Protein tyrosine phosphatase inhibitors and methods of use thereof

Abstract

The present invention relates to compounds of formula (I), wherein R 2 , X, and Z have any of the values ​​defined herein), and pharma- ceutically acceptable salts thereof. TIFF2024543452000028.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 / 278,339, 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), regulates multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, with the highest expression levels in hematopoietic and placental cells (Mosinger, B. Jr. et al., Proc Natl Acad Sci USA 89:499-503; 1992). In humans, PTPN2 expression is post-transcriptionally regulated by the existence of two splice variants: a 45-kDa form containing a nuclear localization signal at the C-terminus upstream of the splice site, and a 48-kDa canonical form with a C-terminal ER retention motif (Tillmann U. et al., Mol Cell Biol 14:3030-3040; 1994). The 45-kDa isoform can passively translocate to the cytoplasm under certain cellular stress conditions. PTPN2 negatively regulates signal transduction of nonreceptor tyrosine kinases (e.g., JAK1 and JAK3), receptor tyrosine kinases (e.g., INSR, EGFR, CSF1R, and PDGFR), transcription factors (e.g., STAT1, STAT3, and STAT5a / b), and Src family kinases (e.g., Fyn and 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 an immunotherapy regimen consisting of a GM-CSF-secreting vaccine (GVAX) plus PD-1 checkpoint blockade (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 depleted under immunotherapy selection pressure, whereas genes involved in the IFNγ signaling pathway (including IFNGR, JAK1, and STAT1) were enriched. These findings suggest a potential 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 a major mechanism for downregulating both the 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)). Therefore, 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, compounds of formula (I): The present invention discloses a compound represented by TIFF2024543452000002.tif23128 or a pharmaceutically acceptable salt thereof, During the ceremony, X is -O- or -N(R a )- and Z is -O- or -N(R 1 )- and R 1 is hydrogen or C 1-6 is alkyl, R 2 is hydrogen, -C 1-6 Alkyl 、 -C 1-6 Alkylene-C3-6 Cycloalkyl, -C 1-6 alkylene-4 to 6-membered heterocyclyl, and -C 1-6 alkylene-phenyl; where -C 1-6 Alkyl 、 -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 alkylene-4 to 6-membered heterocyclyl, and -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 where -C 1-6 When the alkylene-4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be 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, and 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-OC(O)-; R P is independently selected at each occurrence from the group consisting of halogen and hydroxyl; R a is hydrogen and C 1-6 alkyl, C 1-6 Alkyl is optionally selected from halogen, cyano, oxo, hydroxyl, and C 3-6 It may be optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl.

[0008] Brief Description of Sequence Listing The sequence listing entitled "CLS-029PR_ABV21373USL1 SEQ ID List_ST25.txt," including SEQ ID NOs:1-3, which contain the amino acid sequences disclosed herein, is incorporated herein by reference in its entirety. This sequence listing has been submitted herewith via EFS in ASCII text format. This sequence listing was originally created on June 22, 2021, and is 7,282 bytes in size. DETAILED DESCRIPTION OF THE INVENTION

[0009] Detailed Description For example, as used herein, compounds of formula (I): The present invention discloses a compound represented by TIFF2024543452000003.tif23128 or a pharmaceutically acceptable salt thereof, During the ceremony, X is -O- or -N(R a )- and Z is -O- or -N(R 1 )- and R 1 is hydrogen or C 1-6 is alkyl, R 2 is hydrogen, -C 1-6 Alkyl 、 -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 alkylene-4 to 6-membered heterocyclyl, and -C 1-6 alkylene-phenyl; where -C 1-6 Alkyl 、 -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 alkylene-4 to 6-membered heterocyclyl, and -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 where -C1-6 When the alkylene-4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be 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, and 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-OC(O)-; R P is independently selected at each occurrence from the group consisting of halogen and hydroxyl; R a is hydrogen and C 1-6 alkyl, C 1-6 Alkyl is optionally selected from halogen, cyano, oxo, hydroxyl, and C 3-6 It may be optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl.

[0010] The present disclosure provides compounds of formula (Ia) or (Ib): TIFF2024543452000004.tif26128 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 is defined herein.

[0011] The present disclosure provides compounds of formula (Ia-1) or formula (Ia-2): TIFF2024543452000005.tif26128 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 is defined herein.

[0012] In some embodiments, R 1 is hydrogen or C 1-6 In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is methyl.

[0013] The present disclosure provides compounds of formula (Ib-1) or (Ib-2): TIFF2024543452000006.tif23130 or a pharmaceutically acceptable salt thereof, wherein R 2 is defined herein.

[0014] In some embodiments, R 2 is hydrogen, -C 1-6 Alkyl 、 -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 alkylene-4 to 6-membered heterocyclyl, and -C 1-6 alkylene-phenyl; where -C 1-6 Alkyl 、 -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 alkylene-4 to 6-membered heterocyclyl, and -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 where -C 1-6 When the alkylene-4- to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R h may be substituted by:

[0015] In some embodiments, R 2 is R g may be substituted with one, two, or three instances of -C 1-6In some embodiments, R 2 is R g may be substituted with one, two, or three instances of -C 1-6 alkyl, and R g is halogen, hydroxyl, C 1-6 Alkyl, and C 1-6 alkoxy; R g may be substituted with one, two, three or more halogens. In some embodiments, R 2 is R g may be replaced by one, two, or three instances of -C 1-6 alkyl, and R g is halogen, 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.

[0016] In some embodiments, R 2 teeth, TIFF2024543452000007.tif44150.

[0017] In some embodiments, R 2 -C 1-6 Alkylene-C 3-6 is cycloalkyl, and R 2 are optionally R g In some embodiments, R 2 -C 1-6 Alkylene-C 3-6 is cycloalkyl, and R 2 are R gIn some embodiments, R is substituted with one, two, three or more substituents independently selected from 2 -C 1-6 Alkylene-C 3-6 is cycloalkyl, and R 2 are optionally fluorine, hydroxyl, and C, respectively. 1-6 and C 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 with one, two, or three hydroxyl or fluorine. In some embodiments, R 2 -C 1-6 Alkylene-C 3-6 is cycloalkyl, and R 2 are optionally R g and R g is fluorine, C 1-6 independently selected at each occurrence from the group consisting of alkyl, and phenyl; 1-6 Alkyl and phenyl are optionally each R P and R P is independently selected at each occurrence from hydroxyl or fluorine.

[0018] In some embodiments, R 2 teeth, TIFF2024543452000008.tif53143.

[0019] In some embodiments, R 2 -C 1-6 alkylene-4 to 6-membered heterocyclyl, and R 2 are optionally R gand when the 4- to 7-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be substituted by one, two, three or more substituents independently selected from R h In some embodiments, R 2 Optionally, R h and R h is C 1-6 In some embodiments, R 2 teeth, TIFF2024543452000009.tif17162.

[0020] In some embodiments, R 2 is hydrogen.

[0021] The present disclosure provides: 5-[(2R)-4-Fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2S)-4-Fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(2-cyclopentylethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-{[(4-hydroxy-3,3-dimethylbutyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-{[(3-hydroxy-3-methylbutyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-({[2-(3,3-difluorocyclobutyl)ethyl]amino}methyl)-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(4,4-difluorobutyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-({[2-(oxolan-3-yl)ethyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-4-fluoro-6-hydroxy-2-[(propylamino)methyl]-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-2-[(dipropylamino)methyl]-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-2-[(butylamino)methyl]-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-2-[(ethylamino)methyl]-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(cyclopentylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-({[(oxan-4-yl)methyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-{[(3-methylbutyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-{[(2-methylbutyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(cyclopropylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[bis(cyclopropylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(cyclobutylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-({[(oxetan-3-yl)methyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-4-Fluoro-6-hydroxy-2-[({2-[1-(hydroxymethyl)cyclobutyl]ethyl}amino)methyl]-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-4-Fluoro-6-hydroxy-2-[({2-[1-(hydroxymethyl)cyclopentyl]ethyl}amino)methyl]-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-({[3-(2,2-difluoroethoxy)propyl]amino}methyl)-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 4-[({[(2R)-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ 6 tert-butyl 2,5-thiadiazolidin-2-yl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amino)methyl]piperidine-1-carboxylate, 5-[(2R)-4-Fluoro-6-hydroxy-2-({[2-(oxan-4-yl)ethyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-2-[({[(1RS,5SR)-bicyclo[3.1.0]hexan-6-yl]methyl}amino)methyl]-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-{[(3-phenylpropyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-({[2-(2,6,6-trimethylcyclohex-1-en-1-yl)ethyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-({[(3-phenylcyclobutyl)methyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-4-Fluoro-6-hydroxy-2-[({[4-(trifluoromethyl)cyclohexyl]methyl}amino)methyl]-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-4-Fluoro-2-[({[1-(fluoromethyl)cyclopropyl]methyl}amino)methyl]-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2S)-4-Fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(2-ethylbutyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-4-Fluoro-6-hydroxy-2-[(propylamino)methyl]-2,3-dihydro-1H-indol-5-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-{[(2-methoxyethyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(cyclobutylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-({[(oxan-4-yl)methyl]amino}methyl)-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-{[(3-methylbutyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(3,3-difluoropropyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-{[(3,3,3-trifluoropropyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-{[(2-methylbutyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-({[(3,3-difluorocyclobutyl)methyl]amino}methyl)-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[4-fluoro-6-hydroxy-2-({[2-(oxetan-3-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-(2-{[(4,4-difluorobutyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(cyclopentylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(cyclopropylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-{[(pentan-2-yl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-({[(2R)-butan-2-yl]amino}methyl)-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-2-[(butylamino)methyl]-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-(hydroxymethyl)-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(2-cyclopropylethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(3,3-dimethylbutyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-4-Fluoro-6-hydroxy-2-[({[3-(propan-2-yl)cyclobutyl]methyl}amino)methyl]-2,3-dihydro-1H-indol-5-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-2-{[methyl(2-methylpropyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-Fluoro-6-hydroxy-1-methyl-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 , 2,5-thiadiazolidine-1,1,3-trione, and 5-[(2R)-2-{[(3,3-difluoro-2-hydroxypropyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6,2,5-Thiadiazolidine-1,1,3-trione or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the compounds disclosed herein are formulated as a pharmaceutically acceptable composition comprising a disclosed compound and a pharmaceutically 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.

[0023] Table of Exemplary Compounds TIFF2024543452000010.tif138152TIFF2024543452000011.tif230152TIFF2024543452000012.tif231152TIFF2024543452000013.tif215152

[0024] Methods for Making Exemplary Compounds The compounds of the present disclosure may be better understood in connection with the following synthetic schemes and methods, which illustrate means by which the compounds can be prepared. The compounds of the present disclosure can be prepared by a variety of synthetic procedures. Representative synthetic procedures are shown in Schemes 1-2, but are not limited thereto.

[0025] Scheme 1: Representative scheme for synthesizing exemplary compounds of the present disclosure As shown in Scheme 1, compounds of formula (1-2) can be prepared from compounds of formula (1-1). 1-1 -CHO(in the formula, R 1-1 may be substituted C 1-6 Alkyl, optionally substituted -C 1-6 Alkylene-C 3-6 Cycloalkyl, optionally substituted -C 1-6 alkylene-phenyl, or optionally substituted -C1-6 The compound of formula (1-2) can be reductively aminated with an aldehyde, R, in a solvent such as ethanol or a mixture of ethanol and dichloromethane in the presence of triethylamine to give a compound of formula (1-3). 1-1 The compound of formula (1-2) can be reacted with —CHO. The reductive amination can then be completed by treatment with a reducing agent such as sodium borohydride. Compounds of formula (1-2) are representative of compounds of formula (I).

[0026] Scheme 2: Representative scheme for synthesizing exemplary compounds of the present disclosure As shown in Scheme 2, a compound of formula (2-8) can be prepared from a compound of formula (2-1). 2-1 is methyl or t-butyl) to an amine, R 2-2 -NH2(wherein, R 2-2 may be substituted C 1-6 Alkyl, optionally substituted -C 1-6 Alkylene-C 3-6 Cycloalkyl, optionally substituted -C 1-6 alkylene-phenyl, or optionally substituted -C 1-6 The compound of formula (2-1) can be reductively aminated with an amine, R, in a solvent such as 1,2-dichloroethane in the presence of acetic acid, and optionally in the presence of triethylamine, to give a compound of formula (2-2). 2-2The amine of formula (2-2) is then combined with —NH2, followed by treatment with a reducing agent such as sodium triacetoxyborohydride to perform reductive amination. The amine of formula (2-2) is readily protected upon treatment with di-tert-butyl dicarbonate in the presence of N,N-diisopropylethylamine in a solvent such as acetonitrile, dichloromethane, or a mixture thereof, thus affording compounds of formula (2-3). The trifluoroacetyl moiety of the compound of formula (2-3) can be removed by hydrolysis with either sodium methoxide in warm methanol or, optionally, aqueous lithium hydroxide in warm methanol or a mixture of methanol and tetrahydrofuran, to afford compounds of formula (2-4). Compounds of formula (2-4) can be treated with Cl—SO2—NC(O)OCH2CH═CH2 in dichloromethane in the presence of a base such as triethylamine at approximately 0° C. to afford compounds of formula (2-5). Compounds of formula (2-5) can be converted to compounds of formula (2-6) by treatment with a catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base such as potassium carbonate or sodium methoxide in heated methanol. The benzyl moiety of compounds of formula (2-6) can be removed by hydrogenation in the presence of a catalyst such as 10% palladium on carbon in a solvent such as a mixture of water and ethanol to give compounds of formula (2-7). Compounds of formula (2-7) can be treated under acidic conditions such as with trifluoroacetic acid or hydrochloric acid in a solvent such as dichloromethane, acetonitrile, or a mixture thereof, optionally in the presence of propan-1-amine, to give compounds of formula (2-8). Compounds of formula (2-8) are representative of compounds of formula (I).

[0027] Pharmaceutical Composition The present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, e.g., a compound of Formula (I). In some embodiments, the pharmaceutical composition further comprises a pharmaceutically 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.

[0028] 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.

[0029] definition chemical definition Definitions of specific functional groups and chemical terms are provided in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th 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 thEdition, 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.

[0030] Abbreviations used herein have their ordinary meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0031] 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.

[0032] When a range of values ​​is listed, it is intended that each value and subrange within that range be 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.

[0033] The following terms are intended to have the meanings presented below and are useful in describing and understanding the intended scope of the present disclosure.

[0034] "Alkyl" refers to the radical of a straight- or branched-chain saturated hydrocarbon group having from 1 to 20 carbon atoms ("C1-C 20In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1-C 12 In 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). Additional 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 to 5 substituents, 1 to 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 1-6Common abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0035] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkyl, as exemplified but not limited to, by -CHCHCHCH-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred in this disclosure.

[0036] "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 present in the aromatic ring system ("C6-C 14 In some embodiments, an aryl group has 6 ring carbon atoms ("C 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, the aryl group has 14 ring carbon atoms ("C 14 Aryl, for example, anthracyl. The aryl group is, for example, C6-C 10 aryl, the term "membered" referring to a non-hydrogen ring atom within 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-C6 14In certain embodiments, the aryl group is a substituted C-C 14 It is aryl.

[0037] "Halo" or "halogen," independently 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" is meant to include, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0039] "Heteroaryl" refers to the radical of a 5- to 10-membered monocyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in the cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms present in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, provided valence permits.

[0040] "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 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 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C 10Cycloalkyl groups may be described, for example, as C4-C7 membered cycloalkyl, where the term "member" refers 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 aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. As the foregoing examples illustrate, in certain embodiments, a cycloalkyl group is monocyclic ("monocyclic cycloalkyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic cycloalkyl"), and can be saturated or partially unsaturated. Each instance of a cycloalkyl group can 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 can be an unsubstituted C3-C6 alkyl group. 10 In certain embodiments, the cycloalkyl group is a substituted C-C 10 It is cycloalkyl.

[0041] In some embodiments, "cycloalkyl" is a monocyclic saturated cycloalkyl group having 3 to 10 ring carbon atoms ("C3-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-C 10 Examples of C5-C6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-C6 cycloalkyl groups include the aforementioned C5-C6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-C8 cycloalkyl groups include the aforementioned C3-C6 cycloalkyl groups 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 10 In certain embodiments, the cycloalkyl group is a substituted C-C 10 It is cycloalkyl.

[0042] "Heterocyclyl" or "heterocycle" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each 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 can be at a carbon atom or at a nitrogen atom, provided valence permits. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. Heterocyclyl bicyclic systems can 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 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; in such instances, the number of ring members hereafter refers to the number of ring members in the heterocyclyl ring system. Heterocyclyl groups may be described, for example, as 3- to 7-membered heterocyclyls, where the term "members" refers to non-hydrogen ring atoms (i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon) within 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.

[0043] 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 independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "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 independently selected from nitrogen, oxygen, and sulfur (a "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 independently selected from nitrogen, oxygen, and sulfur (a "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.

[0044] 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 fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0045] A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic ring group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines (such as N-methylpiperazine). Specific examples include azetidine, piperidone, and piperazone.

[0046] "Amino" is the radical -NR 70 R 71 refers to R 70 and R 71 are each independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl. In some embodiments, amino refers to NH2.

[0047] "Cyano" refers to the radical -CN.

[0048] "Hydroxy" or "hydroxyl" refers to the radical --OH.

[0049] 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.

[0050] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups defined herein can be 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 atom present on the 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 specified, 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 may be the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, including any of the substituents described herein, that result in the formation of stable compounds. The present disclosure contemplates any and all such combinations in order to arrive at stable compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valences of the heteroatoms and result in the formation of stable moieties.

[0051] 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.

[0052] Other definitions "Treating" or "treatment" refers to a method of alleviating or eliminating a 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 with non-small cell lung cancer is provided, comprising administering to the human subject in need thereof a therapeutically effective amount of a compound of Formula (I).

[0053] The phrase "therapeutically effective amount" refers to the amount of a compound or a pharmaceutically acceptable salt thereof that, when administered for treatment in a particular subject or population of subjects, is sufficient to prevent or 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.

[0054] As defined herein, the terms "inhibition," "inhibit," "inhibitory," and the like, with respect to protein-inhibitor (e.g., antagonist) interactions, mean negatively affecting (e.g., decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor.

[0055] 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.

[0056] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the administration of and absorption by a subject of an active ingredient without causing significant adverse toxicological effects in the patient and that can be included in the compositions of the present disclosure.

[0057] 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).

[0058] In some embodiments, the compounds disclosed herein are formulated as pharmaceutically acceptable compositions comprising a disclosed compound and a pharmaceutically acceptable carrier. [Example]

[0059] 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.

[0060] Synthesis protocol The compounds described herein can be prepared from readily available starting materials with modifications to the specific synthetic protocols described below that would 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 is understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures. General schemes for the preparation of exemplary compounds of the present invention are additionally described in the section entitled "Methods for the Preparation of Exemplary Compounds."

[0061] 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 an appropriate protecting group for a particular functional group, as well as the selection of appropriate conditions for protection and deprotection, are well 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 the references cited therein.

[0062] Abbreviation APCI: atmospheric pressure chemical ionization; Boc: tert-butoxycarbonyl; BrettPhos: 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl; BrettPhos Pd G3 is [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, DMSO is dimethyl sulfoxide, ee is enantiomeric excess, ESI is electrospray ionization, HPLC is high-performance liquid chromatography, id is internal diameter, MS is mass spectrum, NMR is nuclear magnetic resonance, Ph is phenyl, ppm is parts per million, psi is pounds per square inch, PTFE is polytetrafluoroethylene, RockPhos is 2-di(tert-butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl, RockPhos Pd G3 is [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate, RuPhos Pd G3 is (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate, SFC is supercritical fluid chromatography, and v / v is volume / volume.

[0063] Example I-1: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 100) Example I-1A-1 and Example I-1A-2: {[(2S)-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ 6tert-Butyl {[(2R)-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ, 2,5-thiadiazolidin-2-yl)-2,3-dihydro-1-benzofuran-2-yl]methyl}(2-methylpropyl)carbamate (I-1A-1) and {[(2R)-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)-2,3-dihydro-1-benzofuran-2-yl]methyl}(2-methylpropyl)carbamate tert-butyl ester (I-1A-2) Triethylamine (42.5 mg, 0.420 mmol) was added to a suspension of the product of Example I-3 (43 mg, 0.115 mmol) in acetonitrile (1 mL) at 23 °C to give a clear solution. Di-tert-butyl dicarbonate (22.90 mg, 0.105 mmol) was then added, and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with ethyl acetate, washed with 0.2 M HCl and brine, and dried over Na SO . The mixture was filtered and concentrated. The crude residue was dissolved in methanol (5 mL), K CO (200 mg, 1.45 mmol) was added, and the mixture was stirred at ambient temperature for 14 h. The reaction mixture was diluted with 0.2 M HCl (20 mL) and extracted with ethyl acetate. The ethyl acetate fraction was washed with brine and dried over Na SO . The mixture was concentrated, and the residue was purified by SFC to give two peaks. The first peak (Example I-1A-1) was arbitrarily assigned as the (S)-enantiomer (15.9 mg, >99% ee, 29% yield), MS (APCI - ) m / z 472.6 [MH] - The second peak (Example I-1A-2) was arbitrarily assigned as the (R)-enantiomer (24.5 mg, 87% ee, 45% yield), MS (APCI - ) m / z 472.8 [MH] - .

[0064] Preparative SFC was performed on a Waters SFC80Q SFC operated under ChromScope software control. The preparative SFC system was equipped with a CO2 pump, a modifier pump with a four-port solvent selection valve, an automatic backpressure regulator (ABPR), a UV detector, and a six-position fraction collector. The mobile phase consisted of supercritical CO2 supplied by a dry, uncertified CO2 Dewar pressurized to 350 psi, with a methanol (0.1% diethylamine) modifier, at a flow rate of 80 g / min. The column was held at ambient temperature, and the backpressure regulator was set to maintain 150 bar. Samples were dissolved in methanol at a concentration of 8 mg / mL. Samples were loaded into the modifier stream with a 0.2 mL (2 mg) injection. The mobile phase was maintained isocratic with 20% modifier. Fraction collection was time-triggered. The instrument was fitted with a CHIRALPAK® IC column with a 31 mm id x 250 mm length and 5 μm particle size.

[0065] ee % is Waters UPC 2 The analytical ultrafast SFC was performed using an SFC system controlled by Empower software. The SFC system included a six-way column switcher, a sample manager autosampler operated by syringe metering (partial loop injection), a CO2 pump, a binary modifier pump, a column oven, and a convergence manager (ABPR). The mobile phase consisted of bulk-delivered, completely dry CO2 with a methanol (0.1% diethylamine)-CO2 modifier mixture at a flow rate of 1 mL / min. The oven temperature was 35 °C, and the outlet pressure was 150 bar. The mobile phase was a 20% isocratic modifier over 20 min. The retention times of the enantiomers were: 11.114 min for Example I-1A-1 and 12.581 min for Example I-1A-2.

[0066] Example I-1B: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione-trifluoroacetic acid A mixture of the product of Example I-1A-2 (24 mg, 0.051 mmol) (87% ee) and trifluoroacetic acid (148 mg, 1.298 mmol) in dichloromethane (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was triturated with acetonitrile to give the title compound as a trifluoroacetic acid salt (15 mg, 0.031 mmol, 60.7% yield). 1 H NMR (600 MHz, DMSO-d6) δ ppm 9.27 (s, 1H), 8.60 (s, 1H), 8.50 (s, 1H), 6.21 (s, 1H), 5.17 (dq, J = 12.3, 7.0 Hz, 1H), 3.88 (s, 2H), 3.27 (d, J = 6.3 Hz, 2H), 2.94 (dd, J = 15.2, 6.8 Hz, 1H), 2.83 (ddt, J = 19.9, 12.1, 6.1 Hz, 2H), 1.99 (septet, J = 6.8 Hz, 1H), 0.95 (t, J = 6.6 Hz, 6H);MS (APCI - ) m / z 372.4 [MH] - .

[0067] Example I-2: 5-[(2S)-4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 101) The title compound was synthesized as the trifluoroacetate salt from Example I-1A-1 in 39% yield using the same procedure as described in Example I-1B. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.28 (s, 1H), 8.51 (s, 2H), 6.21 (d, J = 1.1 Hz, 1H), 5.22 - 5.10 (m, 1H), 3.88 (s, 2H), 3.26 (d, J = 6.3 MS (APCI) + ) m / z 374.6 [M+H] + .

[0068] Example I-3: 5-(4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 102) Example I-3A: 1-(benzyloxy)-5-bromo-3-fluoro-2-nitrobenzene Benzyl alcohol (2.2 mL, 21.16 mmol) was added to a solution of 5-bromo-1,3-difluoro-2-nitrobenzene (5 g, 19.96 mmol) and cesium carbonate (13 g, 39.9 mmol) in N,N-dimethylformamide (10 mL) at 0° C. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (100 mL) and water (100 mL). The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The organic layers were combined, washed with brine (4×50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO2, dry load on silica, 0-30% ethyl acetate in isohexane) to afford the title compound (5.7 g, 16.25 mmol, 81% yield, 93% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.71-7.51 (m, 2H), 7.48-7.31 (m, 5H), 5.37 (s, 2H).

[0069] Example I-3B: 2-(benzyloxy)-4-bromo-6-fluoroaniline To a suspension of zinc (5.2 g, 80 mmol) and the product of Example I-3A (5.7 g, 16.25 mmol) in methanol / tetrahydrofuran (1:1, 75 mL) at 5° C., saturated aqueous ammonium chloride solution (28 mL) was added over 15 minutes. The reaction mixture was allowed to warm to room temperature over 2 hours and stirred at room temperature for 20 hours. The reaction mixture was cooled to 5° C., and additional zinc (3.2 g, 48.9 mmol) was added, and the reaction mixture was stirred at 5° C. for 5 minutes. Saturated aqueous ammonium chloride solution (17 mL) was added over 10 minutes. The reaction mixture was allowed to warm to room temperature over 1 hour and stirred at room temperature for 100 hours. Diatomaceous earth (5 g) was added to the reaction mixture, and the suspension was filtered through a pad of diatomaceous earth. The filter cake was washed with ethyl acetate (2 × 200 mL). The filtrate was concentrated under reduced pressure and diluted with ethyl acetate (150 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2 × 75 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (4.87 g, 14.80 mmol, 91% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.53 - 7.45 (m, 2H), 7.43 - 7.36 (m, 2H), 7.35 - 7.29 (m, 1H), 7.00 - 6.92 (m, 2H), 5.16 (s, 2H), 4.84 (s, 2H);MS (ESI + ) m / z 298, 296 [M+H] + .

[0070] Example I-3C: N-[2-(benzyloxy)-4-bromo-6-fluorophenyl]-2,2,2-trifluoroacetamide Trifluoroacetic anhydride (2 mL, 14.16 mmol) was slowly added to a solution of the product of Example I-3B (4.2 g, 13.47 mmol) and pyridine (1.6 mL, 19.78 mmol) in dichloromethane (20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes, warmed to room temperature, and stirred for 18 hours. The reaction mixture was quenched with water (10 mL) and diluted with dichloromethane (25 mL) and water (20 mL). The aqueous layer was separated and extracted with dichloromethane (2 × 30 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO, dry load on diatomaceous earth, 0-40% ethyl acetate in isohexane) to afford the title compound (5.0 g, 11.93 mmol, 89% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.04 (s, 1H), 7.50 - 7.20 (m, 7H), 5.24 (s, 2H);MS (ESI - ) m / z 390, 392 [MH] - .

[0071] Example I-3D: N-[6-(benzyloxy)-4-bromo-2-fluoro-3-(prop-2-en-1-yl)phenyl]-2,2,2-trifluoroacetamide n-Butyllithium (2.5 M in hexane) (8.8 mL, 22.00 mmol) was added dropwise to a solution of diisopropylamine (3.2 mL, 22.83 mmol) in tetrahydrofuran (20 mL) at −78° C. The reaction mixture was stirred at −78° C. for 45 minutes. A solution of the product of Example I-3C (4.12 g, 9.98 mmol) in tetrahydrofuran (3 mL) was added dropwise over 10 minutes, and the reaction mixture was stirred at −78° C. for 30 minutes. Allyl bromide (0.9 mL, 10.40 mmol) was added dropwise over 10 minutes, and the mixture was stirred at −78° C. for 45 minutes. The reaction mixture was quenched with 1 M aqueous hydrochloric acid (50 mL) and diluted with ethyl acetate (100 mL) and water (30 mL). The aqueous layer was separated and extracted with ethyl acetate (2×70 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO2, dry loaded on diatomaceous earth, 0-10% ethyl acetate in isohexane) to give the title compound (2.38 g, 4.41 mmol, 44% yield, 80% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.06 (s, 1H), 7.52 - 7.20 - (m, 6H), 5.97 - 5.79 (m, 1H), 5.31 - 5.16 (m, 2H), 5.07 (d, J = 10.1 Hz, 1H), 4.95 (d, J = 17.0 Hz, 1H), 3.53 - 3.37 (m, 2H);MS (ESI - ) m / z 430, 432 [MH] - .

[0072] Example I-3E: N-{6-(benzyloxy)-4-bromo-2-fluoro-3-[(oxiran-2-yl)methyl]phenyl}-2,2,2-trifluoroacetamide 3-Chloroperbenzoic acid (4 g, 17.38 mmol) was added portionwise to a solution of the product of Example I-3D (2.38 g, 4.41 mmol) in dichloromethane (20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour, then warmed to room temperature and stirred for 18 hours. Saturated aqueous sodium thiosulfate (100 mL), saturated aqueous sodium bicarbonate (50 mL), and dichloromethane (50 mL) were added, and the mixture was stirred rapidly for 48 hours. The reaction mixture was diluted with dichloromethane (100 mL), and the aqueous layer was separated. The aqueous layer was extracted with dichloromethane (2 × 100 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO, 0-55% ethyl acetate in isohexane) to afford the title compound (1.9 g, 4.03 mmol, 91% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.08 (s, 1H), 7.49 - 7.24 - (m, 6H), 5.24 (s, 2H), 3.20 - 2.87 - (m, 3H), 2.80 - 2.68 (m, 1H), 2.47 - 2.41 (m, 1H);MS (ESI - ) m / z 446, 448.1 [MH] - .

[0073] Example I-3F: 1-[3-amino-4-(benzyloxy)-6-bromo-2-fluorophenyl]-3-[(2-methylpropyl)amino]propan-2-ol 2-Methylpropan-1-amine (6.00 mL, 60.4 mmol) was added to a solution of the product of Example I-3E (1.9 g, 4.03 mmol) in methanol (15 mL). The reaction mixture was stirred at room temperature for 20 hours and then at 45° C. for 30 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO, 0-15% methanol in dichloromethane) to give the title compound (1.33 g, 2.97 mmol, 74% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.49 (d, J = 7.1 Hz, 2H), 7.45 - 7.28 - (m, 3H), 6.98 (d, J = 1.7 Hz, 1H), 5.14 (s, 2H), 4.85 - 4.54 (m, 3H), 3.86 - 3.68 (m, 1H), 2.82 - 2.62 (m, 2H), 2.53 - 2.36 (m, 2H), 2.29 (d, J = 6.7 Hz, 2H), 1.62 (septet, J = 6.7 Hz, 1H), 0.84 (d, J = 6.7 Hz, 6H);MS (ESI + ) m / z 425, 427 [M+H] + .

[0074] Example I-3G: tert-butyl {3-[3-amino-4-(benzyloxy)-6-bromo-2-fluorophenyl]-2-hydroxypropyl}(2-methylpropyl)carbamate Di-tert-butyl dicarbonate (0.7 g, 3.21 mmol) was added to a solution of the product of Example I-3F (1.33 g, 2.97 mmol) in dichloromethane (15 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give the title compound (1.57 g, 2.83 mmol, 95% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.55 - 7.23 (m, 5H), 6.97 (s, 1H), 5.13 (s, 2H), 4.94 (d, J = 6.2 Hz, 1H), 4.79 (s, 2H), 3.88 (s, 1H), 3.31 - 3.19 (m, 1H), 3.19 - 2.56 (m, 5H), 1.85 (dt, J = 13.6, 6.7 Hz, 1H), 1.30 (d, J = 57.5 Hz, 9H), 0.80 (dd, J = 23.0, 6.7 Hz, 6H);MS (ESI + ) m / z 425, 427 [MC(O)OC(CH3)3+H] + .

[0075] Example I-3H: tert-butyl {[5-amino-6-(benzyloxy)-4-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}(2-methylpropyl)carbamate Cesium carbonate (850 mg, 2.61 mmol) and RockPhos Pd G3 (70 mg, 0.083 mmol) were added to a solution of the product of Example I-3G (500 mg, 0.856 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was purged with nitrogen for 15 minutes, stirred at 100° C. for 25 minutes, cooled to room temperature, and then diluted with ethyl acetate (25 mL), water (20 mL), and brine (15 mL). The aqueous layer was separated and extracted with ethyl acetate (2×20 mL). The organic layers were combined, washed with brine (3×20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO2, dry load on silica, 0-20% ethyl acetate in isohexane) to afford the title compound (307 mg, 0.622 mmol, 73% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.54 - 7.21 (m, 5H), 6.37 (s, 1H), 5.09 (s, 2H), 4.92 (s, 1H), 4.18 - 3.94 (m, 2H), 3.47 (d, J = 14.4 Hz, MS (ESI + ) m / z 345 [MC(O)OC(CH3)3+H] + .

[0076] Example I-3I: tert-butyl {[6-(benzyloxy)-4-fluoro-5-(2,2,2-trifluoroacetamido)-2,3-dihydro-1-benzofuran-2-yl]methyl}(2-methylpropyl)carbamate Trifluoroacetic anhydride (85 μL, 0.602 mmol) was added dropwise to a solution of pyridine (70 μL, 0.865 mmol) and the product of Example I-3H (287 mg, 0.581 mmol) in dichloromethane (1.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, quenched with water (10 mL), and diluted with dichloromethane (10 mL). The aqueous layer was separated and extracted with dichloromethane (2×10 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (410 mg, 0.531 mmol, 91% yield, 70% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.47 - 7.23 (m, 6H), 6.57 (s, 1H), 5.19- 5.00 (m, 3H), 3.48 - 3.21 (m, 3H), 3.18 - 2.80 (m, 3H), 1.96 - 1.76 (m, 1H), 1.39 (d, J = 18.4 Hz, 9H), 0.82 (d, J = 6.5 Hz, 6H);MS (ESI + ) m / z 441 [MC(O)OC(CH3)3+H] + .

[0077] Example I-3J: {[6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methylpropyl)amino]methyl}-4-fluoro-2,3-dihydro-1-benzofuran-5-yl](trifluoroacetyl)amino}acetate methyl Methyl 2-bromoacetate (95 μL, 1.000 mmol) was added to a solution of N,N-diisopropylethylamine (170 μL, 0.973 mmol) and the product of Example I-3I (377 mg, 0.488 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at 60° C. for 1 hour and then cooled to room temperature. Additional methyl 2-bromoacetate (95 μL, 1.000 mmol) was added, and the reaction mixture was stirred at 60° C. for 18 hours before being cooled to room temperature. Additional N,N-diisopropylethylamine (170 μL, 0.973 mmol) and methyl 2-bromoacetate (95 μL, 1.000 mmol) were added, and the reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (20 mL) and water (10 mL). The aqueous layer was separated and extracted with ethyl acetate (2×10 mL). The organic layers were combined, washed with brine (4 x 10 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO, 0-20% ethyl acetate in isohexane) to afford the title compound (305 mg, 0.398 mmol, 82% yield, 80% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.44 - 7.26 (m, 5H), 6.64 (s, 1H), 5.21 - 5.02 (m, 3H), 4.52 (d, J = 17.4 Hz, 1H), 4.13 (d, J = 16.8 Hz, 1H), 3.61 (s, 3H), 3.53 - 3.36 (m, 2H), 3.28 - 3.17 (m, 1H), 3.14 - 2.80 (m, 3H), 1.94 - 1.80 (m, 1H), 1.36 (d, J = 32.4 Hz, 9H), 0.90 - 0.71 (m, 6H);MS (ESI + ) m / z 513 [MC(O)OC(CH3)3+H] + .

[0078] Example I-3K: {[6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methylpropyl)amino]methyl}-4-fluoro-2,3-dihydro-1-benzofuran-5-yl]amino}acetate methyl Sodium methoxide (5.4 M in methanol) (80 μL, 0.431 mmol) was added to a solution of the product of Example I-3J (300 mg, 0.392 mmol) in methanol at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and then at 60° C. for 1 hour. Additional sodium methoxide (5.4 M in methanol) (80 μL, 0.431 mmol) was added, and the reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature and stirred for 18 hours. Additional sodium methoxide (5.4 M in methanol) (80 μL, 0.431 mmol) was added, and the reaction mixture was stirred at 60° C. for 1 hour. Additional sodium methoxide (5.4 M in methanol) (145 μL, 0.784 mmol) was added, and the reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (1.5 mL), and concentrated under reduced pressure to remove methanol. The aqueous suspension was diluted with ethyl acetate (10 mL) and water (5 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the title compound (200 mg, 0.390 mmol, 100% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.51 - 7.26 (m, 5H), 6.42 (s, 1H), 5.10 (s, 2H), 4.95 (d, J = 7.9 Hz, 1H), 4.51 (s, 1H), 3.91 (d, J = 6.7 Hz, 2H), 3.60 (s, 3H), 3.52 - 3.43 (m, 1H), 3.39 - 3.24 (m, 1H), 3.23 - 2.92 (m, 3H), 2.82 (d, J = 16.3 Hz, 1H), 1.93 - 1.81 (m, 1H), 1.38 (d, J = 17.6 Hz, 9H), 0.81 (d, J = 6.8 Hz, 6H);MS (ESI + ) m / z 517 [M+H]+ .

[0079] Example I-3L: {[6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methylpropyl)amino]methyl}-4-fluoro-2,3-dihydro-1-benzofuran-5-yl]({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino}acetate methyl To a solution of chlorosulfonyl isocyanate (0.09 mL, 1.037 mmol) in dichloromethane (1 mL) was added allyl alcohol (0.07 mL, 1.029 mmol) dropwise at 0° C. The resulting solution was stirred at 0° C. for 20 minutes, after which the product of Example I-3K (0.240 g, 0.390 mmol) and triethylamine (0.2 mL, 1.435 mmol) in dichloromethane (1 mL) were added dropwise. The resulting mixture was allowed to stir at room temperature for 30 minutes. The reaction mixture was quenched with water (3 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2×5 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO, 0-40% ethyl acetate in isohexane) to afford the title compound (170 mg, 0.213 mmol, 55% yield, 85% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (s, 1H), 7.55 - 7.22 (m, 5H), 6.69 - 6.32 (m, 2H), 6.01 - 5.64 (m, 2H), 5.34 - 4.96 (m, 4H), 4.80 (d, J = 17.9 Hz, 1H), 4.43 (dt, J = 5.4, 1.6 Hz, 2H), 4.37 - 4.11 (m, 2H), 3.59 (s, 3H), 3.53 - 3.17 (m, 1H), 3.17 - 2.75 (m, 3H), 1.94 - 1.79 (m, 1H), 1.40 (s, 9H), 0.74 - 0.92 (m, 6H);MS (ESI - ) m / z 678 [MH] - .

[0080] Example I-3M: {[6-(benzyloxy)-4-fluoro-5-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)-2,3-dihydro-1-benzofuran-2-yl]methyl}(2-methylpropyl)carbamic acid tert-butyl-ammonia Potassium carbonate (35 mg, 0.253 mmol) was added to a suspension of tetrakis(triphenylphosphine)palladium(0) (11 mg, 9.52 μmol) and the product of Example I-3L (95 mg, 0.119 mmol) in methanol (1 mL). The mixture was stirred at 60° C. for 40 minutes. After cooling to room temperature, ammonium chloride (95 mg, 1.782 mmol) was added to the reaction mixture, and the volatiles were removed in vacuo. The crude residue was subjected to column chromatography (Reveleris® reverse-phase (C18) flash cartridge, dry loaded with diatomaceous earth, 5-70% methanol in 10 mM ammonium bicarbonate) to give the title compound as the ammonium salt (41 mg, 0.067 mmol, 57% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.49 (d, J = 7.2 Hz, 2H), 7.37 - 7.25 (m, 3H), 7.00 (s, 3H), 6.42 (s, 1H), 5.15 - 4.99 (m, 3H), 3.89 (s, 2H), 3.49 (d, J = 14.4 Hz, 1H), 3.41 - 3.19 (m, 2H), 3.15 - 3.06 (m, 1H), 3.04 - 2.94 (m, 1H), 2.89 - 2.79 (m, 1H), 1.94 - 1.81 (m, 1H), 1.39 (d, J = 18.1 Hz, 9H), 0.87 - 0.76 (m, 6H);MS (ESI - ) m / z 562 [MH] - .

[0081] Example I-3N: {[4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ 6,2,5-thiadiazolidin-2-yl)-2,3-dihydro-1-benzofuran-2-yl]methyl}(2-methylpropyl)carbamic acid tert-butyl-ammonia To a solution of the product of Example I-3M (40 mg, 0.067 mmol) in degassed water (0.5 mL) and ethanol (0.5 mL), 10% Pd / C (5 mg) was added. The resulting suspension was stirred under hydrogen (2 bar) for 1 hour. The reaction mixture was filtered through a pad of diatomaceous earth, and the pad was then washed with ethanol (50 mL) and water (50 mL). The volatiles were removed under reduced pressure to give the title compound as the ammonium salt (32 mg, 0.062 mmol, 92% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.14 (s, 1H), 7.09 (s, 3H), 6.12 (s, 1H), 5.03 (s, 1H), 3.87 (s, 2H), 3.51 - 3.25 (m, 2H), 3.19 (dd, J = 15.1, 9.1 Hz, 1H), 3.06 (d, J = 36.2 Hz, 2H), 2.80 (d, J = 15.5 Hz, 1H), 1.95 - 1.83 (m, 1H), 1.40 (s, 9H), 0.82 (d, J = 6.6 Hz, 6H);MS (ESI - ) m / z 472 [MH] - .

[0082] Example I-3O: 5-(4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione Trifluoroacetic acid (25 μL, 0.324 mmol) was added to a solution of the product of Example I-3N (28 mg, 0.054 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 2 hours. 0.7 M NH in water / methanol (95:5) was added until the reaction mixture became basic. The solvent was removed under reduced pressure at room temperature. The crude residue was subjected to column chromatography (Reveleris® reverse-phase (C18) flash cartridge, dry loaded with diatomaceous earth, 5-15% methanol in 10 mM ammonium bicarbonate) to give the title compound (5.46 mg, 0.014 mmol, 26% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.26 (s, 1H), 8.48 (s, 1H), 6.21 (s, 1H), 5.22 - 5.08 (m, 1H), 3.88 (s, 2H), 3.38 - 3.21 (m, 3H), 2.94 MS (ESI + ) m / z 374 [M+H] + .

[0083] Example I-4: 5-[(2R)-2-{[(2-cyclopentylethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 103) Example I-4A: 1-(benzyloxy)-3,5-difluorobenzene To a solution of 3,5-difluorophenol (24.1 g, 185 mmol) in N,N-dimethylformamide (370 mL) was added potassium carbonate (38.3 g, 277 mmol) and benzyl bromide (22.0 mL, 185 mmol), and the reaction mixture was stirred at room temperature. After 17 h, water (800 mL) was added, and the mixture was extracted into heptane (400 mL). The organic extract was washed with saturated aqueous ammonium chloride (3 × 100 mL), dried over sodium sulfate, filtered, and concentrated to give a 43.8 g residue, which was dissolved in heptane (20 mL) and purified by flash chromatography on silica gel (220 g SiO, product elution with a gradient from isocratic heptane to 11% tert-butyl methyl ether / heptane over two column volumes, monitored and collected at 210 nm) to give the title compound (32.1 g, 146 mmol, 79% yield). MS (APCI + ) m / z 221 [M+H] + , but no ionization was observed.

[0084] Example I-4B: (2R)-1-[4-(benzyloxy)-2,6-difluorophenyl]-3-[(2-methoxyethoxy)methoxy]propan-2-ol Three reactions were carried out in the same manner as follows: A solution of the product of Example I-4A (12.8 g, 58.3 mmol) in tetrahydrofuran (259 mL) was cooled to an internal temperature of −75° C., and a 1.9 M solution of phenyllithium in dibutyl ether (33.7 mL, 64.1 mmol) was added dropwise at a rate such that the internal temperature did not exceed −72° C. After stirring at −75° C. for 2 hours, a solution of (2R)-2-{[(2-methoxyethoxy)methoxy]methyl}oxirane (9.45 g, 58.3 mmol) in tetrahydrofuran (65 mL) was added at a rate such that the internal temperature did not exceed −66° C. Then, a solution of boron trifluoride diethyl etherate (11.1 mL, 87.0 mmol) in tetrahydrofuran (65 mL) was added at a rate such that the internal temperature did not exceed −66° C. The reaction mixture was then stirred for an additional 10 minutes, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. After stirring at room temperature for 1 hour, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (30 mL). The mixture was extracted with ethyl acetate (3 × 50 mL), and the combined organic extracts were washed with water (1 × 100 mL) and brine (1 × 100 mL), dried over sodium sulfate, and filtered. The filtrates from the three reactions were combined and concentrated. The crude residue was dissolved in dichloromethane (20 mL) and purified by flash chromatography on silica gel [220 g SiO2, heptane → 25.6% tert-butyl methyl ether / heptane over 15 minutes, hold for 15 minutes, then gradient to 50% tert-butyl methyl ether / heptane over 15 minutes, monitored / collected at 210 nm] to give the title compound (18.9 g, 49.5 mmol, 28% yield). MS (APCI + ) m / z 383 [M+H] + .

[0085] Example I-4C: (2R)-6-(benzyloxy)-4-fluoro-2-{[(2-methoxyethoxy)methoxy]methyl}-2,3-dihydro-1-benzofuran To a solution of the product of Example I-4B (18.93 g, 49.5 mmol) in tetrahydrofuran (330 mL) was added 1 M potassium tert-butoxide solution in tetrahydrofuran (49.5 mL, 49.5 mmol), and the reaction mixture was heated to an internal temperature of 60 °C. After 75 minutes, the mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (100 mL), stirred for 5 minutes, and then extracted with ethyl acetate (2 × 100 mL). The combined organic extracts were washed with brine (1 × 200 mL), dried over sodium sulfate, filtered, and concentrated to give 17.9 g of crude material, which was dissolved in toluene (10 mL) and purified by flash chromatography [220 g SiO, heptane → 18.4% tert-butyl methyl ether / heptane, monitored / collected at 210 nm] to give the title compound (14.9 g, 40.1 mmol, 81% yield). MS (APCI + ) m / z 363 [M+H] + .

[0086] Example I-4D: (2R)-6-(benzyloxy)-5-bromo-4-fluoro-2-{[(2-methoxyethoxy)methoxy]methyl}-2,3-dihydro-1-benzofuran To a solution of the product of Example I-4C (13.8 g, 38.2 mmol) in acetonitrile (255 mL) was added freshly recrystallized N-bromosuccinimide (6.80 g, 38.2 mmol), and the reaction mixture was stirred at room temperature. After 49 min, the mixture was directly concentrated, dissolved in toluene (25 mL), filtered to remove phthalimide, and immediately purified by flash chromatography on silica gel [220 g SiO, heptane → 31% tert-butyl methyl ether / heptane, monitoring / collection at 210 nm] to give the title compound (15.6 g, 35.4 mmol, 93% yield). MS (APCI + ) m / z 442 [M+H] + .

[0087] Example I-4E: [(2R)-6-(benzyloxy)-5-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol To the product of Example I-4D (9.61 g, 21.8 mmol), a 4 M solution of hydrochloric acid in dioxane (109 mL, 436 mmol) was added, and the reaction mixture was stirred at room temperature. After 51 minutes, a 0.5 M solution of zinc chloride in tetrahydrofuran (17.8 g zinc chloride, 131 mmol) was added. After 38 minutes, concentrated hydrochloric acid (18.2 mL, 218 mmol) was added. After 97 minutes, quantitative conversion was observed. The mixture was very slowly poured into saturated aqueous sodium bicarbonate (570 mL, 653 mmol). After effervescence ceased, the mixture was extracted with ethyl acetate (200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude material was dissolved in toluene (10 mL) and purified by flash chromatography on silica gel [120 g SiO, heptane → 45% tert-butyl methyl ether / heptane, monitoring / collection at 210 nm]. The resulting material (8.59 g) was contaminated with a methoxymethyl-related impurity and was dissolved in toluene / dichloromethane (2:1, 15 mL) and purified again by flash chromatography on silica gel (120 g SiO, heptane → 8.7% acetone / heptane, monitored / collected at 210 nm) to give the title compound (4.95 g, 14.0 mmol, 64% yield). MS (APCI + ) m / z 354 [M+H] + .

[0088] Example I-4F: benzyl {[(2R)-6-(benzyloxy)-5-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate A solution of the product of Example I-4E (4.95 g, 14.0 mmol) and triethylamine (3.91 mL, 28.0 mmol) in anhydrous dichloromethane (93 mL) was cooled to an internal temperature of −5° C., and methanesulfonyl chloride (1.31 mL, 16.8 mmol) was added dropwise over 5 minutes. After 10 minutes, the reaction was quenched with saturated aqueous sodium bicarbonate (100 mL), the layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated to give methyl [(2R)-6-(benzyloxy)-5-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanesulfonate (6.01 g, 13.94 mmol, 99% yield), which was used in the subsequent step without further purification. To a solution of the crude intermediate in anhydrous N,N-dimethylformamide (70 mL) was added sodium azide (2.72 g, 41.8 mmol), and the reaction mixture was heated to an internal temperature of 80 °C. After 144 min, the reaction mixture was cooled to room temperature and partitioned between water (2 × 300 mL) and ethyl acetate (200 mL). The organic fraction was washed with brine (1 × 200 mL), dried over sodium sulfate, filtered, and concentrated to give (2R)-2-(azidomethyl)-6-(benzyloxy)-5-bromo-4-fluoro-2,3-dihydro-1-benzofuran (5.24 g, 13.86 mmol, 99% yield), which was used in the subsequent step without further purification. To a solution of the crude product in tetrahydrofuran (56 mL) and water (28 mL), triphenylphosphine (4.41 g, 16.8 mmol) was added, and the reaction mixture was stirred at room temperature. After 65 minutes, the internal temperature was increased to 57°C. After 58 minutes, the internal temperature was increased to 61°C. After 22 minutes, quantitative conversion was achieved. The internal temperature was adjusted to 17°C, and water (28 mL) and 1 M aqueous sodium hydroxide solution (14.0 mL, 14.0 mmol) were added, followed by benzyl chloroformate (2.06 mL, 14.4 mmol), and the reaction mixture was stirred at room temperature. After 10 minutes, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL).The organic layer was washed with brine (1 x 100 mL), dried over sodium sulfate, filtered, and concentrated to give 12.7 g of residue that was dissolved in toluene (15 mL) and purified by flash chromatography on silica gel [120 g SiO, heptane → 18.5% acetone / heptane over 25 min, monitored / collected at 210 nm] to give the title compound (5.82 g, 12.0 mmol, 85% yield over 4 steps). MS (APCI). + ) m / z 487 [M+H] + .

[0089] Example I-4G: tert-butyl {[(2R)-6-(benzyloxy)-2-({[(benzyloxy)carbonyl]amino}methyl)-4-fluoro-2,3-dihydro-1-benzofuran-5-yl]({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino}acetate A catalyst stock solution was prepared as follows: A 100 mL round-bottom flask was charged with 2-methyl-2-butanol (36 mL) and the solvent was deoxygenated by submerged nitrogen sparging for 10 minutes. Solid sodium tert-butoxide (27.5 mg, 0.289 mmol), tris(dibenzylideneacetone)dipalladium(0) (132 mg, 0.144 mmol), and RockPhos (150 mg, 0.318 mmol) were then added, and the resulting mixture was heated to an internal temperature of 80 °C. After 30 minutes, the homogeneous solution was cooled to room temperature. In a separate vessel, a mixture of the product from Example I-4F (5.34 g, 10.98 mmol), sodium trifluoroacetate (1.79 g, 13.2 mmol), tert-butyl-2-aminoacetate (1.73 g, 13.2 mmol), and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, 1.83 g, 13.2 mmol) in 2-methyl-2-butanol (41 mL) was deoxygenated by submerged nitrogen sparging for 20 minutes. Then, 13.7 mL of the catalyst stock solution prepared above was added via cannula, the solution was deoxygenated for an additional 15 minutes, and the reaction mixture was heated to an internal temperature of 70 °C. After 3 hours, an additional charge of catalyst stock solution (13.7 mL) was added. After a total reaction time of 12 hours, proton NMR indicated quantitative conversion. The mixture was then cooled to room temperature and partitioned between ethyl acetate (150 mL) and 0.5 M aqueous hydrochloric acid (200 mL). The organic extract was washed with brine (1 × 80 mL), dried over sodium sulfate, and filtered. Toluene (70 mL) was added to the filtrate. Due to the product's sensitivity to air oxidation in concentrated form, the flask containing the diluted product was attached to a rotary evaporator, and the apparatus was evacuated and back-filled with nitrogen three times before concentrating under nitrogen. Immediately upon concentration, the rotary evaporator was back-filled with nitrogen, and the product-containing flask was quickly removed and placed on a Schlenk line under nitrogen to afford 10.43 g of tert-butyl {[(2R)-6-(benzyloxy)-2-({[(benzyloxy)carbonyl]amino}methyl)-4-fluoro-2,3-dihydro-1-benzofuran-5-yl]amino}acetate, which was partially dissolved in toluene.The crude material was used in the subsequent step without purification.

[0090] To a solution of chlorosulfonyl isocyanate (1.39 mL, 16.0 mmol) in dichloromethane (336 mL) at an internal temperature of −10° C., allyl alcohol (1.09 mL, 16.0 mmol) was added at a rate such that the internal temperature did not exceed 0° C. After 30 min, a preformed solution of crude tert-butyl {[(2R)-6-(benzyloxy)-2-({[(benzyloxy)carbonyl]amino}methyl)-4-fluoro-2,3-dihydro-1-benzofuran-5-yl]amino}acetate and N,N-diisopropylethylamine (3.72 mL, 21.3 mmol) in dichloromethane (17.7 mL) was added at a rate such that the internal temperature did not exceed 0° C. After 15 min, the reaction was quenched with water (50 mL), and the mixture was stirred for 5 min. The layers were then separated. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in dichloromethane / toluene (1:1, 10 mL) and purified by flash chromatography on silica gel [120 g SiO, heptane → 30% acetone / heptane, monitoring / collection at 210 nm] to give the title compound (5.13 g, 7.33 mmol, 69% yield over two steps). MS (APCI + ) m / z 700 [M+H] + .

[0091] Example I-4H: {[(2R)-6-(benzyloxy)-4-fluoro-5-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamic acid benzyl ester To a solution of the product of Example I-4G (2.67 g, 3.82 mmol) in anhydrous methanol (21.2 mL), sodium tert-butoxide solution (5.72 mL, 11.5 mmol, 2 M in tetrahydrofuran) was added, and the solution was deoxygenated by submerged nitrogen sparging for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (22.0 mg, 0.0190 mmol) was then added, and the reaction mixture was heated to an internal temperature of 50°C. After 3 hours, the mixture was cooled to an internal temperature of -9°C and quenched by the addition of hydrochloric acid solution (4.07 mL, 12.2 mmol, 3 M in cyclopentyl methyl ether (CPME)). After stirring for 5 minutes, water (30 mL) was added. After stirring for 5 minutes, the mixture was partitioned between ethyl acetate (120 mL) and water (50 mL). The organic extract was washed with brine (1 × 50 mL), dried over sodium sulfate, filtered, and concentrated. The residue (4.19 g) was dissolved in a mixture of methanol / N,N-dimethylformamide / water (1:1:1, 15 mL), filtered through a glass microfiber frit, and purified by HPLC (Waters XBridge™ BEH C18 OBD Prep Column, 130 Å, 5 μm, 30 mm × 100 mm, flow rate 40 mL / min, 5-100% acetonitrile gradient (5 to 35% over 10 min) in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 with ammonium hydroxide). Concentration of the fractions afforded 2.22 g of the ammonium salt of the title compound. This material was suspended in ethyl acetate (70 mL) and washed with 6 M HCl (50 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to give the title compound (1.98 g, 3.60 mmol, 48.2% yield). MS (APCI + ) m / z 559 [M+H] + .

[0092] Example I-4I: 5-[(2R)-2-(aminomethyl)-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione-hydrogen chloride (1 / 1) A suspension of the product from Example I-4H (1.66 g, 3.07 mmol) and 5% palladium on alumina (0.371 g, 0.174 mmol [Pd]) in tetrahydrofuran (46 mL) and water (15.3 mL) was pressurized to 50 psi with hydrogen gas and stirred at room temperature. After 16 h, 1 M sodium hydroxide (3.07 mL, 3.07 mmol) was added, the solution was stirred for 1 h, additional water / tetrahydrofuran (1:3, 20 mL) was added, and after stirring for 15 min, it was filtered through a 0.45 μM Whatman PTFE filter, and the catalyst bed was rinsed with additional water / tetrahydrofuran (1:3, 20 mL). The mixture was concentrated to give a residue (1.31 g), which was suspended in hydrochloric acid solution (3 M in cyclopentyl methyl ether, 20.4 mL, 61.3 mmol) and stirred at room temperature for 10 min. The resulting precipitate was isolated on a fritted funnel, washed with cyclopentyl methyl ether (2×20 mL), and dried to constant weight to give the title compound (1.05 g, 2.89 mmol, 94% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.4 (br s, 1H), 8.31 (t, J = 6.0 Hz, 3H), 6.33 (s, 1H), 5.12 (m, 1H), 4.28 (s, 2H), 3.31 (dd, J = 15.4, 9.4 MS (APCI - ) m / z 353 [M] - .

[0093] Example I-4J: 5-[(2R)-2-{[(2-cyclopentylethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a 4 mL vial was added the product of Example I-4I (25 mg, 0.074 mmol) and triethylamine (31 μL, 0.22 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (0.75 mL). 2-Cyclopentylacetaldehyde (16.5 mg, 0.15 mmol, 2.0 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (11.2 mg, 0.30 mmol, 4.0 equiv.) was added in one portion, and the mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0 °C in an ice bath, and aqueous hydrochloric acid (2.0 M, 0.74 mL, 1.47 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 (pH 7) in water (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 (11.9 mg, 39.1% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.26 (s, 1H), 8.56 (s, 2H), 6.20 (s, 1H), 5.16 - 5.07 (m, 1H), 3.88 (s, 2H), 3.37 - 3.24 (m, 3H), 2.99 - 2.89 (m, 3H), 1.84 - 1.69 (m, 3H), 1.67 - 1.43 (m, 6H), 1.14 - 1.03 (m, 2H);MS (APCI + ) m / z 414.3 [M+H] + .

[0094] Example I-5: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(4-hydroxy-3,3-dimethylbutyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 104) Example I-5A: Methyl 2,2-dimethyl-4-pentenoate The title compound was synthesized in 71.8% yield from methyl isobutyrate using the procedure described in Example I-23A. 1 H NMR (400MHz 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).

[0095] Example I-5B: 2,2-dimethyl-4-penten-1-ol The title compound was synthesized from Example I-5A in 95% yield in a similar manner to that described in Example I-23B. 1 H NMR (400MHz, 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).

[0096] Example I-5C: tert-butyl[(2,2-dimethyl-4-penten-1-yl)oxy]dimethylsilane The title compound was synthesized from Example I-5B in 74% yield in a similar manner to that described in Example I-23C. 1 H NMR (400MHz, 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).

[0097] Example I-5D: 4-{[tert-butyl(dimethyl)silyl]oxy}-3,3-dimethylbutanal The title compound was synthesized from Example I-5C in 66% yield in a similar manner to that described in Example I-23D. 1 H NMR (400MHz, 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] + .

[0098] Example I-5E: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(4-hydroxy-3,3-dimethylbutyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a 4 mL vial was added the product of Example I-4I (50 mg, 0.14 mmol) and triethylamine (59 μL, 0.42 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL). The product of Example I-5D (65.4 mg, 0.42 mmol, 2.0 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (21.4 mg, 0.57 mmol, 4.0 equiv.) was added in one portion, and the resulting mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was cooled to 0° C. in an ice bath, and aqueous hydrochloric acid (2.0 M, 1.4 mL, 2.8 mmol, 20 equiv.) was added slowly. 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 (pH 7) in water (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 (21.7 mg, 36.8% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 6.17 (s, 1H), 5.09 - 5.00 (m, 1H), 3.88 (s, 2H), 3.28 (dd, J = 15.1, 9.2 Hz, 1H), 3.14 - 3.08 (m, 4H), 2.95 - 2.81 (m, 3H), 1.48 (tt, J = 9.8, 4.9 Hz, 2H), 0.82 (s, 6H);MS (APCI + ) m / z 418.3 [M+H] + .

[0099] Example I-6: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(3-hydroxy-3-methylbutyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ 6,2,5-Thiadiazolidine-1,1,3-trione (Compound 105) To a 4 mL vial was added the product of Example I-4I (50 mg, 0.14 mmol) and triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL). 3-Hydroxy-3-methylbutanal (43.3 mg, 0.42 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (21.4 mg, 0.57 mmol, 4 equiv.) was added in one portion, and the resulting mixture was stirred at ambient temperature for 30 minutes. 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 reaction mixture was purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm × 30 mm). A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 7) in water (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) was used to give the title compound (7.9 mg, 13.8% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.18 (s, 1H), 5.08 (dq, J = 9.5, 6.4 Hz, 1H), 4.08 (d, J = 5.3 Hz, 1H), 3.88 (s, 2H), 3.18 (dd, J = 11.9, 4.8 MS (APCI + ) m / z 404.3 [M+H] + .

[0100] Example I-7: 5-[(2R)-2-({[2-(3,3-difluorocyclobutyl)ethyl]amino}methyl)-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 106) To a 4 mL vial was added the product of Example I-4I (50 mg, 0.14 mmol) and triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL). 2-(3,3-Difluorocyclobutyl)acetaldehyde (56.9 mg, 0.42 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (21.4 mg, 0.57 mmol, 4 equiv.) was added in one portion, and the resulting mixture was stirred at ambient temperature for 30 minutes. 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 5-60% 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 (7.2 mg, 11.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.26 (s, 1H), 8.82 - 8.37 (m, 2H), 6.21 (s, 1H), 5.11 (dq, J = 9.4, 6.3 Hz, 1H), 3.88 (s, 2H), 3.35 (d, J = 9.3 Hz, 1H), 3.26 (d, J = 6.1 Hz, 2H), 2.92 (dt, J = 15.8, 6.9 Hz, 3H), 2.77 - 2.61 (m, 2H), 2.32 - 2.05 (m, 3H), 1.81 (q, J = 7.8 Hz, 2H);MS (APCI + ) m / z 436.3 [M+H] + .

[0101] Example I-8: 5-[(2R)-2-{[(4,4-difluorobutyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 107) To a 4 mL vial was added the product of Example I-4I (50 mg, 0.14 mmol) and triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL). 4,4-Difluorobutanal (45.8 mg, 0.42 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (21.4 mg, 0.57 mmol, 4 equiv.) was added in one portion, and the resulting mixture was stirred at ambient temperature for 30 minutes. 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 (pH 7) in water (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 (10.8 mg, 18.7% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.28 (s, 1H), 8.72 - 8.58 (m, 2H), 6.26 - 5.95 (m, 2H), 5.12 (dq, J = 9.3, 6.4 Hz, 1H), 3.88 (s, 2H), MS (APCI + ) m / z 410.3 [M+H] + .

[0102] Example I-9: 5-[(2R)-4-fluoro-6-hydroxy-2-({[2-(oxolan-3-yl)ethyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 108) To a 4 mL vial was added the product of Example I-4I (50 mg, 0.14 mmol) and triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL). 2-(Tetrahydrofuran-3-yl)acetaldehyde (48.4 mg, 0.42 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (21.4 mg, 0.57 mmol, 4 equiv.) was added in one portion, and the resulting mixture was stirred at ambient temperature for 30 minutes. 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 (pH 7) in water (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 (8.8 mg, 15% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.26 (s, 1H), 8.85 - 7.98 (m, 2H), 6.20 (s, 1H), 5.11 (dq, J = 9.4, 6.4 Hz, 1H), 3.88 (s, 2H), 3.82 - 3.67 (m, 2H), 3.67 - 3.56 (m, 1H), 3.29 - 3.21 (m, 4H), 2.95 (h, J = 7.0, 6.2 Hz, 3H), 2.15 (h, J = 7.1 Hz, 1H), 2.06 - 1.93 (m, 1H), 1.75 - 1.56 (m, 2H), 1.53 - 1.39 (m, 1H); MS (APCI + ) m / z 416.3 [M+H] + .

[0103] Example I-10: 5-{(2R)-4-fluoro-6-hydroxy-2-[(propylamino)methyl]-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 109) To a 4 mL vial was added the product of Example I-4I (50 mg, 0.14 mmol) and triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL). Propionaldehyde (24.6 mg, 0.42 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (21.4 mg, 0.57 mmol, 4 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). A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 7) in water (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) was used to obtain the title compound (2.4 mg, 4.8% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.20 (s, 1H), 5.16 - 5.04 (m, 1H), 3.88 (s, 2H), 3.25 - 3.14 (m, 3H), 2.98 - 2.84 (m, 3H), 1.60 (qt, J = 8.1, 4.0 Hz, 2H), 0.95 - 0.83 (m, 3H);MS (APCI + ) m / z 360.3 [M+H] + .

[0104] Example I-11: 5-{(2R)-2-[(dipropylamino)methyl]-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 110) Example I-11 was isolated as a by-product in the synthesis of Example I-10 (5.9 mg, 10.4% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.38 - 9.11 (m, 2H), 6.19 (s, 1H), 5.29 (s, 1H), 3.88 (s, 2H), 3.54 - 3.34 (m, 4H), 3.11 (s, 3H), 2.89 (dd, J = 15.3, 6.6 Hz, 1H), 1.64 (s, 4H), 0.90 (t, J = 7.5 Hz, 6H);MS (APCI + ) m / z 402.3 [M+H] + .

[0105] Example I-12: 5-{(2R)-2-[(butylamino)methyl]-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 111) To a 4 mL vial was added the product of Example I-4I (50 mg, 0.14 mmol) and triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL). Butyraldehyde (30.6 mg, 0.42 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (21.4 mg, 0.57 mmol, 4 equiv.) was added in one portion, and the resulting mixture was stirred at ambient temperature for 30 minutes. 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). A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 7) in water (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) was used to obtain the title compound (3.8 mg, 7.3% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.20 (s, 1H), 5.11 (dq, J = 8.7, 6.3 Hz, 1H), 3.88 (s, 2H), 3.24 (d, J = 6.2 Hz, 3H), 2.98 - 2.88 (m, 3H), 1.64 - 1.51 (m, 2H), 1.33 (h, J = 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H);MS (APCI + ) m / z 374.3 [M+H] + .

[0106] Example I-13: 5-{(2R)-2-[(ethylamino)methyl]-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl}-1λ 6,2,5-Thiadiazolidine-1,1,3-trione (Compound 112) To a 4 mL vial was added the product of Example I-4I (50 mg, 0.14 mmol) and triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL). Acetaldehyde (10.3 mg, 0.42 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (21.4 mg, 0.57 mmol, 4 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). A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 7) in water (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) was used to obtain the title compound (10.3 mg, 21.1% yield). 1 H NMR (600 MHz, DMSO-d6) δ ppm 9.25 (s, 1H), 8.67 - 8.45 (m, 2H), 6.20 (s, 1H), 5.14 - 5.06 (m, 1H), 3.88 (s, 2H), 3.37 - 3.28 (m, 1H), MS (APCI + ) m / z 346.3 [M+H] + .

[0107] Example I-14: 5-[(2R)-2-{[(cyclopentylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 113) To a 4 mL vial was added the product of Example I-4I (50 mg, 0.14 mmol) and triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL). Cyclopentanecarbaldehyde (41.6 mg, 0.42 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (21.4 mg, 0.57 mmol, 4 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 (pH 7) in water (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 (17.0 mg, 30.2% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.27 (s, 1H), 8.55 (s, 2H), 6.21 (s, 1H), 5.22 - 5.10 (m, 1H), 3.88 (s, 2H), 3.38 - 3.24 (m, 3H), 3.02 - MS (APCI +) m / z 400.3 [M+H] + .

[0108] Example I-15: 5-[(2R)-4-fluoro-6-hydroxy-2-({[(oxan-4-yl)methyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 114) To a 4 mL vial was added the product of Example I-4I (50 mg, 0.14 mmol) and triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL). Tetrahydro-2H-pyran-4-carbaldehyde (48.4 mg, 0.42 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (21.4 mg, 0.57 mmol, 4 equiv.) was added in one portion, and the resulting mixture was stirred at ambient temperature for 30 minutes. 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 (pH 7) in water (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 (17.6 mg, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.18 (s, 1H), 5.07 (dt, J = 13.3, 6.2 Hz, 1H), 3.91 - 3.80 (m, 4H), 3.33 - 3.22 (m, 3H), 3.12 (d, J = 6.1 MS (APCI + ) m / z 416.3 [M+H] + .

[0109] Example I-16: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(3-methylbutyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 115) To a 4 mL vial was added the product of Example I-4I (50 mg, 0.14 mmol) and triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL). Isovaleraldehyde (36.5 mg, 0.42 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (21.4 mg, 0.57 mmol, 4 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). A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 7) in water (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) was used to obtain the title compound (7.2 mg, 13.1% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.20 (s, 1H), 5.17 - 5.05 (m, 1H), 3.88 (s, 2H), 3.37 - 3.33 (m, 1H), 3.25 (d, J = 6.2 Hz, 2H), 2.99 - MS (APCI + ) m / z 388.3 [M+H] + .

[0110] Example I-17: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(2-methylbutyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 116) To a 4 mL vial was added the product of Example I-4I (50 mg, 0.14 mmol) and triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL). 2-Methylbutanal (36.5 mg, 0.42 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (21.4 mg, 0.57 mmol, 4 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). A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 7) in water (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) was used to obtain the title compound (10.8 mg, 19.7% yield). 1H NMR (600 MHz, DMSO-d6) δ ppm 9.26 (s, 1H), 8.71 - 8.36 (m, 2H), 6.21 (s, 1H), 5.21 - 5.13 (m, 1H), 3.88 (s, 2H), 3.29 - 3.25 (m, 3H), 2.99 - 2.89 (m, 2H), 2.83 - 2.73 (m, 1H), 1.79 - 1.74 (m, 1H), 1.49 - 1.35 (m, 1H), 1.23 - 1.12 (m, 1H), 0.94 (t, J = 6.5 Hz, 3H), 0.87 (td, J = 7.4, 1.3 Hz, 3H); MS (APCI + ) m / z 388.3 [M+H] + .

[0111] Example I-18: 5-[(2R)-2-{[(cyclopropylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 117) To a 4 mL vial was added the product of Example I-4I (50 mg, 0.14 mmol) and triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL). Cyclopropanecarbaldehyde (29.7 mg, 0.42 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (21.4 mg, 0.57 mmol, 4 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 (pH 7) in water (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 (11.1 mg, 21.1% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.25 (s, 1H), 8.61 (s, 1H), 6.21 (s, 1H), 5.15 - 5.11 (m, 1H), 3.88 (s, 2H), 3.30 - 3.24 (m, 4H), 3.00 - 2.77 (m, 3H), 1.10 - 0.99 (m, 1H), 0.62 - 0.53 (m, 2H), 0.39 - 0.31 (m, 2H);MS (APCI + ) m / z 372.3 [M+H] + .

[0112] Example I-19: 5-[(2R)-2-{[bis(cyclopropylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6,2,5-Thiadiazolidine-1,1,3-trione (Compound 118) Example I-19 was isolated as a by-product in the synthesis of Example I-18 (11.5 mg, 19.1% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.18 (s, 1H), 4.08 (q, J = 5.3 Hz, 1H), 3.88 (s, 2H), 3.70 - 3.44 (m, 2H), 3.24 - 3.09 (m, 4H), 2.96 (dd, J = 15.2, 6.8 Hz, 2H), 1.30 - 0.85 (m, 2H), 0.83 - 0.12 (m, 8H) + ) m / z 426.4 [M+H] + .

[0113] Example I-20: 5-[(2R)-2-{[(cyclobutylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 119) To a 4 mL vial was added the product of Example I-4I (50 mg, 0.14 mmol) and triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL). Cyclobutanecarbaldehyde (35.7 mg, 0.42 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (21.4 mg, 0.57 mmol, 4 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 5-40% 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 (10.1 mg, 18.6% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (s, 1H), 8.49 - 7.91 (m, 2H), 6.19 (s, 1H), 5.16 - 5.06 (m, 1H), 3.88 (s, 2H), 3.30 - 3.26 (m, 1H), MS (APCI + ) m / z 386.3 [M+H] + .

[0114] Example I-21: 5-[(2R)-4-fluoro-6-hydroxy-2-({[(oxetan-3-yl)methyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 120) To a 4 mL vial was added the product of Example I-4I (50 mg, 0.14 mmol) and triethylamine (57 μL, 0.41 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL). Oxetane-3-carbaldehyde (36.5 mg, 0.42 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (21.4 mg, 0.57 mmol, 4 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 5-40% 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 (13.1 mg, 24% yield). 1 H NMR (600 MHz, DMSO-d6) δ ppm 9.27 (s, 1H), 8.76 - 8.45 (m, 2H), 6.20 (s, 1H), 5.10 (dtd, J = 9.4, 6.9, 5.3 Hz, 1H), 4.68 - 4.61 (m, MS (APCI+ ) m / z 388.3 [M+H] + .

[0115] Example I-22: 5-{(2R)-4-fluoro-6-hydroxy-2-[({2-[1-(hydroxymethyl)cyclobutyl]ethyl}amino)methyl]-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 121) Example I-22A: 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 the addition of tert-butyldimethylchlorosilane (3.58 g, 23.77 mmol) in several portions at 0 °C. The reaction mixture was stirred at 20 °C for 3 h. One additional 500 mg scale reaction was prepared and carried out as described above. These two reaction mixtures were combined and extracted 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).

[0116] Example I-22B: [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]acetaldehyde To a solution of the product of Example I-22A (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 minutes, 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 hours. The mixture was diluted with ethyl acetate (200 mL) and filtered. The filtrate was added to saturated aqueous sodium thiosulfate (300 mL), and the resulting mixture was stirred at 20° C. for 1 hour. The mixture was transferred to a separatory funnel, and the organic phase was separated, 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).

[0117] Example I-22C: 5-{(2R)-4-fluoro-6-hydroxy-2-[({2-[1-(hydroxymethyl)cyclobutyl]ethyl}amino)methyl]-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a 4 mL vial was added the product of Example I-4I (50 mg, 0.14 mmol) and triethylamine (59 μL, 0.42 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL). The product of Example I-22B (68.5 mg, 0.42 mmol, 2.0 equiv.) was added, and the reaction mixture was stirred at ambient temperature for 2 hours. Sodium borohydride (21.4 mg, 0.57 mmol, 4.0 equiv.) was added in one portion, and the resulting mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was cooled to 0° C. in an ice bath, and aqueous hydrochloric acid (2.0 M, 1.4 mL, 2.8 mmol, 20 equiv.) was added slowly, and the reaction 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 (17.2 mg, 28.3% yield). 1 H NMR (600 MHz, DMSO-d6) δ ppm 9.26 (s, 1H), 8.80 - 8.35 (m, 2H), 6.20 (s, 1H), 5.15 - 5.07 (m, 1H), 3.88 (s, 2H), 3.34 (s, 2H), 3.28 (dd, J = 9.1, 4.4 Hz, 3H), 2.97 - 2.89 (m, 3H), 1.87 - 1.73 (m, 6H), 1.72 - 1.64 (m, 2H); + ) m / z 430.4 [M+H] + .

[0118] Example I-23: 5-{(2R)-4-fluoro-6-hydroxy-2-[({2-[1-(hydroxymethyl)cyclopentyl]ethyl}amino)methyl]-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 122) Example I-23A: Methyl 1-allylcyclopentanecarboxylate To a solution of lithium diisopropylamide (122 mL, 243 mmol) in anhydrous tetrahydrofuran (720 mL) was added methyl cyclopentanecarboxylate (24 g, 187 mmol) dropwise under nitrogen at −65° C. The reaction mixture was stirred at −65° C. under nitrogen for 40 minutes, after which 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 hours before being quenched by the dropwise addition of 500 mL of saturated aqueous NH4Cl at 0° C. The resulting mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was chromatographed on silica gel eluting with petroleum ether to give the title compound (31.2 g, 167 mmol, 89% yield). 1 H NMR (400MHz, 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).

[0119] Example I-23B: (1-allylcyclopentyl)methanol To a solution of the product of Example I-23A (15.5 g, 77 mmol, 90% purity) in tetrahydrofuran (300 mL) was added LiAlH (4.65 g, 122 mmol) in portions at 0 °C under nitrogen. The mixture was then stirred at 0 °C for 2 hours under nitrogen. The reaction mixture was quenched by the dropwise addition of 4.65 mL of water at 0 °C, followed by the dropwise addition of 4.65 mL of 15% aqueous NaOH and 13.95 mL of water. A similar reaction was carried out as above, but in one additional 15.5 g batch. 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 was concentrated under reduced pressure to give the title compound (22.5 g, 144 mmol, 94% yield, 90% purity). 1 H NMR (400MHz, 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).

[0120] Example I-23C: tert-butyl(dimethyl){[1-(prop-2-en-1-yl)cyclopentyl]methoxy}silane To a solution of the product of Example I-23B (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, but 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).

[0121] Example I-23D: [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]acetaldehyde To a solution of the product of Example I-23C (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 minutes. Sodium periodate (43.9 g, 205 mmol) was then added in several portions at 0 °C. The mixture was stirred at 20 °C for 2 hours. A similar reaction was carried out as above, but in two additional portions on 14.5 g and 5 g scales. The two reaction mixtures were combined and extracted with ethyl acetate (400 mL). The combined organic fractions were filtered. The filtrate was quenched with saturated aqueous NaSO (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 (400MHz, 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).

[0122] Example I-23E: 5-{(2R)-4-fluoro-6-hydroxy-2-[({2-[1-(hydroxymethyl)cyclopentyl]ethyl}amino)methyl]-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a 4 mL vial was added the product of Example I-4I (50 mg, 0.14 mmol) and triethylamine (59 μL, 0.42 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (1.4 mL). The product of Example I-23D (72.5 mg, 0.42 mmol, 2.0 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (21.4 mg, 0.57 mmol, 4.0 equiv.) was added in one portion, and the resulting mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was cooled to 0° C. in an ice bath, and aqueous hydrochloric acid (2.0 M, 1.4 mL, 2.8 mmol, 20 equiv.) was slowly added. 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 (pH 7) in water (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 (14.8 mg, 23.6% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.25 (s, 1H), 8.74 - 8.35 (m, 2H), 6.20 (s, 1H), 5.16 - 5.05 (m, 1H), 3.88 (s, 2H), 3.30 - 3.24 (m, 3H), 3.16 (s, 2H), 3.03 - 2.88 (m, 3H), 1.67 (td.+ ) m / z 444.4 [M+H] + .

[0123] Example I-24: 5-[(2R)-2-({[3-(2,2-difluoroethoxy)propyl]amino}methyl)-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 123) To a 4 mL vial was added the product of Example I-4I (30 mg, 0.08 mmol) and triethylamine (36 μL, 0.25 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (0.8 mL). 3-(2,2-Difluoroethoxy)propanal (35.4 mg, 0.25 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (13.5 mg, 0.34 mmol, 4 equiv.) was added in one portion, and the resulting mixture was stirred at ambient temperature for 30 minutes. 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 (pH 7) in water (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 (0.8 mg, 2.2% yield). 1H NMR (500 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.29 - 5.99 (m, 2H), 5.20 - 5.11 (m, 1H), 3.97 (s, 2H), 3.74 - 3.60 (m, 4H), 3.42 - 3.25 (m, 3H), 3.10 - 3.04 (m, 2H), 2.96 (dd, J = 15.4, 6.8 Hz, 1H), 1.99 - 1.87 (m, 2H); + ) m / z 440.4 [M+H] + .

[0124] Example I-25: 4-[({[(2R)-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ 6 tert-Butyl 2,5-thiadiazolidin-2-yl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amino)methyl]piperidine-1-carboxylate (Compound 124) To a 4 mL vial was added the product of Example I-4I (30 mg, 0.08 mmol) and triethylamine (36 μL, 0.25 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (0.8 mL). tert-Butyl 4-formylpiperidine-1-carboxylate (54.3 mg, 0.25 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (13.5 mg, 0.34 mmol, 4 equiv.) was added in one portion, and the resulting mixture was stirred at ambient temperature for 30 minutes. 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 (pH 7) in water (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 (0.1 mg, 0.23% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.27 (s, 1H), 5.21 - 5.14 (m, 1H), 4.02 - 3.93 (m, 3H), 3.44 - 3.32 (m, 1H), 3.30 - 3.24 MS (APCI + ) m / z 515.5 [M+H] + .

[0125] Example I-26: 5-[(2R)-4-fluoro-6-hydroxy-2-({[2-(oxan-4-yl)ethyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 125) To a 4 mL vial was added the product of Example I-4I (30 mg, 0.08 mmol) and triethylamine (36 μL, 0.25 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (0.8 mL). 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (32.6 mg, 0.25 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (13.5 mg, 0.34 mmol, 4 equiv.) was added in one portion, and the resulting mixture was stirred at ambient temperature for 30 minutes. 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 (pH 7) in water (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 (4 mg, 11% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.25 - 6.20 (m, 1H), 5.15 - 5.03 (m, 1H), 3.94 (s, 2H), 3.87 - 3.78 (m, 2H), 3.37 - 3.23 MS (APCI +) m / z 430.4 [M+H] + .

[0126] Example I-27: 5-{(2R)-2-[({[(1RS,5SR)-bicyclo[3.1.0]hexan-6-yl]methyl}amino)methyl]-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 126) To a 4 mL vial was added the product of Example I-4I (30 mg, 0.08 mmol) and triethylamine (36 μL, 0.25 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (0.8 mL). Bicyclo[3.1.0]hexane-6-carbaldehyde (28.0 mg, 0.25 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 h. Sodium borohydride (13.5 mg, 0.34 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 slowly added. 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 (pH 7) in water (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 (4.2 mg, 12.1% yield). 1H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.25 (s, 1H), 5.17 - 5.07 (m, 1H), 3.94 (s, 2H), 3.40 - 3.17 (m, 3H), 2.99 - 2.75 (m, MS (APCI + ) m / z 412.3 [M+H] + .

[0127] Example I-28: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(3-phenylpropyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 127) To a 4 mL vial was added the product of Example I-4I (30 mg, 0.08 mmol) and triethylamine (36 μL, 0.25 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (0.8 mL). 3-Phenylpropanal (34.1 mg, 0.25 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (13.5 mg, 0.34 mmol, 4 equiv.) was added in one portion, and the resulting mixture was stirred at ambient temperature for 30 minutes. 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 (pH 7) in water (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 (4.6 mg, 12.5% ​​yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 7.36 - 7.28 (m, 2H), 7.27 - 7.18 (m, 3H), 6.22 (s, 1H), 5.12 - 5.08 (m, 1H), 3.93 (s, MS (APCI + ) m / z 436.4 [M+H] + .

[0128] Example I-29: 5-[(2R)-4-fluoro-6-hydroxy-2-({[2-(2,6,6-trimethylcyclohex-1-en-1-yl)ethyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 128) To a 4 mL vial was added the product of Example I-4I (30 mg, 0.08 mmol) and triethylamine (36 μL, 0.25 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (0.8 mL). 2-(2,6,6-trimethylcyclohex-1-en-1-yl)acetaldehyde (42.3 mg, 0.25 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (13.5 mg, 0.34 mmol, 4 equiv.) was added in one portion, and the resulting mixture was stirred at ambient temperature for 30 minutes. 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 (pH 7) in water (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 (5.4 mg, 13.7% yield). 1H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.24 (s, 1H), 5.18 - 5.07 (m, 1H), 3.94 (s, 2H), 3.40 - 3.26 (m, 3H), 2.99 - 2.85 (m, MS (APCI + ) m / z 468.4 [M+H] + .

[0129] Example I-30: 5-[(2R)-4-fluoro-6-hydroxy-2-({[(3-phenylcyclobutyl)methyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 129) To a 4 mL vial was added the product of Example I-4I (30 mg, 0.08 mmol) and triethylamine (36 μL, 0.25 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (0.8 mL). 3-Phenylcyclobutane-1-carbaldehyde (40.8 mg, 0.25 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (13.5 mg, 0.34 mmol, 4 equiv.) was added in one portion, and the reaction mixture was stirred at ambient temperature for 30 minutes. 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 (6.4 mg, 16.4% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 7.35 - 7.13 (m, 5H), 6.22 (s, 1H), 5.15 - 5.07 (m, 1H), 3.91 (s, 2H), 3.62 - 3.54 (m, 1H), 3.41 - 3.26 (m, 2H), 3.26 - 3.13 (m, 2H), 3.07 - 3.00 (m, 1H), 2.97 - 2.86 (m, 1H), 2.68 - 2.55 (m, 1H), 2.49 - 2.41 (m, 2H), 2.28 - 2.19 (m, 1H), 1.90 - 1.78 (m, 1H); MS (APCI + ) m / z 462.4 [M+H] + .

[0130] Example I-31: 5-{(2R)-4-fluoro-6-hydroxy-2-[({[4-(trifluoromethyl)cyclohexyl]methyl}amino)methyl]-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 130) To a 4 mL vial was added the product of Example I-4I (30 mg, 0.08 mmol) and triethylamine (36 μL, 0.25 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (0.8 mL). 4-(Trifluoromethyl)cyclohexane-1-carbaldehyde (45.8 mg, 0.25 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (13.5 mg, 0.34 mmol, 4 equiv.) was added in one portion, and the resulting mixture was stirred at ambient temperature for 30 minutes. 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 (pH 7) in water (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 (7.4 mg, 18.2% yield). 1H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.24 (s, 1H), 5.21 - 5.11 (m, 1H), 3.94 (s, 2H), 3.40 - 3.19 (m, 3H), 3.09 - 2.79 (m, MS (APCI + ) m / z 482.2 [M+H] + .

[0131] Example I-32: 5-{(2R)-4-fluoro-2-[({[1-(fluoromethyl)cyclopropyl]methyl}amino)methyl]-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 131) To a 4 mL vial was added the product of Example I-4I (30 mg, 0.08 mmol) and triethylamine (36 μL, 0.25 mmol, 3 equiv.) in 3:2 v / v ethanol / dichloromethane (0.8 mL). 1-(Fluoromethyl)cyclopropane-1-carbaldehyde (26.0 mg, 0.25 mmol, 3 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (13.5 mg, 0.34 mmol, 4.0 equiv.) was added in one portion, and the mixture was stirred at ambient temperature for 30 minutes. 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 5-60% 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 (2.0 mg, 5.9% yield). 1 H NMR (400 MHz, DMSO-d6:D2O = 9:1 (v / v)) δ ppm 6.20 (s, 1H), 5.04 - 4.92 (m, 1H), 4.43 (s, 1H), 4.30 (s, 1H), 3.99 (s, 2H), 3.30 - 3.20 (m, 1H), 3.01 - 2.77 (m, 3H), 2.65 - 2.60 (m, 2H), 0.57 - 0.52 (m, 4H);MS (APCI + ) m / z 404.3 [M+H] + .

[0132] Example II-1: 5-[(2S)-4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6,2,5-Thiadiazolidine-1,1,3-trione (Compound 132) Example II-1A: (2R)-2-[(tert-butoxycarbonyl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}propanoate methyl To a solution of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoate (33.6 g, 153 mmol) and tert-butyldimethylchlorosilane (25.4 g, 169 mmol) in tetrahydrofuran (260 mL) was added imidazole (25 g, 367 mmol) in portions over 15 minutes at 0 °C. The resulting mixture was warmed to room temperature and stirred for 18 hours. The reaction was quenched by the addition of methanol (15 mL). The resulting mixture was stirred for 5 minutes and then diluted sequentially with water (50 mL), brine (75 mL), and ethyl acetate (400 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The organic layers were combined, washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (59.8 g, 152 mmol, 99% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 5.34 (d, J = 8.9 Hz, 1H), 4.35 (dt, J = 9.0, 2.9 Hz, 1H), 4.04 (dd, J = 10.1, 2.8 Hz, 1H), 3.82 (dd, J = 10.1, 3.1 Hz, 1H), 3.74 (s, 3H), 1.45 (s, 9H), 0.86 (s, 9H), 0.02 (d, J = 5.4 Hz, 6H).

[0133] Example II-1B: tert-butyl [(2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxypropan-2-yl]carbamate To a solution of the product of Example II-1A (29.85 g, 76 mmol) in tetrahydrofuran (300 mL) was added lithium borohydride (2 M in tetrahydrofuran, 57 mL, 114 mmol) dropwise over 20 minutes at 0° C. The resulting colorless solution was slowly warmed to room temperature and stirred for 80 hours. The mixture was carefully diluted with saturated aqueous ammonium chloride (20 mL), water (75 mL), and ethyl acetate (400 mL). The resulting biphasic mixture was vigorously stirred for 20 minutes and then separated. The aqueous layer was extracted with ethyl acetate (2×100 mL). 1 M aqueous hydrochloric acid (100 mL) was slowly added to the rapidly stirred combined organic layers at 0° C. Upon completion of the addition, the mixture was stirred for an additional 10 minutes. The organic layer was separated, washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was taken up in 20% tert-butyl methyl ether in isohexane (200 mL) and filtered through a pad of a mixture of silica and diatomaceous earth (1:1, 5 × 5 cm), washing with 20% tert-butyl methyl ether in isohexane (3 × 50 mL). The filtrate was concentrated in vacuo to give the title compound (22.73 g, 63.2 mmol, 83% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 3.89 - 3.74 (m, 3H), 3.72 - 3.59 (m, 2H), 1.45 (s, 9H), 0.91 (d, J = 6.4 Hz, 9H), 0.09 (d, J = 9.4 Hz, 6H).

[0134] Example II-1C: (4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-oxo-1,2λ 4 ,3-Oxathiazolidine-3-carboxylic acid tert-butyl ester To a solution of imidazole (17.2 g, 253 mmol) and triethylamine (26.5 mL, 190 mmol) in dichloromethane (200 mL) at −40° C., a 1 M solution of thionyl chloride (76 mL, 76 mmol) in dichloromethane was added dropwise over 5 minutes. After 30 minutes, a solution of the product of Example II-1B (22.73 g, 63.2 mmol) in dichloromethane (45 mL) was added dropwise over 30 minutes via syringe pump. The mixture was allowed to warm slowly to room temperature and stirred for 20 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (125 mL). The aqueous layer was extracted with dichloromethane (2×125 mL). The combined organic layers were washed with brine (125 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was subjected to column chromatography (SiO2, 0-30% ethyl acetate in isohexane) to give the title compound (16.2 g, 41.5 mmol, 66% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 5.07 - 4.90 (m, 1H), 4.86 - 4.66 (m, 1H), 4.24 - 4.01 (m, 2H), 3.85 - 3.69 (m, 1H), 1.61 - 1.47 (m, 9H), 0.96 - 0.81 (m, 9H), 0.16 - 0.00 (m, 6H).

[0135] Example II-1D: (4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dioxo-1,2λ 6 ,3-Oxathiazolidine-3-carboxylic acid tert-butyl ester To a solution of the product of Example II-1C (16.2 g, 41.5 mmol) in acetonitrile (80 mL) and water (20 mL) at 0 °C, ruthenium(III) chloride, HO (0.05 g, 0.222 mmol), and sodium periodate (13.30 g, 62.2 mmol) were added. After 10 minutes, the mixture was filtered through a diatomaceous earth plug (3 × 3 cm), and the solid was washed with ethyl acetate (3 × 50 mL). The filtrate was washed with saturated aqueous sodium thiosulfate (100 mL). The aqueous layer was then extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed sequentially with saturated aqueous sodium thiosulfate (100 mL) and brine (100 mL). The mixture was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was subjected to column chromatography (SiO2, dry load on silica, 0-100% ethyl acetate in isohexane) to give the title compound (12.5 g, 32.3 mmol, 78% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 4.67 - 4.55 (m, 2H), 4.31 - 4.21 (m, 1H), 3.86 (dd, J = 10.2, 4.0 Hz, 1H), 3.83 - 3.70 (m, 1H), 1.55 (s, 9H), 0.89 (s, 9H), 0.08 (d, J = 2.7 Hz, 6H).

[0136] Example II-1E: 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 To a solution of diisopropylamine (4.30 mL, 30.2 mmol) in tetrahydrofuran (65 mL) was added 2.5 M n-butyllithium in hexane (12.0 mL, 30.0 mmol) dropwise over 10 minutes at −78° C. After 15 minutes, a solution of the product of Example I-3C (5.25 g, 13.12 mmol) in tetrahydrofuran (20 mL) was added dropwise over 45 minutes using a syringe pump, while maintaining the temperature below −74° C. After 30 minutes, a solution of the product of Example II-1D (5.33 g, 13.78 mmol) in tetrahydrofuran (15 mL) was added dropwise over 45 minutes using a syringe pump, and the resulting solution was stirred for an additional 90 minutes while maintaining the temperature below −74° C. The reaction was slowly quenched with 1 M aqueous hydrochloric acid (35 mL), and the mixture was allowed to warm to room temperature over 20 minutes. 1M aqueous hydrochloric acid (25 mL) was added and the mixture was stirred at room temperature for an additional 30 minutes. The mixture was diluted with ethyl acetate (200 mL), the layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was subjected to column chromatography (SiO2, dry loaded on silica, 0-10% ethyl acetate in isohexane) to give the title compound (8.06 g, 10.67 mmol, 81% yield, 90% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 7.44 - 7.29 (m, 5H), 7.05 (d, J = 1.8 Hz, 1H), 5.16 - 4.98 (m, 2H), 4.83 (d, J = 9.6 Hz, 1H), 3.99 (s, 1H), 3.68 (d, J = 3.7 Hz, 2H), 3.05 (ddd, J = 12.7, 10.1, 2.4 Hz, 1H), 2.91 (d, J = 14.1 Hz, 1H), 1.38 - 1.13 (m, 9H), 0.93 (s, 9H), 0.08 (d, J = 1.7 Hz, 6H);MS (ESI + ) m / z 579 ( 79 Br), 581 ( 81 Br) [MC(O)OC(CH3)3+H] + .

[0137] Example II-1F: [{6-(benzyloxy)-4-bromo-3-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}propyl]-2-fluorophenyl}(trifluoroacetyl)amino]acetate methyl Methyl bromoacetate (1.1 mL, 11.94 mmol) was added to a suspension of the product of Example II-1E (8.06 g, 10.67 mmol), potassium carbonate (2.95 g, 21.35 mmol), and potassium iodide (1.78 g, 10.72 mmol) in acetone (15 mL) at room temperature. The mixture was then stirred at 60° C. for 5 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate (150 mL) and saturated aqueous ammonium chloride solution (150 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was subjected to column chromatography (SiO, dry load on silica, 0-40% ethyl acetate in isohexane) to give the title compound (8.4 g, 9.50 mmol, 89% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 7.45 - 7.29 (m, 5H), 7.07 (d, J = 7.8 Hz, 1H), 5.11 - 4.98 (m, 2H), 4.82 - 4.67 (m, 1H), 4.53 (dd, J = 24.1, 16.9 Hz, 1H), 4.08 - 3.89 (m, 2H), 3.72 - 3.58 (m, 5H), 3.10 - 2.84 (m, 2H), 1.43 - 1.19 (m, 9H), 1.00 - 0.85 (m, 9H), 0.15 - -0.05 (m, 6H);MS (ESI + ) m / z 773 ( 79 Br), 775 ( 81 Br) [M+Na] + .

[0138] Example II-1G: (2S)-6-(benzyloxy)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-fluoro-5-[(2-methoxy-2-oxoethyl)(trifluoroacetyl)amino]-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Nitrogen was bubbled through a mixture of the product of Example II-1F (4.2 g, 4.75 mmol) and cesium carbonate (4.6 g, 14.12 mmol) in tetrahydrofuran (20 mL) and water (2 mL) for 10 minutes. RuPhos Pd G3 (0.4 g, 0.478 mmol) was added, and nitrogen was bubbled through the mixture for an additional 5 minutes before stirring at 80 °C for 8 hours. The mixture was cooled to room temperature, filtered through a pad of diatomaceous earth (3 × 3 cm), and washed with ethyl acetate (2 × 100 mL). The crude residue was subjected to column chromatography (SiO2, dry load on silica, 0-25% ethyl acetate in isohexane) to give the title compound (3.2 g, 4.77 mmol, 100% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 7.55 - 7.29 (m, 6H), 5.15 - 4.98 (m, 2H), 4.64 (dd, J = 16.8, 6.1 Hz, 1H), 4.49 (s, 1H), 3.89 (dd, J = 16.8, 13.1 Hz, 1H), 3.77 - 3.67 (m, 2H), 3.65 (d, J = 6.2 Hz, 3H), 3.22 - 3.04 (m, 2H), 1.56 (s, 9H), 0.75 (d, J = 20.6 Hz, 9H), 0.04 - -0.10 (m, 6H);MS (ESI + ) m / z 694 [M+H] + .

[0139] Example II-1H: (2S)-6-(benzyloxy)-4-fluoro-2-(hydroxymethyl)-5-[(2-methoxy-2-oxoethyl)(trifluoroacetyl)amino]-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-1G (3.5 g, 5.22 mmol) in tetrahydrofuran (25 mL) at room temperature was added 1 M tetra-N-butylammonium fluoride (5.8 mL, 5.80 mmol) in tetrahydrofuran. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The crude residue was subjected to column chromatography (SiO, dry loaded on silica, 0-60% ethyl acetate in isohexane) to give the title compound (2.41 g, 4.33 mmol, 83% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 7.53 - 7.18 (m, 6H), 5.14 - 4.98 (m, 2H), 4.73 - 4.53 (m, 2H), 3.92 (d, J = 16.9 Hz, 1H), 3.87 - 3.71 (m, 2H), 3.65 (d, J = 4.4 Hz, 3H), 3.27 (td, J = 15.9, 10.1 Hz, 1H), 2.96 (d, J = 15.8 Hz, 1H), 1.76 - 1.45 (m, 9H); - ) m / z 555 [MH] - .

[0140] Example II-1I: (2S)-6-(benzyloxy)-4-fluoro-2-formyl-5-[(2-methoxy-2-oxoethyl)(trifluoroacetyl)amino]-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Dess-Martin periodinane (1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one) (300 mg, 0.707 mmol) was added to a solution of the product of Example II-1H (400 mg, 0.647 mmol) in dichloromethane (0.5 mL) at 0° C. The reaction mixture was then allowed to warm slowly to room temperature and stirred for 18 hours. Saturated aqueous sodium thiosulfate (15 mL) and sodium bicarbonate (15 mL) were added, and the biphasic mixture was diluted with dichloromethane (30 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (3×15 mL) and brine (15 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound (398 mg, 0.574 mmol, 89% yield, 80% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 9.65 (d, J = 19.1 Hz, 1H), 7.43 - 7.29 (m, 6H), 5.17 - 5.02 (m, 2H), 4.94 - 4.79 (m, 1H), 4.67 (d, J = 16.8 Hz, MS (ESI + ) m / z 455 [MC(O)OC(CH3)3+H] + .

[0141] Example II-1J: (2S)-6-(benzyloxy)-4-fluoro-5-[(2-methoxy-2-oxoethyl)(trifluoroacetyl)amino]-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-1I (398 mg, 0.574 mmol) in degassed 1,2-dichloroethane (2 mL), 2-methylpropan-1-amine (110 μL, 1.107 mmol) was added, followed by acetic acid (60 μL, 1.048 mmol). The resulting solution was stirred at room temperature for 20 minutes. Additional 2-methylpropan-1-amine (40 μL, 0.403 mmol) was added, followed by acetic acid (20 μL, 0.349 mmol), and the reaction mixture was stirred at room temperature for 25 minutes. Sodium triacetoxyborohydride (180 mg, 0.849 mmol) was then added, and the mixture was stirred for 45 minutes. The reaction mixture was diluted with water (15 mL) and dichloromethane (20 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 15 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was subjected to column chromatography (12 g SiO2 cartridge, dry loaded on silica, 0-100% ethyl acetate in isohexane) to give the title compound (190 mg, 0.249 mmol, 43% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 7.44 - 7.29 (m, 6H), 5.12 - 5.00 (m, 2H), 4.65 (dd, J = 16.8, 2.5 Hz, 1H), 3.97 - 3.87 (m, 1H), 3.65 (d, J = 4.8 Hz, 3H), 3.36 - 3.11 (m, 2H), 3.10 - 2.71 (m, 2H), 2.68 - 2.34 (m, 1H), 2.07 (s, 2H), 1.91 - 1.74 (m, 1H), 1.62 - 1.48 (m, 9H), 1.01 - 0.83 (m, 6H);MS (ESI + ) m / z 613 [M+H] + .

[0142] Example II-1K: (2S)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methylpropyl)amino]methyl}-4-fluoro-5-[(2-methoxy-2-oxoethyl)(trifluoroacetyl)amino]-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-1J (220 mg, 0.306 mmol) in acetonitrile (3 mL) was added N,N-diisopropylethylamine (0.16 mL, 0.916 mmol) and di-tert-butyl dicarbonate (130 mg, 0.596 mmol) at room temperature. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water (10 mL), diluted with dichloromethane (10 mL), and the layers were separated. The aqueous layer was extracted with dichloromethane (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was subjected to column chromatography (SiO, dry loaded on silica, 12 g cartridge, 0-40% ethyl acetate in isohexane) to afford the title compound (210 mg, 0.280 mmol, 92% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 7.64 - 7.29 (m, 6H), 5.19 - 4.95 (m, 2H), 4.64 (t, J = 16.3 Hz, 2H), 3.92 (dd, J = 16.8, 11.0 Hz, 1H), 3.65 (s, 3H), 3.49 (s, 1H), 3.38 - 3.24 (m, 1H), 3.24 - 2.76 (m, 4H), 2.13 - 1.84 (m, 1H), 1.65 - 1.51 (m, 9H), 1.41 (d, J = 12.3 Hz, 9H), 0.96 - 0.73 (m, 6H);MS (ESI + ) m / z 613 [MC(O)OC(CH3)3+H] + .

[0143] Example II-1L: tert-butyl (2S)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methylpropyl)amino]methyl}-4-fluoro-5-[(2-methoxy-2-oxoethyl)amino]-2,3-dihydro-1H-indole-1-carboxylate To a solution of the product of Example II-1K (520 mg, 0.694 mmol) in methanol (2.5 mL) was added sodium methoxide (0.39 mL, 2.106 mmol) at room temperature. The mixture was then stirred at 50° C. for 1 hour, cooled to room temperature, and diluted with water (10 mL) and tert-butyl methyl ether (15 mL). To the cloudy two-phase mixture was added saturated aqueous ammonium chloride solution (10 mL). The aqueous layer was extracted with tert-butyl methyl ether (3×20 mL). The combined organic layers were washed with brine (15 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound (460 mg, 0.523 mmol, 75% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 7.63 - 7.07 (m, 6H), 5.23 - 5.01 (m, 2H), 4.82 - 4.48 (m, 2H), 3.99 - 3.77 (m, 2H), 3.60 - 3.19 (m, 3H), 3.20 - 2.80 (m, 5H), 2.12 - 1.79 (m, 2H), 1.56 (d, J = 4.2 Hz, 9H), 1.41 (s, 9H), 0.87 (s, 6H);MS (ESI + ) m / z 517 [MC(O)OC(CH3)3+H] + .

[0144] Example II-1M: tert-butyl (2S)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methylpropyl)amino]methyl}-4-fluoro-5-[(2-methoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-2,3-dihydro-1H-indole-1-carboxylate To a solution of chlorosulfonyl isocyanate (0.11 mL, 1.267 mmol) in dichloromethane (1 mL) was added allyl alcohol (90 μL, 1.323 mmol) dropwise at 0° C. The resulting solution was stirred at 0° C. for 20 minutes, and then a solution of the product of Example II-1L (460 mg, 0.523 mmol) and triethylamine (0.25 mL, 1.794 mmol) in dichloromethane (2 mL) was added dropwise. The resulting solution was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water (10 mL) and diluted with dichloromethane (20 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was subjected to column chromatography (SiO2, dry load on silica, 24 g cartridge, 0-35% ethyl acetate in isohexane) to give the title compound (277 mg, 0.249 mmol, 48% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 7.51 - 7.30 (m, 6H), 5.85 - 5.70 (m, 1H), 5.51 - 5.18 (m, 2H), 5.17 - 5.06 (m, 2H), 4.90 - 4.49 (m, 3H), 4.45 - 4.24 (m, 4H), 3.73 - 3.59 (m, 3H), 3.58 - 2.90 (m, 5H), 2.10 - 1.83 (m, 1H), 1.57 (d, J = 15.8 Hz, 9H), 1.42 (s, 9H), 0.88 (t, J = 6.2 Hz, 6H);MS (ESI + ) m / z 801 [M+Na] + .

[0145] Example II-1N: (2S)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methylpropyl)amino]methyl}-4-fluoro-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia To a solution of the product of Example II-1M (230 mg, 0.207 mmol) and potassium carbonate (110 mg, 0.796 mmol) in methanol (1.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol). The reaction mixture was stirred at 60° C. for 30 minutes. The mixture was cooled to room temperature and diluted with methanol (5 mL). Diatomaceous earth was added, and the mixture was concentrated in vacuo. The crude residue was subjected to column chromatography (Reveleris® 24 g reverse-phase (C18) flash cartridge, dry loaded with diatomaceous earth, 5-70% methanol in 10 mM ammonium bicarbonate) to give the title compound as the ammonium salt (133 mg, 0.147 mmol, 71% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.71 - 7.45 (m, 5H), 7.42 - 7.22 (m, 1H), 7.06 (s, 3H), 5.09 (s, 2H), 4.65 (s, 1H), 4.00 - 3.79 (m, 2H), MS (ESI + ) m / z 563 [MC(O)OC(CH3)3+H] + .

[0146] Example II-1O: (2S)-2-{[(tert-butoxycarbonyl)(2-methylpropyl)amino]methyl}-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia To a suspension of the product of Example II-1N (130 mg, 0.143 mmol) in degassed water (0.1 mL) and ethanol (2 mL), 10% Pd / C (15 mg) was added. The resulting suspension was stirred under hydrogen (5 bar) for 1.5 hours. Additional 10% Pd / C (23 mg) was added, and the reaction mixture was stirred under hydrogen (5 bar) for 4 hours. Additional 10% Pd / C (23 mg, 0.022 mmol) was added, and the reaction mixture was stirred under hydrogen (5 bar) for 18 hours. The reaction mixture was filtered through a pad of diatomaceous earth and washed with ethanol (3 × 20 mL). The filtrate was concentrated in vacuo. The crude residue was subjected to column chromatography (Reveleris® 24 g reverse phase (C18) flash cartridge, dry loaded with diatomaceous earth, 5-55% methanol in 10 mM ammonium bicarbonate) to afford the title compound as the ammonium salt (51 mg, 0.082 mmol, 57% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.22 - 6.78 (m, 4H), 4.61 (d, J = 7.9 Hz, 1H), 3.97 - 3.77 (m, 2H), 3.47 - 3.13 (m, 3H), 3.11 - 2.87 (m, MS (ESI - ) m / z 571 [MH] - .

[0147] Example II-1P: 5-[(2S)-4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a solution of the product of Example II-1O (50 mg, 0.081 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.09 mL, 1.168 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with 0.7 M NH3 (5 mL) in methanol:water (95:5) and concentrated in vacuo. The crude residue was subjected to column chromatography (Reveleris® 12 g reverse-phase (C18) flash cartridge, dry loaded with diatomaceous earth, 5-20% methanol in 10 mM ammonium bicarbonate) to give the title compound (7.48 mg, 0.020 mmol, 25% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (s, 1H), 8.18 (s, 2H), 6.02 (s, 1H), 5.93 (s, 1H), 4.20 - 4.07 (m, 1H), 3.84 (s, 2H), 3.18 - 2.93 (m, 3H), 2.87 - 2.62 (m, 3H), 1.97 (septet, J = 6.8 Hz, 1H), 0.95 (d, J = 6.7 Hz, 6H);MS (ESI + ) m / z 373 [M+H] + .

[0148] Example II-2: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 133) Example II-2A: (2S)-2-[(tert-butoxycarbonyl)amino]-3-{[tri(propan-2-yl)silyl]oxy}propanoic acid methyl ester To a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoate (50 g, 228 mmol) and triisopropylchlorosilane (53 mL, 250 mmol) in tetrahydrofuran (450 mL) was added imidazole (34.2 g, 502 mmol) in portions at 0° C. The resulting mixture was warmed to room temperature and stirred for 18 hours. The reaction was quenched by the addition of methanol (20 mL). The resulting mixture was stirred for 5 minutes and then diluted sequentially with 1:1 water:brine (500 mL) and ethyl acetate (300 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×300 mL). The organic layers were combined, washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was subjected to plug chromatography (SiO2, 500 g, 10% ethyl acetate in isohexane) to give the title compound (81.3 g, 195 mmol, 85% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.85 (d, J = 8.2 Hz, 1H), 4.18 (dt, J = 8.2, 5.6 Hz, 1H), 3.88 (d, J = 5.6 Hz, 2H), 3.62 (s, 3H), 1.37 (s, 9H), 1.16 - 0.93 (m, 21H).

[0149] Example II-2B: tert-butyl [(2R)-1-hydroxy-3-{[tri(propan-2-yl)silyl]oxy}propan-2-yl]carbamate To a solution of the product of Example II-2A (81.3 g, 195 mmol) in tetrahydrofuran (500 mL) was added lithium borohydride (2 M in tetrahydrofuran, 136 mL, 273 mmol) dropwise at 0° C. over 1 hour and 20 minutes. The resulting solution was slowly warmed to room temperature and stirred for 80 hours. The mixture was carefully diluted with saturated aqueous ammonium chloride (50 mL), water (100 mL), and ethyl acetate (200 mL). The resulting biphasic mixture was vigorously stirred for 20 minutes. The layers were separated. The aqueous layer was extracted with ethyl acetate (2×200 mL). 1 M aqueous hydrochloric acid (100 mL) was slowly added to the rapidly stirred combined organic layers at 0° C. Upon completion of the addition, the mixture was stirred for an additional 10 minutes. The organic layer was separated, washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (75.8 g, 195 mmol, 100% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.31 (d, J = 8.2 Hz, 1H), 4.53 (t, J = 5.6 Hz, 1H), 3.72 - 3.53 (m, 2H), 3.53 - 3.43 (m, 1H), 3.43 - 3.34 (m, 2H), 1.37 (s, 9H), 1.14 - 0.94 (m, 21H).

[0150] Example II-2C: (4S)-2-oxo-4-({[tri(propan-2-yl)silyl]oxy}methyl)-1,2λ 4 ,3-Oxathiazolidine-3-carboxylic acid tert-butyl ester To a solution of imidazole (21.5 g, 316 mmol) and triethylamine (87 mL, 622 mmol) in dichloromethane (300 mL) at −60° C., thionyl chloride (18.4 mL, 252 mmol) was added dropwise over 15 minutes. After 30 minutes, a solution of the product of Example II-2B (75.8 g, 196 mmol) in dichloromethane (100 mL) was added dropwise over 45 minutes. The mixture was allowed to warm slowly to room temperature and stirred for 18 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (400 mL), and the layers were separated. The aqueous layer was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (125 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was subjected to plug chromatography (SiO2, 10% ethyl acetate in isohexane) to give the title compound (76.8 g, 176 mmol, 89% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 5.13 - 4.92 (m, 1H), 4.88 - 4.71 (m, 1H), 4.27 - 4.13 (m, 1H), 4.13 - 4.04 (m, 1H), 3.89 - 3.76 (m, 1H), 1.52 (s, 9H), 1.18 - 0.93 (m, 21H).

[0151] Example II-2D: (4S)-2,2-dioxo-4-({[tri(propan-2-yl)silyl]oxy}methyl)-1,2λ 6 ,3-Oxathiazolidine-3-carboxylic acid tert-butyl ester To a solution of the product of Example II-2C (10 g, 24.14 mmol) in acetonitrile (100 mL) and water (24 mL) at 0 °C, ruthenium(III) chloride, HO (0.027 g, 0.121 mmol), followed by sodium periodate (7.74 g, 36.2 mmol) were added. After 45 min, the mixture was filtered through a plug of diatomaceous earth, and the solid was washed with ethyl acetate (5 × 50 mL). The filtrate was stirred with saturated aqueous sodium thiosulfate (150 mL) for 10 min. The layers were then separated, and the aqueous layer was extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO2, 120 g, 0-100% dichloromethane in isohexane) to give the title compound (9.518 g, 22.77 mmol, 94% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 4.69 (dd, J = 9.2, 2.1 Hz, 1H), 4.61 (ddd, J = 9.2, 5.9, 0.9 Hz, 1H), 4.29 (dddd, J = 8.3, 6.1, 4.1, 2.1 Hz, 1H), 3.97 (ddd, J = 9.9, 4.1, 0.9 Hz, 1H), 3.86 (dd, J = 9.9, 8.7 Hz, 1H), 1.55 (s, 9H), 1.16 - 1.01 (m, 21H).

[0152] Example II-2E: tert-butyl [(2R)-1-[4-(benzyloxy)-6-bromo-2-fluoro-3-(2,2,2-trifluoroacetamido)phenyl]-3-{[tri(propan-2-yl)silyl]oxy}propan-2-yl]carbamate To a solution of diisopropylamine (7.5 mL, 53.1 mmol) in tetrahydrofuran (80 mL), butyllithium (1.73 M in hexanes) (30 mL, 51.9 mmol) was added dropwise over 15 minutes at −78° C., maintaining the temperature below −63° C. After stirring the solution at −78° C. for 30 minutes, a solution of the product of Example I-3C (10 g, 24.23 mmol) in tetrahydrofuran (40 mL) was added dropwise over 45 minutes using a syringe pump, maintaining the temperature below −67° C. The resulting solution was stirred at −78° C. for 2 hours, after which a solution of the product of Example II-2D (10.6 g, 25.5 mmol) in tetrahydrofuran (40 mL) was added dropwise over 30 minutes using a syringe pump, maintaining the temperature below −67° C. The resulting solution was allowed to stir at −78° C. for 1 hour, then slowly quenched with 1 M aqueous hydrochloric acid (120 mL, 120 mmol) and vigorously stirred at room temperature for 5 minutes. The biphasic mixture was diluted with ethyl acetate (100 mL) and stirred for 5 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 330 g reverse-phase (C18) flash cartridge, dry loaded with diatomaceous earth, 50-100% acetonitrile in water with 0.1% trifluoroacetic acid) to afford the title compound (9.75 g, 13.51 mmol, 53% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.03 (s, 1H), 7.43 - 7.28 (m, 6H), 6.55 - 6.45 (m, 1H), 5.20 (s, 2H), 3.97 - 3.81 (m, 1H), 3.62 (d, J = MS (ESI + ) m / z 621 / 623 [MC(O)OC(CH3)3+H] + .

[0153] Example II-2F: tert-butyl [{6-(benzyloxy)-4-bromo-3-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-{[tri(propan-2-yl)silyl]oxy}propyl]-2-fluorophenyl}(trifluoroacetyl)amino]acetate To a solution of the product of Example II-2E (15.14 g, 19.30 mmol) in acetone (150 mL) was added tert-butyl 2-bromoacetate (3.4 mL, 23.02 mmol), potassium carbonate (6.0 g, 43.46 mmol), and potassium iodide (3.86 g, 23.26 mmol). The resulting suspension was stirred at 55 °C for 2 h and then cooled to room temperature. The solvent was removed, and the residue was partitioned between saturated aqueous ammonium chloride (100 mL) and ethyl acetate (100 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude residue was subjected to column chromatography (SiO, 220 g, 0-30% ethyl acetate in isohexane) to give the title compound (12.82 g, 15.30 mmol, 77%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.47 - 7.29 (m, 6H), 6.52 (d, J = 9.2 Hz, 0.4H), 6.37 (d, J = 9.5 Hz, 0.6H), 5.29 - 5.14 (m, 2H), 4.42 - 4.28 (m, 1H), 4.00 - 3.91 (m, 1H), 3.91 - 3.77 (m, 1H), 3.68 - 3.51 (m, 2H), 2.98 - 2.84 (m, 1H), 2.81 - 2.64 (m, 1H), 1.39 (s, 4H), 1.38 (s, 5H), 1.30 (s, 4H), 1.26 (s, 5H), 1.05 - 0.96 (m, 21H);MS (ESI + ) m / z 858 [M+Na] + .

[0154] Example II-2G: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2-({[tri(propan-2-yl)silyl]oxy}methyl)-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-2F (13.9 g, 15.30 mmol) in dioxane (40 mL) was added a solution of cesium carbonate (9.97 g, 30.6 mmol) in water (4 mL) and BrettPhos (1.232 g, 2.295 mmol). The resulting mixture was degassed under vacuum and backfilled with nitrogen three times. BrettPhos Pd G3 (1.387 g, 1.530 mmol) was added to the mixture, and the reaction mixture was degassed under vacuum and backfilled with nitrogen three times. The reaction mixture was then stirred at 70 °C for 16 h. The reaction mixture was then cooled to room temperature and filtered through a short pad of diatomaceous earth, which was rinsed with ethyl acetate (3 × 30 mL). The filtrate was washed with water (30 mL) and then with brine (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was subjected to column chromatography (SiO2, 220 g cartridge, 0-50% (5% tert-butyl methyl ether in toluene) in isohexane. The resulting crude residue was re-subjected to column chromatography (SiO2, 220 g cartridge, 0-10% tetrahydrofuran in isohexane) to give the title compound (10.10 g, 13.38 mmol, 79% yield).

[0155] Example II-2H: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2-(hydroxymethyl)-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-2G (4.6 g, 5.61 mmol) in tetrahydrofuran (30 mL) at room temperature was added 1 M tetra-N-butylammonium fluoride (6.2 mL, 6.17 mmol) in tetrahydrofuran. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The crude residue was subjected to column chromatography (SiO, 80 g, dry loaded on silica, 0-60% ethyl acetate in isohexane) to give the title compound (3.42 g, 5.09 mmol, 91% yield, 89% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.52 - 7.28 (m, 6H), 5.21 - 5.04 (m, 2H), 4.98 (dt, J = 11.3, 5.9 Hz, 1H), 4.51 - 4.35 (m, 2H), 4.09 - 3.91 (m, 1H), 3.60 - 3.42 (m, 2H), 3.24 - 3.11 (m, 2H), 1.50 (s, 9H), 1.38 (s, 9H);MS (ESI + ) m / z 622 [M+Na] + .

[0156] Example II-2I: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2-formyl-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Dess-Martin periodinane (1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one) (2.379 g, 5.61 mmol) was added to a solution of the product of Example II-2H (3.43 g, 5.10 mmol) in dichloromethane (25 mL) at 0° C. The reaction mixture was then slowly warmed to room temperature and stirred for 3 hours. Saturated aqueous sodium thiosulfate (15 mL) and sodium bicarbonate (15 mL) were added, and the biphasic mixture was stirred for 15 minutes. It was then diluted with dichloromethane (30 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 20 mL). The combined organic layers were washed with saturated aqueous sodium thiosulfate (3 × 15 mL), saturated aqueous sodium bicarbonate (3 × 15 mL), and brine (15 mL). The organic fraction was dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound (3.44 g, 4.61 mmol, 90% yield, 80% purity). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 9.63 (dd, J = 7.0, 1.3 Hz, 1H), 7.54 - 7.26 (m, 6H), 5.30 - 5.01 (m, 3H), 4.42 (dd, J = 16.5, 3.3 Hz, 1H), 3.90 (dd, J = 16.5, 3.9 Hz, 1H), 3.46 - 3.31 (m, 1H), 3.16 (ddd, J = 15.9, 10.4, 4.9 Hz, 1H), 1.50 (s, 9H), 1.39 (d, J = 4.4 Hz, 9H).

[0157] Example II-2J: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-2I (3.92 g, 5.26 mmol) in 1,2-dichloroethane (24 mL), 2-methylpropan-1-amine (1.567 mL, 15.77 mmol) was added, followed by acetic acid (903 μL, 15.77 mmol). The resulting solution was stirred at room temperature for 40 minutes. Sodium triacetoxyborohydride (1.671 g, 7.89 mmol) was then added, and the mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL) and stirred for 10 minutes. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (4.01 g, 5.28 mmol, 100% yield, 86% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.50 - 7.24 (m, 6H), 5.23 - 5.03 (m, 2H), 4.54 - 4.35 (m, 2H), 3.96 (dd, J = 16.7, 2.3 Hz, 1H), 3.90 (s, 2H), 3.23 - 3.08 (m, 1H), 3.07 - 2.95 (m, 1H), 2.81 - 2.70 (m, 1H), 2.41 - 2.23 (m, 2H), 1.66 - 1.55 (m, 1H), 1.50 (s, 9H), 1.38 (s, 9H), 0.96 - 0.74 (m, 6H);MS (ESI + ) m / z 654 [M+H] + .

[0158] Example II-2K: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methylpropyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-2J (4.01 g, 5.28 mmol) in acetonitrile (30 mL) was added N,N-diisopropylethylamine (2.76 mL, 15.83 mmol) and di-tert-butyl dicarbonate (2.303 mg, 10.55 mmol) at room temperature. The mixture was stirred at room temperature for 30 minutes. The reaction was quenched with water (30 mL). The aqueous layer was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO, 80 g cartridge, 0-20% ethyl acetate in isohexane) to give the title compound (3.59 g, 4.52 mmol, 86% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.54 - 7.24 (m, 6H), 5.24 - 5.06 (m, 2H), 4.78 - 4.63 (m, 1H), 4.44 (dd, J = 16.5, 9.6 Hz, 1H), 3.98 - 3.80 (m, 1H), 3.52 - 3.28 (m, 2H), 3.24 - 3.10 (m, 1H), 3.06 - 2.84 (m, 3H), 1.95 - 1.85 (m, 1H), 1.54 (d, J = 2.3 Hz, 9H), 1.46 - 1.29 (m, 18H), 0.94 - 0.78 (m, 6H); MS (ESI + ) m / z 777 [M+Na] + .

[0159] Example II-2L: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methylpropyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Lithium hydroxide (2M aqueous) (5.71 mL, 11.41 mmol) was added to a solution of the product of Example II-2K (3.019 g, 3.80 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized to pH 7 with concentrated hydrochloric acid. The reaction was diluted with ethyl acetate (50 mL) and water (50 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (2.77 g, 3.71 mmol, 97% yield, 88% purity). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.54 - 7.24 (m, 5H), 7.18 (s, 1H), 5.09 (s, 2H), 4.61 (dddd, J = 9.3, 7.5, 5.6, 2.1 Hz, 1H), 3.85 (d, J = 2.0 Hz, 2H), 3.45 - 3.21 (m, 2H), 3.08 - 3.01 (m, 1H), 3.00 (d, J = 7.4 Hz, 2H), 2.84 (dd, J = 15.8, 2.1 Hz, 1H), 1.99 - 1.81 (m, 1H), 1.60 - 1.46 (m, 9H), 1.46 - 1.22 (m, 18H), 0.94 - 0.74 (m, 6H);MS (ESI + ) m / z 658 [M+H] + .

[0160] Example II-2M: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methylpropyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of chlorosulfonyl isocyanate (0.6 mL, 6.91 mmol) in dichloromethane (18 mL) was added allyl alcohol (0.5 mL, 7.35 mmol) dropwise at 0° C. The resulting solution was stirred at 0° C. for 20 minutes, and then a solution of the product of Example II-2L (2.77 g, 3.71 mmol) and triethylamine (1.3 mL, 9.33 mmol) in dichloromethane (18 mL) was added dropwise. The resulting solution was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water (50 mL) and diluted with dichloromethane (50 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was subjected to column chromatography (SiO2, 80 g cartridge, 0-40% tert-butyl methyl ether in isohexane) to give the title compound (2.7 g, 2.80 mmol, 66% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.58 - 7.13 (m, 6H), 6.45 (s, 1H), 6.02 - 5.83 (m, 1H), 5.31 - 4.96 (m, 4H), 4.69 (s, 1H), 4.30 - 4.19 (m, 1H), 3.96 (dt, J = 4.8, 1.7 Hz, 1H), 3.31 (dd, J = 13.9, 5.9 Hz, 1H), 3.20 - 2.96 (m, 3H), 2.86 (t, J = 16.7 Hz, 1H), 1.97 - 1.84 (m, 1H), 1.61 - 1.44 (m, MS (ESI + ) m / z 844 [M+Na] + .

[0161] Example II-2N: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methylpropyl)amino]methyl}-4-fluoro-5-(1,1,4-trioxo-1λ) 6,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia To a solution of the product of Example II-2M (2.7 g, 2.8 mmol) and potassium carbonate (1.545 mg, 11.18 mmol) in methanol (15 mL) was added tetrakis(triphenylphosphine)palladium(0) (323 mg, 0.280 mmol). The reaction mixture was stirred at 60° C. for 1 hour. The mixture was cooled to room temperature and diluted with methanol (10 mL). Diatomaceous earth was added, and the mixture was concentrated in vacuo. The crude residue was subjected to column chromatography (Reveleris® 80 g reverse-phase (C18) flash cartridge, dry loaded with diatomaceous earth, 5-70% methanol in 10 mM ammonium bicarbonate) to give the title compound as the ammonium salt (1.50 g, 1.765 mmol, 63% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.72 - 7.14 (m, 6H), 5.16 - 5.02 (m, 2H), 4.74 - 4.62 (m, 1H), 3.95 (d, J = 13.0 Hz, 1H), 3.88 (d, J = 13.0 Hz, 1H), 3.47 - 3.25 (m, 2H), 3.18 - 2.93 (m, 6H), 2.91 - 2.79 (m, 1H), 1.94 (septet, J = 6.9 Hz, 1H), 1.52 (s, 9H), 1.37 (s, 9H), 0.84 (dd, J = 6.7, 1.6 Hz, 6H); MS (ESI + ) m / z 685 [M+Na] + .

[0162] Example II-2O: (2R)-2-{[(tert-butoxycarbonyl)(2-methylpropyl)amino]methyl}-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia To a suspension of the product of Example II-2N (500 mg, 0.588 mmol) in degassed water (0.1 mL) and ethanol (4 mL) was added 10% Pd / C (125 mg). The resulting suspension was stirred under hydrogen (5 bar) for 24 hours. The reaction mixture was filtered through Whatman glass fiber filter paper and washed with ethanol (3 × 20 mL). The filtrate was concentrated in vacuo. The crude residue was subjected to column chromatography (Reveleris® 40 g reverse-phase (C18) flash cartridge, dry loaded with diatomaceous earth, 5-55% methanol in 10 mM ammonium bicarbonate) to give the title compound as the ammonium salt (188 mg, 0.303 mmol, 52% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.77 - 7.02 (br s, 4H) 7.00 (s, 1H), 4.64 (dddd, J = 9.2, 7.4, 5.6, 2.0 Hz, 1H), 3.99 - 3.82 (m, 2H), 3.35 (qd, J = 14.1, 6.4 Hz, 2H), 3.13 - 2.93 (m, 3H), 2.82 (dd, J = 15.7, 2.0 Hz, 1H), 2.04 (s, 1H), 1.94 (septet, J = 6.9 Hz, 1H), 1.53 (s, 9H), 1.37 (s, 9H), 0.84 (dd, J = 6.7, 1.8 Hz, 6H);MS (ESI + ) m / z 595 [M+Na] + .

[0163] Example II-2P: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a solution of the product of Example II-2O (80 mg, 0.129 mmol) in dichloromethane (1 mL) at room temperature was added trifluoroacetic acid (0.1 mL, 1.298 mmol). The reaction mixture was stirred at room temperature for 2 hours. A second aliquot of trifluoroacetic acid (0.1 mL, 1.298 mmol) was added, and the reaction was stirred for an additional 2 hours. A third aliquot of trifluoroacetic acid (0.1 mL, 1.298 mmol) was added, and the reaction was stirred for an additional 30 minutes. The reaction mixture was neutralized with 0.7 M NH3 in methanol:water (95:5) (7 mL) and concentrated under reduced pressure onto diatomaceous earth (1 g). The crude residue was subjected to column chromatography (Reveleris® 24 g, reverse phase (C18) flash cartridge, dry loaded with diatomaceous earth, 5-20% methanol in 10 mM ammonium bicarbonate) to afford the title compound (34 mg, 0.089 mmol, 69% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (s, 1H), 8.11 (br s, 2H), 6.02 (s, 1H), 5.92 (s, 1H), 4.26 - 4.04 (m, 1H), 3.84 (s, 2H), 3.10 (dd, J = 15.5, 9.3 Hz, 1H), 3.06 - 2.93 (m, 2H), 2.83 - 2.76 (m, 2H), 2.73 (dd, J = 15.5, 6.8 Hz, 1H), 1.96 (septet, J = 6.4 Hz, 1H), 0.95 (d, J = 6.7 Hz, 6H);MS (ESI + ) m / z 373 [M+H] + .

[0164] Example II-3: 5-[(2R)-2-{[(2-ethylbutyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 134) Example II-3A: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-2-{[(2-ethylbutyl)amino]methyl}-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Acetic acid (0.25 mL, 4.37 mmol) was added to a solution of 2-ethylbutan-1-amine (0.59 mL, 4.43 mmol) and the product of Example II-2I (1.06 g, 1.475 mmol) in 1,2-dichloroethane (6 mL). The reaction mixture was stirred at room temperature for 40 minutes. Sodium triacetoxyborohydride (0.47 g, 2.218 mmol) was added, and the reaction mixture was stirred for 30 minutes. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (3 mL) and stirred for 10 minutes. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.95 g, 1.282 mmol, 87% yield, 92% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.52 - 7.21 (m, 6H), 5.26 - 5.02 (m, 2H), 4.55 - 4.31 (m, 2H), 4.11 - 3.83 (m, 2H), 3.22 - 2.87 (m, 2H), 2.83 - 2.67 (m, 1H), 2.45 - 2.27 (m, 2H), 2.04 - 1.93 (m, 1H), 1.56 - 1.44 (m, 9H), 1.42 - 1.33 (m, 9H), 1.26 - 1.15 (m, 4H), 0.89 - 0.68 (m, 6H);MS (ESI + ) m / z 683 [M+H] + .

[0165] Example II-3B: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-ethylbutyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-3A (0.95 g, 1.282 mmol) in acetonitrile (6 mL) was added N,N-diisopropylethylamine (0.672 mL, 3.85 mmol) and di-tert-butyl dicarbonate (0.560 g, 2.56 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with half-saturated brine (30 mL). The mixture was diluted with ethyl acetate (20 mL), and the layers were separated. The aqueous layer was further extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO, 80 g cartridge, 0-40% ethyl acetate in isohexane, 60 mL / min) to afford the title compound (927 mg, 1.126 mmol, 88% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.46 - 7.27 (m, 6H), 5.23 - 5.02 (m, 2H), 4.77 - 4.60 (m, 1H), 4.44 - 4.37 (m, 1H), 4.00 - 3.90 (m, 1H), 3.55 - 2.71 (m, 7H), 1.54 - 1.44 (m, 9H), 1.42 - 1.36 (m, 9H), 1.36 - 1.11 (m, 13H), 0.89 - 0.70 (m, 6H).

[0166] Example II-3C: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-ethylbutyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-3B (927 mg, 1.126 mmol) in methanol (2.8 mL) and tetrahydrofuran (2.80 mL) was added 2 M aqueous lithium hydroxide solution (1.689 mL, 3.38 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was neutralized to pH 7 with 1 M aqueous hydrochloric acid and diluted with water (10 mL). The aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (747 mg, 0.980 mmol, 87% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.55 - 7.27 (m, 5H), 7.16 (s, 1H), 5.24 - 5.03 (m, 2H), 4.80 - 4.59 (m, 1H), 4.55 - 4.37 (m, 1H), 3.95 - 3.78 (m, 2H), 3.44 - 3.24 (m, 2H), 3.21 - 3.03 (m, 3H), 2.91 - 2.75 (m, 1H), 1.70 - 1.46 (m, 9H), 1.46 - 1.32 (m, 18H), 1.32 - 1.13 (m, 5H), 0.84 (tt, J = 7.5, 1.9 Hz, 6H);MS (ESI+) m / z 587 [M+HC(O)OC(CH3)3] +

[0167] Example II-3D: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-ethylbutyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of chlorosulfonyl isocyanate (0.16 mL, 1.843 mmol) in dichloromethane (4.901 mL) was added allyl alcohol (0.13 mL, 1.912 mmol) dropwise at 0° C. The resulting solution was stirred at 0° C. for 20 minutes, and then a solution of the product of Example II-3C (747 mg, 0.980 mmol) and triethylamine (0.34 mL, 2.439 mmol) in dichloromethane (4.90 mL) was added dropwise. The resulting solution was stirred at 0° C. for 30 minutes. The reaction mixture was quenched with water (50 mL) and diluted with dichloromethane (50 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO 2 , 40 g cartridge, 0-40% tert-butyl methyl ether in isohexane, 90 mL / min) to afford the title compound (667 mg, 0.707 mmol, 72% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.67 - 11.44 (m, 1H), 7.67 - 7.00 (m, 6H), 5.80 - 5.61 (m, 1H), 5.27 - 4.99 (m, 4H), 4.77 - 4.56 (m, MS (ESI) - ) m / z 848 [MH] - .

[0168] Example II-3E: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-ethylbutyl)amino]methyl}-4-fluoro-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia A solution of the product of Example II-3D (0.667 g, 0.707 mmol) and potassium carbonate (0.4 g, 2.89 mmol) in methanol (7 mL) was degassed under vacuum and backfilled with nitrogen three times. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.082 g, 0.071 mmol), and the reaction mixture was degassed under vacuum and backfilled with nitrogen three times. The reaction mixture was stirred at 60 °C for 4 hours. The mixture was cooled to room temperature. C18 silica gel (3 g) was added, and the mixture was concentrated in vacuo. The crude residue was subjected to column chromatography (Reveleris® 40 g reverse-phase (C18) flash cartridge, dry-loaded with C18 silica gel, 10-70% methanol in 0.1% ammonium hydroxide, 40 mL / min) to give the title compound as the ammonium salt (444 mg, 0.572 mmol, 81% yield, 89% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.57 - 7.44 (m, 2H), 7.43 - 7.25 (m, 3H), 7.20 (s, 1H), 5.17 - 5.05 (m, 2H), 4.78 - 4.56 (m, 1H), 3.94 (d, J = 13.0 Hz, 1H), 3.87 (d, J = 13.0 Hz, 1H), 3.45 - 3.27 (m, 2H), 3.21 (s, 1H), 3.15 - 2.92 (m, 3H), 2.91 - 2.77 (m, 1H), 1.65 - 1.55 (m, 1H), 1.51 (s, 9H), 1.37 (s, 9H), 1.32 - 1.03 (m, 4H), 0.93 - 0.78 (m, 6H);MS (ESI + ) m / z 714 [M+Na] + .

[0169] Example II-3F: (2R)-2-{[(tert-butoxycarbonyl)(2-ethylbutyl)amino]methyl}-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia To a suspension of the product of Example II-3E ​​(444 mg, 0.558 mmol) in deoxygenated water (0.1 mL) and ethanol (4 mL) was added 10% Pd / C (120 mg). The resulting suspension was stirred under hydrogen (5 bar) for 18 hours. The reaction mixture was filtered through Whatman glass fiber filter paper and washed with ethanol (3 × 20 mL). The filtrate was concentrated under reduced pressure onto C18 silica (1.5 g). The crude residue was subjected to column chromatography (Reveleris® 40 g reverse-phase (C18) flash cartridge, dry load on C18 silica, 5-55% methanol in 10 mM ammonium bicarbonate, 45 mL / min) to give the title compound as the ammonium salt (270 mg, 0.427 mmol, 76% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 6.93 (s, 1H), 4.70 - 4.58 (m, 1H), 3.95 (d, J = 13.0 Hz, 1H), 3.89 (d, J = 13.0 Hz, 1H), 3.41 - 3.26 (m, 2H), 3.17 - 3.00 (m, 3H), 2.78 (dd, J = 15.6, 2.0 Hz, 1H), 1.60 (dt, J = 13.0, 6.9 Hz, 1H), 1.53 (s, 9H), 1.38 (s, 9H), 1.33 - 1.16 (m, 4H), 0.89 - 0.78 (m, 6H); MS (ESI + ) m / z 624 [M+Na] + .

[0170] Example II-3G: 5-[(2R)-2-{[(2-ethylbutyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a solution of the product of Example II-3F (106 mg, 0.163 mmol) in dichloromethane (1 mL) at room temperature was added trifluoroacetic acid (0.188 mL, 2.445 mmol). The reaction mixture was stirred at room temperature for 5 hours. A second aliquot of trifluoroacetic acid (0.188 mL, 2.445 mmol) was added, and the reaction mixture was stirred at room temperature for an additional hour. The reaction mixture was neutralized with 0.7 M NH3 in methanol:water (95:5) (7 mL) and concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 24 g reverse-phase (C18) flash cartridge, dry loaded on C18 silica, 5-20% methanol in 0.1% ammonium hydroxide, 35 mL / min) to give the title compound (59 mg, 0.147 mmol, 84% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.63 (s, 1H), 8.01 (s, 1H), 5.99 (s, 1H), 5.90 (s, 1H), 4.08 (s, 1H), 3.83 (s, 2H), 3.06 (dd, J = 15.5, MS (ESI) + ) m / z 401 [M+H] + .

[0171] Example II-4: 5-{(2R)-4-fluoro-6-hydroxy-2-[(propylamino)methyl]-2,3-dihydro-1H-indol-5-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 135) Example II-4A: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2-[(propylamino)methyl]-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Acetic acid (0.252 mL, 4.40 mmol) was added to a solution of the product of Example II-2I (0.92 g, 1.465 mmol) and propan-1-amine (0.36 mL, 4.4 mmol) in 1,2-dichloroethane (6 mL). The reaction mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.466 g, 2.198 mmol) was added, and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 mL), and the resulting mixture was stirred for 10 minutes. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (983 mg, 1.46 mmol, 99% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.48 - 7.28 (m, 6H), 5.22 - 5.04 (m, 2H), 4.52 - 4.44 (m, 1H), 4.40 (dd, J = 16.7, 4.0 Hz, 1H), 3.97 (dd, J = 16.5, 3.0 Hz, 1H), 3.22 - 3.08 (m, 1H), 3.06 - 2.94 (m, 1H), 2.80 - 2.70 (m, 1H), 2.60 - 2.38 (m, 3H), 1.50 (s, 9H), 1.38 (s, 11H), 0.87 - 0.77 (m, 3H);MS (ESI + ) m / z 640 [M+H] + .

[0172] Example II-4B: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(propyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-4A (983 mg, 1.460 mmol) in acetonitrile (6 mL) was added N,N-diisopropylethylamine (0.765 mL, 4.38 mmol) and di-tert-butyl dicarbonate (637 mg, 2.92 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with half-saturated brine (30 mL). The mixture was diluted with ethyl acetate (20 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO, 80 g cartridge, 0-40% ethyl acetate in isohexane, 60 mL / min) to afford the title compound (831 mg, 1.090 mmol, 75% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.46 - 7.29 (m, 6H), 5.21 - 5.04 (m, 2H), 4.74 - 4.59 (m, 1H), 4.40 (d, J = 16.8 Hz, 1H), 3.98 (d, J = 17.2 Hz, 1H), 3.29 - 3.01 (m, 4H), 3.01 - 2.77 (m, 2H), 1.56 - 1.43 (m, 11H), 1.38 (s, 9H), 1.36 - 1.24 (m, 9H), 0.81 (t, J = 7.3 Hz, 3H).

[0173] Example II-4C: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(propyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-4B (894 mg, 1.172 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL) at room temperature was added a solution of lithium hydroxide monohydrate (246 mg, 5.86 mmol) in water (4 mL). The reaction mixture was then stirred at room temperature for 40 minutes. The reaction mixture was neutralized to pH 7 with 1 M hydrogen chloride (5.86 mL, 5.86 mmol) and diluted with water (10 mL). The aqueous mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (778 mg, 1.088 mmol, 93% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.56 - 7.18 (m, 6H), 5.22 - 4.95 (m, 2H), 4.63 - 4.51 (m, 1H), 3.50 - 3.16 (m, 2H), 3.16 - 2.67 (m, 4H), 1.56 - 1.42 (m, 14H), 1.42 - 1.20 (m, 17H), 0.86 - 0.75 (m, 3H).

[0174] Example II-4D: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(propyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of chlorosulfonyl isocyanate (0.189 mL, 2.175 mmol) in dichloromethane (3 mL) was added allyl alcohol (0.148 mL, 2.175 mmol) dropwise at 0° C. The resulting solution was stirred at 0° C. for 20 minutes, and then a solution of the product of Example II-4C (778 mg, 1.088 mmol) and triethylamine (0.379 mL, 2.72 mmol) in dichloromethane (5 mL) was added dropwise. The resulting solution was stirred at 0° C. for 30 minutes. The reaction mixture was quenched with water (10 mL) and diluted with dichloromethane (10 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (silica gel, 40 g cartridge, 0-100% ethyl acetate in isohexane, 60 mL / min) to give the title compound (394 mg, 0.391 mmol, 36% yield, 80% purity). MS (ESI - ) m / z 805 [MH] - .

[0175] Example II-4E: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(propyl)amino]methyl}-4-fluoro-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia To a solution of the product of Example II-4D (394 mg, 0.391 mmol) and potassium carbonate (220 mg, 1.592 mmol) in methanol (5 mL) was added tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.039 mmol). The reaction mixture was stirred at 60° C. for 1 hour. The mixture was cooled to room temperature and diluted with methanol (10 mL). C18 silica gel (3 g) was added, and the mixture was concentrated in vacuo. The crude residue was subjected to column chromatography (Reveleris® 40 g reverse-phase (C18) flash cartridge, dry-loaded with C18 silica gel, 10-70% methanol in 10 mM ammonium bicarbonate, 60 mL / min) to give the title compound as the ammonium salt (125 mg, 0.169 mmol, 43% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.75 - 7.00 (m, 10H), 5.09 (s, 2H), 4.70 - 4.56 (m, 1H), 4.39 - 4.30 (m, 1H), 3.99 - 3.82 (m, 1H), 3.49 - 3.39 (m, 2H), 3.26 - 3.20 (m, 1H), 3.16 - 2.99 (m, 3H), 2.91 - 2.71 (m, 1H), 1.49 (s, 9H), 1.38 (s, 4H), 1.30 (s, 5H), 0.80 (t, J = 7.4 Hz, 3H);MS (ESI + ) m / z 671 [M+Na] + .

[0176] Example II-4F: (2R)-2-{[(tert-butoxycarbonyl)(propyl)amino]methyl}-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia (partial) To a solution of the product of Example II-4E (125 mg, 0.173 mmol) in degassed water (0.5 mL) and ethanol (4 mL) was added 10% Pd / C (25 mg). The resulting suspension was stirred under hydrogen (5 bar) for 18 hours. The suspension was concentrated under reduced pressure onto C18 silica gel (2 g). The crude residue was subjected to column chromatography (Reveleris® 24 g reverse-phase (C18) flash cartridge, dry loaded with C18 silica, 10-60% methanol in 10 mM ammonium bicarbonate, 40 mL / min) to give the title product as a partial ammonium salt (44 mg, 0.062 mmol, 36% yield, 80% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.36 (s, 1H), 7.27 - 6.59 (m, 3H), 4.65 - 4.51 (m, 1H), 3.95 - 3.80 (m, 2H), 3.48 - 3.39 (m, 2H), 3.24 - MS (ESI + ) m / z 581 [M+Na] + .

[0177] Example II-4G: 5-{(2R)-4-fluoro-6-hydroxy-2-[(propylamino)methyl]-2,3-dihydro-1H-indol-5-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a solution of the product of Example II-4F (44 mg, 0.079 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.073 mL, 0.945 mmol) at room temperature. The reaction mixture was stirred at 25° C. for 4 hours. The mixture was neutralized with 0.7 M ammonia in methanol:water (95:5) (4 mL) and concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 12 g reverse-phase (C18) flash cartridge, dry loaded on C18 silica gel, 10-50% methanol in 10 mM ammonium bicarbonate, 30 mL / min) to give the title compound (11 mg, 0.031 mmol, 39% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (s, 1H), 7.12 (br s, 6H), 6.04 (s, 1H), 5.92 (s, 1H), 4.18 - 4.04 (m, 1H), 3.84 (s, 2H), 3.19 - MS (ESI + ) m / z 359 [M+H] + .

[0178] Example II-5: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(2-methoxyethyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 136) Example II-5A: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2-{[(2-methoxyethyl)amino]methyl}-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Acetic acid (0.252 mL, 4.40 mmol) was added to a solution of the product of Example II-2I (0.92 g, 1.465 mmol) and 2-methoxyethanamine (0.38 mL, 4.4 mmol) in 1,2-dichloroethane (6 mL). The reaction mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.466 g, 2.198 mmol) was added, and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 mL) and stirred for 10 minutes. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (992 mg, 1.437 mmol, 98% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.46 - 7.29 (m, 6H), 5.21 - 5.03 (m, 2H), 4.53 - 4.44 (m, 1H), 4.40 (dd, J = 16.7, 2.0 Hz, 1H), 3.99 - 3.89 (m, 1H), 3.42 - 3.25 (m, 2H), 3.22 (2 s, J = 4.7 Hz, 3H), 3.19 - 3.10 (m, 1H), 3.03 - 2.92 (m, 1H), 2.77 (dd, J = 11.9, 3.8 Hz, 1H), 2.73 - 2.53 (m, 3H), 1.51 (s, 9H), 1.38 (s, 9H);MS (ESI + ) m / z 656 [M+H] + .

[0179] Example II-5B: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methoxyethyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-5A (992 mg, 1.437 mmol) in acetonitrile (6 mL) was added N,N-diisopropylethylamine (0.753 mL, 4.31 mmol) and di-tert-butyl dicarbonate (627 mg, 2.87 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with half-saturated brine (30 mL). The mixture was then diluted with ethyl acetate (20 mL), and the layers were separated. The aqueous layer was further extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO, 80 g cartridge, 0-40% ethyl acetate in isohexane, 60 mL / min) to afford the title compound (894 mg, 1.136 mmol, 79% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.44 - 7.29 (m, 6H), 5.24 - 5.04 (m, 2H), 4.69 (s, 1H), 4.40 (d, J = 16.8 Hz, 1H), 4.03 - 3.93 (m, 1H), MS (ESI + ) m / z 778 [M+Na] + .

[0180] Example II-5C: tert-butyl (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methoxyethyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate To a solution of the product of Example II-5B (831 mg, 1.056 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL) at room temperature was added a solution of lithium hydroxide monohydrate (221 mg, 5.28 mmol) in water (4.00 mL). The reaction mixture was then stirred at room temperature for 40 minutes. The reaction mixture was neutralized to pH 7 with 1 M hydrogen chloride (5.28 mL, 5.28 mmol) and diluted with water (10 mL). The aqueous mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (811 mg, 1.045 mmol, 99% yield, 85% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.58 - 7.15 (m, 6H), 5.13 - 5.03 (m, 2H), 4.74 - 4.50 (m, 1H), 3.84 (s, 2H), 3.51 - 3.35 (m, 3H), 3.35 - 3.13 (m, 6H), 3.12 - 3.00 (m, 1H), 2.86 - 2.64 (m, 1H), 1.57 - 1.43 (m, 9H), 1.43 - 1.20 (m, 18H).

[0181] Example II-5D: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methoxyethyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of chlorosulfonyl isocyanate (0.181 mL, 2.090 mmol) in dichloromethane (3 mL) was added allyl alcohol (0.142 mL, 2.090 mmol) dropwise at 0° C. The resulting solution was stirred at 0° C. for 20 minutes, and then a solution of the product of Example II-5C (811 mg, 1.045 mmol) and triethylamine (0.364 mL, 2.61 mmol) in dichloromethane (3.00 mL) was added dropwise. The resulting solution was stirred at 0° C. for 30 minutes. The reaction mixture was quenched with water (10 mL) and diluted with dichloromethane (10 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (silica gel, 40 g cartridge, 0-100% ethyl acetate in isohexane, 60 mL / min) to afford the title compound (618 mg, 0.676 mmol, 65% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.64 - 11.48 (m, 1H), 7.53 - 7.17 (m, 6H), 5.78 - 5.63 (m, 1H), 5.30 - 5.01 (m, 4H), 4.72 - 4.59 (m, 2H), 4.32 - 4.08 (m, 3H), 3.47 - 3.37 (m, 2H), 3.36 - 3.19 (m, 7H), 3.15 - 3.02 (m, 1H), 2.87 - 2.70 (m, 1H), 1.56 - 1.43 (m, 9H), 1.43 - 1.21 (m, 18H);MS (ESI - ) m / z 821 [MH] - .

[0182] Example II-5E: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methoxyethyl)amino]methyl}-4-fluoro-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia To a solution of the product of Example II-5D (600 mg, 0.656 mmol) and potassium carbonate (363 mg, 2.62 mmol) in methanol (15 mL) was added tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.066 mmol). The reaction mixture was stirred at 60° C. for 1 hour. The mixture was cooled to room temperature and diluted with methanol (10 mL). C18 silica gel (3 g) was added, and the mixture was concentrated in vacuo. The crude residue was subjected to column chromatography (Reveleris® 40 g reverse-phase (C18) flash cartridge, dry-loaded with C18 silica gel, 10-70% methanol in 10 mM ammonium bicarbonate, 60 mL / min) to give the title compound as the ammonium salt (214 mg, 0.232 mmol, 35% yield, 74% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.67 - 7.46 (m, 3H), 7.38 - 7.26 (m, 3H), 7.06 (s, 3H), 5.17 - 5.04 (m, 2H), 4.72 - 4.59 (m, 1H), 4.34 (t, J = 5.1 Hz, 1H), 3.98 - 3.82 (m, 2H), 3.50 - 3.36 (m, 5H), 3.24 (s, 3H), 3.15 - 3.02 (m, 1H), 2.94 - 2.68 (m, 1H), 1.49 (s, 9H), 1.38 (s, 4H), 1.30 (s, 5H);MS (ESI + ) m / z 687 [M+Na] + .

[0183] Example II-5F: (2R)-2-{[(tert-butoxycarbonyl)(2-methoxyethyl)amino]methyl}-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia To a solution of the product of Example II-5E (214 mg, 0.238 mmol) in degassed water (0.5 mL) and ethanol (4 mL), 10% Pd / C (25 mg) was added. The resulting suspension was stirred under hydrogen (5 bar) for 18 hours. The suspension was concentrated under reduced pressure onto C18 silica gel (3 g). The crude residue was subjected to column chromatography (Reveleris® 24 g reverse-phase (C18) flash cartridge, dry loaded with C18 silica, 10-60% methanol in 10 mM ammonium bicarbonate, 40 mL / min) to give the title product as the ammonium salt (100 mg, 0.152 mmol, 64% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.26 (s, 1H), 7.27 - 6.76 (m, 4H), 4.67 - 4.54 (m, 1H), 3.95 - 3.80 (m, 2H), 3.49 - 3.37 (m, 3H), 3.32 MS (ESI + ) m / z 597 [M+Na] + .

[0184] Example II-5G: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(2-methoxyethyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a solution of the product of Example II-5F (100 mg, 0.152 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.181 mL, 2.349 mmol) at room temperature. The reaction mixture was stirred at 25° C. for 20 hours. The reaction mixture was neutralized with 0.7 M NH3 in methanol:water (95:5) (6 mL) and concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 12 g reverse-phase (C18) flash cartridge, dry loaded on C18 silica, 10-50% methanol in 10 mM ammonium bicarbonate, 30 mL / min) to give the title compound (29 mg, 0.077 mmol, 51% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (s, 1H), 8.48 (br s, 1.5H), 6.01 (s, 1H), 5.92 (s, 1H), 4.18 - 4.06 (m, 1H), 3.84 (s, 2H), 3.59 (t, MS (ESI + ) m / z 375 [M+H] + .

[0185] Example II-6: 5-[(2R)-2-{[(cyclobutylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 137) Example II-6A: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-2-{[(cyclobutylmethyl)amino]methyl}-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Acetic acid (0.25 mL, 4.37 mmol) was added to a solution of cyclobutylmethanamine, hydrochloric acid (0.54 g, 4.44 mmol), and the product of Example II-2I (1.06 g, 1.475 mmol) in 1,2-dichloroethane (6 mL). The reaction mixture was stirred at room temperature for 1 hour. Triethylamine (0.6 mL, 4.30 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (470 mg, 2.218 mmol) was added, and the reaction mixture was stirred for 30 minutes. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (3 mL) and stirred for 10 minutes. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.89 g, 1.341 mmol, 91% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm7.49 - 7.25 (m, 6H), 5.23 - 5.02 (m, 2H), 4.52 - 4.31 (m, 2H), 3.96 (dd, J = 16.6, 2.0 Hz, 1H), 3.21 - 3.06 (m, 1H), 2.99 (ddd, J = 16.0, 7.3, 2.6 Hz, 1H), 2.78 - 2.69 (m, 1H), 2.61 - 2.52 (m, 2H), 2.42 - 2.23 (m, 1H), 1.98 - 1.87 (m, 2H), 1.87 - 1.68 (m, 2H), 1.67 - 1.54 (m, 3H), 1.51 (s, 9H), 1.38 (s, 9H);MS (ESI + ) m / z 667 [M+H] + .

[0186] Example II-6B: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(cyclobutylmethyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1 carboxylate tert-butyl To a solution of the product of Example II-6A (1.05 g, 1.341 mmol) in acetonitrile (6 mL) was added N,N-diisopropylethylamine (0.702 mL, 4.02 mmol) and di-tert-butyl dicarbonate (0.585 g, 2.68 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with half-saturated brine (30 mL). The mixture was diluted with ethyl acetate (20 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO, 80 g cartridge, 0-40% ethyl acetate in isohexane, 60 mL / min) to afford the title compound (957 mg, 1.187 mmol, 89% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.49 - 7.26 (m, 6H), 5.25 - 5.05 (m, 2H), 4.66 (s, 1H), 4.40 (d, J = 16.7 Hz, 1H), 3.96 (s, 1H), 3.54 - 2.73 (m, 7H), 1.98 - 1.87 (m, 2H), 1.87 - 1.73 (m, 2H), 1.73 - 1.59 (m, 2H), 1.54 - 1.46 (m, 9H), 1.41 - 1.37 (m, 9H), 1.37 - 1.22 (m, 9H).

[0187] Example II-6C: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(cyclobutylmethyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-6B (957 mg, 1.187 mmol) in methanol (2.8 mL) and tetrahydrofuran (2.8 mL) was added 2 M aqueous lithium hydroxide solution (1.781 mL, 3.56 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was neutralized to pH 7 with 1 M aqueous hydrochloric acid solution and diluted with water (10 mL). The aqueous mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (735 mg, 0.988 mmol, 83% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.53 - 7.44 (m, 2H), 7.44 - 7.28 (m, 3H), 7.17 (s, 1H), 5.09 (s, 2H), 4.65 - 4.55 (m, 1H), 4.54 - 4.46 (m, 1H), 3.84 (dd, J = 6.8, 2.0 Hz, 2H), 3.42 - 3.14 (m, 4H), 3.06 (dd, J = 15.9, 9.2 Hz, 1H), 2.82 (dd, J = 15.9, 2.1 Hz, 1H), 2.62 - 2.52 (m, 1H), 2.07 - 1.91 (m, 2H), 1.91 - 1.74 (m, 2H), 1.74 - 1.60 (m, 2H), 1.51 (s, 9H), 1.46 - 1.25 (m, 18H);MS (ESI+) m / z 570 [M+HC(O)OC(CH3)3] + .

[0188] Example II-6D: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(cyclobutylmethyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of chlorosulfonyl isocyanate (0.16 mL, 1.843 mmol) in dichloromethane (4.94 mL) was added allyl alcohol (0.13 mL, 1.912 mmol) dropwise at 0° C. The resulting solution was stirred at 0° C. for 20 minutes, and then a solution of the product of Example II-6C (0.735 g, 0.988 mmol) and triethylamine (0.35 mL, 2.51 mmol) in dichloromethane (5 mL) was added dropwise. The resulting solution was stirred at 0° C. for 30 minutes. The reaction mixture was quenched with water (50 mL) and diluted with dichloromethane (50 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO 2 , 40 g cartridge, 0-40% tert-butyl methyl ether in isohexane, 90 mL / min) to afford the title compound (665 mg, 0.798 mmol, 81% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.69 - 11.44 (m, 1H), 7.56 - 7.06 (m, 6H), 5.75 - 5.63 (m, 1H), 5.27 - 4.95 (m, 4H), 4.73 - 4.56 (m, 2H), 4.33 - 4.19 (m, 1H), 4.19 - 4.07 (m, 2H), 3.44 - 3.02 (m, 5H), 2.83 (d, J = 15.9 Hz, 1H), 1.97 - 1.87 (m, 2H), 1.87 - 1.73 (m, 2H), 1.73 - 1.60 (m, 2H), 1.48 (s, 9H), 1.42 - 1.21 (m, 19H);MS (ESI - ) m / z 831 [MH] - .

[0189] Example II-6E: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(cyclobutylmethyl)amino]methyl}-4-fluoro-5-(1,1,4-trioxo-1λ) 6,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia A solution of the product of Example II-6D (0.782 g, 0.798 mmol) and potassium carbonate (0.44 g, 3.18 mmol) in methanol (8 mL) was degassed under vacuum and backfilled with nitrogen three times. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.092 g, 0.080 mmol), and the reaction mixture was degassed under vacuum and backfilled with nitrogen three times. The reaction mixture was stirred at 60° C. for 4 hours. The mixture was cooled to room temperature and left overnight. The reaction mixture was diluted with methanol (10 mL). Diatomaceous earth (3 g) was added, and the mixture was concentrated in vacuo. The crude residue was subjected to column chromatography (Reveleris® 40 g reverse-phase (C18) flash cartridge, dry loaded with diatomaceous earth, 5-70% methanol in 10 mM ammonium bicarbonate, 15 mL / min) to afford the title compound as the ammonium salt (608 mg, 0.677 mmol, 85% yield, 80% purity). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.69 - 7.58 (m, 1H), 7.58 - 7.45 (m, 3H), 7.41 - 7.26 (m, 3H), 7.21 (s, 1H), 5.11 (s, 2H), 4.65 (dddd, J = 9.4, 7.5, 5.7, 2.1 Hz, 1H), 3.94 (d, J = 13.0 Hz, 1H), 3.87 (d, J = 13.1 Hz, 1H), 3.39 - 3.25 (m, 2H), 3.07 (ddd, J = 24.4, 12.3, 8.0 Hz, 5H), 2.84 (dt, J = 15.5, 4.0 Hz, 1H), 2.63 - 2.52 (m, 1H), 2.06 - 1.91 (m, 2H), 1.90 - 1.76 (m, 2H), 1.76 - 1.61 (m, 2H), 1.55 - 1.46 (m, 9H), 1.37 (s, 9H);MS (ESI + ) m / z 697 [M+Na] + .

[0190] Example II-6F: (2R)-2-{[(tert-butoxycarbonyl)(cyclobutylmethyl)amino]methyl}-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester To a suspension of the product of Example II-6E (100 mg, 0.111 mmol) in degassed water (0.1 mL) and ethanol (4 mL) was added 10% Pd / C (25 mg). The resulting suspension was stirred under hydrogen (5 bar) for 18 hours. The reaction mixture was filtered through Whatman glass fiber filter paper and washed with ethanol (3 × 10 mL). The filtrate was concentrated under reduced pressure onto C18 silica (1 g). The crude residue was subjected to column chromatography (Reveleris® 24 g reverse-phase (C18) flash cartridge, dry loaded with diatomaceous earth, 5-55% methanol in 10 mM ammonium bicarbonate, 50 mL / min) to give the title compound (44 mg, 0.070 mmol, 63% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 8.65 (s, 1H), 6.99 (s, 1H), 4.69 - 4.54 (m, 1H), 3.97 - 3.84 (m, 2H), 3.39 - 3.17 (m, 4H), 3.11 - 2.95 (m, 1H), 2.81 (dd, J = 15.7, 2.0 Hz, 1H), 2.63 - 2.52 (m, 1H), 2.06 - 1.92 (m, 2H), 1.89 - 1.76 (m, 2H), 1.76 - 1.63 (m, 2H), 1.54 (s, 9H), 1.38 (s, 9H);MS (ESI + ) m / z 607 [M+Na] + .

[0191] Example II-6G: 5-[(2R)-2-{[(cyclobutylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6,2,5-Thiadiazolidine-1,1,3-trione To a solution of the product of Example II-6F (96 mg, 0.148 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.171 mL, 2.226 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 0.7 M NH3 in methanol:water (95:5) (7 mL) and concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 24 g reverse-phase (C18) flash cartridge, dry loaded on C18 silica, 5-20% methanol in 0.1% ammonium hydroxide, 35 mL / min) to give the title compound (56 mg, 0.146 mmol, 98% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (s, 1H), 7.87 (s, 2H), 6.00 (s, 1H), 5.91 (s, 1H), 4.16 - 3.99 (m, 1H), 3.84 (s, 2H), 3.07 (dd, J = 15.5, 9.3 Hz, 1H), 3.01 - 2.83 (m, 4H), 2.71 (dd, J = 15.5, 6.7 Hz, 1H), 2.65 - 2.54 (m, 1H), 2.13 - 1.97 (m, 2H), 1.95 - 1.66 (m, 4H);MS (ESI + ) m / z 385 [M+H] + .

[0192] Example II-7: 5-[(2R)-4-fluoro-6-hydroxy-2-({[(oxan-4-yl)methyl]amino}methyl)-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 138) Example II-7A: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2-({[(oxan-4-yl)methyl]amino}methyl)-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Acetic acid (0.252 mL, 4.40 mmol) was added to a solution of (tetrahydro-2H-pyran-4-yl)methanamine (0.496 mL, 4.40 mmol) and the product of Example II-2I (0.92 g, 1.465 mmol) in 1,2-dichloroethane (6 mL). The reaction mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.466 g, 2.198 mmol) was added, and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 mL) and stirred for 10 minutes. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.0345 g, 1.472 mmol, 100% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.44 - 7.27 (m, 6H), 5.22 - 5.02 (m, 2H), 4.51 - 4.44 (m, 1H), 4.40 (dd, J = 16.6, 5.8 Hz, 1H), 3.96 (dd, J = 3.84 - 3.76 (m, 2H), 3.27 - 3.07 (m, 3H), 3.07 - 2.93 (m, 1H), 2.79 - 2.69 (m, 1H), 2.63 - 2.52 (m, 1H), 2.45 - 2.30 (m, 2H), 1.59 - 1.52 (m, 3H), 1.50 (s, 9H), 1.38 (s, 9H), 1.14 - 0.98 (m, 2H);MS (ESI + ) m / z 696 [M+H] + .

[0193] Example II-7B: (2R)-6-(benzyloxy)-2-({(tert-butoxycarbonyl)[(oxan-4-yl)methyl]amino}methyl)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-7A (1.0345 g, 1.472 mmol) in acetonitrile (6 mL) was added N,N-diisopropylethylamine (0.771 mL, 4.42 mmol) and di-tert-butyl dicarbonate (0.643 g, 2.94 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with half-saturated brine (30 mL). The mixture was diluted with ethyl acetate (20 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO, 80 g cartridge, 0-40% ethyl acetate in isohexane, 60 mL / min) to afford the title compound (1.05 g, 1.253 mmol, 85% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.46 - 7.29 (m, 6H), 5.22 - 5.05 (m, 2H), 4.76 - 4.63 (m, 1H), 4.41 (d, J = 16.8 Hz, 1H), 3.98 (d, J = 16.5 Hz, 1H), 3.89 - 3.78 (m, 2H), 3.33 - 2.64 (m, 9H), 1.55 - 1.47 (m, 9H), 1.47 - 1.40 (m, 2H), 1.40 - 1.37 (m, 9H), 1.37 - 1.20 (m, 9H), 1.20 - 1.06 (m, 2H).

[0194] Example II-7C: tert-butyl (2R)-6-(benzyloxy)-2-({(tert-butoxycarbonyl)[(oxan-4-yl)methyl]amino}methyl)-5-[(2-tert-butoxy-2-oxoethyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate To a solution of the product of Example II-7B (1.05 g, 1.253 mmol) in methanol (3 mL) and tetrahydrofuran (3 mL) was added 2 M aqueous lithium hydroxide solution (1.880 mL, 3.76 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 30 minutes. The reaction mixture was quenched with saturated ammonium chloride (20 mL). The aqueous layer was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (70 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated in isohexane. The solid was separated by decantation to give the title compound (0.472 g, 0.682 mmol, 54% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.53 - 7.44 (m, 2H), 7.40 (t, J = 7.3 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 6.85 (s, 1H), 5.08 (s, 2H), 4.70 (s, 1H), 4.60 (s, 1H), 3.88 - 3.78 (m, 4H), 3.28 - 3.16 (m, 4H), 3.14 - 2.90 (m, 3H), 2.84 - 2.68 (m, 1H), 1.91 - 1.73 (m, 1H), 1.48 (s, 9H), 1.44 - 1.22 (m, 20H), 1.20 - 1.05 (m, 2H);MS (ESI + ) m / z 700 [M+H] + .

[0195] Example II-7D: (2R)-6-(benzyloxy)-2-({(tert-butoxycarbonyl)[(oxan-4-yl)methyl]amino}methyl)-5-[(2-tert-butoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of chlorosulfonyl isocyanate (0.155 mL, 1.785 mmol) in dichloromethane (7 mL) was added allyl alcohol (0.125 mL, 1.838 mmol) dropwise at 0° C. The resulting solution was stirred at 0° C. for 20 minutes, and then a solution of the product of Example II-7C (0.530 g, 0.682 mmol) and triethylamine (0.310 mL, 2.224 mmol) in dichloromethane (7 mL) was added dropwise. The resulting solution was stirred at 0° C. for 50 minutes. The reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and diluted with dichloromethane (50 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.628 g, 0.655 mmol, 96% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.53 - 6.81 (m, 7H), 6.07 - 5.64 (m, 2H), 5.55 - 5.00 (m, 6H), 4.82 - 4.39 (m, 4H), 4.31 - 4.07 (m, 2H), 3.88 - 3.74 (m, 2H), 3.28 - 3.01 (m, 4H), 1.95 - 1.72 (m, 1H), 1.53 - 1.42 (m, 9H), 1.42 - 0.99 (m, 22H);MS (ESI - ) m / z 861 [MH] - .

[0196] Example II-7E: (2R)-6-(benzyloxy)-2-({(tert-butoxycarbonyl)[(oxan-4-yl)methyl]amino}methyl)-4-fluoro-5-(1,1,4-trioxo-1λ 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia (partial) To a solution of the product of Example II-7D (0.628 g, 0.655 mmol) and potassium carbonate (0.402 g, 2.91 mmol) in methanol (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.084 g, 0.073 mmol). The reaction mixture was stirred at 60° C. for 1 hour. The mixture was cooled to room temperature and diluted with methanol (10 mL). Diatomaceous earth (2 g) was added, and the mixture was concentrated in vacuo. The crude residue was subjected to column chromatography (Reveleris® 24 g reverse-phase (C18) flash cartridge, dry loaded with diatomaceous earth, 5-70% methanol in 10 mM ammonium hydroxide, 15 mL / min) to give the title compound as a partial ammonium salt (0.246 g, 0.314 mmol, 48% yield, 92% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.56 - 7.45 (m, 2H), 7.42 - 7.26 (m, 3H), 7.25 - 6.77 (m, 2H), 5.10 (s, 2H), 4.70 - 4.64 (m, 1H), 3.98 - MS (ESI - ) m / z 703 [MH] - .

[0197] Example II-7F: (2R)-2-({(tert-butoxycarbonyl)[(oxan-4-yl)methyl]amino}methyl)-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester To a suspension of the product of Example II-7E (246 mg, 0.314 mmol) in water (2 mL) and 1,4-dioxane (2 mL) was added 10% Pd / C (49 mg). The resulting suspension was stirred under hydrogen (5 bar) for 2 hours. An additional 10% Pd / C (50 mg) was added, and the mixture was stirred under hydrogen (5 bar) for 18 hours. The reaction mixture was filtered through Whatman glass fiber filter paper and washed with ethanol (3 × 20 mL). The filtrate was concentrated under reduced pressure onto diatomaceous earth (4 g). The crude residue was subjected to column chromatography (Reveleris® 40 g reverse-phase (C18) flash cartridge, dry loaded with diatomaceous earth, 5-55% methanol in 10 mM ammonium hydroxide, 25 mL / min) to give the title compound (0.123 g, 0.190 mmol, 61% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 9.20 - 7.66 (m, 1H), 6.99 (s, 1H), 4.71 - 4.60 (m, 1H), 3.89 (dd, 2H), 3.84 (ddd, J = 11.5, 4.4, 2.3 Hz, 2H), 3.42 - 3.18 (m, 4H), 3.12 - 3.01 (m, 3H), 2.81 (dd, J = 15.6, 2.0 Hz, 1H), 1.94 - 1.80 (m, 1H), 1.54 (s, 9H), 1.55 - 1.43 (m, 2H), 1.38 (s, 9H), 1.25 - 1.10 (m, 2H); MS (ESI - ) m / z 613 [MH] - .

[0198] Example II-7G: 5-[(2R)-4-fluoro-6-hydroxy-2-({[(oxan-4-yl)methyl]amino}methyl)-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a solution of the product of Example II-7F (116 mg, 0.189 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.250 mL, 3.24 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Additional trifluoroacetic acid (0.100 mL, 1.298 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was neutralized with 0.7 M NH3 in methanol:water (95:5) (7 mL) and concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 24 g reverse-phase (C18) flash cartridge, dry-loaded with silica gel C18 silica gel, 5-20% methanol in 10 mM ammonium bicarbonate, 25 mL / min) to give the title compound (68.6 mg, 0.156 mmol, 82% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (s, 1H), 6.00 (t, J = 2.2 Hz, 1H), 5.90 (s, 1H), 4.12 - 4.04 (m, 1H), 3.91 - 3.75 (m, 4H), 3.33 - 3.23 (m, 2H), 3.07 (dd, J = 15.5, 9.3 Hz, 1H), 2.97 - 2.86 (m, 2H), 2.81 - 2.75 (m, 2H), 2.71 (dd, J = 15.5, 6.8 Hz, 1H), 1.95 - 1.77 (m, 1H), 1.63 (dtd, J = 13.2, 4.6, 2.3 Hz, 2H), 1.30 - 1.09 (m, 2H);MS (ESI + ) m / z 415 [M+H] + .

[0199] Example II-8: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(3-methylbutyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 139) Example II-8A: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2-{[(3-methylbutyl)amino]methyl}-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Acetic acid (0.25 mL, 4.37 mmol) was added to a solution of 3-methylbutan-1-amine (0.51 mL, 4.39 mmol) and the product of Example II-2I (1.06 g, 1.475 mmol) in 1,2-dichloroethane (6 mL). The reaction mixture was stirred at room temperature for 40 minutes. Sodium triacetoxyborohydride (470 mg, 2.218 mmol) was added, and the reaction mixture was stirred for 30 minutes. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (3 mL) and stirred for 10 minutes. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.97 g, 1.415 mmol, 96% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.52 - 7.25 (m, 6H), 5.23 - 5.02 (m, 2H), 4.54 - 4.33 (m, 2H), 3.96 (d, J = 16.6 Hz, 1H), 3.22 - 3.07 (m, 1H), 3.07 - 2.92 (m, 1H), 2.80 - 2.70 (m, 1H), 2.62 - 2.42 (m, 3H), 1.63 - 1.45 (m, 10H), 1.38 (s, 9H), 1.30 - 1.20 (m, 2H), 0.89 - 0.75 (m, 6H);MS (ESI + ) m / z 669 [M+H] + .

[0200] Example II-8B: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(3-methylbutyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-8A (1.05 g, 1.415 mmol) in acetonitrile (6 mL) was added N,N-diisopropylethylamine (0.742 mL, 4.25 mmol) and di-tert-butyl dicarbonate (0.618 g, 2.83 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with half-saturated brine (30 mL). The mixture was diluted with ethyl acetate (20 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO, 80 g cartridge, 0-40% ethyl acetate in isohexane, 60 mL / min) to afford the title compound (0.995 g, 1.296 mmol, 92% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.47 - 7.29 (m, 6H), 5.23 - 5.04 (m, 2H), 4.66 (s, 1H), 4.40 (d, J = 16.7 Hz, 1H), 4.01 - 3.92 (m, 1H), 3.56 - 2.74 (m, 7H), 1.51 (s, 9H), 1.38 (s, 11H), 1.37 - 1.21 (m, 9H), 0.93 - 0.78 (m, 6H).

[0201] Example II-8C: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(3-methylbutyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-8B (1.07 g, 1.296 mmol) in methanol (3 mL) and tetrahydrofuran (3 mL) was added 2 M aqueous lithium hydroxide solution (1.98 mL, 3.96 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride solution (20 mL). The aqueous layer was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (70 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (0.896 g, 1.134 mmol, 87% yield, 85% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.54 - 7.28 (m, 6H), 5.21 - 4.96 (m, 2H), 4.73 - 4.44 (m, 2H), 3.84 (s, 1H), 3.30 - 2.94 (m, 6H), 2.94 - 2.70 (m, 1H), 1.57 - 1.05 (m, 30H), 0.92 - 0.80 (m, 6H);MS (ESI + ) m / z 672 [M+H] + .

[0202] Example II-8D: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(3-methylbutyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of chlorosulfonyl isocyanate (0.2 mL, 2.303 mmol) in dichloromethane (8 mL) was added allyl alcohol (0.155 mL, 2.279 mmol) dropwise at 0° C. The resulting solution was stirred at 0° C. for 20 minutes, and then a solution of the product of Example II-8C (0.896 g, 1.134 mmol) and triethylamine (0.4 mL, 2.87 mmol) in dichloromethane (8 mL) was added dropwise. The resulting solution was stirred at 0° C. for 45 minutes. The reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and diluted with dichloromethane (50 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO2, 24 g cartridge, 0-50% ethyl acetate in isohexane, 35 mL / min) to give the title compound (0.331 g, 0.373 mmol, 33% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.67 - 11.43 (m, 1H), 7.58 - 7.18 (m, 6H), 5.77 - 5.64 (m, 1H), 5.26 - 4.98 (m, 4H), 4.70 - 4.57 (m, 2H), 4.31 - 4.07 (m, 3H), 3.27 - 2.74 (m, 6H), 1.57 - 1.21 (m, 30H), 0.94 - 0.79 (m, 6H) + ) m / z 857 [M+Na] + .

[0203] Example II-8E: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(3-methylbutyl)amino]methyl}-4-fluoro-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia (partial) To a solution of the product of Example II-8D (0.389 g, 0.354 mmol) and potassium carbonate (0.196 g, 1.416 mmol) in methanol (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.041 g, 0.035 mmol). The reaction mixture was stirred at 60° C. for 1 hour. The mixture was cooled to room temperature and diluted with methanol (10 mL). Diatomaceous earth (1 g) was added, and the mixture was concentrated in vacuo. The crude residue was subjected to column chromatography (Reveleris® 24 g reverse-phase (C18) flash cartridge, dry loaded on silica, 5-70% methanol in 0.1% ammonium hydroxide, 17 mL / min) to give the title compound as a partial ammonium salt (70 mg, 0.088 mmol, 25% yield, 87% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.53 - 7.44 (m, 2H), 7.39 - 7.30 (m, 2H), 7.33 - 7.25 (m, 1H), 7.01 (t, J = 51.1 Hz, 1H), 5.09 (s, 2H), 4.65 - 4.61 (m, 1H), 3.98 - 3.80 (m, 2H), 3.25 - 2.70 (m, 6H), 1.49 (app s, 10H), 1.40 - 1.27 (m, 12H), 0.87 (d, J = 6.5 Hz, 6H) (ESI + ) m / z 699 [M+Na] + .

[0204] Example II-8F: (2R)-2-{[(tert-butoxycarbonyl)(3-methylbutyl)amino]methyl}-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia To a suspension of the product of Example II-8E (70 mg, 0.088 mmol) in water (1 mL) and 1,4-dioxane (1 mL) was added 10% Pd / C (30 mg). The resulting suspension was stirred under hydrogen (5 bar) for 3 hours. An additional 10% Pd / C (10 mg) was added, and the mixture was stirred under hydrogen (5 bar) for 18 hours. The reaction mixture was filtered through a pad of diatomaceous earth and washed with methanol (3 × 10 mL). The filtrate was concentrated under reduced pressure onto reversed-phase C18 silica (1 g). The crude residue was subjected to column chromatography (Reveleris® 24 g reversed-phase (C18) flash cartridge, dry loaded on reversed-phase C18 silica, 5-55% methanol in 10 mM ammonium hydroxide, 18 mL / min) to give the title compound as the ammonium salt (33 mg, 0.054 mmol, 62% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.26 (s, 1H), 7.31 - 6.74 (m, 4H), 4.61 - 4.57 (m, 1H), 3.99 - 3.77 (m, 2H), 3.24 - 2.61 (m, 6H), 1.50 (app MS (ESI), 1.40 - 1.29 (m, 12H), 0.87 (d, J = 6.5 Hz, 6H) - ) m / z 585 [MH] - .

[0205] Example II-8G: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(3-methylbutyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a solution of the product of Example II-8F (56 mg, 0.091 mmol) in 1,4-dioxane (2 mL) at room temperature, trifluoroacetic acid (150 μL, 1.947 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Additional trifluoroacetic acid (200 μL, 2.60 mmol) was added, and the reaction mixture was stirred for 1 hour. 1 M aqueous hydrochloric acid (1 mL) was added, and the reaction mixture was stirred for 1 hour. 6 M aqueous hydrochloric acid (0.5 mL) was added, and the reaction mixture was stirred for 1 hour. The volatiles were removed under reduced pressure. The residue was redissolved in a mixture of 1,4-dioxane (1 mL) and 3 M aqueous hydrochloric acid (0.5 mL) and stirred for 3 hours. The reaction mixture was neutralized with 0.7 M ammonia in methanol (2.5 mL) and concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 12 g reverse phase (C18) flash cartridge, dry loaded onto reverse phase 18 silica, 5-20% methanol in 0.1% ammonium hydroxide, 30 mL / min) to afford the title compound (14.5 mg, 0.036 mmol, 40% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (s, 1H), 8.25 (s, 2H), 6.02 (s, 1H), 5.92 (s, 1H), 4.13 - 4.08 (m, 1H), 3.84 (s, 2H), 3.10 (dd, J = 15.5, 9.3 Hz, 1H), 3.06 - 2.99 (m, 2H), 2.99 - 2.90 (m, 2H), 2.73 (dd, J = 15.5, 6.9 Hz, 1H), 1.67 - 1.54 (m, 1H), 1.54 - 1.44 (m, 2H), 0.89 (d, J = 6.5 Hz, 6H);MS (ESI + ) m / z 387 [M+H] + .

[0206] Example II-9: 5-[(2R)-2-{[(3,3-difluoropropyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 140) Example II-9A: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-2-{[(3,3-difluoropropyl)amino]methyl}-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Acetic acid (0.230 mL, 4.02 mmol) was added to a solution of 3,3-difluoropropan-1-amine hydrochloride (0.529 g, 4.02 mmol) and the product of Example II-2I (1 g, 1.341 mmol) in 1,2-dichloroethane (6 mL). The reaction mixture was stirred at room temperature for 40 minutes. Sodium triacetoxyborohydride (0.426 g, 2.012 mmol) was added, and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (3 mL) and stirred for 10 minutes. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.095 g, 1.297 mmol, 97% yield, 80% purity). MS (ESI + ) m / z 676 [M+H] + .

[0207] Example II-9B: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(3,3-difluoropropyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-9A (1.09 g, 1.291 mmol) in acetonitrile (6 mL) was added N,N-diisopropylethylamine (0.676 mL, 3.87 mmol) and di-tert-butyl dicarbonate (0.563 g, 2.58 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction was quenched with half-saturated brine (10 mL). The mixture was diluted with ethyl acetate (20 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (silica gel, 80 g cartridge, 20% ethyl acetate in isohexane, 60 mL / min) to afford the title compound (965 mg, 1.120 mmol, 83% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.44 - 7.29 (m, 6H), 6.05 (tq, J = 56.3, 4.1 Hz, 1H), 5.18 (dd, J = 12.0, 3.9 Hz, 1H), 5.11 (dd, J = 12.0, 2.1 Hz, 1H), 4.76 - 4.67 (m, 1H), 4.43 (dd, J = 16.5, 9.0 Hz, 1H), 3.87 (dd, J = 27.6, 16.5 Hz, 1H), 3.43 - 3.12 (m, 5H), 2.93 - 2.84 (m, 1H), 2.16 - 2.00 (m, 2H), 1.53 (d, J = 2.4 Hz, 9H), 1.40 (d, J = 2.2 Hz, 9H), 1.36 (d, J = 7.5 Hz, 9H);MS (ESI + ) m / z 798 [M+Na] + .

[0208] Example II-9C: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(3,3-difluoropropyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-9B (965 mg, 1.182 mmol) in methanol (2.5 mL) and tetrahydrofuran (2.5 mL) at room temperature was added a solution of lithium hydroxide monohydrate (149 mg, 3.55 mmol) in water (2.5 mL). The reaction mixture was then stirred at room temperature for 40 minutes. The reaction mixture was neutralized to pH 7 with 1 M hydrogen chloride (3.55 mL, 3.55 mmol) and diluted with water (10 mL). The aqueous mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (803 mg, 1.063 mmol, 90% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.56 - 7.22 (m, 6H), 6.09 (t, J = 56.2 Hz, 2H), 5.08 (s, 2H), 4.74 - 4.49 (m, 1H), 3.85 (s, 2H), 3.45 - MS (ESI + ) m / z 680 [M+H] + .

[0209] Example II-9D: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(3,3-difluoropropyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of chlorosulfonyl isocyanate (0.2 mL, 2.303 mmol) in dichloromethane (3 mL) was added allyl alcohol (0.16 mL, 2.353 mmol) dropwise at 0° C. The resulting solution was stirred at 0° C. for 20 minutes, and then a solution of the product of Example II-9C (803 mg, 1.063 mmol) and triethylamine (0.4 mL, 2.87 mmol) in dichloromethane (5 mL) was added dropwise. The resulting solution was stirred at 0° C. for 30 minutes. The reaction mixture was quenched with water (10 mL) and diluted with dichloromethane (10 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO2, 40 g cartridge, 0-100% ethyl acetate in isohexane, 60 mL / min) to afford the title compound (737 mg, 0.647 mmol, 61% yield, 74% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (s, 1H), 7.53 - 7.22 (m, 6H), 6.10 (t, J = 56.9 Hz, 1H), 5.78 - 5.62 (m, 1H), 5.25 - 5.01 (m, 4H), 4.73 - 4.57 (m, 2H), 4.20 - 4.10 (m, 1H), 3.44 - 3.03 (m, 7H), 2.85 - 2.61 (m, 1H), 2.17 - 2.00 (m, 2H), 1.56 - 1.43 (m, 9H), 1.43 - 1.21 (m, 18H);MS (ESI - ) m / z 841 [MH] - .

[0210] Example II-9E: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(3,3-difluoropropyl)amino]methyl}-4-fluoro-5-(1,1,4-trioxo-1λ 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia To a solution of the product of Example II-9D (737 mg, 0.647 mmol) and potassium carbonate (358 mg, 2.59 mmol) in methanol (8 mL) was added tetrakis(triphenylphosphine)palladium(0) (74.8 mg, 0.065 mmol). The reaction mixture was stirred at 60° C. for 4 hours. The mixture was cooled to room temperature and diluted with methanol (5 mL). C18 silica gel (3 g) was added, and the mixture was concentrated in vacuo. The crude residue was subjected to column chromatography (Reveleris® 40 g reverse-phase (C18) flash cartridge, dry-loaded with C18 silica gel, 10-70% methanol in 10 mM ammonium bicarbonate, 60 mL / min) to give the title compound as the ammonium salt (347 mg, 0.425 mmol, 66% yield, 86% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.68 - 7.24 (m, 6H), 7.11 - 6.91 (m, 3H), 6.09 (t, J = 56.4 Hz, 1H), 5.09 (s, 2H), 4.72 - 4.61 (m, 1H), 3.98 - 3.82 (m, 2H), 3.28 - 3.21 (m, 2H), 3.19 - 3.06 (m, 1H), 2.86 - 2.69 (m, 1H), 2.15 - 1.95 (m, 2H), 1.48 (s, 9H), 1.38 (s, 5H), 1.29 (s, 6H);MS (ESI - ) m / z 683 [MH] - .

[0211] Example II-9F: (2R)-2-{[(tert-butoxycarbonyl)(3,3-difluoropropyl)amino]methyl}-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia To a solution of the product of Example II-9E ​​(347 mg, 0.436 mmol) in degassed water (0.5 mL) and ethanol (4 mL), 10% Pd / C (50 mg) was added. The resulting suspension was stirred under hydrogen (5 bar) for 18 hours. The suspension was concentrated under reduced pressure onto C18 silica gel (3 g). The crude residue was subjected to column chromatography (Reveleris® 24 g reverse-phase (C18) flash cartridge, dry loaded with C18 silica, 10-60% methanol in 10 mM ammonium bicarbonate, 40 mL / min) to give the title product as the ammonium salt (208 mg, 0.323 mmol, 74% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.30 (s, 1H), 7.09 (s, 4H), 6.09 (tt, J = 56.3, 4.1 Hz, 1H), 4.67 - 4.51 (m, 1H), 3.96 - 3.80 (m, 2H), 3.38 - 3.19 (m, 4H), 3.07 (dd, J = 15.7, 9.1 Hz, 1H), 2.82 - 2.59 (m, 1H), 2.14 - 1.96 (m, 2H), 1.49 (s, 9H), 1.38 (s, 4H), 1.32 (s, 5H);MS (ESI - ) m / z 593 [MH] - .

[0212] Example II-9G: 5-[(2R)-2-{[(3,3-difluoropropyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a solution of the product of Example II-9F (99 mg, 0.158 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.18 mL, 2.336 mmol) at room temperature. The reaction mixture was stirred at 25° C. for 7 hours. The reaction mixture was neutralized with 0.7 M NH3 in methanol:water (95:5) (8 mL) and concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 12 g reverse-phase (C18) flash cartridge, dry loaded on C18 silica, 10-50% methanol in 10 mM ammonium bicarbonate, 30 mL / min) to give the title compound (43 mg, 0.109 mmol, 69% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (s, 1H), 8.41 (s, 1H), 6.22 (tt, J = 56.0, 4.1 Hz, 1H), 6.03 (s, 1H), 5.93 (s, 1H), 4.11 (s, 1H), 3.17 - 2.97 (m, 5H), 2.74 (dd, J = 15.6, 7.0 Hz, 1H), 2.32 - 2.14 (m, 2H);MS (ESI + ) m / z 395 [M+H] + .

[0213] Example II-10: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(3,3,3-trifluoropropyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 141) Example II-10A: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2-{[(3,3,3-trifluoropropyl)amino]methyl}-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Acetic acid (0.21 mL, 3.67 mmol) was added to a solution of the product of Example II-2I (0.85 g, 1.282 mmol) and 3,3,3-trifluoropropan-1-amine (0.41 mL, 3.63 mmol) in 1,2-dichloroethane (6 mL). The reaction mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.408 g, 1.924 mmol) was added, and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 mL) and stirred for 10 minutes. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.0577 g, 1.128 mmol, 88% yield, 74% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.48 - 7.28 (m, 6H), 5.24 - 5.01 (m, 3H), 4.53 - 4.44 (m, 1H), 4.44 - 4.34 (m, 1H), 3.99 - 3.93 (m, 1H), 3.63 - 3.54 (m, 1H), 3.23 - 3.09 (m, 1H), 3.01 - 2.93 (m, 1H), 2.82 - 2.64 (m, 2H), 2.64 - 2.52 (m, 1H), 2.42 - 2.23 (m, 2H), 1.51 (s, 7H), 1.47 (s, 2H), 1.38 (s, 9H); MS (ESI + ) m / z 695 [M+H] + .

[0214] Example II-10B: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(3,3,3-trifluoropropyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-10A (1.05 g, 1.211 mmol) in acetonitrile (6 mL) was added N,N-diisopropylethylamine (0.635 mL, 3.63 mmol) and di-tert-butyl dicarbonate (0.529 g, 2.422 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with half-saturated brine (10 mL). The resulting mixture was diluted with ethyl acetate (20 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (silica gel, 80 g cartridge, 20% ethyl acetate in isohexane, 60 mL / min) to afford the title compound (688 mg, 0.823 mmol, 68% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.74 - 7.38 (m, 4H), 7.38 - 7.25 (m, 2H), 5.18 (dd, J = 12.0, 2.7 Hz, 1H), 5.11 (dd, J = 12.0, 4.9 Hz, 1H), 4.77 - 4.67 (m, 1H), 4.44 (dd, J = 16.4, 9.5 Hz, 1H), 3.88 (dd, J = 28.6, 16.5 Hz, 1H), 3.46 - 3.28 (m, 4H), 3.19 (dt, J = 16.6, 8.6 Hz, 1H), 2.99 - 2.84 (m, 1H), 2.57 - 2.42 (m, 2H), 1.53 (d, J = 2.4 Hz, 9H), 1.40 (d, J = 1.8 Hz, 9H), 1.36 (d, J = 6.9 Hz, 9H) + ) m / z 816 [M+Na] + .

[0215] Example II-10C: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(3,3,3-trifluoropropyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-10B (688 mg, 0.823 mmol) in methanol (2.5 mL) and tetrahydrofuran (2.5 mL) at room temperature was added a solution of lithium hydroxide monohydrate (104 mg, 2.470 mmol) in water (2.5 mL). The reaction mixture was then stirred at room temperature for 45 minutes. The reaction mixture was neutralized to pH 7 with 1 M aqueous hydrochloric acid (2.470 mL) and diluted with water (10 mL). The aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (632 mg, 0.543 mmol, 66% yield, 60% purity). MS (ESI + ) m / z 599 [MC(O)OC(CH3)3+H] + .

[0216] Example II-10D: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(3,3,3-trifluoropropyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of chlorosulfonyl isocyanate (0.15 mL, 1.728 mmol) in dichloromethane (3 mL) was added allyl alcohol (0.12 mL, 1.764 mmol) dropwise at 0° C. The resulting solution was stirred at 0° C. for 20 minutes, and then a solution of the product of Example II-10C (632 mg, 0.543 mmol) and triethylamine (0.30 mL, 2.152 mmol) in dichloromethane (5 mL) was added dropwise. The resulting solution was stirred at 0° C. for 30 minutes. The reaction mixture was quenched with water (10 mL) and diluted with dichloromethane (10 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (silica gel, 40 g cartridge, 0-100% ethyl acetate in isohexane, 40 mL / min) to give the title compound (242 mg, 0.143 mmol, 26% yield, 51% purity). MS (ESI + ) m / z 765 [M - CH2CH=CH2- C(CH3)3+ H] + .

[0217] Example II-10E: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(3,3,3-trifluoropropyl)amino]methyl}-4-fluoro-5-(1,1,4-trioxo-1λ 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester To a solution of the product of Example II-10D (242 mg, 0.143 mmol) and potassium carbonate (79 mg, 0.573 mmol) in methanol (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (16.57 mg, 0.014 mmol). The reaction mixture was stirred at 60° C. for 4 hours. The mixture was cooled to room temperature and diluted with methanol (5 mL). C18 silica gel (3 g) was added, and the mixture was concentrated in vacuo. The crude residue was subjected to column chromatography (Reveleris® 40 g reverse-phase (C18) flash cartridge, dry-loaded with C18 silica gel, 10-70% methanol in 10 mM ammonium bicarbonate, 60 mL / min) to give the title compound (37.7 mg, 0.029 mmol, 20% yield, 54% purity). MS (ESI - ) m / z 701 [MH] - .

[0218] Example II-10F: (2R)-2-{[(tert-butoxycarbonyl)(3,3,3-trifluoropropyl)amino]methyl}-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester To a solution of the product of Example II-10E (37.7 mg, 0.029 mmol) in degassed water (0.5 mL) and ethanol (4 mL), 10% Pd / C (10 mg) was added. The resulting suspension was stirred under hydrogen (5 bar) for 18 hours. The suspension was concentrated under reduced pressure onto C18 silica gel (2 g). The crude residue was subjected to column chromatography (Reveleris® 24 g reverse-phase (C18) flash cartridge, dry loaded with C18 silica, 10-60% methanol in 10 mM ammonium bicarbonate, 40 mL / min) to give the title compound (14.5 mg, 0.017 mmol, 58% yield, 71% purity). MS (ESI - ) m / z 611 [MH] - .

[0219] Example II-10G: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(3,3,3-trifluoropropyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a solution of the product of Example II-10F (14.5 mg, 0.017 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.02 mL, 0.260 mmol) at room temperature. The reaction mixture was stirred at 25° C. for 7 hours. The reaction mixture was neutralized with 0.7 M NH3 in methanol:water (95:5) (6 mL) and concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 12 g reverse-phase (C18) flash cartridge, dry loaded on C18 silica, 10-60% methanol in 10 mM ammonium bicarbonate, 30 mL / min) to give the title compound (8.5 mg, 0.020 mmol, quantitative yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (s, 1H), 6.03 (s, 1H), 5.93 (s, 1H), 4.14 - 4.04 (m, 1H), 3.84 (s, 2H), 3.19 (s, 2H), 3.15 - 2.99 (m, 3H), 2.77 - 2.61 (m, 3H);MS (ESI + ) m / z 413 [M+H] + .

[0220] Example II-11: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(2-methylbutyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 142) Example II-11A: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2-{[(2-methylbutyl)amino]methyl}-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Acetic acid (0.23 mL, 4.02 mmol) was added to a solution of 2-methylbutan-1-amine (350 mg, 4.02 mmol) and the product of Example II-2I (0.885 g, 1.335 mmol) in 1,2-dichloroethane (3 mL). The reaction mixture was stirred at room temperature for 2 hours. Additional 2-methylbutan-1-amine (175 mg, 2.008 mmol) and acetic acid (120 mg, 2.003 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (420 mg, 1.982 mmol) was added, and the reaction mixture was stirred for 30 minutes. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (6 mL) and stirred for 10 minutes. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.934 g, 1.189 mmol, 89% yield, 85% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.50 - 7.20 (m, 6H), 5.23 - 4.99 (m, 2H), 4.56 - 4.31 (m, 2H), 4.09 - 3.85 (m, 1H), 3.15 (dt, J = 15.8, 10.0 Hz, 1H), 3.01 (dt, J = 17.1, 4.0 Hz, 1H), 2.79 - 2.70 (m, 1H), 2.64 - 2.21 (m, 6H), 1.50 (s, 9H), 1.38 (s, 9H), 1.12 - 0.96 (m, 1H), 0.92 - 0.71 (m, 6H);MS (ESI + ) m / z 669 [M+H] + .

[0221] Example II-11B: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methylbutyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-11A (935 mg, 1.190 mmol) in acetonitrile (6 mL) was added N,N-diisopropylethylamine (0.63 mL, 3.61 mmol) and di-tert-butyl dicarbonate (520 mg, 2.380 mmol) at room temperature. The mixture was stirred at room temperature for 30 minutes. The reaction was quenched with water (10 mL). The aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO, 24 g cartridge, 0-30% ethyl acetate in isohexane, 32 mL / min) to afford the title compound (770 mg, 0.903 mmol, 76% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.51 - 7.25 (m, 6H), 5.23 - 5.04 (m, 2H), 4.69 (s, 1H), 4.48 - 4.33 (m, 1H), 4.04 - 3.92 (m, 1H), 3.58 - 2.73 (m, 7H), 1.78 - 1.58 (m, 1H), 1.50 (d, J = 4.6 Hz, 9H), 1.43 - 1.19 (m, 18H), 1.13 - 0.98 (m, 1H), 0.92 - 0.73 (m, 6H).

[0222] Example II-11C: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methylbutyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-11B (770 mg, 0.903 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL) at room temperature was added a solution of lithium hydroxide monohydrate (115 mg, 2.74 mmol) in water (4.00 mL). The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was neutralized to pH 7 with 1 M hydrogen chloride solution and diluted with water (10 mL). The aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (586 mg, 0.785 mmol, 87% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.58 - 7.12 (m, 6H), 5.08 (s, 2H), 4.77 - 4.64 (m, 1H), 4.58 (s, 1H), 3.84 (dd, J = 7.1, 2.2 Hz, 2H), 3.50 - 3.28 (m, 1H), 3.27 - 2.89 (m, 5H), 2.88 - 2.61 (m, 1H), 1.81 - 1.57 (m, 1H), 1.47 (s, 9H), 1.34 (s, 18H), 1.04 (dt, J = 10.7, 6.8 Hz, 1H), 0.90 - 0.69 (m, 6H).

[0223] Example II-11D: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methylbutyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of chlorosulfonyl isocyanate (0.14 mL, 1.612 mmol) in dichloromethane (3 mL) was added allyl alcohol (0.11 mL, 1.617 mmol) dropwise at 0° C. The resulting solution was stirred at 0° C. for 30 minutes, and then a solution of the product of Example II-11C (586 mg, 0.785 mmol) and triethylamine (0.27 mL, 1.937 mmol) in dichloromethane (5 mL) was added dropwise. The resulting solution was stirred at 0° C. for 30 minutes. The reaction mixture was quenched with water (10 mL) and diluted with dichloromethane (10 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (silica gel, 40 g cartridge, 0-40% ethyl acetate in isohexane, 40 mL / min) to afford the title compound (530 mg, 0.597 mmol, 76% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.68 - 11.46 (m, 1H), 7.57 - 7.07 (m, 6H), 6.09 - 5.80 (m, 0.5H), 5.79 - 5.62 (m, 0.5H), 5.57 - 5.39 (m, 0.5H), 5.35 - 4.95 (m, 4.5H), 4.78 (dt, J = 6.3, 1.2 Hz, 0.5H), 4.65 (dd, J = 17.6, 10.8 Hz, 2H), 4.42 (dt, J = 5.1, 1.6 Hz, 0.5H), 4.33 - 4.05 (m, 2H), 3.31 - 2.71 (m, 6H), 1.66 (s, 1H), 1.47 (s, 9H), 1.42 - 1.17 (m, 18H), 1.12 - 0.96 (m, 1H), 0.93 - 0.68 (m, 6H).

[0224] Example II-11E: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(2-methylbutyl)amino]methyl}-4-fluoro-5-(1,1,4-trioxo-1λ 6,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia (partial) To a solution of the product of Example II-11D (623 mg, 0.597 mmol) and potassium carbonate (330 mg, 2.388 mmol) in methanol (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (69.0 mg, 0.060 mmol). The reaction mixture was stirred at 60° C. for 5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 40 g reverse-phase (C18) flash cartridge, dry loaded with C18 silica gel, 5-80% methanol in 10 mM ammonium bicarbonate, 40 mL / min) to give the title compound as a partial ammonium salt (279 mg, 0.365 mmol, 61% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.67 - 7.45 (m, 3H), 7.40 - 7.24 (m, 3H), 7.09 (s, 2H), 5.09 (s, 2H), 4.66 (d, J = 7.9 Hz, 1H), 3.99 - 3.80 (m, 2H), 3.42 (s, 0.5H), 3.37 - 2.70 (m, 7.5H), 1.79 - 1.58 (m, 1H), 1.49 (s, 9H), 1.43 - 1.19 (m, 9H), 1.12 - 0.97 (m, 1H), 0.93 - 0.72 (m, 6H);MS (ESI - ) m / z 675 [MH] - .

[0225] Example II-11F: (2R)-2-{[(tert-butoxycarbonyl)(2-methylbutyl)amino]methyl}-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia To a solution of the product of Example II-11E (270 mg, 0.354 mmol) in degassed water (0.5 mL) and ethanol (4 mL) was added 10% Pd / C (36 mg). The resulting suspension was stirred under hydrogen (5 bar) for 18 hours. The reaction mixture was filtered through a pad of diatomaceous earth and concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 24 g reverse-phase (C18) flash cartridge, dry loaded with C18 silica, 5-65% methanol in 10 mM ammonium bicarbonate, 32 mL / min) to give the title compound as the ammonium salt (185 mg, 0.291 mmol, 82% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.26 (s, 1H), 7.29 - 6.75 (m, 4H), 4.61 (s, 1H), 3.98 - 3.76 (m, 2H), 3.52 - 3.16 (m, 3H), 3.04 (dd, J = 15.7, 9.1 Hz, 3H), 2.84-2.63 (m, 1H), 1.79 - 1.56 (m, 1H), 1.50 (s, 9H), 1.34 (d, J = 16.5 Hz, 9H), 1.12 - 0.95 (m, 1H), 0.93 - 0.69 (m, 6H);MS (ESI + ) m / z 587 [M+H] + .

[0226] Example II-11G: 5-[(2R)-4-fluoro-6-hydroxy-2-{[(2-methylbutyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a solution of the product of Example II-11F (165 mg, 0.246 mmol) in dichloromethane (4 mL) at room temperature was added trifluoroacetic acid (0.284 mL, 3.69 mmol). The reaction mixture was stirred at room temperature for 3 hours. Additional trifluoroacetic acid (0.095 mL, 1.230 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Additional trifluoroacetic acid (0.095 mL, 1.230 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 0.7 M NH3 in methanol:water (95:5) (15 mL) and concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 12 g reverse-phase (C18) flash cartridge, dry loaded on C18 silica, 10-35% methanol in 10 mM ammonium bicarbonate, 30 mL / min) to afford the title compound (72.74 mg, 0.178 mmol, 72% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (s, 1H), 8.29 - 8.01 (m, 2H), 6.02 (d, J = 6.3 Hz, 1H), 5.93 (s, 1H), 4.13 (d, J = 8.1 Hz, 1H), 3.84 (s, 2H), 3.17 - 2.95 (m, 3H), 2.91 (dt, J = 13.0, 6.7 Hz, 1H), 2.74 (dt, J = 15.8, 6.4 Hz, 2H), 1.75 (h, J = 6.7 Hz, 1H), 1.48 - 1.35 (m, 1H), 1.27 - 1.10 (m, 1H), 0.99 - 0.80 (m, 6H);MS (ESI + ) m / z 387 [M+H] + .

[0227] Example II-12: 5-[(2R)-2-({[(3,3-difluorocyclobutyl)methyl]amino}methyl)-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 143) Example II-12A: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-2-({[(3,3-difluorocyclobutyl)methyl]amino}methyl)-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Acetic acid (0.217 mL, 3.78 mmol) was added to a solution of (3,3-difluorocyclobutyl)methanamine, hydrochloric acid (0.596 g, 3.78 mmol), and the product of Example II-2I (0.885 g, 1.261 mmol) in 1,2-dichloroethane (3 mL). Triethylamine (0.527 mL, 3.78 mmol) was added, and the reaction mixture was stirred at room temperature for 40 minutes. Sodium triacetoxyborohydride (0.401 g, 1.891 mmol) was added, and the reaction mixture was stirred for 30 minutes. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (6 mL) and stirred for 10 minutes. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.734 g, 1.008 mmol, 80% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.47 - 7.26 (m, 6H), 5.23 - 5.02 (m, 1H), 4.52 - 4.33 (m, 1H), 4.08 - 3.87 (m, 1H), 3.22 - 3.07 (m, 1H), MS (ESI + ) m / z 703 [M+H] + .

[0228] Example II-12B: (2R)-6-(benzyloxy)-2-({(tert-butoxycarbonyl)[(3,3-difluorocyclobutyl)methyl]amino}methyl)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-12A (884 mg, 1.008 mmol) in acetonitrile (4 mL) was added N,N-diisopropylethylamine (0.56 mL, 3.21 mmol) and di-tert-butyl dicarbonate (470 mg, 2.154 mmol) at room temperature. The mixture was stirred at room temperature for 30 minutes. The reaction was quenched with water (10 mL). The aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO, 24 g cartridge, 0-40% ethyl acetate in isohexane, 32 mL / min) to afford the title compound (630 mg, 0.742 mmol, 74% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.48 - 7.27 (m, 6H), 5.25 - 5.04 (m, 2H), 4.69 (s, 1H), 4.40 (d, J = 16.7 Hz, 1H), 4.08 - 3.91 (m, 1H), 3.15 (dd, J = 16.3, 9.3 Hz, 3H), 2.70 - 2.54 (m, 3H), 2.46 - 2.16 (m, 5H), 1.50 (s, 9H), 1.42 - 1.20 (m, 18H).

[0229] Example II-12C: (2R)-6-(benzyloxy)-2-({(tert-butoxycarbonyl)[(3,3-difluorocyclobutyl)methyl]amino}methyl)-5-[(2-tert-butoxy-2-oxoethyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-12B (700 mg, 0.742 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL) at room temperature was added a solution of lithium hydroxide monohydrate (93 mg, 2.226 mmol) in water (4.00 mL). The reaction mixture was then stirred at room temperature for 40 minutes. The reaction mixture was neutralized to pH 7 with 1 M hydrogen chloride (2.25 mL, 2.250 mmol) and diluted with water (10 mL). The aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (535 mg, 0.720 mmol, 97% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.56 - 7.19 (m, 6H), 5.08 (s, 2H), 4.70 (s, 1H), 4.59 (s, 1H), 3.84 (dd, J = 7.2, 2.2 Hz, 2H), 3.45 - 3.16 (m, 3H), 3.15 - 2.97 (m, 1H), 2.84 - 2.54 (m, 3H), 2.45 - 2.16 (m, 4H), 1.47 (s, 9H), 1.42 - 1.20 (m, 18H).

[0230] Example II-12D: (2R)-6-(benzyloxy)-2-({(tert-butoxycarbonyl)[(3,3-difluorocyclobutyl)methyl]amino}methyl)-5-[(2-tert-butoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of chlorosulfonyl isocyanate (0.125 mL, 1.438 mmol) in dichloromethane (3 mL) was added allyl alcohol (0.1 mL, 1.470 mmol) dropwise at 0° C. The resulting solution was stirred at 0° C. for 30 minutes, and then a solution of the product of Example II-12C (534 mg, 0.719 mmol) and triethylamine (0.250 mL, 1.797 mmol) in dichloromethane (5 mL) was added dropwise. The resulting solution was stirred at 0° C. for 30 minutes. The reaction mixture was quenched with water (10 mL) and diluted with dichloromethane (10 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (silica gel, 40 g cartridge, 0-40% ethyl acetate in isohexane, 40 mL / min) to afford the title compound (574 mg, 0.661 mmol, 92% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.68 - 11.46 (m, 1H), 7.60 - 7.01 (m, 6H), 6.07 - 5.94 (m, 0.5H), 5.93 - 5.80 (m, 0.5H), 5.79 - 5.64 (m, 1H), 5.56 - 5.41 (m, 1H), 5.35 - 5.01 (m, 4H), 4.78 (dt, J = 6.2, 1.2 Hz, 1H), 4.65 (dd, J = 17.5, 8.3 Hz, 2H), 4.42 (dt, J = 5.1, 1.6Hz, 1H), 4.32 - 4.04 (m, 3H), 3.18 - 3.03 (m, 1H), 2.88 - 2.54 (m, 3H), 2.46 - 2.20 (m, 3H), 1.56 - 1.15 (m, 27H).

[0231] Example II-12E: (2R)-6-(benzyloxy)-2-({(tert-butoxycarbonyl)[(3,3-difluorocyclobutyl)methyl]amino}methyl)-4-fluoro-5-(1,1,4-trioxo-1λ 6,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia To a solution of the product of Example II-12D (718 mg, 0.661 mmol) and potassium carbonate (365 mg, 2.64 mmol) in methanol (3 mL) was added tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.066 mmol). The reaction mixture was stirred at 60° C. for 5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was diluted with methanol (8 mL), C18 silica gel (3 g) was added, and the mixture was concentrated in vacuo. The crude residue was subjected to column chromatography (Reveleris® 40 g reverse-phase (C18) flash cartridge, dry-loaded with C18 silica gel, 5-75% methanol in 10 mM ammonium bicarbonate, 40 mL / min) to give the title compound as the ammonium salt (195 mg, 0.228 mmol, 35% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.59 - 7.45 (m, 3H), 7.41 - 7.22 (m, 3H), 7.07 (s, 3H), 5.09 (s, 2H), 4.67 (s, 1H), 3.90 (q, J = 13.2 Hz, 2H), 3.30 (d, J = 9.6 Hz, 3H), 3.19 - 3.03 (m, 1H), 2.89 - 2.55 (m, 5H), 2.43 - 2.22 (m, 3H), 1.49 (s, 9H), 1.34 (d, J = 39.1 Hz, 9H);MS (ESI - ) m / z 709 [MH] - .

[0232] Example II-12F: (2R)-2-({(tert-butoxycarbonyl)[(3,3-difluorocyclobutyl)methyl]amino}methyl)-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl-ammonia To a solution of the product of Example II-12E (190 mg, 0.222 mmol) in degassed water (0.5 mL) and ethanol (4 mL) was added 10% Pd / C (23.6 mg). The resulting suspension was stirred under hydrogen (5 bar) for 18 hours. The reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 24 g reverse-phase (C18) flash cartridge, dry loaded with C18 silica, 5-65% methanol in 10 mM ammonium bicarbonate, 32 mL / min) to give the title compound as the ammonium salt (115 mg, 0.171 mmol, 77% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.27 (s, 1H), 7.28 - 6.81 (m, 4H), 4.62 (d, J = 8.7 Hz, 1H), 3.97 - 3.75 (m, 2H), 3.49 - 3.13 (m, 4H), MS (ESI - ) m / z 620 [MH] - .

[0233] Example II-12G: 5-[(2R)-2-({[(3,3-difluorocyclobutyl)methyl]amino}methyl)-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a solution of the product of Example II-12F (115 mg, 0.171 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.198 mL, 2.57 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with 0.7 M NH3 in methanol:water (95:5) (5 mL) and concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 12 g reverse-phase (C18) flash cartridge, dry loaded on C18 silica, 10-35% methanol in 10 mM ammonium bicarbonate, 30 mL / min) to give the title compound (39.31 mg, 0.089 mmol, 52% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (d, J = 2.4 Hz, 1H), 8.35 (s, 2H), 6.01 (s, 1H), 5.93 (s, 1H), 4.11 (s, 1H), 3.84 (s, 2H), 3.20 - 2.92 (m, 5H), 2.81 - 2.64 (m, 3H), 2.57 - 2.36 (m, 3H);MS (ESI + ) m / z 421 [M+H] + .

[0234] Example II-13: 5-[4-fluoro-6-hydroxy-2-({[2-(oxetan-3-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 144) Example II-13A: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2-({[2-(oxetan-3-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Acetic acid (0.22 mL, 3.84 mmol) was added to a solution of 2-(oxetan-3-yl)ethanamine (0.38 g, 3.76 mmol) and the product of Example II-2I (0.885 g, 1.335 mmol) in 1,2-dichloroethane (3 mL). The reaction mixture was stirred at room temperature for 2 hours. Additional 2-(oxetan-3-yl)ethanamine (0.19 g, 1.878 mmol) and acetic acid (0.11 g, 1.832 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.4 g, 1.887 mmol) was added, and the reaction mixture was stirred for 40 minutes. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (6 mL) and stirred for 10 minutes. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.93 g, 1.228 mmol, 92% yield, 90% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.49 - 7.21 (m, 6H), 5.25 - 5.01 (m, 2H), 4.64 - 4.33 (m, 3H), 4.06 - 3.88 (m, 1H), 3.32 (s, 3H), 3.04 - 2.88 (m, 1H), 2.69 - 2.31 (m, J = 1.9 Hz, 7H), 2.29 - 2.10 (m, 1H), 1.76 (dd, J = 18.3, 11.1 Hz, 1H), 1.50 (d, J = 3.0 Hz, 9H), 1.38 (s, 9H);MS (ESI + ) m / z 683 [M+H] + .

[0235] Example II-13B: (2R)-6-(benzyloxy)-2-({(tert-butoxycarbonyl)[2-(oxetan-3-yl)ethyl]amino}methyl)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-13A (846 mg, 1.241 mmol) in acetonitrile (6 mL), N,N-diisopropylethylamine (0.650 mL, 3.72 mmol), 4-dimethylaminopyridine (152 mg, 1.241 mmol), and di-tert-butyl dicarbonate (542 mg, 2.482 mmol) were added sequentially. The reaction mixture was stirred at ambient temperature for 2 hours. Additional portions of di-tert-butyl dicarbonate (271 mg, 1.241 mmol) and 4-dimethylaminopyridine (152 mg, 1.241 mmol) were added, and the reaction mixture was stirred for an additional 30 minutes. The reaction was quenched with half-saturated brine (10 mL). The mixture was diluted with ethyl acetate (20 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (silica gel, 80 g cartridge, 20% isocratic ethyl acetate in isohexane, 60 mL / min) to afford the title compound (442 mg, 0.565 mmol, 45% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.43 - 7.35 (m, 5H), 7.37 - 7.30 (m, 1H), 5.22 - 5.06 (m, 2H), 4.60 - 4.49 (m, 1H), 4.48 - 4.38 (m, 1H), 3.97 - 3.77 (m, 3H), 3.26 - 3.13 (m, 1H), 3.00 - 2.92 (m, 1H), 2.73 - 2.51 (m, 5H), 2.44 - 2.28 (m, 2H), 1.93 - 1.75 (m, 1H), 1.54 (s, 9H), 1.47 - 1.34 (m, 19H); MS (ESI + ) m / z 782 [M+H] + .

[0236] Example II-13C: (2R)-6-(benzyloxy)-2-({(tert-butoxycarbonyl)[2-(oxetan-3-yl)ethyl]amino}methyl)-5-[(2-tert-butoxy-2-oxoethyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-13B (490 mg, 0.564 mmol) in methanol (1.5 mL) and tetrahydrofuran (1.5 mL) at room temperature was added a solution of lithium hydroxide monohydrate (71.0 mg, 1.692 mmol) in water (1.5 mL). The reaction mixture was then stirred at room temperature for 45 minutes. The reaction mixture was neutralized to pH 7 with 1 M hydrogen chloride (1.7 mL, 1.7 mmol) and diluted with water (10 mL). The aqueous mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (371 mg, 0.541 mmol, 96% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.50 - 7.43 (m, 2H), 7.43 - 7.31 (m, 3H), 7.20 (s, 1H), 5.08 (s, 2H), 4.48 - 4.44 (m, 1H), 3.96 - 3.88 (m, 2H), 3.85 (dd, J = 6.7, 2.0 Hz, 2H), 3.12 (ddd, J = 15.9, 9.2, 2.7 Hz, 1H), 2.94 (dt, J = 15.9, 2.7 Hz, 1H), 2.74 - 2.51 (m, 5H), 2.43 - 2.27 (m, 2H), 1.94 - 1.79 (m, 1H), 1.51 (s, 9H), 1.45 - 1.41 (m, 10H), 1.37 (s, 9H);MS (ESI + ) m / z 687 [M+H] + .

[0237] Example II-13D: (2R)-6-(benzyloxy)-2-({(tert-butoxycarbonyl)[2-(oxetan-3-yl)ethyl]amino}methyl)-5-[(2-tert-butoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl A solution of chlorosulfonyl isocyanate (0.094 mL, 1.082 mmol) in dichloromethane (2 mL) was cooled to 0° C., and allyl alcohol (0.074 mL, 1.082 mmol) was added dropwise. The resulting solution was stirred at 0° C. for 20 minutes, and then a solution of the product of Example II-13C (464 mg, 0.541 mmol) and triethylamine (0.189 mL, 1.353 mmol) in dichloromethane (3 mL) was added dropwise. The resulting solution was stirred at 0° C. for 30 minutes. The reaction was diluted with dichloromethane (10 mL) and quenched with water. The layers were separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (silica gel, 40 g cartridge, 0-100% (3:1 ethyl acetate:ethanol) in isohexane, 40 mL / min) to afford the title compound (370 mg, 0.446 mmol, 82% yield). 1H NMR (400 MHz, DMSO-d690 ℃) δ ppm 9.65 (s, 1H), 7.50 (d, J = 6.9 Hz, 2H), 7.44 - 7.32 (m, 3H), 7.17 (s, 1H), 6.49 (s, 2H), 5.93 (ddt, J = 17.3, 10.0, 4.8 Hz, 1H), 5.25 - 5.08 (m, 3H), 5.02 (dq, J = 10.4, 1.8 Hz, 1H), 4.87 - 4.76 (m, 1H), 4.38 - 4.22 (m, 1H), 4.11 - 4.01 (m, 1H), 3.99 - 3.93 (m, 2H), 3.59 - 3.08 (m, 6H), 2.95 - 2.58 (m, 2H), 2.38 - 2.04 (m, 1H), 1.88 - 1.64 (m, 1H), 1.59 - 1.50 (m, 9H), 1.45 (s, 9H), 1.42 - 1.38 (m, 1H), 1.35 (s, 9H);MS (ESI + ) m / z 849 [M+H] + .

[0238] Example II-13E: (2R)-6-(benzyloxy)-2-({(tert-butoxycarbonyl)[2-(oxetan-3-yl)ethyl]amino}methyl)-4-fluoro-5-(1,1,4-trioxo-1λ 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester To a solution of the product of Example II-13D (435 mg, 0.436 mmol) in methanol (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (50.3 mg, 0.044 mmol) and potassium carbonate (241 mg, 1.742 mmol). The reaction mixture was stirred at 60° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 40 g reverse-phase (C18) flash cartridge, 10-100% methanol in 0.1% ammonium hydroxide, 40 mL / min) to afford the title compound (104 mg, 0.120 mmol, 28% yield, 80% purity). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.69 - 7.16 (m, 6H), 5.10 (s, 2H), 4.57 - 4.40 (m, 1H), 3.99 - 3.86 (m, 4H), 3.23 - 3.10 (m, 1H), MS (ESI + ) m / z 691 [M+H] + .

[0239] Example II-13F: (2R)-2-({(tert-butoxycarbonyl)[2-(oxetan-3-yl)ethyl]amino}methyl)-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester To a solution of the product of Example II-13E (104 mg, 0.120 mmol) in ethanol (1.3 mL) and water (0.13 mL) was added 10% palladium on carbon (28.5 mg). The resulting suspension was stirred under hydrogen (5 bar) for 16 hours. The reaction mixture was filtered through Whatman glass fiber filter paper and washed with ethanol (3 x 15 mL). The filtrate was concentrated under reduced pressure, and the crude residue was subjected to column chromatography (Reveleris® 12 g reverse-phase (C18) flash cartridge, dry loaded with C18 silica, 10-50% methanol in 0.1% ammonium hydroxide, 30 mL / min) to give the title compound (27 mg, 0.042 mmol, 35% yield). MS (ESI + ) m / z 601 [M+H] + .

[0240] Example II-13G: 5-[4-fluoro-6-hydroxy-2-({[2-(oxetan-3-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a solution of the product of Example II-13F (25 mg, 0.039 mmol) in dichloromethane (0.7 mL) was added trifluoroacetic acid (0.045 mL, 0.587 mmol) at room temperature. The reaction mixture was stirred at ambient temperature for 3 hours, then cooled to 0° C. and quenched with 0.7 M ammonia in methanol (1.5 mL). The reaction mixture was concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 12 g reverse-phase (C18) flash cartridge, dry loaded with C18 silica, 5% isocratic methanol in 0.1% ammonium hydroxide, 30 mL / min), followed by a second column chromatography (Reveleris® 12 g reverse-phase (C18) flash cartridge, 0% isocratic methanol in 0.1% ammonium hydroxide, 30 mL / min) to give the title compound (8 mg, 0.019 mmol, 49% yield). 1H NMR (400 MHz, DMSO-d690 ℃) δ ppm 8.23 ​​(s, 1H), 5.96 (s, 1H), 5.81 (s, 1H), 4.22 - 4.10 (m, 1H), 3.87 (s, 2H), 3.51 - 3.32 (m, 3H), MS (ESI + ) m / z 401 [M+H] + .

[0241] Example II-14: 5-(2-{[(4,4-difluorobutyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 145) Example II-14A: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-2-{[(4,4-difluorobutyl)amino]methyl}-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Acetic acid (0.220 mL, 3.85 mmol) was added to a solution of 4,4-difluorobutan-1-amine, hydrochloric acid (0.560 g, 3.85 mmol), and the product of Example II-2I (0.85 g, 1.282 mmol) in 1,2-dichloroethane (6 mL). The reaction mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.408 g, 1.924 mmol) was added, and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 mL) and stirred for 10 minutes. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.0144 g, 1.309 mmol, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.46 - 7.29 (m, 6H), 6.21 - 5.87 (m, 1H), 5.21 - 5.03 (m, 2H), 4.47 (s, 1H), 4.40 (dd, J = 16.6, 2.7 Hz, 1H), 3.96 (dd, J = 16.6, 3.3 Hz, 1H), 3.22 - 3.09 (m, 1H), 3.04 - 2.95 (m, 1H), 2.79 - 2.70 (m, 1H), 2.62 - 2.52 (m, 2H), 1.88 - 1.68 (m, 2H), 1.50 (s, 9H), 1.48 - 1.41 (m, 4H), 1.38 (s, 9H);MS (ESI + ) m / z 691 [M+H] + .

[0242] Example II-14B: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(4,4-difluorobutyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-14A (1.01 g, 1.172 mmol) in acetonitrile (6 mL) was added N,N-diisopropylethylamine (0.614 mL, 3.51 mmol) and di-tert-butyl dicarbonate (0.511 g, 2.343 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction was quenched with half-saturated brine (10 mL). The mixture was diluted with ethyl acetate (20 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (silica gel, 80 g cartridge, 20% isocratic ethyl acetate in isohexane, 60 mL / min) to afford the title compound (790 mg, 1.001 mmol, 83% yield). 1H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.44 - 7.29 (m, 6H), 6.03 (tq, J = 56.9, 4.2 Hz, 1H), 5.18 (dd, J = 12.0, 3.9 Hz, 1H), 5.11 (d, J = 11.9 Hz, 1H), 4.75 - 4.65 (m, 1H), 4.43 (dd, J = 16.5, 9.0 Hz, 1H), 3.87 (dd, J = 26.1, 16.5 Hz, 1H), 3.45 - 3.30 (m, 2H), 3.27 - 3.09 (m, 3H), 2.99 - 2.85 (m, 1H), 1.89 - 1.70 (m, 1H), 1.70 - 1.59 (m, 2H), 1.59 - 1.47 (m, 10H), 1.42 - 1.38 (m, 9H), 1.36 (d, J = 7.5Hz, 9H) + ) m / z 812 [M+Na] + .

[0243] Example II-14C: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(4,4-difluorobutyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-14B (930 mg, 1.001 mmol) in methanol (2.5 mL) and tetrahydrofuran (2.5 mL) at room temperature was added a solution of lithium hydroxide monohydrate (126 mg, 3.00 mmol) in water (2.5 mL). The reaction mixture was then stirred at ambient temperature for 45 minutes. The reaction mixture was neutralized to pH 7 with 1 M hydrogen chloride (3.00 mL, 3.00 mmol) and diluted with water (10 mL). The aqueous mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (800 mg, 0.997 mmol, 100% yield, 90% purity). 1H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.54 - 7.43 (m, 2H), 7.47 - 7.35 (m, 2H), 7.38 - 7.29 (m, 1H), 7.17 (s, 1H), 6.02 (tt, J = 56.9, 4.3 Hz, 1H), 5.09 (s, 2H), 4.66 - 4.56 (m, 1H), 4.51 (td, J = 6.7, 2.6 Hz, 1H), 3.85 (dd, J = 6.7, 2.0 Hz, 2H), 3.40 - 3.24 (m, 2H), 3.26 - 3.14 (m, 2H), 3.10 (dd, J = MS (ESI) + ) m / z 717 [M+Na] + .

[0244] Example II-14D: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(4,4-difluorobutyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl A solution of chlorosulfonyl isocyanate (0.153 mL, 1.759 mmol) in dichloromethane (3 mL) was cooled to 0° C., and allyl alcohol (0.120 mL, 1.759 mmol) was added dropwise. The resulting solution was stirred at 0° C. for 20 minutes, and then a solution of the product of Example II-14C (803 mg, 0.880 mmol) and triethylamine (0.307 mL, 2.199 mmol) in dichloromethane (5 mL) was added dropwise. The resulting solution was stirred at 0° C. for 30 minutes. The mixture was diluted with dichloromethane (10 mL), and the reaction was quenched with water (10 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (silica gel, 40 g cartridge, 0-100% ethyl acetate in isohexane, 40 mL / min) to afford the title compound (549 mg, 0.640 mmol, 64% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.54 - 7.43 (m, 2H), 7.43 - 7.27 (m, 3H), 7.24 (s, 1H), 6.45 (s, 2H), 6.21 - 5.85 (m, 2H), 5.26 - 5.07 (m, 3H), 5.02 (dq, J = 10.5, 1.7 Hz, 1H), 4.72 - 4.65 (m, 1H), 4.29 - 4.20 (m, 1H), 3.96 (dt, J = 4.8, 1.7 Hz, 1H), 3.48 - 3.05 (m, 5H), 2.90 - 2.77 (m, 1H), 1.85 - 1.58 (m, 4H), 1.56 - 1.47 (m, 9H), 1.44 - 1.29 (m, 18H).

[0245] Example II-14E: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(4,4-difluorobutyl)amino]methyl}-4-fluoro-5-(1,1,4-trioxo-1λ 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester A solution of the product of Example II-14D (686 mg, 0.640 mmol) in methanol (6 mL) was deoxygenated (nitrogen gas evolution) for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (74.0 mg, 0.064 mmol) and potassium carbonate (354 mg, 2.56 mmol) were added. The reaction mixture was stirred at 60° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 40 g reverse-phase (C18) flash cartridge, dry loaded with C18 silica, 10-100% methanol in 0.1% ammonium hydroxide, 40 mL / min) to give the title compound (315 mg, 0.419 mmol, 66% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.69 - 7.25 (m, 5H), 7.23 (s, 1H), 6.03 (tt, J = 56.9, 4.3 Hz, 1H), 5.11 (s, 2H), 4.72 - 4.64 (m, 1H), 4.05 - 3.91 (m, 2H), 3.42 - 3.29 (m, 2H), 3.26 - 3.05 - (m, 3H), 2.88 - 2.77 (m, 1H), 1.87 - 1.69 (m, 2H), 1.67 - 1.57 (m, 2H), 1.51 (d, J = 6.1 Hz, 9H), 1.37 (s, 9H); MS (ESI - ) m / z 697 [MH] - .

[0246] Example II-14F: (2R)-2-{[(tert-butoxycarbonyl)(4,4-difluorobutyl)amino]methyl}-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ) 6 ,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester To a solution of the product of Example II-14E (315 mg, 0.419 mmol) in ethanol (4 mL) and water (0.4 mL) was added 10% Pd / C (99 mg). The resulting suspension was stirred under hydrogen (5 bar) for 16 hours. The reaction mixture was filtered through Whatman glass fiber filter paper and washed with ethanol (3 × 15 mL). The filtrate was concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 40 g reverse-phase (C18) flash cartridge, dry loaded with C18 silica, 10-100% methanol in 0.1% ammonium hydroxide, 40 mL / min) to give the title compound (177 mg, 0.288 mmol, 69% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 6.75 (s, 1H), 6.03 (tt, J = 56.9, 4.3 Hz, 1H), 4.66 - 4.53 (m, 1H), 3.98 (d, J = 13.0 Hz, 1H), 3.89 (d, J = 12.9 Hz, 1H), 3.43 - 3.31 (m, 1H), 3.31 - 3.18 (m, 4H), 2.77 - 2.68 (m, 1H), 1.86 - 1.70 (m, 2H), 1.68 - 1.59 (m, 2H), 1.52 (s, 9H), 1.39 (s, 9H);MS (ESI + ) m / z 631 [M+Na] + .

[0247] Example II-14G: 5-(2-{[(4,4-difluorobutyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a solution of the product of Example II-14F (170 mg, 0.277 mmol) in dichloromethane (2 mL) at room temperature, trifluoroacetic acid (0.33 mL, 4.28 mmol) was added. The reaction mixture was stirred at ambient temperature for 3 hours. Additional trifluoroacetic acid (0.11 mL, 1.43 mmol) was added in portions, and the reaction mixture was stirred at ambient temperature for 1 hour before being cooled to 0°C. The reaction was then quenched with 0.7 M ammonia in methanol (8.5 mL). The mixture was concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 12 g reverse-phase (C18) flash cartridge, dry loaded with C18 silica, 0-20% methanol in 0.1% ammonium hydroxide, 30 mL / min) to afford the title compound (81 mg, 0.190 mmol, 69% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (s, 1H), 8.34 (s, 2H), 6.14 (tt, J = 56.5, 4.1 Hz, 1H), 6.02 (s, 1H), 5.93 (s, 1H), 4.13 - 4.08 (m, 1H), 3.84 (s, 2H), 3.20 - 3.05 (m, 1H), 3.08 - 2.96 (m, 4H), 2.74 (dd, J = 15.8, 6.8 Hz, 1H), 2.00 - 1.81 (m, 2H), 1.80 - 1.67 (m, 2H);MS (ESI + ) m / z 409 [M+H] + .

[0248] Example II-15: 5-[(2R)-2-{[(cyclopentylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 146) Example II-15A: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-2-{[(cyclopentylmethyl)amino]methyl}-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Acetic acid (0.230 mL, 4.02 mmol) was added to a solution of cyclopentylmethanamine hydrochloride (0.546 g, 4.02 mmol) and the product of Example II-2I (1 g, 1.341 mmol) in 1,2-dichloroethane (6 mL). The reaction mixture was stirred at room temperature for 40 minutes. Sodium triacetoxyborohydride (0.426 g, 2.012 mmol) was added, and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (3 mL) and stirred for 10 minutes. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.06 g, 1.326 mmol, 99% yield, 85% purity). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.49 - 7.28 (m, 6H), 5.28 - 5.03 (m, 2H), 4.57 - 4.48 (m, 1H), 4.43 (dd, J = 16.4, 6.8 Hz, 1H), 3.94 - 3.82 (m, 1H), 3.17 (dt, J = 15.8, 9.9 Hz, 1H), 3.06 - 2.95 (m, 2H), 2.83 (dt, J = 12.3, 3.8 Hz, 1H), 2.76 - 2.60 (m, 1H), 1.99 - 1.87 (m, 1H), 1.75 - 1.59 (m, 2H), 1.59 - 1.43 (m, 13H), 1.40 (s, 9H), 1.23 - 1.07 (m, 3H);MS (ESI + ) m / z 680 [M+H] + .

[0249] Example II-15B: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(cyclopentylmethyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-15A (1.06 g, 1.326 mmol) in acetonitrile (6 mL) was added N,N-diisopropylethylamine (0.695 mL, 3.98 mmol) and di-tert-butyl dicarbonate (0.579 g, 2.65 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction was quenched with half-saturated brine (10 mL). The mixture was diluted with ethyl acetate (20 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (silica gel, 80 g cartridge, 20% ethyl acetate in isohexane, 60 mL / min) to afford the title compound (0.80 g, 1.026 mmol, 76% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.44 - 7.29 (m, 6H), 5.18 (dd, J = 12.0, 5.2 Hz, 1H), 5.11 (d, J = 12.1 Hz, 1H), 4.75 - 4.67 (m, 1H), 4.44 (dd, J = 16.5, 9.6 Hz, 1H), 3.95 - 3.76 (m, 1H), 3.47 - 3.33 (m, 2H), 3.19 - 3.05 (m, 3H), 2.96 - 2.87 (m, 1H), 2.25 - 2.10 (m, 1H), 1.71 - 1.57 (m, 5H), 1.57 - 1.47 (m, 10H), 1.45 - 1.31 (m, 20H);MS (ESI + ) m / z 803 [M+Na] + .

[0250] Example II-15C: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(cyclopentylmethyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-15B (1 g, 1.026 mmol) in methanol (2.8 mL) and tetrahydrofuran (2.8 mL) at room temperature was added 2 M aqueous lithium hydroxide solution (1.5 mL, 3.08 mmol). The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was neutralized to pH 7 with 1 M aqueous hydrochloric acid and diluted with water (10 mL). The aqueous mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (819 mg, 0.958 mmol, 93% yield, 80% purity). MS (ESI + ) m / z 708 [M+Na] + .

[0251] Example II-15D: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(cyclopentylmethyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of chlorosulfonyl isocyanate (0.16 mL, 1.843 mmol) in dichloromethane (5 mL) was added allyl alcohol (0.13 mL, 1.912 mmol) dropwise at 0° C. The resulting solution was stirred at 0° C. for 20 minutes, and then a solution of the product of Example II-15C (0.819 g, 0.958 mmol) and triethylamine (0.35 mL, 2.51 mmol) in dichloromethane (5 mL) was added dropwise. The resulting solution was stirred at 0° C. for 30 minutes. The reaction mixture was quenched with water (50 mL) and diluted with dichloromethane (50 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (SiO2, 40 g cartridge, 0-40% tert-butyl methyl ether in isohexane, 90 mL / min) to afford the title compound (0.605 g, 0.714 mmol, 75% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.75 - 11.42 (m, 1H), 7.59 - 7.14 (m, 6H), 5.83 - 5.62 (m, 1H), 5.29 - 4.98 (m, 4H), 4.65 (dd, J = 17.7, 11.2 Hz, 2H), 4.37 - 4.21 (m, 1H), 4.21 - 4.11 (m, 2H), 3.28 - 3.06 (m, 3H), 2.85 (d, J = 15.9 Hz, 1H), 2.24 - 2.09 (m, 1H), 1.71 - 1.53 (m, 5H), 1.47 (s, 12H), 1.41 - 1.23 (m, 20H);MS (ESI + ) m / z 747 [MC(O)OC(CH3)3+H] + .

[0252] Example II-15E: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(cyclopentylmethyl)amino]methyl}-4-fluoro-5-(1,1,4-trioxo-1λ 6,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester A solution of the product of Example II-15D (0.756 g, 0.714 mmol) and potassium carbonate (0.4 g, 2.89 mmol) in methanol (7 mL) was degassed under vacuum and backfilled with nitrogen three times. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.083 g, 0.071 mmol), and the reaction mixture was degassed under vacuum and backfilled with nitrogen three times. The reaction mixture was stirred at 60 °C for 4 hours and then cooled to room temperature. C18 silica gel (3 g) was added, and the mixture was concentrated in vacuo. The crude residue was subjected to column chromatography (Reveleris® 40 g reverse-phase (C18) flash cartridge, dry-loaded with C18 silica gel, 10-70% methanol in 0.1% ammonium hydroxide, 40 mL / min) to give the title compound (615 mg, 0.774 mmol, 100% yield, 80% purity). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.69 - 7.57 (m, 2H), 7.43 - 7.25 (m, 3H), 7.21 (s, 1H), 5.11 (s, 2H), 4.76 - 4.59 (m, 1H), 3.94 (d, J = 13.0 Hz, 1H), 3.87 (d, J = 13.0 Hz, 1H), 3.47 - 3.29 (m, 2H), 3.17 - 3.06 (m, 3H), 2.86 (dd, J = 15.8, 2.2 Hz, 1H), 2.19 (septet, J = 7.4 Hz, 1H), 1.73 - 1.57 (m, 4H), 1.52 (s, 11H), 1.37 (s, 9H), 1.26 - 1.10 (m, 2H);MS (ESI + ) m / z 711 [M+Na] + .

[0253] Example II-15F: (2R)-2-{[(tert-butoxycarbonyl)(cyclopentylmethyl)amino]methyl}-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ) 6,2,5-Thiadiazolidin-2-yl)-2,3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester To a suspension of the product of Example II-15E (300 mg, 0.340 mmol) in degassed water (0.4 mL) and ethanol (4 mL), 10% Pd / C (72 mg) was added. The resulting suspension was stirred under hydrogen (5 bar) for 24 hours. The reaction mixture was filtered through Whatman glass fiber filter paper and washed with ethanol (3 × 10 mL). The filtrate was concentrated under reduced pressure onto C18 silica (2 g). The crude residue was subjected to column chromatography (Reveleris® 24 g reverse-phase (C18) flash cartridge, dry load on C18 silica, 10-50% methanol in 0.1% ammonium hydroxide, 35 mL / min) to give the title compound (66 mg, 0.105 mmol, 31% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 6.66 (s, 1H), 4.67 - 4.49 (m, 1H), 4.01 (d, J = 13.0 Hz, 1H), 3.89 (d, J = 13.0 Hz, 1H), 3.39 (dd, J = 13.9, 7.7 Hz, 1H), 3.27 (dd, J = 13.9, 5.4 Hz, 1H), 3.18 - 3.08 (m, 3H), 2.93 (dd, J = 15.1, 9.1 Hz, 2H), 2.72 (d, J = 14.7 Hz, 1H), 2.20 (septet, J = 7.4 Hz, 1H), 1.71 - 1.54 (m, 5H), 1.51 (s, 10H), 1.39 (s, 9H), 1.27 - 1.12 (m, 2H);MS (ESI + ) m / z 621 [M+Na] + .

[0254] Example II-15G: 5-[(2R)-2-{[(cyclopentylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione To a solution of the product of Example II-15F (60 mg, 0.095 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.110 mL, 1.432 mmol) at room temperature. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was neutralized with 0.7 M NH3 in methanol:water (95:5) (7 mL) and concentrated under reduced pressure. The crude residue was subjected to column chromatography (Reveleris® 24 g reverse phase (C18) flash cartridge, dry load on C18 silica, 5-20% methanol in 0.1% ammonium hydroxide, 35 mL / min), followed by a second column chromatography (Teledyne ISCO RediSep Rf Gold® 12 g reverse phase (C18) flash cartridge, dry load on C18 silica, 0-20% methanol in 0.1% ammonium hydroxide, 35 mL / min) to give the title compound (33 mg, 0.076 mmol, 80% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (s, 1H), 8.16 (s, 2H), 6.02 (s, 1H), 5.92 (s, 1H), 4.22 - 4.02 (m, 1H), 3.84 (s, 2H), 3.15 - 2.95 (m, 3H), 2.92 (dd, J = 7.3, 1.8 Hz, 2H), 2.73 (dd, J = 15.6, 6.8 Hz, 1H), 2.14 (septet, J = 7.7 Hz, 1H), 1.77 (td, J = 11.3, 6.0 Hz, 2H), 1.68 - 1.44 (m, 4H), 1.22 (td, J = 11.3, 9.7, 4.3 Hz, 2H);MS (ESI + ) m / z 399 [M+H] + .

[0255] Example II-16: 5-[(2R)-2-{[(cyclopropylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (Compound 147) Example II-16A: (2R)-6-(benzyloxy)-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-2-{[(cyclopropylmethyl)amino]methyl}-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl Acetic acid (0.230 mL, 4.02 mmol) was added to a solution of cyclopropylmethanamine (0.349 mL, 4.02 mmol) and the product of Example II-2I (1 g, 1.341 mmol) in 1,2-dichloroethane (6 mL). The reaction mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (0.426 g, 2.012 mmol) was added, and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (3 mL) and stirred for 10 minutes. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (987 mg, 1.287 mmol, 96% yield, 85% purity). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.57 - 7.24 (m, 6H), 5.26 - 5.01 (m, 2H), 4.61 - 4.48 (m, 1H), 4.43 (dd, J = 16.4, 5.9 Hz, 1H), 3.96 - 3.85 (m, 1H), 3.25 - 3.13 (m, 1H), 3.09 - 2.93 (m, 2H), 2.89 (dd, J = 12.0, 3.9 Hz, 1H), 2.70 (dt, J = 12.0, 7.5 Hz, 1H), 2.47 (dd, J = 6.6, 2.3Hz, 2H), 1.53 (s, 9H), 1.40 (s, 9H), 0.96 - 0.79 (m, 1H), 0.50 - 0.35 (m, 2H), 0.21 - 0.05 (m, 2H) + ) m / z 652 [M+H] + .

[0256] Example II-16B: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)(trifluoroacetyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-16A (0.987 g, 1.287 mmol) in acetonitrile (6 mL) was added N,N-diisopropylethylamine (0.675 mL, 3.86 mmol) and di-tert-butyl dicarbonate (0.562 g, 2.57 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with half-saturated brine (10 mL). The mixture was diluted with ethyl acetate (20 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was subjected to column chromatography (silica gel, 40 g cartridge, 0-40% tert-butyl methyl ether in isohexane, 35 mL / min) to afford the title compound (920 mg, 1.187 mmol, 93% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.52 - 7.18 (m, 6H), 5.27 - 5.06 (m, 2H), 4.82 - 4.66 (m, 1H), 4.44 (dd, J = 16.5, 10.4 Hz, 1H), 3.88 (dd, J = 25.3, 16.5 Hz, 1H), 3.54 - 3.34 (m, 2H), 3.25 - 3.07 (m, 2H), 3.07 - 2.85 (m, 2H), 1.62 - 1.45 (m, 9H), 1.45 - 1.30 (m, 18H), 1.08 - 0.89 (m, 1H), 0.55 - 0.38 (m, 2H), 0.28 - 0.15 (m, 2H);MS (ESI + ) m / z 775 [M+Na] + .

[0257] Example II-16C: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of the product of Example II-16B (920 mg, 1.187 mmol) in methanol (2.8 mL) and tetrahydrofuran (2.8 mL) was added 2 M aqueous lithium hydroxide solution (1.781 mL, 3.56 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was neutralized to pH 7 with 1 M aqueous hydrochloric acid solution and diluted with water (10 mL). The aqueous mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (762 mg, 1.162 mmol, 98% yield). 1 H NMR (400 MHz, DMSO-d690 ℃) δ ppm 7.55 - 7.43 (m, 2H), 7.43 - 7.29 (m, 3H), 7.16 (s, 1H), 5.09 (s, 2H), 4.70 - 4.57 (m, 1H), 4.57 - 4.44 (m, 1H), 3.85 (dd, J = 6.7, 2.0 Hz, 2H), 3.46 - 3.28 (m, 2H), 3.19 - 2.95 (m, 3H), 2.85 (dd, J = 15.9, 2.0 Hz, 1H), 1.50 (s, 9H), 1.38 (s, 18H), 1.09 - 0.88 (m, 1H), 0.55 - 0.37 (m, 2H), 0.33 - 0.08 (m, 2H).

[0258] Example II-16D: (2R)-6-(benzyloxy)-2-{[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]methyl}-5-[(2-tert-butoxy-2-oxoethyl)({[(prop-2-en-1-yl)oxy]carbonyl}sulfamoyl)amino]-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate tert-butyl To a solution of chlorosulfonyl isocyanate (0.192 mL, 2.209 mmol) in dichloromethane (5 mL) was added allyl alcohol (0.158 mL, 2.325 mmol) dropwise at 0° C. The resulting solution was stirred at 0° C. for 20 minutes, and then a solution of the product of Example II-16C (0.847 g, 1.162 mmol) and triethylamine (0.405 mL, 2.91 mmol) in dichloromethane (5 mL) was added dropwise. The resulting solution was stirred at 0° C. for 30 minutes. The reaction mixture was quenched with water (50 mL) and diluted with di...

Claims

1. Formula (I): or a pharmaceutically acceptable salt thereof, During the ceremony, X is —O— or —N(R ａ ) - and Z is —O— or —N(R １ ) - and R １ is hydrogen or C １－６ is alkyl, R ２ is hydrogen, -C １－６ Alkyl 、 -C １－６ Alkylene-C ３－６ Cycloalkyl, —C １－６ alkylene-4 to 6-membered heterocyclyl, and —C １－６ alkylene-phenyl; Here, -C １－６ Alkyl 、 -C １－６ Alkylene-C ３－６ Cycloalkyl, —C １－６ alkylene-4 to 6-membered heterocyclyl, and —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, -C １－６ When the alkylene-4 to 6-membered heterocyclyl 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, and 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-O—C(O)—, R Ｐ is independently selected at each occurrence from the group consisting of halogen and hydroxyl; R ａ is hydrogen and C １－６ alkyl, C １－６ Alkyl is optionally selected from halogen, cyano, oxo, hydroxyl, and C ３－６ optionally substituted by one or more substituents independently selected from the group consisting of cycloalkyl; The compound or a pharmaceutically acceptable salt thereof.

2. Formula (Ia) or Formula (Ib):

2. The compound of claim 1, wherein:

3. Formula (Ia-1) or Formula (Ia-2):

3. The compound of claim 2, wherein:

4. R １ The compound of claim 3 wherein is hydrogen.

5. Formula (Ib-1) or Formula (Ib-2):

3. The compound of claim 2, wherein:

6. R ２ But, R ｇ -C １－６ The compound according to any one of claims 1 to 5, which is alkyl.

7. R ｇ However, halogen, 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 independently selected from R Ｐ is independently selected at each occurrence from halogen; The compound of claim 6.

8. R ２ but, 7. The compound of claim 6 selected from the group consisting of:

9. R ２ But, -C １－６ Alkylene-C ３－６ is cycloalkyl, and —C １－６ Alkylene-C ３－６ Cycloalkyl is optionally selected from R ｇ The compound according to any one of claims 1 to 5, optionally substituted by one, two, three or more substituents independently selected from:

10. R ｇ However, fluorine, C １－６ independently selected at each occurrence from the group consisting of alkyl, and phenyl; １－６ alkyl and phenyl are optionally each R Ｐ and optionally substituted by one, two, or three substituents independently selected from R Ｐ is independently selected at each occurrence from hydroxyl or fluorine; The compound of claim 9.

11. R ２ but, 10. The compound of claim 9 selected from the group consisting of:

12. R ２ But, -C １－６ alkylene-4 to 6-membered heterocyclyl, １－６ alkylene-4 to 6-membered heterocyclyl optionally each R ｇ and optionally substituted by one, two, three or more substituents independently selected from -C １－６ When the alkylene-4 to 6-membered heterocyclyl contains a substitutable ring nitrogen atom, the ring nitrogen atom can optionally be R ｈ optionally substituted by The compound according to any one of claims 1 to 5.

13. R ｈ But C １－６ The compound of claim 12, which is alkyl-O-C(O)-.

14. R ２ but, 13. The compound of claim 12 selected from the group consisting of:

15. 5-[(2R)-4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2S)-4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(2-cyclopentylethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-{[(4-hydroxy-3,3-dimethylbutyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-{[(3-hydroxy-3-methylbutyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-({[2-(3,3-difluorocyclobutyl)ethyl]amino}methyl)-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(4,4-difluorobutyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-({[2-(oxolan-3-yl)ethyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-4-fluoro-6-hydroxy-2-[(propylamino)methyl]-2,3-dihydro-1-benzofuran-5-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-2-[(dipropylamino)methyl]-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-2-[(butylamino)methyl]-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-2-[(ethylamino)methyl]-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(cyclopentylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-({[(oxan-4-yl)methyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-{[(3-methylbutyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-{[(2-methylbutyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(cyclopropylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[bis(cyclopropylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(cyclobutylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-({[(oxetan-3-yl)methyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-4-fluoro-6-hydroxy-2-[({2-[1-(hydroxymethyl)cyclobutyl]ethyl}amino)methyl]-2,3-dihydro-1-benzofuran-5-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-4-fluoro-6-hydroxy-2-[({2-[1-(hydroxymethyl)cyclopentyl]ethyl}amino)methyl]-2,3-dihydro-1-benzofuran-5-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-({[3-(2,2-difluoroethoxy)propyl]amino}methyl)-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 4-[({[(2R)-4-fluoro-6-hydroxy-5-(1,1,4-trioxo-1λ ６ tert-butyl 2,5-thiadiazolidin-2-yl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amino)methyl]piperidine-1-carboxylate, 5-[(2R)-4-fluoro-6-hydroxy-2-({[2-(oxan-4-yl)ethyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-2-[({[(1RS,5SR)-bicyclo[3.1.0]hexan-6-yl]methyl}amino)methyl]-4-fluoro-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-{[(3-phenylpropyl)amino]methyl}-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-({[2-(2,6,6-trimethylcyclohex-1-en-1-yl)ethyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-({[(3-phenylcyclobutyl)methyl]amino}methyl)-2,3-dihydro-1-benzofuran-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-4-fluoro-6-hydroxy-2-[({[4-(trifluoromethyl)cyclohexyl]methyl}amino)methyl]-2,3-dihydro-1-benzofuran-5-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-4-fluoro-2-[({[1-(fluoromethyl)cyclopropyl]methyl}amino)methyl]-6-hydroxy-2,3-dihydro-1-benzofuran-5-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2S)-4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(2-ethylbutyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-4-fluoro-6-hydroxy-2-[(propylamino)methyl]-2,3-dihydro-1H-indol-5-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-{[(2-methoxyethyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(cyclobutylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-({[(oxan-4-yl)methyl]amino}methyl)-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-{[(3-methylbutyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(3,3-difluoropropyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-{[(3,3,3-trifluoropropyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-{[(2-methylbutyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-({[(3,3-difluorocyclobutyl)methyl]amino}methyl)-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[4-fluoro-6-hydroxy-2-({[2-(oxetan-3-yl)ethyl]amino}methyl)-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-(2-{[(4,4-difluorobutyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl)-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(cyclopentylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(cyclopropylmethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-{[(pentan-2-yl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-({[(2R)-butan-2-yl]amino}methyl)-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-2-[(butylamino)methyl]-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-(hydroxymethyl)-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(2-cyclopropylethyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-2-{[(3,3-dimethylbutyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-{(2R)-4-fluoro-6-hydroxy-2-[({[3-(propan-2-yl)cyclobutyl]methyl}amino)methyl]-2,3-dihydro-1H-indol-5-yl}-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-2-{[methyl(2-methylpropyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, 5-[(2R)-4-fluoro-6-hydroxy-1-methyl-2-{[(2-methylpropyl)amino]methyl}-2,3-dihydro-1H-indol-5-yl]-1λ ６ , 2,5-thiadiazolidine-1,1,3-trione, and 5-[(2R)-2-{[(3,3-difluoro-2-hydroxypropyl)amino]methyl}-4-fluoro-6-hydroxy-2,3-dihydro-1H-indol-5-yl]-1λ ６ ,2,5-thiadiazolidine-1,1,3-trione 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

16. 16. A pharmaceutically acceptable composition comprising a compound of any one of claims 1 or 15 and a pharmaceutically acceptable carrier.

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