Protein tyrosine phosphatase inhibitors and methods of use thereof

Abstract

The present invention relates to compounds of formula (I), wherein R 1 has any of the values ​​defined herein), and pharma- ceutically acceptable salts thereof. TIFF2024543451000024.tif23128

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 278,336, filed November 11, 2021, the entire disclosure of which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] background Non-receptor type 2 protein tyrosine phosphatase (PTPN2), also known as T-cell protein tyrosine phosphatase (TC-PTP), controls multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, but is most abundant in hematopoietic and placental cells (Mosinger, B. Jr. et al., Proc Natl Acad Sci USA 89:499-503; 1992 (Non-Patent Document 1)). In humans, PTPN2 expression is post-transcriptionally regulated by the presence of two splice variants: a 45 kDa form that contains a nuclear localization signal at the C-terminus from the splice site upstream, and a 48 kDa canonical form that has a C-terminal ER retention motif (Tillmann U. et al., Mol Cell Biol 14:3030-3040; 1994 (Non-Patent Document 2)). The 45 kDa isoform can passively translocate to the cytoplasm under certain cellular stress conditions. PTPN2 negatively regulates the signal transduction of non-receptor tyrosine kinases (e.g., JAK1, JAK3), receptor tyrosine kinases (e.g., INSR, EGFR, CSF1R, PDGFR), transcription factors (e.g., STAT1, STAT3, STAT5a / b), and Src family kinases (e.g., Fyn, Lck). As a critical negative regulator of the JAK-STAT pathway, PTPN2 functions to directly regulate signal transduction through cytokine receptors, including IFNγ.

[0003] Data from a loss-of-function in vivo genetic screen using CRISPR / Cas9 genome editing in a mouse B16F10 transplantable tumor model showed that deletion of the Ptpn2 gene in tumor cells improved response to a GM-CSF-secreting vaccine (GVAX) + PD-1 checkpoint blockade immunotherapy regimen (Manguso RT et al., Nature 547:413-418; 2017). Loss of Ptpn2 sensitized tumors to immunotherapy by enhancing IFNγ-mediated effects on antigen presentation and growth suppression. The same screen also revealed that genes known to be involved in immune evasion, including PD-L1 and CD47, were also depleted under immunotherapy selection pressure, whereas genes involved in the IFNγ signaling pathway (including IFNGR, JAK1, and STAT1) were enriched. These findings point to a putative role for therapeutic strategies that enhance IFNγ sensing and signaling in enhancing the efficacy of cancer immunotherapy regimens.

[0004] Non-receptor type 1 protein tyrosine phosphatase (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B), has been shown to play an important role in insulin and leptin signaling and is the primary mechanism for downregulating both insulin and leptin receptor signaling pathways (Kenner KA et al., J Biol Chem 271:19810-19816, 1996 (Non-Patent Document 4)). PTPN1-deficient animals have improved glucose regulation and lipid profiles and are less likely to gain weight even when fed a high-fat diet (Elchebly M. et al., Science 283:1544-1548, 1999 (Non-Patent Document 5)). Thus, there is a medical need for PTPN1 inhibitors. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Mosinger,B.Jr.et al.,Proc Natl Acad Sci USA 89:499-503;1992 [Non-Patent Document 2] Tillmann U. et al., Mol Cell Biol 14:3030-3040;1994 [Non-Patent Document 3] Manguso RTet al.,Nature 547:413-418;2017 [Non-Patent Document 4] Kenner KA et al., J Biol Chem 271:19810-19816,1996 [Non-Patent Document 5] Elchebly M. et al.,Science 283:1544-1548,1999 Summary of the Invention

[0006] The present disclosure is directed, at least in part, to compounds for inhibiting protein tyrosine phosphatases (e.g., non-receptor type 2 protein tyrosine phosphatase (PTPN2) and / or non-receptor type 1 protein tyrosine phosphatase (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B)).

[0007] For example, as used herein, formula (I): The present invention discloses a compound represented by TIFF2024543451000002.tif23128 or a pharma- ceutical acceptable salt thereof, During the ceremony, R 1 is -NH2, -N(R a )-C 1-8 Alkyl, -N(R a )-C2-6 alkenyl -N(R a )-C 1-6 Alkylene-C 3-6 Cycloalkyl, -N(R a )-C(O)-OC 1-6 Alkyl, -N(R a )-C 1-6Alkylene-4 to 7-membered heterocyclyl, -N(R a )-C 1-6 Alkylene-5-6 membered heteroaryl and -N(R a )-C 1-6 alkylene-phenyl; Here, -N(R a )-C 1-8 Alkyl, -N(R a )-C2-6 alkenyl -N(R a )-C 1-6 Alkylene-C 3-6 Cycloalkyl, -N(R a )-C(O)-OC 1-6 Alkyl, -N(R a )-C 1-6 Alkylene-4 to 7-membered heterocyclyl, -N(R a )-C 1-6 Alkylene-5-6 membered heteroaryl and -N(R a )-C 1-6 The alkylene-phenyl is optionally each R g and optionally substituted on one or more available carbons with one, two, three or more substituents independently selected from Here, -N(R a )-C 1-6 Alkylene-4 to 6-membered heterocyclyl or -N(R a )-C 1-6 When the alkylene-5- to 6-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be selected from the group consisting of R h and optionally substituted by R g is halogen, hydroxyl, C 1-6 Alkyl, phenyl, and C 1-6 independently selected at each occurrence from the group consisting of alkoxy, C 1-6 Alkyl, phenyl, or C 1-6 Alkoxy is optionally represented by R P and optionally substituted by one, two, three or more substituents independently selected from R h is C 1-6Alkyl and C 1-6 independently selected at each occurrence from the group consisting of alkyl-OC(O)-; R P is C 1-6 independently selected at each occurrence from the group consisting of alkyl, halogen and hydroxyl; R a is hydrogen and C 1-6 and each occurrence is independently selected from the group consisting of alkyl.

[0008] Brief Description of the Sequence Listing The sequence listing entitled "CLS-028PR_ABV21372USL1 SEQ ID List_ST25.txt", including SEQ ID NO:1-SEQ ID NO:3, which contain the amino acid sequences disclosed herein, is incorporated herein by reference in its entirety. This sequence listing has been submitted herewith in ASCII text format via EFS. This sequence listing was first created on June 22, 2021, and is 7,282 bytes in size. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Detailed Description For example, as used herein, formula (I): The present invention discloses a compound represented by TIFF2024543451000003.tif23128 or a pharma- ceutical acceptable salt thereof, During the ceremony, R 1 is -NH2, -N(R a )-C 1-8 Alkyl, -N(R a )-C2-6 alkenyl -N(R a )-C 1-6 Alkylene-C 3-6 Cycloalkyl, -N(R a )-C(O)-OC 1-6 Alkyl, -N(R a )-C 1-6 Alkylene-4 to 7-membered heterocyclyl, -N(R a )-C 1-6 Alkylene-5-6 membered heteroaryl and -N(R a )-C1-6 alkylene-phenyl; Here, -N(R a )-C 1-8 Alkyl, -N(R a )-C2-6 alkenyl -N(R a )-C 1-6 Alkylene-C 3-6 Cycloalkyl, -N(R a )-C(O)-OC 1-6 Alkyl, -N(R a )-C 1-6 Alkylene-4 to 7-membered heterocyclyl, -N(R a )-C 1-6 Alkylene-5-6 membered heteroaryl and -N(R a )-C 1-6 The alkylene-phenyl is optionally each R g and optionally substituted on one or more available carbons with one, two, three or more substituents independently selected from Here, -N(R a )-C 1-6 Alkylene-4 to 6-membered heterocyclyl or -N(R a )-C 1-6 When the alkylene-5- to 6-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be selected from the group consisting of R h and optionally substituted by R g is halogen, hydroxyl, C 1-6 Alkyl, phenyl, and C 1-6 independently selected at each occurrence from the group consisting of alkoxy, C 1-6 Alkyl, phenyl, or C 1-6 Alkoxy is optionally represented by R P and optionally substituted by one, two, three or more substituents independently selected from R h is C 1-6 Alkyl and C 1-6 independently selected at each occurrence from the group consisting of alkyl-OC(O)-; R P is C 1-6independently selected at each occurrence from the group consisting of alkyl, halogen and hydroxyl; R a is hydrogen and C 1-6 and each occurrence is independently selected from the group consisting of alkyl.

[0010] In some embodiments, R 1 is -NH2, -N(R a )-C 1-8 Alkyl, -N(R a )-C2-6 alkenyl -N(R a )-C 1-6 Alkylene-C 3-6 Cycloalkyl, -N(R a )-C(O)-OC 1-6 Alkyl, -N(R a )-C 1-6 Alkylene-4 to 7-membered heterocyclyl, -N(R a )-C 1-6 Alkylene-5-6 membered heteroaryl and -N(R a )-C 1-6 alkylene-phenyl; Here, -N(R a )-C 1-8 Alkyl, -N(R a )-C2-6 alkenyl -N(R a )-C 1-6 Alkylene-C 3-6 Cycloalkyl, -N(R a )-C(O)-OC 1-6 Alkyl, -N(R a )-C 1-6 Alkylene-4 to 7-membered heterocyclyl, -N(R a )-C 1-6 Alkylene-5-6 membered heteroaryl and -N(R a )-C 1-6 The alkylene-phenyl is optionally each R g and optionally substituted on one or more available carbons with one, two, three or more substituents independently selected from Here, -N(R a )-C 1-6Alkylene-4 to 6-membered heterocyclyl or -N(R a )-C 1-6 When the alkylene-5- to 6-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be selected from the group consisting of R h may be substituted by:

[0011] In some embodiments, R 1 -N(H)-C 1-8 Alkyl, C 1-8 Alkyl is R g In some embodiments, R 1 -N(H)-C 1-8 In some embodiments, R 1 -N(H)-C 1-6 Alkyl, C 1-6 Alkyl is R g In some embodiments, R 1 -N(H)-C 1-8 Alkyl, C 1-8 Alkyl is R g and R g Fluoro, hydroxyl, C 1-6 Alkyl, and C 1-6 alkoxy, C 1-6 Alkyl and C 1-6 Alkoxy is R P and R P is independently selected at each occurrence from halogen. 1 -N(H)-C 1-8 Alkyl, C 1-8 Alkyl is halogen, C 1-6 Alkyl, or C 1-6 In some embodiments, R is substituted with one or two instances of alkoxy. 1 teeth, TIFF2024543451000004.tif46145.

[0012] In some embodiments, R 1 is -N(H)-C 1-6 Alkylene-C 3-6 cycloalkyl, R 1 , optionally, R g In some embodiments, R 1 is -N(H)-C 1-6 Alkylene-C 3-6 cycloalkyl, optionally containing one, two, three or more substituents (R g ), R g Fluoro, C 1-6 independently selected at each occurrence from the group consisting of alkyl, phenyl, and C 1-6 Alkyl and phenyl are R P and R P is independently selected at each occurrence from fluoro or hydroxyl. 1-6 Alkylene-C 3-6 In embodiments where R is cycloalkyl, 1 are optionally fluorine, C 1-6 may be substituted by one, two, three or more substituents independently selected from the group consisting of alkyl, and phenyl; 1-6 The alkyl may be optionally substituted by one, two or three fluorines. 1-6 Alkylene-C 3-6 In embodiments where R is cycloalkyl, 1 are fluorine and C, respectively. 1-6 substituted by one, two, three or more substituents independently selected from the group consisting of alkyl, phenyl, and C 1-6 The alkyl may be optionally substituted with one, two or three fluorines.

[0013] In some embodiments, R 1 teeth, TIFF2024543451000005.tif76148.

[0014] In some embodiments, R 1 is -N(H)-C 1-6 alkylene-4-6 membered heterocyclyl; R 1 , optionally, R g and when the 4- to 7-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted by one, two, three or more substituents independently selected from R h In some embodiments, R 1 is -N(H)-C 1-6 alkylene-4-6 membered heterocyclyl; R 1 are R g and when the 4- to 7-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted with one, two, three or more substituents independently selected from R h In some embodiments, R 1 is -N(H)-C 1-6 alkylene-4-6 membered heterocyclyl; R 1 are R g and when the 4- to 7-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom is optionally substituted with one, two, three or more substituents independently selected from R h and R h is C 1-6 In some embodiments, R 1 -N(H)-C 1-6 alkylene-4-6 membered heterocyclyl; R 1 are optionally fluorine, C 1-6 may be substituted by one, two, three or more substituents independently selected from the group consisting of alkyl, and phenyl; 1-6The alkyl may be optionally substituted with one, two or three fluorines.

[0015] In some embodiments, R 1 teeth, TIFF2024543451000006.tif19151.

[0016] In some embodiments, R 1 -N(H)-C 1-6 alkylene-phenyl, R 1 , optionally, R g In some embodiments, R may be substituted on one or more available carbons with one, two, three or more substituents independently selected from 1 -N(H)-C 1-6 alkylene-phenyl, R 1 , optionally, R g and R g is C for each occurrence independently. 1-6 It is an alkyl.

[0017] In some embodiments, R 1 teeth, TIFF2024543451000007.tif16128.

[0018] In some embodiments, R 1 -N(H)-C 1-6 alkylene-5-6 membered heteroaryl, R 1 , optionally, R g In some embodiments, R may be substituted on one or more available carbons with one, two, three or more substituents independently selected from 1 -N(H)-C 1-6 alkylene-5-6 membered heteroaryl, R 1, optionally, R g and R g is C for each occurrence independently. 1-6 It is an alkyl.

[0019] In some embodiments, R 1 teeth TIFF2024543451000008.tif11128.

[0020] The present disclosure relates to 5-{(3S)-3-[(4,4-difluorobutyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, [(3S)-5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1λ 6 tert-butyl 2,5-thiadiazolidin-2-yl)-3,4-dihydro-2H-1-benzothiopyran-3-yl]carbamate, 5-[(3S)-3-amino-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-methylbutyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-Fluoro-7-hydroxy-3-({2-[1-(hydroxymethyl)cyclobutyl]ethyl}amino)-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-Fluoro-7-hydroxy-3-({2-[1-(hydroxymethyl)cyclopentyl]ethyl}amino)-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(4-hydroxy-3,3-dimethylbutyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-Fluoro-7-hydroxy-3-(propylamino)-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-methylpentyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-Fluoro-7-hydroxy-3-{[2-(oxan-4-yl)ethyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-Fluoro-7-hydroxy-3-{[(oxan-4-yl)methyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-3-[(cyclopropylmethyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-3-(butylamino)-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(2-methylpropyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-Fluoro-7-hydroxy-3-{[2-(oxolan-3-yl)ethyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-3-[(2,3-dimethylbutyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(propan-2-yl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-3-{[2-(3,3-difluorocyclobutyl)ethyl]amino}-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-3-[(2-cyclohexylethyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-3-[(3-ethylpentyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-3-[(2-cyclopentylethyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-3-(benzylamino)-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-methylbut-2-en-1-yl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-3-[(3,3-dimethylpentyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-fluoro-3-{[(1-fluorocyclopropyl)methyl]amino}-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-3-{[(2,2-difluorocyclopropyl)methyl]amino}-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-Fluoro-7-hydroxy-3-{[(3-methyloxetan-3-yl)methyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-fluoro-3-({[1-(fluoromethyl)cyclopropyl]methyl}amino)-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-3-[(4,4-difluoropentyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-methoxypropyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-Fluoro-7-hydroxy-3-{[3-(1H-pyrazol-1-yl)propyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-Fluoro-7-hydroxy-3-{[2-(1-methylcyclopropyl)ethyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-3-[(2-cyclopropylpropyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-phenylbutyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-Fluoro-7-hydroxy-3-{[(3-phenylcyclobutyl)methyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-phenylpropyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-3-{[3-(2,2-difluoroethoxy)propyl]amino}-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-3-({[(1RS,5SR)-bicyclo[3.1.0]hexan-6-yl]methyl}amino)-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-Fluoro-7-hydroxy-3-({[4-(trifluoromethyl)cyclohexyl]methyl}amino)-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-Fluoro-7-hydroxy-3-{[2-(2,6,6-trimethylcyclohex-1-en-1-yl)ethyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 , 2,5-thiadiazolidine-1,1,3-trione, and 4-({[(3S)-5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1λ 6 ,2,5-Thiadiazolidin-2-yl)-3,4-dihydro-2H-1-benzothiopyran-3-yl]amino}methyl)piperidine-1-carboxylate tert-butyl ester or a pharma- ceutically acceptable salt thereof.

[0021] In some embodiments, the compounds disclosed herein are formulated as a pharma- ceutically acceptable composition comprising a disclosed compound and a pharma- ceutically acceptable carrier. In some embodiments, disclosed herein is a method of treating non-small cell lung cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein.

[0022] Table of Exemplary Compounds TIFF2024543451000009.tif108152TIFF2024543451000010.tif232152TIFF2024543451000011.tif232152TIFF2024543451000012.tif143152

[0023] Methods for Preparing Exemplary Compounds The compounds of the present disclosure can be better understood in connection with the following synthetic schemes and methods, which illustrate the means by which the compounds can be prepared. The compounds of the present disclosure can be prepared by a variety of synthetic procedures. A representative synthetic procedure is shown in Scheme 1, but is not limited thereto.

[0024] Scheme 1: Representative scheme for synthesizing exemplary compounds of the present disclosure. TIFF2024543451000013.tif23131The compound of formula (1-2) is reacted with an aldehyde, R 1-1 -CHO(in the formula, R 1-1 is optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkenyl, optionally substituted 3- to 7-membered heteroalkyl, optionally substituted -C 1-5 Alkylene-C 3-6 Cycloalkyl, optionally substituted -C 1-5 Alkylene-C 3-6 Cycloalkenyl, optionally substituted -C 1-5 Alkylene-C6-10 Aryl, optionally substituted -C 1-5 Alkylene-4 to 6 membered heteroaryl or optionally substituted -C 1-5 The compound of formula (1-1) can be reductively aminated with an aldehyde, R in the presence of a tertiary amine such as triethylamine in a solvent such as ethanol or a mixture of ethanol and dichloromethane. 1-1 -CHO. Subsequent treatment with a reducing agent such as sodium borohydride provides compounds of formula (1-2). Compounds of formula (1-2) are representative of compounds of formula (I).

[0025] Pharmaceutical Compositions The present disclosure provides a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of formula (I). In some embodiments, the pharmaceutical composition further comprises a pharma- ceutically acceptable excipient. In some embodiments, the compound disclosed herein, e.g., a compound of formula (I), is provided in an effective amount in the pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0026] The pharmaceutical compositions provided by the present disclosure include compositions containing an active ingredient (e.g., a compound described herein, including an embodiment or example) in a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, among other things, on the condition being treated. When administered in a method for treating a disease, such compositions will contain an amount of active ingredient effective to achieve the desired result, e.g., inhibiting the activity of a target molecule (e.g., PTPN2 and / or PTPN1) and / or reducing, eliminating, or delaying the progression of disease symptoms. Determining a therapeutically effective amount of a compound disclosed herein is well within the capabilities of one of ordinary skill in the art, especially in light of the detailed disclosure herein.

[0027] definition chemical definition Definitions of certain functional groups and chemical terms are given in more detail below. Chemical elements are defined in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., (inside cover), and specific functional groups are generally defined as set forth therein. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in detail in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3. rd Edition, Cambridge University Press, Cambridge, 1987.

[0028] Abbreviations used herein have their ordinary meaning within the chemical and biological arts. The chemical structures and formulas depicted herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0029] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or more than one analogue.

[0030] When a range of values ​​is listed, it is intended that each value and subrange within that range is encompassed. For example, "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0031] The following terms are intended to have the meanings presented below and are helpful in understanding the description and intended scope of the present disclosure.

[0032] "Alkyl" refers to the radical of a straight or branched chain saturated hydrocarbon group having 1 to 20 carbon atoms ("C1-C 20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1-C 12In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-C4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-C3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-C2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Each example of an alkyl group may be optionally and independently substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents (e.g., 1-5 substituents, 1-3 substituents, or 1 substituent) ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1-10 In certain embodiments, the alkyl group is a substituted C 1-6 It is alkyl. Common abbreviations for alkyl include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0033] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited to, by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred in this disclosure. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. An alkylene group may be described, for example, as a C1-C6 membered alkylene, with the term "membered" referring to a non-hydrogen atom within the moiety.

[0034] "Alkenyl" refers to the radical of a straight or branched chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds and no triple bonds ("C 20 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 10 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-C6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-C5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-C4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-C3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as 2-butenyl) or terminal (such as 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include the aforementioned C 2-4Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Each example of an alkenyl group can be optionally and independently substituted, e.g., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents (e.g., 1-5 substituents, 1-3 substituents, or 1 substituent) ("substituted alkenyl"). In certain embodiments, an alkenyl group can be an unsubstituted C 2-10 In certain embodiments, the alkenyl group is a substituted C 2-6 It is alkenyl.

[0035] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and zero heteroatoms associated with the aromatic ring system (see "C 14 In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 Aryl, for example, anthracyl. The aryl group is, for example, C6-C 10 The term "membered" refers to a non-hydrogen ring atom in the moiety. Aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each example of an aryl group may be optionally and independently substituted, e.g., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C6-C 14In certain embodiments, the aryl group is a substituted C-C 14 It is aryl.

[0036] The term "alkoxy" refers to an -O-alkyl radical, wherein the alkyl residue is as defined above, attached via an oxygen atom.

[0037] "Halo" or "halogen," by itself or as part of another substituent, means, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. The term "halide," by itself or as part of another substituent, refers to a fluoride, chloride, bromide, or iodide atom. In certain embodiments, a halo group is either fluorine or chlorine.

[0038] Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo-C1-C6 alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0039] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms attached to the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or at a nitrogen atom, provided that valence permits. Heteroaryl groups may be described as, for example, 6-10 membered heteroaryl, with the term "member" referring to a non-hydrogen ring atom within the moiety.

[0040] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heteroaryl group may be optionally and independently substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0041] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0042] "Cycloalkyl" refers to a group having 3 to 10 ring carbon atoms ("C3-C 10 "Cycloalkyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having zero heteroatoms in the non-aromatic ring system. In some embodiments, a cycloalkyl group has from 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, a cycloalkyl group has from 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has from 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has from 5 to 10 ring carbon atoms ("C5-C6 cycloalkyl"). 10Cycloalkyl groups may be described, for example, as C4-C7 membered cycloalkyl, with the term "member" referring to a non-hydrogen ring atom within the moiety. Exemplary C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 cycloalkyl groups include, but are not limited to, the C3-C6 cycloalkyl groups described above, as well as cycloheptyl (C7), cycloheptenyl (C7), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), bicyclo[3.1.0]hexanyl, and the like. As the above examples illustrate, in certain embodiments, cycloalkyl groups are monocyclic ("monocyclic cycloalkyl") or contain fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic cycloalkyl"), and may be saturated or partially unsaturated. Each instance of a cycloalkyl group may be optionally and independently substituted, e.g., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C3-C 10 In certain embodiments, the cycloalkyl group is a substituted C-C 10 It is cycloalkyl.

[0043] In some embodiments, "cycloalkyl" is a monocyclic saturated cycloalkyl group having 3 to 10 ring carbon atoms ("C 10In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C6 cycloalkyl"). 10 Examples of C5-C6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-C6 cycloalkyl groups include the C5-C6 cycloalkyl groups mentioned above, as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-C8 cycloalkyl groups include the C3-C6 cycloalkyl groups mentioned above, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C3-C6 cycloalkyl group. 10 In certain embodiments, the cycloalkyl group is a substituted C-C 10 It is cycloalkyl.

[0044] "Heterocyclyl" or "heterocycle" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or at a nitrogen atom, provided that valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more cycloalkyl groups, with the point of attachment being either on the cycloalkyl ring or on the heterocyclyl ring, or in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring, and in such instances, the number of ring members thereafter refers to the number of ring members in the heterocyclyl ring system. Heterocyclyl groups may be described, for example, as 3- to 7-membered heterocyclyl, where the term "member" refers to the non-hydrogen ring atoms (i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon) in the moiety. Each instance of heterocyclyl may be optionally and independently substituted, for example, unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-10 membered heterocyclyl.

[0045] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0046] Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocycles) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 3,4-dihydro-2H-1-benzothiopyran, and the like.

[0047] "Hydroxy" or "hydroxyl" refers to the radical --OH.

[0048] In some embodiments, when one or more nitrogen atoms are present in the disclosed compounds, the nitrogen atoms are oxidized to the corresponding N-oxide.

[0049] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups as defined herein are optionally substituted (e.g., a "substituted" or "unsubstituted" alkyl group, a "substituted" or "unsubstituted" alkenyl group, a "substituted" or "unsubstituted" alkynyl group, a "substituted" or "unsubstituted" cycloalkyl group, a "substituted" or "unsubstituted" heterocyclyl group, a "substituted" or "unsubstituted" aryl group, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted", whether preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that upon substitution gives rise to a stable compound (e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction, etc.). Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position is substituted in any given structure, the substituents are the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, such as any of the substituents described herein, that result in the formation of a stable compound. The present disclosure contemplates any and all such combinations to arrive at a stable compound. For purposes of the present disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0050] Optionally, two or more substituents may be linked to form an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group. Such so-called ring-forming substituents are not necessarily attached to a cyclic base structure, but are typically found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0051] Other definitions "Treating" or "treatment" refers to a method of alleviating or eliminating disease and / or its associated symptoms. In certain embodiments, the compounds disclosed herein are useful for treating non-small cell lung cancer. In certain embodiments, a method of treating a human subject having non-small cell lung cancer is provided, comprising administering to the human subject in need of treatment a therapeutically effective amount of a compound of formula (I).

[0052] The phrase "therapeutically effective amount" refers to an amount of a compound or a pharma- ceutically acceptable salt thereof that, when administered for treatment in a particular subject or population of subjects, is sufficient to prevent the onset of, or to alleviate to some extent, one or more symptoms of the condition or disorder being treated. As used herein, the term "subject" refers to a human. The terms "human", "patient" and "subject" are used interchangeably herein.

[0053] As defined herein, the terms "inhibit," "inhibit," "inhibitory," and the like, with respect to protein-inhibitor (e.g., antagonist) interactions, refer to a negative effect (e.g., a decrease) on the activity or function of a protein relative to the activity or function of the protein in the absence of the inhibitor.

[0054] A "patient" or "subject" in need of treatment refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administration of the compounds or pharmaceutical compositions provided herein. In some embodiments, the patient is a human.

[0055] A "pharmaceutically acceptable excipient" and a "pharmaceutically acceptable carrier" refer to a substance that aids in the administration of an active ingredient to and absorption by a subject without causing significant adverse toxicological effects in the patient and that can be included in a composition of the present disclosure.

[0056] As used herein, the term "PTPN2" refers to non-receptor type 2 protein tyrosine phosphatase. The term "PTPN1" refers to non-receptor type 1 protein tyrosine phosphatase (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B).

[0057] In some embodiments, the compounds disclosed herein are formulated as a pharma- ceutically acceptable composition comprising a disclosed compound and a pharma- ceutically acceptable carrier. EXAMPLES

[0058] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods described herein, and are not to be construed in any way as limiting the scope of this application.

[0059] Synthesis protocol The compounds shown herein can be prepared from readily available starting materials with modifications to the specific synthetic protocols described below that should be known to those skilled in the art. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through routine optimization procedures. General schemes for the preparation of exemplary compounds of the present disclosure are additionally described in the section entitled Preparation of Exemplary Compounds.

[0060] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.The selection of a suitable protecting group for a particular functional group, as well as the selection of suitable conditions for protection and deprotection, are known in the art.For example, numerous protecting groups and their introduction and removal are described in Greene et al., Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0061] Abbreviation APCI is atmospheric pressure chemical ionization, DMSO is dimethylsulfoxide, ESI is electrospray ionization, HPLC is high performance liquid chromatography, MS is mass spectrometry, NMR is nuclear magnetic resonance, ppm is parts per million, and v / v is volume / volume.

[0062] Example 1: 5-{(3S)-3-[(4,4-difluorobutyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 100) Triethylamine (0.06 mL, 0.45 mmol, 3.0 equiv) and a solution of 4,4-difluorobutanal (approximately 25% by weight, 193 mg, 0.45 mmol, 3.0 equiv) in dichloromethane were added sequentially to a suspension of the product of Example 3P (nominal 0.15 mmol, 1 equiv) in 50% ethanol-dichloromethane (0.80 mL, approximately 0.2 M) at 23° C. The reaction mixture was stirred for 2 hours at 23° C. Sodium borohydride (22.5 mg, 0.60 mmol, 4.0 equiv) was added at 23° C. The reaction mixture was stirred for 20 minutes at 23° C. The mixture was diluted with aqueous hydrochloric acid (3 M, 0.20 mL, CAUTION: gas evolution!), water (1.0 mL) and dimethyl sulfoxide (1.0 mL). The diluted mixture was partially concentrated. The partially concentrated mixture was purified by preparative high-performance liquid chromatography (Phenomenex® C8(2) Luna® 5 μm, AXIA™ 30 × 75 mm [3 columns coupled], elution with a 0.1% trifluoroacetic acid-acetonitrile-water [v / v] 5-100% gradient) to give the title compound (19 mg, 24% over three steps). 1 H NMR (600 MHz, DMSO-d6) δ ppm 9.65 (s, 1H), 8.77 (s, 1H), 8.59 (s, 1H), 6.48 (s, 1H), 6.15 (tt, J = 56.6, 4.2 Hz, 1H), 3.95 (s, 2H), MS (APCI - ) m / z 424 [MH] - .

[0063] Example 2: [(3S)-5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1λ 6 ,2,5-Thiadiazolidin-2-yl)-3,4-dihydro-2H-1-benzothiopyran-3-yl]carbamic acid tert-butyl ester (Compound 101) Example 2A: ({(3S)-7-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]-5-fluoro-3,4-dihydro-2H-1-benzothiopyran-6-yl}amino) methyl acetate The title compound was prepared in 95% yield from the product of Example 3D using the procedure described in Example 3H. 1 H NMR (DMSO-d6, 400 MHz) δ ppm 7.29-7.48 (m, 5H), 7.01-7.08 (m, 1H), 6.55 (s, 1H), 5.08 (s, 2H), 4.87-4.94 (m, 1H), 4.00-4.06 (m, 1H), 3.74-3.86 (m, 1H), 3.74-3.86 (m, 1H), 3.74-3.86 (m, 1H), 3.59 (s, 3H), 2.93 (br d, J = 11.6 Hz, 1H), 2.76-2.87 (m, 2H), 2.42-2.48 (m, 1H), 1.40 (s, 9H).

[0064] Example 2B: [{(3S)-7-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]-5-fluoro-3,4-dihydro-2H-1-benzothiopyran-6-yl}({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]acetate methyl The title compound was prepared in 92% yield from the product of Example 2A using the procedure described in Example 3I. MS (ESI + ) m / z 584 [M+H] + .

[0065] Example 2C: [(3S)-7-(benzyloxy)-5-fluoro-6-(1,1,4-trioxo-1λ 6 ,2,5-Thiadiazolidin-2-yl)-3,4-dihydro-2H-1-benzothiopyran-3-yl]carbamic acid tert-butyl ester To a solution of the product of Example 2B (3 g, 4.69 mmol) in methanol (90 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.542 g, 0.469 mmol) and potassium carbonate (1.944 g, 14.07 mmol) under nitrogen at 25° C., and the mixture was stirred at 50° C. under nitrogen for 6 h. One additional batch each of 200 mg and 500 mg scale reactions were run as above. The reaction mixtures were combined and acidified to pH=5-6 with aqueous hydrochloric acid (1 mol / L), then filtered. The filtrate was diluted with water (300 mL) and extracted with ethyl acetate (3×40 mL). The combined organic fractions were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC on a Welch Xtimate® C18 column (250 × 50 mm × 10 μm) eluting with acetonitrile (A)-10 mM NH4HCO3 in H2O (20-55% gradient of A in 30 min) at a flow rate of 80 mL / min to give the title compound (1.7 g, 95% purity, 53.5% yield). 1 H NMR (400 MHz, methanol-d4) δ ppm 7.49 (d, J = 7.34 Hz, 2H), 7.31-7.37 (m, 2H), 7.24-7.30 (m, 1H), 6.66 (d, J = 1.34 Hz, 1H), 5.11 (s, 2H), MS (ESI - ) m / z 522 [MH] - .

[0066] Example 2D: [(3S)-5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1λ 6 ,2,5-Thiadiazolidin-2-yl)-3,4-dihydro-2H-1-benzothiopyran-3-yl]carbamic acid tert-butyl ester A suspension of the product of Example 2C (7 mg, 0.013 mmol), 20% dihydroxypalladium on carbon (18.18 mg, 0.129 mmol) and ammonium formate (16.33 mg, 0.259 mmol) in ethanol (2 mL) was stirred at 60° C. for 2 h. The reaction mixture was filtered through a plug of diatomaceous earth. The filter cake was washed with methanol (3×1.0 mL). The filtrate and washings were combined and concentrated. The residue was purified by preparative HPLC on a Phenomenex® Luna® 10 μm C18 column (30 mm×250 mm) eluted with a gradient of acetonitrile (A) and water containing 0.1% trifluoroacetic acid (B) (0-1 min 10% A, 1-30 min 10-95% linear gradient) at a flow rate of 50 mL / min to give the title compound (3 mg, 54% yield). 1 H NMR (400 MHz, methanol-d4) δ ppm 6.37 (d, J = 1.7 Hz, 1H), 4.17 (s, 2H), 3.93 (s, 1H), 2.96 (d, J = 12.6 Hz, 1H), 2.88 - 2.78 (m, 2H), 2.51 (dd, J = 16.7, 8.9 Hz, 1H), 1.35 (s, 9H);MS (APCI - ) m / z 432.1 [MH] - .

[0067] Example 3: 5-[(3S)-3-amino-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 102) Example 3A: 1-(benzyloxy)-5-bromo-3-fluoro-2-nitrobenzene A solution of potassium tert-butoxide in tetrahydrofuran (1.0 M, 44.0 mL, 44.0 mmol, 1.1 equiv.) was added slowly down the side of the reaction vessel to a suspension of benzyl alcohol (4.60 mL, 44.2 mmol, 1.1 equiv.) and 5-bromo-1,3-difluoro-2-nitrobenzene (10.0 g, 42.0 mmol, 1 equiv.) in tetrahydrofuran (200 mL, 0.21 M) at −67° C. at a rate such that the internal temperature did not exceed −57° C. The reaction mixture was stirred for 5 minutes such that the internal temperature did not exceed −57° C. The product mixture was then diluted sequentially at −78° C. with saturated aqueous ammonium chloride (10 mL), water (50 mL), and ethyl acetate (100 mL). The diluted product mixture was allowed to warm to 23° C. over 30 minutes. The resulting biphasic mixture was then transferred to a separatory funnel and the layers formed were separated. The aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL). The washed organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The resulting residue was precipitated from heptane (125 mL). The mother liquor was concentrated and the resulting residue was triturated with heptane (3×25 mL). The triturated material was combined with the previously precipitated material. The combined material was dried in a vacuum oven at 50° C. to give the title compound (11.3 g, 82%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.63 (t, J = 1.7 Hz, 1H), 7.57 (dd, J = 9.3, 1.7 Hz, 1H), 7.46-7.32 (m, 5H), 5.36 (s, 2H).

[0068] Example 3B: 2-(benzyloxy)-4-bromo-6-fluoroaniline In an ice bath, saturated aqueous ammonium chloride solution (60 mL, 5.3 volume equiv.) was added to a suspension of zinc powder (11.3 g, 173 mmol, 5.0 equiv.) and the product of Example 3A (11.3 g, 34.7 mmol, 1 equiv.) in a 50% methanol-tetrahydrofuran mixture (v / v, 230 mL, 0.15 M) at a rate such that the internal temperature did not exceed 31° C. The reaction vessel was then removed from the cooling bath and allowed to warm to 23° C. over 5 hours. Diatomaceous earth (21 g) was added to the resulting mixture and the resulting slurry was stirred at 23° C. for 10 minutes. The mixture was then filtered through a diatomaceous earth plug (2.0 cm×8.0 cm). The filter cake was washed with methanol (3×30 mL). The filtrate and washings were combined and concentrated. The resulting residue was dissolved in ethyl acetate (200 mL) and the mixture was washed successively with water (50 mL) and brine (50 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The resulting residue was used in the subsequent step without further purification. MS (ESI + ) m / z 296 [M+H] + .

[0069] Example 3C: N-[2-(benzyloxy)-4-bromo-6-fluorophenyl]-2,2,2-trifluoroacetamide Trifluoroacetic anhydride (5.90 mL, 41.8 mmol, 1.2 equiv.) was added via syringe pump over 10 min to a solution of the product of Example 3B (nominal 34.7 mmol, 1 equiv.) in dichloromethane (174 mL, 0.2 M) at 0° C. such that the internal temperature did not exceed 7° C. The reaction mixture was allowed to warm to 23° C. over 18 h. The product mixture was partitioned between water (50 mL) and ethyl acetate (500 mL). The organic layer was washed sequentially with hydrochloric acid solution (1 M, 3×100 mL) and saturated aqueous sodium chloride solution (100 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered. Diatomaceous earth (approximately 50 g) was added to the filtrate and the mixture was concentrated. The resulting residue was purified by flash column chromatography (330 g Teledyne ISCO RediSep Rf Gold® silica column, eluted with ethyl acetate-heptane 0-100% gradient) to give the title compound (9.18 g, 67%, 2 steps). MS (ESI - ) m / z 390 [MH] - .

[0070] Example 3D: tert-Butyl [(2S)-1-[4-(benzyloxy)-6-bromo-2-fluoro-3-(2,2,2-trifluoroacetamido)phenyl]-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl]carbamate A solution of n-butyllithium in hexane (1.91 M, 5.50 mL, 10.50 mmol, 2.1 equiv.) was added to a solution of diisopropylamine (1.57 mL, 11.00 mmol, 2.2 equiv.) in tetrahydrofuran (20.0 mL) at −78° C. The mixture was stirred at −78° C. for 15 min. A solution of the product of Example 3C (2.06 g, 5.25 mmol, 1.05 equiv.) in tetrahydrofuran (6.5 mL) was added dropwise over 20 min at −78° C. via syringe pump. The mixture was stirred at −78° C. for 30 min. (4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dioxo-1,2λ in tetrahydrofuran (6.5 mL, 0.15 M overall). 6A solution of tert-butyl 3-oxathiazolidine-3-carboxylate (1.84 g, 5.00 mmol, 1 equiv., Tetrahedron Lett. 2011, 52, 5229-5233) was added dropwise over 20 min at −78° C. The reaction mixture was stirred at −78° C. for 30 min. Aqueous hydrochloric acid (3 M, 8.33 mL, 25.00 mmol, 5.0 equiv.) was added at −78° C. The resulting mixture was warmed to 23° C. over 20 min. The warmed mixture was diluted with ethyl acetate (100 mL). The resulting biphasic mixture was transferred to a separatory funnel and the layers formed were separated. The aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL). The washed organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The resulting residue was dissolved in ether (20 mL). Diatomaceous earth (approximately 10 g) was added to the solution and the mixture was concentrated. The resulting residue was purified by flash column chromatography (80 g Teledyne ISCO RediSep Rf Gold® silica column, eluted with ethyl acetate-heptane 0-80% gradient) to give the title compound (1.977 g, 58%). MS (APCI + ) m / z 579 [M+HC(O)OC(CH3)3] + .

[0071] Example 3E: Methyl [{6-(benzyloxy)-4-bromo-3-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}propyl]-2-fluorophenyl}(trifluoroacetyl)amino]acetate Methyl bromoacetate (0.22 mL, 2.43 mmol, 1.1 equiv) was added to a suspension of the product of Example 3D (1.5 g, 2.21 mmol, 1 equiv), potassium carbonate (915 mg, 6.62 mmol, 3.0 equiv), and potassium iodide (183 mg, 1.10 mmol, 0.5 equiv) in acetone (11 mL, 0.2 M) at 23° C. The reaction mixture was stirred at 23° C. for 24 h. The mixture was concentrated. The resulting residue was partitioned between ethyl acetate (60 mL) and water (15 mL). The aqueous layer was extracted with ethyl acetate (30 mL). The organic layers were combined and washed with saturated aqueous sodium chloride solution (15 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The title compound obtained was used in the subsequent step without further purification. MS (APCI + ) m / z 651 [M+HC(O)OC(CH3)3] + .

[0072] Example 3F: {[6-(benzyloxy)-4-bromo-3-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropyl}-2-fluorophenyl](trifluoroacetyl)amino}acetate methyl A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 13.3 mL, 13.3 mmol, 1.1 equiv.) was added to a solution of the product of Example 3E (9.07 g, 12.1 mmol, 1 equiv.) in tetrahydrofuran (60.0 mL, 0.2 M) at 23° C. The reaction mixture was stirred at 23° C. for 3 days. The reaction mixture was partitioned between saturated aqueous ammonium chloride solution (15 mL), water (15 mL), and ethyl acetate (200 mL). The organic layer was then separated and washed with saturated aqueous sodium chloride solution (20 mL). The washed organic layer was dried over sodium sulfate and then filtered. Diatomaceous earth (approximately 40 g) was added to the filtrate and the mixture was concentrated. The resulting residue was purified by flash column chromatography (120 g Teledyne ISCO RediSep Rf Gold® silica column, eluted with ethyl acetate-heptane 0-100% gradient) to give the title compound (7.15 g, 93%). MS (APCI+ ) m / z 637 [M+H] + .

[0073] Example 3G: {[6-(benzyloxy)-4-bromo-3-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-[(methanesulfonyl)oxy]propyl}-2-fluorophenyl](trifluoroacetyl)amino}acetate methyl Methanesulfonyl chloride (1.05 mL, 13.46 mmol, 1.2 equiv.) was added to a solution of the product of Example 3F (7.15 g, 11.22 mmol, 1 equiv.) and N,N-diisopropylethylamine (3.92 mL, 22.43 mmol, 2.0 equiv.) in dichloromethane (56 mL, 0.2 M) at 0° C. The reaction mixture was allowed to warm to 23° C. over 12 h. Diatomaceous earth (approximately 30 g) was added to the reaction mixture and the mixture was concentrated. The resulting residue was purified by flash column chromatography (80 g Teledyne ISCO RediSep Rf Gold® silica column, eluting with a 0-100% gradient of ethyl acetate-heptane). The fractions containing the product were combined and concentrated. The resulting residue (7.13 g, <89%) was used in the subsequent step without further purification. MS (APCI + ) m / z 615 [M+HC(O)OC(CH3)3] + .

[0074] Example 3H: {[3-{(2S)-3-(acetylsulfanyl)-2-[(tert-butoxycarbonyl)amino]propyl}-6-(benzyloxy)-4-bromo-2-fluorophenyl](trifluoroacetyl)amino}acetate methyl Potassium thioacetate (1.59 g, 13.95 mmol, 1.4 equiv) was added to a solution of the product of Example 3G (7.13 g, 9.96 mmol, 1 equiv) in N,N-dimethylformamide (50 mL, 0.2 M) at 23° C. The reaction mixture was stirred at 23° C. for 16 h. The reaction mixture was partially concentrated. The resulting residue was partitioned between ethyl acetate (150 mL), water (15 mL), and saturated aqueous ammonium chloride solution (10 mL). The aqueous layer was extracted with ethyl acetate (75 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (3×10 mL). The washed organic layers were dried over sodium sulfate. The dried solution was filtered. Diatomaceous earth (approximately 40 g) was added to the filtrate and the mixture was concentrated. The resulting residue was purified by flash column chromatography (120 g Teledyne ISCO RediSep Rf Gold® silica column, eluting with a gradient of ethyl acetate-heptane 0-100%). The product-containing fractions were combined and concentrated. The resulting residue (5.30 g, <76%) was used in the subsequent step without further purification. MS (APCI + ) m / z 595 [M+HC(O)OC(CH3)3] + .

[0075] Example 3I: [{(3S)-7-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]-5-fluoro-3,4-dihydro-2H-1-benzothiopyran-6-yl}(trifluoroacetyl)amino]acetate methyl A suspension of tris(dibenzylideneacetone)dipalladium(0) (70.0 mg, 0.08 mmol, 5.0 mol%), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Xantphos, 89.0 mg, 0.15 mmol, 10.0 mol%), N,N-diisopropylethylamine (0.05 mL, 0.29 mmol, 3.0 equiv.), and the product of Example 3H (63.0 mg, 0.10 mmol, 1 equiv.) in 1,4-dioxane (0.5 mL, ca. 0.2 M) was deoxygenated by subjecting the vessel to vacuum (ca. 5 s) followed by backfilling with nitrogen (x3). The reaction vessel was placed in a heat block that had been preheated to 100° C. The reaction mixture was stirred at 100° C. for 45 min. The product mixture was cooled to 23° C. The reaction mixture was diluted with ethyl acetate (5 mL). Diatomaceous earth (approximately 1 g) was added to the solution and the mixture was concentrated. The resulting residue was purified by flash column chromatography (40 g Teledyne ISCO RediSep Rf Gold® silica column, eluted with ethyl acetate-heptane 0-100% gradient) to give the title compound (1.49 g, 51%). MS (APCI + ) m / z 573 [M+H] + .

[0076] Example 3J: {[(3S)-3-amino-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl](trifluoroacetyl)amino}acetate methyl A solution of boron trichloride in dichloromethane (41.2 mL, 41.2 mmol, 5.0 equiv.) was slowly added to a solution of the product of Example 3I (4.72 g, 8.24 mmol, 1 equiv.) and pentamethylbenzene (1.34 g, 9.07 mmol, 1.1 equiv.) in dichloromethane (41.2 mL, 0.2 M) at -78°C. The reaction vessel was immediately removed from the cooling bath and allowed to warm to 23°C over 1 h. The product mixture was then cooled to -78°C. The cooled product mixture was diluted with methanol (35 mL). The diluted mixture was allowed to warm to 23°C and concentrated. The resulting residue was used in the subsequent step without further purification. MS (APCI +) m / z 383 [M+H] + .

[0077] Example 3K: [{(3S)-3-[(tert-butoxycarbonyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}(trifluoroacetyl)amino]acetate methyl Di-tert-butyl dicarbonate (2.39 g, 10.7 mmol, 1.3 equiv.) was added to a biphasic mixture of the product of Example 3J (nominal 8.24 mmol, 1 equiv.) and sodium bicarbonate (3.46 g, 41.2 mmol, 5.0 equiv.) in a 20% water-tetrahydrofuran mixture (v / v, 40.0 mL, ca. 0.2 M) at 23° C. The reaction mixture was stirred at 23° C. for 1.5 h. The product mixture was partitioned between ethyl acetate (200 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (25 mL). The washed organic layers were dried over sodium sulfate. The dried solution was filtered and concentrated. The resulting residue was dissolved in 75% acetone-pentane (50 mL). Diatomaceous earth (ca. 20 g) was added to the solution and the mixture was concentrated. The resulting residue was purified by flash column chromatography (330 g Teledyne ISCO RediSep Rf Gold® silica column, eluting with a 0-100% ethyl acetate-heptane gradient) to give the title compound (3.81 g, 96%, 2 steps). 1 H NMR (500 MHz, CDCl3) δ ppm 8.63 (s, 1H), 6.62 (s, 1H), 5.00 (dd, J = 17.4, 3.8 Hz, 1H), 4.97-4.83 (m, 1H), 4.45-4.27 (m, 1H), 3.88 (s, MS (APCI +) m / z 383 [M+HC(O)OC(CH3)3] + .

[0078] Example 3L: [{(3S)-3-[(tert-butoxycarbonyl)amino]-5-fluoro-7-[(2-methoxyethoxy)methoxy]-3,4-dihydro-2H-1-benzothiopyran-6-yl}(trifluoroacetyl)amino]acetate methyl 2-Methoxyethoxymethyl chloride (1.07 mL, 9.48 mmol, 1.2 equiv) was added to a solution of the product of Example 3K (3.81 g, 7.90 mmol, 1 equiv) and N,N-diisopropylethylamine (4.14 mL, 23.7 mmol, 3.0 equiv) in dichloromethane (40.0 mL, 0.2 M) at 0° C. The reaction vessel was immediately removed from the cooling bath and allowed to warm to 23° C. over 1 h. Additional 2-methoxyethoxymethyl chloride (0.20 mL, 1.77 mmol, 0.22 equiv) was added at 23° C. The reaction mixture was stirred at 23° C. for 30 min. The product mixture was partitioned between ethyl acetate (250 mL), heptane (20 mL), water (10 mL), and saturated aqueous ammonium chloride (30 mL). The organic layer was then separated and washed with saturated aqueous sodium chloride solution (30 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The title compound obtained was used in the subsequent step without further purification. MS (APCI + ) m / z 471 [M+HC(O)OC(CH3)3] + .

[0079] Example 3M: ({(3S)-3-[(tert-butoxycarbonyl)amino]-5-fluoro-7-[(2-methoxyethoxy)methoxy]-3,4-dihydro-2H-1-benzothiopyran-6-yl}amino) methyl acetate A solution of sodium methoxide in methanol (0.5 M, 8.00 mL, 4.00 mmol, 3.0 equiv.) was added to the product of Example 3L (759 mg, 1.33 mmol, 1 equiv.) under pure nitrogen. The reaction vessel was placed in a heat block preheated to 60° C. The reaction mixture was stirred at 60° C. for 1.5 h. The product mixture was then cooled to 23° C. The cooled product mixture was concentrated. The resulting residue was partitioned between aqueous hydrochloric acid (1 M, 35 mL) and ethyl acetate (250 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined and washed with saturated aqueous sodium chloride (20 mL). The washed organic layers were dried over sodium sulfate. The dried solution was filtered. Diatomaceous earth (approximately 20 g) was added to the solution and the mixture was concentrated. The resulting residue was purified by flash column chromatography (220 g Teledyne ISCO RediSep Rf Gold® silica column, eluting with a 0-100% ethyl acetate-heptane gradient) to give the title compound (3.33 g, 89%, 2 steps). 1 H NMR (600 MHz, CDCl3) δ ppm 6.69 (s, 1H), 5.25 (s, 2H), 5.04 (bs, 1H), 4.40-431 (m, 2H), 4.04 (dd, J = 6.3, 1.2 Hz, 2H), 3.85-3.82 (m, MS (APCI + ) m / z 475 [M+H] + .

[0080] Example 3N: [{(3S)-3-[(tert-butoxycarbonyl)amino]-5-fluoro-7-[(2-methoxyethoxy)methoxy]-3,4-dihydro-2H-1-benzothiopyran-6-yl}({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]acetate methyl Allyl alcohol (1.05 mL, 15.4 mmol, 2.2 equiv.) was added to a solution of chlorosulfonyl isocyanate (1.34 mL, 15.4 mmol, 2.2 equiv.) in dichloromethane (20.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. A solution of the product of Example 3M (3.33 g, 7.02 mmol, 1 equiv.) and triethylamine (3.91 mL, 28.1 mmol, 4.0 equiv.) in dichloromethane (15.0 mL, approximately 0.2 M overall) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 10 min. The product mixture was partially concentrated. The resulting residue was partitioned between ethyl acetate (75 mL) and water (10 mL). The organic layer was washed with saturated aqueous sodium chloride solution (10 mL). The washed organic layer was dried over sodium sulfate. The dried solution was filtered. Diatomaceous earth (approximately 15 g) was added to the solution and the mixture was concentrated. The resulting residue was purified by flash column chromatography (120 g Teledyne ISCO RediSep Rf Gold® silica column, eluted with ethyl acetate-heptane 0-100% gradient) to give the title compound (3.74 g, 84%). MS (APCI + ) m / z 655 [M+NH4] + .

[0081] Example 3O: [(3S)-5-fluoro-7-[(2-methoxyethoxy)methoxy]-6-(1,1,4-trioxo-1λ 6 ,2,5-Thiadiazolidin-2-yl)-3,4-dihydro-2H-1-benzothiopyran-3-yl]carbamic acid tert-butyl ester A suspension of the product of Example 3N (nominal 0.30 mmol, 1 equiv.), potassium carbonate (122 mg, 0.89 mmol, 3.0 equiv.), and tetrakis(triphenylphosphine)palladium(0) (17.0 mg, 0.02 mmol, 5.0 mol%) in methanol (1.50 mL, 0.2 M) was deoxygenated by subjecting it to vacuum (approximately 5 seconds) followed by backfilling with nitrogen (×3). The reaction vessel was placed in a heat block that had been preheated to 60° C. The reaction mixture was stirred at 60° C. for 45 minutes. The product mixture was then cooled to 23° C. The cooled mixture was filtered through a plug of diatomaceous earth (0.5 cm×1.0 cm). The filter cake was rinsed with ethyl acetate (3×2.0 mL). The filtrates were combined and carefully diluted with aqueous hydrochloric acid (1 M, 25 mL). The resulting biphasic mixture was then transferred to a separatory funnel and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (2 x 50 mL). The organic layers were combined and the combined organic layers were washed with saturated aqueous sodium chloride solution (15 mL). The washed organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The title compound obtained was used in the subsequent step without further purification. 1 H NMR (500 MHz, DMSO-d6) δ ppm 6.70 (s, 1H), 5.18 (s, 2H), 4.13-4.50 (m, 1H), 3.91-3.77 (m, 3H), 3.72 (dd, J = 5.5, 4.0 Hz, 2H), 3.44 (dd, J = 5.5, 4.0 Hz, 2H), 3.16 (d, J = 4.9 Hz, 2H), 3.01 (d, J = 10.6 Hz, 1H), 1.40 (s, 9H); + ) m / z 539 [M+NH4] + .

[0082] Example 3P: 5-[(3S)-3-amino-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione hydrochloride A solution of hydrogen chloride in dioxane (4.0 M, 15.3 mL, 61.4 mmol, 20.0 equiv.) was added to a solution of the product of Example 3O (nominal 3.07 mmol, 1 equiv.) and pentamethylbenzene (1.36 g, 9.20 mmol, 3.0 equiv.) in tetrahydrofuran (10.2 mL, 0.3 M) at 23° C. The reaction mixture was stirred at 23° C. for 2.5 h. The product mixture was diluted with ether (25 mL) to give a suspension. The mother liquor was decanted. The resulting residue was triturated successively with acetonitrile (2×10 mL), ethyl acetate (5×15 mL), and ether (15 mL). The resulting title compound was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (bs, 3H), 6.57 (s, 1H), 4.34 (s, 2H), 3.74 (bs, 1H), 3.26-3.19 (m, 1H), 3.17-3.03 (m, 2H), 2.72 (dd, J = 16.6, 8.6 Hz, 1H);MS (APCI + ) m / z 334 [M+H] + .

[0083] Example 4: 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-methylbutyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 103) Isovaleraldehyde (0.02 mL, 0.19 mmol, 3.8 equiv) was added to a solution of the product of Example 3P (nominal 0.05 mmol, 1 equiv) and triethylamine (0.04 mL, 0.29 mmol, 5.7 equiv) in 50% ethanol-dichloromethane (0.25 mL, 0.2 M) at 23° C. The reaction mixture was stirred at 23° C. for 1.5 h. Sodium borohydride (7.2 mg, 0.19 mmol, 3.8 equiv) was added in one portion at 23° C. The sides of the flask were rinsed with ethanol (0.25 mL). The reaction mixture was stirred at 23° C. for 1 h. The product mixture was concentrated. The resulting residue was dissolved in methanol (1.1 mL) and the solution was purified by high performance liquid chromatography (Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL / min, 5-100% acetonitrile gradient in 0.1% trifluoroacetic acid buffer) to give the title compound (8.0 mg, 31%, 3 steps). 1 H NMR (600 MHz, DMSO-d6) δ ppm 9.59 (s, 1H), 8.69 (s, 1H), 8.51 (s, 1H), 6.47 (s, 1H), 3.92 (s, 2H), 3.80 (bs, 1H), 3.19-3.00 (m, 4H), MS (APCI + ) m / z 404 [M+H] + .

[0084] Example 5: 5-[(3S)-5-fluoro-7-hydroxy-3-({2-[1-(hydroxymethyl)cyclobutyl]ethyl}amino)-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 104) Example 5A: tert-Butyl(dimethyl){[1-(prop-2-en-1-yl)cyclobutyl]methoxy}silane To a solution of (1-allylcyclobutyl)methanol (prepared according to Bioorganic and Medicinal Chemistry, 2002, 10(4), 1093-1106) (2.5 g, 15.85 mmol, 80% purity) in anhydrous tetrahydrofuran (70 mL) was added imidazole (2.158 g, 31.7 mmol) followed by tert-butyldimethylchlorosilane (3.58 g, 23.77 mmol) in portions at 0° C. The reaction mixture was stirred at 20° C. for 3 h. One additional batch of 500 mg scale reaction was prepared and run as above. These two reaction mixtures were combined and diluted with water (200 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (60 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then dissolved in petroleum ether and filtered through silica gel, and the filter cake was washed with petroleum ether (1500 mL). The filtrate was concentrated under reduced pressure to give the title compound (4 g, 90% purity, 86% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 5.79 (ddt, J = 17.07, 10.07, 7.32 Hz, 1H), 4.96-5.10 (m, 2H), 3.44 (s, 2H), 2.21 (d, J = 7.25 Hz, 2H), 1.63-1.92 (m, 6H), 0.92 (s, 9H), -0.05 (s, 6H).

[0085] Example 5B: [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]acetaldehyde To a solution of the product of Example 5A (3 g, 11.23 mmol, 90% purity) in dioxane (120 mL) and water (12 mL) was added dropwise a 0.2 M solution of osmium tetroxide in t-butanol (220 mg, 0.865 mmol) at 20° C. After 15 min, the reaction mixture was cooled to 0° C. and then sodium periodate (9.61 g, 44.9 mmol) was added in portions. After the addition, the mixture was warmed to 20° C. and stirred at that temperature for 3 h. The mixture was diluted with ethyl acetate (200 mL) and filtered. The filtrate was added to a saturated aqueous solution of sodium thiosulfate (300 mL) and the resulting mixture was stirred at 20° C. for 1 h. The mixture was transferred to a separatory funnel and the organic phase was separated. The organic fraction was washed with brine (500 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (3 g, 70% purity, 77% yield), which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ ppm 9.63 (t, J = 2.75 Hz, 1H), 3.56 (s, 2H), 2.46 (d, J = 2.63 Hz, 2H), 1.82-1.90 (m, 6H), 0.89 (s, 9H), 0.02 (s, 6H).

[0086] Example 5C. 5-[(3S)-5-Fluoro-7-hydroxy-3-({2-[1-(hydroxymethyl)cyclobutyl]ethyl}amino)-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione In a 4 mL vial, the product of Example 3P (60 mg, 0.162 mmol) was combined with triethylamine (67.8 μL, 0.487 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.6 mL) to give a suspension. Example 5B (78.6 mg, 0.324 mmol, 2.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (24.5 mg, 0.649 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.6 mL, 3.24 mmol, 20 equiv) was added slowly and the reaction mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (27.2 mg, 37.7% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.47 (d, J = 1.5 Hz, 1H), 3.95 (s, 2H), 3.60 (s, 1H), 3.34 (s, 2H), 3.29 - 3.22 (m, 1H), 3.11 - 2.99 (m, 2H), 2.98 - 2.81 (m, 2H), 2.66 (dd, J = 16.8, 8.1 Hz, 1H), 1.89 - 1.57 (m, 8H); + ) m / z 446.3 [M+H] + .

[0087] Example 6: 5-[(3S)-5-fluoro-7-hydroxy-3-({2-[1-(hydroxymethyl)cyclopentyl]ethyl}amino)-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 105) Example 6A: Methyl 1-(prop-2-en-1-yl)cyclopentane-1-carboxylate Methyl cyclopentanecarboxylate (24 g, 187 mmol) was added dropwise to a solution of 2M lithium diisopropylamide (122 mL, 243 mmol, tetrahydrofuran) in anhydrous tetrahydrofuran (720 mL) under nitrogen at −65° C. The reaction mixture was stirred at −65° C. under nitrogen for 40 min before 3-bromoprop-1-ene (29.4 g, 243 mmol) was added dropwise. The mixture was then warmed to 20° C. and stirred at 20° C. for 16 h before being quenched by the dropwise addition of saturated aqueous NH4Cl (500 mL) at 0° C. The resulting mixture was extracted with ethyl acetate (3×150 mL). The combined organic phase was washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with petroleum ether to give the title compound (31.2 g, 167 mmol, 89% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 5.76 - 5.64 (m, 1H), 5.06 - 4.98 (m, 2H), 3.67 (s, 3H), 2.34 (d, J=7.3 Hz, 2H), 2.11 - 2.02 (m, 2H), 1.69 - 1.58 (m, 4H), 1.58 - 1.46 (m, 2H).

[0088] Example 6B: [1-(prop-2-en-1-yl)cyclopentyl]methanol To a solution of the product of Example 6A (15.5 g, 77 mmol, 90% purity) in tetrahydrofuran (300 mL) was added LiAlH4 (4.65 g, 122 mmol) in portions at 0° C. under nitrogen. The mixture was then stirred at 0° C. under nitrogen for 2 h. The reaction mixture was quenched by dropwise addition of water (4.65 mL) at 0° C., followed by dropwise addition of 15% aqueous NaOH (4.65 mL) and water (13.95 mL). An identical reaction was run as above with one additional portion on a 15.5 g scale. The two reaction mixtures were combined and filtered through a pad of diatomaceous earth. The filter cake was washed with ethyl acetate (1000 mL) and tetrahydrofuran (1000 mL). The filtrate and washings were concentrated under reduced pressure to give the title compound (22.5 g, 144 mmol, 94% yield, 90% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 5.86 (m, 1H), 5.13 - 5.03 (m, 2H), 3.40 (s, 2H), 2.17 (d, J=7.4 Hz, 2H), 1.67 - 1.51 (m, 4H), 1.56 - 1.50 - 1.38 (m, 4H).

[0089] Example 6C: tert-Butyl(dimethyl){[1-(prop-2-en-1-yl)cyclopentyl]methoxy}silane To a solution of the product of Example 6B (10.4 g, 74.2 mmol, 90% purity) and imidazole (12.12 g, 178 mmol) in anhydrous dichloromethane (208 mL) was added tert-butyldimethylchlorosilane (12.30 g, 82 mmol) at 0° C. The mixture was then stirred at 20° C. for 12 h. The same reaction was carried out as above in two additional batches on 2.5 g and 10.4 g scales. These three reaction mixtures were combined, diluted with water (300 mL), and extracted with dichloromethane (3×200 mL). The combined organic fractions were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether to give the title compound (39.35 g, 155 mmol, 93% yield, 90% purity). 1H NMR (400 MHz, CDCl3) δ ppm 5.87 - 5.76 (m, 1H), 5.06 - 4.99 (m, 2H), 3.31 (s, 2H), 2.13 (d, J=7.3 Hz, 2H), 1.61 - 1.54 (m, 4H), 1.47 - 1.32 (m, 4H), 0.88 (s, 9H), 0.04 (s, 6H).

[0090] Example 6D: [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]acetaldehyde To a solution of the product of Example 6C (14.5 g, 51.3 mmol, 90% purity) in water (60 mL) and tetrahydrofuran (300 mL) was added a solution of osmium tetroxide (107 mg, 0.421 mmol) in 2-methylpropan-2-ol (2 mL) at 20° C. The mixture was stirred at 20° C. for 15 min. Sodium periodate (43.9 g, 205 mmol) was then added in portions at 0° C. The mixture was stirred at 20° C. for 2 h. The same reaction was carried out as above with two additional portions on 14.5 g and 5 g scales. The three reaction mixtures were combined, extracted with ethyl acetate (400 mL), and filtered. The filtrate was quenched with saturated aqueous Na2S2O3 (600 mL) and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic phase was washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with petroleum ether to give the title compound (19 g, 70.4 mmol, 57.2% yield, 95% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 9.79 (t, J=2.9 Hz, 1H), 3.41 (s, 2H), 2.39 (d, J=2.9 Hz, 2H), 1.71 - 1.66 (m, 6H), 1.52 - 1.41 (m, 2H), 0.88 (s, 9H), 0.01 (s, 6H).

[0091] Example 6E: 5-[(3S)-5-fluoro-7-hydroxy-3-({2-[1-(hydroxymethyl)cyclopentyl]ethyl}amino)-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ6,2,5-thiadiazolidine-1,1,3-trione In a 4 mL vial, the product of Example 3P (60 mg, 0.162 mmol) was combined with triethylamine (67.8 μL, 0.487 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.6 mL) to give a suspension. The product of Example 6D (83.2 mg, 0.324 mmol, 2.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (24.5 mg, 0.649 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.6 mL, 3.24 mmol, 20 equiv) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (12.8 mg, 17.2% yield). 1H NMR (500 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.53 (d, J = 1.4 Hz, 1H), 4.01 (s, 2H), 3.77 - 3.71 (m, 1H), 3.37 - 3.30 (m, 1H), 3.22 (s, 2H), 3.17 - 2.99 (m, 4H), 2.78 - 2.69 (m, 1H), 1.76 - 1.64 (m, 2H), 1.64 - 1.53 (m, 4H), 1.53 - 1.45 (m, 2H), 1.37 - 1.28 (m, 2H);MS (APCI + ) m / z 460.4 [M+H] + .

[0092] Example 7: 5-{(3S)-5-fluoro-7-hydroxy-3-[(4-hydroxy-3,3-dimethylbutyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 106) Example 7A: Methyl 2,2-dimethyl-4-pentenoate Using the methodology described in Example 6A, the title compound was synthesized from methyl isobutyrate in 71.8% yield. 1 H NMR (400 MHz CDCl3) δ ppm 5.57-5.89 (m, 1H), 4.91-5.16 (m, 2H), 3.56 (s, 3H), 2.27 (m, 2H), 1.17 (s, 6H).

[0093] Example 7B: 2,2-Dimethyl-4-penten-1-ol The title compound was synthesized in 95% yield from the product of Example 7A using the methodology described in Example 6B. 1 H NMR (400 MHz, CDCl3) δ ppm 5.65-5.93 (m, 1H), 4.89-5.11 (m, 2H), 3.19-3.36 (m, 2H), 3.28 (s, 2H), 1.95 (d, J=7.63 Hz, 2H), 0.82 (s, 6H).

[0094] Example 7C: tert-Butyl[(2,2-dimethyl-4-penten-1-yl)oxy]dimethylsilane The title compound was synthesized in 74% yield from the product of Example 7B using the procedure described in Example 6C. 1 H NMR (400 MHz, CDCl3) δ ppm 5.63-6.07 (m, 1H), 4.86-5.21 (m, 2H), 3.21 (s, 2H), 2.00 (d, J=7.50 Hz, 2H), 0.91 (s, 9H), 0.84 (s, 6H), 0.01 (s, 6H).

[0095] Example 7D: 4-{[tert-butyl(dimethyl)silyl]oxy}-3,3-dimethylbutanal The title compound was synthesized in 66% yield from the product of Example 7C using the procedure described in Example 6D. 1 H NMR (400 MHz, CDCl3) δ ppm 9.84 (t, J=3.q Hz, 1 H) 3.35 (s, 2 H) 2.28 (d, J=3.1 Hz, 2 H) 1.02 (s, 6 H) 0.89 (s, 9 H) 0.04 (s, 6 H), MS (ESI + ) m / z 231 [M+H] + .

[0096] Example 7E: 5-{(3S)-5-fluoro-7-hydroxy-3-[(4-hydroxy-3,3-dimethylbutyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione In a 4 mL vial, the product of Example 3P (60 mg, 0.162 mmol) was combined with triethylamine (67.8 μL, 0.487 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.6 mL) to give a suspension. 4-{[tert-butyl(dimethyl)silyl]oxy}-3,3-dimethylbutanal (Example 7D, 74.8 mg, 0.324 mmol, 2.0 equiv.) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (24.5 mg, 0.649 mmol, 4.0 equiv.) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.6 mL, 3.24 mmol, 20 equiv.) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (10.3 mg, 14.4% yield). 1 H NMR (600 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.43 (d, J = 1.3 Hz, 1H), 3.94 (d, J = 1.0 Hz, 2H), 3.69 - 3.65 (m, 1H), 3.34 - 3.27 (m, 1H), 3.19 - 3.11 (m, 1H), 3.08 (s, 2H), 2.95 (dd, J = 16.5, 4.6 Hz, 1H), 2.90 (dd, J = 12.7, 8.9 Hz, 1H), 2.85 - 2.77 (m, 1H), 2.76 - 2.68 (m, 1H), 1.46 - 1.35 (m, 2H), 0.80 (d, J = 1.8 Hz, 6H);MS (APCI +) m / z 434.3 [M+H] + .

[0097] Example 8: 5-[(3S)-5-fluoro-7-hydroxy-3-(propylamino)-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 107) In a 4 mL vial, the product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) to give a suspension. Propionaldehyde (23.6 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.4 mL, 3.24 mmol, 20 equiv) was added slowly and the reaction mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (3.3 mg, 6.5% yield). 1H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.50 (d, J = 1.5 Hz, 1H), 3.97 (s, 2H), 3.79 - 3.73 (m, 1H), 3.31 (d, J = 12.8 Hz, 1H), 3.18 - 2.92 (m, 4H), 2.73 (dd, J = 16.7, 8.2 Hz, 1H), 1.70 - 1.56 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H) + ) m / z 376.3 [M+H] + .

[0098] Example 9: 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-methylpentyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 108) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 3-Methylpentanal (40.6 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.4 mL, 3.24 mmol, 20 equiv) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-80% A, 8.0-8.1 min 80-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (5.5 mg, 9.7% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.50 (d, J = 1.5 Hz, 1H), 3.97 (s, 2H), 3.81 - 3.73 (m, 1H), 3.36 - 3.28 (m, 1H), 3.18 - 2.99 (m, 4H), 2.73 (dd, J = 16.8, 8.3 Hz, 1H), 1.68 - 1.57 (m, 1H), 1.49 - 1.41 (m, 2H), 1.36 - 1.26 (m, 1H), 1.25 - 1.10 (m, 1H), 0.92 - 0.82 (m, 6H);MS (APCI + ) m / z 418.3 [M+H] + .

[0099] Example 10: 5-[(3S)-5-fluoro-7-hydroxy-3-{[2-(oxan-4-yl)ethyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 109) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (52.0 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.4 mL, 3.24 mmol, 20 equiv) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (6.5 mg, 10.8% yield). 1H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.48 (d, J = 1.5 Hz, 1H), 3.96 (s, 2H), 3.87 - 3.79 (m, 2H), 3.62 - 3.53 (m, 1H), 3.34 - 3.22 (m, 3H), 3.12 - 2.89 (m, 4H), 2.71 - 2.60 (m, 1H), 1.62 - 1.44 (m, 5H), 1.24 - 1.10 (m, 2H) + ) m / z 446.4 [M+H] + .

[0100] Example 11: 5-[(3S)-5-fluoro-7-hydroxy-3-{[(oxan-4-yl)methyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 110) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. Tetrahydro-2H-pyran-4-carbaldehyde (46.3 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.4 mL, 3.24 mmol, 20 equiv) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (8.5 mg, 14.6% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.50 (d, J = 1.6 Hz, 1H), 3.97 (s, 2H), 3.91 - 3.82 (m, 2H), 3.75 - 3.70 (m, 1H), 3.36 - 3.23 (m, 3H), 3.21 - 3.07 (m, 2H), 2.98 (qd, J = 12.4, 7.0 Hz, 2H), 2.72 (dd, J = 16.5, 9.0 Hz, 1H), 1.97 - 1.86 (m, 1H), 1.72 - 1.63 (m, 2H), 1.33 - 1.18 (m, 2H);MS (APCI + ) m / z 432.3 [M+H] + .

[0101] Example 12: 5-{(3S)-3-[(cyclopropylmethyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 111) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. Cyclopropanecarbaldehyde (28.4 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.4 mL, 3.24 mmol, 20 equiv) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (9.8 mg, 18.8% yield). 1H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.50 (d, J = 1.5 Hz, 1H), 3.97 (s, 2H), 3.85 - 3.73 (m, 1H), 3.35 - 3.26 (m, 1H), 3.19 - MS (APCI + ) m / z 388.3 [M+H] + .

[0102] Example 13: 5-[(3S)-3-(butylamino)-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 112) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. Butyraldehyde (29.3 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.4 mL, 3.24 mmol, 20 equiv) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (10.0 mg, 19% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.50 (d, J = 1.5 Hz, 1H), 3.97 (s, 2H), 3.81 - 3.72 (m, 1H), 3.36 - 3.27 (m, 1H), 3.20 - MS (APCI + ) m / z 390.3 [M+H] + .

[0103] Example 14: 5-{(3S)-5-fluoro-7-hydroxy-3-[(2-methylpropyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 113) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. Isobutyraldehyde (29.5 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.4 mL, 3.24 mmol, 20 equiv) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (14.1 mg, 26.8% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.50 (d, J = 1.5 Hz, 1H), 3.97 (s, 2H), 3.78 - 3.71 (m, 1H), 3.36 - 3.27 (m, 1H), 3.23 - MS (APCI+ ) m / z 390.3 [M+H] + .

[0104] Example 15: 5-[(3S)-5-fluoro-7-hydroxy-3-{[2-(oxolan-3-yl)ethyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 114) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 2-(tetrahydrofuran-3-yl)acetaldehyde (46.3 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.4 mL, 3.24 mmol, 20 equiv) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (16.1 mg, 27.6% yield). 1H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.51 (d, J = 1.5 Hz, 1H), 3.97 (s, 2H), 3.83 - 3.58 (m, 4H), 3.36 - 3.22 (m, 2H), 3.20 - MS (APCI + ) m / z 432.3 [M+H] + .

[0105] Example 16: 5-{(3S)-3-[(2,3-dimethylbutyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 115) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 2,3-Dimethylbutanal (40.6 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.4 mL, 3.24 mmol, 20 equiv) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-80% A, 8.0-8.1 min 80-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (16.1 mg, 28.6% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.50 (d, J = 1.5 Hz, 1H), 3.97 (s, 2H), 3.76 - 3.71 (m, 1H), 3.37 - 3.26 (m, 1H), 3.23 - MS (APCI + ) m / z 418.3 [M+H] + .

[0106] Example 17: 5-{(3S)-5-fluoro-7-hydroxy-3-[(propan-2-yl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 116) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. Acetone (23.5 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.4 mL, 3.24 mmol, 20 equiv) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (3.2 mg, 6.3% yield). 1 H NMR (600 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.56 (d, J = 1.3 Hz, 1H), 4.04 (s, 2H), 3.79 - 3.73 (m, 1H), 3.59 - 3.49 (m, 1H), 3.34 - 3.29 (m, 1H), 3.19 - 3.07 (m, 2H), 2.70 (dd, J = 16.2, 9.0 Hz, 1H), 1.32 - 1.27 (m, 6H) + ) m / z 376.3 [M+H]+ .

[0107] Example 18: 5-[(3S)-3-{[2-(3,3-difluorocyclobutyl)ethyl]amino}-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 117) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 2-(3,3-difluorocyclobutyl)acetaldehyde (54.4 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.4 mL, 3.24 mmol, 20 equiv) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (6.4 mg, 10.6% yield). 1H NMR (600 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.53 (d, J = 1.4 Hz, 1H), 4.01 (s, 2H), 3.75 - 3.60 (m, 1H), 3.31 (s, 1H), 3.10 (q, J = 13.7 MS (APCI + ) m / z 452.3 [M+H] + .

[0108] Example 19: 5-{(3S)-3-[(2-cyclohexylethyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 118) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 2-Cyclohexylacetaldehyde (48.7 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.4 mL, 3.24 mmol, 20 equiv) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-80% A, 8.0-8.1 min 80-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (11.2 mg, 18.6% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.47 (d, J = 1.5 Hz, 1H), 3.95 (s, 2H), 3.61 - 3.55 (m, 1H), 3.24 (d, J = 12.8 Hz, 1H), 3.10 - 2.88 (m, 4H), 2.63 (dd, J = 16.7, 8.4 Hz, 1H), 1.65 (td, J = 17.8, 15.0, 4.9 Hz, 5H), 1.50 - 1.40 (m, 2H), 1.36 - 1.04 (m, 4H), 0.96 - 0.82 (m, 2H);MS (APCI + ) m / z 444.3 [M+H] + .

[0109] Example 20: 5-{(3S)-3-[(3-ethylpentyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 119) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 3-Ethylpentanal (46.1 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.4 mL, 3.24 mmol, 20 equiv) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-100% A, 8.0-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (11.7 mg, 20.1% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.47 (d, J = 1.5 Hz, 1H), 3.96 (s, 2H), 3.57 - 3.50 (m, 1H), 3.23 (dd, J = 12.0, 2.9 Hz, 1H), MS (APCI+ ) m / z 432.3 [M+H] + .

[0110] Example 21: 5-{(3S)-3-[(2-cyclopentylethyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 120) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 2-Cyclopentylacetaldehyde (45.5 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.4 mL, 3.24 mmol, 20 equiv) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-80% A, 8.0-8.1 min 80-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (18.6 mg, 32% yield). 1H NMR (600 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.57 (d, J = 1.5 Hz, 1H), 4.04 (s, 2H), 3.88 - 3.82 (m, 1H), 3.41 - 3.35 (m, 1H), 3.23 - MS (APCI + ) m / z 430.3 [M+H] + .

[0111] Example 22: 5-[(3S)-3-(benzylamino)-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 121) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. Benzaldehyde (43.0 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.4 mL, 3.24 mmol, 20 equiv) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-80% A, 8.0-8.1 min 80-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (21.2 mg, 37.1% yield). 1 H NMR (500 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 7.55 - 7.38 (m, 5H), 6.53 (s, 1H), 4.20 - 4.07 (m, 2H), 4.03 (s, 2H), 3.56 - 3.37 (m, MS (APCI + ) m / z 424.3 [M+H] + .

[0112] Example 23: 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-methylbut-2-en-1-yl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6,2,5-Thiadiazolidine-1,1,3-trione (Compound 122) In a 4 mL vial, the product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL) to give a suspension. 3-Methoxy-3-methylbutanal (47.1 mg, 0.41 mmol, 3.0 equiv.) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv.) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.4 mL, 3.24 mmol, 20 equiv.) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (13.2 mg, 24.3% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.49 (d, J = 1.6 Hz, 1H), 5.25 (tt, J = 7.3, 1.5 Hz, 1H), 3.97 (s, 2H), 3.68 - 3.57 (m, 3H), MS (APCI + ) m / z 402.3 [M+H] + .

[0113] Example 24: 5-{(3S)-5-fluoro-7-hydroxy-3-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 123) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. Phenylacetaldehyde (48.7 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and aqueous hydrochloric acid (2.0 M, 1.4 mL, 3.24 mmol, 20 equiv) was added slowly and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-80% A, 8.0-8.1 min 80-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (9.7 mg, 16.4% yield). 1 H NMR (500 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 7.36 - 7.21 (m, 5H), 6.47 (d, J = 1.5 Hz, 1H), 3.95 (s, 2H), 3.84 - 3.73 (m, 1H), 3.32 - 3.17 (m, 3H), 3.13 - 3.05 (m, 2H), 2.91 (t, J = 7.9 Hz, 2H), 2.72 (dd, J = 16.7, 8.1 Hz, 1H) +) m / z 438.3 [M+H] + .

[0114] Example 25: 5-{(3S)-3-[(3,3-dimethylpentyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 124) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 3,3-Dimethylpentanal (46.3 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath, saturated ammonium chloride (1.0 mL) was added slowly, and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (21.2 mg, 36.4% yield). 1H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.47 (d, J = 1.5 Hz, 1H), 3.95 (s, 2H), 3.58 - 3.54 (m, 1H), 3.29 - 3.21 (m, 1H), 3.10 - MS (APCI + ) m / z 432.4 [M+H] + .

[0115] Example 26: 5-[(3S)-5-fluoro-3-{[(1-fluorocyclopropyl)methyl]amino}-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 125) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 1-Fluorocyclopropane-1-carbaldehyde (35.7 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath, saturated ammonium chloride (1.0 mL) was added slowly, and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (20.1 mg, 36.6% yield). 1 H NMR (500 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.49 (d, J = 1.4 Hz, 1H), 4.00 (s, 2H), 3.43 - 3.34 (m, 1H), 3.26 - 3.14 (m, 3H), 3.06 - 2.90 (m, 2H), 2.56 - 2.50 (m, 1H), 1.10 - 1.02 (m, 2H), 0.85 - 0.73 (m, 2H);MS (APCI + ) m / z 406.2 [M+H] + .

[0116] Example 27: 5-[(3S)-3-{[(2,2-difluorocyclopropyl)methyl]amino}-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 126) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 2,2-Difluorocyclopropane-1-carbaldehyde (43.0 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath, saturated ammonium chloride (1.0 mL) was added slowly, and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (18.4 mg, 32.2% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.45 (s, 1H), 3.95 (s, 2H), 3.43 - 3.38 (m, 1H), 3.22 - 3.13 (m, 1H), 2.98 (d, J = 20.8 Hz, MS (APCI + ) m / z 424.3 [M+H] + .

[0117] Example 28: 5-[(3S)-5-fluoro-7-hydroxy-3-{[(3-methyloxetan-3-yl)methyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 127) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 3-Methyloxetane-3-carbaldehyde (40.6 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath, saturated ammonium chloride (1.0 mL) was added slowly, and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-40% A, 8.0-8.1 min 40-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (18.1 mg, 32.0% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.49 (d, J = 1.5 Hz, 1H), 4.42 (dd, J = 5.9, 2.2 Hz, 2H), 4.29 - 4.23 (m, 2H), 4.00 (s, 2H), 3.47 - 3.15 (m, 2H), 3.10 - 2.92 (m, 4H), 2.57 - 2.50 (m, 1H), 1.31 (s, 3H);MS (APCI + ) m / z 418.3 [M+H]+ .

[0118] Example 29: 5-[(3S)-5-fluoro-3-({[1-(fluoromethyl)cyclopropyl]methyl}amino)-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 128) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 1-(fluoromethyl)cyclopropane-1-carbaldehyde (41.4 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath, saturated ammonium chloride (1.0 mL) was added slowly, and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (12.8 mg, 22.6% yield). 1H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.45 (d, J = 1.5 Hz, 1H), 4.42 - 4.37 (m, 1H), 4.30 - 4.25 (m, 1H), 3.95 (s, 2H), 3.49 - 3.33 (m, 1H), 3.23 - 3.15 (m, 1H), 3.04 - 2.91 (m, 4H), 2.63 - 2.53 (m, 1H), 0.62 (s, 4H) + ) m / z 420.3 [M+H] + .

[0119] Example 30: 5-{(3S)-3-[(4,4-difluoropentyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 129) In a 1-dram vial, add 5-[(3S)-3-amino-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione hydrochloride (33 mg, 0.089 mmol, Example 3P), dichloromethane (535 μL), ethanol (357 μL), and triethylamine (37.3 μL, 0.268 mmol) were then added. 4,4-Difluoropentanal (32.7 mg, 0.268 mmol) was then added and the solution was stirred for 2 hours before sodium borohydride (13.50 mg, 0.357 mmol) was added in one portion. After 30 minutes, the reaction was quenched with 3M aqueous HCl (595 μL, 1.785 mmol) and the mixture was partially concentrated in vacuo. The solution was diluted with aqueous ammonium bicarbonate (0.025 M in water, acidified to pH 7 by addition of dry ice), loaded onto a 30 g Biotage® Sfar C18 column and purified with a 10-100% gradient of methanol in 0.025 M ammonium bicarbonate in water (acidified to pH 7 by addition of dry ice) to give the title compound (17.8 mg, 0.041 mmol, 45.4% yield).1 H NMR (499.6 MHz, DMSO-d6) δ ppm 9.51 (s, 1H), 8.59 (s, 1H), 6.46 (s, 1H), 3.91 (s, 2H), 3.26 (m, 2H), 3.17-3.04 (m, 4H), 2.71-2.63 (m, 1H), 2.02-1.91 (m, 2H), 1.77-1.70 (m, 2H);MS (APCI + ) m / z 440 [M+H] + .

[0120] Example 31: 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-methoxypropyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 130) In a 1-dram vial, add 5-[(3S)-3-amino-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione hydrochloride (33 mg, 0.089 mmol, Example 3P), dichloromethane (535 μL), ethanol (357 μL), and triethylamine (37.3 μL, 0.268 mmol) were then added. 3-Methoxypropanal (23.12 μL, 0.268 mmol) was then added and the solution was stirred for 2 hours before sodium borohydride (13.50 mg, 0.357 mmol) was added in one portion. After 30 minutes, the reaction was quenched with 3M aqueous ammonium chloride (54.2 μL, 1.785 mmol) and partially concentrated under a stream of nitrogen. The solution was diluted with aqueous ammonium bicarbonate (0.025 M in water, acidified to pH 7 by addition of dry ice), loaded onto a 30 g Biotage® Sfar C18 column and purified with a 10-100% gradient of methanol in 0.025 ammonium bicarbonate in water (acidified to pH 7 by addition of dry ice) to give the title compound (10.2 mg, 0.025 mmol, 28.2% yield). 1H NMR (600.4 MHz, DMSO-d6) δ ppm 9.52 (s, 1), 8.47 (s, 1H), 6.47 (s, 1H), 3.91 (ABq, J = 13.2 Hz, 2H), 3.40 (t, J = 6.0 Hz, 2H), 3.28 (m, (APCI + ) m / z 406 [M+H] + .

[0121] Example 32: 5-[(3S)-5-fluoro-7-hydroxy-3-{[3-(1H-pyrazol-1-yl)propyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 131) In a 4 mL vial, the product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL) to give a suspension. 3-(1H-pyrazol-1-yl)propanal (33.6 mg, 0.27 mmol, 2.0 equiv.) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv.) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath, saturated ammonium chloride (1.0 mL) was added slowly, and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (29.1 mg, 48.8% yield). 1 H NMR (500 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 7.73 - 7.68 (m, 1H), 7.49 - 7.41 (m, 1H), 6.46 (d, J = 1.4 Hz, 1H), 6.26 - 6.23 (m, 1H), 4.19 (t, J = 6.8 Hz, 2H), 3.95 (s, 2H), 3.56 - 3.50 (m, 1H), 3.23 - 3.16 (m, 1H), 3.03 - 2.92 (m, 2H), 2.94 - 2.82 (m, 2H), 2.61 (dd, J = 16.7, 8.1 Hz, 1H), 2.04 (p, J = 7.1 Hz, 2H); MS (APCI + ) m / z 442.3 [M+H] + .

[0122] Example 33: 5-[(3S)-5-fluoro-7-hydroxy-3-{[2-(1-methylcyclopropyl)ethyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 132) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 2-(1-Methylcyclopropyl)acetaldehyde (39.8 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath, saturated ammonium chloride (1.0 mL) was added slowly, and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (15.5 mg, 27.6% yield). 1H NMR (500 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.54 (d, J = 1.4 Hz, 1H), 4.01 (s, 2H), 3.81 - 3.78 (m, 1H), 3.40 - 3.33 (m, 1H), 3.26 - MS (APCI + ) m / z 416.3 [M+H] + .

[0123] Example 34: 5-{(3S)-3-[(2-cyclopropylpropyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 133) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 2-Cyclopropylpropanal (39.8 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath, saturated ammonium chloride (1.0 mL) was added slowly, and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-60% A, 8.0-8.1 min 60-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (12.0 mg, 21.4% yield). 1 H NMR (600 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.39 (s, 1H), 3.86 (d, J = 1.2 Hz, 2H), 3.73 - 3.64 (m, 1H), 3.23 - 3.16 (m, 1H), 3.11 - 2.89 (m, 4H), 2.62 (dd, J = 16.4, 9.5 Hz, 1H), 1.06 - 0.98 (m, 1H), 0.91 (dd, J = 6.8, 1.2 Hz, 3H), 0.52 - 0.46 (m, 1H), 0.40 - 0.29 (m, 2H), 0.17 - 0.12 (m, 1H), -0.01 (dtd, J = 10.8, 6.2, 5.6, 3.1 Hz, 1H);MS (APCI + ) m / z 416.3 [M+H] + .

[0124] Example 35: 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-phenylbutyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 134) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 3-Phenylbutanal (60.1 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and saturated ammonium chloride (1.0 mL) was added slowly. The mixture was then partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-100% A, 8.0-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (2.7 mg, 4.2% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 7.34 (t, J = 7.5 Hz, 2H), 7.30 - 7.19 (m, 3H), 6.49 (s, 1H), 3.96 (s, 2H), 3.87 - 3.74 (m, 1H), 3.27 (s, 1H), 3.06 (d, J = 14.2 Hz, 3H), 2.90 - 2.63 (m, 3H), 1.89 (q, J = 7.9 Hz, 2H), 1.24 (d, J = 6.9 Hz, 3H).

[0125] Example 36: 5-[(3S)-5-fluoro-7-hydroxy-3-{[(3-phenylcyclobutyl)methyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 135) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 3-Phenylcyclobutane-1-carbaldehyde (65.0 mg, 0.41 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and saturated ammonium chloride (1.0 mL) was added slowly. The mixture was then partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-80% A, 8.0-8.1 min 80-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (3.5 mg, 5.5% yield). 1H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 7.38 - 7.16 (m, 5H), 6.50 (d, J = 1.6 Hz, 1H), 3.98 (d, J = 1.5 Hz, 2H), 3.69 - 3.59 (m, 1H), 3.44 - 3.26 (m, 2H), 3.07 (s, 3H), 2.71 (dd, J = 15.0, 10.1 Hz, 1H), 2.53 - 2.44 (m, 3H), 2.36 - 2.22 (m, 1H), 1.92 - 1.81 (m, 2H);MS (APCI + ) m / z 478.4 [M+H] + .

[0126] Example 37: 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-phenylpropyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 136) In a 4 mL vial, the product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL) to give a suspension. 3-Phenylpropanal (54.4 mg, 0.41 mmol, 3.0 equiv.) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv.) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and saturated ammonium chloride (1.0 mL) was added slowly. The mixture was then partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-80% A, 8.0-8.1 min 80-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (13.4 mg, 22% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 7.37 - 7.15 (m, 5H), 6.50 (d, J = 1.5 Hz, 1H), 3.97 (s, 2H), 3.33 - 3.25 (m, 1H), 3.15 - 3.01 (m, 4H), 2.71 (dt, J = 26.9, 8.0 Hz, 3H), 1.98 - 1.86 (m, 2H);MS (APCI + ) m / z 452.4 [M+H] + .

[0127] Example 38: 5-[(3S)-3-{[3-(2,2-difluoroethoxy)propyl]amino}-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6,2,5-Thiadiazolidine-1,1,3-trione (Compound 137) In a 4 mL vial, the product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL) to give a suspension. 3-(2,2-difluoroethoxy)propanal (56.0 mg, 0.41 mmol, 3.0 equiv.) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv.) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and saturated ammonium chloride (1.0 mL) was added slowly. The mixture was then partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-80% A, 8.0-8.1 min 80-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (15.6 mg, 25.4% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.51 (d, J = 1.5 Hz, 1H), 6.12 (tt, J = 54.9, 3.6 Hz, 1H), 3.97 (s, 2H), 3.83 - 3.79 (m, MS (APCI + ) m / z 456.3 [M+H] + .

[0128] Example 39: 5-[(3S)-3-({[(1RS,5SR)-bicyclo[3.1.0]hexan-6-yl]methyl}amino)-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 138) In a 4 mL vial, the product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL) to give a suspension. Bicyclo[3.1.0]hexane-6-carbaldehyde (44.7 mg, 0.41 mmol, 3.0 equiv.) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv.) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath, saturated ammonium chloride (1.0 mL) was added slowly, and the mixture was partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-80% A, 8.0-8.1 min 80-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (16.5 mg, 28.5% yield). 1H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.50 (d, J = 1.5 Hz, 1H), 3.98 (s, 2H), 3.80 - 3.74 (m, 1H), 3.34 - 3.05 (m, 3H), 3.02 - MS (APCI + ) m / z 428.3 [M+H] + .

[0129] Example 40: 5-[(3S)-5-fluoro-7-hydroxy-3-({[4-(trifluoromethyl)cyclohexyl]methyl}amino)-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 139) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 4-(Trifluoromethyl)cyclohexane-1-carbaldehyde (73.1 mg, 0.41 mmol, 3.0 equiv.) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv.) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and saturated ammonium chloride (1.0 mL) was added slowly. The mixture was then partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-80% A, 8.0-8.1 min 80-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (18.6 mg, 27.6% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.50 (d, J = 1.7 Hz, 1H), 3.98 (s, 2H), 3.37 - 3.25 (m, 1H), 3.23 - 3.00 (m, 3H), 2.97 - 2.86 (m, 1H), 2.78 - 2.66 (m, 1H), 2.40 - 2.15 (m, 1H), 2.03 - 1.81 (m, 2H), 1.77 - 1.42 (m, 5H), 1.33 - 1.19 (m, 1H), 1.06 (q, J = 12.7 Hz, 1H);MS (APCI + ) m / z 498.1 [M+H] + .

[0130] Example 41: 5-[(3S)-5-fluoro-7-hydroxy-3-{[2-(2,6,6-trimethylcyclohex-1-en-1-yl)ethyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 140) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. 2-(2,6,6-trimethylcyclohex-1-en-1-yl)acetaldehyde (67.4 mg, 0.41 mmol, 3.0 equiv.) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv.) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and saturated ammonium chloride (1.0 mL) was added slowly. The mixture was then partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-80% A, 8.0-8.1 min 80-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (21.3 mg, 32.6% yield). 1H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.52 (d, J = 1.6 Hz, 1H), 3.97 (s, 2H), 3.86 - 3.81 (m, 1H), 3.32 (d, J = 12.0 Hz, 1H), 3.19 - 3.06 (m, 2H), 3.02 - 2.90 (m, 2H), 2.81 - 2.69 (m, 1H), 2.35 (t, J = 8.9 Hz, 2H), 1.90 (t, J = 6.1 Hz, 2H), 1.63 (s, 3H), 1.55 - 1.51 (m, 2H), 1.44 - 1.36 (m, 2H), 0.99 (s, 6H);MS (APCI + ) m / z 484.4 [M+H] + .

[0131] Example 42: 4-({[(3S)-5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1λ 6 ,2,5-Thiadiazolidin-2-yl)-3,4-dihydro-2H-1-benzothiopyran-3-yl]amino}methyl)piperidine-1-carboxylate tert-butyl (Compound 141) The product of Example 3P (50 mg, 0.14 mmol) was combined with triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL) in a 4 mL vial to give a suspension. tert-Butyl 4-formylpiperidine-1-carboxylate (86.5 mg, 0.41 mmol, 3.0 equiv.) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (20.5 mg, 0.54 mmol, 4.0 equiv.) was added in one portion and the resulting mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled to 0° C. in an ice bath and saturated ammonium chloride (1.0 mL) was added slowly. The mixture was then partially concentrated under a stream of nitrogen. Methanol (1 mL) was added and the mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) using a gradient of methanol (A) and 25 mM ammonium bicarbonate buffer in water (pH 7) (B) at a flow rate of 40 mL / min (0-0.5 min 5% A, 0.5-8.0 min linear gradient 5-80% A, 8.0-8.1 min 80-100% A, 8.1-9.0 min 100% A, 9.0-9.1 min linear gradient 100-5% A, 9.1-10.0 min 5% A) to give the title compound (23.5 mg, 32.8% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.50 (s, 1H), 3.95 (d, J = 18.0 Hz, 4H), 3.81 - 3.71 (m, 1H), 3.34 - 3.22 (m, 1H), 3.20 - MS (APCI + ) m / z 531.4 [M+H] + .

[0132] Biological assays Abbreviation DMEM is Dulbecco's modified Eagle's medium, DMSO is dimethyl sulfoxide, DTT is dithiothreitol, EDTA is ethylenediaminetetraacetic acid, EGTA is ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid, HEPES is 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid, IFNγ is interferon gamma, and Tween® 20 is polyethylene glycol sorbitan monolaurate.

[0133] Example 43: Mobility Shift Assay (MSA) Used to Measure the Potency of PTPN2 Inhibitors Compound activity was measured in an in vitro enzyme reaction using an in-house His-tagged PTPN2 (TC45) protein (SEQ ID NO: 1). The enzyme assay used to measure activity was a mobility shift assay using a LabChip EZ Reader by Caliper Life Sciences. The enzyme reaction was performed in assay buffer (50 mM HEPES pH 7.5, 1 mM EGTA, 10 mM EDTA, 0.01% Tween® 20, and 2 mM DTT). Compounds were dispensed at various concentrations (12 points, 1:3 dilution) into ProxiPlate™ white 384-well (PerkinElmer catalog #6008289) plates using Labcyte Echo. Enzyme (0.5 nM) was incubated with the compounds for 10 minutes at room temperature. Then, the substrate (phosphorylated insulin receptor probe sequence: ((OG488)-(NH-CH2-CH2-O-CH2-CH2-O-CH2-CO)-TRDI-(PY)-ETDYYRKK-NH2) (SEQ ID NO: 2) was added to the plate at 2 μM and incubated for another 10 min at room temperature. Finally, quench solution (water and 4-bromo-3-(2-oxo-2-propoxyethoxy)-5-(3-{[1-(phenylmethanesulfonyl)piperidin-4-yl]amino}phenyl)thiophene-2-carboxylic acid) was added to the plate, followed by EZ The reader (excitation 488 nm, emission 530 nm) was run to measure the % conversion (the amount of phosphorylated substrate dephosphorylated by PTPN2). Each plate contained a 100% control (inhibitor: 4-bromo-3-(2-oxo-2-propoxyethoxy)-5-(3-{[1-(phenylmethanesulfonyl)piperidin-4-yl]amino}phenyl)thiophene-2-carboxylic acid) and a 0% control (DMSO), which were used to calculate the % inhibition. The % inhibition was then used to calculate the IC 50 The value was calculated.

[0134] Example 44: Mobility Shift Assay (MSA) Used to Measure the Potency of PTPN1 Inhibitors Compound activity was measured in an in vitro enzyme reaction using an in-house His-tagged full-length PTPN1 protein (SEQ ID NO: 3). The enzyme assay used to measure activity was a mobility shift assay using a LabChip EZ Reader by Caliper Life Sciences. The enzyme reaction was performed in assay buffer (50 mM HEPES pH 7.5, 1 mM EGTA, 10 mM EDTA, 0.01% Tween® 20, and 2 mM DTT). Compounds were dispensed at various concentrations (12 points, 1:3 dilution) into ProxiPlate™ white 384-well (PerkinElmer catalog #6008289) plates using a Labcyte Echo® liquid handler. Enzyme (0.5 nM) was incubated with compounds for 10 minutes at room temperature. Then, the substrate (phosphorylated insulin receptor probe sequence: ((OG488)-(NH-CH2-CH2-O-CH2-CH2-O-CH2-CO)-TRDI-(PY)-ETDYYRKK-NH2) (SEQ ID NO: 2) was added to the plate at 2 μM and incubated for another 10 min at room temperature. Finally, quench solution (water and 4-bromo-3-(2-oxo-2-propoxyethoxy)-5-(3-{[1-(phenylmethanesulfonyl)piperidin-4-yl]amino}phenyl)thiophene-2-carboxylic acid) was added to the plate, followed by EZ The reader (excitation 488 nm, emission 530 nm) was run to measure the % conversion (the amount of phosphorylated substrate dephosphorylated by PTPN1). Each plate contained a 100% control (inhibitor: 4-bromo-3-(2-oxo-2-propoxyethoxy)-5-(3-{[1-(phenylmethanesulfonyl)piperidin-4-yl]amino}phenyl)thiophene-2-carboxylic acid) and a 0% control (DMSO), which were used to calculate the % inhibition. The % inhibition was then used to calculate the IC 50 The value was calculated.

[0135] Table 1 below shows the IC obtained using the PTPN2 MSA assay and the PTPN1 MSA assay for exemplary compounds of the disclosure. 50The data are summarized in Table 1. In this table, "A" indicates IC<10 nM 50 "B" stands for IC of 10nM to 100nM. 50 "C" stands for IC of 100 nM to over 100 nM 50 It represents.

[0136] Table 1. IC of exemplary compounds of the present disclosure in PTPN2 and PTPN1 mobility shift assays (MSA) 50 value TIFF2024543451000014.tif229152

[0137] Example 45: B16F10 (mouse melanoma cells) Phospho-STAT1 HTRF direct related pharmacodynamics (PD) assay B16F10 cells were grown and maintained in high glucose DMEM (Gibco, Cat #11965-092, Dun Laoghaire Co Dublin) supplemented with 10% fetal bovine serum (Gibco, Cat #10082-139, Dun Laoghaire Co Dublin). Cells were pelleted, resuspended in phenol red-free high glucose DMEM (Gibco, Cat #11054-020, Dun Laoghaire Co Dublin) supplemented with 10% fetal bovine serum, and plated at 11,000 cells per well in a volume of 20 μL in 384-well Corning plates (Product #3765, Corning, NY). For a 10-point dose response, compounds of interest were dosed to cells using an Echo Liquid Handler (Beckman Coulter, Brea, CA) in 3-fold dilutions from a top dose of 50 μM down to 0.002679 μM. Plates were incubated at 37°C for 3 hours, followed by treatment with recombinant mouse IFNγ (R&D Systems, Cat#485-MI, Minneapolis, MN, final concentration 100 nM) for 10 minutes at 37°C to induce STAT1 phosphorylation, followed by treatment with 3.3 μM staurosporine for 1 hour at 37°C to terminate phosphorylation. Media was then aspirated and 20 μL of 1× lysis buffer / blocking reagent (Cisbio Phospho-STAT1 kit, part #63ADK026PEH, Bedford, MA) was added. Plates were placed on a plate shaker at room temperature for 30 minutes, sealed, and stored at -80°C until needed. To thaw plates, add antibody master mix (1:40 Phospho-STAT1 Eu Cryptate antibody, 1:40 Phospho-STAT1 d2 antibody, containing detection buffer, Cisbio Phospho-STAT1 kit, part #63ADK026PEH, Bedford, MA). #Plates were placed on a shaker at room temperature until completely thawed while preparing the 384 ProxiPlate Plus (PerkinElmer, part #6008289, Waltham, Mass.). Antibody master mix was then dispensed at 4 μL per well into a 384 ProxiPlate Plus (PerkinElmer, part #6008289, Waltham, Mass.) and 16 μL of lysate was transferred from the Corning plate to the Proxiplate using a VIAFLO 384 (INTEGRA). Plates were incubated at room temperature for 3 hours and read on an EnVision® (Perkin Elmer) plate reader with laser excitation at 335 nm and emission at 665 nm. All dose-response curves were generated and EC50s calculated using Dotmatics Studies (Bishop's Stortford, UK). EC50s are shown in Table 2.

[0138] Table 2. EC in B16F10 IFNγ-induced STAT1 phosphorylation (pSTAT1) cell assay 50 value TIFF2024543451000015.tif229152

[0139] Example 46: Comparison of thiochroman compounds of the present disclosure with the corresponding chroman analogs in mobility shift assays (MSA) and B16F10 pSTAT1 HTRF direct-related pharmacodynamic (PD) assays Assay data was obtained using PTPN2 mobility shift assay data (biochemical potency) from the protocol described in Example 44, and B16F10 pSTAT1 direct pharmacodynamics (PD) assay data (cellular potency) from the protocol described in Example 45. Data are presented in Table 3 comparing the thiochroman analogs of the present disclosure to the corresponding chroman analogs. As shown in the PTPN2 MSA, 11 of the 13 thiochromans outperform the corresponding chroman analog in biochemical potency. In the pSTAT1 direct pharmacodynamics assay, 9 of the 11 thiochromans outperform the corresponding chroman analog in cellular potency. For 9 of the 11 comparisons, the thiochroman analogs showed a greater potency increase in the cellular assay than the potency increase observed in the corresponding biochemical comparison.

[0140] Table 3. IC in PTPN2 Mobility Shift Assay (MSA) of exemplary thiochroman compounds of the present disclosure 50 values, and EC in B16F10 IFNγ-induced STAT1 phosphorylation (pSTAT1) cell assay 50 Values ​​and comparison with the corresponding chroman analogues TIFF2024543451000016.tif107170TIFF2024543451000017.tif159170

[0141] Equivalents and Scope In the claims, articles such as "a," "an," and "the" may mean one or more, unless indicated to the contrary or otherwise clear from the context. A claim or description containing "or" between one or more elements of a group is considered to be satisfied if one, more than one, or all of the elements of the group are present in, used in, or otherwise relevant to a given product or process, unless indicated to the contrary or otherwise clear from the context. The present disclosure includes embodiments in which exactly one element of a group is present in, used in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which two or more, or all of the elements of a group are present in, used in, or otherwise relevant to a given product or process.

[0142] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more of the limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that is dependent on another claim may be modified to include one or more limitations found in any other claim that is dependent on the same base claim. When elements are presented as a list (e.g., in Markush group format), each subgroup of the elements is also disclosed, and any element(s) may be removed from the group. In general, when the disclosure, or aspects of the disclosure, are referred to as including certain elements and / or features, it should be understood that a particular embodiment of the disclosure, or a particular aspect of the disclosure, consists of or consists essentially of such elements and / or features. For the sake of brevity, those embodiments have not been specifically described in these terms herein. It should also be noted that the terms "comprise" and "contain" are intended to be open and permit the inclusion of additional elements or steps. When ranges are given, the endpoints of the ranges are included. Further, unless otherwise indicated or otherwise clear from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can, in different embodiments of this disclosure, envisage any specific value or subrange within the stated range, down to the tenth of the lower limit of the range, unless the context clearly requires otherwise.

[0143] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if not expressly indicated as excluded herein, since such embodiments are deemed to be known to those skilled in the art. Any particular embodiment of the present disclosure may be excluded from any claim for any reason, whether related to the existence of prior art or not.

[0144] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above description, but rather is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to the description may be made without departing from the spirit or scope of the present disclosure, as defined by the claims.

Claims

1. Formula (I): or a pharmaceutically acceptable salt thereof, During the ceremony, R １ is -NH ２ , -N(R ａ )-C １－８ Alkyl, —N(R ａ )-C ２ - ６ Alkenyl -N(R ａ )-C １－６ Alkylene-C ３－６ cycloalkyl, —N(R ａ )-C(O)-OC １－６ Alkyl, —N(R ａ )-C １－６ alkylene-4 to 7-membered heterocyclyl, —N(R ａ )-C １－６ alkylene-5-6 membered heteroaryl and —N(R ａ )-C １－６ alkylene-phenyl; Here, -N(R ａ )-C １－８ Alkyl, —N(R ａ )-C ２ - ６ Alkenyl -N(R ａ )-C １－６ Alkylene-C ３－６ cycloalkyl, —N(R ａ )-C(O)-OC １－６ Alkyl, —N(R ａ )-C １－６ alkylene-4 to 7-membered heterocyclyl, —N(R ａ )-C １－６ alkylene-5-6 membered heteroaryl and —N(R ａ )-C １－６ The alkylene-phenyl is optionally each R ｇ and optionally substituted on one or more available carbons with one, two, three or more substituents independently selected from Here, -N(R ａ )-C １－６ alkylene-4 to 6-membered heterocyclyl or —N(R ａ )-C １－６ When alkylene-5- to 6-membered heteroaryl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R ｈ and optionally substituted by R ｇ is a halogen, hydroxyl, C １－６ Alkyl, phenyl, and C １－６ independently selected at each occurrence from the group consisting of alkoxy; １－６ Alkyl, phenyl, or C １－６ The alkoxy is optionally each R Ｐ and optionally substituted by one, two, three or more substituents independently selected from R ｈ is C １－６ Alkyl and C １－６ independently selected at each occurrence from the group consisting of alkyl-O—C(O)—; R Ｐ is C １－６ independently selected at each occurrence from the group consisting of alkyl, halogen, and hydroxyl; R ａ is hydrogen and C １－６ independently selected at each occurrence from the group consisting of alkyl, The compound or a pharmaceutically acceptable salt thereof.

2. R １ -N(H)-C １－８ alkyl, C １－８ The alkyl is R ｇ The compound of claim 1, optionally substituted with

3. R ｇ Fluoro, hydroxyl, C １－６ Alkyl, and C １－６ alkoxy; １－６ Alkyl and C １－６ Alkoxy is R Ｐ and optionally substituted by one, two, three or more substituents selected from R Ｐ is independently selected at each occurrence from halogen; The compound of claim 2.

4. R １ but, 4. The compound of claim 2, selected from the group consisting of:

5. R １ But -N(H)-C １－６ Alkylene-C ３－６ cycloalkyl, -N(H)-C １－６ Alkylene-C ３－６ Cycloalkyl is optionally selected from R ｇ 10. The compound of claim 1, optionally substituted with one, two, three or more substituents independently selected from:

6. R ｇ But Fluoro, C １－６ independently selected at each occurrence from the group consisting of alkyl, and phenyl; １－６ Alkyl and phenyl are R Ｐ and optionally substituted by one, two, three or more substituents selected from R Ｐ is independently selected at each occurrence from fluoro or hydroxyl; The compound of claim 5.

7. R １ but, 7. The compound of claim 5, selected from the group consisting of:

8. R １ But -N(H)-C １－６ alkylene-4 to 7 membered heterocyclyl, —N(H)—C １－６ alkylene-4 to 7-membered heterocyclyl is optionally ｇ and when said 4- to 7-membered heterocyclyl contains a substitutable ring nitrogen atom, said ring nitrogen atom is optionally substituted by one, two, three or more substituents independently selected from R ｈ 2. The compound of claim 1, optionally substituted by:

9. R ｈ But C １－６ The compound of claim 8, which is alkyl-O-C(O)-.

10. R １ but, 10. The compound of claim 8 or 9, selected from the group consisting of:

11. R １ -N(H)-C １－６ alkylene-phenyl, —N(H)—C １－６ alkylene-phenyl optionally each R ｇ 10. The compound of claim 1, optionally substituted on one or more available carbons with one, two, three or more substituents independently selected from:

12. R ｇ However, each occurrence is independently C １－６ The compound of claim 11 , wherein the compound is alkyl.

13. R １ but, 12. The compound of claim 11 selected from the group consisting of:

14. R １ -N(H)-C １－６ alkylene-5 to 6-membered heteroaryl, —N(H)—C １－６ alkylene-5- to 6-membered heteroaryl are optionally each R ｇ 10. The compound of claim 1, optionally substituted on one or more available carbons with one, two, three or more substituents independently selected from:

15. R ｇ However, each occurrence is independently C １－６ 15. The compound of claim 14, wherein the compound is alkyl.

16. R １ but 15. The compound of claim 14, wherein:

17. 5-{(3S)-3-[(4,4-difluorobutyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, [(3S)-5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1λ ６ tert-butyl 2,5-thiadiazolidin-2-yl)-3,4-dihydro-2H-1-benzothiopyran-3-yl]carbamate, 5-[(3S)-3-amino-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-methylbutyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-fluoro-7-hydroxy-3-({2-[1-(hydroxymethyl)cyclobutyl]ethyl}amino)-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-fluoro-7-hydroxy-3-({2-[1-(hydroxymethyl)cyclopentyl]ethyl}amino)-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(4-hydroxy-3,3-dimethylbutyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-fluoro-7-hydroxy-3-(propylamino)-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-methylpentyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-fluoro-7-hydroxy-3-{[2-(oxan-4-yl)ethyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-fluoro-7-hydroxy-3-{[(oxan-4-yl)methyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-3-[(cyclopropylmethyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-3-(butylamino)-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(2-methylpropyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-fluoro-7-hydroxy-3-{[2-(oxolan-3-yl)ethyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-3-[(2,3-dimethylbutyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(propan-2-yl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-3-{[2-(3,3-difluorocyclobutyl)ethyl]amino}-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-3-[(2-cyclohexylethyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-3-[(3-ethylpentyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-3-[(2-cyclopentylethyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-3-(benzylamino)-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-methylbut-2-en-1-yl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-3-[(3,3-dimethylpentyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-fluoro-3-{[(1-fluorocyclopropyl)methyl]amino}-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-3-{[(2,2-difluorocyclopropyl)methyl]amino}-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-fluoro-7-hydroxy-3-{[(3-methyloxetan-3-yl)methyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-fluoro-3-({[1-(fluoromethyl)cyclopropyl]methyl}amino)-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-3-[(4,4-difluoropentyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-methoxypropyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-fluoro-7-hydroxy-3-{[3-(1H-pyrazol-1-yl)propyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-fluoro-7-hydroxy-3-{[2-(1-methylcyclopropyl)ethyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-3-[(2-cyclopropylpropyl)amino]-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-phenylbutyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-fluoro-7-hydroxy-3-{[(3-phenylcyclobutyl)methyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(3S)-5-fluoro-7-hydroxy-3-[(3-phenylpropyl)amino]-3,4-dihydro-2H-1-benzothiopyran-6-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-3-{[3-(2,2-difluoroethoxy)propyl]amino}-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-3-({[(1RS,5SR)-bicyclo[3.1.0]hexan-6-yl]methyl}amino)-5-fluoro-7-hydroxy-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-fluoro-7-hydroxy-3-({[4-(trifluoromethyl)cyclohexyl]methyl}amino)-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(3S)-5-fluoro-7-hydroxy-3-{[2-(2,6,6-trimethylcyclohex-1-en-1-yl)ethyl]amino}-3,4-dihydro-2H-1-benzothiopyran-6-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, and 4-({[(3S)-5-fluoro-7-hydroxy-6-(1,1,4-trioxo-1λ ６ ,2,5-thiadiazolidin-2-yl)-3,4-dihydro-2H-1-benzothiopyran-3-yl]amino}methyl)piperidine-1-carboxylate tert-butyl A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

18. 20. A pharmaceutically acceptable composition comprising a compound of any one of claims 1 or 17 and a pharmaceutically acceptable carrier.

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