Protein tyrosine phosphatase inhibitors, compositions and methods of use

Abstract

Disclosed are compounds of Formula (I), pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, and methods of using the same as protein tyrosine phosphatase (PTPN2) inhibitors. These compounds are useful in the treatment of cancers and diseases susceptible to PTPN2 inhibition. # imgabs0 #

Description

[0001] Cross - reference to related applications

[0002] This application claims the priority of U.S. Provisional Application Serial No. 63 / 383,005, filed on November 9, 2022, the entire content of which is incorporated herein by reference. Technical field

[0003] This application discloses compounds, their pharmaceutically acceptable salts, their pharmaceutical compositions and combinations, and methods of using them as inhibitors of protein tyrosine phosphatases. Background of the invention

[0005] Immune checkpoint blockade (ICB) is an innovative immunotherapy that targets immune evasion mechanisms to improve the clinical response of cancer patients. For example, in the treatment of various types of cancer, checkpoint - blocking antibodies target cytotoxic T lymphocyte antigen 4 (CTLA - 4), programmed cell death 1 (PD - 1) and its ligands, such as programmed cell death ligand 1 (PD - L1), thus significantly improving the treatment and survival outcomes of patients with these malignancies.

[0006] However, most patients receiving ICB treatment are either resistant to the treatment or eventually develop drug resistance. Specifically, mutations or deletions in the interferon - γ (IFNγ) signaling pathway are an important mechanism of clinical ICB resistance (Zaretsky, N. Engl. J. Med. 375, 819 - 829). IFNγ is a T - cell - derived cytokine that directly restricts tumor growth via Janus kinase / signal transducer and activator of transcription (JAK / STAT) signaling. In addition, IFNγ indirectly restricts tumor growth by promoting the up - regulation of major histocompatibility complex class I (MHC - I), thereby enabling the presentation of antigens (Ag) to T cells. In vivo CRISPR screening using syngeneic mouse models has revealed the enrichment of the IFNγ pathway in anti - PD - 1 - resistant tumors. These studies have identified the above - mentioned IFNγ pathway members (JAK1 / 2 and STAT1) and interferon - γ receptors (IFNGR1 / IFNGR2) as resistance targets, and have also discovered some newly identified negative regulators, such as PTPN2 and Apelin receptor (APLNR), which represent new therapeutic targets (Charles Sinclair et al., Emerg Top LifeSci. (2021) 5(5):675 - 680).

[0007] Summary data from in vivo gene screening using CRISPR-Cas9 genome editing technology to identify genes contributing to checkpoint blockade resistance indicate that deletion of the protein tyrosine phosphatase (PTPN2) gene in tumor cells can enhance the efficacy of immunotherapy. The PTPN2 gene encodes a protein tyrosine phosphatase that regulates a range of intracellular processes. Deletion of PTPN2 in tumor cells promotes amplification of IFNγ signaling, antigen presentation to T cells, and growth arrest in response to cytokines; these data suggest that PTPN2 therapeutic inhibition may enhance the effectiveness of immunotherapies that elicit an IFNγ response (Manguso, Robert T et al., Nature Vol. 547, 7664 (2017):413-418).

[0008] Non-receptor protein tyrosine phosphatase 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 controls diverse cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is widely 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, expression of PTPN2 is controlled post-transcriptionally by two splice variants: one is a 45 kDa splice variant that contains a nuclear localization signal at the C-terminus upstream of the splice junction; the other is a typical 48 kDa splice variant that contains an endoplasmic reticulum retention motif at the C-terminus (Tillmann U. et al., Mol Cell Biol (1994) 14:3030-3040). Under certain cellular stress conditions, the 45 kDa isoform can be passively transported to the cytosol. Both isoforms possess an N-terminal phosphotyrosine phosphatase catalytic domain and, as a key negative regulator of the JAK-STAT pathway, PTPN2 directly regulates signal transduction through cytokine receptors. The PTPN2 catalytic domain has 74% sequence homology with PTPN1 (also known as PTP1B) and has similar enzyme kinetics (Romsicki Y. et al., Arch Biochem Biophys (2003) 414:40-50).

[0009] The T cell protein tyrosine phosphatase PTPN2 has been further confirmed as a key negative regulator of TCR signaling, thus highlighting the 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, thereby regulating T cell responses. PTPN2 deficiency has been shown to lower the threshold of TCR-dependent CD8 + T cell proliferation in vivo. Consistent with these findings, T cell-specific PTPN2-deficient mice have been shown to develop widespread inflammation and autoimmunity. This autoimmunity is associated with increased levels of pro-inflammatory cytokines in the serum, increased anti-nuclear antibodies, T cell infiltration in non-lymphoid tissues, and liver disease. These data further suggest that PTPN2 is a key negative regulator of TCR signaling that sets the threshold of TCR-induced naive T cell responses to prevent autoimmune and inflammatory diseases.

[0010] In addition to PTPN2 encoding T cell PTP (TCPTP) as a susceptibility gene locus for autoimmune diseases, SNPs in PTPN2 are also associated with the development of type 1 diabetes, rheumatoid arthritis, and Crohn's disease. Furthermore, the type 1 diabetes-related PTPN2 variant rs1893217 (C) is also associated with reduced PTPN2 expression in T cells (Florian Wiede, J Clin Invest. 2011; 121(12):4758-4774).

[0011] The above research results indicate that inhibiting PTPN2 is a potential therapeutic strategy to improve the efficacy of cancer treatment regimens related to ICB resistance. Summary of the Invention

[0013] The present invention relates to compounds, their pharmaceutically acceptable salts, their pharmaceutical compositions, and combinations thereof, which are potent inhibitors of protein tyrosine phosphatases, such as non-receptor protein tyrosine phosphatase type 2 (PTPN2) and / or non-receptor protein tyrosine phosphatase type 1 (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B). The present invention further provides methods for treating, preventing, or ameliorating cancer, including administering to an individual in need an effective amount of a PTPN2 / PTPN1 inhibitor disclosed herein. In a preferred embodiment, the compounds have a monocyclic core structure compared to the compounds reported in the literature, wherein the compounds contain a fused bicyclic core.

[0014] In some embodiments, inhibitors of a protein tyrosine phosphatase (such as PTPN2 and / or PTP1B) are disclosed herein, which comprise the compounds disclosed herein, such as the compounds of formula (I). In other embodiments, methods of treating a disease or disorder are disclosed herein, such as cancer, type 2 diabetes, obesity, metabolic diseases or any other disease, disorder or ailment that responds favorably to treatment with a PTPN2 or PTP1B inhibitor, including administering an effective amount of the compounds disclosed herein, such as the compounds of formula (I). These and other features of the invention will be set forth in expanded form in the present invention.

[0015] The first aspect of the invention provides at least one compound of formula (I) having the following structure:

[0016]

[0017] Wherein, each occurrence independently:

[0018] R 1 is selected from 6-oxo-1,6-dihydropyridin-2-yl,

[0019]

[0020] R 2 is selected from -H, cycloalkyl, alkyl and substituted alkyl;

[0021] R 3 is selected from -H, alkyl, halogen, -CN, -OCH 3 , cycloalkyl, -CF 3 , -C(CH 3 ) 2 R 7 is selected from aryl, substituted alkyl, alkoxy, -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -OCF 3 , -OH and benzyloxy; R 4 is selected from -H, alkyl, substituted alkyl, amine, secondary amine, tertiary amine, -CHF 2 , halogen, -CN,

[0022] -OCH 3 , -N(CH 3 ) 2 , -OCHF 2 , alkoxy, -NHCH 3 , -OH, -CH 2 CH 3 and morpholin-4-yl;

[0023] R5 Selected from -H, alkyl, substituted alkyl, alkoxy, amine, secondary amine, tertiary amine, halogen, -CH 2 CH 3 ,

[0024] -CN, -OCH 3 , -N(CH 3 ) 2 , -NHCH 3 , cyclopropyl, cyclopropoxy, cyclohexyl, -CF 3 ,

[0025] -OH, -Ph, -CH 2 CH 3 , and

[0026]

[0027] R 6 Selected from -H, alkyl, -CH 2 CH 3 , -OCH 3 , -OH and -CF 3 ;

[0028] R 7 Selected from -H and -CH 3 ;

[0029] R 8 Selected from -O- and -CH 2 O-.

[0030] Further disclosed are compounds selected from the following:

[0031] 5-(4-(((4-Cyclopropylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0032] 5-(2-Fluoro-6-hydroxy-4-(((4-(trifluoromethyl)pyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0033] 5-(2-Fluoro-6-hydroxy-4-(((3-(trifluoromethyl)pyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0034] 5-(4-(((5-(tert-Butyl)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0035] 5-(4-(((4,6-Dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0036] 5-(4-(((4-Cyclopropoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0037] 5-(2-Fluoro-6-hydroxy-4-(((4-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0038] 5-(2-Fluoro-6-hydroxy-4-(((5-phenylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0039] 5-(2-Fluoro-6-hydroxy-4-(((4-methoxy-5-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0040] 5-(4-(((5-Cyclopropylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0041] 2-((4-(1,1-Dioxo-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)isonicotinonitrile;

[0042] 5-(2-Fluoro-6-hydroxy-4-(((4-methoxypyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0043] 5-(4-(((4-Ethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0044] 5-(2-Fluoro-6-hydroxy-4-(((5-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0045] 5-(2-Fluoro-6-hydroxy-4-(((3-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0046] 5-(2-Fluoro-4-(((4-fluoropyridin-2-yl)amino)methyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0047] 5-(2-Fluoro-6-hydroxy-4-(((6-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0048] 5-(4-(((4,6-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0049] 5-(4-(((5,6-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0050] 5-(4-(((3,6-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0051] 5-[4-[[(3,6-dimethoxy-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidine-3-one;

[0052] 5-(2-Fluoro-6-hydroxy-4-(((3-methoxy-6-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0053] 5-(4-(((3-ethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0054] 5-(4-(((3,5-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0055] 5-(4-(((3,4-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0056] 5-(4-(((4,5-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0057] 5-(4-(((3,4-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0058] 5-(4-(((4,5-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0059] 5-(2-fluoro-6-hydroxy-4-(((6-methoxy-3-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0060] 5-(4-(((3,5-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0061] 5-(2-fluoro-4-(((5-fluoro-4-methylpyridin-2-yl)amino)methyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0062] 6-((4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)-4-methylnicotinonitrile;

[0063] 5-(2-fluoro-4-(((4-fluoro-5-methylpyridin-2-yl)amino)methyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0064] 5-(2-fluoro-6-hydroxy-4-(((3-methoxypyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0065] 5-(2-fluoro-6-hydroxy-4-(((6-methoxypyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0066] 5-(4-(((5,6-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0067] 5-(2-fluoro-6-hydroxy-4-((pyridin-2-ylamino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0068] 5-(2-Fluoro-6-hydroxy-4-(((5-methoxypyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0069] 5-(2-Fluoro-6-hydroxy-4-(((6-methoxy-4-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0070] 6-((4-(1,1-Dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)cyanopyridine;

[0071] 5-(2-Fluoro-6-hydroxy-4-(((4-methoxy-6-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0072] 5-(4-(((6-(Difluoromethyl)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0073] 5-(4-(((6-(Difluoromethoxy)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0074] 5-(4-(((6-(Dimethylamino)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0075] 5-(2-Fluoro-6-hydroxy-4-(((5-isopropylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0076] 5-(4-(((4-(Benzyloxy)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0077] 5-(4-(((5-(Benzyloxy)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0078] 5-(4-(((6-Bromo-4-methylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0079] 5-(2-Fluoro-6-hydroxy-4-(((4-methyl-6-(morpholin-4-yl)pyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0080] 5-(4-((Cyclopropyl(5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0081] 5-(2-Fluoro-6-hydroxy-4-(((6-oxo-1,6-dihydropyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0082] 5-(2-Fluoro-6-hydroxy-4-(((6-methyl-4-phenoxypyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0083] or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, a compound of formula (I) is formulated into a pharmaceutically acceptable composition comprising the compound of formula (I) and a pharmaceutically acceptable carrier.

[0085] 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 combination of a compound of formula (I) disclosed herein and 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.

[0086] 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, such as a compound of formula (I).

[0087] Further disclosed herein is a method of treating a metabolic disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, such as a compound of formula (I).

[0088] In some embodiments, the method comprises treating cancer. In some embodiments, the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, melanoma or secretory cell carcinoma.

[0089] Also disclosed herein is a composition for treating cancer in a patient in need thereof, wherein the composition comprises a combination of a compound disclosed herein (such as a compound of formula (I)) and 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 anti-PD-1 antibodies and anti-PD-L1 antibodies.

[0090] The present disclosure further provides a composition for treating a metabolic disease in a patient in need thereof, wherein the composition comprises a compound disclosed herein, such as a compound of formula (I). Detailed Description of the Invention

[0092] The present invention relates to compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, which are potent inhibitors of protein tyrosine phosphatases, such as non-receptor protein tyrosine phosphatase type 2 (PTPN2) and / or non-receptor protein tyrosine phosphatase 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 an individual in need thereof an effective amount of a PTPN2 / PTPN1 inhibitor disclosed herein. In a preferred embodiment, the compounds have a monocyclic core structure and contain a fused bicyclic core as compared to the compounds reported in the literature.

[0093] Definitions

[0094] Chemical Definitions

[0095] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition, and specific functional groups are generally defined as described therein. In addition, 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.

[0096] The abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and chemical formulas listed herein are constructed in accordance with the standard chemical valence rules known in the chemical art.

[0097] The compounds described herein may contain one or more asymmetric centers and thus may exist in various isomeric forms, such as 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 separated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the 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 at page 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure also encompasses the compounds described herein in the form of individual isomers or mixtures of multiple isomers that are substantially free of other isomers.

[0098] In the compositions provided herein, enantiomerically pure compounds may coexist with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R-compound may contain, for example, approximately 90% excipient and approximately 10% enantiomerically pure R-compound.

[0099] Those skilled in the art can more readily understand the features and advantages of the invention described in the present disclosure by the following definitions. Certain features of the invention described in the context of separate embodiments may also be combined to form a single embodiment, or extrapolated to include multiple embodiments. The embodiments identified herein as exemplary or preferred are illustrative and not restrictive.

[0100] Unless otherwise expressly stated herein, the singular forms also include the plural forms. For example, "a" can mean one or one or more.

[0101] As used herein, the phrase "compound" refers to at least one compound. For example, the compounds of formula (I) include one compound of formula (I) and two or more compounds of formula (I).

[0102] Unless otherwise specified, any heteroatom with unsatisfied valency is assumed to have hydrogen atoms sufficient to satisfy the valency.

[0103] The definitions set forth herein take precedence over the definitions set forth in any patent, patent application, and / or patent application publication incorporated herein by reference.

[0104] The following are definitions of various terms used to describe the present invention. These definitions apply to the terms used throughout the specification (unless otherwise limited in specific instances), whether used alone or as part of a larger group.

[0105] Throughout the specification, those skilled in the art can select groups and their substituents to provide stable moieties and compounds.

[0106] In accordance with the convention in the art, the following is used in the structural formulas herein to describe the bonds that serve as the attachment points of moieties or substituents to the core or backbone structure.

[0107] As used herein, the terms "halo" and "halogenated" refer to F, Cl, Br, and I.

[0108] The term "cyano" refers to the group -CN.

[0109] The term "amino" refers to the group -NH 2 .

[0110] The term "oxo" refers to the group =O.

[0111] As used herein, the term "alkyl" refers to branched and straight-chain saturated aliphatic hydrocarbon groups containing, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms. Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, and tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When a number appears in subscript form 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" represents straight-chain and branched-chain alkyls having one to six carbon atoms.

[0112] As used herein, the term "fluoroalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4"Fluoroalkyl" is intended to include C substituted by one or more fluorine atoms 1 , C 2 , C 3 and C 4 alkyl. Representative examples of fluoroalkyl include, but are not limited to, -CF 3 and -CH 2 CF 3 .

[0113] The term "cyanoalkyl" includes branched and straight-chain saturated alkyls substituted by one or more cyano groups. By way of example, "cyanoalkyl" includes -CH 2 CN, -CH 2 CH 2 CN and C 1-4 cyanoalkyl.

[0114] The term "aminoalkyl" includes branched and straight-chain saturated alkyls substituted by one or more amino groups. By way of example, "aminoalkyl" includes -CH 2 NH 2 , -CH 2 CH 2 NH 2 and C 1-4 aminoalkyl.

[0115] The term "hydroxyalkyl" includes branched and straight-chain saturated alkyls substituted by one or more hydroxy groups. By way of example, "hydroxyalkyl" includes -CH 2 OH, -CH 2 CH 2 OH and C 1-4 hydroxyalkyl.

[0116] The term "hydroxy-fluoroalkyl" includes branched and straight-chain saturated alkyls substituted by one or more hydroxy groups and one or more fluorine atoms. By way of example, "hydroxy-fluoroalkyl" includes -CHFCH 2 OH, -CH 2 CHFC(CH 3 ) 2 OH and C 1-4 hydroxy-fluoroalkyl.

[0117] As used herein, the terms "cycloalkyl", "carbocyclic" and "carbocyclic group" refer to groups derived from non-aromatic monocyclic or polycyclic hydrocarbon molecules by removing a hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl and cyclohexyl. When a number appears in subscript form after the symbol "C", the subscript more specifically defines the number of carbon atoms that a particular cycloalkyl may contain. By way of example, "C 3 -C 6 cycloalkyl" denotes a cycloalkyl having three to six carbon atoms.

[0118] As used herein, the term "heterocycle" refers to an organic compound having a cyclic structure with both carbon atoms and non-carbon atoms (such as oxygen, nitrogen).

[0119] As used herein, the term "alkoxy" refers to an alkyl group attached to a parent molecular moiety via an oxygen atom, such as methoxy (-OCH 3 ). For example, "C 1-3 alkoxy" represents an alkoxy group having one to three carbon atoms.

[0120] As used herein, the term "alkoxyalkyl" refers to an alkoxy group attached to an alkyl group via its oxygen atom, and the alkyl group is attached to a parent molecular moiety, such as methoxymethyl (-CH 2 OCH 3 ). For example, "C 2-4 alkoxyalkyl" represents an alkoxyalkyl group having two to four carbon atoms, such as -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 OCH 2 CH 3 and -CH 2 CH 2 OCH 2 CH 3 .

[0121] As used herein, the term "amine" refers to a compound in which a nitrogen atom is directly bonded to a number of carbon atoms. Specific examples include derivatives of ammonia (-NH 3 ) produced by successive replacement of three hydrogen atoms by hydrocarbon groups. Depending on the number of carbons bonded to the nitrogen atom, amines are classified as primary (1°), secondary (2°), or tertiary (3°). For example, a primary amine has one carbon bonded to the nitrogen (R-NH 2 ), a secondary amine has two carbons bonded to the nitrogen (R2-NH), and a tertiary amine has three carbons bonded to the nitrogen (R3-N), where R is an alkyl group.

[0122] As used herein, the term "heteroaryl" refers to an aromatic heterocyclic ring having 5 to 10 members and having at least one heteroatom selected from nitrogen, oxygen, and sulfur and containing at least 1 carbon atom, including monocyclic and bicyclic systems.

[0123] The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and having a reasonable benefit / risk ratio.

[0124] The compounds of formula (I) can be provided in the form of an amorphous solid or a crystalline solid. The compounds of formula (I) can be provided in the form of an amorphous solid by freeze-drying.

[0125] It should also be understood that solvates (e.g., hydrates) of the compounds of formula (I) are also encompassed within the scope of the present invention. The term "solvate" refers to the physical association of a compound of formula (I) with one or more solvent molecules, whether organic or inorganic. Such physical association includes hydrogen bonding. In some cases, solvates can be isolated, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Solvation methods are known in the art.

[0126] Various forms of prodrugs are well known in the art and are described in the following:

[0127] a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996);

[0128] b) Design of Pro-drugs, H. Bundgaard, ed., (Elsevier, 1985);

[0129] c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds., Ch 5, pp. 113 - 191 (Harwood Academic Publishers, 1991); and

[0130] d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer, (Wiley-VCH, 2003).

[0131] In addition, after preparation, the compounds of formula (I) can be separated and purified to obtain a composition ("substantially pure") in which the content of the compounds of formula (I) is equal to or greater than 99% by weight, which can then be used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also encompassed herein and are part of the present invention.

[0132] "Stable compounds" and "stable structures" refer to compounds that are stable enough to be isolated to an appropriate purity from a reaction mixture and formulated into an effective therapeutic agent. The present invention aims to embody stable compounds.

[0133] One of ordinary skill in the art should also understand that the compounds described and claimed herein as embodiments of the present invention also exist in "tautomeric" forms. As used herein, tautomers that exist in tautomeric forms refer to structural isomers that can be readily interconverted under rapid equilibrium. As used herein, the process of interconversion is called "tautomerization".

[0134] For example, in the following embodiments, the pyridone tautomers can be represented as follows:

[0135]

[0136] The disclosed structures can be readily interconverted between the structures shown on the left hand side and the structures shown on the right hand side.

[0137] "Therapeutically effective amount" is intended to include the amount of the compounds of the present invention used alone, or the amount of a combination of the claimed compounds, or the amount of a combination of the compounds of the present invention with other active ingredients that are effective as inhibitors or effective in treating or ameliorating cancer.

[0138] As used herein, "treatment" covers treating a disease state in a mammal, particularly a human, and includes: (a) preventing the mammal from developing the disease state, particularly when the mammal is predisposed to developing the disease state but has not been diagnosed as having the disease state; (b) inhibiting the disease state, i.e., arresting its development; and / or (c) alleviating the disease state, i.e., causing the disease state to regress.

[0139] The compounds of the present invention are intended to include all isotopes of the atoms that occur in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general non-limiting example, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13 C and 14 C. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using appropriately isotopically labeled reagents in place of the unlabeled reagents originally used. For example, methyl (-CH 3 ) also includes deuterated methyl, such as -CD 3 .

[0140] The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds which are prepared with relatively non-toxic acids or bases, depending on the particular substituents of the compounds described herein. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either without a solvent or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, magnesium salts, or the like.

[0141] As defined herein, terms such as "inhibit", which relate to protein-inhibitor (e.g., antagonist) interactions, refer to a negative effect (e.g., a decrease) on the activity or function of a protein relative to the protein activity or function in the absence of the inhibitor. In some embodiments, inhibition refers to a reduction of a disease or disease symptom. In some embodiments, inhibition refers to a decrease in the activity of a signal transduction pathway or a signal conduction pathway. Thus, inhibition includes at least partially, partially or completely blocking a stimulus, reducing, preventing or delaying activation, or inactivating, desensitizing or downregulating signal transduction or enzyme activity or the amount of a protein. In some embodiments, inhibition refers to a decrease in the activity of a protein tyrosine phosphatase (e.g., non-receptor protein tyrosine phosphatase type 2 (PTPN2) or non-receptor protein tyrosine phosphatase type 1 (PTP1B)). Thus, inhibition can include at least partially, partially or completely reducing a stimulus; reducing or decreasing activation or inactivation; desensitizing or downregulating signal transduction or enzyme activity or the amount of a protein tyrosine phosphatase, e.g., non-receptor protein tyrosine phosphatase type 2 (PTPN2) or non-receptor protein tyrosine phosphatase type 1 (PTP1B).

[0142] A "patient" or "individual" in need is a living organism that has or is susceptible to a disease or condition that can be treated by administering a compound or pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. 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 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 neonatal human. In some embodiments, the patient is a neonatal mammal. In some embodiments, the patient is an aged animal. In some embodiments, the patient is an aged human. In some embodiments, the patient is an aged mammal. In some embodiments, the patient is an elderly patient.

[0143] "Disease", "disorder", or "condition" refers to a state of life or health of a patient or individual that can be treated with a compound, pharmaceutical composition, or method provided herein. In some embodiments, the compounds and methods described herein include, for example, reducing or eliminating one or more symptoms of a disease, disorder, or condition by administering 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.

[0144] As used herein, the term "signaling pathway" refers to a series of interactions between a cell and optionally extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that convey a change in one component to one or more other components, which in turn may convey the change to additional components, and the change is optionally propagated to other signaling pathway components.

[0145] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate the administration of an active agent to an individual, are absorbed by the individual, and can be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, standard saline solutions, lactated Ringer's solution, standard sucrose, standard glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxy methyl cellulose, polyvinyl pyrrolidone, and pigments, etc. Such formulations can be sterilized and, if desired, mixed with adjuvants (such as lubricants, preservatives, stabilizers, wetting agents, emulsifying agents, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring agents, etc.) that do not react unfavorably with the compounds of the present invention. Those skilled in the art should understand that other pharmaceutical excipients can also be used in the present disclosure.

[0146] The term "formulation" is intended to include capsules in which the active compound is formulated with an encapsulating material as a carrier, where the active ingredient (whether or not it contains other carriers) is encapsulated by the carrier and thus bound thereto.

[0147] Similarly, cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0148] As used herein, the term "administer" means to administer to an individual orally, as a suppository, by topical contact, intravenously, parenterally, intraperitoneally, intramuscularly, intralesionally, intrathecally, intracranially, intranasally, or subcutaneously, or by implantation of a sustained release device, such as a micro-osmotic pump. Administration can be by any route, including parenterally and transmucosally (e.g., buccally, sublingually, transpalatally, gingivally, nasally, vaginally, rectally, or transdermally). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other delivery modes include, but are not limited to, the use of liposomal formulations, intravenous infusions, transdermal patches, etc. "Co-administration" means the administration of the compounds or compositions described herein simultaneously with, before, or after one or more other therapies (e.g., anti-cancer agents, chemotherapeutic agents, or immunotherapeutic agents). The compounds or compositions described herein can be administered alone or in combination to a patient. Co-administration includes the simultaneous or sequential administration of the compounds or compositions alone or in combination (with multiple compounds or agents). Thus, if desired, the formulations can also be used in combination with other active substances (e.g., to reduce metabolic degradation).

[0149] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. Generally, such methods of preparation include the steps of: mixing the disclosed compound(s) (“active ingredient”) with a carrier and / or one or more other accessory ingredients, and then, if necessary and / or desired, shaping and / or encapsulating the product into the desired single-dose or multi-dose unit. The pharmaceutical compositions can be prepared, encapsulated, and / or sold in bulk, as a single unit dose, and / or as multiple single unit doses. As used herein, a “unit dose” refers to an individual dose of a pharmaceutical composition that contains a predetermined amount of the active ingredient. The amount of the active ingredient is usually equal to the dose of the active ingredient to be administered to an individual and / or a suitable fraction of that dose, such as one-half or one-third of that dose.

[0150] Method of treatment

[0151] The present disclosure features compounds, compositions, and methods that include the compounds disclosed herein, such as the compounds of formula (I). In some embodiments, the compounds, compositions, and methods disclosed herein are used for the prevention or treatment of a disease, disorder, or condition. Exemplary diseases, disorders, or conditions include, but are not limited to, cancer, type 2 diabetes, metabolic syndrome, obesity, or metabolic diseases.

[0152] Cancer

[0153] In some embodiments, the compounds disclosed herein (e.g., compounds of formula (I)) are used for the treatment of cancer. As used herein, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas (e.g., papillary adenocarcinomas), lymphomas, leukemias, melanomas, etc., including solid cancers and lymph cancers, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, liver cancer (including hepatocarcinoma), lymphoma, including B acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's lymphomas, small cell lymphomas and large cell lymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL and CML) and / or multiple myeloma. In some other cases, "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, mouth cancer or pharyngeal cancer, laryngeal cancer, kidney cancer, gynecological cancer, brain cancer, central nervous system cancer, peripheral nervous system cancer, blood tissue cancer, small intestine cancer or appendiceal cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer or carcinoma.

[0154] Exemplary cancers treatable 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 breast cancer, ER-negative breast cancer, chemotherapy-resistant breast cancer, herceptin-resistant breast cancer, HER2-positive breast cancer, doxorubicin-resistant breast cancer, tamoxifen-resistant breast cancer, ductal carcinoma of the breast, lobular carcinoma, primary breast cancer, metastatic breast cancer), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid, sarcoma), glioblastoma multiforme, acoustic neuroma, retinoblastoma, astrocytoma, craniopharyngioma, hemangioblastoma, pinealoma, ependymoma, oligodendroglioma, meningioma, glioma or melanoma. Further examples include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer or neuroblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, immunocyte amyloidosis, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, primary macroglobulinemia, primary brain tumor, cancer, malignant insulinoma, malignant carcinoid, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital cancer, malignant hypercalcemia, endometrial cancer, adrenocortical cancer, endocrine or exocrine pancreatic neoplasm, medullary thyroid cancer, medullary carcinoma of the thyroid, melanoma, colorectal cancer, papillary thyroid cancer and hepatocellular carcinoma.

[0155] The first aspect of the invention provides at least one compound of formula (I) having the following structure:

[0156]

[0157] wherein, each occurrence independently:

[0158] R 1 is selected from 6-oxo-1,6-dihydropyridin-2-yl,

[0159]

[0160] R 2 selected from -H, cycloalkyl, alkyl and substituted alkyl;

[0161] R 3 selected from -H, alkyl, halogen, -CN, -OCH 3 , cycloalkyl, -CF 3 , -C(CH 3 ) 2 R 7 selected from aryl, substituted alkyl, alkoxy, -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -OCF 3 , -OH and benzyloxy;

[0162] R 4 selected from -H, alkyl, substituted alkyl, amine, secondary amine, tertiary amine, -CHF 2 , halogen, -CN, -OCH 3 , -N(CH 3 ) 2 , -OCHF 2 , alkoxy, -NHCH 3 , -OH, -CH 2 CH 3 and morpholin-4-yl;

[0163] R 5 selected from -H, alkyl, substituted alkyl, alkoxy, amine, secondary amine, tertiary amine, halogen, -CH 2 CH 3 , -CN, -OCH 3 , -N(CH 3 ) 2 , -NHCH 3 , cyclopropyl, cyclopropoxy, cyclohexyl, -CF 3 , -OH, -Ph, -CH 2 CH 3 and R 6 selected from -H, alkyl, -CH 2 CH 3 , -OCH 3 , -OH and -CF 3 ;

[0164] R 7 selected from -H and -CH 3 ;

[0165] R 8 selected from -O- and -CH 2 O-.

[0166] In one embodiment of the compound of formula (I):

[0167] R 1 is

[0168]

[0169] R 2 selected from -H and cyclopropyl;

[0170] R 3 is selected from -H, -CH 3 , cyclopropyl, phenyl and benzyloxy;

[0171] R 4 is selected from -H, -CH 3 and -Br

[0172] R 5 is selected from -CH 3 and -F;

[0173] R 6 is selected from -H, -CH 3 and -OCH 3 .

[0174] In another embodiment of the compound of formula (I):

[0175] R 3 is -H;

[0176] R 4 is selected from -H, alkyl, halogen and -CN;

[0177] R 5 is selected from -H, and

[0178]

[0179] In one embodiment of the compound of formula (I):

[0180] R 2 is -H;

[0181] R 3 is selected from cyclo group, -CF 3 , -C(CH 3 ) 2 R 7 , aryl and benzyloxy; R 5 is -H;

[0182] R 6 is -H.

[0183] In another embodiment of the compound of formula (I):

[0184] R2 is -H;

[0185] R 4 is selected from -H, -N(CH 3 ) 2 , -OCHF 2 and morpholin-4-yl; R 5 is selected from halogen, -CH 2 CH 3 , -CF 3 , and

[0186]

[0187] R 6 is selected from -H and -CH 2 CH 3 .

[0188] In one embodiment of the compound of formula (I):

[0189] R 3 is -H;

[0190] R 5 is selected from -H, -CH 2 CH 3 , -CN and -CF 3 .

[0191] In another embodiment of the compound of formula (I):

[0192] R 3 is selected from -H, alkyl and -F;

[0193] R 4 is selected from -H, -CHF 2 , halogen, -CN, -OCH 3 , -N(CH 3 ) 2 , -OCHF 2 and morpholin-4-yl.

[0194] In one embodiment of the compound of formula (I)

[0195] R 1 is

[0196]

[0197] R 3 is selected from alkyl, -CN, -OCH 3 and -CF 3 ;

[0198] R 4 is selected from -H, alkyl and -OCH 3;

[0199] R 5 selected from -H, alkyl, and -OCH 3 ;

[0200] R 6 selected from -H and -OCH 3 .

[0201] In another embodiment, the compounds are selected from:

[0202] 5-(4-(((4-Cyclopropylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0203] 5-(2-Fluoro-6-hydroxy-4-(((4-(trifluoromethyl)pyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0204] 5-(2-Fluoro-6-hydroxy-4-(((3-(trifluoromethyl)pyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0205] 5-(4-(((5-(tert-Butyl)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0206] 5-(4-(((4,6-Dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0207] 5-(4-(((4-Cyclopropoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0208] 5-(2-Fluoro-6-hydroxy-4-(((4-Methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0209] 5-(2-Fluoro-6-hydroxy-4-(((5-Phenylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0210] 5-(2-Fluoro-6-hydroxy-4-(((4-Methoxy-5-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0211] 5-(4-(((5-Cyclopropylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0212] 2-((4-(1,1-Dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)isonicotinonitrile;

[0213] 5-(2-Fluoro-6-hydroxy-4-(((4-methoxypyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0214] 5-(4-(((4-Ethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0215] 5-(2-Fluoro-6-hydroxy-4-(((5-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0216] 5-(2-Fluoro-6-hydroxy-4-(((3-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0217] 5-(2-Fluoro-4-(((4-fluoropyridin-2-yl)amino)methyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0218] 5-(2-Fluoro-6-hydroxy-4-(((6-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0219] 5-(4-(((4,6-Dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0220] 5-(4-(((5,6-Dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0221] 5-(4-(((3,6-Dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide;

[0222] 5-[4-[[(3,6-Dimethoxy-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxyphenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0223] 5-(2-Fluoro-6-hydroxy-4-(((3-methoxy-6-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0224] 5-(4-(((3-Ethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0225] 5-(4-(((3,5-Dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0226] 5-(4-(((3,4-Dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0227] 5-(4-(((4,5-Dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0228] 5-(4-(((3,4-Dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0229] 5-(4-(((4,5-Dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0230] 5-(2-Fluoro-6-hydroxy-4-(((6-methoxy-3-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0231] 5-(4-(((3,5-Dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0232] 5-(2-Fluoro-4-(((5-fluoro-4-methylpyridin-2-yl)amino)methyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0233] 6-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)-4-methylnicotinonitrile;

[0234] 5-(2-fluoro-4-(((4-fluoro-5-methylpyridin-2-yl)amino)methyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0235] 5-(2-fluoro-6-hydroxy-4-(((3-methoxypyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0236] 5-(2-fluoro-6-hydroxy-4-(((6-methoxypyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0237] 5-(4-(((5,6-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0238] 5-(2-fluoro-6-hydroxy-4-((pyridin-2-ylamino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0239] 5-(2-fluoro-6-hydroxy-4-(((5-methoxypyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0240] 5-(2-fluoro-6-hydroxy-4-(((6-methoxy-4-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0241] 6-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)cyanopyridine;

[0242] 5-(2-fluoro-6-hydroxy-4-(((4-methoxy-6-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0243] 5-(4-(((6-(difluoromethyl)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0244] 5-(4-(((6-(Difluoromethoxy)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0245] 5-(4-(((6-(Dimethylamino)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0246] 5-(2-Fluoro-6-hydroxy-4-(((5-isopropylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0247] 5-(4-(((4-(Benzyloxy)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0248] 5-(4-(((5-(Benzyloxy)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0249] 5-(4-(((6-Bromo-4-methylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0250] 5-(2-Fluoro-6-hydroxy-4-(((4-methyl-6-(morpholin-4-yl)pyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0251] 5-(4-((Cyclopropyl(5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0252] 5-(2-Fluoro-6-hydroxy-4-(((6-oxo-1,6-dihydropyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0253] 5-(2-Fluoro-6-hydroxy-4-(((6-methyl-4-phenoxypyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide;

[0254] or a pharmaceutically acceptable salt thereof.

[0255] In one embodiment, the present invention includes a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0256] In another embodiment, the present invention includes a method for treating cancer, comprising administering to the 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 lymphoma, 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 liver cancer, lymphoma, including B acute lymphoblastic lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, small lymphoma, Hodgkin lymphoma, leukemia, and multiple myeloma.

[0257] In another embodiment, the present invention includes a method for treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a combination of a compound of formula I and an additional therapeutic agent.

[0258] In one embodiment, the additional therapeutic agent is an immunotherapeutic agent.

[0259] In another embodiment, the immunotherapeutic agent is selected from anti-PD-1 antibody, anti-PD-L1 antibody, and anti-CTLA-4 antibody.

[0260] In one embodiment, the method for treating cancer in a patient in need thereof comprises administering to the patient a pharmaceutically acceptable composition of a compound of formula I in an effective amount.

[0261] In another embodiment, the method for treating cancer is selected from radiation, surgery, chemotherapy, or administration of a biologic drug.

[0262] In one embodiment, the method for treating cancer is administration of a biologic drug, and the biologic drug is a drug that stimulates the immune system.

[0263] In another embodiment, the method for treating cancer comprises administering to an individual an inhibitor of DGKα and / or DGKζ, an antagonist of the PD1 / PD-L1 axis, and an antagonist of CTLA4.

[0264] These embodiments are not intended to limit the scope of the present invention.

[0265] Synthesis method

[0266] The compounds of the present invention can be prepared by the methods and examples presented below, as well as by methods known to those of ordinary skill in the art. In the following individual examples, unless otherwise indicated, the R groups are defined as above for the respective formulas. The optimal reaction conditions and reaction times can vary depending on the reactants used. Unless otherwise stated, those of ordinary skill in the art can easily select solvents, temperature, pressure, and other reaction conditions.

[0267] The intermediates used in the syntheses below are commercially available or can be readily prepared by methods known to those skilled in the art. The progress of the reaction can be monitored by conventional methods, such as thin layer chromatography (TLC) or high performance liquid chromatography - mass spectrometry (HPLC - MS). The intermediates and products can be purified by methods known in the art, including column chromatography, HPLC, preparative TLC, or preparative HPLC.

[0268] Preparation of the related synthetic key intermediate (Int - 2)

[0269] Preparation of 5 - (4 - bromo - 2 - fluoro - 6 - ((4 - methoxybenzyl)oxy)phenyl)-1,2,5 - thiadiazolidine - 3 - one 1,1 - dioxide (Int2) as shown in Scheme 1.

[0270] Scheme 1:

[0271]

[0272] Step 1: Synthesis of 5 - bromo - 1 - fluoro - 3 - ((4 - methoxybenzyl)oxy)-2 - nitrobenzene (1 - 2)

[0273] 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) at room temperature was added K 2 CO 3 (17.4 g, 126.06 mmol) in portions. The resulting mixture was stirred overnight at 70 °C under a nitrogen atmosphere. TLC showed completion of the reaction. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 * 300 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by 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 as a pale yellow solid (10 g, 66.8% yield).

[0274] Step 2: Synthesis of 4 - bromo - 2 - fluoro - 6 - ((4 - methoxybenzyl)oxy)aniline (1 - 3)

[0275] At room temperature, NH 4 Cl (15.16 g, 280.79 mmol) and Fe (15.68 g, 280.79 mmol) were added 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). The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. LCMS showed that the reaction was complete. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE / EA = 9 / 1) to give the desired product 4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]aniline as a pale yellow solid (6 g, 65.50% yield). MS: m / z: C 14 H 13 BrFNO 2 [M+H] + was calculated to be 326, found 326.

[0276] Step 3: Synthesis of tert-butyl (4-bromo-2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)glycinate (1-4)

[0277] At room temperature, K 2 CO 3 (7.49 g, 54.27 mmol) was added 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). The resulting mixture was stirred at 100 °C for 48 h. LCMS showed that the starting material was completely consumed. 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 (H 4 O / ACN containing 0.05% NH 3 to give tert-butyl 2-[4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenylamino]acetate as a white solid (5 g, 62.70% yield). MS: m / z: C 2 H 20 H 23 BrFNO 4 [M+H] + was calculated to be 440, found 440.

[0278] Step 4: Synthesis of tert-butyl N-(4-bromo-2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-N-sulfamoyl-glycinate (1-5)

[0279] At 0 °C, a solution of sulfamoyl chloride (2.6 g, 22.48 mmol) in DMA (4 mL) was added to a stirred solution of tert-butyl 2-[4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenylamino]acetate (3.3 g, 7.49 mmol) in DMA (80 mL). The reaction mixture was stirred overnight at room temperature. LCMS showed complete depletion of the starting material. The mixture was diluted with ethyl acetate (300 mL) and washed six times with brine until all the DMA was removed. 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-phenylamino]acetate (4 g, 7.70 mmol, 102.70% yield) as a brown oil. MS: m / z: C 20 H 24 BrFN 2 O 6 S[M-H] - Calculated for 517, found 517.

[0280] Step 5: Synthesis of 5-(4-bromo-2-fluoro-6-((4-methoxybenzyl)oxy)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (Int-1)

[0281] At 0 °C, MeOH (8.32 g, 46.30 mmol) containing 30% NaOMe was added to a stirred solution of tert-butyl 2-[4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]-N-sulfamoyl-phenylamino]acetate (4 g, 7.70 mmol) in methanol (20 mL). The mixture was stirred overnight at room temperature. LCMS showed complete depletion 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 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 in vacuo. The resulting residue was further purified by reverse phase column (H 4 CO 3 containing 2 O 16 H 14 BrFN 2 O 5S[M-H] - The calculated value of it is 443, and the measured value is 443.

[0282] Step 6: Synthesis of 5-(2-Fluoro-6-((4-methoxybenzyl)oxy)-4-vinylphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (1-6)

[0283] To a solution of 5-[4-Bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidine-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) 3 HBF 4 (0.43 g, 0.90 mmol) and Pd 2 (dba) 3 (0.41 g, 0.45 mmol). The resulting mixture was purged with nitrogen for 5 minutes. Subsequently, the mixture was stirred at 80 °C for 12 h. LCMS showed complete depletion of the starting material. The reaction mixture was filtered and the filtrate was purified directly by a reverse-phase column to give 5-[2-Fluoro-6-[(4-methoxyphenyl)methoxy]-4-vinyl-phenyl]-1,1-dioxo-1,2,5-thiadiazolidine-3-one (1.2 g, 3.05 mmol, 68.08% yield) as a pale yellow semi-solid. MS: m / z: C 18 H 18 FN 2 O 5 S[M-H] - The calculated value of it is 391, and the measured value is 391.

[0284] Step 7: Synthesis of 4-(1,1-Dioxo-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-((4-methoxybenzyl)oxy)benzaldehyde (Int-2)

[0285] To a stirred solution of 5-[2-Fluoro-6-[(4-methoxyphenyl)methoxy]-4-vinyl-phenyl]-1,1-dioxo-1,2,5-thiadiazolidine-3-one (970 mg, 2.47 mmol), citric acid (1.04 g, 4.94 mmol) and NMO (579.18 mg, 4.94 mmol) in tert-butanol (6 mL) and water (6 mL) was added K 2 OsO 4 (91.07 mg, 0.25 mmol). The resulting mixture was stirred at room temperature for 1 h. LCMS showed complete conversion of the starting material to the intermediate. Subsequently, at 0 °C, NaIO 4(1.07 mL, 7.42 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 2 h. LCMS showed the completion of the reaction. The reaction mixture was diluted with water and extracted 4 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% NH 4 CO 3 , H 2 O / ACN) to give 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde as a brown solid (500 mg, 1.26 mmol, 51.20% yield). MS: m / z: C 17 H 15 FN 2 O 6 S[M-H] - calculated for 393, found 393.

[0286] Preparation Example

[0287] Example 1: 5-[4-[[(4-cyclopropyl-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one

[0288]

[0289] Scheme 2:

[0290]

[0291] Step 1: At 0 °C, TMSCl (0.08 mL, 0.63 mmol) was added dropwise to a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (Int-2, 100 mg, 0.25 mmol) and 4-cyclopropylpyridin-2-amine (51.04 mg, 0.38 mmol) in DMF (3 mL). After stirring at 80 °C for 30 min, the mixture was cooled to 0 °C and a solution of BH 3 in THF (1 M, 0.5 mL, 0.48 mmol) was slowly added via syringe. After the addition, the reaction mixture was stirred at 80 °C for 1 h. LCMS showed the completion of the reaction. The mixture was quenched with ice water (0.4 ml) and directly chromatographed by reverse phase column chromatography (containing 0.05% NH 4 HCO 3 in H 2Purified with O and MeCN to obtain 5-[4-[[(4-cyclopropyl-2-pyridinyl)amino]methyl]-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one as a light brown solid (50 mg, 0.09 mmol, 38.47% yield). MS: m / z: C 25 H 24 FN 4 O 5 S[M+H] + The calculated value is 513, and the measured value is 513.

[0292] Step 2: Add TFA (3 mL) to a solution of 5-[4-[[(4-cyclopropyl-2-pyridinyl)amino]methyl]-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one (45 mg, 0.09 mmol) in DCM (3 mL). Stir the mixture at room temperature for 2 h. After monitoring the completion of the reaction by LCMS, concentrate the mixture. The resulting residue was first purified by reverse-phase column chromatography (H2O containing 0.05% NH 4 HCO 3 of H 2 O and MeCN), and then further purified by preparative HPLC to obtain 5-[4-[[(4-cyclopropyl-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxyphenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one as a white solid (11.8 mg, 0.02 mmol, 33.22% yield). MS: m / z: C 17 H 17 N 4 O 4 S[M+H] + The calculated value is 393, and the measured value is 393. 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.77 (d, J = 5.8 Hz, 1H), 6.68 - 6.57 (m, 2H), 6.43 (s, 1H), 6.30 (d, J = 5.8 Hz, 1H), 4.39 (s, 2H), 3.94 (s, 2H), 1.84 (d, J = 9.4 Hz, 1H), 1.09 - 0.96 (m, 2H), 0.82 - 0.65 (m, 2H).

[0293] Preparative HPLC purification conditions: Column: XBridge preparative OBD C18 column, 30 * 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH3 . H 2 O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 7 min, 26% B to 36% B, 36% B; Wavelength: 254 / 220 nm.

[0294] Example 2: 5-[2-Fluoro-6-hydroxy-4-[[[4-(trifluoromethyl)-2-pyridinyl]amino]methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0295]

[0296] According to the preparation of Example 1, 4-(trifluoromethyl)pyridin-2-amine was used in Step 1 to obtain the title compound as a white solid in an overall yield of 17.47%. Reductive amination was carried out at room temperature instead of 80 °C. MS: m / z: C 15 H 12 F 4 N 4 O 4 S[M+H] + Calculated value for is 421; Observed value is 421. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 8.19 (d, J = 5.4 Hz, 1H), 7.81 (s, 1H), 6.91 - 6.76 (m, 2H), 6.74 - 6.66 (m, 2H), 4.48 (s, 2H), 4.37 (s, 2H).

[0297] Preparative HPLC purification conditions: Column: Xselect CSH C18 OBD column, 30 * 150 mm, 5 μm, n; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 10 min, 23% B to 53% B, 53% B; Wavelength: 254 nm.

[0298] Example 3: 5-[2-Fluoro-6-hydroxy-4-[[[3-(trifluoromethyl)-2-pyridinyl]amino]methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0299]

[0300] According to the preparation of Example 1, 3-(trifluoromethyl)pyridin-2-amine was used in Step 1 to obtain the title compound as a white solid in an overall yield of 9.45%. Reductive amination was carried out at room temperature instead of 80 °C. MS: m / z: C 15 H12 F 4 N 4 O 4 S[M+H] + The calculated value of is 421; the measured value is 421. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.10 (s, 1H), 8.22 (s, 1H), 7.80 (t, J = 5.7 Hz, 1H), 7.17 (d, J = 5.6 Hz, 1H), 6.68 (d, J = 10.9 Hz, 3H), 4.55 (d, J = 5.3 Hz, 2H), 4.26 (s, 2H).

[0301] Purification conditions for preparative HPLC: Column: Xselect CSH C18 OBD column, 30 * 150 mm, 5 μm, n; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 10 min, 20% B to 50% B, 50% B; Wavelength: 254 nm.

[0302] Example 4: 5-[4-[[(5-tert-Butyl-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0303]

[0304] Process 3:

[0305]

[0306] Step 1: At 0 °C, trimethylsilyl trifluoromethanesulfonate (0.07 mL, 0.41 mmol) was added to a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxido-1,2,5-thiadiazolidin-2-yl)benzaldehyde (80 mg, 0.20 mmol) and 5-tert-butylpyridin-2-amine (45.71 mg, 0.30 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 1 h. NaBH(AcO) 3 (86.01 mg, 0.41 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for an additional 2 h. LCMS showed complete depletion of the starting material (product 3-1 and the PMB deprotected product 006-03 were formed in a 5 / 4 ratio). The resulting solution was diluted with 30 mL of DCM and concentrated directly in vacuo to give the crude material, which was used in the next step without further purification. MS: m / z: C 24 H 25 FN4 O 5 S[M+H] + The calculated value of is 529, and the measured value is 529. (Note: Depending on the substrate, the PMB protecting group may be completely or partially cleaved during the reductive amination reaction. If it is not completely cleaved, an appropriate amount of TFA can be directly added to the above mixture to drive the deprotection of PMB to completion). Concentrate the resulting solution at low temperature (bath temperature: 25 °C).

[0307] Step 2: Add TFA (3 mL) to a solution of 5-[4-[[(5-tert-butyl-2-pyridinyl)amino]methyl]-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one (80 mg of crude material, purity: 40%) in DCM (3 mL). Stir the mixture at room temperature for 2 h. After monitoring the completion of the reaction by LCMS, dilute the reaction mixture with DCM (20 mL) and concentrate. The resulting residue is purified by reverse-phase column chromatography (containing 0.05% NH 4 HCO 3 of H 2 O and ACN) and further purified by preparative HPLC to obtain 5-[4-[[(5-tert-butyl-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxyphenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one as a white solid (22.4 mg, 0.05 mmol, 35.87% yield). MS: m / z: C 18 H 21 FN 4 O 4 S[M+H] + The calculated value is 409; the measured value is 409. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.02 - 7.65 (m, 2H), 6.81 (d, J = 9.1 Hz, 1H), 6.70 - 6.62 (m, 2H), 4.43 (s, 2H), 3.95 (s, 2H), 1.23 (s, 9H).

[0308] Preparative HPLC purification conditions: Column: XBridge preparative OBD C18 column, 30 * 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 H 2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 8 min, 20% B to 30% B, 30% B; Wavelength: 254 / 220 nm. Example 5: 5-[4-[[(4,6-Dimethyl-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0309]

[0310] According to the preparation of Example 4, 4,6-dimethylpyridin-2-amine was used in Step 1 to obtain the title compound as a white solid in a total yield of 9.46%.

[0311] Step 1: At 0 °C, 4,6-dimethylpyridin-2-amine (161.09 mg, 1.32 mmol) and trimethylsilyl trifluoromethanesulfonate (0.37 mL, 2.03 mmol) were added to a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxido-1,2,5-thiadiazolidin-2-yl)benzaldehyde (400 mg, 1.01 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 1 h. NaBH(AcO) 3 (430.05 mg, 2.03 mmol) was added, and the reaction mixture was stirred at room temperature for another 2 h. LCMS showed complete depletion of the starting material (product 2 and the PMB-deprotected product 013-01 were formed in a 5 / 3 ratio). The resulting solution was diluted with 50 mL of DCM and directly concentrated in vacuo to give the crude material, which was used in the next step without further purification. MS: m / z: C 24 H 25 FN 4 O 5 S[M + H] + Calculated value is 501, found value is 501.

[0312] Step 2: At 0 °C, TFA (10 mL) was added to a solution of 5-[4-[[(4,6-dimethyl-2-pyridinyl)amino]methyl]-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one and 5-(4-(((4,6-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (600 mg of crude material, 1.2 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 2 h. LCMS showed complete depletion of the starting material. The mixture was concentrated and the resulting residue was purified by reverse-phase column chromatography (water and MeCN containing 0.05% TFA) and further purified by preparative HPLC to give 5-[4-[[(4,6-dimethyl-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxyphenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a white solid (329.3 mg, 0.83 mmol, 69.69% yield). MS: m / z: C 16 H 17 FN 4 O 4 S[M+H] + The calculated value for is 381, and the measured value is 381. 1 H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 9.80 (s, 1H), 8.38 (s, 1H), 7.30 - 6.26 (m, 4H), 4.53 (d, J = 5.9 Hz, 2H), 4.04 (s, 2H), 2.42 (s, 3H), 2.30 (s, 3H).

[0313] Preparative HPLC conditions: Column: SunFire preparative C18 OBD column, 30 * 50 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 3% B to 30% B, 30% B in 8 min; Wavelength: 254 / 210 nm.

[0314] Example 6: 5-[4-[[[4-(Cyclopropoxy)-2-pyridinyl]amino]methyl]-2-fluoro-6-hydroxyphenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one

[0315]

[0316] According to the preparation of Example 4, 4-(cyclopropoxy)pyridin-2-amine was used in Step 1 to obtain the title compound as a white solid in an overall yield of 8.36%. MS: m / z: C 17H 17 FN 4 O 5 S[M+H] + The calculated value of 1 HNMR(400MHz, DMSO-d 6 ) δ 12.89 (s, 1H), 9.79 (s, 1H), 8.79 (s, 1H), 7.88 (d, J = 7.2 Hz, 1H), 6.88 - 6.40 (m, 4H), 4.48 (d, J = 5.7 Hz, 2H), 4.07 (dq, J = 6.3, 3.0 Hz, 1H), 4.01 (s, 2H), 0.84 (t, J = 6.1 Hz, 2H), 0.75 (s, 2H).

[0317] Purification conditions for preparative HPLC: Column: SunFire preparative C18 OBD column, 19 * 150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: from 50% B to 70% B in 5.3 min, 70% B; Wavelength: 210 / 254 nm.

[0318] Example 7: 5 - [2 - fluoro - 6 - hydroxy - 4 - [[(4 - methyl - 2 - pyridyl)amino]methyl]phenyl] - 1,1 - dioxido - 1,2,5 - thiadiazolidin - 3 - one

[0319]

[0320] According to the preparation in Example 4, the title compound in the form of a white solid was obtained in a total yield of 4.44% using 4 - methylpyridin - 2 - amine in Step 1.

[0321] MS: m / z: C 15 H 15 FN 4 O 4 S[M+H] + The calculated value of 1 H NMR(400MHz, DMSO - d 6 ) δ 9.74 (s, 1H), 8.80 (s, 1H), 7.85 (d, J = 6.5 Hz, 1H), 6.89 (s, 1H), 6.78 (dd, J = 6.6, 1.5 Hz, 1H), 6.74 - 6.66 (m, 2H), 4.49 (d, J = 5.8 Hz, 2H), 2.35 (s, 3H).

[0322] Purification conditions: Column: SunFire preparative C18 OBD column, 30 * 50 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 8 min, 3% B to 30% B, 30% B; Wavelength: 254 / 210 nm.

[0323] Example 8: 5-[2-Fluoro-6-hydroxy-4-[[(5-phenyl-2-pyridinyl)amino]methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0324]

[0325] According to the preparation of Example 4, 5-phenylpyridin-2-amine was used in Step 1 to obtain the title compound as a white solid in a total yield of 22.55%. MS: m / z: C 20 H 17 FN 4 O 4 S[M + H] + The calculated value is 429; the measured value is 429. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.02 (s, 1H), 8.62 (s, 1H), 8.25 (d, J = 2.4 Hz, 1H), 8.22 - 8.14 (m, 1H), 7.66 (dd, J = 7.4, 1.7 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.42 - 7.34 (m, 1H), 7.04 (d, J = 9.2 Hz, 1H), 6.75 - 6.73 (s, 2H), 4.57 - 4.52 (m, 2H). 4.16 (s, 2H).

[0326] Preparative HPLC purification conditions: Column: XBridge preparative OBD C18 column, 30 * 150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 10 min, 7% B to 37% B, 37% B; Wavelength: 254 nm.

[0327] Example 9: 5-[2-Fluoro-6-hydroxy-4-[[(4-methoxy-5-methyl-2-pyridinyl)amino]methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0328]

[0329] Prepared according to Example 4, using 4-methoxy-5-methyl-pyridin-2-amine in Step 1, the title compound was obtained as a white solid in a total yield of 30.22%. MS: m / z: C 16 H 17 FN 4 O 5 S[M+H] + The calculated value is 397; the measured value is 397. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.60 (s, 1H), 9.61 (s, 1H), 8.55 (s, 1H), 7.70 (d, J = 1.2 Hz, 1H), 6.68 (d, J = 8.9 Hz, 2H), 6.43 (s, 1H), 4.48 (d, J = 6.0 Hz, 2H), 3.93 (d, J = 9.2 Hz, 5H), 2.11 - 1.88 (m, 3H).

[0330] Preparative HPLC purification conditions: Column: Xselect CSH C18 OBD column, 30 * 150 mm, 5 μm, n; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 10 min, 4% B to 34% B, 34% B; Wavelength: 254 nm.

[0331] Example 10: 5-[4-[[(5-Cyclopropyl-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0332]

[0333] Prepared according to Example 4, using 5-cyclopropylpyridin-2-amine in Step 1, the title compound was obtained as a white solid in a total yield of 20.22%. MS: m / z: C 17 H 17 FN 4 O 4 S[M+H] + The calculated value is 393; the measured value is 393. 1 H NMR (400 MHz, DMSO-d 6)δ 9.45 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.68 (s, 1H), 7.33 (d, J = 8.9 Hz, 1H), 6.70 - 6.59 (m, 3H), 4.39 (d, J = 4.8 Hz, 2H), 3.94 (s, 2H), 1.87 - 1.76 (m, 1H), 0.90 - 0.79 (m, 2H), 0.63 - 0.55 (m, 2H). Preparation HPLC purification conditions: Column: XBridge preparative OBD C18 column, 30 * 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 H 2 O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 8 min, 20% B to 30% B, 30% B; Wavelength: 254 / 220 nm.

[0334] Example 11: 2 - [[3 - Fluoro - 5 - hydroxy - 4 - (1,1,4 - trioxo - 1,2,5 - thiadiazolidin - 2 - yl)phenyl]methylamino]pyridine - 4 - carbonitrile

[0335]

[0336] According to the preparation of Example 4, 2 - aminopyridine - 4 - carbonitrile was used in Step 1 to obtain the title compound as a white solid in an overall yield of 30.09%. MS: m / z: C 15 H 12 FN 5 O 4 S [M + H] + The calculated value is 378; the measured value is 378. 1 1H NMR (400 MHz, DMSO - d 6 ) δ 10.30 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.73 (s, 1H), 6.95 - 6.78 (m, 2H), 6.71 - 6.64 (m, 2H), 4.34 (d, J = 10.2 Hz, 2H), 4.43 (s, 2H).

[0337] Preparation HPLC purification conditions: Column: Xselect CSH C18 OBD column, 30 * 150 mm, 5 μm, n; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 10 min, 4% B to 34% B, 34% B; Wavelength: 254 nm.

[0338] Example 12: 5-[2-Fluoro-6-hydroxy-4-[[(4-methoxypyridin-2-yl)amino]methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0339]

[0340] Prepared according to Example 1, using 4-methoxypyridin-2-amine in Step 1, the title compound was obtained as a white solid in 21.91% overall yield. MS: m / z: C 15 H 15 FN 4 O 5 S[M + H] + Calculated value for is 383; found value is 383. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (s, 1H), 8.69 (s, 1H), 7.87 (d, J = 7.2 Hz, 1H), 6.73 - 6.69 (m, 2H), 6.58 (dd, J = 7.2, 2.4 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 4.50 (d, J = 5.8 Hz, 2H), 4.00 (s, 2H), 3.91 (s, 3H).

[0341] Purification conditions for preparative HPLC: Column: Xselect CSH C18 OBD column, 30 * 150 mm, 5 μm, n; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 25% B in 10 min, 25% B; Wavelength: 254 nm.

[0342] Example 13: 5-[4-[[(4-Ethylpyridin-2-yl)amino]methyl]-2-fluoro-6-hydroxyphenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one.

[0343]

[0344] Prepared according to Example 4, using 4-ethylpyridin-2-amine in Step 1, the title compound was obtained as a white solid in 32.57% overall yield. MS: m / z: C 16 H 17 FN 4 O 4 S[M + H] + Calculated value for is 381, found value is 381. 1 H NMR (400 MHz, DMSO-d 6) δ 13.08 (s, 1H), 9.55 (d, J = 6.7 Hz, 1H), 8.24 (s, 1H), 7.86 (d, J = 6.2 Hz, 1H), 7.27 - 6.93 (m, 1H), 6.80 - 6.54 (m, 4H), 4.46 (d, J = 5.8 Hz, 2H), 3.95 (d, J = 1.9 Hz, 2H), 2.59 (q, J = 7.6 Hz, 2H), 1.16 (t, J = 7.5 Hz, 3H).

[0345] Preparative HPLC purification conditions: Column: XBridge C18 OBD preparative column, 5 μM, 19 mm × 250 mm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: within 6 min, 25% B to 55% B, 55% B; Wavelength: 254 nm.

[0346] Example 14: 5-[2-Fluoro-6-hydroxy-4-[[(5-methyl-2-pyridinyl)amino]methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0347]

[0348] According to the preparation of Example 4, 5-methylpyridin-2-amine was used in Step 1 to obtain the title compound as a white solid in a total yield of 24.22%. MS: m / z: C 15 H 15 FN 4 O 4 S [M + H] + Calculated value is 367; Measured value is 367. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.50 (d, J = 4.3 Hz, 1H), 8.02 (s, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.27 - 6.91 (m, 1H), 6.79 (d, J = 8.7 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H), 6.65 (d, J = 8.4 Hz, 2H), 4.42 (d, J = 5.1 Hz, 2H), 3.95 (s, 2H), 2.15 (s, 3H).

[0349] Preparative HPLC purification conditions: Column: XBridge C18 OBD preparative column, 5 μM, 19 mm × 250 mm; Mobile phase A: water (10 mmol / L NH4 HCO 3 ), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: within 6 min, from 25% B to 55% B, then hold at 55% B; Wavelength: 254 nm.

[0350] Example 15: 5-[2-Fluoro-6-hydroxy-4-[[(3-methyl-2-pyridinyl)amino]methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0351]

[0352] Prepared according to Example 4, using 3-methylpyridin-2-amine in step 1, the title compound was obtained as a white solid in 5.38% overall yield. MS: m / z: C 15 H 15 FN 4 O 4 S[M+H] + Calculated value is 367; Observed value is 367. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.70 (s, 1H), 8.23 (s, 1H), 7.79 (t, J = 9.7 Hz, 1H), 7.73 (d, J = 11.2 Hz, 1H), 6.80 (s, 1H), 6.65 (s, 2H), 4.61 - 4.55 (s, 2H), 4.00 (s, J = 9.4 Hz, 2H), 2.28 - 2.15 (m, 3H)

[0353] Preparative HPLC purification conditions: Column: SunFire Preparative C18 OBD column, 19*150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: within 5.3 min, from 40% B to 60% B, then hold at 60% B; Wavelength: 210 / 254 nm.

[0354] Example 16: 5-[2-Fluoro-4-[[(4-fluoro-2-pyridinyl)amino]methyl]-6-hydroxyphenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0355]

[0356] Prepared according to Example 4, using 4-fluoropyridin-2-amine in step 1, the title compound was obtained as a white solid in 5.21% overall yield. MS: m / z: C 14 H 12 F 2 N 4 O4 S[M+H] + The calculated value of is 371; the measured value is 371. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.02 (t, J = 7.0 Hz, 1H), 6.83 - 6.67 (m, 4H), 4.46 (s, 2H), 4.11 (d, J = 4.7 Hz, 2H).

[0357] Preparative HPLC purification conditions: Column: SunFire preparative C18 OBD column, 19 * 150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: within 5.3 min, 35% B to 50% B, 50% B; Wavelength: 210 / 254 nm.

[0358] Example 17: 5-[2-Fluoro-6-hydroxy-4-[[(6-methyl-2-pyridinyl)amino]methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0359]

[0360] According to the preparation of Example 4, 6-methylpyridin-2-amine was used in Step 1 to obtain the title compound as a white solid in a total yield of 29.15%. MS: m / z: C 15 H 15 FN 4 O 4 S[M+H] + The calculated value of is 367; the measured value is 367. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 9.56 (s, 1H), 7.95 (d, J = 41.3 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.26 - 6.93 (m, 1H), 6.72 - 6.58 (m, 4H), 4.47 (d, J = 5.2 Hz, 2H), 3.97 (s, 2H), 2.38 (s, 3H).

[0361] Preparative HPLC purification conditions: Column: XBridge preparative OBD C18 column, 30 * 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 )), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 6 min, 30% B to 60% B, 60% B; Wavelength: 254 / 210 nm.

[0362] Example 18: 5-[4-[[(4,6-Dimethoxy-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0363]

[0364] Procedure 4:

[0365]

[0366] Step 1: At 140 °C, a mixture of 4,6-dichloropyridin-2-amine (2.0 g, 12.27 mmol) in sodium methoxide (30% solution in MeOH, 20 mL) was stirred in a sealed tube for 12 h. LCMS showed complete depletion of the starting material. The resulting solution was purified by reverse-phase column chromatography (H 4 HCO 3 O and MeCN containing 0.05% NH 2 to give 4,6-dimethoxypyridin-2-amine as an off-white solid (193 mg, 1.25 mmol, 10.20% yield). MS: m / z: C 7 H 10 N 2 O 2 [M+H] + calculated to be 155; found 155.

[0367] Step 2: According to the preparation of Example 1, using 4,6-dimethoxypyridin-2-amine in Step 1, the compound 4-3 was obtained as a pale yellow solid in 37.02% yield. MS: m / z: C 24 H 25 FN 4 O 7 S[M+H] + calculated to be 533; found 533.

[0368] Step 3: According to the preparation of Example 1, using 4-3 in Step 2, the title compound was obtained as a white solid in 33.03% yield. MS: m / z: C 16 H 17 FN 4 O 6 S[M+H] + calculated to be 413; found 413. 1 H NMR (400 MHz, DMSO-d 6)δ 10.10 (s, 1H), 7.04 (d, J = 51.1 Hz, 1H), 6.72 - 6.63 (m, 2H), 5.60 (d, J = 17.8 Hz, 2H), 4.34 (s, 2H), 4.24 (s, 2H), 3.75 - 3.65 (m, 6H).

[0369] Preparative HPLC purification conditions: Column: SunFire preparative C18 column, 30 * 150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 7 min, 10% B to 40% B, 40% B; Wavelength: 210 / 254 nm.

[0370] Example 19: 5 - [4 - [[(5,6 - dimethyl - 2 - pyridyl)amino]methyl] - 2 - fluoro - 6 - hydroxy - phenyl] - 1,1 - dioxo - 1,2,5 - thiadiazolidin - 3 - one

[0371]

[0372] According to the preparation of Example 4, 5,6 - dimethylpyridin - 2 - amine was used in Step 1 to obtain the title compound as a white solid in a total yield of 2.24%. MS: m / z: C 16 H 17 FN 4 O 4 S [M + H] + The calculated value is 381; the measured value is 381. 1 1H NMR (400 MHz, DMSO - d 6 ) δ 9.31 (s, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.65 (d, J = 5.8 Hz, 2H), 6.61 (d, J = 1.9 Hz, 1H), 6.60 - 6.53 (m, 1H), 6.20 (d, J = 8.2 Hz, 1H), 4.32 (d, J = 6.2 Hz, 2H), 3.92 (s, 2H), 2.22 (s, 3H), 2.05 (s, 3H). Preparative HPLC purification conditions: Column: SunFire preparative C18 OBD column, 19 * 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 4 3 HCO

[0373] Example 20: 5-[4-[[(3,6-Dimethyl-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0374]

[0375] Prepared according to Example 4, using 3,6-dimethylpyridin-2-amine in Step 1, the title compound was obtained as a white solid in 20.52% overall yield. MS: m / z: C 16 H 17 FN 4 O 4 S[M + H] + Calculated for 381; found 381. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.48 (s, 1H), 9.96 (s, 1H), 8.29 (s, 1H), 7.71 (d, J = 7.3 Hz, 1H), 6.75 - 6.66 (m, 3H), 4.71 (d, J = 5.3 Hz, 2H), 4.13 (d, J = 3.1 Hz, 2H), 2.43 (s, 3H), 2.22 (s, 3H).

[0376] Preparative HPLC purification conditions: Column: SunFire Preparative C18 OBD column, 19 * 150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 40% B to 60% B, 60% B in 5.5 min; Wavelength: 210 / 254 nm.

[0377] Example 21: 5-[4-[[(3,6-Dimethoxy-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0378]

[0379] Procedure 5:

[0380]

[0381] Step 1: To a stirred solution of 6-chloro-2-nitro-pyridin-3-ol (2 g, 11.46 mmol) and MeI (4.88 g, 34.38 mmol) in DMF (20 mL) was added K 2 CO 3(4.74 g, 34.38 mmol). The reactants were stirred at room temperature for 14 h. After completion of the reaction was monitored by LCMS, the mixture was diluted with ethyl acetate and washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (10% to 30% ethyl acetate / petroleum ether) to give 6-chloro-3-methoxy-2-nitropyridine as an off-white solid (1.5 g, 7.95 mmol, 69.42% yield). MS: m / z: C 6 H 5 ClN 2 O 3 [M-H] - Calculated for is 187; found 187.

[0382] Step 2: At 0 °C, zinc powder (3.12 g, 47.73 mmol) was added to a stirred solution of 6-chloro-3-methoxy-2-nitropyridine (1.5 g, 7.95 mmol) and NH 4 Cl (6.81 g, 127.27 mmol) in a mixed solvent of THF (30 mL) and water (10 mL). The mixture was stirred at room temperature for 12 h. After completion of the reaction was monitored by LCMS, the mixture was filtered. The filtrate was diluted with water and the solution was extracted 3 times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (20% to 40% ethyl acetate / petroleum ether) to give 6-chloro-3-methoxypyridin-2-amine as a pale yellow solid (800 mg, 5.04 mmol, 63.41% yield). MS: m / z: C 6 H 7 ClN 2 O [M+H] + Calculated for is 159; found 159.

[0383] Step 3: At 0 °C, 2,2-dimethylpropanoyl chloride (729.91 mg, 6.05 mmol) was added to a stirred solution of 6-chloro-3-methoxypyridin-2-amine (800 mg, 5.04 mmol) and pyridine (1.195 g, 15.13 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 12 h. After completion of the reaction was monitored by LCMS, the mixture was quenched with water. The solution was extracted 3 times with DCM. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0% to 40% ethyl acetate / petroleum ether) to give N-(6-chloro-3-methoxy-2-pyridyl)-2,2-dimethylpropanamide as a white solid (700 mg, 2.88 mmol, 57.17% yield). MS: m / z: C 11 H 15 ClN2 O 2 [M+H] + The calculated value of

[0384] Step 4: Under nitrogen, to N-(6-chloro-3-methoxy-2-pyridinyl)-2,2-dimethyl-propanamide (400 mg, 1.65 mmol) and K 3 PO 4 (698.81 mg, 3.3 mmol) in a stirred solution of 1,4-dioxane (12 mL) and methanol (2 mL), add Pd 2 (dba) 3 (150.92 mg, 0.16 mmol) and t-BuBrettphos (190.52 mg, 0.33 mmol). Stir the mixture at 80 °C under nitrogen for 12 h. After monitoring the completion of the reaction by LCMS, dilute the mixture with ethyl acetate and wash with brine. Dry the organic phase over anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (10% to 40% ethyl acetate / petroleum ether) to obtain N-(3,6-dimethoxy-2-pyridinyl)-2,2-dimethyl-propanamide as a pale yellow solid (140 mg, 0.58 mmol, 35.64% yield). MS: m / z: C 7 H 10 N 2 O 2 [M+H] + The calculated value of is 155; the measured value is 155. Step 5: At 0 °C, add TMSCl (42.7 μL, 0.34 mmol) dropwise to a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (90 mg, 0.23 mmol) and 3,6-dimethoxypyridin-2-amine (45.73 mg, 0.29 mmol) in DMF (9 mL). After stirring the mixture at room temperature for 1 h, add NaBH 3 CN (35.8 mg, 0.57 mmol) to the above mixture. Stir the suspension at room temperature for another 2 h. LCMS shows the completion of the reaction. The resulting solution is directly purified by reverse-phase column chromatography (H containing 0.05% NH 4 HCO 3 of 2Purified with O and MeCN to obtain 5-[4-[[(3,6-dimethoxy-2-pyridinyl)amino]methyl]-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one as a pale yellow oil (100 mg, 0.18 mmol, 82.28% yield). MS: m / z: C 24 H 25 FN 4 O 7 S[M+H] + The calculated value is 533; the measured value is 533.

[0385] Step 6: At 0 °C, add TFA (4 mL) to a stirred solution of 5-[4-[[(3,6-dimethoxy-2-pyridinyl)amino]methyl]-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one (40 mg, 0.08 mmol) in DCM (2 mL). Stir the mixture at room temperature for 2 h. After monitoring the completion of the reaction by LCMS, concentrate the mixture. The resulting residue was purified by reverse-phase column chromatography (containing 0.05% NH 4 HCO 3 of H 2 O and MeCN) and further purified by preparative HPLC to obtain 5-[4-[[(3,6-dimethoxy-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one as a gray solid (7.6 mg, 0.017 mmol, 23.38% yield). MS: m / z: C 16 H 17 FN 4 O 6 S[M+H] + The calculated value is 413, and the measured value is 413. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.21 (s, 3H), 7.03 (s, 1H), 6.46 (d, J = 8.4 Hz, 2H), 5.50 (s, 2H), 3.91 (s, 2H), 3.72 (d, J = 14.2 Hz, 6H), 3.62 (s, 2H).

[0386] Preparative HPLC conditions: Column: XBridge preparative OBD column, 19 * 100 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 8 min, 45% B to 65% B, 65% B; Wavelength: 254 / 210 nm.

[0387] Example 22: 5-[2-Fluoro-6-hydroxy-4-[[(3-methoxy-6-methyl-2-pyridinyl)amino]methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0388]

[0389] According to the preparation of Example 4, 3-methoxy-6-methyl-pyridin-2-amine was used in Step 1 to obtain the title compound as a white solid in an overall yield of 9.32%. MS: m / z: C 16 H 17 FN 4 O 5 S[M+H] + Calculated value for is 397; Observed value is 397. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 7.30 (s, 1H), 6.66 (d, J = 13.0 Hz, 3H), 4.63 (s, 2H), 4.09 (s, 2H), 3.90 (s, 3H), 2.34 (s, 3H). Purification conditions for preparative HPLC: Column: SunFire preparative C18 OBD column, 19 * 150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: within 5.3 min, 30% B to 50% B, 50% B; Wavelength: 210 / 254 nm.

[0390] Example 23: 5-[4-[[(3-Ethyl-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0391]

[0392] According to the preparation of Example 4, 3-ethylpyridin-2-amine was used in Step 1 to obtain the title compound as a white solid in an overall yield of 4.45%. MS: m / z: C 16 H 17 FN 4 O 4 S[M+H] + Calculated value for is 381; Observed value is 381. 1 H NMR (400 MHz, DMSO-d 6)δ: 9.85 (s, 1H), 8.44 (s, 1H), 7.79 (s, 2H), 6.92 - 6.82 (m, 1H), 6.68 (d, J=16.6 Hz, 2H), 4.71 - 4.45 (m, 2H), 4.16 - 3.94 (m, 2H), 2.63 - 2.62 (m, 2H), 1.23 - 1.19 (m, 3H).

[0393] Preparative HPLC purification conditions: Column: SunFire preparative C18 OBD column, 19 * 150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: within 6.5 min, 30% B to 55% B, 55% B; Wavelength: 254 nm.

[0394] Example 24: 5 - [4 - [[(3,5 - dimethyl - 2 - pyridyl)amino]methyl] - 2 - fluoro - 6 - hydroxy - phenyl] - 1,1 - dioxido - 1,2,5 - thiadiazolidin - 3 - one

[0395]

[0396] According to the preparation of Example 4, 3,5 - dimethylpyridin - 2 - amine was used in Step 1 to obtain the title compound as an off - white solid in a total yield of 17.83%. MS: m / z: C 16 H 17 FN 4 O 4 S[M + H] + The calculated value is 381; the measured value is 381. 1 HNMR(400 MHz, DMSO - d 6 )δ 12.93 (s, 1H), 9.64 (s, 1H), 8.27 (s, 1H), 7.68 (d, J=11.8 Hz, 1H), 7.62 (s, 1H), 6.65 (dd, J=13.4, 2.6 Hz, 2H), 4.56 (d, J=5.8 Hz, 2H), 3.98 (s, 2H), 2.32 - 2.12 (m, 6H).

[0397] Preparative HPLC purification conditions: Column: SunFire preparative C18 OBD column, 19 * 150 mm, 5 μm; Mobile phase A: water (0.1% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: within 7 min, 8% B to 40% B, 40% B; Wavelength: 210 / 254 nm.

[0398] Example 25: 5-[4-[[(3,4-Dimethyl-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0399]

[0400] Prepared according to Example 4, using 3,4-dimethylpyridin-2-amine in step 1, the title compound was obtained as an off-white solid in a total yield of 12.02%. MS: m / z: C 16 H 17 FN 4 O 4 S[M+H] + Calculated value for is 381; found value is 381. 1 HNMR(400MHz, DMSO-d 6 ) δ 12.90 (s, 1H), 9.64 (s, 1H), 8.28 (s, 1H), 7.72 (d, J = 6.3 Hz, 1H), 6.81 (d, J = 6.7 Hz, 1H), 6.65 (d, J = 11.6 Hz, 2H), 4.58 (d, J = 6.0 Hz, 2H), 3.97 (s, 2H), 2.34 (d, J = 8.1 Hz, 3H), 2.18 (s, 3H), 2.09 (d, J = 7.1 Hz, 1H).

[0401] Preparative HPLC purification conditions: Column: SunFire Preparative C18 OBD column, 19 * 150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: within 6 min, 25% B to 25% B, 25% B; Wavelength: 210 / 254 nm.

[0402] Example 26: 5-[4-[[(4,5-Dimethoxy-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0403]

[0404] Prepared according to Example 4, using 4,5-dimethoxypyridin-2-amine in step 1, the title compound was obtained as a white solid in a total yield of 21.72%. MS: m / z: C 16 H 17 FN 4 O 6 S[M+H] + Calculated value for is 413; found value is 413. 1HNMR (400 MHz, DMSO-d 6 ) δ 12.57 (s, 1H), 9.82 (s, 1H), 8.52 (s, 1H), 7.43 (d, J = 1.8 Hz, 1H), 6.71 (d, J = 10.1 Hz, 2H), 6.53 (s, 1H), 4.49 (d, J = 5.4 Hz, 2H), 4.05 (d, J = 4.1 Hz, 2H), 3.93 (s, 3H), 3.77 (s, 3H).

[0405] Purification conditions for preparative HPLC: Column: SunFire preparative C18 OBD column, 19 * 150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: from 30% B to 50% B in 5 min, 50% B in 0.3 min; Wavelength: 254 / 210 nm.

[0406] Example 27: 5-[4-[[(3,4-Dimethoxy-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0407]

[0408] Procedure 6:

[0409]

[0410] Step 1: At -70 °C under a nitrogen atmosphere, add a hexane solution of n-butyllithium (17 mL, 43.08 mmol) to a stirred mixture of 3,4-dimethoxypyridine (2.00 g, 14.37 mmol) in THF (100.0 mL). Stir the resulting mixture at -70 °C under a nitrogen atmosphere for 1 h. At -70 °C under a nitrogen atmosphere, add a solution of C 2 Cl 6 (3.41 g, 14.40 mmol) in THF (20 mL) to the above mixture. Stir the resulting mixture at room temperature for 12 h. After monitoring the completion of the reaction by LCMS, quench the reactants with NH 4 Cl at room temperature. Extract the solution 3 times with ethyl acetate. Wash the combined organic layers with brine (200 mL), dry over anhydrous Na 2 SO 4 , filter and concentrate. Purify the residue by silica gel column chromatography (eluting with ethyl acetate) to obtain 2-chloro-3,4-dimethoxypyridine as a white solid (800 mg, 4.61 mmol, 32.06% yield). MS: m / z: C 7 H8 ClNO 2 [M+H] + The calculated value of is 174; the measured value is 174.

[0411] Step 2: At room temperature, Pd(OAc) 2 CO 3 (2.095 g, 15.18 mmol) was added to a stirred mixture of (4-methoxyphenyl)methanamine (813 mg, 5.93 mmol), 2-chloro-3,4-dimethoxypyridine (872 mg, 5.02 mmol) and K 2 (112.77 mg, 0.50 mmol) and BINAP (938.31 mg, 1.51 mmol) in toluene (20 mL). The resulting mixture was stirred at 130 °C under a nitrogen atmosphere for 12 h. LCMS showed complete depletion of the starting materials. The reaction mixture was concentrated and purified by reverse-phase column chromatography to give 3,4-dimethoxy-N-[(4-methoxyphenyl)methyl]pyridin-2-amine (770 mg, 2.81 mmol, 55.88% yield) as a yellow solid. MS: m / z: C 15 H 18 N 2 O 3 [M+H] + The calculated value of is 275; the measured value is 275.

[0412] Step 3: At room temperature, TFA (10 mL) was added to a stirred mixture of 3,4-dimethoxy-N-[(4-methoxyphenyl)methyl]pyridin-2-amine (770 mg, 2.81 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 14 h. After monitoring the completion of the reaction by LCMS, the mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography (with 0.05% NH 4 HCO 3 in H 2 O and MeCN) to give 3,4-dimethoxypyridin-2-amine (300 mg, 1.95 mmol, 69.40% yield) as a white solid. MS: m / z: C 7 H 10 N 2 O 2 [M+H] + The calculated value of is 155; the measured value is 155.

[0413] Step 4: According to the preparation of Example 1, compound 6-5 was prepared as a white solid in 29.62% yield using 3,4-dimethoxypyridin-2-amine in Step 1. After adding TMSCl, the reaction mixture was stirred at 60 °C. MS: m / z: C24 H 25 FN 4 O 7 S[M+H] + The calculated value of

[0414] Step 5: According to the preparation of Example 4, in Step 2, 6-5 was used to obtain the title compound as a white solid in a yield of 20.50%. MS: m / z: C 16 H 17 FN 4 O 6 S[M+H] + The calculated value of 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.47 (s, 1H), 7.79 (d, J = 7.1 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 6.68 (d, J = 9.4 Hz, 2H), 4.56 (d, J = 5.5 Hz, 2H), 4.12 (s, 2H), 4.03 (s, 3H), 3.84 (s, 3H).

[0415] Purification conditions for preparative HPLC: Column: SunFire preparative C18 OBD column, 19 * 150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 6.8 min, 30% B to 50% B, 50% B; Wavelength: 254 / 210 nm.

[0416] Example 28: 5-[4-[[(4,5-Dimethyl-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0417]

[0418] According to the preparation of Example 4, in Step 1, 4,5-dimethylpyridin-2-amine was used to obtain the title compound as a white solid in an overall yield of 11.79%. MS: m / z: C 16 H 17 FN 4 O 4 S[M+H] + The calculated value of 1 H NMR (400 MHz, DMSO-d 6)δ 7.68 (s, 1H), 6.87 (s, 1H), 6.67 (d, J = 9.8 Hz, 2H), 4.45 (s, 2H), 3.95 (s, 2H), 2.27 (s, 3H), 2.10 (s, 3H).

[0419] Preparative HPLC purification conditions: Column: SunFire preparative C18 OBD column, 19 * 150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: within 5.3 min, 50% B to 65% B, 65% B; Wavelength: 210 / 254 nm.

[0420] Example 29: 5-[2-Fluoro-6-hydroxy-4-[[(6-methoxy-3-methyl-2-pyridinyl)amino]methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0421]

[0422] Process 7:

[0423]

[0424] Step 1: At room temperature, add Pd(dppf) 2 Cl 2 (155.66 mg, 0.22 mmol) and a solution of Zn(CH 3 ) 2 (1.37 g, 14.37 mmol) in toluene (8.5 mL) to a stirred mixture of 2-methoxy-5-bromo-6-chloro-pyridine (1 g, 7.19 mmol) in 1,4-dioxane (10 mL). Stir the resulting mixture overnight at 90 °C under a nitrogen atmosphere. After monitoring the completion of the reaction by LCMS, quench the mixture with ice water (20 mL). Extract the solution 3 times with ethyl acetate. Wash the combined organic layers with brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate. Purify the residue by silica gel column chromatography (eluting with petroleum ether) to obtain 2-chloro-6-methoxy-3-methyl-pyridine as a white solid (280.00 mg, 1.77 mmol, 24.7% yield). MS: m / z: C 7 H 8 ClNO [M + H] + Calculated value is 158; Observed value is 158.

[0425] Step 2: Under nitrogen, to 2-chloro-6-methoxy-3-methyl-pyridine (500 mg, 3.17 mmol), (4-methoxyphenyl)methanamine (500 mg, 3.64 mmol), and K2 CO 3 (1313.45 mg, 9.52 mmol) was added to a stirred mixture of Pd(OAc) in toluene (10 mL) 2 (71.23 mg, 0.32 mmol) and BINAP (592.64 mg, 0.95 mmol). The resulting mixture was stirred at 130 °C under a nitrogen atmosphere for 5 h. After monitoring the completion of the reaction by LCMS, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (10% to 30% ethyl acetate / petroleum ether) to give 6-methoxy-N-[(4-methoxyphenyl)methyl]-3-methyl-pyridin-2-amine as a yellow oil (300 mg, 1.1614 mmol, 36.60% yield). MS: m / z: calculated for MS: m / z: C 15 H 18 N 2 O 2 [M + H] + was calculated to be 259; found 259.

[0426] Step 3: At room temperature, TFA (5 mL) was added to a stirred mixture of 6-methoxy-N-[(4-methoxyphenyl)methyl]-3-methyl-pyridin-2-amine (300 mg, 1.16 mmol) in DCM (10 mL). The resulting mixture was stirred at room temperature for 12 h. After monitoring the completion of the reaction by LCMS, the resulting mixture was concentrated under reduced pressure to give 6-methoxy-3-methyl-pyridin-2-amine (500 mg, TFA salt). MS: m / z: calculated for MS: m / z: C 7 H 10 N 2 O [M + H] + was calculated to be 139; found 139.

[0427] Step 4: At 0 °C, 6-methoxy-3-methyl-pyridin-2-amine (56.06 mg, 0.41 mmol) and titanium(IV) isopropoxide chloride (105.48 mg, 0.41 mmol) were added to a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (80 mg, 0.20 mmol) in 1,2-dichloroethane (4 mL). The reaction mixture was stirred at room temperature for 16 h. NaBH 3 CN (0.05 mL, 0.61 mmol) was added to the mixture and the reactants were stirred for an additional 2 h at room temperature. LCMS showed complete depletion of the starting material. The resulting solution was diluted with dichloromethane (10 mL) and concentrated directly in vacuo. The resulting residue was directly purified by reverse-phase column chromatography (containing 0.05% NH4 HCO 3 of H 2 O and MeCN) to give 5-[2-fluoro-4-[[(6-methoxy-3-methyl-2-pyridinyl)amino]methyl]-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one as a pale yellow solid (50 mg, 0.09 mmol, 47.71% yield). MS: m / z: C 24 H 25 FN 4 O 6 S[M + H] + calculated for 517; found 517.

[0428] Step 5: To a stirred solution of 5-[2-fluoro-4-[[(6-methoxy-3-methyl-2-pyridinyl)amino]methyl]-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one (7-5, 93 mg, 0.18 mmol) in DCM (3 mL) was added TFA (3 mL) and the mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was concentrated. The resulting residue was purified by reverse-phase flash chromatography (with 0.05% NH 4 HCO 3 of H 2 O and ACN) and further purified by preparative HPLC to give 5-[2-fluoro-6-hydroxy-4-[[(6-methoxy-3-methyl-2-pyridinyl)amino]methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one as a white solid (8 mg, 12.67% yield). MS: m / z: C 16 H 17 FN 4 O 5 S[M + H] + calculated for 397; found 397. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.20 (s, 1H), 7.17 (d, J = 7.7 Hz, 1H), 6.88 - 6.37 (m, 3H), 5.84 (d, J = 7.7 Hz, 1H), 4.46 (s, 2H), 4.33 (d, J = 4.6 Hz, 2H), 3.64 (s, 3H), 2.03 (s, 3H).

[0429] Preparative HPLC purification conditions: Column: SunFire preparative C18 OBD column, 19 * 150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 6.8 min, 25% B to 45% B, 45% B; Wavelength: 254 / 210 nm.

[0430] Example 30: 5-[4-[[(3,5-Dimethoxy-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0431]

[0432] According to the preparation of Example 4, 3,5-dimethoxypyridin-2-amine was used in Step 1 to obtain the title compound as a white solid in a total yield of 22.59%. MS: m / z: C 16 H 17 FN 4 O 6 S[M+H] + The calculated value is 413; the measured value is 413. 1 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.09 (s, 1H), 7.46 - 7.02 (m, 2H), 6.70 - 6.61 (m, 2H), 4.51 (s, 2H), 4.18 (d, J = 5.7 Hz, 2H), 3.95 (d, J = 2.2 Hz, 3H), 3.76 (s, 3H).

[0433] Preparative HPLC purification conditions: Column: SunFire preparative C18 OBD column, 19 * 150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: within 5.3 min, 25% B to 45% B, 45% B; Wavelength: 210 / 254 nm.

[0434] Example 31: 5-[2-Fluoro-4-[[(5-fluoro-4-methyl-2-pyridinyl)amino]methyl]-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0435]

[0436] According to the preparation of Example 4, 5-fluoro-4-methyl-pyridin-2-amine was used in Step 1 to obtain the title compound as an off-white solid in a total yield of 12.31%. MS: m / z: C 15 H14 F 2 N 4 O 4 S[M+H] + The calculated value of [S[M+H]] is 385; the measured value is 385. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.89 (d, J = 2.6 Hz, 1H), 6.73 - 6.61 (m, 3H), 4.38 (s, 2H), 4.08 (s, 2H), 2.21 (s, 3H).

[0437] Preparative HPLC purification conditions: Column: SunFire preparative C18 OBD column, 30 * 50 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 8 min, 5% B to 30% B, 30% B; Wavelength: 254 / 210 nm.

[0438] Example 32: 6-[[3-Fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]-4-methyl-pyridine-3-carbonitrile

[0439]

[0440] According to the preparation of Example 1, 6-amino-4-methyl-pyridine-3-carbonitrile was used in Step 1 to obtain the title compound as a white solid in an overall yield of 10.68%. MS: m / z: C 16 H 14 FN 5 O 4 S[M+H] + The calculated value of [S[M+H]] is 392; the measured value is 392. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.32 (s, 1H), 7.99 (t, J = 6.1 Hz, 1H), 7.57 (s, 1H), 6.63 - 6.54 (m, 2H), 6.49 (s, 1H), 4.44 (d, J = 6.1 Hz, 2H), 3.93 (s, 2H), 2.28 (s, 3H).

[0441] Preparative HPLC purification conditions: Column: XBridge Shield RP18 OBD column, 19 * 250 mm, 10 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: within 6 min, from 25% B to 35% B, then 35% B; Wavelength: 254 / 210 nm.

[0442] Example 33: 5-[2-Fluoro-4-[[(4-fluoro-5-methyl-2-pyridinyl)amino]methyl]-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0443]

[0444] Prepared according to Example 4, using 4-fluoro-5-methyl-pyridin-2-amine in Step 1, the title compound was obtained as a white solid in a total yield of 5.33%. MS: m / z: C 15 H 14 F 2 N 4 O 4 S[M+H] + Calculated value is 385; Measured value is 385. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.14 (s, 1H), 7.94 (d, J = 9.4 Hz, 1H), 6.72 - 6.61 (m, 3H), 4.43 (s, 2H), 4.13 (s, 2H), 2.08 (s, 3H).

[0445] Purification conditions for preparative HPLC: Column: SunFire preparative C18 OBD column, 19*150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: within 5.3 min, from 25% B to 50% B, then 50% B; Wavelength: 210 / 254 nm.

[0446] Example 34: 5-[2-Fluoro-6-hydroxy-4-[[(3-methoxy-2-pyridinyl)amino]methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0447]

[0448] Prepared according to Example 4, using 3-methoxypyridin-2-amine in Step 1, the title compound was obtained as a brown solid in a total yield of 11.08%. MS: m / z: C 15 H 15 F N 4 O 4 S[M+H] + Calculated value is 383; Measured value is 383.1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.44 (d, J = 6.2 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 6.83 (t, J = 7.1 Hz, 1H), 6.64 (d, J = 10.3 Hz, 2H), 4.54 (s, 2H), 4.39 (s, 0H), 4.00 (s, 2H), 3.94 (s, 3H).

[0449] Preparative HPLC purification conditions: Column: SunFire preparative C18 OBD column, 30 * 50 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 9 min, 4% B to 35% B, 35% B; Wavelength: 254 / 210 nm.

[0450] Example 35: 5-[2-Fluoro-6-hydroxy-4-[[(6-methoxypyridin-2-yl)amino]methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0451]

[0452] Prepared according to Example 4, using 6-methoxypyridin-2-amine in Step 1, the title compound was obtained as a white solid in a total yield of 6.83%. MS: m / z: C 15 H 15 FN 4 O 5 S [M + H] + Calculated value for is 383; Measured value is 383. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 10.32 (s, 1H), 7.39 - 7.29 (m, 1H), 7.18 - 6.91 (m, 1H), 6.80 - 6.61 (m, 2H), 6.03 (dd, J = 7.8, 1.8 Hz, 1H), 5.90 (dd, J = 7.7, 1.7 Hz, 1H), 4.36 (d, J = 2.5 Hz, 4H), 3.71 (d, J = 1.1 Hz, 3H).

[0453] Preparative HPLC purification conditions: Column: SunFire preparative C18 OBD column, 30 * 50 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 8 min, 5% B to 35% B, 35% B; Wavelength: 254 / 210 nm.

[0454] Example 36: 5-[4-[[(5,6-Dimethoxy-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxyphenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0455]

[0456] Prepared according to Example 4. In step 1, 4,5-dimethoxypyridin-2-amine was used to obtain the title compound as an off-white solid in 22.83% overall yield. MS: m / z: C 16 H 17 FN 4 O 6 S[M+H] + Calculated value for is 413; found value is 413. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.48 (s, 2H), 7.09 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 1.9 Hz, 1H), 6.65 - 6.58 (m, 2H), 5.91 (d, J = 8.3 Hz, 1H), 4.27 (d, J = 6.2 Hz, 2H), 3.92 (s, 2H), 3.75 (s, 3H), 3.61 (s, 3H).

[0457] Preparative HPLC purification conditions: Column: XBridge BEH C18 OBD preparative column, 19 * 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 )), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: within 6 min, 27% B to 27% B, 27% B; Wavelength: 254 nm.

[0458] Example 37: 5-[2-Fluoro-6-hydroxy-4-[(2-pyridinylamino)methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0459]

[0460] Prepared according to Example 4. In step 1, pyridin-2-amine was used to obtain the title compound as a white solid in 6.01% overall yield. MS: m / z: C 14 H 13 FN 4 O 4 S[M+H] + Calculated value for is 353; found value is 353. 1 1H NMR (400 MHz, DMSO-d 6) δ 9.54 (s, 1H), 7.95 (d, J = 5.8 Hz, 2H), 7.64 (dd, J = 11.7, 4.6 Hz, 1H), 7.34 - 6.94 (m, 1H), 6.89 - 6.55 (m, 4H), 4.43 (d, J = 5.6 Hz, 2H), 3.96 (s, 2H).

[0461] Preparative HPLC purification conditions: Column: XBridge BEH C18 OBD preparative column, 19 * 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: within 6 min, 13% B to 38% B, 38% B; Wavelength: 254 nm.

[0462] Example 38: 5-[2-Fluoro-6-hydroxy-4-[[(5-methoxypyridin-2-yl)amino]methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0463]

[0464] According to the preparation of Example 4, 5-methoxypyridin-2-amine was used in Step 1 to obtain the title compound as a white solid in an overall yield of 15.72%. MS: m / z: C 15 H 15 FN 4 O 5 S [M + H] + The calculated value is 383; the measured value is 383. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.79 (s, 1H), 8.19 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 2.9 Hz, 1H), 6.92 (d, J = 9.5 Hz, 1H), 6.69 (m, J = 9.2, 1.9 Hz, 2H), 4.44 (s, 2H), 4.06 (m, J = 4.3 Hz, 2H), 3.76 (s, 3H).

[0465] Preparative HPLC purification conditions: Column: SunFire preparative C18 OBD column, 19 * 150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: within 5.3 min, 30% B to 55% B, 55% B; Wavelength: 210 / 254 nm.

[0466] Example 39: 5-(2-Fluoro-6-hydroxy-4-(((6-methoxy-4-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0467]

[0468] Process 8:

[0469]

[0470] Step 1: 4-bromo-6-methoxy-pyridin-2-amine (300 mg, 1.48 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (370.95 mg, 2.96 mmol) and K 2 CO 3 To a stirred solution of (611.7 mg, 4.43 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl 2 (60.33 mg, 0.07 mmol). The reaction mixture was placed under vacuum, sonicated and backfilled with nitrogen. The resulting mixture was stirred at 115 ° C for 20 h. After the reaction was completed by LCMS monitoring, the mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give 6-methoxy-4-methyl-pyridine-2-amine (150 mg, 1.08 mmol, 73.47% yield) as a yellow solid. MS: m / z: C 7 H 10 N 2 O[M+H] + The calculated value is 139; the found value is 139. Step 2: To a solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (100 mg, 0.25 mmol) and 6-methoxy-4-methyl-pyridin-2-amine (52.55 mg, 0.38 mmol) in DCE (10 mL) was added Ti(i-PrO) at 0°C. 4 (143.01 mg, 0.51 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. At 0 °C, NaBH 3 CN (32.02 mg, 0.51 mmol) was added to the mixture. The resulting mixture was stirred for another 30 min at room temperature. After completion, the reaction mixture was concentrated. The resulting residue was dissolved in DMSO and purified by reverse phase column chromatography (containing 0.05% NH 4 HCO 3 H 2Purified with O and MeCN to obtain 5-[2-fluoro-4-[[(6-methoxy-4-methyl-2-pyridinyl)amino]methyl]-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one as a yellow oil (100 mg, 0.12 mmol, 47.56% yield). MS: m / z: C 24 H 25 FN 4 O 6 S[M+H] + The calculated value of is 517; the measured value is 517.

[0471] Step 3: Add TFA (5 mL) to a solution of 5-[2-fluoro-4-[[(6-methoxy-4-methyl-2-pyridinyl)amino]methyl]-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one (100 mg, 0.19 mmol) in DCM (10 mL) and stir the mixture at room temperature for 2 h. After completion, concentrate the reaction mixture. The resulting residue was purified by reverse-phase column chromatography (with 0.05% NH 4 HCO 3 of H 2 O and MeCN) and further purified by preparative HPLC to obtain 5-[2-fluoro-6-hydroxy-4-[[(6-methoxy-4-methyl-2-pyridinyl)amino]methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one as a white solid (10.8 mg, 0.02 mmol, 13.58% yield). MS: m / z: C 16 H 17 FN 4 O 5 S[M+H] + The calculated value of is 397; the measured value is 397. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 7.27 - 7.02 (m, 1H), 6.83 - 6.60 (m, 2H), 5.93 - 5.79 (m, 2H), 4.37 (s, 4H), 3.71 (s, 3H), 2.11 (s, 3H). Preparative HPLC purification conditions: Column: SunFire preparative C18 OBD column, 19 * 150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: within 6 min, 10% B to 30% B, 30% B; Wavelength: 210 / 254 nm.

[0472] Example 40: 6-[[3-Fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]pyridine-2-carbonitrile

[0473]

[0474] Prepared according to Example 1, using 6-aminopyridin-2-amine in Step 1, the title compound was obtained as a white solid in an overall yield of 8.88%. After adding TMSCl, the reaction mixture was stirred at 60 °C instead of room temperature. MS: m / z: C 15 H 12 FN 5 O 4 S[M + H] + Calculated value for is 378; found value is 378. 1 H NMR (400 MHz, methanol-d 4 ) δ 7.52 (dd, J = 8.7, 7.1 Hz, 1H), 7.01 (dd, J = 7.1, 0.8 Hz, 1H), 6.81 - 6.74 (m, 2H), 6.70 (dd, J = 10.6, 1.9 Hz, 1H), 4.50 (s, 2H), 4.41 (s, 2H).

[0475] Preparative HPLC purification conditions: Column: SunFire C18 OBD preparative column, 19 * 250 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 20% B to 55% B in 7 min, 55% B; Wavelength: 254 / 210 nm.

[0476] Example 41: 5-[2-Fluoro-6-hydroxy-4-[[(4-methoxy-6-methyl-2-pyridinyl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one

[0477]

[0478] Prepared according to Example 4, using 4-methoxy-6-methyl-pyridin-2-amine in Step 1, the title compound was obtained as an off-white solid in an overall yield of 3.97%. MS: m / z: C 16 H 17 FN 4 O 5 S[M + H] + Calculated value for is 397; found value is 397. 1 H NMR (400 MHz, DMSO-d 6) δ 6.66 (d, J = 10.8 Hz, 2H), 6.28 (s, 1H), 6.00 (s, 1H), 4.39 (s, 2H), 3.76 (s, 3H), 2.28 (s, 3H).

[0479] Preparative HPLC purification conditions: Column: XBridge Shield RP18 OBD column, 30 * 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 8 min, 53% B to 60% B, 60% B; Wavelength: 254 / 210 nm.

[0480] Example 42: 5-[4-[[[6-(Difluoromethyl)-2-pyridinyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0481]

[0482] According to the preparation of Example 1, 6-(difluoromethyl)pyridin-2-amine was used in Step 1 to obtain the title compound as a white solid in an overall yield of 16.46%. Reductive amination was carried out at 60 °C instead of room temperature. MS: m / z: C 15 H 13 F 3 N 4 O 4 S [M + H] + The calculated value is 403; the measured value is 403. 1 H NMR (400 MHz, DMSO-d 6 + D 2 O) δ 7.58 - 7.50 (m, 1H), 6.82 - 6.48 (m, 5H), 4.38 (s, 2H), 3.94 (s, 2H).

[0483] Preparative HPLC purification conditions: Column: XBridge preparative OBD C18 column, 19 * 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 ),Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: within 6 min, 28% B to 48% B, 48% B; Wavelength: 254 / 210 nm.

[0484] Example 43: 5-[4-[[[6-(Difluoromethoxy)-2-pyridinyl]amino]methyl]-2-fluoro-6-hydroxyphenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0485]

[0486] Prepared according to Example 4, using 6-(difluoromethoxy)pyridin-2-amine in Step 1, the title compound was obtained as an off-white solid in 27.09% overall yield. MS: m / z: C 15 H 13 F 3 N 4 O 5 S[M+H] + Calculated for 419; found 419. 1 H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 73.8 Hz, 1H), 7.48 - 7.38 (m, 2H), 7.18 (s, 2H), 6.67 - 6.62 (m, 1H), 6.29 (d, J = 8.1 Hz, 1H), 6.06 (d, J = 7.5 Hz, 1H), 4.33 (d, J = 6.1 Hz, 2H), 3.93 (s, 2H).

[0487] Preparative HPLC purification conditions: Column: Xselect CSH C18 OBD column, 30 * 150 mm 5 μm, n; Mobile phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 7 min, 24% B to 34% B, within 8.5 min, 34% B to 49% B, 49% B; Wavelength: 254 nm.

[0488] Example 44: 5-(4-(((6-(Dimethylamino)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0489]

[0490] Scheme 9:

[0491]

[0492] Step 1: At 0 °C, TMSCl (0.07 mL, 0.63 mmol) was added dropwise to a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (100 mg, 0.25 mmol) and N,N-dimethylpyridine-2,6-diamine (52.18 mg, 0.38 mmol) in anhydrous DMF (5 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C and DMF (2 mL) containing NaBH 3 CN (32.02 mg, 0.51 mmol) was added. After the addition, the reaction mixture was stirred at room temperature for 12 h. LCMS showed that the reaction was complete. The resulting solution was quenched with ice water (0.5 ml) and purified directly by reverse-phase column chromatography (H 2 O containing 0.05% FA and MeCN) to give 5-[4-[[[6-(dimethylamino)-2-pyridinyl]amino]methyl]-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (50 mg, 0.09 mmol, 38.24% yield) as a pale yellow oil. MS: m / z: C 24 H 22 FN 5 O 5 S[M + H] + calculated for 516; found 516.

[0493] Step 2: At room temperature, TFA (2 mL) was added dropwise to a stirred mixture of 5-[4-[[[6-(dimethylamino)-2-pyridinyl]amino]methyl]-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (50 mg, 0.09 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 1 h. After monitoring the completion of the reaction by LCMS, the mixture was concentrated. The residue was purified by reverse-phase column chromatography (H 4 O containing 0.05% NH 3 HCO 2 and MeCN) and further purified by preparative HPLC to give 5-[4-[[[6-(dimethylamino)-2-pyridinyl]amino]methyl]-2-fluoro-6-hydroxyphenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2.7 mg, 0.006 mmol, 6.75% yield) as a light green solid. MS: m / z: C 16 H 18 FN 5 O 4 S[M + H] +The calculated value is 396, and the measured value is 396. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.39 (s, 1H), 7.13 (t, J = 7.9 Hz, 1H), 6.69 - 6.56 (m, 3H), 5.71 (t, J = 8.3 Hz, 2H), 4.32 (d, J = 6.2 Hz, 2H), 3.93 (s, 2H), 2.90 (d, J = 1.2 Hz, 6H).

[0494] Preparative HPLC conditions: Column: XBridge Shield RP18 OBD column, 30 * 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 . H 2 O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 7.5 min, 25% B to 45% B, 45% B; Wavelength: 254 / 210 nm.

[0495] Example 45: 5-[2-Fluoro-6-hydroxy-4-[[(5-isopropyl-2-pyridinyl)amino]methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0496]

[0497] According to the preparation of Example 1, 5-isopropylpyridin-2-amine was used in Step 1 to obtain the title compound as a white solid in an overall yield of 11.50%. After adding TMSCl, the reaction mixture was stirred at 60 °C instead of 80 °C. MS: m / z: C 17 H 19 FN 4 O 4 S [M + H] + The calculated value is 395; the measured value is 395. 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.81 (s, 1H), 8.84 (s, 1H), 7.96 (d, J = 9.3 Hz, 1H), 7.73 (s, 1H), 7.05 (d, J = 9.3 Hz, 1H), 6.76 - 6.66 (m, 2H), 4.49 (d, J = 5.6 Hz, 2H), 4.03 (s, 2H), 2.88 (m, J = 6.9 Hz, 1H), 1.17 (d, J = 6.9 Hz, 6H).

[0498] Preparative HPLC purification conditions: Column: Xselect CSH C18 OBD column, 30 * 150 mm, 5 μm, n; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 10 min, 3% B to 33% B, 33% B; Wavelength: 254 nm.

[0499] Example 46: 5-[4-[[(4-Benzyloxy-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0500]

[0501] According to the preparation of Example 1, 4-benzyloxypyridin-2-amine was used in Step 1 to obtain the title compound as a white solid in a total yield of 9.27%. After adding TMSCl, the reaction mixture was stirred at 60 °C. MS: m / z: C 21 H 19 FN 4 O 5 S[M + H] + The calculated value is 459; the measured value is 459. 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.81 (d, J = 6.2 Hz, 1H), 7.48 - 7.30 (m, 5H), 6.68 - 6.57 (m, 2H), 6.34 (d, J = 6.3 Hz, 1H), 6.21 (s, 1H), 5.12 (s, 2H), 4.38 (s, 2H), 3.93 (s, 2H).

[0502] Preparative HPLC purification conditions: Column: XBridge preparative OBD C18 column, 30 * 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 H 2 O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 9 min, 23% B to 33% B, 33% B; Wavelength: 254 / 220 nm.

[0503] Example 47: 5-[4-[[(5-Benzyloxy-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one

[0504]

[0505] Prepared according to Example 81, the title compound as a white solid was obtained in 10.23% total yield using 5-benzyloxypyridin-2-amine in Step 1. MS: m / z: C 21 H 19 FN 4 O 5 S[M+H] + Calculated value for is 459; found value is 459. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 7.71 (s, 1H), 7.63 (s, 1H), 7.48 - 7.36 (m, 4H), 7.40 - 7.31 (m, 1H), 6.95 (s, 1H), 6.70 (d, J = 11.0 Hz, 2H), 5.08 (s, 2H), 4.44 (s, 2H), 4.10 (s, 2H).

[0506] Preparative HPLC purification conditions: Column: Xselect CSH C18 OBD column, 30 * 150 mm, 5 μm, n; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 40% B in 10 min, 40% B; Wavelength: 254 nm.

[0507] Example 48: 5-(4-(((6-Bromo-4-methylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0508]

[0509] At 0 °C, trimethylsilyl trifluoromethanesulfonate (0.092 mL, 0.507 mmol) was added to a solution of 4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-((4-methoxybenzyl)oxy)benzaldehyde (Int-2, 100 mg, 0.254 mmol) and 6-bromo-4-methylpyridin-2-amine (95 mg, 0.507 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 h. At 0 °C, NaBH(AcO) was added to the reaction mixture 3(107 mg, 0.507 mmol). The mixture was stirred for an additional 8 h at room temperature. LCMS showed complete depletion of the starting material (50% of the desired product and 5% of the PMB-protected intermediate were observed). The reaction mixture was concentrated, a 1:1 TFA / DCM solution was added to the resulting residue and stirred for 2 h at room temperature. The resulting solution was concentrated at low temperature (bath temperature: 25 °C). The crude material was purified by preparative reverse-phase chromatography using the following conditions: column: XBridge C18, 19 mm × 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 °C. Elution fraction collection was triggered by MS (ESI+). The elution fractions containing the desired product were combined and dried by centrifugal evaporation to give 33.6 mg (29.7% yield) of 5-(4-(((6-bromo-4-methylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide as a white solid. MS: m / z: C 15 H 14 BrFN 4 O 4 S[M+H] + The calculated value for was 445 and the measured value was 445. 1 H NMR (500 MHz, DMSO-d 6 ) δ 6.76 - 6.62 (m, 2H), 6.56 (s, 1H), 6.30 (s, 1H), 4.42 - 4.24 (m, 4H), 2.13 (s, 3H)

[0510] Example 49: 5-(2-Fluoro-6-hydroxy-4-(((4-methyl-6-(morpholin-4-yl)pyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0511]

[0512] Scheme 10:

[0513]

[0514] Step 1: Add 6-bromo-4-methylpyridin-2-amine (1478 mg, 7.9 mmol), morpholine (895 mg, 10.27 mmol) and diisopropylethylamine (4146 μl, 23.8 mmol) to a 250 mL pressure tube. Heat the mixture at 150 °C for 18 h. Quench the reaction mixture with water (10 ml) and extract with EtOAc (2 × 25 ml). Dry the organic phase over sodium sulfate, filter and concentrate to give 740 mg of 4-methyl-6-(morpholin-4-yl)pyridin-2-amine as a brown solid (49% yield) and use it directly in the next step. MS: m / z: C 15 H 14 BrFN 4 O 4 S[M+H] + Calculated for 194, found 194.

[0515] Step 2: At 0 °C, add trimethylsilyl trifluoromethanesulfonate (0.092 mL, 0.507 mmol) to a solution of 4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-((4-methoxybenzyl)oxy)benzaldehyde (Int-2, 100 mg, 0.254 mmol) and 4-methyl-6-(morpholin-4-yl)pyridin-2-amine (98 mg, 0.507 mmol) in DCM (10 mL). Stir the reaction mixture at room temperature for 2 h. At 0 °C, add NaBH(AcO) 3 (107 mg, 0.507 mmol) to the reaction mixture. Stir the mixture at room temperature for an additional 8 h. LCMS shows complete depletion of the starting material (50% of the desired product and 5% of the PMB-protected intermediate were observed). Concentrate the reaction mixture, add a 1:1 TFA / DCM solution to the resulting residue and stir at room temperature for 2 h. Concentrate the resulting solution at low temperature (bath temperature: 25 °C). Purify the crude material by preparative reverse-phase chromatography using the following conditions:

[0516] Column: XBridge C18, 19 mm × 200 mm, 5 μM particles; Flow rate: 20 mL / min; Column temperature: 25 °C. Trigger the collection of elution fractions by MS (ESI+). Combine the elution fractions containing the desired product and dry by centrifugal evaporation. MS: m / z: C 19 H 22 FN 5 O 5 S[M+H] + Calculated for 452, found 452. 1 H NMR (500 MHz, DMSO-d 6)δ 6.76 - 6.61 (m, 2H), 6.00 - 5.88 (m, 1H), 5.88 - 5.77 (m, 1H), 4.44 - 4.30 (m, 2H), 4.21 - 4.05 (m, 2H), 3.77 - 3.60 (m, 3H), 3.57 - 3.41 (m, 3H), 3.40 - 3.28 (m, 2H), 2.13 (s, 3H).

[0517] Example 50: 5-(4-((Cyclopropyl(5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0518]

[0519] Scheme 11:

[0520]

[0521] Step 1: At room temperature, cyclopropylamine (1.729 g, 30.29 mmol) was added to a stirred mixture of 2-fluoro-5-(trifluoromethyl)pyridine (500 mg, 3.03 mmol) in DMSO (8 mL). The resulting mixture was stirred at 130 °C for 2 h. LCMS showed complete depletion of the starting material. The reaction mixture was purified directly by reverse-phase column chromatography to give N-cyclopropyl-5-(trifluoromethyl)pyridin-2-amine as a white solid (400 mg, 1.97 mmol, 65.32% yield). MS: m / z: C 9 H 9 F 3 N 2 [M + H] + Calculated value for is 203, found value is 203.

[0522] Step 2: At 0 °C, TMSOTf (101.33 mg, 0.46 mmol) was added to a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (Int-2 120 mg, 0.30 mmol) and N-cyclopropyl-5-(trifluoromethyl)pyridin-2-amine (92.28 mg, 0.46 mmol) in DCM (8 mL). The reaction mixture was stirred at 50 °C for 2 h. The mixture was cooled to 0 °C, and NaBH(AcO) 3(129.02 mg, 0.61 mmol) was added to the above mixture. The resulting mixture was stirred for an additional 1 h at room temperature. LCMS showed complete depletion of the starting material (50% of the desired product and 8% of the PMB-protected intermediate were observed). Subsequently, TFA (8 mL) was added to the reaction system at 0 °C, and the mixture was stirred for an additional 3 h at room temperature. After monitoring the completion of the reaction by LCMS, the mixture was concentrated. The resulting residue was purified by reverse-phase column chromatography to give 5-[4-[[cyclopropyl-[5-(trifluoromethyl)-2-pyridinyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one as a white solid (14.9 mg, 0.031 mmol, 10.63% yield). MS: m / z: C 18 H 16 F 4 N 4 O 4 S[M+H] + Calculated for 461, found 461. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.41 (s, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 6.46 (d, J = 7.8 Hz, 2H), 4.81 (s, 2H), 3.96 (s, 2H), 2.68 (s, 1H), 0.94 (d, J = 6.6 Hz, 2H), 0.68 (s, 2H).

[0523] Preparative HPLC purification conditions: Column: XBridge Preparative OBD C18 column, 19 * 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 40% B to 55% B in 5.8 min, 55% B; Wavelength: 254 / 210 nm.

[0524] Example 51: 5-(2-Fluoro-6-hydroxy-4-(((6-oxo-1,6-dihydropyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0525]

[0526] Scheme 12:

[0527]

[0528] Step 1: To a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (80 mg, 0.20 mmol) and 6-aminopyridin-2-ol (33.5 mg, 0.30 mmol) was added TMSOTf (135.1 mg, 0.61 mmol) dropwise at 0°C. Subsequently, NaBH(AcO) was slowly added. 3 (86.01 mg, 0.41 mmol). The resulting mixture was stirred at room temperature for 30 min. LCMS showed that the starting material was completely consumed (about 50% of the desired product and 10% of the PMB-protected intermediate were observed). The resulting solution was concentrated at low temperature (water bath temperature: 25°C). The residue was purified by reverse phase column chromatography (containing 0.05% NH 4 HCO 3 H 2 O and MeCN) and further purified by preparative HPLC to give 5-[2-fluoro-6-hydroxy-4-[[(6-oxo-1H-pyridin-2-yl)amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (10.1 mg, 0.03 mmol, 13.24% yield) as an off-white solid. MS: m / z: C 14 H 13 FN 4 O 5 S[M+H] + The calculated value is 369 and the measured value is 369. 1 H NMR (400 MHz, DMSO-d 6 )δ10.19(s,1H),7.37(t,J=8.2Hz,1H),7.01(s,1H),6.68(t,J=5.0Hz,2H),5.71(dd,J=14.7,8.1Hz,2H),4.33(s,2H),4.23(s,2H).

[0529] Preparative HPLC conditions: column: Welch Utimate HS-C18, 21.2*250 mm, 7 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 17% B to 32% B, 32% B in 8 min; wavelength: 254 / 210 nm.

[0530] Example 52: 5-(2-Fluoro-6-hydroxy-4-(((6-methyl-4-phenoxypyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0531]

[0532] Process 13:

[0533]

[0534] Step 1: Add CuBr (11.47 mg, 0.08 mmol) and K 1 , 44 mg, 0.16 mmol) in DMSO (5 mL) to a solution of [N,N'-bis(2,5-dimethylpyrrol-1-yl)oxamide] (L 3 PO 4 (510.05 mg, 2.41 mmol). Stir the mixture at room temperature for 30 min. Add 4-bromo-6-methyl-pyridin-2-amine (300 mg, 1.6 mmol) and phenol (226.42 mg, 2.41 mmol) to the foregoing mixture. Heat the resulting mixture to 120 °C for 16 h. LCMS shows that 80% of the product is formed. The reaction mixture is directly purified by reverse-phase column chromatography (H 4 HCO 3 containing 0.05% NH 2 O and MeCN) to obtain 6-methyl-4-phenoxypyridin-2-amine (160 mg, 0.79 mmol, 49.81% yield) as a brown oil. MS: m / z: C 12 H 12 N 2 O [M+H] + is calculated to be 201 and the measured value is 201.

[0535] Step 2: At 0 °C, add TMSOTf (0.08 mL, 0.46 mmol) dropwise to a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (60 mg, 0.15 mmol) and 6-methyl-4-phenoxypyridin-2-amine (39.6 mg, 0.20 mmol) in DCM (5 mL). Stir the resulting mixture at room temperature for 1 h. Subsequently, cool the reaction mixture to 0 °C and slowly add NaBH(AcO) 3 (43.82 mg, 0.46 mmol). After the addition, stir the reaction mixture at room temperature for another 1 h. LCMS shows that the starting materials are completely depleted (forming approximately 50% of the PMB-deprotected product). Concentrate the resulting solution at low temperature (bath temperature: 25 °C). The residue is purified by reverse-phase column chromatography (H 4 HCO 3 containing 0.05% NH 2It was purified with O and MeCN and further purified by preparative HPLC to obtain 5-[2-fluoro-6-hydroxy-4-[[(6-methyl-4-phenoxy-2-pyridinyl)amino]methyl]phenyl]-1,1-dioxido-1,2,5-thiadiazolidin-3-one as a white solid (19.7 mg, 0.04 mmol, 39.44% yield). MS: m / z: C 21 H 19 FN 4 O 5 S[M+H] + The calculated value is 459, and the measured value is 459. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 12.86 (s, 1H), 9.87 (s, 1H), 8.37 (s, 1H), 7.53 (t, J = 7.9 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 6.61 (d, J = 9.4 Hz, 2H), 6.49 (s, 1H), 6.03 (d, J = 2.3 Hz, 1H), 4.43 (d, J = 5.6 Hz, 2H), 4.09 (d, J = 3.3 Hz, 2H), 2.42 (s, 3H).

[0536] Purification conditions for preparative HPLC: Column: SunFire preparative C18 OBD column, 19 * 150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: from 30% B to 55% B, 55% B within 7.8 min; Wavelength: 254 / 210 nm.

[0537] The compound examples prepared through the above procedure are listed in Table 1.

[0538] Examples of the prepared compounds

[0539] Table 1

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549] Bioanalysis

[0550] The pharmacological properties of the compounds of the present invention can be confirmed by a variety of bioanalyses known in the art. The compounds of the present invention have been subjected to the bioanalyses exemplified below.

[0551] PhosphoSens assay

[0552] Performed as described by the supplier (AssayQuant Technologies, Marlborough, MA) Kinase assay. Briefly, in a 384-well reagent plate, a 10 mM DMSO stock solution was serially diluted at 3-fold intervals to prepare a 1000X compound solution in DMSO. Then 50 nL of the compound dilution series was added to the corresponding wells of a 384-well assay plate. 40 μL of 1× assay buffer (50 mM HEPES pH 7.5, 500 μM EGTA, 10 nM MgCl 2 , 0.01% Brij-35, 1% glycerol, 1 mM DTT and 0.2 mg / mL BSA) containing 1.25× substrate (AQT0264) was transferred to each well of the assay plate to achieve a final substrate concentration of 20 μM. Finally, 10 μL of a 5× PTPN2 enzyme stock solution was added to each well of the assay plate, with a final enzyme concentration of 150 pM. The reaction progress curve was collected by sampling the fluorescence intensity every 71 seconds for one hour at room temperature using a Synergy H4 plate reader (BioTek Instruments / Agilent Technologies, Winooki, VT) at an excitation wavelength of 360 nm (λ ex 360) and an emission wavelength of 480 nm (λ em 480).

[0553] Phosphatase activity assay using DIFMUP as the substrate:

[0554] The PTPN2 biochemical analysis was performed as follows: Prepare a 5× human PTPN2 (SRP5075, MilliporeSigma, Burlington, MA) stock solution and a 1.25× DiFMUP (D6567, ThermoFisher Scientific, Waltham, MA) stock solution in 1× 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. Add 40 μL of the DiFMUP substrate solution (final concentration of 25 mM DiFMUP substrate) to a Corning 3574 384-well white non-binding surface microtiter plate containing 0.05 μL of serially diluted test compounds prepared in DMSO. Start the reaction by adding 10 μL of the enzyme solution to a final PTPN2 concentration of 0.15 nM, and then monitor at λ EX 360 / λ EM 460 every 105 seconds for 60 minutes at room temperature in a BioTek Synergy HTX plate reader (Agilent Technologies, Santa Clara, CA). Fit the initial linear portion of the progress curve according to a linear equation to obtain the slope and convert it to % inhibition based on the 100% activity value of the untreated control. The IC 50 values of each compound were obtained by fitting the % inhibition-compound concentration curve using Dotmatics software (Dotmatics, Bishops Stortford, Hertfordshire, England).

[0555] Cell Proliferation Assay Protocol

[0556] Culture B16-F10 cells (ATCC, Manassas, VA, #CRL-6475) 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). Seed the cells at a density of 100 cells / well in a total volume of 20 μL into two white opaque 384-well tissue culture-treated microtiter plates (PerkinElmer, Waltham, MA, #6007688) and incubate at 37 °C and 5% CO 2Incubate overnight. Next, transfer 30 nL of the compound dissolved in DMSO from the source plate to the target wells using an Echo 650 acoustic liquid handler (Beckman Coulter, Indianapolis, IN). Negative control wells received only 30 nL of DMSO (0.15% final concentration). Return the plates to the incubator for 1 hour, then treat the cells with 5 μL of growth medium or 5 μL of growth medium containing 50 ng / mL recombinant murine IFN-γ protein (R&D Systems, Minneapolis, MN, #485-MI / CF, 10 ng / mL final concentration) using an automated pipetting platform (INTEGRA Biosciences, Hudson, NH). Incubate the plates at 37 °C for 4 days, then analyze cell proliferation using CellTiter-Glo reagent (Promega, Madison, WI, #G7573, 25 μL / well). Collect the luminescence signal intensity using an EnVision 2105 plate reader (PerkinElmer) 15 minutes after the addition of the CellTiter-Glo reagent and analyze with the Dotmatics software platform to calculate the IC 50 value. Identify off-target compound-mediated cytotoxicity by examining growth inhibition in the absence of IFNγ.

[0557] Phospho-STAT1 assay protocol

[0558] Culture B16-F10 cells (ATCC, Manassas, VA, #CRL-6475) 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). Seed the cells 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 incubate at 37 °C and 5% CO 2Incubate overnight. Next, transfer 30 nL of the compound dissolved in DMSO from the source plate to the target wells using an Echo 650 acoustic liquid handler (Beckman Coulter, Indianapolis, IN). Negative control wells receive only 30 nL of DMSO (0.15% final concentration). Return the plates to the incubator for 1 hour, then treat the cells with 5 μL of growth medium or 5 μL of growth medium containing 500 ng / mL recombinant mouse IFN-γ protein (R&D Systems, Minneapolis, MN, #485-MI / CF, 100 ng / mL final concentration) using an automated pipetting platform (INTEGRA Biosciences, Hudson, NH). Incubate the plates at 37 °C for 1 hour and analyze the phosphorylated STAT1 protein content using a phosphorylation-STAT1 (Tyr701) HTRF kit (Cisbio, Bedford, MA, #63ADK026PEH) according to the manufacturer's instructions. After 24 hours, collect the HTRF signal intensity using an EnVision 2105 plate reader (PerkinElmer) and analyze it using the Dotmatics software platform to calculate the IC 50 value.

[0559] Bioanalytical data

[0560] Table 2 is an overview of the bioanalytical data for the prepared examples / embodiments. For IC 50 data, analyze using a high DDT concentration and / or DiFMUP substrate; one can use either analysis by those skilled in the art. Columns or rows with double asterisks indicate that an IC 50 value or embodiment has been provided.

[0561] Table 2

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

Claims

1. A compound having the following structure: Wherein, Each occurrence independently: R 1 selected from 6-oxo-1,6-dihydropyridin-2-yl, R 2 selected from -H, cycloalkyl, alkyl and substituted alkyl; R 3 selected from -H, alkyl, halogen, -CN, -OCH 3 , cycloalkyl, -CF 3 , -C(CH 3 ) 2 R 7 , aryl, substituted alkyl, alkoxy, -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -OCF 3 , -OH and benzyloxy; R 4 selected from -H, alkyl, substituted alkyl, amine, secondary amine, tertiary amine, -CHF 2 , halogen, -CN, -OCH 3 , -N(CH 3 ) 2 , -OCHF 2 , alkoxy, -NHCH 3 , -OH, -CH 2 CH 3 and morpholin-4-yl; R 5 selected from -H, alkyl, substituted alkyl, alkoxy, amine, secondary amine, tertiary amine, halogen, -CH 2 CH 3 , -CN, -OCH 3 , -N(CH 3 ) 2 , -NHCH 3 , cyclopropyl, cyclopropoxy, cyclohexyl, -CF 3 , -OH, -Ph, -CH 2 CH 3 and R 6 selected from -H, alkyl, -CH 2 CH 3 -OCH 3 -OH and -CF 3 ; R 7 selected from -H and -CH 3 ; R 8 Selected from -O- and -CH 2 O-.

2. The compound according to claim 1, Wherein: R 1 For R 2 selected from -H and cyclopropyl; R 3 selected from -H, -CH 3 , cyclopropyl, phenyl and benzyloxy; R 4 selected from -H, -CH 3 and -Br; R 5 selected from -CH 3 and -F; R 6 Selected from -H, -CH 3 and -OCH 3 .

3. The compound according to claim 1, Wherein: R 3 is - H; R 4 selected from -H, alkyl, halogen and -CN; R 5 selected from -H and 4. The compound according to claim 1, Wherein: R 2 is - H; R 3 selected from a cyclo group, -CF 3 , -C(CH 3 ) 2 R 7 , an aryl group, and a benzyloxy group; R 5 is - H; R 6 is -H.

5. The compound according to claim 1, Wherein: R 2 is - H; R 4 Selected from -H, -N(CH 3 ) 2 , -OCHF 2 and morpholin-4-yl; R 5 selected from halogen, -CH 2 CH 3 -, -CF 3 , and R 6 selected from -H and -CH 2 CH 3 。 6. The compound according to claim 1, Wherein: R 3 is -H; R 5 Selected from -H, -CH 2 CH 3 , -CN and -CF 3 .

7. The compound according to claim 1, Wherein: R 3 selected from -H, alkyl, and -F; R 4 Selected from -H, -CHF 2 , halogen, -CN, -OCH 3 , -N(CH 3 ) 2 , -OCHF 2 and morpholin-4-yl.

8. The compound according to claim 1, Wherein: R 1 For R 3 selected from alkyl, -CN, -OCH 3 and -CF 3 ; R 4 selected from -H, alkyl, and -OCH 3 ; R 5 selected from -H, alkyl, and -OCH 3 ; R 6 Selected from -H and -OCH 3 .

9. A compound selected from: 5-(4-(((4-Cyclopropylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-6-hydroxy-4-(((4-(trifluoromethyl)pyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-6-hydroxy-4-(((3-(trifluoromethyl)pyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-[4-[[(3,6-Dimethoxypyridin-2-yl)amino]methyl]-2-fluoro-6-hydroxyphenyl]-1,1-dioxo-1,2,5-thiadiazolidine-3-one; 5-(4-(((4,6-Dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((4-Cyclopropoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-6-hydroxy-4-(((4-Methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-6-hydroxy-4-(((5-Phenylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-6-hydroxy-4-(((4-Methoxy-5-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((5-Cyclopropylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 2-((4-(1,1-Dioxo-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)isonicotinonitrile; 5-(2-Fluoro-6-hydroxy-4-(((4-Methoxypyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((4-Ethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-6-hydroxy-4-(((5-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-6-hydroxy-4-(((3-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-4-(((4-fluoropyridin-2-yl)amino)methyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-6-hydroxy-4-(((6-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((4,6-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((5,6-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((3,6-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-[4-[[(3,6-Dimethoxy-2-pyridinyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidine-3-one; 5-(2-Fluoro-6-hydroxy-4-(((3-methoxy-6-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((3-ethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((3,5-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((3,4-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((4,5-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((3,4-dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((4,5-dimethylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-6-hydroxy-4-(((6-methoxy-3-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((3,5-Dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-4-(((5-fluoro-4-methylpyridin-2-yl)amino)methyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 6-((4-(1,1-Dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)-4-methylnicotinonitrile; 5-(2-Fluoro-4-(((4-fluoro-5-methylpyridin-2-yl)amino)methyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-6-hydroxy-4-(((3-methoxypyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-6-hydroxy-4-(((6-methoxypyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((5,6-Dimethoxypyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-6-hydroxy-4-((pyridin-2-ylamino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-6-hydroxy-4-(((5-methoxypyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-6-hydroxy-4-(((6-methoxy-4-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 6-((4-(1,1-Dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)cyanopyridine; 5-(2-Fluoro-6-hydroxy-4-(((4-methoxy-6-methylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((6-(Difluoromethyl)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((6-(Difluoromethoxy)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((6-(Dimethylamino)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-6-hydroxy-4-(((5-isopropylpyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((4-(Benzyloxy)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((5-(Benzyloxy)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-(((6-Bromo-4-methylpyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-6-hydroxy-4-(((4-methyl-6-(morpholin-4-yl)pyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(4-((Cyclopropyl(5-(trifluoromethyl)pyridin-2-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; 5-(2-Fluoro-6-hydroxy-4-(((6-oxo-1,6-dihydropyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide; and 5-(2-Fluoro-6-hydroxy-4-(((6-methyl-4-phenoxypyridin-2-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide.

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.

11. A method of treating cancer, comprising administering to the 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 cancer, carcinoma, sarcoma, adenocarcinoma, papillary adenocarcinoma, lymphoma, leukemia, melanoma, solid lymphoma, 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 lymphoma, Burkitt lymphoma, small lymphoma, Hodgkin lymphoma, leukemia, and multiple myeloma.

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

13. The method according to claim 12, wherein the additional therapeutic agent is an immunotherapeutic agent.

14. The method according to claim 12, wherein the immunotherapeutic agent is selected from anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-CTLA-4 antibodies.

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

16. The method according to claim 1, wherein the method of treating cancer is selected from radiation, surgery, chemotherapy, or administration of a biologic agent.

17. The method according to claim 16, wherein the method of treating cancer further comprises administering a biologic agent, wherein the biologic agent is a drug that stimulates the immune system.

18. The method according to claim 17, wherein the method further comprises administering to the individual a DGKα and / or DGKζ inhibitor, an antagonist of the PD1 / PD-L1 axis, and an antagonist of CTLA4.

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