCM (6 mL) was added TFA (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. After completion, the reaction mixture was concentrated. The resulting residue was purified by reverse-phase column chromatography (0.05% TFA in HO and MeCN) and further purified by preparative HPLC to give 5-[2-fluoro-6-hydroxy-4-[(thiazol-2-ylamino)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (5.7 mg, 0.01 mmol, 10.64% yield) as a brown solid. MS: m / z: C 12 H 11 Calculated for FN4O4S2: [M+H]+ Measurement: 359; 1 H NMR (400MHz, DMSO-d6) δ 7.13(t,J=3.6Hz,1H), 6.79-6.74(m,1H), 6.66(d,J=12.0Hz,2H), 4.40(s,2H), 4.01(d,J=2.2Hz,2H) Preparative HPLC purification conditions: Column: XBridge Shield RP18 OBD column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 5%B to 35%B, 35%B in 8 min; Wavelength: 254 / 210nm

[0103] Example 10: 5-[2-fluoro-6-hydroxy-4-[(1H-imidazol-2-ylamino)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka]

[0104] The title compound was prepared according to the preparation of Example 5 using 1H-imidazol-2-amine in step 1 in 8.56% overall yield as a white solid. MS: m / z: calculated for C12H12FN5O4S: [M+H] + Measurement: 342; 1 H NMR (400MHz, DMSO-d6+D2O) δ 6.86(s,2H), 6.70(d,J=8.4Hz,2H), 4.38(s,2H), 4.06(s,2H) 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: 60mL / min; Gradient: 10%B to 30%B, 30%B in 6.59min; Wavelength: 254 / 210nm

[0105] Example 11: 5-[2-fluoro-6-hydroxy-4-[[(1-methylimidazol-2-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka]

[0106] Scheme 5: [ka]

[0107] Step 1: To a solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (80 mg, 0.2 mmol) and 1-methylimidazol-2-amine (39.4 mg, 0.41 mmol) in dichloromethane (8 mL) was added a solution of titanium tetraisopropanolate (115.63 mg, 0.41 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. NaBH(AcO) (38.95 mg, 0.41 mmol) was added to the mixture at 0° C. The resulting mixture was stirred at room temperature for an additional 30 minutes. After completion, the reaction mixture was concentrated. The resulting residue was dissolved in DMSO and purified by reverse phase column (0.05% NHHCO in H2O and MeCN) to give 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-[[(1-methylimidazol-2-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (60 mg, 62.5% yield). MS: m / z: C 21 H 22 Calculated for FN5O5S: [M+H] + 476;Measurement:476

[0108] Step 2: The title compound was prepared as a white solid in 30.50% yield using 16-1 in Step 2 according to the preparation of Example 1. MS: m / z: C 13 H 14Calculated for FN5O4S: [M+H] + Measurement: 356; 1 H NMR (400MHz, DMSO-d6) δ 12.40(s,1H), 9.57(s,1H), 8.43(t,J=6.1Hz,1H), 7.10(d,J=2.4Hz,1H), 7.05(d,J= 2.4Hz,1H), 6.73(d,J=11.1Hz,2H), 4.45(d,J=6.1Hz,2H), 3.98(s,2H), 3.54(s,3H)

[0109] 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: 23%B to 45%B, 45%B in 5 min; Wavelength: 210 / 254nm

[0110] Example 12: 5-[2-fluoro-6-hydroxy-4-[[(5-methyl-1,3,4-thiadiazol-2-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka]

[0111] Scheme 6: [ka]

[0112] Step 1: To a stirred mixture of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (50 mg, 0.13 mmol) and 5-methyl-1,3,4-thiadiazol-2-amine (14.6 mg, 0.13 mmol) in DCE (5 mL), TiCl(i-PrO) (65.93 mg, 0.25 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 12 hours. NaBHCN (23.86 mg, 0.38 mmol) was added to the above mixture at 0 °C. The resulting mixture was stirred at room temperature for an additional hour. The reaction mixture was directly purified by reverse-phase column chromatography (0.05% TFA in HO and MeCN) to give 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-[[(5-methyl-1,3,4-thiadiazol-2-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (50 mg of TFA salt, 0.10 mmol, 79.90% yield) as an off-white oil. MS: m / z: C 20 H 20 Calculated for FN5O5S2: [M+H] + 494;Measurement:494

[0113] Step 2: To a stirred mixture of 5-[2-fluoro-6-[(4-methoxyphenyl) methoxy]-4-[(1,3,4-thiadiazol-2-ylamino)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (45 mg, 0.09 mmol) in DCM (4 mL) was added TFA (4 mL) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction was monitored by LCMS, the mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give 5-[2-fluoro-6-hydroxy-4-[[(5-methyl-1,3,4-thiadiazol-2-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (6.6 mg, 0.01 mmol, 18.17% yield) as a white solid. MS: m / z: C 12 H 12Calculated for FN5O4S2: [M+H] + Measurement: 374; 1 H NMR (400MHz, DMSO-d6+D2O) δ 7.58-7.50(m,1H), 6.82-6.48(m,5H), 4.38(s,2H), 3.94(s,2H)

[0114] Preparative HPLC purification conditions: Column: Xbridge-Prep OBD C18 column, 19*250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 28% B to 48% B, 48% B in 6 min; Wavelength: 254 / 210 nm

[0115] Example 13: 5-[2-fluoro-6-hydroxy-4-[[(4-methylthiazol-2-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka]

[0116] The title compound was prepared as a white solid in 14.16% overall yield using 4-methylthiazol-2-amine in step 1 according to the preparation of Example 9. After adding NaBH3CN, the reaction was carried out at 80°C instead of room temperature. MS: m / z: C 13 H 13 Calculated for FN4O4S2: [M+H] + Measurement: 373; 1 H NMR (400MHz, DMSO-d6) δ 6.71-6.58(m,2H), 6.22(d,J=1.3Hz,1H), 4.32(s,2H), 3.99(s,2H), 2.07(s,3H)

[0117] Preparative HPLC purification conditions: Column: Xbridge-Shield RP18 OBD column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 55%B to 75%B, 75%B in 8 min; Wavelength: 254 / 210nm

[0118] Example 14: 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-[[(3-methylisothiazol-5-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka]

[0119] The title compound was prepared according to the preparation of Example 4 using 3-methylisothiazol-5-amine in step 1 in 7.31% overall yield as a white solid. MS: m / z: C 13 H 13 Calculated for FN4O4S2: [M+H] + Measurement: 373; 1 H NMR (400MHz, DMSO-d6) δ 10.37(s,1H), 7.80(s,1H), 6.78-6.62(m,2H), 6.03(s,1H), 4.34(s,2H), 4.23(s,2H), 2.16(s,3H) Purification conditions: The compound was purified by reverse phase column chromatography (0.05% NH4HCO3 in H2O and MeCN).

[0120] Example 15: 5-[2-fluoro-6-hydroxy-4-[[(3-methyl-1H-pyrazol-5-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka]

[0121] The title compound was prepared according to the preparation of Example 9 using 5-methyl-1H-pyrazol-3-amine in step 1 in 12.20% overall yield as a white solid. MS: m / z: C 13 H 14 Calculated for FN5O4S: [M+H] + Measurement: 356; 1 H NMR (400MHz, DMSO-d6) δ 13.8-12.8(m,1H), 9.60(s,1H), 7.47(s,1H), 6.63(d,J=12.5Hz,2H), 5.60(s,1H), 4.22(s,2H), 3.99(s,2H), 2.19(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: 60mL / min; Gradient: 40%B to 60%B, 60%B in 6.58min; Wavelength: 254 / 210nm

[0122] Example compounds prepared by the above procedures are listed in Table 1. Examples of compounds produced Table 1

[0123] [Table 1] [Table 2]

[0124] 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 exemplary biological assays have been carried out with the compounds of this invention.

[0125] Assay The PhosphoSens® kinase assay was performed according to the supplier's instructions (AssayQuant Technologies, Marlborough, MA). Briefly, 1000X solutions of compounds were prepared in DMSO by serially diluting 10 mM DMSO stocks at 3-fold intervals in a 384-well reagent plate. 50 nL of the serially diluted compounds were then added to the corresponding wells of a 384-well assay plate. A mixture (40 mL) of 1.25X substrate (AQT0264) in 1X assay buffer (50 mM HEPES pH 7.5, 500 μM EGTA, 10 nM MgCl2, 0.01% Brij-35, 1% glycerol, 1 mM DTT, and 0.2 mg / mL BSA) was transferred to each well of the assay plate, resulting in a final substrate concentration of 20 μM. Finally, 10 mL of 5X PTPN2 enzyme stock was added to each well of the assay plate to give a final enzyme concentration of 150 pM. Reaction progress curves were measured using a Synergy H4 plate reader (BioTek Instruments / Agilent Technologies, Winooski, VT) at room temperature with an excitation wavelength of 360 nm (λ ex 360) and emission wavelength 480 nm (λ em The data was generated by sampling the fluorescence intensity of 480 every 71 seconds for 1 hour.

[0126] Assay of phosphotase activity using DiFMUP as a substrate A 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 a 1X reaction buffer consisting of 50 mM HEPES (pH 7.4), 1 mM EDTA, 150 mM NaCl, 0.2 mg / mL BSA, 100 U / mL catalase, and 10 mM DTT. For a final concentration of 25 mM DiFMUP substrate, 40 mL of DiFMUP substrate solution was added to a Corning 3574 384-well white, non-binding surface microtiter plate containing 0.05 mL of serially diluted test compounds prepared in DMSO. The reaction was initiated by adding 10 mL of enzyme solution for a final concentration of 0.15 nM PTPN2, and the reaction was monitored at λ 0.05 in a BioTek Synergy HTX plate reader (Agilent Technologies, Santa Clara, CA). EX 360 / λ EM The cells were monitored at room temperature for 60 minutes at 460°C every 105 seconds. The initial linear portion of the progress curve was fitted according to a linear equation to obtain the slope, and the activity of the control treated without inhibitor was set at 100% and converted to % inhibition. The IC of each compound 50 Values ​​were obtained by fitting % inhibition versus compound concentration curves using Dotmatics software (Dotmatics Ltd., Bishops Stortford, Hertfordshire, England).

[0127] Cell proliferation assay protocol B16-F10 cells (ATCC, Manassas, VA, #CRL-6475) were cultured in DMEM growth medium (ThermoFisher Scientific, Waltham, MA, #11995-040) supplemented with 10% heat-inactivated FBS (ThermoFisher Scientific, #16140-071) and 1% penicillin / streptomycin (ThermoFisher Scientific, #15140-122). Cells were seeded at a density of 100 cells / well in two white, opaque, 384-well tissue-culture-treated microplates (PerkinElmer, Waltham, MA, #6007688) in a total volume of 20 μL and incubated overnight at 37°C and 5% CO. Next, 30 nL of compound dissolved in DMSO was transferred from the source plate to the target wells using an Echo 650 acoustic liquid handler (Beckman Coulter, Indianapolis, IN). Negative control wells received 30 nL of DMSO alone (0.15% final concentration). The plate was returned to the incubator for 1 hour, and then the cells were treated with either 5 μL of growth medium or 5 μL of growth medium containing 50 ng / mL recombinant mouse IFN-gamma protein (R&D Systems, Minneapolis, MN, #485-MI / CF, 10 ng / mL final concentration) using an assisted automated pipetting platform (INTEGRA Biosciences, Hudson, NH). Plates were incubated at 37°C for 4 days, and cell proliferation was assayed using CellTiter-Glo reagent (Promega, Madison, WI, #G7573, 25 μL per well). Luminescent signal intensities were collected using an EnVision 2105 plate reader (PerkinElmer) 15 min after addition of CellTiter-Glo reagent and analyzed using the Dotmatics software platform to determine the IC values ​​of compounds. 50 Off-target compound-mediated cytotoxicity was identified by checking growth inhibition in the absence of IFNg.

[0128] Phospho-STAT1 assay protocol B16-F10 cells (ATCC, Manassas, VA, #CRL-6475) were cultured in DMEM growth medium (ThermoFisher Scientific, Waltham, MA, #11995-040) supplemented with 10% heat-inactivated FBS (ThermoFisher Scientific, #16140-071) and 1% penicillin / streptomycin (ThermoFisher Scientific, #15140-122). Cells were seeded at a density of 10,000 cells / well in a total volume of 20 μL into white, opaque, 384-well tissue-culture-treated microplates (PerkinElmer, Waltham, MA, #6007688) and incubated overnight at 37°C and 5% CO. Next, 30 nL of compound dissolved in DMSO was transferred from the source plate to the target wells using an Echo 650 acoustic liquid handler (Beckman Coulter, Indianapolis, IN). Negative control wells received 30 nL of DMSO alone (0.15% final concentration). The plate was returned to the incubator for 1 hour, after which the cells were treated with either 5 μL of growth medium or 5 μL of growth medium containing 500 ng / mL recombinant mouse IFN-gamma protein (R&D Systems, Minneapolis, MN, #485-MI / CF, 100 ng / mL final concentration) using an assisted automated pipetting platform (INTEGRA Biosciences, Hudson, NH). Plates were incubated at 37°C for 1 hour, and STAT1 protein phosphorylation levels were assayed using a phospho-STAT1 (Tyr701) HTRF kit (Cisbio, Bedford, MA, #63ADK026PEH) according to the manufacturer's instructions. HTRF signal intensities were collected after 24 hours using an EnVision 2105 plate reader (PerkinElmer) and analyzed using the Dotmatics software platform to determine the IC values ​​of compounds. 50 The value was calculated.

[0129] Biological Assay Data Table 2 summarizes the biological assay data for the prepared examples / embodiments. IC 50 For data, high DDT concentration and / or DiFMUP substrate assays were used; either assay can be used by one skilled in the art. Rows or columns with double asterisks indicate that one IC50 value or embodiment was provided.

[0130] Table 2 [Table 3] [Table 4] [Table 5]

Claims

1. The following structural formula (I): 【Chemistry 1】 wherein, for each occurrence, independently: R １ is 1H-1,2,4-triazol-3-yl, 【Chemistry 2】 selected from the group consisting of: R ２ is selected from the group consisting of —H, alkyl, and substituted alkyl; R ３ is selected from the group consisting of —H, alkyl, and substituted alkyl; R ４ is selected from the group consisting of —H, alkyl, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, aryl, and substituted aryl; R ５ is selected from the group consisting of -H, alkyl, substituted alkyl, branched alkyl, alkoxy, halogen, cyano, amine, hydroxy, aryl, and substituted aryl. A compound represented by the formula:

2. R １ but, 【Transformation 3】 selected from the group consisting of: R ３ is -H and -CH ３ selected from the group consisting of: R ４ is -H or -CH ３ is The compound according to claim 1.

3. R １ but 【Chemistry 4】 and R ４ is -H and -CH ３ selected from the group consisting of The compound according to claim 1.

4. R １ but 【Transformation 5】 and R ４ But -H, -CH ３ and 2,4-dimethylphenyl; R ５ is -H and -CH ３ selected from the group consisting of The compound according to claim 1.

5. R １ but 【Transformation 6】 selected from the group consisting of: R ４ is -H and -CH ３ selected from the group consisting of The compound according to claim 1.

6. R １ but 【Transformation 7】 and R ３ is -H and -CH ３ selected from the group consisting of: R ４ is -H or -CH ３ and R ５ is -H or -CH ３ is The compound according to claim 1.

7. 5-(4-(((4-(2,4-dimethylphenyl)thiazol-2-yl)(methyl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((1H-pyrazol-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((isoxazol-3-ylamino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-methylisoxazol-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((1H-1,2,4-triazol-3-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((1-methyl-1H-pyrazol-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((1,3,4-thiadiazol-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-methyl-1H-imidazol-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((thiazol-2-ylamino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((1H-imidazol-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((1-methyl-1H-imidazol-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((5-methyl-1,3,4-thiadiazol-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((4-methylthiazol-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((3-methylisothiazol-5-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(((3-methyl-1H-pyrazol-5-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 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) of claim 1, or a pharmaceutically acceptable salt thereof, wherein the cancer / disease is selected from human cancer, carcinoma, sarcoma, adenocarcinoma, papillary adenocarcinoma, lymphoma, leukemia, melanoma, solid lymphoid cancer, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, liver cancer (including hepatocellular carcinoma), lymphoma (including B-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 said patient an effective amount of a compound of claim 1 in combination with an additional therapeutic agent.

11. 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 said patient an effective amount of the pharmaceutically acceptable composition of claim 1.

14. 10. The method of claim 1, wherein the cancer treatment method is selected from radiation therapy, surgery, chemotherapy, or administration of a biological drug.

15. 15. The method of claim 14, wherein the method for treating cancer further comprises administering a biological drug, the biological drug being a drug that stimulates the immune system.

16. The method of claim 15, further comprising administering to the subject an inhibitor of DGKα and / or DGKζ, an antagonist of the PD1 / PD-L1 axis, and an antagonist of CTLA4.

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