Protein tyrosine phosphatase inhibitors, compositions and methods of use

Abstract

Formula (I) as defined herein Disclosed are compounds of TIFF2025504969000209.tif54153 and pharma- ceutical acceptable salts thereof, pharmaceutical compositions thereof, combinations thereof, and methods of using same as inhibitors of protein tyrosine phosphatase 2 (PTPN2). These compounds are useful for treating cancers and diseases susceptible to PTPN2 inhibition.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 305,022, filed January 31, 2022, which is incorporated by reference in its entirety.

[0002] FIELD OF THE PRESENT ART Disclosed are compounds as protein tyrosine phosphatase inhibitors, pharma- ceutically acceptable salts thereof, pharmaceutical compositions thereof and combinations thereof, and methods of using them. [Background technology]

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

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

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

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

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

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

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

[0010] The present disclosure relates to compounds, pharma- ceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, that are effective inhibitors of protein tyrosine phosphatases (e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) and / or protein tyrosine phosphatase non-receptor type 1 (PTPN1, also known as protein tyrosine phosphatase-1B (PTP1B)). The present invention further provides a method of treating, preventing, or ameliorating cancer, comprising administering to a subject in need thereof an effective amount of a PTPN2 / PTPN1 inhibitor of the present disclosure. In a preferred embodiment, the compounds have a monocyclic core structure, as compared to compounds described in the literature that contain a fused bicyclic core structure.

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

[0012] The first aspect of the present invention relates to a compound having at least one formula (I): [ka] [In the formula, R 1 is -H, heteroaryl, -CONHR 3 , -CH2N(R 5 )CH2R 4 , 4-aminopiperidin-1-yl, [ka] selected from the group consisting of; R 2 is -H, [ka] selected from the group consisting of; R 3 is selected from the group consisting of heteroalicyclic groups and -CH2CH2N(CH3)2; R 4 is selected from the group consisting of alkyl, heteroaryl, carbocyclic, and 1-methyl-1H-pyrazol-4-yl; R 5 is selected from the group consisting of alkyl and carbocyclic groups; R 6 is selected from the group consisting of -H and alkyl; R7 is selected from the group consisting of CH and N; R 8 -CH2-, -NH-, -CH2CH2NHCH2-, [ka] selected from the group consisting of; R 9 -CH2-, -NH-, -O-, -CH(R 31 )- and -N(R 32 )- selected from the group consisting of; R 10 is selected from the group consisting of -H, alkyl, -N(CH3)2, and -CH2CH2OCH3; R 11 -CH=, -N=, and -C(R 33 )= selected from the group consisting of; R 12 -CH=, -N=, and -C(R 34 )= selected from the group consisting of; R 13 is selected from the group consisting of -CH= and -N=; R 14 is -H, alkyl, phenoxy, and [ka] selected from the group consisting of; R 15 -NH-, -O-, and -N(R 35 )- selected from the group consisting of; R 16 is selected from the group consisting of -H, -OH, -OCH3, and -N(CH3)2; R 17 is selected from the group consisting of -H and -OCH3; R 18 is -CH=, -N=, and [ka] selected from the group consisting of; R 19is selected from the group consisting of -CH=, -N=, and -CCH3=; R 20 is selected from the group consisting of -H and -CN; R 21 is selected from the group consisting of -H, alkyl, and halogen; R 22 -NHCH2-, -CH2N(R 6 )CH2-, and [ka] selected from the group consisting of; R 23 -CH=, -N=, and -C(R 36 )= selected from the group consisting of; R 24 is selected from the group consisting of -H, alkyl, halogen, and -CN; R 25 is selected from the group consisting of -H and halogen; R 26 -CH2-, -NH-, -O-, -CH(R 37 )-, -C(CH3)2-, and [ka] selected from the group consisting of; R 27 is selected from the group consisting of -CH2- and -CO-; R 28 is selected from the group consisting of -H, alkyl, and carbocyclic groups; R 29 -O-, -CH(R 38 )- and -N(R 39 )- selected from the group consisting of; R 30 is selected from the group consisting of -CH2-, -O-, and -C(CH3)2-; R 31 are -OH, halogens, carboaryls, -OCH3, -N(CH3)2, -CH2N(CH3)2, -OCH(CH3)2, and -CH2CH2R. 40CH3; R 32 is alkyl, -CCH3O, -CH2CH2OCH3, -CH2CONHCH3, and -R 27 CH2CH(CH3)2; R 33 is selected from the group consisting of halogen, -OCH3, and cyclopropylmethoxy; R 34 is alkyl, halogen, -OCH2CH3, -C(CH3)2R 41 , -CH2NHCCH3O, (pyrrolidin-1-yl)methyl, benzyl, [ka] selected from the group consisting of; R 35 -CCH3O, -R 27 CH2R 42 , and -SO2R 43 selected from the group consisting of; R 36 is selected from the group consisting of halogen and -CN; R 37 is selected from the group consisting of -NH2, -N(CH3)2, -CONHCH3, and -NHCCH3O; R 38 is selected from the group consisting of halogen and -N(CH3)2; R 39 is alkyl; R 40 is selected from the group consisting of -CH2- and -O-; R 41 is selected from the group consisting of -OH, alkyl, and -CN; R 42 is selected from the group consisting of alkyl and -COOH; R 43 is selected from the group consisting of alkyl, carbocyclic, and 3-fluorophenyl. The present invention provides a compound of the formula:

[0013] Additionally: 5-(2-fluoro-6-hydroxy-4-(piperidin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-[2-fluoro-6-hydroxy-4-(4-piperidyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-(2-fluoro-6-hydroxy-4-(1-methylpiperidin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-[2-fluoro-6-hydroxy-4-(1-methyl-4-piperidyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-(2-fluoro-6-hydroxy-4-(1-isopentylpiperidin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-[2-fluoro-6-hydroxy-4-(1-isopentyl-4-piperidyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-(2-fluoro-6-hydroxy-4-(pyridin-2-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(pyridin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(pyridin-4-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-[4-(4-benzylphenyl)-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(3-phenylphenyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-4-[4-(4-fluorophenyl)phenyl]-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(4-morpholinophenyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(3-phenoxyphenyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(4-isobutylphenyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(3-morpholinophenyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-(4-cyclopropylphenyl)-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(4-phenyl-2-thienyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[4-(pyrrolidin-1-ylmethyl)phenyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(2-phenyl-4-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[3-(cyclopropylmethoxy)-5-methyl-phenyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[4-(1-hydroxy-1-methyl-ethyl)phenyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(6-methoxy-3-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(3-quinolyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(2-methoxy-3-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(6-hydroxy-3-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[6-(4-methylpiperazin-1-yl)-3-pyridyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(5-methoxy-3-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[6-(dimethylamino)-3-pyridyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(6-phenyl-3-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-(2-fluoro-6-hydroxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((4-isopentylpiperazin-1-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-((4-(dimethylamino)piperidin-1-yl)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-[4-[(cyclohexylamino)methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[(tetrahydropyran-4-ylamino)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-(2-fluoro-6-hydroxy-4-((4-(3-methylbutanoyl)piperazin-1-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((4,4-dimethylcyclohexyl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-((4-acetylpiperazin-1-yl)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((piperidin-4-ylamino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((1-ethylpiperidin-4-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(morpholinomethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-4-((4-fluoropiperidin-1-yl)methyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-((cyclohexyl(methyl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 2-Fluoro-5-[[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]methyl]benzonitrile; 5-[2-fluoro-6-hydroxy-4-[[2-(1-methyl-4-piperidyl)ethylamino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[(4-phenyl-1-piperidyl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[[cyclopropyl(propyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[[cyclobutylmethyl(methyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 3-[[[3-Fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methyl-methyl-amino]methyl]benzonitrile; 5-[4-[[[(1R)-3,3-dimethylcyclohexyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[(4-hydroxy-1-piperidyl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[(4-methoxy-1-piperidyl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[(4-isopropoxy-1-piperidyl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[[4-(2-methoxyethyl)-1-piperidyl]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[[4-[(dimethylamino)methyl]-1-piperidyl]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[(4-butyl-1-piperidyl)methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; (1r,4r)-4-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)-N-methylcyclohexane-1-carboxamide; 2-(4-(4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)piperazin-1-yl)-N-methylacetamide; N-((1r,4r)-4-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)cyclohexyl)acetamide; (R)-5-(2-fluoro-6-hydroxy-4-((piperidin-3-ylamino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; (R)-5-(2-fluoro-6-hydroxy-4-(((1-isopentylpiperidin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-[2-fluoro-6-hydroxy-4-[[[(3S)-1-isopentyl-3-piperidyl]amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; (R)-5-(2-fluoro-6-hydroxy-4-(((tetrahydro-2H-pyran-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; (S)-5-(2-fluoro-6-hydroxy-4-((piperidin-3-ylamino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; (S)-5-(4-(((3,3-dimethylcyclohexyl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; (S)-5-(2-fluoro-6-hydroxy-4-(((tetrahydro-2H-pyran-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-[4-[[[(3R)-1-acetyl-3-piperidyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-4-[[[(3R)-1-(3-fluorophenyl)sulfonyl-3-piperidyl]amino]methyl]-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-4-[[[(3S)-1-(3-fluorophenyl)sulfonyl-3-piperidyl]amino]methyl]-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[[[(3S)-1-acetyl-3-piperidyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[[[(3R)-1-methylsulfonyl-3-piperidyl]amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[[[(3S)-1-cyclopropylsulfonyl-3-piperidyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[[[(3R)-1-cyclopropylsulfonyl-3-piperidyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[[[(3S)-1-methylsulfonyl-3-piperidyl]amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 3-[(3S)-3-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]-1-piperidyl]-3-oxo-propanoic acid; 5-[4-[[(4,4-dimethylcyclohexyl)-methyl-amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[[cyclobutylmethyl(propyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]pyridine-3-carbonitrile; 5-[4-[(2-chloro-5-fluoro-anilino)methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 4-Chloro-3-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]benzonitrile; 5-[4-[[(4-cyclopropyl-2-pyridyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-(2-fluoro-6-hydroxy-4-(4-isopentylpiperazin-1-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(4-aminopiperidin-1-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(piperazin-1-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(4-(dimethylamino)piperidin-1-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(piperidin-4-ylamino)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((1-isopentylpiperidin-4-yl)amino)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((1-(2-methoxyethyl)piperidin-4-yl)amino)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; N-(2-(dimethylamino)ethyl)-4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzamide; 4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxy-N-(piperidin-4-yl)benzamide; (S)-4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxy-N-(piperidin-3-yl)benzamide; (R)-4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxy-N-(piperidin-3-yl)benzamide; N-((1r,4r)-4-aminocyclohexyl)-4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzamide; N-((1r,4r)-4-(dimethylamino)cyclohexyl)-4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzamide; 5-(3-(((4,4-dimethylcyclohexyl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-3-((4-fluoropiperidin-1-yl)methyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-3-(morpholinomethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(3-((cyclohexylamino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-3-(((tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(3-((4-(dimethylamino)piperidin-1-yl)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-3-((4-methylpiperazin-1-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-[2-fluoro-6-hydroxy-3-[(4-isopentylpiperazin-1-yl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-(2-fluoro-6-hydroxy-3-(piperidin-4-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; and 5-(2-fluoro-6-hydroxy-3-(1-methylpiperidin-4-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide Disclosed is a compound selected from the group consisting of:

[0014] In some embodiments, the compound of formula (I) is formulated as a pharma- ceutically acceptable composition comprising a compound of formula (I) and a pharma- ceutically acceptable carrier.

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

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

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

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

[0019] Also disclosed are compositions for use in treating cancer in a patient in need thereof, the compositions comprising a compound of the present disclosure (e.g., a compound of Formula (I)) in combination with another therapeutic agent. In some embodiments, the other therapeutic agent is an immunotherapeutic agent. For example, in some embodiments, the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody.

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

[0021] The present disclosure relates to compounds, pharma- ceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, which are effective as inhibitors of protein tyrosine phosphatases, such as protein tyrosine phosphatase non-receptor type 2 (PTPN2) and / or protein tyrosine phosphatase non-receptor type 1 (PTPN1, also known as protein tyrosine phosphatase-1B (PTP1B)). The present invention further provides a method of treating, preventing, or ameliorating cancer, comprising administering to a subject in need thereof an effective amount of a PTPN2 / PTPN1 inhibitor of the present disclosure. In comparison to compounds described in the literature that contain a fused bicyclic core structure, the compounds of the present application have a monocyclic core structure in a preferred embodiment.

[0022] definition chemical definition Definitions of specific functional groups and chemical terms are described in detail below. Chemical elements are listed in the Periodic Table of the Elements as per the CAS version, Handbook of Chemistry and Physics, 75 thEd., and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry and specific functional groups and reactivities are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0023] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of atom valency known in the chemical arts.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0038] The term "alkyl" as used herein refers to both branched and straight chain saturated aliphatic hydrocarbon groups, for example, having 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl (e.g., n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When a number appears in subscript after the symbol "C," the subscript more specifically qualifies the number of carbon atoms that a particular group may contain. For example, "C 1-6 "Alkyl" means straight and branched chain alkyl groups having from 1 to 6 carbon atoms.

[0039] As used herein, the term "fluoroalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, 1-4 "Fluoroalkyl" is meant to include C1, C2, C3, and C4 alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF3 and -CH2CF3.

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

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

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

[0043] The term "hydroxy-fluoroalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups and one or more fluorine atoms. For example, "hydroxy-fluoroalkyl" includes -CHFCHOH, -CHCHFC(CH)OH, and -CHFCH(CH)OH. 1-4 Hydroxy-fluoroalkyl is an example.

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

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

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

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

[0048] As used herein, the term "heteroaryl" refers to a 5-10 membered aromatic heterocycle having at least one heteroatom selected from nitrogen, oxygen and sulfur and containing at least one carbon atom, and includes both monocyclic and bicyclic structures.

[0049] As used herein, the phrase "pharmacologically acceptable" refers to compounds, substances, compositions, and / or dosage forms that are suitable, within the scope of ordinary medical judgment, for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, and which are consistent with a reasonable benefit / risk ratio.

[0050] The compound of formula (I) may be provided as an amorphous solid or a crystalline solid. The compound of formula (I) may be provided as an amorphous solid by lyophilization.

[0051] In addition, solvates (e.g., hydrates) of the compounds of formula (I) should be considered within the scope of the present invention. The term "solvate" refers to a physical association of a compound of formula (I) with one or more organic or inorganic solvent molecules. This physical association includes hydrogen bonding. In some cases, it is possible to isolate the solvate, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase and isolable solvates. Examples of solvates include hydrates, ethanolates, methanolates, isopropanolates, solvates of acetonitrile, and solvates of ethyl acetate. Methods of solvation are known in the art.

[0052] Various forms of prodrugs are well known in the art: a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996); b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113-191 (Harwood Academic Publishers, 1991); and d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer, (Wiley-VCH, 2003) It is described in.

[0053] In addition, the compounds of formula (I) may be prepared, isolated, purified, and obtained as compositions containing 99% or greater of the compound of formula (I) ("substantially pure"), which are then used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also considered herein to be part of the invention.

[0054] By "stable compound" and "stable structure" is intended a compound that is sufficiently robust that it will not decompose upon isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent. The present invention embodies stable compounds.

[0055] "Therapeutically effective amount" is intended to include the amount of a compound of the invention alone, or in combination with the claimed compounds, or in combination with other active ingredients, that is effective in the inhibition or treatment or amelioration of cancer.

[0056] As used herein, the term "treating" or "treatment" includes the treatment of a condition in a mammal, particularly a human, and includes (a) preventing the mammal from acquiring a condition that arises in that mammal if the mammal is susceptible to the condition, particularly if the mammal has not yet been diagnosed as suffering from the condition; (b) inhibiting the condition, i.e., arresting the progression of the condition; and / or (c) palliating the condition, i.e., reducing the condition.

[0057] The compounds of the present invention are intended to include all isotopes of atoms contained in the compounds. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13 C and 14C. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those of skill in the art, or by methods analogous to those described herein, substituting the appropriate isotopically labeled reagent for the non-labeled reagent used elsewhere. For example, methyl (-CH3) also includes a deuterated methyl group (e.g., -CD3).

[0058] The term "pharmaceutical acceptable salt" means to include salts of active compounds prepared with relatively less toxic acids or bases depending on the specific substituents in the compounds described herein.When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by reacting the compounds in neutral state with a sufficient amount of the desired base in either pure solvent or suitable inert solvent.Examples of pharmaceutical acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amine salts, or magnesium salts, or similar salts.

[0059] As defined herein, the terms "inhibit", "inhibit" and the like with respect to the interaction of a protein inhibitor (e.g., an antagonist) refer to negatively affecting (e.g., decreasing) the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to the alleviation of a disease or a symptom of a disease. In some embodiments, inhibition refers to the decrease in the activity of a signal transduction pathway or a signal transduction pathway. Thus, at least in part, inhibition includes partial or complete inhibition of stimulation, reduction, suppression, or delay of activation, or inactivation, blunting, or downregulation of signal transduction or enzyme activity or amount of protein. In some embodiments, inhibition refers to the decrease in the activity of a protein tyrosine phosphatase (e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) or protein tyrosine phosphatase non-receptor type 1 (PTP1B)). Thus, at least in part, inhibition can include partial or complete reduction in stimulation, decreased or reduced activation, or inactivation, slowing, or downregulation of signal transduction or enzymatic activity or the amount of a protein tyrosine phosphatase (e.g., protein tyrosine phosphatase non-receptor type 2 (PTPN2) or protein tyrosine phosphatase non-receptor type 1 (PTP1B)).

[0060] A "patient" or "subject" refers to an organism suffering from a disease or susceptible to symptoms that can be treated by administration of a compound or pharmaceutical composition described herein. Examples include, but are not limited to, humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammalian animals. In some embodiments, the patient is a human. In some embodiments, the patient is a farm animal. In some embodiments, the patient is a dog. In some embodiments, the patient is a parrot. In some embodiments, the patient is a livestock animal. In some embodiments, the patient is a mammal. In some embodiments, the patient is a cat. In some embodiments, the patient is a horse. In some embodiments, the patient is a cow. In some embodiments, the patient is a dog. In some embodiments, the patient is a cat. In some embodiments, the patient is an ape. In some embodiments, the patient is a monkey. In some embodiments, the patient is a mouse. In some embodiments, the patient is a laboratory animal. In some embodiments, the patient is a rat. In some embodiments, the patient is a hamster. In some embodiments, the patient is a test animal. In some embodiments, the patient is a newborn animal. In some embodiments, the patient is a newborn. In some embodiments, the patient is a newborn mammal. In some embodiments, the patient is an elderly animal. In some embodiments, the patient is an elderly person. In some embodiments, the patient is an elderly mammal. In some embodiments, the patient is an elderly patient.

[0061] "Disease", "disorder" or "condition" refers to a condition of a patient or subject that can be treated by the compounds, pharmaceutical compositions, or methods described herein. In some embodiments, the compounds and methods described herein include reducing or eliminating one or more symptoms of a disease, disorder, or condition, for example, by administering a compound of the present disclosure, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the present disclosure or a pharma- ceutically acceptable salt thereof and a pharma- ceutical acceptable carrier.

[0062] As used herein, the term "signal transduction pathway" refers to a series of interactions between cellular and any extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that transmit a change in one component to one or more other components, which in turn transmit the change to other components, as appropriate, and so on to other signal transduction pathway components.

[0063] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that can be included in the compositions of the present disclosure to facilitate administration of an active agent to a subject and facilitate absorption by the subject without causing significant toxic side effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, carbohydrates (e.g., lactose, amylose, or starch), fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations are sterilized and may be mixed with auxiliary agents (e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for adjusting osmotic pressure, buffers, coloring agents, and / or aromatic substances) that do not adversely react with the disclosed compounds, as necessary. Those of skill in the art will recognize that other excipients are useful in the present disclosure.

[0064] The term "formulation" is intended to include a formulation in which an encapsulating material surrounds and combines with an active compound as a carrier to form a capsule, which may or may not contain other carriers other than the encapsulating material. Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid preparations suitable for oral administration.

[0065] As used herein, the term "administering" refers to oral administration, administration as a suppository, topical administration, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, or subcutaneous administration to a subject, or implantation of a delayed release device (e.g., a mini-osmotic pump). Administration is by any route, including parenteral administration and administration via mucous membranes (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or dermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other delivery methods include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. By "concomitant with" it is meant that a compound or composition described herein is administered simultaneously with, immediately before, or immediately after administration of one or more other therapeutic agents (e.g., anti-cancer, chemotherapeutic, or immunotherapeutic agents). The compounds or compositions described herein can be administered to patients alone or in combination. Combination is intended to include simultaneous or sequential administration of the compounds or compositions alone or in combination (with one or more compounds or drugs). Thus, the formulations can also be combined with other active substances, if desired (e.g., to prevent metabolic degradation).

[0066] The pharmaceutical compositions described herein may be prepared by any method known in pharmacology. In general, such preparation methods include the steps of bringing the disclosed compound ("active ingredient") into association with the carrier and / or one or more other accessory ingredients, and then shaping and / or packaging the product into the desired single unit dose or multiple unit doses, as necessary and / or desired. The pharmaceutical compositions may be prepared, packaged, and / or sold in bulk in single unit doses and / or multiple unit doses. As used herein, a "unit dose" is a respective amount of pharmaceutical composition containing a predetermined amount of active ingredient. The amount of active ingredient is generally equal to the dose of active ingredient administered to a subject and / or an appropriate fraction of that dose (e.g., one-half or one-third of that dose).

[0067] Treatment method The present disclosure features compounds, compositions, and methods that include the disclosed compounds (e.g., compounds of formula (I)). In some embodiments, the disclosed compounds, compositions, and methods are used to prevent or treat a disease, disorder, or condition. Examples of diseases, disorders, or conditions include, but are not limited to, cancer, type 2 diabetes, metabolic syndrome, obesity, or metabolic disease.

[0068] cancer In some embodiments, the compounds of the present disclosure (e.g., compounds of formula (I)) are used to treat cancer.As used herein, "cancer" refers to human carcinoma and epithelial carcinoma, non-epithelial carcinoma, adenocarcinoma (e.g., papillary adenocarcinoma), lymphoma, leukemia, melanoma, etc. (including solid cancer and lymphatic cancer), kidney, breast, lung, bladder, colon, ovary, prostate, pancreas, stomach, brain, head and neck, skin, uterus, testis, glioma, esophagus, liver cancer including hepatocellular carcinoma, B-cell acute lymphoblastic lymphoma, non-Hodgkin's lymphoma (e.g., Burkitt's lymphoma, small cell type, and large cell type lymphoma), lymphoma including Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), and / or multiple myeloma. In yet another example, "cancer" refers to lung cancer, breast cancer, ovarian cancer, epithelial ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, non-epithelial malignant tumors, bladder cancer, osteosarcoma, biliary tract cancer, adrenal cancer, salivary gland cancer, bronchial cancer, oral cancer, oral or pharyngeal cancer, laryngeal cancer, kidney cancer, gynecological cancer, brain cancer, central nervous system cancer, peripheral nervous system cancer, cancer of the blood tissue, small intestine or appendix cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, liver cancer, head and neck cancer, renal cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, or epithelial malignant tumors.

[0069] Examples of cancers that may be treated with the compounds, pharmaceutical compositions, or methods described herein include lymphoma, B cell lymphoma, heavy chain disease, alpha chain disease, gamma chain disease, mu chain disease, Waldenstrom's macroglobulinemia, benign monoclonal gammopathy, non-epithelial malignancies, bladder cancer, osteosarcoma, brain cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., ER positive, ER negative, chemotherapy resistant, Herceptin-resistant, HER2 positive ... The cancer types include, for example, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, non-epithelial malignant tumor), glioblastoma multiforme, acoustic neuroma, retinoblastoma, astrocytoma, craniopharyngioma, hemangioblastoma, pineal tumor, ependymoma, oligodendroglioma, meningioma, glioma, or melanoma. Further examples include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach, uterine cancer or medulloblastoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, immunocytic amyloidosis, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant insulin-producing islet cell tumors, malignant carcinoid, bladder cancer, precancerous lesions of the skin, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine system of the pancreas, medullary thyroid cancer, melanoma, colorectal cancer, papillary thyroid cancer, and hepatocellular carcinoma.

[0070] The first aspect of the present invention relates to a compound having at least one formula (I): [ka] [In the formula, R 1 is -H, heteroaryl, -CONHR 3 , -CH2N(R 5 )CH2R 4, 4-aminopiperidin-1-yl, [ka] selected from the group consisting of; R 2 is -H, [ka] selected from the group consisting of; R 3 is selected from the group consisting of heteroalicyclic groups and -CH2CH2N(CH3)2; R 4 is selected from the group consisting of alkyl, heteroaryl, carbocyclic, and 1-methyl-1H-pyrazol-4-yl; R 5 is selected from the group consisting of alkyl and carbocyclic groups; R 6 is selected from the group consisting of -H and alkyl; R 7 is selected from the group consisting of CH and N; R 8 -CH2-, -NH-, -CH2CH2NHCH2-, [ka] selected from the group consisting of; R 9 -CH2-, -NH-, -O-, -CH(R 31 )- and -N(R 32 )- selected from the group consisting of; R 10 is selected from the group consisting of -H, alkyl, -N(CH3)2, and -CH2CH2OCH3; R 11 -CH=, -N=, and -C(R 33 )= selected from the group consisting of; R 12 -CH=, -N=, and -C(R 34 )= selected from the group consisting of; R 13is selected from the group consisting of -CH= and -N=; R 14 is -H, alkyl, phenoxy, and [ka] selected from the group consisting of; R 15 -NH-, -O-, and -N(R 35 )- selected from the group consisting of; R 16 is selected from the group consisting of -H, -OH, -OCH3, and -N(CH3)2; R 17 is selected from the group consisting of -H and -OCH3; R 18 is -CH=, -N=, and [ka] selected from the group consisting of; R 19 is selected from the group consisting of -CH=, -N=, and -CCH3=; R 20 is selected from the group consisting of -H and -CN; R 21 is selected from the group consisting of -H, alkyl, and halogen; R 22 -NHCH2-, -CH2N(R 6 )CH2-, and [ka] selected from the group consisting of; R 23 -CH=, -N=, and -C(R 36 )= selected from the group consisting of; R 24 is selected from the group consisting of -H, alkyl, halogen, and -CN; R 25 is selected from the group consisting of -H and halogen; R 26 -CH2-, -NH-, -O-, -CH(R37 )-, -C(CH3)2-, and [ka] selected from the group consisting of; R 27 is selected from the group consisting of -CH2- and -CO-; R 28 is selected from the group consisting of -H, alkyl, and carbocyclic groups; R 29 -O-, -CH(R 38 )- and -N(R 39 )- selected from the group consisting of; R 30 is selected from the group consisting of -CH2-, -O-, and -C(CH3)2-; R 31 are -OH, halogens, carboaryls, -OCH3, -N(CH3)2, -CH2N(CH3)2, -OCH(CH3)2, and -CH2CH2R. 40 CH3; R 32 is alkyl, -CCH3O, -CH2CH2OCH3, -CH2CONHCH3, and -R 27 CH2CH(CH3)2; R 33 is selected from the group consisting of halogen, -OCH3, and cyclopropylmethoxy; R 34 is alkyl, halogen, -OCH2CH3, -C(CH3)2R 41 , -CH2NHCCH3O, (pyrrolidin-1-yl)methyl, benzyl, [ka] selected from the group consisting of; R 35 -CCH3O, -R 27 CH2R 42 , and -SO2R 43 selected from the group consisting of; R 36 is selected from the group consisting of halogen and -CN; R 37 is selected from the group consisting of -NH2, -N(CH3)2, -CONHCH3, and -NHCCH3O; R 38 is selected from the group consisting of halogen and -N(CH3)2; R 39 is alkyl; R 40 is selected from the group consisting of -CH2- and -O-; R 41 is selected from the group consisting of -OH, alkyl, and -CN; R 42 is selected from the group consisting of alkyl and -COOH; R 43 is selected from the group consisting of alkyl, carbocyclic, and 3-fluorophenyl. The present invention provides a compound of the formula:

[0071] In another embodiment of the compound of formula (I), R 1 -H, 1H-pyrrol-2-yl, furan-2-yl, 1H-imidazol-5-yl, 1,2-oxazol-5-yl, 1H-1,2,3-triazol-5-yl, 1,3,4-oxadiazol-2-yl, 1H-1,2,3,4-tetrazol-5-yl, thiophen-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyrimidin-4-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1λ 4 -Pyran-1-ylium-4-yl, -CONHR 3 , -CH2N(R 5 )CH2R 4 , 4-aminopiperidin-1-yl, [ka] is selected from the group consisting of:

[0072] In certain embodiments of the compound of Formula (I), R 3is selected from the group consisting of aziridin-1-yl, 2,5-dihydro-1H-pyrrol-1-yl, 2,5-dihydrofuran-3-yl, 4,5-dihydro-1H-imidazol-2-yl, pyrrolidin-1-yl, oxolan-2-yl, imidazolidin-4-yl, 1,3-dioxolan-2-yl, 1,3-thiazolidin-3-yl, piperidin-1-yl, oxan-2-yl, 1,3-diazinan-5-yl, morpholin-4-yl, 1,3,5-triazinan-2-yl, 1,3-dioxan-2-yl, and -CHCHN(CH).

[0073] In another embodiment of the compound of formula (I), R 3 is selected from the group consisting of aziridin-1-yl, 2,5-dihydro-1H-pyrrol-1-yl, 2,5-dihydrofuran-3-yl, 4,5-dihydro-1H-imidazol-2-yl, pyrrolidin-1-yl, oxolan-2-yl, imidazolidin-4-yl, 1,3-dioxolan-2-yl, 1,3-thiazolidin-3-yl, piperidin-1-yl, oxan-2-yl, 1,3-diazinan-5-yl, morpholin-4-yl, 1,3,5-triazinan-2-yl, 1,3-dioxan-2-yl, and -CHCHN(CH); R 4 are -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -C(CH3)3, pentyl, -CH2CH2CH(CH3)2, -CH2C(CH3)3, hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, 1H-pyrrol-2-yl, furan-2-yl, 1H-imidazo 1,2-oxazol-5-yl, 1H-1,2,3-triazol-5-yl, 1,3,4-oxadiazol-2-yl, thiophen-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyrimidin-4-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1λ 4-pyran-1-ylium-4-yl, cyclopropyl, cyclobutyl, cyclopent-2-en-1-yl, cyclopentyl, cyclohexa-1,4-dien-1-yl, cyclohex-3-en-1-yl, cyclohexyl, adamantan-1-yl, decahydronaphthalen-1-yl, 1-methyl-1H-pyrazol-4-yl, [ka] is selected from the group consisting of:

[0074] In certain embodiments of the compound of Formula (I), R 5 are -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -C(CH3)3, pentyl, -CH2CH2CH(CH3)2, -CH2C(CH3)3, hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, cyclopropyl, cyclobutyl, cyclopent-2-en-1-yl, cyclopentyl, cyclohexa-1,4-dien-1-yl, cyclohex-3-en-1-yl, cyclohexyl, adamantan-1-yl, decahydronaphthalen-1-yl, [ka] is selected from the group consisting of:

[0075] In another embodiment of the compound of formula (I), R 6 is selected from the group consisting of -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -C(CH3)3, pentyl, -CH2CH2CH(CH3)2, -CH2C(CH3)3, hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, and 4,8,12-trimethyltridecyl.

[0076] In certain embodiments of the compound of Formula (I), R 31are -OH, -F, -Cl, -Br, -I, phenyl, 2,3-dihydro-1H-inden-5-yl, naphthalen-1-yl, azulen-1-yl, 1,2-dihydroacenaphthylene-5-yl, 9H-fluoren-2-yl, phenanthren-3-yl, anthracen-9-yl, pyren-1-yl, fluoranthene-3-yl, tetraphen-7-yl, -OCH3, -N(CH3)2, -CH2N(CH3)2, -OCH(CH3)2, -CH2CH2R 40 CH3, [ka] is selected from the group consisting of:

[0077] In another embodiment of the compound of formula (I), R 32 are -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -C(CH3)3, pentyl, -CH2CH2CH(CH3)2, -CH2C(CH3)3, hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, -CCH3O, -CH2CH2OCH3, -CH2CONHCH3, and -R 27 CH2CH(CH3)2.

[0078] In certain embodiments of the compound of Formula (I), R 10 is selected from the group consisting of -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -C(CH3)3, pentyl, -CH2CH2CH(CH3)2, -CH2C(CH3)3, hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, -N(CH3)2, and -CH2CH2OCH3.

[0079] In another embodiment of the compound of formula (I), R 10is selected from the group consisting of -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -C(CH3)3, pentyl, -CH2CH2CH(CH3)2, -CH2C(CH3)3, hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, -N(CH3)2, and -CH2CH2OCH3; R 33 is selected from the group consisting of -F, -Cl, -Br, -I, -OCH3, and cyclopropylmethoxy.

[0080] In certain embodiments of the compound of Formula (I), R 34 are -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -C(CH3)3, pentyl, -CH2CH2CH(CH3)2, -CH2C(CH3)3, hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, -F, -Cl, -Br, -I, -OCH2CH3, -C(CH3)2R 41 , -CH2NHCCH3O, (pyrrolidin-1-yl)methyl, benzyl, [ka] is selected from the group consisting of:

[0081] In another embodiment of the compound of formula (I), R 14 are -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -C(CH3)3, pentyl, -CH2CH2CH(CH3)2, -CH2C(CH3)3, hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, phenoxy, and [ka] selected from the group consisting of; R 25 is selected from the group consisting of -H, -F, -Cl, -Br, and -I; R 41 is selected from the group consisting of -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -C(CH3)3, pentyl, -CH2CH2CH(CH3)2, -CH2C(CH3)3, hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, and -CN.

[0082] In another embodiment of the compound of formula (I), R 42 is selected from the group consisting of -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -C(CH3)3, pentyl, -CH2CH2CH(CH3)2, -CH2C(CH3)3, hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, and -COOH.

[0083] In certain embodiments of the compound of Formula (I), R 43 is selected from the group consisting of -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -C(CH3)3, pentyl, -CH2CH2CH(CH3)2, -CH2C(CH3)3, hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, a carbocyclic group, and 3-fluorophenyl.

[0084] In another embodiment of the compound of formula (I), R 6 is selected from the group consisting of -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -C(CH3)3, pentyl, -CH2CH2CH(CH3)2, -CH2C(CH3)3, hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, and 4,8,12-trimethyltridecyl; R 21is selected from the group consisting of -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -C(CH3)3, pentyl, -CH2CH2CH(CH3)2, -CH2C(CH3)3, hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, -F, -Cl, -Br, and -I; R 24 is selected from the group consisting of -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -C(CH3)3, pentyl, -CH2CH2CH(CH3)2, -CH2C(CH3)3, hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, -F, -Cl, -Br, -I, and -CN; R 28 is selected from the group consisting of -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -C(CH3)3, pentyl, -CH2CH2CH(CH3)2, -CH2C(CH3)3, hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, and carbocyclic groups; R 36 is selected from the group consisting of -F, -Cl, -Br, -I, and -CN; R 38 is selected from the group consisting of -F, -Cl, -Br, -I, and -N(CH3)2; R 39 is selected from the group consisting of -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -C(CH3)3, pentyl, -CH2CH2CH(CH3)2, -CH2C(CH3)3, hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, and 4,8,12-trimethyltridecyl.

[0085] In certain embodiments, the present invention encompasses a pharmaceutical composition comprising a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier.

[0086] In another embodiment, the present invention includes a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the cancer / disease is selected from human carcinoma, epithelial carcinoma, non-epithelial carcinoma, adenocarcinoma, papillary adenocarcinoma, lymphoma, leukemia, melanoma, solid tumors, cancer of the lymphatic system, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, gastric cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, liver cancer including hepatocellular carcinoma, lymphoma including B-cell acute lymphoblastic lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, small cell lymphoma, Hodgkin's lymphoma, leukemia, and multiple myeloma.

[0087] In another embodiment, the present invention encompasses a method of treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) in combination with another therapeutic agent.

[0088] In certain embodiments, the additional therapeutic agent is an immunotherapeutic agent.

[0089] In another embodiment, the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody.

[0090] In certain embodiments, the method of treating cancer includes administering to a patient in need of cancer treatment an effective amount of a pharma- ceutically acceptable composition comprising Formula (I).

[0091] In another embodiment of the method of treating cancer, the one or more other cancer therapies include radiation therapy, surgical therapy, chemotherapy, or administration of a biopharmaceutical.

[0092] In one embodiment of the above method, the one or more other cancer therapies are administering a biopharmaceutical that is an agent that stimulates the immune system, and the method is characterized by administering to the subject an inhibitor of DGKα and / or DGKζ, an antagonist of PD1 / PD-L1 binding, and an antagonist of CTLA4.

[0093] Additionally: 5-(2-fluoro-6-hydroxy-4-(piperidin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-[2-fluoro-6-hydroxy-4-(4-piperidyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-(2-fluoro-6-hydroxy-4-(1-methylpiperidin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-[2-fluoro-6-hydroxy-4-(1-methyl-4-piperidyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-(2-fluoro-6-hydroxy-4-(1-isopentylpiperidin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-[2-fluoro-6-hydroxy-4-(1-isopentyl-4-piperidyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-(2-fluoro-6-hydroxy-4-(pyridin-2-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(pyridin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(pyridin-4-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-[4-(4-benzylphenyl)-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(3-phenylphenyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-4-[4-(4-fluorophenyl)phenyl]-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(4-morpholinophenyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(3-phenoxyphenyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(4-isobutylphenyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(3-morpholinophenyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-(4-cyclopropylphenyl)-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(4-phenyl-2-thienyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[4-(pyrrolidin-1-ylmethyl)phenyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(2-phenyl-4-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[3-(cyclopropylmethoxy)-5-methyl-phenyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[4-(1-hydroxy-1-methyl-ethyl)phenyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(6-methoxy-3-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(3-quinolyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(2-methoxy-3-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(6-hydroxy-3-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[6-(4-methylpiperazin-1-yl)-3-pyridyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(5-methoxy-3-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[6-(dimethylamino)-3-pyridyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-(6-phenyl-3-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-(2-fluoro-6-hydroxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((4-isopentylpiperazin-1-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-((4-(dimethylamino)piperidin-1-yl)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-[4-[(cyclohexylamino)methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[(tetrahydropyran-4-ylamino)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-(2-fluoro-6-hydroxy-4-((4-(3-methylbutanoyl)piperazin-1-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((4,4-dimethylcyclohexyl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-((4-acetylpiperazin-1-yl)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((piperidin-4-ylamino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(((1-ethylpiperidin-4-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(morpholinomethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-4-((4-fluoropiperidin-1-yl)methyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-((cyclohexyl(methyl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 2-Fluoro-5-[[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]methyl]benzonitrile; 5-[2-fluoro-6-hydroxy-4-[[2-(1-methyl-4-piperidyl)ethylamino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[(4-phenyl-1-piperidyl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[[cyclopropyl(propyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[[cyclobutylmethyl(methyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 3-[[[3-Fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methyl-methyl-amino]methyl]benzonitrile; 5-[4-[[[(1R)-3,3-dimethylcyclohexyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[(4-hydroxy-1-piperidyl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[(4-methoxy-1-piperidyl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[(4-isopropoxy-1-piperidyl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[[4-(2-methoxyethyl)-1-piperidyl]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[[4-[(dimethylamino)methyl]-1-piperidyl]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[(4-butyl-1-piperidyl)methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; (1r,4r)-4-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)-N-methylcyclohexane-1-carboxamide; 2-(4-(4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)piperazin-1-yl)-N-methylacetamide; N-((1r,4r)-4-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)cyclohexyl)acetamide; (R)-5-(2-fluoro-6-hydroxy-4-((piperidin-3-ylamino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; (R)-5-(2-fluoro-6-hydroxy-4-(((1-isopentylpiperidin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-[2-fluoro-6-hydroxy-4-[[[(3S)-1-isopentyl-3-piperidyl]amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; (R)-5-(2-fluoro-6-hydroxy-4-(((tetrahydro-2H-pyran-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; (S)-5-(2-fluoro-6-hydroxy-4-((piperidin-3-ylamino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; (S)-5-(4-(((3,3-dimethylcyclohexyl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; (S)-5-(2-fluoro-6-hydroxy-4-(((tetrahydro-2H-pyran-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-[4-[[[(3R)-1-acetyl-3-piperidyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-4-[[[(3R)-1-(3-fluorophenyl)sulfonyl-3-piperidyl]amino]methyl]-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-4-[[[(3S)-1-(3-fluorophenyl)sulfonyl-3-piperidyl]amino]methyl]-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[[[(3S)-1-acetyl-3-piperidyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[[[(3R)-1-methylsulfonyl-3-piperidyl]amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[[[(3S)-1-cyclopropylsulfonyl-3-piperidyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[[[(3R)-1-cyclopropylsulfonyl-3-piperidyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[2-fluoro-6-hydroxy-4-[[[(3S)-1-methylsulfonyl-3-piperidyl]amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 3-[(3S)-3-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]-1-piperidyl]-3-oxo-propanoic acid; 5-[4-[[(4,4-dimethylcyclohexyl)-methyl-amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[4-[[cyclobutylmethyl(propyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]pyridine-3-carbonitrile; 5-[4-[(2-chloro-5-fluoro-anilino)methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 4-Chloro-3-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]benzonitrile; 5-[4-[[(4-cyclopropyl-2-pyridyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-(2-fluoro-6-hydroxy-4-(4-isopentylpiperazin-1-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(4-aminopiperidin-1-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(piperazin-1-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(4-(4-(dimethylamino)piperidin-1-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-(piperidin-4-ylamino)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((1-isopentylpiperidin-4-yl)amino)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-4-((1-(2-methoxyethyl)piperidin-4-yl)amino)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; N-(2-(dimethylamino)ethyl)-4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzamide; 4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxy-N-(piperidin-4-yl)benzamide; (S)-4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxy-N-(piperidin-3-yl)benzamide; (R)-4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxy-N-(piperidin-3-yl)benzamide; N-((1r,4r)-4-aminocyclohexyl)-4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzamide; N-((1r,4r)-4-(dimethylamino)cyclohexyl)-4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzamide; 5-(3-(((4,4-dimethylcyclohexyl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-3-((4-fluoropiperidin-1-yl)methyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-3-(morpholinomethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(3-((cyclohexylamino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-3-(((tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(3-((4-(dimethylamino)piperidin-1-yl)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-(2-fluoro-6-hydroxy-3-((4-methylpiperazin-1-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; 5-[2-fluoro-6-hydroxy-3-[(4-isopentylpiperazin-1-yl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; 5-(2-fluoro-6-hydroxy-3-(piperidin-4-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide; and 5-(2-fluoro-6-hydroxy-3-(1-methylpiperidin-4-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide Disclosed is a compound selected from the group consisting of:

[0094] Synthesis method The compounds of the present invention may be prepared from the methods and examples shown below and from methods known to those skilled in the art. In each of the following examples, the R group is defined as above in each formula unless otherwise specified. Optimum reaction conditions and reaction times may vary depending on the reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions can be readily selected by those skilled in the art.

[0095] The intermediates used in the following syntheses are either commercially available or readily prepared by methods known to those skilled in the art. Reaction progress may be monitored by conventional methods, such as thin layer chromatography (TLC) or high performance liquid chromatography-mass spectrometry (HPLC-MS). Intermediates and products may be purified by methods known in the art, such as column chromatography, HPLC, preparative TLC or preparative HPLC.

[0096] Preparation of the Examples Example 1: 5-(2-fluoro-6-hydroxy-4-(piperidin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] [ka]

[0097] Step 1: To a solution of 5-[4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (intermediate 1, 200 mg, 0.45 mmol) in 1,4-dioxane (3 mL) and water (0.30 mL), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (208.33 mg, 0.67 mmol), Pd(dppf)Cl2 (73.36 mg, 0.09 mmol), Na2CO3 (142.84 mg, 1.35 mmol) were added. The mixture was stirred at 80° C. for 3 hours under nitrogen atmosphere, and after completion, the resulting mixture was cooled at room temperature and then filtered. The organic solvent was evaporated and the crude residue was purified by reverse-phase flash chromatography (0.5% TFA in water and MeCN) to give tert-butyl 5-[3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (100 mg, 0.18 mmol, 41% yield) as a pale yellow oil. MS: m / z: Theoretical: C 26 H 30 FN3O7S [MH] + 546; Observations: 546

[0098] Step 2: Under nitrogen atmosphere, Pd / C (90 mg, 0.85 mmol) was added to a solution of tert-butyl 5-[3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (90 mg, 0.16 mmol) in ethanol (5 mL), then H2 was introduced into the reaction system, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered to give tert-butyl 3-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]piperidine-1-carboxylate (70 mg, 0.15 mmol, 94% yield) as a light yellow solid. MS: m / z: Theoretical value: C 18 H 24 FN3O6S [MH] + 428; Observed: 428

[0099] Step 3: To a solution of tert-butyl 3-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]piperidine-1-carboxylate (65 mg, 0.15 mmol) in DCM (2 mL) was added TFA (2 mL) at 0° C. and the mixture was stirred at room temperature for 2 h. After evaporation of the solvent, the resulting residue was purified by preparative HPLC to give 5-[2-fluoro-6-hydroxy-4-(3-piperidyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (28.4 mg, 0.0823 mmol, 54% yield) as an off-white solid. MS: m / z: Theoretical value: C 13 H 16 FN3O4[MH] + Observations: 328; 1 H NMR (400MHz, DMSO-d6) δ 7.37-7.24(m, 2H), 6.65-6.56(m, 2H), 3.94(s, 2H), 3.16-3.12(m, 2H), 2.77-2.71(m, 3H), 1.86-1.80(m, 2H), 1.65-1.51(m, 2H)

[0100] Preparative HPLC conditions: XBridge Pre OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B to 20%B in 7min, then eluted at 20%B; Wavelength: 254 / 220nm

[0101] Example 2: 5-[2-fluoro-6-hydroxy-4-(4-piperidyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 1 in 14% overall yield as a white solid using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate in step 1. MS: m / z: Calculated: C 13 H 16 FN3O4S [M+H] + Observed values: 330; 1 H NMR (400MHz, DMSO-d6) δ 9.69(s, 1H), 8.58-8.53(m, 1H), 8.29(d, J=12.0Hz, 1H), 6.55(d, J=1.9Hz, 2H), 4.04(s, 2H), 3.37(d, J=12.5Hz, 2H), 3.11-2.95(m, 2H), 2.81-2.76(m, 1H), 1.93(d, J=13.7Hz, 2H), 1.80-1.65(m, 2H)

[0102] Preparative HPLC conditions: Column: Xselect CSH OBD column 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B to 20%B in 7 min, then 20%B; Wavelength: 254 / 220nm

[0103] Example 3: 5-(2-fluoro-6-hydroxy-4-(1-methylpiperidin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in 10% overall yield as an off-white solid according to the procedure of Example 1 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine in step 1. MS: m / z: Calculated: C 14 H 18 FN3O4[MH] - Observations: 342; 1 H NMR (400MHz, DMSO-d6) δ 9.50-9.31(m, 1H), 6.66-6.62(m, 2H), 3.94(s, 2H), 2.96-2.92(m, 2H), 2.76-2.72(m, 1H), 2.39-2.36(m, 3H), 2.20-2.18(m, 2H), 1.78-1.72(m, 2H), 1.68-1.58(m, 1H), 1.49-1.33(m, 1H)

[0104] Preparative HPLC conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH3·H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~22%B for 7min, then 22%B; Wavelength: 254 / 220nm

[0105] Example 4: 5-[2-fluoro-6-hydroxy-4-(1-methyl-4-piperidyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 9% overall yield as a white solid following the procedure of Example 1 using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine in step 1. MS: m / z: Calculated: C 14 H 18 FN3O4S [M+H] + Observations: 344; 1 H NMR (400MHz, DMSO-d6) δ 9.85(s, 1H), 9.41- 9.30(m, 1H), 6.64-6.57(m, 2H), 4.16-4.08(m, 2H), 3.51(d, J=12.0Hz, 2H), 3.10-3.05(m, 2H), 2.81(d, J=4.3Hz, 2H), 2.76-2.68(m, 2H), 2.00(d, J=14.0Hz, 2H), 1.89-1.68(m, 2H)

[0106] Preparative HPLC conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~22%B for 7 min, then 22%B; Wavelength: 254 / 220nm

[0107] Example 5: 5-(2-fluoro-6-hydroxy-4-(1-isopentylpiperidin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] To a stirred solution of 5-[2-fluoro-6-hydroxy-4-(3-piperidyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one hydrochloride (Example 1, 35 mg, 0.10 mmol) and 3-methylbutanal (16.48 mg, 0.19 mmol) in DCM (2 mL) was added DIEA (0.02 mL, 0.190 mmol) and AcOH (0.02 mL, 0.290 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h, and NaBH(OAc)3 (40.56 mg, 0.190 mmol) was added to the mixture at 0° C. and stirred at room temperature for 1 h. The reaction mixture was concentrated and the crude product was purified by preparative HPLC to give 5-[2-fluoro-6-hydroxy-4-(1-isopentyl-3-piperidyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (10.2 mg, yield: 226%) as a white solid. MS: m / z: Calculated: C 18 H 26 FN3O4S[M+H] + 400; Observed values: 400; 1 H NMR (400MHz, DMSO-d6) δ 9.90(s, 1H), 9.22(s, 1H), 6.70-6.44(dd, J=11.0, 1.9Hz, 2H), 4.11(d, J=2.6Hz, 2H), 3.51(d, J=11.4Hz, 2H), 3.11-2.97(m, 3H), 2.95-2.84(m, 2H), 2.00-1.75(t, J=13.6Hz, 3H), 1.68-1.51(m, 4H), 0.90(d, J=5.1Hz, 6H)

[0108] Example 6: 5-[2-fluoro-6-hydroxy-4-(1-isopentyl-4-piperidyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 27% overall yield as a white solid according to the procedure of Example 5 using 5-[2-fluoro-6-hydroxy-4-(4-piperidyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one in step 1. MS: m / z: Calculated: C 18 H 26 FN3O4S [M+H] + 400; Observed values: 400; 1 H NMR (300MHz, DMSO-d6) δ 9.92(s, 1H), 9.10(s, 1H), 6.66-6.55(m, 2H), 4.14(s, 2H), 3.59(d, J=12.0Hz, 2H), 3.31-2.93(m, 4H), 2.77(t, J=12.3Hz, 1H), 2.01(d, J=13.8Hz, 2H), 1.89-1.72(m, 2H), 1.68-1.40(m, 3H), 0.99-0.93(m, 6H)

[0109] Preparative HPLC conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 10%B~35%B for 7 minutes, then 35%B; Wavelength: 254 / 220nm

[0110] Example 7: 5-(2-fluoro-6-hydroxy-4-(pyridin-2-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] [ka] Step 1: To a solution of 5-[4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Intermediate 1, 120 mg, 0.27 mmol) and tributyl(2-pyridyl)stannane (198 mg, 0.54 mmol) in dioxane (6 mL) was added CsF (123 mg, 0.81 mmol) and PdCl2[P(cy)3]2 (20 mg, 0.03 mmol) at room temperature. The resulting suspension was evacuated and degassed with nitrogen three times and stirred at 100 °C for 16 h. The reaction mixture was concentrated and the resulting residue was purified by reverse phase column (0.05% NH4HCO3 aqueous solution, MeCN) to give 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-(2-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (100 mg, 0.23 mmol, 84% yield). MS: m / z: Theoretical value: C 21 H 18 FN3O5S[M+H] + 444; Observed: 444

[0111] Step 2: The title compound was prepared according to the procedure of Example 1 using 7-1 in step 3 in 23.97% yield as an off-white solid. MS: m / z: Calculated: C 13 H 10 FN3O4S[M+H] + Observations: 324; 1 H NMR (400MHz, DMSO-d6) δ 8.72(s, 1H), 7.89-7.86(m, 2H), 7.23-7.48(m, 3H), 4.06(s, 2H) Preparative HPLC purification conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05%NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 5%B~20%B for 10min, then 20%B; Wavelength: 254 / 220nm

[0112] Example 8: 5-(2-fluoro-6-hydroxy-4-(pyridin-3-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 7 in 22% overall yield as an off-white solid using 3-(tributylstannyl)pyridine in step 1. MS: m / z: Calculated: C 13 H 10 FN3O4S [M+H] + Observations: 324; 1 H NMR (400MHz, DMSO-d6) δ 8.79(d, J=2.4Hz, 1H), 8.54(dd, J=4.8, 1.6Hz, 1H), 8.03(dt, J=8.1, 1.8Hz, 1H), 7.49(dd, J=8.0, 4.8Hz, 1H), 7.06(dd, J=11.0, 2.1Hz, 1H), 6.99(t, J=1.6Hz, 1H), 4.04(s, 2H)

[0113] Preparative HPLC purification conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05%NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 5%B~25%B for 12min, then 25%B; Wavelength: 254 / 220nm

[0114] Example 9: 5-(2-fluoro-6-hydroxy-4-(pyridin-4-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] [ka]

[0115] Step 1: To a sealed vessel was added 5-[4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Intermediate 1, 120 mg, 0.27 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (83 mg, 0.40 mmol), Na2CO3 (90 mg, 0.81 mmol), 1,4-dioxane (12 mL), water (2 mL), and Pd(dppf)Cl2 (22 mg, 0.03 mmol). The reaction was purged with N2 and stirred at 80 °C overnight. Upon completion, the reaction mixture was filtered, concentrated under reduced pressure and the crude product was purified by reverse phase column (0.05% NH4HCO3 aqueous solution, MeCN) to give 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-(4-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (50 mg, 0.11 mmol, 42% yield) as an off-white solid. MS: m / z: Theoretical value: C 21 H 18 FN3O4S[M+H] + 444; Observed: 444

[0116] Step 2: To a stirred solution of 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-(4-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (35 mg, 0.08 mmol) in DCM (6 mL) was added TFA (6 mL) at 0° C. and stirred at room temperature for 6 h. The reaction was concentrated and the resulting residue was purified by preparative HPLC to give 5-[2-fluoro-6-hydroxy-4-(4-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (11.5 mg, 0.03 mmol, 44% yield) as a yellow solid. MS: m / z: Theoretical: C 13 H 10 FN3O4S[M+H] + Observations: 324; 1H NMR (400MHz, DMSO-d6) δ 10.41(s, 1H), 8.83(s, 2H), 8.04(d, J=5.6Hz, 2H), 7.42-7.35(m, 1H), 7.23-7.17(m, 1H), 4.23(s, 2H)

[0117] Preparative HPLC purification conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 20%B~34%B for 10min, then 34%B~100%B for 5min; Wavelength: 254 / 220nm

[0118] Example 10: 5-[4-(4-benzylphenyl)-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 9 using (4-benzylphenyl)boronic acid in step 1 in 26% overall yield as a white solid. MS: m / z: Calculated: C 21 H 17 FN2O4S[M+H] + Observations: 413; 1 H NMR (400MHz, DMSO-d6+D2O) δ 7.58-7.52(m, 2H), 7.37-7.16(m, 7H), 6.96(d, J=10.5Hz, 2H), 4.05-3.97(m, 4H)

[0119] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 33%B~43%B for 8 minutes, then 43%B; Wavelength: 254 / 220nm

[0120] Example 11: 5-[2-fluoro-6-hydroxy-4-(3-phenylphenyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 31% overall yield as a white solid following the procedure of Example 9 using (3-phenylphenyl)boronic acid in step 1. MS: m / z: Calculated: C 20 H 15 FN2O4S[MH] - Observations: 397; 1 H NMR (300MHz, DMSO-d6) δ 7.85(t, J=1.8Hz, 1H), 7.82-7.73(m, 2H), 7.72-7.69(m, 1H), 7.67-7.57(m, 2H), 7.55-7.46(m, 2H), 7.45-7.36(m, 1H), 7.17-7.04(m, 2H), 4.08(s, 2H)

[0121] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 30%B to 40%B in 8min, then 40%B; Wavelength: 254 / 220nm

[0122] Example 12: 5-[2-fluoro-4-[4-(4-fluorophenyl)phenyl]-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 34% overall yield as a white solid following the procedure of Example 9 using [4-(4-fluorophenyl)phenyl]boronic acid in step 1. MS: m / z: Calculated: C 20 H 14 F2N2O4S[MH] -Observed: 415; 1 H NMR (300MHz, DMSO-d6) δ 7.83-7.67(m, 6H), 7.32(dd, J=9.8, 7.9Hz, 1H), 7.23(s, 1H), 7.11-6.98(m, 2H), 4.01(s, 2H)

[0123] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 30%B~42%B for 9 minutes, then 42%B; Wavelength: 254 / 220nm

[0124] Example 13: 5-[2-fluoro-6-hydroxy-4-(4-morpholinophenyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 18% overall yield as a white solid following the procedure of Example 9 using (4-morpholinophenyl)boronic acid in step 1. MS: m / z: Calculated: C 18 H 18 FN3O5S[M+H] + 408; Observations: 408; 1 H NMR (400MHz, DMSO-d6+D2O) δ 7.33-7.29(t, J=7.9Hz, 1H), 7.11-7.04(m, J=2.1Hz, 1H), 7.02-7.00(m, J=7.2, 1.6Hz, 1H), 6.98-6.72(m, 3H), 4.01(s, 2H), 3.79-3.72(m, 4H), 3.21-3.15(m, 4H)

[0125] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 17%B~30%B for 8 minutes, then 30%B; Wavelength: 254 / 220nm

[0126] Example 14: 5-[2-fluoro-6-hydroxy-4-(3-phenoxyphenyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 33% overall yield as a white solid following the procedure of Example 9 using (3-phenoxyphenyl)boronic acid in step 1. MS: m / z: Calculated: C 20 H 15 FN2O5S[MH] - Observations: 413; 1 H NMR (400MHz, DMSO-d6+D2O) δ 7.50-7.38(m, 4H), 7.24-7.2(d, J=2.1Hz, 1H), 7.19-7.17(m, 1H), 7.16-7.07(m, 2H), 7.03-6.97(m, 2H), 6.93(t, J=1.6Hz, 1H), 4.00(s, 2H)

[0127] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3+0.1% NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: Elute from 32%B to 42%B for 8 minutes, then elute at 42%B; Wavelength: 254 / 220nm

[0128] Example 15: 5-[2-fluoro-6-hydroxy-4-(4-isobutylphenyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 19% overall yield as a white solid following the procedure of Example 9 using (4-isobutylphenyl)boronic acid in step 1. MS: m / z: Calculated: C 18 H 19 FN2O4S[MH] - Observations: 377; 1 H NMR (400MHz, DMSO-d6+D2O) δ 7.50-7.38(m, 4H), 7.24-7.2(d, J=2.1Hz, 1H), 7.19-7.17(m, 1H), 7.16-7.07(m, 2H), 7.03-6.97(m, 2H), 6.93(t, J=1.6Hz, 1H), 4.00(s, 2H)

[0129] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: eluted at 32%B~42%B for 8 minutes, then eluted at 42%B; Wavelength: 254 / 220nm

[0130] Example 16: 5-[2-fluoro-6-hydroxy-4-(3-morpholinophenyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 9 using (3-morpholinophenyl)boronic acid in step 1 in 31% overall yield as a white solid. MS: m / z: Calculated: C 18 H 18 FN3O5S[M+H] + 408; Observations: 408; 1H NMR (400MHz, DMSO-d6+D2O) δ 7.55-7.47(m, 2H), 7.05-6.98(m, 2H), 6.97-6.91(m, 2H), 4.00(s, 2H), 3.82-3.72(m, 4H), 3.20-3.13(m, 4H)

[0131] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: Elute with 20%B~30%B for 8 minutes, then elute with 30%B; Wavelength: 254 / 220nm

[0132] Example 17: 5-[4-(4-cyclopropylphenyl)-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 37% overall yield as a white solid following the procedure of Example 9 using (4-cyclopropylphenyl)boronic acid in step 1. MS: m / z: Calculated: C 17 H 15 FN2O4S[MH] - Observations: 361; 1 H NMR (300MHz, DMSO-d6) δ 7.50(d, J=8.0Hz, 2H), 7.16(d, J=8.1Hz, 2H), 7.01-6.91(m, 2H), 4.02(s, 2H), 2.08-1.85(m, 1H), 1.12-0.82(m, 2H), 0.76-0.65(m, 2H)

[0133] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: eluted at 27%B~47%B for 8 minutes, then eluted at 47%B; Wavelength: 254 / 220nm

[0134] Example 18: 5-[2-fluoro-6-hydroxy-4-(4-phenyl-2-thienyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 13% overall yield as a white solid following the procedure of Example 9 using (4-phenyl-2-thienyl)boronic acid in step 1. MS: m / z: Calculated: C 18 H 13 FN2O4S2[MH] - 403; Observed: 403; 1 H NMR (300MHz, DMSO-d6) δ 7.99(d, J=1.5Hz, 1H), 7.88(d, J=1.4Hz, 1H), 7.83-7.74(m, 2H), 7.45(t, J=7.6Hz, 2H), 7.33(t, J=7.3Hz, 1H), 7.16(dd, J=11.2, 2.1Hz, 1H), 7.02(t, J=1.6Hz, 1H), 4.03(s, 2H)

[0135] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 in water), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 30%B to 40%B in 8min, then 40%B; Wavelength: 254 / 220nm

[0136] Example 19: 5-[2-fluoro-6-hydroxy-4-[4-(pyrrolidin-1-ylmethyl)phenyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 25% overall yield as a white solid following the procedure of Example 9 using 1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidine in step 1. MS: m / z: Calculated: C 19 H 20 FN3O4S[M+H] + Observed values: 406; 1 H NMR (400MHz, DMSO-d6) δ 9.73-9.68(m, 2H), 7.77-7.71(m, 2H), 7.63-7.57(m, 2H), 7.09-6.96(m, 2H), 4.39(d, J=4.1Hz, 2H), 4.01(s, 2H), 3.41-3.34(m, 2H), 3.13(s, 1H), 2.05(s, 2H), 1.87(s, 2H)

[0137] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 5%B~35%B for 10min, then 35%B; Wavelength: 254nm

[0138] Example 20: 5-[2-fluoro-6-hydroxy-4-(2-phenyl-4-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] [ka]

[0139] Step 1: To a stirred mixture of 4-bromo-2-phenyl-pyridine (300 mg, 1.28 mmol) and bis(pinacolato)diboron (488.16 mg, 1.92 mmol) in 1,4-dioxane (6 mL) was added KOAc (377.32 mg, 3.84 mmol) and Pd(dppf)Cl2 (0.21 g, 0.26 mmol). The resulting mixture was then degassed by bubbling nitrogen through the solution for 5 min. It was then stirred at 100 °C for 16 h, at which time LCMS showed the reaction to be complete. The resulting mixture was filtered and the filtrate was concentrated. The resulting residue was purified by reverse phase flash column chromatography to give 2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (320 mg, 1.6 mmol, 88% yield) as a pale yellow oil. MS: m / z: Theoretical value: C 17 H 20 BNO2[M-83] - 198; Observed: 198

[0140] Step 2: Compound 9-3 was prepared in 86% yield as a yellow solid following the procedure of Example 9 using 2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in step 1. MS: m / z: Calculated: C 27 H 22 FN3O5S[M+H] + 520; Observed: 520

[0141] Step 3: The title compound was prepared as a white solid in 24% yield according to the preparation of Example 9 using 9-3 in step 2. MS: m / z: Calculated: C 19 H 14 FN3O4S[M+H] + 400; Observed values: 400; 1H NMR (300MHz, DMSO-d6) δ 8.73(d, J=5.2Hz, 1H), 8.31-8.18(m, 3H), 7.63(dd, J=5.2, 1.7Hz, 1H), 7.59-7.42(m, 3H), 7.32(dd, J=11.1, 2.0Hz, 1H), 7.20(t, J=1.7Hz, 1H), 4.07(s, 2H)

[0142] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 23%B~33%B for 8 minutes, then 33%B; Wavelength: 254 / 220nm

[0143] Example 21: 5-[4-[3-(cyclopropylmethoxy)-5-methyl-phenyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] [ka]

[0144] Step 1: Compound 10-1 was prepared as a brown semi-liquid in 85% yield according to the preparation of Example 9 using [3-(cyclopropylmethoxy)-5-methyl-phenyl]boronic acid in step 1. MS: m / z: Calculated: C 19 H 19 FN2O5S[MH] - 525; Observed: 525

[0145] Step 2: To a stirred solution of 5-[4-[3-(cyclopropylmethoxy)-5-methyl-phenyl]-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (10-1, 90 mg, 0.17 mmol) in methanol (15 mL) was added Pd / C (80 mg, 0.75 mmol) under N2 atmosphere. H2 was then charged to the reaction and the resulting mixture was stirred at ambient temperature for 2 h, when LCMS showed complete consumption of starting material. The mixture was filtered and the filtrate was concentrated. The resulting residue was purified by preparative HPLC to give 5-[4-[3-(cyclopropylmethoxy)-5-methyl-phenyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (31.1 mg, 0.07 mmol) as a white solid. MS: m / z: Theoretical value: C 19 H 19 FN2O5S[MH] - 405; Observed: 405; 1 H NMR (400MHz, DMSO-d6+D2O) δ 7.01-6.93(m, 3H), 6.91(t, J=2.0Hz, 1H), 6.80-6.75(m, 1H), 4.05(s, 2H), 3.86(d, J=7.0Hz, 2H), 2.33(s, 3H), 1.26-1.20(m, 1H), 0.63-0.50(m, 2H), 0.37-0.29(m, 2H)

[0146] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 water), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 30%B to 40%B in 8min, then 40%B; Wavelength: 254 / 220nm

[0147] Example 22: 5-[2-fluoro-6-hydroxy-4-[4-(1-hydroxy-1-methyl-ethyl)phenyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 66% overall yield as a white solid according to the preparation of Example 19 using [4-(1-hydroxy-1-methyl-ethyl)phenyl]boronic acid in step 1. MS: m / z: Calculated: C 17 H 17 FN2O5S[MH] - Observations: 379; 1 H NMR (400MHz, DMSO-d6) δ 7.53(d, J=2.2Hz, 4H), 6.96(d, J=8.6Hz, 2H), 4.04(s, 2H), 1.43(s, 6H)

[0148] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~23%B for 8 minutes, then 23%B; Wavelength: 254 / 220nm

[0149] Example 23: 5-[2-fluoro-6-hydroxy-4-(6-methoxy-3-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 9 in 40% overall yield as a white solid using 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in step 1. MS: m / z: Calc.: C 14 H 12 FN3O5S[M+H] + Observations: 354; 1H NMR (300MHz, DMSO-d6) δ 8.45(d, J=2.5Hz, 1H), 7.98(dd, J=8.7, 2.6Hz, 1H), 7.04-7.00(m, 1H), 6.98-6.87(m, 2H), 4.01(s, 2H), 3.90(s, 3H)

[0150] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 15%B~20%B for 8 minutes, then 20%B; Wavelength: 254 / 220nm

[0151] Example 24: 5-[2-fluoro-6-hydroxy-4-(3-quinolyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 14% overall yield as a white solid following the procedure of Example 9 using 3-quinolylboronic acid in step 1. MS: m / z: Calculated: C 17 H 12 FN3O4S[M+H] + Observations: 374; 1 H NMR (300MHz, DMSO-d6) δ 9.21(d, J=2.3Hz, 1H), 8.65(d, J=2.4Hz, 1H), 8.11-8.02(m, 2H), 7.80(t, J=7.7Hz, 1H), 7.67(t, J=7.5Hz, 1H), 7.27(dd, J=11.4, 1.9Hz, 1H), 7.20(s, 1H), 4.05(s, 2H)

[0152] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 16%B~23%B for 9 minutes, then 23%B; Wavelength: 254 / 220nm

[0153] Example 25: 5-[2-fluoro-6-hydroxy-4-(2-methoxy-3-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 38% overall yield as a white solid following the procedure of Example 9 using (2-methoxy-3-pyridyl)boronic acid in step 1. MS: m / z: Calculated: C 14 H 12 FN3O5S[M+H] + Observations: 354; 1 H NMR (400MHz, DMSO-d6) δ 8.19(dd, J=4.9, 1.9Hz, 1H), 7.75(dd, J=7.4, 1.9Hz, 1H), 7.11(dd, J=7.3, 5.0Hz, 1H), 6.93-6.85(m, 2H), 4.05(s, 2H), 3.90(s, 3H)

[0154] Preparative HPLC purification conditions: XBridge Prep Phenyl OBD column, 19*250mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 5%B~10%B for 7min, then 10%B; Wavelength: 254 / 220nm

[0155] Example 26: 5-[2-fluoro-6-hydroxy-4-(6-hydroxy-3-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 9 in 22% overall yield as an off-white solid using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol in step 1. MS: m / z: Calculated: C 13 H 10 FN3O5S[MH] - Observations: 338; 1 H NMR (300MHz, DMSO-d6) δ 7.83(dd, J=9.5, 2.8Hz, 1H), 7.73(d, J=2.8Hz, 1H), 6.94(dd, J=11.5, 2.1Hz, 1H), 6.89-6.82(m, 1H), 6.48(d, J=9.5Hz, 1H), 4.02(s, 2H)

[0156] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~15%B for 8 minutes, then 15%B; Wavelength: 254 / 220nm

[0157] Example 27: 5-[2-fluoro-6-hydroxy-4-[6-(4-methylpiperazin-1-yl)-3-pyridyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 23% overall yield as a white solid according to the procedure of Example 9 using 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine in step 1. MS: m / z: Calculated: C 18 H 20 FN5O4S[M+H] + Observations: 422; 1H NMR (400MHz, DMSO-d6) δ 9.52(s, 1H), 8.43(d, 1H), 7.86(m, 1H), 7.02-6.92(m, 3H), 3.99(d, 2H), 3.71-3.67(m, 4H), 2.90-2.85(d, 4H), 2.58-2.47(m, 3H)

[0158] Preparative HPLC purification conditions: Xselect Peptide CSH C18 19*150mm 5μm; Mobile phase A: Water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: eluted at 12%B~42%B for 10 minutes, then eluted at 42%B; Wavelength: 254nm

[0159] Example 28: 5-[2-fluoro-6-hydroxy-4-(5-methoxy-3-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 44% overall yield as a white solid following the procedure of Example 9 using 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine in step 1. MS: m / z: Calc.: C 14 H 12 FN3O5S[M+H] + Observations: 354; 1 H NMR (300MHz, DMSO-d6) δ 8.43(d, J=1.8Hz, 1H), 8.30(d, J=2.7Hz, 1H), 7.59(dd, J=2.8, 1.9Hz, 1H), 7.13(dd, J=11.3, 2.1Hz, 1H), 7.08-7.01(m, 1H), 4.02(s, 2H), 3.91(s, 3H)

[0160] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3+0.1%NH3 . H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 16%B~23%B in 9 min, then 23%B; Wavelength: 254 / 220nm

[0161] Example 29: 5-[4-[6-(dimethylamino)-3-pyridyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 9 in 27% overall yield as a white solid using N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine in step 1. MS: m / z: Calculated: C 15 H 15 FN4O4S[M+H] + Observations: 367; 1 H NMR (400MHz, DMSO-d6) δ 8.38(d, 1H), 7.78(m, 1H), 6.98-6.88(m, 2H), 6.71(d, 1H), 3.99(s, 2H), 3.06(s, 6H)

[0162] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 12%B~42%B for 10min, then 42%B; Wavelength: 254nm

[0163] Example 30: 5-[2-fluoro-6-hydroxy-4-(6-phenyl-3-pyridyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared in 25% overall yield as a pale yellow solid according to the preparation of Example 9 using (6-phenyl-3-pyridyl)boronic acid in step 1. MS: m / z: Calculated: C 19 H 14 FN3O4S[M+H] + 400; Observed values: 400; 1 H NMR (400MHz, DMSO-d6) δ 10.58(s, 1H), 8.96(d, J=2.4Hz, 1H), 8.15(dd, J=5.9, 2.9Hz, 3H), 8.09(d, J=8.4Hz, 1H), 7.53(t, J=7.4Hz, 2H), 7.47(dd, J=8.2, 6.0Hz, 1H), 7.25(dd, J=11.0, 1.9Hz, 1H), 7.11(s, 1H), 4.39(s, 2H)

[0164] Preparative HPLC purification conditions: Xselect Peptide CSH C18, 19*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 30%B~30%B for 7 minutes, then 30%B; Wavelength: 254nm

[0165] Example 31: 5-(2-fluoro-6-hydroxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] [ka]

[0166] Step 1: To a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (Intermediate 2, 65 mg, 0.16 mmol) and 1-methylpiperazine (33.02 mg, 0.33 mmol) in DCM (2 mL) was added AcOH (0.02 mL, 0.33 mmol) and the mixture was stirred for 1 h at 0° C. Then NaBH(OAc)3 (69.86 mg, 0.33 mmol) was added at 0° C. and the mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated and directly purified by reverse phase column (0.05% aqueous NH4HCO3 and acetonitrile) to give 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-[(4-methylpiperazin-1-yl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (70 mg, 0.15 mmol, 89% yield) as a brown solid. MS: m / z theoretical: C 22 H 27 FN4O5S[M+H] + 479; Observations: 479

[0167] Step 2: To a stirred solution of 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-[(4-methylpiperazin-1-yl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (70 mg, 0.15 mmol) in DCM (2 mL) was added TFA (1 mL) at 0° C., and the mixture was stirred at room temperature for 2 hours. After stirring was complete, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC to give 5-[2-fluoro-6-hydroxy-4-[(4-methylpiperazin-1-yl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (12.3 mg, 0.0332 mmol, 23% yield) as a white solid. MS: m / z theoretical: C 14 H 19 FN4O4S[M+H] + Observations: 359; 1H NMR (400MHz, DMSO-d6) δ 9.42(s, 1H), 6.63(d, J=17.8Hz, 2H), 3.95(d, J=3.4Hz, 2H), 2.78(s, 4H), 2.54(s, 6H), 2.48(s, 3H)

[0168] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B to 20%B in 7min, then 20%B; Wavelength: 254 / 220nm

[0169] Example 32: 5-(2-fluoro-6-hydroxy-4-((4-isopentylpiperazin-1-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in 9.7% overall yield as a white solid following the procedure of Example 31 using 1-isopentylpiperazine hydrochloride in step 1. MS: m / z theoretical: C 18 H 27 FN4O4S[M+H] + Observed: 415; 1 H NMR (400MHz, DMSO-d6) δ 9.91(s, 1H)6.71(d, J=3.8Hz, 2H), 4.12(s, 2H), 3.64-3.44(m, 6H), 3.07(s, 6H), 1.65-1.45(m, 3H), 0.90(d, J=6.5Hz, 6H)

[0170] Preparative HPLC purification conditions: Atlantis Prep T3 OBD column, 19*250mm 10μ; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 5%B~35%B for 7 min, then 35%B; Wavelength: 254 / 210nm

[0171] Example 33: 5-(4-((4-(dimethylamino)piperidin-1-yl)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 31 in 13% overall yield as a white solid using N,N-dimethylpiperidin-4-amine in step 1. MS: m / z theoretical: C 16 H 23 FN4O4S[M+H] + Observations: 387; 1 H NMR (400MHz, DMSO-d6) δ 9.40(s, 1H), 6.67-6.57(m, 2H), 3.95(s, 2H), 3.39(s, 2H),2.89(d, J=11.3Hz, 2H), 2.81(s, 1H), 2.59(s, 1H), 2.51(d, J=1.8Hz, 6H), 1.96(t, J=11.5Hz, 2H), 1.87(d, J=11.3Hz, 2H), 1.61-1.48(m, 2H)

[0172] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B to 20%B in 7min, then 20%B; Wavelength: 254 / 220nm

[0173] Example 34: 5-[4-[(cyclohexylamino)methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 11% overall yield as a white solid following the procedure of Example 31 using cyclohexanamine in step 1. MS: m / z theoretical: C 15 H 20 FN3O4S[M+H] + Observations: 358; 1 H NMR (400MHz, DMSO-d6) δ 9.57(s, 1H), 8.37-8.31(m, 1H), 6.86-6.78(m, 2H), 3.99(d, J=25.2Hz, 4H), 2.93(s, 1H), 2.09-2.02(m, 2H), 1.80-1.73(m, 2H), 1.61(d, J=12.4Hz, 1H), 1.45-0.95(m, 5H)

[0174] Preparative HPLC purification conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~10%B for 10min, then 10%B; Wavelength: 254 / 220nm

[0175] Example 35: 5-[2-fluoro-6-hydroxy-4-[(tetrahydropyran-4-ylamino)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 7.4% overall yield as an off-white semi-liquid following the procedure of Example 31 using tetrahydropyran-4-amine in step 1. MS: m / z theoretical: C 14 H 18 FN3O5S[M+H] + Observed values: 360; 1H NMR (400MHz, DMSO-d6) δ 9.82(s, 1H), 8.85(s, 2H), 6.97-6.69(m, 2H), 4.11(s, 2H), 3.97(s, 2H), 3.93(dd, J=11.1, 4.4Hz, 2H), 3.30(dd, J=11.9, 1.9Hz, 3H), 2.05-1.96(m, 2H), 1.65-1.51(m, 2H), 1.24(s, 0H)

[0176] Preparative HPLC purification conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~10%B in 11min, then 10%B; Wavelength: 254 / 220nm

[0177] Example 36: 5-(2-fluoro-6-hydroxy-4-((4-(3-methylbutanoyl)piperazin-1-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] [ka]

[0178] Step 1: To a solution of 1-[(4-methoxyphenyl)methyl]piperazine (300 mg, 1.45 mmol) and TEA (0.59 mL, 4.36 mmol) in DCM (15 mL) was added a solution of 3-methylbutanoyl chloride (263.05 mg, 2.18 mmol) in DCM (1 mL) at 0° C., and the mixture was stirred for 1 h. After the stirring was completed, the reaction mixture was quenched with water and extracted with EA. The combined organic layers were subsequently washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 1-[4-[(4-methoxyphenyl)methyl]piperazin-1-yl]-3-methyl-butan-1-one (240 mg, 0.83 mmol, 57% yield) as a white solid. MS: m / z: Theoretical: C 17 H 26 N2O2[M+H] + 291; Observations: 291

[0179] Step 2: To a stirred mixture of 1-[4-[(4-methoxyphenyl)methyl]piperazin-1-yl]-3-methyl-butan-1-one (230 mg, 0.79 mmol) in methanol (4 mL) and 2M HCl (1 mL) was added Pd / C (230 mg) under N2 atmosphere. H2 was then added and the mixture was stirred at room temperature for 2 h. The resulting mixture was filtered through Celite and washed with methanol. The filtrate was concentrated to give 3-methyl-1-piperazin-1-yl-butan-1-one as an off-white solid. MS: m / z: Calculated: C9H 18 NO[M+H] + 171; Observations: 171

[0180] Step 3: To a mixture of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (intermediate 2, 95 mg, 0.24 mmol), 3-methyl-1-piperazin-1-yl-butan-1-one hydrochloride (49.79 mg, 0.24 mmol) and DIEA (0.06 mL, 0.72 mmol) in ethanol (1 mL), solutions of ZnCl2 / THF (0.7 M, 1.40 mL) and NaBH3CN (63.70 mg, 0.96 mmol) in ethanol (2 mL) were added, respectively, and the mixture was stirred at 80 °C for 2 h. After stirring, the reaction mixture was concentrated and the resulting residue was purified by reverse phase column chromatography to give 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-[[4-(3-methylbutanoyl)piperazin-1-yl]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (100 mg, 0.18 mmol, 76% yield) as an off-white solid. MS: m / z: Theoretical value: C 26 H 33 FN4O6S [M+H] + 549; Observations: 549

[0181] Step 4: To a stirred solution of 5-[2-fluoro-6-[(4-methoxyphenyl)methoxy]-4-[[4-(3-methylbutanoyl)piperazin-1-yl]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (100 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 stirring was complete, the reaction mixture was concentrated. The resulting residue was purified by preparative HPLC to give 5-[2-fluoro-6-hydroxy-4-[[4-(3-methylbutanoyl)piperazin-1-yl]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (11.8 mg, 0.03 mmol, 15% yield) as an off-white solid. MS: m / z: Theoretical value: C 13 H 16 FN3O5S[M+H] + Observations: 429; 1H NMR (400MHz, DMSO-d6) δ 6.67-6.63(m, 2H), 3.96(s, 2H), 3.46(d, J=9.4Hz, 6H), 2.38-2.27(m, 4H), 2.17(d, J=6.9Hz, 2H), 2.02-1.89(m, 1H), 0.88(d, J=6.6Hz, 6H)

[0182] Preparative HPLC purification conditions: XBridge Prep Phenyl OBD column, 19*250mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 17%B~22%B for 8min, then 22%B; Wavelength: 254 / 220nm

[0183] Example 37: 5-(4-(((4,4-dimethylcyclohexyl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 36 in 18% overall yield as a white solid using 4,4-dimethylcyclohexanamine in step 3. MS: m / z: Calculated: C 17 H 24 FN3O4S[M+H] + Observations: 386; 1 H NMR (400MHz, DMSO-d6) δ 6.82-6.78(m, 2H), 4.02-3.98(m, 4H), 2.89-2.84(m, 1H), 1.92-1.82(m, 2H), 1.58-1.32(m, 4H), 1.25-1.12(m, 2H), 0.90(s, 6H)

[0184] Preparative HPLC conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 30%B~60%B for 7 min, then 60%B; Wavelength: 254 / 220nm

[0185] Example 38: 5-(4-((4-acetylpiperazin-1-yl)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 36 using 1-piperazin-1-ylethanone in step 3 in 22% overall yield as a white solid. MS: m / z: Calc: C 15 H 19 FN4O5S[M+H] + Observations: 387; 1 H NMR (400MHz, DMSO-d6) δ 10.14(s, 1H), 9.82(br, 1H), 6.97-6.83(m, 2H), 4.48-4.22(m, 3H), 4.16-3.92(m, 3H), 3.39-2.78(m, 6H), 2.04(s, 3H)

[0186] Preparative HPLC purification conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 5%B~20%B for 10min, then 20%B; Wavelength: 254 / 220nm

[0187] Example 39: 5-(2-fluoro-6-hydroxy-4-((piperidin-4-ylamino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 36 using tert-butyl 4-aminopiperidine-1-carboxylate in step 3 in 11% overall yield as a white solid. MS: m / z: Theoretical value: C 14 H 19 FN4O4S[M+H] + Observations: 359; 1 H NMR (400MHz, DMSO-d6) δ 6.67-6.66(m, 2H), 3.94(s, 2H), 3.62(s, 3H), 3.17-3.09(m, 3H), 2.81-2.74(m, 2H), 2.62-2.56(m, 1H), 1.91-1.85(m, 2H), 1.41-1.32(m, 2H)

[0188] Example 40: 5-(4-(((1-ethylpiperidin-4-yl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 36 using 1-ethylpiperidin-4-amine in step 3 in 22% overall yield as a white solid. MS: m / z: Calc: C 16 H 23 FN4O4S[MH] - Observations: 387; 1 H NMR (300MHz, DMSO-d6) δ 6.74-6.72(m, 2H), 3.94(s, 2H), 3.76(s, 2H), 3.58-3.51(m, 3H), 3.13-3.15(m, 2H), 2.86-2.51(m, 3H), 2.18-1.95(m, 2H), 1.69-1.49(m, 2H), 1.07(t, J=7.2Hz, 3H)

[0189] Preparative HPLC purification conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 5%B~20%B for 10min, then 20%B; Wavelength: 254 / 220nm

[0190] Example 41: 5-(2-fluoro-6-hydroxy-4-(morpholinomethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 36 using morpholine in step 3 in 16% overall yield as a white solid. MS: m / z: Calculated: C 13 H 16 FN3O5S[M+H] + Observations: 346; 1 H NMR (400MHz, DMSO-d6) δ 10.45-9.87(m, 2H), 6.94-6.84(m, 2H), 4.31-4.12(m, 4H), 3.95(s, 2H), 3.62(s, 2H), 3.27(s, 2H), 3.12(s, 2H)

[0191] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~15%B for 7 min, then 15%B; Wavelength: 254 / 220nm

[0192] Example 42: 5-(2-fluoro-4-((4-fluoropiperidin-1-yl)methyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 36 in 27% overall yield as a white solid using 4-fluoropiperidine hydrochloride in step 3. MS: m / z: Calculated: C 14 H 17 F2N3O4S[MH] + Observed values: 360; 1 H NMR (400MHz, DMSO-d6) δ 10.05(d, J=293.2Hz, 2H), 6.95-6.85(m, 2H), 4.99(d, J=47.9Hz, 1H), 4.50-4.06(m, 4H), 3.47-2.85(m, 4H), 2.38-1.77(m, 4H)

[0193] Preparative HPLC conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 5%B~20%B for 10min, then 20%B; Wavelength: 254 / 220nm

[0194] Example 43: 5-(4-((cyclohexyl(methyl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 36 in 17% overall yield as a white solid using N-methylcyclohexanamine in step 3. MS: m / z: Calculated: C 16 H 22 FN3O4S[M+H] + Observations: 372; 1H NMR (300MHz, DMSO-d6) δ 10.17(s, 1H), 9.19(s, 1H), 6.98-6.84(m, 2H), 4.42-4.31(m, 1H), 4.15-4.01(m, 3H), 3.24(t, J=11.8Hz, 1H), 2.61(d, J=4.8Hz, 3H), 2.03(t, J=12.2Hz, 2H), 1.84(s, 2H), 1.62(d, J=12.1Hz, 1H), 1.57-1.39(m, 2H), 1.36-1.08(m, 3H)

[0195] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 5%B~30%B for 7 min, then 30%B; Wavelength: 254 / 220nm

[0196] Example 44: 5-(2-fluoro-6-hydroxy-4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 36 using 1-(2-methoxyethyl)piperazine in step 3 in 12% overall yield as a white solid. MS: m / z: Calculated: C 16 H 23 FN4O5S[M+H] + 403; Observed: 403; 1 H NMR (400MHz, DMSO-d6) δ 9.44-9.40(m, 2H), 6.64(d, J=12.5Hz, 2H), 3.95(s, 2H), 3.68(s, 1H), 3.52(s, 1H), 3.33(s, 4H), 3.27(s, 3H), 3.19-2.69(m, 6H)

[0197] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 19*250mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 5%B~20%B for 10min, then 20%B; Wavelength: 254 / 220nm

[0198] Example 45: 2-Fluoro-5-[[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]methyl]benzonitrile [ka] The title compound was prepared as prepared in Example 36 using 5-(aminomethyl)-2-fluoro-benzonitrile in step 3 in 30% overall yield as a white solid. MS: m / z: Calculated: C 17 H 14 F2N4O4S[MH] - 407; Observations: 407; 1 H NMR (400MHz, DMSO-d6) δ 10.01(s, 1H), 9.20(s, 2H), 8.06(dd, J=6.2, 2.4Hz, 1H), 7.90-7.87(m, 1H), 7.65(t, J=9.1Hz, 1H), 6.89-6.78(m, 2H), 4.25(s, 2H), 4.20-4.01(m, 4H)

[0199] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~25%B for 10min, then 25%B; Wavelength: 254nm

[0200] Example 46: 5-[2-fluoro-6-hydroxy-4-[[2-(1-methyl-4-piperidyl)ethylamino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 36 in 24% overall yield as a white solid using 2-(1-methyl-4-piperidyl)ethanamine in step 3. MS: m / z: Calculated: C 17 H 25 FN4O4S[M+H] + 401; Observed: 401; 1 H NMR (400MHz, DMSO-d6) δ 9.88(s, 1H), 9.33(s, 1H), 8.81(s, 1H), 6.89-6.80(m, 2H), 4.07(d, J=5.3Hz, 2H), 4.00(d, J=3.7Hz, 2H), 3.42(d, J=12.1Hz, 2H), 2.96(s, 2H), 2.93-2.79(m, 2H), 2.76(d, J=4.1Hz, 3H), 1.85(d, J=13.8Hz, 2H), 1.71-1.54(m, 3H), 1.31-1.29(m, 2H)

[0201] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 1%B~8%B for 10min, then 8%B; Wavelength: 254nm

[0202] Example 47: 5-[2-fluoro-6-hydroxy-4-[(4-phenyl-1-piperidyl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 36 using 4-phenylpiperidine in step 3 in 22% overall yield as a white solid. MS: m / z: Calculated: C 20 H 22 FN3O4S[M+H] + Observed values: 420; 1H NMR (400MHz, DMSO-d6) δ 9.79-9.19(d, 1H), 7.33-7.23(m, J=9.3, 5.6Hz, 5H), 6.85(d, J=11.0Hz, 2H), 4.09-3.99(m, 4H), 3.41(s, 2H), 2.75(d, 3H), 1.93 -1.83(m, 4H)

[0203] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 19*250mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 in water), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 30%B to 40%B in 8min, then 40%B; Wavelength: 254 / 220nm

[0204] Example 48: 5-[4-[[cyclopropyl(propyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 36 in 20% overall yield as a white solid using N-propylcyclopropanamine in step 3. MS: m / z: Calculated: C 15 H 20 FN3O4S[M+H] + Observations: 358; 1 H NMR (400MHz, DMSO-d6) δ 10.00(s, 1H), 9.11(s, 1H), 6.91-6.75(m, 2H), 4.34(s, 2H), 4.07(s, 2H), 3.08(s, 2H), 2.85-2.65(m, 1H), 1.94-1.60(m, 2H), 1.00-0.60(m, 7H)

[0205] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~25%B for 10min, then 25%B; Wavelength: 254nm

[0206] Example 49: 5-[4-[[cyclobutylmethyl(methyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 36 using 1-cyclobutyl-N-methyl-methanamine in step 3 in 28% overall yield as a white solid. MS: m / z: Calculated: C 15 H 20 FN3O4S[M+H] + Observations: 358; 1 H NMR (300MHz, DMSO-d6) δ 6.80(d, J=8.2Hz, 2H), 4.03(s, 2H), 4.01-3.91(m, 2H),2.85(s, 2H), 2.77-2.65(m, 1H), 2.45(s, 3H), 2.07-2.01(m, 2H), 1.92-1.60(m, 4H)

[0207] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 28%B~38%B for 8 minutes, then 38%B; Wavelength: 254 / 220nm

[0208] Example 50: 3-[[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methyl-methyl-amino]methyl]benzonitrile [ka] The title compound was prepared as prepared in Example 36 using 3-(methylaminomethyl)benzonitrile in step 3 in 42% overall yield as a white solid. MS: m / z: Calculated: C 18 H 17 FN4O4S[M+H] + 405; Observed: 405; 1 H NMR (400MHz, DMSO-d6) δ 10.15(s, 1H), 9.84(s, 1H), 8.03(d, J=1.7Hz, 1H), 7.97-7.86(m, 2H), 7.71(t, J=7.8Hz, 1H), 6.92(dd, J=10.5, 1.9Hz, 1H), 6.86(t, J=1.5Hz, 1H), 4.51-4.40(m, 2H), 4.31-4.17(m, 2H), 4.12(s, 2H), 2.56(s, 3H)

[0209] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 9%B~39%B for 10min, then 39%B; Wavelength: 254nm

[0210] Example 51: 5-[4-[[[(1R)-3,3-dimethylcyclohexyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 36 in 21% overall yield as a white solid using (1R)-3,3-dimethylcyclohexanamine in step 3. MS: m / z: Calculated: C 17 H 24 FN3O4S[M+H] + Observations: 386; 1H NMR (400MHz, DMSO-d6) δ 9.94(s, 1H), 8.70-8.60(m, 2H),6.90-6.80(m, 2H), 4.06(d, J=22.5Hz, 4H), 3.30-3.15(m, 1H), 2.10(d, J=12.0Hz, 1H), 1.85-1.77(m, 1H), 1.64(dt, J=13.6, 3.0Hz, 1H), 1.43(dtd, J=13.4, 9.8, 3.5Hz, 1H), 1.34(d, J=13.6Hz, 1H), 1.26-1.02(m, 3H), 0.96(s, 3H), 0.89(s, 3H)

[0211] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~32%B for 10min, then 32%B; Wavelength: 254nm

[0212] Example 52: 5-[2-fluoro-6-hydroxy-4-[(4-hydroxy-1-piperidyl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 36 using piperidin-4-ol in step 3 in 26% overall yield as a white solid. MS: m / z: Calc: C 14 H 18 FN3O5S[M+H] + Observed values: 360; 1 H NMR (400MHz, DMSO-d6) δ 9.73(s, 1H), 6.78(s, 2H), 4.93(s, 1H), 4.14(s, 1H), 3.97(s, 2H), 3.60-3.3(m, 4H), 3.13(s, 2H), 1.81(s, 2H), 1.53(s, 2H)

[0213] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~12%B for 9 minutes, then 12%B; Wavelength: 254 / 220nm

[0214] Example 53: 5-[2-fluoro-6-hydroxy-4-[(4-methoxy-1-piperidyl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 36 using 4-methoxypiperidine in step 3 in 26% overall yield as a white solid. MS: m / z: Calc: C 15 H 20 FN3O5S[M+H] + Observations: 374; 1 H NMR (400MHz, DMSO-d6) δ 6.79(d, J=8.1Hz, 2H), 3.99(d, J=1.9Hz, 2H), 3.90(s, 1H), 3.76(s, 1H), 3.37(s, 1H), 3.24(d, J=2.5Hz, 3H), 2.98(s, 2H), 2.84-2.62(m, 2H), 2.21-1.33(m, 4H)

[0215] Preparative HPLC purification conditions: XBridge Prep Phenyl OBD column, 19*250mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 5%B~11%B for 8 minutes, then 11%B; Wavelength: 254 / 220nm

[0216] Example 54: 5-[2-fluoro-6-hydroxy-4-[(4-isopropoxy-1-piperidyl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 36 using 4-(2-methoxyethyl)piperidine in step 3 in 29% overall yield as a white solid. MS: m / z: Calculated: C 17 H 24 FN3O5S[M+H] + 402; Observed: 402; 1 H NMR (400MHz, DMSO-d6) δ 9.73(s, 1H), 6.79(s, 2H), 4.14(s, 1H), 3.96(s, 2H), 3.66-3.61(m, 1H), 3.03(s, 5H), 1.84(s, 2H), 1.52(s, 2H), 1.07(d, J=6.0Hz, 6H)

[0217] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 17%B~27%B for 9 minutes, then 27%B; Wavelength: 254 / 220nm

[0218] Example 55: 5-[2-fluoro-6-hydroxy-4-[[4-(2-methoxyethyl)-1-piperidyl]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 36 using 4-(2-methoxyethyl)piperidine in step 3 in 17% overall yield as a brown solid. MS: m / z: Calc.: C 17 H 24 FN3O5S[M+H]+ 402; Observed: 402; 1 H NMR (400MHz, DMSO-d6) δ 10.24(s, 1H), 9.35(s, 1H), 6.94-6.82(m, 2H), 4.18(dd, J=9.9, 4.1Hz, 4H), 3.35-3.22(m, 4H), 3.21(s, 3H), 2.95-2.86(m, 2H), 1.85(d, J=14.0Hz, 2H), 1.74(s, 1H), 1.48-1.27(m, 4H)

[0219] Preparative HPLC purification conditions: Xselect Peptide CSH C18, 19*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~20%B for 10 minutes, then 20%B; Wavelength: 254nm

[0220] Example 56: 5-[4-[[4-[(dimethylamino)methyl]-1-piperidyl]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 36 in 25% overall yield as an off-white solid using N,N-dimethyl-1-(4-piperidyl)methanamine in step 3. MS: m / z: Calculated: C 17 H 25 FN4O4S[M+H] + 401; Observed: 401; 1 H NMR (400MHz, DMSO-d6) δ 9.39(s, 1H), 6.62(d, J=20.8Hz, 2H), 3.94(s, 2H), 3.41(s,2H), 2.82(s, 4H), 2.57(s, 6H), 1.97(s, 2H), 1.68(d, J=12.4Hz, 3H), 1.18(d, J=12.2Hz, 2H)

[0221] Preparative HPLC purification conditions: XBridge Prep Phenyl OBD column, 19*250mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 5%B~10%B for 7min, then 10%B; Wavelength: 254 / 220nm

[0222] Example 57: 5-[4-[(4-butyl-1-piperidyl)methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 36 using 4-butylpiperidine in step 3 in 24% overall yield as a white solid. MS: m / z: Calculated: C 18 H 26 FN3O4S[M+H] + 400; Observed values: 400; 1 H NMR (400MHz, DMSO-d6) δ 10.08(s, 1H), 9.24(s, 1H), 6.93-6.81(m, 2H), 4.19(d, J=4.8Hz, 2H), 4.12-4.01(m, 2H), 3.35(d, J=12.2Hz, 2H), 2.93-2.85(m, 2H), 1.84(d, J=13.7Hz, 2H), 1.37-1.16(m, 9H), 0.88-0.84(m, 3H)

[0223] Preparative HPLC purification conditions: Xselect Peptide CSH C18, 19*150mm 5μm, 1; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~20%B for 10 minutes, then 20%B; Wavelength: 254nm

[0224] Example 58: (1r,4r)-4-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)-N-methylcyclohexane-1-carboxamide [ka] [ka]

[0225] Step 1: To a stirred solution of 4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (500 mg, 2.06 mmol) in DMF (20 mL) was added HATU (1170 mg, 3.08 mmol), methanamine (190 mg, 6.17 mmol), and DIEA (1.37 mL, 8.22 mmol) at 0° C., and the mixture was stirred at room temperature overnight. The reaction was quenched by addition of brine (10 mL), extracted with EA, dried, and concentrated to give tert-butyl N-[4-(methylcarbamoyl)cyclohexyl]carbamate (500 mg, 1.95 mmol, 95% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ 7.66-7.63(m, 1H), 6.70(d, J=8.0Hz, 1H), 3.20-3.07(m, 1H), 2.61-2.53(m, 3H), 2.01-1.96(m, 1H), 1.82-1.73(m, 2H), 1.73-1.65(m, 2H), 1.40-1.29(m, 11H), 1.19-1.04(m, 2H)

[0226] Step 2: To a solution of tert-butyl N-[4-(methylcarbamoyl)cyclohexyl]carbamate (500 mg, 1.95 mmol) in 1,4-dioxane (10 mL) was added HCl-dioxane (4 M, 10 mL) and stirred at room temperature for 3 h. After evaporation of the solvent, the crude material obtained was used in the next step without further purification.

[0227] Step 3: Compound 11-4 was prepared as a colorless semi-liquid in 44% yield according to the preparation of Example 36 using (1r,4r)-4-amino-N-methylcyclohexane-1-carboxamide hydrochloride in step 3. The compound was purified by reverse phase column (0.5% NH4HCO3H2O in water, MeCN). MS: m / z: Calculated: C 25 H 31 FN4O6S[M+H] + 535; Observed: 535

[0228] Step 4: The title compound was prepared as prepared in Example 36 using 13-4 in step 4 in 28% yield as a white solid. MS: m / z: Calc: C 17 H 23 FN4O5S[M+H] + Observed: 415; 1 H NMR (400MHz, DMSO-d6) δ 9.79(s, 1H), 8.65(s, 2H), 7.72-7.69(m, 1H), 6.87-6.78(m, 2H), 4.10-4.07(m, 2H), 3.97(s, 2H), 3.06(s, 1H), 2.61-2.55(m, 3H), 2.19-2.01(m, 3H), 1.83-1.79(m, 2H), 1.46-1.24(m, 4H)

[0229] Preparative HPLC purification conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 20%B~34%B for 10min, then 34%B~100%B for 5min; Wavelength: 254 / 220nm

[0230] Example 59: 2-(4-(4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)piperazin-1-yl)-N-methylacetamide [ka] The title compound was prepared as prepared in Example 36 using N-methyl-2-(piperazin-1-yl)acetamide in step 3 in 9.5% overall yield as a yellow solid. MS: m / z: Calculated: C 16 H 22 FN5O5S[M+H] + Observations: 416; 1 H NMR (300MHz, DMSO-d6) δ 6.89-6.78(m, 2H), 4.17(s, 2H), 3.97(s, 2H), 3.58(d, J=4.3Hz, 2H), 3.08(s, 8H), 2.65(s, 3H)

[0231] Preparative HPLC purification conditions: Atlantis Prep T3 OBD column, 19*250mm 10μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 2%B~11%B for 10min, then 11%B; Wavelength: 254 / 220nm

[0232] Example 60: N-((1r,4r)-4-((4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzyl)amino)cyclohexyl)acetamide [ka] The title compound was prepared as prepared in 6% overall yield as a white solid following the procedure of Example 59 using tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate in step 1. MS: m / z: Calculated: C 17 H 23 FN4O5S[M+H] + Observed: 415; 1H NMR (400MHz, DMSO-d6) δ 7.74(d, J=7.8Hz, 1H), 6.78(d, J=9.0Hz, 2H), 3.96(s, 3H), 2.78-3.01(m, 3H),2.04(d, J=12.2Hz, 2H), 1.86-1.78(m, 2H), 1.77(s, 3H), 1.29(d, J=10.8Hz, 2H), 1.21-1.10(m, 2H)

[0233] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 3%B~27%B for 8min, then 27%B; Wavelength: 254 / 220nm

[0234] Example 61: (R)-5-(2-fluoro-6-hydroxy-4-((piperidin-3-ylamino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 36 in 27% overall yield as a white solid using tert-butyl (R)-3-aminopiperidine-1-carboxylate in step 3. MS: m / z: Calculated: C 14 H 19 FN4O4S [M+H] + Observations: 359; 1 H NMR (400MHz, DMSO-d6) δ 6.74-6.66(m, 2H), 4.00(s, 2H), 3.61(s, 2H), 3.11-2.96(m, 2H), 2.74-2.53(m, 3H), 1.92-1.71(m, 2H), 1.42-1.27(m, 2H)

[0235] Preparative HPLC conditions: XBridge Prep Phenyl OBD column, 19*250mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 8%B~13%B for 10 minutes, then 13%B; Wavelength: 254 / 220nm

[0236] Example 62: (R)-5-(2-fluoro-6-hydroxy-4-(((1-isopentylpiperidin-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka]

[0237] TIFF2025504969000097.tif102153

[0238] Step 1: To a solution of tert-butyl N-[(3R)-3-piperidyl]carbamate (500 mg, 2.5 mmol), 3-methylbutanal (430 mg, 4.99 mmol), DIEA (1.25 mL, 7.49 mmol) and AcOH (0.29 mL, 4.99 mmol) were added and stirred at room temperature for 0.5 h. NaBH3CN (313.58 mg, 4.99 mmol) was added at 0° C. and the mixture was stirred at room temperature for 2 h. The reaction was concentrated, diluted with EA, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product obtained was used in the next step without further purification. MS: m / z: Theoretical value: C 15 H 30 N2O2[M+H] + 271; Observations: 271

[0239] Step 2: To a solution of tert-butyl N-[(3R)-1-isopentyl-3-piperidyl]carbamate (200 mg, 0.74 mmol) in 1,4-dioxane (5 mL) was added HCl(g) (4 M in 1,4-dioxane, 5 mL) and stirred at room temperature for 3 h. The reaction was concentrated and the crude product was used in the next step without further purification. MS: m / z: Calculated: C 10 H 22 N2[M+H] + 171; Observations: 171

[0240] Step 3: Compound 14-4 was prepared as an off-white semi-liquid in 86% yield according to the preparation of Example 36 using (R)-1-isopentylpiperidin-3-amine hydrochloride in step 3. MS: m / z: Calculated: C 27 H 37 FN4O5S[M+H] + 549; Observations: 549

[0241] Step 4: The title compound was prepared as prepared in Example 36 using 14-4 in step 4 in 33% yield as an off-white solid. MS: m / z: Calc: C 19 H 29 FN4O4S[M+H] + Observations: 429; 1 H NMR (300MHz, DMSO-d6) δ 9.76-9.61(m, 1H), 6.77-6.74(m, 2H), 3.94(s, 2H), 3.79(s, 2H), 3.36-3.15(m, 5H), 2.44-2.34(m, 2H), 1.96-1.73(m, 2H), 1.65-1.34(m, 5H), 0.88(d, J=6.5Hz, 6H)

[0242] Preparative HPLC purification conditions: XBridge Shield RP18 OBD column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 8%B~24%B for 10min, then 24%B; Wavelength: 254 / 220nm

[0243] Example 63: 5-[2-fluoro-6-hydroxy-4-[[[(3S)-1-isopentyl-3-piperidyl]amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 62 in 3% overall yield as a purple semi-liquid using tert-butyl N-[(3S)-3-piperidyl]carbamate in step 3. MS: m / z: Calculated: C 19 H 29 FN4O4S [M+H] + Observations: 429; 1 H NMR (300MHz, DMSO-d6) δ 10.09-9.85(m, 2H), 6.89(d, J=10.8Hz, 2H), 4.36(s, 2H), 4.18(s, 2H), 3.82(s, 2H), 3.17 (p, J=6.5Hz, 3H), 2.98-2.87(m, 2H), 2.29-1.89(m, 2H), 1.72 -1.58(m, 5H), 0.91(d, J=5.8Hz, 6H)

[0244] Preparative HPLC purification conditions: Column: XBridge Prep Phenyl OBD column, 19*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~20%B for 10min, then 20%B; Wavelength: 254nm; RT1(min): 7.98; Runs: 0

[0245] Example 64: (R)-5-(2-fluoro-6-hydroxy-4-(((tetrahydro-2H-pyran-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 36 using (3R)-tetrahydropyran-3-amine in step 3 in 6.6% overall yield as a yellow solid. MS: m / z: Calculated: C 14 H 18 FN3O5S[M+H] + Observed values: 360; 1 H NMR (300MHz, DMSO-d6) δ 9.88(s, 1H), 8.87(s, 2H), 6.94-6 .79(m, 2H), 4.12(s, 2H), 4.01(s, 2H), 3.96-3.85(m, 1H), 3.71-3.64(m, 1H), 3.56-3.47(m, 2H), 3.20(s, 1H), 2.09-2.06(m, 1H), 1.85-1.63(m, 2H), 1.57-1.45(m, 1H)

[0246] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~12%B for 7 min, then 12%B; Wavelength: 254 / 220nm

[0247] Example 65: (S)-5-(2-fluoro-6-hydroxy-4-((piperidin-3-ylamino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 36 in 21% overall yield as a tan solid using tert-butyl (S)-3-aminopiperidine-1-carboxylate in step 3. MS: m / z: Theoretical value: C 14 H 19 FN4O4S [M+H] + Observations: 359; 1 H NMR (300MHz, DMSO-d6) δ 6.78-6.72(m, 2H), 3.98(s, 2H), 3.64(s, 2H), 3.17-2.89(m, 2H), 2.79-2.54(m, 3H), 2.01-1.69(m, 2H), 1.35-1.14(m, 2H)

[0248] Preparative HPLC conditions: XBridge Prep Phenyl OBD column, 19*250mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 7%B~12%B elution for 10 minutes, then 12%B; Wavelength: 254 / 220nm

[0249] Example 66: (S)-5-(4-(((3,3-dimethylcyclohexyl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in 16% overall yield as a pale pink solid according to the preparation of Example 36 using (1S)-3,3-dimethylcyclohexanamine hydrochloride in step 3. MS: m / z: Calculated: C 17 H 24 FN3O4S [M+H] + Observations: 386; 1H NMR (300MHz, DMSO-d6) δ 9.78(s, 1H), 8.58(s, 2H), 6.95-6.79(m, 2H), 4.08(t, J=6.2Hz, 2H), 3.98(s, 2H), 3.21(s, 1H), 2.10(d, J=12.1Hz, 1H), 1.82(d, J=12.4Hz, 1H), 1.65(d, J=13.6Hz, 1H), 1.39(dd, J=26.9, 13.5Hz, 1H), 1.27-1.00(m, 4H), 0.96(s, 3H), 0.89(s, 3H)

[0250] Preparative HPLC conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 12%B~25%B for 10min, then 25%B; Wavelength: 254 / 220nm

[0251] Example 67: (S)-5-(2-fluoro-6-hydroxy-4-(((tetrahydro-2H-pyran-3-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 36 using (S)-tetrahydro-2H-pyran-3-amine in step 3 in 22% overall yield as an off-white solid. MS: m / z: Calculated: C 14 H 18 FN3O5S[M+H] + Observed values: 360; 1 H NMR (300MHz, DMSO-d6) δ 6.72-6.69(m, 2H), 3.94(s, 2H), 3.87-3.73(m, 2H), 3.69-3.66(m, 2H), 3.31-3.17(m, 3H), 1.96-1.91(m, 1H), 1.76-1.64(m, 1H), 1.47-1.44(m, 2H)

[0252] Preparative HPLC purification conditions: XBridge Shield RP18 OBD column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~17%B for 7min, then 17%B; Wavelength: 254 / 220nm

[0253] Example 68: 5-[4-[[[(3R)-1-acetyl-3-piperidyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] [ka]

[0254] Step 1: To a mixture of tert-butyl N-[(3R)-3-piperidyl]carbamate (350 mg, 1.75 mmol) and TEA (0.91 mL, 5.24 mmol) / DCM (7 mL) was added dropwise at 0° C., and the mixture was stirred for 1 h. After stirring was completed, the resulting solution was concentrated under reduced pressure. The residue was purified by reverse phase column (0.05% NH4HCO3 aqueous solution, MeCN) to give tert-butyl N-[(3R)-1-acetyl-3-piperidyl]carbamate (400 mg, 1.65 mmol, 94% yield) as a pale yellow oil. MS: m / z: Theoretical value: C 12 H 22 N2O3[M+H] + 243; Observations: 243

[0255] Step 2: A mixture of tert-butyl N-[(3R)-1-acetyl-3-piperidyl]carbamate (390 mg, 1.61 mmol) in DCM (3 mL) and 4 M HCl / EA (3 mL) was added to a pear-shaped flask (50 mL) at room temperature and stirred at room temperature for 3 h. The reaction was concentrated and the resulting crude product was used in the next step without further purification.

[0256] Step 3: Compound 15-4 was prepared in 63% yield as an off-white solid according to the preparation of Example 36 using 1-[(3R)-3-amino-1-piperidyl]ethanone hydrochloride in step 3. MS: m / z: Calculated: C 24 H 29 FN4O6S[M+H] + 521; Observations: 521

[0257] Step 4: The title compound was prepared as prepared in Example 36 using 15-4 in step 4 in 29% yield as an off-white solid. MS: m / z: Calculated: C 16 H 21 FN4O5S[M+H] + 401; Observed: 401; 1 H NMR (300MHz, DMSO-d6) δ 6.88(dd, J=12.7, 2.2Hz, 2H), 4.31-4.07(m, 3H), 3.99(s, 2H), 3.63-3.47(m, 2H), 3.33-3.07(m, 3H), 2.79(d, J=30.6Hz, 0H), 2.03(s, 4H), 1.73(d, J=32.4Hz, 2H), 1.50(s, 1H)

[0258] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 3%B~26%B for 8 min, then 26%B; Wavelength: 254 / 220nm

[0259] Example 69: 5-[2-fluoro-4-[[[(3R)-1-(3-fluorophenyl)sulfonyl-3-piperidyl]amino]methyl]-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 68 using 3-fluorobenzenesulfonyl chloride in step 1 in 42% overall yield as a white solid. MS: m / z: Calculated: C 20 H 22 F2N4O6S2[M+H] + Observations:517; 1 H NMR (300MHz, DMSO-d6) δ 7.85-7.48(m, 4H), 6.77(s, 2H), 3.99(s, 2H), 3.91(s, 2H), 3.62(d, J=10.2Hz, 2H), 3.35(d, J=11.7Hz, 1H), 2.95(s, 1H), 2.47(s, 1H), 2.01-1.74(m, 2H), 1.62-1.08(m, 2H)

[0260] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 3%B~26%B for 8 min, then 26%B; Wavelength: 254 / 220nm

[0261] Example 70: 5-[2-fluoro-4-[[[(3S)-1-(3-fluorophenyl)sulfonyl-3-piperidyl]amino]methyl]-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] [ka]

[0262] Step 1: Compound 16-2 was prepared in 93% yield as a white solid following the procedure of Example 68 using 3-fluorobenzenesulfonyl chloride in step 1. MS: m / z: Calculated: C 19 H 21 FN2O4S[MH] - 391; Observations: 391

[0263] Step 2: To a stirred mixture of benzyl N-[(3S)-1-(3-fluorophenyl)sulfonyl-3-piperidyl]carbamate (600 mg, 1.53 mmol) in DCM (10 mL) was added TMSI (458.88 mg, 2.29 mmol) at 0° C. and stirred at room temperature for 2 h. After completion of the reaction as monitored by LCMS, the mixture was concentrated. The resulting residue was purified by reverse phase column to give (3S)-1-(3-fluorophenyl)sulfonylpiperidin-3-amine (300 mg, 1.16 mmol, 76% yield) as a black solid. MS: m / z: Theoretical value: C 11 H 15 FN2O2S[M+H] + 259; Observed: 259

[0264] Step 3: Using (3S)-1-(3-fluorophenyl)sulfonylpiperidin-3-amine in step 3 as prepared in Example 36, compound 16-4 was prepared in 59% yield as a yellow solid. MS: m / z: Calculated: C 28 H 30 F2N4O7S2[M+H] + 637; Observed: 637

[0265] Step 4: The title compound was prepared as prepared in Example 36 using 16-4 in step 4 as a white solid in 44% yield. MS: m / z: Calc: C 20 H 22 F2N4O6S2[M+H] + Observations:517; 1H NMR (400MHz, DMSO-d6) δ 7.75-7.65(m, 1H), 7.63-7.53(m, 3H), 6.69-6.59(m, 2H), 6.07(s, 1H), 3.94(s, 2H), 3.63(d, J=2.6Hz, 2H), 3.57-3.50(m, 1H), 3.39(d, J=11.6Hz, 1H), 3.33(s, 1H), 2.39-2.32(m, 1H), 2.15-2.12(m, 1H), 1.81-1.65(m, 2H), 1.43(t, J=11.4Hz, 1H), 1.04-1.02(m, 1H)

[0266] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 5%B~35%B for 10min, then 35%B; Wavelength: 254nm

[0267] Example 71: 5-[4-[[[(3S)-1-acetyl-3-piperidyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 15% overall yield as a white solid following the procedure of Example 70 using acetyl chloride in step 1. MS: m / z: Calculated: C 16 H 21 FN4O5S[M+H] + 401; Observed: 401; 1H NMR (400MHz, DMSO-d6) δ 9.67(s, 1H), 6.81(dd, J=10.7, 5.1Hz, 2H), 4.24(d, J=11.6Hz, 1H), 4.02(s, 1H), 3.96(s, 3H), 3.58(dt, J=13.5, 4.4Hz, 1H), 3.19-3.11(m, 1H), 2.97(s, 2H), 2.08-2.04(m, 4H), 1.81-1.73(m, 1H), 1.60-1.20(m, 2H)

[0268] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 3%B~20%B for 9 minutes, then 20%B; Wavelength: 254 / 220nm

[0269] Example 72: 5-[2-fluoro-6-hydroxy-4-[[[(3R)-1-methylsulfonyl-3-piperidyl]amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 20% overall yield as a white solid following the procedure of Example 70 using methanesulfonyl chloride in step 1. MS: m / z: Calculated: C 15 H 21 FN4O6S2[M+H] + Observations: 437; 1 H NMR (300MHz, DMSO-d6) δ 6.93-6.82(m, 2H), 4.22-4.05(m, 2H), 4.02(s, 2H), 3.70(dd, J=12.0, 3.5Hz, 1H), 3.38-3.28(m, 2H), 2.94(s, 5H), 2.07(s, 1H), 1.90(d, J=5.6Hz, 1H), 1.59(q, J=7.8, 6.1Hz, 2H)

[0270] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~11%B for 9 min, then 11%B; Wavelength: 254 / 220nm

[0271] Example 73: 5-[4-[[[(3S)-1-cyclopropylsulfonyl-3-piperidyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 17% overall yield as a white solid following the procedure of Example 70 using cyclopropanesulfonyl chloride in step 1. MS: m / z: Calculated: C 17 H 23 FN4O6S2[M+H] + Observations: 463; 1 H NMR (300MHz, DMSO-d6) δ 6.93-6.81(m, 2H), 4.13-4.06(m, J=3.8Hz, 4H), 3.75(dd, J=12.1, 3.4Hz, 1H), 3.39(d, J=12.6Hz, 2H), 3.12-2.93(m, 2H), 2.68-2.52(m, 1H), 2.06(d, J=8.0Hz, 2H), 1.89(s, 2H), 1.08-0.89(m, 4H)

[0272] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 5%B~35%B for 10min, then 35%B; Wavelength: 254nm

[0273] Example 74: 5-[4-[[[(3R)-1-cyclopropylsulfonyl-3-piperidyl]amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 15% overall yield as a white solid following the procedure of Example 70 using cyclopropanesulfonyl chloride in step 1. MS: m / z: Calculated: C 17 H 23 FN4O6S2[M+H] + Observations: 463; 1 H NMR (400MHz, DMSO-d6) δ 10.12(s, 1H), 8.99-8.86(d, 2H), 6.93-6.83(m, 2H), 4.15-4.10(d, 4H), 3.40(d, J=11.6Hz, 2H), 3.05(dd, J=12.1, 8.6Hz, 2H), 2.70-2.59(m, 1H), 2.53(s, 1H), 2.12(s, 1H), 1.89(s, 1H), 1.59(t, J=10.4Hz, 2H), 1.07-0.91(m, 4H)

[0274] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 5%B~35%B for 10min, then 35%B; Wavelength: 254nm

[0275] Example 75: 5-[2-fluoro-6-hydroxy-4-[[[(3S)-1-methylsulfonyl-3-piperidyl]amino]methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in 43% overall yield as a white solid following the procedure of Example 70 using methanesulfonyl chloride in step 1. MS: m / z: Calculated: C 15 H 21 FN4O6S2[M+H] + Observations: 437; 1 H NMR (300MHz, DMSO-d6) δ 9.99(s, 1H), 9.02(s, 1H), 8.91(s, 1H), 6.93-6.81(m, 2H), 4.14(s, 2H), 4.05(s, 2H), 3.70(d, J=12.6Hz, 1H), 3.34-3.30(m, 2H), 3.06-2.88(m, 2H), 2.95-2.90(s, 3H), 2.05(s, 1H), 1.89(s, 1H), 1.59(d, J=8.4Hz, 2H)

[0276] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~28%B for 7 min, then 28%B; Wavelength: 254nm

[0277] Example 76: 3-[(3S)-3-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]-1-piperidyl]-3-oxo-propanoic acid [ka] The title compound was prepared as prepared in 6% overall yield as a white solid following the procedure of Example 70 using 3-benzyloxy-3-oxo-propanoic acid in step 1. MS: m / z: Calculated: C 17 H 21 FN4O7S[M+H] + Observed: 445; 1H NMR (300MHz, DMSO-d6) δ 10.00(s, 1H), 8.84(s, 2H), 6.93-6.81(m, 2H), 4.46-4.35(m, 1H), 4.32-3.87(m, 6H), 3.37-2.81(m, 4H), 2.35-1.25(m, 4H)

[0278] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~20%B for 10min, then 20%B; Wavelength: 254nm

[0279] Example 77: 5-[4-[[(4,4-dimethylcyclohexyl)-methyl-amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] [ka]

[0280] Step 1: Di-tert-butyl dicarbonate (686.16 mg, 3.14 mmol) was added dropwise to a mixture of 4,4-dimethylcyclohexanamine (400 mg, 3.14 mmol) and TEA (1.64 mL, 9.43 mmol) / methanol (10 mL) at 0° C., and the mixture was stirred at 60° C. overnight. After completion of the reaction monitored by TLC, the mixture was cooled with ice water. The solution was extracted with ethyl acetate three times, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (PE:EA=8:1) to obtain tert-butyl N-(4,4-dimethylcyclohexyl)carbamate (700 mg, 3.07 mmol, 98% yield) as a white solid. MS: m / z: Theoretical value: C 13 H 25 NO2[M+H]+ Observations:228; 1 H NMR (300 MHz, chloroform-d) δ 4.42(s, 1H), 3.37(s, 1H), 1.77-1.75(m, 2H), 1.44(s, 9H), 1.38-1.21(m, 6H), 0.90(d, J=2.9Hz, 6H).

[0281] Step 2: To a mixture of tert-butyl N-(4,4-dimethylcyclohexyl)carbamate (700 mg, 3.08 mmol) and iodomethane (1.31 g, 9.24 mmol) in THF (10 mL) was added dropwise NaH (221.7 mg, 9.24 mmol) at 0° C. and stirred at 80° C. for 2 h. LCMS showed the reaction was complete. The resulting solution was cooled with ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (PE:EA=8:1) to give tert-butyl N-(4,4-dimethylcyclohexyl)-N-methyl-carbamate (420 mg, 1.74 mmol, 57% yield) as a yellow oil. MS: m / z: Theoretical value: C 14 H 27 NO2[M+H-56+41] + 227; Observed: 227

[0282] Step 3: To a stirred solution of tert-butyl N-(4,4-dimethylcyclohexyl)-N-methyl-carbamate (400 mg, 1.66 mmol) in 1,4-dioxane (4 mL) was added HCl (4M in dioxane, 4 mL, 1.66 mmol) and stirred at room temperature overnight. After completion of the reaction, monitored by LCMS, the mixture was concentrated to give N,4,4-trimethylcyclohexanamine hydrochloride (200 mg, 1.12 mmol, 68% yield) as a white solid. MS: m / z: Theoretical value: C9H 19 N[M+H] + 141; Observed: 141

[0283] Step 4: To a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (Intermediate 2, 100 mg, 0.25 mmol), N,4,4-trimethylcyclohexanamine hydrochloride (67.59 mg, 0.38 mmol) and DIEA (0.08 mL, 1.01 mmol) in ethanol (8 mL) was added a solution of ZnCl2 (0.7 M, in THF, 1.45 mL, 1.01 mmol) and stirred at 80° C. for 30 min, and NaBH3CN (64.91 mg, 1.01 mmol) was added to the mixture. The mixture was stirred at room temperature for 12 h. After completion of the reaction as monitored by LCMS, the mixture was concentrated. The resulting residue was purified by reverse phase column to give 5-[4-[[(4,4-dimethylcyclohexyl)-methyl-amino]methyl]-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (44 mg, 0.08 mmol, 33% yield) as an off-white solid. MS: m / z: Theoretical value: C 26 H 34 FN3O5S[M+H] + 520; Observed: 520

[0284] Step 5: The title compound was prepared as prepared in Example 36 using 17-5 in step 4 in 35% yield as a white solid. MS: m / z: Calc: C 18 H 26 FN3O4S[M+H] + 400; Observed values: 400; 1 H NMR (400MHz, DMSO-d6) δ 9.85(s, 1H), 9.18(s, 1H), 6.86(d, J=15.2Hz, 2H), 6.67(s, 1H), 4.37(s, 1H), 4.07(s, 1H), 3.96(s, 2H), 3.32(s, 1H), 2.64(s, 3H), 2.13(s, 1H), 1.86(s, 1H), 1.65(s, 2H), 1.47(s, 2H), 1.23(s, 2H), 0.91(d, J=7.4Hz, 6H)

[0285] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3+0.1%NH3 . H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 27%B~37%B in 8 min, then 37%B; Wavelength: 254 / 220nm

[0286] Example 78: 5-[4-[[cyclobutylmethyl(propyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] [ka]

[0287] Step 1: Cyclobutanecarbonyl chloride (1.20 g, 10.15 mmol) was added to a stirred solution of propan-1-amine (500 mg, 8.46 mmol) and TEA (4.42 mL, 25.38 mmol) in DCM (8 mL) at 0° C. and stirred at 0° C. for 1 h. After completion of the reaction, monitored by LCMS, the mixture was diluted with DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (PE:EA=4:1) to give N-propylcyclobutanecarboxamide (600 mg, 4.24 mmol, 50% yield) as an off-white solid. MS: m / z: Theoretical value: C8H 15 NO[M+H] + 142; Observed: 142

[0288] Step 2: A solution of N-propylcyclobutanecarboxamide (500 mg, 3.54 mmol) in THF (2 mL) was added to a stirred solution of LiAlH4 (393.03 mg, 10.62 mmol) in THF (8 mL) and stirred at 80 °C overnight. LCMS showed complete consumption of starting material. The mixture was quenched with water (4 mL), the suspension was filtered, and (Boc)2O (1.15 g, 5.31 mmol) was added to the filtrate. The mixture was stirred for 1 h, the resulting solution was extracted with ethyl acetate, the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel column chromatography to give tert-butyl N-(cyclobutylmethyl)-N-propyl-carbamate (700 mg, 3.07 mmol, 87% yield) as a white solid. MS: m / z: Theoretical value: C 13 H 25 NO2[M+H] + 228; Observed: 228

[0289] Step 3: To a stirred solution of tert-butyl N-(cyclobutylmethyl)-N-propyl-carbamate (690 mg, 3.04 mmol) in 1,4-dioxane (4 mL) was added a solution of HCl / dioxane (4 M, 4 mL) and stirred at room temperature overnight. After completion of the reaction, monitored by LCMS, the mixture was concentrated to give N-(cyclobutylmethyl)propan-1-amine hydrochloride (350 mg, 2.1382 mmol, 70% yield) as a white solid. MS: m / z: Theoretical value: C8H 17 N[M+H] + 128; Observed: 128

[0290] Step 4: The title compound was prepared as prepared in Example 77 using 18-4 in step 4 in 51% yield as a white solid. MS: m / z: Calc: C 25 H 32 FN3O5S[M+H] + 505; Observed: 505

[0291] Step 5: The title compound was prepared as prepared in Example 36 using 18-5 in step 4 in 53% yield as a white solid. MS: m / z: Calc: C 17 H 24 FN3O4S[M+H] + Observations: 386; 1 H NMR (300MHz, DMSO-d6) δ 10.16(s, 1H), 9.28(s, 1H), 6.91(dd, J=10.6, 1.9Hz, 1H), 6.84(t, J=1.5Hz, 1H), 4.20 (S, 2H), 4.19(d, J=5.1Hz, 2H), 3.11(t, J=5.7Hz, 2H), 2.91(dt, J=12.9, 6.0Hz, 2H), 2.75(s, 1H), 2.09(dd, J=8.3, 4.7Hz, 2H), 1.96-1.75(m, 3H), 1.73(s, 3H), 0.88(t, J=7.3Hz, 3H)

[0292] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 7%B~37%B for 10min, then 37%B; Wavelength: 254nm

[0293] Compound 80-1: 5-[2-fluoro-6-hydroxy-4-[(imidazo[1,2-a]pyridin-7-ylamino)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] [ka]

[0294] Step 1: To a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (Intermediate 2, 95 mg, 0.24 mmol) and imidazo[1,2-a]pyridin-7-amine (48.11 mg, 0.36 mmol) in dry DMF (5 mL) was added TMSCl (0.08 mL, 0.60 mmol) dropwise at 0° C. and the resulting mixture was stirred at 60° C. for 30 min. The reaction mixture was then cooled to 0° C. and a solution of BH3 / THF (1 M, 0.5 mL, 0.48 mmol) was added slowly via syringe. After addition, the mixture was stirred at 60° C. for 1 h and LCMS showed the reaction was complete. The resulting solution was quenched with ice water (0.5 mL) and directly purified on a reverse phase column (0.05% aqueous NH4HCO3 and MeCN) to give 5-[2-fluoro-4-[(imidazo[1,2-a]pyridin-7-ylamino)methyl]-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (55 mg, 0.11 mmol, 45% yield) as a pale yellow oil. MS: m / z: Theoretical: C 24 H 22 FN5O5S [M+H] + 512; Observed value: 512[M+H] +

[0295] Step 2: To a solution of 5-[2-fluoro-4-[(imidazo[1,2-a]pyridin-7-ylamino)methyl]-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (19-1, 50 mg, 0.10 mmol) in DCM (1 mL) was added TFA (2 mL) at 0° C. and the mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. After concentration, the resulting crude was first purified by reverse phase column (0.05% NH4HCO3 aqueous solution and MeCN) and then further purified by preparative HPLC to give 5-[2-fluoro-6-hydroxy-4-[(imidazo[1,2-a]pyridin-7-ylamino)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (8.5 mg, 0.02 mmol, 22% yield) as a white solid. MS: m / z: Theoretical: C 16 H 14 FN5O4S [M+H] + 392; Observed value: 392 [M+H] + ; 1 H NMR (300MHz, DMSO-d6) δ 8.30(d, J=7.4Hz, 1H), 7.69(d, J=1.9Hz, 1H), 7.45(d, J=1.9Hz, 1H), 6.79-6.64(m, 3H), 6.29(d, J=2.2Hz, 1H), 4.32(s, 2H), 3.96(s, 2H), 2.35(s, 0H)

[0296] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~20%B for 9 minutes, then 20%B; Wavelength: 254 / 220nm

[0297] Example 79: 5-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]pyridine-3-carbonitrile [ka] The title compound was prepared as per the preparation of compound 80-1 using 5-aminopyridine-3-carbonitrile in step 1 in 22% overall yield as a white solid. MS: m / z: Calculated: C 15 H 12 FN5O4S[M+H] + Observations: 378; 1 H NMR (300MHz, DMSO-d6) δ 6.95-6.52(m, 4H), 4.41(s, 2H), 3.95(s, 2H), 2.38(s, 6H)

[0298] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 3%B~32%B for 8 minutes, then 32%B; Wavelength: 254 / 220nm

[0299] Example 80: 5-[4-[(2-chloro-5-fluoro-anilino)methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as per the preparation of compound 80-1 in 11% overall yield as a white solid using 2-chloro-5-fluoroaniline in step 1. The reductive amination was carried out at room temperature instead of 60° C. MS: m / z: Theoretical value: C 15 H 12 ClF2N3O4S[M+H] + 404; Observed: 404; 1 H NMR (300MHz, DMSO-d6) δ 7.28(dd, J=8.7, 6.0Hz, 1H), 6.71(d, J=8.9Hz, 2H), 6.58-6.13(m, 2H), 4.49-4.12(m, 4H)

[0300] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 26%B~56%B for 10min, then 56%B; Wavelength: 254nm

[0301] Example 81: 4-chloro-3-[[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]methylamino]benzonitrile [ka] The title compound was prepared as prepared in 12% overall yield as a white solid following the procedure of Example 80 using 3-amino-4-chloro-benzonitrile in step 1. MS: m / z: Calculated: C 16 H 12 ClFN4O4S[MH] - 409; Observations: 409; 1 H NMR (300MHz, DMSO-d6) δ 10.38(s, 1H), 7.49(d, J=8.1Hz, 1H), 7.00(dd, J=8.1, 1.9Hz, 1H), 6.93(d, J=1.9Hz, 1H), 6.78-6.68(m, 3H), 4.41(d, J=4.6Hz, 4H)

[0302] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 30%B~60%B for 10min, then 60%B; Wavelength: 254nm

[0303] Example 82: 5-[4-[[(4-cyclopropyl-2-pyridyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared for compound 80-1 in 12% overall yield as a white solid using 4-cyclopropylpyridin-2-amine in step 1. Reductive amination was performed at 80° C. instead of 60° C. MS: m / z: Calculated: C 17 H 17 N4O4S[M+H] + Observations: 393; 1 H NMR (300MHz, DMSO-d6) δ 7.77(d, J=5.8Hz, 1H), 6.68-6.57(m, 2H), 6.43(s, 1H), 6.30(d, J=5.8Hz, 1H), 4.39(s, 2H), 3.94(s, 2H), 1.84(d, J=9.4Hz, 1H), 1.09-0.96(m, 2H), 0.82-0.65(m, 2H)

[0304] Preparative HPLC purification conditions: Column: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3+0.1%NH3 . H2O), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 26%B~36%B in 7 min, then 36%B; Wavelength: 254 / 220nm

[0305] Example 83: 5-(2-fluoro-6-hydroxy-4-(4-isopentylpiperazin-1-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] [ka]

[0306] Step 1: To a stirred solution of 1-[(4-methoxyphenyl)methyl]piperazine (200 mg, 0.97 mmol) and 3-methylbutanal (167 mg, 1.94 mmol) in DCM (8.0 mL) was added CH3COOH (0.11 mL, 1.94 mmol) and stirred at ambient temperature for 30 min. NaBH3CN (0.17 mL, 1.94 mmol) was added at 0 °C and the mixture was stirred at ambient temperature for 2 h, after which LCMS showed complete consumption of starting material. The reaction was quenched with saturated aqueous NH4Cl (5 mL) and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude was purified by reverse phase column to give 1-isopentyl-4-[(4-methoxyphenyl)methyl]piperazine (200 mg, 0.72 mmol, 75% yield). MS: m / z: Theoretical: C 17 H 28 NO [M+H] + 277; Observed: 277

[0307] Step 2: To a stirred solution of 1-isopentyl-4-[(4-methoxyphenyl)methyl]piperazine (200 mg, 0.72 mmol) in a mixture of methanol (8 mL) and 2M HCl (2.0 mL) was added Pd / C (100 mg) under N2 atmosphere. H2 was then added to the reaction and the resulting mixture was stirred at ambient temperature overnight. Upon completion, the mixture was filtered and the filtrate was concentrated. The resulting residue was azeotroped twice with toluene to remove residual water to give 1-isopentylpiperazine hydrochloride as a white solid. MS: m / z: Theoretical value: C9H 20 N2[M+H] + 157; Observed: 157

[0308] Step 3: To a stirred solution of 5-[4-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Intermediate 1, 120 mg, 0.27 mmol) and 1-isopentylpiperazine hydrochloride (103.88 mg, 0.54 mmol) in 1,4-dioxane (8.0 mL) was added Cs2CO3 (0.07 mL, 0.81 mmol) and (DiMeIHeptCl)Pd(cinnamyl)Cl (27.89 mg, 0.03 mmol). The resulting suspension was evacuated and degassed with nitrogen three times and stirred at 100 °C for 16 h. After stirring, the mixture was concentrated and the resulting residue was purified with a reverse phase column (0.05% NH4HCO3 aqueous solution, MeCN) to give 5-[2-fluoro-4-(4-isopentylpiperazin-1-yl)-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (70 mg, 0.13 mmol, 50% yield). MS: m / z: Theoretical value: C 25 H 33 FN4O5S [M+H] + 521; Observations: 521

[0309] Step 4: To a stirred solution of 5-[2-fluoro-4-(4-isopentylpiperazin-1-yl)-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (65 mg, 0.12 mmol) in DCM (3 mL), TFA (6 mL) was added and the mixture was stirred at room temperature overnight. After stirring was completed, the mixture was concentrated and the resulting residue was purified by preparative HPLC to give 5-[2-fluoro-6-hydroxy-4-(4-isopentylpiperazin-1-yl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (10.5 mg, 0.02 mmol, 20% yield) as a white solid. MS: m / z: Theoretical value: C 17 H 25 FN4O4S [M+H] + 401; Observed: 401; 1H NMR (400MHz, DMSO-d6) δ 9.57(s, 2H), 6.43(dd, J=13.5, 2.7Hz, 1H), 6.29(s, 1H), 4.05(d, J=16.3Hz, 2H), 3.83(d, J=13.1Hz, 2H), 3.55(d, J=11.7Hz, 2H), 3.15(d, J=11.0Hz, 2H), 3.09(d, J=8.8Hz, 2H), 3.00(d, J=13.0Hz, 2H), 1.66-1.50(m, 3H), 0.91(d, J=6.1Hz, 6H)

[0310] Preparative HPLC conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 15%B~30%B for 8min, then 30%B; Wavelength: 254 / 220nm

[0311] Example 84: 5-(4-(4-aminopiperidin-1-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 83 in 12% overall yield as a purple solid using tert-butyl N-(4-piperidyl)carbamate in step 3. MS: m / z: Calculated: C 13 H 17 FN4O4S[M+H] + Observed: 345; 1 H NMR (400MHz, DMSO-d6) δ 7.93(s, 2H), 6.31 -6.21(m, 2H), 3.88(s, 2H), 3.75(d, J=13.4Hz, 2H), 3.51-3.21(m, 1H), 2.89-2.78(m, 2H), 1.91-1.80(m, 2H), 1.54-1.51(m, 2H)

[0312] Preparative HPLC purification conditions: XBridge Shield RP18 OBD column, 19*250mm, 10μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 2%B to 20%B in 7min, then 20%B; Wavelength: 254 / 220nm

[0313] Example 85: 5-(2-fluoro-6-hydroxy-4-(piperazin-1-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 83 in 8% overall yield as a white solid using tert-butyl piperazine-1-carboxylate in step 3. MS: m / z: Calculated: C 12 H 15 FN4O4S[MH] - Observations: 329; 1 H NMR (300MHz, DMSO-d6) δ 9.91(d, J=3.2Hz, 1H), 9.24(s, 1H), 6.28-6.45(m, 2H), 4.01(s, 2H), 3.38(s, 4H), 3.18(s, 4H)

[0314] Example 86: 5-(2-fluoro-6-hydroxy-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 83 using 1-(2-methoxyethyl)piperazine in step 3 in 14% overall yield as an off-white solid. MS: m / z: Calculated: C 15 H 21 FN4O5S[M+H] + Observations: 389; 1H NMR (400MHz, DMSO-d6) δ 9.62(s, 1H), 9.23(s, 1H), 6.41(dd, J=13.5, 2.6Hz, 1H), 6.28(d, J=2.7Hz, 1H), 3.93(s, 2H), 3.81(d, J=12.3Hz, 2H), 3.68(t, J=4.8Hz, 2H), 3.60-3.46(m, 5H), 3.15-3.09(m, 6H)

[0315] Preparative HPLC purification conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 5%B~20%B for 10min, then 20%B; Wavelength: 254 / 220nm

[0316] Example 87: 5-(4-(4-(dimethylamino)piperidin-1-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 83 using N,N-dimethylpiperidin-4-amine in step 3 in 12% overall yield as an off-white solid. MS: m / z: Calculated: C 15 H 21 FN4O4S[M+H] + Observations: 373; 1 H NMR (400MHz, DMSO-d6) δ 9.46-9.39(m, 2H), 6.31(dd, J=13.8, 2.7Hz, 1H), 6.17(d, J=2.7Hz, 1H), 4.02(s, 2H), 3.78(d, J=13.1Hz, 2H), 3.30-3.23(m, 1H), 2.72-2.66(m, 8H), 1.96-1.93(m, 2H), 1.58-1.47(m, 2H)

[0317] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~15%B for 7 min, then 15%B; Wavelength: 254 / 220nm

[0318] Example 88: 5-(2-fluoro-6-hydroxy-4-(piperidin-4-ylamino)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 83 using tert-butyl 4-aminopiperidine-1-carboxylate in step 3 in 5% overall yield as a white solid. MS: m / z: Theoretical value: C 13 H 17 FN4O4S[MH] + Observations: 343; 1 H NMR (400MHz, DMSO-d6) δ 9.32(s, 1H), 8.50(s, 1H), 8.32(s, 1H), 6.39-5.89(m, 3H), 4.06(s, 2H), 3.51-3.42(m, 1H), 3.30 -3.27(m, 2H), 3.04-2.96(m, 2H), 2.14-1.95(m, 2H), 1.62-1.41(m, 2H)

[0319] Preparative HPLC purification conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 20%B~34%B for 10min, then 34%B~100%B for 5min; Wavelength: 254 / 220nm

[0320] Example 89: 5-(2-fluoro-6-hydroxy-4-((1-isopentylpiperidin-4-yl)amino)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 83 in 2.6% overall yield as a pink solid using 1-isopentylpiperidin-4-amine hydrochloride in step 3. MS: m / z: Calculated: C 18 H 27 FN4O4S[M+H] + Observed: 415; 1 H NMR (400MHz, DMSO-d6) δ 8.72(s, 1H), 5.94-5.91(m, 3H), 3.83(s, 2H), 2.85(s, 7H), 1.98(s, 2H), 1.58-1.45(m, 5H), 0.89(d, J=6.5Hz, 6H)

[0321] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 13%B~33%B for 8min, then 33%B; Wavelength: 254 / 220nm

[0322] Example 90: 5-(2-fluoro-6-hydroxy-4-((1-(2-methoxyethyl)piperidin-4-yl)amino)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 83 using 1-(2-methoxyethyl)piperidin-4-amine in step 3 in 4.9% overall yield as a pink solid. MS: m / z: Calculated: C 16 H 23 FN4O5S [M+H] + 403; Observed: 403; 1H NMR (400MHz, DMSO-d6) δ 8.70(br, 1H), 5.95-5.70(m, 3H), 3.85(br, 2H), 3.61(br, 2H), 3.53-2.95(m, 10 H), 2.12-1.93(m, 2H), 1.68-1.47(m, 2H)

[0323] Preparative HPLC purification conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.1% NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 5%B~20%B for 10min, then 20%B; Wavelength: 254 / 220nm

[0324] Example 91: N-(2-(dimethylamino)ethyl)-4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzamide [ka] [ka]

[0325] Step 1: To a stirred solution of 3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzoic acid (Intermediate 3, 100 mg, 0.24 mmol) and N',N'-dimethylethane-1,2-diamine (32.22 mg, 0.37 mmol) in DMF (4 mL) was added HATU (138.90 mg, 0.37 mmol) and DIEA (0.12 mL, 0.73 mmol) and the mixture was stirred at ambient temperature for 2 h. After stirring, the reaction mixture was purified by reverse phase column chromatography to obtain N-[2-(dimethylamino)ethyl]-3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzamide (80 mg, 0.16 mmol, 68% yield). MS: m / z: Theoretical value: C21 H 25 FN4O6S[M+H] + 481; Observations: 481

[0326] Step 2: To a stirred solution of N-[2-(dimethylamino)ethyl]-3-fluoro-5-[(4-methoxyphenyl)methoxy]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzamide (23-1, 70 mg, 0.15 mmol) in DCM (4 mL) was added TFA (8 mL) at 0° C. and the mixture was stirred at ambient temperature for 3 h. After completion of stirring, the reaction mixture was concentrated and purified by preparative HPLC to give N-[2-(dimethylamino)ethyl]-3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzamide (23.90 mg, 0.06 mmol, 44% yield) as a white solid. MS: m / z: Theoretical: C 13 H 17 FN4O5S[M+H] + Observations: 361; 1 H NMR (300MHz, DMSO-d6) δ 9.91(d, J=3.2Hz, 1H), 9.24(s, 1H), 8.64(t, J=5.6Hz, 1H), 7.24-7.10(m, 2H), 4.01(s, 2H), 3.57(d, J=5.8Hz, 2H), 3.25(t, J=5.9Hz, 2H), 2.84(s, 6H)

[0327] Preparative HPLC conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 12%B~25%B for 10min, then 25%B; Wavelength: 254 / 220nm

[0328] Example 92: 4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxy-N-(piperidin-4-yl)benzamide [ka] The title compound was prepared as prepared in Example 91 in 38% overall yield as an off-white solid using tert-butyl 4-aminopiperidine-1-carboxylate in step 1. MS: m / z: Calculated: C 14 H 17 FN 4 O5S[M+H] + Observations: 373; 1 H NMR (300MHz, DMSO-d6) δ 10.04(s, 1H), 8.61-8.41(m, 2H), 8.26(s, 1H), 7.21-7.11(m, 2H), 4.16-4.03(m, 3H), 3.34-3.29(m, 2H), 3.07-3.00(m, 2H), 1.98-1.94(m, 2H), 1.80-1.58(m, 2H)

[0329] Preparative HPLC purification conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 20%B~34%B for 10min, then 34%B~100%B for 5min; Wavelength: 254 / 220nm

[0330] Example 93: (S)-4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxy-N-(piperidin-3-yl)benzamide [ka] The title compound was prepared as prepared in Example 91 in 34% overall yield as a white solid using tert-butyl (3S)-3-aminopiperidine-1-carboxylate in step 1. MS: m / z: Theoretical value: C 14 H 17 FN4O5S[M+H] + Observations: 373; 1H NMR (400MHz, DMSO-d6) δ 10.72-9.62(m, 1H), 8.58(s, 2H), 8.44(s, 1H), 7.20-7.18(m, 2H), 4.22-4.11(m, 2H), 3.21-3.18(m, 1H), 2.86-2.78(m, 2H), 2.69(s, 2H), 1.91-1.88(m, 2H), 1.69-1.56(m, 2H)

[0331] Preparative HPLC purification conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 20%B~34%B for 10min, then 34%B~100%B for 5min; Wavelength: 254 / 220nm

[0332] Example 94: (R)-4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxy-N-(piperidin-3-yl)benzamide [ka] The title compound was prepared as prepared in Example 91 in 12% overall yield as a white solid using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in step 1. MS: m / z: Calculated: C 14 H 17 FN4O5S[M+H] + Observations: 373; 1 H NMR (300MHz, DMSO-d6) δ 7.21-7.10(m, 2H), 4.00(s, 2H), 3.88(d, J=10.0Hz, 1H), 3.12-3.01(m, 1H), 2.98-2.86(m, 1H), 2.61-2.51(m, 2H), 1.84(s, 1H), 1.72(s, 1H), 1.52(q, J=10.2, 9.3Hz, 2H)

[0333] Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 3%B~10%B for 8min, then 10%B; Wavelength: 254 / 220nm

[0334] Example 95: N-((1r,4r)-4-aminocyclohexyl)-4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzamide [ka] The title compound was prepared as a white solid in 1.1% overall yield according to the preparation of Example 91 using tert-butyl N-(4-aminocyclohexyl)carbamate in step 1. MS: m / z: Calculated: C 17 H 23 FN4O5S [M+H] + Observed: 415; 1 H NMR (300MHz, DMSO-d6) δ 8.30(d, J=7.9Hz, 1H), 7.22-7.08(m, 2H), 4.00(s, 2H), 3.76-3.68(m, 1H),2.98(s,1H), 1.96(s, 2H), 1.90(s, 2H), 1.40-1.29(m, 4H) Preparative HPLC purification conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: MeOH; Flow rate: 60mL / min; Gradient: 2%B~15%B for 9 min, then 15%B; Wavelength: 254 / 220nm

[0335] Example 96: N-((1r,4r)-4-(dimethylamino)cyclohexyl)-4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-hydroxybenzamide [ka] The title compound was prepared as prepared in 14% overall yield as an off-white solid according to the preparation of Example 91 using (1r,4r)-N1,N1-dimethylcyclohexane-1,4-diamine in step 1. MS: m / z: Calculated: C 17 H 23 FN4O5S[M+H] + Observed: 415; 1 H NMR (400MHz, DMSO-d6) δ 9.81(s, 1H), 8.26(d, J=7.6Hz, 1H), 7.16-7.07(m, 2H), 3.99(s, 2H), 3.78-3.73(m, 1H), 3.19-3.13(m, 1H), 2.75(s, 6H), 2.02-1.94(m, 4H),1.57-1.53(m, 2H), 1.43-1.40(m, 2H)

[0336] Preparative HPLC purification conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 5%B~20%B for 10min, then 20%B; Wavelength: 254 / 220nm

[0337] Example 97: 5-(3-(((4,4-dimethylcyclohexyl)amino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] [ka] A solution of 2-fluoro-4-[(4-methoxyphenyl)methoxy]-3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzaldehyde (intermediate 5, 120 mg, 0.30 mmol) and 4,4-dimethylcyclohexanamine (77.43 mg, 0.61 mmol) in ethanol (2 mL) was added to a solution of ZnCl2 / THF (0.7 M, 1.22 mmol, 1.74 mL) and NaBH3CN (76.48 mg, 1.22 mmol) in ethanol (8 mL), and the mixture was stirred at 80° C. for 2 hours. After the stirring was completed, the reaction mixture was concentrated, and the resulting residue was purified by reverse phase column to obtain the crude product. This was further purified by preparative HPLC to give 5-[3-[[(4,4-dimethylcyclohexyl)amino]methyl]-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (19.7 mg, 0.05 mmol, 17% yield) as a white solid. MS: m / z: Calculated: C 17 H 24 FN3O4S[M+H] + Observations: 386; 1 H NMR (400MHz, DMSO-d6) δ 9.82(s, 1H), 8.49(s, 2H), 7.39-7.35(m, 1H), 6.86-6.81(m, 1H), 4.13-4.02(m, 4H), 3.00(s, 1H), 1.92-1.90(m, 2H), 1.63-1.49(m, 2H), 1.43(d, J=13.6Hz, 2H), 1.25-1.19(m, 2H), 0.90(s, 6H)

[0338] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 14%B~36%B for 7 min, then 36%B; Wavelength: 254 / 220nm

[0339] Example 98: 5-(2-fluoro-3-((4-fluoropiperidin-1-yl)methyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 97 using 4-fluoropiperidine in 18% yield as an off-white solid. MS: m / z: Calculated: C 14 H 17 F2N3O4S[M+H] + Observations: 362; 1 H NMR (300MHz, DMSO-d6) δ 7.43-7.11(m, 1H), 6.99-6.82(m, 1H), 5.06-4.87(s, 1H), 4.30(d, J=9.5Hz, 2H), 4.06(d, J=2.4Hz, 2H), 3.32 -3.17(m, 4H), 2.29-1.78(m, 4H)

[0340] Preparative HPLC purification conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~30%B for 7 min, then 30%B; Wavelength: 254 / 220nm

[0341] Example 99: 5-(2-fluoro-6-hydroxy-3-(morpholinomethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 97 using morpholine in 24% overall yield as an off-white solid. MS: m / z: Calculated: C 13 H 16 FN3O5S[M+H] + Observations: 346; 1H NMR (300 MHz, methanol-d4) δ 7.10-7.06(m, 1H), 6.68-6.61(m, 1H), 4.30(s, 2H), 3.88-3.68(m, 6H), 2.69(s, 4H)

[0342] Preparative HPLC purification conditions: Xselect CSH OBD column, 30*150mm, 5μm; Mobile phase A: water (0.05% NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 20%B~34%B in 10min, then 34%B~100%B in 6min; Wavelength: 254 / 220nm

[0343] Example 100: 5-(3-((cyclohexylamino)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 97 using cyclohexanamine in 19% yield as an off-white solid. MS: m / z: Calculated: C 15 H 20 FN3O4S[M+H] + Observations: 358; 1 H NMR (300MHz, DMSO-d6) δ 9.63(br, 1H), 8.50(br, 2H), 7.34(dd, J=8.6, 6.1Hz, 1H), 6.88-6.75(m, 1H), 4.08(s, 2H), 3.95(s, 2H), 3.04(s, 1H), 2.09(d, J=10.3Hz, 2H), 1.77(d, J=11.4Hz, 2H), 1.61(d, J=12.2Hz, 1H), 1.59-1.27(m, 5H)

[0344] Preparative HPLC conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~30%B for 10min, then 30%B; Wavelength: 254nm

[0345] Example 101: 5-(2-fluoro-6-hydroxy-3-(((tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 97 using tetrahydro-2H-pyran-4-amine in 14% yield as an off-white solid. MS: m / z: Calc.: C 14 H 18 FN3O5S[M+H] + Observed values: 360; 1 H NMR (300MHz, DMSO-d6) δ 9.75(s, 1H), 8.66(s, 2H), 7.36(dd, J=8.6, 6.1Hz, 1H), 6.94-6.77(m, 1H), 4.10(s, 2H), 3.94(d, J=21.4Hz, 4H), 3.31(t, J=11.5Hz, 3H), 2.01(d, J=12.4Hz, 2H), 1.68-1.50(m, 2H)

[0346] Preparative HPLC conditions: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~13%B for 7 minutes, then 13%B; Wavelength: 254 / 220nm

[0347] Example 102: 5-(3-((4-(dimethylamino)piperidin-1-yl)methyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 97 using N,N-dimethylpiperidin-4-amine in 12% yield as a white solid. MS: m / z: Calc.: C 16 H 23 FN4O4S[M+H] + Observations: 387; 1 H NMR (300MHz, DMSO-d6) δ 7.19-7.01(m, 1H), 6.69-6.63(m, 1H), 3.99(s, 2H), 3.60(s, 2H), 2.99(d, J=11.8Hz, 3H), 2.69(s, 6H), 2.17-2.03(m, 2H), 2.02-1.89(m, 2H), 1.72-1.55(m, 2H)

[0348] Preparative HPLC purification conditions: Atlantis Prep T3 OBD column, 19*250mm 10μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 10%B~20%B for 9min, then 20%B; Wavelength: 254 / 220nm

[0349] Example 103: 5-(2-fluoro-6-hydroxy-3-((4-methylpiperazin-1-yl)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 97 using 1-methylpiperazine in 13% overall yield as an off-white solid. MS: m / z: Calculated: C 14 H 19 FN4O4S[M+H] + Observations: 359; 1H NMR (400MHz, DMSO-d6) δ 7.11-7.07(m, 1H), 6.86-6.64(m, 1H), 4.00(s, 2H), 3.61(s, 2H), 2.74-2.53(m, 8H), 2.44-2.27(m, 3H)

[0350] Preparative HPLC conditions: XBridge Prep Phenyl OBD column, 19*250mm, 5μm; Mobile phase A: Water (10mmol / L NH4HCO3+0.1%NH3 aqueous solution), Mobile phase B: ACN; Flow rate: 25mL / min; Gradient: 5%B~10%B elution in 8 minutes; Wavelength: 254 / 220nm

[0351] Example 104: 5-[2-fluoro-6-hydroxy-3-[(4-isopentylpiperazin-1-yl)methyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one [ka] The title compound was prepared as prepared in Example 97 using 1-isopentylpiperazine in 17% overall yield as a white solid. MS: m / z: Calculated: C 18 H 27 FN4O4S[M+H] + Observed: 415; 1 H NMR (400MHz, DMSO-d6) δ 7.31(dd, J=8.6, 6.3Hz, 1H), 6.81(dd, J=10.0, 8.6Hz, 1H), 4.09(s, 2H), 4.04-3.97(m, 2H), 3.56(s, 1H), 3.41-2.83(m, 7H), 2.55-2.45(m, 2H), 1.55-1.45(m, 3H), 0.90(d, J=6.5Hz, 6H)

[0352] Preparative HPLC conditions: Column: Xselect CSH C18 OBD column, 30*150mm 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~17%B for 7 min, then 17%B; Wavelength: 254 / 220nm

[0353] Example 105: 5-(2-fluoro-6-hydroxy-3-(piperidin-4-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] [ka]

[0354] Step 1: To a suspension of 5-[3-bromo-2-fluoro-6-[(4-methoxyphenyl)methoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Intermediate 4, 110 mg, 0.25 mmol) in 1,4-dioxane (3 mL) and water (0.30 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (114.58 mg, 0.37 mmol), Pd(dppf)Cl2 (40.35 mg, 0.05 mmol), and Na2CO3 (78.56 mg, 0.74 mmol) and the mixture was purged with N2 and stirred at 80 °C for 3 h. After stirring, the solvent was concentrated under reduced pressure, and the resulting crude residue was purified with a reverse phase column (0.5% TFA aqueous solution, MeCN) to obtain tert-butyl 4-[2-fluoro-4-[(4-methoxyphenyl)methoxy]-3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (120 mg, 0.22 mmol, 89% yield) as a pale yellow solid. MS: m / z: Theoretical value: C 26 H 30 FN3O7S[M+H] + 548; Observations: 448

[0355] Step 2: To a solution of tert-butyl 4-[2-fluoro-4-[(4-methoxyphenyl)methoxy]-3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (110 mg, 0.20 mmol) in ethanol (3 mL) and DCM (3 mL) was added Pd(OH)2 / C (50 mg, 0.47 mmol), and the mixture was degassed and purged with H2 three times. It was then stirred at room temperature under H2 atmosphere for 12 hours. The reaction mixture was filtered and concentrated to give tert-butyl 4-[2-fluoro-4-hydroxy-3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]piperidine-1-carboxylate (70 mg, 0.16 mmol, 81% yield) as a pale yellow oil. It was used directly in the next step without further purification. MS: m / z: Calc:C 18 H 24 FN3O6S [M+H] + 430; Observed value: 374 [M+H-56] +

[0356] Step 3: To a solution of tert-butyl 4-[2-fluoro-4-hydroxy-3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]piperidine-1-carboxylate (110 mg, 0.26 mmol) in DCM (2 mL) was added TFA (1 mL) and the mixture was stirred at room temperature for 2 h. After evaporation of the solvent, the crude product obtained was purified by preparative HPLC to give 5-[2-fluoro-6-hydroxy-3-(4-piperidyl)phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (13.8 mg, 0.04 mmol, 16% yield) as a purple solid. MS: m / z: Theoretical: C 13 H 16 FN3O4S[M+H] + Observed values: 330; 1H NMR (400MHz, DMSO-d6) δ 7.14-7.07(m, 1H), 6.79-6.73(m, 1H), 3.97(s, 2H), 3.42-3.36(m, 2H), 3.16-2.95(m, 3H), 2.02-1.65(m, 4H)

[0357] Preparative HPLC conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B~15%B for 8min, then 15%B; Wavelength: 254 / 220nm

[0358] Example 106: 5-(2-fluoro-6-hydroxy-3-(1-methylpiperidin-4-yl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide [ka] The title compound was prepared as prepared in Example 105 using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine in step 1 in 29% overall yield as a white solid. MS: m / z: Calculated: C 14 H 18 FN3O4S[M+H] + Observations: 344; 1 H NMR (400MHz, DMSO-d6) δ 8.90(s, 1H), 7.12-7.05(m, 1H), 6.75-6.63(m, 1H), 3.95(s, 2H), 3.42-3.33(m, 2H), 2.98-2.94(m, 3H), 2.69(s, 3H), 2.03-1.70(m, 4H)

[0359] Preparative HPLC conditions: XBridge Prep OBD C18 column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 2%B to 20%B in 7min, then 20%B; Wavelength: 254 / 220nm

[0360] The example compounds prepared by the above methods are listed in Table 1. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16]

[0361] Biological assays The pharmacological properties of the compounds of the invention may be confirmed by a number of biological assays known in the art. The following biological assays have been carried out with the compounds of the invention.

[0362] Assay PhosphoSens® Kinase Assay was performed as described by the manufacturer (AssayQuant Technologies, Marlborough, MA). Briefly, 1000-fold diluted DMSO solutions of compounds were made in a 384-well reagent plate by performing 3-fold serial dilutions with a 10 mM DMSO stock solution. 50 nL of serially diluted compound solution was then added to the corresponding wells of the 384-well assay plate. 40 mL of 1.25-fold diluted substrate (AQT0264) / 1-fold assay buffer (50 mM HEPES pH 7.5, 500 μM EGTA, 10 nM MgCl2, 0.01% Brij-35, 1% glycerol, 1 mM DTT, and 0.2 mg / mL BSA) was added to each well of the assay plate to give a final substrate concentration of 20 μM. Finally, 10 mL of 5-fold diluted PTPN2 enzyme stock solution was added to each well of the assay plate to give a final enzyme concentration of 150 pM. 360nm(λ ex 360) excitation wavelength and 480 nm (λ em The fluorescence intensity was measured at a wavelength of 480 (C480) every 71 seconds at room temperature for 1 hour using a Synergy H4 plate reader (BioTek Instruments / Agilent Technologies, Winooski, VT), and a reaction progress curve was created.

[0363] Cell Proliferation Assay Protocol B16-F10 cells (ATCC, Manassas, VA, #CRL-6475) were cultured in DMEM basal medium (ThermoFisher Scientific, #11995-040) supplemented with 10% heat-inactivated FBS (ThermoFisher Scientific, Waltham, MA, #16140-071) and 1% penicillin / streptomycin (ThermoFisher Scientific, #15140-122). Cells were seeded into two opaque white 384-well tissue culture treated microplates (PerkinElmer, Waltham, MA, #6007688) at a density of 100 cells / well in a total volume of 20 μL and incubated overnight at 37°C and 5% CO2. DMSO solutions of compounds (30 nL) were then transferred from the original plate to the desired wells using an Echo650 acoustic liquid handler (Beckman Coulter, Indianapolis, IN). Negative control wells received only DMSO (30 nL, final concentration 0.15%). Plates were returned to the incubator and after 1 h, cells were then treated with either basal medium (5 μL) or basal medium (5 μL) containing 50 ng / mL of mouse IFN-γ recombinant protein (R&D Systems, Minneapolis, MN, #485-MI / CF, final concentration 10 ng / mL) using an ASSIST automated dispenser (INTEGRA Biosciences, Hudson, NH). Plates were incubated at 37°C for 4 days and cell proliferation assays were performed using CellTiter-Glo reagent (Promega, Madison, WI, #G7573, 25 μL / well). Luminescence signal intensity was measured 15 min after addition of CellTiter-Glo reagent using an EnVision 2105 plate reader (PerkinElmer) and analyzed using the Dotmatics software platform to calculate compound IC50 values. Off-target compounds causing cytotoxicity were identified by confirming growth inhibition in the absence of IFNγ.

[0364] Phospho-STAT1 Assay Protocol B16-F10 cells (ATCC, Manassas, VA, #CRL-6475) were cultured in DMEM basal medium (ThermoFisher Scientific, #11995-040) supplemented with 10% heat-inactivated FBS (ThermoFisher Scientific, Waltham, MA, #16140-071) and 1% penicillin / streptomycin (ThermoFisher Scientific, #15140-122). Cells were seeded into opaque white 384-well tissue culture treated microplates (PerkinElmer, Waltham, MA, #6007688) at a density of 10,000 cells / well in a total volume of 20 μL and incubated overnight at 37°C and 5% CO2. Compound DMSO solutions (30 nL) were then transferred from the original plate to the desired wells using an Echo650 acoustic liquid handler (Beckman Coulter, Indianapolis, IN). Negative control wells received only DMSO (30 nL, 0.15% final concentration). Plates were returned to the incubator for 1 h, after which cells were treated with either basal medium (5 μL) or basal medium (5 μL) containing 500 ng / mL of mouse IFN-γ recombinant protein (R&D Systems, Minneapolis, MN, #485-MI / CF, 100 ng / mL final concentration) using an ASSIST automated dispenser (INTEGRA Biosciences, Hudson, NH). Plates were incubated at 37°C for 1 h and assayed for levels of phosphorylated STAT1 protein using the Phospho-STAT1 (Tyr701) HTRF kit (Cisbio, Bedford, MA, #63ADK026PEH) according to the manufacturer's instructions. HTRF signal intensity was measured after 24 hours using an EnVision 2105 plate reader (PerkinElmer) and analyzed using the Dotmatics software platform to calculate compound IC50 values. [Table 17] [Table 18]

Table 19

Table 20

Table 21

Table 22

Table 23

Table 24

Table 25

Table 26

Claims

1. Formula (I): 【change】 [In the formula, R 1 is -H, heteroaryl, -CONHR 3 , -CH 2 N(R 5 )CH 2 R 4 , 4-aminopiperidin-1-yl, 【Chemistry 1】 selected from the group consisting of; R 2 is -H, 【Chemistry 2】 selected from the group consisting of; R 3 represents a heteroalicyclic group and -CH 2 CH 2 N(CH 3 ) 2 selected from the group consisting of; R 4 is selected from the group consisting of alkyl, heteroaryl, carbocyclic, and 1-methyl-1H-pyrazol-4-yl; R 5 is selected from the group consisting of alkyl and carbocyclic groups; R 6 is selected from the group consisting of -H and alkyl; R 7 is selected from the group consisting of CH and N; <h2 style=";text-align:left;direction:ltr">R<h2 style=";text-align:left;direction:ltr"> 8 <h2 style=";text-align:left;direction:ltr">は、-CH<h2 style=";text-align:left;direction:ltr"> 2 <h2 style=";text-align:left;direction:ltr"> -NH-CH<h2 style=";text-align:left;direction:ltr"> 2 <h2 style=";text-align:left;direction:ltr"> CH<h2 style=";text-align:left;direction:ltr"> 2 <h2 style=";text-align:left;direction:ltr"> NHCH<h2 style=";text-align:left;direction:ltr"> 2 <h2 style=";text-align:left;direction:ltr"> -、 【Chemistry 3】 selected from the group consisting of; R 9 is -CH 2 -, -NH-, -O-, -CH(R 31 )- and -N(R 32 )- selected from the group consisting of; R 10 is -H, alkyl, -N(CH 3 ) 2 , and -CH 2 CH 2 OCH 3 selected from the group consisting of; R 11 -CH=, -N=, and -C(R 33 )= selected from the group consisting of; R 12 -CH=, -N=, and -C(R 34 )= selected from the group consisting of; R 13 is selected from the group consisting of -CH= and -N=; R 14 is -H, alkyl, phenoxy, and 【Chemistry 4】 selected from the group consisting of; R 15 -NH-, -O-, and -N(R 35 )- selected from the group consisting of; R 16 -H, -OH, -OCH 3 , and -N(CH 3 ) 2 selected from the group consisting of; R 17 -H and -OCH 3 selected from the group consisting of; R 18 is -CH=, -N=, and 【Chemistry 5】 selected from the group consisting of; R 19 -CH=, -N=, and -CCH 3 = selected from the group consisting of; R 20 is selected from the group consisting of -H and -CN; R 21 is selected from the group consisting of -H, alkyl, and halogen; R 22 -NHCH 2 -, -CH 2 N(R 6 )CH 2 - and 【Chemistry 6】 selected from the group consisting of; R 23 -CH=, -N=, and -C(R 36 )= selected from the group consisting of; R 24 is selected from the group consisting of -H, alkyl, halogen, and -CN; R 25 is selected from the group consisting of -H and halogen; R 26 is -CH 2 -, -NH-, -O-, -CH(R 37 )-, -C(CH 3 ) 2 - and 【Chemistry 7】 selected from the group consisting of; R 27 is -CH 2 -CO-; R 28 is selected from the group consisting of -H, alkyl, and carbocyclic groups; R 29 -O-, -CH(R 38 )- and -N(R 39 )- selected from the group consisting of; R 30 is -CH 2 -, -O-, and -C(CH 3 ) 2 - selected from the group consisting of; R 31 is -OH, halogen, carboaryl, -OCH 3 , -N(CH 3 ) 2 , -CH 2 N(CH 3 ) 2 , -OCH(CH 3 ) 2 , and -CH 2 CH 2 R 40 CH 3 selected from the group consisting of; R 32 is alkyl, -CCH 3 O, -CH 2 CH 2 OCH 3 , -CH 2 CONHCH 3 , and -R 27 CH 2 CH(CH 3 ) 2 selected from the group consisting of; R 33 is halogen, -OCH 3 and cyclopropylmethoxy; R 34 is alkyl, halogen, -OCH 2 CH 3 , -C(CH 3 ) 2 R 41 , -CH 2 NHCCH 3 O, (pyrrolidin-1-yl)methyl, benzyl, 【Chemistry 8】 selected from the group consisting of; R 35 -CCH 3 O, -R 27 CH 2 R 42 , and -SO 2 R 43 selected from the group consisting of; R 36 is selected from the group consisting of halogen and -CN; R 37 is -NH 2 , -N(CH 3 ) 2 , -CONHCH 3 , and -NHCCH 3 Selected from the group consisting of O; R 38 is halogen and -N(CH 3 ) 2 selected from the group consisting of; R 39 is alkyl; R 40 is -CH 2 - and -O-; R 41 is selected from the group consisting of -OH, alkyl, and -CN; R 42 is selected from the group consisting of alkyl and -COOH; R 43 is selected from the group consisting of alkyl, carbocyclic, and 3-fluorophenyl. A compound having the formula:

2. In the formula, R 1 However, -H, 1H-pyrrol-2-yl, furan-2-yl, 1H-imidazol-5-yl, 1,2-oxazol-5-yl, 1H-1,2,3-triazol-5-yl, 1,3,4-oxadiazol-2-yl, 1H-1,2,3,4-tetrazol-5-yl, thiophen-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyrimidin-4-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1λ 4 -Pyran-1-ylium-4-yl, -CONHR 3 , -CH 2 N(R 5 )CH 2 R 4 , 4-aminopiperidin-1-yl, 【Chemistry 9】 2. The compound of claim 1, selected from the group consisting of:

3. In the formula, R 3 are aziridin-1-yl, 2,5-dihydro-1H-pyrrol-1-yl, 2,5-dihydrofuran-3-yl, 4,5-dihydro-1H-imidazol-2-yl, pyrrolidin-1-yl, oxolan-2-yl, imidazolidin-4-yl, 1,3-dioxolan-2-yl, 1,3-thiazolidin-3-yl, piperidin-1-yl, oxan-2-yl, 1,3-diazinan-5-yl, morpholin-4-yl, 1,3,5-triazinan-2-yl, 1,3-dioxan-2-yl, and -CH 2 CH 2 N(CH 3 ) 2 The compound according to claim 1, selected from the group consisting of

4. During the ceremony, R 3 are aziridin-1-yl, 2,5-dihydro-1H-pyrrol-1-yl, 2,5-dihydrofuran-3-yl, 4,5-dihydro-1H-imidazol-2-yl, pyrrolidin-1-yl, oxolan-2-yl, imidazolidin-4-yl, 1,3-dioxolan-2-yl, 1,3-thiazolidin-3-yl, piperidin-1-yl, oxan-2-yl, 1,3-diazinan-5-yl, morpholin-4-yl, 1,3,5-triazinan-2-yl, 1,3-dioxan-2-yl, and -CH 2 CH 2 N(CH 3 ) 2 selected from the group consisting of; R 4 But -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , Pentyl, -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, 1H-pyrrol-2-yl, furan-2-yl, 1H-imidazol-5-yl, 1,2-oxazol-5-yl, 1H-1,2,3-triazol-5-yl, 1,3,4-oxadiazol-2-yl, thiophen-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyrimidin-4-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1λ 4 -pyran-1-ylium-4-yl, cyclopropyl, cyclobutyl, cyclopent-2-en-1-yl, cyclopentyl, cyclohexa-1,4-dien-1-yl, cyclohex-3-en-1-yl, cyclohexyl, adamantan-1-yl, decahydronaphthalen-1-yl, 1-methyl-1H-pyrazol-4-yl, 【Chemistry 10】 2. The compound of claim 1, selected from the group consisting of:

5. In the formula, R 5 But -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , Pentyl, -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, cyclopropyl, cyclobutyl, cyclopent-2-en-1-yl, cyclopentyl, cyclohexa-1,4-dien-1-yl, cyclohex-3-en-1-yl, cyclohexyl, adamantan-1-yl, decahydronaphthalen-1-yl, 【Chemistry 11】 2. The compound of claim 1, selected from the group consisting of:

6. In the formula, R 6 But, -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , Pentyl, -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 2. The compound of claim 1, wherein the aryl group is selected from the group consisting of hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, and 4,8,12-trimethyltridecyl.

7. In the formula, R 31 -OH, -F, -Cl, -Br, -I, phenyl, 2,3-dihydro-1H-inden-5-yl, naphthalen-1-yl, azulen-1-yl, 1,2-dihydroacenaphthylene-5-yl, 9H-fluoren-2-yl, phenanthren-3-yl, anthracen-9-yl, pyren-1-yl, fluoranthene-3-yl, tetraphen-7-yl, -OCH 3 , -N(CH 3 ) 2 , -CH 2 N(CH 3 ) 2 , -OCH(CH 3 ) 2 , -CH 2 CH 2 R 40 CH 3 , 【Chemistry 12】 2. The compound of claim 1, selected from the group consisting of:

8. In the formula, R 32 But -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , Pentyl, -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, -CCH 3 O, -CH 2 CH 2 OCH 3 , -CH 2 CONHCH 3 , and -R 27 CH 2 CH(CH 3 ) 2 2. The compound of claim 1, selected from the group consisting of:

9. In the formula, R 10 But, -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , Pentyl, -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, -N(CH 3 ) 2 , and -CH 2 CH 2 OCH 3 2. The compound of claim 1, selected from the group consisting of:

10. During the ceremony, R 10 But, -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , Pentyl, -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, -N(CH 3 ) 2 , and -CH 2 CH 2 OCH 3 selected from the group consisting of; R 33 But -F, -Cl, -Br, -I, -OCH 3 and cyclopropylmethoxy; 2. The compound of claim 1.

11. In the formula, R 34 But -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , Pentyl, -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, -F, -Cl, -Br, -I, -OCH 2 CH 3 , -C(CH 3 ) 2 R 41 , -CH 2 NHCCH 3 O, (pyrrolidin-1-yl)methyl, benzyl, 【Chemistry 13】 2. The compound of claim 1, selected from the group consisting of:

12. During the ceremony, R 14 But, -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , Pentyl, -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, phenoxy, and 【Chemistry 14】 selected from the group consisting of; R 25 is selected from the group consisting of -H, -F, -Cl, -Br, and -I; R 41 -OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , Pentyl, -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, and -CN; 2. The compound of claim 1.

13. In the formula, R 42 But -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , Pentyl, -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 5. The compound of claim 1, wherein the aryl group is selected from the group consisting of hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, and -COOH.

14. In the formula, R 43 But -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , Pentyl, -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, carbocyclic groups, and 3-fluorophenyl.

15. During the ceremony, R 6 But, -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , Pentyl, -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, and 4,8,12-trimethyltridecyl; R 21 But, -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , Pentyl, -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, -F, -Cl, -Br, and -I; R 24 But, -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , Pentyl, -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, -F, -Cl, -Br, -I, and -CN; R 28 But, -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , Pentyl, -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, 4,8,12-trimethyltridecyl, and carbocyclic groups; R 36 is selected from the group consisting of -F, -Cl, -Br, -I, and -CN; R 38 -F, -Cl, -Br, -I, and -N(CH 3 ) 2 selected from the group consisting of; R 39 But -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , Pentyl, -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , hexyl, heptyl, 6-methylheptan-2-yl, decyl, hexadecyl, and 4,8,12-trimethyltridecyl; 2. The compound of claim 1.

16. below, 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 【Table 11】 【Table 12】 【Table 13】 【Table 14】 【Table 15】 【Table 16】 A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

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

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

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

20. 20. The method of claim 18, wherein the additional therapeutic agent is an immunotherapeutic agent.

21. 20. The method of claim 19, wherein the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody.

22. 13. A method for treating cancer, comprising administering to a patient in need of such treatment an effective amount of the pharma- ceutically acceptable composition of claim 1.

23. 22. The method of claim 21, wherein the one or more other cancer therapies include radiation therapy, surgical therapy, chemotherapy, or administration of a biopharmaceutical.

24. 23. The method of claim 22, wherein the one or more other cancer therapies is administering a biopharmaceutical that is an agent that stimulates the immune system.

25. The method according to claim 22, characterized in that an inhibitor of DGKα and / or DGKζ, an antagonist of PD1 / PD-L1 binding and an antagonist of CTLA4 are administered to the subject.

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